US20070078146A1 - Substituted pyrazoles as p38 kinase inhibitors - Google Patents

Substituted pyrazoles as p38 kinase inhibitors Download PDF

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US20070078146A1
US20070078146A1 US10/840,734 US84073404A US2007078146A1 US 20070078146 A1 US20070078146 A1 US 20070078146A1 US 84073404 A US84073404 A US 84073404A US 2007078146 A1 US2007078146 A1 US 2007078146A1
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alkyl
aryl
hydroxy
optionally substituted
amino
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Ashok Naraian
Michael Clare
Paul Collins
Joyce Crich
Rajesh Devraj
Daniel Flynn
Lifeng Geng
Matthew Graneto
Cathleen Hanau
Gunnar Hanson
Susan Hartmann
Michael Hepperle
He Huang
Ish Khanna
Francis Koszyk
Shuyuan Liao
Suzanne Metz
Win Naing
Richard Partis
Thao Perry
Shashidhar Rao
Shaun Selness
Michael South
Michael Stealey
John Talley
Michael Vazquez
John Walker
Richard Weier
Xiangdong Xu
Syaulan Yang
Yi Yu
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Pharmacia LLC
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    • C07D495/04—Ortho-condensed systems

Definitions

  • This invention relates to a novel group of pyrazole compounds, compositions and methods for treating p38 kinase mediated disorders.
  • Mitogen-activated protein kinases is a family of proline-directed serine/threonine kinases that activate their substrates by dual phosphorylation.
  • the kinases are activated by a variety of signals including nutritional and osmotic stress, UV light, growth factors, endotoxin and inflammatory cytokines.
  • the p38 MAP kinase group is a MAP family of various isoforms, including p38 ⁇ , p38 ⁇ and p38 ⁇ , and is responsible for phosphorylating and activating transcription factors (e.g. ATF2, CHOP and MEF2C) as well as other kinases (e.g. MAPKAP-2 and MAPKAP-3).
  • the p38 isoforms are activated by bacterial lipopolysaccharide, physical and chemical stress and by pro-inflammatory cytokines, including tumor necrosis factor (TNF- ⁇ ) and interleukin-1 (IL-1).
  • pro-inflammatory cytokines including tumor necrosis factor (TNF- ⁇ ) and interleukin-1 (IL-1).
  • TNF- ⁇ tumor necrosis factor
  • IL-1 interleukin-1
  • the products of the p38 phosphorylation mediate the production of inflammatory cytokines, including TNF and IL-1, and cyclooxygenase-2.
  • TNF- ⁇ is a cytokine produced primarily by activated monocytes and macrophages. Excessive or unregulated TNF production has been implicated in mediating a number of diseases. Recent studies indicate that TNF has a causative role in the pathogenesis of rheumatoid 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.
  • HSV-1 herpes simplex virus type-1
  • HSV-2 herpes simplex virus type-2
  • CMV cytomegalovirus
  • VZV varicella-zoster virus
  • Epstein-Barr virus Epstein-Barr virus
  • human herpesvirus-6 HHV-6
  • human herpesvirus-7 HHV-7
  • HHV-8 human herpesvirus-8
  • pseudorabies and rhinotracheitis among others.
  • IL-8 is another pro-inflammatory cytokine, which is produced by mononuclear cells, fibroblasts, endothelial cells, and keratinocytes, and is associated with conditions including inflammation.
  • IL-1 is produced by activated monocytes and macrophages and is involved in the inflammatory response. IL-1 plays a role in many pathophysiological responses including rheumatoid arthritis, fever and reduction of bone resorption.
  • TNF, IL-1 and IL-8 affect a wide variety of cells and tissues and are important inflammatory mediators of a wide variety of disease states and conditions.
  • the inhibition of these cytokines by inhibition of the p38 kinase is of benefit in controlling, reducing and alleviating many of these disease states.
  • EP 515,041 describes pyrimidyl substituted pyrazole derivatives as novel agricultural fungicides.
  • Japanese Patent 4,145,081 describes pyrazolecarboxylic acid derivatives as herbicides.
  • Japanese Patent 5,345,772 describes novel pyrazole derivatives as inhibiting acetylcholinesterase.
  • 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.
  • the invention's pyrazolyl compounds are found to show usefulness as p38 kinase inhibitors.
  • a class of substituted pyrazolyl compounds useful in treating p38 mediated disorders is defined by Formula IA:
  • R 1 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, alkylthioalkeny
  • R 1 has the formula wherein:
  • i is an integer from 0 to 9;
  • R 25 is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene; and
  • R 26 is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkylene, aralkyl, alkoxycarbonylalkylene, and alkylaminoalkyl;
  • R 27 is selected from alkyl, cycloalkyl, alkynyl, aryl, heterocyclyl, aralkyl, cycloalkylalkylene, cycloalkenylalkylene, cycloalkylarylene, cycloalkylcycloalkyl, heterocyclylalkylene, alkylarylene, alkylaralkyl, aralkylarylene, alkylheterocyclyl, alkylheterocyclylalkylene, alkylheterocyclylarylene, aralkylheterocyclyl, alkoxyalkylene, alkoxyarylene, alkoxyaralkyl, alkoxyheterocyclyl, alkoxyalkoxyarylene, aryloxyarylene, aralkoxyarylene, alkoxyheterocyclylalkylene, aryloxyalkoxyarylene, alkoxycarbonylalkylene, alkoxycarbonylheterocycly
  • R 27 is —CHR 28 R 29 wherein R 28 is alkoxycarbonyl, and R 29 is selected from aralkyl, aralkoxyalkylene, heterocyclylalkylene, alkylheterocyclylalkylene, alkoxycarbonylalkylene, alkylthioalkylene, and aralkylthioalkylene; wherein said aralkyl and heterocylcyl groups are optionally substituted with one or more radicals independently selected from alkyl and nitro; or
  • R 26 and R 27 together with the nitrogen atom to which they are attached form a heterocycle, wherein said heterocycle is optionally substituted with one or more radicals independently selected from alkyl, aryl, heterocyclyl, heterocyclylalkylene, alkylheterocyclylalkylene, aryloxyalkylene, alkoxyarylene, alkylaryloxyalkylene, alkylcarbonyl, alkoxycarbonyl, aralkoxycarbonyl, alkylamino and alkoxycarbonylamino; wherein said aryl, heterocyclylalkylene and aryloxyalkylene radicals are optionally substituted with one or more radicals independently selected from halogen, alkyl and alkoxy; and
  • R 2 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, alkylaminoarylene
  • R 2 is R 200 -heterocyclyl-R 201 , R 200 -aryl-R 201 or R 200 -cycloalkyl-R 201 wherein:
  • R 200 is selected from:
  • R 200 represents a bond
  • R 201 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
  • R 202 and R 203 are independently selected from hydrido, alkyl, aryl and aralkyl;
  • y and z are independently 0, 1, 2, 3, 4, 5 or 6 wherein y+z is less than or equal to 6;
  • z 0, 1 or 2;
  • R 2 is —NHCR 204 R 205 wherein R 204 is alkylaminoalkylene, and R 205 is aryl; or
  • R 2 is —C(NR 206 )R 207 wherein R 206 is selected from hydrogen and hydroxy, and R 207 is selected from alkyl, aryl and aralkyl; or
  • R 2 has the formula: wherein:
  • j is an integer from 0 to 8.
  • n 0 or 1
  • R 30 and R 31 are independently selected from hydrogen, alkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, aminoalkyl, alkylaminoalkyl, aminocarbonylalkyl, alkoxyalkyl, and alkylcarbonyloxyalkyl; and
  • R 32 is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene;
  • R 33 is selected from hydrogen, alkyl, —C(O)R 35 , —C(O)OR 35 , —SO 2 R 36 , —C(O)NR 37 R 38 , and —SO 2 NR 39 R 40 , wherein R 35 , R 36 , R 37 , R 38 , R 39 and R 40 are independently selected from hydrocarbon, heterosubstituted hydrocarbon and heterocyclyl; and
  • R 34 is selected from hydrogen, alkyl, aminocarbonyl, alkylaminocarbonyl, and arylaminocarbonyl; or
  • R 2 is —CR 41 R 42 wherein R 41 is aryl, and R 42 is hydroxy;
  • R 3 is selected from pyridinyl, pyrimidinyl, quinolinyl, purinyl, maleimidyl, pyridonyl, thiazolyl, thiazolylalkyl, thiazolylamino,
  • R 3 pyridinyl, pyrimidinyl, quinolinyl, purinyl, maleimidyl, pyridonyl, thiazolyl, thiazolylalkyl, thiazolylamino, 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, hetero
  • R 4 is selected from hydrido, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, and heterocyclyl, wherein R 4 is optionally substituted with one or more radicals independently selected from halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylthio, arylthio, alkylthioalkylene, arylthioalkylene, alkylsulfinyl, alkylsulfinylalkylene, arylsulfinylalkylene, alkylsulfonyl, alkylsulfonylalkylene, arylsulfonylalkylene, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, hal
  • R 3 is not 2-pyridinyl when R 4 is a phenyl ring containing a 2-hydroxy substituent and when R 1 is hydrido;
  • R 2 is selected from aryl, heterocyclyl, unsubstituted cycloalkyl and cycloalkenyl when R 4 is hydrido;
  • R 4 is not methylsulfonylphenyl or aminosulfonylphenyl
  • R 1 is not methylsulfonylphenyl
  • R 2 is as defined above, and
  • R 1 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, alkeny
  • R 1 has the formula wherein:
  • i is an integer from 0 to 9;
  • R 25 is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene; and
  • R 26 is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkylene, aralkyl, allcoxycarbonylalkylene, and alkylaminoalkyl;
  • R 27 is selected from alkyl, cycloalkyl, alkynyl, aryl, heterocyclyl, aralkyl, cycloalkylalkylene, cycloalkenylalkylene, cycloalkylarylene, cycloalkylcycloalkyl, heterocyclylalkylene, alkylarylene, alkylaralkyl, aralkylarylene, alkylheterocyclyl, alkylheterocyclylalkylene, alkylheterocyclylarylene, aralkylheterocyclyl, alkoxyalkylene, alkoxyarylene, alkoxyaralkyl, alkoxyheterocyclyl, alkoxyalkoxyarylene, aryloxyarylene, aralkoxyarylene, alkoxyheterocyclylalkylene, aryloxyalkoxyarylene, alkoxycarbonylalkylene, alkoxycarbonylheterocycly
  • R 27 is —CHR 28 R 29 wherein R 28 is alkoxycarbonyl, and R 29 is selected from aralkyl, aralkoxyalkylene, heterocyclylalkylene, alkylheterocyclylalkylene, alkoxycarbonylalkylene, alkylthioalkylene, and aralkylthioalkylene; wherein said aralkyl and heterocylcyl groups are optionally substituted with one or more radicals independently selected from alkyl and nitro; or
  • R 26 and R 27 together with the nitrogen atom to which they are attached form a heterocycle, wherein said heterocycle is optionally substituted with one or more radicals independently selected from alkyl, aryl, heterocyclyl, heterocyclylalkylene, alkylheterocyclylalkylene, aryloxyalkylene, alkoxyarylene, alkylaryloxyalkylene, alkylcarbonyl, alkoxycarbonyl, aralkoxycarbonyl, alkylamino and alkoxycarbonylamino; wherein said aryl, heterocyclylalkylene and aryloxyalkylene radicals are optionally substituted with one or more radicals independently selected from halogen, alkyl and alkoxy; and
  • R 3 is selected from pyridinyl, pyrimidinyl, quinolinyl, purinyl, maleimidyl, pyridonyl, thiazolyl, thiazolylalkyl, thiazolylamino,
  • R 3 pyridinyl, pyrimidinyl, quinolinyl, purinyl, maleimidyl, pyridonyl, thiazolyl, thiazolylalkyl, thiazolylamino, 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
  • R 4 is selected from hydrido, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, and heterocyclyl, wherein R 4 is optionally substituted with one or more radicals independently selected from halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylthio, arylthio, alkylthioalkylene, arylthioalkylene, alkylsulfinyl, alkylsulfinylalkylene, arylsulfinylalkylene, alkylsulfonylalkylene, arylsulfonylalkylene, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarboiiyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino
  • 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:
  • R 1 is selected from hydrido, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, cycloalkylalkylene, cycloalkenylalkylene, heterocyclylalkylene, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aralkyl, aralkenyl, aralkynyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxyalkyl, alkenoxyalkyl, alkynoxyalkyl, aryloxyalkyl, heterocyclyloxyalkyl, alkoxyalkoxy, mercaptoalkyl, alkylthioalkylene, alkenylthioalkylene, alkylthioalkenylene, amino, aminoalkyl,
  • R 25 is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene; and
  • R 26 is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkylene, aralkyl, alkoxycarbonylalkylene, and alkylaminoalkyl;
  • R 27 is selected from alkyl, cycloalkyl, alkynyl, aryl, heterocyclyl, aralkyl, cycloalkylalkylene, cycloalkenylalkylene, cycloalkylarylene, cycloalkylcycloalkyl, heterocyclylalkylene, alkylarylene, alkylaralkyl, aralkylarylene, alkylheterocyclyl, alkylheterocyclylalkylene, alkylheterocyclylarylene, aralkylheterocyclyl, alkoxyalkylene, alkoxyarylene, alkoxyaralkyl, alkoxyheterocyclyl, alkoxyalkoxyarylene, aryloxyarylene, aralkoxyarylene, alkoxyheterocyclylalkylene, aryloxyalkoxyarylene, alkoxycarbonylalkylene, alkoxycarbonylheterocycly
  • R 27 is —CHR 28 R 29 wherein R 28 is alkoxycarbonyl, and R 29 is selected from aralkyl, aralkoxyalkylene, heterocyclylalkylene, alkylheterocyclylalkylene, alkoxycarbonylalkylene, alkylthioalkylene, and aralkylthioalkylene; wherein said aralkyl and heterocylcyl groups are optionally substituted with one or more radicals independently selected from alkyl and nitro; or
  • R 2 6 and R 27 together with the nitrogen atom to which they are attached form a heterocycle, wherein said heterocycle is optionally substituted with one or more radicals independently selected from alkyl, aryl, heterocyclyl, heterocyclylalkylene, alkylheterocyclylalkylene, aryloxyalkylene, alkoxyarylene, alkylaryloxyalkylene, alkylcarbonyl, alkoxycarbonyl, aralkoxycarbonyl, alkylamino and alkoxycarbonylamino; wherein said aryl, heterocyclylalkylene and aryloxyalkylene radicals are optionally substituted with one or more radicals independently selected from halogen, alkyl and alkoxy; and
  • R 2 is selected from hydrido, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, haloalkyl, hydroxyalkyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, heterocyclylalkylamino, aralkylamino, aminoalkyl, aminoaryl, aminoalkylamino, arylaminoalkylene, alkylaminoalkylene, arylaminoarylene, alkylaminoarylene, alkylaminoarylene, alkylaminoalkylamino, cycloalkyl, cycloalkenyl, alkoxy, heterocyclyloxy, alkylthio, arylthio, heterocyclylthio, carboxy, carboxyalkyl, carboxycyclo
  • R 2 has the formula:
  • j is an integer from 0 to 8.
  • n 0 or 1
  • R 30 and R 31 are independently selected from hydrogen, alkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, aminoalkyl, alkylaminoalkyl, aminocarbonylalkyl, alkoxyalkyl, and alkylcarbonyloxyalkyl; and
  • R 32 is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene;
  • R 33 is selected from hydrogen, alkyl, —C(O)R 35 , —C(O)OR 35 , —SO 2 R 36 , —C(O)NR 37 R 38 , and —SO 2 NR 39 R 40 , wherein R 35 , R 36 , R 37 , R 38 , R 39 and R 40 are independently selected from hydrocarbon, heterosubstituted hydrocarbon and heterocyclyl; and
  • R 34 is selected from hydrogen, alkyl, aminocarbonyl, alkylaminocarbonyl, and arylaminocarbonyl; or
  • R 2 is —CR 41 R 42 wherein R 41 is aryl, and R 42 is hydroxy;
  • R 3 is selected from pyridinyl, pyrimidinyl, quinolinyl, purinyl,
  • R 43 is selected from hydrogen, alkyl, aminoalkyl, alkoxyalkyl, alkenoxyalkyl, and aryloxyalkyl;
  • R 3 pyridinyl, pyrimidinyl, quinolinyl and purinyl groups are optionally substituted with one or more radicals independently selected from halo, alkyl, aralkyl, aralkenyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, aralkoxy, heterocyclylalkoxy, amino, alkylamino, alkenylamino, alkynylamino, cycloalkylamino, cycloalkenylamino, arylamino, heterocyclylamino, aminocarbonyl, cyano, hydroxy, hydroxyalkyl, alkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl,
  • R 4 is selected from hydrido, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, and heterocyclyl, wherein R 4 is optionally substituted with one or more radicals independently selected from halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylthio, arylthio, alkylthioalkylene, arylthioalkylene, alkylsulfinyl, alkylsulfinylalkylene, arylsulfinylalkylene, alkylsulfonyl, alkylsulfonylalkylene, arylsulfonylalkylene, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, hal
  • R 3 is not 2-pyridinyl when R 4 is a phenyl ring containing a 2-hydroxy substituent and when R 1 is hydrido; further provided R 2 is selected from aryl, heterocyclyl, unsubstituted cycloalkyl and cycloalkenyl when R 4 is hydrido; and further provided R 4 is not methylsulfonylphenyl; or
  • 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.
  • 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.
  • cancers 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.
  • 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
  • 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.
  • 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, LTB 4 antagonists and LTA 4 hydrolase inhibitors.
  • TNF mediated disorder refers to any and all disorders and disease states in which TNF plays a role, either by control of TNF itself, or by TNF causing another monokine to be released, such as but not limited to IL-1, IL-6 or IL-8.
  • TNF a disease state in which, for instance, IL-1 is a major component, and whose production or action, is exacerbated or secreted in response to TNF, would therefore be considered a disorder mediated by TNF.
  • p38 mediated disorder refers to any and all disorders and disease states in which p38 plays a role, either by control of p38 itself, or by p38 causing another factor to be released, such as but not limited to IL-1, IL-6 or IL-8.
  • IL-1 IL-6
  • IL-8 another factor to be released
  • TNF- ⁇ has close structural homology with TNF- ⁇ (also known as cachectin) and since each induces similar biologic responses and binds to the same cellular receptor, the synthesis of both TNF- ⁇ and TNF- ⁇ 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
  • R 1 is selected from hydrido, lower alkyl, lower cycloalkyl, lower alkenyl, lower alkynyl, lower heterocyclyl, lower cycloalkylalkylene, lower haloalkyl, lower hydroxyalkyl, lower aralkyl, lower alkoxyalkyl, lower mercaptoalkyl, lower alkylthioalkylene, amino, lower alkylamino, lower arylamino, lower alkylaminoalkylene, and lower heterocyclylalkylene; or
  • R 1 has the formula
  • i 0, 1 or 2;
  • R 25 is selected from hydrogen, lower alkyl, lower phenylalkyl, lower heterocyclylalkyl, lower alkoxyalkylene, lower phenoxyalkylene, lower aminoalkyl, lower alkylaminoalkyl, lower phenoxyaminoalkyl, lower alkylcarbonylalkylene, lower phenoxycarbonylalkylene, and lower heterocyclylcarbonylaminoalkylene; and
  • R 26 is selected from hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkylalkylene, lower phenylalkyl, lower alkoxycarbonylalkylene, and lower alkylaminoalkyl;
  • R 27 is selected from lower alkyl, lower cycloalkyl, lower alkynyl, aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclyl, lower phenylalkyl, lower cycloalkylalkylene, lower cycloalkenylalkylene, lower cycloalkylarylene, lower cycloalkylcycloalkyl, lower heterocyclylalkylene, lower alkylphenylene, lower alkylphenylalkyl, lower phenylalkylphenylene, lower alkylheterocyclyl, lower alkylheterocyclylalkylene, lower alkylheterocyclylphenylene, lower phenylalkylheterocyclyl, lower alkoxyalkylene, lower alkoxyphenylene, lower alkoxyphenylene, lower alkoxyphenylalkyl, lower alkoxyheterocyclyl, lower alkoxyalkoxy
  • R 27 is —CHR 46 R 47 wherein R 46 is lower alkoxycarbonyl, and R 47 is selected from lower phenylalkyl, lower phenylalkoxyalkylene, lower heterocyclylalkylene, lower alkylheterocyclylalkylene, lower alkoxycarbonylalkylene, lower alkylthioalkylene, and lower phenylalkylthioalkylene; wherein said phenylalkyl and heterocylcyl groups are optionally substituted with one or more radicals independently selected from lower alkyl and nitro; or
  • R 26 and R 27 together with the nitrogen atom to which they are attached form a 4-8 membered ring heterocycle, wherein said heterocycle is optionally substituted with one or more radicals independently selected from lower alkyl, aryl selected from phenyl, biphenyl and naphthyl, heterocyclyl, heterocyclylalkylene, lower alkylheterocyclylalkylene, lower phenoxyalkylene, lower alkoxyphenylene, lower alkylphenoxyalkylene, lower alkylcarbonyl, lower alkoxycarbonyl, lower phenylalkoxycarbonyl, lower alkylamino and lower alkoxycarbonylamino; wherein said aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclylalkylene and lower phenoxyalkylene radicals are optionally substituted with one or more radicals independently selected from halogen, lower alkyl and lower alkoxy; and
  • R 2 is selected from hydrido, 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 alkoxycarbonylheterocyclyl
  • R 2 has the formula:
  • j 0, 1 or 2;
  • n 0;
  • R 30 and R 31 are independently selected from hydrogen, alkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, aminoalkyl, alkylaminoalkyl, aminocarbonylalkyl, alkoxyalkyl, and alkylcarbonyloxyalkyl; and
  • R 32 is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene; and
  • R 33 is selected from hydrogen, alkyl, —C(O)R 35 , —C(O)OR 35 , —SO 2 R 36 , —C(O)NR 37 R 38 , and —SO 2 NR 39 R 40 ;
  • R 35 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, arylcarbonyloxyalky
  • R 35 is CHR 45 R 49 wherein R 48 is arylsulfonylamino or alkylarylsulfonylamino, and R 49 is selected from aralkyl, amino, alkylamino, and aralkylamino; or
  • R 35 is —NR 50 R 51 wherein R 51 is alkyl, and R 51 is aryl;
  • R 36 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 alkyl;
  • R 37 is selected from hydrogen and alkyl
  • R 38 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 optional
  • R 38 is —CR 52 R 53 wherein R 52 is alkoxycarbonyl, and R 53 is alkylthioalkylene; or
  • R 39 and R 40 have the same definition as R 26 and R 27 in claim 1 ; or
  • R 2 is —CR 54 R 55 wherein R 54 is phenyl and R 55 is hydroxy; or
  • R 2 is selected from the group consisting of
  • k is an integer from 0 to 3;
  • R 56 is hydrogen or lower alkyl
  • R 57 is hydrogen or lower alkyl
  • R 56 and R 57 form a lower alkylene bridge
  • R 58 is selected from hydrogen, alkyl, aralkyl, aryl, heterocyclyl, heterocyclylalkyl, alkoxycarbonyl, alkylsulfonyl, aralkylsulfonyl, arylsulfonyl, —C(O)R 59 , —SO 2 R 60 , and —C(O)NHR 61 ;
  • R 59 is selected from alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, alkylarylene, aralkyl, alkylheterocyclyl, alkoxy, alkenoxy, aralkoxy, alkoxyalkylene, alkoxyarylene, alkoxyaralkyl; wherein said aryl, heterocyclyl, and aralkyl groups are optionally substituted with one or more radicals independently selected from alkyl, halo, hydroxy, haloalkyl, alkoxy, haloalkoxy, keto, amino, nitro, and cyano; and
  • R 60 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
  • R 61 is selected from alkyl, aryl, alkylarylene, and alkoxyarylene; wherein said aryl group is optionally substituted with one or more radicals independently selected from alkyl, halo, hydroxy, haloalkyl, alkoxy, haloalkoxy, keto, amino, nitro, and cyano; and
  • R 3 is selected from pyridinyl, pyrimidinyl, quinolinyl, purinyl, and
  • R 43 is selected from hydrogen, lower alkyl, lower aminoalkyl, lower alkoxyalkyl, lower alkenoxyalkyl and lower aryloxyalkyl;
  • R 3 pyridinyl, pyrimidinyl, quinolinyl and purinyl groups are optionally substituted with one or more radicals independently selected from lower alkylthio, lower alkylsulfonyl, aminosulfonyl, halo, lower alkyl, lower aralkyl, lower phenylalkenyl, lower phenylheterocyclyl, carboxy, lower alkylsulfinyl, cyano, lower alkoxycarbonyl, aminocarbonyl, lower alkylcarbonylamino, lower haloalkyl, hydroxy, lower alkoxy, amino, lower cycloalkylamino, lower alkylamino, lower alkenylamino, lower alkynylamino, lower aminoalkyl, arylamino, lower aralkylamino, nitro, halosulfonyl, lower alkylcarbonyl, lower alkoxycarbonylamino, lower alkoxycarbony
  • R 4 is selected from hydrido, lower cycloalkyl, lower cycloalkenyl, aryl selected from phenyl, biphenyl, and naphthyl, and 5- or 6-membered heterocyclyl; wherein the lower cycloalkyl, lower cycloalkenyl, aryl and 5-10 membered heterocyclyl groups of R 4 are optionally substituted with one or more radicals independently selected from lower alkylthio, lower alkylsulfonyl, lower alkylsulfinyl, halo, lower alkyl, lower alkynyl, lower alkoxy, lower aryloxy, lower aralkoxy, lower heterocyclyl, lower haloalkyl, amino, cyano, nitro, lower alkylamino, and hydroxy; or
  • a class of compounds of particular interest consists of these compounds of Formula I wherein
  • R 1 is selected from hydrido, methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloroethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, ethenyl, propenyl, ethynyl, propargyl, 1-propynyl, 2-propynyl, piperidinyl, piperazinyl, morpholinyl, benzyl, phenylethyl, morpholinylmethyl, morpholinylethyl, pyrrolidinylmethyl, piperazinylmethyl, piperid
  • R 2 is selected from hydrido, chloro, fluoro, bromo, methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl, phenyl, biphenyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, liydroxymethyl, hydroxyethyl, pyridinyl, isothiazolyl, isoxazolyl, thienyl, thiazolyl, oxazolyl, pyrimidinyl, quinolyl, isoquinolinyl, imidazolyl, benzimid
  • R 2 is —CR 54 R 55 wherein R 54 is phenyl and R 55 is hydroxy;
  • R 3 is selected from pyridinyl, pyrimidinyl, and purinyl; wherein R 3 is optionally substituted with one or more radicals independently selected from methylthio, methylsulfinyl, methylsulfonyl, fluoro, chloro, bromo, aminosulfonyl, methyl, ethyl, isopropyl, tert-butyl, isobutyl, cyano, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methylcarbonylamino, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, dichloromethyl, chloromethyl, hydroxy, fluorophenylmethyl, fluorophenylethyl, chlorophenylmethyl, chlorophenylethyl, fluorophenylethenyl, chlorophenylethenyl, fluorophenylpyrazolyl, chlorophenylpyrazoly
  • R 4 is selected from hydrido, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, phenyl, biphenyl, morpholinyl, pyrrolidinyl, piperazinyl, piperidinyl, pyridinyl, thienyl, isothiazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, quinolyl, isoquinolinyl, imidazolyl, benzimidazolyl, furyl, pyrazinyl, dihydropyranyl, dihydropyridinyl, dihydrofuryl, tetrahydropyranyl, tetrahydrofuryl, benzofuryl, dihydr
  • Another class of compounds of particular interest consists of these compounds of Formula I wherein
  • R 1 is hydrido, methyl, ethyl, propargyl, hydroxyethyl, dimethylaminoethyl, diethylaminoethyl or morpholinylethyl;
  • R 2 is selected from hydrido, methyl, ethyl, propyl, phenyl, trifluoromethyl, methoxycarbonylethyl, N,N-dimethylamino, N-phenylamino, piperidinyl, piperazinyl, pyridinyl, N-methylpiperazinyl, and piperazinylamino; wherein the phenyl, piperidinyl, and pyridinyl groups are optionally substituted with one or more radicals independently selected from fluoro, chloro, bromo, methyl, ethyl, and trifluoromethyl;
  • R 3 is selected from pyridinyl, pyrimidinyl or quinolinyl; wherein R 3 is optionally substituted with one or-more radicals independently selected from fluoro, bromo, methyl, cyano, methoxycarbonyl, aminocarbonyl, benzyl, phenethyl, acetyl, hydroxyl, methoxy, dimethylamino, benzylamino, phenethylamino, aminomethyl, amino, hydroxy, and methylcarbonyl;
  • R 4 is selected from phenyl, quinolyl, biphenyl, pyridinyl, thienyl, furyl, dihydropyranyl, benzofuryl, dihydrobenzofuryl, and benzodioxolyl; wherein the cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups of R 4 are optionally substituted with one or more radicals independently selected from methylthio, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino, and hydroxy; or
  • a class of compounds of specific interest consists of those compounds of Formula I wherein
  • R 1 is hydrido or methyl
  • R 2 is selected from hydrido, methyl or ethyl
  • R 3 is selected from pyridinyl, pyrimidinyl or quinolinyl; wherein R 3 is optionally substituted with one or more radicals independently selected from fluoro, bromo, methyl, cyano, methoxycarbonyl, aminocarbonyl, benzyl, phenethyl, acetyl, hydroxyl, methoxy, dimethylamino, benzylamino, phenethylamino, aminomethyl, amino, hydroxy, and methylcarbonyl;
  • R 4 is selected from phenyl which is optionally substituted with one or more radicals independently selected from methylthio, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino, and hydroxy; or
  • Still another class of compounds of particular interest consists of those compounds of Formula I wherein
  • R 1 is selected from hydrido, methyl, ethyl, propyl, 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, piperid
  • R 2 has the formula:
  • j 0, 1 or 2;
  • n 0;
  • R 30 and R 31 are independently selected from hydrogen and lower alkyl
  • R 32 is selected from hydrogen, lower alkyl, lower phenylalkyl, lower heterocyclylalkyl, lower alkoxyalkylene, aryloxyalkylene, aminoalkyl, lower alkylaminoalkyl, lower phenylaminoalkyl, lower alkylcarbonylalkylene, lower phenylcarbonylalkylene, and lower heterocyclylcarbonylaminoalkylene;
  • R 33 is selected from hydrogen, lower alkyl, —C(O)R 35 , —C(O)OR 35 , —SO 2 R 36 , —C(O)NR 37 R 38 , and —SO 2 NR 39 R 40 ;
  • R 35 is selected from lower alkyl, lower cycloalkyl, lower haloalkyl, lower alkenyl, aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclyl, lower phenylalkyl, lower phenylcycloalkyl, lower cycloalkenylalkylene, lower heterocyclylalkylene, lower alkylphenylene, lower alkylheterocyclyl, phenylphenylene, lower phenylheterocyclyl, lower alkoxy, lower alkenoxy, lower alkoxyalkylene, lower alkoxyphenylalkyl, lower alkoxyphenylene, lower phenoxyalkylene, lower phenylalkoxyalkylene, lower cycloalkyloxyalkylene, lower alkoxycarbonyl, lower heterocyclylcarbonyl, lower alkylcarbonyloxyalkylene, lower alkylcarbonyloxyphenylene, lower alkoxycarbon
  • R 35 is CHR 48 R 49 wherein R 48 is phenylsulfonylamino or lower alkylphenylsulfonylamino, and R 49 is selected from lower phenylalkyl, amino, lower alkylamino, and lower phenylalkylamino; or
  • R 35 is —NR 50 R 51 wherein R 50 is lower alkyl, and R 51 is aryl selected from phenyl, biphenyl and naphthyl; and
  • R 36 is selected from lower alkyl, lower haloalkyl, aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclyl, lower cycloalkylalkylene, lower alkylphenylene, lower alkenylphenylene, phenylphenylene, lower phenylalkyl, lower phenylalkenyl, lower heterocyclylheterocyclyl, carboxyphenylene, lower alkoxyphenylene, lower alkoxycarbonylphenylene, lower alkylcarbonylaminophenylene, lower alkylcarbonylaminoheterocyclyl, lower phenylcarbonylaminoalkylheterocyclyl, lower alkylaminophenylene, lower alkylamino, lower alkylaminophenylene, lower alkylamino, lower alkylaminophenylene, lower alkylamino, lower alkylaminophenylene, lower alkylamino,
  • R 37 is selected from hydrogen and lower alkyl
  • R 38 is selected from hydrogen, lower alkyl, lower alkenyl, aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclyl, lower phenylalkyl, lower alkylphenylene, lower phenylcycloalkyl, phenylphenylene, lower cycloalkylalkylene, lower heterocyclylalkylene, lower alkylheterocyclylalkylene, lower phenylalkylheterocyclyl, lower alkoxyalkylene, lower alkoxyphenylene, lower phenoxyphenylene, phenylcarbonyl, lower alkoxycarbonyl, lower alkoxycarbonylalkylene, lower alkoxycarbonylphenylene, lower alkylcarbonylcarbonylalkylene, lower alkylaminoalkylene, lower alkylaminophenylalkyl, lower alkylcarbonylaminoalkylene, lower alkylthiophenylene, lower
  • R 38 is —CR 52 R 53 wherein R 52 is lower alkoxycarbonyl, and R 53 is lower alkylthioalkylene; or
  • R 37 and R 38 together with the nitrogen atom to which they are attached form a 4-8 membered ring heterocycle
  • R 39 and R 40 have the same definition as R 26 and R 27 in claim 2 ; or
  • k is an integer from 0 to 2;
  • R 56 is hydrogen or lower alkyl
  • R 57 is hydrogen or lower alkyl
  • R 58 is selected from hydrogen, lower alkyl, lower phenylalkyl, aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclyl, lower heterocyclylalkyl, lower alkoxycarbonyl, lower alkylsulfonyl, lower phenylalkylsulfonyl, lower phenylsulfonyl, —C(O)R 59 , —SO 2 R 60 , and —C(O)NHR 61 ;
  • R 59 is selected from lower alkyl, lower haloalkyl, lower cycloalkyl, aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclyl, lower alkylphenylene, lower phenylalkyl, lower alkylheterocyclyl, lower alkoxy, lower alkenoxy, 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
  • R 60 is selected from lower alkyl, aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclyl, lower alkylphenylene, lower alkylheterocyclyl, lower phenylalkyl, lower heterocyclylheterocyclyl, lower alkoxyphenylene, lower alkylamino, lower alkylaminophenylene, lower alkylsulfonylphenylene, and lower phenylsulfonylheterocyclyl; wherein said aryl 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
  • R 61 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
  • R 3 is selected from pyridinyl, pyrimidinyl, and purinyl; wherein R 3 is optionally substituted with one or more radicals independently selected from methylthio, methylsulfinyl, methylsulfonyl, fluoro, chloro, bromo, aminosulfonyl, methyl, ethyl, isopropyl, tert-butyl, isobutyl, cyano, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methylcarbonylamino, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, dichloromethyl, chloromethyl, hydroxy, fluorophenylmethyl, fluorophenylethyl, chlorophenylmethyl, chlorophenylethyl, fluorophenylethenyl, chlorophenylethenyl, fluorophenylpyrazolyl, chlorophenylpyrazoly
  • R 4 is selected from hydrido, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, phenyl, biphenyl, morpholinyl, pyrrolidinyl, piperazinyl, piperidinyl, pyridinyl, thienyl, isothiazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, quinolyl, isoquinolinyl, imidazolyl, benzimidazolyl, furyl, pyrazinyl, dihydropyranyl, dihydropyridinyl, dihydrofuryl, tetrahydropyranyl, tetrahydrofuryl, benzofuryl, dihydr
  • Still another class of compounds of particular interest consists of those compounds of Formula I wherein
  • R 1 is hydrido, methyl, ethyl, propargyl, hydroxyethyl, dimethylaminoethyl, diethylaminoethyl or morpholinylethyl;
  • R 2 has the formula:
  • j 0, 1 or 2;
  • n 0;
  • R 30 is hydrogen
  • R 31 is selected from hydrogen and lower alkyl
  • R 32 is selected from hydrogen and lower alkyl
  • R 33 is selected from lower alkyl, —C(O)R 35 , —C(O)OR 35 , —SO 2 R 36 , —C(O)NR 37 R 38 , and —SO 2 NR 39 R 40 ;
  • R 35 is selected from lower alkyl, lower cycloalkyl, phenyl, lower heterocyclyl, lower alkylphenylene, lower alkoxy, lower alkenoxy, lower alkoxyalkylene, lower phenoxyalkylene, and lower phenylalkoxyalkylene; wherein said phenyl and lower phenoxyalkylene groups are optionally substituted with one or more radicals independently selected from lower alkyl, halo, and lower haloalkyl; and
  • R 36 is selected from lower alkyl, phenyl, lower heterocyclyl, lower alkylphenylene, phenylphenylene, lower phenylalkyl, lower alkylheterocyclyl, lower heterocyclylheterocyclyl, lower alkoxyphenylene, and lower alkylamino; wherein said phenyl and lower heterocyclyl groups are optionally substituted with one or more radicals independently selected from lower alkyl, halo, hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, nitro, and cyano; and
  • R 37 is hydrogen
  • R 38 is selected from lower alkyl, phenyl, and lower alkylphenylene
  • R 39 and R 40 have the same definition as R 26 and R 27 in claim 2 ;
  • k is an integer from 0 or 1;
  • R 56 is hydrogen
  • R 57 is hydrogen
  • R 58 is selected from —C(O)R 59 and —SO 2 R 60 ;
  • R 59 is selected from lower alkyl, lower cycloalkyl, phenyl, lower alkylphenylene, and lower alkoxyalkylene; wherein said phenyl group is optionally substituted with one or more radicals independently selected from lower alkyl, halo, hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, nitro, and cyano; and
  • R 60 is selected from lower alkyl
  • R 3 is selected from pyridinyl, pyrimidinyl or quinolinyl; wherein R 3 is optionally substituted with one or more radicals independently selected from fluoro, bromo, methyl, cyano, methoxycarbonyl, aminocarbonyl, benzyl, phenethyl, acetyl, hydroxyl, methoxy, dimethylamino, benzylamino, phenethylamino, aminomethyl, amino, hydroxy, and methylcarbonyl; and
  • R 4 is selected from phenyl, quinolyl, biphenyl, pyridinyl, thienyl, furyl, dihydropyranyl, benzofuryl, dihydrobenzofuryl, and benzodioxolyl; wherein the cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups of R 4 are optionally substituted with one or more radicals independently selected from methylthio, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino, and hydroxy; or
  • Still another class of compounds of specific interest consists of those compounds of Formula I wherein
  • R 1 is hydrido or methyl
  • R 3 is selected from pyridinyl, pyrimidinyl or quinolinyl; wherein R 3 is optionally substituted with one or more radicals independently selected from fluoro, bromo, methyl, cyano, methoxycarbonyl, aminocarbonyl, benzyl, phenethyl, acetyl, hydroxyl, methoxy, dimethylamino, benzylamino, phenethylamino, aminomethyl, amino, hydroxy, and methylcarbonyl; and
  • R 4 is selected from phenyl which is optionally substituted with one or more radicals independently selected from methylthio, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino, and hydroxy; or
  • the compounds of Formula I and/or 1A satisfy one or more of the following conditions:
  • R 1 is hydrido or lower alkyl; more preferably, R 1 is hydrido or methyl; and still more preferably, R 1 is hydrido;
  • R 2 is hydrido or lower alkyl; more preferably, R 2 is hydrido or methyl; and still more preferably, R 2 is hydrido;
  • R 2 comprises a piperidinyl, piperazinyl or cyclohexyl moiety
  • R 3 is substituted or unsubstituted pyridinyl; and preferably, the pyridinyl is a 4-pyridinyl; or
  • R 4 is substituted or unsubstituted phenyl; and preferably, R 4 is phenyl substituted with halo.
  • R 3 is substituted pyrimidinyl
  • at least one R 3 substitutent is attached to the carbon atom positioned between two nitrogen atoms of the pyrimidinyl ring.
  • a family of specific compounds of particular interest within Formula I and/or 1A consists of compounds, tautomers and pharmaceutically-acceptable salts thereof as follows:
  • Z represents a carbon atom or a nitrogen atom
  • R 1 is selected from hydrido, lower alkyl, lower hydroxyalkyl, lower alkynyl, lower heterocycyl, lower aralkyl, lower aminoalkyl and lower alkylaminoalkyl;
  • R 2 is selected from hydrido, lower alkyl, aryl selected from phenyl, biphenyl, and naphthyl, 5- or 6-membered heterocyclyl selected from piperidinyl, piperazinyl, imidazolyl, pyridinyl and morpholinyl, lower haloalkyl, lower hydroxyalkyl, lower alkoxycarbonyl, lower alkylamino, lower alkylaminoalkyl, phenylamino, lower aralkyl, lower aralkylamino, lower alkylaminoalkylamino, lower aminoalkyl, lower aminoalkylamino, lower alkynylamino, lower heterocyclylamino, lower heterocyclylalkyl, lower heterocyclylalkylamino, lower alkylheterocyclyl, lower carboxycycloalkyl, lower carboxyalkylamino, lower alkoxyalkylamino, lower alkoxycarbonylamin
  • R 2 is —CR 54 R 55 wherein R 54 is phenyl and R 55 is hydroxy;
  • R 4 is selected from hydrido, lower cycloalkyl, lower cycloalkenyl, lower cycloalkyldienyl, 5- or 6-membered heterocyclyl, and aryl selected from phenyl, biphenyl, naphthyl; wherein R 4 is optionally substituted at a substitutable position with one or more radicals independently selected from halo, lower alkyl, lower alkoxy, aryloxy, lower aralkoxy, lower haloalkyl, lower alkylthio, lower alkylamino, nitro, hydroxy; and
  • R 5 is selected from halo, amino, cyano, aminocarbonyl, lower alkyl, lower alkoxy, hydroxy, lower aminoalkyl, lower aralkyl, lower aralkyloxy, lower aralkylamino, lower alkoxycarbonyl, lower alkylamino, lower alkylcarbonyl, lower aralkenyl, lower arylheterocyclyl, carboxy, lower cycloalkylamino, lower alkoxycarbonylamino, lower alkoxyaralkylamino, lower alkylaminoalkylamino, lower heterocyclylamino, lower heterocyclylalkylamino, lower aralkylheterocyclylamino, lower alkylaminocarbonyl, lower alkylcarbonyl, lower alkoxyaralkylamino, hydrazinyl, and lower alkylhydrazinyl, or —NR 62 R 63 wherein R 62 is lower alkylcarbonyl
  • a preferred class of compounds consists of those compounds of Formula IX
  • R 1 is selected from hydrido, methyl, ethyl, hydroxyethyl and propargyl;
  • R 2 is selected from hydrido, methyl, ethyl, propyl, phenyl, trifluoromethyl, hydroxyethyl, methoxycarbonylethyl, ethoxycarbonylethyl, N-methylamino, N,N-dimethylamino, N-ethylamino, N,N-diethylamino, N-propylamino, N-phenylamino, aminomethyl, aminoethyl, aminoethylamino, aminopropylamino, propargylamino, benzylamino, dimethylaminopropylamino, morpholinylpropylamino, morpholinylethylamino, piperidinyl, piperazinyl, imidazolyl, morpholinyl, pyridinyl, carboxymethylamino, methoxyethylamino, (1,1-dimethyl)ethylcarbonyl, (1,
  • R 4 is selected from cyclohexyl, cyclohexenyl, cyclohexadienyl, phenyl, quinolyl, biphenyl, pyridinyl, thienyl, furyl, dihydropyranyl, benzofuryl, dihydrobenzofuryl, and benzodioxolyl; wherein R 4 is optionally substituted with one or more radicals independently selected from methylthio, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino, and hydroxy; and
  • R 5 is selected from fluoro, chloro, bromo, methyl, fluorophenylethyl, fluorophenylethenyl, fluorophenylpyrazolyl, cyano, methoxycarbonyl, aminocarbonyl, acetyl, hydroxy, carboxy, methoxy, methylamino, dimethylamino, 2-methylbutylamino, ethylamino, dimethylaminoethylamino, hydroxypropylamino, hydroxyethylamino, imidazolylamino, morpholinylethylamino, (1-ethyl-2-hydroxy)ethylamino, piperidinylamino, pyridinylmethylamino, phenylmethylpiperidinylamino, aminomethyl, cyclopropylamino, amino, hydroxy, methylcarbonyl, ethoxycarbonylamino, methoxyphenylmethylamino, pheny
  • Z represents a carbon atom or a nitrogen atom
  • R 1 is selected from lower alkyl, lower hydroxyalkyl, lower alkynyl, lower aminoalkyl and lower alkylaminoalkyl;
  • R 2 is selected from hydrido, lower alkyl, aryl 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 alkoxycarbonylamin
  • R 2 is —CR 54 R 55 wherein R 54 is phenyl and R 55 is hydroxy;
  • R 4 is selected from 5- or 6-membered heteroaryl, and aryl selected from phenyl, biphenyl, and naphthyl; wherein R 4 is optionally substituted with one or more radicals independently selected from halo, lower alkyl, lower alkoxy, aryloxy, lower aralkoxy, lower haloalkyl, lower alkylthio, lower alkylamino, nitro, hydroxy; and
  • R 5 is selected from halo, amino, cyano, aminocarbonyl, lower alkyl, lower alkoxy, hydroxy, lower aminoalkyl, lower aralkyl, lower aralkyloxy, lower aralkylamino, lower alkoxycarbonyl, lower alkylamino, lower alkylcarbonyl, lower aralkenyl, lower arylheterocyclyl, carboxy, lower cycloalkylamino, lower alkoxycarbonylamino, lower alkoxyaralkylamino, lower alkylaminoalkylamino, lower heterocyclylamino, lower heterocyclylalkylamino, lower aralkylheterocyclylamino, lower alkylaminocarbonyl, lower alkylcarbonyl, lower alkoxyaralkylamino, hydrazinyl, and lower alkylhydrazinyl, or —NR 62 R 63 wherein R 62 is lower alkylcarbonyl
  • a preferred class of compounds consists of those compounds of Formula X
  • R 1 is selected from methyl, ethyl, hydroxyethyl and propargyl
  • R 2 is selected from methyl, ethyl, propyl, phenyl, trifluoromethyl, hydroxyethyl, methoxycarbonylethyl, ethoxycarbonylethyl, N-methylamino, N,N-dimethylamino, N-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, methoxyeth
  • R 4 is selected from phenyl, quinolyl, biphenyl, pyridinyl, thienyl, furyl, dihydropyranyl, benzofuryl, dihydrobenzofuryl, and benzodioxolyl; wherein R 4 is optionally substituted with one or more radicals independently selected from methylthio, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino, and hydroxy; and
  • R 5 is selected from fluoro, chloro, bromo, methyl, fluorophenylethyl, fluorophenylethenyl, fluorophenylpyrazolyl, cyano, methoxycarbonyl, aminocarbonyl, acetyl, hydroxy, carboxy, methoxy, methylamino, dimethylamino, 2-methylbutylamino, ethylamino, dimethylaminoethylamino, hydroxypropylamino, hydroxyethylamino, propargylamino, imidazolylamino, morpholinylethylamino, (1-ethyl-2-hydroxy)ethylamino, piperidinylamino, pyridinylmethylamino, phenylmethylpiperidinylamino, aminomethyl, cyclopropylamino, amino, hydroxy, methylcarbonyl, ethoxycarbonylamino, methoxyphenylmethyl
  • Z represents a carbon atom or a nitrogen atom
  • R 1 is selected from lower alkyl, lower hydroxyalkyl, lower alkynyl, lower aminoalkyl and lower alkylaminoalkyl;
  • R 2 is selected from hydrido, lower alkyl, aryl 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 alkoxycarbonylamin
  • R 2 is —CR 54 R 55 wherein R 54 is phenyl and R 55 is hydroxy;
  • R 4 is selected from 5- or 6-membered heteroaryl, and aryl selected from phenyl, biphenyl, and naphthyl; wherein R 4 is optionally substituted with one or more radicals independently selected from halo, lower alkyl, lower alkoxy, aryloxy, lower aralkoxy, lower haloalkyl, lower alkylthio, lower alkylamino, nitro, hydroxy; and
  • R 5 is selected from halo, amino, cyano, aminocarbonyl, lower alkyl, lower alkoxy, hydroxy, lower aminoalkyl, lower aralkyl, lower aralkyloxy, lower aralkylamino, lower alkoxycarbonyl, lower alkylamino, lower alkylcarbonyl, lower aralkenyl, lower arylheterocyclyl, carboxy, lower cycloalkylamino, lower alkoxycarbonylamino, lower alkoxyaralkylamino, lower alkylaminoalkylamino, lower heterocyclylamino, lower heterocyclylalkylamino, lower aralkylheterocyclylamino, lower alkylaminocarbonyl, lower alkylcarbonyl, lower alkoxyaralkylamino, hydrazinyl, and lower alkylhydrazinyl, or —NR 62 R 63 wherein R 62 is lower alkylcarbonyl
  • a preferred class of compounds consists of those compounds of Formula XI
  • R 1 is selected from methyl, ethyl, hydroxyethyl and propargyl
  • R 2 is selected from methyl, ethyl, propyl, phenyl, trifluoromethyl, hydroxyethyl, methoxycarbonylethyl, ethoxycarbonylethyl, N-methylamino, N,N-dimethylamino, N-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)
  • R 4 is selected from phenyl, quinolyl, biphenyl, pyridinyl, thienyl, furyl, dihydropyranyl, benzofuryl, dihydrobenzofuryl, and benzodioxolyl; wherein R 4 is optionally substituted with one or more radicals independently selected from methylthio, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino, and hydroxy; and
  • R 5 is selected from fluoro, chloro, bromo, methyl, fluorophenylethyl, fluorophenylethenyl, fluorophenylpyrazolyl, cyano, methoxycarbonyl, aminocarbonyl, acetyl, hydroxy, carboxy, methoxy, methylamino, dimethylamino, 2-methylbutylamino, ethylamino, dimethylaminoethylamino, hydroxypropylamino, hydroxyethylamino, imidazolylamino, morpholinylethylamino, (1-ethyl-2-hydroxy)ethylamino, piperidinylamino, pyridinylmethylamino, phenylmethylpiperidinylamino, aminomethyl, cyclopropylamino, amino, hydroxy, methylcarbonyl, ethoxycarbonylamino, methoxyphenylmethylamino, pheny
  • a preferred class of compounds consists of those compounds of Formula IX wherein
  • Z represents a carbon atom or a nitrogen atom
  • R 1 is selected from hydrido, lower alkyl, lower hydroxyalkyl, lower alkynyl, lower aminoalkyl and lower alkylaminoalkyl;
  • R 2 is selected from hydrido, lower alkyl, aryl selected from phenyl, biphenyl, and naphthyl, 5- or 6-membered heterocyclyl selected from piperidinyl, piperazinyl, imidazolyl, pyridinyl and morpholinyl, lower haloalkyl, lower hydroxyalkyl, lower alkoxycarbonyl, lower alkylamino, lower alkylaminoalkyl, phenylamino, lower aralkyl, lower aralkylamino, lower alkylaminoalkylamino, lower aminoalkyl, lower aminoalkylamino, lower alkynylamino, lower heterocyclylamino, lower heterocyclylalkyl, lower heterocyclylalkylamino, lower alkylheterocyclyl, lower carboxycycloalkyl, lower carboxyalkylamino, lower alkoxyalkylamino, lower alkoxycarbonylamin
  • R 2 is —CR 54 R 55 wherein R 54 is phenyl and R 55 is hydroxy;
  • R 4 is phenyl that is optionally substituted with one or more radicals independently selected from halo, lower alkyl, lower alkoxy, aryloxy, lower aralkoxy, lower haloalkyl, lower alkylthio, lower alkylamino, nitro, hydroxy; and
  • R 5 is selected from halo, amino, cyano, aminocarbonyl, lower alkyl, lower alkoxy, hydroxy, lower aminoalkyl, lower aralkyl, lower aralkyloxy, lower aralkylamino, lower alkoxycarbonyl, lower alkylamino, lower alkylcarbonyl, lower aralkenyl, lower arylheterocyclyl, carboxy, lower cycloalkylamino, lower alkoxycarbonylamino, lower alkoxyaralkylamino, lower alkylaminoalkylamino, lower heterocyclylamino, lower heterocyclylalkylamino, lower aralkylheterocyclylamino, lower alkylaminocarbonyl, lower alkylcarbonyl, lower alkoxyaralkylamino, hydrazinyl, and lower alkylhydrazinyl, or —NR 62 R 63 wherein R 62 is lower alkylcarbonyl
  • a class of compounds of specific interest consists of those compounds of Formula IX wherein
  • R 1 is selected from hydrido, methyl, ethyl, hydroxyethyl and propargyl;
  • R 2 is selected from methyl, ethyl, propyl, phenyl, trifluoromethyl, hydroxyethyl, methoxycarbonylethyl, ethoxycarbonylethyl, N-methylamino, N,N-dimethylamino, N-ethylamino, N,N-diethylamino, N-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)
  • R 4 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
  • R 5 is selected from fluoro, chloro, bromo, methyl, fluorophenylethyl, fluorophenylethenyl, fluorophenylpyrazolyl, cyano, methoxycarbonyl, aminocarbonyl, acetyl, hydroxy, carboxy, methoxy, methylamino, dimethylamino, 2-methylbutylamino, ethylamino, dimethylaminoethylamino, hydroxypropylamino, hydroxyethylamino, imidazolylamino, morpholinylethylamino, (1-ethyl-2-hydroxy)ethylamino, piperidinylamino, pyridinylmethylamino, phenylmethylpiperidinylamino, aminomethyl, cyclopropylamino, amino, hydroxy, methylcarbonyl, ethoxycarbonylamino, methoxyphenylmethylamino, pheny
  • Another class of compounds of specific interest consists of those compounds of Formula IX wherein
  • R 1 is selected from hydrido, lower alkyl, lower hydroxyalkyl and lower alkynyl
  • R 2 is selected from hydrido and lower alkyl
  • R 4 is selected from phenyl and benzodioxolyl; wherein phenyl is optionally substituted with one or more halo radicals; and
  • R 5 is selected from hydrido, halo and alkylhydrazinyl
  • Still another class of compounds of specific interest consists of those compounds of Formula IX wherein;
  • Z represents a carbon atom
  • R 1 is selected from hydrido, methyl, hydroxyethyl, propargyl
  • R 2 is hydrido
  • R 4 is selected from phenyl and benzodioxolyl; wherein phenyl is optionally substituted with one or more radicals independently selected from chloro, fluoro and bromo; and
  • R 5 is selected from hydrido, fluoro, and 1-methylhydrazinyl
  • a preferred class of compounds of specific interest consists of those compounds of Formula IX wherein
  • Z represents a carbon atom
  • R 1 is selected from hydrido and methyl
  • R 4 is selected from phenyl that is optionally substituted with one or more radicals independently selected from chloro, fluoro and bromo;
  • R 5 is selected from hydrido and fluoro
  • Z represents a carbon atom or a nitrogen atom
  • R 1 is selected from hydrido, lower alkyl, lower hydroxyalkyl, lower alkynyl, lower aralkyl, lower aminoalkyl and lower alkylaminoalkyl;
  • R 2 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
  • R 2 is R 200 -heterocyclyl-R 201 or R 200 -cycloalkyl-R 201 wherein:
  • R 200 is selected from:
  • R 200 represents a bond
  • R 201 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
  • R 202 and R 203 are independently selected from hydrido, lower alkyl, aryl and lower aralkyl;
  • y is 0, 1, 2 or 3;
  • R 4 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
  • R 5 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 alkylhydra
  • 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.
  • 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.
  • R 2 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;
  • R 1 is selected from hydrido, methyl, ethyl, hydroxyethyl and propargyl;
  • R 2 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,
  • R 2 is R 200 -piperidinyl-R 201 , R 200 -piperazinyl-R 201 , or R 200 -cyclohexyl-R 201 wherein:
  • R 200 is selected from:
  • R 201 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, piperid
  • R 202 and R 203 are independently selected from hydrido, methyl, ethyl, propyl, butyl, phenyl and benzyl;
  • y 0, 1 or 2;
  • R 4 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
  • R 5 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, piperidin
  • R 1 is selected from hydrido, methyl, ethyl, hydroxyethyl and propargyl;
  • R 2 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,
  • R 4 is phenyl, wherein said phenyl is optionally substituted with one or more radicals independently selected from fluoro, chloro, methyl, ethyl, methoxy and ethoxy; and
  • R 5 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, cyclopropy
  • a subclass of compounds of particular interest consists of those compounds of Formula XA wherein:
  • R 1 is selected from hydrido, methyl, ethyl, hydroxyethyl and propargyl;
  • R 2 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
  • R 4 is phenyl, wherein said phenyl is optionally substituted with one or more radicals independently selected from fluoro, chloro, methyl, ethyl, methoxy and ethoxy; and
  • R 5 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, aminomethyl, cyclopropylamino, amino, ethoxycarbonylamino, methoxyphenylmethylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethyla
  • a subclass of compounds of specific interest consists of those compounds of Formula XA wherein:
  • R 1 is hydrido
  • R 2 is selected from hydrido, methylaminopropylamino, dimethylaminopropylamino, ethylaminopropylamino, diethylaminopropylamino, morpholinylmethylamino, morpholinylethylamino, and morpholinylpropylamino;
  • R 4 is phenyl, wherein said phenyl is optionally substituted with one or more radicals independently selected from fluoro, chloro, methyl, and methoxy;
  • R 5 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 subclass of compounds of high interest consists of those compounds of Formula XA wherein:
  • R 1 is selected hydrido
  • R 2 is selected from hydrido, dimethylaminopropylamino, diethylaminopropylamino, morpholinylethylamino, and morpholinylpropylamino;
  • R 4 is phenyl, wherein said phenyl is optionally substituted with one or more radicals independently selected from fluoro, chloro, methyl, and methoxy;
  • R 5 is selected from hydrido, hydroxypropylamino, hydroxycyclohexylamino, diethylaminoethylamino; or
  • R 1 is selected from hydrido, methyl, ethyl, hydroxyethyl and propargyl;
  • R 2 is R 200 -piperidinyl-R 201 wherein:
  • R 200 is selected from:
  • R 200 represents a bond
  • R 201 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, piperid
  • R 4 is phenyl, wherein said phenyl is optionally substituted with one or more radicals independently selected from fluoro, chloro, methyl, ethyl, methoxy and ethoxy; and
  • R 5 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, cyclopropy
  • a subclass of compounds of particular interest consists of those compounds of Formula XA wherein:
  • R 1 is selected from hydrido, methyl, ethyl, hydroxyethyl and propargyl;
  • R 2 is R 200 -piperidinyl-R 201 wherein:
  • R 200 is selected from:
  • R 200 represents a bond
  • R 201 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, propoxypheny
  • R 202 is selected from hydrido, methyl, ethyl, phenyl and benzyl;
  • R 4 is phenyl, wherein said phenyl is optionally substituted with one or more radicals independently selected from fluoro, chloro, methyl, ethyl, methoxy and ethoxy; and
  • R 5 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, aminomethyl, cyclopropylamino, amino, ethoxycarbonylamino, methoxyphenylmethylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethyla
  • a subclass of compounds of specific interest consists of those compounds of Formula XA wherein:
  • R 1 is hydrido
  • R 2 is R 200 -piperidinyl-R 201 wherein:
  • R 200 is selected from:
  • R 200 represents a bond
  • R 201 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, e
  • R 202 is selected from hydrido, methyl phenyl and benzyl
  • R 4 is phenyl, wherein said phenyl is optionally substituted with one or more radicals independently selected from fluoro, chloro, methyl, and methoxy;
  • R 5 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 subclass of compounds of high interest consists of those compounds of Formula XA wherein:
  • R 1 is hydrido
  • R 2 is R 200 -piperidinyl-R 201 wherein:
  • R 200 is selected from:
  • R 200 represents a bond
  • R 201 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
  • R 202 is selected from hydrido and methyl
  • R 4 is phenyl, wherein said phenyl is optionally substituted with one or more radicals independently selected from fluoro, chloro, methyl, and methoxy;
  • R 5 is selected from hydrido, hydroxypropylamino, hydroxycyclohexylamino, diethylaminoethylamino; or
  • R 1 is selected from hydrido, methyl, ethyl, hydroxyethyl and propargyl;
  • R 2 is R 200 -piperazinyl-R 201 wherein:
  • R 200 is selected from:
  • R 200 represents a bond
  • R 201 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, piperid
  • R 202 and R 203 are independently selected from hydrido, methyl, ethyl, propyl, butyl, phenyl and benzyl;
  • R 4 is phenyl, wherein said phenyl is optionally substituted with one or more radicals independently selected from fluoro, chloro, methyl, ethyl, methoxy and ethoxy; and
  • R 5 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, cyclopropy
  • a subclass of compounds of particular interest consists of those compounds of Formula XA wherein:
  • R 1 is selected from hydrido, methyl, ethyl, hydroxyethyl and propargyl;
  • R 2 is R 200 piperazinyl-R 201 wherein:
  • R 200 is selected from:
  • R 200 represents a bond
  • R 201 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, me
  • R 202 and R 203 are independently selected from hydrido, methyl, ethyl, phenyl and benzyl;
  • y 0, 1 or 2;
  • R 4 is phenyl, wherein said phenyl is optionally substituted with one or more radicals independently selected from fluoro, chloro, methyl, ethyl, methoxy and ethoxy; and
  • R 5 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, aminomethyl, cyclopropylamino, amino, ethoxycarbonylamino, methoxyphenylmethylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethyla
  • a subclass of compounds of specific interest consists of those compounds of Formula XA wherein:
  • R 1 is hydrido
  • R 2 is R 200 -piperazinyl-R 201 wherein:
  • R 200 is selected from:
  • R 200 represents a bond
  • R 201 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
  • R 202 is selected from hydrido, methyl, ethyl, phenyl and benzyl;
  • y 0, 1 or 2;
  • R 4 is phenyl, wherein said phenyl is optionally substituted with one or more radicals independently selected from fluoro, chloro, methyl, and methoxy;
  • R 5 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 subclass of compounds of high interest consists of those compounds of Formula XA wherein:
  • R 1 is hydrido
  • R 2 is R 200 -piperazinyl-R 201 wherein:
  • R 200 is selected from:
  • R 200 represents a bond
  • R 201 represents one or more radicals selected from the group consisting of hydrido, methyl, cyclopropyl, propargyl, and benzyl;
  • R 202 is selected from hydrido and methyl
  • R 4 is phenyl, wherein said phenyl is optionally substituted with one or more radicals independently selected from fluoro, chloro, methyl, and methoxy;
  • R 5 is selected from hydrido, hydroxypropylamino, hydroxycyclohexylamino, and diethylaminoethylamino; or
  • R 1 is selected from hydrido, methyl, ethyl, hydroxyethyl and propargyl;
  • R 2 is R 200 -cyclohexyl-R 201 wherein:
  • R 200 is selected from:
  • R 200 represents a bond
  • R 201 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, piperid
  • R 202 and R 203 are independently selected from hydrido, methyl, ethyl, propyl, butyl, phenyl and benzyl;
  • y 0, 1 or 2;
  • R 4 is phenyl, wherein said phenyl is optionally substituted with one or more radicals independently selected from fluoro, chloro, methyl, ethyl, methoxy and ethoxy; and
  • R 5 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, cyclopropy
  • a subclass of compounds of particular interest consists of those compounds of Formula XA wherein:
  • R 1 is selected from hydrido, methyl, ethyl, hydroxyethyl and propargyl;
  • R 2 is R 200 -cyclohexyl-R 201 wherein:
  • R 200 is selected from:
  • R 200 represents a bond
  • R 201 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, prop
  • R 202 and R 203 are independently selected from hydrido, methyl, ethyl, phenyl and benzyl;
  • R 4 is phenyl, wherein said phenyl is optionally substituted with one or more radicals independently selected from fluoro, chloro, methyl, ethyl, methoxy and ethoxy; and
  • R 5 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, aminomethyl, cyclopropylamino, amino, ethoxycarbonylamino, methoxyphenylmethylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethyla
  • a subclass of compounds of specific interest consists of those compounds of Formula XA wherein:
  • R 1 is hydrido
  • R 2 is R 200 -cyclohexyl-R 201 wherein:
  • R 200 is selected from:
  • R 200 represents a bond
  • R 201 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, methoxye
  • R 202 is selected from hydrido, methyl, phenyl and benzyl;
  • R 4 is phenyl, wherein said phenyl is optionally substituted with one or more radicals independently selected from fluoro, chloro, methyl, and methoxy;
  • R 5 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 subclass of compounds of high interest consists of those compounds of Formula XA wherein:
  • R 1 is hydrido
  • R 2 is R 200 -cyclohexyl-R 201 wherein:
  • R 200 is selected from:
  • R 200 represents a bond
  • R 201 represents one or more radicals selected from the group consisting of amino, aminomethyl, N,N-dimethylamino, and N-isopropylamino;
  • R 202 is selected from hydrido and methyl
  • R 4 is phenyl, wherein said phenyl is optionally substituted with one or more radicals independently selected from fluoro, chloro, methyl, and methoxy;
  • R 5 is selected from hydrido, hydroxypropylamino, hydroxycyclohexylamino, and diethylaminoethylamino; or
  • R 1 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, alkylthioalkeny
  • R 1 has the formula wherein:
  • R 25 is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene; and
  • R 26 is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkylene, aralkyl, alkoxycarbonylalkylene, and alkylaminoalkyl;
  • R 27 is selected from alkyl, cycloalkyl, alkynyl, aryl, heterocyclyl, aralkyl, cycloalkylalkylene, cycloalkenylalkylene, cycloalkylarylene, cycloalkylcycloalkyl, heterocyclylalkylene, alkylarylene, alkylaralkyl, aralkylarylene, alkylheterocyclyl, alkylheterocyclylalkylene, alkylheterocyclylarylene, aralkylheterocyclyl, alkoxyalkylene, alkoxyarylene, alkoxyaralkyl, alkoxyheterocyclyl, alkoxyalkoxyarylene, aryloxyarylene, aralkoxyarylene, alkoxyheterocyclylalkylene, aryloxyalkoxyarylene, alkoxycarbonylalkylene, alkoxycarbonylheterocycly
  • R 27 is —CHR 28 R 29 wherein R 28 is alkoxycarbonyl, and R 29 is selected from aralkyl, aralkoxyalkylene, heterocyclylalkylene, alkylheterocyclylalkylene, alkoxycarbonylalkylene, alkylthioalkylene, and aralkylthioalkylene; wherein said aralkyl and heterocylcyl groups are optionally substituted with one or more radicals independently selected from alkyl and nitro; or
  • R 26 and R 27 together with the nitrogen atom to which they are attached form a heterocycle, wherein said heterocycle is optionally substituted with one or more radicals independently selected from alkyl, aryl, heterocyclyl, heterocyclylalkylene, alkylheterocyclylalkylene, aryloxyalkylene, alkoxyarylene, alkylaryloxyalkylene, alkylcarbonyl, alkoxycarbonyl, aralkoxycarbonyl, alkylamino and alkoxycarbonylamino; wherein said aryl, heterocyclylalkylene and aryloxyalkylene radicals are optionally substituted with one or more radicals independently selected from halogen, alkyl and alkoxy; and
  • R 2 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, heterocyclylalkyl
  • R 2 is R 200 -heterocyclyl-R 201 , R 200 -aryl-R 201 , or R 200 -cycloalkyl-R 201 wherein:
  • R 200 is selected from:
  • R 200 represents a bond
  • R 201 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
  • R 202 and R 203 are independently selected from hydrido, alkyl, aryl and aralkyl;
  • y and z are independently 0, 1, 2, 3, 4, 5 or 6 wherein y+z is less than or equal to 6;
  • z 0, 1 or 2;
  • R 2 is —NHCR 204 R 205 wherein R 204 is alkylaminoalkylene, and R 205 is aryl; or
  • R 2 is —C(NR 206 )R 201 wherein R 206 is selected from hydrogen and hydroxy, and R 207 is selected from alkyl, aryl and aralkyl; and
  • R 3 is selected from pyridinyl, pyrimidinyl, quinolinyl, purinyl, maleimidyl, pyridonyl, thiazolyl, thiazolylalkyl, thiazolylamino, wherein the R 3 pyridinyl, pyrimidinyl, quinolinyl, purinyl, maleimidyl, pyridonyl, thiazolyl, thiazolylalkyl, thiazolylamino, 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, aralk
  • R 4 is selected from hydrido, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, and heterocyclyl, wherein R 4 is optionally substituted with one or more radicals independently selected from halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylthio, arylthio, alkylthioalkylene, arylthioalkylene, alkylsulfinyl, alkylsulfinylalkylene, arylsulfinylalkylene, alkylsulfonyl, alkylsulfonylalkylene, arylsulfonylalkylene, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, hal
  • R 1 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, alkylthioalkeny
  • R 1 has the formula
  • i is an integer from 0 to 9;
  • R 25 is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene; and
  • R 26 is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkylene, aralkyl, alkoxycarbonylalkylene, and alkylaminoalkyl;
  • R 27 is selected from alkyl, cycloalkyl, alkynyl, aryl, heterocyclyl, aralkyl, cycloalkylalkylene, cycloalkenylalkylene, cycloalkylarylene, cycloalkylcycloalkyl, heterocyclylalkylene, alkylarylene, alkylaralkyl, aralkylarylene, alkylheterocyclyl, alkylheterocyclylalkylene, alkylheterocyclylarylene, aralkylheterocyclyl, alkoxyalkylene, alkoxyarylene, alkoxyaralkyl, alkoxyheterocyclyl, alkoxyalkoxyarylene, aryloxyarylene, aralkoxyarylene, alkoxyheterocyclylalkylene, aryloxyalkoxyarylene, alkoxycarbonylalkylene, alkoxycarbonylheterocycly
  • R 27 is —CHR 28 R 29 wherein R 28 is alkoxycarbonyl, and R 29 is selected from aralkyl, aralkoxyalkylene, heterocyclylalkylene, alkylheterocyclylalkylene, alkoxycarbonylalkylene, alkylthioalkylene, and aralkylthioalkylene; wherein said aralkyl and heterocylcyl groups are optionally substituted with one or more radicals independently selected from alkyl and nitro; or
  • R 26 and R 27 together with the nitrogen atom to which they are attached form a heterocycle, wherein said heterocycle is optionally substituted with one or more radicals independently selected from alkyl, aryl, heterocyclyl, heterocyclylalkylene, alkylheterocyclylalkylene, aryloxyalkylene, alkoxyarylene, alkylaryloxyalkylene, alkylcarbonyl, alkoxycarbonyl, aralkoxycarbonyl, alkylamino and alkoxycarbonylamino; wherein said aryl, heterocyclylalkylene and aryloxyalkylene radicals are optionally substituted with one or more radicals independently selected from halogen, alkyl and alkoxy; and
  • R 2 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, alkylaminoarylene, al
  • R 2 is R 200 -heterocyclyl-R 201 , R 200 -aryl-R 201 , or R 200 -cycloalkyl-R 201 wherein:
  • R 200 is selected from:
  • R 200 represents a bond
  • R 201 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
  • R 202 and R 203 are independently selected from hydrido, alkyl, aryl and aralkyl;
  • y and z are independently 0, 1, 2, 3, 4, 5 or 6 wherein y+z is less than or equal to 6;
  • z 0, 1 or 2;
  • R 2 is —NHCR 204 R 205 wherein R 204 is alkylaminoalkylene, and R 205 is aryl; or R 2 is —C(NR 206 )R 207 wherein R 206 is selected from hydrogen and hydroxy, and R 207 is selected from alkyl, aryl and aralkyl; or
  • R 2 has the formula: wherein:
  • j is an integer from 0 to 8.
  • n 0 or 1
  • R 30 and R 31 are independently selected from hydrogen, alkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, aminoalkyl, alkylaminoalkyl, aminocarbonylalkyl, alkoxyalkyl, and alkylcarbonyloxyalkyl; and
  • R 32 is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene;
  • R 33 is selected from hydrogen, alkyl, —C(O)R 35 ,
  • R 35 , R 36 , R 37 , R 38 , R 39 and R 40 are independently selected from hydrocarbon, heterosubstituted hydrocarbon and heterocyclyl;
  • R 34 is selected from hydrogen, alkyl, aminocarbonyl, alkylaminocarbonyl, and arylaminocarbonyl; or
  • R 2 is —CR 41 R 42 wherein R 41 is aryl, and R 42 is hydroxy;
  • R 3 is selected from pyridinyl, pyrimidinyl, quinolinyl, purinyl, maleimidyl, pyridonyl, thiazolyl, thiazolylalkyl, thiazolylamino, wherein the R 3 pyridinyl, pyrimidinyl, quinolinyl, purinyl, maleimidyl, pyridonyl, thiazolyl, thiazolylalkyl, thiazolylamino, groups are substituted with one or more radicals independently selected from keto, haloarylamino, alkoxyalkylene, alkenoxyalkylene, aryloxyalkyl, alkoxyalkylamino, alkylaminoalkoxy, alkoxyarylamino, alkylsulfonylamino, aryl(hydroxyalkyl)amino, alkylaminoalkylaminoalkylamino, alkylheterocyclylamin
  • R 4 is selected from hydrido, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, and heterocyclyl, wherein R 4 is optionally substituted with one or more radicals independently selected from halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylthio, arylthio, alkylthioalkylene, arylthioalkylene, alkylsulfinyl, alkylsulfinylalkylene, arylsulfinylalkylene, alkylsulfonyl, alkylsulfonylalkylene, arylsulfonylalkylene, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, hal
  • R 1 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, alkylthioalkeny
  • R 1 has the formula wherein:
  • i is an integer from 0 to 9;
  • R 25 is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene; and
  • R 26 is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkylene, aralkyl, alkoxycarbonylalkylene, and alkylaminoalkyl;
  • R 27 is selected from alkyl, cycloalkyl, alkynyl, aryl, heterocyclyl, aralkyl, cycloalkylalkylene, cycloalkenylalkylene, cycloalkylarylene, cycloalkylcycloalkyl, heterocyclylalkylene, alkylarylene, alkylaralkyl, aralkylarylene, alkylheterocyclyl, alkylheterocyclylalkylene, alkylheterocyclylarylene, aralkylheterocyclyl, alkoxyalkylene, alkoxyarylene, alkoxyaralkyl, alkoxyheterocyclyl, alkoxyalkoxyarylene, aryloxyarylene, aralkoxyarylene, alkoxyheterocyclylalkylene, aryloxyalkoxyarylene, alkoxycarbonylalkylene, alkoxycarbonylheterocycly
  • R 27 is —CHR 28 R 29 wherein R 28 is alkoxycarbonyl, and R 29 is selected from aralkyl, aralkoxyalkylene, heterocyclylalkylene, alkylheterocyclylalkylene, alkoxycarbonylalkylene, alkylthioalkylene, and aralkylthioalkylene; wherein said aralkyl and heterocylcyl groups are optionally substituted with one or more radicals independently selected from alkyl and nitro; or
  • R 26 and R 27 together with the nitrogen atom to which they are attached form a heterocycle, wherein said heterocycle is optionally substituted with one or more radicals independently selected from alkyl, aryl, heterocyclyl, heterocyclylalkylene, alkylheterocyclylalkylene, aryloxyalkylene, alkoxyarylene, alkylaryloxyalkylene, alkylcarbonyl, alkoxycarbonyl, aralkoxycarbonyl, alkylamino and alkoxycarbonylamino; wherein said aryl, heterocyclylalkylene and aryloxyalkylene radicals are optionally substituted with one or more radicals independently selected from halogen, alkyl and alkoxy; and
  • R 2 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, alkylaminoarylene
  • R 2 is R 200 -heterocyclyl-R 201 , R 200 -aryl-R 201 , or R 200 -cycloalkyl-R 201 wherein:
  • R 200 is selected from:
  • R 200 represents a bond
  • R 201 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
  • R 202 and R 203 are independently selected from hydrido, alkyl, aryl and aralkyl;
  • y and z are independently 0, 1, 2, 3, 4, 5 or 6 wherein y+z is less than or equal to 6;
  • z 0, 1 or 2;
  • R 2 is —NHCR 204 R 205 wherein R 204 is alkylaminoalkylene, and R 205 is aryl; or
  • R 2 is —C(NR 206 )R 207 wherein R 206 is selected from hydrogen and hydroxy, and R 207 is selected from alkyl, aryl and aralkyl; or
  • R 2 has the formula:
  • j is an integer from 0 to 8.
  • n 0 or 1
  • R 30 and R 31 are independently selected from hydrogen, Alkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, aminoalkyl, alkylaminoalkyl, aminocarbonylalkyl, alkoxyalkyl, and alkylcarbonyloxyalkyl; and
  • R 32 is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene;
  • R 33 is selected from hydrogen, alkyl, —C(O)R 35 , —C(O)OR 35 , —SO 2 R 36 , —C(O)NR 37 R 38 , and —SO 2 NR 39 R 40 , wherein R 35 , R 36 , R 37 , R 38 , R 39 and R 40 are independently selected from hydrocarbon, heterosubstituted hydrocarbon and heterocyclyl; and
  • R 34 is selected from hydrogen, alkyl, aminocarbonyl, alkylaminocarbonyl, and arylaminocarbonyl; or
  • R 2 is —CR 41 R 42 wherein R 41 is aryl, and R 42 is hydroxy;
  • R 3 is selected from maleimidyl, pyridonyl, thiazolyl, thiazolylalkyl, thiazolylamino, wherein the R 3 maleimidyl, pyridonyl, thiazolyl, thiazolylalkyl, thiazolylamino, 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, cycloalkenylamin
  • R 4 is selected from hydrido, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, and heterocyclyl, wherein R 4 is optionally substituted with one or more radicals independently selected from halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylthio, arylthio, alkylthioalkylene, arylthioalkylene, alkylsulfinyl, alkylsulfinylalkylene, arylsulfinylalkylene, alkylsulfonyl, alkylsulfonylalkylene, arylsulfonylalkylene, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, hal
  • R 3 is other than maleimidyl or pyridonyl having the structures: respectively, wherein R 43 is selected from hydrogen, alkyl, aminoalkyl, alkoxyalkyl, alkenoxyalkyl, and aryloxyalkyl; or
  • Another group of compounds of interest consists of compounds of Formula IB:
  • R 3 pyridinyl, pyrimidinyl, quinolinyl, purinyl, maleimidyl, pyridonyl, thiazolyl, thiazolylalkyl, thiazolylamino,
  • R 3 is optionally substituted pyridinyl or pyrimidinyl. In still another embodiment, R 3 is unsubstituted pyridinyl
  • Still another group of compounds of interest consists of the compounds, their tautomers and their pharmaceutically acceptable salts, of the group consisting of:
  • hydro denotes a single hydrogen atom (H). This hydrido radical may be attached, for example, to an oxygen atom to form a hydroxyl radical or two hydrido radicals may be attached to a carbon atom to form a methylene (—CH 2 —) radical.
  • alkyl alkylsulfonyl
  • alkoxyalkyl alkoxyalkyl
  • cyanoalkyl and “mercaptoalkyl
  • alkyll embraces linear or branched radicals having one to about twenty carbon atoms or, preferably, one to about twelve carbon atoms.
  • alkyl radicals are “lower alkyl” radicals having one to about ten carbon atoms. Most preferred are lower alkyl radicals having one to about six carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl and the like.
  • alkenyl embraces linear or branched radicals having at least one carbon-carbon double bond of two to about twenty carbon atoms or, preferably, two to about twelve carbon atoms.
  • alkenyl radicals are “lower alkenyl” radicals having two to about six carbon atoms.
  • alkenyl radicals include ethenyl, allyl, propenyl, butenyl and 4-methylbutenyl.
  • alkenyl and lower alkenyl embrace radicals having “cis” and “trans” orientations, or alternatively, “E” and “Z” orientations.
  • alkynyl embraces linear or 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.
  • alkynyl radicals are “lower alkynyl” radicals having two to about six carbon atoms.
  • alkynyl radicals include propargyl, 1-propynyl, 2-propynyl, 1-butyne, 2-butynyl and 1-pentynyl.
  • cycloalkyl embraces saturated carbocyclic radicals having three to about twelve carbon atoms.
  • cycloalkyl embraces saturated carbocyclic radicals having three to about twelve carbon atoms.
  • More preferred cycloalkyl radicals are “lower cycloalkyl” radicals having three to about eight carbon atoms.
  • radicals examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • cycloalkylalkylene embraces alkyl radicals substituted with a cycloalkyl radical. More preferred cycloalkylalkylene radicals are “lower cycloalkylalkylene” which embrace lower alkyl radicals substituted with a lower cycloalkyl radical as defined above. Examples of such radicals include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl.
  • cycloalkenyl embraces partially unsaturated carbocyclic radicals having three to twelve carbon atoms.
  • Cycloalkenyl radicals that are partially unsaturated carbocyclic radicals that contain two double bonds (that may or may not be conjugated) can be called “cycloalkyldienyl”. More preferred cycloalkenyl radicals are “lower cycloalkenyl” radicals having four to about eight carbon atoms. Examples of such radicals include cyclobutenyl, cyclopentenyl and cyclohexenyl.
  • halo means halogens such as fluorine, chlorine, bromine or iodine.
  • haloalkyl embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above.
  • a monohaloalkyl radical for one example, may have either an iodo, bromo, chloro or fluoro atom within the radical.
  • Dihalo and polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals.
  • “Lower haloalkyl” embraces radicals having one to six carbon atoms.
  • haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.
  • hydroxyalkyl embraces linear or branched alkyl radicals having one to about ten carbon atoms any one of which may be substituted with one or more hydroxyl radicals.
  • More preferred hydroxyalkyl radicals are “lower hydroxyalkyl” radicals having one to six carbon atoms and one or more hydroxyl radicals. Examples of such radicals include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl.
  • the terms “alkoxy” and “alkyloxy” embrace linear or branched oxy-containing radicals each having alkyl portions of one to about ten carbon atoms. More preferred alkoxy radicals are “lower alkoxy” radicals having one to six carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy and tert-butoxy.
  • alkoxyalkyl embraces alkyl radicals having one or more alkoxy radicals attached to the alkyl radical, that is, to form monoalkoxyalkyl and dialkoxyalkyl radicals.
  • the “alkoxy” radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide haloalkoxy radicals.
  • aryl alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such rings may be attached together in a pendent manner or may be fused.
  • aryl embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl.
  • Aryl moieties may also be substituted at a substitutable position with one or more substituents selected independently from halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylthio, arylthio, alkylthioalkylene, arylthioalkylene, alkylsulfinyl, alkylsulfinylalkylene, arylsulfinylalkylene, alkylsulfonyl, alkylsulfonylalkylene, arylsulfonylalkylene, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl,
  • heterocyclyl embraces saturated, partially unsaturated and unsaturated heteroatom-containing ring-shaped radicals, which can also be called “heterocyclyl”, “heterocycloalkenyl” and “heteroaryl” correspondingly, where the heteroatoms may be selected from nitrogen, sulfur and oxygen.
  • saturated heterocyclyl radicals include saturated 3 to 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms (e.g. pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.); saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (e.g.
  • heterocyclyl radicals include dihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazole.
  • Heterocyclyl radicals may include a pentavalent nitrogen, such as in tetrazolium and pyridinium radicals.
  • heteroaryl embraces unsaturated heterocyclyl radicals.
  • 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.
  • 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,
  • 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.
  • thiazolyl, thiadiazolyl e.g., 1,2,4- thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.
  • unsaturated condensed heterocyclyl group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms e.g., be
  • heterocycle also embraces radicals where heterocyclyl radicals are fused with aryl or cycloalkyl radicals. Examples of such fused bicyclic radicals include benzofuran, benzothiophene, and the like. Said “heterocyclyl group” may have 1 to 3 substituents such as alkyl, hydroxyl, halo, alkoxy, oxo, amino, alkylthio and alkylamino.
  • heterocyclylalkylene embraces heterocyclyl-substituted alkyl radicals.
  • heterocyclylalkylene radicals are “lower heterocyclylalkylene” radicals having one to six carbon atoms and a heterocyclyl radicals.
  • alkylthio embraces radicals containing a linear or branched alkyl radical, of one to about ten carbon atoms attached to a divalent sulfur atom.
  • More preferred alkylthio radicals are “lower alkylthio” radicals having alkyl radicals of one to six carbon atoms. Examples of such lower alkylthio radicals are methylthio, ethylthio, propylthio, butylthio and hexylthio.
  • 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.
  • 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, —SO 2 —.
  • 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.
  • halo atoms such as fluoro, chloro or bromo
  • halosulfonyl embraces halo radicals attached to a sulfonyl radical. Examples of such halosulfonyl radicals include chlorosulfonyl, and bromosulfonyl.
  • halosulfonyl radicals include chlorosulfonyl, and bromosulfonyl.
  • sulfamyl denote NH 2 O 2 S—.
  • 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.
  • 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, ⁇ -hydroxybutyric, galactaric and galacturonic acids.
  • carbonyl whether used alone or with other terms, such as “alkoxycarbonyl”, denotes —(C ⁇ O)—.
  • carboxy or “carboxyl”, whether used alone or with other terms, such as “carboxyalkyl”, denotes —CO 2 H.
  • carboxyalkyl embraces alkyl radicals substituted with a carboxy radical. More preferred are “lower carboxyalkyl” which embrace lower alkyl radicals as defined above, and may be additionally substituted on the alkyl radical with halo. Examples of such lower carboxyalkyl radicals include carboxymethyl, carboxyethyl and carboxypropyl.
  • alkoxycarbonyl means a radical containing an alkoxy radical, as defined above, attached via an oxygen atom to a carbonyl radical.
  • lower alkoxycarbonyl radicals with alkyl portions having one to six carbons.
  • lower alkoxycarbonyl (ester) radicals include substituted or unsubstituted methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and hexyloxycarbonyl.
  • alkoxycarbonylalkyl embraces alkyl radicals substituted with a alkoxycarbonyl radical as defined above. More preferred are “lower alkoxycarbonylalkyl” radicals with alkyl portions having one to six carbons.
  • alkoxycarbonylalkyl radicals examples include substituted or unsubstituted methoxycarbonylmethyl, ethoxycarbonylmethyl, methoxycarbonyl-ethyl and ethoxycarbonylethyl.
  • 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.
  • aralkyl embraces aryl-substituted alkyl radicals such as benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, and diphenylethyl.
  • the aryl in said aralkyl may be additionally substituted with one or more substituents selected independently from halo, alkyl, alkoxy, halkoalkyl, haloalkoxy, amino and nitro.
  • substituents selected independently from halo, alkyl, alkoxy, halkoalkyl, haloalkoxy, amino and nitro.
  • benzyl and phenylmethyl are interchangeable.
  • heterocyclylalkylene embraces saturated and partially unsaturated heterocyclyl-substituted alkyl radicals (also can be called heterocycloalkylalkylene and heterocycloalkenylalkylene correspondingly), such as 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.
  • aryloxy embraces aryl radicals attached through an oxygen atom to other radicals.
  • aralkoxy embraces aralkyl radicals attached through an oxygen atom to other radicals.
  • aminoalkyl embraces alkyl radicals substituted with amino radicals. More preferred are “lower aminoalkyl” radicals. Examples of such radicals include aminomethyl, aminoethyl, and the like.
  • alkylamino denotes amino groups which are substituted with one or two alkyl radicals. Preferred are “lower alkylamino” radicals having alkyl portions having one to six carbon atoms.
  • Suitable lower alkylamino may be monosubstituted N-alkylamino or disubstituted N,N-alkylamino, such as N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino or the like.
  • arylamino denotes amino groups which are substituted with one or two aryl radicals, such as N-phenylamino.
  • the “arylamino” radicals may be further substituted on the aryl ring portion of the radical.
  • aminocarbonyll denotes an amide group of the formula —C( ⁇ O)NH 2 .
  • 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.
  • alkylcarbonylamino embraces amino groups which are substituted with one alkylcarbonyl radicals.
  • alkylcarbonylamino radicals are “lower alkylcarbonylamino” having lower alkylcarbonyl radicals as defined above attached to amino radicals.
  • alkylaminoalkylene embraces radicals having one or more alkyl radicals attached to an aminoalkyl radical.
  • hydrocarbon moieties described herein are organic compounds or radicals consisting exclusively of the elements carbon and hydrogen. These moieties include alkyl, alkenyl, alkynyl, and aryl moieties. These moieties also include alkyl, alkenyl, alkynyl, and aryl moieties substituted with other aliphatic or cyclic hydrocarbon groups, such as alkaryl, alkenaryl and alkynaryl. Preferably, these moieties comprise 1 to 20 carbon atoms.
  • 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.
  • substituents include lower alkoxy such as methoxy, ethoxy, butoxy; halogen such as chloro or fluoro; ethers; acetals; ketals; esters; heterocyclyl such as furyl or thienyl; alkanoxy; hydroxy; protected hydroxy; acyl; acyloxy; nitro; cyano; amino; and amido.
  • each alkyl radical of a pyrazole ring substituent comprising one or more alkyl radicals has one to about six carbon atoms; each alkenyl radical of a pyrazole ring substituent comprising one or more alkenyl radicals has two to about six carbon atoms; each alkynyl radical of a pyrazole ring substituent comprising one or more alkynyl radicals has two to about six carbon atoms; each.
  • cycloalkyl or cycloalkenyl radical of a pyrazole ring substituent comprising one or more cycloalkyl and/or cycloalkenyl radicals is a 3 to 8 membered ring 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).
  • the pyrazoles of Formula I and I′ are magnetically and structurally equivalent because of the prototropic tautomeric nature of the hydrogen:
  • 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.
  • the substituent at the 4-position of the pyrazole ring is one that is a partial mimic of the adenine ring of ATP, although it may be further elaborated.
  • it is a planar substituent terminated by a suitable. hydrogen bond acceptor functionality. It is hypothesized that this acceptor hydrogen bonds to the backbone N—H of the Met 106 residue while one edge of this substituent is in contact with bulk solvent.
  • substitution on the nitrogen atom at the 1- or 2-position of the pyrazole ring is well tolerated and can provide increased potency. It is hypothesized that a hydrogen substituent attached to one of the ring nitrogen atoms is hydrogen bonded to Asp 165 .
  • 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.
  • these substituents each have a molecular weight less than about 360 atomic mass units. More preferably, these substituents each have a molecular weight less than about less than about 250 atomic mass units. Still more preferably, these substituents have a combined molecular weight less than about 360 atomic mass units.
  • a class of substituted pyrazoles of particular interest consists of those compounds having the formula:
  • R 1 is a hydrocarbyl, heterosubstituted hydrocarbyl or heterocyclyl radical having a molecular weight less than about 360 atomic mass units;
  • R 2 is a hydrocarbyl, heterosubstituted hydrocarbyl or heterocyclyl radical that binds with p38 kinase at said ATP binding site of p38 kinase;
  • R 3 is a hydrocarbyl, heterosubstituted hydrocarbyl or heterocyclyl radical having a hydrogen bond acceptor functionality
  • R 4 is a hydrocarbyl, heterosubstituted hydrocarbyl or heterocyclyl radical having a molecular weight less than about 360 atomic mass units;
  • R 3 is not 2-pyridinyl when R 4 is a phenyl ring containing a 2-hydroxy substituent and when R 1 is hydrido; further provided R 2 is selected from aryl, heterocyclyl, unsubstituted cycloalkyl and cycloalkenyl when R 4 is hydrido; and further provided R 4 is not methylsulfonylphenyl; or
  • R 1 , R 2 , R 3 and R 4 preferably are selected from the corresponding groups of the compounds of Formula I and/or IA. More preferably, R 3 is an optionally substituted pyridinyl or pyrimidinyl, R 4 is a halo substituted phenyl, and R 1 and R 2 have the definitions set forth immediately above.
  • a class of substituted pyrazoles of particular interest consists of those compounds of Formula XI wherein
  • R 1 is a hydrocarbyl, heterosubstituted hydrocarbyl or heterocyclyl radical having a molecular weight less than about 360 atomic mass units;
  • R 2 is a hydrocarbyl, heterosubstituted hydrocarbyl or heterocyclyl radical wherein said radical binds with Lys 52 , Glu 69 , Leu 73 , Ile 82 , Leu 84 , Leu 101 , and Thr 103 sidechains at said ATP binding site of p38 kinase, said radical being substantially disposed within a hydrophobic cavity formed during said binding by p38 kinase at the ATP binding site; and
  • R 3 is a hydrocarbyl, heterosubstituted hydrocarbyl or heterocyclyl radical having a hydrogen bond acceptor functionality that hydrogen bonds with the N—H backbone of Met 106 of p38 kinase;
  • R 4 is a hydrocarbyl, heterosubstituted hydrocarbyl or heterocyclyl radical having a molecular weight less than about 360 atomic mass units.
  • the present invention also comprises a therapeutic method of treating a TNF mediated disorder, a p38 kinase mediated disorder, inflammation and/or arthritis in a subject, the method comprising treating a subject having or susceptible to such disorder or condition with a therapeutically-effective amount of a compound of Formula I and/or IA.
  • 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
  • R 1 is selected from hydrido, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, cycloalkylalkylene, cycloalkenylalkylene, heterocyclylalkylene, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aralkyl, aralkenyl, aralkynyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxyalkyl, alkenoxyalkyl, alkynoxyalkyl, aryloxyalkyl, heterocyclyloxyalkyl, alkoxyalkoxy, mercaptoalkyl, alkylthioalkylene, alkenylthioalkylene, alkylthioalkenylene, amino, aminoalkyl,
  • i is an integer from 0 to 9;
  • R 25 is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene; and
  • R 26 is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkylene, aralkyl, alkoxycarbonylalkylene, and alkylaminoalkyl;
  • R 27 is selected from alkyl, cycloalkyl, alkynyl, aryl, heterocyclyl, aralkyl, cycloalkylalkylene, cycloalkenylalkylene, cycloalkylarylene, cycloalkylcycloalkyl, heterocyclylalkylene, alkylarylene, alkylaralkyl, aralkylarylene, alkylheterocyclyl, alkylheterocyclylalkylene, alkylheterocyclylarylene, aralkylheterocyclyl, alkoxyalkylene, alkoxyarylene, alkoxyaralkyl, alkoxyheterocyclyl, alkoxyalkoxyarylene, aryloxyarylene, aralkoxyarylene, alkoxyheterocyclylalkylene, aryloxyalkoxyarylene, alkoxycarbonylalkylene, alkoxycarbonylheterocycly
  • R 27 is —CHR 28 R 29 wherein R 28 is alkoxycarbonyl, and R 29 is selected from aralkyl, aralkoxyalkylene, heterocyclylalkylene, alkylheterocyclylalkylene, alkoxycarbonylalkylene, alkylthioalkylene, and aralkylthioalkylene; wherein said aralkyl and heterocylcyl groups are optionally substituted with one or more radicals independently selected from alkyl and nitro; or
  • R 26 and R 27 together with the nitrogen atom to which they are attached form a heterocycle, wherein said heterocycle is optionally substituted with one or more radicals independently selected from alkyl, aryl, heterocyclyl, heterocyclylalkylene, alkylheterocyclylalkylene, aryloxyalkylene, alkoxyarylene, alkylaryloxyalkylene, alkylcarbonyl, alkoxycarbonyl, aralkoxycarbonyl, alkylamino and alkoxycarbonylamino; wherein said aryl, heterocyclylalkylene and aryloxyalkylene radicals are optionally substituted with one or more radicals independently selected from halogen, alkyl and alkoxy; and
  • R 2 is selected from hydrido, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, haloalkyl, hydroxyalkyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, heterocyclylalkylamino, aralkylamino, aminoalkyl, aminoaryl, aminoalkylamino, arylaminoalkylene, alkylaminoalkylene, arylaminoarylene, alkylaminoarylene, alkylaminoarylene, alkylaminoalkylamino, cycloalkyl, cycloalkenyl, alkoxy, heterocyclyloxy, alkylthio, arylthio, heterocyclylthio, carboxy, carboxyalkyl, carboxycyclo
  • j is an integer from 0 to 8.
  • n 0 or 1
  • R 30 and R 31 are independently selected from hydrogen, alkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, aminoalkyl, alkylaminoalkyl, aminocarbonylalkyl, alkoxyalkyl, and alkylcarbonyloxyalkyl; and
  • R 32 is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene;
  • R 33 is selected from hydrogen, alkyl, —C(O)R 35 , —C(O)OR 35 , —SO 2 R 36 , —C(O)NR 37 R 38 , and —SO 2 NR 39 R 40 , wherein R 35 , R 36 , R 37 , R 38 , R 39 and R 40 are independently selected from hydrocarbon, heterosubstituted hydrocarbon and heterocyclyl; and
  • R 34 is selected from hydrogen, alkyl, aminocarbonyl, alkylaminocarbonyl, and arylaminocarbonyl; or
  • R 2 is —CR 41 R 42 wherein R 41 is aryl, and R 42 is hydroxy;
  • R 3 is selected from pyridinyl, pyrimidinyl, quinolinyl, purinyl,
  • R 43 is selected from hydrogen, alkyl, aminoalkyl, alkoxyalkyl, alkenoxyalkyl, and arylcxyalkyl;
  • R 3 pyridinyl, pyrimidinyl, quinolinyl and purinyl groups are optionally substituted with one or more radicals independently selected from halo, alkyl, aralkyl, aralkenyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, aralkoxy, heterocyclylalkoxy, amino, alkylamino, alkenylamino, alkynylamino, cycloalkylamino, cycloalkenylamino, arylamino, heterocyclylamino, aminocarbonyl, cyano, hydroxy, hydroxyalkyl, alkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl,
  • R 4 is selected from hydrido, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, and heterocyclyl, wherein R 4 is optionally substituted with one or more radicals independently selected from halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylthio, arylthio, alkylthioalkylene, arylthioalkylene, alkylsulfinyl, alkylsulfinylalkylene, arylsulfinylalkylene, alkylsulfonyl, alkylsulfonylalkylene, arylsulfonylalkylene, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, hal
  • R 3 is not 2-pyridinyl when R 4 is a phenyl ring containing a 2-hydroxy substituent and when R 1 is hydrido; further provided Ra is selected from aryl, heterocyclyl, unsubstituted cycloalkyl and cycloalkenyl when R 4 is hydrido; and further provided R 4 is not methylsulfonylphenyl; or
  • 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.
  • pharmaceutically-acceptable salts and prodrugs thereof are also included in the family of compounds of Formulae I and/or IA.
  • 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.
  • organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclyl, carboxylic and sulfonic classes of organic acids, example of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, stearic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, cyclohexylaminosulfonic, algenic, ⁇ -hydroxybutyric, galactaric and
  • 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: wherein R 3 and R 4 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.
  • 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.
  • Scheme I shows the synthesis of pyrazole 5 by two routes.
  • ketone 3 is first converted to epoxide 4, such as by treatment with hydrogen peroxide solution at room temperature, in the presence of base such as sodium hydroxide.
  • Treatment of epoxide 4 with hydrazine in ethanol or other suitable solvent at a temperature ranging up to reflux yields pyrazole 5.
  • ketone 3 is condensed directly with tosyl hydrazide in the presence of an acid such as acetic acid, at reflux, to provide pyrazole 5.
  • an acid such as acetic acid
  • the intermediate tosyl hydrazone 6 may be isolated, conversion of it to pyrazole 5 is effected by treatment with a base, such as potassium hydroxide, in a suitable solvent, such as ethylene glycol, at a temperature ranging from 25° C. up to 150° C.
  • Scheme II shows the synthesis of pyrazole 12 of the present invention.
  • a base such as sodium bis(trimethylsilyl)amide
  • a suitable solvent such as tetrahydrofuran
  • ketone 9 Treatment of ketone 9 or a hydrohalide salt of ketone 9 with a halogenating agent, such as bromine, N-bromosuccinimide or N-chlorosuccinimide, in suitable solvents, such as acetic acid, methylene chloride, methanol, or combinations thereof, forms the a-halogenated ketone 10 (wherein X is halo).
  • a halogenating agent such as bromine, N-bromosuccinimide or N-chlorosuccinimide
  • hydrohalide salts include the hydrochloride and hydrobromide salts.
  • Reaction of haloketone 10 with thiosemicarbazide 11 (where R 6 and R 7 can be hydrido, lower alkyl, phenyl, heterocyclyl and the like or where R 6 and R 7 form a heterocyclyl ring optionally containing an additional heteroatom) provides pyrazole 12.
  • 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.
  • Compound 12 contains a second derivatizable nitrogen atom
  • substituents may be placed on that atom by methods known to those skilled in the art.
  • 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.
  • 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.
  • an alkyl halide such as propargyl bromide
  • Scheme III shows the synthesis of pyrazole 19 in more general form by three routes.
  • ketone 13 is condensed with hydrazine 14 to give the substituted hydrazide 16, which is then reacted with acyl halide or anhydride 17 at low temperature to provide acyl hydrazone 18.
  • acyl hydrazone 18 Upon heating at a temperature up to 200° C., acyl hydrazone 18 is converted to pyrazole 19.
  • Route 2 acyl hydrazone 18 is formed directly by reaction of ketone 13 with acyl hydrazide 15, formed by reaction of hydrazine with a carboxylic acid ester, at room temperature. Heating acyl hydrazone 18 as above then provides pyrazole 19.
  • ketone 13 is treated with acyl hydrazide 15 at a suitable temperature, ranging from room temperature to about 200° C., to give pyrazole 19 directly.
  • this condensation may be carried out in an acidic solvent, such as acetic acid, or in a solvent containing acetic acid.
  • Synthetic Scheme IV describes the preparation of pyrazole 19.
  • Scheme V shows the two step synthesis of the 3-substituted 4-pyridyl-5-arylpyrazoles 33 of the present invention by cyclization of hydrazone dianions with carboxylates.
  • step 1 the reaction of substituted pyridylmethyl ketones 31 (prepared, for example, as later described in Scheme IX) with hydrazines in the presence of solvents such as ethanol gives ketohydrazones 32.
  • suitable hydrazines include, but are not limited to, phenylhydrazine and p-methoxyphenylhydrazine.
  • step 2 the hydrazones 32 are treated with two equivalents of a base such as sodium bis(trimethylsilyl)amide in a suitable solvent such as tetrahydrofuran to generate dianions.
  • a base such as sodium bis(trimethylsilyl)amide
  • a suitable solvent such as tetrahydrofuran
  • the dianions then are condensed with esters such as methyl isonicotinate, methyl cyclopropanecarboxylate, to give the desired pyrazoles 33.
  • esters such as methyl isonicotinate, methyl cyclopropanecarboxylate
  • Scheme VI shows an alternative method for synthesizing pyrazoles which are unsubstituted at the 5 position of the ring.
  • a heteroarylmethyl ketone 34 is synthesized by first treating a heteroarylmethane with a strong base such as lithium hexamethyldisilazide or lithium diisopropylamide.
  • suitable heteroarylmethanes are 4-methylpyridine, 4-methylpyrimidine, 2,4-dimethylpyridine, 2-chloro-4-methylpyrimidine, 2-chloro-4-methylpyridine and 2-fluoro-4-methylpyridine.
  • the resulting heteroarylmethyl lithium species is then reacted with a substituted benzoate ester to produce ketone 34.
  • Ketone 34 is converted to the aminomethylene derivative 35 by reaction with an aminomethylenating agent such as dimethylformamide dimethyl acetal or tert-butoxybis(dimethylamino)methane.
  • Ketone 35 is converted to pyrazole 36 by treatment with hydrazine.
  • Ketone 34 is first converted to hydrazone 37 by reaction with the appropriate substituted hydrazine.
  • suitable hydrazines are N-methylhydrazine and N-(2-hydroxyethyl)hydrazine.
  • Reaction of hydrazone 37 with an aminomethylenating agent produces pyrazole 38.
  • suitable aminomethylenating agents include dimethylformamide dimethyl acetal and tert-butoxybis(dimethylamino)methane.
  • R 3 substituent of pyrazoles 36 and 38 bears a leaving group such as a displaceable halogen
  • subsequent treatment with an amine produces an amino-substituted heteroaromatic derivative.
  • amines include benzylamine, cyclopropylamine and ammonia.
  • the leaving group may also be replaced with other nucleophiles such as mercaptides and alkoxides.
  • substitutable R 3 groups include, but are not limited to, 2-chloropyridinyl and 2-bromopyridinyl groups.
  • Oxidation of pyrazole 5 gives carboxylic acid 39, which is then reduced to hydroxymethyl compound 40, or coupled with amine NR 10 R 11 (wherein R 10 and R 11 are independently selected, for example, from hydrogen, alkyl and aryl, or together with the nitrogen atom to which they are attached form a 4-8 membered ring that may contain one or more additional heteroatoms selected from oxygen, nitrogen or sulfur) to form amide 41 followed by reduction to generate amine derivative 42.
  • Scheme VIII illustrates the synthesis of pyrazoles 44 and 45 from pyrazole 43.
  • the alkylation of the ring nitrogen atoms of pyrazole 43 can be accomplished using conventional techniques.
  • an appropriate base for example, sodium hydride
  • an alkyl halide for example, CH 3 I
  • Scheme IX illustrates the synthesis of 3-aryl-4-pyridyl-pyrazoles of the present invention.
  • Benzoate 46 is reacted with pyridine 47 in the presence of a strong base, such as an alkali metal hexamethyldisilazide (preferably sodium hexamethyldisilazide or lithium hexamethyldisilazide), in a suitable solvent, such as tetrahydrofuran, to give desoxybenzoin 48.
  • Desoxybenzoin 48 is then converted to ketone 49 by treatment with an excess of dimethylformamide dimethyl acetal.
  • Ketone 49 is then reacted with hydrazine hydrate in a suitable solvent such as ethanol to yield pyrazole 50.
  • R 12 represents one or more radicals independently selected from the optional substituents previously defined for R 4 .
  • R 12 is hydrogen, alkyl, halo, trifluoromethyl, methoxy or cyano, or represents methylenedioxy.
  • the 3-aryl-4-pyrimidinyl-pyrazoles of the present invention can be synthesized in the manner of Scheme IX by replacing pyridine 47 with the corresponding pyrimidine.
  • Schemes X through XVII can be employed to synthesize 3-aryl-4-pyrimidinyl-pyrimidines corresponding to the 3-aryl-4-pyrimidinyl-pyrazoles shown in those schemes.
  • Scheme X illustrates one variation of Scheme IX that can be used to synthesize 3-aryl-4-pyridyl-pyrazoles that are further substituted on the nitrogen atom at position 1 of the pyrazole ring. If desoxybenzoin 48 (prepared in accordance with Scheme IX) instead is first converted to hydrazone 51 by treatment with hydrazine and hydrazone 51 is then treated with dimethylformamide dimethyl acetal, then the resulting product is pyrazole 52.
  • Schemes XI through XVIII illustrate further modifications that can be made to Scheme IX to synthesize other 3-aryl-4-pyridyl-pyrazoles having alternative substituents.
  • X is chloro, fluoro or bromo
  • R 13 is, for example, hydrogen, alkyl, phenyl, aralkyl, heteroarylalkyl, amino or alkylamino
  • R 20 is, for example, hydrogen or alkyl.
  • n is 1, 2, 3, 4 or 5; and R 14 and R 15 are independently selected from, for example, hydrogen, alkyl or aryl, or together with the nitrogen atom to which they are attached form a 4-7 membered ring that may contain one or more additional heteroatoms selected from oxygen, nitrogen or sulfur.
  • R 16 is selected, for example, from hydrogen, alkyl and phenyl.
  • R 17 is selected, for example, from alkyl, phenylalkyl and heterocyclylalkyl.
  • Carboxamide 69 is converted to its methyl ester 70 by reaction with dimethylformamide dimethyl acetal in methanol.
  • the ester 70 is converted to its carboxylic acid 71 by saponification.
  • Typical saponification conditions include reaction with a base such as sodium hydroxide or potassium hydroxide in a suitable solvent such as ethanol or ethanol and water or methanol and water or the like.
  • Ester 70 is also convertible to substituted amide 72 by treatment with a desired amine, such as methylamine at a suitable temperature. Temperatures may range from room temperature to 180° C.
  • R 18 and R 19 are independently selected, for example, from hydrogen, alkyl and aryl, or together with the nitrogen atom to which they are attached form a 4-8 membered ring that may contain one or more additional heteroatoms selected from oxygen, nitrogen or sulfur.
  • suitable derivatives of dimethylformamide include tert.-butoxybis(dimethylamino)methane and dimethylformamide dimethyl acetal.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the tert.-butoxycarbonyl group of 84 may be reduced with a reagent such as lithium aluminum hydride to provide the methyl derivative 85.
  • Scheme XXI shows the synthesis of pyrazoles 92.
  • ketone 88 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 R 3 is typically heteroaryl, preferably pyridinyl or pyrimidinyl, and more preferably 4-pyridinyl.
  • Substituent R 4 is typically aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkyl or aralkyl, and is preferably a substitued phenyl.
  • R 103 can be, for example, lower alkyl.
  • ketone 88 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.
  • 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.
  • 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.
  • 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.
  • R 104 and R 105 can be independent radicals or can form a heterocyclyl ring that is optionally substituted and/or contains an additional heteroatom.
  • 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.
  • a chlorinating agent such as phosphorous trichloride
  • 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 R 106 and R 107 substituents include, for example, hydrogen and alkyl.
  • 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.
  • acylating agents such as benzyliminodiacetic acid and N,N-dimethylglycine
  • Typical R 108 and R 109 substituents include, for example, hydrogen, alkyl and acyl.
  • 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.
  • a suitable base such as sodium hydride or potassium t-butoxide
  • 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.
  • an appropriate alkylating agent such as methyl iodide, benzyl bromide, or trimethylsilylchloride
  • 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.
  • 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 —NCH 3 , 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.
  • a solvent such as tetrahydrofuran or ethanol
  • 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.
  • Scheme XXVI shows the synthesis of pyrazole 112.
  • a suitable solvent such as toluene
  • an amine such as thiomorpholine
  • Thioamide 110 may be isolated or used directly in the next reaction step.
  • a suitable base such as potassium t-butoxide
  • Alkylated thioamide 111 can be cyclized with hydrazine (or substituted hydrazine), in a solvent, such as tetrahydrofuran or ethanol, to generate pyrazole 112.
  • 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.
  • alkylating agents such as alkyl halides or Michael acceptors, including, but not limited to, methyl chloroacetate, ethyl acrylate, and benzyl bromide
  • a suitable base such as potassium carbonate, sodium ethoxide or triethylamine
  • solvent such as dimetliylformainide or ethanol
  • Scheme XXVIII shows the synthesis of pyrazole 117.
  • Pyrazoles containing acid labile amine protecting groups such as pyrazole 115
  • a suitable acid catalyst such as trifluoroacetic acid in dichloromethane or HCl in ethanol or dioxane
  • 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.
  • N-methylation can be performed directly, using formaldehyde and formic acid in ethanol/water at reflux to give pyrazole 117 wherein R 114 is methyl.
  • Scheme XXIX shows the synthesis of pyrazole 120.
  • Pyrazoles containing base labile esters such as pyrazole 118
  • a suitable base such as, sodium hydroxide
  • 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.
  • a suitable coupling reagent such as 1-(3-dimethylaminopropyl)3-ethylcarbodiiminde hydrochloride or O-benzotriazol-1-yl-N,N,N
  • 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.
  • an appropriate amine for example N-methylpiperazine
  • a suitable solvent such as dimethylformamide or methanol
  • Step 1 Preparation of 4-(3-fluoro-4-methoxylphenyl)-3-pyridyl-3-butene-2-one
  • step 1 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 CH 2 Cl 2 (150 ml), washed with H 2 O (2 ⁇ 100 ml), dried (Na 2 SO 4 ), filtered, and concentrated.
  • 4-Pyridylacetone was prepared according to the method of Ippolito et al, U.S. Pat. 4,681,944.
  • step 1 4-pyridylacetone (step 1) (1 g, 7.4 mmol) was condensed with benzaldehyde (790 mg, 7.4 mmol) in benzene (15 mL) containing piperidine (50 mg) at reflux.
  • step 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 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.
  • step 1 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).
  • step 2 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 C 16 H 15 N 3 (249.32): C, 77.08; H, 6.06; N, 16.85. Found: C, 76.66; H, 5.91; N, 16.84.
  • 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 C 16 H 15 N 3 (249.32): C, 77.08; H, 6.06; N, 16.85. Found: C, 76.97; H, 6.09; N; 16.90.
  • Example A-10 The same procedure as for the preparation of Example A-10 was used, substituting 4-formylbiphenyl in place of piperonal, to give 4-[5-[(1,1′-biphenyl)-4-yl]-3-methyl-1H-pyrazol-4-yl]pyridine as a white solid: MS (M+H): 312 (base peak).
  • Example A-10 The same procedure for the preparation of Example A-10 was used, substituting 3-phenoxybenzaldehyde in place of piperonal, to give 4-[3-methyl-5-[3-(phenoxyphenyl)-1H-pyrazol-4-yl]pyridine as a white solid.
  • Example A-10 The same procedure for the preparation of Example A-10 was used, substituting 3-benzyloxybenzaldehyde in place of piperonal, to give 4-[3-methyl-5-[3-(phenylmethoxy)phenyl]-1H-pyrazol-4-yl]pyridine as a white solid: MS (M + H): 342 (base peak).
  • Example A-2 4-(3-methyl-5-phenyl-1H-pyrazol-4-yl)pyridine (2.06 g, 8.76 mmol) in a mixture of CH 2 Cl 2 (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 K 2 CO 3 solution (25%, 15 mL), and concentrated. The resulting residue was partitioned between EtOAc (2.0 L) and H 2 O (500 mL).
  • step 1 To a solution of 1-fluoro-4-(4′-pyridylacetyl)benzene (step 1) (10.0 g, 0.046 mol) in acetic acid (200 mL) was added a solution of bromine (8.2 g, 0.052 mol) in acetic acid (20 mL) dropwise. The reaction mixture was stirred at room temperature overnight. After the solvent was removed, the residue was triturated with ethyl acetate. A yellow solid formed, which was filtered and air-dried to give 1-fluoro-4-(41 -pyridylbromoacetyl)benzene (14.5 g). The compound was used in next step without further purification.
  • step 2 A mixture of 1-fluoro-4-(4′-pyridylbromoacetyl)-benzene (step 2) (3.8 g, 0.01 mol) and 4,4-dimethylamino-3-thiosemicarbazide (1.2 g, 0.01 mol) in ethanol (10 mL) was heated at reflux for 30 minutes. The dark green solution was cooled and poured into water (100 mL). The aqueous phase was extracted with methylene chloride (100 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated.
  • Step 1 Preparation of 1-fluoro-4-(4 ⁇ -pyridylacetyl) benzene N-benzoylhydrazone
  • step 1 1-Fluoro-4-(4′-pyridylacetyl)benzene N-benzoylhydrazone (step 1) (0.50 g, 1.5 mmol) was heated at 180° C. under N 2 for 15 minutes, then cooled. The resulting solid was purified by chromatography (silica gel, 1:1 ethyl acetate/hexane) to give 4-[5-(4-fluorophenyl)-3-phenyl-1H-pyrazol-4-yl]pyridine (0.25 g, 53%) as a pale yellow solid: m.p.: 265-267° C. Anal. Calc'd for C 20 H 14 FN 3 +0.25 H 2 O: C, 75.10; H, 4.57; N, 13.14. Found: C, 74.98; H, 4.49; N, 12.87.
  • step 2 A mixture of 3-(4′-pyridylacetyl)toluene (2.11 g, 0.01 mol) and trifluoroacetyl hydrazide (step 2) (1.0 g, 0.01 mol) was heated at 200° C. under N 2 for 15 minutes. 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 C 16 H 12 F 3 N 3 : C, 63.36; H, 3.99; N, 13.85. Found: C, 63.6; H, 4.00; N, 13.70.
  • 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 C 15 H 19 N 3 : C, 73.56; H, 7.98; N, 17.16. Found: C, 73.72; H, 7.91; N, 19.98.

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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
Figure US20070078146A1-20070405-C00001
wherein R1, R2, R3 and R4 are as described in the specification.

Description

    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.
    • 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:
    Figure US20070078146A1-20070405-C00002
  • 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
    Figure US20070078146A1-20070405-C00003
    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:
    Figure US20070078146A1-20070405-C00004
    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,
    Figure US20070078146A1-20070405-C00005
  • wherein the R3 pyridinyl, pyrimidinyl, quinolinyl, purinyl, maleimidyl, pyridonyl, thiazolyl, thiazolylalkyl, thiazolylamino,
    Figure US20070078146A1-20070405-C00006
    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
    Figure US20070078146A1-20070405-C00007
    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,
    Figure US20070078146A1-20070405-C00008
  • wherein the R3 pyridinyl, pyrimidinyl, quinolinyl, purinyl, maleimidyl, pyridonyl, thiazolyl, thiazolylalkyl, thiazolylamino,
    Figure US20070078146A1-20070405-C00009
    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:
    Figure US20070078146A1-20070405-C00010
  • 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
        Figure US20070078146A1-20070405-C00011
  • 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:
    Figure US20070078146A1-20070405-C00012
  • 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,
    Figure US20070078146A1-20070405-C00013
  • 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
    Figure US20070078146A1-20070405-C00014
  • 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:
    Figure US20070078146A1-20070405-C00015
  • 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
    Figure US20070078146A1-20070405-C00016
  • 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
    Figure US20070078146A1-20070405-C00017
  • 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:
    Figure US20070078146A1-20070405-C00018
  • 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
        Figure US20070078146A1-20070405-C00019
  • 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:
    Figure US20070078146A1-20070405-C00020
  • 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
        Figure US20070078146A1-20070405-C00021
  • 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:
    Figure US20070078146A1-20070405-C00022
  • 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:
    Figure US20070078146A1-20070405-C00023
  • 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:
    Figure US20070078146A1-20070405-C00024
  • 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:
    Figure US20070078146A1-20070405-C00025
  • 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:
    Figure US20070078146A1-20070405-C00026
    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:
    Figure US20070078146A1-20070405-C00027
  • 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:
    Figure US20070078146A1-20070405-C00028
  • 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,
    Figure US20070078146A1-20070405-C00029
     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:
    Figure US20070078146A1-20070405-C00030
  • 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
    Figure US20070078146A1-20070405-C00031
    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,
    Figure US20070078146A1-20070405-C00032
    wherein the R3 pyridinyl, pyrimidinyl, quinolinyl, purinyl, maleimidyl, pyridonyl, thiazolyl, thiazolylalkyl, thiazolylamino,
    Figure US20070078146A1-20070405-C00033
    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
    Figure US20070078146A1-20070405-C00034
  • 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:
    Figure US20070078146A1-20070405-C00035
    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,
    Figure US20070078146A1-20070405-C00036
    wherein the R3 pyridinyl, pyrimidinyl, quinolinyl, purinyl, maleimidyl, pyridonyl, thiazolyl, thiazolylalkyl, thiazolylamino,
    Figure US20070078146A1-20070405-C00037
    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
    Figure US20070078146A1-20070405-C00038
    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:
    Figure US20070078146A1-20070405-C00039
  • 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,
    Figure US20070078146A1-20070405-C00040
    wherein the R3 maleimidyl, pyridonyl, thiazolyl, thiazolylalkyl, thiazolylamino,
    Figure US20070078146A1-20070405-C00041
    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:
    Figure US20070078146A1-20070405-C00042
    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:
    Figure US20070078146A1-20070405-C00043
  • 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,
        Figure US20070078146A1-20070405-C00044
  • wherein the R3 pyridinyl, pyrimidinyl, quinolinyl, purinyl, maleimidyl, pyridonyl, thiazolyl, thiazolylalkyl, thiazolylamino,
    Figure US20070078146A1-20070405-C00045
  • 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:
    Figure US20070078146A1-20070405-C00046
    Figure US20070078146A1-20070405-C00047
    Figure US20070078146A1-20070405-C00048
  • 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:
    Figure US20070078146A1-20070405-C00049
  • 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:
    Figure US20070078146A1-20070405-C00050
  • 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
    Figure US20070078146A1-20070405-C00051
  • 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
        Figure US20070078146A1-20070405-C00052
  • 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:
        Figure US20070078146A1-20070405-C00053
  • 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,
    Figure US20070078146A1-20070405-C00054
  • 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:
    Figure US20070078146A1-20070405-C00055
    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.
    Figure US20070078146A1-20070405-C00056
  • 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.
    Figure US20070078146A1-20070405-C00057
  • 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.
    Figure US20070078146A1-20070405-C00058
  • 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.
    Figure US20070078146A1-20070405-C00059
  • Synthetic Scheme IV describes the preparation of pyrazole 19.
    Figure US20070078146A1-20070405-C00060
  • 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.
    Figure US20070078146A1-20070405-C00061
  • 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.
    Figure US20070078146A1-20070405-C00062
  • 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.
    Figure US20070078146A1-20070405-C00063
  • 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.
    Figure US20070078146A1-20070405-C00064
  • 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.
    Figure US20070078146A1-20070405-C00065
  • 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.
    Figure US20070078146A1-20070405-C00066
    Figure US20070078146A1-20070405-C00067
  • 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.
    Figure US20070078146A1-20070405-C00068
    Figure US20070078146A1-20070405-C00069
    Figure US20070078146A1-20070405-C00070
  • 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.
    Figure US20070078146A1-20070405-C00071
  • In Scheme XVI, R16 is selected, for example, from hydrogen, alkyl and phenyl.
    Figure US20070078146A1-20070405-C00072
  • In Scheme XVII, R17 is selected, for example, from alkyl, phenylalkyl and heterocyclylalkyl.
    Figure US20070078146A1-20070405-C00073
  • 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.
    Figure US20070078146A1-20070405-C00074
  • 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.
    Figure US20070078146A1-20070405-C00075
  • 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.
    Figure US20070078146A1-20070405-C00076
  • 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.
    Figure US20070078146A1-20070405-C00077
  • 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.
    Figure US20070078146A1-20070405-C00078
  • 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).
    Figure US20070078146A1-20070405-C00079
  • 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.
    Figure US20070078146A1-20070405-C00080
  • 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.
    Figure US20070078146A1-20070405-C00081
  • 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.
    Figure US20070078146A1-20070405-C00082
  • 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.
    Figure US20070078146A1-20070405-C00083
  • 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.
    Figure US20070078146A1-20070405-C00084
  • 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
  • Figure US20070078146A1-20070405-C00085
    • 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
  • Figure US20070078146A1-20070405-C00086
    • 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
  • Figure US20070078146A1-20070405-C00087
    • 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
  • Figure US20070078146A1-20070405-C00088
    • 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
  • Figure US20070078146A1-20070405-C00089
    • 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
  • Figure US20070078146A1-20070405-C00090
    • 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
  • Figure US20070078146A1-20070405-C00091
    • 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
  • Figure US20070078146A1-20070405-C00092
    • 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
  • Figure US20070078146A1-20070405-C00093
    • 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
  • Figure US20070078146A1-20070405-C00094
    • 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
  • Figure US20070078146A1-20070405-C00095
    • 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
  • Figure US20070078146A1-20070405-C00096
    • 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
  • Figure US20070078146A1-20070405-C00097
    • 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
  • Figure US20070078146A1-20070405-C00098
    • 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
  • Figure US20070078146A1-20070405-C00099
    • 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
  • Figure US20070078146A1-20070405-C00100
    • 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
  • Figure US20070078146A1-20070405-C00101
    • 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
  • Figure US20070078146A1-20070405-C00102
    • 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
  • Figure US20070078146A1-20070405-C00103
    • 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
  • Figure US20070078146A1-20070405-C00104
    • 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
  • Figure US20070078146A1-20070405-C00105
    • 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
  • Figure US20070078146A1-20070405-C00106
    • 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
  • Figure US20070078146A1-20070405-C00107
  • 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
  • Figure US20070078146A1-20070405-C00108
    • 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
  • Figure US20070078146A1-20070405-C00109
    • 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:
    No m.p. or Anal.Calc'd Anal. Calc'd (calcd/found)
    A- R1 R2 R3 R4 DSC(° C.) Formula C H N
    44 H
    Figure US20070078146A1-20070405-C00110
    Figure US20070078146A1-20070405-C00111
    Figure US20070078146A1-20070405-C00112
         		175.6 C16H15N3O.0.15H2O 71.70/71.92 5.75/5.76 15.68/15.29
    45 H
    Figure US20070078146A1-20070405-C00113
    Figure US20070078146A1-20070405-C00114
    Figure US20070078146A1-20070405-C00115
         		— C17H19N3 77.54/77.13 6.51/6.28 15.96/15.69
    46 H
    Figure US20070078146A1-20070405-C00116
    Figure US20070078146A1-20070405-C00117
    Figure US20070078146A1-20070405-C00118
         		412.1 C15H11N3F2 66.42/66.12 4.09/3.86 15.49/15.25
    47 H
    Figure US20070078146A1-20070405-C00119
    Figure US20070078146A1-20070405-C00120
    Figure US20070078146A1-20070405-C00121
         		168.5 C17H17N3O.0.15H2O 72.40/72.39 6.18/5.87 14.90/14.50
    48 H
    Figure US20070078146A1-20070405-C00122
    Figure US20070078146A1-20070405-C00123
    Figure US20070078146A1-20070405-C00124
         		211.2 C16H12N3F3.0.2H2O 62.62/62.64 4.07/4.06 13.69/13.35
    49 H
    Figure US20070078146A1-20070405-C00125
    Figure US20070078146A1-20070405-C00126
    Figure US20070078146A1-20070405-C00127
         		— C13H11N3S 64.71/64.44 4.59/4.58 17.41/17.27
    50 H
    Figure US20070078146A1-20070405-C00128
    Figure US20070078146A1-20070405-C00129
    Figure US20070078146A1-20070405-C00130
         		189.2 C15H11N3Cl2 59.23/59.22 3.65/3.24 13.81/13.81
    51 H
    Figure US20070078146A1-20070405-C00131
    Figure US20070078146A1-20070405-C00132
    Figure US20070078146A1-20070405-C00133
         		211.7 C15H12N3Cl.0.15H2O 66.13/66.33 4.55/4.62 15.42/15.05
    52 H
    Figure US20070078146A1-20070405-C00134
    Figure US20070078146A1-20070405-C00135
    Figure US20070078146A1-20070405-C00136
         		219.8 C16H14N3Cl 64.11/63.85 4.71/4.69 14.02/13.93
    53 H
    Figure US20070078146A1-20070405-C00137
    Figure US20070078146A1-20070405-C00138
    Figure US20070078146A1-20070405-C00139
         		163.4 C19H17N3O2Cl 64.32/63.98 4.83/5.08 11.84/11.80
    54
    Figure US20070078146A1-20070405-C00140
    Figure US20070078146A1-20070405-C00141
    Figure US20070078146A1-20070405-C00142
         		H — C15H12N3F.0.2H2O 70.15/70.18 4.86/4.60 16.35/16.47
    55 H
    Figure US20070078146A1-20070405-C00143
    Figure US20070078146A1-20070405-C00144
         		H — C14H10N3F 70.28/69.97 4.21/3.84 17.56/17.53
  • 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
  • Figure US20070078146A1-20070405-C00145
  • 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
  • Figure US20070078146A1-20070405-C00146
  • 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
  • Figure US20070078146A1-20070405-C00147
  • 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
  • Figure US20070078146A1-20070405-C00148
  • 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
  • Figure US20070078146A1-20070405-C00149
  • 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
  • Figure US20070078146A1-20070405-C00150
  • 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
  • Figure US20070078146A1-20070405-C00151
  • 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
  • Figure US20070078146A1-20070405-C00152
  • 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
  • Figure US20070078146A1-20070405-C00153
  • 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.[
    Figure US20070078146A1-20070405-P00999
    • EXAMPLE A-164
  • Figure US20070078146A1-20070405-C00154
  • 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
  • Figure US20070078146A1-20070405-C00155
  • 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
  • Figure US20070078146A1-20070405-C00156
  • 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
  • Figure US20070078146A1-20070405-C00157
  • 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
  • Figure US20070078146A1-20070405-C00158
  • 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
  • Figure US20070078146A1-20070405-C00159
  • 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
  • Figure US20070078146A1-20070405-C00160
  • 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
  • Figure US20070078146A1-20070405-C00161
  • 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
  • Figure US20070078146A1-20070405-C00162
  • 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 2
    General Microanalysis DSC
    Example Procedure Formula C calc C found H calc H found N calc N found deg C.
    A-173 Sch. II C24H25ClN6.3HCl.1.5H2O 50.63 50.58 4.96 5.03 14.76 14.68 182
    A-174 Sch. II C25H24ClN5.0.125H2O 69.47 69.33 5.60 5.56 16.20 16.11 259
    A-175 Sch. II C17H17FN6.1.25H2O 48.64 48.45 4.56 4.86 20.02 20.24  82
    A-176 Sch. II C22H26ClN5O2 61.75 61.57 6.12 6.04 16.37 16.34 217
    A-177 Sch. II C17H18ClN5.3HCl.H2O 44.85 44.96 4.65 4.87 15.38 15.17 220
    A-178 Sch. II C21H24ClN5O2.0.125H2O 60.61 60.51 5.81 5.81 16.83 16.64 232
    A-179 Sch. II C25H30ClN5O3 62.04 61.76 6.25 6.25 14.47 14.37 220
    A-180 Sch. II C22H25FN6O2.0.5H2O 60.96 60.86 5.81 6.21 19.39 19.47 N.D.
    A-181 Sch. II C22H25ClFN5O2 59.26 58.98 5.65 5.55 15.71 15.36 210
    A-182 Sch. II C20H22ClN5.0.75H2O 62.98 62.97 5.81 5.64 18.36 17.83 271
    A-183 Sch. II C16H19Cl4N5.3HCl 45.41 45.37 4.53 4.74 120
    • EXAMPLE A-173
  • Figure US20070078146A1-20070405-C00163
  • N-[5-(4-chlorophenyl)-4-[2-(phenylmethyl)amino]-4-pyridinyl]-1H-pyrazol-3-yl]-1,3-propanediamine, trihydrochloride
    • EXAMPLE A-174
  • Figure US20070078146A1-20070405-C00164
  • 1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-(phenylmethyl)piperazine
    • EXAMPLE A-175
  • Figure US20070078146A1-20070405-C00165
  • Isolated as 4-[3-(4-fluorophenyl)-5-(1-piperazinyl)-1H-pyrazol-4-yl]pyrimidine, dihydrochloride
    • EXAMPLE A-176
  • Figure US20070078146A1-20070405-C00166
  • 1,1-dimethylethyl [3-[[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]amino]propyl]carbamate
    • EXAMPLE A-177
  • Figure US20070078146A1-20070405-C00167
  • Isolated as N-[5-[4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1,3-propanediamine, trihydrochloride monohydrate
    • EXAMPLE A-178
  • Figure US20070078146A1-20070405-C00168
  • 1,1-dimethylethyl [2-[[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]amino]ethyl]carbamate
    • EXAMPLE A-179
  • Figure US20070078146A1-20070405-C00169
  • 1,1-dimethylethyl 4-[5-(4-chlorophenyl)-1-(2-hydroxyethyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1-piperazinecarboxylate
    • EXAMPLE A-180
  • Figure US20070078146A1-20070405-C00170
    1,1-dimethylethyl 4-[5-(4-fluorophenyl)-4-(4-pyrimidinyl)-1H-pyrazol-3-yl]-1-piperazinecarboxylate
    • EXAMPLE A-181
  • Figure US20070078146A1-20070405-C00171
    1,1-dimethylethyl [3-[[5-(4-chlorophenyl)-4-(2-fluoro-4-pyridinyl)-1H-pyrazol-3-yl]amino)propyl]carbamate
    • EXAMPLE A-182
  • Figure US20070078146A1-20070405-C00172
    1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-ethylpiperazine
    • EXAMPLE A-183
  • Figure US20070078146A1-20070405-C00173
  • 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
  • Figure US20070078146A1-20070405-C00174
    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
  • Figure US20070078146A1-20070405-C00175
  • 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
  • Figure US20070078146A1-20070405-C00176
  • 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
  • Figure US20070078146A1-20070405-C00177
  • 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
  • Figure US20070078146A1-20070405-C00178
  • 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
  • Figure US20070078146A1-20070405-C00179
  • 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
  • Figure US20070078146A1-20070405-C00180
    • 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
  • Figure US20070078146A1-20070405-C00181
    • 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
    Figure US20070078146A1-20070405-C00182
    • 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
  • Figure US20070078146A1-20070405-C00183
    • 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
    Figure US20070078146A1-20070405-C00184
    • 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
    Figure US20070078146A1-20070405-C00185
    • 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
    Figure US20070078146A1-20070405-C00186
    • 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
  • Figure US20070078146A1-20070405-C00187
    • 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.
    Figure US20070078146A1-20070405-C00188
    • 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
  • Figure US20070078146A1-20070405-C00189
    • 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
  • Figure US20070078146A1-20070405-C00190
    • 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
  • Figure US20070078146A1-20070405-C00191
    • 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
  • Figure US20070078146A1-20070405-C00192
    • 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
  • Figure US20070078146A1-20070405-C00193
    • 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
    Figure US20070078146A1-20070405-C00194
    • 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
    Figure US20070078146A1-20070405-C00195
    • 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
  • Figure US20070078146A1-20070405-C00196
    • 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
  • Figure US20070078146A1-20070405-C00197
    • 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
  • Figure US20070078146A1-20070405-C00198
    • 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
  • Figure US20070078146A1-20070405-C00199
    • 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
    Figure US20070078146A1-20070405-C00200
  • 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
  • Figure US20070078146A1-20070405-C00201
    • 4-(1,5-dimethyl-3-phenyl-1H-pyrazol-4-yl)pyridine
  • Figure US20070078146A1-20070405-C00202
  • 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
  • Figure US20070078146A1-20070405-C00203
    • 4-[3-(4-chlorophenyl)-1,5-dimethyl-1H-pyrazol-4-yl]pyridine
  • Figure US20070078146A1-20070405-C00204
    • 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
  • Figure US20070078146A1-20070405-C00205
    • 4-[5-ethyl-1-methyl-3-(3-methylphenyl)-1H-pyrazol-4-yl]pyridine
  • Figure US20070078146A1-20070405-C00206
    • 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
  • Figure US20070078146A1-20070405-C00207
    • 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
  • Figure US20070078146A1-20070405-C00208
    • 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
  • Figure US20070078146A1-20070405-C00209
    • 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
  • Figure US20070078146A1-20070405-C00210
    • 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
  • Figure US20070078146A1-20070405-C00211
    • 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
  • Figure US20070078146A1-20070405-C00212
    • 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
  • Figure US20070078146A1-20070405-C00213
    • 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
  • Figure US20070078146A1-20070405-C00214
    • 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
  • Figure US20070078146A1-20070405-C00215
    • 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
  • Figure US20070078146A1-20070405-C00216
    • 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
  • Figure US20070078146A1-20070405-C00217
    • 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
  • Figure US20070078146A1-20070405-C00218
    • 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
  • Figure US20070078146A1-20070405-C00219
    • 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
  • Figure US20070078146A1-20070405-C00220
    • 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
    Figure US20070078146A1-20070405-C00221
  • 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
    Figure US20070078146A1-20070405-C00222
  • 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
    Figure US20070078146A1-20070405-C00223
  • 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
  • Figure US20070078146A1-20070405-C00224
    • 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
  • Figure US20070078146A1-20070405-C00225
    • 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
  • Figure US20070078146A1-20070405-C00226
    • 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
  • Figure US20070078146A1-20070405-C00227
    • 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
  • Figure US20070078146A1-20070405-C00228
    • 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
  • Figure US20070078146A1-20070405-C00229
    • 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
  • Figure US20070078146A1-20070405-C00230
    • 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 3
    Microanalysis
    General MS water EtOAc
    Example Procedure M + 1 C calc C found H calc H found N calc N found added added
    A-227 IX 240 69 69 4.3 4.6 17.2 16.8 0.25
    A-228 IX 266 65.69 65.69 4.41 4.33 15.32 14.98
    A-229 XI 254 70.6 70.6 4.8 4.5 16.5 16.3 0.1
    A-230 IX 256 65.76 65.48 3.94 3.78 16.43 16.52
    A-231 XI 280 64.18 63.95 4.39 4.31 13.86 13.90
    A-232 XI 271 66.79 66.79 4.48 4.24 15.58 15.32
    A-233 XI 284 66.9 66.8 5 5 14.6 14.9 0.2
    A-234 XI 270 65.9 65.6 4.6 4.6 15.4 15.4 0.2
    A-235 XI 264 77 76.7 6.5 6.5 15.8 15.7 0.1
    A-236 IX 221 75.38 75.44 5.06 5.1 18.84 19 0.1
    A-237 IX 290 61.52 61.67 3.58 3.51 14.35 14.32
    A-238 XI 304 63.36 63.28 3.99 3.91 13.85 13.83
    A-239 IX 258 65.37 65.39 3.53 3.52 16.33 16.31
    A-240 IX 274 61.44 61.14 3.31 3.01 15.35 14.95
    A-241 IX 300 56.02 55.99 3.36 3.26 14.00 14.01
    A-242 XI 272 66.42 66.41 4.09 4.04 15.49 15.32
    A-243 XI 314 57.34 57.22 3.85 3.68 13.37 13.27
    A-244 IX 342 76.39 76.16 4.81 4.51 12.31 12.05 0.25
    A-245 XII 341 64.89 64.65 6.36 6.17 15.93 15.82 0.6
    A-246 XII 391 66.08 66.18 5.04 5.56 14.01 12.26 0.5
    A-247 XII 362 64.46 64.16 4.65 4.34 18.79 18.65 0.6
    A-249 XII 258 64.91 64.84 3.58 3.63 16.22 15.98 0.1
    A-250 IX 348 48.44 48.07 2.9 2.82 12.1 12.01
    A-251 XI 362 49.88 49.89 3.35 3.51 11.63 11.54
    A-252 XI 304 63.36 63.34 3.99 3.96 13.85 13.81
    A-253 XII 377 68.24 68.17 5 4.71 14.47 14.34 0.6
    A-254 XII 363 66.31 66.12 4.77 4.31 14.73 14.6 1
    A-215 XIV 265 67.3 67.4 3.5 3.4 20.9 20.7 0.2
    A-255 XII 298 64.63 64.64 5.42 5.41 23.55 23.32
    A-256 XI 272 66.42 66.58 4.09 4.26 15.49 14.78
    A-257 IX 276 60.11 60.4 3.06 3.18 15.02 14.73 0.25
    A-258 IX 254
    A-259 XI 268 71.89 71.63 5.28 5.24 15.72 15.84
    A-260 X 290 62.28 62.41 3.48 3.48 14.53 14.51
    A-261 X, XV 311 69.26 69.2 6.2 6.25 17.95 17.89 0.1
    A-262 XI 376 72.71 72.5 5.17 4.98 11.06 10.99 0.25
    A-263 XII 428 70.81 70.59 6.28 6.45 15.88 15.08 0.75
    A-264 XII 326 63.79 63.76 6.39 6.09 20.66 20.45 0.75
    A-265 IX 400 66.18 66.77 4.1 4.23 16.78 15.83 1
    A-266 XII 368 62.32 62.38 6.28 6.5 18.17 17.56 1
    A-267 XI 302 62.66 62.85 4.47 4.34 13.7 13.53 0.4
    A-268 XII 349 62.9 63.2 5.2 4.8 22.7 22.5 0.75 0.1
    A-269 XI, XV 371 61.85 61.84 5.71 5.24 14.42 14.17 1
    A-270 XI, XV 404 70.66 70.7 4.82 4.61 10.3 10.15 0.25
    A-271 XI, XV 329 65.8 65.3 5.5 5.6 17.1 16.8
    A-272 XI 406 69.95 70.13 5.35 5.28 10.14 9.89 0.5
    A-273 XI 354 66.9 67.2 6.9 6.6 19.1 18.7 0.2 0.1
    A-274 XI, XII, 434 63.6 63.1 6.3 5.8 14.4 14 2 0.2
    XV
    A-275 XI, XV 433 70.44 70.74 6.18 6.3 12.64 12.05 0.6
    A-276 XI, XII, 476 65.9 66.2 6.1 6.1 13.3 13.6 0.5 0.5
    XV
    A-277 XII 338 61.11 63.02 6.48 6.39 18.75 16.61
    A-278 XI, XV 357 64.2 63.8 6.5 6 15 14.8 1
    A-279 XI, XII, 462 67.4 67.1 6.7 6.2 13.6 13.7 0.6 0.5
    XV
    A-280 XII 299 61.27 61.47 5.37 5.11 17.86 17.21 0.9
    A-281 XII 313 64.63 64.94 5.55 5.63 17.73 17.48 0.2
    A-282 XII 313 64.63 64.81 5.55 5.43 17.73 17.38 0.3
    A-283 XI, XII 407 67.2 67 5 5.2 13.6 13.2 0.25
    A-284 XI, XV 339 70 70.3 6.9 6.9 16.3 16.2 0.25
    A-285 XI, XII, 476 68.2 68.5 5.7 6.2 14.7 13.6
    XV
    A-286 XVII 382 59.77 59.69 6.81 6.56 16.6 16.65 2.25
    A-287 XVII 340 56.07 56.26 7.31 7.1 17.21 17.27 3.75
    A-288 XVII 293 69.42 69.4 4.52 4.6 19.05 19.09 0.1
    A-289 XI, XII 407 68 67.5 5 4.5 13.8 13.5
    A-290 XI, XII 407 64 64.5 5.3 4.9 13 12.4 1.4
    A-291 IX 290 74.7 74.9 4.2 4.2 14.5 14.5
    A-292 XVII 326 61.22 61.46 4.77 4.53 16.8 16.97 0.4
    A-293 XVII 313 55.75 55.98 4.85 4.02 16.25 16.37 1.8
    A-294 XI 278 73.6 73.2 4.4 4.2 15.2 15
    A-295 XI 278 67.9 67.7 4.9 4.3 14 13.7 1.3
    A-296 IX 70.3 70.4 4.5 4.7 25.2 25.4
    A-297 IX 57.9 57.7 3.1 2.9 14.5 14.5
    • EXAMPLE A-227
  • Figure US20070078146A1-20070405-C00231
    • 4-[3-(3-fluorophenyl)-1H-pyrazol-4-yl]pyridine EXAMPLE A-228
  • Figure US20070078146A1-20070405-C00232
    • 4-[3-(1,3-benzodioxol-5-yl)-1H-pyrazol-4-yl]pyridine EXAMPLE A-229
  • Figure US20070078146A1-20070405-C00233
    • 4-[3-(3-fluorophenyl) 1-methyl-1H-pyrazol-4-yl pyridine
  • Figure US20070078146A1-20070405-C00234
    Figure US20070078146A1-20070405-C00235
    • EXAMPLE A-230
  • Figure US20070078146A1-20070405-C00236
    • 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
  • Figure US20070078146A1-20070405-C00237
    • 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
  • Figure US20070078146A1-20070405-C00238
    • 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
  • Figure US20070078146A1-20070405-C00239
    • 2-methyl-4-[1-methyl-3 (or 5)-(3-methylphenyl)-1H-pyrazol-4-yl]pyridine EXAMPLE A-236
  • Figure US20070078146A1-20070405-C00240
    • 4-(3-phenyl-1H-pyrazol-4-yl)pyridine EXAMPLE A-237
  • Figure US20070078146A1-20070405-C00241
    • 4-[3-[3-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl]pyridine EXAMPLE A-238
  • Figure US20070078146A1-20070405-C00242
    • 4-[1-methyl-3-[3-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl]pyridine EXAMPLE A-239
  • Figure US20070078146A1-20070405-C00243
    • 4-[3-(3,4-difluorophenyl)-1H-pyrazol-4-yl]pyridine EXAMPLE A-240
  • Figure US20070078146A1-20070405-C00244
    • 4-[3-(4-chlorophenyl)-1H-pyrazol-4-yl)-2-fluoropyridine EXAMPLE A-241
  • Figure US20070078146A1-20070405-C00245
    • 4-[3-(4-bromophenyl)-1H-pyrazol-4yl]pyridine EXAMPLE A-242
  • Figure US20070078146A1-20070405-C00246
    • 4-[3-(3,4-difluorophenyl)-1-methyl-1H-pyrazol-4-yl]pyridine EXAMPLE A-243
  • Figure US20070078146A1-20070405-C00247
    • 4-[3-(4-bromophenyl)-1-methyl-1H-pyrazol-4-yl]pyridine EXAMPLE A-244
  • Figure US20070078146A1-20070405-C00248
    • (E)-4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-(2-phenylethenyl)pyridine EXAMPLE A-245
  • Figure US20070078146A1-20070405-C00249
    • (S)-4-[3-(4-chlorophenyl)-1H-pyrazol-4-yl]-N-(2-methylbutyl)-2-pyridinamine EXAMPLE A-246
  • Figure US20070078146A1-20070405-C00250
    • 4-[3-(4-chlorophenyl)-1H-pyrazol-4-yl]-N-[(4-methoxyphenyl)methyl]-2-pyridinamine EXAMPLE A-247
  • Figure US20070078146A1-20070405-C00251
    • N-[4-[3-(4-chlorophenyl)-1H-pyrazol-4-yl]-2-pyridinyl]-2-pyridinemethanamine EXAMPLE A-248
  • Figure US20070078146A1-20070405-C00252
    • 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
  • Figure US20070078146A1-20070405-C00253
    • 2-fluoro-4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]pyridine EXAMPLE A-250
  • Figure US20070078146A1-20070405-C00254
    • 4-[3-(4-iodophenyl)-1H-pyrazol-4-yl]pyridine EXAMPLE A-251
  • Figure US20070078146A1-20070405-C00255
    • 4-[3-(4-iodophenyl)-1-methyl-1H-pyrazol-4-yl]pyridine EXAMPLE A-252
  • Figure US20070078146A1-20070405-C00256
    • 4-[1-methyl-3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl]pyridine EXAMPLE A-253
  • Figure US20070078146A1-20070405-C00257
    • N-[1-(4-fluorophenyl)ethyl]-4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinamine EXAMPLE A-254
  • Figure US20070078146A1-20070405-C00258
    • N-[(3-fluorophenyl)methyl]-4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinamine EXAMPLE A-255
  • Figure US20070078146A1-20070405-C00259
    • 4-[3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]-2-(1-methylhydrazino)pyridine EXAMPLE A-256
  • Figure US20070078146A1-20070405-C00260
    • 2-fluoro-4-[3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]pyridine EXAMPLE A-257
  • Figure US20070078146A1-20070405-C00261
    • 4-[3-(3,4-difluorophenyl)-1H-pyrazol-4-yl]-2-fluoropyridine EXAMPLE A-258
  • Figure US20070078146A1-20070405-C00262
    • 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-3-methylpyridine EXAMPLE A-259
  • Figure US20070078146A1-20070405-C00263
    • 4-[3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]-3-methylpyridine EXAMPLE A-260
  • Figure US20070078146A1-20070405-C00264
    • 4-[3-(3,4-difluorophenyl)-1-methyl-1H-pyrazol-4-yl]-2-fluoropyridine EXAMPLE A-261
  • Figure US20070078146A1-20070405-C00265
    • 3-(4-fluorophenyl)-N,N-dimethyl-4-(4-pyridinyl)-1H-pyrazole-1-ethanamine EXAMPLE A-262
  • Figure US20070078146A1-20070405-C00266
    • 2-[2-(4-fluorophenyl)ethyl]-4-[3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]pyridine EXAMPLE A-263
  • Figure US20070078146A1-20070405-C00267
    • 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N-[1-(phenylmethyl)-4-piperidinyl]-2-pyridinamine EXAMPLE A-264
  • Figure US20070078146A1-20070405-C00268
    • N′-[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinyl]-N,N-dimethyl-1,2-ethanediamine EXAMPLE A-265
  • Figure US20070078146A1-20070405-C00269
    • 2,4-bis[3-(4-fluorophenyl)-1H-pyrazol-4-yl]pyridine EXAMPLE A-266
  • Figure US20070078146A1-20070405-C00270
    • N-[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinyl]-4-morpholineethanamine EXAMPLE A-267
  • Figure US20070078146A1-20070405-C00271
    • 3-(4-fluorophenyl)-4-(2-fluoro-4-pyridinyl)-1H-pyrazole-1-ethanol EXAMPLE A-268
  • Figure US20070078146A1-20070405-C00272
    • 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N-(2-(1H-imidazol-1-yl)ethyl]-2-pyridinamine EXAMPLE A-269
  • Figure US20070078146A1-20070405-C00273
    • 4-[2-[3-(4-fluorophenyl)-4-(2-fluoro-4-pyridinyl)-1H-pyrazol-1-yl]ethyl]morpholine EXAMPLE A-270
  • Figure US20070078146A1-20070405-C00274
    • (E)-3-(4-fluorophenyl)-4-[2-[2-(4-fluorophenyl)ethenyl]-4-pyridinyl]-1H-pyrazole-1-ethanol EXAMPLE A-271
  • Figure US20070078146A1-20070405-C00275
    • 3-(4-fluorophenyl)-4-(2-fluoro-4-pyridinyl)-N,N-dimethyl-1H-pyrazole-1-ethanamine EXAMPLE A-272
  • Figure US20070078146A1-20070405-C00276
    • 3-(4-fluorophenyl)-4-[2-[2-(4-fluorophenyl)ethyl]-4-pyridinyl]-1H-pyrazole-1-ethanol EXAMPLE A-273
  • Figure US20070078146A1-20070405-C00277
    • 4-[1-[(2-(dimethylamino)ethyl]-3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N,N-dimethyl-2-pyridinamine EXAMPLE A-274
  • Figure US20070078146A1-20070405-C00278
    • 4-[1-[2-(dimethylamino)ethyl]-3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N-[(4-fluorophenyl)methyl]-2-pyridinamine EXAMPLE A-275
  • Figure US20070078146A1-20070405-C00279
    • 3-(4-fluorophenyl)-4-[2-[2-(4-fluorophenyl)ethyl]-4-pyridinyl]-N,N-dimethyl-1H-pyrazole-1-ethanamine EXAMPLE A-276
  • Figure US20070078146A1-20070405-C00280
    • N-[(4-fluorophenyl)methyl]-4-[3(or 5)-(4-fluorophenyl)-1-[[2-(4-morpholinyl)ethyl]-1H-pyrazol-4-yl]-2-pyridinamine EXAMPLE A-277
  • Figure US20070078146A1-20070405-C00281
    • 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N-4-piperadinyl-2-pyridinamine EXAMPLE A-278
  • Figure US20070078146A1-20070405-C00282
    • N,N-diethyl-3-(4-fluorophenyl)-4-(2-fluoro-4-pyridinyl)-1H-pyrazole-1-ethanamine EXAMPLE A-279
  • Figure US20070078146A1-20070405-C00283
    • 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
  • Figure US20070078146A1-20070405-C00284
    • 2-[[4-[3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]-2-pyridinyl]amino]ethanol EXAMPLE A-282
  • Figure US20070078146A1-20070405-C00285
    • 3-[[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinyl]amino]-1-propanol EXAMPLE A-283
  • Figure US20070078146A1-20070405-C00286
    • 3 (or 5)-(4-fluorophenyl)-4-[2-[[(4-fluorophenyl)methyl]amino]-4-pyridinyl]-1H-pyrazole-1-ethanol EXAMPLE A-284
  • Figure US20070078146A1-20070405-C00287
    • N,N-diethyl-3-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazole-1-ethanamine EXAMPLE A-285
  • Figure US20070078146A1-20070405-C00288
    • N-[(4-fluorophenyl)methyl]-4-[3-(4-fluorophenyl)-1-[2-(4-morpholinyl)ethyl]-1H-pyrazol-4-yl]-2-pyridinamine EXAMPLE A-286
  • Figure US20070078146A1-20070405-C00289
    • N-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-morpholinepropanamine EXAMPLE A-287
  • Figure US20070078146A1-20070405-C00290
    • N′-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-N,N-dimethyl-1,3-propanediamine EXAMPLE A-288
  • Figure US20070078146A1-20070405-C00291
    • 5-(4-fluorophenyl)-N-2-propynyl-4-(4-pyridinyl)-1H-pyrazol-3-amine EXAMPLE A-289
  • Figure US20070078146A1-20070405-C00292
    • 3-(4-fluorophenyl)-4-[2-[[(4-fluorophenyl)methyl]amino]-4-pyridinyl]-1H-pyrazole-1-ethanol EXAMPLE A-290
  • Figure US20070078146A1-20070405-C00293
    • 5-(4-fluorophenyl)-4-[2-[[(4-fluorophenyl)methyl]amino]-4-pyridinyl]-1H-pyrazole-1-ethanol EXAMPLE A-291
  • Figure US20070078146A1-20070405-C00294
    • 4-[3-[(4-fluorophenyl)-1H-pyrazol-4-yl]quinoline EXAMPLE A-292
  • Figure US20070078146A1-20070405-C00295
    • N-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]glycine methyl ester EXAMPLE A-293
  • Figure US20070078146A1-20070405-C00296
    • N-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]glycine EXAMPLE A-294
  • Figure US20070078146A1-20070405-C00297
    • 4-[3-(4-fluorophenyl)-1-(2-propynyl)-1H-pyrazol-4-yl]pyridine EXAMPLE A-295
  • Figure US20070078146A1-20070405-C00298
    • 4-[5-(4-fluorophenyl)-1-(2-propynyl)-1H-pyrazol-4-yl]pyridine EXAMPLE A-296
  • Figure US20070078146A1-20070405-C00299
    • 4,4′-(1H-pyrazole-3,4-diyl)bis[pyridine] EXAMPLE A-297
  • Figure US20070078146A1-20070405-C00300
    • 4-[3-(3,4-dichlorophenyl)-1H-pyrazol-4-yl]pyridine EXAMPLE A-298
  • Figure US20070078146A1-20070405-C00301
    • 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
  • Figure US20070078146A1-20070405-C00302
    • 2-Chloro-4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]pyrimidine
  • Step 1:
    Figure US20070078146A1-20070405-C00303
  • 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
    Figure US20070078146A1-20070405-C00304
    • 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
    Figure US20070078146A1-20070405-C00305
    • (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
  • Figure US20070078146A1-20070405-C00306
    • 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
  • Figure US20070078146A1-20070405-C00307
    • 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N,N-dimethyl-2-pyrimidinamine
  • Step 1: Preparation of
    Figure US20070078146A1-20070405-C00308
  • 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
  • Figure US20070078146A1-20070405-C00309
    • 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
  • Figure US20070078146A1-20070405-C00310
    • 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
  • Figure US20070078146A1-20070405-C00311
    • 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
  • Figure US20070078146A1-20070405-C00312
    • 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
  • Figure US20070078146A1-20070405-C00313
    • 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
  • Figure US20070078146A1-20070405-C00314
    • 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
  • Figure US20070078146A1-20070405-C00315
    • 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
  • Figure US20070078146A1-20070405-C00316
    • 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
  • Figure US20070078146A1-20070405-C00317
    • 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
  • Figure US20070078146A1-20070405-C00318
    • 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
  • Figure US20070078146A1-20070405-C00319
    • 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:
    Figure US20070078146A1-20070405-C00320
    Step 1: Preparation of 5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazole-3-carboxylic acid, monohydrate
    Figure US20070078146A1-20070405-C00321
    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
    Figure US20070078146A1-20070405-C00322
  • 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:
    Figure US20070078146A1-20070405-C00323
    Step 1: Preparation of 1-[[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]carbonyl]piperazine, monhydrate
    Figure US20070078146A1-20070405-C00324
  • 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:
    Figure US20070078146A1-20070405-C00325
    Step 1: Preparation of ethyl 1-[(1,1-dimethylethoxy)carbonyl]-4-piperidineacetate
    Figure US20070078146A1-20070405-C00326
  • 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
    Figure US20070078146A1-20070405-C00327
  • 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
    Figure US20070078146A1-20070405-C00328
  • 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
    Figure US20070078146A1-20070405-C00329
  • 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
    Figure US20070078146A1-20070405-C00330
  • 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
  • Figure US20070078146A1-20070405-C00331
    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:
    Figure US20070078146A1-20070405-C00332
  • 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:
    Figure US20070078146A1-20070405-C00333
  • 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:
    Figure US20070078146A1-20070405-C00334
  • 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:
    Figure US20070078146A1-20070405-C00335
  • 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:
    Figure US20070078146A1-20070405-C00336
  • 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:
    Figure US20070078146A1-20070405-C00337
  • 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:
    Figure US20070078146A1-20070405-C00338
  • 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:
    Figure US20070078146A1-20070405-C00339
  • 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:
    Figure US20070078146A1-20070405-C00340
  • 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:
    Figure US20070078146A1-20070405-C00341
  • 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:
    Figure US20070078146A1-20070405-C00342
  • 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 3-1
    Theoretical Found
    EXAMPLE FORMULA MW C H N C H N DSC (mp)
    A-328 C18H18ClN5.1/8H2O 342.08 63.20 5.30 20.47 63.04 5.36 20.33 199° C.
    A-329 C23H33ClN6O2 533.08 65.34 6.24 15.77 64.98 6.11 15.58 (168-171° C.)
    A-330 C23H25ClN5O2 457.94 60.33 5.50 15.29 59.97 5.52 15.17 (253-255° C.)
    A-331 C22H24ClN5O2 425.92 62.04 5.68 16.44 61.64 5.94 16.29 (273-275° C.)
    A-332 C19H23Cl4N5.H2O 481.26 47.42 4.82 14.35 47.66 5.11 13.74 (217-219° C.)
    A-333 C21H20ClN5.2.5H2O 422.92 59.64 4.77 16.56 59.67 4.88 15.96 (247° C.) (d)
    A-334 C20H22ClN5.1/4H2O 372.39 64.51 5.96 18.81 64.79 5.97 18.95 242° C.
    A-335 C24H22ClN5.3/4H2O 429.44 67.13 5.16 16.31 67.04 5.31 16.32 230° C.
    A-336 C25H24ClN5O.1/4H2O 450.46 66.66 5.37 15.55 66.64 5.11 15.69 (270-271° C.)
    A-337 C22H24FN5O2.H2O 427.48 61.81 5.66 16.38 61.88 5.96 16.41 249° C.
    A-338 C20H22FN5.1/2H2O 360.44 66.65 6.15 19.43 66.74 6.59 19.37 241° C.
    A-339 C19H20FN5.3HCl.1/2H2O 455.79 50.07 5.09 15.30 49.87 5.47 15.30 (237-239° C.)
    • EXAMPLE A-328
  • Figure US20070078146A1-20070405-C00343
    • 1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]piperazine EXAMPLE A-329
  • Figure US20070078146A1-20070405-C00344
    • 1,1-dimethylethyl [3-[[5-(4-chlorophenyl)-4-(2-[(phenylmethyl)amino]-4-pyridinyl-1H-pyrazol-3-yl]amino]propyl]carbamate EXAMPLE A-330
  • Figure US20070078146A1-20070405-C00345
  • 1,1-dimethylethyl 4-[5-(4-chlorophenyl)-4-(2-fluoro-4-pyridinyl)-1H-pyrazol-3-yl]-1-piperazinecarboxylate
    • EXAMPLE A-331
  • Figure US20070078146A1-20070405-C00346
    • ethyl 4-[[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]amino]-1-piperidinecarboxylate EXAMPLE A-332
  • Figure US20070078146A1-20070405-C00347
    • N-[5-(4-chlorophenyl)-4-(4-pyridinyl)-3H-pyrazol-3-yl]-4-piperidineamine, trihydrochloride, monohydrate EXAMPLE A-333
  • Figure US20070078146A1-20070405-C00348
  • 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
  • Figure US20070078146A1-20070405-C00349
    • N-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1-methyl-4-piperidinamine EXAMPLE A-335
  • Figure US20070078146A1-20070405-C00350
    • 1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-phenylpiperazine EXAMPLE A-336
  • Figure US20070078146A1-20070405-C00351
    • 1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-(2-methoxyphenyl)piperazine EXAMPLE A-337
  • Figure US20070078146A1-20070405-C00352
    • Ethyl 4-[[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]amino]-1-piperidinecarboxylate, monohydrate EXAMPLE A-338
  • Figure US20070078146A1-20070405-C00353
    • N-[5-(4-fluorophenyl)-4-(pyridinyl)-1H-pyrazol-3-yl]-1-methyl-4-piperidinamine EXAMPLE A-339
  • Figure US20070078146A1-20070405-C00354
    • 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
    Figure US20070078146A1-20070405-C00355
  • 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
  • Figure US20070078146A1-20070405-C00356
    • 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
  • Figure US20070078146A1-20070405-C00357
    • 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
  • Figure US20070078146A1-20070405-C00358
    • 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 3-2
    Microanalysis
    MS C C H H N N Water EtOAc CHCl3 Toluene HCl
    Example General M+ Found Found Calc Found Calc Found Added Added Added Added Added
    A-346 XII
    A-347 XII 329 59.33 59.59 5.65 5.47 15.55 15.41 0.8 0.2
    A-348 XII 439 68.46 66.59 8.04 8.48 19.16 16.17
    A-349 XII 397 61.85 61.99 7.79 7.52 17.45 17.39 1.3 0.7
    A-350 XII 449 66.29 66.75 7.60 7.68 17.84 17.00 1.25
    A-351 XII 352 68.36 57.51 6.31 7.31 19.93 17.17
    A-352 XII 366 69.02 66.27 6.62 6.59 19.16 18.22
    A-353 XII 430 69.26 71.50 7.40 6.91 18.36 14.87
    A-354 XII 355 70.48 70.12 6.80 7.15 13.99 13.91 0.5
    A-355 XII 341 66.73 67.09 6.29 6.77 16.04 15.78 0.1
    A-356 XVII 410 63.42 63.61 6.00 6.06 16.81 16.63 0.4
    A-357 XVII 392 54.37 53.93 5.91 6.32 13.78 14.68 0.4
    A-358 XII 394 70.20 68.50 7.17 7.68 17.80 16.58
    A-359 XVII 396 69.21 69.33 7.68 8.01 17.55 17.61 0.2
    A-360 XVII 366 50.81 50.74 5.97 5.80 14.11 14.00 1.2 3
    A-361 XII 389 71.12 68.67 5.45 5.64 14.42 12.90
    A-362 XII 375 70.57 68.54 5.12 5.39 14.96 13.90
    A-363 XII 389 71.12 68.86 5.45 5.58 14.42 13.09
    A-364 XVII 368 68.31 68.39 7.15 7.49 18.97 18.93 0.1
    A-365 XVII 338 48.72 48.57 5.47 5.45 14.95 14.79 1.2 3
    A-366 XII 397 56.34 56.21 7.31 7.03 17.92 17.89 2 1
    A-367 XVII 321 70.25 69.83 5.43 5.62 17.25 17.82 0.25
    A-368 XII 313 64.66 64.28 5.73 5.62 16.76 16.93 0.25
    A-369 XII 412 66.76 66.60 7.36 7.61 16.93 16.74 0.1
    A-370 XII 313 64.66 64.36 5.73 5.59 16.76 16.82 0.25
    A-371 XVII 63.78 63.63 6.37 6.09 17.71 17.24 1
    A-372 XII 68.63 68.80 7.26 7.53 17.40 17.14 0.5
    A-373 XVII 389 58.10 57.99 5.00 4.88 17.83 17.48 0.25
    A-374 XII 354 67.97 67.23 6.84 6.81 19.81 19.38
    A-375 XII 366 68.18 68.06 6.67 6.80 18.93 18.56 0.25
    A-376 XII 375 70.57 68.19 5.12 6.06 14.96 13.13
    A-377 XII 396 64.14 64.44 6.99 6.78 16.02 16.02 0.35
    A-378 XVII 337 66.42 66.44 5.22 4.91 16.31 16.27 0.4
    A-379 XVII 339 62.76 62.80 6.04 5.43 15.41 15.17 1.4
    A-380 XVII 381 63.31 63.40 5.19 5.82 14.06 13.84 1 1
    A-381 XVII 307 70.57 69.69 4.94 5.00 18.29 17.68
    A-382 XVII
    A-383 XVII
    A-384 320 55.48 53.44 5.64 5.00 17.03 21.60
    A-385 XI 280 52.65 52.51 5.98 5.17 10.83 11.12 1
    A-386 XII 351 64.96 64.77 5.82 5.34 14.85 15.03 1 0.1
    A-387 XII 353 65.29 65.62 6.32 6.14 14.64 14.47 0.7 0.2
    A-388 394 54.93 55.34 6.21 6.79 13.93 14.01 3
    • EXAMPLE A-346
  • Figure US20070078146A1-20070405-C00359
    • N-[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinyl]-4-methyl-1-piperazinepropanamine(2E)-2-butenedioate (1:1) EXAMPLE A-347
  • Figure US20070078146A1-20070405-C00360
  • 3-[[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinyl]amino]-1,2-propanediol;
    • EXAMPLE A-348
  • Figure US20070078146A1-20070405-C00361
  • N,N,N″-triethyl-N′-[2-[[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinyl]amino]ethyl]-1,3-propanediamine;
    • EXAMPLE A-349
  • Figure US20070078146A1-20070405-C00362
  • N-[2-[[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2pyridinyl]amino]ethyl]-N,N′,N′-trimethyl-1,3-propanediamine;
    • EXAMPLE A-350
  • Figure US20070078146A1-20070405-C00363
  • N-(2-[1,4′-bipiperidin]-1′-ylethyl)-4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinamine;
    • EXAMPLE A-351
  • Figure US20070078146A1-20070405-C00364
  • 4-(3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N-(4-piperidinylmethyl)-2-pyridinamine;
    • EXAMPLE A-352
  • Figure US20070078146A1-20070405-C00365
  • N-(1-ethyl-4-piperidinyl)-4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl)-2-pyridinamine;
    • EXAMPLE A-353
  • Figure US20070078146A1-20070405-C00366
  • N2,N2-diethyl-N1-[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinyl]-1-phenyl-1,2-ethanediamine;
    • EXAMPLE A-354
  • Figure US20070078146A1-20070405-C00367
  • (2S)-2-[[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl)-2-pyridinyl]amino]-4-methyl-1-pentanol;
    • EXAMPLE A-355
  • Figure US20070078146A1-20070405-C00368
  • 2-[[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinyl]amino]-3-methyl-1-butanol;
    • EXAMPLE A-356
  • Figure US20070078146A1-20070405-C00369
  • ethyl 4-[[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinyl]amino]-1-piperidinecarboxylate;
    • EXAMPLE A-357
  • Figure US20070078146A1-20070405-C00370
  • 4-[3-(4-fluorophenyl)-5-(4-(1-pyrrolidinyl)-1-piperidinyl]-1H-pyrazol-4-yl]pyridine, trihydrochloride;
    • EXAMPLE A-358
  • Figure US20070078146A1-20070405-C00371
  • N-[2-(1-ethyl-2-piperidinyl)ethyl]-4-(3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinamine;
    • EXAMPLE A-359
  • Figure US20070078146A1-20070405-C00372
  • N1,N1,-diethyl-N4-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1,4-pentanediamine;
    • EXAMPLE A-360
  • Figure US20070078146A1-20070405-C00373
  • 1-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-N,N-dimethyl-4-piperidinamine, trihydrochloride;
    • EXAMPLE A-361
  • Figure US20070078146A1-20070405-C00374
  • (βR)-β-[[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinyl]amino]benzene propanol;
    • EXAMPLE A-362
  • Figure US20070078146A1-20070405-C00375
  • (βS)-β-[[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinyl]amino]benzene ethanol;
    • EXAMPLE A-363
  • Figure US20070078146A1-20070405-C00376
  • (βS)-β-[[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinyl]amino]benzene propanol;
    • EXAMPLE A-364
  • Figure US20070078146A1-20070405-C00377
  • N,N-diethyl-N′-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1,3-propanediamine;
    • EXAMPLE A-365
  • Figure US20070078146A1-20070405-C00378
  • 1-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-piperidinamine, trihydrochloride;
    • EXAMPLE A-366
  • Figure US20070078146A1-20070405-C00379
  • N1,N1-diethyl-N4-[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyrimidinyl]-1,4-pentanediamine;
    • EXAMPLE A-367
  • Figure US20070078146A1-20070405-C00380
  • 1-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1,2,3,6-hexahydropyridine;
    • EXAMPLE A-368
  • Figure US20070078146A1-20070405-C00381
  • (2R)-1-[[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinyl]amino]-2-propanol;
    • EXAMPLE A-369
  • Figure US20070078146A1-20070405-C00382
  • N4-[4-[3-(4-chlorophenyl)-1H-pyrazol-4-yl]-2-pyridinyl]-N1,N1-diethyl-1,4-pentanediamine;
    • EXAMPLE A-370
  • Figure US20070078146A1-20070405-C00383
  • (2S)-1-[[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinyl]amino]-2-propanol;
    • EXAMPLE A-371
  • Figure US20070078146A1-20070405-C00384
  • ethyl 4-[5-phenyl-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1-piperazinecarboxylate;
    • EXAMPLE A-372
  • Figure US20070078146A1-20070405-C00385
  • 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N-[3-(2-inethyl-1-piperidinyl)propyl]-2-pyridinamine;
    • EXAMPLE A-373
  • Figure US20070078146A1-20070405-C00386
  • 1-[5-(3,4-dichlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-methylpiperazine;
    • EXAMPLE A-374
  • Figure US20070078146A1-20070405-C00387
  • N,N-diethyl-N′-[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinyl]-1,2-ethanediamine;
    • EXAMPLE A-375
  • Figure US20070078146A1-20070405-C00388
  • 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N-[2-(1-piperidinyl)ethyl]-2-pyridinamine;
    • EXAMPLE A-376
  • Figure US20070078146A1-20070405-C00389
  • (βR)-β-[[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinyl]amino]benzene ethanol;
    • EXAMPLE A-377
  • Figure US20070078146A1-20070405-C00390
  • N1,N1-diethyl-N4-[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinyl]-1,4-pentanediamine;
    • EXAMPLE A-378
  • Figure US20070078146A1-20070405-C00391
  • 1-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-piperidinone;
    • EXAMPLE A-379
  • Figure US20070078146A1-20070405-C00392
  • 1-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-piperidinol;
    • EXAMPLE A-380
  • Figure US20070078146A1-20070405-C00393
  • 8-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1,4-dioxa-8-azaspiro[4.5]decane;
    • EXAMPLE A-381
  • Figure US20070078146A1-20070405-C00394
  • 5-(4-fluorophenyl)-N-methyl-N-2-propynyl-4-(4-pyridinyl)-1H-pyrazol-3-amine;
    • EXAMPLE A-382
  • Figure US20070078146A1-20070405-C00395
  • 4-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]morpholine;
    • EXAMPLE A-383
  • Figure US20070078146A1-20070405-C00396
  • 1-[5-(3,4-difluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-methylpiperazine;
    • EXAMPLE A-384
  • Figure US20070078146A1-20070405-C00397
  • 1-methyl-4-[5-phenyl-4-(4-pyridinyl)-1H-pyrazol-3-yl]piperazine;
    • EXAMPLE A-385
  • Figure US20070078146A1-20070405-C00398
  • 4-[3-(4-fluorophenyl)-1-(2-propenyl)-1H-pyrazol-4-yl]pyridine, monohydrochloride;
    • EXAMPLE A-386
  • Figure US20070078146A1-20070405-C00399
  • trans-4-[[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinyl]amino]cyclohexanol;
    • EXAMPLE A-387
  • Figure US20070078146A1-20070405-C00400
  • 4-[[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinyl]amino]cyclohexanone;
    • EXAMPLE A-388
  • Figure US20070078146A1-20070405-C00401
  • 1-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-N,N-diethyl-4-piperidinamine, trihydrochloride;
    • EXAMPLE A-389
  • Figure US20070078146A1-20070405-C00402
  • 1-[5-(3-tolyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl-4-methylpiperazine:
    Step 1. Preparation of 1-tolyl-2-(4-pyridyl)ethanone
    Figure US20070078146A1-20070405-C00403
  • 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
    Figure US20070078146A1-20070405-C00404
  • 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
    Figure US20070078146A1-20070405-C00405
  • 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
  • Figure US20070078146A1-20070405-C00406
  • 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
  • Figure US20070078146A1-20070405-C00407
    • 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
  • Figure US20070078146A1-20070405-C00408
  • 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
  • Figure US20070078146A1-20070405-C00409
  • 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
  • Figure US20070078146A1-20070405-C00410
  • 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
  • Figure US20070078146A1-20070405-C00411
  • 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
  • Figure US20070078146A1-20070405-C00412
  • 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
  • Figure US20070078146A1-20070405-C00413
  • 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
  • Figure US20070078146A1-20070405-C00414
  • 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
  • Figure US20070078146A1-20070405-C00415
  • 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
  • Figure US20070078146A1-20070405-C00416
  • 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
  • Figure US20070078146A1-20070405-C00417
  • 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
  • Figure US20070078146A1-20070405-C00418
  • 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
  • Figure US20070078146A1-20070405-C00419
  • 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
  • Figure US20070078146A1-20070405-C00420
  • 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
  • Figure US20070078146A1-20070405-C00421
  • 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
  • Figure US20070078146A1-20070405-C00422
  • 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
  • Figure US20070078146A1-20070405-C00423
  • 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
  • Figure US20070078146A1-20070405-C00424
    • 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
  • Figure US20070078146A1-20070405-C00425
    • 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
  • Figure US20070078146A1-20070405-C00426
    • 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
  • Figure US20070078146A1-20070405-C00427
    • 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
  • Figure US20070078146A1-20070405-C00428
    • 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
  • Figure US20070078146A1-20070405-C00429
    • 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
  • Figure US20070078146A1-20070405-C00430
    • 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
  • Figure US20070078146A1-20070405-C00431
    • 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
  • Figure US20070078146A1-20070405-C00432
    • 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
  • Figure US20070078146A1-20070405-C00433
    • 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
  • Figure US20070078146A1-20070405-C00434
    • 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
  • Figure US20070078146A1-20070405-C00435
    • 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
  • Figure US20070078146A1-20070405-C00436
    • 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
  • Figure US20070078146A1-20070405-C00437
    • 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
  • Figure US20070078146A1-20070405-C00438
    • 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
  • Figure US20070078146A1-20070405-C00439
    • 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
  • Figure US20070078146A1-20070405-C00440
    • 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
  • Figure US20070078146A1-20070405-C00441
    • 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
  • Figure US20070078146A1-20070405-C00442
    • 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
  • Figure US20070078146A1-20070405-C00443
    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
  • Figure US20070078146A1-20070405-C00444
  • 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
  • Figure US20070078146A1-20070405-C00445
    • 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
  • Figure US20070078146A1-20070405-C00446
    • 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
  • Figure US20070078146A1-20070405-C00447
  • 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
  • Figure US20070078146A1-20070405-C00448
  • 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
  • Figure US20070078146A1-20070405-C00449
  • 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
  • Figure US20070078146A1-20070405-C00450
  • 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
  • Figure US20070078146A1-20070405-C00451
  • 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
  • Figure US20070078146A1-20070405-C00452
    • 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
  • Figure US20070078146A1-20070405-C00453
    • 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
  • Figure US20070078146A1-20070405-C00454
  • 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
  • Figure US20070078146A1-20070405-C00455
  • 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
  • Figure US20070078146A1-20070405-C00456
  • 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
  • Figure US20070078146A1-20070405-C00457
  • 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
  • Figure US20070078146A1-20070405-C00458
  • 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
  • Figure US20070078146A1-20070405-C00459
  • 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
  • Figure US20070078146A1-20070405-C00460
  • 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
  • Figure US20070078146A1-20070405-C00461
  • 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
  • Figure US20070078146A1-20070405-C00462
  • 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
  • Figure US20070078146A1-20070405-C00463
  • 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
  • Figure US20070078146A1-20070405-C00464
    • 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
  • Figure US20070078146A1-20070405-C00465
  • 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
  • Figure US20070078146A1-20070405-C00466
  • 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
  • Figure US20070078146A1-20070405-C00467
  • 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
  • Figure US20070078146A1-20070405-C00468
  • 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
  • Figure US20070078146A1-20070405-C00469
  • 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
  • Figure US20070078146A1-20070405-C00470
  • 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
  • Figure US20070078146A1-20070405-C00471
    • [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
  • Figure US20070078146A1-20070405-C00472
  • 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
  • Figure US20070078146A1-20070405-C00473
  • 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
  • Figure US20070078146A1-20070405-C00474
    • 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
  • Figure US20070078146A1-20070405-C00475
  • 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
  • Figure US20070078146A1-20070405-C00476
  • 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
  • Figure US20070078146A1-20070405-C00477
  • 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
  • Figure US20070078146A1-20070405-C00478
  • 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
  • Figure US20070078146A1-20070405-C00479
  • 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
  • Figure US20070078146A1-20070405-C00480
  • 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
  • Figure US20070078146A1-20070405-C00481
  • 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
  • Figure US20070078146A1-20070405-C00482
  • 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
  • Figure US20070078146A1-20070405-C00483
    • 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
  • Figure US20070078146A1-20070405-C00484
    • 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
  • Figure US20070078146A1-20070405-C00485
  • 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
  • Figure US20070078146A1-20070405-C00486
  • 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
  • Figure US20070078146A1-20070405-C00487
  • 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
  • Figure US20070078146A1-20070405-C00488
  • 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
  • Figure US20070078146A1-20070405-C00489
  • 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
  • Figure US20070078146A1-20070405-C00490
  • 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
  • Figure US20070078146A1-20070405-C00491
  • 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
  • Figure US20070078146A1-20070405-C00492
  • 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
  • Figure US20070078146A1-20070405-C00493
  • 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
  • Figure US20070078146A1-20070405-C00494
  • 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
  • Figure US20070078146A1-20070405-C00495
  • 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
  • Figure US20070078146A1-20070405-C00496
  • 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
  • Figure US20070078146A1-20070405-C00497
  • 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
  • Figure US20070078146A1-20070405-C00498
  • 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
  • Figure US20070078146A1-20070405-C00499
  • 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
  • Figure US20070078146A1-20070405-C00500
    • 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:
    Figure US20070078146A1-20070405-C00501
    • 4-[3-(4-chlorophenyl)-5-(1-piperazinyl)-1H-pyrazol-4-yl]pyrimidine
  • Figure US20070078146A1-20070405-C00502
    • 1-[5-(4-bromophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]piperazine
  • Figure US20070078146A1-20070405-C00503
    • 1-[4-(4-pyridinyl)-5-[4-(trifluoromethyl)phenyl]-1H-pyrazol-3-yl]piperazine
  • Figure US20070078146A1-20070405-C00504
    • 4-[5-(1-piperazinyl-4-(4-pyridinyl)-1H-pyrazol-3-yl]benzonitrile
  • Figure US20070078146A1-20070405-C00505
    • 1-[5-(4-ethynylphyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]piperazine
  • Figure US20070078146A1-20070405-C00506
    • 5-(4-fluorophenyl)-4-(4-pyridinyl)-N-3-pyrrolidinyl-1H-pyrazol-3-amine
  • Figure US20070078146A1-20070405-C00507
    • 5-(4-chlorophenyl)-4-(4-pyridinyl)-N-3-pyrrolidinyl-1H-pyrazol-3-amine
  • Figure US20070078146A1-20070405-C00508
    • N-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-piperidinamine
  • Figure US20070078146A1-20070405-C00509
    • 3-(4-fluorophenyl)-5-(1-piperazinyl)-4-(4-pyridinyl)-1H-pyrazole-1-ethanol
  • Figure US20070078146A1-20070405-C00510
    • 3-(4-chlorophenyl)-5-(1-piperazinyl)-4-(4-pyridinyl)-1H-pyrazole-1-ethanol
  • Figure US20070078146A1-20070405-C00511
    • 4-[2-aminoethyl)-2-(4-fluorophenyl)-4,5,6,7-tetrahydro-3-(4-pyridinyl)pyrazolo[1,5-a]pyrimidin-6-ol
  • Figure US20070078146A1-20070405-C00512
    • 4-(2-aminoethyl)-2-(4-chlorophenyl)-4,5,6,7-tetrahydro-3-(4-pyridinyl)pyrazolo[1,5-a]pyrimidin-6-ol
  • Figure US20070078146A1-20070405-C00513
    • 3-(4-chlorophenyl)-4-(4-pyrimidinyl)-1H-pyrazole-1-ethanol
  • Figure US20070078146A1-20070405-C00514
    • 5-(4-fluorophenyl)-4-(4-pyrimidinyl)-1H-pyrazole-3-ethanamine
  • Figure US20070078146A1-20070405-C00515
    • 5-(4-chlorophenyl)-4-(4-pyrimidinyl)-1H-pyrazole-3-ethanamine
  • Figure US20070078146A1-20070405-C00516
    • 4-[3-(4-fluorophenyl)-5-(4-piperidinyl)-1H-pyrazol-4-yl]pyrimidine
  • Figure US20070078146A1-20070405-C00517
    • 4-[3-(4-chlorophenyl)-5-(4-piperidinyl)-1H-pyrazol-4-yl]pyrimidine
  • Figure US20070078146A1-20070405-C00518
    • N-[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyrimidinyl]acetamide
  • Figure US20070078146A1-20070405-C00519
    • N-[4-[3-(4-chlorophenyl)-1H-pyrazol-4-yl]-2-pyrimidinyl]acetamide
  • Figure US20070078146A1-20070405-C00520
    • N-[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyrimidinylpropanamide
  • Figure US20070078146A1-20070405-C00521
    • N-[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyrimidinyl]propanamide
  • Figure US20070078146A1-20070405-C00522
    • 6-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-1H-purine
  • Figure US20070078146A1-20070405-C00523
    • 6-[3-(4-chlorophenyl)-1H-pyrazol-4-yl]-1H-purine
  • Figure US20070078146A1-20070405-C00524
    • N-[4-[3-(4-chlorophenyl)-1H-pyrazol-4-yl]-2-pyrimidinyl]-N-(phenylmethyl)acetamide
  • Figure US20070078146A1-20070405-C00525
    • N-[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyrimidinyl]-N-(phenylmethyl)propanamide
  • Figure US20070078146A1-20070405-C00526
    • N-[4-[3-(4-chlorophenyl)-1H-pyrazol-4-yl]-2-pyrimidinyl]-N-(phenylmethyl)propanamide
  • Figure US20070078146A1-20070405-C00527
    • 1-[2-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]ethyl]piperazine
  • Figure US20070078146A1-20070405-C00528
    • 1-[2-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]ethyl]-4-methylpiperazine
  • Figure US20070078146A1-20070405-C00529
    • 1-[2-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]ethyl]piperazine
  • Figure US20070078146A1-20070405-C00530
    • 1-[2-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]ethyl]-4-methylpiperazine
  • Figure US20070078146A1-20070405-C00531
    • 1-[[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]methylpiperazine
  • Figure US20070078146A1-20070405-C00532
    • 1-[[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]methyl]-4-methylpiperazine
  • Figure US20070078146A1-20070405-C00533
    • 4-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1-piperazineethanol
  • Figure US20070078146A1-20070405-C00534
    • 4-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1-piperazineethanamine
  • Figure US20070078146A1-20070405-C00535
    • 4-[5-[4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1-piperazineethanol
  • Figure US20070078146A1-20070405-C00536
    • 4-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1-piperazineethanamine
  • Figure US20070078146A1-20070405-C00537
    • 4-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1,2,6-trimethylpiperazine
  • Figure US20070078146A1-20070405-C00538
    • 1-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-3,5-dimethylpiperazine
  • Figure US20070078146A1-20070405-C00539
    • 4-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1,2,6-trimethylpiperazine
  • Figure US20070078146A1-20070405-C00540
    • 4-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1,2-dimethylpiperazine
  • Figure US20070078146A1-20070405-C00541
    • 1-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-3-methylpiperazine
  • Figure US20070078146A1-20070405-C00542
    • 4-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1,2-dimethylpiperazine
  • Figure US20070078146A1-20070405-C00543
    • 5-(4-chlorophenyl)-4-(4-pyridinyl)-N-3-pyrrolidinyl-1H-pyrazol-3-amine
  • Figure US20070078146A1-20070405-C00544
    • 5-(4-chlorophenyl)-N-(1-methyl-3-pyrrolidinyl)-4-(4-pyridinyl)-1H-pyrazol-3-amine
  • Figure US20070078146A1-20070405-C00545
    • 5-(4-fluorophenyl)-4-(4-pyridinyl)-N-3-pyrrolidinyl-1H-pyrazol-3-amine
  • Figure US20070078146A1-20070405-C00546
    • 5-(4-fluorophenyl)-N-(1-methyl-3-pyrrolidinyl)-4-(4-pyridinyl)-1H-pyrazol-3-amine
  • Figure US20070078146A1-20070405-C00547
    • 1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-3-pyrrolidinamine
  • Figure US20070078146A1-20070405-C00548
    • 1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-N,N-dimethyl-3-pyrrolidinamine
  • Figure US20070078146A1-20070405-C00549
    • 1-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-3-pyrrolidinamine
  • Figure US20070078146A1-20070405-C00550
    • 1-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-N,N-dimethyl-3-pyrrolidinamine
  • Figure US20070078146A1-20070405-C00551
    • 5-(4-chlorophenyl)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-4-(4-pyridinyl)-1H-pyrazol-3-amine
  • Figure US20070078146A1-20070405-C00552
    • 5-(4-fluorophenyl)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-4-(4-pyridinyl)-1H-pyrazol-3-amine
  • Figure US20070078146A1-20070405-C00553
    • N-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-3-piperidinamine
  • Figure US20070078146A1-20070405-C00554
    • N-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1-methyl-3-piperidinamine
  • Figure US20070078146A1-20070405-C00555
    • N-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-3-piperidinamine
  • Figure US20070078146A1-20070405-C00556
    • N-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1-methyl-3-piperidinamine
  • Figure US20070078146A1-20070405-C00557
    • 4-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-2-piperazinemethanol
  • Figure US20070078146A1-20070405-C00558
    • 4-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-2-piperazinemethanamine
  • Figure US20070078146A1-20070405-C00559
    • 4-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1-methyl-2-piperazinemethanol
  • Figure US20070078146A1-20070405-C00560
    • 4-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1-methyl-2-piperazinemethanamine
  • Figure US20070078146A1-20070405-C00561
    • 4-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-2-piperazinemethanol
  • Figure US20070078146A1-20070405-C00562
    • 4-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-2-piperazinemethanamine
  • Figure US20070078146A1-20070405-C00563
    • 4-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1-methyl-2-piperazinemethanol
  • Figure US20070078146A1-20070405-C00564
    • 4-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1-methyl-2-piperazinemethanamine
  • Figure US20070078146A1-20070405-C00565
    • 4-[3-(4-chlorophenyl)-5-(4-methyl-1-piperazinyl)-1H-pyrazol-4-yl]-N-methyl-2-pyrimidinamine
  • Figure US20070078146A1-20070405-C00566
    • 4-[3-(4-fluorophenyl)-5-(4-methyl-1-piperazinyl)-1H-pyrazol-4-yl]-N-methyl-2-pyrimidinamine
  • Figure US20070078146A1-20070405-C00567
    • 1-[[5-(4-chliorophlenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]methyl]-4-piperidinol
  • Figure US20070078146A1-20070405-C00568
    • 1-[[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]methyl-4-piperidinol
  • Figure US20070078146A1-20070405-C00569
    • 4-[3-(4-chlorophenyl)-5-(4-methyl-1-piperazinyl)-1H-pyrazol-4-yl]pyrimidine
  • Figure US20070078146A1-20070405-C00570
    • 4-[3-(4-fluorophenyl)-5-(4-methyl-1-piperazinyl)-1H-pyrazol-4-yl]pyrimidine
  • Figure US20070078146A1-20070405-C00571
    • 4-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-2-piperazinecarboxylic acid
  • Figure US20070078146A1-20070405-C00572
    • ethyl 4-[5[-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-2-piperazinecarboxylate
  • Figure US20070078146A1-20070405-C00573
    • 4-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1-methyl-2-piperazinecarboxylic acid
  • Figure US20070078146A1-20070405-C00574
    • ethyl 4-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1-methyl-2-piperazinecarboxylate
  • Figure US20070078146A1-20070405-C00575
    • 4-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1-methyl-2-piperazinecarboxamide
  • Figure US20070078146A1-20070405-C00576
    • 4-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-2-piperazinecarboxamide
  • Figure US20070078146A1-20070405-C00577
    • 4-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-2-piperazinecarboxylic acid
  • Figure US20070078146A1-20070405-C00578
    • ethyl 4-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-2-piperazinecarboxylate
  • Figure US20070078146A1-20070405-C00579
    • 4-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-2-piperazinecarboxamide
  • Figure US20070078146A1-20070405-C00580
    • 4-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1-methyl-2-piperazinecarboxylic acid
  • Figure US20070078146A1-20070405-C00581
    • ethyl 4-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1-methyl-2-piperazinecarboxylate
  • Figure US20070078146A1-20070405-C00582
    • 4-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1-methyl-2-piperazinecarboxamide
  • Figure US20070078146A1-20070405-C00583
    • N-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1-ethyl-4-piperidinamine
  • Figure US20070078146A1-20070405-C00584
    • N-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1-(phenylmethyl)-4-piperidinamine
  • Figure US20070078146A1-20070405-C00585
    • 1-acetyl-N-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-piperidinamine
  • Figure US20070078146A1-20070405-C00586
    • N-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1-(2-propynyl)-4-piperidinamine
  • Figure US20070078146A1-20070405-C00587
    • N-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1-cyclopropyl-4-piperidinamine
  • Figure US20070078146A1-20070405-C00588
    • N-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1-(methoxyacetyl)-4-piperidinamine
  • Figure US20070078146A1-20070405-C00589
    • N-[5-(40-chlrophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1-(methylethyl)-4-piperidinamine
  • Figure US20070078146A1-20070405-C00590
    • N-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1-propyl-4-piperidinamine
  • Figure US20070078146A1-20070405-C00591
    • ethyl 4-[[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]amino]-1-piperidinecarboxylate
  • Figure US20070078146A1-20070405-C00592
    Figure US20070078146A1-20070405-C00593
  • Additional compounds of specific interest include the compounds of Tables 3-3, 3-4, 3-5 and 3-6:
    TABLE 3-3
    Figure US20070078146A1-20070405-C00594
    R2 R5 R12
    4-piperidinyl methyl m- or p-fluoro
    4-piperidinyl ethyl m- or p-fluoro
    4-piperidinyl amino m- or p-fluoro
    4-piperidinyl methylamino m- or p-fluoro
    4-piperidinyl dimethylamino m- or p-fluoro
    4-piperidinyl ethylamino m- or p-fluoro
    4-piperidinyl diethylamino m- or p-fluoro
    4-piperidinyl propylamino m- or p-fluoro
    4-piperidinyl dipropylamino m- or p-fluoro
    4-piperidinyl hydroxyethylamino m- or p-fluoro
    4-piperidinyl 1-hydroxy-1,1- m- or p-fluoro
    dimethylethyl
    4-piperidinyl methoxyethylamino m- or p-fluoro
    4-piperidinyl methyl m- or p-chloro
    4-piperidinyl ethyl m- or p-chloro
    4-piperidinyl amino m- or p-chloro
    4-piperidinyl methylamino m- or p-chloro
    4-piperidinyl dimethylamino m- or p-chloro
    4-piperidinyl ethylamino m- or p-chloro
    4-piperidinyl diethylamino m- or p-chloro
    4-piperidinyl propylamino m- or p-chloro
    4-piperidinyl dipropylamino m- or p-chloro
    4-piperidinyl hydroxyethylamino m- or p-chloro
    4-piperidinyl 1-hydroxy-1,1- m- or p-chloro
    dimethylethyl
    4-piperidinyl methoxyethylamino m- or p-chloro
    4-piperidinyl methyl m- or p-methyl
    4-piperidinyl ethyl m- or p-methyl
    4-piperidinyl amino m- or p-methyl
    4-piperidinyl methylamino m- or p-methyl
    4-piperidinyl dimethylamino m- or p-methyl
    4-piperidinyl ethylamino m- or p-methyl
    4-piperidinyl diethylamino m- or p-methyl
    4-piperidinyl propylamino m- or p-methyl
    4-piperidinyl dipropylamino m- or p-methyl
    4-piperidinyl hydroxyethylamino m- or p-methyl
    4-piperidinyl 1-hydroxy-1,1- m- or p-methyl
    dimethyl ethyl
    4-piperidinyl methoxyethylamino m- or p-methyl
    4-piperazinyl methyl m- or p-fluoro
    4-piperazinyl ethyl m- or p-fluoro
    4-piperazinyl amino m- or p-fluoro
    4-piperazinyl methylamino m- or p-fluoro
    4-piperazinyl dimethylamino m- or p-fluoro
    4-piperazinyl ethylamino m- or p-fluoro
    4-piperazinyl diethylamino m- or p-fluoro
    4-piperazinyl propylamino m- or p-fluoro
    4-piperazinyl dipropylamino m- or p-fluoro
    4-piperazinyl hydroxyethylamino m- or p-fluoro
    4-piperazinyl 1-hydroxy-1,1- m-or p-fluoro
    dimethylethyl
    4-piperazinyl methoxyethylamino m- or p-fluoro
    4-piperazinyl methyl m- or p-chloro
    4-piperazinyl ethyl m- or p-chloro
    4-piperazinyl amino m- or p-chloro
    4-piperazinyl methylamino m- or p-chloro
    4-piperazinyl dimethylamino m- or p-chloro
    4-piperazinyl ethylamino m- or p-chloro
    4-piperazinyl diethylamino m- or p-chloro
    4-piperazinyl propylamino m- or p-chloro
    4-piperazinyl dipropylamino m- or p-chloro
    4-piperazinyl hydroxyethylamino m- or p-chloro
    4-piperazinyl 1-hydroxy-1,1- m- or p-chloro
    dimethylethyl
    4-piperazinyl methoxyethylamino m- or p-chloro
    4-piperazinyl methyl m- or p-methyl
    4-piperazinyl ethyl m- or p-methyl
    4-piperazinyl amino m- or p-methyl
    4-piperazinyl methylamino m- or p-methyl
    4-piperazinyl dimethylamino m- or p-methyl
    4-piperazinyl ethylamino m- or p-methyl
    4-piperazinyl diethylamino m- or p-methyl
    4-piperazinyl propylamino m- or p-methyl
    4-piperazinyl dipropylamino m- or p-methyl
    4-piperazinyl hydroxyethylamino m-or p-methyl
    4-piperazinyl 1-hydroxy-1,1- m- or p-methyl
    dimethylethyl
    4-piperazinyl methoxyethylamino m- or p-methyl
    aminocyclohexyl methyl m- or p-fluoro
    aminocyclohexyl ethyl m- or p-fluoro
    aminocyclohexyl amino m- or p-fluoro
    aminocyclohexyl methylamino m- or p-fluoro
    aminocyclohexyl dimethylamino m- or p-fluoro
    aminocyclohexyl ethylamino m- or p-fluoro
    aminocyclohexyl diethylamino m- or p-fluoro
    aminocyclohexyl propylamino m- or p-fluoro
    aminocyclohexyl dipropylamino m- or p-fluoro
    aminocyclohexyl hydroxyethylamino m- or p-fluoro
    aminocyclohexyl 1-hydroxy-1,1- m- or p-fluoro
    dimethylethyl
    aminocyclohexyl methoxyethylamino m- or p-fluoro
    aminocyclohexyl methyl m- or p-chloro
    aminocyclohexyl ethyl m- or p-chloro
    aminocyclohexyl amino m- or p-chloro
    aminocyclohexyl methylamino m- or p-chloro
    aminocyclohexyl dimethylamino m- or p-chloro
    aminocyclohexyl ethylamino m- or p-chloro
    aminocyclohexyl diethylamino m- or p-chloro
    aminocyclohexyl propylamino m- or p-chloro
    aminocyclohexyl dipropylamino m- or p-chloro
    aminocyclohexyl hydroxyethylamino m- or p-chloro
    aminocyclohexyl 1-hydroxy-1,1- m- or p-chloro
    dimethylethyl
    aminocyclohexyl methoxyethylamino m- or p-chloro
    aminocyclohexyl methyl m- or p-methyl
    aminocyclohexyl ethyl m- or p-methyl
    aminocyclohexyl amino m- or p-methyl
    aminocyclohexyl methylamino m- or p-methyl
    aminocyclohexyl dimethylamino m- or p-methyl
    aminocyclohexyl ethylamino m- or p-methyl
    aminocyclohexyl diethylamino m- or p-methyl
    aminocyclohexyl propylamino m- or p-methyl
    aminocyclohexyl dipropylamino m- or p-methyl
    aminocyclohexyl hydroxyethylamino m- or p-methyl
    aminocyclohexyl 1-hydroxy-1,1- m- or p-methyl
    dimethylethyl
    aminocyclohexyl methoxyethylamino m- 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 3-4
    Figure US20070078146A1-20070405-C00595
    R4 R3 R200 R201
    4-pyridyl 4-methylphenyl H O
    4-pyridyl 4-methylphenyl CH3 O
    4-pyrimidyl 4-methylphenyl H O
    4-pyrimidyl 4-methylphenyl CH3 O
    4-pyridyl 4-methylphenyl H S
    4-pyridyl 4-methylphenyl CH3 S
    4-pyrimidyl 4-methylphenyl H S
    4-pyrimidyl 4-methylphenyl CH3 S
    4-pyridyl 3-methylphenyl H O
    4-pyridyl 3-methylphenyl CH3 O
    4-pyrimidyl 3-methylphenyl H O
    4-pyrimidyl 3-methylphenyl CH3 O
    4-pyridyl 3-methylphenyl H S
    4-pyridyl 3-methylphenyl CH3 S
    4-pyrimidyl 3-rnethylphenyl H S
    4-pyrimidyl 3-methylphenyl CH3 S
  • TABLE 3-5
    Figure US20070078146A1-20070405-C00596
    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
    Figure US20070078146A1-20070405-C00597
    R4 R3 R400
    p-Cl phenyl 4-pyridyl —SO2CH3
    p-Cl phenyl 4-pyridyl —CH2CN
    p-Cl phenyl 4-pyridyl
    Figure US20070078146A1-20070405-C00598
    p-Cl phenyl
    Figure US20070078146A1-20070405-C00599
         		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 4
    p38 kinase
    Example IC50 (μM)
    1 4.6
    2 1.5
    8 <0.1
    16 3.8
    23 1.5
    25 2.6
    26 0.7
    28 0.3
    33 2.5
    34 8.0
    36 12.1
    38 0.8
    39 1.1
    40 1.3
    42 0.3
    43 <0.1
    44 <0.1
    45 <0.1
    46 <0.1
    47 3.2
    48 1.8
    50 2.3
    51 <0.1
    52 0.1
    53 0.9
    54 0.7
    55 6.4
    143 <0.1

    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 5
    Human PBM Assay U937 Cell Assay
    Example IC50 (μM) IC50 ((μM)
    1 0.5
    2 1.6 0.578
    4 0.1 0.222
    5 0.274
    7 0.2 0.201
    8 <0.1
    9 0.4
    10 0.7 1.687
    12 8.5
    13 4.8
    14 1.2
    17 1.1
    19 0.3 0.484
    20 1.089
    21 0.077
    22 3.2
    24 8.2
    26 <0.1 0.029
    27 2.7
    28 0.1
    29 2.2
    30 2.6
    31 0.8 1.053
    32 2.696
    33 0.4
    34 0.5
    35 0.7
    36 1.4
    37 1.5 0.099
    38 0.2 0.208
    39 0.7 0.244
    40 0.4
    41 1.0
    42 0.7
    43 <0.1 0.243
    44 0.4 0.477
    45 <0.1 0.04
    46 0.329
    47 2.359
    48 2.2 0.522
    49 6.8
    50 0.9
    51 0.074
    54 0.2 0.13
    55 <0.1 0.228
    143 0.301

    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 6
    mLPS mLPS mLPS
    Example p381 p382 U937 8 h 6 h dose 1 h, 30 mpk
    A-212 0.49 0.74 0.0967 20 10 93
    A-208 0.104 0.049 0.1896 98 30 97
    A-227 0.06 96
    A-228 0.76 0.339 0.4173 32 30 92
    A-229 1.4 0.4622 76 91
    A-230 0.42 0.178 96
    A-231 0.174 0.3225 86 30 94
    A-232 0.048 96
    A-233 0.044 53
    A-234 0.103
    A-235 0.104 56
    A-236 0.237 94
    A-237 0.093 0.087 60
    A-238 0.177 0.4016
    A-239 0.034 51 30 87
    A-240 0.961 78 30 85
    A-241 0.338 79 30 87
    A-242 0.047 95 30 87
    A-243 0.729 82
    A-244 0.099
    A-245 <.001 0.0337 65
    A-246 0.403 0.592 0.4952
    A-247 <0.01 0.166
    A-249 0.432 73 30 86
    A-250 2.873
    A-251 0.637 32 87
    A-252 0.774 1.197 48 30 75
    A-253 <.001 0.0044 61
    A-254 0.081 0.1411
    A-215 2.34 0.2976 38 30 80
    A-256 0.813 0.4562
    A-257 1.081 <.01 0.5167
    A-213 0.22 57
    A-258 0.48 1.2083 68
    A-259 0.17 0.7574 62
    A-210 0.16 0.1983 85 30 93
    A-260 0.23 1.2821 47 30 79
    A-214 0.06 1.4006 70
    A-261 0.008 0.2542 48 30 92
    A-216 0.018 1.8287 27 30 91
    A-262 <0.1 0.3267 45
    A-263 <0.01 <0.1 0.5434 49
    A-264 0.2594 61
    A-265 <0.1 0.6016 32
    A-266 0.5393 0
    A-267 0.43 2.6681 80
    A-268 <0.01 0.0074 11
    A-217 0.697 0.3486 9
    A-269 >10 uM 51
    A-270 0.015 0.3466 53
    A-271 0.216 4.2144 68
    A-272 0.073 0.583 −8
    A-273 6.98 >10 43
    A-274 <0.1 0.92 21 30
    A-275 10.142 >10
    A-276 0.176 0.45 −24 30
    A-277 0.026 33 30
    A-278 0.285 2.3 62 30
    A-279 0.005 0.7 64 30
    A-280 0.134 15 30
    A-281 0.053 22 30
    A-218 0.044 18 30
    A-282 0.045 0.0973 30 30
    A-283 <0.1 0.7998 −20 30
    A-284 0.98 0.5088 −1
    A-285 <0.1 0.1795 11 30
    A-286 0.057 0.09 29 30
    A-287 0.041 0.27 −24 30
    A-288 0.017 0.3 40 30
    A-289 <0.1 0.14 44 30
    A-290 6.0191 4 30
    A-291 0.388 1.1309 36 30
    A-292 1.15 >10
    A-293 0.73
    A-294 0.015 0.5 61 30
    A-295 7.66 >10 94 30
    A-296 26
    A-297 0.52 0.17 89 30

    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 7
    Compound % Inhibition of Arthritis
    A-210 58.5 @ 15 mpk
    A-172 49.3 @ 100 mpk
    A-189 51.6 @ 30 mpk
    A-208 97.5 @ 60 mpk
    A-208 75.0 @ 60 mpk
  • Additional results for selected compounds obtained using the above-described assays are set forth in Tables 8, 9 and 10 below:
    TABLE 8
    Rat LPS TNF
    Assay % Inhibition- p38α Kinase
    Inhibition Human Whole Assay
    (Dose in Blood Assay IC50 in μM
    Example mg/kg) (μM) (% DMSO)
    A-313, Step 1 1.34 (1) 
    A-313, Step 3 96.0 (20.0) 0.12 0.036 (1) 
    0.37 (10)
    A-314, Step 1 0.85 (1) 
    0.37 (10)
    A-314, Step 2   0 (1.0) 0.47 0.032 (10) 
    53.0 (5.0) 
    85.0 (20.0)
    A-315 1.75 0.049 (10) 
    A-317 58.0 (3.0)  0.45 0.07 (10)
    10.0 (3.0)  0.11 (10)
    69.0 (10.0)
    A-318 54.0 (3.0)  0.167 0.29 (1) 
    0.58 (10)
    0.37 (10)
     0.6 (10)
    A-319 62.0 (3.0)  >25.0 6.06 (1) 
    0.13 (10)
    A-320 1.0 (3.0) 0.27 (1) 
    0.05 (10)
    0.15 (10)
    A-321 >25.0 0.77 (1) 
    (dihydrate)
    A-321 14.0 (3.0) 
    (monosodium
    salt
    dihydrate)
    A-322 51.5 (3.0)  4.2 0.15 (10)
    0.25 (10)
    A-323 40.0 (30.0) 0.39 (10)
    54.0 (30.0)
    A-324 44.0 (3.0)  0.08 (10)
    A-325 25.0 (3.0)  0.057 0.021 (1) 
    11.0 (30.0) <0.1 (10)
    A-326   0 (10.0) >25.0 0.97 (10)
    A-327 83.0 (20.0) 0.18 0.15 (10)
    A-328 0.012 (1) 
    A-331 13.0 (20.0)  >100 (1) 
    0.64 (10)
    A-332 33.0 (1.0)  0.45 0.04 (1) 
    26.0 (3.0)  0.04 (10)
    25.0 (5.0)  0.015 (10) 
    −85.0 (10.0)   <0.1 (10)
    A-333 69.0 (5.0)  0.585 0.052 (10) 
    A-334 95.0 (20.0) 0.22 0.07 (10)
    57.0 (5.0) 
    36.0 (1.0) 
    A-335 >25.0 89.9 (10)
    A-336 1.16 (10)
    A-337 >25.0 1.35 (10)
    A-338 0.059 0.018 (10) 
    A-339 0.056 0.052 (10) 
    A-342 98.0 (20.0) 0.31 0.012 (10) 
    A-343 96.0 (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.
    Figure US20070078146A1-20070405-P00001
  • 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.
    Figure US20070078146A1-20070405-P00002
  • 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.
    Figure US20070078146A1-20070405-P00003
  • 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.
    Figure US20070078146A1-20070405-C00600
  • 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.
    Figure US20070078146A1-20070405-C00601
  • 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.
    Figure US20070078146A1-20070405-C00602
  • 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.
    Figure US20070078146A1-20070405-C00603
  • 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.
    Figure US20070078146A1-20070405-C00604
  • 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.
    Figure US20070078146A1-20070405-C00605
  • 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.
    Figure US20070078146A1-20070405-C00606
  • 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.
    Figure US20070078146A1-20070405-C00607
  • 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.
    Figure US20070078146A1-20070405-C00608
  • 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.
    Figure US20070078146A1-20070405-C00609
  • 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.
    Figure US20070078146A1-20070405-C00610
  • 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.
    Figure US20070078146A1-20070405-C00611
    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.
    Figure US20070078146A1-20070405-C00612
  • 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.
    Figure US20070078146A1-20070405-C00613
  • 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.
    Figure US20070078146A1-20070405-C00614
  • 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.
    Figure US20070078146A1-20070405-C00615
    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.
    Figure US20070078146A1-20070405-C00616
    Observed
    Calcd. Mass Spec
    Example# R2 RJ % Yield Mass Spec (M + H)
    B-0001
    Figure US20070078146A1-20070405-C00617
    Figure US20070078146A1-20070405-C00618
         		85 397 398
    B-0002
    Figure US20070078146A1-20070405-C00619
    Figure US20070078146A1-20070405-C00620
         		94 412 413
    B-0003
    Figure US20070078146A1-20070405-C00621
    Figure US20070078146A1-20070405-C00622
         		91 340 341
    B-0004
    Figure US20070078146A1-20070405-C00623
    Figure US20070078146A1-20070405-C00624
         		79 368 369
    B-0005
    Figure US20070078146A1-20070405-C00625
    Figure US20070078146A1-20070405-C00626
         		92 498 499
    B-0006
    Figure US20070078146A1-20070405-C00627
    Figure US20070078146A1-20070405-C00628
         		92 416 417
    B-0007
    Figure US20070078146A1-20070405-C00629
    Figure US20070078146A1-20070405-C00630
         		86 450 451
    B-0008
    Figure US20070078146A1-20070405-C00631
    Figure US20070078146A1-20070405-C00632
         		86 448 449
    B-0009
    Figure US20070078146A1-20070405-C00633
    Figure US20070078146A1-20070405-C00634
         		83 368 369
    B-0010
    Figure US20070078146A1-20070405-C00635
    Figure US20070078146A1-20070405-C00636
         		86 338 339
    B-0011
    Figure US20070078146A1-20070405-C00637
    Figure US20070078146A1-20070405-C00638
         		92 402 403
    B-0012
    Figure US20070078146A1-20070405-C00639
    Figure US20070078146A1-20070405-C00640
         		74 442 443
    B-0013
    Figure US20070078146A1-20070405-C00641
    Figure US20070078146A1-20070405-C00642
         		91 446 447
    B-0014
    Figure US20070078146A1-20070405-C00643
    Figure US20070078146A1-20070405-C00644
         		84 352 353
    B-0015
    Figure US20070078146A1-20070405-C00645
    Figure US20070078146A1-20070405-C00646
         		94 380 381
    B-0016
    Figure US20070078146A1-20070405-C00647
    Figure US20070078146A1-20070405-C00648
         		89 440 441
    B-0017
    Figure US20070078146A1-20070405-C00649
    Figure US20070078146A1-20070405-C00650
         		83 498 499
    B-0028
    Figure US20070078146A1-20070405-C00651
    Figure US20070078146A1-20070405-C00652
         		92 456 457
    B-0029
    Figure US20070078146A1-20070405-C00653
    Figure US20070078146A1-20070405-C00654
         		89 428 429
    B-0030
    Figure US20070078146A1-20070405-C00655
    Figure US20070078146A1-20070405-C00656
         		37 498 499
    B-0031
    Figure US20070078146A1-20070405-C00657
    Figure US20070078146A1-20070405-C00658
         		18 407 408
    B-0032
    Figure US20070078146A1-20070405-C00659
    Figure US20070078146A1-20070405-C00660
         		86 462 463
    B-0033
    Figure US20070078146A1-20070405-C00661
    Figure US20070078146A1-20070405-C00662
         		3 352 —
    B-0034
    Figure US20070078146A1-20070405-C00663
    Figure US20070078146A1-20070405-C00664
         		92 446 447
    B-0035
    Figure US20070078146A1-20070405-C00665
    Figure US20070078146A1-20070405-C00666
         		28 569 570
    B-0036
    Figure US20070078146A1-20070405-C00667
    Figure US20070078146A1-20070405-C00668
         		93 416 417
    B-0037
    Figure US20070078146A1-20070405-C00669
    Figure US20070078146A1-20070405-C00670
         		91 422 423
    B-0038
    Figure US20070078146A1-20070405-C00671
    Figure US20070078146A1-20070405-C00672
         		84 390 393
    B-0039
    Figure US20070078146A1-20070405-C00673
    Figure US20070078146A1-20070405-C00674
         		87 402 403
    B-0040
    Figure US20070078146A1-20070405-C00675
    Figure US20070078146A1-20070405-C00676
         		92 416 417
    B-0041
    Figure US20070078146A1-20070405-C00677
    Figure US20070078146A1-20070405-C00678
         		75 444 445
    B-0042
    Figure US20070078146A1-20070405-C00679
    Figure US20070078146A1-20070405-C00680
         		54 390 391
    B-0043
    Figure US20070078146A1-20070405-C00681
    Figure US20070078146A1-20070405-C00682
         		80 396 397
    B-0044
    Figure US20070078146A1-20070405-C00683
    Figure US20070078146A1-20070405-C00684
         		81 310 311
    B-0045
    Figure US20070078146A1-20070405-C00685
    Figure US20070078146A1-20070405-C00686
         		91 408 409
    B-0046
    Figure US20070078146A1-20070405-C00687
    Figure US20070078146A1-20070405-C00688
         		25 464 465
    B-0047
    Figure US20070078146A1-20070405-C00689
    Figure US20070078146A1-20070405-C00690
         		88 430 431
    B-0048
    Figure US20070078146A1-20070405-C00691
    Figure US20070078146A1-20070405-C00692
         		95 414 415
  • By analogy to the procedure identified above for the preparation of Examples B0001-B0048, the following examples B-0049 through B-1573 were prepared.
    Figure US20070078146A1-20070405-C00693
    Calcd. Observed
    % Mass Spec
    Example# R2 RJ Yield Spec (M + H)
    B-0049
    Figure US20070078146A1-20070405-C00694
    Figure US20070078146A1-20070405-C00695
         		85 414 415
    B-0050
    Figure US20070078146A1-20070405-C00696
    Figure US20070078146A1-20070405-C00697
         		9 458 459
    B-0051
    Figure US20070078146A1-20070405-C00698
    Figure US20070078146A1-20070405-C00699
         		91 426 427
    B-0052
    Figure US20070078146A1-20070405-C00700
    Figure US20070078146A1-20070405-C00701
         		79 407 408
    B-0053
    Figure US20070078146A1-20070405-C00702
    Figure US20070078146A1-20070405-C00703
         		92 407 408
    B-0054
    Figure US20070078146A1-20070405-C00704
    Figure US20070078146A1-20070405-C00705
         		92 363 364
    B-0055
    Figure US20070078146A1-20070405-C00706
    Figure US20070078146A1-20070405-C00707
         		86 505 506
    B-0056
    Figure US20070078146A1-20070405-C00708
    Figure US20070078146A1-20070405-C00709
         		86 487 488
    B-0057
    Figure US20070078146A1-20070405-C00710
    Figure US20070078146A1-20070405-C00711
         		83 394 395
    B-0058
    Figure US20070078146A1-20070405-C00712
    Figure US20070078146A1-20070405-C00713
         		86 462 463
    B-0059
    Figure US20070078146A1-20070405-C00714
    Figure US20070078146A1-20070405-C00715
         		92 466 467
    B-0060
    Figure US20070078146A1-20070405-C00716
    Figure US20070078146A1-20070405-C00717
         		74 456 457
    B-0061
    Figure US20070078146A1-20070405-C00718
    Figure US20070078146A1-20070405-C00719
         		35 458 459
    B-0062
    Figure US20070078146A1-20070405-C00720
    Figure US20070078146A1-20070405-C00721
         		94 458 459
    B-0063
    Figure US20070078146A1-20070405-C00722
    Figure US20070078146A1-20070405-C00723
         		87 372 373
    B-0064
    Figure US20070078146A1-20070405-C00724
    Figure US20070078146A1-20070405-C00725
         		5 394 395
    B-0065
    Figure US20070078146A1-20070405-C00726
    Figure US20070078146A1-20070405-C00727
         		87 420 395
    B-0066
    Figure US20070078146A1-20070405-C00728
    Figure US20070078146A1-20070405-C00729
         		89 350 351
    B-0067
    Figure US20070078146A1-20070405-C00730
    Figure US20070078146A1-20070405-C00731
         		92 386 387
    B-0068
    Figure US20070078146A1-20070405-C00732
    Figure US20070078146A1-20070405-C00733
         		89 432 433
    B-0069
    Figure US20070078146A1-20070405-C00734
    Figure US20070078146A1-20070405-C00735
         		37 390 391
    B-0070
    Figure US20070078146A1-20070405-C00736
    Figure US20070078146A1-20070405-C00737
         		18 432 433
    B-0071
    Figure US20070078146A1-20070405-C00738
    Figure US20070078146A1-20070405-C00739
         		86 440 441
    B-0072
    Figure US20070078146A1-20070405-C00740
    Figure US20070078146A1-20070405-C00741
         		3 432 433
    B-0073
    Figure US20070078146A1-20070405-C00742
    Figure US20070078146A1-20070405-C00743
         		92 450 451
    B-0074
    Figure US20070078146A1-20070405-C00744
    Figure US20070078146A1-20070405-C00745
         		28 390 391
    B-0075
    Figure US20070078146A1-20070405-C00746
    Figure US20070078146A1-20070405-C00747
         		93 402 403
    B-0076
    Figure US20070078146A1-20070405-C00748
    Figure US20070078146A1-20070405-C00749
         		91 400 401
    B-0077
    Figure US20070078146A1-20070405-C00750
    Figure US20070078146A1-20070405-C00751
         		84 382 383
    B-0078
    Figure US20070078146A1-20070405-C00752
    Figure US20070078146A1-20070405-C00753
         		87 396 397
    B-0079
    Figure US20070078146A1-20070405-C00754
    Figure US20070078146A1-20070405-C00755
         		92 364 365
    B-0080
    Figure US20070078146A1-20070405-C00756
    Figure US20070078146A1-20070405-C00757
         		75 447 448
    B-0081
    Figure US20070078146A1-20070405-C00758
    Figure US20070078146A1-20070405-C00759
         		54 370 371
    B-0082
    Figure US20070078146A1-20070405-C00760
    Figure US20070078146A1-20070405-C00761
         		80 430 431
    B-0083
    Figure US20070078146A1-20070405-C00762
    Figure US20070078146A1-20070405-C00763
         		81 382 383
    B-0084
    Figure US20070078146A1-20070405-C00764
    Figure US20070078146A1-20070405-C00765
         		91 464 465
    B-0085
    Figure US20070078146A1-20070405-C00766
    Figure US20070078146A1-20070405-C00767
         		25 462 463
    B-0086
    Figure US20070078146A1-20070405-C00768
    Figure US20070078146A1-20070405-C00769
         		88 432 433
    B-0087
    Figure US20070078146A1-20070405-C00770
    Figure US20070078146A1-20070405-C00771
         		95 416 417
    B-0088
    Figure US20070078146A1-20070405-C00772
    Figure US20070078146A1-20070405-C00773
         		438 439
    B-0090
    Figure US20070078146A1-20070405-C00774
    Figure US20070078146A1-20070405-C00775
         		444 445
    B-0091
    Figure US20070078146A1-20070405-C00776
    Figure US20070078146A1-20070405-C00777
         		368 369
    B-0092
    Figure US20070078146A1-20070405-C00778
    Figure US20070078146A1-20070405-C00779
         		506 507
    B-0093
    Figure US20070078146A1-20070405-C00780
    Figure US20070078146A1-20070405-C00781
         		436 437
    B-0094
    Figure US20070078146A1-20070405-C00782
    Figure US20070078146A1-20070405-C00783
         		461 462
    B-0095
    Figure US20070078146A1-20070405-C00784
    Figure US20070078146A1-20070405-C00785
         		408 409
    B-0097
    Figure US20070078146A1-20070405-C00786
    Figure US20070078146A1-20070405-C00787
         		14 486 487
    B-0098
    Figure US20070078146A1-20070405-C00788
    Figure US20070078146A1-20070405-C00789
         		8 465 —
    B-0099
    Figure US20070078146A1-20070405-C00790
    Figure US20070078146A1-20070405-C00791
         		75 464 465
    B-0100
    Figure US20070078146A1-20070405-C00792
    Figure US20070078146A1-20070405-C00793
         		72 388 389
    B-0101
    Figure US20070078146A1-20070405-C00794
    Figure US20070078146A1-20070405-C00795
         		23 408 409
    B-0102
    Figure US20070078146A1-20070405-C00796
    Figure US20070078146A1-20070405-C00797
         		37 487 488
    B-0103
    Figure US20070078146A1-20070405-C00798
    Figure US20070078146A1-20070405-C00799
         		11 492 493
    B-0114
    Figure US20070078146A1-20070405-C00800
    Figure US20070078146A1-20070405-C00801
         		14 453 454
    B-0115
    Figure US20070078146A1-20070405-C00802
    Figure US20070078146A1-20070405-C00803
         		33 453
    B-0116
    Figure US20070078146A1-20070405-C00804
    Figure US20070078146A1-20070405-C00805
         		11 459 487
    B-0117
    Figure US20070078146A1-20070405-C00806
    Figure US20070078146A1-20070405-C00807
         		77 438 439
    B-0118
    Figure US20070078146A1-20070405-C00808
    Figure US20070078146A1-20070405-C00809
         		52 422 423
    B-0119
    Figure US20070078146A1-20070405-C00810
    Figure US20070078146A1-20070405-C00811
         		82 434 435
    B-0120
    Figure US20070078146A1-20070405-C00812
    Figure US20070078146A1-20070405-C00813
         		49 422 423
    B-0121
    Figure US20070078146A1-20070405-C00814
    Figure US20070078146A1-20070405-C00815
         		64 414 415
    B-0122
    Figure US20070078146A1-20070405-C00816
    Figure US20070078146A1-20070405-C00817
         		87 501 502
    B-0123
    Figure US20070078146A1-20070405-C00818
    Figure US20070078146A1-20070405-C00819
         		100 450 451
    B-0124
    Figure US20070078146A1-20070405-C00820
    Figure US20070078146A1-20070405-C00821
         		87 456 457
    B-0125
    Figure US20070078146A1-20070405-C00822
    Figure US20070078146A1-20070405-C00823
         		45 472 473
    B-0126
    Figure US20070078146A1-20070405-C00824
    Figure US20070078146A1-20070405-C00825
         		100 476 477
    B-0127
    Figure US20070078146A1-20070405-C00826
    Figure US20070078146A1-20070405-C00827
         		100 433 434
    B-0128
    Figure US20070078146A1-20070405-C00828
    Figure US20070078146A1-20070405-C00829
         		100 482 —
    B-0129
    Figure US20070078146A1-20070405-C00830
    Figure US20070078146A1-20070405-C00831
         		96 480 481
    B-0130
    Figure US20070078146A1-20070405-C00832
    Figure US20070078146A1-20070405-C00833
         		93 468 469
    B-0131
    Figure US20070078146A1-20070405-C00834
    Figure US20070078146A1-20070405-C00835
         		90 468 469
    B-0132
    Figure US20070078146A1-20070405-C00836
    Figure US20070078146A1-20070405-C00837
         		78 436 437
    B-0133
    Figure US20070078146A1-20070405-C00838
    Figure US20070078146A1-20070405-C00839
         		76 426 427
    B-0134
    Figure US20070078146A1-20070405-C00840
    Figure US20070078146A1-20070405-C00841
         		87 444 445
    B-0135
    Figure US20070078146A1-20070405-C00842
    Figure US20070078146A1-20070405-C00843
         		67 476 477
    B-0136
    Figure US20070078146A1-20070405-C00844
    Figure US20070078146A1-20070405-C00845
         		100 570 —
    B-0137
    Figure US20070078146A1-20070405-C00846
    Figure US20070078146A1-20070405-C00847
         		35 480 481
    B-0138
    Figure US20070078146A1-20070405-C00848
    Figure US20070078146A1-20070405-C00849
         		60 500 —
    B-0139
    Figure US20070078146A1-20070405-C00850
    Figure US20070078146A1-20070405-C00851
         		73 585 586
    B-0140
    Figure US20070078146A1-20070405-C00852
    Figure US20070078146A1-20070405-C00853
         		62 434 459
    B-0141
    Figure US20070078146A1-20070405-C00854
    Figure US20070078146A1-20070405-C00855
         		100 483 484
    B-0142
    Figure US20070078146A1-20070405-C00856
    Figure US20070078146A1-20070405-C00857
         		90 444 445
    B-0143
    Figure US20070078146A1-20070405-C00858
    Figure US20070078146A1-20070405-C00859
         		61 492 493
    B-0144
    Figure US20070078146A1-20070405-C00860
    Figure US20070078146A1-20070405-C00861
         		49 448 449
    B-0145
    Figure US20070078146A1-20070405-C00862
    Figure US20070078146A1-20070405-C00863
         		48 433 434
    B-0146
    Figure US20070078146A1-20070405-C00864
    Figure US20070078146A1-20070405-C00865
         		32 415 416
    B-0147
    Figure US20070078146A1-20070405-C00866
    Figure US20070078146A1-20070405-C00867
         		67 471 472
    B-0148
    Figure US20070078146A1-20070405-C00868
    Figure US20070078146A1-20070405-C00869
         		79 465 —
    B-0149
    Figure US20070078146A1-20070405-C00870
    Figure US20070078146A1-20070405-C00871
         		65 353 354
    B-0150
    Figure US20070078146A1-20070405-C00872
    Figure US20070078146A1-20070405-C00873
         		53 465 466
    B-0151
    Figure US20070078146A1-20070405-C00874
    Figure US20070078146A1-20070405-C00875
         		68 401 402
    B-0152
    Figure US20070078146A1-20070405-C00876
    Figure US20070078146A1-20070405-C00877
         		39 383 —
    B-0153
    Figure US20070078146A1-20070405-C00878
    Figure US20070078146A1-20070405-C00879
         		96 427 428
    B-0154
    Figure US20070078146A1-20070405-C00880
    Figure US20070078146A1-20070405-C00881
         		44 459 460
    B-0155
    Figure US20070078146A1-20070405-C00882
    Figure US20070078146A1-20070405-C00883
         		74 479 480
    B-0156
    Figure US20070078146A1-20070405-C00884
    Figure US20070078146A1-20070405-C00885
         		44 459 460
    B-0157
    Figure US20070078146A1-20070405-C00886
    Figure US20070078146A1-20070405-C00887
         		72 415 416
    B-0158
    Figure US20070078146A1-20070405-C00888
    Figure US20070078146A1-20070405-C00889
         		96 445 446
    B-0159
    Figure US20070078146A1-20070405-C00890
    Figure US20070078146A1-20070405-C00891
         		97 411 412
    B-0160
    Figure US20070078146A1-20070405-C00892
    Figure US20070078146A1-20070405-C00893
         		49 417 418
    B-0161
    Figure US20070078146A1-20070405-C00894
    Figure US20070078146A1-20070405-C00895
         		93 459 460
    B-0162
    Figure US20070078146A1-20070405-C00896
    Figure US20070078146A1-20070405-C00897
         		91 405 406
    B-0163
    Figure US20070078146A1-20070405-C00898
    Figure US20070078146A1-20070405-C00899
         		94 455 456
    B-0164
    Figure US20070078146A1-20070405-C00900
    Figure US20070078146A1-20070405-C00901
         		84 455 456
    B-0165
    Figure US20070078146A1-20070405-C00902
    Figure US20070078146A1-20070405-C00903
         		52 411 412
    B-0166
    Figure US20070078146A1-20070405-C00904
    Figure US20070078146A1-20070405-C00905
         		72 417 418
    B-0167
    Figure US20070078146A1-20070405-C00906
    Figure US20070078146A1-20070405-C00907
         		66 447 448
    B-0168
    Figure US20070078146A1-20070405-C00908
    Figure US20070078146A1-20070405-C00909
         		27 415 416
    B-0169
    Figure US20070078146A1-20070405-C00910
    Figure US20070078146A1-20070405-C00911
         		91 415 416
    B-0170
    Figure US20070078146A1-20070405-C00912
    Figure US20070078146A1-20070405-C00913
         		8 351 352
    B-0171
    Figure US20070078146A1-20070405-C00914
    Figure US20070078146A1-20070405-C00915
         		10 437 438
    B-0172
    Figure US20070078146A1-20070405-C00916
    Figure US20070078146A1-20070405-C00917
         		62 471 472
    B-0173
    Figure US20070078146A1-20070405-C00918
    Figure US20070078146A1-20070405-C00919
         		40 455 456
    B-0174
    Figure US20070078146A1-20070405-C00920
    Figure US20070078146A1-20070405-C00921
         		92 405 406
    B-0175
    Figure US20070078146A1-20070405-C00922
    Figure US20070078146A1-20070405-C00923
         		96 387 388
    B-0176
    Figure US20070078146A1-20070405-C00924
    Figure US20070078146A1-20070405-C00925
         		25 415 416
    B-0177
    Figure US20070078146A1-20070405-C00926
    Figure US20070078146A1-20070405-C00927
         		100 397 398
    B-0178
    Figure US20070078146A1-20070405-C00928
    Figure US20070078146A1-20070405-C00929
         		34 429 430
    B-0179
    Figure US20070078146A1-20070405-C00930
    Figure US20070078146A1-20070405-C00931
         		72 429 430
    B-0180
    Figure US20070078146A1-20070405-C00932
    Figure US20070078146A1-20070405-C00933
         		91 463 464
    B-0181
    Figure US20070078146A1-20070405-C00934
    Figure US20070078146A1-20070405-C00935
         		100 463 464
    B-0182
    Figure US20070078146A1-20070405-C00936
    Figure US20070078146A1-20070405-C00937
         		50 447 448
    B-0183
    Figure US20070078146A1-20070405-C00938
    Figure US20070078146A1-20070405-C00939
         		22 455 456
    B-0184
    Figure US20070078146A1-20070405-C00940
    Figure US20070078146A1-20070405-C00941
         		63 465 466
    B-0185
    Figure US20070078146A1-20070405-C00942
    Figure US20070078146A1-20070405-C00943
         		65 471 472
    B-0186
    Figure US20070078146A1-20070405-C00944
    Figure US20070078146A1-20070405-C00945
         		42 429 430
    B-0187
    Figure US20070078146A1-20070405-C00946
    Figure US20070078146A1-20070405-C00947
         		62 481 482
    B-0188
    Figure US20070078146A1-20070405-C00948
    Figure US20070078146A1-20070405-C00949
         		98 439 440
    B-0189
    Figure US20070078146A1-20070405-C00950
    Figure US20070078146A1-20070405-C00951
         		21 453 454
    B-0190
    Figure US20070078146A1-20070405-C00952
    Figure US20070078146A1-20070405-C00953
         		57 417 418
    B-0191
    Figure US20070078146A1-20070405-C00954
    Figure US20070078146A1-20070405-C00955
         		24 477 478
    B-0192
    Figure US20070078146A1-20070405-C00956
    Figure US20070078146A1-20070405-C00957
         		35 455 456
    B-0193
    Figure US20070078146A1-20070405-C00958
    Figure US20070078146A1-20070405-C00959
         		42 378 379
    B0194
    Figure US20070078146A1-20070405-C00960
    Figure US20070078146A1-20070405-C00961
         		65 365 366
    B-0195
    Figure US20070078146A1-20070405-C00962
    Figure US20070078146A1-20070405-C00963
         		93 587 588
    B-0196
    Figure US20070078146A1-20070405-C00964
    Figure US20070078146A1-20070405-C00965
         		82 365 366
    B-0197
    Figure US20070078146A1-20070405-C00966
    Figure US20070078146A1-20070405-C00967
         		100 587 588
    B-0198
    Figure US20070078146A1-20070405-C00968
    Figure US20070078146A1-20070405-C00969
         		86 373 374
    B-0199
    Figure US20070078146A1-20070405-C00970
    Figure US20070078146A1-20070405-C00971
         		81 373 374
    B-0200
    Figure US20070078146A1-20070405-C00972
    Figure US20070078146A1-20070405-C00973
         		78 373 374
    B-0201
    Figure US20070078146A1-20070405-C00974
    Figure US20070078146A1-20070405-C00975
         		95 352 353
    B-0202
    Figure US20070078146A1-20070405-C00976
    Figure US20070078146A1-20070405-C00977
         		100 416 417
    B-0203
    Figure US20070078146A1-20070405-C00978
    Figure US20070078146A1-20070405-C00979
         		69 354 355
    B-0204
    Figure US20070078146A1-20070405-C00980
    Figure US20070078146A1-20070405-C00981
         		93 340 341
    B-0205
    Figure US20070078146A1-20070405-C00982
    Figure US20070078146A1-20070405-C00983
         		94 354 355
    B-0206
    Figure US20070078146A1-20070405-C00984
    Figure US20070078146A1-20070405-C00985
         		79 424 425
    B-0207
    Figure US20070078146A1-20070405-C00986
    Figure US20070078146A1-20070405-C00987
         		82 326 327
    B-0208
    Figure US20070078146A1-20070405-C00988
    Figure US20070078146A1-20070405-C00989
         		88 378 379
    B-0209
    Figure US20070078146A1-20070405-C00990
    Figure US20070078146A1-20070405-C00991
         		83 362 363
    B-0210
    Figure US20070078146A1-20070405-C00992
    Figure US20070078146A1-20070405-C00993
         		100 364 365
    B-0211
    Figure US20070078146A1-20070405-C00994
    Figure US20070078146A1-20070405-C00995
         		60 325 326
    B-0212
    Figure US20070078146A1-20070405-C00996
    Figure US20070078146A1-20070405-C00997
         		79 339 340
    B-0213
    Figure US20070078146A1-20070405-C00998
    Figure US20070078146A1-20070405-C00999
         		71 353 354
    B-0214
    Figure US20070078146A1-20070405-C01000
    Figure US20070078146A1-20070405-C01001
         		77 311 312
    B-0215
    Figure US20070078146A1-20070405-C01002
    Figure US20070078146A1-20070405-C01003
         		24 353 354
    B-0216
    Figure US20070078146A1-20070405-C01004
    Figure US20070078146A1-20070405-C01005
         		339 340
    B-0217
    Figure US20070078146A1-20070405-C01006
    Figure US20070078146A1-20070405-C01007
         		381 382
    B-0218
    Figure US20070078146A1-20070405-C01008
    Figure US20070078146A1-20070405-C01009
         		365 366
    B-0219
    Figure US20070078146A1-20070405-C01010
    Figure US20070078146A1-20070405-C01011
         		401 402
    B-0220
    Figure US20070078146A1-20070405-C01012
    Figure US20070078146A1-20070405-C01013
         		415 416
    B-0221
    Figure US20070078146A1-20070405-C01014
    Figure US20070078146A1-20070405-C01015
         		367 368
    B-0222
    Figure US20070078146A1-20070405-C01016
    Figure US20070078146A1-20070405-C01017
         		96 486 487
    B-0223
    Figure US20070078146A1-20070405-C01018
    Figure US20070078146A1-20070405-C01019
         		100 465 466
    B-0224
    Figure US20070078146A1-20070405-C01020
    Figure US20070078146A1-20070405-C01021
         		75 486 509a
    B-0225
    Figure US20070078146A1-20070405-C01022
    Figure US20070078146A1-20070405-C01023
         		100 442 443
    B-0226
    Figure US20070078146A1-20070405-C01024
    Figure US20070078146A1-20070405-C01025
         		88 482 483
    B-0227
    Figure US20070078146A1-20070405-C01026
    Figure US20070078146A1-20070405-C01027
         		73 482 483
    B-0228
    Figure US20070078146A1-20070405-C01028
    Figure US20070078146A1-20070405-C01029
         		37 452 —
    B-0229
    Figure US20070078146A1-20070405-C01030
    Figure US20070078146A1-20070405-C01031
         		100 476 477
    B-0230
    Figure US20070078146A1-20070405-C01032
    Figure US20070078146A1-20070405-C01033
         		94 476 477
    B-0231
    Figure US20070078146A1-20070405-C01034
    Figure US20070078146A1-20070405-C01035
         		100 460 461
    B-0232
    Figure US20070078146A1-20070405-C01036
    Figure US20070078146A1-20070405-C01037
         		90 440 441
    B-0233
    Figure US20070078146A1-20070405-C01038
    Figure US20070078146A1-20070405-C01039
         		99 476 477
    B-0234
    Figure US20070078146A1-20070405-C01040
    Figure US20070078146A1-20070405-C01041
         		100 486 487, 489
    B-0235
    Figure US20070078146A1-20070405-C01042
    Figure US20070078146A1-20070405-C01043
         		89 486 487, 489
    B-0236
    Figure US20070078146A1-20070405-C01044
    Figure US20070078146A1-20070405-C01045
         		100 476 477
    B-0237
    Figure US20070078146A1-20070405-C01046
    Figure US20070078146A1-20070405-C01047
         		100 476 477
    B-0238
    Figure US20070078146A1-20070405-C01048
    Figure US20070078146A1-20070405-C01049
         		92 438 —
    B-0249
    Figure US20070078146A1-20070405-C01050
    Figure US20070078146A1-20070405-C01051
         		100 516 517, 519
    B-0250
    Figure US20070078146A1-20070405-C01052
    Figure US20070078146A1-20070405-C01053
         		72 458 —
    B-0251
    Figure US20070078146A1-20070405-C01054
    Figure US20070078146A1-20070405-C01055
         		100 427 428
    B-0252
    Figure US20070078146A1-20070405-C01056
    Figure US20070078146A1-20070405-C01057
         		100 450 451
    B-0253
    Figure US20070078146A1-20070405-C01058
    Figure US20070078146A1-20070405-C01059
         		100 472 473
    B-0254
    Figure US20070078146A1-20070405-C01060
    Figure US20070078146A1-20070405-C01061
         		100 433 434
    B-0255
    Figure US20070078146A1-20070405-C01062
    Figure US20070078146A1-20070405-C01063
         		84 547 548
    B-0256
    Figure US20070078146A1-20070405-C01064
    Figure US20070078146A1-20070405-C01065
         		100 484 507a
    B-0257
    Figure US20070078146A1-20070405-C01066
    Figure US20070078146A1-20070405-C01067
         		85 534 535
    B-0258
    Figure US20070078146A1-20070405-C01068
    Figure US20070078146A1-20070405-C01069
         		100 491 492
    B-0259
    Figure US20070078146A1-20070405-C01070
    Figure US20070078146A1-20070405-C01071
         		100 554 555
    B-0260
    Figure US20070078146A1-20070405-C01072
    Figure US20070078146A1-20070405-C01073
         		91 500 501
    B-0261
    Figure US20070078146A1-20070405-C01074
    Figure US20070078146A1-20070405-C01075
         		100 486 487
    B-0262
    Figure US20070078146A1-20070405-C01076
    Figure US20070078146A1-20070405-C01077
         		100 481 482
    B-0263
    Figure US20070078146A1-20070405-C01078
    Figure US20070078146A1-20070405-C01079
         		100 554 555
    B-0264
    Figure US20070078146A1-20070405-C01080
    Figure US20070078146A1-20070405-C01081
         		75 375 376
    B-0265
    Figure US20070078146A1-20070405-C01082
    Figure US20070078146A1-20070405-C01083
         		71 459 460
    B-0266
    Figure US20070078146A1-20070405-C01084
    Figure US20070078146A1-20070405-C01085
         		100 412 413
    B-0267
    Figure US20070078146A1-20070405-C01086
    Figure US20070078146A1-20070405-C01087
         		100 386 387
    B-0268
    Figure US20070078146A1-20070405-C01088
    Figure US20070078146A1-20070405-C01089
         		89 406 407
    B-0269
    Figure US20070078146A1-20070405-C01090
    Figure US20070078146A1-20070405-C01091
         		84 386 387
    B-0270
    Figure US20070078146A1-20070405-C01092
    Figure US20070078146A1-20070405-C01093
         		92 440 441
    B-0271
    Figure US20070078146A1-20070405-C01094
    Figure US20070078146A1-20070405-C01095
         		98 428 429
    B-0272
    Figure US20070078146A1-20070405-C01096
    Figure US20070078146A1-20070405-C01097
         		57 498 499
    B-0273
    Figure US20070078146A1-20070405-C01098
    Figure US20070078146A1-20070405-C01099
         		100 440 441
    B-0274
    Figure US20070078146A1-20070405-C01100
    Figure US20070078146A1-20070405-C01101
         		94 397 398
    B-0275
    Figure US20070078146A1-20070405-C01102
    Figure US20070078146A1-20070405-C01103
         		90 422 423
    B-0276
    Figure US20070078146A1-20070405-C01104
    Figure US20070078146A1-20070405-C01105
         		100 408 409
    B-0277
    Figure US20070078146A1-20070405-C01106
    Figure US20070078146A1-20070405-C01107
         		88 408 409
    B-0278
    Figure US20070078146A1-20070405-C01108
    Figure US20070078146A1-20070405-C01109
         		100 426 427
    B-0279
    Figure US20070078146A1-20070405-C01110
    Figure US20070078146A1-20070405-C01111
         		54 440 441
    B-0280
    Figure US20070078146A1-20070405-C01112
    Figure US20070078146A1-20070405-C01113
         		79 414 415
    B-0281
    Figure US20070078146A1-20070405-C01114
    Figure US20070078146A1-20070405-C01115
         		82 458 459
    B-0282
    Figure US20070078146A1-20070405-C01116
    Figure US20070078146A1-20070405-C01117
         		89 426 427
    B-0283
    Figure US20070078146A1-20070405-C01118
    Figure US20070078146A1-20070405-C01119
         		90 458 459
    B-0284
    Figure US20070078146A1-20070405-C01120
    Figure US20070078146A1-20070405-C01121
         		100 458 459
    B-0285
    Figure US20070078146A1-20070405-C01122
    Figure US20070078146A1-20070405-C01123
         		94 458 459
    B-0286
    Figure US20070078146A1-20070405-C01124
    Figure US20070078146A1-20070405-C01125
         		100 458 459
    B-0287
    Figure US20070078146A1-20070405-C01126
    Figure US20070078146A1-20070405-C01127
         		96 458 459
    B-0288
    Figure US20070078146A1-20070405-C01128
    Figure US20070078146A1-20070405-C01129
         		100 458 459
    B-0289
    Figure US20070078146A1-20070405-C01130
    Figure US20070078146A1-20070405-C01131
         		96 406 407
    B-0290
    Figure US20070078146A1-20070405-C01132
    Figure US20070078146A1-20070405-C01133
         		96 386 387
    B-0291
    Figure US20070078146A1-20070405-C01134
    Figure US20070078146A1-20070405-C01135
         		95 440 441
    B-0292
    Figure US20070078146A1-20070405-C01136
    Figure US20070078146A1-20070405-C01137
         		94 390 391
    B-0293
    Figure US20070078146A1-20070405-C01138
    Figure US20070078146A1-20070405-C01139
         		100 408 409
    B-0294
    Figure US20070078146A1-20070405-C01140
    Figure US20070078146A1-20070405-C01141
         		100 440 441
    B-0295
    Figure US20070078146A1-20070405-C01142
    Figure US20070078146A1-20070405-C01143
         		91 408 409
    B-0296
    Figure US20070078146A1-20070405-C01144
    Figure US20070078146A1-20070405-C01145
         		96 426 427
    B-0297
    Figure US20070078146A1-20070405-C01146
    Figure US20070078146A1-20070405-C01147
         		88 390 391
    B-0298
    Figure US20070078146A1-20070405-C01148
    Figure US20070078146A1-20070405-C01149
         		95 408 409
    B-0299
    Figure US20070078146A1-20070405-C01150
    Figure US20070078146A1-20070405-C01151
         		90 408 409
    B-0300
    Figure US20070078146A1-20070405-C01152
    Figure US20070078146A1-20070405-C01153
         		95 406 407
    B-0301
    Figure US20070078146A1-20070405-C01154
    Figure US20070078146A1-20070405-C01155
         		99 450 451, 453
    B-0302
    Figure US20070078146A1-20070405-C01156
    Figure US20070078146A1-20070405-C01157
         		94 440 441
    B-0303
    Figure US20070078146A1-20070405-C01158
    Figure US20070078146A1-20070405-C01159
         		100 378 379
    B-0304
    Figure US20070078146A1-20070405-C01160
    Figure US20070078146A1-20070405-C01161
         		100 391 392
    B-0305
    Figure US20070078146A1-20070405-C01162
    Figure US20070078146A1-20070405-C01163
         		70 326 327
    B-0306
    Figure US20070078146A1-20070405-C01164
    Figure US20070078146A1-20070405-C01165
         		59 340 341
    B-0307
    Figure US20070078146A1-20070405-C01166
    Figure US20070078146A1-20070405-C01167
         		59 354 355
    B-0308
    Figure US20070078146A1-20070405-C01168
    Figure US20070078146A1-20070405-C01169
         		60 368 369
    B-0309
    Figure US20070078146A1-20070405-C01170
    Figure US20070078146A1-20070405-C01171
         		61 352 353
    B-0310
    Figure US20070078146A1-20070405-C01172
    Figure US20070078146A1-20070405-C01173
         		61 366 367
    B-0311
    Figure US20070078146A1-20070405-C01174
    Figure US20070078146A1-20070405-C01175
         		65 356 357
    B-0322
    Figure US20070078146A1-20070405-C01176
    Figure US20070078146A1-20070405-C01177
         		64 474 475
    B-0323
    Figure US20070078146A1-20070405-C01178
    Figure US20070078146A1-20070405-C01179
         		58 474 475
    B-0324
    Figure US20070078146A1-20070405-C01180
    Figure US20070078146A1-20070405-C01181
         		60 422 423
    B-0325
    Figure US20070078146A1-20070405-C01182
    Figure US20070078146A1-20070405-C01183
         		64 422 423
    B-0326
    Figure US20070078146A1-20070405-C01184
    Figure US20070078146A1-20070405-C01185
         		58 422 423
    B-0327
    Figure US20070078146A1-20070405-C01186
    Figure US20070078146A1-20070405-C01187
         		63 378 379
    B-0328
    Figure US20070078146A1-20070405-C01188
    Figure US20070078146A1-20070405-C01189
         		68 389 390
    B-0329
    Figure US20070078146A1-20070405-C01190
    Figure US20070078146A1-20070405-C01191
         		63 362 363
    B-0330
    Figure US20070078146A1-20070405-C01192
    Figure US20070078146A1-20070405-C01193
         		48 376 377
    B-0331
    Figure US20070078146A1-20070405-C01194
    Figure US20070078146A1-20070405-C01195
         		66 424 425
    B-0332
    Figure US20070078146A1-20070405-C01196
    Figure US20070078146A1-20070405-C01197
         		61 442 443
    B-0333
    Figure US20070078146A1-20070405-C01198
    Figure US20070078146A1-20070405-C01199
         		60 458 459
    B-0334
    Figure US20070078146A1-20070405-C01200
    Figure US20070078146A1-20070405-C01201
         		55 502 503
    B-0335
    Figure US20070078146A1-20070405-C01202
    Figure US20070078146A1-20070405-C01203
         		60 454 455
    B-0336
    Figure US20070078146A1-20070405-C01204
    Figure US20070078146A1-20070405-C01205
         		100 500 501
    B-0337
    Figure US20070078146A1-20070405-C01206
    Figure US20070078146A1-20070405-C01207
         		65 458 —
    B-0338
    Figure US20070078146A1-20070405-C01208
    Figure US20070078146A1-20070405-C01209
         		69 502 503
    B-0339
    Figure US20070078146A1-20070405-C01210
    Figure US20070078146A1-20070405-C01211
         		68 454 —
    B-0340
    Figure US20070078146A1-20070405-C01212
    Figure US20070078146A1-20070405-C01213
         		77 492 493
    B-0341
    Figure US20070078146A1-20070405-C01214
    Figure US20070078146A1-20070405-C01215
         		64 458 459
    B-0342
    Figure US20070078146A1-20070405-C01216
    Figure US20070078146A1-20070405-C01217
         		41 438 —
    B-0343
    Figure US20070078146A1-20070405-C01218
    Figure US20070078146A1-20070405-C01219
         		63 430 431
    B-0344
    Figure US20070078146A1-20070405-C01220
    Figure US20070078146A1-20070405-C01221
         		96 464 465
    B-0345
    Figure US20070078146A1-20070405-C01222
    Figure US20070078146A1-20070405-C01223
         		62 507 508
    B-0346
    Figure US20070078146A1-20070405-C01224
    Figure US20070078146A1-20070405-C01225
         		56 497 498
    B-0347
    Figure US20070078146A1-20070405-C01226
    Figure US20070078146A1-20070405-C01227
         		61 341 342
    B-0348
    Figure US20070078146A1-20070405-C01228
    Figure US20070078146A1-20070405-C01229
         		3 367 —
    B-0349
    Figure US20070078146A1-20070405-C01230
    Figure US20070078146A1-20070405-C01231
         		57 403 404
    B-0350
    Figure US20070078146A1-20070405-C01232
    Figure US20070078146A1-20070405-C01233
         		57 481 482
    B-0351
    Figure US20070078146A1-20070405-C01234
    Figure US20070078146A1-20070405-C01235
         		31 355 356
    B-0352
    Figure US20070078146A1-20070405-C01236
    Figure US20070078146A1-20070405-C01237
         		51 397 398
    Figure US20070078146A1-20070405-C01238
    Calcd. Observed
    % Mass Spec
    Example# R2 RJ Yield Spec (M + H)
    B-0353
    Figure US20070078146A1-20070405-C01239
    Figure US20070078146A1-20070405-C01240
         		71 382 383
    B-0354
    Figure US20070078146A1-20070405-C01241
    Figure US20070078146A1-20070405-C01242
         		35 512 513
    B-0355
    Figure US20070078146A1-20070405-C01243
    Figure US20070078146A1-20070405-C01244
         		37 352 353
    B-0356
    Figure US20070078146A1-20070405-C01245
    Figure US20070078146A1-20070405-C01246
         		57 404 405
    B-0357
    Figure US20070078146A1-20070405-C01247
    Figure US20070078146A1-20070405-C01248
         		88 366 367
    B-0358
    Figure US20070078146A1-20070405-C01249
    Figure US20070078146A1-20070405-C01250
         		88 410 411
    B-0359
    Figure US20070078146A1-20070405-C01251
    Figure US20070078146A1-20070405-C01252
         		100 324 325
    B-0360
    Figure US20070078146A1-20070405-C01253
    Figure US20070078146A1-20070405-C01254
         		56 364 365
    B-0361
    Figure US20070078146A1-20070405-C01255
    Figure US20070078146A1-20070405-C01256
         		70 350 351
    B-0362
    Figure US20070078146A1-20070405-C01257
    Figure US20070078146A1-20070405-C01258
         		100 464 465
    B-0363
    Figure US20070078146A1-20070405-C01259
    Figure US20070078146A1-20070405-C01260
         		73 512 513
    B-0364
    Figure US20070078146A1-20070405-C01261
    Figure US20070078146A1-20070405-C01262
         		88 377 378
    B-0365
    Figure US20070078146A1-20070405-C01263
    Figure US20070078146A1-20070405-C01264
         		70 396 397
    B-0366
    Figure US20070078146A1-20070405-C01265
    Figure US20070078146A1-20070405-C01266
         		100 354 355
    B-0367
    Figure US20070078146A1-20070405-C01267
    Figure US20070078146A1-20070405-C01268
         		71 416 417
    B-0368
    Figure US20070078146A1-20070405-C01269
    Figure US20070078146A1-20070405-C01270
         		100 354 355
    B-0369
    Figure US20070078146A1-20070405-C01271
    Figure US20070078146A1-20070405-C01272
         		40 440 441
    B-0370
    Figure US20070078146A1-20070405-C01273
    Figure US20070078146A1-20070405-C01274
         		94 364 365
    B-0371
    Figure US20070078146A1-20070405-C01275
    Figure US20070078146A1-20070405-C01276
         		88 460 461
    B-0372
    Figure US20070078146A1-20070405-C01277
    Figure US20070078146A1-20070405-C01278
         		69 430 431
    B-0373
    Figure US20070078146A1-20070405-C01279
    Figure US20070078146A1-20070405-C01280
         		100 430 431
    B-0374
    Figure US20070078146A1-20070405-C01281
    Figure US20070078146A1-20070405-C01282
         		75 400 401
    B-0375
    Figure US20070078146A1-20070405-C01283
    Figure US20070078146A1-20070405-C01284
         		74 386 387
    B-0376
    Figure US20070078146A1-20070405-C01285
    Figure US20070078146A1-20070405-C01286
         		53 378 379
    B-0377
    Figure US20070078146A1-20070405-C01287
    Figure US20070078146A1-20070405-C01288
         		71 387 388
    B-0378
    Figure US20070078146A1-20070405-C01289
    Figure US20070078146A1-20070405-C01290
         		69 387 388
    B-0379
    Figure US20070078146A1-20070405-C01291
    Figure US20070078146A1-20070405-C01292
         		66 387 388
    B-0380
    Figure US20070078146A1-20070405-C01293
    Figure US20070078146A1-20070405-C01294
         		85 416 417
    B-0381
    Figure US20070078146A1-20070405-C01295
    Figure US20070078146A1-20070405-C01296
         		93 430 431
    B-0382
    Figure US20070078146A1-20070405-C01297
    Figure US20070078146A1-20070405-C01298
         		84 382 383
    B-0383
    Figure US20070078146A1-20070405-C01299
    Figure US20070078146A1-20070405-C01300
         		74 583 584
    B-0384
    Figure US20070078146A1-20070405-C01301
    Figure US20070078146A1-20070405-C01302
         		63 438 439
    B-0392
    Figure US20070078146A1-20070405-C01303
    Figure US20070078146A1-20070405-C01304
         		100 440 441
    B-0393
    Figure US20070078146A1-20070405-C01305
    Figure US20070078146A1-20070405-C01306
         		75 388 389
    B-0394
    Figure US20070078146A1-20070405-C01307
    Figure US20070078146A1-20070405-C01308
         		92 402 403
    B-0395
    Figure US20070078146A1-20070405-C01309
    Figure US20070078146A1-20070405-C01310
         		87 374 375
    B-0396
    Figure US20070078146A1-20070405-C01311
    Figure US20070078146A1-20070405-C01312
         		86 360 361
    B-0397
    Figure US20070078146A1-20070405-C01313
    Figure US20070078146A1-20070405-C01314
         		81 452 453
    B-0398
    Figure US20070078146A1-20070405-C01315
    Figure US20070078146A1-20070405-C01316
         		88 428 429
    B-0399
    Figure US20070078146A1-20070405-C01317
    Figure US20070078146A1-20070405-C01318
         		99 436 437
    B-0400
    Figure US20070078146A1-20070405-C01319
    Figure US20070078146A1-20070405-C01320
         		82 482 483
    B-0401
    Figure US20070078146A1-20070405-C01321
    Figure US20070078146A1-20070405-C01322
         		94 367 368
    B-0402
    Figure US20070078146A1-20070405-C01323
    Figure US20070078146A1-20070405-C01324
         		73 325 326
    B-0403
    Figure US20070078146A1-20070405-C01325
    Figure US20070078146A1-20070405-C01326
         		91 415 416
    B-0404
    Figure US20070078146A1-20070405-C01327
    Figure US20070078146A1-20070405-C01328
         		41 379 380
    B-0405
    Figure US20070078146A1-20070405-C01329
    Figure US20070078146A1-20070405-C01330
         		88 395 396
    B-0406
    Figure US20070078146A1-20070405-C01331
    Figure US20070078146A1-20070405-C01332
         		100 419 420
    B-0407
    Figure US20070078146A1-20070405-C01333
    Figure US20070078146A1-20070405-C01334
         		52 353 354
    B-0408
    Figure US20070078146A1-20070405-C01335
    Figure US20070078146A1-20070405-C01336
         		83 339 340
    B-0409
    Figure US20070078146A1-20070405-C01337
    Figure US20070078146A1-20070405-C01338
         		74 415 416
    B-0410
    Figure US20070078146A1-20070405-C01339
    Figure US20070078146A1-20070405-C01340
         		100 419 420
    B-0411
    Figure US20070078146A1-20070405-C01341
    Figure US20070078146A1-20070405-C01342
         		94 429 430
    B-0412
    Figure US20070078146A1-20070405-C01343
    Figure US20070078146A1-20070405-C01344
         		91 365 366
    B-0413
    Figure US20070078146A1-20070405-C01345
    Figure US20070078146A1-20070405-C01346
         		79 367 368
    B-0414
    Figure US20070078146A1-20070405-C01347
    Figure US20070078146A1-20070405-C01348
         		85 429 430
    B-0415
    Figure US20070078146A1-20070405-C01349
    Figure US20070078146A1-20070405-C01350
         		82 401 402
    B-0416
    Figure US20070078146A1-20070405-C01351
    Figure US20070078146A1-20070405-C01352
         		93 429 430
    B-0417
    Figure US20070078146A1-20070405-C01353
    Figure US20070078146A1-20070405-C01354
         		97 429 430
    B-0418
    Figure US20070078146A1-20070405-C01355
    Figure US20070078146A1-20070405-C01356
         		100 419 420
    B-0419
    Figure US20070078146A1-20070405-C01357
    Figure US20070078146A1-20070405-C01358
         		100 431 432
    B-0420
    Figure US20070078146A1-20070405-C01359
    Figure US20070078146A1-20070405-C01360
         		36 381 382
    B-0421
    Figure US20070078146A1-20070405-C01361
    Figure US20070078146A1-20070405-C01362
         		96 353 354
    B-0422
    Figure US20070078146A1-20070405-C01363
    Figure US20070078146A1-20070405-C01364
         		100 461 462
    B-0423
    Figure US20070078146A1-20070405-C01365
    Figure US20070078146A1-20070405-C01366
         		100 408 407
    B-0424
    Figure US20070078146A1-20070405-C01367
    Figure US20070078146A1-20070405-C01368
         		76 366 367
    B-0425
    Figure US20070078146A1-20070405-C01369
    Figure US20070078146A1-20070405-C01370
         		21 368 369
    B-0426
    Figure US20070078146A1-20070405-C01371
    Figure US20070078146A1-20070405-C01372
         		100 354 344
    B-0427
    Figure US20070078146A1-20070405-C01373
    Figure US20070078146A1-20070405-C01374
         		100 379 380
    B-0428
    Figure US20070078146A1-20070405-C01375
    Figure US20070078146A1-20070405-C01376
         		100 379 380
    B-0429
    Figure US20070078146A1-20070405-C01377
    Figure US20070078146A1-20070405-C01378
         		86 368 369
    B-0430
    Figure US20070078146A1-20070405-C01379
    Figure US20070078146A1-20070405-C01380
         		51 500 501
    B-0431
    Figure US20070078146A1-20070405-C01381
    Figure US20070078146A1-20070405-C01382
         		76 479 480
    B-0432
    Figure US20070078146A1-20070405-C01383
    Figure US20070078146A1-20070405-C01384
         		90 500 501
    B-0433
    Figure US20070078146A1-20070405-C01385
    Figure US20070078146A1-20070405-C01386
         		96 456 457
    B-0434
    Figure US20070078146A1-20070405-C01387
    Figure US20070078146A1-20070405-C01388
         		75 496 497
    B-0435
    Figure US20070078146A1-20070405-C01389
    Figure US20070078146A1-20070405-C01390
         		52 496 497
    B-0436
    Figure US20070078146A1-20070405-C01391
    Figure US20070078146A1-20070405-C01392
         		73 506
    B-0437
    Figure US20070078146A1-20070405-C01393
    Figure US20070078146A1-20070405-C01394
         		19 466
    B-0438
    Figure US20070078146A1-20070405-C01395
    Figure US20070078146A1-20070405-C01396
         		100 490 491
    B-0439
    Figure US20070078146A1-20070405-C01397
    Figure US20070078146A1-20070405-C01398
         		67 464 465
    B-0440
    Figure US20070078146A1-20070405-C01399
    Figure US20070078146A1-20070405-C01400
         		96 472 473
    B-0441
    Figure US20070078146A1-20070405-C01401
    Figure US20070078146A1-20070405-C01402
         		87 472 473
    B-0442
    Figure US20070078146A1-20070405-C01403
    Figure US20070078146A1-20070405-C01404
         		72 481 482
    B-0443
    Figure US20070078146A1-20070405-C01405
    Figure US20070078146A1-20070405-C01406
         		66 473 474
    B-0444
    Figure US20070078146A1-20070405-C01407
    Figure US20070078146A1-20070405-C01408
         		80 515 516
    B-0445
    Figure US20070078146A1-20070405-C01409
    Figure US20070078146A1-20070405-C01410
         		94 490 491
    B-0446
    Figure US20070078146A1-20070405-C01411
    Figure US20070078146A1-20070405-C01412
         		84 464 465
    B-0447
    Figure US20070078146A1-20070405-C01413
    Figure US20070078146A1-20070405-C01414
         		89 470 471
    B-0448
    Figure US20070078146A1-20070405-C01415
    Figure US20070078146A1-20070405-C01416
         		100 490 491
    B-0449
    Figure US20070078146A1-20070405-C01417
    Figure US20070078146A1-20070405-C01418
         		100 474 475
    B-0450
    Figure US20070078146A1-20070405-C01419
    Figure US20070078146A1-20070405-C01420
         		100 447 445
    B-0451
    Figure US20070078146A1-20070405-C01421
    Figure US20070078146A1-20070405-C01422
         		100 454 455
    B-0452
    Figure US20070078146A1-20070405-C01423
    Figure US20070078146A1-20070405-C01424
         		95 495 497
    B-0453
    Figure US20070078146A1-20070405-C01425
    Figure US20070078146A1-20070405-C01426
         		100 490 491
    B-0454
    Figure US20070078146A1-20070405-C01427
    Figure US20070078146A1-20070405-C01428
         		100 500 501
    B-0455
    Figure US20070078146A1-20070405-C01429
    Figure US20070078146A1-20070405-C01430
         		96 500 501
    B-0456
    Figure US20070078146A1-20070405-C01431
    Figure US20070078146A1-20070405-C01432
         		89 494 495
  • Calcd. Observed
    % Mass Spec
    Example# R2 RJ Yield Spec (M + H)
    B-0457
    Figure US20070078146A1-20070405-C01433
    Figure US20070078146A1-20070405-C01434
         		93 482 483
    B-0458
    Figure US20070078146A1-20070405-C01435
    Figure US20070078146A1-20070405-C01436
         		100 490 491
    B-0459
    Figure US20070078146A1-20070405-C01437
    Figure US20070078146A1-20070405-C01438
         		100 490 491
    B-0460
    Figure US20070078146A1-20070405-C01439
    Figure US20070078146A1-20070405-C01440
         		93 450 451
    B-0461
    Figure US20070078146A1-20070405-C01441
    Figure US20070078146A1-20070405-C01442
         		84 452 453
    B-0462
    Figure US20070078146A1-20070405-C01443
    Figure US20070078146A1-20070405-C01444
         		96 456 457
    B-0463
    Figure US20070078146A1-20070405-C01445
    Figure US20070078146A1-20070405-C01446
         		66 456 457
    B-0464
    Figure US20070078146A1-20070405-C01447
    Figure US20070078146A1-20070405-C01448
         		69 490 491
    B-0465
    Figure US20070078146A1-20070405-C01449
    Figure US20070078146A1-20070405-C01450
         		86 490 491
    B-0466
    Figure US20070078146A1-20070405-C01451
    Figure US20070078146A1-20070405-C01452
         		78 474 475
    B-0467
    Figure US20070078146A1-20070405-C01453
    Figure US20070078146A1-20070405-C01454
         		78 470 471
    B-0468
    Figure US20070078146A1-20070405-C01455
    Figure US20070078146A1-20070405-C01456
         		91 450 451
    B-0469
    Figure US20070078146A1-20070405-C01457
    Figure US20070078146A1-20070405-C01458
         		85 436 437
    B-0470
    Figure US20070078146A1-20070405-C01459
    Figure US20070078146A1-20070405-C01460
         		99 466 467
    B-0471
    Figure US20070078146A1-20070405-C01461
    Figure US20070078146A1-20070405-C01462
         		100 490 491
    B-0472
    Figure US20070078146A1-20070405-C01463
    Figure US20070078146A1-20070405-C01464
         		37 482 483
    B-0473
    Figure US20070078146A1-20070405-C01465
    Figure US20070078146A1-20070405-C01466
         		92 462 463
    B-0474
    Figure US20070078146A1-20070405-C01467
    Figure US20070078146A1-20070405-C01468
         		99 530 532
    B-0475
    Figure US20070078146A1-20070405-C01469
    Figure US20070078146A1-20070405-C01470
         		55 472 473
    B-0476
    Figure US20070078146A1-20070405-C01471
    Figure US20070078146A1-20070405-C01472
         		89 441 442
    B-0477
    Figure US20070078146A1-20070405-C01473
    Figure US20070078146A1-20070405-C01474
         		79 464 465
    B-0478
    Figure US20070078146A1-20070405-C01475
    Figure US20070078146A1-20070405-C01476
         		92 486 487
    B-0479
    Figure US20070078146A1-20070405-C01477
    Figure US20070078146A1-20070405-C01478
         		97 447 448
    B-0480
    Figure US20070078146A1-20070405-C01479
    Figure US20070078146A1-20070405-C01480
         		75 561 562
    B-0481
    Figure US20070078146A1-20070405-C01481
    Figure US20070078146A1-20070405-C01482
         		74 498 499
    B-0482
    Figure US20070078146A1-20070405-C01483
    Figure US20070078146A1-20070405-C01484
         		57 548 549
    B-0483
    Figure US20070078146A1-20070405-C01485
    Figure US20070078146A1-20070405-C01486
         		83 505 506
    B-0484
    Figure US20070078146A1-20070405-C01487
    Figure US20070078146A1-20070405-C01488
         		100 568 569
    B-0485
    Figure US20070078146A1-20070405-C01489
    Figure US20070078146A1-20070405-C01490
         		100 495 496
    B-0486
    Figure US20070078146A1-20070405-C01491
    Figure US20070078146A1-20070405-C01492
         		100 426 427
    B-0487
    Figure US20070078146A1-20070405-C01493
    Figure US20070078146A1-20070405-C01494
         		32 389 390
    B-0488
    Figure US20070078146A1-20070405-C01495
    Figure US20070078146A1-20070405-C01496
         		100 588 569
    B-0489
    Figure US20070078146A1-20070405-C01497
    Figure US20070078146A1-20070405-C01498
         		91 500 501
    B-0490
    Figure US20070078146A1-20070405-C01499
    Figure US20070078146A1-20070405-C01500
         		40 473 474
    B-0491
    Figure US20070078146A1-20070405-C01501
    Figure US20070078146A1-20070405-C01502
         		73 514 515
    B-0492
    Figure US20070078146A1-20070405-C01503
    Figure US20070078146A1-20070405-C01504
         		89 400 401
    B-0493
    Figure US20070078146A1-20070405-C01505
    Figure US20070078146A1-20070405-C01506
         		100 420 421
    B-0494
    Figure US20070078146A1-20070405-C01507
    Figure US20070078146A1-20070405-C01508
         		100 400 401
    B-0495
    Figure US20070078146A1-20070405-C01509
    Figure US20070078146A1-20070405-C01510
         		100 454 455
    B-0496
    Figure US20070078146A1-20070405-C01511
    Figure US20070078146A1-20070405-C01512
         		100 442 443
    B-0497
    Figure US20070078146A1-20070405-C01513
    Figure US20070078146A1-20070405-C01514
         		50 512 513
    B-0498
    Figure US20070078146A1-20070405-C01515
    Figure US20070078146A1-20070405-C01516
         		100 454 455
    B-0499
    Figure US20070078146A1-20070405-C01517
    Figure US20070078146A1-20070405-C01518
         		98 411 412
    B-0500
    Figure US20070078146A1-20070405-C01519
    Figure US20070078146A1-20070405-C01520
         		100 436 437
    B-0501
    Figure US20070078146A1-20070405-C01521
    Figure US20070078146A1-20070405-C01522
         		100 422 423
    B-0502
    Figure US20070078146A1-20070405-C01523
    Figure US20070078146A1-20070405-C01524
         		100 422 423
    B-0503
    Figure US20070078146A1-20070405-C01525
    Figure US20070078146A1-20070405-C01526
         		92 440 441
    B-0504
    Figure US20070078146A1-20070405-C01527
    Figure US20070078146A1-20070405-C01528
         		67 454 455
    B-0505
    Figure US20070078146A1-20070405-C01529
    Figure US20070078146A1-20070405-C01530
         		68 428 429
    B-0506
    Figure US20070078146A1-20070405-C01531
    Figure US20070078146A1-20070405-C01532
         		98 472 473
    B-0507
    Figure US20070078146A1-20070405-C01533
    Figure US20070078146A1-20070405-C01534
         		82 440 441
    B-0508
    Figure US20070078146A1-20070405-C01535
    Figure US20070078146A1-20070405-C01536
         		99 472 473
    B-0509
    Figure US20070078146A1-20070405-C01537
    Figure US20070078146A1-20070405-C01538
         		100 472 473
    B-0510
    Figure US20070078146A1-20070405-C01539
    Figure US20070078146A1-20070405-C01540
         		96 472 473
    B-0511
    Figure US20070078146A1-20070405-C01541
    Figure US20070078146A1-20070405-C01542
         		100 472 473
    B-0512
    Figure US20070078146A1-20070405-C01543
    Figure US20070078146A1-20070405-C01544
         		100 472 473
    B-0513
    Figure US20070078146A1-20070405-C01545
    Figure US20070078146A1-20070405-C01546
         		100 472 473
    B-0514
    Figure US20070078146A1-20070405-C01547
    Figure US20070078146A1-20070405-C01548
         		100 420 421
    B-0515
    Figure US20070078146A1-20070405-C01549
    Figure US20070078146A1-20070405-C01550
         		100 400 401
    B-0516
    Figure US20070078146A1-20070405-C01551
    Figure US20070078146A1-20070405-C01552
         		100 454 455
    B-0517
    Figure US20070078146A1-20070405-C01553
    Figure US20070078146A1-20070405-C01554
         		100 404 405
    B-0518
    Figure US20070078146A1-20070405-C01555
    Figure US20070078146A1-20070405-C01556
         		99 422 423
    B-0519
    Figure US20070078146A1-20070405-C01557
    Figure US20070078146A1-20070405-C01558
         		100 454 455
    B-0520
    Figure US20070078146A1-20070405-C01559
    Figure US20070078146A1-20070405-C01560
         		98 422 423
    B-0521
    Figure US20070078146A1-20070405-C01561
    Figure US20070078146A1-20070405-C01562
         		99 440 441
    B-0522
    Figure US20070078146A1-20070405-C01563
    Figure US20070078146A1-20070405-C01564
         		88 404 405
    B-0523
    Figure US20070078146A1-20070405-C01565
    Figure US20070078146A1-20070405-C01566
         		100 422 423
    B-0524
    Figure US20070078146A1-20070405-C01567
    Figure US20070078146A1-20070405-C01568
         		100 422 423
    B-0525
    Figure US20070078146A1-20070405-C01569
    Figure US20070078146A1-20070405-C01570
         		100 420 421
    B-0526
    Figure US20070078146A1-20070405-C01571
    Figure US20070078146A1-20070405-C01572
         		100 464 465
    B-0527
    Figure US20070078146A1-20070405-C01573
    Figure US20070078146A1-20070405-C01574
         		100 454 455
    B-0528
    Figure US20070078146A1-20070405-C01575
    Figure US20070078146A1-20070405-C01576
         		100 392 393
    B-0529
    Figure US20070078146A1-20070405-C01577
    Figure US20070078146A1-20070405-C01578
         		94 405 406
    Figure US20070078146A1-20070405-C01579
    Calcd. Observed
    % Mass Spec
    Example# R2 RJ Yield Spec (M + H)
    B-0530
    Figure US20070078146A1-20070405-C01580
    Figure US20070078146A1-20070405-C01581
         		67 382 383
    B-0531
    Figure US20070078146A1-20070405-C01582
    Figure US20070078146A1-20070405-C01583
         		66 512 513
    B-0532
    Figure US20070078146A1-20070405-C01584
    Figure US20070078146A1-20070405-C01585
         		37 352 353
    B-0533
    Figure US20070078146A1-20070405-C01586
    Figure US20070078146A1-20070405-C01587
         		56 404 405
    B-0534
    Figure US20070078146A1-20070405-C01588
    Figure US20070078146A1-20070405-C01589
         		100 366 367
    B-0535
    Figure US20070078146A1-20070405-C01590
    Figure US20070078146A1-20070405-C01591
         		100 410 411
    B-0536
    Figure US20070078146A1-20070405-C01592
    Figure US20070078146A1-20070405-C01593
         		41 324 325
    B-0537
    Figure US20070078146A1-20070405-C01594
    Figure US20070078146A1-20070405-C01595
         		100 364 365
    B-0538
    Figure US20070078146A1-20070405-C01596
    Figure US20070078146A1-20070405-C01597
         		29 350 351
    B-0539
    Figure US20070078146A1-20070405-C01598
    Figure US20070078146A1-20070405-C01599
         		70 464 465
    B-0540
    Figure US20070078146A1-20070405-C01600
    Figure US20070078146A1-20070405-C01601
         		50 512 513
    B-0541
    Figure US20070078146A1-20070405-C01602
    Figure US20070078146A1-20070405-C01603
         		61 377 378
    B-0542
    Figure US20070078146A1-20070405-C01604
    Figure US20070078146A1-20070405-C01605
         		61 396 397
    B-0543
    Figure US20070078146A1-20070405-C01606
    Figure US20070078146A1-20070405-C01607
         		59 354 355
    B-0544
    Figure US20070078146A1-20070405-C01608
    Figure US20070078146A1-20070405-C01609
         		45 416 417
    B-0545
    Figure US20070078146A1-20070405-C01610
    Figure US20070078146A1-20070405-C01611
         		100 454 455
    B-0546
    Figure US20070078146A1-20070405-C01612
    Figure US20070078146A1-20070405-C01613
         		44 440 441
    B-0547
    Figure US20070078146A1-20070405-C01614
    Figure US20070078146A1-20070405-C01615
         		64 364 365
    B-0548
    Figure US20070078146A1-20070405-C01616
    Figure US20070078146A1-20070405-C01617
         		89 460 461
    B-0549
    Figure US20070078146A1-20070405-C01618
    Figure US20070078146A1-20070405-C01619
         		100 430 431
    B-0550
    Figure US20070078146A1-20070405-C01620
    Figure US20070078146A1-20070405-C01621
         		100 4.30 431
    B-0551
    Figure US20070078146A1-20070405-C01622
    Figure US20070078146A1-20070405-C01623
         		81 400 401
    B-0552
    Figure US20070078146A1-20070405-C01624
    Figure US20070078146A1-20070405-C01625
         		38 386 387
    B-0553
    Figure US20070078146A1-20070405-C01626
    Figure US20070078146A1-20070405-C01627
         		31 378 379
    B-0554
    Figure US20070078146A1-20070405-C01628
    Figure US20070078146A1-20070405-C01629
         		100 387 388
    B-0555
    Figure US20070078146A1-20070405-C01630
    Figure US20070078146A1-20070405-C01631
         		66 387 388
    B-0556
    Figure US20070078146A1-20070405-C01632
    Figure US20070078146A1-20070405-C01633
         		32 387 388
    B-0557
    Figure US20070078146A1-20070405-C01634
    Figure US20070078146A1-20070405-C01635
         		70 416 417
    B-0558
    Figure US20070078146A1-20070405-C01636
    Figure US20070078146A1-20070405-C01637
         		57 430 431
    B-0559
    Figure US20070078146A1-20070405-C01638
    Figure US20070078146A1-20070405-C01639
         		74 382 383
    B-0560
    Figure US20070078146A1-20070405-C01640
    Figure US20070078146A1-20070405-C01641
         		36 583 584
    B-0561
    Figure US20070078146A1-20070405-C01642
    Figure US20070078146A1-20070405-C01643
         		51 438 439
    B-0562
    Figure US20070078146A1-20070405-C01644
    Figure US20070078146A1-20070405-C01645
         		88 440 441
    B-0563
    Figure US20070078146A1-20070405-C01646
    Figure US20070078146A1-20070405-C01647
         		68 422 423
    B-0564
    Figure US20070078146A1-20070405-C01648
    Figure US20070078146A1-20070405-C01649
         		47 388 389
    B-0565
    Figure US20070078146A1-20070405-C01650
    Figure US20070078146A1-20070405-C01651
         		100 448 449
    B-0566
    Figure US20070078146A1-20070405-C01652
    Figure US20070078146A1-20070405-C01653
         		76 436 437
    B-0567
    Figure US20070078146A1-20070405-C01654
    Figure US20070078146A1-20070405-C01655
         		99 458 459
    B-0568
    Figure US20070078146A1-20070405-C01656
    Figure US20070078146A1-20070405-C01657
         		45 414 415
    B-0569
    Figure US20070078146A1-20070405-C01658
    Figure US20070078146A1-20070405-C01659
         		88 440 441
    B-0570
    Figure US20070078146A1-20070405-C01660
    Figure US20070078146A1-20070405-C01661
         		61 388 389
    B-0571
    Figure US20070078146A1-20070405-C01662
    Figure US20070078146A1-20070405-C01663
         		58 402 403
    B-0572
    Figure US20070078146A1-20070405-C01664
    Figure US20070078146A1-20070405-C01665
         		75 374 375
    B-0573
    Figure US20070078146A1-20070405-C01666
    Figure US20070078146A1-20070405-C01667
         		72 360 361
    B-0574
    Figure US20070078146A1-20070405-C01668
    Figure US20070078146A1-20070405-C01669
         		97 452 453
    B-0575
    Figure US20070078146A1-20070405-C01670
    Figure US20070078146A1-20070405-C01671
         		71 428 429
    B-0576
    Figure US20070078146A1-20070405-C01672
    Figure US20070078146A1-20070405-C01673
         		88 436 437
    B-0577
    Figure US20070078146A1-20070405-C01674
    Figure US20070078146A1-20070405-C01675
         		72 482 483
    B-0578
    Figure US20070078146A1-20070405-C01676
    Figure US20070078146A1-20070405-C01677
         		89 367 388
    B-0579
    Figure US20070078146A1-20070405-C01678
    Figure US20070078146A1-20070405-C01679
         		100 325 326
    B-0580
    Figure US20070078146A1-20070405-C01680
    Figure US20070078146A1-20070405-C01681
         		75 415 416
    B-0581
    Figure US20070078146A1-20070405-C01682
    Figure US20070078146A1-20070405-C01683
         		44 379 380
    B-0582
    Figure US20070078146A1-20070405-C01684
    Figure US20070078146A1-20070405-C01685
         		75 395 396
    B-0583
    Figure US20070078146A1-20070405-C01686
    Figure US20070078146A1-20070405-C01687
         		80 419 420
    B-0584
    Figure US20070078146A1-20070405-C01688
    Figure US20070078146A1-20070405-C01689
         		57 353 354
    B-0585
    Figure US20070078146A1-20070405-C01690
    Figure US20070078146A1-20070405-C01691
         		83 339 340
    B-0586
    Figure US20070078146A1-20070405-C01692
    Figure US20070078146A1-20070405-C01693
         		71 415 416
    B-0587
    Figure US20070078146A1-20070405-C01694
    Figure US20070078146A1-20070405-C01695
         		100 419 420
    B-0588
    Figure US20070078146A1-20070405-C01696
    Figure US20070078146A1-20070405-C01697
         		94 429 430
    B-0589
    Figure US20070078146A1-20070405-C01698
    Figure US20070078146A1-20070405-C01699
         		78 365 386
    B-0590
    Figure US20070078146A1-20070405-C01700
    Figure US20070078146A1-20070405-C01701
         		82 367 368
    B-0591
    Figure US20070078146A1-20070405-C01702
    Figure US20070078146A1-20070405-C01703
         		72 429 430
    B-0592
    Figure US20070078146A1-20070405-C01704
    Figure US20070078146A1-20070405-C01705
         		82 401 402
    B-0593
    Figure US20070078146A1-20070405-C01706
    Figure US20070078146A1-20070405-C01707
         		88 429 430
    B-0594
    Figure US20070078146A1-20070405-C01708
    Figure US20070078146A1-20070405-C01709
         		100 429 430
    B-0595
    Figure US20070078146A1-20070405-C01710
    Figure US20070078146A1-20070405-C01711
         		99 419 420
    B-596
    Figure US20070078146A1-20070405-C01712
    Figure US20070078146A1-20070405-C01713
         		93 431 432
    B-597
    Figure US20070078146A1-20070405-C01714
    Figure US20070078146A1-20070405-C01715
         		40 381 382
    B-0598
    Figure US20070078146A1-20070405-C01716
    Figure US20070078146A1-20070405-C01717
         		93 353 354
    B-0599
    Figure US20070078146A1-20070405-C01718
    Figure US20070078146A1-20070405-C01719
         		100 461 462
    B-0600
    Figure US20070078146A1-20070405-C01720
    Figure US20070078146A1-20070405-C01721
         		98 406 407
    B-0601
    Figure US20070078146A1-20070405-C01722
    Figure US20070078146A1-20070405-C01723
         		66 366 367
    B-0602
    Figure US20070078146A1-20070405-C01724
    Figure US20070078146A1-20070405-C01725
         		25 368 369
    B-0603
    Figure US20070078146A1-20070405-C01726
    Figure US20070078146A1-20070405-C01727
         		90 354 355
    B-0604
    Figure US20070078146A1-20070405-C01728
    Figure US20070078146A1-20070405-C01729
         		86 379 380
    B-0605
    Figure US20070078146A1-20070405-C01730
    Figure US20070078146A1-20070405-C01731
         		87 379 380
    B-0606
    Figure US20070078146A1-20070405-C01732
    Figure US20070078146A1-20070405-C01733
         		72 368 369
    B-0607
    Figure US20070078146A1-20070405-C01734
    Figure US20070078146A1-20070405-C01735
         		34 500 501
    B-0608
    Figure US20070078146A1-20070405-C01736
    Figure US20070078146A1-20070405-C01737
         		100 479 480
    B-0609
    Figure US20070078146A1-20070405-C01738
    Figure US20070078146A1-20070405-C01739
         		82 500 501
    B-0610
    Figure US20070078146A1-20070405-C01740
    Figure US20070078146A1-20070405-C01741
         		100 456 457
    B-0611
    Figure US20070078146A1-20070405-C01742
    Figure US20070078146A1-20070405-C01743
         		76 496 497
    B-0612
    Figure US20070078146A1-20070405-C01744
    Figure US20070078146A1-20070405-C01745
         		69 496 497
    B-0613
    Figure US20070078146A1-20070405-C01746
    Figure US20070078146A1-20070405-C01747
         		61 506
    B-0614
    Figure US20070078146A1-20070405-C01748
    Figure US20070078146A1-20070405-C01749
         		18 466
    B-0615
    Figure US20070078146A1-20070405-C01750
    Figure US20070078146A1-20070405-C01751
         		100 490 491
    B-0616
    Figure US20070078146A1-20070405-C01752
    Figure US20070078146A1-20070405-C01753
         		77 464 465
    B-0617
    Figure US20070078146A1-20070405-C01754
    Figure US20070078146A1-20070405-C01755
         		93 472 473
    B-0618
    Figure US20070078146A1-20070405-C01756
    Figure US20070078146A1-20070405-C01757
         		84 472 473
    B-0619
    Figure US20070078146A1-20070405-C01758
    Figure US20070078146A1-20070405-C01759
         		71 481 482
    B-0620
    Figure US20070078146A1-20070405-C01760
    Figure US20070078146A1-20070405-C01761
         		89 473 474
    B-0621
    Figure US20070078146A1-20070405-C01762
    Figure US20070078146A1-20070405-C01763
         		68 515 516
    B-0622
    Figure US20070078146A1-20070405-C01764
    Figure US20070078146A1-20070405-C01765
         		70 490 491
    B-0623
    Figure US20070078146A1-20070405-C01766
    Figure US20070078146A1-20070405-C01767
         		92 464 465
    B-0624
    Figure US20070078146A1-20070405-C01768
    Figure US20070078146A1-20070405-C01769
         		98 470 471
    B-0625
    Figure US20070078146A1-20070405-C01770
    Figure US20070078146A1-20070405-C01771
         		96 490 491
    B-0626
    Figure US20070078146A1-20070405-C01772
    Figure US20070078146A1-20070405-C01773
         		100 474 475
    B-0627
    Figure US20070078146A1-20070405-C01774
    Figure US20070078146A1-20070405-C01775
         		100 447 448
    B-0628
    Figure US20070078146A1-20070405-C01776
    Figure US20070078146A1-20070405-C01777
         		64 454 455
    B-0629
    Figure US20070078146A1-20070405-C01778
    Figure US20070078146A1-20070405-C01779
         		100 496 497
    B-0630
    Figure US20070078146A1-20070405-C01780
    Figure US20070078146A1-20070405-C01781
         		85 490 491
    B-0631
    Figure US20070078146A1-20070405-C01782
    Figure US20070078146A1-20070405-C01783
         		75 500 501
    B-0632
    Figure US20070078146A1-20070405-C01784
    Figure US20070078146A1-20070405-C01785
         		83 500 501
    B-0633
    Figure US20070078146A1-20070405-C01786
    Figure US20070078146A1-20070405-C01787
         		58 494 495
    B-0634
    Figure US20070078146A1-20070405-C01788
    Figure US20070078146A1-20070405-C01789
         		63 482 483
    B-0635
    Figure US20070078146A1-20070405-C01790
    Figure US20070078146A1-20070405-C01791
         		95 490 491
    B-0636
    Figure US20070078146A1-20070405-C01792
    Figure US20070078146A1-20070405-C01793
         		100 490 491
    B-0637
    Figure US20070078146A1-20070405-C01794
    Figure US20070078146A1-20070405-C01795
         		91 450 451
    B-0638
    Figure US20070078146A1-20070405-C01796
    Figure US20070078146A1-20070405-C01797
         		96 436 437
    B-0639
    Figure US20070078146A1-20070405-C01798
    Figure US20070078146A1-20070405-C01799
         		100 456 457
    B-0640
    Figure US20070078146A1-20070405-C01800
    Figure US20070078146A1-20070405-C01801
         		100 456 457
    B-0641
    Figure US20070078146A1-20070405-C01802
    Figure US20070078146A1-20070405-C01803
         		88 490 491
    B-0642
    Figure US20070078146A1-20070405-C01804
    Figure US20070078146A1-20070405-C01805
         		99 490 491
    B-0643
    Figure US20070078146A1-20070405-C01806
    Figure US20070078146A1-20070405-C01807
         		92 474 475
    B-0644
    Figure US20070078146A1-20070405-C01808
    Figure US20070078146A1-20070405-C01809
         		100 470 471
    B-0645
    Figure US20070078146A1-20070405-C01810
    Figure US20070078146A1-20070405-C01811
         		92 450 451
    B-0646
    Figure US20070078146A1-20070405-C01812
    Figure US20070078146A1-20070405-C01813
         		100 436 437
    B-0647
    Figure US20070078146A1-20070405-C01814
    Figure US20070078146A1-20070405-C01815
         		90 466 467
    B-0648
    Figure US20070078146A1-20070405-C01816
    Figure US20070078146A1-20070405-C01817
         		94 490 491
    B-0649
    Figure US20070078146A1-20070405-C01818
    Figure US20070078146A1-20070405-C01819
         		57 482
    B-0650
    Figure US20070078146A1-20070405-C01820
    Figure US20070078146A1-20070405-C01821
         		82 462 463
    B-0651
    Figure US20070078146A1-20070405-C01822
    Figure US20070078146A1-20070405-C01823
         		100 530 531
    B-0652
    Figure US20070078146A1-20070405-C01824
    Figure US20070078146A1-20070405-C01825
         		53 472
    B-0653
    Figure US20070078146A1-20070405-C01826
    Figure US20070078146A1-20070405-C01827
         		84 441 442
    B-0654
    Figure US20070078146A1-20070405-C01828
    Figure US20070078146A1-20070405-C01829
         		92 464 465
    B-0655
    Figure US20070078146A1-20070405-C01830
    Figure US20070078146A1-20070405-C01831
         		100 486 487
    B-0656
    Figure US20070078146A1-20070405-C01832
    Figure US20070078146A1-20070405-C01833
         		98 447 448
    B-0657
    Figure US20070078146A1-20070405-C01834
    Figure US20070078146A1-20070405-C01835
         		85 561 562
    B-0658
    Figure US20070078146A1-20070405-C01836
    Figure US20070078146A1-20070405-C01837
         		92 498 499
    B-0659
    Figure US20070078146A1-20070405-C01838
    Figure US20070078146A1-20070405-C01839
         		46 548 549
    B-0660
    Figure US20070078146A1-20070405-C01840
    Figure US20070078146A1-20070405-C01841
         		80 505 506
    B-0661
    Figure US20070078146A1-20070405-C01842
    Figure US20070078146A1-20070405-C01843
         		100 568 569
    B-0662
    Figure US20070078146A1-20070405-C01844
    Figure US20070078146A1-20070405-C01845
         		98 495 496
    B-0663
    Figure US20070078146A1-20070405-C01846
    Figure US20070078146A1-20070405-C01847
         		74 426 427
    B-0664
    Figure US20070078146A1-20070405-C01848
    Figure US20070078146A1-20070405-C01849
         		30 389 390
    B-0665
    Figure US20070078146A1-20070405-C01850
    Figure US20070078146A1-20070405-C01851
         		100 568 569
    B-0666
    Figure US20070078146A1-20070405-C01852
    Figure US20070078146A1-20070405-C01853
         		93 500 501
    B-0667
    Figure US20070078146A1-20070405-C01854
    Figure US20070078146A1-20070405-C01855
         		54 473 474
    B-0668
    Figure US20070078146A1-20070405-C01856
    Figure US20070078146A1-20070405-C01857
         		66 514 515
    B-0669
    Figure US20070078146A1-20070405-C01858
    Figure US20070078146A1-20070405-C01859
         		65 400 401
    B-0670
    Figure US20070078146A1-20070405-C01860
    Figure US20070078146A1-20070405-C01861
         		45 420 421
    B-0671
    Figure US20070078146A1-20070405-C01862
    Figure US20070078146A1-20070405-C01863
         		43 400 401
    B-0672
    Figure US20070078146A1-20070405-C01864
    Figure US20070078146A1-20070405-C01865
         		45 454 455
    B-0673
    Figure US20070078146A1-20070405-C01866
    Figure US20070078146A1-20070405-C01867
         		41 442 443
    B-0674
    Figure US20070078146A1-20070405-C01868
    Figure US20070078146A1-20070405-C01869
         		16 512 513
    B-0675
    Figure US20070078146A1-20070405-C01870
    Figure US20070078146A1-20070405-C01871
         		39 454 455
    B-0676
    Figure US20070078146A1-20070405-C01872
    Figure US20070078146A1-20070405-C01873
         		34 411 412
    B-0677
    Figure US20070078146A1-20070405-C01874
    Figure US20070078146A1-20070405-C01875
         		46 436 437
    B-0678
    Figure US20070078146A1-20070405-C01876
    Figure US20070078146A1-20070405-C01877
         		37 422 423
    B-0679
    Figure US20070078146A1-20070405-C01878
    Figure US20070078146A1-20070405-C01879
         		34 422 423
    B-0680
    Figure US20070078146A1-20070405-C01880
    Figure US20070078146A1-20070405-C01881
         		60 440 441
    B-0681
    Figure US20070078146A1-20070405-C01882
    Figure US20070078146A1-20070405-C01883
         		31 454 455
    B-0682
    Figure US20070078146A1-20070405-C01884
    Figure US20070078146A1-20070405-C01885
         		37 428 429
    B-0683
    Figure US20070078146A1-20070405-C01886
    Figure US20070078146A1-20070405-C01887
         		46 472 473
    B-0684
    Figure US20070078146A1-20070405-C01888
    Figure US20070078146A1-20070405-C01889
         		50 440 441
    B-0685
    Figure US20070078146A1-20070405-C01890
    Figure US20070078146A1-20070405-C01891
         		44 472 473
    B-0686
    Figure US20070078146A1-20070405-C01892
    Figure US20070078146A1-20070405-C01893
         		66 472 473
    B-0687
    Figure US20070078146A1-20070405-C01894
    Figure US20070078146A1-20070405-C01895
         		57 472 473
    B-0688
    Figure US20070078146A1-20070405-C01896
    Figure US20070078146A1-20070405-C01897
         		52 472 473
    B-0689
    Figure US20070078146A1-20070405-C01898
    Figure US20070078146A1-20070405-C01899
         		42 472 473
    B-0690
    Figure US20070078146A1-20070405-C01900
    Figure US20070078146A1-20070405-C01901
         		34 472 473
    B-0691
    Figure US20070078146A1-20070405-C01902
    Figure US20070078146A1-20070405-C01903
         		52 420 421
    B-0692
    Figure US20070078146A1-20070405-C01904
    Figure US20070078146A1-20070405-C01905
         		41 400 401
    B-0693
    Figure US20070078146A1-20070405-C01906
    Figure US20070078146A1-20070405-C01907
         		56 454 455
    B-0694
    Figure US20070078146A1-20070405-C01908
    Figure US20070078146A1-20070405-C01909
         		38 404 405
    B-0695
    Figure US20070078146A1-20070405-C01910
    Figure US20070078146A1-20070405-C01911
         		43 422 423
    B-0696
    Figure US20070078146A1-20070405-C01912
    Figure US20070078146A1-20070405-C01913
         		57 454 455
    B-0697
    Figure US20070078146A1-20070405-C01914
    Figure US20070078146A1-20070405-C01915
         		51 422 423
    B-0698
    Figure US20070078146A1-20070405-C01916
    Figure US20070078146A1-20070405-C01917
         		59 440 441
    B-0699
    Figure US20070078146A1-20070405-C01918
    Figure US20070078146A1-20070405-C01919
         		46 404 405
    B-0700
    Figure US20070078146A1-20070405-C01920
    Figure US20070078146A1-20070405-C01921
         		47 422 423
    B-0701
    Figure US20070078146A1-20070405-C01922
    Figure US20070078146A1-20070405-C01923
         		46 422 423
    B-0702
    Figure US20070078146A1-20070405-C01924
    Figure US20070078146A1-20070405-C01925
         		43 420 421
    B-0703
    Figure US20070078146A1-20070405-C01926
    Figure US20070078146A1-20070405-C01927
         		57 464 465
    B-0704
    Figure US20070078146A1-20070405-C01928
    Figure US20070078146A1-20070405-C01929
         		44 454 455
    B-0705
    Figure US20070078146A1-20070405-C01930
    Figure US20070078146A1-20070405-C01931
         		33 392 393
    B-0706
    Figure US20070078146A1-20070405-C01932
    Figure US20070078146A1-20070405-C01933
         		35 405 406
    Figure US20070078146A1-20070405-C01934
    Calcd. Observed
    % Mass Spec
    Example# R2 RJ Yield Spec (M + H)
    B-0707
    Figure US20070078146A1-20070405-C01935
    Figure US20070078146A1-20070405-C01936
         		76 516 517
    B-0708
    Figure US20070078146A1-20070405-C01937
    Figure US20070078146A1-20070405-C01938
         		61 498 499
    B-0709
    Figure US20070078146A1-20070405-C01939
    Figure US20070078146A1-20070405-C01940
         		37 464 465
    B-0710
    Figure US20070078146A1-20070405-C01941
    Figure US20070078146A1-20070405-C01942
         		76 524 525
    B-0711
    Figure US20070078146A1-20070405-C01943
    Figure US20070078146A1-20070405-C01944
         		75 512 513
    B-0712
    Figure US20070078146A1-20070405-C01945
    Figure US20070078146A1-20070405-C01946
         		91 534 535
    B-0713
    Figure US20070078146A1-20070405-C01947
    Figure US20070078146A1-20070405-C01948
         		42 490 491
    B-0714
    Figure US20070078146A1-20070405-C01949
    Figure US20070078146A1-20070405-C01950
         		87 516 517
    B-0715
    Figure US20070078146A1-20070405-C01951
    Figure US20070078146A1-20070405-C01952
         		60 464 465
    B-0716
    Figure US20070078146A1-20070405-C01953
    Figure US20070078146A1-20070405-C01954
         		59 478 479
    B-0717
    Figure US20070078146A1-20070405-C01955
    Figure US20070078146A1-20070405-C01956
         		61 450 451
    B-0718
    Figure US20070078146A1-20070405-C01957
    Figure US20070078146A1-20070405-C01958
         		65 436 437
    B-0719
    Figure US20070078146A1-20070405-C01959
    Figure US20070078146A1-20070405-C01960
         		84 528 529
    B-0720
    Figure US20070078146A1-20070405-C01961
    Figure US20070078146A1-20070405-C01962
         		69 504 505
    B-0721
    Figure US20070078146A1-20070405-C01963
    Figure US20070078146A1-20070405-C01964
         		63 512 513
    B-0722
    Figure US20070078146A1-20070405-C01965
    Figure US20070078146A1-20070405-C01966
         		88 558 559
    B-0723
    Figure US20070078146A1-20070405-C01967
    Figure US20070078146A1-20070405-C01968
         		68 443 444
    B-0724
    Figure US20070078146A1-20070405-C01969
    Figure US20070078146A1-20070405-C01970
         		75 401 402
    B-0725
    Figure US20070078146A1-20070405-C01971
    Figure US20070078146A1-20070405-C01972
         		83 491 492
    B-0726
    Figure US20070078146A1-20070405-C01973
    Figure US20070078146A1-20070405-C01974
         		24 455 456
    B-0727
    Figure US20070078146A1-20070405-C01975
    Figure US20070078146A1-20070405-C01976
         		67 471 472
    B-0728
    Figure US20070078146A1-20070405-C01977
    Figure US20070078146A1-20070405-C01978
         		89 495 496
    B-0729
    Figure US20070078146A1-20070405-C01979
    Figure US20070078146A1-20070405-C01980
         		38 429 430
    B-0730
    Figure US20070078146A1-20070405-C01981
    Figure US20070078146A1-20070405-C01982
         		76 415 416
    B-0731
    Figure US20070078146A1-20070405-C01983
    Figure US20070078146A1-20070405-C01984
         		60 491 492
    B-0732
    Figure US20070078146A1-20070405-C01985
    Figure US20070078146A1-20070405-C01986
         		86 495 496
    B-0733
    Figure US20070078146A1-20070405-C01987
    Figure US20070078146A1-20070405-C01988
         		81 505 506
    B-0734
    Figure US20070078146A1-20070405-C01989
    Figure US20070078146A1-20070405-C01990
         		87 441 442
    B-0735
    Figure US20070078146A1-20070405-C01991
    Figure US20070078146A1-20070405-C01992
         		83 443 444
    B-0736
    Figure US20070078146A1-20070405-C01993
    Figure US20070078146A1-20070405-C01994
         		91 505 506
    B-0737
    Figure US20070078146A1-20070405-C01995
    Figure US20070078146A1-20070405-C01996
         		9 477 —
    B-0738
    Figure US20070078146A1-20070405-C01997
    Figure US20070078146A1-20070405-C01998
         		87 505 506
    B-0739
    Figure US20070078146A1-20070405-C01999
    Figure US20070078146A1-20070405-C02000
         		82 505 506
    B-0740
    Figure US20070078146A1-20070405-C02001
    Figure US20070078146A1-20070405-C02002
         		85 495 496
    B-0741
    Figure US20070078146A1-20070405-C02003
    Figure US20070078146A1-20070405-C02004
         		68 507 508
    B-0742
    Figure US20070078146A1-20070405-C02005
    Figure US20070078146A1-20070405-C02006
         		14 457 —
    B-0743
    Figure US20070078146A1-20070405-C02007
    Figure US20070078146A1-20070405-C02008
         		77 429 430
    B-0744
    Figure US20070078146A1-20070405-C02009
    Figure US20070078146A1-20070405-C02010
         		88 537 538
    B-0745
    Figure US20070078146A1-20070405-C02011
    Figure US20070078146A1-20070405-C02012
         		82 482 483
    B-0746
    Figure US20070078146A1-20070405-C02013
    Figure US20070078146A1-20070405-C02014
         		74 442 443
    B-0747
    Figure US20070078146A1-20070405-C02015
    Figure US20070078146A1-20070405-C02016
         		83 444 445
    B-0748
    Figure US20070078146A1-20070405-C02017
    Figure US20070078146A1-20070405-C02018
         		94 430 431
    B-0749
    Figure US20070078146A1-20070405-C02019
    Figure US20070078146A1-20070405-C02020
         		100 455 456
    B-0750
    Figure US20070078146A1-20070405-C02021
    Figure US20070078146A1-20070405-C02022
         		100 455 456
    B-0751
    Figure US20070078146A1-20070405-C02023
    Figure US20070078146A1-20070405-C02024
         		48 444 445
    B-0752
    Figure US20070078146A1-20070405-C02025
    Figure US20070078146A1-20070405-C02026
         		84 516 517
    B-0753
    Figure US20070078146A1-20070405-C02027
    Figure US20070078146A1-20070405-C02028
         		67 498 499
    B-0754
    Figure US20070078146A1-20070405-C02029
    Figure US20070078146A1-20070405-C02030
         		31 464 465
    B-0755
    Figure US20070078146A1-20070405-C02031
    Figure US20070078146A1-20070405-C02032
         		85 524 525
    B-0756
    Figure US20070078146A1-20070405-C02033
    Figure US20070078146A1-20070405-C02034
         		77 512 513
    B-0757
    Figure US20070078146A1-20070405-C02035
    Figure US20070078146A1-20070405-C02036
         		57 534 535
    B-0758
    Figure US20070078146A1-20070405-C02037
    Figure US20070078146A1-20070405-C02038
         		36 490 491
    B-0759
    Figure US20070078146A1-20070405-C02039
    Figure US20070078146A1-20070405-C02040
         		79 516 517
    B-0760
    Figure US20070078146A1-20070405-C02041
    Figure US20070078146A1-20070405-C02042
         		53 464 465
    B-0761
    Figure US20070078146A1-20070405-C02043
    Figure US20070078146A1-20070405-C02044
         		50 478 479
    B-0762
    Figure US20070078146A1-20070405-C02045
    Figure US20070078146A1-20070405-C02046
         		60 450 451
    B-0763
    Figure US20070078146A1-20070405-C02047
    Figure US20070078146A1-20070405-C02048
         		75 436 437
    B-0764
    Figure US20070078146A1-20070405-C02049
    Figure US20070078146A1-20070405-C02050
         		43 528 529
    B-0765
    Figure US20070078146A1-20070405-C02051
    Figure US20070078146A1-20070405-C02052
         		75 504 505
    B-0766
    Figure US20070078146A1-20070405-C02053
    Figure US20070078146A1-20070405-C02054
         		67 512 513
    B-0767
    Figure US20070078146A1-20070405-C02055
    Figure US20070078146A1-20070405-C02056
         		43 558 559
    B-0768
    Figure US20070078146A1-20070405-C02057
    Figure US20070078146A1-20070405-C02058
         		78 443 444
    B-0769
    Figure US20070078146A1-20070405-C02059
    Figure US20070078146A1-20070405-C02060
         		76 401 402
    B-0770
    Figure US20070078146A1-20070405-C02061
    Figure US20070078146A1-20070405-C02062
         		57 491 492
    B-0771
    Figure US20070078146A1-20070405-C02063
    Figure US20070078146A1-20070405-C02064
         		14 455 456
    B-0772
    Figure US20070078146A1-20070405-C02065
    Figure US20070078146A1-20070405-C02066
         		72 471 472
    B-0773
    Figure US20070078146A1-20070405-C02067
    Figure US20070078146A1-20070405-C02068
         		100 495 496
    B-0774
    Figure US20070078146A1-20070405-C02069
    Figure US20070078146A1-20070405-C02070
         		41 429 430
    B-0775
    Figure US20070078146A1-20070405-C02071
    Figure US20070078146A1-20070405-C02072
         		91 415 416
    B-0776
    Figure US20070078146A1-20070405-C02073
    Figure US20070078146A1-20070405-C02074
         		64 491 492
    B-0777
    Figure US20070078146A1-20070405-C02075
    Figure US20070078146A1-20070405-C02076
         		90 495 496
    B-0778
    Figure US20070078146A1-20070405-C02077
    Figure US20070078146A1-20070405-C02078
         		19 505 506
    B-0779
    Figure US20070078146A1-20070405-C02079
    Figure US20070078146A1-20070405-C02080
         		79 441 442
    B-0780
    Figure US20070078146A1-20070405-C02081
    Figure US20070078146A1-20070405-C02082
         		40 443 444
    B-0781
    Figure US20070078146A1-20070405-C02083
    Figure US20070078146A1-20070405-C02084
         		93 505 506
    B-0782
    Figure US20070078146A1-20070405-C02085
    Figure US20070078146A1-20070405-C02086
         		57 477 478
    B-0783
    Figure US20070078146A1-20070405-C02087
    Figure US20070078146A1-20070405-C02088
         		99 505 506
    B-0784
    Figure US20070078146A1-20070405-C02089
    Figure US20070078146A1-20070405-C02090
         		100 505 506
    B-0786
    Figure US20070078146A1-20070405-C02091
    Figure US20070078146A1-20070405-C02092
         		91 507 508
    B-0787
    Figure US20070078146A1-20070405-C02093
    Figure US20070078146A1-20070405-C02094
         		15 457 458
    B-0788
    Figure US20070078146A1-20070405-C02095
    Figure US20070078146A1-20070405-C02096
         		48 429 430
    B-0789
    Figure US20070078146A1-20070405-C02097
    Figure US20070078146A1-20070405-C02098
         		91 537 538
    B-0790
    Figure US20070078146A1-20070405-C02099
    Figure US20070078146A1-20070405-C02100
         		93 482 483
    B-0791
    Figure US20070078146A1-20070405-C02101
    Figure US20070078146A1-20070405-C02102
         		76 442 443
    B-0792
    Figure US20070078146A1-20070405-C02103
    Figure US20070078146A1-20070405-C02104
         		96 444 445
    B-0793
    Figure US20070078146A1-20070405-C02105
    Figure US20070078146A1-20070405-C02106
         		54 430 431
    B-0794
    Figure US20070078146A1-20070405-C02107
    Figure US20070078146A1-20070405-C02108
         		100 455 456
    B-0795
    Figure US20070078146A1-20070405-C02109
    Figure US20070078146A1-20070405-C02110
         		100 455 456
    B-0796
    Figure US20070078146A1-20070405-C02111
    Figure US20070078146A1-20070405-C02112
         		94 444 445
    B-0797
    Figure US20070078146A1-20070405-C02113
    Figure US20070078146A1-20070405-C02114
         		90 458 459
    B-0799
    Figure US20070078146A1-20070405-C02115
    Figure US20070078146A1-20070405-C02116
         		82 428 429
    B-0800
    Figure US20070078146A1-20070405-C02117
    Figure US20070078146A1-20070405-C02118
         		92 480 481
    B-0801
    Figure US20070078146A1-20070405-C02119
    Figure US20070078146A1-20070405-C02120
         		82 442 443
    B-0802
    Figure US20070078146A1-20070405-C02121
    Figure US20070078146A1-20070405-C02122
         		95 486 487
    B-0803
    Figure US20070078146A1-20070405-C02123
    Figure US20070078146A1-20070405-C02124
         		89 400 401
    B-0804
    Figure US20070078146A1-20070405-C02125
    Figure US20070078146A1-20070405-C02126
         		87 440 441
    B-0805
    Figure US20070078146A1-20070405-C02127
    Figure US20070078146A1-20070405-C02128
         		100 426 427
    B-0806
    Figure US20070078146A1-20070405-C02129
    Figure US20070078146A1-20070405-C02130
         		99 540 541
    B-0807
    Figure US20070078146A1-20070405-C02131
    Figure US20070078146A1-20070405-C02132
         		96 588 559
    B-0808
    Figure US20070078146A1-20070405-C02133
    Figure US20070078146A1-20070405-C02134
         		82 453 454
    B-0809
    Figure US20070078146A1-20070405-C02135
    Figure US20070078146A1-20070405-C02136
         		92 472 473
    B-0810
    Figure US20070078146A1-20070405-C02137
    Figure US20070078146A1-20070405-C02138
         		98 430 431
    B-0811
    Figure US20070078146A1-20070405-C02139
    Figure US20070078146A1-20070405-C02140
         		88 492 493
    B-0812
    Figure US20070078146A1-20070405-C02141
    Figure US20070078146A1-20070405-C02142
         		81 530 531
    B-0813
    Figure US20070078146A1-20070405-C02143
    Figure US20070078146A1-20070405-C02144
         		98 516 517
    B-0814
    Figure US20070078146A1-20070405-C02145
    Figure US20070078146A1-20070405-C02146
         		100 440 441
    B-0815
    Figure US20070078146A1-20070405-C02147
    Figure US20070078146A1-20070405-C02148
         		100 536 537
    B-0816
    Figure US20070078146A1-20070405-C02149
    Figure US20070078146A1-20070405-C02150
         		99 506 507
    B-0817
    Figure US20070078146A1-20070405-C02151
    Figure US20070078146A1-20070405-C02152
         		98 506 507
    B-0818
    Figure US20070078146A1-20070405-C02153
    Figure US20070078146A1-20070405-C02154
         		86 476 477
    B-0819
    Figure US20070078146A1-20070405-C02155
    Figure US20070078146A1-20070405-C02156
         		90 462 463
    B-0820
    Figure US20070078146A1-20070405-C02157
    Figure US20070078146A1-20070405-C02158
         		91 454 455
    B-0821
    Figure US20070078146A1-20070405-C02159
    Figure US20070078146A1-20070405-C02160
         		69 463 464
    B-0822
    Figure US20070078146A1-20070405-C02161
    Figure US20070078146A1-20070405-C02162
         		79 463 464
    B-0823
    Figure US20070078146A1-20070405-C02163
    Figure US20070078146A1-20070405-C02164
         		79 463 464
    B-0824
    Figure US20070078146A1-20070405-C02165
    Figure US20070078146A1-20070405-C02166
         		82 492 493
    B-0825
    Figure US20070078146A1-20070405-C02167
    Figure US20070078146A1-20070405-C02168
         		100 506 507
    B-0826
    Figure US20070078146A1-20070405-C02169
    Figure US20070078146A1-20070405-C02170
         		97 458 459
    B-0827
    Figure US20070078146A1-20070405-C02171
    Figure US20070078146A1-20070405-C02172
         		100 659 660
    B-0828
    Figure US20070078146A1-20070405-C02173
    Figure US20070078146A1-20070405-C02174
         		97 514 515
    B-0829
    Figure US20070078146A1-20070405-C02175
    Figure US20070078146A1-20070405-C02176
         		63 458 459
    B-830
    Figure US20070078146A1-20070405-C02177
    Figure US20070078146A1-20070405-C02178
         		70 588 589
    B-0831
    Figure US20070078146A1-20070405-C02179
    Figure US20070078146A1-20070405-C02180
         		100 428 429
    B-0832
    Figure US20070078146A1-20070405-C02181
    Figure US20070078146A1-20070405-C02182
         		81 480 481
    B-0833
    Figure US20070078146A1-20070405-C02183
    Figure US20070078146A1-20070405-C02184
         		73 442 443
    B-0834
    Figure US20070078146A1-20070405-C02185
    Figure US20070078146A1-20070405-C02186
         		79 486 487
    B-0835
    Figure US20070078146A1-20070405-C02187
    Figure US20070078146A1-20070405-C02188
         		5 400 401
    B-0836
    Figure US20070078146A1-20070405-C02189
    Figure US20070078146A1-20070405-C02190
         		28 440 441
    B-0837
    Figure US20070078146A1-20070405-C02191
    Figure US20070078146A1-20070405-C02192
         		81 426 427
    B-0838
    Figure US20070078146A1-20070405-C02193
    Figure US20070078146A1-20070405-C02194
         		84 540 541
    B-0839
    Figure US20070078146A1-20070405-C02195
    Figure US20070078146A1-20070405-C02196
         		80 588 589
    B-0840
    Figure US20070078146A1-20070405-C02197
    Figure US20070078146A1-20070405-C02198
         		71 453 454
    B-0841
    Figure US20070078146A1-20070405-C02199
    Figure US20070078146A1-20070405-C02200
         		55 472 473
    B-0842
    Figure US20070078146A1-20070405-C02201
    Figure US20070078146A1-20070405-C02202
         		71 430 431
    B-0843
    Figure US20070078146A1-20070405-C02203
    Figure US20070078146A1-20070405-C02204
         		68 492 493
    B-0844
    Figure US20070078146A1-20070405-C02205
    Figure US20070078146A1-20070405-C02206
         		61 530 531
    B-0845
    Figure US20070078146A1-20070405-C02207
    Figure US20070078146A1-20070405-C02208
         		84 516 517
    B-0846
    Figure US20070078146A1-20070405-C02209
    Figure US20070078146A1-20070405-C02210
         		87 440 441
    B-0847
    Figure US20070078146A1-20070405-C02211
    Figure US20070078146A1-20070405-C02212
         		86 536 537
    B-0848
    Figure US20070078146A1-20070405-C02213
    Figure US20070078146A1-20070405-C02214
         		79 506 507
    B-0849
    Figure US20070078146A1-20070405-C02215
    Figure US20070078146A1-20070405-C02216
         		81 506 507
    B-0850
    Figure US20070078146A1-20070405-C02217
    Figure US20070078146A1-20070405-C02218
         		69 476 477
    B-0851
    Figure US20070078146A1-20070405-C02219
    Figure US20070078146A1-20070405-C02220
         		83 462 463
    B-0852
    Figure US20070078146A1-20070405-C02221
    Figure US20070078146A1-20070405-C02222
         		77 454 455
    B-0853
    Figure US20070078146A1-20070405-C02223
    Figure US20070078146A1-20070405-C02224
         		87 463 464
    B-0854
    Figure US20070078146A1-20070405-C02225
    Figure US20070078146A1-20070405-C02226
         		73 463 464
    B-0855
    Figure US20070078146A1-20070405-C02227
    Figure US20070078146A1-20070405-C02228
         		92 463 464
    B-0856
    Figure US20070078146A1-20070405-C02229
    Figure US20070078146A1-20070405-C02230
         		75 492 493
    B-0857
    Figure US20070078146A1-20070405-C02231
    Figure US20070078146A1-20070405-C02232
         		86 506 507
    B-0858
    Figure US20070078146A1-20070405-C02233
    Figure US20070078146A1-20070405-C02234
         		84 458 459
    B-0859
    Figure US20070078146A1-20070405-C02235
    Figure US20070078146A1-20070405-C02236
         		80 659 660
    B-0860
    Figure US20070078146A1-20070405-C02237
    Figure US20070078146A1-20070405-C02238
         		94 514 515
    Figure US20070078146A1-20070405-C02239
    Calcd. Observed
    % Mass Spec
    Example# R2 RJ Yield Spec (M + H)
    B-0861
    Figure US20070078146A1-20070405-C02240
    Figure US20070078146A1-20070405-C02241
         		84 583 584
    B-0862
    Figure US20070078146A1-20070405-C02242
    Figure US20070078146A1-20070405-C02243
         		96 475 476
    B-0863
    Figure US20070078146A1-20070405-C02244
    Figure US20070078146A1-20070405-C02245
         		69 423 424
    B-0864
    Figure US20070078146A1-20070405-C02246
    Figure US20070078146A1-20070405-C02247
         		86 437 438
    B-0865
    Figure US20070078146A1-20070405-C02248
    Figure US20070078146A1-20070405-C02249
         		62 395 —
    B-0866
    Figure US20070078146A1-20070405-C02250
    Figure US20070078146A1-20070405-C02251
         		81 421 422
    B-0867
    Figure US20070078146A1-20070405-C02252
    Figure US20070078146A1-20070405-C02253
         		100 535 536
  • Observed
    Calcd. Mass
    % Mass Spec
    Example# R2 RJ Yield Spec (M + H)
    B-0868
    Figure US20070078146A1-20070405-C02254
    Figure US20070078146A1-20070405-C02255
         		89 583 584
    B-0869
    Figure US20070078146A1-20070405-C02256
    Figure US20070078146A1-20070405-C02257
         		100 448 449
    B-0870
    Figure US20070078146A1-20070405-C02258
    Figure US20070078146A1-20070405-C02259
         		100 425 426
    B-0871
    Figure US20070078146A1-20070405-C02260
    Figure US20070078146A1-20070405-C02261
         		100 487 488
    B-0872
    Figure US20070078146A1-20070405-C02262
    Figure US20070078146A1-20070405-C02263
         		78 501 502
    B-0873
    Figure US20070078146A1-20070405-C02264
    Figure US20070078146A1-20070405-C02265
         		78 471 472
    B-0874
    Figure US20070078146A1-20070405-C02266
    Figure US20070078146A1-20070405-C02267
         		92 475 476
    B-0875
    Figure US20070078146A1-20070405-C02268
    Figure US20070078146A1-20070405-C02269
         		37 458 459
    B-0876
    Figure US20070078146A1-20070405-C02270
    Figure US20070078146A1-20070405-C02271
         		69 507 508
    B-0877
    Figure US20070078146A1-20070405-C02272
    Figure US20070078146A1-20070405-C02273
         		70 445 446
    B-0878
    Figure US20070078146A1-20070405-C02274
    Figure US20070078146A1-20070405-C02275
         		91 431 432
    B-0879
    Figure US20070078146A1-20070405-C02276
    Figure US20070078146A1-20070405-C02277
         		92 511 512
    B-0880
    Figure US20070078146A1-20070405-C02278
    Figure US20070078146A1-20070405-C02279
         		89 410 411
    B-0881
    Figure US20070078146A1-20070405-C02280
    Figure US20070078146A1-20070405-C02281
         		84 490 491
    B-0882
    Figure US20070078146A1-20070405-C02282
    Figure US20070078146A1-20070405-C02283
         		85 500 501
    B-0883
    Figure US20070078146A1-20070405-C02284
    Figure US20070078146A1-20070405-C02285
         		85 424 425
    B-0884
    Figure US20070078146A1-20070405-C02286
    Figure US20070078146A1-20070405-C02287
         		86 532 533
    Figure US20070078146A1-20070405-C02288
    Observed
    Calcd. Mass
    % Mass Spec
    Example# R2 RJ Yield Spec (M + H)
    B-0885
    Figure US20070078146A1-20070405-C02289
    Figure US20070078146A1-20070405-C02290
         		51 583 —
    B-0886
    Figure US20070078146A1-20070405-C02291
    Figure US20070078146A1-20070405-C02292
         		97 475 —
    B-0887
    Figure US20070078146A1-20070405-C02293
    Figure US20070078146A1-20070405-C02294
         		29 423 424
    B-0888
    Figure US20070078146A1-20070405-C02295
    Figure US20070078146A1-20070405-C02296
         		82 437 438
    B-0889
    Figure US20070078146A1-20070405-C02297
    Figure US20070078146A1-20070405-C02298
         		93 395 396
    B-0890
    Figure US20070078146A1-20070405-C02299
    Figure US20070078146A1-20070405-C02300
         		91 421 422
    B-0891
    Figure US20070078146A1-20070405-C02301
    Figure US20070078146A1-20070405-C02302
         		43 535 536
    B-0892
    Figure US20070078146A1-20070405-C02303
    Figure US20070078146A1-20070405-C02304
         		62 583 584
    B-0893
    Figure US20070078146A1-20070405-C02305
    Figure US20070078146A1-20070405-C02306
         		95 448 449
    B-0894
    Figure US20070078146A1-20070405-C02307
    Figure US20070078146A1-20070405-C02308
         		100 425 426
    B-0895
    Figure US20070078146A1-20070405-C02309
    Figure US20070078146A1-20070405-C02310
         		76 487 488
    B-0896
    Figure US20070078146A1-20070405-C02311
    Figure US20070078146A1-20070405-C02312
         		62 501 502
    B-0897
    Figure US20070078146A1-20070405-C02313
    Figure US20070078146A1-20070405-C02314
         		80 471 472
    B-0898
    Figure US20070078146A1-20070405-C02315
    Figure US20070078146A1-20070405-C02316
         		79 475 476
    B-0899
    Figure US20070078146A1-20070405-C02317
    Figure US20070078146A1-20070405-C02318
         		70 458 459
    B-0900
    Figure US20070078146A1-20070405-C02319
    Figure US20070078146A1-20070405-C02320
         		62 507 508
    B-0901
    Figure US20070078146A1-20070405-C02321
    Figure US20070078146A1-20070405-C02322
         		43 445 446
    B-0902
    Figure US20070078146A1-20070405-C02323
    Figure US20070078146A1-20070405-C02324
         		93 431 432
    B-0903
    Figure US20070078146A1-20070405-C02325
    Figure US20070078146A1-20070405-C02326
         		100 511 512
    B-0904
    Figure US20070078146A1-20070405-C02327
    Figure US20070078146A1-20070405-C02328
         		95 410 411
    B-0905
    Figure US20070078146A1-20070405-C02329
    Figure US20070078146A1-20070405-C02330
         		89 490 491
    B-0906
    Figure US20070078146A1-20070405-C02331
    Figure US20070078146A1-20070405-C02332
         		69 500 501
    B-0907
    Figure US20070078146A1-20070405-C02333
    Figure US20070078146A1-20070405-C02334
         		28 424 425
    B-0908
    Figure US20070078146A1-20070405-C02335
    Figure US20070078146A1-20070405-C02336
         		64 532 533
    Figure US20070078146A1-20070405-C02337
    Observed
    Calcd. Mass
    % Mass Spec
    Example# R2 RJ Yield Spec (M + H)
    B-0909
    Figure US20070078146A1-20070405-C02338
    Figure US20070078146A1-20070405-C02339
         		83 542 543
    B-0910
    Figure US20070078146A1-20070405-C02340
    Figure US20070078146A1-20070405-C02341
         		80 434 435
    B-0911
    Figure US20070078146A1-20070405-C02342
    Figure US20070078146A1-20070405-C02343
         		91 382 383
    B-0912
    Figure US20070078146A1-20070405-C02344
    Figure US20070078146A1-20070405-C02345
         		100 396 397
    B-0913
    Figure US20070078146A1-20070405-C02346
    Figure US20070078146A1-20070405-C02347
         		94 354 355
    B-0914
    Figure US20070078146A1-20070405-C02348
    Figure US20070078146A1-20070405-C02349
         		95 380 381
    B-0915
    Figure US20070078146A1-20070405-C02350
    Figure US20070078146A1-20070405-C02351
         		98 494 495
    B-0916
    Figure US20070078146A1-20070405-C02352
    Figure US20070078146A1-20070405-C02353
         		84 542 543
    B-0917
    Figure US20070078146A1-20070405-C02354
    Figure US20070078146A1-20070405-C02355
         		79 407 408
    B-0918
    Figure US20070078146A1-20070405-C02356
    Figure US20070078146A1-20070405-C02357
         		89 384 385
    B-0919
    Figure US20070078146A1-20070405-C02358
    Figure US20070078146A1-20070405-C02359
         		91 446 447
    B-0920
    Figure US20070078146A1-20070405-C02360
    Figure US20070078146A1-20070405-C02361
         		99 460 461
    B-0921
    Figure US20070078146A1-20070405-C02362
    Figure US20070078146A1-20070405-C02363
         		84 430 431
    B-0922
    Figure US20070078146A1-20070405-C02364
    Figure US20070078146A1-20070405-C02365
         		81 434 435
    B-0923
    Figure US20070078146A1-20070405-C02366
    Figure US20070078146A1-20070405-C02367
         		76 417 418
    B-0924
    Figure US20070078146A1-20070405-C02368
    Figure US20070078146A1-20070405-C02369
         		70 466 467
    B-0925
    Figure US20070078146A1-20070405-C02370
    Figure US20070078146A1-20070405-C02371
         		64 404 405
    B-0926
    Figure US20070078146A1-20070405-C02372
    Figure US20070078146A1-20070405-C02373
         		47 390 391
    B-0927
    Figure US20070078146A1-20070405-C02374
    Figure US20070078146A1-20070405-C02375
         		89 470 471
    B-0928
    Figure US20070078146A1-20070405-C02376
    Figure US20070078146A1-20070405-C02377
         		53 369 370
    B-0929
    Figure US20070078146A1-20070405-C02378
    Figure US20070078146A1-20070405-C02379
         		100 449 450
    B-0930
    Figure US20070078146A1-20070405-C02380
    Figure US20070078146A1-20070405-C02381
         		14 459 460
    B-0931
    Figure US20070078146A1-20070405-C02382
    Figure US20070078146A1-20070405-C02383
         		41 383 384
    B-0932
    Figure US20070078146A1-20070405-C02384
    Figure US20070078146A1-20070405-C02385
         		94 491 492
    Figure US20070078146A1-20070405-C02386
    Observed
    Calcd. Mass
    % Mass Spec
    Example# R2 RJ Yield Spec (M + H)
    B-0933
    Figure US20070078146A1-20070405-C02387
    Figure US20070078146A1-20070405-C02388
         		48 447 448
    B-0934
    Figure US20070078146A1-20070405-C02389
    Figure US20070078146A1-20070405-C02390
         		44 429 430
    B-0935
    Figure US20070078146A1-20070405-C02391
    Figure US20070078146A1-20070405-C02392
         		33 485 486
    B-0936
    Figure US20070078146A1-20070405-C02393
    Figure US20070078146A1-20070405-C02394
         		30 479 —
    B-0937
    Figure US20070078146A1-20070405-C02395
    Figure US20070078146A1-20070405-C02396
         		68 367 368
    B-0938
    Figure US20070078146A1-20070405-C02397
    Figure US20070078146A1-20070405-C02398
         		72 479 480
    B-0939
    Figure US20070078146A1-20070405-C02399
    Figure US20070078146A1-20070405-C02400
         		76 415 416
    B-0940
    Figure US20070078146A1-20070405-C02401
    Figure US20070078146A1-20070405-C02402
         		36 397 398
    B-0941
    Figure US20070078146A1-20070405-C02403
    Figure US20070078146A1-20070405-C02404
         		41 441 442
    B-0942
    Figure US20070078146A1-20070405-C02405
    Figure US20070078146A1-20070405-C02406
         		27 473 474
    B-0943
    Figure US20070078146A1-20070405-C02407
    Figure US20070078146A1-20070405-C02408
         		55 493 494
    B-0944
    Figure US20070078146A1-20070405-C02409
    Figure US20070078146A1-20070405-C02410
         		53 473 474
    B-0945
    Figure US20070078146A1-20070405-C02411
    Figure US20070078146A1-20070405-C02412
         		82 429 430
    B-0946
    Figure US20070078146A1-20070405-C02413
    Figure US20070078146A1-20070405-C02414
         		100 459 460
    B-0947
    Figure US20070078146A1-20070405-C02415
    Figure US20070078146A1-20070405-C02416
         		60 425 426
    B-0948
    Figure US20070078146A1-20070405-C02417
    Figure US20070078146A1-20070405-C02418
         		100 431 432
    B-0949
    Figure US20070078146A1-20070405-C02419
    Figure US20070078146A1-20070405-C02420
         		98 473 474
    B-0950
    Figure US20070078146A1-20070405-C02421
    Figure US20070078146A1-20070405-C02422
         		64 419 420
    B-0951
    Figure US20070078146A1-20070405-C02423
    Figure US20070078146A1-20070405-C02424
         		100 469 470
    B-0952
    Figure US20070078146A1-20070405-C02425
    Figure US20070078146A1-20070405-C02426
         		61 469 470
    B-0953
    Figure US20070078146A1-20070405-C02427
    Figure US20070078146A1-20070405-C02428
         		67 425 426
    B-0954
    Figure US20070078146A1-20070405-C02429
    Figure US20070078146A1-20070405-C02430
         		62 431 432
    B-0955
    Figure US20070078146A1-20070405-C02431
    Figure US20070078146A1-20070405-C02432
         		39 461 462
    B-0956
    Figure US20070078146A1-20070405-C02433
    Figure US20070078146A1-20070405-C02434
         		66 429 430
    B-0957
    Figure US20070078146A1-20070405-C02435
    Figure US20070078146A1-20070405-C02436
         		93 429 430
    B-0958
    Figure US20070078146A1-20070405-C02437
    Figure US20070078146A1-20070405-C02438
         		86 365 366
    B-0959
    Figure US20070078146A1-20070405-C02439
    Figure US20070078146A1-20070405-C02440
         		73 451 452
    B-0960
    Figure US20070078146A1-20070405-C02441
    Figure US20070078146A1-20070405-C02442
         		98 485 486
    B-0961
    Figure US20070078146A1-20070405-C02443
    Figure US20070078146A1-20070405-C02444
         		100 469 470
    B-0962
    Figure US20070078146A1-20070405-C02445
    Figure US20070078146A1-20070405-C02446
         		100 419 420
    B-0963
    Figure US20070078146A1-20070405-C02447
    Figure US20070078146A1-20070405-C02448
         		83 401 402
    B-0964
    Figure US20070078146A1-20070405-C02449
    Figure US20070078146A1-20070405-C02450
         		38 429 430
    B-0965
    Figure US20070078146A1-20070405-C02451
    Figure US20070078146A1-20070405-C02452
         		90 411 412
    B-0966
    Figure US20070078146A1-20070405-C02453
    Figure US20070078146A1-20070405-C02454
         		76 443 444
    B-0967
    Figure US20070078146A1-20070405-C02455
    Figure US20070078146A1-20070405-C02456
         		100 443 444
    B-0968
    Figure US20070078146A1-20070405-C02457
    Figure US20070078146A1-20070405-C02458
         		100 477 478
    B-0969
    Figure US20070078146A1-20070405-C02459
    Figure US20070078146A1-20070405-C02460
         		77 477 478
    B-0970
    Figure US20070078146A1-20070405-C02461
    Figure US20070078146A1-20070405-C02462
         		38 461 462
    B-0971
    Figure US20070078146A1-20070405-C02463
    Figure US20070078146A1-20070405-C02464
         		95 469 470
    B-0972
    Figure US20070078146A1-20070405-C02465
    Figure US20070078146A1-20070405-C02466
         		98 479 480
    B-0973
    Figure US20070078146A1-20070405-C02467
    Figure US20070078146A1-20070405-C02468
         		96 485 486
    B-0974
    Figure US20070078146A1-20070405-C02469
    Figure US20070078146A1-20070405-C02470
         		74 443 444
    B-0975
    Figure US20070078146A1-20070405-C02471
    Figure US20070078146A1-20070405-C02472
         		100 495 496
    B-0976
    Figure US20070078146A1-20070405-C02473
    Figure US20070078146A1-20070405-C02474
         		70 453 454
    B-0977
    Figure US20070078146A1-20070405-C02475
    Figure US20070078146A1-20070405-C02476
         		100 467 468
    B-0978
    Figure US20070078146A1-20070405-C02477
    Figure US20070078146A1-20070405-C02478
         		91 431 432
    B-0979
    Figure US20070078146A1-20070405-C02479
    Figure US20070078146A1-20070405-C02480
         		54 491 492
    B-0980
    Figure US20070078146A1-20070405-C02481
    Figure US20070078146A1-20070405-C02482
         		65 469 470
    B-0981
    Figure US20070078146A1-20070405-C02483
    Figure US20070078146A1-20070405-C02484
         		78 382 383
    B-0982
    Figure US20070078146A1-20070405-C02485
    Figure US20070078146A1-20070405-C02486
         		82 512 813
    B-0983
    Figure US20070078146A1-20070405-C02487
    Figure US20070078146A1-20070405-C02488
         		94 352 353
    B-0984
    Figure US20070078146A1-20070405-C02489
    Figure US20070078146A1-20070405-C02490
         		81 404 405
    B-0985
    Figure US20070078146A1-20070405-C02491
    Figure US20070078146A1-20070405-C02492
         		84 366 367
    B-0986
    Figure US20070078146A1-20070405-C02493
    Figure US20070078146A1-20070405-C02494
         		80 410 411
    B-0987
    Figure US20070078146A1-20070405-C02495
    Figure US20070078146A1-20070405-C02496
         		85 324 325
    B-0988
    Figure US20070078146A1-20070405-C02497
    Figure US20070078146A1-20070405-C02498
         		91 364 365
    B-0989
    Figure US20070078146A1-20070405-C02499
    Figure US20070078146A1-20070405-C02500
         		88 350 351
    B-0990
    Figure US20070078146A1-20070405-C02501
    Figure US20070078146A1-20070405-C02502
         		68 464 465
    B-0991
    Figure US20070078146A1-20070405-C02503
    Figure US20070078146A1-20070405-C02504
         		86 512 513
    B-0992
    Figure US20070078146A1-20070405-C02505
    Figure US20070078146A1-20070405-C02506
         		79 377 378
    B-0993
    Figure US20070078146A1-20070405-C02507
    Figure US20070078146A1-20070405-C02508
         		81 396 397
    B-0994
    Figure US20070078146A1-20070405-C02509
    Figure US20070078146A1-20070405-C02510
         		100 354 355
    B-0995
    Figure US20070078146A1-20070405-C02511
    Figure US20070078146A1-20070405-C02512
         		75 416 417
    B-0996
    Figure US20070078146A1-20070405-C02513
    Figure US20070078146A1-20070405-C02514
         		65 454 455
    B-0997
    Figure US20070078146A1-20070405-C02515
    Figure US20070078146A1-20070405-C02516
         		64 440 441
    B-0998
    Figure US20070078146A1-20070405-C02517
    Figure US20070078146A1-20070405-C02518
         		81 364 355
    B-0999
    Figure US20070078146A1-20070405-C02519
    Figure US20070078146A1-20070405-C02520
         		79 460 461
    B-1000
    Figure US20070078146A1-20070405-C02521
    Figure US20070078146A1-20070405-C02522
         		84 430 431
    B-1001
    Figure US20070078146A1-20070405-C02523
    Figure US20070078146A1-20070405-C02524
         		78 430 431
    B-1002
    Figure US20070078146A1-20070405-C02525
    Figure US20070078146A1-20070405-C02526
         		85 400 401
    B-1003
    Figure US20070078146A1-20070405-C02527
    Figure US20070078146A1-20070405-C02528
         		53 386 387
    B-1004
    Figure US20070078146A1-20070405-C02529
    Figure US20070078146A1-20070405-C02530
         		87 378 379
    B-1005
    Figure US20070078146A1-20070405-C02531
    Figure US20070078146A1-20070405-C02532
         		57 387 388
    B-1006
    Figure US20070078146A1-20070405-C02533
    Figure US20070078146A1-20070405-C02534
         		80 387 388
    B-1007
    Figure US20070078146A1-20070405-C02535
    Figure US20070078146A1-20070405-C02536
         		54 387 388
    B-1008
    Figure US20070078146A1-20070405-C02537
    Figure US20070078146A1-20070405-C02538
         		64 416 417
    B-1009
    Figure US20070078146A1-20070405-C02539
    Figure US20070078146A1-20070405-C02540
         		81 430 431
    B-1010
    Figure US20070078146A1-20070405-C02541
    Figure US20070078146A1-20070405-C02542
         		81 382 383
    B-1011
    Figure US20070078146A1-20070405-C02543
    Figure US20070078146A1-20070405-C02544
         		66 583 584
    B-1012
    Figure US20070078146A1-20070405-C02545
    Figure US20070078146A1-20070405-C02546
         		69 438 439
    B-1013
    Figure US20070078146A1-20070405-C02547
    Figure US20070078146A1-20070405-C02548
         		53 440 441
    B-1014
    Figure US20070078146A1-20070405-C02549
    Figure US20070078146A1-20070405-C02550
         		61 422 423
    B-1015
    Figure US20070078146A1-20070405-C02551
    Figure US20070078146A1-20070405-C02552
         		47 388 389
    B-1016
    Figure US20070078146A1-20070405-C02553
    Figure US20070078146A1-20070405-C02554
         		74 448 449
    B-1017
    Figure US20070078146A1-20070405-C02555
    Figure US20070078146A1-20070405-C02556
         		63 436 437
    B-1018
    Figure US20070078146A1-20070405-C02557
    Figure US20070078146A1-20070405-C02558
         		82 458 459
    B-1019
    Figure US20070078146A1-20070405-C02559
    Figure US20070078146A1-20070405-C02560
         		41 414 415
    B-1020
    Figure US20070078146A1-20070405-C02561
    Figure US20070078146A1-20070405-C02562
         		100 440 441
    B-1021
    Figure US20070078146A1-20070405-C02563
    Figure US20070078146A1-20070405-C02564
         		100 388 389
    B-1022
    Figure US20070078146A1-20070405-C02565
    Figure US20070078146A1-20070405-C02566
         		74 402 403
    B-1023
    Figure US20070078146A1-20070405-C02567
    Figure US20070078146A1-20070405-C02568
         		76 374 375
    B-1024
    Figure US20070078146A1-20070405-C02569
    Figure US20070078146A1-20070405-C02570
         		73 360 361
    B-1025
    Figure US20070078146A1-20070405-C02571
    Figure US20070078146A1-20070405-C02572
         		100 452 453
    B-1026
    Figure US20070078146A1-20070405-C02573
    Figure US20070078146A1-20070405-C02574
         		95 428 429
    B-1027
    Figure US20070078146A1-20070405-C02575
    Figure US20070078146A1-20070405-C02576
         		98 436 437
    B-1028
    Figure US20070078146A1-20070405-C02577
    Figure US20070078146A1-20070405-C02578
         		100 482 483
    B-1029
    Figure US20070078146A1-20070405-C02579
    Figure US20070078146A1-20070405-C02580
         		98 367 368
    B-1030
    Figure US20070078146A1-20070405-C02581
    Figure US20070078146A1-20070405-C02582
         		88 325 326
    B-1031
    Figure US20070078146A1-20070405-C02583
    Figure US20070078146A1-20070405-C02584
         		97 415 416
    B-1032
    Figure US20070078146A1-20070405-C02585
    Figure US20070078146A1-20070405-C02586
         		64 379 380
    B-1033
    Figure US20070078146A1-20070405-C02587
    Figure US20070078146A1-20070405-C02588
         		83 395 396
    B-1034
    Figure US20070078146A1-20070405-C02589
    Figure US20070078146A1-20070405-C02590
         		67 419 420
    B-1035
    Figure US20070078146A1-20070405-C02591
    Figure US20070078146A1-20070405-C02592
         		73 353 354
    B-1036
    Figure US20070078146A1-20070405-C02593
    Figure US20070078146A1-20070405-C02594
         		79 339 340
    B-1037
    Figure US20070078146A1-20070405-C02595
    Figure US20070078146A1-20070405-C02596
         		78 415 416
    B-1038
    Figure US20070078146A1-20070405-C02597
    Figure US20070078146A1-20070405-C02598
         		100 419 420
    B-1039
    Figure US20070078146A1-20070405-C02599
    Figure US20070078146A1-20070405-C02600
         		95 429 430
    B-1040
    Figure US20070078146A1-20070405-C02601
    Figure US20070078146A1-20070405-C02602
         		91 365 366
    B-1041
    Figure US20070078146A1-20070405-C02603
    Figure US20070078146A1-20070405-C02604
         		88 367 368
    B-1042
    Figure US20070078146A1-20070405-C02605
    Figure US20070078146A1-20070405-C02606
         		78 429 430
    B-1043
    Figure US20070078146A1-20070405-C02607
    Figure US20070078146A1-20070405-C02608
         		79 401 402
    B-1044
    Figure US20070078146A1-20070405-C02609
    Figure US20070078146A1-20070405-C02610
         		93 429 430
    B-1045
    Figure US20070078146A1-20070405-C02611
    Figure US20070078146A1-20070405-C02612
         		100 429 430
    B-1046
    Figure US20070078146A1-20070405-C02613
    Figure US20070078146A1-20070405-C02614
         		94 419 420
    B-1047
    Figure US20070078146A1-20070405-C02615
    Figure US20070078146A1-20070405-C02616
         		100 431 432
    B-1048
    Figure US20070078146A1-20070405-C02617
    Figure US20070078146A1-20070405-C02618
         		58 381 382
    B-1049
    Figure US20070078146A1-20070405-C02619
    Figure US20070078146A1-20070405-C02620
         		97 353 354
    B-1050
    Figure US20070078146A1-20070405-C02621
    Figure US20070078146A1-20070405-C02622
         		100 461 462
    B-1051
    Figure US20070078146A1-20070405-C02623
    Figure US20070078146A1-20070405-C02624
         		88 406 407
    B-1052
    Figure US20070078146A1-20070405-C02625
    Figure US20070078146A1-20070405-C02626
         		82 366 367
    B-1053
    Figure US20070078146A1-20070405-C02627
    Figure US20070078146A1-20070405-C02628
         		21 368
    B-1054
    Figure US20070078146A1-20070405-C02629
    Figure US20070078146A1-20070405-C02630
         		98 354 355
    B-1055
    Figure US20070078146A1-20070405-C02631
    Figure US20070078146A1-20070405-C02632
         		100 379 380
    B-1056
    Figure US20070078146A1-20070405-C02633
    Figure US20070078146A1-20070405-C02634
         		85 379 380
    B-1057
    Figure US20070078146A1-20070405-C02635
    Figure US20070078146A1-20070405-C02636
         		30 368 369
    B-1058
    Figure US20070078146A1-20070405-C02637
    Figure US20070078146A1-20070405-C02638
         		35 500 501
    B-1059
    Figure US20070078146A1-20070405-C02639
    Figure US20070078146A1-20070405-C02640
         		77 479 480
    B-1060
    Figure US20070078146A1-20070405-C02641
    Figure US20070078146A1-20070405-C02642
         		37 500 501
    B-1061
    Figure US20070078146A1-20070405-C02643
    Figure US20070078146A1-20070405-C02644
         		86 456 457
    B-1062
    Figure US20070078146A1-20070405-C02645
    Figure US20070078146A1-20070405-C02646
         		58 496 497
    B-1063
    Figure US20070078146A1-20070405-C02647
    Figure US20070078146A1-20070405-C02648
         		59 496 497
    B-1064
    Figure US20070078146A1-20070405-C02649
    Figure US20070078146A1-20070405-C02650
         		58 506 —
    B-1065
    Figure US20070078146A1-20070405-C02651
    Figure US20070078146A1-20070405-C02652
         		24 466 —
    B-1066
    Figure US20070078146A1-20070405-C02653
    Figure US20070078146A1-20070405-C02654
         		100 490 491
    B-1067
    Figure US20070078146A1-20070405-C02655
    Figure US20070078146A1-20070405-C02656
         		74 464 465
    B-1068
    Figure US20070078146A1-20070405-C02657
    Figure US20070078146A1-20070405-C02658
         		79 472 473
    B-1069
    Figure US20070078146A1-20070405-C02659
    Figure US20070078146A1-20070405-C02660
         		97 472 473
    B-1070
    Figure US20070078146A1-20070405-C02661
    Figure US20070078146A1-20070405-C02662
         		54 481 482
    B-1071
    Figure US20070078146A1-20070405-C02663
    Figure US20070078146A1-20070405-C02664
         		67 473 474
    B-1072
    Figure US20070078146A1-20070405-C02665
    Figure US20070078146A1-20070405-C02666
         		35 515 516
    B-1073
    Figure US20070078146A1-20070405-C02667
    Figure US20070078146A1-20070405-C02668
         		100 490 491
    B-1074
    Figure US20070078146A1-20070405-C02669
    Figure US20070078146A1-20070405-C02670
         		100 464 465
    B-1075
    Figure US20070078146A1-20070405-C02671
    Figure US20070078146A1-20070405-C02672
         		100 470 471
    B-1076
    Figure US20070078146A1-20070405-C02673
    Figure US20070078146A1-20070405-C02674
         		93 490 491
    B-1077
    Figure US20070078146A1-20070405-C02675
    Figure US20070078146A1-20070405-C02676
         		100 474 475
    B-1078
    Figure US20070078146A1-20070405-C02677
    Figure US20070078146A1-20070405-C02678
         		80 447 448
    B-1079
    Figure US20070078146A1-20070405-C02679
    Figure US20070078146A1-20070405-C02680
         		85 454 455
    B-1080
    Figure US20070078146A1-20070405-C02681
    Figure US20070078146A1-20070405-C02682
         		100 496 497
    B-1081
    Figure US20070078146A1-20070405-C02683
    Figure US20070078146A1-20070405-C02684
         		100 490 491
    B-1082
    Figure US20070078146A1-20070405-C02685
    Figure US20070078146A1-20070405-C02686
         		100 500 501
    B-1083
    Figure US20070078146A1-20070405-C02687
    Figure US20070078146A1-20070405-C02688
         		93 500 501
    B-1084
    Figure US20070078146A1-20070405-C02689
    Figure US20070078146A1-20070405-C02690
         		81 494 495
    B-1085
    Figure US20070078146A1-20070405-C02691
    Figure US20070078146A1-20070405-C02692
         		93 482 483
    B-1086
    Figure US20070078146A1-20070405-C02693
    Figure US20070078146A1-20070405-C02694
         		92 490 491
    B-1087
    Figure US20070078146A1-20070405-C02695
    Figure US20070078146A1-20070405-C02696
         		100 490 491
    B-1088
    Figure US20070078146A1-20070405-C02697
    Figure US20070078146A1-20070405-C02698
         		97 450 451
    B-1089
    Figure US20070078146A1-20070405-C02699
    Figure US20070078146A1-20070405-C02700
         		100 436 437
    B-1090
    Figure US20070078146A1-20070405-C02701
    Figure US20070078146A1-20070405-C02702
         		100 456 457
    B-1091
    Figure US20070078146A1-20070405-C02703
    Figure US20070078146A1-20070405-C02704
         		100 456 457
    B-1092
    Figure US20070078146A1-20070405-C02705
    Figure US20070078146A1-20070405-C02706
         		96 490 491
    B-1093
    Figure US20070078146A1-20070405-C02707
    Figure US20070078146A1-20070405-C02708
         		100 490 491
    B-1094
    Figure US20070078146A1-20070405-C02709
    Figure US20070078146A1-20070405-C02710
         		100 474 475
    B-1095
    Figure US20070078146A1-20070405-C02711
    Figure US20070078146A1-20070405-C02712
         		81 470 471
    B-1096
    Figure US20070078146A1-20070405-C02713
    Figure US20070078146A1-20070405-C02714
         		77 450 451
    B-1097
    Figure US20070078146A1-20070405-C02715
    Figure US20070078146A1-20070405-C02716
         		100 436 437
    B-1098
    Figure US20070078146A1-20070405-C02717
    Figure US20070078146A1-20070405-C02718
         		93 466 467
    B-1099
    Figure US20070078146A1-20070405-C02719
    Figure US20070078146A1-20070405-C02720
         		100 490 491
    B-1100
    Figure US20070078146A1-20070405-C02721
    Figure US20070078146A1-20070405-C02722
         		47 482 —
    B-1101
    Figure US20070078146A1-20070405-C02723
    Figure US20070078146A1-20070405-C02724
         		64 462 463
    B-1102
    Figure US20070078146A1-20070405-C02725
    Figure US20070078146A1-20070405-C02726
         		98 530 531
    B-1103
    Figure US20070078146A1-20070405-C02727
    Figure US20070078146A1-20070405-C02728
         		65 472 —
    B-1104
    Figure US20070078146A1-20070405-C02729
    Figure US20070078146A1-20070405-C02730
         		88 441 442
    B-1105
    Figure US20070078146A1-20070405-C02731
    Figure US20070078146A1-20070405-C02732
         		100 464 465
    B-1106
    Figure US20070078146A1-20070405-C02733
    Figure US20070078146A1-20070405-C02734
         		91 486 487
    B-1107
    Figure US20070078146A1-20070405-C02735
    Figure US20070078146A1-20070405-C02736
         		96 447 448
    B-1108
    Figure US20070078146A1-20070405-C02737
    Figure US20070078146A1-20070405-C02738
         		55 561 562
    B-1109
    Figure US20070078146A1-20070405-C02739
    Figure US20070078146A1-20070405-C02740
         		100 498 499
    B-1110
    Figure US20070078146A1-20070405-C02741
    Figure US20070078146A1-20070405-C02742
         		73 548 549
    B-1111
    Figure US20070078146A1-20070405-C02743
    Figure US20070078146A1-20070405-C02744
         		94 505 506
    B-1112
    Figure US20070078146A1-20070405-C02745
    Figure US20070078146A1-20070405-C02746
         		100 568 569
    B-1113
    Figure US20070078146A1-20070405-C02747
    Figure US20070078146A1-20070405-C02748
         		100 495 496
    B-1114
    Figure US20070078146A1-20070405-C02749
    Figure US20070078146A1-20070405-C02750
         		73 426 427
    B-1115
    Figure US20070078146A1-20070405-C02751
    Figure US20070078146A1-20070405-C02752
         		30 389 390
    B-1116
    Figure US20070078146A1-20070405-C02753
    Figure US20070078146A1-20070405-C02754
         		100 568 569
    B-1117
    Figure US20070078146A1-20070405-C02755
    Figure US20070078146A1-20070405-C02756
         		83 500 501
    B-1118
    Figure US20070078146A1-20070405-C02757
    Figure US20070078146A1-20070405-C02758
         		55 473 —
    B-1119
    Figure US20070078146A1-20070405-C02759
    Figure US20070078146A1-20070405-C02760
         		70 514 515
    B-1120
    Figure US20070078146A1-20070405-C02761
    Figure US20070078146A1-20070405-C02762
         		84 400 401
    B-1121
    Figure US20070078146A1-20070405-C02763
    Figure US20070078146A1-20070405-C02764
         		86 420 421
    B-1122
    Figure US20070078146A1-20070405-C02765
    Figure US20070078146A1-20070405-C02766
         		90 400 401
    B-1123
    Figure US20070078146A1-20070405-C02767
    Figure US20070078146A1-20070405-C02768
         		100 454 455
    B-1124
    Figure US20070078146A1-20070405-C02769
    Figure US20070078146A1-20070405-C02770
         		91 442 443
    B-1125
    Figure US20070078146A1-20070405-C02771
    Figure US20070078146A1-20070405-C02772
         		50 512 513
    B-1126
    Figure US20070078146A1-20070405-C02773
    Figure US20070078146A1-20070405-C02774
         		85 454 455
    B-1127
    Figure US20070078146A1-20070405-C02775
    Figure US20070078146A1-20070405-C02776
         		93 411 412
    B-1128
    Figure US20070078146A1-20070405-C02777
    Figure US20070078146A1-20070405-C02778
         		87 436 437
    B-1129
    Figure US20070078146A1-20070405-C02779
    Figure US20070078146A1-20070405-C02780
         		78 422 423
    B-1130
    Figure US20070078146A1-20070405-C02781
    Figure US20070078146A1-20070405-C02782
         		96 422 423
    B-1131
    Figure US20070078146A1-20070405-C02783
    Figure US20070078146A1-20070405-C02784
         		84 440 441
    B-1132
    Figure US20070078146A1-20070405-C02785
    Figure US20070078146A1-20070405-C02786
         		77 454 455
    B-1133
    Figure US20070078146A1-20070405-C02787
    Figure US20070078146A1-20070405-C02788
         		62 428 429
    B-1134
    Figure US20070078146A1-20070405-C02789
    Figure US20070078146A1-20070405-C02790
         		91 472 473
    B-1135
    Figure US20070078146A1-20070405-C02791
    Figure US20070078146A1-20070405-C02792
         		85 440 441
    B-1136
    Figure US20070078146A1-20070405-C02793
    Figure US20070078146A1-20070405-C02794
         		82 472 473
    B-1137
    Figure US20070078146A1-20070405-C02795
    Figure US20070078146A1-20070405-C02796
         		95 472 473
    B-1138
    Figure US20070078146A1-20070405-C02797
    Figure US20070078146A1-20070405-C02798
         		100 472 473
    B-1139
    Figure US20070078146A1-20070405-C02799
    Figure US20070078146A1-20070405-C02800
         		100 472 473
    B-1140
    Figure US20070078146A1-20070405-C02801
    Figure US20070078146A1-20070405-C02802
         		92 472 473
    B-1141
    Figure US20070078146A1-20070405-C02803
    Figure US20070078146A1-20070405-C02804
         		100 472 473
    B-1142
    Figure US20070078146A1-20070405-C02805
    Figure US20070078146A1-20070405-C02806
         		88 420 421
    B-1143
    Figure US20070078146A1-20070405-C02807
    Figure US20070078146A1-20070405-C02808
         		90 400 401
    B-1144
    Figure US20070078146A1-20070405-C02809
    Figure US20070078146A1-20070405-C02810
         		87 454 455
    B-1145
    Figure US20070078146A1-20070405-C02811
    Figure US20070078146A1-20070405-C02812
         		93 404 405
    B-1146
    Figure US20070078146A1-20070405-C02813
    Figure US20070078146A1-20070405-C02814
         		90 422 423
    B-1147
    Figure US20070078146A1-20070405-C02815
    Figure US20070078146A1-20070405-C02816
         		100 454 455
    B-1148
    Figure US20070078146A1-20070405-C02817
    Figure US20070078146A1-20070405-C02818
         		87 422 423
    B-1149
    Figure US20070078146A1-20070405-C02819
    Figure US20070078146A1-20070405-C02820
         		87 440 441
    B-1150
    Figure US20070078146A1-20070405-C02821
    Figure US20070078146A1-20070405-C02822
         		90 404 405
    B-1151
    Figure US20070078146A1-20070405-C02823
    Figure US20070078146A1-20070405-C02824
         		82 422 423
    B-1152
    Figure US20070078146A1-20070405-C02825
    Figure US20070078146A1-20070405-C02826
         		85 422 423
    B-1153
    Figure US20070078146A1-20070405-C02827
    Figure US20070078146A1-20070405-C02828
         		90 420 421
    B-1154
    Figure US20070078146A1-20070405-C02829
    Figure US20070078146A1-20070405-C02830
         		78 464 465
    B-1155
    Figure US20070078146A1-20070405-C02831
    Figure US20070078146A1-20070405-C02832
         		79 454 455
    B-1156
    Figure US20070078146A1-20070405-C02833
    Figure US20070078146A1-20070405-C02834
         		95 392 393
    B-1157
    Figure US20070078146A1-20070405-C02835
    Figure US20070078146A1-20070405-C02836
         		81 405 406
    Figure US20070078146A1-20070405-C02837
    Observed
    Calcd. Mass
    % Mass Spec
    Example# R2 RJ Yield Spec (M + H)
    B-1158
    Figure US20070078146A1-20070405-C02838
    Figure US20070078146A1-20070405-C02839
         		54 396 397
    B-1159
    Figure US20070078146A1-20070405-C02840
    Figure US20070078146A1-20070405-C02841
         		42 526 527
    B-1160
    Figure US20070078146A1-20070405-C02842
    Figure US20070078146A1-20070405-C02843
         		27 366 367
    B-1161
    Figure US20070078146A1-20070405-C02844
    Figure US20070078146A1-20070405-C02845
         		58 418 419
    B-1162
    Figure US20070078146A1-20070405-C02846
    Figure US20070078146A1-20070405-C02847
         		62 380 381
    B-1163
    Figure US20070078146A1-20070405-C02848
    Figure US20070078146A1-20070405-C02849
         		58 424 425
    B-1164
    Figure US20070078146A1-20070405-C02850
    Figure US20070078146A1-20070405-C02851
         		67 338 339
    B-1165
    Figure US20070078146A1-20070405-C02852
    Figure US20070078146A1-20070405-C02853
         		66 378 379
    B-1166
    Figure US20070078146A1-20070405-C02854
    Figure US20070078146A1-20070405-C02855
         		65 364 365
    B-1167
    Figure US20070078146A1-20070405-C02856
    Figure US20070078146A1-20070405-C02857
         		64 478 479
    B-1168
    Figure US20070078146A1-20070405-C02858
    Figure US20070078146A1-20070405-C02859
         		76 526 527
    B-1169
    Figure US20070078146A1-20070405-C02860
    Figure US20070078146A1-20070405-C02861
         		70 391 392
    B-1170
    Figure US20070078146A1-20070405-C02862
    Figure US20070078146A1-20070405-C02863
         		76 410 411
    B-1171
    Figure US20070078146A1-20070405-C02864
    Figure US20070078146A1-20070405-C02865
         		82 368 369
    B-1172
    Figure US20070078146A1-20070405-C02866
    Figure US20070078146A1-20070405-C02867
         		73 430 431
    B-1173
    Figure US20070078146A1-20070405-C02868
    Figure US20070078146A1-20070405-C02869
         		74 468 469
    B-1174
    Figure US20070078146A1-20070405-C02870
    Figure US20070078146A1-20070405-C02871
         		83 454 455
    B-1175
    Figure US20070078146A1-20070405-C02872
    Figure US20070078146A1-20070405-C02873
         		76 378 379
    B-1176
    Figure US20070078146A1-20070405-C02874
    Figure US20070078146A1-20070405-C02875
         		96 474 475
    B-1177
    Figure US20070078146A1-20070405-C02876
    Figure US20070078146A1-20070405-C02877
         		94 444 445
    B-1178
    Figure US20070078146A1-20070405-C02878
    Figure US20070078146A1-20070405-C02879
         		90 444 445
    B-1179
    Figure US20070078146A1-20070405-C02880
    Figure US20070078146A1-20070405-C02881
         		57 414 415
    B-1180
    Figure US20070078146A1-20070405-C02882
    Figure US20070078146A1-20070405-C02883
         		75 400 401
    B-1181
    Figure US20070078146A1-20070405-C02884
    Figure US20070078146A1-20070405-C02885
         		66 392 393
    B-1182
    Figure US20070078146A1-20070405-C02886
    Figure US20070078146A1-20070405-C02887
         		74 401 402
    B-1183
    Figure US20070078146A1-20070405-C02888
    Figure US20070078146A1-20070405-C02889
         		62 401 402
    B-1184
    Figure US20070078146A1-20070405-C02890
    Figure US20070078146A1-20070405-C02891
         		51 401 402
    B-1185
    Figure US20070078146A1-20070405-C02892
    Figure US20070078146A1-20070405-C02893
         		90 430 431
    B-1186
    Figure US20070078146A1-20070405-C02894
    Figure US20070078146A1-20070405-C02895
         		86 444 445
    B-1187
    Figure US20070078146A1-20070405-C02896
    Figure US20070078146A1-20070405-C02897
         		74 396 397
    B-1188
    Figure US20070078146A1-20070405-C02898
    Figure US20070078146A1-20070405-C02899
         		76 597 598
    B-1189
    Figure US20070078146A1-20070405-C02900
    Figure US20070078146A1-20070405-C02901
         		60 452 453
    B-1190
    Figure US20070078146A1-20070405-C02902
    Figure US20070078146A1-20070405-C02903
         		44 454 455
    B-1191
    Figure US20070078146A1-20070405-C02904
    Figure US20070078146A1-20070405-C02905
         		47 436 437
    B-1192
    Figure US20070078146A1-20070405-C02906
    Figure US20070078146A1-20070405-C02907
         		50 402 403
    B-1193
    Figure US20070078146A1-20070405-C02908
    Figure US20070078146A1-20070405-C02909
         		62 462 463
    B-1194
    Figure US20070078146A1-20070405-C02910
    Figure US20070078146A1-20070405-C02911
         		49 450 451
    B-1195
    Figure US20070078146A1-20070405-C02912
    Figure US20070078146A1-20070405-C02913
         		61 472 473
    B-1196
    Figure US20070078146A1-20070405-C02914
    Figure US20070078146A1-20070405-C02915
         		52 428 429
    B-1197
    Figure US20070078146A1-20070405-C02916
    Figure US20070078146A1-20070405-C02917
         		54 454 455
    B-1198
    Figure US20070078146A1-20070405-C02918
    Figure US20070078146A1-20070405-C02919
         		44 402 403
    B-1199
    Figure US20070078146A1-20070405-C02920
    Figure US20070078146A1-20070405-C02921
         		67 416 417
    B-1200
    Figure US20070078146A1-20070405-C02922
    Figure US20070078146A1-20070405-C02923
         		45 388 389
    B-1201
    Figure US20070078146A1-20070405-C02924
    Figure US20070078146A1-20070405-C02925
         		52 374 375
    B-1202
    Figure US20070078146A1-20070405-C02926
    Figure US20070078146A1-20070405-C02927
         		100 466 467
    B-1203
    Figure US20070078146A1-20070405-C02928
    Figure US20070078146A1-20070405-C02929
         		91 442 443
    B-1204
    Figure US20070078146A1-20070405-C02930
    Figure US20070078146A1-20070405-C02931
         		100 450 451
    B-1205
    Figure US20070078146A1-20070405-C02932
    Figure US20070078146A1-20070405-C02933
         		83 496 497
    B-1206
    Figure US20070078146A1-20070405-C02934
    Figure US20070078146A1-20070405-C02935
         		97 381 382
    B-1207
    Figure US20070078146A1-20070405-C02936
    Figure US20070078146A1-20070405-C02937
         		100 339 340
    B-1208
    Figure US20070078146A1-20070405-C02938
    Figure US20070078146A1-20070405-C02939
         		90 429 430
    B-1209
    Figure US20070078146A1-20070405-C02940
    Figure US20070078146A1-20070405-C02941
         		69 393 394
    B-1210
    Figure US20070078146A1-20070405-C02942
    Figure US20070078146A1-20070405-C02943
         		35 409 410
    B-1211
    Figure US20070078146A1-20070405-C02944
    Figure US20070078146A1-20070405-C02945
         		100 433 434
    B-1212
    Figure US20070078146A1-20070405-C02946
    Figure US20070078146A1-20070405-C02947
         		83 367 368
    B-1213
    Figure US20070078146A1-20070405-C02948
    Figure US20070078146A1-20070405-C02949
         		78 353 354
    B-1214
    Figure US20070078146A1-20070405-C02950
    Figure US20070078146A1-20070405-C02951
         		68 429 430
    B-1215
    Figure US20070078146A1-20070405-C02952
    Figure US20070078146A1-20070405-C02953
         		65 433 434
    B-1216
    Figure US20070078146A1-20070405-C02954
    Figure US20070078146A1-20070405-C02955
         		91 443 444
    B-1217
    Figure US20070078146A1-20070405-C02956
    Figure US20070078146A1-20070405-C02957
         		99 379 380
    B-1218
    Figure US20070078146A1-20070405-C02958
    Figure US20070078146A1-20070405-C02959
         		92 381 382
    B-1219
    Figure US20070078146A1-20070405-C02960
    Figure US20070078146A1-20070405-C02961
         		74 443 444
    B-1220
    Figure US20070078146A1-20070405-C02962
    Figure US20070078146A1-20070405-C02963
         		67 415 416
    B-1221
    Figure US20070078146A1-20070405-C02964
    Figure US20070078146A1-20070405-C02965
         		14 443 444
    B-1222
    Figure US20070078146A1-20070405-C02966
    Figure US20070078146A1-20070405-C02967
         		19 443 444
    B-1223
    Figure US20070078146A1-20070405-C02968
    Figure US20070078146A1-20070405-C02969
         		71 433 434
    B-1224
    Figure US20070078146A1-20070405-C02970
    Figure US20070078146A1-20070405-C02971
         		100 445 446
    B-1225
    Figure US20070078146A1-20070405-C02972
    Figure US20070078146A1-20070405-C02973
         		75 395 396
    B-1226
    Figure US20070078146A1-20070405-C02974
    Figure US20070078146A1-20070405-C02975
         		58 367 368
    B-1227
    Figure US20070078146A1-20070405-C02976
    Figure US20070078146A1-20070405-C02977
         		98 475 476
    B-1228
    Figure US20070078146A1-20070405-C02978
    Figure US20070078146A1-20070405-C02979
         		71 420 421
    B-1229
    Figure US20070078146A1-20070405-C02980
    Figure US20070078146A1-20070405-C02981
         		85 380 381
    B-1230
    Figure US20070078146A1-20070405-C02982
    Figure US20070078146A1-20070405-C02983
         		10 382 —
    B-1231
    Figure US20070078146A1-20070405-C02984
    Figure US20070078146A1-20070405-C02985
         		66 368 369
    B-1232
    Figure US20070078146A1-20070405-C02986
    Figure US20070078146A1-20070405-C02987
         		100 393 394
    B-1233
    Figure US20070078146A1-20070405-C02988
    Figure US20070078146A1-20070405-C02989
         		96 393 394
    B-1234
    Figure US20070078146A1-20070405-C02990
    Figure US20070078146A1-20070405-C02991
         		66 382 383
    B-1235
    Figure US20070078146A1-20070405-C02992
    Figure US20070078146A1-20070405-C02993
         		50 514 515
    B-1236
    Figure US20070078146A1-20070405-C02994
    Figure US20070078146A1-20070405-C02995
         		100 493 494
    B-1237
    Figure US20070078146A1-20070405-C02996
    Figure US20070078146A1-20070405-C02997
         		91 514 515
    B-1238
    Figure US20070078146A1-20070405-C02998
    Figure US20070078146A1-20070405-C02999
         		100 470 471
    B-1239
    Figure US20070078146A1-20070405-C03000
    Figure US20070078146A1-20070405-C03001
         		71 510 511
    B-1240
    Figure US20070078146A1-20070405-C03002
    Figure US20070078146A1-20070405-C03003
         		27 510 511
    B-1241
    Figure US20070078146A1-20070405-C03004
    Figure US20070078146A1-20070405-C03005
         		73 520
    B-1242
    Figure US20070078146A1-20070405-C03006
    Figure US20070078146A1-20070405-C03007
         		26 480 481
    B-1243
    Figure US20070078146A1-20070405-C03008
    Figure US20070078146A1-20070405-C03009
         		100 504
    B-1244
    Figure US20070078146A1-20070405-C03010
    Figure US20070078146A1-20070405-C03011
         		52 478 479
    B-1245
    Figure US20070078146A1-20070405-C03012
    Figure US20070078146A1-20070405-C03013
         		100 486 487
    B-1246
    Figure US20070078146A1-20070405-C03014
    Figure US20070078146A1-20070405-C03015
         		56 486 487
    B-1247
    Figure US20070078146A1-20070405-C03016
    Figure US20070078146A1-20070405-C03017
         		43 495 496
    B-1248
    Figure US20070078146A1-20070405-C03018
    Figure US20070078146A1-20070405-C03019
         		61 487 488
    B-1249
    Figure US20070078146A1-20070405-C03020
    Figure US20070078146A1-20070405-C03021
         		32 529 530
    B-1250
    Figure US20070078146A1-20070405-C03022
    Figure US20070078146A1-20070405-C03023
         		56 504 505
    B-1251
    Figure US20070078146A1-20070405-C03024
    Figure US20070078146A1-20070405-C03025
         		58 478 479
    B-1252
    Figure US20070078146A1-20070405-C03026
    Figure US20070078146A1-20070405-C03027
         		98 484 485
    B-1253
    Figure US20070078146A1-20070405-C03028
    Figure US20070078146A1-20070405-C03029
         		59 504 505
    B-1254
    Figure US20070078146A1-20070405-C03030
    Figure US20070078146A1-20070405-C03031
         		100 488 489
    B-1255
    Figure US20070078146A1-20070405-C03032
    Figure US20070078146A1-20070405-C03033
         		96 461
    B-1256
    Figure US20070078146A1-20070405-C03034
    Figure US20070078146A1-20070405-C03035
         		79 468 469
    B-1257
    Figure US20070078146A1-20070405-C03036
    Figure US20070078146A1-20070405-C03037
         		63 510 511
    B-1258
    Figure US20070078146A1-20070405-C03038
    Figure US20070078146A1-20070405-C03039
         		100 504 505
    B-1259
    Figure US20070078146A1-20070405-C03040
    Figure US20070078146A1-20070405-C03041
         		95 514 515
    B-1260
    Figure US20070078146A1-20070405-C03042
    Figure US20070078146A1-20070405-C03043
         		92 514 515
    B-1261
    Figure US20070078146A1-20070405-C03044
    Figure US20070078146A1-20070405-C03045
         		98 508 509
    B-1262
    Figure US20070078146A1-20070405-C03046
    Figure US20070078146A1-20070405-C03047
         		97 496 497
    B-1263
    Figure US20070078146A1-20070405-C03048
    Figure US20070078146A1-20070405-C03049
         		100 504 505
    B-1264
    Figure US20070078146A1-20070405-C03050
    Figure US20070078146A1-20070405-C03051
         		100 504 505
    B-1265
    Figure US20070078146A1-20070405-C03052
    Figure US20070078146A1-20070405-C03053
         		100 464 465
    B-1266
    Figure US20070078146A1-20070405-C03054
    Figure US20070078146A1-20070405-C03055
         		79 466 451
    B-1267
    Figure US20070078146A1-20070405-C03056
    Figure US20070078146A1-20070405-C03057
         		100 470 471
    B-1268
    Figure US20070078146A1-20070405-C03058
    Figure US20070078146A1-20070405-C03059
         		87 470 471
    B-1269
    Figure US20070078146A1-20070405-C03060
    Figure US20070078146A1-20070405-C03061
         		100 504 505
    B-1270
    Figure US20070078146A1-20070405-C03062
    Figure US20070078146A1-20070405-C03063
         		100 504 505
    B-1271
    Figure US20070078146A1-20070405-C03064
    Figure US20070078146A1-20070405-C03065
         		56 488 489
    B-1272
    Figure US20070078146A1-20070405-C03066
    Figure US20070078146A1-20070405-C03067
         		98 484 485
    B-1273
    Figure US20070078146A1-20070405-C03068
    Figure US20070078146A1-20070405-C03069
         		90 464 465
    B-1274
    Figure US20070078146A1-20070405-C03070
    Figure US20070078146A1-20070405-C03071
         		87 450 451
    B-1275
    Figure US20070078146A1-20070405-C03072
    Figure US20070078146A1-20070405-C03073
         		94 480 481
    B-1276
    Figure US20070078146A1-20070405-C03074
    Figure US20070078146A1-20070405-C03075
         		100 504 505
    B-1277
    Figure US20070078146A1-20070405-C03076
    Figure US20070078146A1-20070405-C03077
         		60 496 511
    B-1278
    Figure US20070078146A1-20070405-C03078
    Figure US20070078146A1-20070405-C03079
         		68 476 477
    B-1279
    Figure US20070078146A1-20070405-C03080
    Figure US20070078146A1-20070405-C03081
         		100 544 545
    B-1280
    Figure US20070078146A1-20070405-C03082
    Figure US20070078146A1-20070405-C03083
         		68 486 —
    B-1281
    Figure US20070078146A1-20070405-C03084
    Figure US20070078146A1-20070405-C03085
         		98 455 456
  • Calcd. Observed
    % Mass Spec
    Example# R2 RJ Yield Spec (M + H)
    B-1282
    Figure US20070078146A1-20070405-C03086
    Figure US20070078146A1-20070405-C03087
         		100 478 479
    B-1283
    Figure US20070078146A1-20070405-C03088
    Figure US20070078146A1-20070405-C03089
         		58 500 501
    B-1284
    Figure US20070078146A1-20070405-C03090
    Figure US20070078146A1-20070405-C03091
         		58 461 462
    B-1285
    Figure US20070078146A1-20070405-C03092
    Figure US20070078146A1-20070405-C03093
         		65 575 576
    B-1286
    Figure US20070078146A1-20070405-C03094
    Figure US20070078146A1-20070405-C03095
         		87 512 513
    B-1287
    Figure US20070078146A1-20070405-C03096
    Figure US20070078146A1-20070405-C03097
         		79 562 563
    B-1288
    Figure US20070078146A1-20070405-C03098
    Figure US20070078146A1-20070405-C03099
         		100 519 520
    B-1289
    Figure US20070078146A1-20070405-C03100
    Figure US20070078146A1-20070405-C03101
         		77 582 583
    B-1290
    Figure US20070078146A1-20070405-C03102
    Figure US20070078146A1-20070405-C03103
         		100 509 510
    B-1291
    Figure US20070078146A1-20070405-C03104
    Figure US20070078146A1-20070405-C03105
         		91 440 441
    B-1292
    Figure US20070078146A1-20070405-C03106
    Figure US20070078146A1-20070405-C03107
         		35 403 404
    B-1293
    Figure US20070078146A1-20070405-C03108
    Figure US20070078146A1-20070405-C03109
         		73 582 583
    B-1294
    Figure US20070078146A1-20070405-C03110
    Figure US20070078146A1-20070405-C03111
         		49 514 515
    B-1295
    Figure US20070078146A1-20070405-C03112
    Figure US20070078146A1-20070405-C03113
         		48 487 —
    B-1296
    Figure US20070078146A1-20070405-C03114
    Figure US20070078146A1-20070405-C03115
         		76 528 529
    B-1297
    Figure US20070078146A1-20070405-C03116
    Figure US20070078146A1-20070405-C03117
         		62 447 448
    B-1298
    Figure US20070078146A1-20070405-C03118
    Figure US20070078146A1-20070405-C03119
         		66 452 453
    B-1299
    Figure US20070078146A1-20070405-C03120
    Figure US20070078146A1-20070405-C03121
         		65 479 431
    B-1300
    Figure US20070078146A1-20070405-C03122
    Figure US20070078146A1-20070405-C03123
         		71 444 445
    B-1301
    Figure US20070078146A1-20070405-C03124
    Figure US20070078146A1-20070405-C03125
         		100 472 473
    B-1302
    Figure US20070078146A1-20070405-C03126
    Figure US20070078146A1-20070405-C03127
         		75 410 411
    B-1303
    Figure US20070078146A1-20070405-C03128
    Figure US20070078146A1-20070405-C03129
         		74 424 425
    B-1304
    Figure US20070078146A1-20070405-C03130
    Figure US20070078146A1-20070405-C03131
         		11 430 431
    B-1305
    Figure US20070078146A1-20070405-C03132
    Figure US20070078146A1-20070405-C03133
         		2 424 —
    B-1306
    Figure US20070078146A1-20070405-C03134
    Figure US20070078146A1-20070405-C03135
         		30 433 434
    B-1307
    Figure US20070078146A1-20070405-C03136
    Figure US20070078146A1-20070405-C03137
         		100 522 523
    B-1308
    Figure US20070078146A1-20070405-C03138
    Figure US20070078146A1-20070405-C03139
         		100 508 509
    B-1309
    Figure US20070078146A1-20070405-C03140
    Figure US20070078146A1-20070405-C03141
         		100 448 449
    B-1310
    Figure US20070078146A1-20070405-C03142
    Figure US20070078146A1-20070405-C03143
         		26 430 431
    B-1311
    Figure US20070078146A1-20070405-C03144
    Figure US20070078146A1-20070405-C03145
         		45 397 398
    B-1312
    Figure US20070078146A1-20070405-C03146
    Figure US20070078146A1-20070405-C03147
         		14 507 508
    B-1313
    Figure US20070078146A1-20070405-C03148
    Figure US20070078146A1-20070405-C03149
         		67 450 451
    B-1314
    Figure US20070078146A1-20070405-C03150
    Figure US20070078146A1-20070405-C03151
         		69 444 445
    B-1315
    Figure US20070078146A1-20070405-C03152
    Figure US20070078146A1-20070405-C03153
         		57 450 451
    B-1316
    Figure US20070078146A1-20070405-C03154
    Figure US20070078146A1-20070405-C03155
         		75 393 394
    B-1317
    Figure US20070078146A1-20070405-C03156
    Figure US20070078146A1-20070405-C03157
         		100 461 462
    B-1318
    Figure US20070078146A1-20070405-C03158
    Figure US20070078146A1-20070405-C03159
         		31 450 451
    B-1319
    Figure US20070078146A1-20070405-C03160
    Figure US20070078146A1-20070405-C03161
         		23 464 465
    B-1320
    Figure US20070078146A1-20070405-C03162
    Figure US20070078146A1-20070405-C03163
         		59 512 513
    B-1321
    Figure US20070078146A1-20070405-C03164
    Figure US20070078146A1-20070405-C03165
         		63 414 415
    B-1322
    Figure US20070078146A1-20070405-C03166
    Figure US20070078146A1-20070405-C03167
         		45 434 435
    B-1323
    Figure US20070078146A1-20070405-C03168
    Figure US20070078146A1-20070405-C03169
         		53 414 415
    B-1324
    Figure US20070078146A1-20070405-C03170
    Figure US20070078146A1-20070405-C03171
         		32 468 469
    B-1325
    Figure US20070078146A1-20070405-C03172
    Figure US20070078146A1-20070405-C03173
         		45 456 457
    B-1326
    Figure US20070078146A1-20070405-C03174
    Figure US20070078146A1-20070405-C03175
         		50 526 527
    B-1327
    Figure US20070078146A1-20070405-C03176
    Figure US20070078146A1-20070405-C03177
         		55 468 469
    B-1328
    Figure US20070078146A1-20070405-C03178
    Figure US20070078146A1-20070405-C03179
         		29 425 426
    B-1329
    Figure US20070078146A1-20070405-C03180
    Figure US20070078146A1-20070405-C03181
         		67 450 451
    B-1330
    Figure US20070078146A1-20070405-C03182
    Figure US20070078146A1-20070405-C03183
         		59 436 437
    B-1331
    Figure US20070078146A1-20070405-C03184
    Figure US20070078146A1-20070405-C03185
         		45 436 437
    B-1332
    Figure US20070078146A1-20070405-C03186
    Figure US20070078146A1-20070405-C03187
         		81 454 455
    B-1333
    Figure US20070078146A1-20070405-C03188
    Figure US20070078146A1-20070405-C03189
         		23 468 469
    B-1334
    Figure US20070078146A1-20070405-C03190
    Figure US20070078146A1-20070405-C03191
         		53 442 443
    B-1335
    Figure US20070078146A1-20070405-C03192
    Figure US20070078146A1-20070405-C03193
         		81 486 487
    B-1336
    Figure US20070078146A1-20070405-C03194
    Figure US20070078146A1-20070405-C03195
         		69 454 455
    B-1337
    Figure US20070078146A1-20070405-C03196
    Figure US20070078146A1-20070405-C03197
         		67 486 487
    B-1338
    Figure US20070078146A1-20070405-C03198
    Figure US20070078146A1-20070405-C03199
         		39 486 487
    B-1339
    Figure US20070078146A1-20070405-C03200
    Figure US20070078146A1-20070405-C03201
         		61 486 487
    B-1340
    Figure US20070078146A1-20070405-C03202
    Figure US20070078146A1-20070405-C03203
         		49 486 487
    B-1341
    Figure US20070078146A1-20070405-C03204
    Figure US20070078146A1-20070405-C03205
         		55 486 487
    B-1342
    Figure US20070078146A1-20070405-C03206
    Figure US20070078146A1-20070405-C03207
         		51 486 487
    B-1343
    Figure US20070078146A1-20070405-C03208
    Figure US20070078146A1-20070405-C03209
         		72 434 435
    B-1344
    Figure US20070078146A1-20070405-C03210
    Figure US20070078146A1-20070405-C03211
         		52 414 415
    B-1345
    Figure US20070078146A1-20070405-C03212
    Figure US20070078146A1-20070405-C03213
         		43 468 469
    B-1346
    Figure US20070078146A1-20070405-C03214
    Figure US20070078146A1-20070405-C03215
         		40 418 419
    B-1347
    Figure US20070078146A1-20070405-C03216
    Figure US20070078146A1-20070405-C03217
         		67 436 437
    B-1348
    Figure US20070078146A1-20070405-C03218
    Figure US20070078146A1-20070405-C03219
         		39 468 469
    B-1349
    Figure US20070078146A1-20070405-C03220
    Figure US20070078146A1-20070405-C03221
         		68 436 437
    B-1350
    Figure US20070078146A1-20070405-C03222
    Figure US20070078146A1-20070405-C03223
         		73 454 455
    B-1351
    Figure US20070078146A1-20070405-C03224
    Figure US20070078146A1-20070405-C03225
         		54 418 419
    B-1352
    Figure US20070078146A1-20070405-C03226
    Figure US20070078146A1-20070405-C03227
         		77 436 437
    B-1353
    Figure US20070078146A1-20070405-C03228
    Figure US20070078146A1-20070405-C03229
         		66 436 437
    B-1354
    Figure US20070078146A1-20070405-C03230
    Figure US20070078146A1-20070405-C03231
         		58 434 435
    B-1355
    Figure US20070078146A1-20070405-C03232
    Figure US20070078146A1-20070405-C03233
         		77 478 479
    B-1356
    Figure US20070078146A1-20070405-C03234
    Figure US20070078146A1-20070405-C03235
         		50 468 469
    B-1357
    Figure US20070078146A1-20070405-C03236
    Figure US20070078146A1-20070405-C03237
         		36 406 407
    B-1358
    Figure US20070078146A1-20070405-C03238
    Figure US20070078146A1-20070405-C03239
         		39 419 420
    Figure US20070078146A1-20070405-C03240
    Calcd. Observed
    % Mass Spec
    Example# R2 RJ Yield Spec (M + H)
    B-1359
    Figure US20070078146A1-20070405-C03241
    Figure US20070078146A1-20070405-C03242
         		95 552 553
    B-1360
    Figure US20070078146A1-20070405-C03243
    Figure US20070078146A1-20070405-C03244
         		77 444 445
    B-1361
    Figure US20070078146A1-20070405-C03245
    Figure US20070078146A1-20070405-C03246
         		100 392 393
    B-1362
    Figure US20070078146A1-20070405-C03247
    Figure US20070078146A1-20070405-C03248
         		85 406 407
    B-1363
    Figure US20070078146A1-20070405-C03249
    Figure US20070078146A1-20070405-C03250
         		100 364 365
    B-1364
    Figure US20070078146A1-20070405-C03251
    Figure US20070078146A1-20070405-C03252
         		99 390 391
    B-1365
    Figure US20070078146A1-20070405-C03253
    Figure US20070078146A1-20070405-C03254
         		92 504 505
    B-1366
    Figure US20070078146A1-20070405-C03255
    Figure US20070078146A1-20070405-C03256
         		100 552 553
    B-1367
    Figure US20070078146A1-20070405-C03257
    Figure US20070078146A1-20070405-C03258
         		100 417 418
    B-1368
    Figure US20070078146A1-20070405-C03259
    Figure US20070078146A1-20070405-C03260
         		86 394 395
    B-1369
    Figure US20070078146A1-20070405-C03261
    Figure US20070078146A1-20070405-C03262
         		100 456 457
    B-1370
    Figure US20070078146A1-20070405-C03263
    Figure US20070078146A1-20070405-C03264
         		100 470 471
    B-1371
    Figure US20070078146A1-20070405-C03265
    Figure US20070078146A1-20070405-C03266
         		77 440 441
    B-1372
    Figure US20070078146A1-20070405-C03267
    Figure US20070078146A1-20070405-C03268
         		100 444 445
    B-1373
    Figure US20070078146A1-20070405-C03269
    Figure US20070078146A1-20070405-C03270
         		42 427 428
    B-1374
    Figure US20070078146A1-20070405-C03271
    Figure US20070078146A1-20070405-C03272
         		60 476 477
    B-1375
    Figure US20070078146A1-20070405-C03273
    Figure US20070078146A1-20070405-C03274
         		94 414 415
    B-1376
    Figure US20070078146A1-20070405-C03275
    Figure US20070078146A1-20070405-C03276
         		87 400 401
    B-1377
    Figure US20070078146A1-20070405-C03277
    Figure US20070078146A1-20070405-C03278
         		100 480 481
    B-1378
    Figure US20070078146A1-20070405-C03279
    Figure US20070078146A1-20070405-C03280
         		95 379 380
    B-1379
    Figure US20070078146A1-20070405-C03281
    Figure US20070078146A1-20070405-C03282
         		93 459 460
    B-1380
    Figure US20070078146A1-20070405-C03283
    Figure US20070078146A1-20070405-C03284
         		89 469 470
    B-1381
    Figure US20070078146A1-20070405-C03285
    Figure US20070078146A1-20070405-C03286
         		84 393 394
    B-1382
    Figure US20070078146A1-20070405-C03287
    Figure US20070078146A1-20070405-C03288
         		85 501 502
    B-1383
    Figure US20070078146A1-20070405-C03289
    Figure US20070078146A1-20070405-C03290
         		46 416 417
    B-1384
    Figure US20070078146A1-20070405-C03291
    Figure US20070078146A1-20070405-C03292
         		56 432 433
    B-1385
    Figure US20070078146A1-20070405-C03293
    Figure US20070078146A1-20070405-C03294
         		59 426 427
    B-1386
    Figure US20070078146A1-20070405-C03295
    Figure US20070078146A1-20070405-C03296
         		50 427 428
    B-1387
    Figure US20070078146A1-20070405-C03297
    Figure US20070078146A1-20070405-C03298
         		12 427 428
    B-1388
    Figure US20070078146A1-20070405-C03299
    Figure US20070078146A1-20070405-C03300
         		66 504 505
    B-1389
    Figure US20070078146A1-20070405-C03301
    Figure US20070078146A1-20070405-C03302
         		48 460 461
    B-1390
    Figure US20070078146A1-20070405-C03303
    Figure US20070078146A1-20070405-C03304
         		44 494 495
    B-1391
    Figure US20070078146A1-20070405-C03305
    Figure US20070078146A1-20070405-C03306
         		50 456 457
    B-1392
    Figure US20070078146A1-20070405-C03307
    Figure US20070078146A1-20070405-C03308
         		47 451 452
    B-1393
    Figure US20070078146A1-20070405-C03309
    Figure US20070078146A1-20070405-C03310
         		44 444 445
    B-1394
    Figure US20070078146A1-20070405-C03311
    Figure US20070078146A1-20070405-C03312
         		52 460 461
    B-1395
    Figure US20070078146A1-20070405-C03313
    Figure US20070078146A1-20070405-C03314
         		77 440 441
    B-1396
    Figure US20070078146A1-20070405-C03315
    Figure US20070078146A1-20070405-C03316
         		58 451 452
    B-1397
    Figure US20070078146A1-20070405-C03317
    Figure US20070078146A1-20070405-C03318
         		64 460 461
    B-1398
    Figure US20070078146A1-20070405-C03319
    Figure US20070078146A1-20070405-C03320
         		65 504 505
    B-1399
    Figure US20070078146A1-20070405-C03321
    Figure US20070078146A1-20070405-C03322
         		50 494 495
    B-1400
    Figure US20070078146A1-20070405-C03323
    Figure US20070078146A1-20070405-C03324
         		74 440 441
    B-1401
    Figure US20070078146A1-20070405-C03325
    Figure US20070078146A1-20070405-C03326
         		76 462 463
    B-1402
    Figure US20070078146A1-20070405-C03327
    Figure US20070078146A1-20070405-C03328
         		65 462 463
    B-1403
    Figure US20070078146A1-20070405-C03329
    Figure US20070078146A1-20070405-C03330
         		64 445 446
    B-1404
    Figure US20070078146A1-20070405-C03331
    Figure US20070078146A1-20070405-C03332
         		70 512 513
    B-1405
    Figure US20070078146A1-20070405-C03333
    Figure US20070078146A1-20070405-C03334
         		57 512 513
    B-1406
    Figure US20070078146A1-20070405-C03335
    Figure US20070078146A1-20070405-C03336
         		73 512 513
    B-1407
    Figure US20070078146A1-20070405-C03337
    Figure US20070078146A1-20070405-C03338
         		80 512 513
    B-1408
    Figure US20070078146A1-20070405-C03339
    Figure US20070078146A1-20070405-C03340
         		2 512 513
    B-1409
    Figure US20070078146A1-20070405-C03341
    Figure US20070078146A1-20070405-C03342
         		62 512 513
    B-1410
    Figure US20070078146A1-20070405-C03343
    Figure US20070078146A1-20070405-C03344
         		42 512 513
    B-1411
    Figure US20070078146A1-20070405-C03345
    Figure US20070078146A1-20070405-C03346
         		19 462 463
    B-1412
    Figure US20070078146A1-20070405-C03347
    Figure US20070078146A1-20070405-C03348
         		74 462 463
    B-1413
    Figure US20070078146A1-20070405-C03349
    Figure US20070078146A1-20070405-C03350
         		75 494 495
    B-1414
    Figure US20070078146A1-20070405-C03351
    Figure US20070078146A1-20070405-C03352
         		68 462 463
    B-1415
    Figure US20070078146A1-20070405-C03353
    Figure US20070078146A1-20070405-C03354
         		48 462 463
    B-1416
    Figure US20070078146A1-20070405-C03355
    Figure US20070078146A1-20070405-C03356
         		48 494 495
    B-1417
    Figure US20070078146A1-20070405-C03357
    Figure US20070078146A1-20070405-C03358
         		57 494 495
    B-1418
    Figure US20070078146A1-20070405-C03359
    Figure US20070078146A1-20070405-C03360
         		49 494 495
    B-1419
    Figure US20070078146A1-20070405-C03361
    Figure US20070078146A1-20070405-C03362
         		39 494 495
    B-1420
    Figure US20070078146A1-20070405-C03363
    Figure US20070078146A1-20070405-C03364
         		72 378 379
    B-1421
    Figure US20070078146A1-20070405-C03365
    Figure US20070078146A1-20070405-C03366
         		74 406 407
    B-1422
    Figure US20070078146A1-20070405-C03367
    Figure US20070078146A1-20070405-C03368
         		68 394 395
    B-1423
    Figure US20070078146A1-20070405-C03369
    Figure US20070078146A1-20070405-C03370
         		57 408 409
    B-1424
    Figure US20070078146A1-20070405-C03371
    Figure US20070078146A1-20070405-C03372
         		77 422 423
    B-1425
    Figure US20070078146A1-20070405-C03373
    Figure US20070078146A1-20070405-C03374
         		26 408 409
    B-1426
    Figure US20070078146A1-20070405-C03375
    Figure US20070078146A1-20070405-C03376
         		41 406 407
    B-1427
    Figure US20070078146A1-20070405-C03377
    Figure US20070078146A1-20070405-C03378
         		37 404 405
    B-1428
    Figure US20070078146A1-20070405-C03379
    Figure US20070078146A1-20070405-C03380
         		60 456 457
    B-1429
    Figure US20070078146A1-20070405-C03381
    Figure US20070078146A1-20070405-C03382
         		2 418 419
    B-1430
    Figure US20070078146A1-20070405-C03383
    Figure US20070078146A1-20070405-C03384
         		61 442 443
    B-1431
    Figure US20070078146A1-20070405-C03385
    Figure US20070078146A1-20070405-C03386
         		64 428 429
    B-1432
    Figure US20070078146A1-20070405-C03387
    Figure US20070078146A1-20070405-C03388
         		71 429 430
    B-1433
    Figure US20070078146A1-20070405-C03389
    Figure US20070078146A1-20070405-C03390
         		74 462 463
    B-1434
    Figure US20070078146A1-20070405-C03391
    Figure US20070078146A1-20070405-C03392
         		88 466 467
    B-1435
    Figure US20070078146A1-20070405-C03393
    Figure US20070078146A1-20070405-C03394
         		75 481 482
    B-1436
    Figure US20070078146A1-20070405-C03395
    Figure US20070078146A1-20070405-C03396
         		71 504 505
    B-1437
    Figure US20070078146A1-20070405-C03397
    Figure US20070078146A1-20070405-C03398
         		63 468 469
    B-1438
    Figure US20070078146A1-20070405-C03399
    Figure US20070078146A1-20070405-C03400
         		78 502 503
    B-1439
    Figure US20070078146A1-20070405-C03401
    Figure US20070078146A1-20070405-C03402
         		70 545 546
    B-1440
    Figure US20070078146A1-20070405-C03403
    Figure US20070078146A1-20070405-C03404
         		62 535 536
    B-1441
    Figure US20070078146A1-20070405-C03405
    Figure US20070078146A1-20070405-C03406
         		82 608
    B-1442
    Figure US20070078146A1-20070405-C03407
    Figure US20070078146A1-20070405-C03408
         		79 555 556
    B-1443
    Figure US20070078146A1-20070405-C03409
    Figure US20070078146A1-20070405-C03410
         		28 513 514
    B-1444
    Figure US20070078146A1-20070405-C03411
    Figure US20070078146A1-20070405-C03412
         		75 522 523
    B-1445
    Figure US20070078146A1-20070405-C03413
    Figure US20070078146A1-20070405-C03414
         		74 526 527
    B-1446
    Figure US20070078146A1-20070405-C03415
    Figure US20070078146A1-20070405-C03416
         		70 570 571
    B-1447
    Figure US20070078146A1-20070405-C03417
    Figure US20070078146A1-20070405-C03418
         		73 506 507
    B-1448
    Figure US20070078146A1-20070405-C03419
    Figure US20070078146A1-20070405-C03420
         		76 530 531
    B-1449
    Figure US20070078146A1-20070405-C03421
    Figure US20070078146A1-20070405-C03422
         		82 530 531
    B-1450
    Figure US20070078146A1-20070405-C03423
    Figure US20070078146A1-20070405-C03424
         		83 530 531
    B-1451
    Figure US20070078146A1-20070405-C03425
    Figure US20070078146A1-20070405-C03426
         		74 530 531
    B-1452
    Figure US20070078146A1-20070405-C03427
    Figure US20070078146A1-20070405-C03428
         		76 530 531
    B-1453
    Figure US20070078146A1-20070405-C03429
    Figure US20070078146A1-20070405-C03430
         		73 530 531
    B-1454
    Figure US20070078146A1-20070405-C03431
    Figure US20070078146A1-20070405-C03432
         		81 498 499
    B-1455
    Figure US20070078146A1-20070405-C03433
    Figure US20070078146A1-20070405-C03434
         		83 498 499
    B-1456
    Figure US20070078146A1-20070405-C03435
    Figure US20070078146A1-20070405-C03436
         		78 498 499
    B-1457
    Figure US20070078146A1-20070405-C03437
    Figure US20070078146A1-20070405-C03438
         		74 496 497
    B-1458
    Figure US20070078146A1-20070405-C03439
    Figure US20070078146A1-20070405-C03440
         		82 540 541
    B-1459
    Figure US20070078146A1-20070405-C03441
    Figure US20070078146A1-20070405-C03442
         		80 476 477
    B-1460
    Figure US20070078146A1-20070405-C03443
    Figure US20070078146A1-20070405-C03444
         		78 530 531
    B-1461
    Figure US20070078146A1-20070405-C03445
    Figure US20070078146A1-20070405-C03446
         		82 487 488
    B-1462
    Figure US20070078146A1-20070405-C03447
    Figure US20070078146A1-20070405-C03448
         		71 540 541
    B-1463
    Figure US20070078146A1-20070405-C03449
    Figure US20070078146A1-20070405-C03450
         		78 506 507
    B-1464
    Figure US20070078146A1-20070405-C03451
    Figure US20070078146A1-20070405-C03452
         		83 480 481
    B-1465
    Figure US20070078146A1-20070405-C03453
    Figure US20070078146A1-20070405-C03454
         		84 496 497
    B-1466
    Figure US20070078146A1-20070405-C03455
    Figure US20070078146A1-20070405-C03456
         		80 540 541
    B-1467
    Figure US20070078146A1-20070405-C03457
    Figure US20070078146A1-20070405-C03458
         		79 476 477
    B-1468
    Figure US20070078146A1-20070405-C03459
    Figure US20070078146A1-20070405-C03460
         		79 530 531
    B-1469
    Figure US20070078146A1-20070405-C03461
    Figure US20070078146A1-20070405-C03462
         		75 487 488
    B-1470
    Figure US20070078146A1-20070405-C03463
    Figure US20070078146A1-20070405-C03464
         		80 480 481
    B-1471
    Figure US20070078146A1-20070405-C03465
    Figure US20070078146A1-20070405-C03466
         		74 496 497
    B-1472
    Figure US20070078146A1-20070405-C03467
    Figure US20070078146A1-20070405-C03468
         		75 540 541
    B-1473
    Figure US20070078146A1-20070405-C03469
    Figure US20070078146A1-20070405-C03470
         		77 476 477
    B-1474
    Figure US20070078146A1-20070405-C03471
    Figure US20070078146A1-20070405-C03472
         		81 530 531
    B-1475
    Figure US20070078146A1-20070405-C03473
    Figure US20070078146A1-20070405-C03474
         		70 487 488
    B-1476
    Figure US20070078146A1-20070405-C03475
    Figure US20070078146A1-20070405-C03476
         		54 540 541
    B-1477
    Figure US20070078146A1-20070405-C03477
    Figure US20070078146A1-20070405-C03478
         		79 546 547
    B-1478
    Figure US20070078146A1-20070405-C03479
    Figure US20070078146A1-20070405-C03480
         		87 394 395
    B-1479
    Figure US20070078146A1-20070405-C03481
    Figure US20070078146A1-20070405-C03482
         		41 504 505
    B-1480
    Figure US20070078146A1-20070405-C03483
    Figure US20070078146A1-20070405-C03484
         		87 451 452
    B-1481
    Figure US20070078146A1-20070405-C03485
    Figure US20070078146A1-20070405-C03486
         		18 416 417
    B-1482
    Figure US20070078146A1-20070405-C03487
    Figure US20070078146A1-20070405-C03488
         		77 427 428
    B-1483
    Figure US20070078146A1-20070405-C03489
    Figure US20070078146A1-20070405-C03490
         		74 406 407
    B-1484
    Figure US20070078146A1-20070405-C03491
    Figure US20070078146A1-20070405-C03492
         		82 422 423
    B-1485
    Figure US20070078146A1-20070405-C03493
    Figure US20070078146A1-20070405-C03494
         		85 460 461
    B-1486
    Figure US20070078146A1-20070405-C03495
    Figure US20070078146A1-20070405-C03496
         		64 406 407
    B-1487
    Figure US20070078146A1-20070405-C03497
    Figure US20070078146A1-20070405-C03498
         		71 392 393
    B-1488
    Figure US20070078146A1-20070405-C03499
    Figure US20070078146A1-20070405-C03500
         		82 427 428
    B-1489
    Figure US20070078146A1-20070405-C03501
    Figure US20070078146A1-20070405-C03502
         		87 444 445
    B-1490
    Figure US20070078146A1-20070405-C03503
    Figure US20070078146A1-20070405-C03504
         		81 462 463
    B-1491
    Figure US20070078146A1-20070405-C03505
    Figure US20070078146A1-20070405-C03506
         		87 462 463
    B-1492
    Figure US20070078146A1-20070405-C03507
    Figure US20070078146A1-20070405-C03508
         		69 364 365
    B-1493
    Figure US20070078146A1-20070405-C03509
    Figure US20070078146A1-20070405-C03510
         		53 417 418
    B-1494
    Figure US20070078146A1-20070405-C03511
    Figure US20070078146A1-20070405-C03512
         		17 426 427
    B-1495
    Figure US20070078146A1-20070405-C03513
    Figure US20070078146A1-20070405-C03514
         		79 460 461
    B-1496
    Figure US20070078146A1-20070405-C03515
    Figure US20070078146A1-20070405-C03516
         		80 444 445
    B-1497
    Figure US20070078146A1-20070405-C03517
    Figure US20070078146A1-20070405-C03518
         		82 460 461
    B-1498
    Figure US20070078146A1-20070405-C03519
    Figure US20070078146A1-20070405-C03520
         		72 378 379
    B-1499
    Figure US20070078146A1-20070405-C03521
    Figure US20070078146A1-20070405-C03522
         		70 432 433
    B-1500
    Figure US20070078146A1-20070405-C03523
    Figure US20070078146A1-20070405-C03524
         		68 390 391
    B-1501
    Figure US20070078146A1-20070405-C03525
    Figure US20070078146A1-20070405-C03526
         		63 394 395
    B-1502
    Figure US20070078146A1-20070405-C03527
    Figure US20070078146A1-20070405-C03528
         		78 408 409
    B-1503
    Figure US20070078146A1-20070405-C03529
    Figure US20070078146A1-20070405-C03530
         		55 404 405
    B-1504
    Figure US20070078146A1-20070405-C03531
    Figure US20070078146A1-20070405-C03532
         		39 418 419
    B-1505
    Figure US20070078146A1-20070405-C03533
    Figure US20070078146A1-20070405-C03534
         		69 540 541
    B-1506
    Figure US20070078146A1-20070405-C03535
    Figure US20070078146A1-20070405-C03536
         		69 462 463
    B-1507
    Figure US20070078146A1-20070405-C03537
    Figure US20070078146A1-20070405-C03538
         		70 496 497
    B-1508
    Figure US20070078146A1-20070405-C03539
    Figure US20070078146A1-20070405-C03540
         		65 480 481
    B-1509
    Figure US20070078146A1-20070405-C03541
    Figure US20070078146A1-20070405-C03542
         		56 414 415
    B-1510
    Figure US20070078146A1-20070405-C03543
    Figure US20070078146A1-20070405-C03544
         		62 400 401
    B-1511
    Figure US20070078146A1-20070405-C03545
    Figure US20070078146A1-20070405-C03546
         		30 468 469
    B-1512
    Figure US20070078146A1-20070405-C03547
    Figure US20070078146A1-20070405-C03548
         		50 476 477
    B-1513
    Figure US20070078146A1-20070405-C03549
    Figure US20070078146A1-20070405-C03550
         		44 540 541
    B-1514
    Figure US20070078146A1-20070405-C03551
    Figure US20070078146A1-20070405-C03552
         		42 530 531
    B-1515
    Figure US20070078146A1-20070405-C03553
    Figure US20070078146A1-20070405-C03554
         		68 496 497
    B-1516
    Figure US20070078146A1-20070405-C03555
    Figure US20070078146A1-20070405-C03556
         		27 429 430
    B-1517
    Figure US20070078146A1-20070405-C03557
    Figure US20070078146A1-20070405-C03558
         		92 466 467
    B-1518
    Figure US20070078146A1-20070405-C03559
    Figure US20070078146A1-20070405-C03560
         		33 379 380
    B-1519
    Figure US20070078146A1-20070405-C03561
    Figure US20070078146A1-20070405-C03562
         		50 393 394
    B-1520
    Figure US20070078146A1-20070405-C03563
    Figure US20070078146A1-20070405-C03564
         		82 435 436
    B-1521
    Figure US20070078146A1-20070405-C03565
    Figure US20070078146A1-20070405-C03566
         		86 509 510
    B-1522
    Figure US20070078146A1-20070405-C03567
    Figure US20070078146A1-20070405-C03568
         		12 405 406
    B-1523
    Figure US20070078146A1-20070405-C03569
    Figure US20070078146A1-20070405-C03570
         		59 459 460
    B-1524
    Figure US20070078146A1-20070405-C03571
    Figure US20070078146A1-20070405-C03572
         		81 459 460
    B-1525
    Figure US20070078146A1-20070405-C03573
    Figure US20070078146A1-20070405-C03574
         		57 419 420
    B-1526
    Figure US20070078146A1-20070405-C03575
    Figure US20070078146A1-20070405-C03576
         		73 410 411
    B-1527
    Figure US20070078146A1-20070405-C03577
    Figure US20070078146A1-20070405-C03578
         		66 520 521
    B-1528
    Figure US20070078146A1-20070405-C03579
    Figure US20070078146A1-20070405-C03580
         		91 467 468
    B-1529
    Figure US20070078146A1-20070405-C03581
    Figure US20070078146A1-20070405-C03582
         		73 432 433
    B-1530
    Figure US20070078146A1-20070405-C03583
    Figure US20070078146A1-20070405-C03584
         		91 443 444
    B-1531
    Figure US20070078146A1-20070405-C03585
    Figure US20070078146A1-20070405-C03586
         		74 422 423
    B-1532
    Figure US20070078146A1-20070405-C03587
    Figure US20070078146A1-20070405-C03588
         		68 438 439
    B-1543
    Figure US20070078146A1-20070405-C03589
    Figure US20070078146A1-20070405-C03590
         		82 476 477
    B-1544
    Figure US20070078146A1-20070405-C03591
    Figure US20070078146A1-20070405-C03592
         		76 460 461
    B-1545
    Figure US20070078146A1-20070405-C03593
    Figure US20070078146A1-20070405-C03594
         		77 476 477
    B-1546
    Figure US20070078146A1-20070405-C03595
    Figure US20070078146A1-20070405-C03596
         		76 394 395
    B-1547
    Figure US20070078146A1-20070405-C03597
    Figure US20070078146A1-20070405-C03598
         		58 448 449
    B-1548
    Figure US20070078146A1-20070405-C03599
    Figure US20070078146A1-20070405-C03600
         		83 406 407
    B-1549
    Figure US20070078146A1-20070405-C03601
    Figure US20070078146A1-20070405-C03602
         		67 410 411
    B-1550
    Figure US20070078146A1-20070405-C03603
    Figure US20070078146A1-20070405-C03604
         		37 424 425
    B-1551
    Figure US20070078146A1-20070405-C03605
    Figure US20070078146A1-20070405-C03606
         		55 420 421
    B-1552
    Figure US20070078146A1-20070405-C03607
    Figure US20070078146A1-20070405-C03608
         		23 434 435
    B-1553
    Figure US20070078146A1-20070405-C03609
    Figure US20070078146A1-20070405-C03610
         		83 556 557
    B-1554
    Figure US20070078146A1-20070405-C03611
    Figure US20070078146A1-20070405-C03612
         		84 478 479
    B-1555
    Figure US20070078146A1-20070405-C03613
    Figure US20070078146A1-20070405-C03614
         		93 512 513
    B-1556
    Figure US20070078146A1-20070405-C03615
    Figure US20070078146A1-20070405-C03616
         		83 496 497
    B-1557
    Figure US20070078146A1-20070405-C03617
    Figure US20070078146A1-20070405-C03618
         		62 430 431
    B-1558
    Figure US20070078146A1-20070405-C03619
    Figure US20070078146A1-20070405-C03620
         		45 416 417
    B-1559
    Figure US20070078146A1-20070405-C03621
    Figure US20070078146A1-20070405-C03622
         		67 484 485
    B-1560
    Figure US20070078146A1-20070405-C03623
    Figure US20070078146A1-20070405-C03624
         		16 492 493
    B-1561
    Figure US20070078146A1-20070405-C03625
    Figure US20070078146A1-20070405-C03626
         		84 556 557
    B-1562
    Figure US20070078146A1-20070405-C03627
    Figure US20070078146A1-20070405-C03628
         		74 546 547
    B-1563
    Figure US20070078146A1-20070405-C03629
    Figure US20070078146A1-20070405-C03630
         		72 512 513
    B-1564
    Figure US20070078146A1-20070405-C03631
    Figure US20070078146A1-20070405-C03632
         		57 445 446
    B-1565
    Figure US20070078146A1-20070405-C03633
    Figure US20070078146A1-20070405-C03634
         		64 482 483
    B-1566
    Figure US20070078146A1-20070405-C03635
    Figure US20070078146A1-20070405-C03636
         		71 395 396
    B-1567
    Figure US20070078146A1-20070405-C03637
    Figure US20070078146A1-20070405-C03638
         		54 409 410
    B-1568
    Figure US20070078146A1-20070405-C03639
    Figure US20070078146A1-20070405-C03640
         		76 451 452
    B-1569
    Figure US20070078146A1-20070405-C03641
    Figure US20070078146A1-20070405-C03642
         		70 525 526
    B-1570
    Figure US20070078146A1-20070405-C03643
    Figure US20070078146A1-20070405-C03644
         		79 421 422
    B-1571
    Figure US20070078146A1-20070405-C03645
    Figure US20070078146A1-20070405-C03646
         		60 475 476
    B-1572
    Figure US20070078146A1-20070405-C03647
    Figure US20070078146A1-20070405-C03648
         		77 475 476
    B-1573
    Figure US20070078146A1-20070405-C03649
    Figure US20070078146A1-20070405-C03650
         		65 435 436
  • proton NMR data for selected members from Examples B-0001 through B-1573 sre shown in the following table.
    Plate ID 1H NMR(solvent), d ppm
    B-0120 (DMF-d7) d 8.53(bd, J=4.99Hz, 2H), 7.44-7.24(m, 11H), 4.41(s, 2H), 4.31(br, 2H)
    B-0224 (DMF-d7) d 8.56(bd, J=4.98Hz, 2H), 7.78-7.69(m, 4H), 7.39-7.19(m, 6H),
    4.23(br, 2H)
    B-0235 (DMF-d7) d 8.47(br, 2H), 7.91-7.75(m, 3H), 7.57-7.53(m, 1H), 7.38-7.34(m,
    2H), 7.21-7.13(m, 4H), 4.20(br, 2H)
    B-0244 (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-0643 7.18(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-1165 Hz, 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-1171 6.83(br, 1H), 7.02(t, J=8.7Hz, 2H), 7.15(d, J=5.6Hz, 2H), 7.40(m, 2H),
    8.59(d, J=5.0Hz, 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 # R2 RL
    Figure US20070078146A1-20070405-C03651
    Examples B-1574 through B-1597 are prepared from Scaffold C-27
    B-1574
    Figure US20070078146A1-20070405-C03652
    Figure US20070078146A1-20070405-C03653
    B-1575
    Figure US20070078146A1-20070405-C03654
    Figure US20070078146A1-20070405-C03655
    B-1576
    Figure US20070078146A1-20070405-C03656
    Figure US20070078146A1-20070405-C03657
    B-1577
    Figure US20070078146A1-20070405-C03658
    Figure US20070078146A1-20070405-C03659
    B-1578
    Figure US20070078146A1-20070405-C03660
    Figure US20070078146A1-20070405-C03661
    B-1579
    Figure US20070078146A1-20070405-C03662
    Figure US20070078146A1-20070405-C03663
    B-1580
    Figure US20070078146A1-20070405-C03664
    Figure US20070078146A1-20070405-C03665
    B-1581
    Figure US20070078146A1-20070405-C03666
    Figure US20070078146A1-20070405-C03667
    B-1582
    Figure US20070078146A1-20070405-C03668
    Figure US20070078146A1-20070405-C03669
    B-1583
    Figure US20070078146A1-20070405-C03670
    Figure US20070078146A1-20070405-C03671
    B-1584
    Figure US20070078146A1-20070405-C03672
    Figure US20070078146A1-20070405-C03673
    B-1585
    Figure US20070078146A1-20070405-C03674
    Figure US20070078146A1-20070405-C03675
    B-1586
    Figure US20070078146A1-20070405-C03676
    Figure US20070078146A1-20070405-C03677
    B-1587
    Figure US20070078146A1-20070405-C03678
    Figure US20070078146A1-20070405-C03679
    B-1588
    Figure US20070078146A1-20070405-C03680
    Figure US20070078146A1-20070405-C03681
    B-1589
    Figure US20070078146A1-20070405-C03682
    Figure US20070078146A1-20070405-C03683
    B-1590
    Figure US20070078146A1-20070405-C03684
    Figure US20070078146A1-20070405-C03685
    B-1591
    Figure US20070078146A1-20070405-C03686
    Figure US20070078146A1-20070405-C03687
    B-1592
    Figure US20070078146A1-20070405-C03688
    Figure US20070078146A1-20070405-C03689
    B-1593
    Figure US20070078146A1-20070405-C03690
    Figure US20070078146A1-20070405-C03691
    B-1594
    Figure US20070078146A1-20070405-C03692
    Figure US20070078146A1-20070405-C03693
    B-1595
    Figure US20070078146A1-20070405-C03694
    Figure US20070078146A1-20070405-C03695
    B-1596
    Figure US20070078146A1-20070405-C03696
    Figure US20070078146A1-20070405-C03697
    B-1597
    Figure US20070078146A1-20070405-C03698
    Figure US20070078146A1-20070405-C03699
    Figure US20070078146A1-20070405-C03700
    Examples B-1598 through B-1621 are prep ared from Scaffold C-28
    B-1598
    Figure US20070078146A1-20070405-C03701
    Figure US20070078146A1-20070405-C03702
    B-1599
    Figure US20070078146A1-20070405-C03703
    Figure US20070078146A1-20070405-C03704
    B-1600
    Figure US20070078146A1-20070405-C03705
    Figure US20070078146A1-20070405-C03706
    B-1601
    Figure US20070078146A1-20070405-C03707
    Figure US20070078146A1-20070405-C03708
    B-1602
    Figure US20070078146A1-20070405-C03709
    Figure US20070078146A1-20070405-C03710
    B-1603
    Figure US20070078146A1-20070405-C03711
    Figure US20070078146A1-20070405-C03712
    B-1604
    Figure US20070078146A1-20070405-C03713
    Figure US20070078146A1-20070405-C03714
    B-1605
    Figure US20070078146A1-20070405-C03715
    Figure US20070078146A1-20070405-C03716
    B-1606
    Figure US20070078146A1-20070405-C03717
    Figure US20070078146A1-20070405-C03718
    B-1607
    Figure US20070078146A1-20070405-C03719
    Figure US20070078146A1-20070405-C03720
    B-1608
    Figure US20070078146A1-20070405-C03721
    Figure US20070078146A1-20070405-C03722
    B-1609
    Figure US20070078146A1-20070405-C03723
    Figure US20070078146A1-20070405-C03724
    B-1610
    Figure US20070078146A1-20070405-C03725
    Figure US20070078146A1-20070405-C03726
    B-1611
    Figure US20070078146A1-20070405-C03727
    Figure US20070078146A1-20070405-C03728
    B-1612
    Figure US20070078146A1-20070405-C03729
    Figure US20070078146A1-20070405-C03730
    B-1613
    Figure US20070078146A1-20070405-C03731
    Figure US20070078146A1-20070405-C03732
    B-1614
    Figure US20070078146A1-20070405-C03733
    Figure US20070078146A1-20070405-C03734
    B-1615
    Figure US20070078146A1-20070405-C03735
    Figure US20070078146A1-20070405-C03736
    B-1616
    Figure US20070078146A1-20070405-C03737
    Figure US20070078146A1-20070405-C03738
    B-1617
    Figure US20070078146A1-20070405-C03739
    Figure US20070078146A1-20070405-C03740
    B-1618
    Figure US20070078146A1-20070405-C03741
    Figure US20070078146A1-20070405-C03742
    B-1619
    Figure US20070078146A1-20070405-C03743
    Figure US20070078146A1-20070405-C03744
    B-1620
    Figure US20070078146A1-20070405-C03745
    Figure US20070078146A1-20070405-C03746
    B-1621
    Figure US20070078146A1-20070405-C03747
    Figure US20070078146A1-20070405-C03748
    Figure US20070078146A1-20070405-C03749
    Examples B-1622 through B-1645 are prepared from Scaffold C-38
    B-1622
    Figure US20070078146A1-20070405-C03750
    Figure US20070078146A1-20070405-C03751
    B-1623
    Figure US20070078146A1-20070405-C03752
    Figure US20070078146A1-20070405-C03753
    B-1624
    Figure US20070078146A1-20070405-C03754
    Figure US20070078146A1-20070405-C03755
    B-1625
    Figure US20070078146A1-20070405-C03756
    Figure US20070078146A1-20070405-C03757
    B-1626
    Figure US20070078146A1-20070405-C03758
    Figure US20070078146A1-20070405-C03759
    B-1627
    Figure US20070078146A1-20070405-C03760
    Figure US20070078146A1-20070405-C03761
    B-1628
    Figure US20070078146A1-20070405-C03762
    Figure US20070078146A1-20070405-C03763
    B-1629
    Figure US20070078146A1-20070405-C03764
    Figure US20070078146A1-20070405-C03765
    B-1630
    Figure US20070078146A1-20070405-C03766
    Figure US20070078146A1-20070405-C03767
    B-1631
    Figure US20070078146A1-20070405-C03768
    Figure US20070078146A1-20070405-C03769
    B-1632
    Figure US20070078146A1-20070405-C03770
    Figure US20070078146A1-20070405-C03771
    B-1633
    Figure US20070078146A1-20070405-C03772
    Figure US20070078146A1-20070405-C03773
    B-1634
    Figure US20070078146A1-20070405-C03774
    Figure US20070078146A1-20070405-C03775
    B-1635
    Figure US20070078146A1-20070405-C03776
    Figure US20070078146A1-20070405-C03777
    B-1636
    Figure US20070078146A1-20070405-C03778
    Figure US20070078146A1-20070405-C03779
    B-1637
    Figure US20070078146A1-20070405-C03780
    Figure US20070078146A1-20070405-C03781
    B-1638
    Figure US20070078146A1-20070405-C03782
    Figure US20070078146A1-20070405-C03783
    B-1639
    Figure US20070078146A1-20070405-C03784
    Figure US20070078146A1-20070405-C03785
    B-1640
    Figure US20070078146A1-20070405-C03786
    Figure US20070078146A1-20070405-C03787
    B-1641
    Figure US20070078146A1-20070405-C03788
    Figure US20070078146A1-20070405-C03789
    B-1642
    Figure US20070078146A1-20070405-C03790
    Figure US20070078146A1-20070405-C03791
    B-1643
    Figure US20070078146A1-20070405-C03792
    Figure US20070078146A1-20070405-C03793
    B-1644
    Figure US20070078146A1-20070405-C03794
    Figure US20070078146A1-20070405-C03795
    B-1645
    Figure US20070078146A1-20070405-C03796
    Figure US20070078146A1-20070405-C03797
    Figure US20070078146A1-20070405-C03798
    Examples B-1646 through B-1669 are prepared from Scaffold C-39
    B-1646
    Figure US20070078146A1-20070405-C03799
    Figure US20070078146A1-20070405-C03800
    B-1647
    Figure US20070078146A1-20070405-C03801
    Figure US20070078146A1-20070405-C03802
    B-1648
    Figure US20070078146A1-20070405-C03803
    Figure US20070078146A1-20070405-C03804
    B-1649
    Figure US20070078146A1-20070405-C03805
    Figure US20070078146A1-20070405-C03806
    B-1650
    Figure US20070078146A1-20070405-C03807
    Figure US20070078146A1-20070405-C03808
    B-1651
    Figure US20070078146A1-20070405-C03809
    Figure US20070078146A1-20070405-C03810
    B-1652
    Figure US20070078146A1-20070405-C03811
    Figure US20070078146A1-20070405-C03812
    B-1653
    Figure US20070078146A1-20070405-C03813
    Figure US20070078146A1-20070405-C03814
    B-1654
    Figure US20070078146A1-20070405-C03815
    Figure US20070078146A1-20070405-C03816
    B-1655
    Figure US20070078146A1-20070405-C03817
    Figure US20070078146A1-20070405-C03818
    B-1656
    Figure US20070078146A1-20070405-C03819
    Figure US20070078146A1-20070405-C03820
    B-1657
    Figure US20070078146A1-20070405-C03821
    Figure US20070078146A1-20070405-C03822
    B-1658
    Figure US20070078146A1-20070405-C03823
    Figure US20070078146A1-20070405-C03824
    B-1659
    Figure US20070078146A1-20070405-C03825
    Figure US20070078146A1-20070405-C03826
    B-1660
    Figure US20070078146A1-20070405-C03827
    Figure US20070078146A1-20070405-C03828
    B-1661
    Figure US20070078146A1-20070405-C03829
    Figure US20070078146A1-20070405-C03830
    B-1662
    Figure US20070078146A1-20070405-C03831
    Figure US20070078146A1-20070405-C03832
    B-1663
    Figure US20070078146A1-20070405-C03833
    Figure US20070078146A1-20070405-C03834
    B-1664
    Figure US20070078146A1-20070405-C03835
    Figure US20070078146A1-20070405-C03836
    B-1665
    Figure US20070078146A1-20070405-C03837
    Figure US20070078146A1-20070405-C03838
    B-1666
    Figure US20070078146A1-20070405-C03839
    Figure US20070078146A1-20070405-C03840
    B-1667
    Figure US20070078146A1-20070405-C03841
    Figure US20070078146A1-20070405-C03842
    B-1668
    Figure US20070078146A1-20070405-C03843
    Figure US20070078146A1-20070405-C03844
    B-1669
    Figure US20070078146A1-20070405-C03845
    Figure US20070078146A1-20070405-C03846
    Figure US20070078146A1-20070405-C03847
    Examples B-1670 through B-1693 are prepared from Scaffold C-65
    B-1670
    Figure US20070078146A1-20070405-C03848
    Figure US20070078146A1-20070405-C03849
    B-1671
    Figure US20070078146A1-20070405-C03850
    Figure US20070078146A1-20070405-C03851
    B-1672
    Figure US20070078146A1-20070405-C03852
    Figure US20070078146A1-20070405-C03853
    B-1673
    Figure US20070078146A1-20070405-C03854
    Figure US20070078146A1-20070405-C03855
    B-1674
    Figure US20070078146A1-20070405-C03856
    Figure US20070078146A1-20070405-C03857
    B-1675
    Figure US20070078146A1-20070405-C03858
    Figure US20070078146A1-20070405-C03859
    B-1676
    Figure US20070078146A1-20070405-C03860
    Figure US20070078146A1-20070405-C03861
    B-1677
    Figure US20070078146A1-20070405-C03862
    Figure US20070078146A1-20070405-C03863
    B-1678
    Figure US20070078146A1-20070405-C03864
    Figure US20070078146A1-20070405-C03865
    B-1679
    Figure US20070078146A1-20070405-C03866
    Figure US20070078146A1-20070405-C03867
    B-1680
    Figure US20070078146A1-20070405-C03868
    Figure US20070078146A1-20070405-C03869
    B-1681
    Figure US20070078146A1-20070405-C03870
    Figure US20070078146A1-20070405-C03871
    B-1682
    Figure US20070078146A1-20070405-C03872
    Figure US20070078146A1-20070405-C03873
    B-1683
    Figure US20070078146A1-20070405-C03874
    Figure US20070078146A1-20070405-C03875
    B-1684
    Figure US20070078146A1-20070405-C03876
    Figure US20070078146A1-20070405-C03877
    B-1685
    Figure US20070078146A1-20070405-C03878
    Figure US20070078146A1-20070405-C03879
    B-1686
    Figure US20070078146A1-20070405-C03880
    Figure US20070078146A1-20070405-C03881
    B-1687
    Figure US20070078146A1-20070405-C03882
    Figure US20070078146A1-20070405-C03883
    B-1688
    Figure US20070078146A1-20070405-C03884
    Figure US20070078146A1-20070405-C03885
    B-1689
    Figure US20070078146A1-20070405-C03886
    Figure US20070078146A1-20070405-C03887
    B-1690
    Figure US20070078146A1-20070405-C03888
    Figure US20070078146A1-20070405-C03889
    B-1691
    Figure US20070078146A1-20070405-C03890
    Figure US20070078146A1-20070405-C03891
    B-1692
    Figure US20070078146A1-20070405-C03892
    Figure US20070078146A1-20070405-C03893
    B-1693
    Figure US20070078146A1-20070405-C03894
    Figure US20070078146A1-20070405-C03895
    Figure US20070078146A1-20070405-C03896
    Examples B-1694 through B-1717 are prepared from Scaffold C-66
    B-1694
    Figure US20070078146A1-20070405-C03897
    Figure US20070078146A1-20070405-C03898
    B-1695
    Figure US20070078146A1-20070405-C03899
    Figure US20070078146A1-20070405-C03900
    B-1696
    Figure US20070078146A1-20070405-C03901
    Figure US20070078146A1-20070405-C03902
    B-1697
    Figure US20070078146A1-20070405-C03903
    Figure US20070078146A1-20070405-C03904
    B-1698
    Figure US20070078146A1-20070405-C03905
    Figure US20070078146A1-20070405-C03906
    B-1699
    Figure US20070078146A1-20070405-C03907
    Figure US20070078146A1-20070405-C03908
    B-1700
    Figure US20070078146A1-20070405-C03909
    Figure US20070078146A1-20070405-C03910
    B-1701
    Figure US20070078146A1-20070405-C03911
    Figure US20070078146A1-20070405-C03912
    B-1702
    Figure US20070078146A1-20070405-C03913
    Figure US20070078146A1-20070405-C03914
    B-1703
    Figure US20070078146A1-20070405-C03915
    Figure US20070078146A1-20070405-C03916
    B-1704
    Figure US20070078146A1-20070405-C03917
    Figure US20070078146A1-20070405-C03918
    B-1705
    Figure US20070078146A1-20070405-C03919
    Figure US20070078146A1-20070405-C03920
    B-1706
    Figure US20070078146A1-20070405-C03921
    Figure US20070078146A1-20070405-C03922
    B-1707
    Figure US20070078146A1-20070405-C03923
    Figure US20070078146A1-20070405-C03924
    B-1708
    Figure US20070078146A1-20070405-C03925
    Figure US20070078146A1-20070405-C03926
    B-1709
    Figure US20070078146A1-20070405-C03927
    Figure US20070078146A1-20070405-C03928
    B-1710
    Figure US20070078146A1-20070405-C03929
    Figure US20070078146A1-20070405-C03930
    B-1711
    Figure US20070078146A1-20070405-C03931
    Figure US20070078146A1-20070405-C03932
    B-1712
    Figure US20070078146A1-20070405-C03933
    Figure US20070078146A1-20070405-C03934
    B-1713
    Figure US20070078146A1-20070405-C03935
    Figure US20070078146A1-20070405-C03936
    B-1714
    Figure US20070078146A1-20070405-C03937
    Figure US20070078146A1-20070405-C03938
    B-1715
    Figure US20070078146A1-20070405-C03939
    Figure US20070078146A1-20070405-C03940
    B-1716
    Figure US20070078146A1-20070405-C03941
    Figure US20070078146A1-20070405-C03942
    B-1717
    Figure US20070078146A1-20070405-C03943
    Figure US20070078146A1-20070405-C03944
    Figure US20070078146A1-20070405-C03945
    Examples B-1718 through B-1741 are prepared from Scaffold C-69
    B-1718
    Figure US20070078146A1-20070405-C03946
    Figure US20070078146A1-20070405-C03947
    B-1719
    Figure US20070078146A1-20070405-C03948
    Figure US20070078146A1-20070405-C03949
    B-1720
    Figure US20070078146A1-20070405-C03950
    Figure US20070078146A1-20070405-C03951
    B-1721
    Figure US20070078146A1-20070405-C03952
    Figure US20070078146A1-20070405-C03953
    B-1722
    Figure US20070078146A1-20070405-C03954
    Figure US20070078146A1-20070405-C03955
    B-1723
    Figure US20070078146A1-20070405-C03956
    Figure US20070078146A1-20070405-C03957
    B-1724
    Figure US20070078146A1-20070405-C03958
    Figure US20070078146A1-20070405-C03959
    B-1725
    Figure US20070078146A1-20070405-C03960
    Figure US20070078146A1-20070405-C03961
    B-1726
    Figure US20070078146A1-20070405-C03962
    Figure US20070078146A1-20070405-C03963
    B-1727
    Figure US20070078146A1-20070405-C03964
    Figure US20070078146A1-20070405-C03965
    B-1728
    Figure US20070078146A1-20070405-C03966
    Figure US20070078146A1-20070405-C03967
    B-1729
    Figure US20070078146A1-20070405-C03968
    Figure US20070078146A1-20070405-C03969
    B-1730
    Figure US20070078146A1-20070405-C03970
    Figure US20070078146A1-20070405-C03971
    B-1731
    Figure US20070078146A1-20070405-C03972
    Figure US20070078146A1-20070405-C03973
    B-1732
    Figure US20070078146A1-20070405-C03974
    Figure US20070078146A1-20070405-C03975
    B-1733
    Figure US20070078146A1-20070405-C03976
    Figure US20070078146A1-20070405-C03977
    B-1734
    Figure US20070078146A1-20070405-C03978
    Figure US20070078146A1-20070405-C03979
    B-1735
    Figure US20070078146A1-20070405-C03980
    Figure US20070078146A1-20070405-C03981
    B-1736
    Figure US20070078146A1-20070405-C03982
    Figure US20070078146A1-20070405-C03983
    B-1737
    Figure US20070078146A1-20070405-C03984
    Figure US20070078146A1-20070405-C03985
    B-1738
    Figure US20070078146A1-20070405-C03986
    Figure US20070078146A1-20070405-C03987
    B-1739
    Figure US20070078146A1-20070405-C03988
    Figure US20070078146A1-20070405-C03989
    B-1740
    Figure US20070078146A1-20070405-C03990
    Figure US20070078146A1-20070405-C03991
    B-1741
    Figure US20070078146A1-20070405-C03992
    Figure US20070078146A1-20070405-C03993
    Figure US20070078146A1-20070405-C03994
    Examples B-1742 through B-1765 are prepared from Scaffold C-70
    B-1742
    Figure US20070078146A1-20070405-C03995
    Figure US20070078146A1-20070405-C03996
    B-1743
    Figure US20070078146A1-20070405-C03997
    Figure US20070078146A1-20070405-C03998
    B-1744
    Figure US20070078146A1-20070405-C03999
    Figure US20070078146A1-20070405-C04000
    B-1745
    Figure US20070078146A1-20070405-C04001
    Figure US20070078146A1-20070405-C04002
    B-1746
    Figure US20070078146A1-20070405-C04003
    Figure US20070078146A1-20070405-C04004
    B-1747
    Figure US20070078146A1-20070405-C04005
    Figure US20070078146A1-20070405-C04006
    B-1748
    Figure US20070078146A1-20070405-C04007
    Figure US20070078146A1-20070405-C04008
    B-1749
    Figure US20070078146A1-20070405-C04009
    Figure US20070078146A1-20070405-C04010
    B-1750
    Figure US20070078146A1-20070405-C04011
    Figure US20070078146A1-20070405-C04012
    B-1751
    Figure US20070078146A1-20070405-C04013
    Figure US20070078146A1-20070405-C04014
    B-1752
    Figure US20070078146A1-20070405-C04015
    Figure US20070078146A1-20070405-C04016
    B-1753
    Figure US20070078146A1-20070405-C04017
    Figure US20070078146A1-20070405-C04018
    B-1754
    Figure US20070078146A1-20070405-C04019
    Figure US20070078146A1-20070405-C04020
    B-1755
    Figure US20070078146A1-20070405-C04021
    Figure US20070078146A1-20070405-C04022
    B-1756
    Figure US20070078146A1-20070405-C04023
    Figure US20070078146A1-20070405-C04024
    B-1757
    Figure US20070078146A1-20070405-C04025
    Figure US20070078146A1-20070405-C04026
    B-1758
    Figure US20070078146A1-20070405-C04027
    Figure US20070078146A1-20070405-C04028
    B-1759
    Figure US20070078146A1-20070405-C04029
    Figure US20070078146A1-20070405-C04030
    B-1760
    Figure US20070078146A1-20070405-C04031
    Figure US20070078146A1-20070405-C04032
    B-1761
    Figure US20070078146A1-20070405-C04033
    Figure US20070078146A1-20070405-C04034
    B-1762
    Figure US20070078146A1-20070405-C04035
    Figure US20070078146A1-20070405-C04036
    B-1763
    Figure US20070078146A1-20070405-C04037
    Figure US20070078146A1-20070405-C04038
    B-1764
    Figure US20070078146A1-20070405-C04039
    Figure US20070078146A1-20070405-C04040
    B-1765
    Figure US20070078146A1-20070405-C04041
    Figure US20070078146A1-20070405-C04042
    Figure US20070078146A1-20070405-C04043
    Examples B-1766 through B-1789 are prepared from Scaffold C-71
    B-1766
    Figure US20070078146A1-20070405-C04044
    Figure US20070078146A1-20070405-C04045
    B-1767
    Figure US20070078146A1-20070405-C04046
    Figure US20070078146A1-20070405-C04047
    B-1768
    Figure US20070078146A1-20070405-C04048
    Figure US20070078146A1-20070405-C04049
    B-1769
    Figure US20070078146A1-20070405-C04050
    Figure US20070078146A1-20070405-C04051
    B-1770
    Figure US20070078146A1-20070405-C04052
    Figure US20070078146A1-20070405-C04053
    B-1771
    Figure US20070078146A1-20070405-C04054
    Figure US20070078146A1-20070405-C04055
    B-1772
    Figure US20070078146A1-20070405-C04056
    Figure US20070078146A1-20070405-C04057
    B-1773
    Figure US20070078146A1-20070405-C04058
    Figure US20070078146A1-20070405-C04059
    B-1774
    Figure US20070078146A1-20070405-C04060
    Figure US20070078146A1-20070405-C04061
    B-1775
    Figure US20070078146A1-20070405-C04062
    Figure US20070078146A1-20070405-C04063
    B-1776
    Figure US20070078146A1-20070405-C04064
    Figure US20070078146A1-20070405-C04065
    B-1777
    Figure US20070078146A1-20070405-C04066
    Figure US20070078146A1-20070405-C04067
    B-1778
    Figure US20070078146A1-20070405-C04068
    Figure US20070078146A1-20070405-C04069
    B-1779
    Figure US20070078146A1-20070405-C04070
    Figure US20070078146A1-20070405-C04071
    B-1780
    Figure US20070078146A1-20070405-C04072
    Figure US20070078146A1-20070405-C04073
    B-1781
    Figure US20070078146A1-20070405-C04074
    Figure US20070078146A1-20070405-C04075
    B-1782
    Figure US20070078146A1-20070405-C04076
    Figure US20070078146A1-20070405-C04077
    B-1783
    Figure US20070078146A1-20070405-C04078
    Figure US20070078146A1-20070405-C04079
    B-1784
    Figure US20070078146A1-20070405-C04080
    Figure US20070078146A1-20070405-C04081
    B-1785
    Figure US20070078146A1-20070405-C04082
    Figure US20070078146A1-20070405-C04083
    B-1786
    Figure US20070078146A1-20070405-C04084
    Figure US20070078146A1-20070405-C04085
    B-1787
    Figure US20070078146A1-20070405-C04086
    Figure US20070078146A1-20070405-C04087
    B-1788
    Figure US20070078146A1-20070405-C04088
    Figure US20070078146A1-20070405-C04089
    B-1789
    Figure US20070078146A1-20070405-C04090
    Figure US20070078146A1-20070405-C04091
    Figure US20070078146A1-20070405-C04092
    Examples B-1790 through B-1813 are prepared from Scaffold C-72
    B-1790
    Figure US20070078146A1-20070405-C04093
    Figure US20070078146A1-20070405-C04094
    B-1791
    Figure US20070078146A1-20070405-C04095
    Figure US20070078146A1-20070405-C04096
    B-1792
    Figure US20070078146A1-20070405-C04097
    Figure US20070078146A1-20070405-C04098
    B-1793
    Figure US20070078146A1-20070405-C04099
    Figure US20070078146A1-20070405-C04100
    B-1794
    Figure US20070078146A1-20070405-C04101
    Figure US20070078146A1-20070405-C04102
    B-1795
    Figure US20070078146A1-20070405-C04103
    Figure US20070078146A1-20070405-C04104
    B-1796
    Figure US20070078146A1-20070405-C04105
    Figure US20070078146A1-20070405-C04106
    B-1797
    Figure US20070078146A1-20070405-C04107
    Figure US20070078146A1-20070405-C04108
    B-1798
    Figure US20070078146A1-20070405-C04109
    Figure US20070078146A1-20070405-C04110
    B-1799
    Figure US20070078146A1-20070405-C04111
    Figure US20070078146A1-20070405-C04112
    B-1800
    Figure US20070078146A1-20070405-C04113
    Figure US20070078146A1-20070405-C04114
    B-1801
    Figure US20070078146A1-20070405-C04115
    Figure US20070078146A1-20070405-C04116
    B-1802
    Figure US20070078146A1-20070405-C04117
    Figure US20070078146A1-20070405-C04118
    B-1803
    Figure US20070078146A1-20070405-C04119
    Figure US20070078146A1-20070405-C04120
    B-1804
    Figure US20070078146A1-20070405-C04121
    Figure US20070078146A1-20070405-C04122
    B-1805
    Figure US20070078146A1-20070405-C04123
    Figure US20070078146A1-20070405-C04124
    B-1806
    Figure US20070078146A1-20070405-C04125
    Figure US20070078146A1-20070405-C04126
    B-1807
    Figure US20070078146A1-20070405-C04127
    Figure US20070078146A1-20070405-C04128
    B-1808
    Figure US20070078146A1-20070405-C04129
    Figure US20070078146A1-20070405-C04130
    B-1809
    Figure US20070078146A1-20070405-C04131
    Figure US20070078146A1-20070405-C04132
    B-1810
    Figure US20070078146A1-20070405-C04133
    Figure US20070078146A1-20070405-C04134
    B-1811
    Figure US20070078146A1-20070405-C04135
    Figure US20070078146A1-20070405-C04136
    B-1812
    Figure US20070078146A1-20070405-C04137
    Figure US20070078146A1-20070405-C04138
    B-1813
    Figure US20070078146A1-20070405-C04139
    Figure US20070078146A1-20070405-C04140
    Figure US20070078146A1-20070405-C04141
    Examples B-1814 through B-1837 are prepared from Scaffold C-73
    B-1814
    Figure US20070078146A1-20070405-C04142
    Figure US20070078146A1-20070405-C04143
    B-1815
    Figure US20070078146A1-20070405-C04144
    Figure US20070078146A1-20070405-C04145
    B-1816
    Figure US20070078146A1-20070405-C04146
    Figure US20070078146A1-20070405-C04147
    B-1817
    Figure US20070078146A1-20070405-C04148
    Figure US20070078146A1-20070405-C04149
    B-1818
    Figure US20070078146A1-20070405-C04150
    Figure US20070078146A1-20070405-C04151
    B-1819
    Figure US20070078146A1-20070405-C04152
    Figure US20070078146A1-20070405-C04153
    B-1820
    Figure US20070078146A1-20070405-C04154
    Figure US20070078146A1-20070405-C04155
    B-1821
    Figure US20070078146A1-20070405-C04156
    Figure US20070078146A1-20070405-C04157
    B-1822
    Figure US20070078146A1-20070405-C04158
    Figure US20070078146A1-20070405-C04159
    B-1823
    Figure US20070078146A1-20070405-C04160
    Figure US20070078146A1-20070405-C04161
    B-1824
    Figure US20070078146A1-20070405-C04162
    Figure US20070078146A1-20070405-C04163
    B-1825
    Figure US20070078146A1-20070405-C04164
    Figure US20070078146A1-20070405-C04165
    B-1826
    Figure US20070078146A1-20070405-C04166
    Figure US20070078146A1-20070405-C04167
    B-1827
    Figure US20070078146A1-20070405-C04168
    Figure US20070078146A1-20070405-C04169
    B-1828
    Figure US20070078146A1-20070405-C04170
    Figure US20070078146A1-20070405-C04171
    B-1829
    Figure US20070078146A1-20070405-C04172
    Figure US20070078146A1-20070405-C04173
    B-1830
    Figure US20070078146A1-20070405-C04174
    Figure US20070078146A1-20070405-C04175
    B-1831
    Figure US20070078146A1-20070405-C04176
    Figure US20070078146A1-20070405-C04177
    B-1832
    Figure US20070078146A1-20070405-C04178
    Figure US20070078146A1-20070405-C04179
    B-1833
    Figure US20070078146A1-20070405-C04180
    Figure US20070078146A1-20070405-C04181
    B-1834
    Figure US20070078146A1-20070405-C04182
    Figure US20070078146A1-20070405-C04183
    B-1835
    Figure US20070078146A1-20070405-C04184
    Figure US20070078146A1-20070405-C04185
    B-1836
    Figure US20070078146A1-20070405-C04186
    Figure US20070078146A1-20070405-C04187
    B-1837
    Figure US20070078146A1-20070405-C04188
    Figure US20070078146A1-20070405-C04189
    Figure US20070078146A1-20070405-C04190
    Examples B-1838 through B-1861 are prepared from Scaffold C-33
    B-1838
    Figure US20070078146A1-20070405-C04191
    Figure US20070078146A1-20070405-C04192
    B-1839
    Figure US20070078146A1-20070405-C04193
    Figure US20070078146A1-20070405-C04194
    B-1840
    Figure US20070078146A1-20070405-C04195
    Figure US20070078146A1-20070405-C04196
    B-1841
    Figure US20070078146A1-20070405-C04197
    Figure US20070078146A1-20070405-C04198
    B-1842
    Figure US20070078146A1-20070405-C04199
    Figure US20070078146A1-20070405-C04200
    B-1843
    Figure US20070078146A1-20070405-C04201
    Figure US20070078146A1-20070405-C04202
    B-1844
    Figure US20070078146A1-20070405-C04203
    Figure US20070078146A1-20070405-C04204
    B-1845
    Figure US20070078146A1-20070405-C04205
    Figure US20070078146A1-20070405-C04206
    B-1846
    Figure US20070078146A1-20070405-C04207
    Figure US20070078146A1-20070405-C04208
    B-1847
    Figure US20070078146A1-20070405-C04209
    Figure US20070078146A1-20070405-C04210
    B-1848
    Figure US20070078146A1-20070405-C04211
    Figure US20070078146A1-20070405-C04212
    B-1849
    Figure US20070078146A1-20070405-C04213
    Figure US20070078146A1-20070405-C04214
    B-1850
    Figure US20070078146A1-20070405-C04215
    Figure US20070078146A1-20070405-C04216
    B-1851
    Figure US20070078146A1-20070405-C04217
    Figure US20070078146A1-20070405-C04218
    B-1852
    Figure US20070078146A1-20070405-C04219
    Figure US20070078146A1-20070405-C04220
    B-1853
    Figure US20070078146A1-20070405-C04221
    Figure US20070078146A1-20070405-C04222
    B-1854
    Figure US20070078146A1-20070405-C04223
    Figure US20070078146A1-20070405-C04224
    B-1855
    Figure US20070078146A1-20070405-C04225
    Figure US20070078146A1-20070405-C04226
    B-1856
    Figure US20070078146A1-20070405-C04227
    Figure US20070078146A1-20070405-C04228
    B-1857
    Figure US20070078146A1-20070405-C04229
    Figure US20070078146A1-20070405-C04230
    B-1858
    Figure US20070078146A1-20070405-C04231
    Figure US20070078146A1-20070405-C04232
    B-1859
    Figure US20070078146A1-20070405-C04233
    Figure US20070078146A1-20070405-C04234
    B-1860
    Figure US20070078146A1-20070405-C04235
    Figure US20070078146A1-20070405-C04236
    B-1861
    Figure US20070078146A1-20070405-C04237
    Figure US20070078146A1-20070405-C04238
    Figure US20070078146A1-20070405-C04239
    Examples B-1862 through B-1885 are prepared from Scaffold C-45
    B-1862
    Figure US20070078146A1-20070405-C04240
    Figure US20070078146A1-20070405-C04241
    B-1863
    Figure US20070078146A1-20070405-C04242
    Figure US20070078146A1-20070405-C04243
    B-1864
    Figure US20070078146A1-20070405-C04244
    Figure US20070078146A1-20070405-C04245
    B-1865
    Figure US20070078146A1-20070405-C04246
    Figure US20070078146A1-20070405-C04247
    B-1866
    Figure US20070078146A1-20070405-C04248
    Figure US20070078146A1-20070405-C04249
    B-1867
    Figure US20070078146A1-20070405-C04250
    Figure US20070078146A1-20070405-C04251
    B-1868
    Figure US20070078146A1-20070405-C04252
    Figure US20070078146A1-20070405-C04253
    B-1869
    Figure US20070078146A1-20070405-C04254
    Figure US20070078146A1-20070405-C04255
    B-1870
    Figure US20070078146A1-20070405-C04256
    Figure US20070078146A1-20070405-C04257
    B-1871
    Figure US20070078146A1-20070405-C04258
    Figure US20070078146A1-20070405-C04259
    B-1872
    Figure US20070078146A1-20070405-C04260
    Figure US20070078146A1-20070405-C04261
    B-1873
    Figure US20070078146A1-20070405-C04262
    Figure US20070078146A1-20070405-C04263
    B-1874
    Figure US20070078146A1-20070405-C04264
    Figure US20070078146A1-20070405-C04265
    B-1875
    Figure US20070078146A1-20070405-C04266
    Figure US20070078146A1-20070405-C04267
    B-1876
    Figure US20070078146A1-20070405-C04268
    Figure US20070078146A1-20070405-C04269
    B-1877
    Figure US20070078146A1-20070405-C04270
    Figure US20070078146A1-20070405-C04271
    B-1878
    Figure US20070078146A1-20070405-C04272
    Figure US20070078146A1-20070405-C04273
    B-1879
    Figure US20070078146A1-20070405-C04274
    Figure US20070078146A1-20070405-C04275
    B-1880
    Figure US20070078146A1-20070405-C04276
    Figure US20070078146A1-20070405-C04277
    B-1881
    Figure US20070078146A1-20070405-C04278
    Figure US20070078146A1-20070405-C04279
    B-1882
    Figure US20070078146A1-20070405-C04280
    Figure US20070078146A1-20070405-C04281
    B-1883
    Figure US20070078146A1-20070405-C04282
    Figure US20070078146A1-20070405-C04283
    B-1884
    Figure US20070078146A1-20070405-C04284
    Figure US20070078146A1-20070405-C04285
    B-1885
    Figure US20070078146A1-20070405-C04286
    Figure US20070078146A1-20070405-C04287
    Figure US20070078146A1-20070405-C04288
    Examples B-1886 through B-1909 prepared from Scaffold C-42
    B-1886
    Figure US20070078146A1-20070405-C04289
    Figure US20070078146A1-20070405-C04290
    B-1887
    Figure US20070078146A1-20070405-C04291
    Figure US20070078146A1-20070405-C04292
    B-1888
    Figure US20070078146A1-20070405-C04293
    Figure US20070078146A1-20070405-C04294
    B-1889
    Figure US20070078146A1-20070405-C04295
    Figure US20070078146A1-20070405-C04296
    B-1890
    Figure US20070078146A1-20070405-C04297
    Figure US20070078146A1-20070405-C04298
    B-1891
    Figure US20070078146A1-20070405-C04299
    Figure US20070078146A1-20070405-C04300
    B-1892
    Figure US20070078146A1-20070405-C04301
    Figure US20070078146A1-20070405-C04302
    B-1893
    Figure US20070078146A1-20070405-C04303
    Figure US20070078146A1-20070405-C04304
    B-1894
    Figure US20070078146A1-20070405-C04305
    Figure US20070078146A1-20070405-C04306
    B-1895
    Figure US20070078146A1-20070405-C04307
    Figure US20070078146A1-20070405-C04308
    B-1896
    Figure US20070078146A1-20070405-C04309
    Figure US20070078146A1-20070405-C04310
    B-1897
    Figure US20070078146A1-20070405-C04311
    Figure US20070078146A1-20070405-C04312
    B-1898
    Figure US20070078146A1-20070405-C04313
    Figure US20070078146A1-20070405-C04314
    B-1899
    Figure US20070078146A1-20070405-C04315
    Figure US20070078146A1-20070405-C04316
    B-1900
    Figure US20070078146A1-20070405-C04317
    Figure US20070078146A1-20070405-C04318
    B-1901
    Figure US20070078146A1-20070405-C04319
    Figure US20070078146A1-20070405-C04320
    B-1902
    Figure US20070078146A1-20070405-C04321
    Figure US20070078146A1-20070405-C04322
    B-1903
    Figure US20070078146A1-20070405-C04323
    Figure US20070078146A1-20070405-C04324
    B-1904
    Figure US20070078146A1-20070405-C04325
    Figure US20070078146A1-20070405-C04326
    B-1905
    Figure US20070078146A1-20070405-C04327
    Figure US20070078146A1-20070405-C04328
    B-1906
    Figure US20070078146A1-20070405-C04329
    Figure US20070078146A1-20070405-C04330
    B-1907
    Figure US20070078146A1-20070405-C04331
    Figure US20070078146A1-20070405-C04332
    B-1908
    Figure US20070078146A1-20070405-C04333
    Figure US20070078146A1-20070405-C04334
    B-1909
    Figure US20070078146A1-20070405-C04335
    Figure US20070078146A1-20070405-C04336
    Figure US20070078146A1-20070405-C04337
    Examples B-1910 through B-1933 are prepared from Scaffold C-44
    B-1910
    Figure US20070078146A1-20070405-C04338
    Figure US20070078146A1-20070405-C04339
    B-1911
    Figure US20070078146A1-20070405-C04340
    Figure US20070078146A1-20070405-C04341
    B-1912
    Figure US20070078146A1-20070405-C04342
    Figure US20070078146A1-20070405-C04343
    B-1913
    Figure US20070078146A1-20070405-C04344
    Figure US20070078146A1-20070405-C04345
    B-1914
    Figure US20070078146A1-20070405-C04346
    Figure US20070078146A1-20070405-C04347
    B-1915
    Figure US20070078146A1-20070405-C04348
    Figure US20070078146A1-20070405-C04349
    B-1916
    Figure US20070078146A1-20070405-C04350
    Figure US20070078146A1-20070405-C04351
    B-1917
    Figure US20070078146A1-20070405-C04352
    Figure US20070078146A1-20070405-C04353
    B-1918
    Figure US20070078146A1-20070405-C04354
    Figure US20070078146A1-20070405-C04355
    B-1919
    Figure US20070078146A1-20070405-C04356
    Figure US20070078146A1-20070405-C04357
    B-1920
    Figure US20070078146A1-20070405-C04358
    Figure US20070078146A1-20070405-C04359
    B-1921
    Figure US20070078146A1-20070405-C04360
    Figure US20070078146A1-20070405-C04361
    B-1922
    Figure US20070078146A1-20070405-C04362
    Figure US20070078146A1-20070405-C04363
    B-1923
    Figure US20070078146A1-20070405-C04364
    Figure US20070078146A1-20070405-C04365
    B-1924
    Figure US20070078146A1-20070405-C04366
    Figure US20070078146A1-20070405-C04367
    B-1925
    Figure US20070078146A1-20070405-C04368
    Figure US20070078146A1-20070405-C04369
    B-1926
    Figure US20070078146A1-20070405-C04370
    Figure US20070078146A1-20070405-C04371
    B-1927
    Figure US20070078146A1-20070405-C04372
    Figure US20070078146A1-20070405-C04373
    B-1928
    Figure US20070078146A1-20070405-C04374
    Figure US20070078146A1-20070405-C04375
    B-1929
    Figure US20070078146A1-20070405-C04376
    Figure US20070078146A1-20070405-C04377
    B-1930
    Figure US20070078146A1-20070405-C04378
    Figure US20070078146A1-20070405-C04379
    B-1931
    Figure US20070078146A1-20070405-C04380
    Figure US20070078146A1-20070405-C04381
    B-1932
    Figure US20070078146A1-20070405-C04382
    Figure US20070078146A1-20070405-C04383
    B-1933
    Figure US20070078146A1-20070405-C04384
    Figure US20070078146A1-20070405-C04385
    Figure US20070078146A1-20070405-C04386
    Examples B-1934 through B-1957 are prepared from Scaffold C-41
    B-1934
    Figure US20070078146A1-20070405-C04387
    Figure US20070078146A1-20070405-C04388
    B-1935
    Figure US20070078146A1-20070405-C04389
    Figure US20070078146A1-20070405-C04390
    B-1936
    Figure US20070078146A1-20070405-C04391
    Figure US20070078146A1-20070405-C04392
    B-1937
    Figure US20070078146A1-20070405-C04393
    Figure US20070078146A1-20070405-C04394
    B-1938
    Figure US20070078146A1-20070405-C04395
    Figure US20070078146A1-20070405-C04396
    B-1939
    Figure US20070078146A1-20070405-C04397
    Figure US20070078146A1-20070405-C04398
    B-1940
    Figure US20070078146A1-20070405-C04399
    Figure US20070078146A1-20070405-C04400
    B-1941
    Figure US20070078146A1-20070405-C04401
    Figure US20070078146A1-20070405-C04402
    B-1942
    Figure US20070078146A1-20070405-C04403
    Figure US20070078146A1-20070405-C04404
    B-1943
    Figure US20070078146A1-20070405-C04405
    Figure US20070078146A1-20070405-C04406
    B-1944
    Figure US20070078146A1-20070405-C04407
    Figure US20070078146A1-20070405-C04408
    B-1945
    Figure US20070078146A1-20070405-C04409
    Figure US20070078146A1-20070405-C04410
    B-1946
    Figure US20070078146A1-20070405-C04411
    Figure US20070078146A1-20070405-C04412
    B-1947
    Figure US20070078146A1-20070405-C04413
    Figure US20070078146A1-20070405-C04414
    B-1948
    Figure US20070078146A1-20070405-C04415
    Figure US20070078146A1-20070405-C04416
    B-1949
    Figure US20070078146A1-20070405-C04417
    Figure US20070078146A1-20070405-C04418
    B-1950
    Figure US20070078146A1-20070405-C04419
    Figure US20070078146A1-20070405-C04420
    B-1951
    Figure US20070078146A1-20070405-C04421
    Figure US20070078146A1-20070405-C04422
    B-1952
    Figure US20070078146A1-20070405-C04423
    Figure US20070078146A1-20070405-C04424
    B-1953
    Figure US20070078146A1-20070405-C04425
    Figure US20070078146A1-20070405-C04426
    B-1954
    Figure US20070078146A1-20070405-C04427
    Figure US20070078146A1-20070405-C04428
    B-1955
    Figure US20070078146A1-20070405-C04429
    Figure US20070078146A1-20070405-C04430
    B-1956
    Figure US20070078146A1-20070405-C04431
    Figure US20070078146A1-20070405-C04432
    B-1957
    Figure US20070078146A1-20070405-C04433
    Figure US20070078146A1-20070405-C04434
    Figure US20070078146A1-20070405-C04435
    Examples B-1958 through B-1981 are prepared from Scaffold C-43
    B-1958
    Figure US20070078146A1-20070405-C04436
    Figure US20070078146A1-20070405-C04437
    B-1959
    Figure US20070078146A1-20070405-C04438
    Figure US20070078146A1-20070405-C04439
    B-1960
    Figure US20070078146A1-20070405-C04440
    Figure US20070078146A1-20070405-C04441
    B-1961
    Figure US20070078146A1-20070405-C04442
    Figure US20070078146A1-20070405-C04443
    B-1962
    Figure US20070078146A1-20070405-C04444
    Figure US20070078146A1-20070405-C04445
    B-1963
    Figure US20070078146A1-20070405-C04446
    Figure US20070078146A1-20070405-C04447
    B-1964
    Figure US20070078146A1-20070405-C04448
    Figure US20070078146A1-20070405-C04449
    B-1965
    Figure US20070078146A1-20070405-C04450
    Figure US20070078146A1-20070405-C04451
    B-1966
    Figure US20070078146A1-20070405-C04452
    Figure US20070078146A1-20070405-C04453
    B-1967
    Figure US20070078146A1-20070405-C04454
    Figure US20070078146A1-20070405-C04455
    B-1968
    Figure US20070078146A1-20070405-C04456
    Figure US20070078146A1-20070405-C04457
    B-1969
    Figure US20070078146A1-20070405-C04458
    Figure US20070078146A1-20070405-C04459
    B-1970
    Figure US20070078146A1-20070405-C04460
    Figure US20070078146A1-20070405-C04461
    B-1971
    Figure US20070078146A1-20070405-C04462
    Figure US20070078146A1-20070405-C04463
    B-1972
    Figure US20070078146A1-20070405-C04464
    Figure US20070078146A1-20070405-C04465
    B-1973
    Figure US20070078146A1-20070405-C04466
    Figure US20070078146A1-20070405-C04467
    B-1974
    Figure US20070078146A1-20070405-C04468
    Figure US20070078146A1-20070405-C04469
    B-1975
    Figure US20070078146A1-20070405-C04470
    Figure US20070078146A1-20070405-C04471
    B-1976
    Figure US20070078146A1-20070405-C04472
    Figure US20070078146A1-20070405-C04473
    B-1977
    Figure US20070078146A1-20070405-C04474
    Figure US20070078146A1-20070405-C04475
    B-1978
    Figure US20070078146A1-20070405-C04476
    Figure US20070078146A1-20070405-C04477
    B-1979
    Figure US20070078146A1-20070405-C04478
    Figure US20070078146A1-20070405-C04479
    B-1980
    Figure US20070078146A1-20070405-C04480
    Figure US20070078146A1-20070405-C04481
    B-1981
    Figure US20070078146A1-20070405-C04482
    Figure US20070078146A1-20070405-C04483
    Figure US20070078146A1-20070405-C04484
    Examples B-1982 through B-2005 are prepared from Scaffold C-30
    B-1982
    Figure US20070078146A1-20070405-C04485
    Figure US20070078146A1-20070405-C04486
    B-1983
    Figure US20070078146A1-20070405-C04487
    Figure US20070078146A1-20070405-C04488
    B-1984
    Figure US20070078146A1-20070405-C04489
    Figure US20070078146A1-20070405-C04490
    B-1985
    Figure US20070078146A1-20070405-C04491
    Figure US20070078146A1-20070405-C04492
    B-1986
    Figure US20070078146A1-20070405-C04493
    Figure US20070078146A1-20070405-C04494
    B-1987
    Figure US20070078146A1-20070405-C04495
    Figure US20070078146A1-20070405-C04496
    B-1988
    Figure US20070078146A1-20070405-C04497
    Figure US20070078146A1-20070405-C04498
    B-1989
    Figure US20070078146A1-20070405-C04499
    Figure US20070078146A1-20070405-C04500
    B-1990
    Figure US20070078146A1-20070405-C04501
    Figure US20070078146A1-20070405-C04502
    B-1991
    Figure US20070078146A1-20070405-C04503
    Figure US20070078146A1-20070405-C04504
    B-1992
    Figure US20070078146A1-20070405-C04505
    Figure US20070078146A1-20070405-C04506
    B-1993
    Figure US20070078146A1-20070405-C04507
    Figure US20070078146A1-20070405-C04508
    B-1994
    Figure US20070078146A1-20070405-C04509
    Figure US20070078146A1-20070405-C04510
    B-1995
    Figure US20070078146A1-20070405-C04511
    Figure US20070078146A1-20070405-C04512
    B-1996
    Figure US20070078146A1-20070405-C04513
    Figure US20070078146A1-20070405-C04514
    B-1997
    Figure US20070078146A1-20070405-C04515
    Figure US20070078146A1-20070405-C04516
    B-1998
    Figure US20070078146A1-20070405-C04517
    Figure US20070078146A1-20070405-C04518
    B-1999
    Figure US20070078146A1-20070405-C04519
    Figure US20070078146A1-20070405-C04520
    B-2000
    Figure US20070078146A1-20070405-C04521
    Figure US20070078146A1-20070405-C04522
    B-2001
    Figure US20070078146A1-20070405-C04523
    Figure US20070078146A1-20070405-C04524
    B-2002
    Figure US20070078146A1-20070405-C04525
    Figure US20070078146A1-20070405-C04526
    B-2003
    Figure US20070078146A1-20070405-C04527
    Figure US20070078146A1-20070405-C04528
    B-2004
    Figure US20070078146A1-20070405-C04529
    Figure US20070078146A1-20070405-C04530
    B-2005
    Figure US20070078146A1-20070405-C04531
    Figure US20070078146A1-20070405-C04532
    Figure US20070078146A1-20070405-C04533
    Examples B-2006 through B-2029 are prepared from Scaffold C-60
    B-2006
    Figure US20070078146A1-20070405-C04534
    Figure US20070078146A1-20070405-C04535
    B-2007
    Figure US20070078146A1-20070405-C04536
    Figure US20070078146A1-20070405-C04537
    B-2008
    Figure US20070078146A1-20070405-C04538
    Figure US20070078146A1-20070405-C04539
    B-2009
    Figure US20070078146A1-20070405-C04540
    Figure US20070078146A1-20070405-C04541
    B-2010
    Figure US20070078146A1-20070405-C04542
    Figure US20070078146A1-20070405-C04543
    B-2011
    Figure US20070078146A1-20070405-C04544
    Figure US20070078146A1-20070405-C04545
    B-2012
    Figure US20070078146A1-20070405-C04546
    Figure US20070078146A1-20070405-C04547
    B-2013
    Figure US20070078146A1-20070405-C04548
    Figure US20070078146A1-20070405-C04549
    B-2014
    Figure US20070078146A1-20070405-C04550
    Figure US20070078146A1-20070405-C04551
    B-2015
    Figure US20070078146A1-20070405-C04552
    Figure US20070078146A1-20070405-C04553
    B-2016
    Figure US20070078146A1-20070405-C04554
    Figure US20070078146A1-20070405-C04555
    B-2017
    Figure US20070078146A1-20070405-C04556
    Figure US20070078146A1-20070405-C04557
    B-2018
    Figure US20070078146A1-20070405-C04558
    Figure US20070078146A1-20070405-C04559
    B-2019
    Figure US20070078146A1-20070405-C04560
    Figure US20070078146A1-20070405-C04561
    B-2020
    Figure US20070078146A1-20070405-C04562
    Figure US20070078146A1-20070405-C04563
    B-2021
    Figure US20070078146A1-20070405-C04564
    Figure US20070078146A1-20070405-C04565
    B-2022
    Figure US20070078146A1-20070405-C04566
    Figure US20070078146A1-20070405-C04567
    B-2023
    Figure US20070078146A1-20070405-C04568
    Figure US20070078146A1-20070405-C04569
    B-2024
    Figure US20070078146A1-20070405-C04570
    Figure US20070078146A1-20070405-C04571
    B-2025
    Figure US20070078146A1-20070405-C04572
    Figure US20070078146A1-20070405-C04573
    B-2026
    Figure US20070078146A1-20070405-C04574
    Figure US20070078146A1-20070405-C04575
    B-2027
    Figure US20070078146A1-20070405-C04576
    Figure US20070078146A1-20070405-C04577
    B-2028
    Figure US20070078146A1-20070405-C04578
    Figure US20070078146A1-20070405-C04579
    B-2029
    Figure US20070078146A1-20070405-C04580
    Figure US20070078146A1-20070405-C04581
    Figure US20070078146A1-20070405-C04582
    Examples B-2030 through B-2053 are prepared from Scaffold C-36
    B-2030
    Figure US20070078146A1-20070405-C04583
    Figure US20070078146A1-20070405-C04584
    B-2031
    Figure US20070078146A1-20070405-C04585
    Figure US20070078146A1-20070405-C04586
    B-2032
    Figure US20070078146A1-20070405-C04587
    Figure US20070078146A1-20070405-C04588
    B-2033
    Figure US20070078146A1-20070405-C04589
    Figure US20070078146A1-20070405-C04590
    B-2034
    Figure US20070078146A1-20070405-C04591
    Figure US20070078146A1-20070405-C04592
    B-2035
    Figure US20070078146A1-20070405-C04593
    Figure US20070078146A1-20070405-C04594
    B-2036
    Figure US20070078146A1-20070405-C04595
    Figure US20070078146A1-20070405-C04596
    B-2037
    Figure US20070078146A1-20070405-C04597
    Figure US20070078146A1-20070405-C04598
    B-2038
    Figure US20070078146A1-20070405-C04599
    Figure US20070078146A1-20070405-C04600
    B-2039
    Figure US20070078146A1-20070405-C04601
    Figure US20070078146A1-20070405-C04602
    B-2040
    Figure US20070078146A1-20070405-C04603
    Figure US20070078146A1-20070405-C04604
    B-2041
    Figure US20070078146A1-20070405-C04605
    Figure US20070078146A1-20070405-C04606
    B-2042
    Figure US20070078146A1-20070405-C04607
    Figure US20070078146A1-20070405-C04608
    B-2043
    Figure US20070078146A1-20070405-C04609
    Figure US20070078146A1-20070405-C04610
    B-2044
    Figure US20070078146A1-20070405-C04611
    Figure US20070078146A1-20070405-C04612
    B-2045
    Figure US20070078146A1-20070405-C04613
    Figure US20070078146A1-20070405-C04614
    B-2046
    Figure US20070078146A1-20070405-C04615
    Figure US20070078146A1-20070405-C04616
    B-2047
    Figure US20070078146A1-20070405-C04617
    Figure US20070078146A1-20070405-C04618
    B-2048
    Figure US20070078146A1-20070405-C04619
    Figure US20070078146A1-20070405-C04620
    B-2049
    Figure US20070078146A1-20070405-C04621
    Figure US20070078146A1-20070405-C04622
    B-2050
    Figure US20070078146A1-20070405-C04623
    Figure US20070078146A1-20070405-C04624
    B-2051
    Figure US20070078146A1-20070405-C04625
    Figure US20070078146A1-20070405-C04626
    B-2052
    Figure US20070078146A1-20070405-C04627
    Figure US20070078146A1-20070405-C04628
    B-2053
    Figure US20070078146A1-20070405-C04629
    Figure US20070078146A1-20070405-C04630
    Figure US20070078146A1-20070405-C04631
    Examples B-2054 through B-2077 are prepared from Scaffold C-34
    B-2054
    Figure US20070078146A1-20070405-C04632
    Figure US20070078146A1-20070405-C04633
    B-2055
    Figure US20070078146A1-20070405-C04634
    Figure US20070078146A1-20070405-C04635
    B-2056
    Figure US20070078146A1-20070405-C04636
    Figure US20070078146A1-20070405-C04637
    B-2057
    Figure US20070078146A1-20070405-C04638
    Figure US20070078146A1-20070405-C04639
    B-2058
    Figure US20070078146A1-20070405-C04640
    Figure US20070078146A1-20070405-C04641
    B-2059
    Figure US20070078146A1-20070405-C04642
    Figure US20070078146A1-20070405-C04643
    B-2060
    Figure US20070078146A1-20070405-C04644
    Figure US20070078146A1-20070405-C04645
    B-2061
    Figure US20070078146A1-20070405-C04646
    Figure US20070078146A1-20070405-C04647
    B-2062
    Figure US20070078146A1-20070405-C04648
    Figure US20070078146A1-20070405-C04649
    B-2063
    Figure US20070078146A1-20070405-C04650
    Figure US20070078146A1-20070405-C04651
    B-2064
    Figure US20070078146A1-20070405-C04652
    Figure US20070078146A1-20070405-C04653
    B-2065
    Figure US20070078146A1-20070405-C04654
    Figure US20070078146A1-20070405-C04655
    B-2066
    Figure US20070078146A1-20070405-C04656
    Figure US20070078146A1-20070405-C04657
    B-2067
    Figure US20070078146A1-20070405-C04658
    Figure US20070078146A1-20070405-C04659
    B-2068
    Figure US20070078146A1-20070405-C04660
    Figure US20070078146A1-20070405-C04661
    B-2029
    Figure US20070078146A1-20070405-C04662
    Figure US20070078146A1-20070405-C04663
    B-2070
    Figure US20070078146A1-20070405-C04664
    Figure US20070078146A1-20070405-C04665
    B-2071
    Figure US20070078146A1-20070405-C04666
    Figure US20070078146A1-20070405-C04667
    B-2072
    Figure US20070078146A1-20070405-C04668
    Figure US20070078146A1-20070405-C04669
    B-2073
    Figure US20070078146A1-20070405-C04670
    Figure US20070078146A1-20070405-C04671
    B-2074
    Figure US20070078146A1-20070405-C04672
    Figure US20070078146A1-20070405-C04673
    B-2075
    Figure US20070078146A1-20070405-C04674
    Figure US20070078146A1-20070405-C04675
    B-2076
    Figure US20070078146A1-20070405-C04676
    Figure US20070078146A1-20070405-C04677
    B-2077
    Figure US20070078146A1-20070405-C04678
    Figure US20070078146A1-20070405-C04679
    Figure US20070078146A1-20070405-C04680
    Examples B-2078 through B-2101are prepared from Scaffold C-57
    B-2078
    Figure US20070078146A1-20070405-C04681
    Figure US20070078146A1-20070405-C04682
    B-2079
    Figure US20070078146A1-20070405-C04683
    Figure US20070078146A1-20070405-C04684
    B-2080
    Figure US20070078146A1-20070405-C04685
    Figure US20070078146A1-20070405-C04686
    B-2081
    Figure US20070078146A1-20070405-C04687
    Figure US20070078146A1-20070405-C04688
    B-2082
    Figure US20070078146A1-20070405-C04689
    Figure US20070078146A1-20070405-C04690
    B-2083
    Figure US20070078146A1-20070405-C04691
    Figure US20070078146A1-20070405-C04692
    B-2084
    Figure US20070078146A1-20070405-C04693
    Figure US20070078146A1-20070405-C04694
    B-2085
    Figure US20070078146A1-20070405-C04695
    Figure US20070078146A1-20070405-C04696
    B-2086
    Figure US20070078146A1-20070405-C04697
    Figure US20070078146A1-20070405-C04698
    B-2087
    Figure US20070078146A1-20070405-C04699
    Figure US20070078146A1-20070405-C04700
    B-2088
    Figure US20070078146A1-20070405-C04701
    Figure US20070078146A1-20070405-C04702
    B-2089
    Figure US20070078146A1-20070405-C04703
    Figure US20070078146A1-20070405-C04704
    B-2090
    Figure US20070078146A1-20070405-C04705
    Figure US20070078146A1-20070405-C04706
    B-2091
    Figure US20070078146A1-20070405-C04707
    Figure US20070078146A1-20070405-C04708
    B-2092
    Figure US20070078146A1-20070405-C04709
    Figure US20070078146A1-20070405-C04710
    B-2093
    Figure US20070078146A1-20070405-C04711
    Figure US20070078146A1-20070405-C04712
    B-2094
    Figure US20070078146A1-20070405-C04713
    Figure US20070078146A1-20070405-C04714
    B-2095
    Figure US20070078146A1-20070405-C04715
    Figure US20070078146A1-20070405-C04716
    B-2096
    Figure US20070078146A1-20070405-C04717
    Figure US20070078146A1-20070405-C04718
    B-2097
    Figure US20070078146A1-20070405-C04719
    Figure US20070078146A1-20070405-C04720
    B-2098
    Figure US20070078146A1-20070405-C04721
    Figure US20070078146A1-20070405-C04722
    B-2099
    Figure US20070078146A1-20070405-C04723
    Figure US20070078146A1-20070405-C04724
    B-2100
    Figure US20070078146A1-20070405-C04725
    Figure US20070078146A1-20070405-C04726
    B-2101
    Figure US20070078146A1-20070405-C04727
    Figure US20070078146A1-20070405-C04728
    Figure US20070078146A1-20070405-C04729
    Examples B-2102 through B-2125 are prepared from Scaffold C-52
    B-2102
    Figure US20070078146A1-20070405-C04730
    Figure US20070078146A1-20070405-C04731
    B-2103
    Figure US20070078146A1-20070405-C04732
    Figure US20070078146A1-20070405-C04733
    B-2104
    Figure US20070078146A1-20070405-C04734
    Figure US20070078146A1-20070405-C04735
    B-2105
    Figure US20070078146A1-20070405-C04736
    Figure US20070078146A1-20070405-C04737
    B-2106
    Figure US20070078146A1-20070405-C04738
    Figure US20070078146A1-20070405-C04739
    B-2107
    Figure US20070078146A1-20070405-C04740
    Figure US20070078146A1-20070405-C04741
    B-2108
    Figure US20070078146A1-20070405-C04742
    Figure US20070078146A1-20070405-C04743
    B-2109
    Figure US20070078146A1-20070405-C04744
    Figure US20070078146A1-20070405-C04745
    B-2110
    Figure US20070078146A1-20070405-C04746
    Figure US20070078146A1-20070405-C04747
    B-2111
    Figure US20070078146A1-20070405-C04748
    Figure US20070078146A1-20070405-C04749
    B-2112
    Figure US20070078146A1-20070405-C04750
    Figure US20070078146A1-20070405-C04751
    B-2113
    Figure US20070078146A1-20070405-C04752
    Figure US20070078146A1-20070405-C04753
    B-2114
    Figure US20070078146A1-20070405-C04754
    Figure US20070078146A1-20070405-C04755
    B-2115
    Figure US20070078146A1-20070405-C04756
    Figure US20070078146A1-20070405-C04757
    B-2116
    Figure US20070078146A1-20070405-C04758
    Figure US20070078146A1-20070405-C04759
    B-2117
    Figure US20070078146A1-20070405-C04760
    Figure US20070078146A1-20070405-C04761
    B-2118
    Figure US20070078146A1-20070405-C04762
    Figure US20070078146A1-20070405-C04763
    B-2119
    Figure US20070078146A1-20070405-C04764
    Figure US20070078146A1-20070405-C04765
    B-2120
    Figure US20070078146A1-20070405-C04766
    Figure US20070078146A1-20070405-C04767
    B-2121
    Figure US20070078146A1-20070405-C04768
    Figure US20070078146A1-20070405-C04769
    B-2122
    Figure US20070078146A1-20070405-C04770
    Figure US20070078146A1-20070405-C04771
    B-2123
    Figure US20070078146A1-20070405-C04772
    Figure US20070078146A1-20070405-C04773
    B-2124
    Figure US20070078146A1-20070405-C04774
    Figure US20070078146A1-20070405-C04775
    B-2125
    Figure US20070078146A1-20070405-C04776
    Figure US20070078146A1-20070405-C04777
    Figure US20070078146A1-20070405-C04778
    Examples B-2126 through B-2149 are prepared from Scaffold C-56
    B-2126
    Figure US20070078146A1-20070405-C04779
    Figure US20070078146A1-20070405-C04780
    B-2127
    Figure US20070078146A1-20070405-C04781
    Figure US20070078146A1-20070405-C04782
    B-2128
    Figure US20070078146A1-20070405-C04783
    Figure US20070078146A1-20070405-C04784
    B-2129
    Figure US20070078146A1-20070405-C04785
    Figure US20070078146A1-20070405-C04786
    B-2130
    Figure US20070078146A1-20070405-C04787
    Figure US20070078146A1-20070405-C04788
    B-2131
    Figure US20070078146A1-20070405-C04789
    Figure US20070078146A1-20070405-C04790
    B-2132
    Figure US20070078146A1-20070405-C04791
    Figure US20070078146A1-20070405-C04792
    B-2133
    Figure US20070078146A1-20070405-C04793
    Figure US20070078146A1-20070405-C04794
    B-2134
    Figure US20070078146A1-20070405-C04795
    Figure US20070078146A1-20070405-C04796
    B-2135
    Figure US20070078146A1-20070405-C04797
    Figure US20070078146A1-20070405-C04798
    B-2136
    Figure US20070078146A1-20070405-C04799
    Figure US20070078146A1-20070405-C04800
    B-2137
    Figure US20070078146A1-20070405-C04801
    Figure US20070078146A1-20070405-C04802
    B-2138
    Figure US20070078146A1-20070405-C04803
    Figure US20070078146A1-20070405-C04804
    B-2139
    Figure US20070078146A1-20070405-C04805
    Figure US20070078146A1-20070405-C04806
    B-2140
    Figure US20070078146A1-20070405-C04807
    Figure US20070078146A1-20070405-C04808
    B-2141
    Figure US20070078146A1-20070405-C04809
    Figure US20070078146A1-20070405-C04810
    B-2142
    Figure US20070078146A1-20070405-C04811
    Figure US20070078146A1-20070405-C04812
    B-2143
    Figure US20070078146A1-20070405-C04813
    Figure US20070078146A1-20070405-C04814
    B-2144
    Figure US20070078146A1-20070405-C04815
    Figure US20070078146A1-20070405-C04816
    B-2145
    Figure US20070078146A1-20070405-C04817
    Figure US20070078146A1-20070405-C04818
    B-2146
    Figure US20070078146A1-20070405-C04819
    Figure US20070078146A1-20070405-C04820
    B-2147
    Figure US20070078146A1-20070405-C04821
    Figure US20070078146A1-20070405-C04822
    B-2148
    Figure US20070078146A1-20070405-C04823
    Figure US20070078146A1-20070405-C04824
    B-2149
    Figure US20070078146A1-20070405-C04825
    Figure US20070078146A1-20070405-C04826
    Figure US20070078146A1-20070405-C04827
    Examples B-2150 through B-2173 are prepared from Scaffold C-32
    B-2150
    Figure US20070078146A1-20070405-C04828
    Figure US20070078146A1-20070405-C04829
    B-2151
    Figure US20070078146A1-20070405-C04830
    Figure US20070078146A1-20070405-C04831
    B-2152
    Figure US20070078146A1-20070405-C04832
    Figure US20070078146A1-20070405-C04833
    B-2153
    Figure US20070078146A1-20070405-C04834
    Figure US20070078146A1-20070405-C04835
    B-2154
    Figure US20070078146A1-20070405-C04836
    Figure US20070078146A1-20070405-C04837
    B-2155
    Figure US20070078146A1-20070405-C04838
    Figure US20070078146A1-20070405-C04839
    B-2156
    Figure US20070078146A1-20070405-C04840
    Figure US20070078146A1-20070405-C04841
    B-2157
    Figure US20070078146A1-20070405-C04842
    Figure US20070078146A1-20070405-C04843
    B-2158
    Figure US20070078146A1-20070405-C04844
    Figure US20070078146A1-20070405-C04845
    B-2159
    Figure US20070078146A1-20070405-C04846
    Figure US20070078146A1-20070405-C04847
    B-2160
    Figure US20070078146A1-20070405-C04848
    Figure US20070078146A1-20070405-C04849
    B-2161
    Figure US20070078146A1-20070405-C04850
    Figure US20070078146A1-20070405-C04851
    B-2162
    Figure US20070078146A1-20070405-C04852
    Figure US20070078146A1-20070405-C04853
    B-2163
    Figure US20070078146A1-20070405-C04854
    Figure US20070078146A1-20070405-C04855
    B-2164
    Figure US20070078146A1-20070405-C04856
    Figure US20070078146A1-20070405-C04857
    B-2165
    Figure US20070078146A1-20070405-C04858
    Figure US20070078146A1-20070405-C04859
    B-2166
    Figure US20070078146A1-20070405-C04860
    Figure US20070078146A1-20070405-C04861
    B-2167
    Figure US20070078146A1-20070405-C04862
    Figure US20070078146A1-20070405-C04863
    B-2168
    Figure US20070078146A1-20070405-C04864
    Figure US20070078146A1-20070405-C04865
    B-2169
    Figure US20070078146A1-20070405-C04866
    Figure US20070078146A1-20070405-C04867
    B-2170
    Figure US20070078146A1-20070405-C04868
    Figure US20070078146A1-20070405-C04869
    B-2171
    Figure US20070078146A1-20070405-C04870
    Figure US20070078146A1-20070405-C04871
    B-2172
    Figure US20070078146A1-20070405-C04872
    Figure US20070078146A1-20070405-C04873
    B-2173
    Figure US20070078146A1-20070405-C04874
    Figure US20070078146A1-20070405-C04875
    Figure US20070078146A1-20070405-C04876
    Examples 2174 through B-2197 are prepared from Scaffold C-64
    B-2174
    Figure US20070078146A1-20070405-C04877
    Figure US20070078146A1-20070405-C04878
    B-2175
    Figure US20070078146A1-20070405-C04879
    Figure US20070078146A1-20070405-C04880
    B-2176
    Figure US20070078146A1-20070405-C04881
    Figure US20070078146A1-20070405-C04882
    B-2177
    Figure US20070078146A1-20070405-C04883
    Figure US20070078146A1-20070405-C04884
    B-2178
    Figure US20070078146A1-20070405-C04885
    Figure US20070078146A1-20070405-C04886
    B-2179
    Figure US20070078146A1-20070405-C04887
    Figure US20070078146A1-20070405-C04888
    B-2180
    Figure US20070078146A1-20070405-C04889
    Figure US20070078146A1-20070405-C04890
    B-2181
    Figure US20070078146A1-20070405-C04891
    Figure US20070078146A1-20070405-C04892
    B-2182
    Figure US20070078146A1-20070405-C04893
    Figure US20070078146A1-20070405-C04894
    B-2183
    Figure US20070078146A1-20070405-C04895
    Figure US20070078146A1-20070405-C04896
    B-2184
    Figure US20070078146A1-20070405-C04897
    Figure US20070078146A1-20070405-C04898
    B-2185
    Figure US20070078146A1-20070405-C04899
    Figure US20070078146A1-20070405-C04900
    B-2186
    Figure US20070078146A1-20070405-C04901
    Figure US20070078146A1-20070405-C04902
    B-2187
    Figure US20070078146A1-20070405-C04903
    Figure US20070078146A1-20070405-C04904
    B-2188
    Figure US20070078146A1-20070405-C04905
    Figure US20070078146A1-20070405-C04906
    B-2189
    Figure US20070078146A1-20070405-C04907
    Figure US20070078146A1-20070405-C04908
    B-2190
    Figure US20070078146A1-20070405-C04909
    Figure US20070078146A1-20070405-C04910
    B-2191
    Figure US20070078146A1-20070405-C04911
    Figure US20070078146A1-20070405-C04912
    B-2192
    Figure US20070078146A1-20070405-C04913
    Figure US20070078146A1-20070405-C04914
    B-2193
    Figure US20070078146A1-20070405-C04915
    Figure US20070078146A1-20070405-C04916
    B-2194
    Figure US20070078146A1-20070405-C04917
    Figure US20070078146A1-20070405-C04918
    B-2195
    Figure US20070078146A1-20070405-C04919
    Figure US20070078146A1-20070405-C04920
    B-2196
    Figure US20070078146A1-20070405-C04921
    Figure US20070078146A1-20070405-C04922
    B-2197
    Figure US20070078146A1-20070405-C04923
    Figure US20070078146A1-20070405-C04924
    Figure US20070078146A1-20070405-C04925
    Examples B-2198 through B-2221 re prepared from Scaffold C-22
    B-2198
    Figure US20070078146A1-20070405-C04926
    Figure US20070078146A1-20070405-C04927
    B-2199
    Figure US20070078146A1-20070405-C04928
    Figure US20070078146A1-20070405-C04929
    B-2200
    Figure US20070078146A1-20070405-C04930
    Figure US20070078146A1-20070405-C04931
    B-2201
    Figure US20070078146A1-20070405-C04932
    Figure US20070078146A1-20070405-C04933
    B-2202
    Figure US20070078146A1-20070405-C04934
    Figure US20070078146A1-20070405-C04935
    B-2203
    Figure US20070078146A1-20070405-C04936
    Figure US20070078146A1-20070405-C04937
    B-2204
    Figure US20070078146A1-20070405-C04938
    Figure US20070078146A1-20070405-C04939
    B-2205
    Figure US20070078146A1-20070405-C04940
    Figure US20070078146A1-20070405-C04941
    B-2206
    Figure US20070078146A1-20070405-C04942
    Figure US20070078146A1-20070405-C04943
    B-2207
    Figure US20070078146A1-20070405-C04944
    Figure US20070078146A1-20070405-C04945
    B-2208
    Figure US20070078146A1-20070405-C04946
    Figure US20070078146A1-20070405-C04947
    B-2209
    Figure US20070078146A1-20070405-C04948
    Figure US20070078146A1-20070405-C04949
    B-2210
    Figure US20070078146A1-20070405-C04950
    Figure US20070078146A1-20070405-C04951
    B-2211
    Figure US20070078146A1-20070405-C04952
    Figure US20070078146A1-20070405-C04953
    B-2212
    Figure US20070078146A1-20070405-C04954
    Figure US20070078146A1-20070405-C04955
    B-2213
    Figure US20070078146A1-20070405-C04956
    Figure US20070078146A1-20070405-C04957
    B-2214
    Figure US20070078146A1-20070405-C04958
    Figure US20070078146A1-20070405-C04959
    B-2215
    Figure US20070078146A1-20070405-C04960
    Figure US20070078146A1-20070405-C04961
    B-2216
    Figure US20070078146A1-20070405-C04962
    Figure US20070078146A1-20070405-C04963
    B-2217
    Figure US20070078146A1-20070405-C04964
    Figure US20070078146A1-20070405-C04965
    B-2218
    Figure US20070078146A1-20070405-C04966
    Figure US20070078146A1-20070405-C04967
    B-2219
    Figure US20070078146A1-20070405-C04968
    Figure US20070078146A1-20070405-C04969
    B-2220
    Figure US20070078146A1-20070405-C04970
    Figure US20070078146A1-20070405-C04971
    B-2221
    Figure US20070078146A1-20070405-C04972
    Figure US20070078146A1-20070405-C04973
    Figure US20070078146A1-20070405-C04974
    Examples B-2222 through B-2245 are prepared from Scaffold C-29
    B-2222
    Figure US20070078146A1-20070405-C04975
    Figure US20070078146A1-20070405-C04976
    B-2223
    Figure US20070078146A1-20070405-C04977
    Figure US20070078146A1-20070405-C04978
    B-2224
    Figure US20070078146A1-20070405-C04979
    Figure US20070078146A1-20070405-C04980
    B-2225
    Figure US20070078146A1-20070405-C04981
    Figure US20070078146A1-20070405-C04982
    B-2226
    Figure US20070078146A1-20070405-C04983
    Figure US20070078146A1-20070405-C04984
    B-2227
    Figure US20070078146A1-20070405-C04985
    Figure US20070078146A1-20070405-C04986
    B-2228
    Figure US20070078146A1-20070405-C04987
    Figure US20070078146A1-20070405-C04988
    B-2229
    Figure US20070078146A1-20070405-C04989
    Figure US20070078146A1-20070405-C04990
    B-2230
    Figure US20070078146A1-20070405-C04991
    Figure US20070078146A1-20070405-C04992
    B-2231
    Figure US20070078146A1-20070405-C04993
    Figure US20070078146A1-20070405-C04994
    B-2232
    Figure US20070078146A1-20070405-C04995
    Figure US20070078146A1-20070405-C04996
    B-2233
    Figure US20070078146A1-20070405-C04997
    Figure US20070078146A1-20070405-C04998
    B-2234
    Figure US20070078146A1-20070405-C04999
    Figure US20070078146A1-20070405-C05000
    B-2235
    Figure US20070078146A1-20070405-C05001
    Figure US20070078146A1-20070405-C05002
    B-2236
    Figure US20070078146A1-20070405-C05003
    Figure US20070078146A1-20070405-C05004
    B-2237
    Figure US20070078146A1-20070405-C05005
    Figure US20070078146A1-20070405-C05006
    B-2238
    Figure US20070078146A1-20070405-C05007
    Figure US20070078146A1-20070405-C05008
    B-2239
    Figure US20070078146A1-20070405-C05009
    Figure US20070078146A1-20070405-C05010
    B-2240
    Figure US20070078146A1-20070405-C05011
    Figure US20070078146A1-20070405-C05012
    B-2241
    Figure US20070078146A1-20070405-C05013
    Figure US20070078146A1-20070405-C05014
    B-2242
    Figure US20070078146A1-20070405-C05015
    Figure US20070078146A1-20070405-C05016
    B-2243
    Figure US20070078146A1-20070405-C05017
    Figure US20070078146A1-20070405-C05018
    B-2244
    Figure US20070078146A1-20070405-C05019
    Figure US20070078146A1-20070405-C05020
    B-2245
    Figure US20070078146A1-20070405-C05021
    Figure US20070078146A1-20070405-C05022
    Figure US20070078146A1-20070405-C05023
    Examples B-2246 through B-2269 are prepared from Scaffold C-35
    B-2246
    Figure US20070078146A1-20070405-C05024
    Figure US20070078146A1-20070405-C05025
    B-2247
    Figure US20070078146A1-20070405-C05026
    Figure US20070078146A1-20070405-C05027
    B-2248
    Figure US20070078146A1-20070405-C05028
    Figure US20070078146A1-20070405-C05029
    B-2249
    Figure US20070078146A1-20070405-C05030
    Figure US20070078146A1-20070405-C05031
    B-2250
    Figure US20070078146A1-20070405-C05032
    Figure US20070078146A1-20070405-C05033
    B-2251
    Figure US20070078146A1-20070405-C05034
    Figure US20070078146A1-20070405-C05035
    B-2252
    Figure US20070078146A1-20070405-C05036
    Figure US20070078146A1-20070405-C05037
    B-2253
    Figure US20070078146A1-20070405-C05038
    Figure US20070078146A1-20070405-C05039
    B-2254
    Figure US20070078146A1-20070405-C05040
    Figure US20070078146A1-20070405-C05041
    B-2255
    Figure US20070078146A1-20070405-C05042
    Figure US20070078146A1-20070405-C05043
    B-2256
    Figure US20070078146A1-20070405-C05044
    Figure US20070078146A1-20070405-C05045
    B-2257
    Figure US20070078146A1-20070405-C05046
    Figure US20070078146A1-20070405-C05047
    B-2258
    Figure US20070078146A1-20070405-C05048
    Figure US20070078146A1-20070405-C05049
    B-2259
    Figure US20070078146A1-20070405-C05050
    Figure US20070078146A1-20070405-C05051
    B-2260
    Figure US20070078146A1-20070405-C05052
    Figure US20070078146A1-20070405-C05053
    B-2261
    Figure US20070078146A1-20070405-C05054
    Figure US20070078146A1-20070405-C05055
    B-2262
    Figure US20070078146A1-20070405-C05056
    Figure US20070078146A1-20070405-C05057
    B-2263
    Figure US20070078146A1-20070405-C05058
    Figure US20070078146A1-20070405-C05059
    B-2264
    Figure US20070078146A1-20070405-C05060
    Figure US20070078146A1-20070405-C05061
    B-2265
    Figure US20070078146A1-20070405-C05062
    Figure US20070078146A1-20070405-C05063
    B-2266
    Figure US20070078146A1-20070405-C05064
    Figure US20070078146A1-20070405-C05065
    B-2267
    Figure US20070078146A1-20070405-C05066
    Figure US20070078146A1-20070405-C05067
    B-2268
    Figure US20070078146A1-20070405-C05068
    Figure US20070078146A1-20070405-C05069
    B-2269
    Figure US20070078146A1-20070405-C05070
    Figure US20070078146A1-20070405-C05071
    • 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.
    Figure US20070078146A1-20070405-C05072
    R2
    Figure US20070078146A1-20070405-C05073
         		Yield Calcd. Mass Spec. Observed Mass Spec M + H
    B-2270
    Figure US20070078146A1-20070405-C05074
    Figure US20070078146A1-20070405-C05075
         		12 352 353
    B-2271
    Figure US20070078146A1-20070405-C05076
    Figure US20070078146A1-20070405-C05077
         		39 432 433
    B-2272
    Figure US20070078146A1-20070405-C05078
    Figure US20070078146A1-20070405-C05079
         		26 400 —
    B-2273
    Figure US20070078146A1-20070405-C05080
    Figure US20070078146A1-20070405-C05081
         		14 396 397
    B-2274
    Figure US20070078146A1-20070405-C05082
    Figure US20070078146A1-20070405-C05083
         		40 434 435
    B-2275
    Figure US20070078146A1-20070405-C05084
    Figure US20070078146A1-20070405-C05085
         		43 443 —
    B-2276
    Figure US20070078146A1-20070405-C05086
    Figure US20070078146A1-20070405-C05087
         		35 364 365
    B-2277
    Figure US20070078146A1-20070405-C05088
    Figure US20070078146A1-20070405-C05089
         		33 490 —
    B-2278
    Figure US20070078146A1-20070405-C05090
    Figure US20070078146A1-20070405-C05091
         		53 460 461
    B-2279
    Figure US20070078146A1-20070405-C05092
    Figure US20070078146A1-20070405-C05093
         		10 420 —
    B-2280
    Figure US20070078146A1-20070405-C05094
    Figure US20070078146A1-20070405-C05095
         		7 435 436
    B-2281
    Figure US20070078146A1-20070405-C05096
    Figure US20070078146A1-20070405-C05097
         		18 401 402
    B-2282
    Figure US20070078146A1-20070405-C05098
    Figure US20070078146A1-20070405-C05099
         		22 390 413a aM + Na
    B-2283
    Figure US20070078146A1-20070405-C05100
    Figure US20070078146A1-20070405-C05101
         		10 394 417a aM + Na
    p
    B-2284
    Figure US20070078146A1-20070405-C05102
    Figure US20070078146A1-20070405-C05103
         		7 423 —
    B-2285
    Figure US20070078146A1-20070405-C05104
    Figure US20070078146A1-20070405-C05105
         		23 450 —
    B-2286
    Figure US20070078146A1-20070405-C05106
    Figure US20070078146A1-20070405-C05107
         		4 506 —
    B-2287
    Figure US20070078146A1-20070405-C05108
    Figure US20070078146A1-20070405-C05109
         		5 437 438
    B-2288
    Figure US20070078146A1-20070405-C05110
    Figure US20070078146A1-20070405-C05111
         		8 435 436
    B-2289
    Figure US20070078146A1-20070405-C05112
    Figure US20070078146A1-20070405-C05113
         		4 450 451
    B-2290
    Figure US20070078146A1-20070405-C05114
    Figure US20070078146A1-20070405-C05115
         		9 456 457
    B-2291
    Figure US20070078146A1-20070405-C05116
    Figure US20070078146A1-20070405-C05117
         		9 415 416
    B-2292
    Figure US20070078146A1-20070405-C05118
    Figure US20070078146A1-20070405-C05119
         		5 368 369
    B-2293
    Figure US20070078146A1-20070405-C05120
    Figure US20070078146A1-20070405-C05121
         		5 366 367
    B-2294
    Figure US20070078146A1-20070405-C05122
    Figure US20070078146A1-20070405-C05123
         		5 381 382
    B-2295
    Figure US20070078146A1-20070405-C05124
    Figure US20070078146A1-20070405-C05125
         		16 410 411
    B-2296
    Figure US20070078146A1-20070405-C05126
    Figure US20070078146A1-20070405-C05127
         		4 483 —
    B-2297
    Figure US20070078146A1-20070405-C05128
    Figure US20070078146A1-20070405-C05129
         		7 490 —
    B-2298
    Figure US20070078146A1-20070405-C05130
    Figure US20070078146A1-20070405-C05131
         		4 537 —
    B-2299
    Figure US20070078146A1-20070405-C05132
    Figure US20070078146A1-20070405-C05133
         		4 507 508
    B-2300
    Figure US20070078146A1-20070405-C05134
    Figure US20070078146A1-20070405-C05135
         		7 442 —
    B-2301
    Figure US20070078146A1-20070405-C05136
    Figure US20070078146A1-20070405-C05137
         		20 396 397
    B-2302
    Figure US20070078146A1-20070405-C05138
    Figure US20070078146A1-20070405-C05139
         		30 459 —
    B-2303
    Figure US20070078146A1-20070405-C05140
    Figure US20070078146A1-20070405-C05141
         		6 482
    B-2304
    Figure US20070078146A1-20070405-C05142
    Figure US20070078146A1-20070405-C05143
         		5 395 396
    B-2305
    Figure US20070078146A1-20070405-C05144
    Figure US20070078146A1-20070405-C05145
         		10 460 —
    B-2306
    Figure US20070078146A1-20070405-C05146
    Figure US20070078146A1-20070405-C05147
         		11 466 467
    B-2307
    Figure US20070078146A1-20070405-C05148
    Figure US20070078146A1-20070405-C05149
         		5 421 422
    B-2308
    Figure US20070078146A1-20070405-C05150
    Figure US20070078146A1-20070405-C05151
         		26 470 —
    B-2309
    Figure US20070078146A1-20070405-C05152
    Figure US20070078146A1-20070405-C05153
         		24 424 425
    B-2310
    Figure US20070078146A1-20070405-C05154
    Figure US20070078146A1-20070405-C05155
         		9 348 —
    B-2311
    Figure US20070078146A1-20070405-C05156
    Figure US20070078146A1-20070405-C05157
         		21 338 339
    B-2312
    Figure US20070078146A1-20070405-C05158
    Figure US20070078146A1-20070405-C05159
         		29 398 399
    B-2313
    Figure US20070078146A1-20070405-C05160
    Figure US20070078146A1-20070405-C05161
         		6 410 —
    B-2314
    Figure US20070078146A1-20070405-C05162
    Figure US20070078146A1-20070405-C05163
         		15 363 364
    B-2315
    Figure US20070078146A1-20070405-C05164
    Figure US20070078146A1-20070405-C05165
         		11 444 —
    B-2316
    Figure US20070078146A1-20070405-C05166
    Figure US20070078146A1-20070405-C05167
         		11 418 —
    B-2317
    Figure US20070078146A1-20070405-C05168
    Figure US20070078146A1-20070405-C05169
         		36 428 —
  • 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.
    Figure US20070078146A1-20070405-C05170
    R2
    Figure US20070078146A1-20070405-C05171
         		Yield Calcd. Mass Spec. Observed Mass Spec M + H
    B-2318
    Figure US20070078146A1-20070405-C05172
    Figure US20070078146A1-20070405-C05173
         		23 426 427
    B-2319
    Figure US20070078146A1-20070405-C05174
    Figure US20070078146A1-20070405-C05175
         		23 394 —
    B-2320
    Figure US20070078146A1-20070405-C05176
    Figure US20070078146A1-20070405-C05177
         		50 490 491
    B-2321
    Figure US20070078146A1-20070405-C05178
    Figure US20070078146A1-20070405-C05179
         		49 426 427
    B-2322
    Figure US20070078146A1-20070405-C05180
    Figure US20070078146A1-20070405-C05181
         		40 366 367
    B-2323
    Figure US20070078146A1-20070405-C05182
    Figure US20070078146A1-20070405-C05183
         		68 410 411
    B-2324
    Figure US20070078146A1-20070405-C05184
    Figure US20070078146A1-20070405-C05185
         		57 456 457
    B-2325
    Figure US20070078146A1-20070405-C05186
    Figure US20070078146A1-20070405-C05187
         		41 382 383
    B-2326
    Figure US20070078146A1-20070405-C05188
    Figure US20070078146A1-20070405-C05189
         		71 440 441
    B-2327
    Figure US20070078146A1-20070405-C05190
    Figure US20070078146A1-20070405-C05191
         		36 464 465
    B-2328
    Figure US20070078146A1-20070405-C05192
    Figure US20070078146A1-20070405-C05193
         		32 467 468
    B-2329
    Figure US20070078146A1-20070405-C05194
    Figure US20070078146A1-20070405-C05195
         		34 465 466
    B-2330
    Figure US20070078146A1-20070405-C05196
    Figure US20070078146A1-20070405-C05197
         		26 364 365
    B-2331
    Figure US20070078146A1-20070405-C05198
    Figure US20070078146A1-20070405-C05199
         		38 464 465
    B-2332
    Figure US20070078146A1-20070405-C05200
    Figure US20070078146A1-20070405-C05201
         		33 483 484
    B-2333
    Figure US20070078146A1-20070405-C05202
    Figure US20070078146A1-20070405-C05203
         		36 378 379
    B-2334
    Figure US20070078146A1-20070405-C05204
    Figure US20070078146A1-20070405-C05205
         		44 428 429
    B-2335
    Figure US20070078146A1-20070405-C05206
    Figure US20070078146A1-20070405-C05207
         		27 406 407
    B-2336
    Figure US20070078146A1-20070405-C05208
    Figure US20070078146A1-20070405-C05209
         		41 428 429
    B-2337
    Figure US20070078146A1-20070405-C05210
    Figure US20070078146A1-20070405-C05211
         		26 423 424
    B-2338
    Figure US20070078146A1-20070405-C05212
    Figure US20070078146A1-20070405-C05213
         		33 469 470
    B-2339
    Figure US20070078146A1-20070405-C05214
    Figure US20070078146A1-20070405-C05215
         		52 518 519
    B-2340
    Figure US20070078146A1-20070405-C05216
    Figure US20070078146A1-20070405-C05217
         		64 442 443
    B-2341
    Figure US20070078146A1-20070405-C05218
    Figure US20070078146A1-20070405-C05219
         		41 350 351
    B-2342
    Figure US20070078146A1-20070405-C05220
    Figure US20070078146A1-20070405-C05221
         		34 414 415
    B-2343
    Figure US20070078146A1-20070405-C05222
    Figure US20070078146A1-20070405-C05223
         		29 424 425
    B-2344
    Figure US20070078146A1-20070405-C05224
    Figure US20070078146A1-20070405-C05225
         		33 492 493
    B-2345
    Figure US20070078146A1-20070405-C05226
    Figure US20070078146A1-20070405-C05227
         		30 420 421
    B-2346
    Figure US20070078146A1-20070405-C05228
    Figure US20070078146A1-20070405-C05229
         		35 474 475
    B-2347
    Figure US20070078146A1-20070405-C05230
    Figure US20070078146A1-20070405-C05231
         		34 392 393
    B-2348
    Figure US20070078146A1-20070405-C05232
    Figure US20070078146A1-20070405-C05233
         		51 458 459
    B-2349
    Figure US20070078146A1-20070405-C05234
    Figure US20070078146A1-20070405-C05235
         		73 517 518
    B-2350
    Figure US20070078146A1-20070405-C05236
    Figure US20070078146A1-20070405-C05237
         		22 448 449
    B-2351
    Figure US20070078146A1-20070405-C05238
    Figure US20070078146A1-20070405-C05239
         		64 486 487
    B-2352
    Figure US20070078146A1-20070405-C05240
    Figure US20070078146A1-20070405-C05241
         		41 482 483
    B-2353
    Figure US20070078146A1-20070405-C05242
    Figure US20070078146A1-20070405-C05243
         		57 438 439
    B-2354
    Figure US20070078146A1-20070405-C05244
    Figure US20070078146A1-20070405-C05245
         		63 484 485
    B-2355
    Figure US20070078146A1-20070405-C05246
    Figure US20070078146A1-20070405-C05247
         		28 536 537
    B-2356
    Figure US20070078146A1-20070405-C05248
    Figure US20070078146A1-20070405-C05249
         		29 408 409
    B-2357
    Figure US20070078146A1-20070405-C05250
    Figure US20070078146A1-20070405-C05251
         		41 436 437
    B-2358
    Figure US20070078146A1-20070405-C05252
    Figure US20070078146A1-20070405-C05253
         		41 451 452
    B-2359
    Figure US20070078146A1-20070405-C05254
    Figure US20070078146A1-20070405-C05255
         		57 502 503
    B-2360
    Figure US20070078146A1-20070405-C05256
    Figure US20070078146A1-20070405-C05257
         		46 496 497
    B-2361
    Figure US20070078146A1-20070405-C05258
    Figure US20070078146A1-20070405-C05259
         		13 476 477
    B-2362
    Figure US20070078146A1-20070405-C05260
    Figure US20070078146A1-20070405-C05261
         		46 493 494
    B-2363
    Figure US20070078146A1-20070405-C05262
    Figure US20070078146A1-20070405-C05263
         		57 396 397
    B-2364
    Figure US20070078146A1-20070405-C05264
    Figure US20070078146A1-20070405-C05265
         		61 438 439
    B-2365
    Figure US20070078146A1-20070405-C05266
    Figure US20070078146A1-20070405-C05267
         		72 424 425
    B-2366
    Figure US20070078146A1-20070405-C05268
    Figure US20070078146A1-20070405-C05269
         		34 380 381
    B-2367
    Figure US20070078146A1-20070405-C05270
    Figure US20070078146A1-20070405-C05271
         		52 480 481
    B-2368
    Figure US20070078146A1-20070405-C05272
    Figure US20070078146A1-20070405-C05273
         		35 407 407
    B-2369
    Figure US20070078146A1-20070405-C05274
    Figure US20070078146A1-20070405-C05275
         		31 435 436
    B-2370
    Figure US20070078146A1-20070405-C05276
    Figure US20070078146A1-20070405-C05277
         		33 414 415
    B-2371
    Figure US20070078146A1-20070405-C05278
    Figure US20070078146A1-20070405-C05279
         		28 366 367
    B-2372
    Figure US20070078146A1-20070405-C05280
    Figure US20070078146A1-20070405-C05281
         		37 422 423
    B-2373
    Figure US20070078146A1-20070405-C05282
    Figure US20070078146A1-20070405-C05283
         		50 432 433
    B-2374
    Figure US20070078146A1-20070405-C05284
    Figure US20070078146A1-20070405-C05285
         		29 382 383
    B-2375
    Figure US20070078146A1-20070405-C05286
    Figure US20070078146A1-20070405-C05287
         		35 395 396
    B-2376
    Figure US20070078146A1-20070405-C05288
    Figure US20070078146A1-20070405-C05289
         		36 428 429
    B-2377
    Figure US20070078146A1-20070405-C05290
    Figure US20070078146A1-20070405-C05291
         		68 438 439
    B-2378
    Figure US20070078146A1-20070405-C05292
    Figure US20070078146A1-20070405-C05293
         		55 446 447
    B-2379
    Figure US20070078146A1-20070405-C05294
    Figure US20070078146A1-20070405-C05295
         		33 364 365
    B-2380
    Figure US20070078146A1-20070405-C05296
    Figure US20070078146A1-20070405-C05297
         		51 421 422
    B-2381
    Figure US20070078146A1-20070405-C05298
    Figure US20070078146A1-20070405-C05299
         		52 429 430
    B-2382
    Figure US20070078146A1-20070405-C05300
    Figure US20070078146A1-20070405-C05301
         		48 407 408
    B-2383
    Figure US20070078146A1-20070405-C05302
    Figure US20070078146A1-20070405-C05303
         		53 382 383
    B-2384
    Figure US20070078146A1-20070405-C05304
    Figure US20070078146A1-20070405-C05305
         		38 447 448
    B-2385
    Figure US20070078146A1-20070405-C05306
    Figure US20070078146A1-20070405-C05307
         		59 498 450
    B-2386
    Figure US20070078146A1-20070405-C05308
    Figure US20070078146A1-20070405-C05309
         		45 429 430
    B-2387
    Figure US20070078146A1-20070405-C05310
    Figure US20070078146A1-20070405-C05311
         		74 558 —
    B-2388
    Figure US20070078146A1-20070405-C05312
    Figure US20070078146A1-20070405-C05313
         		53 475 —
    B-2389
    Figure US20070078146A1-20070405-C05314
    Figure US20070078146A1-20070405-C05315
         		33 493 494
    B-2390
    Figure US20070078146A1-20070405-C05316
    Figure US20070078146A1-20070405-C05317
         		53 487 488
    B-2391
    Figure US20070078146A1-20070405-C05318
    Figure US20070078146A1-20070405-C05319
         		30 435 436
    B-2392
    Figure US20070078146A1-20070405-C05320
    Figure US20070078146A1-20070405-C05321
         		57 464 465
    B-2393
    Figure US20070078146A1-20070405-C05322
    Figure US20070078146A1-20070405-C05323
         		50 418 419
    B-2394
    Figure US20070078146A1-20070405-C05324
    Figure US20070078146A1-20070405-C05325
         		65 488 489
    B-2395
    Figure US20070078146A1-20070405-C05326
    Figure US20070078146A1-20070405-C05327
         		59 437 438
    B-2396
    Figure US20070078146A1-20070405-C05328
    Figure US20070078146A1-20070405-C05329
         		34 534 535
    B-2397
    Figure US20070078146A1-20070405-C05330
    Figure US20070078146A1-20070405-C05331
         		32 516 517
    B-2398
    Figure US20070078146A1-20070405-C05332
    Figure US20070078146A1-20070405-C05333
         		81 533 534
    B-2399
    Figure US20070078146A1-20070405-C05334
    Figure US20070078146A1-20070405-C05335
         		55 502 —
    B-2400
    Figure US20070078146A1-20070405-C05336
    Figure US20070078146A1-20070405-C05337
         		34 381 382
    B-2401
    Figure US20070078146A1-20070405-C05338
    Figure US20070078146A1-20070405-C05339
         		32 378 379
    B-2402
    Figure US20070078146A1-20070405-C05340
    Figure US20070078146A1-20070405-C05341
         		71 519 520
    B-2403
    Figure US20070078146A1-20070405-C05342
    Figure US20070078146A1-20070405-C05343
         		68 527 528
    B-2404
    Figure US20070078146A1-20070405-C05344
    Figure US20070078146A1-20070405-C05345
         		62 447 448
    B-2405
    Figure US20070078146A1-20070405-C05346
    Figure US20070078146A1-20070405-C05347
         		71 536 537
    B-2406
    Figure US20070078146A1-20070405-C05348
    Figure US20070078146A1-20070405-C05349
         		47 394 395
    B-2407
    Figure US20070078146A1-20070405-C05350
    Figure US20070078146A1-20070405-C05351
         		65 508 509
    B-2408
    Figure US20070078146A1-20070405-C05352
    Figure US20070078146A1-20070405-C05353
         		34 495 496
    B-2409
    Figure US20070078146A1-20070405-C05354
    Figure US20070078146A1-20070405-C05355
         		47 448 449
    B-2410
    Figure US20070078146A1-20070405-C05356
    Figure US20070078146A1-20070405-C05357
         		73 542 543
    B-2411
    Figure US20070078146A1-20070405-C05358
    Figure US20070078146A1-20070405-C05359
         		81 489 490
    B-2412
    Figure US20070078146A1-20070405-C05360
    Figure US20070078146A1-20070405-C05361
         		54 409 410
    B-2413
    Figure US20070078146A1-20070405-C05362
    Figure US20070078146A1-20070405-C05363
         		37 493 494
    B-2414
    Figure US20070078146A1-20070405-C05364
    Figure US20070078146A1-20070405-C05365
         		14 473 474
    B-2415
    Figure US20070078146A1-20070405-C05366
    Figure US20070078146A1-20070405-C05367
         		19 421 422
    B-2416
    Figure US20070078146A1-20070405-C05368
    Figure US20070078146A1-20070405-C05369
         		13 386 387
    B-2417
    Figure US20070078146A1-20070405-C05370
    Figure US20070078146A1-20070405-C05371
         		29 414 415
    B-2418
    Figure US20070078146A1-20070405-C05372
    Figure US20070078146A1-20070405-C05373
         		6 420 421
    B-2419
    Figure US20070078146A1-20070405-C05374
    Figure US20070078146A1-20070405-C05375
         		10 454 —
    B-2420
    Figure US20070078146A1-20070405-C05376
    Figure US20070078146A1-20070405-C05377
         		5 442 443
    B-2421
    Figure US20070078146A1-20070405-C05378
    Figure US20070078146A1-20070405-C05379
         		28 454 455
    B-2422
    Figure US20070078146A1-20070405-C05380
    Figure US20070078146A1-20070405-C05381
         		47 420 421
    B-2423
    Figure US20070078146A1-20070405-C05382
    Figure US20070078146A1-20070405-C05383
         		53 400 401
    B-2424
    Figure US20070078146A1-20070405-C05384
    Figure US20070078146A1-20070405-C05385
         		15 400 401
    B-2425
    Figure US20070078146A1-20070405-C05386
    Figure US20070078146A1-20070405-C05387
         		18 522 523
    B-2426
    Figure US20070078146A1-20070405-C05388
    Figure US20070078146A1-20070405-C05389
         		38 464 465
    B-2427
    Figure US20070078146A1-20070405-C05390
    Figure US20070078146A1-20070405-C05391
         		26 468 469
    B-2428
    Figure US20070078146A1-20070405-C05392
    Figure US20070078146A1-20070405-C05393
         		22 432 433
    B-2429
    Figure US20070078146A1-20070405-C05394
    Figure US20070078146A1-20070405-C05395
         		41 404 405
    B-2430
    Figure US20070078146A1-20070405-C05396
    Figure US20070078146A1-20070405-C05397
         		15 476 477
    B-2431
    Figure US20070078146A1-20070405-C05398
    Figure US20070078146A1-20070405-C05399
         		6 446 447
    B-2432
    Figure US20070078146A1-20070405-C05400
    Figure US20070078146A1-20070405-C05401
         		37 404 405
    B-2433
    Figure US20070078146A1-20070405-C05402
    Figure US20070078146A1-20070405-C05403
         		8 428 429
    B-2434
    Figure US20070078146A1-20070405-C05404
    Figure US20070078146A1-20070405-C05405
         		13 476 477
    B-2435
    Figure US20070078146A1-20070405-C05406
    Figure US20070078146A1-20070405-C05407
         		23 442 443
    B-2436
    Figure US20070078146A1-20070405-C05408
    Figure US20070078146A1-20070405-C05409
         		5 486 487
    B-2437
    Figure US20070078146A1-20070405-C05410
    Figure US20070078146A1-20070405-C05411
         		4 492 493
    B-2438
    Figure US20070078146A1-20070405-C05412
    Figure US20070078146A1-20070405-C05413
         		58 422 423
    B-2439
    Figure US20070078146A1-20070405-C05414
    Figure US20070078146A1-20070405-C05415
         		12 454 455
    B-2440
    Figure US20070078146A1-20070405-C05416
    Figure US20070078146A1-20070405-C05417
         		8 521 522
    B-2441
    Figure US20070078146A1-20070405-C05418
    Figure US20070078146A1-20070405-C05419
         		6 443 444
    B-2442
    Figure US20070078146A1-20070405-C05420
    Figure US20070078146A1-20070405-C05421
         		37 514 515
    B-2443
    Figure US20070078146A1-20070405-C05422
    Figure US20070078146A1-20070405-C05423
         		15 518 —
    B-2444
    Figure US20070078146A1-20070405-C05424
    Figure US20070078146A1-20070405-C05425
         		52 520 —
    B-2445
    Figure US20070078146A1-20070405-C05426
    Figure US20070078146A1-20070405-C05427
         		33 517 518
    B-2446
    Figure US20070078146A1-20070405-C05428
    Figure US20070078146A1-20070405-C05429
         		70 500 501
    B-2447
    Figure US20070078146A1-20070405-C05430
    Figure US20070078146A1-20070405-C05431
         		56 488 489
    B-2448
    Figure US20070078146A1-20070405-C05432
    Figure US20070078146A1-20070405-C05433
         		51 522 523
    B-2449
    Figure US20070078146A1-20070405-C05434
    Figure US20070078146A1-20070405-C05435
         		19 512 513
    B-2450
    Figure US20070078146A1-20070405-C05436
    Figure US20070078146A1-20070405-C05437
         		16 538 539
    B-2451
    Figure US20070078146A1-20070405-C05438
    Figure US20070078146A1-20070405-C05439
         		71 511 512
    B-2452
    Figure US20070078146A1-20070405-C05440
    Figure US20070078146A1-20070405-C05441
         		71 500 501
    B-2453
    Figure US20070078146A1-20070405-C05442
    Figure US20070078146A1-20070405-C05443
         		61 470 —
    B-2454
    Figure US20070078146A1-20070405-C05444
    Figure US20070078146A1-20070405-C05445
         		15 472 473
    B-2455
    Figure US20070078146A1-20070405-C05446
    Figure US20070078146A1-20070405-C05447
         		39 520 —
    B-2456
    Figure US20070078146A1-20070405-C05448
    Figure US20070078146A1-20070405-C05449
         		51 533 534
    B-2457
    Figure US20070078146A1-20070405-C05450
    Figure US20070078146A1-20070405-C05451
         		55 540 —
    B-2458
    Figure US20070078146A1-20070405-C05452
    Figure US20070078146A1-20070405-C05453
         		22 488 489
    B-2459
    Figure US20070078146A1-20070405-C05454
    Figure US20070078146A1-20070405-C05455
         		8 486 487
    B-2460
    Figure US20070078146A1-20070405-C05456
    Figure US20070078146A1-20070405-C05457
         		13 534 535
    B-2461
    Figure US20070078146A1-20070405-C05458
    Figure US20070078146A1-20070405-C05459
         		13 542 —
    • EXAMPLE C-1 5-Aminomethyl-4-(4-Pyridyl)-3-(4-Fluorophenyl) Payrazole
  • Figure US20070078146A1-20070405-C05460
  • 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-1
    MW, M + H
    Example Calculated
    No. Structure Found +H NMR (solvent), ppm
    C-2 
    Figure US20070078146A1-20070405-C05461
         		323.1672 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 
    Figure US20070078146A1-20070405-C05462
         		282.127 (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 
    Figure US20070078146A1-20070405-C05463
         		282.127 (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 
    Figure US20070078146A1-20070405-C05464
         		323.1672 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 
    Figure US20070078146A1-20070405-C05465
         		359 359 (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 
    Figure US20070078146A1-20070405-C05466
         		359 359 (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 
    Figure US20070078146A1-20070405-C05467
         		313.1465 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 
    Figure US20070078146A1-20070405-C05468
         		313.1465 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-10
    Figure US20070078146A1-20070405-C05469
         		354 354 (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-11
    Figure US20070078146A1-20070405-C05470
         		354 354 (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-12
    Figure US20070078146A1-20070405-C05471
         		283.1359 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-13
    Figure US20070078146A1-20070405-C05472
         		297.1515 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-14
    Figure US20070078146A1-20070405-C05473
         		284.0829 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-15
    Figure US20070078146A1-20070405-C05474
         		285 285 (DMSO-d6): 8.53(br, 2H), 7.56(br, 2H), 7.26(m, 4H), 3.75(br, 2H)
    C-16
    Figure US20070078146A1-20070405-C05475
         		329, 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-17
    Figure US20070078146A1-20070405-C05476
         		339 339 (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-18
    Figure US20070078146A1-20070405-C05477
         		339 339 (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-19
    Figure US20070078146A1-20070405-C05478
         		383, 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.
    TABLE C-2
    Cmpd.
    No. Structure
    C-22
    Figure US20070078146A1-20070405-C05479
    C-23
    Figure US20070078146A1-20070405-C05480
    C-24
    Figure US20070078146A1-20070405-C05481
    C-25
    Figure US20070078146A1-20070405-C05482
    C-26
    Figure US20070078146A1-20070405-C05483
    C-27
    Figure US20070078146A1-20070405-C05484
    C-28
    Figure US20070078146A1-20070405-C05485
    C-29
    Figure US20070078146A1-20070405-C05486
    C-30
    Figure US20070078146A1-20070405-C05487
    C-31
    Figure US20070078146A1-20070405-C05488
    C-32
    Figure US20070078146A1-20070405-C05489
    C-33
    Figure US20070078146A1-20070405-C05490
    C-34
    Figure US20070078146A1-20070405-C05491
    C-35
    Figure US20070078146A1-20070405-C05492
    C-36
    Figure US20070078146A1-20070405-C05493
    C-37
    Figure US20070078146A1-20070405-C05494
    C-38
    Figure US20070078146A1-20070405-C05495
    C-39
    Figure US20070078146A1-20070405-C05496
    C-40
    Figure US20070078146A1-20070405-C05497
    C-41
    Figure US20070078146A1-20070405-C05498
    C-42
    Figure US20070078146A1-20070405-C05499
    C-43
    Figure US20070078146A1-20070405-C05500
    C-44
    Figure US20070078146A1-20070405-C05501
    C-45
    Figure US20070078146A1-20070405-C05502
    C-46
    Figure US20070078146A1-20070405-C05503
    C-47
    Figure US20070078146A1-20070405-C05504
    C-48
    Figure US20070078146A1-20070405-C05505
  • Figure US20070078146A1-20070405-C05506
    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
  • Figure US20070078146A1-20070405-C05507
  • 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
  • Figure US20070078146A1-20070405-C05508
  • 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
  • Figure US20070078146A1-20070405-C05509
  • 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.
    Figure US20070078146A1-20070405-C05510
  • 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.
    Figure US20070078146A1-20070405-C05511
  • 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.
    Figure US20070078146A1-20070405-C05512
    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.
    Figure US20070078146A1-20070405-C05513
  • 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-3
    Example No. Structure
    C-53
    Figure US20070078146A1-20070405-C05514
    C-54
    Figure US20070078146A1-20070405-C05515
    C-55
    Figure US20070078146A1-20070405-C05516
    C-56
    Figure US20070078146A1-20070405-C05517
    C-57
    Figure US20070078146A1-20070405-C05518
    C-58
    Figure US20070078146A1-20070405-C05519
    C-59
    Figure US20070078146A1-20070405-C05520
    • 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.
    Figure US20070078146A1-20070405-C05521
    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.
    Figure US20070078146A1-20070405-C05522
    • EXAMPLE C-61
  • Figure US20070078146A1-20070405-C05523
  • Example C-61 is prepared according to the method described in example C-60, substituting 1,4-dibromobutane for methyl iodide.
    • EXAMPLE C-62
  • Figure US20070078146A1-20070405-C05524
  • 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.
    Figure US20070078146A1-20070405-C05525
    • EXAMPLE C-64
  • Figure US20070078146A1-20070405-C05526
  • Using the method described in Schemes C-6 and C-7, Example 64 is prepared.
    • EXAMPLE C-65
  • Figure US20070078146A1-20070405-C05527
  • Using the method described in Schemes C-6 and C-7, Example 65 is prepared.
    • EXAMPLE C-66
  • Figure US20070078146A1-20070405-C05528
  • 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
  • Figure US20070078146A1-20070405-C05529
    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
  • Figure US20070078146A1-20070405-C05530
    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
  • Figure US20070078146A1-20070405-C05531
    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
  • Figure US20070078146A1-20070405-C05532
    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
  • Figure US20070078146A1-20070405-C05533
    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
  • Figure US20070078146A1-20070405-C05534
    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
  • Figure US20070078146A1-20070405-C05535
    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.
    Figure US20070078146A1-20070405-C05536
  • 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.
    Figure US20070078146A1-20070405-C05537
  • 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.
    Figure US20070078146A1-20070405-C05538
  • 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.
    Figure US20070078146A1-20070405-C05539
  • 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
  • Figure US20070078146A1-20070405-C05540
  • 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
  • Figure US20070078146A1-20070405-C05541
  • 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
  • Figure US20070078146A1-20070405-C05542
  • 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
  • Figure US20070078146A1-20070405-C05543
  • 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
  • Figure US20070078146A1-20070405-C05544
  • 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
  • Figure US20070078146A1-20070405-C05545
  • 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
  • Figure US20070078146A1-20070405-C05546
  • 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
  • Figure US20070078146A1-20070405-C05547
  • 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
  • Figure US20070078146A1-20070405-C05548
    • 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
  • Figure US20070078146A1-20070405-C05549
  • 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
  • Figure US20070078146A1-20070405-C05550
  • 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
  • Figure US20070078146A1-20070405-C05551
  • 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
  • Figure US20070078146A1-20070405-C05552
  • 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
  • Figure US20070078146A1-20070405-C05553
  • 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
  • Figure US20070078146A1-20070405-C05554
  • 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
  • Figure US20070078146A1-20070405-C05555
  • 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
  • Figure US20070078146A1-20070405-C05556
  • 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
  • Figure US20070078146A1-20070405-C05557
  • 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
  • Figure US20070078146A1-20070405-C05558
  • 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
  • Figure US20070078146A1-20070405-C05559
  • 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
  • Figure US20070078146A1-20070405-C05560
  • 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
  • Figure US20070078146A1-20070405-C05561
  • 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
  • Figure US20070078146A1-20070405-C05562
  • 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
  • Figure US20070078146A1-20070405-C05563
  • 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
  • Figure US20070078146A1-20070405-C05564
  • 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
  • Figure US20070078146A1-20070405-C05565
  • 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
  • Figure US20070078146A1-20070405-C05566
  • 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
  • Figure US20070078146A1-20070405-C05567
  • 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
  • Figure US20070078146A1-20070405-C05568
  • 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
  • Figure US20070078146A1-20070405-C05569
  • 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
  • Figure US20070078146A1-20070405-C05570
  • 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
  • Figure US20070078146A1-20070405-C05571
  • 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
  • Figure US20070078146A1-20070405-C05572
  • 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
  • Figure US20070078146A1-20070405-C05573
  • 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
  • Figure US20070078146A1-20070405-C05574
  • 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
  • Figure US20070078146A1-20070405-C05575
  • 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
  • Figure US20070078146A1-20070405-C05576
  • 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
  • Figure US20070078146A1-20070405-C05577
  • 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
  • Figure US20070078146A1-20070405-C05578
  • 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
  • Figure US20070078146A1-20070405-C05579
  • 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
  • Figure US20070078146A1-20070405-C05580
  • 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
  • Figure US20070078146A1-20070405-C05581
  • 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
  • Figure US20070078146A1-20070405-C05582
  • 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
  • Figure US20070078146A1-20070405-C05583
  • 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
  • Figure US20070078146A1-20070405-C05584
  • 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
  • Figure US20070078146A1-20070405-C05585
  • 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
  • Figure US20070078146A1-20070405-C05586
  • 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
  • Figure US20070078146A1-20070405-C05587
  • 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
  • Figure US20070078146A1-20070405-C05588
  • 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
  • Figure US20070078146A1-20070405-C05589
  • 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
  • Figure US20070078146A1-20070405-C05590
  • 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
  • Figure US20070078146A1-20070405-C05591
  • 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
  • Figure US20070078146A1-20070405-C05592
  • 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
  • Figure US20070078146A1-20070405-C05593
  • 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
  • Figure US20070078146A1-20070405-C05594
  • 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
  • Figure US20070078146A1-20070405-C05595
  • 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
  • Figure US20070078146A1-20070405-C05596
  • 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
  • Figure US20070078146A1-20070405-C05597
  • 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
  • Figure US20070078146A1-20070405-C05598
  • 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
  • Figure US20070078146A1-20070405-C05599
  • 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
  • Figure US20070078146A1-20070405-C05600
  • 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
  • Figure US20070078146A1-20070405-C05601
  • 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
  • Figure US20070078146A1-20070405-C05602
  • 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
  • Figure US20070078146A1-20070405-C05603
  • 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
  • Figure US20070078146A1-20070405-C05604
  • 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
  • Figure US20070078146A1-20070405-C05605
  • 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
  • Figure US20070078146A1-20070405-C05606
    • EXAMPLE C-141 5-(4-piperidinyl)-4-[4-(2-thiomethyl)pyrimidinyl]-3-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05607
    • EXAMPLE C-142 5-(4-N-methylpiperidinyl)-4-[4-(2-thiomethyl)pyrimidinyl]-3-4-(chloropbenyl) pyrazole
  • Figure US20070078146A1-20070405-C05608
    • EXAMPLE C-143 5-(4-N-t-butoxycarbonylpiperidinyl)-4-[4-(2-methanesulfonyl)pyrimidinyl]-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05609
    • EXAMPLE C-144 5-(4-piperidinyl)-4-[4-(2-methanesulfonyl)pyrimidinyl]-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05610
    • EXAMPLE C-145 5-(4-N-methylpiperidinyl)-4-[4-(2-methanesulfonyl)pyrimidinyl]-3-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05611
    • EXAMPLE C-146 5-(4-N-t-butoxycarbonylpiperidinyl)-4-[4-(2-amino)pyrimidinyl]-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05612
    • EXAMPLE C-147 5-(4-piperidinyl)-4-[4-(2-amino)pyrimidinyl]-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05613
    • EXAMPLE C-148 5-(4-N-methylpiperidinyl)-4-[4-(2-amino)pyrimidinyl]-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05614
    • EXAMPLE C-149 5-(4-N-t-butoxycarbonylpiperidinyl)-4-[4-(2-methylamino)pyrimidinyl]-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05615
    • EXAMPLE C-150 5-(4-piperidinyl)-4-[4-(2-methylamino)pyrimidinyl]-3-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05616
    • EXAMPLE C-151 5-(4-N-methylpiperidinyl)-4-[4-(2-methylamino)pyrimidinyl]-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05617
    • EXAMPLE C-152 5-(4-N-t-butoxycarbonylpiperidinyl)-4-[4-(2-isopropylamino)pyrimidinyl]-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05618
    • EXAMPLE C-153 5-(4-piperidinyl)-4-[4-(2-isopropylamino)pyrimidinyl]-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05619
    • EXAMPLE C-154 5-(4-N-methylpiperidinyl)-4-[4-(2-isopropylamino)pyrimidinyl]-3-(4-chlorophenyl) pyrazole
  • Figure US20070078146A1-20070405-C05620
    • EXAMPLE C-155 5-(4-N-t-butoxycarbonylpiperidinyl)-4-[4-(2-(2-methoxyethylamino))pyrimidinyl]-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05621
    • EXAMPLE C-156 5-(4-piperidinyl)-4-[4-(2-(2-methoxyethylamino))pyrimidinyl]-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05622
    • EXAMPLE C-157 5-(4-N-methylpiperidinyl)-4-[4-(2-(2-methoxyethylamino))pyrimidinyl]-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05623
    • EXAMPLE C-158 5-(4-N-t-butoxycarbonylpiperidinyl)-4-[4-(2-methoxy)pyrimidinyl]-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05624
    • EXAMPLE C-159 5-(4-piperidinyl)-4-[4-(2-methoxy)pyrimidinyl]-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05625
    • EXAMPLE C-160 5-(4-N-methylpiperidinyl)-4-[4-(2-methoxy)pyrimidinyl]-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05626
    • EXAMPLE C-161 5-(4-N-t-butoxycarbonylpiperidinyl)-4-[4-(2-isopropoxy)pyrimidinyl]-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05627
    • EXAMPLE C-162 5-(4-piperidinyl)-4-[4-(2-isopropoxy)pyrimidinyl]-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05628
    • EXAMPLE C-163 5-(4-N-methylpiperidinyl)-4-[4-(2-isopropoxy)pyrimidinyl]-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05629
    • EXAMPLE C-164 5-(4-N-t-butoxycarbonylpiperidinyl)-4-[4-(2-(2-N,N-dimethylamino)ethoxy)pyrimidinyl]-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05630
    • EXAMPLE C-165 5-(4-piperidinyl)-4-[4-(2-(2-N,N-dimethylamino)ethoxy)pyrimidinyl]-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05631
    • EXAMPLE C-166 5-(4-N-methylpiperidinyl)-4-[4-(2-(2-N,N-dimethylamino)ethoxy)pyrimidinyl]-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05632
    • EXAMPLE C-167 5-(N-acetylhydroxylimido-4-piperidyl)-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05633
    • EXAMPLE C-168 5-(N-benzylhydroxylimido-4-piperidyl)-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05634
    • EXAMPLE C-169 5-(N-phenylacethydroxylimido-4-piperidyl)-4-(4-pyridyl) -3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05635
    • EXAMPLE C-170 5-[N-methyl-4-(3,4-dehydro)piperidyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05636
    • EXAMPLE C-171 5-[N-isopropyl-4-(3,4-dehydro)piperidyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05637
    • EXAMPLE C-172 5-[N-benzyl-4-(3,4-dehydro)piperidyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05638
    • EXAMPLE C-173 5-[N-methyl-4-(4-fluoro)piperidyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05639
    • EXAMPLE C-174 5-[N-methyl-4-(4-hydroxy)piperidyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05640
    • EXAMPLE C-175 5-[N-methyl-4-(4-methoxy)piperidyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05641
    • EXAMPLE C-176 5-[N-methyl-4-(2,5-tetramethyl-4-fluoro)piperidyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05642
    • EXAMPLE C-177 5-[N-methyl-4-(2,5-tetramethyl-4-hydroxy)piperidyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05643
    • EXAMPLE C-178 5-[N-methyl-4-(2,5-tetramethyl-4-methoxy)piperidyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05644
    • EXAMPLE C-179 5-[4-(3-fluoro)piperidyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05645
    • EXAMPLE C-180 5-[4-(N-methyl-3-fluoro)piperidyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05646
    • EXAMPLE C-181 5-[4-(N-isopropyl-3-fluoro)piperidyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05647
    • EXAMPLE C-182 5-[4-(N-benzyl-3-fluoro)piperidyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05648
    • EXAMPLE C-183 5-[4-(N-acetyl-3-fluoro)piperidyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05649
    • EXAMPLE C-184 5-[4-(2-oxo)piperidyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05650
    • EXAMPLE C-185 5-[4-(N-methyl-2-oxo)piperidyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05651
    • EXAMPLE C-186 5-[4-(N-isopropyl-2-oxo)piperidyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05652
    • EXAMPLE C-187 5-[4-(N-benzyl-2-oxo)piperidyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05653
    • EXAMPLE C-188 5-[4-(N-acetyl-2-oxo)piperidyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05654
    • EXAMPLE C-189 5-[5-(2-oxo)piperidyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05655
    • EXAMPLE C-190 5-[5-(N-methyl-2-oxo)piperidyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05656
    • EXAMPLE C-191 5-[5-(N-isopropyl-2-oxo)piperidyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05657
    • EXAMPLE C-192 5-[5-(N-benzyl-2-oxo)piperidyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05658
    • EXAMPLE C-193 5-[5-(N-acetyl-2-oxo)piperidyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05659
    • EXAMPLE C-194 5-(N-acethydroxylimido-3-piperidyl)-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05660
    • EXAMPLE C-195 5-(N-benzhydroxylimido-3-piperidyl)-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05661
    • EXAMPLE C-196 5-(N-phenacethydroxylimido-3-piperidyl)-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05662
    • EXAMPLE C-197 5-(2-morpholinyl)-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05663
    • EXAMPLE C-198 5-(N-methyl-2-morpholinyl)-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05664
    • EXAMPLE C-199 5-(N-isopropyl-2-morpholinyl)-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05665
    • EXAMPLE C-200 5-(N-benzyl-2-morpholinyl)-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05666
    • EXAMPLE C-201 5-(N-acetyl-2-morpholinyl)-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05667
    • EXAMPLE C-202 5-[trans-4-(N-t-butoxycarbonylamino)methylcyclohexyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05668
    • EXAMPLE C-203 5-(trans-4-aminomethylcyclohexyl)-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05669
    • EXAMPLE C-204 5-[trans-4-(N-isopropylamino)methylcyclohexyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05670
    • EXAMPLE C-205 5-[trans-4-(N,N-dimethylamino)methylcyclohexyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05671
    • EXAMPLE C-206 5-[trans-4-(N-acetylamino)methylcyclohexyl)]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05672
    • EXAMPLE C-207 5-[trans-4-(N-t-butoxycarbonylamino)cyclohexyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05673
    • EXAMPLE C-208 5-(trans-4-aminocyclohexyl)-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05674
    • EXAMPLE C-209 5-[trans-4-(N,N-dimethylamino)cyclohexyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05675
    • EXAMPLE C-210 5-[trans-4-(N-isopropylamino)cyclohexyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05676
    • EXAMPLE C-211 5-[trans-4-(N-acetylamino)cyclohexyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05677
    • EXAMPLE C-212 5-[cis-4-(N-t-butoxycarbonyl)methylaminocyclohexyl)]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05678
    • EXAMPLE C-213 5-(cis-4-methylaminocyclohexyl)-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05679
    • EXAMPLE C-214 5-[cis-4-(N,N-dimethyl)methylaminocyclohexyl)]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05680
    • EXAMPLE C-215 5-[cis-4-(N-isopropyl)methylaminocyclohexyl)]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05681
    • EXAMPLE C-216 5-[cis-4-(N-acetyl)methylaminocyclohexyl)]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05682
    • EXAMPLE C-217 5-[3-(1,1-dimethyl-1-(N-t-butoxycarbonylamino)propyl-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05683
    • EXAMPLE C-218 5-[3-(1,1-dimethyl-1-amino)propyl-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05684
    • EXAMPLE C-219 5-[3-(1,1-dimethyl-1-(N,N-dimethylamino)propyl-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05685
    • EXAMPLE C-220 5-[3-(1,1-dimethyl-1-(N-isopropylamino)propyl-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05686
    • EXAMPLE C-221 5-[3-(1,1-dimethyl-1-(N-acetylamino)propyl-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05687
    • EXAMPLE C-222 5-[4-(1-carboxamidino)benzyl-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05688
    • EXAMPLE C-223 5-[4-(1-N-methylcarboxamidino)benzyl-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05689
    • EXAMPLE C-224 5-[4-(1-N-benzylcarboxamidino)benzyl-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05690
    • EXAMPLE C-225 5-[3-(1-carboxamidino)benzyl-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05691
    • EXAMPLE C-226 5-[3-(1-N-methylcarboxamidino)benzyl-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05692
    • EXAMPLE C-227 5-[3-(1-N-benzylcarboxamidino)benzyl-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05693
    • EXAMPLE C-228 5-[3-(N-t-butoxycarbonyl)aminobenzyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05694
    • EXAMPLE C-229 5-(3-aminobenzyl)-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05695
    • EXAMPLE C-230 5-8 3-(N,N-dimethylamino)benzyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05696
    • EXAMPLE C-231 5-[3-(N-isopropylamino)benzyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05697
    • EXAMPLE C-232 5-[3-(N-benzylamino)benzyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05698
    • EXAMPLE C-233 5-[3-(N-acetylamino)benzyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05699
    • EXAMPLE C-234 5-[4-(2-amino)methylimidazolyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05700
    • EXAMPLE C-235 5-[4-(2-N,N-dimethylamino)methylimidazolyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05701
    • EXAMPLE C-236 5-[4-(2-N-isopropylamino)methylimidazolyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05702
    • EXAMPLE C-237 5-[4-(2-N-benzylamino)methylimidazolyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05703
    • EXAMPLE C-238 5-[4-(2-N-acetylamino)methylimidazolyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05704
    • EXAMPLE C-239 5-[4-(2-amino)methyloxazolyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05705
    • EXAMPLE C-240 5-[4-(2-N,N-dimethylamino)methyloxazolyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05706
    • EXAMPLE C-241 5-[4-(2-N-isopropylamino)methyloxazolyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05707
    • EXAMPLE C-242 5-[4-(2-N-benzylamino)methyloxazolyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05708
    • EXAMPLE C-243 5-[4-(2-N-acetylamino)methyloxazolyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05709
    • EXAMPLE C-244 5-[4-(2-amino)methylthiazolyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05710
    • EXAMPLE C-245 5-[4-(2-N,N-dimethylamino)methylthiazolyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05711
    • EXAMPLE C-246 5-[4-(2-N-isopropylamino)methylthiazolyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05712
    • EXAMPLE C-247 5-[4-(2-N-benzylamino)methylthiazolyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05713
    • EXAMPLE C-248 5-[4-(2-N-acetylamino)methylthiazolyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05714
    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 kinase U937 Cell IC50, uM Mouse LPS Model % Rat LPS Model %
    IC50, uM or % or % TNF inhib @ dose inhib @ dose
    Example# inhib@conc. (uM) inhib@conc. (uM) @predose time @predose time
    B-0001 53.0% @1.0 uM 40.0% @1.0 uM
    B-0002 71.0% @1.0 uM 28.0% @10.0 uM
    B-0003 70.0% @1.0 uM 76.0% 10.0 uM
    B-0004 80.0% @1.0 uM 4.61 uM
    B-0005 95.0% @1.0 uM 2.97 uM
    B-0006 82.0% @1.0 uM 80% @10.0 uM
    B-0007 74.0% @1.0 uM 85.0% @10.0 uM
    B-0008 42.0% @1.0 uM 65.0% @10.0 uM
    B-0009 0.04 uM 0.72 uM
    B-0010 0.52 uM 0.65 uM
    B-0011 0.03 uM 4.47 uM
    B-0012 30.0% @1.0 uM 44.0% @1.0 uM
    B-0013 70.0% @1.0 uM 84.0% @10.0 uM
    B-0014 79.0% @1.0 uM 80.0% @10.0 uM
    B-0015 82.0% @1.0 uM 80.0% @10.0 uM
    B-0016 94.0% @1.0 uM 3.98 uM
    B-0017 56.0% @1.0 uM 79.0% @10.0 uM
    B-0018 60.0% @1.0 uM 59.0% @10.0 uM
    B-0019 84.0% @1.0 uM 100.0% @10.0 uM
    B-0020 73.0% @1.0 uM 81.0% @10.0 uM
    B-0021 68.0% @1.0 uM 76.0% @10.0 uM
    B-0022 69.0% @1.0 uM 44.0@1.0 uM
    B-0023 90.0% @1.0 uM 77.0% @10.0 uM
    B-0024 94.0% @1.0 uM 52.0% @1.0 uM
    B-0025 89.0% @1.0 uM 79.0% @10.0 uM
    B-0026 96.0% @1.0 uM 3.27 uM
    B-0027 94.0% @1.0 uM 11.0 uM
    B-0028 69.0% @1.0 uM 45.0% @10.0 uM
    B-0029 91.0% @1.0 uM 58.0% @10.0 uM
    B-0030 92.0% @1.0 uM 75.0% @10.0 uM
    B-0031 94.0% @1.0 uM 100.0% @10.0 uM
    B-0032 94.0% @1.0 uM 78.0% @10.0 uM
    B-0033 97.0% @1.0 uM 10.0 uM
    B-0034 95.0% @1.0 uM 10.0 uM
    B-0035 94.0% @1.0 uM 10.0 uM
    B-0036 92.0% @1.0 uM 8.24 uM
    B-0037 91.0% @1.0 uM 86.0% @10.0 uM
    B-0038 71.0% @1.0 uM 84.0% @10.0 uM
    B-0039 89.0% @1.0 uM 72.0% @10.0 uM
    B-0040 93.0% @1.0 uM 2.3 uM
    B-0041 65.0% @1.0 uM 66.0% @10.0 uM
    B-0042 94.0% @1.0 uM 2.76 uM
    B-0043 0.22 uM 0.54 uM
    B-0044 0.14 uM 0.19 uM
    B-0045 94.0% @1.0 uM 1.01 uM
    B-0046 96.0% @1.0 uM 54.0% @1.0 uM
    B-0047 94.0% @1.0 uM 74.0% @10.0 uM
    B-0048 94.0% @1.0 uM 76.0% @10.0 uM
    B-0049 88% @1.0 uM 33.0% @1.0 uM
    B-0050 73% @1.0 uM 34.0% @1.0 uM
    B-0051 3.3 uM 2.15 uM 47% @100 mpk@-6 h   79% @3 mpk@-4 h
    B-0052 92% @1.0 uM 15.0% @1.0 uM
    B-0053 95% @1.0 uM 34.0% @1.0 uM
    B-0054 90% @1.0 uM 30.0% @1.0 uM
    B-0055 93% @1.0 uM >1.0 uM
    B-0056 96% @1.0 uM 21.0% @1.0 uM
    B-0057 96% @1.0 uM 29.0% @1.0 uM
    B-0058 79% @1.0 uM 18.0% @1.0 uM
    B-0059 83% @1.0 uM 35.0% @1.0 uM
    B-0060 73% @1.0 uM 22.0% @1.0 uM
    B-0061 62% @1.0 uM 27.0% @1.0 uM
    B-0062 94% @1.0 uM 36.0% @1.0 uM
    B-0063 96% @1.0 uM 40.0% @1.0 uM
    B-0064 90% @1.0 uM 4.0% @1.0 uM
    B-0065 83% @1.0 uM 21.0% @1.0 uM
    B-0066 94% @1.0 uM 28.0% @1.0 uM
    B-0067 91% @1.0 uM 1.0% @1.0 uM
    B-0068 72% @1.0 uM 22.0% @1.0 uM
    B-0069 96% @1.0 uM 37.0% @1.0 uM
    B-0070 92% @1.0 uM 30.0% @1.0 uM
    B-0071 86% @1.0 uM 31.0% @1.0 uM
    B-0072 77% @1.0 uM 32.0% @1.0 uM
    B-0073 91% @1.0 uM 24.0% @1.0 uM
    B-0074 92% @1.0 uM 42.0% @1.0 uM
    B-0075 91% @1.0 uM 35.0% @1.0 uM
    B-0076 58% @1.0 uM 21.0% @1.0 uM
    B-0077 0.8 uM 10.0 uM
    B-0078 80% @1.0 uM 20.0% @1.0 uM
    B-0079 93% @1.0 uM 13.0% @1.0 uM
    B-0080 73% @1.0 uM 73.0% @1.0 uM
    B-0081 92% @1.0 uM 13.0% @1.0 uM
    B-0082 47% @1.0 uM 27.0% @1.0 uM
    B-0083 0.22 uM 6.51 uM
    B-0084 56% @1.0 uM 30.0% @1.0 uM
    B-0085 83% @1.0 uM 21.0% @1.0 uM
    B-0086 91% @1.0 uM 37.0% @1.0 uM
    B-0087 0.55 uM 2.26 uM   38% @30 mpk@-6 h
    B-0088 96% @1.0 uM 9.0% @1.0 uM
    B-0089 0.04 uM 3.33 uM
    B-0090 98% @1.0 uM 52.0% @1.0 uM
    B-0091 96% @1.0 uM 40.0% @1.0 uM
    B-0092 97% @1.0 uM 34.0% @1.0 uM
    B-0093 3.18 uM 1.25 uM   30% @30 mpk@-6 h
    B-0094 96% @1.0 uM 52.0% @1.0 uM
    B-0095 98% @1.0 uM 38.0% @1.0 uM
    B-0096 91% @1.0 uM 22.0% @1.0 uM
    B-0097 72.0% @10.0 uM 38.0% @1.0 uM
    B-0098 66.0% @10.0 uM 12.0% @1.0 uM
    B-0099 43.0% @1.0 uM >1.0 uM
    B-0100 75.0% @1.0 uM 5.0 uM
    B-0101 71.0% @1.0 uM 2.11 uM
    B-0102 81.0% @1.0 uM 15.0% @1.0 uM
    B-0103 71.0% @1.0 uM 6.0% @1.0 uM
    B-0104 56.0% @1.0 uM 2.78 uM
    B-0105 78.0% @1.0 uM 5.0 uM
    B-0106 62.0% @1.0 uM 5.0 uM
    B-0107 0.27 uM 5.0 uM
    B-0108 61.0% @1.0 uM 4.85 uM
    B-0109 45.0% @1.0 uM 19.0% @1.0 uM
    B-0110 66.0% @1.0 uM 13.0% @1.0 uM
    B-0111 57.0% @1.0 uM >1.0 uM
    B-0112 97.0% @1.0 uM 1.12 uM
    B-0113 75.0% @1.0 uM 43.0% @1.0 uM
    B-0114 45.0% @1.0 uM 3.92 uM
    B-0115 47.0% @1.0 uM 2.0% @1.0 uM
    B-0116 73.0% @1.0 uM 35.0% @1.0 uM
    B-0117 0.46 uM 1.78 uM   30% @30 mpk@-6 h
    B-0118 1.18 uM 1.29 uM
    B-0119 89.0% @10.0 uM 2.78 uM
    B-0120 0.008 uM 0.21 uM   77% @100 mpk@-6 h 70% @3 mpk@-4 h
    B-0121 79.0% @1.0 uM 1.22 uM
    B-0122 79.0% @10.0 uM 2.0% @1.0 uM
    B-0123 59.0% @1.0 uM >1.0 uM
    B-0124 73.0% @1.0 uM 15.0% @1.0 uM
    B-0125 70.0% @10.0 uM 17.0% @1.0 uM
    B-0126 66.0% @1.0 uM 1.57 uM
    B-0127 82.0% @1.0 uM 0.96 uM
    B-0128 78.0% @1.0 uM 1.81 uM
    B-0129 51.0% @1.0 uM 31.0% @1.0 uM
    B-0130 69.0% @1.0 uM 58.0% @1.0 uM
    B-0131 43.0% @1.0 uM 46.0% @1.0 uM
    B-0132 76.0% @1.0 uM 8.0% @1.0 uM
    B-0133 51.0% @1.0 uM 42.0% @1.0 uM
    B-0134 60.0% @1.0 uM 2.17 uM
    B-0135 78.0% @1.0 uM 58.0% @1.0 uM
    B-0136 77.0% @1.0 uM 44.0% @1.0 uM
    B-0137 41.0% @1.0 uM 37.0% @1.0 uM
    B-0138 50.0% @1.0 uM 32.0% @1.0 uM
    B-0139 54.0% @10.0 uM 17.0% @1.0 uM
    B-0140 67% @10.0 uM 9.0% @1.0 uM
    B-0141 78.0% @1.0 uM 10.0% @1.0 uM
    B-0142 86.0% @1.0 uM 12.0% @1.0 uM
    B-0143 42.0% @1.0 uM 3.63 uM
    B-0144 86.0% @1.0 uM 43.0% @1.0 uM
    B-0145 54.0% @10.0 uM 12.0% @1.0 uM
    B-0146 77.0% @10.0 uM 28.0% @1.0 uM
    B-0147 44.0% @1.0 uM 22.0% @1.0 uM
    B-0148 51.0% @1.0 uM >1.0 uM
    B-0149 1.15 uM 10.0 uM
    B-0150 27.0% @10.0 uM 35.0% @1.0 uM
    B-0151 43.0% @1.0 uM 30.0% @1.0 uM
    B-0152 51.0% @1.0 uM 24.0% @1.0 uM
    B-0153 57.0% @1.0 uM 21.0% @1.0 uM
    B-0154 65.0% @10.0 uM 14.0% @1.0 uM
    B-0155 40.0% @10.0 uM 26.0% @1.0 uM
    B-0156 42.0% @10.0 uM 13.0% @1.0 uM
    B-0157 48.0% @10.0 uM 9.0% @1.0 uM
    B-0158 58.0% @10.0 uM 39.0% @1.0 uM
    B-0159 54.0% @10.0 uM 5.0% @1.0 uM
    B-0160 59.0% @10.0 uM 26.0% @1.0 uM
    B-0161 72.0% @10.0 uM 13.0% @1.0 uM
    B-0162 23% @1.0 uM 2.05 uM
    B-0163 20.0% @10.0 uM 10.0% @1.0 uM
    B-0164 37.0% @10.0 uM 20.0% @1.0 uM
    B-0165 70.0% @10.0 uM 19.0% @1.0 uM
    B-0166 45.0% @10.0 uM 37.0% @1.0 uM
    B-0167 40.0% @1.0 uM 37.0% @1.0 uM
    B-0168 44% @1.0 uM 2.36 uM
    B-0169 43.0% @1.0 uM 21.0% @1.0 uM
    B-0170 43.0% @1.0 uM 30.0% @1.0 uM
    B-0171 61.0% @10.0 uM 21.0% @1.0 uM
    B-0172 16.0% @10.0 uM 11.0% @1.0 uM
    B-0173 33.0% @10.0 uM 48.0% @1.0 uM
    B-0174 54.0% @10.0 uM 43.0% @1.0 uM
    B-0175 41.0% @10.0 uM 31.0% @1.0 uM
    B-0176 50.0% @1.0 uM 30.0% @1.0 uM
    B-0177 70.0% @10.0 uM 27.0% @1.0 uM
    B-0178 12.0% @10.0 uM 35.0% @1.0 uM
    B-0179 27.0% @10.0 uM 37.0% @1.0 uM
    B-0180 34.0% @10.0 uM 23.0% @1.0 uM
    B-0181 5.0% @1.0 uM 2.0% @1.0 uM
    B-0182 39.0% @10.0 uM 40.0% @1.0 uM
    B-0183 12.0% @10.0 uM 34.0% @1.0 uM
    B-0184 66.0% @10.0 uM 17.0% @1.0 uM
    B-0185 65.0% @10.0 uM 25.0% @1.0 uM
    B-0186 40.0% @1.0 uM 25.0% @1.0 uM
    B-0187 4.0% @10.0 uM 14.0% @1.0 uM
    B-0188 70.0% @10.0 uM 35.0% @1.0 uM
    B-0189 42.0% @10.0 uM 9.0% @1.0 uM
    B-0190 59.0% @10.0 uM 31.0% @1.0 uM
    B-0191 40.0% @1.0 uM 29.0% @1.0 uM
    B-0192 12.0% @10.0 uM 47.0% @1.0 uM
    B-0193 0.54 uM 6% @1.0 uM
    B-0194 1.31 uM 22% @1.0 uM
    B-0195 1.03 uM 55% @1.0 uM
    B-0196 2.24 uM >1.0 uM
    B-0197 2.0 uM 14% @1.0 uM
    B-0198 1.2 uM 2% @1.0 uM
    B-0199 1.34 uM 3% @1.0 uM
    B-0200 1.31 uM 16% @1.0 uM
    B-0201 0.29 uM 59% @1.0 uM
    B-0202 0.55 uM 2.26 uM
    B-0203 0.16 uM 65% @1.0 uM
    B-0204 0.21 uM 48% @1.0 uM
    B-0205 0.096 uM 54% @1.0 uM
    B-0206 5.76 uM 14% @1.0 uM
    B-0207 0.12 uM 52% @1.0 uM
    B-0208 0.067 uM >1.0 uM
    B-0209 0.29 uM 8% @1.0 uM
    B-0210 0.057 uM 67% @1.0 uM
    B-0211 0.25 uM 30% @1.0 uM
    B-0212 0.12 uM 28% @1.0 uM
    B-0213 0.31 uM 39% @1.0 uM
    B-0214 0.16 uM 50% @1.0 uM
    B-0215 0.11 uM 51% @1.0 uM
    B-0216 0.56 uM >1.0 uM
    B-0217 0.55 uM >1.0 uM
    B-0218 0.53 uM 18% @1.0 uM
    B-0219 0.91 uM 18% @1.0 uM
    B-0220 0.13 uM 40% @1.0 uM
    B-0221 2.4 uM >1.0 uM
    B-0222 0.4 uM 29.0% @1.0 uM
    B-0223 0.2 uM 1.0% @1.0 uM
    B-0224 <0.1 uM 93.0% @1.0 uM
    B-0225 0.047 uM 37.0% @1.0 uM
    B-0226 0.074 uM 20.0% @1.0 uM
    B-0227 0.045 uM 1.0% @1.0 uM
    B-0228 0.15 uM 44.0% @1.0 uM
    B-0229 <0.1 uM 61.0% @1.0 uM
    B-0230 0.041 uM 30.0% @1.0 uM
    B-0231 0.055 uM 40.0% 1.0 uM
    B-0232 0.048 uM 24.0% @1.0 uM
    B-0233 0.095 uM 43.0% @1.0 uM
    B-0234 0.11 uM 68.0% @1.0 uM
    B-0235 1.31 uM 90.0% @1.0 uM
    B-0236 0.077 uM 46.0% @1.0 uM
    B-0237 0.13 uM 60.0% @1.0 uM
    B-0238 0.47 uM 82.0% @1.0 uM
    B-0239 5.73 uM 84.0% @1.0 uM
    B-0240 0.2 uM 70.0% @1.0 uM
    B-0241 0.1 uM 45.0% @1.0 uM
    B-0242 <0.1 uM 78.0% @1.0 uM
    B-0243 0.039 uM 53.0% @1.0 uM
    B-0244 0.02 uM 57.0% @1.0 uM
    B-0245 0.13 uM 24.0% @1.0 uM
    B-0246 <0.1 uM >1.0 uM
    B-0247 0.082 uM 75.0% @1.0 uM
    B-0248 <0.1 uM 11.0% @1.0 uM
    B-0249 <0.1 uM 75.0% @1.0 uM
    B-0250 0.28 uM 36.0% @1.0 uM
    B-0251 0.31 uM 1.0% @1.0 uM
    B-0252 0.041 uM 54.0% @1.0 uM
    B-0253 0.061 uM 74.0% @1.0 uM
    B-0254 0.12 uM 59.0% @1.0 uM
    B-0255 0.32 uM 68.0% @1.0 uM
    B-0256 <0.1 uM 88.0% @1.0 uM
    B-0257 1.71 uM 11.0% @1.0 uM
    B-0258 0.37 uM 63.0% @1.0 uM
    B-0259 0.35 uM 58.0% @1.0 uM
    B-0260 0.56 uM 23.0% @1.0 uM
    B-0261 0.49 uM 23.0% @1.0 uM
    B-0262 0.41 uM 89.0% @1.0 uM
    B-0263 0.62 uM 64.0% @1.0 uM
    B-0264 0.14 uM 18.0% @1.0 uM
    B-0265 0.92 uM 24.0% @1.0 uM
    B-0266 0.25 uM 24.0% @1.0 uM
    B-0267 0.48 uM 11.0% @1.0 uM
    B-0268 3.39 uM 19.0% @1.0 uM
    B-0269 9.81 uM 19.0% @1.0 uM
    B-0270 5.79 uM 13.0% @1.0 uM
    B-0271 7.55 uM 12.0% @1.0 uM
    B-0272 1.81 uM 48.0% @1.0 uM
    B-0273 5.03 uM 13.0% @1.0 uM
    B-0274 2.68 uM 25.0% @1.0 uM
    B-0275 2.67 uM 33.0% @1.0 uM
    B-0276 1.25 uM 26.0% @1.0 uM
    B-0277 0.68 uM 34.0% @1.0 uM
    B-0278 1.26 uM 36.0% @1.0 uM
    B-0279 1.39 uM 33.0% @1.0 uM
    B-0280 0.86 uM 18.0% @1.0 uM
    B-0281 7.37 uM 24.0% @1.0 uM
    B-0282 0.75 uM 38.0% @1.0 uM
    B-0283 6.66 uM 29.0% @1.0 uM
    B-0284 0.083 uM 65.0% @1.0 uM
    B-0285 4.57 uM 29.0% @1.0 uM
    B-0286 0.33 uM 50.0% @1.0 uM
    B-0287 4.0 uM 22.0% @1.0 uM
    B-0288 4.46 uM 26.0% @1.0 uM
    B-0289 0.15 uM 55.0% @1.0 uM
    B-0290 0.66 uM 44.0% @1.0 uM
    B-0291 1.33 uM 20.0% @1.0 uM
    B-0292 0.22 uM 28.0% @1.0 uM
    B-0293 0.66 uM 53.0% @1.0 uM
    B-0294 0.68 uM 45.0% @1.0 uM
    B-0295 0.82 uM 45.0% @1.0 uM
    B-0296 8.03 uM 36.0% @1.0 uM
    B-0297 0.78 uM 30.0% @1.0 uM
    B-0298 0.58 uM 48.0% @1.0 uM
    B-0299 0.87 uM 54.0% @1.0 uM
    B-0300 0.78 uM 32.0% @1.0 uM
    B-0301 0.19 uM 50.0% @1.0 uM
    B-0302 4.02 uM 24.0% @1.0 uM
    B-0303 0.22 uM 10.0% @1.0 uM
    B-0304 0.56 uM 28.0% @1.0 uM
    B-0305
    B-0306
    B-0307
    B-0308
    B-0309
    B-0310
    B-0311
    B-0312
    B-0313
    B-0314
    B-0315
    B-0316
    B-0317
    B-0318
    B-0319
    B-0320
    B-0321
    B-0322
    B-0323
    B-0324
    B-0325
    B-0326
    B-0327
    B-0328
    B-0329
    B-0330
    B-0331
    B-0332
    B-0333
    B-0334
    B-0335
    B-0336
    B-0337
    B-0338
    B-0339
    B-0340
    B-0341
    B-0342
    B-0343
    B-0344
    B-0345
    B-0346
    B-0347
    B-0348
    B-0349
    B-0350
    B-0351
    B-0352
    B-0353 1.37 uM 55% @1.0 uM
    B-0354 1.0 uM 0.66 uM   51% @30 mpk@-6 h 54% @3 mpk@-4 h
    B-0355 0.75 uM 40.0% @1.0 uM
    B-0356 0.66 uM 24.0% @1.0 uM
    B-0357 1.46 uM 0.66 uM
    B-0358 0.37 uM 17.0% @1.0 uM
    B-0359 0.45 uM 47.0% @1.0 uM
    B-0360 1.6 uM 19.0% @1.0 uM
    B-0361 0.33 uM 46.0% @1.0 uM
    B-0362 0.52 uM 27.0% @1.0 uM
    B-0363 4.67 uM 25.0% @1.0 uM
    B-0364 1.44 uM 27.0% @1.0 uM
    B-0365 0.96 uM 27.0% @1.0 uM
    B-0366 0.7 uM 46.0% @1.0 uM
    B-0367 1.0 uM 23.0% @1.0 uM
    B-0368 1.0 uM 0.64 uM   37% @30 mpk@-6 h
    B-0369 0.16 uM 57.0% @1.0 uM
    B-0370 0.65 uM 28.0% @1.0 uM
    B-0371 0.49 uM 28.0% @1.0 uM
    B-0372 0.35 uM 29.0% @1.0 uM
    B-0373 0.45 uM 18.0% @1.0 uM
    B-0374 1.38 uM 12.0% @1.0 uM
    B-0375 1.0 uM 19.0% @1.0 uM
    B-0376 2.99 uM 12.0% @1.0 uM
    B-0377 1.29 uM 36.0% @1.0 uM
    B-0378 1.1 uM 36.0% @1.0 uM
    B-0379 0.53 uM 24.0% @1.0 uM
    B-0380 1.41 uM 32.0% @1.0 uM
    B-0381 0.22 uM 47.0% @1.0 uM
    B-0382 0.41 uM 32.0% @1.0 uM
    B-0383 1.43 uM 10.0% @1.0 uM
    B-0384 4.02 uM 16.0% @1.0 uM
    B-0385 0.057 uM 0.9 uM   30% @30 mpk@-6 h  0% @3 mpk@-4 h
    B-0386 0.13 uM 54.0% @1.0 uM
    B-0387 0.41 uM 52.0% @1.0 uM
    B-0388 <0.1 uM 36.0% @1.0 uM
    B-0389 0.01 uM 0.05 uM 62% @3 mpk@-4 h
    B-0390 0.089 uM 55.0% @1.0 uM
    B-0391 0.86 uM 18.0% @1.0 uM
    B-0392 0.13 uM 57.0% @1.0 uM
    B-0393 0.043 uM 66.0% @1.0 uM
    B-0394 0.13 uM 45.0% @1.0 uM
    B-0395 0.087 uM 48.0% @1.0 uM
    B-0396 0.097 uM 0.44 uM
    B-0397 0.17 uM 41.0% @1.0 uM
    B-0398 0.054 uM 66.0% @1.0 uM
    B-0399 0.14 uM 39.0% @1.0 uM
    B-0400 0.16 uM 25.0% @1.0 uM
    B-0401 0.46 uM 52.0% @1.0 uM
    B-0402 0.14 uM 1.51 uM
    B-0403 1.77 uM 2.42 uM
    B-0404 0.31 uM 48.0% @1.0 uM
    B-0405 0.79 uM 30.0% @1.0 uM
    B-0406 0.54 uM 35.0% @1.0 uM
    B-0407 0.76 uM 27.0% @1.0 uM
    B-0408 0.5 uM 50.0% @1.0 uM
    B-0409 0.53 uM 30.0% @1.0 uM
    B-0410 0.38 uM 44.0% @1.0 uM
    B-0411 0.62 uM 50.0% @1.0 uM
    B-0412 0.24 uM 48.0% @1.0 uM
    B-0413 0.18 uM 55.0% @1.0 uM
    B-0414 2.54 uM 25.0% @1.0 uM
    B-0415 0.42 uM 43.0% @1.0 uM
    B-0416 0.32 uM 34.0% @1.0 uM
    B-0417 0.91 uM 28.0% @1.0 uM
    B-0418 0.22 uM 27.0% @1.0 uM
    B-0419 0.85 uM 41.0% 21.0 uM
    B-0420 0.83 uM 49.0% @1.0 uM
    B-0421 0.46 uM 57.0% @1.0 uM
    B-0422 <0.1 uM 40.0% @1.0 uM
    B-0423 0.18 uM 33.0% @1.0 uM
    B-0424 0.083 uM 32.0% @1.0 uM
    B-0425 0.26 uM 54.0% @1.0 uM
    B-0426 0.055 uM 0.74 uM 41% @3 mpk@-4 h
    B-0427 0.63 uM 39.0% @1.0 uM
    B-0428 0.99 uM 27.0% @1.0 uM
    B-0429 0.27 uM 45.0% @1.0 uM
    B-0430 0.29 uM 75.0% @1.0 uM
    B-0431 0.21 uM 64.0% @1.0 uM
    B-0432 <0.1 uM 89.0% @1.0 uM
    B-0433 <0.1 uM 92.0% @1.0 uM
    B-0434 0.12 uM 65.0% @1.0 uM
    B-0435 0.3 uM 61.0% @1.0 uM
    B-0436 1.11 uM 71.0% @1.0 uM
    B-0437 0.58 uM 59.0% @1.0 uM
    B-0438 <0.1 uM 91.0% @1.0 uM
    B-0439 2.12 uM 65.0% @1.0 uM
    B-0440 0.66 uM 63.0% @1.0 uM
    B-0441 0.8 uM 58.0% @1.0 uM
    B-0442 <0.1 uM 91.0% @1.0 uM
    B-0443 2.01 uM 71.0% @1.0 uM
    B-0444 1.01 uM 51.0% @1.0 uM
    B-0445 <0.1 uM 83.0% @1.0 uM
    B-0446 0.78 uM 80.0% @1.0 uM
    B-0447 0.19 uM 71.0% @1.0 uM
    B-0448 0.4 uM 79.0% @1.0 uM
    B-0449 0.83 uM 81.0% @1.0 uM
    B-0450 0.26 uM 81.0% @1.0 uM
    B-0451 0.071 uM 83.0% @1.0 uM   42% @30 mpk@-6 h
    B-0452 0.7 uM 75.0% @1.0 uM
    B-0453 0.47 uM 75.0% @1.0 uM
    B-0454 0.11 uM 80.0% @1.0 uM
    B-0455 <0.1 uM 95.0% @1.0 uM 36% @3 mpk %-4 h
    B-0456 1.81 uM 67.0% @1.0 uM
    B-0457 0.089 uM 81.0% @1.0 uM
    B-0458 0.033 uM 70.0% @1.0 uM
    B-0459 0.099 uM 76.0% @1.0 uM
    B-0460 0.061 uM 92.0% @1.0 uM
    B-0461 0.025 uM 96.0% @1.0 uM
    B-0462 <0.1 uM 97.0% @1.0 uM
    B-0463 0.052 uM 95.0% @1.0 uM
    B-0464 <0.1 uM 91.0% @1.0 uM
    B-0465 0.084 uM 98.0% @1.0 uM
    B-0466 <0.1 uM 98.0% @1.0 uM  0% @3 mpk@-4 h
    B-0467 <0.1 uM 77.0% @1.0 uM
    B-0468 0.031 uM 93.0% @1.0 uM
    B-0469 0.056 uM 92.0% @1.0 uM
    B-0470 0.063 uM 92.0% @1.0 uM
    B-0471 0.027 uM 97.0% @1.0 uM
    B-0472 0.19 uM 54.0% @1.0 uM
    B-0473 0.004 uM 95.0% @1.0 uM
    B-0474 0.024 uM 86.0% @1.0 uM
    B-0475 0.21 uM 74.0% @1.0 uM
    B-0476 0.56 uM 69.0% @1.0 uM
    B-0477 1.48 uM 96.0% @1.0 uM
    B-0478 0.034 uM 87.0% @1.0 uM
    B-0479 0.031 uM 90.0% @1.0 uM 15% @3 mpk@-4 h
    B-0480 0.12 uM 88.0% @1.0 uM
    B-0481 0.014 uM 95.0% @1.0 uM 56% @3 mpk@-4 h
    B-0482 0.97 uM 68.0% @1.0 uM
    B-0483 0.57 uM 68.0% @1.0 uM
    B-0484 0.28 uM 62.0% @1.0 uM
    B-0485 0.04 uM 95.0% @1.0 uM
    B-0486 0.24 uM 80.0% @1.0 uM
    B-0487 0.11 uM 89.0% @1.0 uM 54% @3 mpk@-4 h
    B-0488 0.62 uM 88.0% @1.0 uM
    B-0489 0.3 uM 80.0% @1.0 uM
    B-0490 0.91 uM 74.0% @1.0 uM
    B-0491 0.43 uM 66.0% @1.0 uM
    B-0492 0.069 uM 42.0% @1.0 uM
    B-0493 0.3 uM 36.0% @1.0 uM
    B-0494 0.13 uM 30.0% @1.0 uM
    B-0495 0.12 uM 25.0% @1.0 uM
    B-0496 0.83 uM 16.0% @1.0 uM
    B-0497 0.44 uM 31.0% @1.0 uM
    B-0498 0.33 uM 11.0% @1.0 uM
    B-0499 0.39 uM 37.0% @1.0 uM
    B-0500 0.26 uM 41.0% @1.0 uM
    B-0501 0.049 uM 52.0% @1.0 uM
    B-0502 0.065 uM 48.0% @1.0 uM
    B-0503 0.16 uM 73.0% @1.0 uM
    B-0504 0.4 uM 43.0% @1.0 uM
    B-0505 0.28 uM 44.0% @1.0 uM
    B-0506 0.94 uM 43.0% @1.0 uM
    B-0507 0.18 uM 75.0% @1.0 uM
    B-0508 2.0 uM 48.0% @1.0 uM
    B-0509 0.1 uM 86.0% @1.0 uM
    B-0510 0.69 uM 61.0% @1.0 uM
    B-0511 0.007 uM 90.0% @1.0 uM
    B-0512 1.0 uM 53.0% @1.0 uM
    B-0513 0.72 uM 52.0% @1.0 uM
    B-0514 0.14 uM 87.0% @1.0 uM
    B-0515 0.42 uM 61.0% @1.0 uM
    B-0516 0.37 uM 84.0% @1.0 uM
    B-0517 0.094 uM 52.0% @1.0 uM
    B-0518 0.11 uM 64.0% @1.0 uM
    B-0519 0.043 uM 87.0% @1.0 uM
    B-0520 0.4 uM 67.0% @1.0 uM
    B-0521 1.37 uM 52.0% @1.0 uM
    B-0522 0.15 uM 75.0% @1.0 uM
    B-0523 0.19 uM 83.0% @1.0 uM
    B-0524 0.4 uM 77.0% @1.0 uM
    B-0525 0.16 uM 76.0% @1.0 uM
    B-0526 0.031 uM 87.0% @1.0 uM
    B-0527 1.09 uM 63.0% @1.0 uM
    B-0528 0.14 uM 70.0% @1.0 uM
    B-0529 0.11 uM 73.0% @1.0 uM
    B-0530 5.53 uM 45.0% @1.0 uM
    B-0531 0.5 uM 48.0% @1.0 uM
    B-0532 0.45 uM 1.01 uM   41% @30 mpk@-6 h
    B-0533 1.23 uM 47.0% @1.0 uM
    B-0534 0.41 uM 54.0% @1.0 uM
    B-0535 0.44 uM 0.87 uM
    B-0536 0.46 uM 0.15 uM
    B-0537 3.44 uM 51.0% @1.0 uM
    B-0538 1.13 uM 45.0% @1.0 uM
    B-0539 2.84 uM 21.0% @1.0 uM
    B-0540 3.62 uM 54.0% @1.0 uM
    B-0541 3.24 uM 28.0% @1.0 uM
    B-0542 1.55 uM 50.0% @1.0 uM
    B-0543 1.56 uM 43.0% @1.0 uM
    B-0544 1.12 uM 27.0% @1.0 uM
    B-0545 1.06 uM 41.0% @1.0 uM
    B-0546 1.04 uM 18.0% @1.0 uM
    B-0547 1.24 uM 21.0% @1.0 uM
    B-0548 1.77 uM 28.0% @1.0 uM
    B-0549 2.22 uM 22.0% @1.0 uM
    B-0550 2.41 uM 14.0% @1.0 uM
    B-0551 1.08 uM 56.0% @1.0 uM
    B-0552 0.13 uM 46.0% @1.0 uM
    B-0553 1.44 uM 47.0% @1.0 uM
    B-0554 2.58 uM 20.0% @1.0 uM
    B-0555 1.87 uM 34.0% @1.0 uM
    B-0556 0.49 uM 39.0% @1.0 uM
    B-0557 1.37 uM 32.0% @1.0 uM
    B-0558 0.85 uM 33.0% @1.0 uM
    B-0559 0.53 uM 49.0% @1.0 uM
    B-0560 2.57 uM 31.0% @1.0 uM
    B-0561 2.07 uM 40.0% @1.0 uM
    B-0562 0.22 uM 0.3 uM  5% @3 mpk@-4 h
    B-0563 0.18 uM 0.13 uM
    B-0564 0.82 uM 58% @1.0 uM
    B-0565 0.23 uM 0.59 uM
    B-0566 <0.1 uM 0.17 uM  0% @3 mpk@-4 h
    B-0567 0.14 uM 0.28 uM
    B-0568 1.22 uM 46.0% @1.0 uM
    B-0569 0.15 uM 0.26 uM
    B-0570 0.27 uM 46.0% @1.0 uM
    B-0571 0.38 uM 44.0% @1.0 uM
    B-0572 0.27 uM 41.0% @1.0 uM
    B-0573 0.36 uM 1.7 uM
    B-0574 0.13 uM 0.66 uM 37% @3 mpk@-4 h
    B-0575 0.032 uM 0.17 uM
    B-0576 0.068 uM 0.39 uM 65% @3 mpk@-4 h
    B-0577 0.091 uM 66.0% @1.0 uM
    B-0578 1.88 uM 47.0% @1.0 uM
    B-0579 0.11 uM 79.0% @1.0 uM
    B-0580 2.23 uM 0.84 uM
    B-0581 0.26 uM 2.17 uM
    B-0582 1.03 uM 37.0% @1.0 uM
    B-0583 3.93 uM 26.0% @1.0 uM
    B-0584 0.66 uM 54.0% @1.0 uM
    B-0585 0.83 uM 79.0% @1.0 uM   50% @30 mpk@-6 h
    B-0586 0.81 uM 51.0% @1.0 uM
    B-0587 6.84 uM 38% @1.0 uM
    B-0588 12.8 uM 42% @1.0 uM
    B-0589 1.71 uM 42% @1.0 uM
    B-0590 1.57 uM 38.0 uM
    B-0591 3.59 uM 29.0% @1.0 uM
    B-0592 1.62 uM 45.0% @1.0 uM
    B-0593 1.22 uM 36.0% @1.0 uM
    B-0594 — 41.0% @1.0 uM
    B-0595 2.42 uM 22.0% @1.0 uM
    B-0596 20.0 uM 41.0% @1.0 uM
    B-0597 1.68 uM 63.0% @1.0 uM
    B-0598 2.12 uM 50.0% @1.0 uM
    B-0599 4.16 uM 21.0% @1.0 uM
    B-0600 0.002 uM 28.0% @1.0 uM
    B-0601 0.089 uM 1.31 uM 43% @3 mpk %-4 h
    B-0602 0.97 uM 61.0% @1.0 uM
    B-0603 0.09 uM 51.0% @1.0 uM
    B-0604 0.3 uM 20.0% @1.0 uM
    B-0605 0.18 uM 47.0% @1.0 uM
    B-0606 0.17 uM 53.0% @1.0 uM
    B-0607 2.79 uM 70.0% @1.0 uM
    B-0608 0.059 uM 73.0% @1.0 uM
    B-0609 <0.1 uM 87.0% @1.0 uM
    B-0610 <0.1 uM 88.0% @1.0 uM
    B-0611 0.65 uM 60.0% @1.0 uM
    B-0612 0.16 uM 60.0% @1.0 uM
    B-0613 0.17 uM 76.0% @1.0 uM
    B-0614 0.76 uM 70.0% @1.0 uM  0% @3 mpk@-4 h
    B-0615 0.08 uM 83.0% @1.0 uM
    B-0616 0.38 uM 87.0% @1.0 uM
    B-0617 0.045 uM 92.0% @1.0 uM
    B-0618 0.37 uM 80.0% @1.0 uM
    B-0619 <0.1 uM 88.0% @1.0 uM
    B-0620 1.59 uM 58.0% @1.0 uM
    B-0621 0.36 uM 68.0% @1.0 uM
    B-0622 0.076 uM 78.0% @1.0 uM
    B-0623 0.12 uM 76.0% @1.0 uM
    B-0624 0.085 uM 54.0% @1.0 uM
    B-0625 0.023 uM 88.0% @1.0 uM
    B-0626 <0.1 uM 85.0% @1.0 uM
    B-0627 0.25 uM 69.0% @1.0 uM
    B-0628 0.023 uM 72.0% @1.0 uM
    B-0629 0.2 uM 79.0% @1.0 uM
    B-0630 0.06 uM 77.0% @1.0 uM
    B-0631 0.065 uM 81.0% @1.0 uM
    B-0632 <0.1 uM 79.0% @1.0 uM
    B-0633 0.6 uM 80.0% @1.0 uM
    B-0634 0.6 uM 40.0% @1.0 uM
    B-0635 0.15 uM 55.0% @1.0 uM
    B-0636 <0.1 uM 86.0% @1.0 uM
    B-0637 0.11 uM 92.0% @1.0 uM
    B-0638 0.25 uM 89.0% @1.0 uM
    B-0639 0.051 uM 93.0% @1.0 uM 50% @3 mpk@-4 h
    B-0640 0.36 uM 94.0% @1.0 uM
    B-0641 0.58 uM 65.0% @1.0 uM
    B-0642 0.49 uM 90.0% @1.0 uM
    B-0643 0.069 uM 85.0% @1.0 uM  0% @3 mpk@-4 h
    B-0644 0.058 uM 89.0% @1.0 uM
    B-0645 0.58 uM 80.0% @1.0 uM
    B-0646 0.26 uM 94.0% @1.0 uM
    B-0647 1.61 uM 76.0% @1.0 uM
    B-0648 <0.1 uM 83.0% @1.0 uM
    B-0649 0.83 uM 39.0% @1.0 uM
    B-0650 0.006 uM 95.0% @1.0 uM  8% @3 mpk@-4 h
    B-0651 1.78 uM 81.0% @1.0 uM
    B-0652 0.19 uM 83.0% @1.0 uM
    B-0653 2.01 uM 74.0% @1.0 uM
    B-0654 5.97 uM 78.0% @1.0 uM
    B-0655 1.25 uM 76.0% @1.0 uM
    B-0656 0.007 uM 95.0% @1.0 uM 28% @3 mpk@-4 h
    B-0657 0.17 uM 83.0% @1.0 uM
    B-0658 1.14 uM 91.0% @1.0 uM
    B-0659 2.64 uM 87.0% @1.0 uM
    B-0660 0.088 uM 92.0% @1.0 uM
    B-0661 <0.1 uM 90.0% @1.0 uM
    B-0662 <0.1 uM 95.0% @1.0 uM
    B-0663 0.88 uM 74.0% @1.0 uM
    B-0664 0.39 uM 80.0% @1.0 uM
    B-0665 0.47 uM 72.0% @1.0 uM
    B-0666 0.17 uM 73.0% @1.0 uM
    B-0667 0.83 uM 75.0% @1.0 uM
    B-0668 0.27 uM 78.0% @1.0 uM
    B-0669 0.89 uM 34.0% @1.0 uM
    B-0670 3.15 uM 32.0% @1.0 uM
    B-0671 6.38 uM 36.0% @1.0 uM
    B-0672 6.59 uM 32.0% @1.0 uM
    B-0673 8.54 uM 48.0% @1.0 uM
    B-0674 2.81 uM 42.0% @1.0 uM
    B-0675 5.42 uM 3.0% @1.0 uM
    B-0676 2.09 uM 22.0% @1.0 uM
    B-0677 1.63 uM 25.0% @1.0 uM
    B-0678 0.38 uM 52.0% @1.0 uM
    B-0679 0.062 uM 45.0% @1.0 uM
    B-0680 0.42 uM 67.0% @1.0 uM
    B-0681 1.96 uM 17.0% @1.0 uM
    B-0682 0.76 uM 39.0% @1.0 uM
    B-0683 13.0 uM 32.0% @1.0 uM
    B-0684 0.54 uM 68.0% @1.0 uM
    B-0685 15.4 uM 33.0% @1.0 uM
    B-0686 0.42 uM 59.0% @1.0 uM
    B-0687 10.1 uM 15.0% @1.0 uM
    B-0688 0.66 uM 58.0% @1.0 uM
    B-0689 14.6 uM 27.0% @1.0 uM
    B-0690 27.1 uM 36.0% @1.0 uM
    B-0691 0.16 uM 48.0% @1.0 uM
    B-0692 0.38 uM 29.0% @1.0 uM
    B-0693 0.39 uM 28.0% @1.0 uM
    B-0694 0.62 uM 21.0% @1.0 uM
    B-0695 0.23 uM 32.0% @1.0 uM
    B-0696 0.085 uM 35.0% @1.0 uM
    B-0697 0.45 uM 44.0% @1.0 uM
    B-0698 2.33 uM 43.0% @1.0 uM
    B-0699 0.34 uM 31.0% @1.0 uM
    B-0700 0.24 uM 56.0% @1.0 uM
    B-0701 0.39 uM 45.0% @1.0 uM
    B-0702 0.036 uM 39.0% @1.0 uM
    B-0703 0.12 uM 39.0% @1.0 uM
    B-0704 2.19 uM 29.0% @1.0 uM
    B-0705 0.44 uM 21.0% @1.0 uM
    B-0706 0.44 uM 32.0% @1.0 uM
    B-0707 1.7 uM
    B-0708 2.1 uM
    B-0709 0.84 uM
    B-0710 1.99 uM
    B-0711 1.99 uM
    B-0712 2.9 uM
    B-0713 4.3 uM
    B-0714 3.7 uM
    B-0715 3.2 uM
    B-0716 4.6 uM
    B-0717 4.3 uM
    B-0718 1.4 uM
    B-0719 3.4 uM
    B-0720 1.3 uM
    B-0721 3.8 uM
    B-0722 0.07 uM >1.0 uM
    B-0723 0.47 uM
    B-0724 0.06 uM 17.0% @1.0 uM
    B-0725 9.7 uM
    B-0726 1.4 uM
    B-0727 0.51 uM
    B-0728 20.0 uM
    B-0729 0.87 uM
    B-0730 0.25 uM 11.0% @1.0 uM
    B-0731 0.87 uM >1.0 uM
    B-0732 14.0 uM
    B-0733 32.0 uM
    B-0734 0.92 uM
    B-0735 1.0 uM
    B-0736 26.0 uM
    B-0737 2.6 uM
    B-0738 2.7 uM
    B-0739 4.1 uM
    B-0740 4.4 uM
    B-0741 26.0 uM
    B-0742 2.2 uM
    B-0743 1.2 uM
    B-0744 23.0 uM
    B-0745 6.0 uM
    B-0746 0.01 uM 22.0% @1.0 uM
    B-0747 1.1 uM
    B-0748 1.2 uM
    B-0749 4.4 uM
    B-0750 0.92 uM
    B-0751 1.6 uM
    B-0752 0.33 uM
    B-0753 0.37 uM
    B-0754 0.55 uM
    B-0755 2.3 uM
    B-0756 0.94 uM
    B-0757 0.54 uM 16.0% @1.0 uM
    B-0758 1.5 uM
    B-0759 0.3 uM
    B-0760 0.01 uM 13.0% @1.0 uM
    B-0761 <0.1 uM
    B-0762 0.13 uM 5.0% @1.0 uM
    B-0763 0.015 uM 17.0% @1.0 uM
    B-0764 0.67 uM 26.0% @1.0 uM
    B-0765 0.3 uM 29.0% @1.0 uM
    B-0766 0.95 uM
    B-0767 0.08 uM
    B-0768 1.4 uM
    B-0769 12.7 uM
    B-0770 2.3 uM
    B-0771 0.5 uM
    B-0772 0.8 uM
    B-0773 14.0 uM
    B-0774 1.5 uM
    B-0775 0.6 uM >1.0 uM
    B-0776 0.9 uM >1.0 uM
    B-0777 21.0 uM
    B-0778 51.0 uM
    B-0779 0.5 uM
    B-0780 1.1 uM
    B-0781 48.0 uM
    B-0782 22.0 uM
    B-0783 8.0 uM
    B-0784 7.0 uM
    B-0785 23.0 uM
    B-0786 24.0 uM
    B-0787 1.5 uM
    B-0788 1.2 uM
    B-0789 33.0 uM
    B-0790 1.0 uM 4.0% @1.0 uM
    B-0791 0.3 uM >1.0 uM
    B-0792 1.1 uM
    B-0793 0.3 uM
    B-0794 2.9 uM 2.0% @1.0 uM
    B-0795 1.9 uM 11.0% @1.0 uM
    B-0796 1.4 uM
    B-0797 1.04 uM —
    B-0798 1.73 uM —
    B-0799 — >1.0 uM
    B-0800 1.01 uM >1.0 uM
    B-0801 0.67 uM >1.0 uM
    B-0802 — >1.0 uM
    B-0803 0.057 uM 53.0% @1.0 uM
    B-0804 0.3 uM 32.0% @1.0 uM
    B-0805 0.71 uM >1.0 uM
    B-0806 3.28 uM >1.0 uM
    B-0807 10.8 uM —
    B-0808 3.09 uM >1.0 uM
    B-0809 1.22 uM 7.0% @1.0 uM
    B-0810 1.11 uM >1.0 uM
    B-0811 2.79 uM 2.0% @1.0 uM
    B-0812 2.12 uM >1.0 uM
    B-0813 3.02 uM >1.0 uM
    B-0814 — >1.0 uM
    B-0815 2.11 uM >1.0 uM
    B-0816 3.46 uM >1.0 uM
    B-0817 3.07 uM 33.0% @1.0 uM
    B-0818 4.97 uM >1.0 uM
    B-0819 1.08 uM >1.0 uM
    B-0820 1.64 uM 3.0% @1.0 uM
    B-0821 1.44 uM —
    B-0822 1.33 uM —
    B-0823 2.39 uM >1.0 uM
    B-0824 3.41 uM —
    B-0825 — —
    B-0826 1.74 uM —
    B-0827 15.6 uM —
    B-0828 7.9 uM —
    B-0829 0.61 uM 65.0% @1.0 uM
    B-0830 0.54 uM 34.0% @1.0 uM
    B-0831 0.9 uM >1.0 uM
    B-0832 1.49 uM —
    B-0833 0.95 uM 23.0% @1.0 uM
    B-0834 1.25 uM —
    B-0835 — —
    B-0836 1.24 uM —
    B-0837 1.96 uM >1.0 uM
    B-0838 3.1 uM —
    B-0839 4.3 uM —
    B-0840 0.63 uM 47.0% @1.0 uM
    B-0841 0.32 uM 36.0% @1.0 uM
    B-0842 0.74 uM 63.0% @1.0 uM
    B-0843 0.61 uM >1.0 uM
    B-0844 0.4 uM 25.0% @1.0 uM
    B-0845 1.78 uM —
    B-0846 1.8 uM —
    B-0847 0.73 uM 21.0% @1.0 uM
    B-0848 1.56 uM —
    B-0849 1.25 uM —
    B-0850 1.81 uM —
    B-0851 0.91 uM 390% @1.0 uM
    B-0852 1.02 uM —
    B-0853 — 38.0% @1.0 uM
    B-0854 — 25.0% @1.0 uM
    B-0855 — 8.0% @1.0 uM
    B-0856 — 38.0% @1.0 uM
    B-0857 6.25 uM —
    B-0858 2.1 uM 48.0% @1.0 uM
    B-0859 39.5 uM —
    B-0860 38.1 uM —
    B-0861 1.32 uM 12.0% @1.0 uM
    B-0862 2.15 uM 4.0% @1.0 uM
    B-0863 0.81 uM 25.0% @1.0 uM
    B-0864 0.39 uM 40.% @1.0 uM
    B-0865 0.66 uM 46.0% @1.0 uM
    B-0866 1.38 uM 28.0% @1.0 uM
    B-0867 0.62 uM >1.0 uM
    B-0868 3.28 uM 8.0% @1.0 uM
    B-0869 4.19 uM >1.0 uM
    B-0870 3.13 uM >1.0 uM
    B-0871 1.9 uM >1.0 uM
    B-0872 3.13 uM 3.0% @1.0 uM
    B-0873 6.92 uM >1.0 uM
    B-0874 1.92 uM >1.0 uM
    B-0875 2.13 uM 8% @1.0 uM
    B-0876 0.89 uM >1.0 uM
    B-0877 1.17 uM 13.0% @1.0 uM
    B-0878 0.65 uM 19.0% @1.0 uM
    B-0879 0.87 uM 1.0% @1.0 uM
    B-0880 0.15 uM 40.0% @1.0 uM
    B-0881 1.36 uM >1.0 uM
    B-0882 1.48 uM 9% @1.0 uM
    B-0883 1.06 uM >1.0 uM
    B-0884 1.89 uM —
    B-0885
    B-0886
    B-0887
    B-0888
    B-0889
    B-0890
    B-0891
    B-0892
    B-0893
    B-0894
    B-0895
    B-0896
    B-0897
    B-0898
    B-0899
    B-0900
    B-0901
    B-0902
    B-0903
    B-0904
    B-0905
    B-0906
    B-0907
    B-0908
    B-0909
    B-0910
    B-0911
    B-0912
    B-0913
    B-0914
    B-0915
    B-0916
    B-0917
    B-0918
    B-0919
    B-0920
    B-0921
    B-0922
    B-0923
    B-0924
    B-0925
    B-0926
    B-0927
    B-0928
    B-0929
    B-0930
    B-0931
    B-0932
    B-0933 47.0% @1.0 uM 37.0% @1.0 uM
    B-0934 67.0% @1.0 uM 36.0% @1.0 uM
    B-0935 69.0% @1.0 uM 54.0% @1.0 uM
    B-0936 69.0% @1.0 uM >1.0 uM
    B-0937 64.0% @1.0 uM 1.74 uM
    B-0938 51.0% @1.0 uM 29.0% @1.0 uM
    B-0939 78.0% @1.0 uM 14.0% @1.0 uM
    B-0940 56.0% @1.0 uM 22.0% @1.0 uM
    B-0941 81.0% @1.0 uM 25.0% @1.0 uM
    B-0942 82.0% @1.0 uM 2.0% @1.0 uM
    B-0943 63.0% @10.0 uM 24.0% @1.0 uM
    B-0944 45.0% @1.0 uM 27.0% @1.0 uM
    B-0945 96.0% @1.0 uM 0.93 uM
    B-0946 76.0% @1.0 uM 31.0% @1.0 uM
    B-0947 69.0% @1.0 uM 34.0% @1.0 uM
    B-0948 68.0% @1.0 uM 1.81 uM
    B-0949 90.0% @1.0 uM 17.0% @1.0 uM
    B-0950 81.0% @1.0 uM 0.58 uM
    B-0951 82.0% @1.0 uM 20.0% @1.0 uM
    B-0952 44.0% @1.0 uM 21.0% @1.0 uM
    B-0953 63.0% @1.0 uM 25.0% @1.0 uM
    B-0954 62.0% @1.0 uM 0.52 uM
    B-0955 49.0% @1.0 uM 0.54 uM
    B-0956 56.0% @1.0 uM 1.33 uM
    B-0957 79.0% @1.0 uM 22.0% @1.0 uM
    B-0958 74.0% @1.0 uM 0.38 uM
    B-0959 83.0% @1.0 uM 3.90% @1.0 uM
    B-0960 48.0% @1.0 uM 4.0% @1.0 uM
    B-0961 79.0% @1.0 uM 23.0% @1.0 uM
    B-0962 85.0% @1.0 uM 2.71 uM
    B-0963 76.0% @1.0 uM 39.0% @1.0 uM
    B-0964 94.0% @1.0 uM 5.0 uM
    B-0965 74.0% @1.0 uM 1.1 uM
    B-0966 50.0% @1.0 uM 5.0% @1.0 uM
    B-0967 80.0% @1.0 uM 29.0% @1.0 uM
    B-0968 35.0% @1.0 uM 26.0% @1.0 uM
    B-0969 63.0% @1.0 uM 35.0% @1.0 uM
    B-0970 76.0% @10.0 uM 0.88 uM
    B-0971 61.0% @1.0 uM 39.0% @1.0 uM
    B-0972 85.0% @1.0 uM 2.0% @1.0 uM
    B-0973 66.0% @10.0 uM 48.0% @1.0 uM
    B-0974 57.0% @1.0 uM 47.0% @1.0 uM
    B-0975 82.0% @1.0 uM 32.0% @1.0 uM
    B-0976 79.0% @1.0 uM 36.0% @1.0 uM
    B-0977 60.0% @1.0 uM 26.0% @1.0 uM
    B-0978 59.0% @1.0 uM 36.0% @1.0 uM
    B-0979 56.0% @10.0 uM 23.0% @1.0 uM
    B-0980 68.0% @1.0 uM 31.0% @1.0 uM
    B-0981 62.0% @1.0 uM 57.0% @1.0 uM
    B-0982 65.0% @1.0 uM 23.0% @1.0 uM
    B-0983 75.0% @1.0 uM 0.8 uM
    B-0984 60.0% @1.0 uM 51.0% @1.0 uM
    B-0985 86.0% @1.0 uM 0.75 uM
    B-0986 70.0% @1.0 uM 71.0% @1.0 uM
    B-0987 78.0% @1.0 uM 79.0% @1.0 uM
    B-0988 72.0% @1.0 uM 65.0% @1.0 uM
    B-0989 85.0% @1.0 uM 0.85 uM
    B-0990 — 26.0% @1.0 uM
    B-0991 58.0% @1.0 uM 33.0% @1.0 uM
    B-0992 77.0% @1.0 uM 45.0% @1.0 uM
    B-0993 57.0% @1.0 uM 73.0% @1.0 uM
    B-0994 55.0% @1.0 uM 43.0% @1.0 uM
    B-0995 53.0% @1.0 uM 14.0% @1.0 uM
    B-0996 54.0% @1.0 uM 27.0% @1.0 uM
    B-0997 69.0% @1.0 uM 22.0% @1.0 uM
    B-0998 67.0% @1.0 uM 25.0% @1.0 uM
    B-0999 61.0% @1.0 uM 24.0% @1.0 uM
    B-1000 55.0% @1.0 uM 42.0% @1.0 uM
    B-1001 63.0% @1.0 uM 31.0% @1.0 uM
    B-1002 70.0% @1.0 uM 41.0% @1.0 uM
    B-1003 74.0% @1.0 uM 29.0% @1.0 uM
    B-1004 79.0% @1.0 uM 45.0% @1.0 uM
    B-1005 58.0% @1.0 uM 23.0% @1.0 uM
    B-1006 69.0% @1.0 uM 38.0% @1.0 uM
    B-1007 52.0% @1.0 uM 34.0% @1.0 uM
    B-1008 54.0% @1.0 uM 23.0% @1.0 uM
    B-1009 80.0% @1.0 uM 55.0% @1.0 uM
    B-1010 75.0% @1.0 uM 1.0 uM
    B-1011 72.0% 21.0 uM 17.0% @1.0 uM
    B-1012 — 20.0% @1.0 uM
    B-1013 85.0% @1.0 uM 7.0% @1.0 uM
    B-1014 88.0% @1.0 uM 20.0% @1.0 uM
    B-1015 77.0% @1.0 uM 34.0% @1.0 uM
    B-1016 58.0% @1.0 uM 10.0% @1.0 uM
    B-1017 96.0% @1.0 uM 58.0% @1.0 uM
    B-1018 88.0% @1.0 uM 34.0% @1.0 uM
    B-1019 82.0% @1.0 uM 66.0% @1.0 uM
    B-1020 87.0% @1.0 uM 36.0% @1.0 uM
    B-1021 82.0% @1.0 uM 35.0% @1.0 uM
    B-1022 84.0% @1.0 uM 53.0% @1.0 uM
    B-1023 93.0% @1.0 uM 70.0% @1.0 uM
    B-1024 89.0% @1.0 uM 57.0% @1.0 uM
    B-1025 61.0% @1.0 uM 23.0% @1.0 uM
    B-1026 87.0% @1.0 uM 53.0% @1.0 uM
    B-1027 58.0% @1.0 uM 18.0% @1.0 uM
    B-1028 70.0% @1.0 uM 17.0% @1.0 uM
    B-1029 69.0% @1.0 uM 54.0% @1.0 uM
    B-1030 76.0% @1.0 uM 60.0% @1.0 uM
    B-1031 69.0% @1.0 uM 42.0% @1.0 uM
    B-1032 76.0% @1.0 uM 37.0% @1.0 uM
    B-1033 86.0% @1.0 uM 34.0% @1.0 uM
    B-1034 66.0% @1.0 uM 39.0% @1.0 uM
    B-1035 75.0% @1.0 uM 52.0% @1.0 uM
    B-1036 68.0% @1.0 uM 68.0% @1.0 uM
    B-1037 — 41.0% @1.0 uM
    B-1038 57.0% @1.0 uM 0.57 uM
    B-1039 — 133 uM
    B-1040 72.0% @1.0 uM 0.38 uM
    B-1041 70.0% @1.0 uM 73.0% @1.0 uM
    B-1042 79.0% @1.0 uM 12.0% @1.0 uM
    B-1043 64.0% @1.0 uM 53.0% @1.0 uM
    B-1044 94.0% @1.0 uM 0.93 uM
    B-1045 78.0% @1.0 uM 25.0% @1.0 uM
    B-1046 72.0% @1.0 uM 66.0% @1.0 uM
    B-1047 72.0% @1.0 uM 58.0% @1.0 uM
    B-1048 67.0% @1.0 uM 19.0% @1.0 uM
    B-1049 67.0% @1.0 uM 65.0% @1.0 uM
    B-1050 — 0.54 uM
    B-1051 68.0% @1.0 uM 41% @1.0 uM
    B-1052 69.0% @1.0 uM 66% @1.0 uM
    B-1053 78.0% @1.0 uM 0.4 uM
    B-1054 79.0% @1.0 uM 55.0% @1.0 uM
    B-1055 89.0% @1.0 uM 63.0% @1.0 uM
    B-1056 89.0% @1.0 uM 0.76 uM
    B-1057 85.0% @1.0 uM 0.72 uM
    B-1058 0.66 uM 43.0% @1.0 uM
    B-1059 0.18 uM 24.0% @1.0 uM
    B-1060 0.11 uM 32.0% @1.0 uM
    B-1061 0.03 uM 19.0% @1.0 uM
    B-1062 <0.1 uM 26.0% @1.0 uM
    B-1063 0.16 uM 44.0% @1.0 uM
    B-1064 0.39 uM 50.0% @1.0 uM
    B-1065 0.56 uM 40.0% @1.0 uM
    B-1066 <0.1 uM 39.0% @1.0 uM
    B-1067 1.6 uM 32.0% @1.0 uM
    B-1068 0.48 uM 24.0% @1.0 uM
    B-1069 0.22 uM 27.0% @1.0 uM
    B-1070 <0.1 uM 44.0% @1.0 uM
    B-1071 <0.1 uM 48.0% @1.0 uM
    B-1072 0.38 uM 28.0% @1.0 uM
    B-1073 <0.1 uM 21.0% @1.0 uM
    B-1074 0.23 uM 33.0% @1.0 uM
    B-1075 0.03 uM 29.0% @1.0 uM
    B-1076 0.08 uM 31.0% @1.0 uM
    B-1077 <0.1 uM 38.0% @1.0 uM
    B-1078 0.26 uM 48.0% @1.0 uM
    B-1079 <0.1 uM 40.0% @1.0 uM
    B-1080 0.19 uM 28.0% @1.0 uM
    B-1081 <0.1 uM 37.0% @1.0 uM
    B-1082 <0.1 uM 54.0% @1.0 uM
    B-1083 <0.1 uM 23.0% @1.0 uM
    B-1084 0.43 uM 29.0% @1.0 uM
    B-1085 <0.1 uM 29.0% @1.0 uM
    B-1086 <0.1 uM 42.0% @1.0 uM
    B-1087 0.05 uM 32.0% @1.0 uM
    B-1088 0.73 uM 49.0% @1.0 uM
    B-1089 <0.1 uM 39.0% @1.0 uM
    B-1090 <0.1 uM 90.0% @1.0 uM
    B-1091 <0.1 uM 73.0% @1.0 uM
    B-1092 0.27 uM 85.0% @1.0 uM
    B-1093 0.33 uM 36.0% @1.0 uM
    B-1094 0.013 uM 69.0% @1.0 uM
    B-1095 <0.1 uM 70.0% @1.0 uM
    B-1096 <0.1 uM 32.0% @1.0 uM
    B-1097 <0.1 uM 44.0% @1.07 uM
    B-1098 <0.1 uM 82.0% @1.0 uM
    B-1099 0.26 uM 74.0% @1.0 uM
    B-1100 0.22 uM 56.0% @1.0 uM
    B-1101 0.026 uM 82.0% @1.0 uM
    B-1102 0.035 uM 83.0% @1.0 uM
    B-1103 0.094 uM 90.0% @1.0 uM
    B-1104 0.12 uM 69.0% @1.0 uM
    B-1105 <0.1 uM 84.0% @1.0 uM
    B-1106 <0.1 uM 86.0% @1.0 uM
    B-1107 0.057 uM 84.0% @1.0 uM
    B-1108 0.22 uM 81.0% @1.0 uM
    B-1109 0.054 uM 80.0% @1.0 uM
    B-1110 0.47 uM 64.0% @1.0 uM
    B-1111 0.19 uM 64.0% @1.0 uM
    B-1112 0.58 uM 43.0% @1.0 uM
    B-1113 <0.1 uM 72.0% @1.0 uM
    B-1114 0.069 uM 51.0% @1.0 uM
    B-1115 0.024 uM 89.0% @1.0 uM
    B-1116 0.41 uM 81.0% @1.0 uM
    B-1117 0.13 uM 73.0% @1.0 uM
    B-1118 0.33 uM 91.0% @1.0 uM
    B-1119 0.35 uM 80.0% @1.0 uM
    B-1120 0.47 uM 9.0% @1.0 uM
    B-1121 3.58 uM 29.0% @1.0 uM
    B-1122 1.84 uM 32.0% @1.0 uM
    B-1123 2.93 uM 27.0% @1.0 uM
    B-1124 1.49 uM 52.0% @1.0 uM
    B-1125 0.56 uM 41.0% @1.0 uM
    B-1126 1.5 uM >1.0 uM
    B-1127 0.71 uM 7.0% @1.0 uM
    B-1128 2.55 uM 26.0% @1.0 uM
    B-1129 1.07 uM 46.0% @1.0 uM
    B-1130 0.5 uM 29.0% @1.0 uM
    B-1131 0.076 uM 34.0% @1.0 uM
    B-1132 0.72 uM 11.0% @1.0 uM
    B-1133 0.38 uM 33.0% @1.0 uM
    B-1134 1.71 uM 33.0% @1.0 uM
    B-1135 0.23 uM 38.0% @1.0 uM
    B-1136 1.17 uM 40.0% @1.0 uM
    B-1137 0.038 uM 35.0% @1.0 uM
    B-1138 1.82 uM >1.0 uM
    B-1139 0.041 uM 29.0% @1.0 uM
    B-1140 1.68 uM 39.0% @1.0 uM
    B-1141 2.47 uM 32.0% @1.0 uM
    B-1142 0.11 uM 37.0% @1.0 uM
    B-1143 0.17 uM 40.0% @1.0 uM
    B-1144 0.44 uM 72.0% @1.0 uM
    B-1145 1.07 uM 71.0% @1.0 uM
    B-1146 0.47 uM 61.0% @1.0 uM
    B-1147 0.095 uM 53.0% @1.0 uM
    B-1148 0.43 uM 61.0% @1.0 uM
    B-1149 1.55 uM 48.0% @1.0 uM
    B-1150 0.47 uM 75.0% @1.0 uM
    B-1151 0.32 uM 72.0% @1.0 uM
    B-1152 0.73 uM 53.0% @1.0 uM
    B-1153 2.22 uM 52.0% @1.0 uM
    B-1154 0.085 uM 46.0% @1.0 uM
    B-1155 3.22 uM 30.0% @1.0 uM
    B-1156 0.27 uM 78.0% @1.0 uM
    B-1157 0.26 uM 66.0% @1.0 uM
    B-1158 74% @1.0 uM 0.68 uM   53% @30 mpk@-6 h
    B-1159 66.0% @1.0 uM 1.03 uM   60% @30 mpk@-6 h
    B-1160 79.0% @1.0 uM 0.38 uM
    B-1161 64.0% 21.0 uM 0.93 uM   40% @30 mpk@-6 h 45% @3 mpk@-4 h
    B-1162 79.0% @1.0 uM 0.59 uM   40% @30 mpk@-6 h
    B-1163 74.0% @1.0 uM 0.37 uM
    B-1164 — 0.35 uM
    B-1165 66.0% @1.0 uM 0.99 uM
    B-1166 77.0% @1.0 uM 0.39 uM   50% @30 mpk@-6 h 50% @3 mpk@-4 h
    B-1167 70.0% @1.0 uM 1.06 uM
    B-1168 66.0% @1.0 uM 0.63 uM
    B-1169 80.0% @1.0 uM 0.11 uM
    B-1170 82.0% @1.0 uM 0.57 uM
    B-1171 78.0% @1.0 uM 0.23 uM
    B-1172 68.0% @1.0 uM 1.95 uM
    B-1173 65.0% @1.0 uM 62% @1.0 uM
    B-1174 80.0% @1.0 uM 0.86 uM
    B-1175 72.0% @1.0 uM 1.83 uM
    B-1176 67.0% @1.0 uM 67.0% @1.0 uM
    B-1177 70.0% @1.0 uM 1.16 uM
    B-1178 92.0% @1.0 uM 1.61 uM
    B-1179 86.0% @1.0 uM 0.41 uM
    B-1180 78.0% @1.0 uM 0.53 uM
    B-1181 79.0% @1.0 uM 66% @1.0 uM
    B-1182 72.0% @1.0 uM 0.65 uM
    B-1183 77.0% @1.0 uM 0.2 uM
    B-1184 69.0% @1.0 uM 0.63 uM
    B-1185 71.0% @1.0 uM 0.79 uM
    B-1186 83.0% @1.0 uM 60% @1.0 uM
    B-1187 76.0% @1.0 uM 1.89 uM
    B-1188 — 36.0% @1.0 uM
    B-1189 68.0% @1.0 uM 0.83 uM
    B-1190 78.0% @1.0 uM 62.0% @1.0 uM
    B-1191 74.0% @1.0 uM 57.0% @1.0 uM
    B-1192 84.0% @1.0 uM 0.47 uM
    B-1193 69.0% @1.0 uM 65.0% @1.0 uM
    B-1194 87.0% @1.0 uM 0.58 uM
    B-1195 52.0% @1.0 uM 60.0% @1.0 uM
    B-1196 74.0% @1.0 uM 68.0% @1.0 uM
    B-1197 77.0% @1.0 uM 45.0% @1.0 uM
    B-1198 92.0% @1.0 uM 0.46 uM
    B-1199 87.0% @1.0 uM 49.0% @1.0 uM
    B-1200 95.0% @1.0 uM 0.64 uM
    B-1201 84.0% @1.0 uM 0.51 uM
    B-1202 71.0% @1.0 uM 58.0% @1.0 uM
    B-1203 84.0% @1.0 uM 58.0% @1.0 uM
    B-1204 68.0% @1.0 uM 59.0% @1.0 uM
    B-1205 74.0% @1.0 uM 46.0% @1.0 uM
    B-1206 81.0% @1.0 uM 0.34 uM
    B-1207 90.0% @1.0 uM 58.0% @1.0 uM
    B-1208 82.0% @1.0 uM 51.0% @1.0 uM
    B-1209 86.0% @1.0 uM 55.0% @1.0 uM
    B-1210 82.0% @1.0 uM 57.0% @1.0 uM
    B-1211 88.0% @1.0 uM 59.0% @1.0 uM
    B-1212 90.0% @1.0 uM 57.0% @1.0 uM
    B-1213 84.0% @1.0 uM 0.62 uM
    B-1214 76.0% @1.0 uM 58.0% @1.0 uM
    B-1215 86.0% @1.0 uM 0.23 uM
    B-1216 88.0% @1.0 uM 0.18 uM
    B-1217 87.0% @1.0 uM 0.46 uM
    B-1218 88.0% @1.0 uM 76.0% @1.0 uM
    B-1219 85.0% @1.0 uM 37.0% @1.0 uM
    B-1220 81.0% @1.0 uM 53.0% @1.0 uM
    B-1221 82.0% @1.0 uM 44.0% @1.0 uM
    B-1222 65.0% @1.0 uM 9.0% @1.0 uM
    B-1223 80.0% @1.0 uM 61.0% @1.0 uM
    B-1224 82.0% @1.0 uM 74.0% @1.0 uM
    B-1225 89.0% @1.0 uM 73.0% @1.0 uM
    B-1226 89.0% @1.0 uM 0.18 uM
    B-1227 83.0% @1.0 uM 0.22 uM
    B-1228 90.0% @1.0 uM 0.72 uM
    B-1229 87.0% @1.0 uM 0.65 uM
    B-1230 90.0% @1.0 uM 0.25 uM
    B-1231 94.0% @1.0 uM 0.56 uM
    B-1232 81.0% @1.0 uM 54.0% @1.0 uM
    B-1233 85.0% @1.0 uM 0.36 uM
    B-1234 89.0% @1.0 uM 0.49 uM
    B-1235 0.04 uM 76.0% @1.0 uM
    B-1236 0.1 uM 53.0% @1.0 uM
    B-1237 0.22 uM 39.0% @1.0 uM
    B-1238 0.14 uM 16.0% @1.0 uM
    B-1239 <0.1 uM 38.0% @1.0 uM
    B-1240 <0.1 uM 59.0% @1.0 uM
    B-1241 0.04 uM 81.0% @1.0 uM
    B-1242 0.08 uM 83.0% @1.0 uM
    B-1243 0.04 uM 47.0% @1.0 uM
    B-1244 0.26 uM 44.0% @1.0 uM
    B-1245 0.49 uM 42.0% @1.0 uM
    B-1246 0.27 uM 40.0% @1.0 uM
    B-1247 <0.1 uM 58.0% @1.0 uM
    B-1248 <0.1 uM 68.0% @1.0 uM
    B-1249 0.24 uM 60.0% @1.0 uM
    B-1250 0.14 uM 18.0% @1.0 uM
    B-1251 0.41 uM 38.0% @1.0 uM
    B-1252 0.17 uM 46.0% @1.0 uM
    B-1253 0.15 uM 57.0% @1.0 uM
    B-1254 0.16 uM 68.0% @1.0 uM
    B-1255 12.9 uM 75.0% @1.0 uM
    B-1256 0.12 uM 41.0% @1.0 uM
    B-1257 1.48 uM 40.0% @1.0 uM
    B-1258 0.07 uM 56.0% @1.0 uM
    B-1259 <0.1 uM 0.48 uM
    B-1260 0.11 uM 48.0% @1.0 uM
    B-1261 0.74 uM 44.0% @1.0 uM
    B-1262 <0.1 uM 63.0% @1.0 uM
    B-1263 1.05 uM 57.0% @1.0 uM
    B-1264 0.32 uM 47.0% @1.0 uM
    B-1265 0.43 uM 51.0% @1.0 uM
    B-1266 <0.1 uM 58.0% @1.0 uM
    B-1267 <0.1 uM 73.0% @1.0 uM
    B-1268 <0.1 uM 79.0% @1.0 uM
    B-1269 0.46 uM 84.0% @1.0 uM
    B-1270 0.47 uM 83.0% @1.0 uM
    B-1271 0.13 uM 74.0% @1.0 uM
    B-1272 0.014 uM 38.0% @1.0 uM
    B-1273 <0.1 uM 36.0% @1.0 uM
    B-1274 <0.1 uM 41.0% @1.0 uM
    B-1275 <0.1 uM 50.0% @1.0 uM
    B-1276 0.062 uM 11.0% @1.0 uM
    B-1277 <0.1 uM 47.0% @1.0 uM
    B-1278 0.12 uM 85.0% @1.0 uM
    B-1279 <0.1 uM 79.0% @1.0 uM
    B-1280 0.039 uM 83.0% @1.0 uM
    B-1281 <0.1 uM 85.0% @1.0 uM
    B-1282 <0.1 uM 75.0% @1.0 uM
    B-1283 <0.1 uM 64.0% @1.0 uM
    B-1284 <0.1 uM 75.0% @1.0 uM
    B-1285 0.057 uM 80.0% @1.0 uM
    B-1286 0.15 uM 78.0%21.0 uM
    B-1287 0.25 uM 55.0% @1.0 uM
    B-1288 0.15 uM 74.0% @1.0 uM
    B-1289 0.73 uM 35.0% @1.0 uM
    B-1290 0.26 uM 75.0% @1.0 uM
    B-1291 0.097 uM 55.0% @1.0 uM
    B-1292 0.01 uM 74.0% @1.0 uM
    B-1293 0.31 uM 48.0% @1.0 uM
    B-1294 0.013 uM 54.0% @1.0 uM
    B-1295 0.079 uM 74.0% @1.0 uM
    B-1296 0.038 uM 48.0% @1.0 uM
    B-1297 0.02 uM >1.0 uM
    B-1298 0.055 uM 20.0% @1.0 uM
    B-1299 0.091 uM >1.0 uM
    B-1300 0.071 uM 18.0% @1.0 uM
    B-1301 0.12 uM 15.0% @1.0 uM
    B-1302 0.023 uM 11.0% @1.0 uM
    B-1303 0.08 uM >1.0 uM
    B-1304 0.11 uM 10.0% @1.0 uM
    B-1305 0.64 uM 9.0% @1.0 uM
    B-1306 0.11 uM >1.0 uM
    B-1307 0.009 uM 16.0% @1.0 uM
    B-1308 <0.1 uM >1.0 uM
    B-1309 0.045 uM >1.0 uM
    B-1310 0.12 uM 11.0% @1.0 uM
    B-1311 0.05 uM 57.0% @1.0 uM
    B-1312 0.35 uM >1.0 uM
    B-1313 0.035 uM 37.0% @1.0 uM
    B-1314 0.045 uM 24.0% @1.0 uM
    B-1315 0.055 uM 12.0% @1.0 uM
    B-1316 0.026 uM 36.0% @1.0 uM
    B-1317 0.019 uM 9.0% @1.0 uM
    B-1318 <0.1 uM 1.0% @1.0 uM
    B-1319 0.24 uM >1.0 uM
    B-1320 0.047 uM 43.0% @1.0 uM
    B-1321 0.47 uM 66.0% @1.0 uM
    B-1322 0.12 uM 87.0% @1.0 uM
    B-1323 0.013 uM 85.0% @1.0 uM
    B-1324 0.16 uM 83.0% @1.0 uM
    B-1325 0.27 uM 95.0% @1.0 uM
    B-1326 0.092 uM 84.0% @1.0 uM
    B-1327 0.13 uM 65.0% @1.0 uM
    B-1328 0.032 uM 86.0% @1.0 uM
    B-1329 0.66 uM 54.0% @1.0 uM
    B-1330 0.053 uM 85.0% @1.0 uM
    B-1331 0.004 uM 85.0% @1.0 uM
    B-1332 0.007 uM 81.0% @1.0 uM
    B-1333 0.45 uM 76.0% @1.0 uM
    B-1334 0.13 uM 73.0% @1.0 uM
    B-1335 0.097 uM 63.0% @1.0 uM
    B-1336 0.072 uM 83.0% @1.0 uM
    B-1337 0.4 uM 90.0% @1.0 uM
    B-1338 0.18 uM 73.0% @1.0 uM
    B-1339 0.12 uM 67.0% @1.0 uM
    B-1340 0.043 uM 63.0% @1.0 uM
    B-1341 0.42 uM 52.0% @1.0 uM
    B-1342 0.25 uM 59.0% @1.0 uM
    B-1343 0.065 uM 83.0% @1.0 uM
    B-1344 0.014 uM 86.0% @1.0 uM
    B-1345 0.27 uM 73.0% @1.0 uM
    B-1346 0.043 uM 86.0% @1.0 uM
    B-1347 0.021 uM 84.0% @1.0 uM
    B-1348 0.009 uM 69.0% @1.0 uM
    B-1349 0.037 uM 86.0% @1.0 uM
    B-1350 0.019 uM 78.0% @1.0 uM
    B-1351 0.068 uM 78.0% @1.0 uM
    B-1352 0.013 uM 76.0% @1.0 uM
    B-1353 0.062 uM 80.0% @1.0 uM
    B-1354 0.013 uM 83.0% @1.0 uM
    B-1355 0.07 uM 75.0% @1.0 uM
    B-1356 0.059 uM 91.0% @1.0 uM
    B-1357 0.18 uM 84.0% @1.0 uM
    B-1358 0.16 uM 76.0% @1.0 uM
    B-1359 0.005 84.0% @1.0 uM
    B-1360 0.11 0.15 uM 54% @3 mpk@-4 h
    B-1361 0.03 0.29 uM
    B-1362 0.003 0.29 uM
    B-1363 0.009 0.28 uM 51.0% @30 pmk @- 53% @3 mpk@-4 h
    6 H
    B-1364 0.009 0.27 uM 53.0% @30 mpk@- 17% @3 mpk@-4 h
    6.0 H
    B-1365 0.17 88.0% @1.0 uM
    B-1366 0.04 0.27 uM
    B-1367 <0.1 0.22 uM
    B-1368 0.031 0.33 uM 44.0% @30 mpk @-
    B-1369 <0.1 0.29 uM
    B-1370 <0.1 0.77 uM
    B-1371 0.06 83.0% @1.0 uM
    B-1372 <0.1 0.41 uM 48.0% @30 mpk @-
    B-1373 0.016 0.17 uM
    B-1374 <0.1 0.28 uM
    B-1375 0.01 0.25 uM
    B-1376 0.009 0.26 uM  3.0% @30 mpk @-6 H
    B-1377 0.12 5.0 uM
    B-1378 0.02 1.04 uM
    B-1379 <0.1 0.092 uM
    B-1380 <0.1 0.26 uM
    B-1381 0.055 0.73 uM
    B-1382 <0.1 0.44 uM
    B-1383 0.0012 0.15 uM
    B-1384 0.57 0.37 uM
    B-1385 <0.1 0.11 uM
    B-1386 <0.1 0.25 uM
    B-1387 <0.1 0.1 uM
    B-1388 0.57 1.38 uM
    B-1389 0.06 0.57 uM
    B-1390 <0.1 71.0% @1.0 uM
    B-1391 0.016 uM 82.0% @1.0 uM
    B-1392 0.059 uM 82.0% @1.0 uM
    B-1393 3.17 uM 80.0% @1.0 uM
    B-1394 0.32 uM 78.0% @1.0 uM
    B-1395 1.48 61.0% @1.0 uM
    B-1396 1.55 73.0% @1.0 uM
    B-1397 0.92 85.0% @1.0 uM
    B-1398 0.67 83.0% @1.0 uM
    B-1399 0.14 74.0% @1.0 uM
    B-1400 0.024 83.0% @1.0 uM
    B-1401 0.033 75.0% @1.0 uM
    B-1402 0.12 76.0% @1.0 uM
    B-1403 4.54 71% @1.0 uM
    B-1404 0.6 70% @1.0 uM
    B-1405 0.28 70% @1.0 uM
    B-1406 1.39 56.0% @1.0 uM
    B-1407 0.4 71.0% @1.0 uM
    B-1408 0.27 69.0% @1.0 uM
    B-1409 <0.1 72.0% @1.0 uM
    B-1410 <0.1 69% @1.0 uM
    B-1411 <0.1 81.0% @1.0 uM
    B-1412 0.097 80.0% @1.0 uM
    B-1413 0.016 78.0% @1.0 uM
    B-1414 0.025 83.0% @1.0 uM
    B-1415 1.41 79.0% @1.0 uM
    B-1416 0.14 81.0% @1.0 uM
    B-1417 0.069 69.0% @1.0 uM
    B-1418 1.01 82.0% @1.0 uM
    B-1419 0.3 84.0% @1.0 uM
    B-1420 <0.1 82.0% @1.0 uM
    B-1421 0.014 75.0% @1.0 uM
    B-1422 0.58 68.0% @1.0 uM
    B-1423 1.58 84.0% @1.0 uM
    B-1424 0.86 76.0% @1.0 uM
    B-1425 0.09 83.0% @1.0 uM
    B-1426 0.19 80.0% @1.0 uM
    B-1427 <0.1 84.0% @1.0 uM
    B-1428 <0.1 86.0% @1.0 uM
    B-1429 <0.1 87.0% @1.0 uM
    B-1430 0.75 uM 35.0% @1.0 uM
    B-1431 0.36 uM 58.0% @1.0 uM
    B-1432 0.11 uM 51.0% @1.0 uM
    B-1433 0.26 uM 21.0% @1.0 uM
    B-1434 0.19 uM 28.0% @1.0 uM
    B-1435 1.8 uM 45.0% @1.0 uM
    B-1436 1.0 uM 20.0% @1.0 uM
    B-1437 0.3 uM 23.0% @1.0 uM
    B-1438 2.01 uM 27.0% @1.0 uM
    B-1439 1.7 uM 17.0% @1.0 uM
    B-1440 0.87 uM 3.0% @1.0 uM
    B-1441 1.95 uM 66.0% @1.0 uM
    B-1442 1.54 uM 18.0% @1.0 uM
    B-1443 0.014 uM 83.0% @1.0 uM
    B-1444 0.3 uM 24.0% @1.0 uM
    B-1445 0.43 uM 27.0% @1.0 uM
    B-1446 0.77 uM 36.0% @1.0 uM
    B-1447 0.5 uM 34.0% @1.0 uM
    B-1448 1.43 uM 22.0% @1.0 uM
    B-1449 1.61 uM 50.0% @1.0 uM
    B-1450 2.1 uM 49.0% @1.0 uM
    B-1451 2.88 uM 50% @1.0 uM
    B-1452 2.41 uM 47.0% @1.0 uM
    B-1453 2.53 uM 49.0% @1.0 uM
    B-1454 1.6 uM 12.0% @1.0 uM
    B-1455 1.21 uM 8.0% @1.0 uM
    B-1456 1.29 uM >1.0 uM
    B-1457 0.43 uM 43.0% @1.0 uM
    B-1458 0.95 uM 65.0% @1.0 uM
    B-1459 0.67 uM 46.0% @1.0 uM
    B-1460 0.96 uM 29.0% @1.0 uM
    B-1461 0.4 uM 39.0% @1.0 uM
    B-1462 0.22 uM 50.0% @1.0 uM
    B-1463 2.34 uM 26.0% @1.0 uM
    B-1464 1.18 uM 27.0% @1.0 uM
    B-1465 3.23 uM 31.0% @1.0 uM
    B-1466 1.69 uM >1.0 uM
    B-1467 1.22 uM 1.0% @1.0 uM
    B-1468 1.61 uM 10.0% @1.0 uM
    B-1469 0.37 uM 14.0% @1.0 uM
    B-1470 0.6 uM 28.0% @1.0 uM
    B-1471 0.85 uM 25.0% @1.0 uM
    B-1472 0.93 uM 12.0% @1.0 uM
    B-1473 1.24 uM 14.0% @1.0 uM
    B-1474 1.23 uM 31.0% @1.0 uM
    B-1475 2.1 uM 24.0% @1.0 uM
    B-1476 0.047 uM 42.0% @1.0 uM
    B-1477 2.5 uM 34.0% @1.0 uM
    B-1478
    B-1479
    B-2270 0.72 uM 31% @10.0 uM
    B-2271 0.93 uM 38% @10.0 uM
    B-2272 0.26 uM 53.0% @10.0 uM
    B-2273 1.92 uM 39.0% @10.0 uM
    B-2274 0.26 uM 59.0% @10.0 uM
    B-2275 2.16 uM 53.0% @10.0 uM
    B-2276 11.5 uM 37.0% @10.0 uM
    B-2277 14.9 uM 44.0% @10.0 uM
    B-2278 0.8 uM 51.0% @10.0 uM
    B-2279 0.32 uM 36.0% @10.0 uM
    B-2280 0.4 uM 57.0% @10.0 uM
    B-2281 0.81 uM 60.0% @10.0 uM
    B-2282 0.91 uM 41.0% @10.0 uM
    B-2283 0.04 uM 53.0% @10.0 uM
    B-2284 4.61 uM 62.0% @10.0 uM
    B-2285 2.29 uM 49.0% @10.0 uM
    B-2286 0.017 uM 0.78 uM   25% @30 mpk@-1 h
    B-2287 2.56 uM 61.0% @10.0 uM
    B-2288 6.51 uM 46.0% @10.0 uM
    B-2289 3.0 uM 30.0% @10.0 uM
    B-2290 2.37 uM 59.0% @10.0 uM
    B-2291 0.019 uM 41% @10.0 uM
    B-2292 8.82 uM 57.0% @10.0 uM
    B-2293 2.11 uM 56.0% @10.0 uM
    B-2294 1.68 uM 50.0% @10.0 uM
    B-2295 1.79 uM 56.0% @10.0 uM
    B-2296 17.3 uM 63.0% @10.0 uM
    B-2297 3.59 uM 57.0% @10.0 uM
    B-2298 0.29 uM 4.22 uM
    B-2299 1.97 uM 62.0% @10.0 uM
    B-2300 0.07 uM 43.0% @10.0 uM
    B-2301 0.18 uM 44.0% @10.0 uM
    B-2302 1.0 uM 58.0% @1.0 uM
    B-2303 0.011 uM 54.0% @10.0 uM
    B-2304 1.41 uM 50.0% @10.0 uM
    B-2305 0.54 uM 60.0% @10.0 uM
    B-2306 5.88 uM 39.0% @10.0 uM
    B-2307 2.29 uM 69.0% @10.0 uM
    B-2308 0.66 uM 56.0% @10.0 uM
    B-2309 0.29 uM 47.0% @10.0 uM
    B-2310 0.12 uM 1.2 uM   50% @30 mpk@-6 h
    B-2311 7.18 uM 60% @10.0 uM
    B-2312 2.93 uM 43.0% @10.0 uM
    B-2313 42.3 uM 58.0% @10.0 uM
    B-2314 11.0 uM 66.0% @10.0 uM
    B-2315 0.49 uM 36.0% @10.0 uM
    B-2316 0.46 uM 58.0% @10.0 uM
    B-2317 1.0 uM 60.0% @10.0 uM
    B-2318 73.0% @10.0 uM 25.0% @10.0 uM
    B-2319 75.0% @10.0 uM 40.0% @10.0 uM
    B-2320 44.0% @10.0 uM 35.0% @10.0 uM
    B-2321 69.0% @10.0 uM 27.0% @10.0 uM
    B-2322 76.0% @10.0 uM 38.0% @10.0 uM
    B-2323 69.0% @10.0 uM 46.0% @10.0 uM
    B-2324 58.0% @10.0 uM 36.0% @10.0 uM
    B-2325 60.0% @10.0 uM 51.0% @10.0 uM
    B-2326 76.0% @10.0 uM 33.0% @10.0 uM
    B-2327 76.0% @10.0 uM 23.0% @10.0 uM
    B-2328 65.0% @10.0 uM 28.0% @10.0 uM
    B-2329 72.0% @10.0 uM 53.0% @10.0 uM
    B-2330 81.0% @10.0 uM 37.0% @10.0 uM
    B-2331 74.0% @10.0 uM 44.0% @10.0 uM
    B-2332 70.0% @10.0 uM 47.0% @10.0 uM
    B-2333 58.0% @10.0 uM 36.0% @10.0 uM
    B-2334 81.0% @10.0 uM 45.0% @10.0 uM
    B-2335 82.0% @10.0 uM 50.0% @10.0 uM
    B-2336 48.0% @10.0 uM 35.0% @10.0 uM
    B-2337 46.0% @10.0 uM 59.0% @10.0 uM
    B-2338 73.0% @10.0 uM 50.0% @10.0 uM
    B-2339 84.0% @10.0 uM >10.0 uM
    B-2340 35.0% @10.0 uM 12.0% @10.0 uM
    B-2341 75.0% @10.0 uM 50.0% @10.0 uM
    B-2342 83.0% @10.0 uM 46.0% @10.0 uM
    B-2343 43.0% @10.0 uM 27.0% @10.0 uM
    B-2344 71.0% @10.0 uM 50.0% @10.0 uM
    B-2345 64.0% @10.0 uM 38.0% @10.0 uM
    B-2346 45.0% @10.0 uM 48.0% @10.0 uM
    B-2347 49.0% @10.0 uM 50.0% @10.0 uM
    B-2348 76.0% @10.0 uM 48.0% @10.0 uM
    B-2349 75.0% @10.0 uM 27.0% @10.0 uM
    B-2350 38.0% @10.0 uM 56.0% @10.0 uM
    B-2351 77.0% @10.0 uM 1.0% @10.0 uM
    B-2352 37.0% @10.0 uM 19.0% @10.0 uM
    B-2353 38.0% @10.0 uM 33.0% @10.0 uM
    B-2354 65.0% @10.0 uM 25.0% @10.0 uM
    B-2355 84.0% @10.0 uM 50.0% @10.0 uM
    B-2356 77.0% @10.0 uM 45.0% @10.0 uM
    B-2357 47.0% @10.0 uM 41.0% @10.0 uM
    B-2358 17.0% @10.0 uM 52.0% @10.0 uM
    B-2359 76.0% @10.0 uM 35.0% @10.0 uM
    B-2360 45.0% @10.0 uM >10.0 uM
    B-2361 19.0% @10.0 uM 46.0% @10.0 uM
    B-2362 60% @100.0 uM 39.0% @10.0 uM
    B-2363 44.0% @10.0 uM 1.0% @10.0 uM
    B-2364 47.0% @10.0 uM 4.0% @10.0 uM
    B-2365 82.0% @10.0 uM 43.0% @10.0 uM
    B-2366 70.0% @10.0 uM 59.0% @10.0 uM
    B-2367 46.0% @10.0 uM 40.0% @1.0 uM
    B-2368 65.0% @10.0 uM 55.0% @10.0 uM
    B-2369 32.0% @10.0 uM >10.0 uM
    B-2370 73% @100.0 uM 20.0% @10.0 uM
    B-2371 54.0% @10.0 uM 36.0% @10.0 uM
    B-2372 55.0% @100.0 uM >10.0 uM
    B-2373 50.0% @100.0 uM 6% @10.0 uM
    B-2374 35.0% @10.0 uM 20.0% @10.0 uM
    B-2375 62.0% @100.0 uM >10.0 uM
    B-2376 32.0% @10.0 uM 17.0% @10.0 uM
    B-2377 34.0% @10.0 uM 17.0% @10.0 uM
    B-2378 48.0% @10.0 uM 61.0% @10.0 uM
    B-2379 73.0% @100.0 uM 45.0% @1.0 uM
    B-2380 81% @100.0 uM 53.0% @10.0 uM
    B-2381 68% @100.0 uM 2.0% @10.0 uM
    B-2382 51.0% @10.0 uM 24.0% @10.0 uM
    B-2383 63.0% @10.0 uM 35.0% @10.0 uM
    B-2384 49% @100.0 uM 10.0% @10.0 uM
    B-2385 79.0% @10.0 uM 19.0% @10.0 uM
    B-2386 38.0% @10.0 uM 19.0% @10.0 uM
    B-2387 50.0% @100.0 uM >10.0 uM
    B-2388 42.0% @10.0 uM 24.0% @10.0 uM
    B-2389 39.0% @10.0 uM 29.0% @10.0 uM
    B-2390 34.0% @10.0 uM 27.0% @1.0 uM
    B-2391 40.0% @10.0 uM 59.0% @10.0 uM
    B-2392 63.0% @10.0 uM 46.0% @10.0 uM
    B-2393 43.0% @10.0 uM >10.0 uM
    B-2394 37.0% @10.0 uM 22.0% @10.0 uM
    B-2395 32.0% @10.0 uM 28.0% @10.0 uM
    B-2396 75.0% @10.0 uM >10.0 uM
    B-2397 83.0% @10.0 uM 22.0% @10.0 uM
    B-2398 55% @100.0 uM 10.0% @10.0 uM
    B-2399 69.0% @10.0 uM 18.0% @10.0 uM
    B-2400 60.0% @10.0 uM 40.0% @10.0 uM
    B-2401 78.0% @10.0 uM 44.0% @10.0 uM
    B-2402 43.0% @10.0 uM 52.0% @10.0 uM
    B-2403 72% @100.0 uM 52.0% @10.0 uM
    B-2404 58% @100.0 uM 52.0% @10.0 uM
    B-2405 47% @100.0 uM >10.0 uM
    B-2406 45.0% @10.0 uM 24.0% @10.0 uM
    B-2407 47% @100.0 uM 27.0% @10.0 uM
    B-2408 39.0% @10.0 uM 10.0% @10.0 uM
    B-2409 78.0% @10.0 uM 26.0% @10.0 uM
    B-2410 33.0% @10.0 uM 32.0% @10.0 uM
    B-2411 26% @100.0 uM 13.0% @10.0 uM
    B-2412 40.0% @10.0 uM 31.0% @10.0 uM
    B-2413 75.0% @10.0 uM 37.0% @10.0 uM
    B-2414 86.0% @10.0 uM 38.0% @10.0 uM
    B-2415 94.0% @10.0 uM 50.0% @10.0 uM
    B-2416 85.0% @10.0 uM 43.0% @1.0 uM
    B-2417 83.0% @10.0 uM 18.0% @10.0 uM
    B-2418 88.0% @10.0 uM 34.0% @10.0 uM
    B-2419 86.0% @10.0 uM 66.0% @10.0 uM
    B-2420 70.0% @10.0 uM 34.0% @10.0 uM
    B-2421 89.0% 210.0 uM 38.0% @10.0 uM
    B-2422 90.0% @10.0 uM 17.0% @10.0 uM
    B-2423 85.0% @10.0 uM >10.0 uM
    B-2424 86.0% @10.0 uM 43.0% @10.0 uM
    B-2425 79.0% @10.0 uM 42.0% @10.0 uM
    B-2426 88.0% @10.0 uM 53.0% @10.0 uM
    B-2427 87.0% @10.0 uM 59.0% @10.0 uM
    B-2428 82.0% @10.0 uM 50.0% @10.0 uM
    B-2429 92.0% @10.0 uM 32.0% @10.0 uM
    B-2430 90.0% @10.0 uM 61.0% @10.0 uM
    B-2431 85.0% 210.0 uM 68.0% @10.0 uM
    B-2432 86.0% 210.0 uM 40.0% @10.0 uM
    B-2433 94.0% @10.0 uM 84.0% @10.0 uM
    B-2434 92.0% @10.0 uM 63.0% @10.0 uM
    B-2435 84.0% @10.0 uM 4.0% @10.0 uM
    B-2436 80.0% @10.0 uM 54.0% @10.0 uM
    B-2437 82.0% @10.0 uM 41.0% @10.0 uM
    B-2438 75.0% @10.0 uM 40.0% @10.0 uM
    B-2439 81.0% @10.0 uM 44.0% @10.0 uM
    B-2440 77.0% @10.0 uM 78.0% @10.0 uM
    B-2441 86.0% @10.0 uM 46.0% @10.0 uM
    B-2442 86.0% @10.0 uM >10.0 uM
    B-2443 84.0% @10.0 uM 44.0% @10.0 uM
    B-2444 89.0% @10.0 uM 7.0% @10.0 uM
    B-2445 94.0% @10.0 uM 15.0% @10.0 uM
    B-2446 90.0% @10.0 uM 28.0% @10.0 uM
    B-2447 94.0% @10.0 uM >10.0 uM
    B-2448 75.0% @10.0 uM 30.0% @10.0 uM
    B-2449 86.0% @10.0 uM 42.0% @10.0 uM
    B-2450 87.0% @10.0 uM 46.0% @1.0 uM
    B-2451 87.0% @10.0 uM 45.0% @10.0 uM
    B-2452 89.0% @10.0 uM 33.0% @10.0 uM
    B-2453 91.0% @10.0 uM >10.0 uM
    B-2454 88.0% @10.0 uM 40.0% @10.0 uM
    B-2455 87.0% @10.0 uM 54.0% @10.0 uM
    B-2456 86.0% @10.0 uM 53.0% @10.0 uM
    B-2457 90.0% @10.0 uM 18.0% @10.0 uM
    B-2458 83.0% @10.0 uM 36.0% @10.0 uM
    B-2459 82.0% @10.0 uM 81.0% @10.0 uM
    B-2460 80.0% @10.0 uM 79.0% @10.0 uM
    B-2461 67.0% @10.0 uM 59.0% @10.0 uM

    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 Model
    P38 alpha Human Whole Blood % Inhibition@
    kinase IC50, μM or dose@predose
    Example# IC50, μM % Inhib@conc. (μM) time
    C-74 0.037 0.56 54% @5 mpk@-4 h
    C-75 0.045 0.4 71% @5 mpk@-4 h
    C-76 0.07 3.24 66% @5 mpk@-4 h
    C-77 0.071 8.2 92% @5 mpk@-4 h
    C-78 0.068 10.5 87% @5 mpk@-4 h
    C-79 0.045 0.52 83% @5 mpk@-4 h
    C-80 0.008 51% @ 5 μM
    C-81 0.037 40% @ 5 μM
    C-82 0.15 7.31
    C-83 0.24 1.23 25% @5 mpk@-4 h
    C-84 0.048 0.88 22% @5 mpk@-4 h
    C-85 0.57 >25
    C-86 0.007 0.19 66% @5 mpk@-4 h
    C-87 0.027 0.34
    C-88 0.012 0.3 59% @5 mpk@-4 h
    C-89 0.039 0.12 27% @5 mpk@-4 h
    C-90 0.037 0.48
    C-91 0.054 2.31 63% @5 mpk@-4 h
    C-92 0.024 0.28 66% @5 mpk@-4 h
    C-93 0.009 0.38 50% @5 mpk@-4 h
    C-94 0.02 0.27 73% @5 mpk@-4 h
    C-95 0.13 3.91 32% @5 mpk@-4 h
    C-96 0.077 2.1 38% @5 mpk@-4 h
    C-97 0.025 3.83 21% @5 mpk@-4 h
    C-98 0.016 0.64 78% @5 mpk@-4 h
    C-99 0.062 0.38 36% @5 mpk@-4 h
    C-100 0.027 0.27 44% @5 mpk@-4 h
    C-101 0.083 3.71 52% @5 mpk@-4 h
    C-102 0.29 7.56 72% @5 mpk@-4 h
    C-105 0.033 0.13 46% @5 mpk@-4 h
    C-106 0.026 0.44 23% @5 mpk@-4 h
    C-107 0.014 0.38 11% @5 mpk@-4 h
    C-108 0.02 0.73  0% @5 mpk@-4 h
    C-111 0.21 6.05 39% @5 mpk@-4 h
    C-112 0.54 6.36 89% @5 mpk@-4 h
    C-113 0.082 2.72 77% @5 mpk@-4 h
    C-114 0.11 1.73 39% @5 mpk@-4 h
    C-115 0.042 10.2 39% @5 mpk@-4 h
    C-116 0.429 0.50 53% @5 mpk@-4 h
    C-117 3.42 7.26 71% @5 mpk@-4 h
    C-118 0.298 >25 39% @5 mpk@-4 h
    C-120 0.7 18.6 26% @5 mpk@-4 h
    C-121 0.11 15.3 39% @5 mpk@-4 h
    C-122 0.025 55% @5 mpk@-4 h
    C-123 0.67 >25.0
    C-124 0.17 4.56 51% @20 mpk@-4 h
    C-125 7.22 >25.0
    C-126 0.71 >25.0  6% @20 mpk@-4 h
    C-127 0.038 0.27 53% @5 mpk@-4 h
    C-128 0.09 2.22 63% @5 mpk@-4 h
    C-132 0.086 44% @ 5 μM
    C-133 0.16 4.54 55% @5 mpk@-4 h
    C-135 6.0
    C-136 0.032
    C-137 0.051 58% @5 mpk@-4 h
    C-138 0.28 0.68 26% @5 mpk@-4 h
    C-139 0.2 3.66 46% @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.
    Figure US20070078146A1-20070405-C05715
    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
  • Figure US20070078146A1-20070405-C05716
  • 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).
    Figure US20070078146A1-20070405-C05717
  • 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.
    Figure US20070078146A1-20070405-C05718
  • 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:
    Figure US20070078146A1-20070405-C05719
  • 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).
    Figure US20070078146A1-20070405-C05720
  • 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.
    Figure US20070078146A1-20070405-C05721
  • 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
  • Figure US20070078146A1-20070405-C05722
  • 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)
  • Figure US20070078146A1-20070405-C05723
  • 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
  • Figure US20070078146A1-20070405-C05724
  • 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
  • Figure US20070078146A1-20070405-C05725
  • 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
  • Figure US20070078146A1-20070405-C05726
  • 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
  • Figure US20070078146A1-20070405-C05727
  • 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
  • Figure US20070078146A1-20070405-C05728
  • 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
  • Figure US20070078146A1-20070405-C05729
  • 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
  • Figure US20070078146A1-20070405-C05730
  • 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
  • Figure US20070078146A1-20070405-C05731
  • 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
  • Figure US20070078146A1-20070405-C05732
  • 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
  • Figure US20070078146A1-20070405-C05733
  • 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
  • Figure US20070078146A1-20070405-C05734
    • EXAMPLE D-15 5-[4-N-(2-hydroxy-2-(3-chlorophenyl)acetyl)piperidyl]-4-(4-pyrimidyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05735
    • EXAMPLE D-16 5-[4-N-(1-hydroxy-1-cyclohexylacetyl)piperidyl]-4-(4-pyrimidyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05736
    • EXAMPLE D-17 5-[4-N-(2-hydroxy-1-cyclohexylacetyl)piperidyll-4-(4-pyrimidyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05737
    • EXAMPLE D-18 5-[4-N-(3-hydroxy-1-cyclohexylacetyl)piperidyl]-4-(4-pyrimidyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05738
    • EXAMPLE D-19 5-[4-N-(4-hydroxy-1-cyclohexylacetyl)piperidyl]-4-(4-pyrimidyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05739
    • EXAMPLE D-20 5-[4-N-(1-hydroxy-1-cyclopentylacetyl)piperidyl]-4-(4-pyrimidyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05740
    • EXAMPLE D-21 5-[4-N-(2-hydroxy-1-cyclopentylacetyl)piperidyl]-4-(4-pyrimidyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05741
    • EXAMPLE D-22 5-[4-N-(3-hydroxy-1-cyclopentylacetyl)piperidyl]-4-(4-pyrimidyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05742
    • EXAMPLE D-23 5-[4-N-(3-hydroxypropionyl)piperidyl]-4-(4-pyrimidyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05743
    • EXAMPLE D-24 5-[4-N-(2-hydroxy-3,3,3-trifluoropropionyl)piperidyl]-4-(4-pyrimidyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05744
    • EXAMPLE D-25 5-[4-N-(2-hydroxy-3-methylbutyryl)piperidyl]-4-(4-pyrimidyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05745
    • EXAMPLE D-26 5-[4-N-(2-hydroxyisocaproyl)piperidyl]-4-(4-pyrimidyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05746
    • EXAMPLE D-27 5-[4-N-(2-hydroxy-2-cyclohexylacetyl)piperidyl]-4-(4-pyrimidyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05747
    • EXAMPLE D-28 5-(4-N-(2-hydroxy-2-(4-methoxyphenyl)acetyl)piperidyl]-4-(4-pyrimidyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05748
    • EXAMPLE D-29 5-[4-N-(2-hydroxy-2-(3-methoxyphenyl)acetyl)piperidyl]-4-(4-pyrimidyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05749
    • EXAMPLE D-30 5-[4-N-(2-hydroxy-2-(4-trifluoromethylphenyl)acetyl)piperidyl]-4-(4-pyrimidyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05750
    • EXAMPLE D-31 5-[4-N-(2-hydroxy-3-phenylpropionyl)piperidyl]-4-(4-pyrimidyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05751
    • EXAMPLE D-32 5-[4-N-(2-hydroxy-3-(4-hydroxyphenyl)propionyl)piperidyl]-4-(4-pyrimidyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05752
    • EXAMPLE D-33 5-[4-N-(2-hydroxy-3-imidazolpropionyl)piperidyl]-4-(4-pyrimidyl)-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05753
  • 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.
    Figure US20070078146A1-20070405-C05754
  • 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
  • Figure US20070078146A1-20070405-C05755
    • EXAMPLE D-35 5-[4-N-(2-hydroxyacetyl)piperidyl]-4-[4-(2-methanesulfonyl)pyrimidyl]-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05756
    • EXAMPLE D-36 5-[4-N-(2-hydroxyacetyl)piperidyl]-4-[4-(2-amino)pyrimidyl]-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05757
    • EXAMPLE D-37 5-[4-N-(2-hydroxyacetyl)piperidyl]-4-[4-(2-methylamino)pyrimidyl]-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05758
    • EXAMPLE D-38 5-[4-N-(2-hydroxyacetyl)piperidyl]-4-[4-(2-isopropylamino)pyrimidyl]-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05759
    • EXAMPLE D-39 5-[4-N-(2-hydroxyacetyl)piperidyl]-4-[4-(2-S-methylbenzylamino)pyrimidyl]-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05760
    • EXAMPLE D-40 5-[4-N-(2-hydroxyacetyl)piperidyl]-4-[4-(2-R-methylbenzylamino)pyrimidyl]-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05761
    • EXAMPLE D-41 5-[4-N-(2-hydroxyacetyl)piperidyl]-4-[4-(2-methoxy)pyrimidyl]-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05762
    • EXAMPLE D-42 5-[4-N-(2-hydroxyacetyl)piperidyl]-4-[4-(p-fluorophenoxy)pyrimidyl]-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05763
    • EXAMPLE D-43 5-[4-N-(2-hydroxyacetyl)piperidyl]-4-[4-(p-fluoroanilino)pyrimidyl]-3-(4-chlorophenyl)pyrazole
  • Figure US20070078146A1-20070405-C05764
  • 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.
    Figure US20070078146A1-20070405-C05765
    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.
    Figure US20070078146A1-20070405-C05766
  • An additional group of compounds of interest includes the following:
    Figure US20070078146A1-20070405-C05767
  • 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 % Inh
    p38 alpha HWB IC50 @1.0 @5.0 ratLPS/% Inh
    Example IC50 (uM) (uM) (mg/kg) (mg/kg) @20.0 (mg/kg)
    D-1 0.17 83.0
    D-2 0.084 1.79 89.0 95.0
    D-3 0.095 0.46 69.0 88.0 91.0
    D-4 0.91 1.55 42.3 83.0 99.0
    D-5 0.14 4.09 65.0 78.5 83.0
    D-6 0.083 1.33 82.0 96.0 100
    D-7 0.44 >25.0 0
    D-8 0.18 1.3 65 85
    D-9 1.63 15.8 5 86
    D-10 3.95 14.8 80
    D-11 0.16 1.5 43 86
    D-12 0.82 7.06 71 91
    D-13 0.33 8.36 53 87

Claims (160)

1. A compound of Formula IB:
Figure US20070078146A1-20070405-C05768
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
Figure US20070078146A1-20070405-C05769
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 may be 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 may be 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 may be optionally substituted with one or more radicals independently selected from halogen, alkyl and alkoxy; and
R2 is 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
R2 is piperidinyl substituted with one or more substituents selected from hydroxycycloalkyl and alkoxycycloalkyl, and wherein said hydroxycycloalkyl and alkoxycycloalkyl 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; and
R3 is selected from pyridinyl, pyrimidinyl, quinolinyl, purinyl, maleimidyl, pyridonyl, thiazolyl, thiazolylalkyl, thiazolylamino,
Figure US20070078146A1-20070405-C05770
wherein the R3 pyridinyl, pyrimidinyl, quinolinyl, purinyl, maleimidyl, pyridonyl, thiazolyl, thiazolylalkyl, thiazolylamino,
Figure US20070078146A1-20070405-C05771
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; 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; or
a pharmaceutically-acceptable salt or tautomer thereof.
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:
Figure US20070078146A1-20070405-C05772
Figure US20070078146A1-20070405-C05773
4. A compound of claim 1 having Formula XB:
Figure US20070078146A1-20070405-C05774
wherein
Z represents a carbon atom or a nitrogen atom;
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; and
R2 is piperidinyl substituted with one or more substituents selected from hydroxyalkyl, hydroxyalkenyl, alkoxyalkylene, alkoxyalkenylene, hydroxyalkylcarbonyl, and hydroxyalkenylcarbonyl, wherein said hydroxyalkyl, hydroxyalkenyl, alkoxyalkylene, alkoxyalkenylene, hydroxyalkylcarbonyl, and hydroxyalkenylcarbonyl 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 and hydroxycycloalkylcarbonyl, wherein said hydroxycycloalkyl 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; and
R4 is selected from 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, 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; and
R5 represents 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; or
a pharmaceutically-acceptable salt or tautomer thereof.
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:
Figure US20070078146A1-20070405-C05775
wherein:
Z represents a carbon atom or a nitrogen atom;
R400 is selected from hydroxyalkyl, hydroxyalkylcarbonyl and alkoxyalkylene, wherein said hydroxyalkyl, hydroxyalkylcarbonyl and alkoxyalkylene 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
R400 is hydroxycycloalkylcarbonyl that is 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; and
R401a and R401b are independently selected from hydrogen, halo, haloalkyl, haloalkoxy, alkoxy, cyano, hydroxy, alkyl, alkenyl, and alkynyl, wherein said haloalkyl, haloalkoxy, alkoxy, 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; and
R402 is 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; or
a pharmaceutically-acceptable salt or tautomer thereof.
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:
Figure US20070078146A1-20070405-C05776
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
Figure US20070078146A1-20070405-C05777
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 may be 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 may be 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 may be optionally substituted with one or more radicals independently selected from halogen, alkyl and alkoxy; and
R2 is cyclohexyl substituted with one or more substituents selected from optionally substituted hydroxyalkyl, alkylaminoalkylene and cycloalkylamino; and
R3 is selected from pyridinyl, pyrimidinyl, quinolinyl, purinyl, maleimidyl, pyridonyl, thiazolyl, thiazolylalkyl, thiazolylamino,
Figure US20070078146A1-20070405-C05778
wherein the R3 pyridinyl, pyrimidinyl, quinolinyl, purinyl, maleimidyl, pyridonyl, thiazolyl, thiazolylalkyl, thiazolylamino,
Figure US20070078146A1-20070405-C05779
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; 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; or
a pharmaceutically-acceptable salt or tautomer thereof.
40. A compound of claim 39 selected from compounds, their tautomers and their pharmaceutically acceptable salts, of the group consisting of:
Figure US20070078146A1-20070405-C05780
41. A compound of claim 39 having Formula XC:
Figure US20070078146A1-20070405-C05781
wherein
Z represents a carbon atom or a nitrogen atom;
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; and
R2 is cyclohexyl substituted with one or more substituents selected from optionally substituted hydroxyalkyl, alkylaminoalkylene and cycloalkylamino; and
R4 is selected from 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, 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; and
R5 represents 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; or
a pharmaceutically-acceptable salt or tautomer thereof.
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:
Figure US20070078146A1-20070405-C05782
wherein:
Z represents a carbon atom or a nitrogen atom;
R403 is selected from hydroxyalkyl, alkylaminoalkylene and cycloalkylamino; and
R404a and R404b are independently selected from hydrogen, halo, haloalkyl, haloalkoxy, alkoxy, cyano, hydroxy, alkyl, alkenyl, and alkynyl, wherein said haloalkyl, haloalkoxy, alkoxy, 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; and
R405 is 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; or
a pharmaceutically-acceptable salt or tautomer thereof.
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:
Figure US20070078146A1-20070405-C05783
wherein:
Z represents a carbon atom or a nitrogen atom;
R403 is selected from alkylamino; and
R404a and R404b are independently selected from hydrogen, halo, haloalkyl, haloalkoxy, alkoxy, cyano, hydroxy, alkyl, alkenyl, and alkynyl, wherein said haloalkyl, haloalkoxy, alkoxy, 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; and
R405 is 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; or
a pharmaceutically-acceptable salt or tautomer thereof.
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:
Figure US20070078146A1-20070405-C05784
wherein:
Z represents a carbon atom or a nitrogen atom;
R406 is alkynyl; and
R407a and R407b are independently selected from hydrogen, halo, haloalkyl, haloalkoxy, alkoxy, cyano, hydroxy, alkyl, alkenyl, and alkynyl, wherein said haloalkyl, haloalkoxy, alkoxy, 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; and
R408 is 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; or
a pharmaceutically-acceptable salt or tautomer thereof.
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
Figure US20070078146A1-20070405-C05785
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
Figure US20070078146A1-20070405-C05786
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, and alkylaminosulfonylarylene; wherein said alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, alkylheterocyclylarylene, alkoxyarylene, aryloxyarylene, arylaminocarbonylalkylene, aryloxycarbonylarylene, arylcarbonylarylene, alkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, and alkylsulfonylarylene groups may be 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 may be 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 may be optionally substituted with one or more radicals independently selected from halogen, alkyl and alkoxy; and
R2 is selected from mercapto, aryl(hydroxyalkyl)amino, N-alkyl-N-alkynyl-amino, aminocarbonylalkylene, alkylcarbonylaminoalkylene, aminoalkylcarbonylaminoalkylene, alkylaminoalkylcarbonylamino, aminoalkylthio, alkylaaminocarbonylalkylthio, alkylaminoalkylaminocarbonylalkylthio, cyanoalkylthio, alkenylthio, alkynylthio, carboxyalkylthio, alkoxycarbonylalkylthio, alkylsulfinyl, alkylsulfonyl, alkoxyalkyl, alkoxyalkylthio, alkoxycarbonylalkylamino, alkoxycarbonylaminoalkylene, alkoxycarbonylaminoalkoxy, aralkythio, heterocyclylalkylthio, aminoalkoxy, cyanoalkoxy, carboxyalkoxy, aryloxy, aralkoxy, alkenyloxy, alkynyloxy, and heterocyclylalkyloxy; 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—; and
—O—;
or R200 represents a bond;
R201 represents one or more radicals selected from the group consisting of hydroxy, hydroxyalkyl, cycloalkyl, hydroxyalkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, haloarylcarbonyl, alkoxyalkylene, alkoxyarylene, carboxyalkylcarbonyl, alkoxyalkylcarbonyl, heterocyclylalkylcarbonyl, alkylsulfonylalkylene, aminoalkyl, aralkylamino, alkylaminoalkylene, aminocarbonyl, alkylcarbonylamino, alkylcarbonylaminoalkylene, alkylaminoalkylcarbonyl, alkylaminoalkylcarbonylamino, aminoalkylcarbonylaminoalkyl, alkoxycarbonylamino, alkoxyalkylcarbonylamino, alkoxycarbonylaminoalkylene, alkylimidocarbonyl, amidino, alkylamidino, aralkylamidino, guanidino, guanidinoalkylene, and 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
x 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; and
R3 is selected from pyridinyl, pyrimidinyl, quinolinyl, purinyl, maleimidyl, pyridonyl, thiazolyl, thiazolylalkyl, thiazolylamino,
Figure US20070078146A1-20070405-C05787
wherein the R3 pyridinyl, pyrimidinyl, quinolinyl, purinyl, maleimidyl, pyridonyl, thiazolyl, thiazolylalkyl, thiazolylamino,
Figure US20070078146A1-20070405-C05788
groups may be 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, and —NR44R45 wherein R44 is alkylcarbonyl or amino, and R45is 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 —R200-heterocyclyl-R201, —R200-aryl-R201 or —R200-unsubstituted cycloalkyl-R201 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.
94. A compound of Formula IXA:
Figure US20070078146A1-20070405-C05789
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 lower hydroxyalkylamino; 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 hydroxy, lower hydroxyalkyl, lower cycloalkyl, lower hydroxyalkylcarbonyl, lower cycloalkylcarbonyl, arylcarbonyl, haloarylcarbonyl, lower alkoxyalkylene, lower alkoxyarylene, lower carboxyalkylcarbonyl, lower alkoxyalkylcarbonyl, lower heterocyclylalkylcarbonyl, lower alkylsulfonylalkylene, amino, lower aminoalkyl, 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.
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:
Figure US20070078146A1-20070405-C05790
wherein:
Z represents a carbon atom or a nitrogen atom; and
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 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, 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, 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.
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:
Figure US20070078146A1-20070405-C05791
wherein:
Z represents a carbon atom or a nitrogen atom; and
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, 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 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, 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.
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:
Figure US20070078146A1-20070405-C05792
wherein:
Z represents a carbon atom or a nitrogen atom; and
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, 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 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, 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.
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:
Figure US20070078146A1-20070405-C05793
Figure US20070078146A1-20070405-C05794
Figure US20070078146A1-20070405-C05795
126. A compound of Formula IA
Figure US20070078146A1-20070405-C05796
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
Figure US20070078146A1-20070405-C05797
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 may be 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 may be optionally substituted with one or more radicals independently selected from alkyl and nitro; or
R26 nd 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 may be optionally substituted with one or more radicals independently selected from halogen, alkyl and alkoxy; and
R2 is 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—; and
—O—;
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, and 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
x is 0, 1 or 2; and
R3 is selected from pyridinyl, pyrimidinyl, quinolinyl, purinyl, maleimidyl, pyridonyl, thiazolyl, thiazolylalkyl, thiazolylamino,
Figure US20070078146A1-20070405-C05798
wherein the R3 pyridinyl, pyrimidinyl, quinolinyl, purinyl, maleimidyl, pyridonyl, thiazolyl, thiazolylalkyl, thiazolylamino,
Figure US20070078146A1-20070405-C05799
groups may be 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, and —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 that R4 is not methylsulfonylphenyl or aminosulfonylphenyl; and
further provided that R1 is not methylsulfonylphenyl; or
a pharmaceutically-acceptable salt or tautomer thereof.
127. A compound of Formula IA
Figure US20070078146A1-20070405-C05800
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
Figure US20070078146A1-20070405-C05801
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 may be 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 may be 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 may be optionally substituted with one or more radicals independently selected from halogen, alkyl and alkoxy; and
R2 is R200-aryl-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—NR300—;
—(CH2)y—NR202—(CH2)z1—;
—(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—; and
—O—;
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, and alkylsulfonylamino; and
R202 and R203 are independently selected from hydrido, alkyl, aryl and aralkyl; and
R300 is selected from alkyl, aryl and aralkyl; and
y and z are independently 0, 1, 2, 3, 4, 5 or 6 wherein y+z; and y1 is 1, 2, 3, 4, 5 or 6; wherein y+z and y1+z are less than or equal to 6; and
x is 0, 1 or 2; and
R3 is selected from pyridinyl, pyrimidinyl, quinolinyl, purinyl, maleimidyl, pyridonyl, thiazolyl, thiazolylalkyl, thiazolylamino,
Figure US20070078146A1-20070405-C05802
wherein the R3 pyridinyl, pyrimidinyl, quinolinyl, purinyl, maleimidyl, pyridonyl, thiazolyl, thiazolylalkyl, thiazolylamino,
Figure US20070078146A1-20070405-C05803
groups may be 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, and —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 that R4 is not methylsulfonylphenyl or aminosulfonylphenyl; and
further provided that R1 is not methylsulfonylphenyl; or
a pharmaceutically-acceptable salt or tautomer thereof.
128. A compound of Formula IA
Figure US20070078146A1-20070405-C05804
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
Figure US20070078146A1-20070405-C05805
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 may be 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 may be 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 may be optionally substituted with one or more radicals independently selected from halogen, alkyl and alkoxy; and
R2 is R200-heterocyclyl-R201 wherein:
R200 is selected from:
—(CR301R302)y—;
—C(O)—(CH2)y1—;
—C(O)—O—(CH2)y—;
—(CH2)y—C(O)—;
—O—(CH2)y—C(O)
—NR303—;
—NR303—(CH2)y—;
—(CH2)y—NR202—;
—(CH2)y1—NR202—(CH2)z1—;
—(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—; and
—(CH2)y—O—;
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, and alkylsulfonylamino; and
R202 and R203 are independently selected from hydrido, alkyl, aryl and aralkyl; and
R301 and R302 are independently selected from aryl and aralkyl; and
R303 is selected from alkyl, aryl and aralkyl; and
y and z are independently 0, 1, 2, 3, 4, 5 or 6; and y1 is 1, 2, 3, 4, 5 or 6; wherein y+z and y1+z are less than or equal to 6; and
x is 0, 1 or 2; wherein either x or y is other than 0 when R200 is —S(O)x—(CR202R203)y—; and
R3 is selected from pyridinyl, pyrimidinyl, quinolinyl, purinyl, maleimidyl, pyridonyl, thiazolyl, thiazolylalkyl, thiazolylamino,
Figure US20070078146A1-20070405-C05806
wherein the R3 pyridinyl, pyrimidinyl, quinolinyl, purinyl, maleimidyl, pyridonyl, thiazolyl, thiazolylalkyl, thiazolylamino,
Figure US20070078146A1-20070405-C05807
groups may be 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, and —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.
129. A compound of Formula IA
Figure US20070078146A1-20070405-C05808
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
Figure US20070078146A1-20070405-C05809
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 may be optionally substituted with one or more radicals independently selected from alkyl, halo, haloalkyl, alkoxy, keto, amino, nitro, and cyano; or
R27 is —CHR20R29 wherein R28 is alkoxycarbonyl, and R29 is selected from aralkyl, aralkoxyalkylene, heterocyclylalkylene, alkylheterocyclylalkylene, alkoxycarbonylalkylene, alkylthioalkylene, and aralkylthioalkylene; wherein said aralkyl and heterocylcyl groups may be 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 may be 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 may be 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, and 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
x 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:
Figure US20070078146A1-20070405-C05810
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,
Figure US20070078146A1-20070405-C05811
wherein the R3 maleimidyl, pyridonyl, thiazolyl, thiazolylalkyl, thiazolylamino,
Figure US20070078146A1-20070405-C05812
groups may be 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, and —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
Figure US20070078146A1-20070405-C05813
wherein R43 is selected from hydrogen, alkyl, aminoalkyl, alkoxyalkyl, alkenoxyalkyl, and aryloxyalkyl; and
further provided R2 is selected from aryl, heterocyclyl, unsubstituted cycloalkyl and cycloalkenyl when R1 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.
130. A compound of Formula IA
Figure US20070078146A1-20070405-C05814
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
Figure US20070078146A1-20070405-C05815
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 may be 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 may be 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 may be 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 may be 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—; and
—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, and 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
x 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:
Figure US20070078146A1-20070405-C05816
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, hetero substituted 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,
Figure US20070078146A1-20070405-C05817
wherein the R3 pyridinyl, pyrimidinyl, quinolinyl, purinyl 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, alkoxycarbonylheterocyclylamino and haloalkylsulfonyl; and
wherein the R3 maleimidyl, pyridonyl, thiazolyl, thiazolylalkyl, thiazolylamino,
Figure US20070078146A1-20070405-C05818
groups may be 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, and —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
provided R3 is not
Figure US20070078146A1-20070405-C05819
wherein R43 is selected from hydrogen, alkyl, aminoalkyl, alkoxyalkyl, alkenoxyalkyl, and aryloxyalkyl; 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.
131. A compound of Formula IA
Figure US20070078146A1-20070405-C05820
wherein
R1 is selected from hydroxy and alkoxyaryl; 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 may be 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—; and
—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, and 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
x 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:
Figure US20070078146A1-20070405-C05821
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,
Figure US20070078146A1-20070405-C05822
wherein the R3 pyridinyl, pyrimidinyl, quinolinyl, purinyl, maleimidyl, pyridonyl, thiazolyl, thiazolylalkyl, thiazolylamino,
Figure US20070078146A1-20070405-C05823
groups may be 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, and —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; or
a pharmaceutically-acceptable salt or tautomer thereof.
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
Figure US20070078146A1-20070405-C05824
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
Figure US20070078146A1-20070405-C05825
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, and alkylaminosulfonylarylene; wherein said alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, alkylheterocyclylarylene, alkoxyarylene, aryloxyarylene, arylaminocarbonylalkylene, aryloxycarbonylarylene, arylcarbonylarylene, alkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, and alkylsulfonylarylene groups may be 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 may be 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 may be optionally substituted with one or more radicals independently selected from halogen, alkyl and alkoxy; and
R2 is selected from mercapto, aryl(hydroxyalkyl)amino, N-alkyl-N-alkynyl-amino, aminocarbonylalkylene, alkylcarbonylaminoalkylene, aminoalkylcarbonylaminoalkylene, alkylaminoalkylcarbonylamino, aminoalkylthio, alkylaminocarbonylalkylthio, alkylaminoalkylaminocarbonylalkylthio, cyanoalkylthio, alkenylthio, alkynylthio, carboxyalkylthio, alkoxycarbonylalkylthio, alkylsulfinyl, alkylsulfonyl, alkoxyalkyl, alkoxyalkylthio, alkoxycarbonylalkylamino, alkoxycarbonylaminoalkylene, alkoxycarbonylaminoalkoxy, aralkythio, heterocyclylalkylthio, aminoalkoxy, cyanoalkoxy, carboxyalkoxy, aryloxy, aralkoxy, alkenyloxy, alkynyloxy, and heterocyclylalkyloxy; 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—; and
—O—;
or R200 represents a bond;
R201 represents one or more radicals selected from the group consisting of hydroxy, hydroxyalkyl, cycloalkyl, hydroxyalkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, haloarylcarbonyl, alkoxyalkylene, alkoxyarylene, carboxyalkylcarbonyl, alkoxyalkylcarbonyl, heterocyclylalkylcarbonyl, alkylsulfonylalkylene, aminoalkyl, aralkylamino, alkylaminoalkylene, aminocarbonyl, alkylcarbonylamino, alkylcarbonylaminoalkylene, alkylaminoalkylcarbonyl, alkylaminoalkylcarbonylamino, aminoalkylcarbonylaminoalkyl, alkoxycarbonylamino, alkoxyalkylcarbonylamino, alkoxycarbonylaminoalkylene, alkylimidocarbonyl, amidino, alkylamidino, aralkylamidino, guanidino, guanidinoalkylene, and 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
x 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; and
R3 is selected from pyridinyl, pyrimidinyl, quinolinyl, purinyl, maieimidyl, pyridonyl, thiazolyl, thiazolylalkyl, thiazolylamino,
Figure US20070078146A1-20070405-C05826
wherein the R3 pyridinyl, pyrimidinyl, quinolinyl, purinyl, maleimidyl, pyridonyl, thiazolyl, thiazolylalkyl, thiazolylamino,
Figure US20070078146A1-20070405-C05827
groups may be 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, heterocyclyloxycarbbnyl, 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, and —NR44R45 wherein R44 is alkylcarbonyl or amino, and R4s 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,
said method comprising the steps of treating a substituted ketone with an acyl hydrazide to give the pyrazole.
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:
Figure US20070078146A1-20070405-C05828
or a tautomer or pharmaceutically acceptable salt thereof.
146. A compound of claim 71 that is:
Figure US20070078146A1-20070405-C05829
or a tautomer or pharmaceutically acceptable salt thereof.
147. A compound of claim 39 that is:
Figure US20070078146A1-20070405-C05830
or a tautomer or pharmaceutically acceptable salt thereof.
148. The compound:
Figure US20070078146A1-20070405-C05831
or a tautomer or pharmaceutically acceptable salt thereof.
149. A compound of claim 1 that is:
Figure US20070078146A1-20070405-C05832
or a tautomer or pharmaceutically acceptable salt thereof.
150. The compound:
Figure US20070078146A1-20070405-C05833
or a tautomer or pharmaceutically acceptable salt thereof.
151. A compound of claim 1 that is:
Figure US20070078146A1-20070405-C05834
or a tautomer or pharmaceutically acceptable salt thereof.
152. A compound of claim 1 that is:
Figure US20070078146A1-20070405-C05835
or a tautomer or pharmaceutically acceptable salt thereof.
153. A compound of claim 1 that is:
Figure US20070078146A1-20070405-C05836
or a tautomer or pharmaceutically acceptable salt thereof.
154. A compound of claim 39 that is:
Figure US20070078146A1-20070405-C05837
or a tautomer or pharmaceutically acceptable salt thereof.
155. A compound of claim 1 that is:
Figure US20070078146A1-20070405-C05838
or a tautomer or pharmaceutically acceptable salt thereof.
156. A compound of claim 82 that is:
Figure US20070078146A1-20070405-C05839
or a tautomer or pharmaceutically acceptable salt thereof.
157. A compound of claim 42 that is:
Figure US20070078146A1-20070405-C05840
or a tautomer or pharmaceutically acceptable salt thereof.
158. A compound of claim 71 that is:
Figure US20070078146A1-20070405-C05841
or a tautomer or pharmaceutically acceptable salt thereof.
159. A compound of claim 71 that is:
Figure US20070078146A1-20070405-C05842
or a tautomer or pharmaceutically acceptable salt thereof.
160. A compound of claim 70 wherein R404a is meta-chloro or para-chloro.
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