AU754830C - Substituted pyrazoles as p38 kinase inhibitors - Google Patents

Substituted pyrazoles as p38 kinase inhibitors

Info

Publication number
AU754830C
AU754830C AU75883/98A AU7588398A AU754830C AU 754830 C AU754830 C AU 754830C AU 75883/98 A AU75883/98 A AU 75883/98A AU 7588398 A AU7588398 A AU 7588398A AU 754830 C AU754830 C AU 754830C
Authority
AU
Australia
Prior art keywords
pyrazol
methyl
alkyl
pyridine
fluorophenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
AU75883/98A
Other versions
AU754830B2 (en
AU7588398A (en
Inventor
Ashok Anantanarayan
Michael Clare
Paul W. Collins
Joyce Zuowu Crich
Rajesh Devraj
Daniel L. Flynn
Lifeng Geng
Gunnar J. Hanson
Ish K. Khanna
Francis J Koszyk
Shuyuan Liao
Richard A. Partis
Shashidhar N. Rao
Shaun Raj Selness
Michael S. South
Michael A Stealey
Richard M. Weier
Xiangdong Xu
Yi Yu
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
GD Searle LLC
Original Assignee
GD Searle LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by GD Searle LLC filed Critical GD Searle LLC
Publication of AU7588398A publication Critical patent/AU7588398A/en
Publication of AU754830B2 publication Critical patent/AU754830B2/en
Assigned to G.D. SEARLE LLC reassignment G.D. SEARLE LLC Request to Amend Deed and Register Assignors: G.D. SEARLE & CO.
Application granted granted Critical
Publication of AU754830C publication Critical patent/AU754830C/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Landscapes

  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Rheumatology (AREA)
  • Immunology (AREA)
  • Pulmonology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Pain & Pain Management (AREA)
  • Vascular Medicine (AREA)
  • Endocrinology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Obesity (AREA)
  • Cardiology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Urology & Nephrology (AREA)
  • Dermatology (AREA)
  • Transplantation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Description

SUBSTITUTED PYRAZOLES AS p38 KINASE INHIBITORS
Cross-Reference to Related Application
This application claims priority from U.S. Provisional Application Serial No. 60/047,570 filed May 22, 1997.
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, p38(S 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
SUBSmUTE8HEET(RULE26) 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-β) , 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. Patent 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 November 12, 1992, describes pyrazoles as novel fungicides. U. S. Patent No. 3,984,431, to Cueremy and Renault, describes derivatives of pyrazole-5-acetic acid as having anti- inflammatory activity. Specifically, [1-
SU3SnTUTCESH£Er(RULE&6 isobutyl-3 , 4 -diphenyl-IH-pyrazol-5-yl] acetic acid is described. U. S. Patent No. 3,245,093 to Hinsgen et al , describes a process for preparing pyrazoles. WO 83/00330, published February 3, 1983, describes a new process for the preparation of diphenyl-3 , 4 -methyl -5- pyrazole derivatives. WO 95/06036, published March 2, 1995, describes a process for preparing pyrazole derivatives. US patent 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) -lH-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. Patent No. 5,134,142, to Matsuo et al . describes 1,5-diaryl pyrazoles as having anti-inflammatory activity. U.S. Patent 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) -1- (4- methylsulfinylphenyl) -4- (4-pyridyl) -5H-pyrazole is described. WO 96/03385, published February 8, 1996, describes 3 , 4-substituted pyrazoles, as having anti-
SUBSmUTESHEET( l£26) inflammatory activity. Specifically, 4- [l-ethyl-4- (4- pyridyl ) -5-trifluoromethyl - IH-pyrazol-3 - yl] benzenesulfonamide is described.
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 I:
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,
8ϋBSϊ πESHEET(RUlE2β) 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
C—CCH ll /
C— N
\ 27
(ID
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,
βϋBSm TESHEEr(WΛJE2β) 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
8UBSΠTUTE8HEEΓ(RUIE2^ 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, heterocyclylalkylammo, aralkylamino, aminoalkyl, aminoaryl, aminoalkylamino, arylaminoalkylene, alkylammoalkylene, 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, heterocyclylalkylammo, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, and aralkylsulfonyl ; or R2 has the formula:
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(0)R35, -C(0)OR35, -S02R36, -C(0)NR37R38, and -S02NR39R40, 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 ,
,43
(IV) (V)
SUDSTΠUTH 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 , aminosul onyl, alkylaminoalkylamino, hydroxyalkylamino, aralkylamino, heterocyclylalkylammo, 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, alkylammoalkylene, arylaminoalkylene, aminoalkylamino, and hydroxy; provided R3 is not 2 -pyridinyl when R4 is a phenyl
SϋBSTπUTESt€Er(RϋLE2β) 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 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 or a pharmaceutically acceptable salt thereof. Compounds of Formula I would be useful for, but not limited to, the treatment of inflammation in a subject, 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, 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, cancer, diabetes, systemic lupus erthrematosis (SLE) , 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.
SUBSfmUTESHEET(RϋLE26) 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-jS 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-/3 are inhibited by the compounds of the present invention and thus are herein referred to collectively as "TNF" unless
8UB5 UTE8HEET(RULE26) 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 alkylammoalkylene, and lower heterocyclylalkylene; or
R1 has the formula a 2 5 0 C— C CH3) C— N
I ,27
H di :
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 alkylphenyl lkyl , lower phenylalkylphenylene, lower alkylheterocyclyl, lower alkylheterocyclylalkylene, lower
8UBSmUTESHEET(RULE26) 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 alkylammoalkylene, 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
SϋBSTπUTE8HEET(RULE26) 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 :
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(0)R35, -C(0)OR35, -S02R36, -C(0)NR37R38, and -S02NR39R40; wherein R35 is selected from alkyl, cycloalkyl, haloalkyl, alkenyl, aryl, heterocyclyl, aralkyl, arylcycloalkyl , cycloalkenylalkylene, heterocyclylalkylene, alkylarylene, alkylheterocyclyl, 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 CHR48R49 wherein R48 is arylsulfonylamino or alkylarylsulfonylammo, and R49 is selected from aralkyl, amino, alkylamino, and aralkylamino; or
R35 is -NR50R51 wherein R50 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 ,
SUBSmWE8HEEr(RULE26) 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 , alkylammoalkylene , 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 R2S 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
(VI ) (VI I ) (VI I I ) wherein k is an integer from 0 to 3; and
R56 is hydrogen or lower alkyl; and
R57 is hydrogen or lower alkyl; or
R5δ and R57 form a lower alkylene bridge; and
R58 is selected from hydrogen, alkyl, aralkyl, aryl, heterocyclyl, heterocyclylalkyl, alkoxycarbonyl, alkylsulfonyl, aralkylsulfonyl , arylsulfonyl , -C(0)R59, -S02R60, and -C(0)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
8lffiSmUTESHEEr(RϋUE26) 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
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 alkoxyphenylalkylammo, lower alkylaminoalkylamino, lower hydroxyalkylamino, lower heterocyclylamino, lower heterocyclylalkylamino, lower phenylalkylheterocyclylamino, lower alkylaminocarbonyl, lower alkoxyphenylalkylammo, 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 , methylaminoethy1 , dimethylaminoethyl, ethylaminoethyl , diethylaminoethyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclohexylmethyl , hydroxymethyl , hydroxyethyl , mercaptomethyl , and methylthiomethyl; and
R2 is selected from hydrido, chloro, fluoro, bromo,
SUBSrmjreSHEET(RULH26) methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl, phenyl, biphenyl, fluoromethyl , difluoromethyl , trifluoromethyl, chloromethyl , dichloromethyl , trichloromethyl , pentafluoroethyl , heptafluoropropyl , difluorochloromethyl , dichlorofluoromethyl , difluoroethyl , difluoropropyl , dichloroethyl , dichloropropyl, hydroxymethyl , hydroxyethyl , pyridinyl, isothiazolyl , isoxazolyl, thienyl , thiazolyl, oxazolyl, pyrimidinyl, quinolyl , isoquinolinyl , imidazolyl, 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, carboxymethy1amino, 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-methyl- hydrazinyl, or -NR62R63 wherein R62 is methylcarbonyl or amino, and R63 is methyl, ethyl or phenylmethy1 ; and
R4 is selected from hydrido, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl , cyclohexadienyl , phenyl,
SUBSTrTUTESBECT(RULE26) 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, methy1sulfinyl, 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,
eϋBs ιπE €Er(RϋLE2 ) 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,
StffiSmUTCSHEET(RULE26) 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:
,30 ,32
I
•C— CH23
(III)
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 (0) R35 , -C (0) OR35 , -S02R36 , -C (0) NR37R38 , and -S02NR39R40 ;
suBsπτuτESBεεr(RULE2β) 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
8UBSππjTESHEEr(RυL£2β) 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 alkylammoalkylene, lower alkylaminophenylalkyl, lower alkylcarbonylaminoalkylene, lower alkylthiophenylene, lower alkylsulfonylphenylalkyl, and lower
sυBSτrruτESH£B"(RU&£2β& 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 R2S and R27 in claim 2; or
R2 is selected from the group consisting of
CHPD„_
(VI) (VII) (VIII) 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(0)R59, -SO2RS0, and -C(0)NHR61; wherein R59 is selected from lower alkyl, lower haloalkyl, lower cycloalkyl, aryl selected from phenyl, biphenyl and naphthyl , lower heterocyclyl , lower
SUBSTmjTE8HEET(RULE26) 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,
SUBSmUFESHEEr(RULE26) 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, (l-ethyl-2-hydroxy) ethylamino, piperidinylamino, pyridinylmethylamino, phenylmethylpiperidinylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminocarbonyl , ethylaminocarbonyl , methylcarbonyl , methoxyphenylmethylamino, hydrazinyl, 1-methyl- hydrazinyl, 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
SUBSfmUTESHECT(RUL£26) 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:
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(0)R35, -C(0)OR35, -S02R36, -C(0)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
SUBSOTTUTESH£Er(RULE26) 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
(VI) (VII) (VIII) wherein k is an integer from 0 or 1; and
R56 is hydrogen; and
R57 is hydrogen; and
R58 is selected from -C(0)R59 and -S02R60; 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
3UeSTmreSHEET(RULE26) 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,
8Urølll>iπE8KEEr( ULE2β 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 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 ; 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 consists of compounds, tautomers and pharmaceutically-acceptable salts thereof as follows:
4- [5- (3-fluoro-4-methoxyphenyl) -3 -methyl-IH-pyrazol -4- yl] pyridine; 4 - (3 -methyl -5-phenyl-IH-pyrazol-4 -yl ) pyridine ;
4- [5-methyl -3- (2-methylphenyl) -IH-pyrazol-4 -yl] pyridine; 4- [3- (4 -fluorophenyl) -5-methyl-lH-pyrazol-4-yl] pyridine; 4- [5-methyl-3- (4-methylphenyl) -IH-pyrazol-4 -yl] pyridine; 4- [5-methyl-3- [4- (methylthio) phenyl] -lH-pyrazol-4- yl] pyridine;
4- [3- (4-chlorohpenyl) -5-methyl-lH-pyrazol-4-yl] pyridine;
SUBSmUTESHEET(raJLE-a6) 4- [3 -methyl -5- (3-methylphenyl) -lH-pyrazol-4-yl] pyridine;
4- [5- (2 , 5-dimethylphenyl) -3 -methyl-IH-pyrazol-4 yl] pyridine;
4- [5- (1, 3-benzodioxol-5-yl) -3 -methyl -IH-pyrazol-4- yl] pyridine;
4- [3 -methyl -5- (4-phenoxyphenyl) -lH-pyrazol-4-yl] pyridine;
4- [5- [ (1, 1' -biphenyl) -4-yl] -3 -methyl-IH-pyrazol -4- yl] pyridine;
4- [3 -methyl-5- [3- (phenoxyphenyl) -IH-pyrazol-4- yl] pyridine ;
4- [3 -methyl-5- [3- (phenylmethoxy) phenyl] -lH-pyrazol-4- yl] pyridine;
4- [3 -methyl-5- [2- (phenylmethoxy) phenyl] -lH-pyrazol-4- yl] pyridine; 2- [3 -methyl-4- (4-pyridinyl) -IH-pyrazol-4-yl] phenol ;
3- [3-methyl-4- (4-pyridinyl) - IH-pyrazol-4-yl] phenol ;
1-hydroxy-4 - (3 -methyl-5-phenyl- IH-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) -lH-pyrazol-3- amine; 4- [5- (4 -fluorophenyl) -3-phenyl-lH-pyrazol-4- yl] pyridine;
4- [5- (3-methylphenyl) -3- (trifluoromethyl) -lH-pyrazol-4- yl] pyridine; 4- [3- (4 -fluorophenyl) -4- (4-pyridinyl) -IH- pyrazol-5-yl] pyridine ;
4- (5-cyclohexyl) -3 -methyl-IH-pyrazol-4-yl) pyridine; 4- [5- (3-fluoro-5-methoxyphenyl) -3-methyl-lH-pyrazol-4- yl] pyridine; 4- [5- (3-methylphenyl) -3 -propyl-IH-pyrazol-4-yl] pyridine;
4- [ (3 -methyl -5-phenyl -IH-pyrazol -4-yl) methyl] pyridine; 4- [3 , 5-bis (3-methylphenyl) -IH-pyrazol-4-yl] yridine; 4- [4 -methyl-2- (2-trifluorophenyl) -lH-pyrazol-4- yl] pyridine ; 4- [3- (2-chlorophenyl) -5-methyl-IH-pyrazol-4-yl] pyridine ; 4- [5-methyl-3- (2 , 4-dimethylphenyl) -IH-pyrazol -4-
yl] pyridine;
4- [5- (4 -chlorophenyl) -1, 3 -dimethyl -IH-pyrazol -4- yl] pyridine;
4- [3- (3-fluoro-2-methylphenyl) -5-methyl-IH-pyrazol-4- yl] pyridine ;
4- [3- (3 , 5-dimethylphenyl) -5-methyl -IH-pyrazol -4 - yl] pyridine;
4- [3- (3 , 5-dimethoxyphenyl) -5-methyl -IH-pyrazol-4- yl] pyridine; 4- [5-methyl -3- (3-nitrophenyl) - IH-pyrazol-4-yl] pyridine ;
N,N-dimethyl-4- [5-methyl -4- (4-pyridinyl) -lH-pyrazol-3 yl] benzenamine ;
4- [3- (2 , 3 -dihydrobenzofuran-5-yl) -5-methyl -IH-pyrazol-4- yl] pyridine; 4- [3- (4-bromophenyl) -5 -methyl-IH-pyrazol -4-yl] pyridine;
4- [3- (2 -fluorophenyl) -5-methyl-lH-pyrazol-4-yl] pyridine;
4- [3- (3-fluorophenyl) -5-methyl -IH-pyrazol -4-yl] pyridine;
4- [3 -methyl-5- [3- (trifluoromethyl) phenyl] -IH-pyrazol-4- yl] pyridine; 4- (3 -ethyl-4 -phenyl-IH-pyrazol -4-yl) pyridine;
4- [5- (3-methoxyphenyl) -3 -methyl -IH-pyrazol-4 -yl }pyridine ; 4- [3-ethyl-5- (3-methylphenyl) - IH-pyrazol -4-yl] pyridine; 4- [5- (3 , 4 -difluorophenyl) -3-methyl-lH-pyrazol-4- yl] pyridine; 4- [5- (3-ethoxyphenyl) -3-methyl-lH-pyrazol-4-yl] pyridine; 4- [3-methyl-5- [4- (trifluoromethyl) phenyl] -IH-pyrazol -4- yl] pyridine;
4- [3-methyl-5- (3-thienyl) -lH-pyrazol-4-yl] pyridine; 4- [5- (2 , 4 -dichlorophenyl) -3 -methyl -IH-pyrazol -4- yl] pyridine;
4- [5- (3 -chlorophenyl) -3-methyl-lH-pyrazol-4-yl] pyridine; 4- [5- (3-chloro-4-methoxyphenyl) -3 -methyl -IH-pyrazol-4- yl] pyridine; ethyl 3- (4 -chlorophenyl) -4- (4 -pyridinyl) -lH-pyrazole-5- propanoate;
4- [3- (4-fluorophenyl) -l-methyl-pyrazol-4-yl] yridine;
SUBSTmJTESHECT(RULE26) 5- [5- (3 -chlorophenyl) -3-methyl-lH-pyrazol-4-yl] pyrimidin-
2 -amine;
5- [3 -methyl-5- (3-methylphenyl) - IH-pyrazol -4 -yl] pyrimidin-
2 -amine; 5- [3 -methyl -5- (2-methylphenyl) -IH-pyrazol -4 -yl] pyrimidin-
2 -amine;
5- [5- (4 -chlorophenyl) -3-methyl-lH-pyrazol-4-yl] pyrimidin-
2 -amine;
5- [5- (4 -fluorophenyl) -3-methyl-lH-pyrazol-4-yl] pyrimidin- 2 -amine;
5- [5- (4-methoxyphenyl) -3 -methyl -IH-pyrazol-4- yl] pyrimidin-2-amine;
5- [5- (3 -chlorophenyl) -3-methyl-lH-pyrazol-4-yl] pyridin-2- amine ; 4- [5- (3 -chlorophenyl) -3-methyl-lH-pyrazol-4-yl] pyridin-2- amine ;
4- [5- (3-methylphenyl) -3-methyl-lH-pyrazol-4-yl] pyridin-2- amine ;
4- [5- (2-methylphenyl) -3-methyl-lH-pyrazol-4-yl] pyridin-2- amine;
4- [5- (4-chlorophenyl) -3-methyl-lH-pyrazol-4-yl] pyridin-2- amine ;
4- [5- (4 -fluorophenyl) -3-methyl-lH-pyrazol-4-yl] pyridin-2- amine ; 4- [5- (4-methoxyphenyl) -3-methyl-lH-pyrazol-4-yl] pyridin- 2-amine;
5- [5- (3 -chlorophenyl) -3 -methyl -IH-pyrazol -4-yl] -2- methoxypyridine ; 2-methoxy-5- [3-methyl-5- (3-methylphenyl) -lH-pyrazol-4- yl] pyridine;
2-methoxy-5- [5- (4-methoxyphenyl) -3-methyl-lH-pyrazol-4- yl] pyridine;
4- [5- (3 -chlorophenyl) -3 -methyl-IH-pyrazol-4-yl] -2- methoxypyridine ; 2-methoxy-4- [3-methyl-5- (3-methylphenyl) -IH-pyrazol-4- yl] pyridine;
2-methoxy-4- [3 -methyl -5- (2-methylphenyl) -lH-pyrazol-4- yl] pyridine;
4- [5- (4 -chlorophenyl) -3 -methyl -IH-pyrazol -4-yl] -2- methoxypyridine ; 4- [5- (4 -fluorophenyl) -3-methyl-lH-pyrazol-4-yl] -2- methoxypyridine ;
2 -methoxy-4- [3-methyl-5- (4-methylphenyl) -IH-pyrazol-4- yl] pyridine;
5- [5- (3 -chlorophenyl) -3-methyl-lH-pyrazol-4-yl] pyridin-2- ol;
4- [5- (3 -chlorophenyl) -3-methyl-lH-pyrazol-4-yl] pyridin-2- ol;
4- [5- (3-methylphenyl) -3 -methyl-IH-pyrazol-4-yl] pyridin-2- ol; 4- [5- (2-methylphenyl) -3-methyl-lH-pyrazol-4-yl] pyridin-2- ol;
4- [5- (4 -chlorophenyl) -3-methyl-lH-pyrazol-4-yl] pyridin-2- ol;
4- [5- (4 -fluorophenyl) -3-methyl-lH-pyrazol-4-yl] pyridin-2- ol;
4- [5- (4-methoxyphenyl) -3 -methyl-IH-pyrazol-4-yl] pyridin- 2-ol;
5- [5- (3 -chlorophenyl) -3-methyl-lH-pyrazol-4-yl] pyridine- 2 -methanamine ; 4- [5- (3-chlorophenyl) -3-methyl-lH-pyrazol-4-yl] pyridine- 2 -methanamine ;
4- [5- (3-methylphenyl) -3 -methyl -IH-pyrazol-4-yl] pyridine- 2 -methanamine ; 4- [5- (2-methylphenyl) -3-methyl-lH-pyrazol-4-yl] pyridine- 2 -methanamine ;
4- [5- (4 -chlorophenyl) -3-methyl-lH-pyrazol-4-yl] pyridine- 2 -methanamine ;
4- [5- ( -fluorophenyl) -3-methyl-lH-pyrazol-4-yl] pyridine- 2-methanamine ; 4- [5- (4-methoxyphenyl) -3 -methyl-IH-pyrazol -4-yl] pyridine- 2 -methanamine;
SU8SmUTESHEET(RULE26) 5- [5- (3 -chlorophenyl) -3 -methyl -IH-pyrazol -4-yl] pyridine-
2 -carboxamide;
4- [5- (3 -chlorophenyl) -3 -methyl -IH-pyrazol -4 -yl] pyridine-
2 -carboxamide ; 4- [5- (3-methylphenyl) -3-methyl-lH-pyrazol-4-yl] pyridine-
2 -carboxamide ;
4- [5- (2-methylphenyl) -3-methyl-lH-pyrazol-4-yl] pyridine-
2 -carboxamide ;
4- [5- (4 -chlorophenyl) -3-methyl-lH-pyrazol-4-yl] pyridine- 2 -carboxamide ;
4- [5- (4 -fluorophenyl) -3 -methyl -IH-pyrazol -4-yl] pyridine-
2 -carboxamide ;
4- [5- (4-methoxyphenyl) -3-methyl-lH-pyrazol-4-yl] pyridine-
2 -carboxamide; 4- [5- (3-fluoro-4-methoxyphenyl) -3-methyl-lH-pyrazol-4- yl] pyridine;
4- [5- (4-fluoro-3-methoxyphenyl) -3-methyl-lH-pyrazol-4- yl] pyridine;
4- [5- (4-chloro-3-methoxyphenyl) -3-methyl-lH-pyrazol-4- yl] pyridine;
4- [5- (2 , 3 -dihydrobenzofuran-6-yl) -3-methyl-lH-pyrazol-4- yl] pyridine;
4- [5- (benzofuran-6-yl) -3-methyl-lH-pyrazol-4-yl] pyridine;
4- [5- (3-fluoro-5-methoxyphenyl) -3 -methyl -IH-pyrazol-4- yl] pyridine ;
4- [5- (3-chloro-5-methoxyphenyl) -3-methyl-lH-pyrazol-4- yl] pyridine;
4- [5- (1-cyclohexyen-l-yl) -3 -methyl-IH-pyrazol -4- yl] pyridine; 4- [5- (1, 3-cyclohexadien-l-yl) -3 -methyl-IH-pyrazol-4- yl] pyridine;
4- [5- (5, 6-dihydro-2H-pyran-4-yl) -3 -methyl-IH-pyrazol-4- yl] pyridine;
4- (5-cyclohexyl-3 -methyl -IH-pyrazol -4 -yl ) pyridine ; 4- [5- (4-methoxy-3-methylphenyl) -3-methyl-lH-pyrazol-4- yl] pyridine;
sυ3SτmπESκεεr(RULE£@) 4- [5- (3-methoxy-4-methylphenyl) -3 -methyl -IH-pyrazol-4- yl] pyridine;
4- [5- (3-methoxy-5-methylphenyl) -3 -methyl-IH-pyrazol -4- yl] pyridine; 4- [5- (3-furyl) -3 -methyl-IH-pyrazol -4-yl] pyridine;
2 -methyl -4 - (3 -methyl -5-phenyl-IH-pyrazol -4 -yl ) pyridine ;
2 -methoxy-4 - (3 -methyl -5 -phenyl- IH-pyrazol -4 -yl ) pyridine ; methyl 4- (3-methyl-5-phenyl-lH-pyrazol-4-yl) pyri-dine-2- carboxylate; 4- (3 -methyl-5-phenyl-IH-pyrazol -4-yl) pyridine-2- carboxamide;
1- [4- (3 -methyl-5-phenyl -IH-pyrazol -4-yl) pyridin-2- yl] ethanone;
N,N-dimethyl-4- (3 -methyl -5 -phenyl -IH-pyrazol-2- yl ) pyridin-2 -amine ;
3 -methyl-4 - (3 -methyl-5-phenyl - IH-pyrazol-4 -yl ) pyridine ;
3 -methoxy-4 - (3 -methyl-5 -phenyl -IH-pyrazol -4 -yl) pyridine ; methyl 4- (3 -methyl-5-phenyl-IH-pyrazol-4yl) pyridine-3- carboxylate; 4- (3 -methyl-5-phenyl-IH-pyrazol-4 -yl) pyridine-3 - carboxamide ;
1- [4- (3-methyl-5-phenyl-lH-pyrazol-4-yl)pyridin-3- yl] ethanone;
3 -bromo-4 - (3 -methyl-5 -phenyl - IH-pyrazol-4 -yl) pyridine ; N,N-dimethyl-4- (3 -methyl -5-phenyl-IH-pyrazol-2- yl) pyridin-3-amine;
2 -methyl-4 - (3 -methyl-5-phenyl- IH-pyrazol-4-yl) pyrimidine ; 4 - (3 -methyl-5-phenyl -IH-pyrazol -4-yl) pyrimidine ; 2 -methoxy-4 - (3 -methyl -5-phenyl -IH-pyrazol -4 - yl ) pyrimidine;
4 - (3 -methyl -5-phenyl-IH-pyrazol-4-yl) pyrimidin-2 -amine ; N,N-dimethyl-4- (3 -methyl -5-phenyl-IH-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) -IH-pyrazole;
8U8STrrUTESHEET(RULE26) 4- (3-furyl) -3 -methyl -5-phenyl -lH-pyrazole,• 3 -methyl -5-phenyl -4- (2-thienyl) -lH-pyrazole; 4- (2 -furyl) -3 -methyl -5-phenyl -lH-pyrazole; 4- (3-isothiazolyl) -3-methyl-5-phenyl-lH-pyrazole 4- (3-isoxazolyl) -3 -methyl -5 -phenyl-lH-pyrazole;
4- (5-isothiazolyl) -3 -methyl -5-phenyl-lH-pyrazole; 4- (5-isoxazolyl) -3 -methyl -5-phenyl -lH-pyrazole,• 3 -methyl-5-phenyl -4- (5-thiazolyl) -lH-pyrazole; 3 -methyl -4- (5-oxazolyl) -5 -phenyl -lH-pyrazole; 4- [3- (4 -fluorophenyl) -lH-pyrazol-4-yl] pyridine;
2 -methyl -4- [3- (3-methylphenyl) - IH-pyrazol -4-yl] pyridine; 4- ( l-methyl-3 -phenyl -IH-pyrazol -4-yl) pyridine; 4- (3 -phenyl -IH-pyrazol -4-yl) pyridine; 2 -methyl-4- (3 -phenyl -IH-pyrazol-4-yl) pyridine;
4ι-- r[3o-_ /(3 -chlorophenyl) -1-methyl -pyrazol-4-yl] pyridine; 4 ■ϊ-- [ L3J-- (44'± --cKmhs.il±oKrLoupphLiet-iniiyyl± ) i -- 1 j.--meetLhXiyylι--ppyyrxaeizool± --4έ --yyl±]j pyyrjLixduij-niiefcj ;; 4- [3- (3 -m pyridine; 4- [3- (4 -chlorophenyl) -lH-pyrazol-4-yl] pyridine; 4- [3- (3 -chlorophenyl) -lH-pyrazol-4-yl] -2-methylpyridine; 4- - [[33-- ((33--ff lluuoorroopphheennyyll)) --ll--mmeetthhyyll--llHH--ppyyrraazzooll--44--yyll]] ppyyrriiddiinnee;; 4-- [ [33-- ((33--ff lluuoorroopphheennyyll)) --llHH--ppyyrraazzooll--44--yyll]] pyyrriiddiinnee;; - [3- (3 -chlorophenyl) -1 -methyl -pyrazol -4-yl] -2- methylpyridine ; 5- (4 -chlorophenyl) -N-phenyl-4- (4-pyridinyl) -lH-pyrazol-3- amine;
5- (4 -chlorophenyl) -N-methyl-4- (4-pyridinyl) -lH-pyrazol-3- amine ;
5- (4 -chlorophenyl) -N,N-dimethyl -4- (4-pyridinyl) -IH- pyrazol -3 -amine dihydrate; 5- (3 -fluorophenyl) -N,N-dimethyl-4- (4-pyridinyl) -IH- pyrazol-3 -amine ;
N,N-dimethyl-5- (3-methylphenyl) -4- (4-pyridinyl) -IH- pyrazol-3 -amine; N-methyl-5- (3-methylphenyl) -4- (4-pyridinyl) -lH-pyrazol-3* amine;
N-ethyl-5- (3-methylphenyl) -4- (4 -pyridinyl) -IH-pyrazol-3-
SU8STJTUTESHEEr(RUlJEa6) amine ;
N,N-diethyl-5- (3-methylphenyl) -4- (4-pyridinyl) -IH- pyrazol -3 -amine ;
5- (4-chlorophenyl) - N,N-diethyl-4- (4-pyridinyl) -1H- pyrazol -3 -amine;
4- [5- (4 -chlorophenyl) -4- (4-pyridinyl) -lH-pyrazol-3- yl] morpholine;
5- (4 -chlorophenyl) -N-propyl-4- (4-pyridinyl) -lH-pyrazol-3* amine ; 5- (4 -chlorophenyl) -N- (phenylmethyl) -4- (4-pyridinyl) -IH- pyrazol-3 -amine hydrate (2:1);
5- (4 -chlorophenyl) -N- (2-methoxyethyl) -4- (4 -pyridinyl) -IH- pyrazol-3 -amine monohydrate;
1, 1-dimethylethyl 4- [5- (4 -chlorophenyl) -4- (4-pyridinyl) • lH-pyrazol-3-yl] -1-piperazinecarboxylate;
1- [5- (4 -chlorophenyl) -4- (4-pyridinyl) -lH-pyrazol-3- yl] piperazine trihydrochloride;
1- [5- (4 -chlorophenyl) -4- (4-pyridinyl) -lH-pyrazol-3-yl] -4* methylpiperazine ; 1, 1-dimethylethyl 4- [5- (4-fluorophenyl) -4- (4-pyridinyl) -
IH-pyrazol-3 -yl] -1-piperazinecarboxylate;
1- [5- (4-fluorophenyl) -4- (4-pyridinyl) -lH-pyrazol-3- yl] piperazine trihydrochloride;
1- [5- (4 -chlorophenyl) -4- (4-pyridinyl) -lH-pyrazol-3- yl] piperazine;
N- [5- (4 -chlorophenyl) -4- [2- (phenylmethyl) amino] -4- pyridinyl] -IH-pyrazol-3 -yl] -1, 3-propanediamine, trihydrochloride;
1- [5- (4 -chlorophenyl) -4- (4 -pyridinyl) -IH-pyrazol-3 -yl] -4 (phenylmethyl) piperazine;
4- [3- (4-fluorophenyl) -5- (1-piperazinyl) -lH-pyrazol-4- yl] pyrimidine , dihydrochloride ;
1, 1-dimethylethyl [3- [ [5- (4 -chlorophenyl) -4- (4- pyridinyl) -IH-pyrazol-3 -yl] amino] propyl] carbamate; N- [5- [4 -chlorophenyl) -4- (4-pyridinyl) -lH-pyrazol-3-yl] -
1, 3-propanediamine, trihydrochloride monohydrate;
gyBsππy sHEEr iLEZβ) 1, 1-dimethylethyl [2- [ [5- (4 -chlorophenyl) -4- (4- pyridinyl) -IH-pyrazol-3 -yl] amino] ethyl] carbamate;
1, 1-dimethylethyl 4- [5- (4 -chlorophenyl) -1- (2- hydroxyethyl) -4- (4 -pyridinyl) -IH-pyrazol-3 -yl] -1- piperazinecarboxylate;
1, 1-dimethylethyl 4- [5- (4-fluorophenyl) -4- (4- pyrimidinyl) -lH-pyrazol-3-yl]
1, 1-dimethylethyl [3- [ [5- (4 -chlorophenyl) -4- (2-fluoro-4- pyridinyl ) - IH-pyrazol -3 -yl] mino] propyl] carbamate ; 1- [5- (4 -chlorophenyl) -4- (4-pyridinyl) -IH-pyrazol-3 -yl] -4* ethylpiperazine ;
N- [5- (4-chlorophenyl) -4- (4-pyridinyl) -lH-pyrazol-3-yl] -
1 , 2 -ethanediamine ;
4- [3- (2, 6 -difluorophenyl) - 5-methyl-IH-pyrazol -4- yl] pyridine ;
4- [3- (3-ethylphenyl) -5-methyl-lH-pyrazol-4-yl] pyridine;
4- [3- (3 -chlorophenyl) -5-ethyl -IH-pyrazol-4-yl] pyridine;
4- [3-ethyl-5- (3-ethylphenyl) -lH-pyrazol-4-yl] pyridine;
4- [3- (4 -chlorophenyl) -5- (1-methylethyl) -IH-pyrazol-4- yl] pyridine;
4- [3-cyclopropyl-5- (4-fluorophenyl) -lH-pyrazol-4- yl] pyridine;
4- [3- (4-fluorophenyl) -5- (trifluoromethyl) -lH-pyrazol-4- yl] pyridine; 4- [5- (cyclopropyl-3- (4- (fluorophenyl) -1-methyl-lH- 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) -lH-pyrazole-1-ethanol ;
4- [3- (4 -fluorophenyl) -1- (2-hydroxyethyl) -4- (4-pyridinyl) lH-pyrazol-5-yl] -2 (1H) -pyridinone;
1-acetyl-4- [3- (4-fluorophenyl) -1- (2-hydroxyethyl) -4- (4- pyridinyl) -lH-pyrazol-5-yl] -2 (1H) -pyridinone;
Ethyl 2- [3- (4-fluorophenyl) -1- (2-hydroxyethyl) -4- (4- pyridinyl) -IH-pyrazol-5-yl] cyclopropanecarboxylate;
2- [3- (4-fluorophenyl) -1- (2 -hydroxyethyl) -4- (4-pyridinyl) -
IH-pyrazol-5-yl] cyclopropanecarboxylic acid;
3- (4-fluorophenyl) -5- (4-imidazolyl) -4- (4-pyridinyl) -1H- pyrazole-1-ethanol ; 4- [3- (4-chloro-3-methylphenyl) -lH-pyrazol-4-yl] pyridine
5- (4-fluorophenyl) -4- (4-pyridinyl) -lH-pyrazole-3- carboxylic acid;
5- (4-fluorophenyl) -4- (4-pyridinyl) -lH-pyrazole-3- methanol ; 1- [ [5- (4 -fluorophenyl) -4- (4-pyridinyl) -lH-pyrazol-3- yl] carbonyl] piperazine;
1, 1-dimethylethyl 4- [ [5- (4-fluorophenyl) -4- (4-pyridinyl) -
IH-pyrazol-3 -yl] carbonyl] - 1 -piperazinecarboxylate ;
4- (1, 5-dimethyl -3 -phenyl -IH-pyrazol -4-yl) pyridine; 4- (1, 3-dimethyl-5-phenyl-lH-pyrazol-4-yl] pyridine;
4- [3- (4 -chlorophenyl) -1, 5 -dimethyl -IH-pyrazol-4- yl] pyridine;
4- [5- (4 -chlorophenyl) -1 , 3 -dimethyl -IH-pyrazol -4- yl] pyridine; 4- [5-ethyl- l-methyl-3- (3-methylphenyl) -IH-pyrazol-4- yl] pyridine;
4- [3-ethyl-l-methyl-5- (3-methylphenyl) -IH-pyrazol-4- yl] pyridine;
4- [3- (4 -chlorophenyl) -l-ethyl-5-methyl-lH-pyrazol-4- yl] pyridine;
4- [3- (4 -chlorophenyl) -2-ethyl-5-methyl-lH-pyrazol-4- yl] pyridine;
4- [3- (4-fluorophenyl) - IH-pyrazol -4-yl] pyridine;
4- [3- (2 -chlorophenyl) -IH-pyrazol-4-yl] pyridine; 3- (4-fluorophenyl) -4- (4-pyridinyl) -lH-pyrazole-1-ethanol ;
3- (4-fluorophenyl) -4- (4 -pyrimidinyl) -IH-pyrazole-l- ethanol ;
4- [3- (4-fluorophenyl) - 1-methyl-IH-pyrazol-4-yl] pyridine;
2- [ [4- [3- (4 -fluorophenyl) -lH-pyrazol-4-yl] -2- pyridinyl] amino] -1-butanol;
4- [5-bromo-3- (4-fluorophenyl) -1-methyl -IH-pyrazol-4-
SUBS αTE8hEEr(RϋlE26) yl] pyridine;
4- [3- (4 -fluorophenyl) -lH-pyrazol-4-yl] -2- pyridinecarbonitrile ;
4- [2- [3- (4-fluorophenyl) -4- (4-pyridinyl) -lH-pyrazol-1- yl] ethyl] morpholine;
3- (4-fluorophenyl) -l-methyl-α-phenyl-4- (4-pyridinyl) -1H- pyrazole-5-methanol ;
N- [5- (4-fluorophenyl) -4- (4-pyridinyl) -lH-pyrazol-3-yl] -4- morpholineethanamine ; 4- [3- (3 -chlorophenyl) -lH-pyrazol-4-yl] -2 (1H) -pyridinone hydrazone;
4- [3- (3 -chlorophenyl) -IH-pyrazol -4-yl] -N- (phenylmethyl) -
2 -pyridinamine ;
4- [3- (3 -chlorophenyl) -lH-pyrazol-4-yl] -N- (phenylethyl) -2- pyridinamine;
[3- (3 -chlorophenyl) -lH-pyrazol-4-yl] -N-ethyl-2- pyridinamine ;
4- [3- (4-fluorophenyl) -lH-pyrazol-4-yl] pyridinecarboxamide ; Methyl 4- [3- (4-fluorophenyl) -lH-pyrazol-4-yl] -2- pyridinecarboxylate ;
4- [3- (4-fluorophenyl) -lH-pyrazol-4-yl] -N-methyl-2- pyridinecarboxamide ;
4- [3- (4 -fluorophenyl) -lH-pyrazol-4-yl] -2- pyridinecarboxylic acid;
4- [3- (3-fluorophenyl) -IH-pyrazol -4-yl] pyridine;
4- [3- (1, 3-benzodioxol-5-yl) -IH-pyrazol -4-yl] pyridine4- [3-
(3 -fluorophenyl) -1-methyl-IH-pyrazol -4 -yl] pyridine ;
4- [3- (4 -chlorophenyl) -IH-pyrazol -4-yl] pyridine; 4- [3- (1, 3-benzodioxol-5-y) -1-methyl -IH-pyrazol -4-yl] pyrid ine;
4- [3- (4 -chlorophenyl) -l-methyl-lH-pyrazol-4-yl] pyridine;
4- [3- (3 -chlorophenyl) -1-methyl -IH-pyrazol-4-yl] -2-methylp yridine; 4- [5- (3 -chlorophenyl) -1-methyl -IH-pyrazol-4 -yl] -2-methylpyridine;
4- [3- (3 -chlorophenyl) -l-methyl-lH-pyrazol-4-yl] pyridine;
4- [5- (3 -chlorophenyl) -1-methyl -IH-pyrazol -4-yl] pyridine; 2 -methyl -4- [l-methyl-3- (3-methylphenyl) -lH-pyrazol-4 -yl] pyridine;
2 -methyl -4- [1 -methyl-5- (3-methylphenyl) -lH-pyrazol-4 -yl] pyridine ;
(3 -phenyl - IH-pyrazol-4 -yl ) pyridine ;
4- [[33-- [[33-- ((ttrriifflluuoorroommeetthhyyll )) pphheennyyll]] --IlHH--ppyyrraazol-4-yl] pyridine
4- [l-methyl-3- [3- (trifluoromethyl) phenyl] -lH-pyrazol-4-yl ] pyridine;
4- [3- (3 , 4 -difluorophenyl) - IH-pyrazol -4-yl] pyridine;
4- [3- (4 - -cchnlioorroopphneennyyli)) --liHH--ppyyrraazzooll--44--yyll]j --2--frliuuoor: opyridine ; -bromophenyl) -lH-pyrazol-4yl] pyridine;
4- [3- (3 , 4 -difluorophenyl) -1-methyl -IH-pyrazol -4-yl] pyridi nnee;; 4 4- [3- (4 -bromophenyl) -l-methyl-lH-pyrazol-4-yl] pyridine;
(E) -4- [3- (4 -fluorophenyl) -lH-pyrazol-4-yl] -2- (2-phenyleth enyl ) pyridine ;
(S) -4- [3- (4 -chlorophenyl) -lH-pyrazol-4-yl] -N- (2-methylbut yl)- 2 -pyridinamine;
4- [3- (4 -chlorophenyl) -lH-pyrazol-4-yl] -N- [ (4-methoxy- phenyl ) methyl] - 2 -pyridinamine;
N- [4- [3- (4 -chlorophenyl) -lH-pyrazol-4-yl] -2-pyridinyl] -
2 -pyridinemethanamine ; N- [4- [3- (4 -fluorophenyl) -lH-pyrazol-4-yl] -2-pyridinyl] -
2 -pyridinemethanamine ;
2-fluoro-4- [3- (4-fluorophenyl) -lH-pyrazol-4-yl] pyridine;
4- [3- (4-iodophenyl) -IH-pyrazol-4-yl] pyridine;
4- [3- (4-iodophenyl) -l-methyl-lH-pyrazol-4-yl] pyridine; 4- [l-methyl-3- [4- (trifluoromethyl) phenyl] -lH-pyrazol-4-yl
] pyridine;
N- [1- (4-fluorophenyl) ethyl] -4- [3- (4-fluorophenyl) -IH-pyra zol-4-yl] -2 -pyridinamine;
N- [ (3-fluorophenyl) methyl] -4- [3- (4-fluorophenyl) -IH-pyraz ol-4-yl] -2 -pyridinamine;
4- [3- (4-fluorophenyl) -l-methyl-lH-pyrazol-4-yl] -2- (1-
SUBSTΠUΓESHECT(RULE26) methylhydrazino) pyridine ;
2-fluoro-4- [3- (4-fluorophenyl) -l-methyl-lH-pyrazol-4-yl] p yridine;
4- [3- (3 , 4 -difluorophenyl) -lH-pyrazol-4-yl] -2-fluoro- pyridine;
4- [3- (4-fluorophenyl) -lH-pyrazol-4-yl] -3-methylpyridine;
4- [3- (4-fluorophenyl) -l-methyl-lH-pyrazol-4-yl] -3-methyl- pyridine;
4- [3- (3, 4 -difluorophenyl) -1-methyl-IH-pyrazol -4-yl] -2 -flu oropyridine;
3- (4-fluorophenyl) -N,N-dimethyl-4- (4-pyridinyl) -IH-pyrazo le-1-ethanamine;
2- [2- (4 -fluorophenyl) ethyl] -4- [3- (4-fluorophenyl) -1- methyl -IH-pyrazol -4 -yl] pyridine ; 4- [3- (4 -fluorophenyl) -IH-pyrazol -4-yl] -N- [1-
(phenylmethyl) -4 -piperidinyl] -2 -pyridinamine;
N' - [4- [3- (4-fluorophenyl) -IH-pyrazol-4-yl] -2 -pyridinyl] -
N,N-dimethyl -1, 2-ethanediamine;
2 , 4-bis [3- (4-fluorophenyl) -lH-pyrazol-4-yl] pyridine; N- [4- [3- (4 -fluorophenyl) -lH-pyrazol-4-yl] -2-pyridinyl] -4- morpholineethanamine ;
3- (4-fluorophenyl) -4- (2-fluoro-4 -pyridinyl) -lH-pyrazole-
1-ethanol ;
4- [3- (4 -fluorophenyl) -lH-pyrazol-4-yl] -N- [2- (lH-imidazol- 1-yl) ethyl] -2-pyridinamine;
4- [2- [3- (4 -fluorophenyl) -4- (2-fluoro-4 -pyridinyl) -IH- pyrazol-1-yl] ethyl] morpholine;
(E) -3- (4 -fluorophenyl) -4- [2- [2- (4-fluorophenyl) ethenyl] -
4-pyridinyl] -lH-pyrazole-1-ethanol ; 3- (4-fluorophenyl) -4- (2-fluoro-4 -pyridinyl) -N,N-dimethyl- lH-pyrazole-1-ethanamine ;
3- (4-fluorophenyl) -4- [2- [2- (4-fluorophenyl) ethyl] -4- pyridinyl] -lH-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-
SUSOTFUπKSHEεr(RULE£6) 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] -lH-pyrazol-4-yl] -2- pyridinamine ;
4- [3- (4-fluorophenyl) -lH-pyrazol-4-yl] -N-4-piperadinyl-2- pyridinamine ;
N,N-diethyl-3- (4-fluorophenyl) -4- (2-fluoro-4-pyridinyl) - lH-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) -lH-pyrazol-4-yl] -2- pyridinyl] amino] ethanol ; 2- [ [4- [3- (4 -fluorophenyl) -l-methyl-lH-pyrazol-4-yl] -2- pyridinyl] amino] ethanol ;
3- [ [4- [3- (4 -fluorophenyl) -lH-pyrazol-4-yl] -2- pyridinyl] amino] -1-propanol ;
3- (4-fluorophenyl) -4- [2- [ [ (4-fluorophenyl) methyl] amino] - 4-pyridinyl] -lH-pyrazole-1-ethanol ;
5- (4-fluorophenyl) -4- [2- [ [ (4-fluorophenyl) methyl] amino] -
4 -pyridinyl] -lH-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] -lH-pyrazol-4-yl] -2 -pyridinamine;
N- [5- (4-fluorophenyl) -4- (4-pyridinyl) -lH-pyrazol-3-yl] -4* morpholinepropanamine ;
N' - [5- (4-fluorophenyl) -4- (4-pyridinyl) -lH-pyrazol-3-yl] - N,N-dimethyl-l, 3-propanediamine;
5- (4-fluorophenyl) -N-2 -propynyl-4- (4-pyridinyl) -IH- pyrazol -3 -amine ;
3- (4-fluorophenyl) -4- [2- [ [ (4-fluorophenyl) methyl] amino] -
4-pyridinyl] -lH-pyrazole-1-ethanol ; 5- (4-fluorophenyl) -4- [2- [ [ (4-fluorophenyl) methyl] amino] -
4 -pyridinyl] -lH-pyrazole-1-ethanol ;
4- [3- [ (4-fluorophenyl) -IH-pyrazol -4-yl] quinoline;
N- [5- (4-fluorophenyl) -4- (4-pyridinyl) -lH-pyrazol-3- yl]glycine methyl ester;
N- [5- (4-fluorophenyl) -4- (4-pyridinyl) -IH-pyrazol -3- yl]glycine;
4- [3- (4-fluorophenyl) -1- (2-propynyl) -lH-pyrazol-4- yl] pyridine;
4- [5- (4-fluorophenyl) -1- (2 -propynyl) -IH-pyrazol -4- yl] pyridine; 4,4'- (lH-pyrazole-3 , 4-diyl) bis [pyridine] ;
4- [3- (3 , 4-dichlorophenyl) - IH-pyrazol -4-yl] pyridine;
N- [5- (4 -chlorophenyl) -4- (4-pyridinyl) -lH-pyrazol-3-yl] -4- piperidinamine ;
2-Chloro-4- [3- (4-fluorophenyl) - IH-pyrazol -4- yl] pyrimidine;
4- [3- (4-fluorophenyl) -lH-pyrazol-4-yl] -2 (IH) -pyrimidinone hydrazone;
4- [3- (4 -fluorophenyl) -lH-pyrazol-4-yl] -N,N-dimethyl-2- pyrimidinamine ; 4- [3- (4 -fluorophenyl) -IH-pyrazol-4-yl] -N-methyl -2- pyrimidinamine ;
4- [3- (4-fluorophenyl) -IH-pyrazol -4-yl] -N- (phenylmethyl) - 2 -pyrimidinamine ;
N-cyclopropyl-4- [3- (4-fluorophenyl) -lH-pyrazol-4-yl] -2- pyrimidinamine;
4- [3- (4-fluorophenyl) -lH-pyrazol-4-yl] -N- [ (4- methoxyphenyl ) methyl] -2 -pyrimidinamine ;
4- [3- (4-fluorophenyl) -lH-pyrazol-4-yl] -2 -pyrimidinamine; N- [4- [3- (4-fluorophenyl) -lH-pyrazol-4-yl] -2 -pyrimidinyl] - N- (phenylmethyl) acetamide;
Ethyl [4- [3- (4-fluorophenyl) -lH-pyrazol-4-yl] -2- pyrimidinyl] carbamate;
4- [3- (3-methylphenyl) - IH-pyrazol-4-yl] pyrimidine;
4- [3- (4 -chlorophenyl) -lH-pyrazol-4-yl] pyrimidine; 4- [3- (3-fluorophenyl) -lH-pyrazol-4-yl] pyrimidine; and
4- [3- (4-fluorophenyl) -lH-pyrazol-4-yl] pyrimidine .
Within Formula I there is another subclass of compounds of high interest represented by 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 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
8ϋBSπTUTESHEET(RϋL£2β) 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,
8ϋBSπTϋTESHEEr(R £S6) 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, dimethyl minopropylamino, morpholinylpropylamino, morpholinylethylamino, piperidinyl, piperazinyl, imidazolyl, morpholinyl, pyridinyl, carboxymethylamino, methoxyethylamino, (1,1- dimethyl) ethylcarbonyl, (1,1- dimethyl) ethylcarbonylaminopropylamino, (1,1- dimethyl) ethylcarbonylaminoethylamino, piperazinylcarbonyl , 1, 1-dimethyl - ethylpiperazinylcarbonyl ; wherein the phenyl, piperidinyl, piperazinyl, imidazolyl, morpholinyl, and pyridinyl groups are optionally substituted 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,
8UBSTmπESHEET(RULE26) 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 - NRS2R63 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:
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
8UBSTTrtfTE8HEEr(RULE28) 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
$UBOTWTESHEEr(RULE2β) 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-dimethyl- ethylpiperazinylcarbonyl ; 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
8UBSITTUTESHEET(RϋLE26) 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, (l-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 XI:
8lΛSπτUTESHEEr(RϋlE2β)
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-
8ϋBS πUTE8HEET(WlE2β) 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 -dimethyl - ethylpiperazinylcarbonyl ; 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, dimethylammoethylamino, hydroxypropylamino, hydroxyethylamino , imidazolylamino, morpholinylethylamino, (1 -ethyl -2 -hydroxy) ethylamino, piperidinylamino, pyridinylmethylamino, phenylmethylpiperidinylamino, aminomethyl, cyclopropylamino, amino, hydroxy, methylcarbonyl,
8U@gmUTE8HEE]"(RL)LE26) ethoxycarbonylamino, methoxyphenylmethylamino, phenylmethylamino , fluorophenylmethylamino , fluorophenylethylamino , methylaminocarbonyl , methylcarbonyl, hydrazinyl, and 1-methylhydrazinyl , or - NRS2R63 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
SUBSmure$HEET(RULE26) 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- ropylamino, 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 -dimethyl - ethylpiperazinylcarbonyl ; 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
SUBSTTrUTCSHEEr(RULE26) 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
βUrøIUϊESHEET(RUlE26} 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 .
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 "alkyl" 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
SUBSm ϋTESHEEr(RULE26) 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-butenyl 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,
Sy@gπ iπE8H£Er(R £2β 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
8UBSπTϋTESHEEr(fU£2β) 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, alkylammoalkylene, 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. lH-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
SUBSnTuTESHEET(R JE26) 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 (=0) - 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, butylsulfinyl and 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
SϋrøTTUTESI«Er(ME26) radicals. The term "halosulfonyl" embraces halo radicals attached to a sulfonyl radical . Examples of such halosulfonyl radicals include chlorosulfonyl , and bromosulfonyl . The terms " sulfamyl", "aminosulfonyl" 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 arpyl 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, /3-hydroxybutyric, galactaric and galacturonic acids. The term "carbonyl", whether used alone or with other terms, such as "alkoxycarbonyl", denotes - (C=0) - . 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
8ϋBSmUTE8HEEr(RUUE26) 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 pyrrolidmylmethyl, 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
SUBSnTUTE8HEET(RULE26) 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
"aminocarbonyl" denotes an amide group of the formula - C(=0)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
SυeSπTTUTESHEET(RULE26) 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 Formulas I and IX. As illustrated below, the pyrazoles of Formula I and I' are magnetically and structurally equivalent because of the prototropic
tautomeric nature of the hydrogen:
C ID C l J
The present invention also comprises compounds of Formula I, IX, X 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, 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
8ϋBSTπUTESH££T(RULE26) 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
8yøgπTϋTE8t Er(RϋLE26} 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:
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
SUeSTTRJTESHEET(RULE26) 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 .
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
SyeOTTUTES ErCR ESβ) or susceptible to such disorder or condition with a therapeutically-effective amount of a compound of Formula I
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 , alkylammoalkylene, alkylsulfonylalkylene, acyl, acyloxycarbonyl, alkoxycarbonylalkylene , aryloxycarbonylalkylene , heterocyclyloxycarbonylalkylene , alkoxycarbonylarylene , aryloxycarbonylarylene, heterocyclyloxycarbonylarylene, alkylcarbonylalkylene , arylcarbonylalkylene , heterocyclylcarbonylalkylene , alkylcarbonylarylene , arylcarbonylarylene , heterocyclylcarbonylarylene ,
SυBSTπuTESKΞET(RϋLE26) alkylcarbonyloxyalkylene, arylcarbonyloxyalkylene, heterocyclylcarbonyloxyalkylene , alkylcarbonyloxyarylene , arylcarbonyloxyarylene, and heterocyclylcarbonyloxyarylene ; or R1 has the formula r-, 2 5 n
— C — C H 2 , - C_ N
\ 2 7
R
( I I )
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 , alkylammoalkylene , 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
SUBSOTTUΪESHEET(RULE26) 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, alkylammoalkylene, 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 :
,32
-CCH -N
(III)
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(0)R35, -C(0)OR35, -S02R36, -C(0)NR37R38, and -S02NR39R40, 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 ,
(IV) (V) 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,
8ϋBSϊ πE8HEET(F%iU£26) 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 .
Also included in the family of compounds of Formula I are the pharmaceutically-acceptable salts 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 Formula I 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 include metallic salts and organic salts. More preferred metallic salts include, but are not limited to appropriate alkali metal (group la) salts, alkaline earth metal (group Ila) 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-
8UBSnTUTESHEET(WJLE26) methylglucamine) and procaine . All of these salts may be prepared by conventional means from the corresponding compound of Formulas I-III by reacting, for example, the appropriate acid or base with the compound of Formulas I- III.
General Synthetic Procedures
The compounds of the invention can be prepared according to the following procedures of Schemes I -XVIII 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.
SCHEME I
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, /3-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.
SUBSTmnESHEET(RULE26) SCHEME II
N H N H 2
1 2
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 α-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 hyrido, 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 .
SCHEME III
1 9
βϋBSπTUTESt€ETCRϋLE∑e) 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.
SCHEME IV
8UeSfmUTE8HEET(RULE26) Synthetic Scheme IV describes the preparation of pyrazole 19.
SCHEME V
31 32
33
X = ha I y a l y l n1 _ Me, CH2CH2OH eye I opropy I , 4- py r ϊ dy I , 4- i mi dazo l y l
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.
SUBSmTUTESHEEr(RUL£26) 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.
8UBSmU1ESHE£r(RULE2e) SCHEME VI
Rd R4
X
35
36
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.
SCHEME VII
σ.
EDC/^OEjT NHR10R11
42
41
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.
SCHEME VIII
Base R1-X
44 45
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.
8UBSmUmSHEEr(RULE26) SCHEME IX
y ldisi lazide n, RT
"desoxybenzo i n '
d i me t hy I f or mam i e dimethyl aceta C4 fold excess) tetrahydrofuran 1 volume)
RT
49
5D
SUB§mU!£8HEET(BULE26) 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 .
SlKnTUTESHEEr(RULE26) SCHEME X
52
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 .
8UB8mUΪESHEET(RULE28)
inor product
54
SCHEME XII
5 5
5 6
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.
SU8STmnESHEET(RULE26) SCHEME XIII
52 57
SCHEME XIV
59
s smuτE® Er(Ra £e) SCHEME XV
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.
SCHEME XVI
57 64
In Scheme XVI, R16 is selected, for example, from hydrogen, alkyl and phenyl.
SCHEME XVII
6 6
In Scheme XVII, R17 is selected, for example, from alkyl, phenylalkyl and heterocyclylalkyl.
SϋBSITrϋTESHEET(Rl E26) SCHEME XVIII
7 2
7 1
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
8UBSOTTUTCSHEEr(RUi£26) 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. The following examples contain detailed descriptions of the methods of preparation of compounds of Formulas I, XI, X and XI. 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
SUSSmTUreSHEEr(RUUE26) nuclear Overhauser effect (NOE) experiments.
The following abbreviations are used:
HCl - hydrochloric acid
MgSθ4 - magnesium sulfate Na2Sθ4 - sodium sulfate
NaIθ4 - sodium periodate
NaHS03 - 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
CH-CA - methylene chloride K2C03 - potassium carbonate
KMn04 - 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
SUBSmUTESHEEKRULEaβ) DSC - differential scanning calorimetry b.p. - boiling point m.p. - melting point eq - equivalent
RT - room temperature
Example A-l
4-[ 5- 3-f I uoro-4-methoxypheny I ) - 3- methy I - 1H-pyrazo I - 4- y I ]pyr i d I ne 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- IH-pyrazol -4 -yll 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 CH2CI2 (150 ml) , washed with H2O
(2x100 ml), dried ( 2S04), 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 -IH-pyrazol-4-yl] pyridine as a pale yellow solid (213 mg, 20.7%): Anal. Calc'd for
C16-H14N3OF.O.I H2O: C, 67.41; H, 5.02; N, 14.74. Found: C, 67.37; H, 4.88; N, 14.35.
Example A-2
4-C3-rnethyl-5-pheny l-1H-pyrazol-4-y1) py r i d i ne
Step 1: Preparation of 4-pyridylacetone
4-Pyridylacetone was prepared according to the method of Ippolito et al , U.S. Patent 4,681,944.
Step 2: Preparation of 4-phenyl-3- (4-pyridyl) -3-butene-
2 -one
Using the procedure of Example A-l, 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-l, 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
QUβgπTUTESHEEriF JEfiβ) 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 , - epoxy-2-butanone (270 mg, 20%) .
Step 4: Preparation of 4- (3 -methyl -5 -phenyl -IH-pyrazol - 4-yl) pyridine
Using the procedure of Example A-l, 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 -IH-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
4-[5-methyl-3-C2-methylphenyl)-1H- pyrazol -4-y1]pyr idi ne
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
SUB5FffitflESH£Er(RULE8 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) (l.Og, 4.2 mmol) in methyl alcohol (18 ml), a solution of H2O2 (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 Na2Sθ4, 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) IH- pyrazol -4 -yll yridine
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) -IH- pyrazol -4-yl] pyridine : Anal. Calc'd for CχgHi5N3 (249.32): C, 77.08; H, 6.06; N, 16.85. Found: C, 76.66; H, 5.91; N, 16.84.
sϋ8S UTEStCEr(RϋLE2β) Example A- 4
4-[ 5-methy l -3-C4-f l uoropheny l )- 1H- pyrazo l -4-y l]pyr i d i ne
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
4-[5-methyl-3-C4-methy lphenyl)-1H- pyrazo l-4-y1]pyr i i ne
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
4-[5-methyl-3-[4-C'ϊiethylthio)pheny l]- 1H-pyrazol-4-y1]pyr idine
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.
SUBSmure8HEET(RULE26) Example A- 7
4-[3-C4-chlorophenyl)-5-methy l-1H- pyrazol -4-y1]pyr idi ne
By following the method of Example A-5 and substituting p-chlorobenzaldehyde for p-tolualdehyde, the titled product was obtained. Anal. Calc'd for C15H12N3CI (269.77): C, 66.79; H, 4.48; N, 15.58. Found: C, 66.43; H, 4.44; N, 15.78.
Example A-8
4-[ 3-methy l-5-C3-methy Ipheny I )-1H- pyrazol-4-y1]pyr idine
By following the method of Example A- 5 and substituting m-tolualdehyde for p-tolualdehyde, the titled product was obtained: Anal. Calc'd for C15H15N3 + O.2H2O: C, 75.98; H, 6.14; N, 16.61. Found: C, 76.06; H, 6.05; N, 16.38
Example A- 9
4- [ 5- C 2 , 5-dιmethy Ipheny I)- 3-methy I 1H-pyrazo I -4-y1]pyr i d i ne
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 4- O.IH2O: C, 77.01; H, 6.54; N, 15.85. Found: C, 76.96; H, 6.81; N, 15.51.
Example A-10
4-[5-C1, 3-benzodιoxol-5-y1)-3-methyl 1H-pyrazol-4-y1]pyr idi ne
4-Pyridylacetone (1.5 g, 12 mmol), piperonal (1.6 g, 10.6 mmol), acetic acid (110 mg, 1.8 mmol), and piperidine (110 mg, 1.3 mmol) were dissolved in toluene
SϋBSπTUπfESHEETCRϋLESβ) (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 (MgS04) , 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-lH-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
4-[ 3-methy I - 5-C4-phenoxypheny I _) ■ 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
SUBSfmUTE8HEET(RUlE26) 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) -IH-pyrazol -4-yl] pyridine was obtained (100 mg, 66% yield) : Anal. Calc'd for C21H17N3O 4- 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
4-[ 5-[ [ 1 , 1 -b ipheny l]-4-y1]-3-methy I 1H-pyrazol-4-y1]pyr dine
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- lH-pyrazol-4-yl] pyridine as a white solid: MS (M+H): 312 (base peak) .
Example A-13
4-[ 3-methy I - 5-[ 3-(phenoxypheny 1 ). 1H-pyrazo I -4-y1]pyr i d i ne
sϋBsτπiπESHEEr(RϋLE2e) 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) - lH-pyrazol-4-yl] pyridine as a white solid.
Example A-14
4- [ 3-methy I - 5- [ 3-Cpheny I methoxy)pheny I ]■ 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] -lH-pyrazol-4-yl] pyridine as a white solid: MS (M+H) : 342 (base peak) .
Example A-15
4-[ 3-methy l-5-[ 2-Cpheny I ethoxy - pheny I ]-1H-pyrazo I -4-y1]pyr idi ne
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] -IH-pyrazol-4-yl] pyridine . MS (M+H) : 342 (base peak) .
Example A-16
2- [ 3-methy I -4-(4-pyr j d i ny ! )- IH- pyrazo I -4-y1]pheno I
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) -IH- pyrazol -4-yl] phenol : MS (M+H): 252 (base peak).
Example A-17
3-[ 3-methy l-4-C4-pyr id i ny I)- IH- pyrazo I -4-y1]pheno I
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).
SUBSmu SHECT(RULE28) Example A-18
1-hydroxy-4-[ 3-methy I -5-pheny I - 1 H- pyrazo I -4-y 1] pyr idi nium
To a solution of 4- (3 -methyl -5-phenyl- IH-pyrazol -4- yl) pyridine (Example A-2) (2.06 g, 8.76 mmol) in a mixture of CH2CI2 (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 2h, 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 MgSθ4 , filtered and concentrated to give l-hydroxy-4- [3- methyl-5-phenyl-lH-pyrazol-4-yl] pyridinium (1.12 g, 54.5%): MS (M+H): 252 (base peak).
Example A-19
5-C 4- f I uoropheny I ) - N , N-dimethy I - 4- C 4- pyr idi ny I )- 1H-pyrazo I - 3- am i ne 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 X 200 mL) . The combined organic layers were washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to give 1-fluoro-4- (4 ' - pyridylacetyl) benzene (19.9 g, 92 %) as an oil which solidified upon standing: m.p.: 90-91 °C; 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- (4' -pyridylbromoacetyl) benzene (14.5 g) . The compound was used in next step without further purification.
8ϋBSTπUTE8HEEr(RϋLE2β) Step 3: Preparation of 5- (4 -fluorophenyl ) -N, N-dimethyl- 4- (4-pyridinyl) -lH-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- ( -pyridinyl) -IH-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
5- C 4- f I uoropheny I )-N-pheny I - 4 - C4-pyr id i ny I)- 1H-pyrazo l-3-amι ne
5- (4 -Fluorophenyl) -N-phenyl-4- (4-pyridinyl) -IH- 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.
SUBSπTFUπreSHEET(RULE2θ) Example A-21
4- [ 5- C 4- f I uoropheny I ) - 3-pheny I - IH- pyrazo I - 4-y 1] pyr id i ne
Step 1: Preparation of 1-fluoro-4- (40- 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 cone. 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- F5- (4-fluorophenyl) -3 -phenyl- IH-pyrazol -4 -yll pyridine l-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 -IH-pyrazol -4-yl] pyridine (0.25 g, 53 %) as a pale yellow solid: m.p.: 265-267 °C. Anal. Calc'd for C20H14F 3 + 0.25 H2O: C, 75.10; H, 4.57; N, 13.14. Found: C, 74.98; H, 4.49; N, 12.87.
SUBSTnUTE8HEET(RUL£26) Example A- 22
4-[ 5-[3-methy I pheny I ) - 3- C t r if l uoromethyl)* 1H-pyrazo l-4-y1]pyr i di ne
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) -IH-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) -lH-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
4 - [ 3- C 4- f I uoropheny I )-4-C4-pyr i d i ny I )■ 1H-pyrazol-5-y1]pyridine
A mixture of 1-fluoro-4- (4 ' -pyridylacetyl) benzene (1.0 g, 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 (DarcoΦ) in boiling MeOH (100 mL) , followed by filtration and concentration, to give 4 - [3 - (4-fluorophenyl) -4- (4-pyridinyl) -IH-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 . I/4H2O: C, 71.13; H, 4.24; N, 17.46. Found: C, 70.88; H, 3.87; N, 17.38.
SUBSΠ IΠE8HEEΓ(RULE26) Example A- 24
4-C 5-cyc l ohexy l )- 3-met hy l - 1H- pyrazo l -4- y 1)pyr i d i ne
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-l, step 1 by replacing of 3- fluoro-p-anisaldehyde with cyclohexanecarboxaldehyde .
Step 2: Preparation of 4- (5-cyclohexyl) -3-methyl-lH- pyrazol -4 -yl ) pyridine
4- (5 -Cyclohexyl) -3 -methyl-IH-pyrazol -4-yl) pyridine was prepared by the method for Example A-l, 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
uoro-5-methoxypheny I )- 3- methy I - 1H-pyrazo I -4-y1]pyr i d i ne
4- {5- (3-Fluoro-5-methoxyphenyl) -3 -methyl -3 -methyl- IH-pyrazol -4 -yl }pyridine was prepared by the method of Example A-l, 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:
Sl SnTUTESHEEr(RULE26)
8UBsπmπESBEεr(RUL£26)
SUBSmUTE8HEET(RULE26) The following pyrazoles could be prepared by the procedures described above :
Example A-56 5- [5- (3 -chlorophenyl) -3 -methyl-IH-pyrazol - 4-yl] pyrimidin-2 -amine ;
Example A-57 5- [3 -methyl -5- (3 -methylphenyl) - IH-pyrazol -
4 -yl] pyrimidin-2 -amine ;
Example A-58 5- [3 -methyl -5- (2 -methylphenyl) -lH-pyrazol-
4 -yl] pyrimidin-2 -amine ; Example A-59 5- [5- (4 -chlorophenyl) -3 -methyl -IH-pyrazol-
4-yl] pyrimidin-2 -amine;
Example A-60 5- [5- (4-fluorophenyl) -3 -methyl -IH-pyrazol-
4-yl] pyrimidin-2 -amine;
Example A-61 5- [5- (4 -methoxyphenyl) -3 -methyl -IH-pyrazol- 4-yl] pyrimidin-2 -amine;
Example A-62 5- [5- (3 -chlorophenyl) -3 -methyl- IH-pyrazol -
4-yl] pyridin-2 -amine ;
Example A-63 4- [5- (3 -chlorophenyl) -3 -methyl -IH-pyrazol-
4-yl] pyridin-2 -amine; Example A-64 4- [5- (3 -methylphenyl) -3 -methyl-IH-pyrazol-
4-yl] pyridin-2 -amine;
Example A-65 4- [5- (2 -methylphenyl) -3 -methyl -IH-pyrazol-
4-yl] pyridin-2 -amine ;
Example A-66 4- [5- (4-chlorophenyl) -3 -methyl-IH-pyrazol - 4-yl] pyridin-2 -amine ;
Example A-67 4- [5- (4-fluorophenyl) -3-methyl-lH-pyrazol-4- yl] pyridin-2 -amine;
Example A-68 4- [5- (4-methoxyphenyl) -3 -methyl-IH-pyrazol-
4-yl] pyridin-2-amine; Example A-69 5- [5- (3 -chlorophenyl) -3 -methyl -IH-pyrazol-
4-yl] -2-methoxypyridine;
Example A-70 2 -methoxy-5- [3 -methyl-5- (3 -methylphenyl ) -
IH-pyrazol -4-yl] pyridine;
Example A-71 2 -methoxy-5- [5- (4 -methoxyphenyl) -3 -methyl - IH-pyrazol-4-yl] pyridine;
Example A-72 4- [5- (3 -chlorophenyl) -3 -methyl-IH-pyrazol- 4-yl] -2-methoxypyridine;
Example A-73 2 -methoxy-4- [3 -methyl -5- (3 -methylphenyl ) -
IH-pyrazol-4 -yl] pyridine ;
Example A-74 2 -methoxy-4- [3 -methyl-5- (2 -methylphenyl) - IH-pyrazol-4-yl] pyridine;
Example A-75 4- [5- (4-chlorophenyl) -3 -methyl-IH-pyrazol-
4-yl] -2-methoxypyridine;
Example A-76 4- [5- (4-fluorophenyl) -3 -methyl -IH-pyrazol -
4-yl] -2-methoxypyridine; Example A-77 2 -methoxy-4- [3 -methyl-5- (4 -methylphenyl) -
IH-pyrazol -4-yl] pyridine;
Example A-78 5- [5- (3 -chlorophenyl) -3 -methyl -IH-pyrazol -
4-yl] pyridin-2-ol ;
Example A-79 4- [5- (3 -chlorophenyl) -3 -methyl -IH-pyrazol - 4-yl] pyridin-2-ol;
Example A-80 4- [5- (3 -methylphenyl) -3 -methyl-IH-pyrazol-
4-yl] pyridin-2-ol ;
Example A-81 4- [5- (2 -methylphenyl) -3 -methyl -IH-pyrazol-
4-yl] pyridin-2-ol; Example A-82 4- [5- (4 -chlorophenyl) -3 -methyl -IH-pyrazol -
4-yl] pyridin-2-ol;
Example A-83 4- [5- (4-fluorophenyl) -3 -methyl -IH-pyrazol -
4-yl]pyridin-2-ol;
Example A-84 4- [5- (4-methoxyphenyl) -3-methyl-lH-pyrazol* 4-yl]pyridin-2-ol;
Example A-85 5- [5- (3 -chlorophenyl) -3 -methyl -IH-pyrazol-
4-yl] pyridine-2 -methanamine;
Example A-86 4- [5- (3 -chlorophenyl) -3 -methyl -IH-pyrazol -
4 -yl] pyridine-2 -methanamine ; Example A-87 4- [5- (3 -methylphenyl) -3 -methyl -IH-pyrazol -
4-yl] pyridine-2 -methanamine;
Example A-88 4- [5- (2 -methylphenyl) -3 -methyl -IH-pyrazol-
4-yl] pyridine-2 -methanamine;
Example A-89 4- [5- (4 -chlorophenyl) -3 -methyl-IH-pyrazol - 4-yl] pyridine-2 -methanamine;
Example A-90 4- [5- (4-fluorophenyl) -3 -methyl-IH-pyrazol-
8ϋBSπTUTE8HEEr( ϋLE2β) 4-yl] pyridine-2 -methanamine;
Example A-91 4- [5- (4 -methoxyphenyl) -3 -methyl -IH-pyrazol -
4-yl] pyridine-2 -methanamine;
Example A-92 5- [5- (3 -chlorophenyl) -3 -methyl -IH-pyrazol - 4-yl] pyridine-2 -carboxamide ;
Example A-93 4- [5- (3 -chlorophenyl) -3 -methyl-IH-pyrazol-
4-yl] pyridine-2 -carboxamide ;
Example A-94 4- [5- (3 -methylphenyl) -3 -methyl -IH-pyrazol-
4-yl] pyridine-2 -carboxamide; Example A-95 4- [5- (2 -methylphenyl) -3 -methyl-IH-pyrazol-
4-yl] pyridine-2-carboxamide;
Example A-96 4- [5- (4 -chlorophenyl) -3-methyl-lH-pyrazol-
4-yl] pyridine-2 -carboxamide ;
Example A-97 4- [5- (4-fluorophenyl) -3-methyl-lH-pyrazol- 4-yl] pyridine-2 -carboxamide;
Example A-98 4- [5- (4 -methoxyphenyl) -3 -methyl- lH-pyrazol-
4 -yl] pyridine-2 -carboxamide ;
Example A-99 4- [5- (3-fluoro-4 -methoxyphenyl) -3 -methyl-
IH-pyrazol-4-yl] pyridine; Example A-100 4- [5- (4-fluoro-3 -methoxyphenyl) -3 -methyl-
IH-pyrazol-4 -yl] pyridine ;
Example A-101 4- [5- (4 -chloro-3 -methoxyphenyl) -3 -methyl-
IH-pyrazol- -yl] pyridine ;
Example A-102 4- [5- (2 , 3-dihydrobenzofuran-6-yl) -3- methyl -IH-pyrazol-4 -yl] pyridine ;
Example A-103 4- [5- (benzofuran-6-yl) -3-methyl-lH- pyrazol-4-yl] pyridine;
Example A-104 4- [5- (3-fluoro-5-methoxyphenyl) -3 -methyl -
IH-pyrazol-4-yl] pyridine; Example A-105 4- [5- (3 -chloro-5-methoxyphenyl) -3 -methyl-
IH-pyrazol-4-yl] pyridine;
Example A-106 4- [5- (1-cyclohexyen-l-yl) -3-methyl-lH- pyrazol-4-yl] pyridine;
Example A-107 4- [5- (1, 3-cyclohexadien-l-yl) -3-methyl-lH- pyrazol-4-yl] pyridine;
Example A-108 4- [5- (5 , 6-dihydro-2H-pyran-4-yl) -3 -methyl-
IH-pyrazol-4-yl] pyridine;
Example A-109 4- (5-cyclohexyl -3 -methyl -IH-pyrazol -4- yl) pyridine;
Example A-110 4- [5- (4 -methoxy-3 -methylphenyl) -3 -methyl - lH-pyrazol-4-yl] pyridine;
Example A-lll 4- [5- (3 -methoxy-4 -methylphenyl) -3 -methyl - lH-pyrazol-4-yl] pyridine;
Example A-112 4- [5- (3 -methoxy-5-methylphenyl) -3 -methyl -
IH-pyrazol -4-yl] pyridine; Example A-113 4- [5- (3-furanyl) -3 -methyl-IH-pyrazol -4- yl] pyridine;
Example A-114 2 -methyl -4- (3 -methyl-5-phenyl -IH-pyrazol -
4 -yl) pyridine ;
Example A-115 2 -methoxy-4- (3 -methyl -5 -phenyl- IH-pyrazol - 4-yl) pyridine;
Example A-116 methyl 4- (3-methyl-5-phenyl-lH-pyrazol-4- yl) pyridine-2 -carboxylate ;
Example A-117 4- (3 -methyl -5-phenyl-IH-pyrazol-4- yl) yridine-2 -carboxamide ; Example A-118 1- [4- (3-methyl-5-phenyl-lH-pyrazol-4- yl) pyridin-2 -yl] ethanone;
Example A-119 N,N-dimethyl-4- (3 -methyl-5-phenyl -IH- pyrazol-2 -yl) pyridin-2 -amine ;
Example A-120 3-methyl-4- (3 -methyl-5-phenyl-IH-pyrazol - 4-yl) pyridine;
Example A-121 3 -methoxy-4- (3 -methyl-5-phenyl-IH-pyrazol-
4-yl) yridine ;
Example A-122 methyl 4- (3 -methyl-5-phenyl-IH-pyrazol-4- yl) pyridine-3 -carboxylate ; Example A-123 4- (3 -methyl-5-phenyl-IH-pyrazol-4- yl) pyridine-3 -carboxamide ;
Example A-124 1- [4- (3 -methyl-5-phenyl-IH-pyrazol-4- yl) pyridin-3 -yl] ethanone ;
Example A-125 3 -bromo-4 - (3 -methyl-5-phenyl-IH-pyrazol-4* yl) pyridine;
Example A-126 N,N-dimethyl-4- (3 -methyl-5-phenyl-IH-
6UBST1TUTE8HEET(RULE26) pyrazol -2 -yl) pyridin-3 -amine ;
Example A-127 2-methyl-4- (3 -methyl-5-phenyl-IH-pyrazol - 4 -yl ) pyrimidine ;
Example A-128 4- (3 -methyl -5-phenyl -IH-pyrazol-4- yl) pyrimidine;
Example A-129 2 -methoxy-4- (3 -methyl -5-phenyl -IH-pyrazol -
4 -yl) pyrimidine ;
Example A-130 4- (3-methyl-5-phenyl-lH-pyrazol-4- yl) pyrimidin-2 -amine; Example A-131 N,N-dimethyl-4- (3 -methyl -5-phenyl-lH- pyrazol -4 -yl) pyrimidin-2 -amine ;
Example A-132 4- (5, 6-dihydro-2H-pyran-4-yl) -3-methyl-5- phenyl- lH-pyrazole ; Example A-133 3 -methyl-5-phenyl-4- (3-thienyl) -1H- pyrazole;
Example A-134 4- (3-furanyl) -3 -methyl -5-phenyl-lH- pyrazole;
Example A-135 3 -methyl-5-phenyl-4- (2-thienyl) -1H- pyrazole; Example A-136 4- (2-furanyl) -3 -methyl-5-phenyl-lH- pyrazole;
Example A-137 4- (3-isothiazolyl) -3 -methyl-5-phenyl -lH- pyrazole; Example A-138 4- (3-isoxazolyl) -3 -methyl-5-phenyl-1H- pyrazole;
Example A-139 4- (5-isothiazolyl) -3 -methyl-5-phenyl-lH- pyrazole;
Example A-140 4- (5-isoxazolyl) -3 -methyl-5-phenyl-lH- pyrazole; Example A-141 3 -methyl -5-phenyl -4- (5-thiazolyl) -1H- pyrazole;
Example A-142 3 -methyl -4- (5-oxazolyl) -5-phenyl -IH- pyrazole; Example A-143 2-methyl-4- [3- (3 -methylphenyl) -lH-pyrazol- 4-yl] pyridine;
Example A- 144 4- (l-methyl-3-phenyl-lH-pyrazol-4-yl) pyridine;
Example A-145 4- (3 -phenyl -IH-pyrazol -4-yl) pyridine;
Example A-146 2-methyl-4- (3-phenyl-lH-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) -lH-pyrazol-4- yl] pyridine; Example A-150 4- [3- (4 -chlorophenyl) -IH-pyrazol -4 - yl] pyridine;
Example A-151 4- [3- (3 -chlorophenyl) -lH-pyrazol-4-yl] -2- methylpyridine ;
Example A-152 4- [3- (3 -fluorophenyl) -1-methyl- IH-pyrazol - 4-yl] pyridine;
Example A-153 4- [3- (3-fluorophenyl) -lH-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
5- (4 -chlorophenyl) -N-phenyl-4- (4 -pyridinyl) -IH-
SU3STITUTESHEET(RULE26) pyrazol -3 -amine: DSC 261 °C. Anal. Calc'd for C20H15C1N4 + 0.25 H20 (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
5- (4 -chlorophenyl) -N-methyl-4- (4-pyridinyl) -lH-pyrazol-3- amine: DSC 260 °C. Anal. Calc'd for C15H13C1N4 + 0.125 H20 (MW 287.00) : C, 62.77, H, 4.57, N, 19.52. Found: C, 62.78, H, 4.33, N, 19.22.
Example A- 157
5- (4 -chlorophenyl) -N,N-dimethyl-4- (4-pyridinyl) -1H- pyrazol -3 -amine dihydrate : DSC 230 °C. Anal. Calc'd for C16H15C1N4 + 2 H20 (MW 334.81) : C, 57.40, H, 4.52, N, 16.73. Found: C, 57.72, H, 4.85, N, 16.54.
Example A- 158
5- (3-f luorophenyl) -N,N-dimethyl-4- (4-pyridinyl) -IH- pyrazol -3 -amine : DSC 227 °C. Anal. Calc'd for C16H15FN4 + 0.125 H20 (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
N,N-dimethyl-5- (3 -methylphenyl) -4- (4-pyridinyl) -IH- pyrazol -3 -amine : DSC 222 °C. Anal. Calc'd for C17H18N4 + 0.25 H20 (MW 282.86) : C, 72.19, H, 6.41, N, 19.81. Found: C, 71.99, H, 6.46, N, 19.90.
Sϋ8SmϋTESHEEr(Rϋl£2β) Example A-160
N-methyl -5- (3 -methylphenyl) -4- (4 -pyridinyl) - IH-pyrazol -3* amine: DSC 226 °C. Anal. Calc'd for C16H16N4 + 0.125 H20 (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
N-ethyl-5- (3 -methylphenyl) -4- (4-pyridinyl) -lH-pyrazol-3- amine: DSC 227 °C. Anal. Calc'd for C17H18N4 + 0.125 H20 (MW 280.61) : C, 72.77, H, 6.47, N, 19.97. Found: C, 72.63, H, 6.40, N, 19.73.
Example A- 162
N,N-diethyl-5- (3 -methylphenyl) -4- (4-pyridinyl) -IH- 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
5- (4 -chlorophenyl ) - N,N-diethyl-4- (4-pyridinyl) -IH- pyrazol -3 -amine : m.p. 260-261°C. Anal. Calc'd for C18H19C1N4 (MW 326.83) : C, 66.15, H, 5.86, N, 17.14. Found: C, 66.03, H, 5.72, N, 17.23.A[
Example A-164
4- [5- (4 -chlorophenyl) -4- (4-pyridinyl) -lH-pyrazol-3- yl] morphol ine: DSC 279 °C. Anal. Calc'd for C18H17C1N40 + 0.25 H20 (MW 345.32) : C, 62.61, H, 4.96, N, 16.23. Found: C, 62.52, H, 4.77, N, 16.52.
Example A- 165
5- (4 -chlorophenyl) -N-propyl-4- (4 -pyridinyl) - IH-pyrazol -3- amine: DSC 244 °C. Anal. Calc'd for C17H17C1N4 + 0.125 H20 (MW 315.06) : C, 64.81, H, 5.44, N, 17.78. Found: C, 64.94, H, 5.43, N, 17.78.
Example A-166
Isolated as 5- (4 -chlorophenyl) -N- (phenylmethyl) -4- (4- pyridinyl) -IH-pyrazol -3 -amine hydrate (2:1) : DSC 237 °< Anal. Calc'd for C21H17C1N4 + 0. 5 H20 (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
Isolated as 5- (4 -chlorophenyl) -N- (2-methoxyethyl) -4- (4- pyridinyl) -IH-pyrazol -3 -amine monohydrate: DSC 223 °C. Anal. Calc'd for C17H17C1N40 + H20 (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
1, 1-dimethylethyl 4- [5- (4 -chlorophenyl) -4- (4-pyridinyl] lH-pyrazol-3-yl] -1-piperazinecarboxylate: DSC 251 °C. Anal. Calc'd for C23H26C1N50 (MW 439.95) : C, 62.79, H, 5.96, N, 15.92. Found: C, 62.40, H, 5.82, N, 15.82.
Example A- 169
Isolated as 1- [5- (4 -chlorophenyl) -4- (4 -pyridinyl) -IH- pyrazol -3 -yl] piperazine trihydrochloride: DSC 99 °C.
S BgπTUTESBEETCRUlESir) Anal. Calc'd for C18H18C1N4 + 3 HCl (MW 449.21) : C, 48.13, H, 4.71, N, 15.59. Found: C, 47.76, H, 5.07, N, 15.51.
Example A- 170
1- [5- (4 -chlorophenyl) -4- (4-pyridinyl) -IH-pyrazol -3 -yl] -4* methylpiperazine: m.p. 247-249 °C. Anal. Calc'd for C19H20C1N5 + 0.75 H20 (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
1, 1-dimethylethyl 4- [5- (4-fluorophenyl) -4- (4-pyridinyl) ■ lH-pyrazol-3-yl] -1-piperazinecarboxylate : m.p. 243-244
SU88frrrUTESHEET(RUL£26) °C. Anal Calc'd for C23H26FN502 + 0.5 (MW
467.55) : C, 64.22, H, 6.47, N, 14.98 Found: C, 63.90,
H, 6.61, N, 14.88.
Example A- 172
1- [5- (4-f luorophenyl) -4- (4-pyridinyl) -lH-pyrazol-3- yl] piperazine trihydrochloride: m.p. 204-206 °C. Anal. Calc'd for C18H18Fn5 + 3 HCl + 0.5 H20 (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) -IH-pyrazol -3- yl] piperazine: m.p. 264-265 °C. Anal. Calc'd for
C18H18C1N5 + 0.125 H20 (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.
SUBSπTUΪESHEEr(RUlE26) TABLE 2
Example A-173
N- [5- (4 -chlorophenyl) -4- [2- (phenylmethyl) amino] -4* pyridinyl] - IH-pyrazol -3 -yl] - 1 , 3 -propanediamine , trihydrochloride
Example A-174
1- [5- (4 -chlorophenyl) -4- (4-pyridinyl) -IH-pyrazol-3- yl] -4- (phenylmethyl) piperazine
Example A-175
Isolated as 4- [3- (4-fluorophenyl) -5- (1-piperazinyl) -1H- pyrazol-4-yl] pyrimidine, dihydrochloride
Example A-176
HBoc
1, 1-dimethylethyl [3- [ [5- (4-chlorophenyl) -4- (4- pyridinyl) -IH-pyrazol-3 -yl] amino] propyl] carbamate
sϋBSπτuτESt«εr(RϋiE26) Example A-177
Isolated as N- [5- [4 -chlorophenyl) -4- (4-pyridinyl) -IH- pyrazol -3 -yl] - 1 , 3 -propanediamine , trihydrochloride monohydrate
Example A-178
1, 1-dimethylethyl [2- [ [5- (4 -chlorophenyl) -4- (4- pyridinyl) -IH-pyrazol-3 -yl] amino] ethyl] carbamate
Example A-179
1, 1-dimethylethyl 4- [5- (4 -chlorophenyl) -1- (2- hydroxyethyl) -4- (4-pyridinyl) -lH-pyrazol-3-yl] -1* piperazinecarboxylate
Example A-180
Boc
1, 1-dimethylethyl 4- [5- (4-fluorophenyl) -4- (4- pyrimidinyl) -IH-pyrazol-3 -yl] -1-piperazinecarboxylate
SUBSTπUTESHEEr(RUUE2β) Example A-181
HBoc
1, 1-dimethylethyl [3- [ [5- (4 -chlorophenyl) -4- (2-fluoro-4* pyridinyl) -IH-pyrazol-3 -yl] amino] propyl] carbamate
Example A-182
1- [5- (4 -chlorophenyl) -4- (4-pyridinyl) -lH-pyrazol-3-yl] -4- ethylpiperazine
8UBSTπiπESH£Er(RϋLE26) Example A-183
N- [5- (4 -chlorophenyl) -4- (4-pyridinyl) -lH-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
4- [3- (2 , 6-difluorophenyl) -5-methyl-IH-pyrazol-4- yl] pyridine: Anal. Calc'd for C^H^F^ : C, 66.42; H,
4.09; N, 15.49. Found: C, 66.20; H, 3.94; N, 15.16; m.p.
SϋBSTϊ UfTESHEEr( ϋLE26) 236.67 °C.
Example A-185
4- [3- (3-ethylphenyl) - 5 -methyl -IH-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
4- [3- (3 -chlorophenyl) -5-ethyl-lH-pyrazol-4-yl] pyridine : Anal Calc'd for C16H14ClN3-»0.1 mole H20: 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
4- [3-ethyl-5- (3-ethylphenyl) -lH-pyrazol-4-yl] pyridine : Anal. Calc'd for C18H19N3-»0.1 mole H20: 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
4- [3- (4 -chlorophenyl) -5- (1-methylethyl) -lH-pyrazol-4- yl] pyridine: Anal. Calc'd for C17H16C1N2»0.4M EtOAc : C, 67.08; H, 5.81; N, 12.62. Found: C, 67.40; H, 6.15; N, 12.34.
gyBgπT TESHEETCR BZβ Example A-189
4- [3-cyclopropyl-5- (4-fluorophenyl) -lH-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
4- [3- (4-fluorophenyl) -5- (trifluoromethyl) -IH-pyrazol-4- yl] pyridine
This compound was prepared by the same procedure as
SϋBSTπU E8HEH(RϋlB265 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
4- [5- (cyclopropyl-3- (4- (fluorophenyl) -1-methyl -IH- pyrazol -4 -yl] pyridine
Step 1: Preparation of 1- (4-fluorophenyl) -2- (4- pyridinyl) ethanone methylhydrazone
NHMe
1- C 4- f I uoropheny I ~_ - 2 - <_ 4 - p r i d i ny I )et anone methy I hydrazone
SU3STfrϋTE8HEEr(Rl»JE2β) 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-IH-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- lH-pyrazol -4-yl] pyridine, as a light yellow solid (55% yield), mp : 129-130 °C; XH NMR (CDCL3) : δ 8.53 (m, 2H) , 7.32 (m, 2H) , 7.14 (m, 2H) , 6.97 (m, 2H) , 4.00 (s, 3H) , 1.83 (m, IH) , 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. Of
Example A-192
5-cyclopropyl-3- (4-fluorophenyl) -4- (4 -pyridinyl) -1H- pyrazole-1-ethanol
Step 1: Preparation of 1- (4 -fluorophenyl) -2- (4- pyridinyl) ethanone (2 -hydroxyethyl) hydrazone
1-(4-f I uoropheny I )-2-C4-pyr i d i ny I )et anoπe C 2- hydroxyethy I _) 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 F2-I" 1(1,1- dimethylethyl) dimethylsilyll oxyl ethyl] hydrazone
H,CH,OS i - t- BuMe.
1-(4-f l uoropheny l }-2-(1-pyr idi πy l)etHanone [ 2-[[C l, 1-dι met y let y Odιmethyl 5i ly l ]oxy]et y l] 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- [ t (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-l- F2- F F (1 , 1-dimethylethyl) dimethylsilyll oxyl ethyl] -3 , 4 -diphenyl -lH-pyrazole
5-cyclopropy l-1-[2-[[C1, 1- lmet y lethy Q di ethylsi iyl]oxy]etiιyl]-3,4-dlphenyl-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-l- [2- [ [ (1, 1- dimethylethyl) dimethylsilyl] oxy] ethyl] -3 , 4-diphenyl-1H- pyrazole, as a light yellow oil (35% yield) , 1H NMR (CDCL3) : δ 8.53 (m, 2H) , 7.32 (m, 2H) , 7.14 (d, J = 5.6
Hz, 2H) , 6.97 (m, 2H) , 4.47 (t, J" = 4.8 Hz, 2H) , 4.14 (t, J = 4.8 Hz, 2H) , 1.93 (m, IH) , 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.
SυSSTrrUTESHEET(RULE26) Step 4: Preparation of 5 -cyclopropyl-3- (4-fluorophenyl) - 4- (4 -pyridinyl) -lH-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) -lH-pyrazole-1-ethanol, as a pale yellow solid, mp : 155-157 °C; XH NMR (CDCL3) : δ 8.53 (br s, 2H) , 7.32 (m, 2H) , 7.14 (d, J" = 5.6 Hz, 2H) , 6.97 (m, 2H) , 4.42 (t, J = 4.8 Hz, 2H) , 4.14 (t, J" = 4.8 Hz, 2H) , 1.83 (m, IH) , 0.93 (m, 2H) , 0.35 (m, 2H) ; Anal. Calc'd For C19H18FN30: C, 70.57; H, 5.61; N, 12.99. Found: C, 70.46; H, 5.87; N, 12.84.
Example A-193
3- (4-fluorophenyl) -5- (2 -methoxy-4 -pyridinyl) -4- (4- pyridinyl ) -lH-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 g, 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) -lH-pyrazole-1- ethanol, as a yellow solid, mp : 168-169 °C; H NMR
(CDCL3) : δ 8.42 (m, 2H) , 8.20 (dd, J - 0.7, 5.2 Hz, IH) , 7.37 (m, 2H) , 7.02 (m, 2H) , 6.95 (m, 2H) , 6.71 (dd, J" = 1.4, 5.2 Hz, IH) , 6.66 (t, J = 0.7 Hz, IH) , 4.20 (m, 2H) , 4.14 (m, 2H) , 3.95 (s, 3H) ; Anal. Calc'd for C22H19FN402 : C, 67.86; H, 4.91; N, 14.35. Found: C, 67.46; H, 5.08; N, 14.03.
4- [1- [2- [ [ (1, 1-dimethylethyl) dimethylsilyl] - oxy] ethyl] -3- (4-fluorophenyl-4- (4-pyridinyl) -IH-pyrazol* 5-yl] -2-methoxypyridine
8UBSn7OTE8HEET(RU£26) A second compound, 4- [1- [2- [[ (1, 1-dimethylethyl) dimethylsilyl] oxy] ethyl] -3- (4-fluorophenyl -4- (4- pyridinyl) -IH-pyrazol-5-yl] -2 -methoxypyridine also was isolated from the above reaction as a yellow oil by chromatography. XH NMR (CDCL3) : δ 8.45 (m, 2H) , 8.20 (m, IH) , 7.40 (m, 2H) , 7.04 (m, 2H) , 6.93 (m, 2H) , 6.81 (m, 2H) , 4.24 (m, 2H) , 4.14 (m, 2H) , 3.98 (s, 3H) , 0.83 (s, 9H) , 0.02 (s, 6H) .
Example A-194
4- [3- (4-fluorophenyl) -1- (2 -hydroxyethyl) -4- (4-pyridinyl) - IH-pyrazol-5 -yl] -2 (IH) -pyridinone
To a solution of 3- (4-fluorophenyl) -5- (2-methoxy-4- pyridinyl) -4- (4-pyridinyl) -lH-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/NH40H, 5:94:1) to give 0.07 g of product, 4- [3- (4-fluorophenyl) -1- (2- hydroxyethyl) -4- (4-pyridinyl) -lH-pyrazol-5-yl] -2 (IH) -
Sl©δπTUfTE8HEEr(RULE2β) pyridinone, as a yellow solid (32% yield), mp : 250-251 °C; 'H NMR (DMSO-d6) : δ 11.74 (s, IH) , 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, IH) , 6.05 (d, J" = 5.2 Hz, IH) , 5.0 (m, IH) , 4.13 (m, 2H) , 3.81 (m, 2H) ; Anal. Calc'd for C21H17FN4O2»0.2 H20: C, 66.06; H, 4.65; N, 14.67. Found: C, 66.31; H, 4.49; N, 14.27.
Example A-195
l-acetyl-4- [3- (4-fluorophenyl) -1- (2 -hydroxyethyl) -4- (4-pyridinyl) -lH-pyrazol-5-yl] -2 (IH) -pyridinone
l-acetyl-4- [3- (4-fluorophenyl) -1- (2 -hydroxyethyl) -4- (4 -pyridinyl) -IH-pyrazol -5-yl] -2 (IH) -pyridinone was obtained as a byproduct of the reaction of Example A-194 in the form of a yellow solid (38% yield), mp : 220-221 °C; K NMR (CDC13) : δ 8.50 (m, 2H) , 7.39 (m, 3H) , 7.02 (m, 4H) , 6.59 (m, IH) 6.08 (dd, J = 1.4, 5.2 Hz, IH) , 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 H20: C, 65.46; H, 4.63; N, 13.28. Found: C, 65.09; H, 4.64; N, 12.99.
SϋBSmTϋTESHEET(RU E2β) Example A-196
Ethyl 2- [3- (4-fluorophenyl) -1- (2 -hydroxyethyl) -4- (4- pyridinyl) -IH-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 g of product, ethyl 2- [3- (4-fluorophenyl) -1- (2 -hydroxyethyl) -4- (4-pyridinyl) - IH-pyrazol-5-yl] cyclopropanecarboxylate, as a light yellow oil (35% yield), XH NMR (CDCL3) : δ 8.55 (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, IH) , 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 H20: C, 66.07; H, 5.67; N, 10.51 Found: C,
gyrøTOTESHEETlRϋlBaβ) 65.89; H, 5.80; N, 9.95
Example A-197
2- [3- (4-fluorophenyl) -1- (2 -hydroxyethyl) -4- (4-pyridinyl) - lH-pyrazol-5-yl] cyclopropanecarboxylic acid
To a solution of ethyl 2- [3- (4-fluorophenyl) -1- (2- hydroxyethyl) -4- (4-pyridinyl) -IH-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 IN HCl and stirred for 30 minutes. The pH was then adjusted to 5-6 by addition of IN 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) -IH-pyrazol-5-yl] cyclopropanecarboxylic acid, as a white solid (60% yield), mp : 253-255 °C; XH NMR (CD3OD) : δ 8.46 (m, 2H) , 7.32 (m, 2H) , 7.25 (m, 2H) , 7.04 (m, 2H) , 4.39 (t, J = 5.0 Hz, 2H) , 4.03 (m, 2H) , 2.60 (m, IH) , 1.51 (m, 2H) , 0.97 (m, 2H) ; Anal. Calc'd For
SUBSmUTESHEET(RULE28) C20H18FN3O3: C, 65.39; H, 4.94; N, 11.44 Found: C, 64.92; H, 4.77; N, 11.20.
Example A-198
3- (4-fluorophenyl) -5- (4-imidazolyl) -4- (4-pyridinyl) -1H- pyrazole-1-ethanol
Step 1: Preparation of methyl 1- F F2- (trimethylsilyl) ethoxy] methyl] -lH-pyrrole-3 -carboxylate
C02 e
TMS r
methyl 1- [ [2- (trimethylsilyl) ethoxy] methyl] -lH-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- Fl- F2- F F (1 , 1-dimethylethyl) dimethylsilyl] oxyl ethyl] -3- (4-fluorophenyl-5- Fl- F F (2- trimethysilyl) ethoxy] methyl -IH-imidizol-4 -yl] -IH-pyrazol- 4-yl1 pyridine
OS i C t- Bi e.
4- [1- [2 [ [ (1, 1-dimethylethyl) dimethylsilyl] - oxy] ethyl] -3- (4-fluorophenyl) -5- [1- [ [2- trimethylsilyl) ethoxy] methyl] -lH-imidazol-4-yl] -IH- 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
SUBSOTRJTC$HEEr(RUlJE26) 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; XH NMR (CDCL3) : δ 8.48 (d, J" = 6.0 Hz, 2H) , 7.68 (d, J" = 1.3 Hz, IH) , 7.38 (d, J" = 6.0 Hz, 2H) , 7.10 (m, 2H) , 7.00 (m, 2H) , 6.93 (d, J = 1.3 Hz , IH) , 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 C31H44FN502Si2 : 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) -IH-pyrazole-l-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 (1.0 M in THF) . After the mixture was heated at reflux for 3 hours, the solvent was removed and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude product was purified on silica gel (methylene chloride/methanol, 95:5) to give 0.22 g of the product, 3- (4-fluorophenyl) -5- (4-imidazolyl) -4- (4-pyridinyl) -1H- pyrazole-1-ethanol, as a white solid (63% yield), mp : 227-228 °C; 'H NMR (DMSO-d6) : δ 8.45 (m, 2H) , 7.83 (s, IH) , 7.35 (m, 2H) , 7.15 (m, 4H) , 7.09 (s, IH) , 5.20 (br s, IH) , 4.32 (s, 2H) , 3.81 (m, 2H) ; Anal. Calc'd For
C19H16FN50: 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
SUB§TπUTESBEEr(RULE2β) corresponding starting reagents:
Example A-199
4- [3- (4 -chloro-3 -methylphenyl) -IH-pyrazol -4-yl] pyridine
Anal. Calc'd for C15H12N3C1 (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:
5- (4 -fluorophenyl) -4- (4-pyridinyl) -lH-pyrazole-3- carboxylic acid
gUBSmUIESHEEUROEZe) A mixture of 4- [3- (4-fluorophenyl) -5-methyl- IH- 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 IN 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) -lH-pyrazole-3-carboxylic acid (isolated as the monohydrate salt) (2.9777 g, 43.7 %) . Anal. Calc'd for C15H10N3FO2.H20 (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
5- (4-fluorophenyl) -4- (4 -pyridinyl) -lH-pyrazole-3 -methanol
To a suspension of 5- (4-fluorophenyl) -4- (4- pyridinyl) -lH-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 IN lithium aluminum hydride in THF (4.0 ml,
gUBSπTU1E8HEET(RtøE2ft 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 MgS04 to give a crude product (0.45 g) . Recrystallization of the crude product from methanol gave 5- (4 -fluorophenyl) -4- (4- pyridinyl) -lH-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
1- [ [5- (4-fluorophenyl) -4- (4-pyridinyl) -lH-pyrazol-3* yl] carbonyl] piperazine
SUBSmUTESHEET(RULE26) Step 1: Preparation of 1 , 1-dimethylethyl 4- F F5- (4- fluorophenyl) -4- (4-pyridinyl) -lH-pyrazol-3-yl] carbonyl]
1-piperazinecarboxylate
To a solution of 5- (4-fluorophenyl) -4- (4-pyridinyl) - lH-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 NaHC03 solution, water and brine, and dried over MgS04. 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) -lH-pyrazol-3-yl] carbonyl] - 1-piperazinecarboxylate (1.2372 g, 78.4%) was obtained by chromatography. Anal. Calc'd for C24H26N503F. (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).
gUrøπUTESHEEr(RUlE26) Step 2: Preparation of 1- F F5- (4-fluorophenyl) -4- (4- pyridinyl) -IH-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) -lH-pyrazol-3- yl] carbonyl] piperazine (isolated as the bis (trifluoroacetate) , monohydrate salt) (0.2400g, 100%) as a white solid. Anal. Calc'd for C19H18N5OF.2CF3COOH.H20(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
4- (1 , 5-dimethyl-3 -phenyl- IH-pyrazol-4 -yl) pyridine
8UBSTmfl£SHEEr(RULE26)
4- (1, 3 -dimethyl-5-phenyl-IH-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 -IH-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 Na2S04, 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-IH-pyrazol-4-yl] pyridine, and the second material off the column was 4- (1, 5-dimethyl-3 -phenyl-IH-pyrazol-4- yl) pyridine.
Major isomer (4- (1, 5-dimethyl-3 -phenyl-IH-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
8UBSπiUTES ET(RUJE26) Example A-204
4- [3- (4 -chlorophenyl) -1, 5-dimethyl -IH-pyrazol-4- yl] pyridine
4- [5- (4 -chlorophenyl) -1, 3 -dimethyl-IH-pyrazol-4- yl] pyridine (the compound of Example A-32)
4- [3- (4 -chlorophenyl) -1, 5-dimethyl-IH-pyrazol-4- yl]pyridine and 4- [5- (4 -chlorophenyl) -1 , 3 -dimethyl-IH- pyrazol-4-yl] pyridine were prepared by the same procedure as described for Example A-203 by replacing 4-(3-methyl- 5-phenyl -IH-pyrazol-4-yl) pyridine with 4- (3- (4- chlorophenyl) -5-methyl-IH-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 C16H14N3C1 (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.
SUBSmiπESHECT(RULE26) Minor Isomer (4- [5- (4 -chlorophenyl) -1 , 3 -dimethyl -IH- pyrazol -4-yl] pyridine) : m.p. : 82-88 °C. Anal, calc'd for C16H14N3C1: C, 67.72; H, 4.97; N, 14.81; Found: C, 67.56; H, 4.96; N, 14.73.
Example A-205
4- [5-ethyl-1-methyl -3- (3 -methylphenyl) -lH-pyrazol-4* yl] pyridine
4- [3-ethyl-l-methyl-5- (3 -methylphenyl) -lH-pyrazol-4- yl] pyridine
4- [5 -ethyl-1-methyl-3- (3 -methylphenyl) -lH-pyrazol-4- yl]pyridine and 4- [3 -ethyl-1-methyl -5- (3 -methylphenyl) - IH-pyrazol-4-yl] pyridine were prepared by the same procedure as described for Example A-203 by replacing 4- (3 -methyl-5-phenyl -IH-pyrazol -4-yl) pyridine with 4- (3- (4- methylphenyl) -5-ethyl-IH-pyrazol -4-yl) pyridine (prepared
SU8§fmUFESHECT(RULE26) 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 MH20: C, 75.73; H, 7.03; N, 14.77. Found: C, 76.03; H, 6.87 N, 14.28.
Minor Isomer (4- [3 -ethyl -l-methyl-5- (3 -methylphenyl) -1H- pyrazol-4-yl] pyridine) : Anal. Calc'd for
C18H19NO3«0.30MH2O: C, 76.46; H, 6.99; N, 14.86. Found: C, 76.58; H, 6.98; N, 14.63.
Example A- 206
4- [3- (4 -chlorophenyl) - 1 -ethyl -5 -methyl -IH-pyrazol -4- yl]pyridine: Anal. Calc'd for C17H16N3C1 (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
SUBSflmumSHEEURυLE∞) 4- [3- (4 -chlorophenyl) -2-ethyl-5-methyl-lH-pyrazol-4- yl]pyridine: Anal. Calc'd for C17H16N3C1 (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
4- [3- (4-fluorophenyl) -lH-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 (50.45g, 0.3 moles), maintained at 20 °C, was added lithium bis (trimethylsilylamide) (600 mL (IM)) 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-
8UBSπrπUϊESHEEr(RUlE2β) fluorobenzoyl-4 ' -pyridyl methane, in 90% yield (58g) . 1H NMR was consistent with the proposed structure.
Step 2 : To a suspension of the desoxybenzoin prepared in step 1 (30g, 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%). XH NMR was consistent with the proposed structure.
Step 3 :
The vinyl amine prepared in step 2 (33.9g, 0.1255 moles) was dissolved in 125 mL of ethanol and cooled to 0 °C. Hydrazine hydrate (8.0g of anhydrous or 16. Og. 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% HCl. 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) -lH-pyrazol-4-yl] pyridine . Yield: 27.3g. (91%). Mass spectrum: m/z = 240. XH 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.
gUBSmiJIESI€ETtf BSβ) Example A-209
4- [3- (2 -chlorophenyl) -lH-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 C14H10C1N3 : 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-MO and A-211 illustrate were prepared in accordance with the chemistry described above (particularly in Scheme X) :
Example A-210
3- (4 -fluorophenyl) -4- (4-pyridinyl) -lH-pyrazole-1-ethanol
SUBSTITUTESHEEr(R .E26} The desoxybenzoin prepared in step 1 of Example A- 208, 4-fluorobenzoyl -4' -pyridyl methane, (12.7g, 0.059 moles) was mixed with 90% hydroxyethyl hydrazine (5.3g, 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 *H 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 80C for lOmin, 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) -lH-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) -lH-pyrazole- 1-ethanol. Total yield: {12.3 + 3.3 + 0.4 + 0.4} = 16.4g. (97.6%) . Mass spectrum, m/z = 284. H NMR was consistent with the proposed structure. Anal, calc'd for C16H14FN30 + H20: C, 63.78; H, 5.35; N, 13.95. Found: C, 63.55; H, 5.07; N, 13.69.
6UBSπ UTE8HEEr(RϋLE2β) Example A-211
3- (4-fluorophenyl) -4- (4 -pyrimidinyl) -lH-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
4- [3- (4-fluorophenyl) -1-methyl-IH-pyrazol -4-yl] pyridine
The vinyl amine prepared in Step 2 of Example A-208 (5.0g, 0.0185 moles) was taken up in ethanol (75mL) and cooled to 0 °C. Methyl hydrazine (1.7g, 0.037 moles) in ethanol (75mL) 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
SUBOTU!ESHEET( JE26) mL) and the water layer treated with activated charcoal (0.5g). 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: 2.1g. (45%). Mass spectrum, m/z = 254 (base peak). Anal, calc'd for C15H12FN3 + 0.2 H20 : 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
2- [ [4- [3- (4 -fluorophenyl) -lH-pyrazol-4-yl] -2- pyridinyl] amino] -1-butanol
An intimate mixture of 2-fluoro-pyridinyl pyrazole (0.2g, (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-l-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) -lH-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. XH 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
4- [5-bromo-3- (4-fluorophenyl) -1-methyl-IH-pyrazol-4- yl] pyridine
To a solution of 4- [3- (4 -fluorophenyl) -1-methyl-lH- pyrazol-4-yl] yridine (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
S STΓΠJTE8HEEΓ(RULE26) that the reaction was complete. The mixture was quenched slowly with K2C03 (25g) . When pH was about 5, a precipitate was formed. The precipitate was washed with water (50mL x 5) to give 4- [5-bromo-3- (4-fluorophenyl) -1- methyl-lH-pyrazol-4-yl] pyridine (1.24g, 35%): mp 174.38°C; Mass spectrum m/z = 332, 334; 1H NMR was consistent with the proposed structure. Anal. Calc'd for .2 H20: 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
4- [3- (4 -fluorophenyl) -lH-pyrazol-4-yl] -2- pyridinecarbonitrile
Step 1 : To a solution of 4- [3- (4-fluorophenyl) -IH-pyrazol-4- yl] pyridine (4.3g, 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. K2C03 (10%, 100 mL) was added to the residue. A precipitate was formed, filtered and washed with water (30 mL x 3) to give the
8UBSπmUTE8HEET(RaE26) corresponding N- oxide ( 3 . 764g , 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 K2C03 (10%, 20 mL) , water
(50 mL) , brine (50 mL) , dried over MgS04, filtered and concentrated to give 4- [3- (4-fluorophenyl) -lH-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 C15H9N4F»0.2 H20: 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
4- [2- F3- (4 -fluorophenyl) -4- (4-pyridinyl) -lH-pyrazol-1- yl] ethyl] morpholine
8UBSniUIESHEEr(RULE265 Step 1 :
3- (4-fluorophenyl) -4- (4 -pyridinyl) -lH-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. Ig) . H 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) -IH-pyrazol-1- yl] ethyl] morpholine as a solid. Yield: 4.5g (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.
8UBSmUTESHEET(RULE26) The compound of Example A-217 was prepared in accordance with the chemistry of Scheme XVI :
Example A-217
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-IH-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, IN) 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 MgS04, 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+l) ; XH 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.
8UBSfmUTESHEET(RULE26) The compound of Example A-218 was prepared in accordance with the chemistry described above (particularly Scheme XVII) :
Example A-218
N- [5- (4-fluorophenyl) -4- (4-pyridinyl) -lH-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 g, 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) -lH-pyrazol-3-yl] -4- morpholineethanamine, which was re-filtered and dried.
SU8SnTuTESHEET(RU E26) Yield: 0.95g. (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
4- F3- (3 -chlorophenyl) -lH-pyrazol-4-yl] -2 (IH) -pyridinone hydrazone Step 1: Preparation of (E) -2- (2 -bromo-4 -pyridinyl) -N,N- dimethylethenamine
4-Methyl-2-bromopyridine (1.0 g, 5.8 mmol) and t- butoxybis (dimethylamino) methane (5 ml) were heated 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
8UBSn TES&€ET(RULE26) oil suitable for use in step 2
Step 2: Preparation of (Z) -2- (2 -bromo-4-pyridinyl) -1- (3* chlorophenyl) -3- (dimethylamino) -2-propen-l-one
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-l-one, as a glass which was used in step 3 without further purification.
Step 3: Preparation of 2-bromo-4- F3- (3 -chlorophenyl) -IH- pyrazol -4-yl1 pyridine
SUBSTΓΓUTESHEET(RULE26) 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) -lH-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) -IH-pyrazol -4-yl] - 2 (IH) -pyridinone hydrazone (190 mg, 36%) as a crystalline solid: m.p. 163-164 °C; MS (M+H) = 286. Anal. Calc'd for C14H12N5C1: C, 58.85; H, 4.23; N, 24.51. Found: C, 58.53; H, 4.28; N, 24.87.
Example A-220
4- [3- (3 -chlorophenyl) -IH-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
SUBSmUTESHEET(RϋLE26) and the residue chromatographed on silica gel using mixtures of ethyl acetate and toluene to give 4- [3- (3- chlorophenyl) -lH-pyrazol-4-yl] -N- (phenylmethyl) -2- pyridinamine (110 mg, 61%) as a solid, m.p. 179-180 °C.
Anal. Calc'd For C21H17C1N4 : C, 69.90; H, 4.75; N, 15.53. Found: C, 69.69; H, 4.81; N, 15.11.
Example A-221
4- [3- (3 -chlorophenyl) -lH-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) -IH-pyrazol-4-yl] -N- (phenylethyl) -2- pyridinamine (230 mg, 81%) as a solid, m.p. 185-186 °C.
Anal. Calc'd For C22H19C1N4 : C, 70.49; H, 5.11; N, 14.95. Found: C, 70.29; H, 5.15; N, 14.66.
SUBSTrrUTESHEET(RULE26) Example A-222
4- [3- (3 -chlorophenyl) -lH-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) -lH-pyrazol-4-yl] -N-ethyl -2 -pyridinamine
(125 mg, 46%) as a solid, m.p. 186-187 °C.
Anal. Calc'd For C1SH1SC1N4 : 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:
BUBSmUffiSH£ET(RULE26) Example A-223
4- [3- (4-fluorophenyl) -IH-pyrazol -4-yl] -2- pyridinecarboxamide
Step 1 :
To a suspension of 4- [3- (4-fluorophenyl) -IH-pyrazol - 4-yl] pyridine (prepared as set forth in Example A-208) (8.8 g, 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- F3- (4-fluorophenyl) -IH-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
8ϋBS UTE8t€ET(R JE2β) 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) -lH-pyrazol-4-yl] -2- pyridinecarbonitrile (90%) as a pale yellow solid, mp : 238-239°C.
Step 3: Preparation of 4- F3- (4 -fluorophenyl) -IH-pyrazol- 4-yl] -2-pyridinecarboxamide :
To a solution of 4- [3- (4-fluorophenyl) -IH-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) -lH-pyrazol-4-yl] -2- pyridinecarboxamide as a white solid (67% yield), mp : 230-231 °C. Anal. Calc'd for C^H^F^O: C, 63.83; H, 3.93; N, 19.85. Found C, 63.42; H, 3.66; N, 19.58.
Example A-224
8UBSrmraSH£ET(RUL£26) Methyl 4- [3- (4-fluorophenyl) -lH-pyrazol-4-yl] -2- pyridinecarboxylate
To a suspension of 4- [3- (4-fluorophenyl) -IH-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 4hours. After cooling, the precipitate was collected by filtration and air-dried to give 2.0 g of methyl 4- [3- (4- fluorophenyl) -lH-pyrazol-4-yl] -2-pyridinecarboxylate as a white solid (69% yield), mp : 239-241°C. Anal. Calc'd for C16H12FN302: C, 64.64; H, 4.07; N, 14.13. Found: C, 64.36; H, 4.10; N, 14.27.
Example A-225
4- [3- (4-fluorophenyl) -lH-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
SUBSTπυTESHEET(RULE26) 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 C16H13FN40 + 0.4 H20: C, 63.32; H, 4.58; N, 18.46. Found C, 63.10; H, 4.62; N, 18.35.
Example A-226
4- [3- (4-fluorophenyl) -lH-pyrazol-4-yl] -2- pyridinecarboxylic acid
To a solution of 4- [3- (4-fluorophenyl ) -IH-pyrazol-4- yl] -2-pyridinecarboxylate prepared as set forth in Example A-224 (0.90 g, 0.003 mol) in 10 mL of ethanol was added a solution of sodium hydroxide (0.24 g, 0.006 mol) in 5 mL of water. The reaction mixture was 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) -IH-pyrazol-4-yl] -2-pyridinecarboxylic
8UBS rTESH£ET(RULE2fi) acid as a white solid (73% yield), mp : 245°C(dec) . Anal Calc'd for C15H10FN3O + 0.2 H20: 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.
SUBSnTUfTESHEET(RUL£26) TABLE 3
l\3 σ
CD
to o
t
Example A-227
- [3- (3-fluorophenyl) -IH-pyrazol-4-yl] pyridine
Example A-228
- [3- (1, 3-benzodioxol-5-yl) -lH-pyrazol-4-yl] pyridine
Example A-229
SUBSπTUTESHEET(RULE26) - [3- (3 -fluorophenyl) -1-methyl-IH-pyrazol -4-yl] pyridine
Example A-230
- [3- (4 -chlorophenyl) -IH-pyrazol -4-yl] pyridine
4- [3- (1, 3-benzodioxol-5-y) -1-methyl-IH-pyrazol-4-yl] pyrid ine
Example A-232
4- [3- (4 -chlorophenyl) -1-methyl -IH-pyrazol -4-yl] pyridine
Example A-233
4- [3- (3 -chlorophenyl) -1-methyl-IH-pyrazol -4-yl] -2-methylp yridine and 4- [5- (3 -chlorophenyl) -1-methyl -lH-pyrazol-4 -yl] -2-methylpyridine
Example A-234
4- [3- (3 -chlorophenyl) -l-methyl-lH-pyrazol-4-yl] pyridine and
4- [5- (3 -chlorophenyl) -l-methyl-lH-pyrazol-4-yl] pyridine
Example A-235
2 -methyl-4- [l-methyl-3 (or
5) - (3 -methylphenyl) -IH-pyrazol -4 -yl] pyridine
Example A-236
4 - (3 -phenyl - IH-pyrazol-4 -yl) pyridine
Example A-237
4- [3- [3- (trifluoromethyl) phenyl] -lH-pyrazol-4-yl] pyridine
8UBSmUTESBECT(RUiE2B) Example A-238
4- [l-methyl-3- [3- (trifluoromethyl) phenyl] -lH-pyrazol-4- yl] pyridine
Example A-239
F
\
N— H
4- [3- (3 , 4 -difluorophenyl) -IH-pyrazol -4-yl] pyridine
8UBSmUTESHEEr(RULE2β) Example A-240
- [3- (4 -chlorophenyl) -lH-pyrazol-4-yl] -2-fluoropyridine
Example A-241
- [3- (4 -bromophenyl) - IH-pyrazol -4yl] pyridine
Example A-242
- [3- (3 , 4 -dif luorophenyl) -l-methyl-lH-pyrazol-4-yl] pyridi
ne
Example A-243
4- [3- (4 -bromophenyl) -1-methyl-IH-pyrazol-4-yl] pyridine
Example A-244
(E) -4- [3- (4 -fluorophenyl) -lH-pyrazol-4-yl] -2- (2-phenyleth enyl) pyridine
β BsrmresHEEURUiEaβ) Example A-245
(S) -4- [3- (4-chlorophenyl) -lH-pyrazol-4-yl] -N- (2-methylbut yl) - 2 -pyridinamine
Example A-246
.
4- [3- (4 -chlorophenyl) -IH-pyrazol-4-yl] -N- [ (4-methoxyphenyl) methyl] - 2 -pyridinamine
8UBsrrπuτESHεεr(RULE26} Example A-247
N- [4- [3- (4 -chlorophenyl) -lH-pyrazol-4-yl] -2-pyridinyl] 2 -pyridinemethanamine
Example A-248
N- [4- [3- (4-fluorophenyl) -lH-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.
SUBSTITUTE SH£ET(RULE 26) Example A-249
-fluoro-4- [3- (4-fluorophenyl) -IH-pyrazol -4-yl] pyridine
Example A-250
- [3- (4-iodophenyl) -IH-pyrazol -4-yl] pyridine
Example A-251
.
- [3- (4-iodophenyl) -1-methyl-IH-pyrazol-4-yl] pyridine Example A-252
4- [l-methyl-3- [4- (trifluoromethyl) henyl] -IH-pyrazol -4-yl ] pyridine
Example A-253
N- [1- (4-fluorophenyl) ethyl] -4- [3- (4-fluorophenyl) -IH-pyra zol-4-yl] - 2 -pyridinamine
βϋrø UTESHEεriRULESβ) Example A-254
N- [ (3-fluorophenyl) methyl] -4- [3- (4-fluorophenyl) -IH-pyraz ol-4-yl] - 2 -pyridinamine
Example A-255
4- [3- ( -fluorophenyl) -l-methyl-lH-pyrazol-4-yl] -2- (1- methylhydrazino) pyridine
gU8SmiffESBEEr(RULE26} Example A-256
2-fluoro-4- [3- (4-fluorophenyl) -l-methyl-lH-pyrazol-4-yl] p yridine
Example A-257
4- [3- (3, 4 -dif luorophenyl) -lH-pyrazol-4-yl] -2-fluoro- pyridine
SUBSTmπESHECT(RtfJE2β) Example A- 258
4- [3- (4-fluorophenyl) -lH-pyrazol-4-yl] -3-methylpyridine
Example A-259
4- [3- (4-fluorophenyl) -1-methyl-IH-pyrazol -4-yl] -3-methylp yridine
Example A-260
4- [3- (3, 4 -difluorophenyl) -l-methyl-lH-pyrazol-4-yl] -2-flu oropyridine
Example A-261
3- (4-fluorophenyl) -N,N-dimethyl-4- (4-pyridinyl) -IH-pyrazo le-1 -ethanamine
Example A-262
2- [2- (4-fluorophenyl) ethyl] -4- [3- (4-fluorophenyl) -1- methyl-IH-pyrazol -4-yl] pyridine
8ϋBSπTUTESHEET(RU E26) Example A-263
- [3- (4 -fluorophenyl) -IH-pyrazol -4-yl] -N- [1- (phenylmethyl) -4 -piperidinyl] -2 -pyridinamine
Example A-264
N' - [4- [3- (4 -fluorophenyl) -lH-pyrazol-4-yl] -2-pyridinyl] N,N-dimethyl-l, 2-ethanediamine
8yrøϊTUTE8HEEr(RUl£2 } Example A-265
2 , 4-bis [3- (4-fluorophenyl) -IH-pyrazol-4-yl] pyridine
Example A-2 6
N- [4- [3- (4 -fluorophenyl) -lH-pyrazol-4-yl] -2-pyridinyl] -4* morpholineethanamine
SUBSmUTESHEEr(RULE28) Example A-267
- (4-fluorophenyl) -4- (2-fluoro-4 -pyridinyl) -lH-pyrazole- -ethanol
Example A-268
- [3- (4 -fluorophenyl) -lH-pyrazol-4-yl] -N- [2- (IH-imidazol- -yl) ethyl] -2 -pyridinamine
SUBSπiUTESHEET(RULE8) Example A-269
4- [2- [3- (4 -fluorophenyl) -4- (2-fluoro-4 -pyridinyl) -IH- pyrazol -1-yl] ethyl] morpholine
Example A-270
(E) -3- (4-fluorophenyl) -4- [2- [2- (4-fluorophenyl) ethenyl] 4 -pyridinyl] -lH-pyrazole-1-ethanol
8UBSmUIE8HEEr(RULE2e) Example A-271
.
3- (4-fluorophenyl) -4- (2-fluoro-4 -pyridinyl) -N,N-dimethyl- lH-pyrazole-1-ethanamine
Example A-272
3- (4-fluorophenyl) -4- [2- [2- (4-fluorophenyl) ethyl] -4* pyridinyl] -lH-pyrazole-1-ethanol
8UB9mUTESHEET(R £26) Example A-273
4- [1- [2- (dimethylamino) ethyl] -3- (4-fluorophenyl) -IH- pyrazol-4-yl] -N,N-dimethyl -2 -pyridinamine
Example A-274
4- [1- [2- (dimethylamino) ethyl] -3- (4-fluorophenyl) -1H- pyrazol-4-yl] -N- [ (4-fluorophenyl) methyl] -2 -pyridinamine
SUBSΠTUTESHEEΓ(RU E26) Example A-275
3- (4 -fluorophenyl) -4- [2- [2- (4-fluorophenyl) ethyl] -4* pyridinyl] -N,N-dimethyl -lH-pyrazole-1-ethanamine
Example A-276
N- [ (4-fluorophenyl) methyl] -4- [3 (or 5) - (4-fluorophenyl) -1- [ [2- (4 -morpholinyl) ethyl] -lH-pyrazol-4-yl] -2 -pyridinamine
SUB$mUTESHE£T{RUtE26) Example A-277
4- [3- (4-fluorophenyl) -lH-pyrazol-4-yl] -N-4-piperadinyl-2* pyridinamine
Example A-278
N,N-diethyl-3- (4-fluorophenyl) -4- (2-fluoro-4 -pyridinyl] lH-pyrazole-1-ethanamine
a snτιπEStcEr(RϋLE2β) Example A-279
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) -lH-pyrazol-4-yl] -2- pyridinyl] amino] ethanol
Example A-281
2- [ [4- [3- (4-fluorophenyl) -1-methyl-IH-pyrazol-4-yl] -2- pyridinyl] amino] ethanol
8ϋBSmϋTESHEET(RϋUE26) Example A-282
3- [ [4- [3- (4-fluorophenyl) -lH-pyrazol-4-yl] -2* pyridinyl] amino] -1-propanol
Example A-283
3 (or 5) - (4 -fluorophenyl) -4- [2- [ [ (4- fluorophenyl) methyl] amino] -4-pyridinyl] -lH-pyrazole-1- ethanol
SϋBSTπi TESHEEr(raJUE26) Example A-284
N,N-diethyl-3- (4-fluorophenyl) -4- (4-pyridinyl) -1H- pyrazole-1-ethanamine
Example A-285
N- [ (4-fluorophenyl) methyl] -4- [3- (4-fluorophenyl) -1- [2- (4- morpholinyl) ethyl] -lH-pyrazol-4-yl] -2 -pyridinamine
Example A-286
N- [5- (4-fluorophenyl) -4- (4-pyridinyl) -lH-pyrazol-3-yl] -4* morpholinepropanamine
SUB3TTTUTESHEET(RULE26) Example A-287
N' - [5- (4-fluorophenyl) -4- (4-pyridinyl) -lH-pyrazol-3-yl] N,N-dimethyl-1 , 3-propanediamine
Example A-288
F
5- (4-fluorophenyl) -N-2 -propynyl-4- (4-pyridinyl) -IH- pyrazol -3 -amine
Example A-289
SUSSmUTESHEET (RULE26) - (4-fluorophenyl) -4- [2- [ [ (4-fluorophenyl) methyl] amino] -pyridinyl] -IH-pyrazole-1-ethanol
Example A-290
- (4-fluorophenyl) -4- [2- [ [ (4-fluorophenyl) methyl] amino] -pyridinyl] -lH-pyrazole-1-ethanol
Example A-291
- [3- [ (4-f luorophenyl) -lH-pyrazol-4-yl] quinoline
8UBSmUTESHEET(RaE26) Example A-292
N- [5- (4-fluorophenyl) -4- (4-pyridinyl) - IH-pyrazol -3* yl]glycine methyl ester
Example A-293
NH
HN-
C02H
N- [5- (4-fluorophenyl) -4- (4-pyridinyl) -IH-pyrazol -3* yl]glycine
Example A-294
4- [3- (4-fluorophenyl) -1- (2-propynyl) -lH-pyrazol-4* yl] pyridine
Example A-295
4- [5- (4-f luorophenyl) -1- (2-propynyl) -lH-pyrazol-4* yl] pyridine
Example A- 296
H
4,4'- (lH-pyrazole-3 , 4-diyl) bis [pyridine]
Example A- 297
8U8SπTϋTESHEET(RUE26) 4- [3- (3 , 4-dichlorophenyl) -IH-pyrazol-4-yl] pyridine
Example A-298
N-[ 5- C 4- c h I oropheny I ) - 4-
C4-pyrιdιnyl)-1H-pyrazol-3-yl]
-4-pιperιdιnamιne
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
2-Chloro-4- [3- (4-fluorophenyl) -IH-pyrazol -4-yl] pyrimidine
Step 1
SUrøπϋTESHEErCRDlESβ)
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! J£ fluorophenyl) ethanone
2- C 2- c h loro-4-pyr i ldi ny I}- 1- C 4- f I uoropheny I ^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
SUBSmTUTESHEEr(R £26) 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 5 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.
0 Step 3: Preparation of (E) -2- (2-chloro-4-pyrimidinyl) -3- (dimethylamino) -1- (4-fluorophenyl) -2-propen-l-one
C E3-2-C2-ch l oro-4-pyr ι m ι d ι ny l 3- 3-Cd ι methy l amι noD- 1-C4-f luoropheny l3-2-propen-ι-one
A mixture of the compound prepared in step 2 (4.7 g, 0.017 mol) in 100 mL of dimethylformamide dimethyl acetal 5 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.
0 Step 4: Preparation of 2-chloro-4- [3- (4-fluorophenyl) -
IH-pyrazol-4 -yl] yrimidine
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 5 was collected by filtration and air-dried to give 1.85 g of 2-chloro-4- [3- (4-fluorophenyl) -IH-pyrazol-4-
8UBSπTiπESHEEr(RυUE2β) yl] pyrimidine as a yellow solid, mp : 204-205 °C; Anal Calc'd for C13H8C1FN4: 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
4- [3- (4-fluorophenyl) -lH-pyrazol-4-yl] -2 (IH) -pyrimidinone hydrazone
A solution of the compound prepared in step 3 of Example A-299 (1.5 g) and hydrazine hydrate (5mL) 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) -lH-pyrazol-4-yl] - 2 (IH) -pyrimidinone hydrazone, as a pale yellow solid (38% yield), mp : 149-150 °C; Anal. Calc'd for C^H^FNg : C, 57.77; H, 4.10; N, 31.10. Found: C, 57.70; H, 4.31; N, 30.73.
8UrøTTUTESKEEr(RULE26) Example A-301
4- [3- (4-fluorophenyl) -lH-pyrazol-4-yl] -N,N-dimethyl- 2 -pyrimidinamine
Step 1 : Preparation of
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- F3- (4-fluorophenyl) - IH-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) -lH-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
8UBSπTϋTE8HEET(RυLE2β) 4- [3- (4-fluorophenyl] ■ lH-pyrazol -4 -yl ] -N-methyl -2 - pyrimidinamine
A suspension of 2-chloro-4- [3- (4-fluorophenyl) -IH- 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
4- [3- (4-fluorophenyl) -lH-pyrazol-4-yl] -N- (phenylmethyl) - 2 -pyrimidinamine
This compound was synthesize by refluxing 2-chloro- 4- [3- (4-fluorophenyl) -lH-pyrazol-4-yl] pyrimidine prepared in accordance with Example A-299 in benzylamine overnight. The product, 4- [3- (4 -fluorophenyl) -IH- pyrazol -4-yl] -N- (phenylmethyl) -2 -pyrimidinamine, was obtained as a white solid in 95% yield; mp : 216-217 °C;
SUBS!TrϋTE8HEEr(W JE2β) 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
N-cyclopropyl-4- [3- (4-fluorophenyl) -IH-pyrazol -4-yl] -2- pyrimidinamine
This compound was synthesized by stirring 2-chloro- 4- [3- (4-fluorophenyl) -lH-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) - IH-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.
SUBSΠTIΠE8HEEΓ(RULE26) Example A-305
4- [3- (4-fluorophenyl) -lH-pyrazol-4-yl] -N- [ (4- methoxyphenyl ) methyl] -2 -pyrimidinamine
This compound was synthesized by refluxing 2-chloro- 4- [3- (4-fluorophenyl) -IH-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 C21H18FN50: C, 67.19; H, 4.83, N, 18.66. Found: C, 67.01; H, 5.11; N, 18.93.
Example A-306
aUBST iTESHEEr(R JE2S) 4- [3- (4-fluorophenyl) -lH-pyrazol-4-yl] -2 -pyrimidinamine
A solution of 4- [3- (4-fluorophenyl) -lH-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) -IH-pyrazol -4-yl] -2 -pyrimidinamine, as a pale yellow solid (59% yield), mp : 273-274 °C; Anal. Calc'd for C13H10FN5-0.25 H20: C, 60.11; H, 4.07; N, 26.96. Found: C, 60.15; H, 3.82; N, 26.38.
Example A-307
N- [4- [3- (4 -fluorophenyl) -lH-pyrazol-4-yl] -2 -pyrimidinyl] - N- (phenylmethyl) acetamide
To a mixture of 4- [3- (4 -fluorophenyl)-IH-pyrazol-4- yl] -N- (phenylmethyl) -2 -pyrimidinamine prepared in accordance with Example A-303 (0.15 g, 0.00043 mol), DMAP
SϋBSmUTESHEETlRiΛ Se) (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 NaHC03, 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) -lH-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
Ethyl [4- [3- (4-fluorophenyl) -lH-pyrazol-4-yl] -2- pyrimidinyl] carbamate
To a suspension of 4- [3- (4-fluorophenyl) -IH-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
8UBBPπiUTE8lcεr(RϋlE26) 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) -lH-pyrazol-4-yl] -2- pyrimidinyl] carbamate, as a white solid (46% yield), mp : 163-165 °C; Anal. Calc'd for C16H14FN502 : C, 58.71; H, 4.31; N, 21.04. Found: C, 59.22; H, 4.51; N, 21.66.
Example A-309
4- [3- (3 -methylphenyl) -IH-pyrazol -4-yl] pyrimidine
This compound was prepared by the same procedure as described for Example A-208 except that l-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.
SUBSrnUmSHEET(RUL£26) Example A-310
4- [3- (4 -chlorophenyl) -IH-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-»0.25MH20: 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
4- [3- (3-fluorophenyl) -lH-pyrazol-4-yl] pyrimidine
This compound was prepared according to the chemistry described in Schemes VI and IX by selection of
SϋrøT TΞSHΞEr(RU E26) 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
4- [3- (4-fluorophenyl) -IH-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.
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:
8uBSnTUTESHEET(RULE2S)
4-[ 3-C4-ch I oropheπy I ) - 5- C 1-p i peraz i ny I ) - 1H-pyrazo I 4-y l]pyr imidi ne
1 - [ 5-C4-bromopheny I ) - 4-
C4-pyr idi ny I }-1H-pyrazo [ — 3 — y | ]p i peraz i ne
1-[4-C4-pyr i d I ny I } - 5- [4-Ctr if luoromethy I ] p he ny I ] ■
1H-pyrazol-3-yl]pιperazι ne
4-[5-C1-pιperazιnyl-4-ζ4-pyr idinyl) -1H-pyrazol-3-y l]benzonιtr ι le
SUBSniUTESHEEr(RUL£26)
1-[5-(4-ethyny Ipheny l)-4-(1-pyr idi ny I) -1H-pyrazol-3-yl]piperazine
5- C 4- f I uoropheny I 3-4- C4-pyridinyl)-N-3-pyrrol idiny 1H-pyrazol-3-amine
5-C4-ch I oropheny I ) - 4- C4-pyridinyl)-N-3-pyrrol idinyl 1H-pyrazo I - 3- am I ne
suesι ι?εs€Er(R JE2@)
N- [ 5- C 4- f I uoropheny I 3-4- (4-pyr idi ny I )-1H-pyrazo l-3-y I] -4-pιper ιdι namιne
3- C 4- f I uoropheny I 3-5- (1— iperaz i ny l 4- C4-pyr ιdιnyl3-1H-pyrazole- 1-ethano I
6UBSTΓΓUTESHEEΓ(RULE26)
3-(4-ch I oropheny I )- 5- —piperaz i ny I 3 - 4 - C4-pyrιdιnyl3-1H-pyrazole- -ethano I
4- [ -amι noethy l3-2-[4-f I uoro p e-ny I 3-4, 5, 6, 7- tetrahy ro-
3-C4-pyr idi ny l3pyrazo lo [ 1 , 5-a]pyr imi i n- 6- o I
4- [ 2-amι noethy l3-2-C4-ch loro phe-ny I 3-4, 5, 6, 7-tetrahydro- 3-C4-pyr i i ny l3pyrazo lo [1,5-a]pyr imidin-6-ol
3-C4-ch loropheny I 3~4~C4-pyr i m i d i ny I 3 ■ 1H-pyrazo le- 1-ethano I
6υBSπTϋTESHEET(RϋLE2β)
5- 4- f I uoropheny l3~4-C4-pyr i midi ny 1 - 1H-pyrazo I e-3-ethanamι ne
5-C4-chlorophenyl3-4-C4-pyrιmιdιnyl3- 1H-pyrazo I e- 3-ethanam i ne
4-[ 3- 4- f luoropheny l3-5-C4-pιper idi ny I 3 - 1H-pyrazol-4-y l]pyr imidi ne
4-[ 3-C4-ch I oropheny I 3-5-C -P i per i d i ny I • 1H-pyrazol-4-yl]pyr imidine
N-[4-[ 3-C 4-f I uoropheny l3-1H-pyrazo l-4-y I ] ■ 2-pyr i midi ny l]acetamι de
N-[4-[3-C4-chloropheny l3-1H-pyrazol-4-y l] 2-pyr i idi ny I ] ace t am i de
SUBSTTΓUTESHEEΓ(RULE26)
N-[4-[3-C4-f luorophenyl3-1H-pyrazol-4-y l] 2-pyr i midi ny Ipropanamide
N-[4-[3-C4-f I uoropheny l3-1H-pyrazol-4-y I ] ■ 2-pyr i midi ny l]propanamιde
3- £ 4- f I uoropheny I 3- H-pyrazo I -4-y I ] - 1H-pur i ne
g gSimiTESHEEriRϋtB
6- [ 3-C4-ch loropheny I 3- 1H-pyrazo l-4-y I ]- 1H-pur i ne
N-[4-[ 3-C4-ch loropheny l]-1H-pyrazo I -4-y I] 2-pyr imidi ny l]-N-Cpheny Imethy I )acetamι de
N-[ 4-[ 3- 4- f I uoropheny I 3- 1H-pyrazo I -4-y I ] - 2-pyr imidi ny l]-N-Cpheny Imethy I )propanam i de
SUBSTΠIΠESHEEΓ(RULE26)
N-[4-[ 3-C4-ch I oropheny I 3- 1H-pyrazo I -4-y I ] - 2-pyr i i d i ny l ]- N-Cpheny I methy I )propanam ide
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.l. 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 WI) , 2 μl of 50 mM dNTP's, 4 μl of 5X buffer, 2 μl of 100 mM DTT and 1 μl (200 U) of Superscript II ™ AMV reverse transcriptase. Random primer, dNTP's and Superscript TM reagents were all purchased from Life-Technologies, Gaithersburg, MA. 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 dH2θ, 2 μl 50 mM dNTP's, 1 μl each of forward and reverse primers
8UBSmUϊESHEET(RULE28) (50 pmol/μl) , 10 μl of 10X buffer and 1 μl Expand TM 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 f°r 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 ™ 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.
SUBST1TUTESH£ET(RU E26) 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 KC1 , 10 M Na2HP04, 1.8 mM KH2P04/ 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 X 1 minutes (pulsed) on ice. Lysed cell material was removed by centrifugation (12,000 x 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 x g, 5 min) and washed with 2 x 150 ml PBS/1% Triton X-100,
suesmurESHEεr(R JE26} followed by 4 x 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 x g, 5 min) and washed 2 x 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 0 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.
SUBSTTrUTE8HEET(RUUE26) 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
SUBSmUTESHEEr(RULE26) 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 lOOμM to O.OOlμM in 1% DMSO. Each concentration of inhibitor was tested in triplicate. Compounds were evaluated in 50μl 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, 50μM unlabeled ATP, 25 μg EGFRP (200μM) , 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 : l,p38 :MKK6) for one hour at 30 °C in the presence of 50μM ATP. Following incubation for 60 minutes at room temperature, the reaction was stopped by addition of 150μl of AG 1X8 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 50μl of clarified solution head volume was transferred from the reaction wells to Microlite-2 plates. 150μl of Microscint 40 was then added to each well of the Microlite plate, and the plate was sealed, mixed, and counted.
SϋBSTmπEStCET(R £26) TABLE 4
Example p38 kinase IC50 (uM)
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 x 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 x g for 10 minutes at room temperature. The cells were resuspended
8UBSπTUTE8HEEr(R .E26) 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. Supematants were then removed and tested by ELISA for TNF-a and ILl-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 Histiocvtic Lymphoma Cell Line:
U937 cells (ATCC) were propagated in RPMI 1640 containing 10% fetal bovine serum, 100 IU/ l 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 x 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
syasrnuTESHEEriwJtEse) 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.
8UBSmirrESHEEr(R -E26) TABLE 5
Example Human PBM Assay U937 Cell Assay IC50 (uM) IC50 ( (nM)
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
$UBSmUTESHEET(WJl£2β) 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
8UBSπTUTESHEEr(RULE28) 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.
gUBSntU ESHEETlW tESfi) TABLE 6
8UBSπTUTESHEETCRULE2β)
p38α in vitro assay results based on PHAS-I assay procedure p38α in vitro assay results based on EGFRP assay procedure
SUBSnTUTESHEET(RULE26) 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/l male mice by injection of 50 μg of chick type II collagen (CII)
(provided by Dr. Marie Griffiths, Univ. of Utah, Salt Lake City, UT) 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
SUBSπrUTESHEET(RULE26) 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 Q,
-*o 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
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
SυBSTTrUTESHEET(RULE2β) 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.
SUBSrmJTESHEET(R £26} 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
8UBSTmrrESHEET(R JE2e) 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.
SUBSπTϋTE8HEEr(RϋUE26) Description of parallel array synthesis methodology utilized to prepare compounds of Examples B-i, B-ii, and B-iii.
Scheme B-l 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 Bl. Each reaction vessel Bl 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
eUBSmUTESHΞΞT(RULE26) 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 Bl 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 BIO which houses the quadrant collection vial racks Bll. The desired products are obtained as filtrates in unique collection vials B9. Removal of solvent from these collection vials affords desired products.
8ϋBSπTϋlB8HEET(R JE26)
Scheme B-2 illustrates the various utilizations of functionalized resins to purify reaction vessel products B22 prior to filtration from the fritted vessels Bl into collection vials B9. Said functionalized resins perform as 1) resin-bound reagents B12, which give rise to resin- bound reagent byproducts B13 ; 2) sequestrants B14 or B15 of excess solution-phase reactants B16 or B17 , respectively. Solution-phase reactants B16 and B17 contain inherent reactive functionality -rfi and -rf2
8UBSrnimSHEET(R £28 which enable their chemoselective sequestration by the complementary reactive functionality -Crfi 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 -Cmr attached to resin B18; 4) reaction- quenching resins B20 which give rise to quenched resins B21. Resin B20 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) sequestrants 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-hmdered reactants and/or electron deficient nucleophiles, contain poorly sequestrable functionality
(rfl in this case is a poorly sequestable functionality) .
These poorly sequestable reactants B16 can be transformed in si tu to more robustly sequestrable species B27 through their reaction with sequestration-enabling-reagents B26. B26 contain highly reactive, complementary functionality Crfi which reacts with B16 to form B27 in situ . The
8U8STΠUΓESHEEΓ(RULE26) bifunctional molecular recognition functionality, mr, contained within B26 is also present on the in si tu derivatized B27. Both B26 and B27 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 .
8UBSmUTE$HEEr(R JE26) Scheme B-2
C
Denotes insoluble resin
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
8UB8fmUTESHEET(RuUE26) 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
SUBafTnUTE8HEET(RU E26) collection vial is prepared 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 #4DUP and #4TRIP 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 # VNlOO 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 .
8UBSnTUreSHEEr(RUL£26) 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 HP1100 MSD (G1946A) mass spectrometer; this unit is also equipped with a model# G1322A solvent degasser, model # G1312A binary pump, a model # G1316A column heater, and a model # G1315A diode array detector. The HP unit has been interfaced with a commercially available autosampler 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 (HPLC) 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
gyBSπTϋTE8*€ET(R £26 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.
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
SUrøπUTES»CEr(RυLE2β) 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 v2.2.2.1.0A. 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-F+ 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
8UBSπTUTESHEET(RϋUE26) declare the quantity of each component to be utilized. The quantity of each component can be identified by its molarity and volumetric amounts (ul) 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
@UBSrnUTESCET(RaE26) 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 uL, 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 compound's 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
8UBSΠTUΓESHEEΓ(RULE26) 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 robotics hardware by Bohdan Automation, Inc. Mundelein, Illinois, 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 functionality 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-QAs 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
8UBS !UϊESHEεr(RULES£} 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.
Scheme B-4
Scheme B-5 specifically illustrates the derivatization of the primary amine-containing scaffold Cl 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
8C©STπUTESHEET(RULE26) addressed format. A solution of the desired primary amine-containing scaffold Cl (limiting amount,) in dimethylformamide (DMF) is added to the reaction vessels followed by a 4.0 fold Ξtoichiometric 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 Ξtoichiometric 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 Cl 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 Cl 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 tranΞfer 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.
SUBS UTE»CEr(RUl£26) Scheme B-5
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,
ggBSπTϋTESHEEriRϋl£26) sulfonyl chlorides, activated esters of carboxylic acids, activated carbamates, and isocyanates . Reaction of Ξcaffold 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 R-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-phaΞe 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.
SUBSTWUTE8HEEr(F%Λ££6) Scheme B-6
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 Ξcaffold 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 Ξtoichiometric excess when R-Q is a Ξulfonyl chloride, or
1.25 fold Ξtoichiometric excess when R -Q is an isocyanate . The reaction mixtures are incubated at
8UBSΠTUTESHEEΓ(RULE26) ambient temperature for 2-6 h. Each reaction vessel is then charged with a large excess (15-20 fold stoichiometric excess) of the amine-functionalized resin B33 and the isocyanate-functionalized resin B32. The i 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 theΞe 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.
aUBSmUTE8HEEr(RUlE26) Scheme B-7
B39 B36
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 excesΞ of an optionally unique electrophile RL-Q into each vessel. Reaction of scaffold C-ii with R-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.
gUβgiπUlESHEEURUUi*) 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 sequeΞtration- enabling reagent phenylsulfonylisocyanate B41. This reagent B41 reacts with remaining secondary amine scaffold C-ii, converting C-ii to the in si tu-derivatized compound B42. SubΞequent incubation of these vessel mixtures with a large excess (15-20 fold stoichiometric excess) of the amine-functionalized resin B33 sequesters the solution-phaΞe species RL-Q, HQ, B41, and B42 as the resin-bound adducts B40, B36, B44 , and B43, respectively. The resin-charged reaction block is Ξhaken 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.
SUBSnrnUTESHEEr(RULE26) Scheme B-8
B44
Scheme B-9 illustrates the method of Scheme B-8 using scaffold C-2. A solution of the scaffold C-2 (limiting
8UBSπTUTESHEET(RU E26) 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 Ξtoichiometric excess is used when R-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 si tu-derivatized compound B45. Subsequent incubation of these vessel mixtures with a large excess (15-20 fold stoichiometric excess) of the amine-functionalized resin B33 sequeΞters the solution- phase species RL-Q, HQ, B41, and B45 as the resin-bound adducts B40, B36, B4 , 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 filtrateΞ containing the purified productΞ B-ii. Concentration of the filtrates affordΞ the purified products B-ii.
SUBSmUTESHEET(RU-E26)
B44
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
8UBSTOnESHEEUBUl£«) 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 sequeΞtration-enabling-reagent B50 ( fcetra- fluorophthalic anhydride) . The reagent B50 reacts with remaining excess amine B47 to afford the in si tu- 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, B50, and any remaining acid Ξcaffold C-iii as resin-bound adducts B52 , B53, and B54, respectively. Filtration of soluton-phase products B-iii away from these resin-bound adducts and rinsing of the resin beds with a polar aprotic Ξolvent and/or halogenated solvent affordΞ filtrateΞ containing purified products B-iii. Concentration of the filtrates affords purified B-iii.
Scheme B-10
B 7
C-iii
B-iii
(remaining)
8UBS rTUTESHEET(Rϋ E26) Scheme B-ll illustrates the conversion of the acid containing scaffold C-49 to the desired amide products B- iii in a parallel ΞyntheΞiΞ format. A limiting amount of the scaffold C-49 is added as a Ξolution 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 Ξolution of a unique amine B47 (1.5 fold Ξtoichiometric excess) to each vessel . The parallel reaction block is then agitated vertically on an orbital Ξhaker 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 reΞulting solutions (filtrates) containing a mixture of the desired amide products B-iii, excess amines B47 and any unreacted acid containing Ξcaffold C- 49, are treated with tetrafluorophthalic anhydride B50. B50 convertΞ the excess amines B47 in each filtrate vessel to its respective sequeΞtrable 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 adductΞ 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
-SUBSrmjI£SHEET(RULE26) dimethylformamide affords filtrates containing the purified products B-iii. Concentration of the filtrates affords the purified products B-iii.
amSTI UTE8HEEr(RϋL£26) Scheme B-U
NH2
B33
B52
Although Schemes B-l through B-ll 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 clasΞical Ξynthetic organic chemiΞtry 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 cryΞtallization) .
A general ΞyntheΞis of pyridylpyrazole scaffolds C-i, C- ii, and C-iii is depicted in Scheme C-l.
Step A: Picoline iΞ treated with a baΞe chosen from but not limited to n-butyllithium (n-BuLi) , lithium di-iso- propylamide (LDA) , lithium hexamethyldisilazide (LiHMDS) , potasΞium 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 Ξolution iΞ then added to a Ξolution 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.
8UBSTΠUTESHEEΓ(RULE26) 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 hourΞ . An appropriately ΞubΞtituted activated ester or acid halide derived from R4-C02H is then added as a solution in THF, ether, or dioxane to the monoketone anion of B57 while the temperature iΞ maintained between -50 °C and 50 °C . The reΞulting mixture iΞ allowed to Ξtir at the specified temperature for a period of time from 5 minutes to three hours. The reΞulting 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 adjuΞted to between 4 and 8 utilizing an inorganic or organic acid chosen from HOAc, H2S04, HCl, or HN03. The temperature during this Ξtep 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) nC02alkyl wherein Q is halogen. C-i or C-ii is treated with a baΞe chosen from NaH, NaOEt, KOtBu, or NEt3 in an organic solvent such as THF, methylene chloride, dioxane, or DMF at temperatures
between -20 °C and 150 °C and reaction times between 30 minuteΞ and 12 hours . The reΞulting alkylated pyridyl pyrazole ester iΞ 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 productΞ C-iv are alΞO formed. The desired C-iii can be separated away from C-iv by chromatographic purification or by fractional crystallization.
SUeSffmJTESHEET(RULE26) Scheme C-1
B56
StepB 1) Base
2) XCOR4
C-iii C-iv
A ΞyntheΞiΞ of pyridylpyrazole Ξcaffold C-1 is depicted in Scheme C-2.
Step A:
8 BSfi πE8t€ET(RϋLE2β) Picoline is added to a Ξolution of LiHMDS in THF at room temperature over a time period ranging from 30 minutes to 1 hour. The resulting solution is Ξtirred 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 waΞhed with cold hexanes leaving the pyridyl monoketone B61 for use in Step B. Step B:
The pyridyl monoketone B61 iΞ 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 iΞ adjuΞted to between 6 and 7 with acetic acid. Hydrazine hydrate iΞ then added dropwise to the mixture as a solution in water over 30 minutes to lh 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
8UBSrmUTESHEET(RULE26) silica gel chromatography, giving rise to purified C- lCbz.
Step: D
The Cbz protecting group contained in compound C-lCbz is cleaved using hydrogen gaΞ under pressure and Pd-C in methanol Ξolvent. The resulting amine C-1 is obtained by filtration and concentration.
8U8SimjT£SHEET(R JE26) Scheme C-2
8UBSTTTUTESHEET(RULE26) A number of pyridyl pyrazole ΞcaffoldΞ 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 iΞ then added to a Ξolution of an appropriately activated ester analog of a carboxylic acid CbzNRH-(CH2) nCRF (RG) -C02H or BocNRH-(CH2) nCRF(RG) -C02H, 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, 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. The anion sometimeΞ precipitateΞ 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 Ξpecified temperature for a period of time from ranging from 5 minuteΞ to 3 hourΞ . The resulting pyridyl diketone intermediate B67 is utilized without further purification in Step C.
Step C: The Ξolution 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, H2S04, HCl, or HN03. The temperature during this step iΞ 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 iΞ 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 scaffoldΞ 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 hourΞ . The CBZ carbamate protecting groupΞ are cleaved UΞing hydrogen gas under pressure and Pd-C in an alcoholic solvent. The resulting amines C-v are then optionally crystallized or purified by chromatography.
SUBSππTUTESHEEr(RULE26) Scheme C-3
C-v
8UBSmiUTESHE£r(RULE26 The ΞyntheΞiΞ of scaffolds C-vi is accompliΞhed 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 Ξtirring iΞ continued for several hours. The mixture iΞ then quenched with acid and allowed to warm to room temperature and Ξtirred 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 .
aβgmuiEaeEURUtE*) Scheme C-4
B68 B69
C-vi
The synthesiΞ of maleimide-containing Ξcaffolds C-vii is accomplished as shown in Scheme C-5.
The maleimide pyrazole scaffolds C-vii are synthesized as depicted in scheme C-5. CondenΞation 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)
&JBSm!fϊESHEEr(RUl£28) catalyst and base to afford compound B73. The methylene poΞition of B73 i 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.
Scheme C-5
B70 (X is chloro, bromo, or triflate)
B75
Scheme C-6 illustrates the syntheΞis of the maleimide pyrazole scaffold C-63 wherein R4 i hydrogen. The Ξynthesis 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
SUBSOTTUTESHEET(RULE26) Pd2(dba)3 and sodium t-butoxide to form the fluoroacetophenone substituted maleimide B79. The B79 is treated with tert-butoxybi (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.
Scheme C-6
NHoNH,
Scheme C-7 illustrates the synthesiΞ of maleimide- containing ΞcaffoldΞ C-64 and C-65. TheΞe ΞcaffoldΞ C-49 and C-50 are ΞyntheΞized according to the general methodΞ
8UB3 UTE8HEEr(RϋiJE2ø) illuΞtrated in Scheme C-5 and exemplified with the utilization of N-hydroxyΞuccinimides B82 and B83 to afford the maleimide-containing pyrazoleΞ B86 and B87 , reΞpectively . Optional removal of the 2,4- dimethoxylbenzyl groupΞ with CAN and ΞubΞequent removal of the Boc-protecting groups with trifluoroacetic acid (TFA) affordΞ the Ξcaffolds C-64 and C-65.
Scheme C-7
8UB3i IE8HEEr(RULE26) 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.
B32 4-benzyloxybenzaldehyde functionalized polystyrene. Novabiochem cat. #01-64-0182
B33 Prepared as reported in D. L. Flynn et al,
J. American Chemical Society (1997) H9, 4874-4881.
Methylisocyanate functionalized polystyrene.
B38 Λ Novabiochem cat. # 01-64-0169 l\F=C=0
B48 , prepared as reported Tetrahedron Letters
Benzenesulfonylisocyanate, purchased from Aldrich Chemical Company. Cat# 23,229-7
Tetra-fluorophthalic anhydride, purchased
B50 from Aldrich Chemical Company. Cat # 33,901-6
Experimental procedure for the parallel synthesis of a series of amides, carbamates, ureas and sulfona ides 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 Ξolution of the chloroformates in dichloroethane or c) 313 uL of a 0.2 M Ξolution of the iΞocyanates 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
8UaSTπϋTESHEET(RaE26) 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 polyalde yde resin B32 (2.9 mmol/g resin). Each reaction vessel was diluted with 1 mL dimethylformamide and 1 L 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 Ξeparated from the inΞoluble quenched byproducts by filtration and collected in individual conical vialΞ . Each vessel was rinsed twice with dichloroethane (1 mL) and the rinsings were alΞo 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.
-mggfπϋ!E8HEEr(RUlE2β
_ . . Observed -, ... . ■ alcd. .. _
Example* R %Yιeld .. _ Mass Spec Mass Spec (||+|JJ
SUBSffmπESHEEURULESβ) _ , , Observed Calcd.
Example* %Yield .. _ Mass Spec Mass Spec (M+H)
iUBSπiUIESHEEI(RUEa) _ , . Observed Calcd.
Example* R %Yιeld .. _ Mass Spec Mass Spec ... JT (M+H)
8UBSTmJϊESHEEr(RUt£26) Observed
Example* %Yield ,, _ ' Mass Spec Mass Spec ... JT (M+H)
8UDSmHE8HEEr(RULE20 _ . . Observed
Example* « «»■ ■ . Calcd. .. _ %Yιeld ,. _ Mass Spec Mass Spec (M+R)
8ϋBSTπUTESHEEr(RlΛ£a) _ , . Observed Calcd.
Example* %Yield ,, _ Mass Spec Mass SDΘC μ (M+H)
By analogy to the procedure identified above for the preparation of Examples B0001-B0048, the following examples B-0049 through B-1573 were prepared.
gϋBSπTUTESkCEriRϋlESβ) 52940
334
Example*
_ , . Observed -., .-■ ■ . Caicd. .. _ %Yιeld .. _ Mass Spec Mass Spec (M+H)
røπιuιε8ic r(RϋLE2B) 2940
335
Example*
Observed
%Yield „ ° Mass Spec Mass Spec (|j|+H)
SUBsπnjrESHEEr(RaE2β) 52940
336
Example* r Observed
%Yield ,_ ' Mass Spec
Mass Spec
H (M+H)
ajBgrm SHEεr(RUL 26) Example*
_ . , Observed Calcd. %Yιeld ., _ Mass Spec Mass Spec (M+H)
8UBSπnπE8HEEr(RϋLE26) 52940
338
Example*
_ . . Observed Calcd. %Yιeld ., _ Mass Spec
MaSS SpθC (M+H)
83Tπ ESH T(R'JLE 6) 52940
339
Example*
_ . , Observed „, .,. . , Calcd.
%Yιeld .. __ Mass Spec Mass Spec
Example*
_ , . Observed Calcd. %Yield .. _ Mass Spec Mass Spec ^
yggjjjyjESHEETCRULEaδ) Example*
Observed
%Yield .. _ ' Mass Spec Mass Spec (M+H)
SUBSππJ E8HEET(RULE26) Example*
Observed
Calcd.
Rz %Yield Mass Spec Mass Spec
(M+H)
βesπ fεδi€ErcR ai Example*
_ , , Observed Calcd. %Yield ., _ Mass Spec Mass Spec (||+H)
8UBSΠ UFTE8HEEΓ(RULE26) Example*
Observed
%Yield .. A Mass Spec Mass Spec (M+| )
SiBSTlUTE8HEET(RiJE26) Example*
_ , , Observed Calcd. %Yield .. _ Mass Spec Mass Spec (|jW|)
SUBSmureSHEET(RULE26)
_ , . Observed Calcd.
Example* %Yield .. _ Mass Spec Mass Spec (M+| )
SUeSffifUTESHEET(RULE26) Observed
Example* %Yield .. A Mass Spec Mass Spec (M+H)
8UBSnUnE8HEET(RULE26) Observed
Example* R2 %Yield .. _ ' Mass Spec Mass Spec (M+H)
8UB3πnπESHEεr(RUiJE2β) Observed
Example* %Yield ., caic°- Mass Spec Mass Spec (M+H)
$UB8πτrUTESHEEr(RULE26) Observed
Example* %Yield „ A Mass Spec Mass Spec (M+H)
$UBSmnreSHEEr(RULE26) _ , , Observed Calcd.
Example* R %Yιeld .. „ Mass Spec Mass Spec (||+|JJ
8ϋB8Tπ TE8tCEr(RϋLEiS)
Observed
Example* RJ %Yield .. „ ' Mass Spec Mass Spec (M+H)
ayB8τπuiE8i€Er(RyiEgi _ . . Observed Calcd.
Example* R %Yield .. _ Mass Spec Mass Spec (M+| )
SUBSTπUTESHEET(Rϋ E26) _ , . Observed Calcd.
Example* R %Yιeld .. _ Mass Spec Mass Spec (M+H)
_ , , Observed Calcd.
Example* R %Yield .. _ Mass Spec Mass Spec (|y|+H)
8UBSnnnE8HEET(R JE26)
_ . . Observed Calcd.
Example* %Yιeld .. „ Mass Spec Mass Spec (M+H)
aggπwrneHEEURWE*) _ . . Observed ., . . . Calcd. .. _
Example* %Yιeld .. _ Mass Spec Mass Spec (|y|+H)
guagrmπESHEEURuiEsβ) 35i
Observed
Example* R: %Yield ,. a (y' Mass Spec Mass Spec (M+R)
-M$nTU]£SHEET(RULE26) Observed
Calcd.
Example* R: %Yield Mass Spec Mass Spec
(M+H)
SUBSTmπE8HEET(R JE2β) Observed
Example* R %Yield .. A Mass Spec Mass Spec ... JT (M+H)
SUBSTπiπE8HEEr(R JE2β
_ , _, Observed Calcd.
Example* %Yιeld .. _ Mass Spec Mass Sϋec
H (M+H)
8UBSmυTESHEEr(RULE2β) _ , , Observed Calcd.
Example* %Yield ., _ Mass Spec Mass Spec ... JT (M+H)
_ , . Observed Calcd.
Example* %Yield .. _ Mass Spec Mass Spec (||+H)
SlBSTmπESHEET(RULE26) Observed
Calcd.
Example* %Yield Mass Spec Mass Spec
(M+H)
SUBSπTtπE8HEEr(RULE£β _ , . Observed Calcd.
Example* R %Yιeld .. „ Mass Spec Mass Spec (||+|JJ
SUBSTI7UTESHEEΓ(RULE26)
_ . , Observed Calcd.
Example* %Yield .. _ Mass Spec Mass Spec (M+H)
&βS!BUmδHEEr(RULE&l) _ . , Observed Calcd.
Example* %Yield .. _ Mass Spec Mass Spec (M+H)
$UeSTTrUTESHECT(RULE26) Observed
Example* %Yield .. _ ' Mass Spec Mass Spec (M+H)
SϋBS UTESHE£T(RU£26) Observed
Example* %Yield _, Mass Spec Mass Spec ^
SUBarTTTU7ESHEEr(RULE26) _ , , Observed Calcd.
Example* %Yield .. . Mass Spec Mass Spec ... JT (M+H)
SU8SmϋTE8HEEr(R JE26) Observed
Example* R %Yield .. A Mass Spec Mass Spec (M+H)
8UBSTITUrε8HEEr(RULE2β)
__. , __, Observed Calcd.
Example* %Yield ., _ Mass Spec Mass Spec (M+||)
aBSdmflESHEET(RULEfi6) Observed
Example* %Yield .. "I Mass Spec Mass Spec (M+H)
βϋBOTUTESHEET RϋlB∑β) Observed
Example* %Yield .. Ca{c°- Mass Spec Mass Spec (M+H)
8UBSr πE8HEET(RϋLE£6 Observed
Example* %Yield ,. ° Mass Spec Mass Spec (ft/|+H)
8 KTπUTESHEET(RULE26)
Observed
Example* %Yield .. ^ Mass Spec Mass Spec (M+H)
SUBSflπUTESKEET(RULE26) Observed
Example* %Yield .. ° Mass Spec Mass Spec (|y|+H)
SUBSπTrUTESHEET(RULE26) 37£
_ . . Observed Calcd.
Example* %Yield ,. . Mass Spec Mass Spec (M+H)
8UBSπTUrrEδHEET(RϋLE26) „ . . Observed Calcd.
Example* RJ %Yield ,. „ Mass Spec Mass Spec μ (M+H)
Observed
Example* %Yield .. _ ' Mass Spec Mass Spec (M+| )
SU8SmUTESHEEr(RULE26)
_ . . Observed « »»■ . . caicd. .. _
Example* R %Yιeld .. _ Mass Spec Mass Spec (M+H)
sϋBSπTUTESHEET(RϋLE2fl) _ , . Observed Calcd.
Example* R2 %Yield ,. _ Mass Spec Mass Spec
Observed
Calcd.
Example* %Yield Mass Spec Mass Spec
(M+H)
8UBSmiiTESHEET(RUL£26) Observed
Example* %Yield ., _ ' Mass Spec Mass Spec (|y(+H)
SϋBSTπUTE8HEET(RU Eβ6
Observed
Calcd.
Example* R %Yield Mass Spec Mass Spec
(M+H)
βurømπE8HEEr(RULE8i) _ . . Observed Calcd.
Example* %Yield .. _ Mass Spec Mass Spec (||+H)
SUBSmUTE8HEET(RULE26 _ . . Observed Calcd.
Example* %Yield .. _ Mass Spec Mass Spec
(M+H)
6UBSmUTESHEEr(RULE£6) _, , . Observed Calcd.
Example* %Yιeld .. „ Mass Spec Mass Spec (M+R)
SlBSnTUTE8HEEr(RUL£26)
_ , _, Observed Calcd.
Example* %Yιeld .. _ Mass Spec Mass Spec (M+H)
Sl SmaTESHEET(RULE26) _ , . Observed Ca cd.
Example* %Yield .. " Mass Spec Mass Spec
SUBSmWESHEET(RULE2e) _ . . Observed
Example* . %..Y...ιel ■d_■ .. Calc _d. . M.ass S _pec Mass Spec (M+H)
8ϋB5ϊmrrE8HEET(RULEfiβ) _ . . Observed Calcd.
Example* %Yιeld .. _ Mass Spec Mass Spec (|y|+H)
Observed
Example* R %Yield .. A Mass Spec Mass Spec (M+H)
8ϋBδπnHE8HEEr(RUUE2β)
_ . . Observed Calcd.
Example* %Yield ,. _ Mass Spec Mass Spec ^
SUBSTrrαTESHEEr(FlϋL££β) _ . . Observed
Example* - %,Y.ιe ■ld ■ ., Calc _α. . M.ass S _pec Mass SDΘC μ (M+H)
SU8STTrUTESHEET(RULE£6) Observed
Example* %Yield .. _ " Mass Spec Mass Spec (|/|+H)
8UB8flmRflESHEET(RUJE&6) _ , . Observed Calcd.
Example* %Yield ., _ Mass Spec Mass Spec {M .
SUBSπTUTESHEET(RULE£β)
Observed
Calcd.
Example* %Yield Mass Spec Mass Spec
(M+H)
SUΘSmU1E8HEET(RU£&9 Observed
Calcd.
Example* %Yield Mass Spec Mass Spec
(M+H)
SϋBSTπUTESHEET(RUlE£6) Observed
Example* %Yield .. _ ' Mass Spec Mass Spec (M+H)
®jBg ϋTE8»CEr(RUUEββ) _ . . Observed Calcd.
Example* %Yield .. _ Mass Spec Mass Spec
SUBSTITlJTESHEEr(RULE£6) _ , , Observed Calcd.
Example* %Yield ,, _ Mass Spec Mass Spec (M+| *
SUBSnrUTESHEET(RULE£6)
_ , . Observed Calcd.
Example* R %Yield .. _ Mass Spec Mass Spec
SUBSTrrϋTESHEEr(RULEfiβ) _ . . Observed
Example* », w ■ i Calcd. .. _. %Yιeld ,. _ Mass Spec Mass Spec (M+H)
SUBSTrrUTESHEET(RULE£6> _ , , Observed Calcd.
Example* %Yield ., _ Mass Spec Mass Spec (M+H)
SUBSTlTUTESHEEr(RU E£6) _ , , Observed Calcd.
Example* %Yιeld ., _ Mass Spec Mass Spec (||+| )
_ . __, Observed Ca cd.
Example* %Yield .. A. Mass Spec Mass Spec (M+H)
Observed
Example* %Yield .. _ ' Mass Spec Mass Spec (M+H)
8UBSi nE8HEET(RUL£eS) _ . . Observed
Example* « %, ,Y»•ιe .ld.. ,. Calc _d. . M.ass S _pec Mass Spec (||+H)
SϋBSTmXΪE8HEεr(RϋLE£β) _ . . Observed - %.,Y ...ιel ■d i ,. caic
Example* _d. . M.ass S _pec Mass Spec ... JT (M+H)
Sl®S(πiiπE8HEEr(RlAEβ6
_ . . Observed „, ■.#■ i ■ Calcd. . . _
Example* R %Yιeld .. _ Mass Spec Mass Spec (||+H)
SUBSTrTUTESHEEr(RULE26) _ . . Observed Calcd.
Example* %Yield ., _ Mass Spec Mass Spec (ft/|+H)
sϋBSrrϊUTESHEET(R £2β) _ . . Observed „,«,■ ■ ■ Calcd. .. _
Example* %Yιeld .. „ Mass Spec Mass Spec ... JT (M+H)
Observed
Example* %Yield .. _ ' Mass Spec Mass Spec (M+H)
___ , . Observed Calcd.
Example* R %Yield ., _ Mass Spec Mass Spec (M+H)
SUBSn7UTESHEET(RULE26)
_ , , Observed Calcd.
Example* RJ %Yield .. _ Mass Spec Mass Spec (||+||)
8ϋBSTπUTESt«Er(R £26) Observed
Calcd.
Example* %Yield Mass Spec Mass Spec
(M+H)
Sl®SrπUTESHEET(RϋLE26) _ , . Observed Calcd.
Example* R %Yield ., _ Mass Spec Mass Spec (|/|+H)
_ , . Observed Calcd.
Example* %Yιeld .. _ Mass Spec Mass Spec (M J
slBSrnUTESHEEr(RUl£26) _ . . Observed Calcd.
Example* %Yield ., _ Mass Spec Mass Spec (||+||)
_ . . Observed Calcd.
Example* %Yield „ _ Mass Spec Mass Spec ^
SUBSπTϋTESHEET(RUl£26) _ , , Observed Calcd.
Example* %Yield ,. _ Mass Spec Mass Spec (M+H)
SUBSTπϋTESHEΞT(R .E26) _, , , Observed Ca cd.
Example* %Yield .. ^"l"- Mass Spec Mass Spec (M+H)
SlBSmUlESHEET(RULE26) Λ , , Observed Calcd.
Example* R: %Yield .. _ Mass Spec Mass Spec (M+H)
SU8SffϊTUTESHEET(RULE26) _ , . Observed Calcd.
Example* R %Yield .. _ Mass Spec Mass Spec ,,, JT (M+H)
8ϋBSmϋTESHEEr(RULE2β)
Observed
Example* %Yield .. AT Mass Spec Mass Spec (|y|+H)
gyggπTUTESHEETCB JESβ _ . . Observed Λ, w ■ ■ Calcd. .. _
Example* R2 %Yιeld .. _ Mass Spec Mass Spec (M+H)
Sl©SmUTE8HEET(RUJE26) Observed
Example* %Yield ,. Caic°- Mass Spec Mass Spec ... JT (M+H)
SUBSTΠUTESBEET (RULE26) _ , , Observed Calcd.
Example* %Yιeld .. _ Mass Spec Mass Spec {M+H)
SϋBSTrτϋTESHEEr(aa£2β)
___ . , Observed Calcd.
Example* R %Yield .. _ Mass Spec Mass Spec (| |+H)
Observed
Example* %Yield .. a c_ ' Mass Spec Mass Spec (M+H)
SUBSTΠUTESHEEΓ(R JE26) _ , . Observed Calcd.
Example* %Yield .. _ Mass Spec Mass Spec (ft/|+H)
SUBSTrrUTESHEETCRUJEae) _ , . Observed ~, ... . . caicd. .. _
Example* %Yιeld .. _ Mass Spec Mass Spec (M+H)
SUBSπTUTESHEET(RUUE26)
Observed
Example* R2 %Yield ,, Mass Spec Mass Spec (M+H)
SU8STϊTl!ΪESHEEr(RUUE2β) κ35
_ , . Observed „,w ■ . Calcd. -. _
Example* %Yιeld .. _ Mass Spec Mass Spec (M+H)
8ϋBSπ TESHEET(RUiH2β)
_ , . Observed Calcd.
Example* %Yield .. _ Mass Spec Mass Soec μ (M+H)
SUBg WESHEET(RULEi
Observed
Example* R2 RJ %Yιeld ,, ^ Mass Spec Mass SDΘC μ (M+H)
SUBSTrrUTESHECT(RϋLE26) Observed
Example* R2 %Yield .„ caic°- Mass Spec Mass Spec (M+H)
Observed
Example* %Yield .. _ ' Mass Spec Mass Spec (M+ |)
_ . . Observed Calcd.
Example* %Yιeld ,. _ Mass Spec Mass SDΘC μ (M+H)
gUOOTfrϋTE €E CR Eaβ _ . . Observed -, .,. ■ ■ caicd. .. _
Example* RJ %Yιeld „ ._ Mass Spec Mass Spec ... JT (M+H)
SUBSTnUTESHEET(RULE26) _ . . Observed Calcd.
Example* %Yield .. _ Mass Spec Mass SDΘC μ (M+H)
SUBSTrrUTESHEETCRUlEaβ
. . ... Observed
Example* « «• .J Calcd. Mass ,, _
%Yιeld „ Mass Spec
SpβC (M+H)
SUBSTπUTESHEEr(RULE2β) - . .. .. Observed Calcd. Mass
Example* %Yield _ Mass Spec
SpβC (M+H)
SUBSnTUTESHEET(RULE£β) - . -, .. Observed
Example* , %,,«Y•ιe .ld-. Calc _d. Mass , M.ass S _pec
SPΘC (M+H)
8UBS UTESHEETCRULE26) ~ .
„,,,. , , Cal
Example* %Yιeld
- . . .. Observed
Example* % -,-Y.■ιe .ld-. Calc _d. Mass . M.ass Spec
SpΘC (M+H)
8UBSTπυTESHEET(RULE26) „, »,. .J Calcd. Mass .,
Example* %Yιeld Mass Spec
P6C (M+H)
suesτ
_, . __, Observed Calcd.
Example* %Yield .. „ Mass Spec Mass Spec (||+H)
8UBSπτUTE8HEEr(B,ΛE2β> _ . . Observed Calcd.
Example* R* %Yield ., _ Mass Spec
Mass Spec (M+||)
gUBSTmJTESHΞET(RULE£β) _ , . Observed Calcd.
Example* RJ %Yield ., „ Mass Spec
Mass Spec (M+||)
SUBSTTrUTESHEET(RUJE26) _ . . Observed Calcd.
Example* RJ %Yield ., _ Mass Spec
Mass Spec (M+H)
SU83TnUTE8HEEr(RULE26)
~ . .. .. Observed
Example* %Yield Ca,cd Mass Mass Spec SpeC (M+H)
8ϋBSmϋTESHEET(RϋLEδβ) Observed
Calcd. Mass
Example* %Yield Mass Spec Spec
(M+H)
sϋBSmuτE^ECTC^ ^2β) - . m, .. Observed
<>, «• ... Calcd. Mass .. _
Example* %Yιeld „ Mass Spec
SpβC (M+H)
SUBSππXTESHEETCR JE2β) ~ . J .. Observed Calcd. Mass
Example* %Yield ,_ Mass Spec
SpβC (M+H)
SUBSnTUTESH£ET(RULE£6) -. . . .. Observed
Example* „, .,. ... Calcd. Mass .. „
%Yιeld _ Mass Spec
SpβC (M+H)
SUBSTlTUTESHEEr(RULE2fl)
~ . -. .. Observed o, w ... Calcd. Mass ..
Example* %Yιeld _ Mass Spec
SPΘC (M+H)
« . _... Observed
Example* „,»,- ... Calcd. Mass ., „
%Yιeld _ Mass Spec
SpeC (M+H)
8UBSTrrUTESHEET(RULE2β) - . . .. Observed Calcd. Mass
Example* %Yield _ Mass Spec
SpβC (M+H)
- . J .. Observed
Calcd. Mass
Example* R %Yιeld _ Mass Spec
Spec μ (M+H)
$UBSnTUTESHEET(RULE26)
_ . . ,, Observed
Example* %Yield Calcd Mass Mass Spec SPΘC (M+H)
SUBSTnrUTES€ET(RULE26) - . _. .. Observed
„,„■ ... Calcd. Mass ..
Example* %Yιeld _ Mass Spec
SPΘC (M+H)
SUBSrmjTESHEETCRULE26) - . m, .. Observed
Example* - %,, Y.,ι■el .d-. Calc _d. Mass , M.ass S _pec
SpβC (M+H)
SUBSTΪTUTESH£Er(RULE.26) - . m, .. Observed
.>,.,. . . Calcd. Mass ..
Example* %Yιeld _ Mass Spec
SPΘC (M+H)
8UBSπTUTESHEETCRULE26)
_ . . „ Observed Calcd. Mass
Example* %Yιeld _ Mass Spec
SpβC (M+H)
8ϋBSnTϋTΕSHEET(RULE26) - . J .. Observed
„,»,. ... Calcd. Mass ..
Example* %Yιeld _ Mass Spec
SpβC (M+H)
SUBSTiππESHEEr(RULE26) C -a .lcd ... . M.ass Observed
Example* RJ %Yield _ Mass Spec
SpβC (M+H)
SUBSΠTUTES^EEΓ(RU E26) - . . .. Observed
Example* - %,Y.,■ιe .ld.. Calc _d. Mass , M.ass Spec
SpeC (M+H)
SUBSπTU71SHEEr(RULE26) - . -, .. Observed Calcd. Mass
Example* R %Yιeld _ Mass Spec
SpeC (M+H)
SUBSTTFUTESHEET(RULE26)
_ , . Observed Calcd.
Example* %Yield .. _ Mass Spec Mass Spec ... JT (M+H)
8UBSmU 8HEEr(Rϋi£2e) ._ . __. Observed
Example* m., ... . . Calcd. .. Λ %Yιeld .. _ Mass Spec Mass Spec ... JT (M+H)
SUBgπTUTESHEEr(RULEaβ) _ . . Observed .., ... . . Calcd. .. _
Example* %Yιeld .. _ Mass Spec Mass Spec JT
(M+H)
8UBSTrrUTESHEET(RULE26) Observed
Example* %Yield .. A Mass Spec Mass Spec (ft/|+H)
SUBSTTTϋTESHEErCRUΕaβ)
_ , , Observed Calcd.
Example* %Yιeld .. „ Mass Spec Mass SDΘC μ (M+H)
SUBSTrarTESHEET(RU£26) _ , , Observed Calcd.
Example* %Yield ,. _ Mass Spec Mass Spec ... JT (M+H)
QyBSrnUTEStCETCRULE _ . . Observed Ca cd.
Example* %Yield ,, JJ Mass Spec Mass Spec (M+H)
SUBSTITUTESHEET(RϋLE26) Observed
Example* %Yield .. A Mass Spec Mass Spec ... JT (M+H)
_ , , Observed Calcd.
Example* %Yield .. _ Mass Spec Mass Spec (M+R)
SUBSTrrUTESHEET(RUJE26) q-oi
Observed
Example* %Yield .. „ Mass Spec Mass Spec (M+H)
SU*BSTrrUTESHEEr(RULE£6) Observed
Example* %Yield .. _ ' Mass Spec Mass Spec (M+H)
SϋBSTmJTESHEETCRULE26) Observed
Example* %Yield .. _ ' Mass Spec Mass Spec (M+H)
SUBSπTUTESHEEURULEO) Observed
Example* %Yield .. A Mass Spec Mass Spec (ft/|+H)
SϋBSπTUTCSHEETC ULEaβ)
_ , . Observed Calcd.
Example* %Yιeld .. _ Mass Spec Mass Spec (M+H)
SUBaπrrrϋTESH ETCRϋLESβ) Observed
Example* %Yield .. A Mass Spec Mass Spec {M+H)
SUBSnTUTESHEET(RULE26) Observed
Example* %Yield ,. *' Mass Spec Mass Spec (|y|+H)
SUBSTTTUTESHEETCRULESβ) _ . , Observed Calcd.
Example* %Yield ., _ Mass Spec Mass Spec (||+||)
SUBSmϋTEShEErCRϋlJE2β)
_ . , Observed Calcd.
Example* R %Yield .. _ Mass Spec Mass Spec
SyBSπTUTESHEEURUtESΦ Observed
Example* %Yield .. _ ' Mass Spec Mass Spec (M+| )
SI STTΠJΓESHEET(RULE26) _ . , Observed Calcd.
Example* %Yιeld , . _ Mass Spec Mass Spec ,,, J: (M+H)
Observed
Example* R: %Yield .. ' Mass Spec
Mass Spec {M+H)
gUBSmUIESHEETCRULE-*) Observed
Calcd.
Example* RJ %Yield Mass Spec Mass Spec
(M+H)
suBsπππHSH£Er(RυLE2β) Observed
Calcd.
Example* R RJ %Yield Mass Spec Mass Spec
(M+H)
SUBSmUTESHEET(RULE26) Observed
Calcd.
Example* %Yield Mass Spec Mass Spec
(M+H)
Observed
Example* R %Yield „ a C-_ " Mass Spec Mass Spec ,,, JT (M+H)
gyggnTUTESHEETCRULBSe)
Observed
Calcd. Mass
Example* RL %Yield Mass Spec Spec
(M+H)
SUBSTnUTESHEETCR JEae Observed
Calcd. Mass
Example* RL %Yield Mass Spec Spec
(M+H)
SUBSTπUTESHEET(RULE2β) Observed
Calcd. Mass
Example* RL %Yield Mass Spec Spec
(M+H)
SϋBST πESϊ«ET(RϋU 2β)
- . ., .. Observed
Example* « %,»Y»ι■el .d.. Calcd. Mass Mass Spec peC (M+H)
- , . .. Observed n, w ... Calcd. Mass
Example* R2 %Yιeld _ Mass Spec
SpβC (M+H)
SUBSTπUTeSHEEr(BULE2β) ~ . m, .. Observed Calcd. Mass
Example* R %Yield _ Mass Spec
S βC (M+H)
SUBSfmUTE8HEET(RULE2e) -. . m, .. Observed
Example* - %.,Y■ιe .ld. Calc _d. Mass . M.ass „ Spec
SpβC (M+H)
SU3ST TE8rEEr(RU E&6) - . ., .. Observed
Example* Λ,w ... Calcd. Mass
RL %Yιeld _ Mass Spec
SpβC (M+H)
50*4
- . ^ .. Observed
-, .,■ ... Calcd. Mass ..
Example* RL %Yιeld _ Mass Spec
SpeC (M+H)
SU3STπUlHεH£ET(RUL££β) _ . . ,, Observed
„,,.. . . Calcd. Mass ..
Example* R: %Yιeld Mass Spec peC (M+H)
SUBSπTLπESHEEr(RυiE2β) - . J .. Observed
Example* R %Yield Calc e d-Mass Mass Spec S eC (M+H)
SϋBSTmjTESHEET(RϋLE26) Observed
Calcd. Mass
Example* %Yield Mass Spec Spec
(M+H)
~ . . .. Observed
Calcd. Mass _
Example* R RL %Yιeld _ Mass Spec
SpβC (M+H)
8tfi9mUllSHEET(RULE26) - . J .. Observed
„, ».. . . Calcd. Mass ,.
Example* R RL %Yιeld -. Mass Spec
SPΘC (M+H)
8U8Sπ UTESHEET(RϋL£26)
_ . . Observed Calcd.
Example* R2 %Yield ,, _ Mass Spec Mass Spec JT
(M+H)
SUBSΩΪlfl£SH£Er(RULE£β) Observed
Example* R2 RL %Yield ,, _ ' Mass Spec Mass Spec ^
8JBSTrrUTESHEET(RϋLE26) _ , . Observed Calcd. _
Example* RL %Yield .. _ Mass Spec Mass Spec (|j/|+H)
SUBSTΠUIESHEEΓ(RULE&6) _ , , Observed Calcd.
Example* %Yield ,, _ Mass Spec Mass Spec (M+H)
SυBST JTEStCEr(RϋLE2« _ . . Observed „,„• . ■ calcd. .. _
Example* %Yιeld . « _ Mass Spec Mass Spec ^
SyBSrraπESHEETCRϋLESβ) _ . . Observed Calcd.
Example* %Yield .. _ Mass Spec Mass Spec μ (M+H)
- . . .. Observed -,.,■ ... Calcd. Mass
Example* %Yιeld „ Mass Spec
SPΘC (M+H)
SUrøTOTE8t Er(RULE2β) Observed
Calcd. Mass
Example* R %Yield Mass Spec Spec
(M+H)
SUBSπTiπE8HEET(RϋUE26) Observed
Calcd. Mass
Example* %Yield Mass Spec Spec
(M+H)
suesffmπESBEεr(Rui£26$ Observed
Calcd. Mass
Example* RL %Yield Mass Spec Spec
(M+H)
8i STπUTE8HEE (WlE2β) Observed
Calcd. Mass
Example* RL %Yield Mass Spec Spec
(M+H)
gy®grnUTESHEET(R JE26) Observed
Calcd. Mass
Example* %Yield Mass Spec Spec
(M+H)
8UBSπTUTE8HEET(RUl£26)
Proton NMR data for selected members from Examples B-0001 through B-1573 are shown in the following table.
sϋBsrπuτESt€Er(RUiJEfiβ5
S BSmϋTESHEEr(RϋlE2β) Plate ID 1 H NMR(solvent), d ppm
(CDCI3), 1.94(br, 2H), 2.53(s, 3H), 2.85(t, J = 6.2 Hz, 2H), 3.65(br, 2H),
B-1179 6.15(br, 1 H), 7.04(m, 3H), 7.22(m, 3H), 7.41 (br, 4H), 8.60(br, 2H).
(CDCI3), 2.00(br, 2H), 2.85(br, 2H), 3.64(br, 2H), 7.03(br, 3H), 7.17(br, 2H),
B-1183 7.36(br, 2H), 7.66(br, 2H), 8.60(br, 2H), 8.77(br, 2H).
(DMSO), 1.76(br, 2H), 2.66(br, 2H), 2.91 (br, 2H), 4.30(s, 2H), 7.18(br, 5H),
B-1194 7.35(m, 6H), 8.54(d, J = 5.8 Hz, 2H).
(DMSO), 1.17(br, 3H), 1 .76(br, 2H), 2.71 (br, 2H), 2.97(br, 4H), 7.18(br, 4H),
B-1200 7.36(br, 2H), 8.54(br, 2H).
(DMSO), 1.03(s, 6H), 1.68(br, 2H), 2.63(br, 2H), 3.00(br, 2H), 3.65(br, 1 H),
B-1206 5.69(m, 2H). 7.16(br, 4H), 7.35(br, 2H), 8.54(br, 2H).
(DMSO), 1.75(m, 2H), 2.14(s, 6H), 2.66(br, 2H), 3.10(br, 2H), 7.04(br, 3H),
B-1216 7.18(br, 4H), 7.35(m, 2H), 7.47(br, 1 H), 8.54(d, J = 4.8 Hz, 2H).
(DMF), 1.25(br, 3H), 2.01 (br, 2H), 3.35(br, 4H), 6.20(s, 1 H), 6.30(s, 1 H),
B-1226 7.42(br, 4H), 7.65(br, 2H), 8.77(s, 2H).
(DMSO-d6), 1.80(br, 4H), 2.82(br, 1 H), 2.94(br, 1 H), 3.10(br, 1 H), 3.60(br, 1 H),
B-1360 4.54(br, 1 H), 7.18(m, 4H), 7.30(m, 4H), 7.46(m, 2H), 8.54(br, 2H).
(DMSO-d6), 0.99(br, 6H), 1.73(br, 4H), 2.89(br, 2H), 3.03(m, 1 H), 4.04(br, 2H),
B-1361 4.44(m, 1 H), 7.18(m, 4H), 7.30(m, 2H), 8.57(d, J = 4.64 Hz, 2H).
(DMSO-d6), 1 J8(br, 4H), 2.01 (s, 3H), 2.89(br, 1 H), 3.05(br, 1 H), 3.34(br, 1 H),
B-1363 3.85(br, 1 H), 4.48(br, 1 H), 7.12(br, 2H), 7.21 (br, 2H), 7.30(br, 2H), 8.69(br, 2H), (CDCI3), 0.78(dd, J = 3.0, 2.9 Hz, 2H), 1.00(s, 2H), 1.78(m, 1 H), 1.86(b, 4H), 2.64(m, 1 H), 2.99(m, 1 H), 3.16(m, 1 H), 4.33(br, 1 H), 4.70(br, 1 H), 6.99(m, 2H),
B-1364 7.14(s, 2H), 7.29(m, 2H), 8.64(s, 2H).
(CDCI3), 1.89(s, 4H), 2.65(m, 1 H), 2.96(m, 1 H), 3.06(m, 1 H), 3.43(s, 3H), 3.93(d, J = 13.2 Hz, 1 H), 4.09(d, J = 13.5 Hz, 1 H), 4.18(d, J = 13.5 Hz, 1 H),
B-1368 4.68(d, J = 12.4 Hz, 1 H), 7.60(m, 2H), 7.12(s, 2H), 7.26(m, 2H), 8.63(s, 2H).
SϋBSπTUTE8HEEr(F E2β)
By analogy to the procedure identified above for the preparation of Examples B0001-B0048, the following examples B-1574 through B-2269 are prepared.
SUBSTmjreSHEET(RULE26)
Examples B-1574 through B-1597 are prepared from Scaffold C-27
Example* RL
SUBSTr-fUTESHEET(RULE26)
SUBSπrUTESHEET(RULE26)
su& ruiESHεεr(RULE&ς)
Examples B-1598 through B-1621 are prepared from Scaffold C-28
Example*
SUBST1 UTESHEEΓ(RULE26) Example*
SUBSTTTlJTESHEEr(RULE26) Example*
8ϋBSTπU,ΕSHEET(RULE2β)
Examples B-1622 through B-1645 are prepared from Scaffold C-38
Example* RL
8UBSTnfUTESHEEr(RULE26) Example*
8ϋBSπTUTESHEEr(R JEa6) Example*
SUBSTrTUTESHEEURUUEfiβ)
Examples B-1646 through B-1669 are prepared from Scaffold C-39
Example* R
8UBSPrnUTESHEET(R JE26) Example*
Example* RL
$U8SmUTESHEET(RULE26)
Examples B-1670 through B-1693 are prepared from Scaffold C-65
Example* RL
SUBSmUTESHEEURUiJEββ) Example* RL
8U8STlTUTESI-EEr(RULE26) Example* RL
auesmu!E8J«Er(RULEa8)
Examples B-1694 through B-1 17 are prepared from Scaffold C-66
Example* RL
SUBSπTUϊE$HEET(RULE26) Example* RL
SUBSπTUIESHEEr(RULEEβ) Example*
Examples B-1718 through B-1741 are prepared from Scaffold C-69
Example* RL
SUBSτπU!ESHEEr(Rl E26) Example*
SUBSTΠUTESHEETCRULEO) 54
Example* RL
Examples B-1742 through B-1765 are prepared from Scaffold C-70
Example* RL
SϋBSTπUTESHEEr(Rϋl£δ« Example*
SUΞSmUTESHEETfRULEfiβ} Example*
SUBSπTUTESHEErCRϋ ESβ
Examples B-1766 through B-1789 are prepared from Scaffold C-71
Example* RL
®je2TϊτuτESi-EEy{ E«ri Example* RL
8ϋBSTπUTESHEEr(R £2β) Example* RL
SUBSmU1ESHEET(RULE26) 1
Examples B-1790 through B-1813 are prepared from Scaffold C-72
Example*
SUB8CTnUTESHEET(BULE£6) Example*
8UBSπTUTE8HEEr(RULE86) Example*
SUBSTπUTE8HEεr(RUlESQ
Examples B-1814 through B-1837 are prepared from Scaffold C-73
Example* RL
Example* RL
SUBSnTUTESHEEr(RULEBβ) Example* RL
8UBS UTE8HEEr(RULE2e}
Examples B-1838 through B-1861 are prepared from Scaffold C-33
Example*
8UBS UTESHEET(RULE26) Example*
SU8SmUTESBEET(RULE28) Example* RL
SUBSmUTE8HEEr(RuLE28)
Examples B-1862 through B-1885 are prepared from Scaffold C-45
Example* RL
sυBεπrιπESHEεr(RULE26) Example* R
suB5rπυiEsεεr(RULE26) Example* R
Examples B-1886 through B-1909 prepared from Scaffold C-42
Example*
SUBSTmjTESHEET(RϋLE2β) Example*
SUBSΠΠJTESHEEΓ(RUIE8B) Example*
SϋBSimπESHEEr(RULEa6)
Examples B-1910 through B-1933 are prepared from Scaffold C-44
Example* RL
SUBSfflTUTESHEEr(RULEfi6) Example*
8lBSπTUTE8HEEr(RϋLE2β) Example*
SUBSnTUTESEETCRULEOJ
Examples B-1934 through B-1957 are prepared from Scaffold C-41
Example*
Example* RL
SϋBSπTϋTESHEET(RULE2β) Example* R2
8ϋBsrrruτE»cEr( ιiJE2β)
Examples B-1958 through B-1981 are prepared from Scaffold C-43
Example* R RL
Example* RL
8UBSmUTESHEET(RUlH«» Example* RL
Examples B-1982 through B-2005 are prepared from Scaffold C-30
Example* RL
gyBSmUlESHEET RULESe) Example*
8UBSmUlBSHEEr(BULE26) Example* RL
SUeSTTΪ TESH*EEr(RULE26)
BStr!UTE83r Er(RuLE26)
8U8SmUTESHEEr(RaE26)
SUBSmTUTESHEET(RULE26)
Examples B-2030 through B-2053 are prepared from Scaffold C-36
Example* R*
SlffiSmUTESHEEr(RϋUE2β) Example* R2
8UBBπiWE8HEEr(RUUE2β) Example*
8UBSmUTESHEET(miLE26)
Examples B-2054 through B-2077 are prepared from Scaffold C-34
Example* R2
SU^FΠUTESHEEΓ(RULES6) Example*
8U35πtUTE8HEEr(RU£2β) Example*
SUBOTTUTESHEmR ESB)
Examples B-2078 through B-2101 are prepared from Scaffold C-57
Example*
gyrøπru aeErofWLEα) Example*
SUBStmπESHEEURULEO) Example*
8UBSn7UTESHEET(RULEW)
Examples B-2102 through B-2125 are prepared from Scaffold C-52
Example*
SUBSmϋTESt€Er (RULE&J) Example*
SUBS UTESHEETlRULEae) Example*
8UBSmUlESHEET(BULE86)
Examples B-2126 through B-2149 are prepared from Scaffold C-56
Example* R:
sϋBSπTUTESHEET(RϋLE26) Example*
Example*
SUBSmUTE8HEEr(RϋLE»)
8ϋBsπroiEacEr(fflJiJEaβ)
8UBS UTESH£ET(RULE26)
8UBSπππESH£Er(R £2β)
SUBST!7UTESHEEr(RULE26)
SUBSπTUreSHEEr(RULE26)
SUBSπTUrE8HEEr(RUUEaβ)
Examples B-2222 through B-2245 are prepared from Scaffold C-29
Example* R2
SUBSTmJTESHEEr(RULE26) Example*
Example*
8U8smυreSHEEUBUlE«)
SUBSmUTESHEET(FHJLE26)
SUBSπTϋTESHEETC ∑β)
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
suBsmxresHEET Juaβ*) 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.
SϋBST1TϋTESHEEr(RϋLE2β)
SUBSTmJTESHEEr(RULE26)
SUBSTrrUTESHEET(RULE26)
SϋBSTrTUTE8HEEr(RϋLE2β)
suBsπrπ τESHεεr(RULE2Q
SUBS&rroTESHE UL£2fi)
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.
8ϋB8 U7ESHEET(RULE2β)
SUBSmUTESHEEr(RULE2fi)
$UBSffmreSHEET(RUUE26)
8UBSmUTESHEEr(RliLE26)
$UB§fTOTESH-EEr(RUL£26)
SUBSnTUTESHEET(RULE26)
SUBSTrTUTESHΞET(RULEaβ)
S03gπTDreSHEET(Rϋ!JE2β)
SUBSnTUTESHEEr(RUUE26)
SUBSnTUTE8HEET(RULE26)
su8sπτατE8i«εrRϋLE8β)
SϋBSπTUTESHEET υiEδβ
gUBgππjIESHEETtRULEββ)
8UBSπVUIESHEεr(RUl£2@)
SlrøiπUTESHEET(RULEi6)
SUBSΠTUESHEEΓ(RULE26)
Example C-1
5-AMINOMETHYL-4- (4-PYRIDYL) -3- (4-FLUOROPHENYL) PYRAZOLE
1- (4-fluorophenyl) -2- (4-pyridyl) -1-ethanone. 4- picoline (40 g, 0.43 mol) was added to 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 (2x200 mL) . The organic layer was washed with brine (1x200 mL) and dried over
Na2S04. 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 (CDC13) 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 (CDCI3) 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 C23H2oN402F (M+H): 216.0825. Found: 216.0830 (Δ mmu = 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 wtih 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 lh. 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 inlOO L 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 (3x300 mL) . The organic layer was
SU8ST1TUTESHEET(RULE26) dried (Na2S04) , filtered and evaporated to leave 157 g of a crude reddish oil.
The oil was suspended in CH2CI2 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) : XH NMR (DMF-d7) δ 13.36 (s, IH) , 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 NMR (DMF-d7) δ -114.9 (m) , -116.8 (m) (split fluorine signal is due to the pyrazole 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 C23H2o 402F (M+H): 403.1570. Found: 403.1581 (Δ mmu = 1.1).
5-aminomethyl-4- (4-pyridyl) -3- ( -fluorophenyl) pyrazole. To a IL 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 (3x50 mL) and
SUBSTrrUrESHEET(RULE26) the filtrate was concentrated to give 4.5 g of an off- white solid (94%: H NMR (DMS0-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 (Δ mmu = 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.
gUBSπnπESHE RW-E*)
srørrruτESHEer(RULEBs)
SUBSmUTESHEET(RUlJE26)
SU8SmUTESHEET(RULE26)
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
$υBSTmjrTESHEEr(RULE2β)
sϋBs uτE8ϊ«Er( «JEae5
SUBSTrrUTESHEET(RULE26)
Example C-49
Step A
The pyrazole (2.60 g, 10.3 mmol) from example 4 was suspended in 52 L of dichloroethane and 52 mL of 2.5 M
SUBSmUmSHEER ϋlEaβ) 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
5 temperature for 4 h. The mixture was poured onto 200 mL of CH2CI2 and 200 mL of H20. The phases were separated and the organic phase was washed with water (1x100 mL) and brine (1x100 mL) . The organic layer was dried over Na2S04 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
0 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 5 with propylene oxide (10.3 mmol) and was stirred for lh 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 Et20 and the title compound Example C-49 was 0 isolated by filtration to afford 3.0 g of an off-white solid (95%). Mass spec: M+H cald: 312; found 312. Jϊ NMR (DMS0-d6) : 8.81 (d, J = 6.4 Hz, 2H) , 7.73 (d, J =
SUBS1TrUTESHEET(Rϋ E26) 5.8 Hz, 2H) , 7.40 (m, 2H) , 7.23 (t, J .5 Hz, IH) 5.1< (s, 2H) , 2.40 (s, 3H) .
Example C-50
According to the procedure described above in Example C- 49, Example C-50 was also prepared starting from 4- [3- (4- fluorophenyl) -lH-pyrazole-4-yl] pyridine . Mass spec: M+H cald: 298; found 298. XH NMR (DMSO-d6): 8.75 (d, J = 6.4 Hz, 2H) , 8.68 (s, IH) , 7.78 (d, J = 6.6 Hz, 2H) , 7.52 (dd, J = 5.4, 8.5 Hz, 2H) , 7.31 (t, J = 8.9 Hz, 2H) , 5.16 (s, 2H) .
Example C-51
Starting 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.
SUBSππUTESHEEr(RULE26) Example C-52
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.
Step B: A solution of the pyridyl monoketone in ether, THF, tBuOH, or dioxane is added to a base chosen from but
SUBSΠTUTESHEEΓ (RULESI) 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.
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, H2S04, HCl, or HN03. 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.
SUBSrnUreSHEEr(Rt}LJE2
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.
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
8uBSmUrESHEEr(RUlJE26)
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.
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.
StepB
Example C-61
Example C-61 is prepared according to the method described in example C-60, substituting 1 , 4-dibromobutane for methyl iodide.
Example C-62
SU8SmUTESHEEr(RULE26)
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.
8lrørπUTE8HEEr(RϋL£26)
Example C-64
Using the method described in Schemes C-6 and C-7, Example 64 is prepared.
Example C-65
Using the method described in Schemes C- and C-7 , Example 65 is prepared.
Example C-66
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.
8UBSOTTUTESHEET(RULitS) Example C- 67
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
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.
SUBSrnUTE8HEEr(R £28) Example C-69
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
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
8UBSniUTE8HEEr(RUlJE26) 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
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
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.
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 vi tro P38-alpha kinase inhibitory data are shown in the column identified as:
"P38 alpha kinase IC50# uM or % inhib & cone. (uM)"
In vi tro 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 @ cone, (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
SUBSTITUTESHEEr(RLΛ£26) indicates the number of hours before LPS challenge when the compound is administered.
βoBgπw sHEεr BϋUEW
SUBSπTUTESHEET(RULE2β)
SUBSTrπJTESHEET(RULE2β)
su Bs uTESHSEr<«»£*>
8ϋBS πE8HEEr(Rϋl£2β)
$UBSmTUTESHEET(RUl£2φ
SUBSTnunESHEET(RULE26)
suBsπnπεsHEεr(RULE&θ)
SUBSπUπESHEETCRϋUEfiβ)
SϋBSIπUlESt€Er(RULEϊe)
SUBSmϋlE8HEEr(RULE8β)
SUBSΠUJTESHEEURUIEEB)
SUBSrnuTE8HEEr(uLE2e)
SUBgmUrESHEEr(RULE26)
StBaπTπJTESHEEr(RϋLE26)
SUBSΠTUTESHEEΓ (RULE∞)
8UBSTπUreSHEET(Rυi£2β)
SυB8mmESHEEr(RULE28)
SUBSTrnJTESHEET(RULE26)
SUBSTπuTESHEEr( ULEgB)
SϋBSπTϋTESHEET(RULE26) 685
SUBamUTESHEB-CRULESS)
SUBSmUTESHEET(RUUE26)
SUBSTπUTESHEET(RUL£2β)
QϋBgπTϋTESHEET aEfiβ)
SlBSmUTESHEET(R ££6)
SUBSrnUTESHEET(RuL£26)
SUBSTΪ LTUTESHEETlROLEaei
su esτrπjmsHEET(RUiEa&
SUBSTπiπE8H£ET(R JE26)
SUBSTTΓUTESHEEΓ(R _E26)
SUBSmUTE8HEET(RUUE26)
SUBSππJTE8HEEr(Rϋl£2β)
SϋBSTπUTESHEEr(RϋLE£6)
SUBSmUTESHEET(RULE26)
SUBSnnUTESHEET(RUUEfiflJ

Claims (139)

WHAT WE CLAIM IS:
1. A compound of Formula I
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, alkeny1sulfinyl, 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,
SϋBSmϋTESHEεT(RϋLE26) arylcarbonyloxyarylene, and heterocyclylcarbonyloxyarylene ; or R1 has the formula
R I2S ' II R-
— C—CCH __ -
I ,27
H (ID
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,
OygSmUTESBEErCRULEfifi) 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;
$UBSmUmSHEET(RULE26) and
100 R2 is selected from hydrido, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, haloalkyl, hydroxyalkyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, heterocyclylalkylamino, aralkylamino,
105 aminoalkyl, aminoaryl, aminoalkylamino, arylaminoalkylene, alkylammoalkylene, arylaminoarylene, alkylaminoarylene, alkylaminoalkylamino, cycloalkyl, cycloalkenyl, alkoxy, heterocyclyloxy, alkylthio, arylthio, heterocyclylthio, carboxy, carboxyalkyl,
110 carboxycycloalkyl, carboxycycloalkenyl, carboxyalkylamino, alkoxycarbonyl, heterocyclylcarbonyl, alkoxycarbonylalkyl , alkoxycarbonylheterocyclyl , alkoxycarbonylheterocyclylcarbonyl , alkoxyalkylamino, alkoxycarbonylaminoalkylamino, and heterocyclylsulfonyl;
115 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,
120 epoxyalkyl, amino (hydroxyalkyl) carboxy, alkoxy, aryloxy, aralkoxy, haloalkyl, alkylamino, alkynylamino, alkylaminoalkylamino, heterocyclylalkylamino, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, and aralkylsulfonyl; or
125 R2 has the formula:
wherein : j is an integer from 0 to 8 ; and m is 0 or 1; and 130 R30 and R31 are independently selected from hydrogen,
SUBSΓΠUΓESHEEΓ(RULE26) alkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, aminoalkyl, alkylaminoalkyl, aminocarbonylalkyl , alkoxyalkyl, and alkylcarbonyloxyalkyl; and
R32 is selected from hydrogen, alkyl, aralkyl, 135 heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene;
R33 is selected from hydrogen, alkyl, -C(0)R35, 140 -C(0)OR35, -S02R36, -C(0)NR37R38, and -S02NR39R40, 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, 145 alkylaminocarbonyl, and arylaminocarbonyl ; or
R2 is -CR1R42 wherein R41 is aryl, and R42 is hydroxy; and
R3 is selected from pyridinyl, pyrimidinyl, quinolinyl, purinyl,
150 (IV) (V) wherein R43 is selected from hydrogen, alkyl, aminoalkyl, alkoxyalkyl, alkenoxyalkyl, and aryloxyalkyl; and wherein the R3 pyridinyl, pyrimidinyl, quinolinyl and
155 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,
160 aralkoxy, heterocyclylalkoxy, amino, alkylamino,
8UBSTnrUTESHEET(RULE26) alkenylamino, alkynylamino, cycloalkylamino, cycloalkenylamino, arylamino, heterocyclylamino, aminocarbonyl, cyano, hydroxy, hydroxyalkyl, alkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl,
165 alkoxycarbonylamino, alkoxyaralkylamino, aminosulfinyl, aminosulfonyl, alkylaminoalkylamino, hydroxyalkylamino, aralkylamino, heterocyclylalkylamino, aralkylheterocyclylamino, nitro, alkylaminocarbonyl, alkylcarbonylamino, halosulfonyl, aminoalkyl, haloalkyl,
170 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
175 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,
180 alkylsulfonyl, alkylsulfonylalkylene, arylsulfonylalkylene, alkoxy, aryloxy, aralkoxy, aminocarbonyl , alkylaminocarbonyl , arylaminocarbonyl , alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, cyano, nitro, alkylamino, arylamino, alkylammoalkylene,
185 arylaminoalkylene, aminoalkyla ino, 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
190 hydrido; and further provided R4 is not methylsulfonylphenyl; or a pharmaceutically-acceptable salt or tautomer thereof .
SUBSmUTESHEEURULEaβ
2. A compound of Claim 1 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 alkylammoalkylene, and lower heterocyclylalkylene; or
R1 has the formula
-CCHpD .-
27
(II)
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
SUBSTITUTE$HEEr(RULE26) 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 alkylammoalkylene, 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 alkylaminosulfonyIpheny1ene ; 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
SUBSmUTE8HEEr(RLM£26) 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
SUBSΠTUTESHEEΓ(RULE26) aminoalkyl, lower aminoalkylamino, lower
105 alkylaminoalkylamino, lower cycloalkyl, lower alkenyl, lower alkoxycarbonylalkyl, lower cycloalkenyl, lower carboxyalkylamino, lower alkoxycarbonyl, lower heterocyclylcarbonyl, lower alkoxycarbonylheterocyclyl, lower alkoxycarbonylheterocyclylcarbonyl ,
110 alkoxycarbonylalkyl, lower alkoxyalkylamino, lower alkoxycarbonylaminoalkylamino, lower heterocyclylsulfonyl, lower heterocyclyloxy, and lower heterocyclylthio; wherein the aryl, heterocylyl, heterocyclylalkyl, cycloalkyl, and cycloalkenyl groups
115 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
120 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
125 R2 has the formula:
, 30 , 3 2
C — C C H 2χ R 3 1
( I I I )
wherein : j is 0, 1 or 2; and m is 0; 130 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, 135 heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene,
SUBSπTUFEδKEEr(RULE£8) aminoalkyl, alkylaminoalkyl, arylaminoalkyl , alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene ; and
R33 is selected from hydrogen, alkyl, -C(0)R35,
140 -C(0)OR35, -S02R3S, -C(0)NR37R38, and -S02NR39R40; wherein R35 is selected from alkyl, cycloalkyl, haloalkyl, alkenyl, aryl, heterocyclyl, aralkyl, arylcycloalkyl , cycloalkenylalkylene , heterocyclylalkylene, alkylarylene, alkylheterocyclyl,
145 arylarylene, arylheterocyclyl, alkoxy, alkenoxy, alkoxyalkylene, alkoxyaralkyl, alkoxyarylene, aryloxyalkylene, aralkoxyalkylene, cycloalkyloxyalkylene, alkoxycarbonyl , heterocyclylcarbonyl , alkylcarbonyloxyalkylene , alkylcarbonyloxyarylene ,
150 alkoxycarbonylalkylene, alkoxycarbonylarylene, aralkoxycarbonylheterocyclyl , alkylcarbonylheterocyclyl , arylcarbonyloxyalkylarylene, and alkylthioalkylene; wherein said aryl, heterocyclyl, aralkyl, alkylarylene, arylheterocyclyl, alkoxyarylene, aryloxyalkylene,
155 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
160 R35 is CHR48R49 wherein R48 is arylsulfonylamino or alkylarylsulfonylammo, and R49 is selected from aralkyl, amino, alkylamino, and aralkylamino; or
R35 is -NR50R51 wherein R50 is alkyl, and R51 is aryl; and
165 wherein R36 is selected from alkyl, haloalkyl, aryl, heterocyclyl, cycloalkylalkylene, alkylarylene, alkenylarylene, arylarylene, aralkyl, aralkenyl, heterocyclylheterocyclyl, carboxyarylene , alkoxyarylene, alkoxycarbonylarylene , alkylcarbonylaminoarylene ,
170 alkylcarbonylaminoheterocyclyl, arylcarbonylaminoalkylheterocyclyl , alkylaminoarylene ,
8υrømπBSHEEr(RϋiJE2β) alkylamino, alkylaminoarylene, alkylsulfonylarylene, alkylsulfonylaralkyl, and arylsulfonylheterocyclyl; wherein said aryl, heterocyclyl, cycloalkylalkylene,
175 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
180 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,
185 aralkylheterocyclyl, alkoxyalkylene, alkoxyarylene, aryloxyarylene, arylcarbonyl , alkoxycarbonyl, alkoxycarbonylalkylene , alkoxycarbonylarylene, alkylcarbonylcarbonylalkylene , alkylammoalkylene , alkylaminoaralkyl , alkylcarbonylaminoalkylene,
190 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,
195 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
200 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
SUB3TΓΠJTESH£ΞT( ULE£6) 205
(VI ) (VII ) (VIII) wherein k is an integer from 0 to 3 ; and
Rb is hydrogen or lower alkyl; and
210 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(0)R59,
215 -S02R60, and -C(0)NHR61; wherein R59 is selected from alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, alkylarylene, aralkyl, alkylheterocyclyl, alkoxy, alkenoxy, aralkoxy, alkoxyalkylene, alkoxyarylene, alkoxyaralkyl; wherein
220 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
225 wherein R60 is selected from alkyl, aryl, heterocyclyl, alkylarylene, alkylheterocyclyl, aralkyl, heterocyclylheterocyclyl, alkoxyarylene, alkylamino, alkylaminoarylene, alkylsulfonylarylene, and arylsulfonylheterocyclyl; wherein said aryl,
230 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
SUBSTTIUTESHEEr(RULE26) wherein R61 is selected from alkyl, aryl, 235 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 240 R3 is selected from pyridinyl, pyrimidinyl, quinolinyl, purinyl, and
wherein R43 is selected from hydrogen, lower alkyl, lower aminoalkyl, lower alkoxyalkyl, lower alkenoxyalkyl
245 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,
250 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,
255 lower alkenylamino, lower alkynylamino, lower aminoalkyl, arylamino, lower aralkylamino, nitro, halosulfonyl, lower alkylcarbonyl, lower alkoxycarbonylamino, lower alkoxyphenylalkylammo, lower alkylaminoalkylamino, lower hydroxyalkylamino, lower heterocyclylamino, lower
260 heterocyclylalkylamino, lower phenylalkylheterocyclylamino, lower alkylaminocarbonyl, lower alkoxyphenylalkylammo, hydrazinyl, lower alkylhydrazinyl, or -NR62R63 wherein R62 is lower alkylcarbonyl or amino, and R63 is lower alkyl or lower
SUBSTTRnESH£Er(RUlEg 265 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
270 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
275 heterocyclyl, lower haloalkyl, amino, cyano, nitro, lower alkylamino, and hydroxy; or a pharmaceutically-acceptable salt or tautomer thereof.
3. A compound of Claim 2 wherein
R1 is selected from hydrido, methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl , 5 dichloromethyl, trichloroethyl, pentafluoroethyl, heptafluoropropyl , difluorochloromethyl , dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, ethenyl, propenyl, ethynyl, propargyl, 1-propynyl, 2-propynyl, piperidinyl,
10 piperazinyl, morpholinyl, benzyl, phenylethyl, morpholinylmethyl, morpholinylethyl, pyrrolidinylmethyl, piperazinylmethyl , piperidinyImethy1 , pyridinylmethy1 , thienylmethyl , methoxymethyl , ethoxymethyl, amino, methylamino, dimethylamino, phenylamino,
15 methylaminomethyl , dimethylaminomethyl, methylaminoethyl , dimethylaminoethyl, ethylaminoethyl, diethylaminoethyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, hydroxymethyl , hydroxyethyl , mercaptomethyl , and methylthiomethyl ; and
20 R2 is selected from hydrido, chloro, fluoro, bromo, methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl, phenyl, biphenyl, fluoromethyl, difluoromethyl,
SUBSmrUTESHEEr(RULE26) trifluoromethyl, chloromethyl , dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, hydroxymethyl, 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
8lBSTπU7ESBEEr(RULEfi8) 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, (l-ethyl-2-hydroxy) ethylamino, piperidinylamino, pyridinylmethylamino, phenylmethylpiperidinylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminocarbonyl, ethylaminocarbonyl , methylcarbonyl, methoxyphenylmethylamino, hydrazinyl, 1-methyl- hydrazinyl, 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, eyelopentenyl, cyclohexenyl, cyclohexadienyl, phenyl, biphenyl, morpholinyl, pyrrolidinyl, piperazinyl, piperidinyl, pyridinyl, thienyl, isothiazolyl,
SϋBSπTϋTESHEEr(RϋLE26) 95 isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, quinolyl, isoquinolinyl, imidazolyl, benzimidazolyl, furyl, pyrazinyl, dihydropyranyl , dihydropyridinyl , dihydrofuryl , tetrahydropyranyl, tetrahydrofuryl, benzofuryl, dihydrobenzofuryl , and benzodioxolyl; wherein
100 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,
105 methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, fluoromethyl, difluoromethyl, amino, cyano, nitro, dimethylamino, and hydroxy; or a pharmaceutically-acceptable salt or tautomer thereof.
4. A compound of Claim 3 wherein
R1 is hydrido, methyl, ethyl, propargyl, hydroxyethyl, dimethylaminoethyl, diethylaminoethyl or morpholinylethyl ; 5 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 10 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 15 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; 20 R4 is selected from phenyl, quinolyl, biphenyl, pyridinyl, thienyl, furyl, dihydropyranyl, benzofuryl,
SUBSTnUrESHEET(RUL£26) 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.
5. A compound of Claim 4 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.
6. A compound of Claim 2 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,
$UBSmUTESHEEr(RUlE2β) morpholmylmethyl, morpholinylethyl, pyrrolidinylmethyl, piperazinylmethyl, piperidinylmethyl, pyridinylmethyl, thienylmethyl, methoxymethyl , ethoxymethyl, amino, methylamino, dimethylamino, phenylamino, methylammomethyl, dimethylaminomethyl, methylaminoethyl , dimethylaminoethyl, ethylaminoethyl, diethylaminoethyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, hydroxymethyl, hydroxyethyl, mercaptomethyl , and methylthiomethyl; and R2 has the formula:
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(0)R35, -C(0)OR35, -S02R36, -C(0)NR37R38, and -S02NR39R40; 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
suBSτrτurrESHEEr(RUJEfiβ) 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 alkylphenylsulfonylammo, 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
SUBSmUTESHEET(RULE26) alkylaminophenylene, lower alkylamino, lower 80 alkylaminophenylene, lower alkylsulfonylphenylene, lower alkylsulfonylphenylalkyl, and lower phenylsulfonylheterocyclyl; wherein said aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclyl, lower cycloalkylalkylene, lower phenylalkyl, lower 85 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; 90 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 95 naphthyl, lower heterocyclyl, lower phenylalkyl, lower alkylphenylene, lower phenylcycloalkyl, phenylphenylene , lower cycloalkylalkylene, lower heterocyclylalkylene, lower alkylheterocyclylalkylene, lower phenylalkylheterocyclyl, lower alkoxyalkylene, lower
100 alkoxyphenylene, lower phenoxyphenylene, phenylcarbonyl , lower alkoxycarbonyl, lower alkoxycarbonylalkylene, lower alkoxycarbonylphenylene , lower alkylcarbonylcarbonylalkylene, lower alkylammoalkylene, lower alkylaminophenylalkyl , lower
105 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
110 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,
SϋBSTmjrTE8t€Er(Rl E26) 115 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 120 R2 is selected from the group consisting of
(VI) (VII) (VIII) wherein k is an integer from 0 to 2; and 125 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, 130 lower alkoxycarbonyl, lower alkylsulfonyl, lower phenylalkylsulfonyl, lower phenylsulfonyl, -C(0)R59, -S02R60, and -C(0)NHR61; wherein R59 is selected from lower alkyl, lower haloalkyl, lower cycloalkyl, aryl selected from phenyl, 135 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 140 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
SUBSπTUTESHEET(RULEEa) haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino,
145 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
150 heterocyclylheterocyclyl, lower alkoxyphenylene, lower alkylamino, lower alkylaminophenylene, lower alkylsulfonylphenylene, and lower phenylsulfonylheterocyclyl; wherein said aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclyl,
155 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
160 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,
165 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,
170 methylsulfinyl, methylsulfonyl, fluoro, chloro, bromo, aminosulfonyl, methyl, ethyl, isopropyl, tert-butyl, isobutyl, cyano, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methylcarbonylamino, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl,
175 dichloromethyl, chloromethyl , hydroxy, fluorophenylmethyl , fluorophenylethyl , chlorophenylmethyl , chlorophenylethyl , fluorophenylethenyl, chlorophenylethenyl, fluorophenylpyrazolyl, chlorophenylpyrazolyl , carboxy,
suBsπTu aeErc ABSβ 180 methoxy, ethoxy, propyloxy, n-butoxy, methylamino, ethylamino, dimethylamino, diethylamino, 2- methylbutylamino, propargylamino, aminomethyl, aminoethyl, N-methyl-N-phenylamino, phenylamino, diphenylamino, benzylamino, phenethylamino,
185 cyclopropylamino, nitro, chlorosulfonyl, amino, methylcarbonyl , methoxycarbonylamino, ethoxycarbonylamino, methoxyphenylmethylamino, N,N- dimethylaminoethylamino, hydroxypropylamino, hydroxyethylamino, imidazolylethylamino,
190 morpholinylethylamino, (1-ethyl-2-hydroxy) ethylamino, piperidinylamino, pyridinylmethylamino, phenylmethylpiperidinylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminocarbonyl, ethylaminocarbonyl , methylcarbonyl,
195 methoxyphenylmethylamino, hydrazinyl, 1-methyl- hydrazinyl, 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,
200 eyelopentenyl, cyclohexenyl, cyclohexadienyl, phenyl, biphenyl, morpholinyl, pyrrolidinyl, piperazinyl, piperidinyl, pyridinyl, thienyl, isothiazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, quinolyl, isoquinolinyl, imidazolyl, benzimidazolyl, furyl,
205 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
210 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,
215 dimethylamino, and hydroxy; or
SUBSfrπUTESHEEr(RυiJE2β) a pharmaceutically-acceptable salt or tautomer thereof.
7. A compound of Claim 6 wherein
R1 is hydrido, methyl, ethyl, propargyl, hydroxyethyl, dimethylaminoethyl, diethylaminoethyl or morpholinylethyl ; R2 has the formula:
, 30 , 32
FT y
• C — C H 2D ] - - N I
( I II )
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(0)R35, -C(0)OR3S, -S02R36, -C(0)NR37R38, and -S02NR39R40; 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
SUBSmUmSHEEF(RlMJE26) 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
(VI ) (VI I ) (VI I I ) wherein k is an integer from 0 or 1; and
R56 is hydrogen; and
R57 is hydrogen; and
R58 is selected from -C(0)R59 and -S02R60; 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,
SUBSTΠUΓESHEEΓ(RULE26) 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 .
8. A compound of Claim 7 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.
9. A compound of Claim 1 wherein R1 is hydrido.
10. A compound of Claim 2 wherein R1 is hydrido.
11. A compound of Claim 3 wherein R1 is hydrido.
12. A compound of Claim 6 wherein R1 is hydrido.
SUBSTπUTESHEEr(RUL£2β)
13. A compound of Claim 3 wherein R1 is methyl or ethyl .
14. A compound of Claim 6 wherein R1 is methyl or ethyl .
15. A compound of Claim 2 wherein R2 is hydrido.
16. A compound of Claim 3 wherein R2 is hydrido.
17. A compound of Claim 2 wherein R4 is optionally substituted phenyl.
18. A compound of Claim 3 wherein R4 is optionally substituted phenyl.
19. A compound of Claim 6 wherein R4 is optionally substituted phenyl.
20. A compound of Claim 2 wherein R1 and R2 are selected independently from hydrido, methyl and ethyl.
21. A compound of Claim 3 wherein R1 and R2 are selected independently from hydrido, methyl and ethyl
22. A compound of Claim 2 wherein R1 and R2 are selected independently from hydrido, methyl and ethyl; and R4 is optionally substituted phenyl.
23. A compound of Claim 3 wherein R1 and R2 are selected independently from hydrido, methyl and ethyl; and R4 is optionally substituted phenyl.
24. A compound of Formula IX
SyBgnTUrTESHEETC ULESe)
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 -CR5R55 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.
25. A compound of Claim 24 wherein
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,
SUB8TπUTESHEEr(RlA£2β) 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-dimethyl- ethylpiperazinylcarbonyl ; 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,
sυBSτπiJTESHεεr( uuΞ26) 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.
26. A compound of Claim 24 wherein R1 is hydrido.
27. A compound of Claim 25 wherein R1 is hydrido.
28. A compound of Claim 24 wherein R1 is lower alkyl,
29. A compound of Claim 25 wherein R1 is lower alkyl
30. A compound of Claim 24 wherein R2 is hydrido.
31. A compound of Claim 25 wherein R2 is hydrido.
32. A compound of Claim 24 wherein R1 and R2 are selected independently from hydrido, methyl and ethyl.
33. A compound of Claim 25 wherein R1 and R2 are selected independently from hydrido, methyl and ethyl.
34. A compound of Claim 25 wherein Z represents a carbon atom.
35. A compound of Formula X
SUBSTπUTESHEEr(RULE2β)
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
Si FFUTESBEEr(RULE26) 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 -NR6R63 wherein R62 is lower alkylcarbonyl or amino, and R63 is lower alkyl or lower phenylalkyl; or a pharmaceutically-acceptable salt or tautomer thereof.
36. A compound of Claim 35 wherein 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,
SUBSTmflΕSHEET(RULE£β) 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-dimethyl- ethylpiperazinylcarbonyl; 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, hydroxypropylammo, hydroxyethylamino, propargylamino, imidazolylamino, morpholinylethylamino, (1-ethyl-2-hydroxy) ethylamino, piperidinylamino, pyridinylmethylamino, phenylmethylpiperidinylamino, aminomethyl , cyclopropylamino, amino; hydroxy, methylcarbonyl, ethoxycarbonylamino, methoxyphenylmethylamino, phenylmethylamino, fluorophenylmethylamino, 100 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.
37. A compound of Claim 35 wherein R1 is lower alkyl.
38. A compound of Claim 36 wherein R1 is lower alkyl,
39. A compound of Claim 35 wherein R2 is hydrido.
40. A compound of Claim 36 wherein R2 is hydrido.
41. A compound of Claim 35 wherein R1 is methyl or ethyl, and R2 is selected from hydrido, methyl and ethyl.
42. A compound of Claim 36 wherein R1 is methyl or ethyl, and R2 is selected from hydrido, methyl and ethyl.
43. A compound of Claim 35 wherein Z represents a carbon atom.
44. A compound of Formula XI
SUBSTmπEδHEET(RULE26) 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 R5B 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,
8UBSTUUTE8HEEr(RlJLE2e) 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.
45. A compound of Claim 44 wherein
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-dimethyl- ethylpiperazinylcarbonyl; 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, hydroxypropylammo, hydroxyethylamino, imidazolylamino, morpholinylethylamino, (1-ethyl-2 -hydroxy) ethylamino, piperidinylamino, pyridinylmethylamino, phenylmethylpiperidinylamino, aminomethyl , eyelopropylamino, 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.
46. A compound of Claim 44 wherein R1 is lower alkyl.
47. A compound of Claim 45 wherein R1 is lower alkyl,
48. A compound of Claim 44 wherein R2 is hydrido.
49. A compound of Claim 45 wherein R2 is hydrido.
SUBSmUTESH£ET(RULE26)
50. A compound of Claim 44 wherein R1 is methyl or ethyl, and R2 is selected from hydrido, methyl and ethyl,
51. A compound of Claim 45 wherein R1 is methyl or ethyl, and R2 is selected from hydrido, methyl and ethyl
52. A compound of Claim 44 wherein Z represents a carbon atom.
53. A compound 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
8UBSTnUTESHEET(RULE26) 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
Rs 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
SUBSTπUTESHEEr(RULE2β} thereof .
54. A compound of Claim 53 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-dimethyl- ethylpiperazinylcarbonyl; 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,
SUBSmTUTrESHEEr(RULE26) hydroxyethylamino, imidazolylamino, morpholinylethylamino, (l-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 .
55. A compound of Claim 53 wherein R1 is hydrido or lower alkyl .
56. A compound of Claim 54 wherein R1 is hydrido or lower alkyl .
57. A compound of Claim 53 wherein R1 is hydrido.
58. A compound of Claim 54 wherein R1 is hydrido.
59. A compound of Claim 53 wherein R2 is hydrido.
60. A compound of Claim 54 wherein R2 is hydrido.
61. A compound of Claim 53 wherein R4 is phenyl substituted with one or more fluoro, chloro or bromo.
62. A compound of Claim 54 wherein R4 is phenyl substituted with one or more fluoro, chloro or bromo.
63. A compound of Claim 53 wherein R1 and R2 are selected independently from hydrido, methyl and ethyl.
SUBSTmJϊESHEET(RUlJEfiβ)
64. A compound of Claim 54 wherein R1 and R2 are selected independently from hydrido, methyl and ethyl.
65. A compound of Claim 53 wherein Z represents a carbon atom.
66. A compound 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.
67. A compound of Claim 66 wherein Z represents a carbon atom; and
R1 is selected from hydrido, methyl, hydroxyethyl, propargyl ; and
SU8STITUTESHEEr(RUL£26) 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 .
68. A compound of Claim 67 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.
69. A compound of Claim 1 selected from compounds, their tautomers and their pharmaceutically acceptable salts, of the group consisting of
4- [5- (3-fluoro-4 -methoxyphenyl) -3-methyl-lH-pyrazol-4- yl] pyridine;
4- (3 -methyl-5-phenyl-IH-pyrazol-4-yl) pyridine ;
4- [5-methyl-3- (2 -methylphenyl) -lH-pyrazol-4-yl] pyridine;
4- [3- (4-fluorophenyl) -5-methyl-lH-pyrazol-4-yl] pyridine;
4- [5-methyl-3- (4-methylphenyl) -lH-pyrazol-4-yl] pyridine; 4- [5-methyl-3- [4- (methylthio) phenyl] -lH-pyrazol-4- yl] pyridine;
4- [3- (4-chlorohpenyl) -5-methyl-IH-pyrazol-4-yl] pyridine;
4- [3-methyl-5- (3 -methylphenyl) -lH-pyrazol-4-yl] pyridine;
4- [5- (2, 5-dimethylphenyi) -3 -methyl-IH-pyrazol-4- yl] pyridine;
4- [5- (1, 3-benzodioxol-5-yl) -3-methyl-lH-pyrazol-4- yl] pyridine;
4- [3-methyl-5- (4 -phenoxyphenyl) -lH-pyrazol-4-yl] pyridine ;
4- [5- [ (1, 1' -biphenyl) -4-yl] -3-methyl-lH-pyrazol-4- yl] pyridine;
4- [3-methyl-5- [3- (phenoxyphenyl) -lH-pyrazol-4- yl] pyridine;
4- [3-methyl-5- [3- (phenylmethoxy) phenyl] -lH-pyrazol-4- yl] pyridine; 4- [3-methyl-5- [2- (phenylmethoxy) phenyl] -lH-pyrazol-4- yl] pyridine;
2- [3-methyl-4- (4-pyridinyl) -lH-pyrazol-4-yl] phenol;
3- [3-methyl-4- (4-pyridinyl) -IH-pyrazol-4-yl] phenol ; 1-hydroxy-4- (3 -methyl-5-phenyl-IH-pyrazol-4- yl] pyridinium;
5- (4-fluorophenyl) -N, N-dimethyl-4- (4-pyridinyl) -IH- pyrazol-3 -amine ;
5- (4-fluorophenyl) -N-phenyl-4- (4-pyridinyl) -lH-pyrazol-3- amine; 4- [5- (4-fluorophenyl) -3 -phenyl-IH-pyrazol-4- yl] pyridine;
4- [5- (3 -methylphenyl) -3- (trifluoromethyl) -lH-pyrazol-4- yl] pyridine;4- [3- (4-fluorophenyl) -4- (4-pyridinyl) -IH- pyrazol-5-yl] pyridine; 4- (5-cyclohexyl) -3 -methyl-IH-pyrazol-4-yl) pyridine; 4- [5- (3-fluoro-5-methoxyphenyl) -3 -methyl-IH-pyrazol-4- yl] pyridine;
4- [5- (3 -methylphenyl) -3 -propyl-IH-pyrazol-4-yl] yridine; 4- [ (3-methyl-5-phenyl-lH-pyrazol-4-yl) methyl] pyridine; 4- [3 , 5-bis (3 -methylphenyl) -lH-pyrazol-4-yl] pyridine; 4- [4-methyl-2- (2 -trifluorophenyl) -lH-pyrazol-4- yl] pyridine;
4- [3- (2-chlorophenyl) -5-methyl-lH-pyrazol-4-yl] pyridine; 4- [5-methyl-3- (2 , 4-dimethylphenyl) -lH-pyrazol-4- yylx]j pyyr.iludiinuce;;
4- [5- (4-chlorophenyl) -1, 3-dimethyl-lH-pyrazol-4- yl] pyridine;
4- [3- (3-fluoro-2-methylphenyl) -5-methyl-IH-pyrazol■ •4-
SϋBSmUTE8HEET(RϋlJE26) yl] pyridine;
4- [3- (3, 5-dimethylphenyl) -5-methyl-lH-pyrazol-4- yl] pyridine;
4- [3- (3, 5-dimethoxyphenyl) -5-methyl-lH-pyrazol-4- yl] pyridine;
4- [5-methyl-3- (3-nitrophenyl) -IH-pyrazol-4-yl] pyridine;
N,N-dimethyl-4- [5-methyl-4- (4-pyridinyl) -lH-pyrazol-3 yl] benzenamine;
4- [3- (2 , 3-dihydrobenzofuran-5-yl) -5-methyl-IH-pyrazol-4- yl] pyridine;
4- [3- (4-bromophenyl) -5-methyl-lH-pyrazol-4-yl] pyridine;
4- [3- (2-fluorophenyl) -5-methyl-lH-pyrazol-4-yl] pyridine; 4- [3- (3-fluorophenyl) -5-methyl-lH-pyrazol-4-yl] pyridine;
4- [3-methyl-5- [3- (trifluoromethyl) phenyl] -lH-pyrazol-4 yl] pyridine;
4 - (3 -ethyl-4 -phenyl-IH-pyrazol-4-yl) yridine ;
4- [5- (3-methoxyphenyl) -3 -methyl-IH-pyrazol-4-yl}pyridine; 4- [3-ethyl-5- (3 -methylphenyl) -lH-pyrazol-4-yl] pyridine;
4- [5- (3, 4 -difluorophenyl) -3 -methyl-IH-pyrazol-4- yl] pyridine;
4- [5- (3-ethoxyphenyl) -3-methyl-lH-pyrazol-4-yl] pyridine;
4- [3-methyl-5- [4- (trifluoromethyl) phenyl] -lH-pyrazol-4- yl] pyridine ;
4- [3-methyl-5- (3-thienyl) -lH-pyrazol-4-yl] pyridine ;
4- [5- (2, 4-dichlorophenyl) -3-methyl-IH-pyrazol-4- yl] pyridine;
4- [5- (3 -chlorophenyl) -3-methyl-lH-pyrazol-4-yl] pyridine; 4- [5- (3 -chloro-4-methoxyphenyl) -3 -methyl-IH-pyrazol-4- yl] pyridine; ethyl 3- (4 -chlorophenyl) -4- (4-pyridinyl) -lH-pyrazole-5- propanoate;
4- [3- (4-fluorophenyl) -l-methyl-pyrazol-4-yl] pyridine; 5- [5- (3 -chlorophenyl) -3 -methyl-IH-pyrazol-4-yl] pyrimidin-
2 -amine ;
5- [3-methyl-5- (3-methylphenyl) -IH-pyrazol-4-yl] pyrimidin-
2 -amine ;
SUBSmUTESHEEr(RUL£26) 5- [3-methyl-5- (2-methylphenyl) -IH-pyrazol-4 -yl] pyrimidin- 2 -amine;
5- [5- (4 -chlorophenyl) -3-methyl-lH-pyrazol-4-yl] pyrimidin-
2 -amine;
5- [5- (4-fluorophenyl) -3-methyl-lH-pyrazol-4-yl] pyrimidin-
2 -amine; 5- [5- ( -methoxyphenyl) -3 -methyl-IH-pyrazol-4- yl] pyrimidin-2-amine ;
5- [5- (3 -chlorophenyl) -3-methyl-lH-pyrazol-4-yl] pyridin-2- amine ;
4- [5- (3 -chlorophenyl) -3 -methyl-IH-pyrazol-4-yl] pyridin-2- amine;
4- [5- (3 -methylphenyl) -3-methyl-lH-pyrazol-4-yl] pyridin-2- amine ;
4- [5- (2-methylphenyl) -3-methyl-lH-pyrazol-4-yl] pyridin-2- amine ; 4- [5- (4-chlorophenyl) -3-methyl-lH-pyrazol-4-yl] pyridin-2- amine ;
4- [5- (4-fluorophenyl) -3-methyl-lH-pyrazol-4-yl] pyridin-2- amine ;
4- [5- (4-methoxyphenyl) -3-methyl-lH-pyrazol-4-yl] pyridin- 2-amine;
5- [5- (3 -chlorophenyl) -3-methyl-IH-pyrazol-4-yl] -2- methoxypyridine ;
2 -methoxy-5- [3 -methyl-5- (3 -methylphenyl) -IH-pyrazol-4- yl] pyridine; 2-methoxy-5- [5- (4-methoxyphenyl) -3-methyl-lH-pyrazol-4- yl] pyridine;
4- [5- (3 -chlorophenyl) -3-methyl-lH-pyrazol-4-yl] -2- methoxypyridine ;
2-methoxy-4- [3-methyl-5- (3 -methylphenyl) -IH-pyrazol-4- yl] pyridine ;
2-methoxy-4- [3-methyl-5- (2-methylphenyl) -lH-pyrazol-4- yl] pyridine;
4- [5- (4 -chlorophenyl) -3 -methyl-IH-pyrazol-4-yl] -2- methoxypyridine ;
SϋBSπTUTE8HEEr(Rϋl£26) 125 4- [5- (4 -fluorophenyl) -3-methyl-lH-pyrazol-4-yl] -2- methoxypyridine ;
2-methoxy-4- [3 -methyl-5- (4-methylphenyl) -lH-pyrazol-4- yl] pyridine;
5- [5- (3 -chlorophenyl) -3-methyl-lH-pyrazol-4-yl] pyridin-2- 130 ol;
4- [5- (3 -chlorophenyl) -3-methyl-lH-pyrazol-4-yl] pyridin-2- ol;
4- [5- (3 -methylphenyl) -3-methyl-lH-pyrazol-4-yl] pyridin-2- ol; 135 4- [5- (2 -methylphenyl) -3-methyl-lH-pyrazol-4-yl] pyridin-2- ol;
4- [5- (4 -chlorophenyl) -3-methyl-lH-pyrazol-4-yl] pyridin-2- ol;
4- [5- (4-fluorophenyl) -3-methyl-lH-pyrazol-4-yl] yridin-2- 140 ol;
4- [5- (4 -methoxyphenyl) -3-methyl-lH-pyrazol-4-yl] pyridin-
2-ol;
5- [5- (3 -chlorophenyl) -3 -methyl-IH-pyrazol-4-yl] pyridine-
2 -methanamine ; 145 4- [5- (3 -chlorophenyl) -3 -methyl-IH-pyrazol-4-yl] pyridine-
2 -methanamine;
4- [5- (3 -methylphenyl) -3-methyl-lH-pyrazol-4-yl] pyridine-
2-methanamine ;
4- [5- (2-methylphenyl) -3 -methyl-IH-pyrazol-4-yl] pyridine- 150 2-methanamine;
4- [5- (4-chlorophenyl) -3-methyl-lH-pyrazol-4-yl] pyridine-
2-methanamine ;
4- [5- (4-fluorophenyl) -3-methyl-lH-pyrazol-4-yl] pyridine-
2-methanamine ; 155 4- [5- (4-methoxyphenyl) -3-methyl-lH-pyrazol-4-yl] pyridine-
2-methanamine ;
5- [5- (3 -chlorophenyl) -3 -methyl-IH-pyrazol-4-yl] pyridine-
2-carboxamide ;
4- [5- (3 -chlorophenyl) -3 -methyl-IH-pyrazol-4-yl] yridine- 160 2-carboxamide;
SϋBSiπUTESHEEr(RϋLE28) 4- [5- (3 -methylphenyl) -3 -methyl-IH-pyrazol-4-yl] pyridine-
2 -carboxamide ;
4- [5- (2 -methylphenyl) -3 -methyl-IH-pyrazol-4-yl] pyridine-
2 -carboxamide ; 4- [5- (4 -chlorophenyl) -3-methyl-lH-pyrazol-4-yl] pyridine-
2 -carboxamide ;
4- [5- (4-fluorophenyl) -3-methyl-lH-pyrazol-4-yl] pyridine-
2 -carboxamide;
4- [5- (4-methoxyphenyl) -3-methyl-lH-pyrazol-4-yl] pyridine- 2 -carboxamide ;
4- [5- (3-fluoro-4 -methoxyphenyl) -3-methyl-lH-pyrazol-4- yl] pyridine;
4- [5- (4-fluoro-3 -methoxyphenyl) -3-methyl-lH-pyrazol-4- yl] pyridine; 4- [5- (4 -chloro-3 -methoxyphenyl) -3-methyl-lH-pyrazol-4- yl] pyridine;
4- [5- (2, 3-dihydrobenzofuran-6 -yl) -3 -methyl-IH-pyrazol-4- yl] pyridine;
4- [5- (benzofuran-6-yl) -3 -methyl-IH-pyrazol-4-yl] pyridine; 4- [5- (3-fluoro-5-methoxyphenyl) -3-methyl-lH-pyrazol-4- yl] pyridine;
4- [5- (3 -chloro-5-methoxyphenyl) -3 -methyl-lH-pyrazol-4- yl] pyridine ;
4- [5- (1-cyclohexyen-l-yl) -3 -methyl-IH-pyrazol-4- yl] pyridine;
4- [5- (1, 3-cyclohexadien-l-yl) -3 -methyl-IH-pyrazol-4 - yl] pyridine;
4- [5- (5, 6-dihydro-2H-pyran-4-yl) -3 -methyl-IH-pyrazol-4- yl] pyridine; 4- (5-cyclohexyl-3-methyl-lH-pyrazol-4-yl) pyridine;
4- [5- (4-methoxy-3 -methylphenyl) -3 -methyl-IH-pyrazol-4- yl] pyridine;
4- [5- (3 -methoxy-4 -methylphenyl) -3 -methyl-IH-pyrazol-4- yl] pyridine; 4- [5- (3 -methoxy-5-methylphenyl) -3-methyl-lH-pyrazol-4- yl] pyridine;
8UBSTnUTESHEET(RULE26) 4-[5- (3-furyl) -3-methyl-lH-pyrazol-4-yl] pyridine;
2 - -m...ethnyyll--44-- ((33*-methyl-5-phenyl-IH-pyrazol-4-yl) pyridine;
2-methoxy-4 - (3 -methyl-5-phenyl-IH-pyrazol-4 -yl) pyridine ; methyl 4- (3-methyl-5-phenyl-lH-pyrazol-4-yl) pyri-dine-2- carboxylate ;
4- (3 -methyl-5-phenyl-IH-pyrazol-4-yl) pyridine-2- carboxamide ;
1- [4- (3-methyl-5-phenyl-lH-pyrazol-4-yl)pyridin-2- yl] ethanone ,•
N,N-dimethyl-4- (3 -methyl-5-phenyl-IH-pyrazol-2- yl) pyridin-2-amine;
3 -methyl-4 - (3 -methyl-5-phenyl-IH-pyrazol-4 -yl) pyridine ;
3 -methoxy-4- (3 -methyl-5-phenyl-IH-pyrazol-4 -yl) pyridine ; methyl 4- (3 -methyl-5-phenyl-IH-pyrazol-4-yl) pyridine-3 - carboxylate;
4 - (3 -methyl-5-phenyl-IH-pyrazol-4 -yl) pyridine-3 - carboxamide ;
1- [4- (3-methyl-5-phenyl-lH-pyrazol-4-yl)pyridin-3- yl] ethanone;
3 -bromo-4 - (3 -methyl-5-phenyl-IH-pyrazol-4 -yl) pyridine ;
N,N-dimethyl-4- (3 -methyl-5-phenyl-IH-pyrazol-2- yl) pyridin-3 -amine ;
2-methyl-4- (3 -methyl-5-phenyl-IH-pyrazol-4 -yl) pyrimidine ; 4- (3 -methyl-5-phenyl-IH-pyrazol-4-yl) pyrimidine;
2-methoxy-4 - (3 -methyl-5-phenyl-IH-pyrazol-4- yl) pyrimidine ;
4- (3 -methyl-5-phenyl-IH-pyrazol-4 -yl) pyrimidin-2-amine ;
N,N-dimethyl-4- (3 -methyl-5-phenyl-IH-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) -lH-pyrazole;
4- (3-furyl) -3 -methyl-5-phenyl-lH-pyrazole ;
33 --mmeethyl-5-phenyl-4- (2-thienyl) -lH-pyrazole;
44 - (2 -furyl) -3 -methyl-5-phenyl-lH-pyrazole ;
4- (3-isothiazolyl) -3 -methyl-5-phenyl-lH-pyrazole
4- (3-isoxazolyl) -3 -methyl-5-phenyl-lH-pyrazole;
4- (5-isothiazolyl) -3 -methyl-5-phenyl-lH-pyrazole; 4- (5-isoxazolyl) -3 -methyl-5-phenyl-lH-pyrazole ,•
3 -methyl-5-phenyl-4- (5-thiazolyl) -lH-pyrazole;
3-methyl-4- (5-oxazolyl) -5 -phenyl-lH-pyrazole;
4- [3- (4-fluorophenyl) -lH-pyrazol-4-yl] pyridine ;
2-methyl-4- [3- (3 -methylphenyl) -lH-pyrazol-4-yl] pyridine; 4- (1-methyl-3 -phenyl-IH-pyrazol-4-yl) pyridine;
4- (3 -phenyl-IH-pyrazol-4 -yl) pyridine ;
2 -methyl-4 - (3 -phenyl-IH-pyrazol-4 -yl) pyridine ;
4- [3- (3 -chlorophenyl) -1-methyl-pyrazol-4-yl] pyridine;
4- [3- (4 -chlorophenyl) -l-methyl-pyrazol-4-yl] pyridine; 4- [3- (3 -chlorophenyl) -IH-pyrazol-4-yl] pyridine;
4- [3- (4 -chlorophenyl) -lH-pyrazol-4-yl] pyridine;
4- [3- (3 -chlorophenyl) -lH-pyrazol-4-yl] -2-methylpyridine;
4- [3- (3-fluorophenyl) -l-methyl-lH-pyrazol-4-yl] pyridine;
4- [3- (3-fluorophenyl) -IH-pyrazol-4-yl] pyridine; 4- [3- (3 -chlorophenyl) -l-methyl-pyrazol-4-yl] -2- methylpyridine ;
5- ( -chlorophenyl) -N-phenyl-4- (4 -pyridinyl) -IH-pyrazol-3 amine ;
5- (4-chlorophenyl) -N-methyl-4- (4 -pyridinyl) -IH-pyrazol-3 amine;
5- (4 -chlorophenyl) -N,N-dimethyl-4- (4 -pyridinyl) -IH- pyrazol-3 -amine dihydrate;
5- (3-fluorophenyl) -N,N-dimethyl-4- (4-pyridinyl) -IH- pyrazol-3 -amine ; N,N-dimethyl-5- (3 -methylphenyl) -4- (4-pyridinyl) -1H- vrazol-3 -amine ; methyl-5- (3 -methylphenyl) -4- (4 -pyridinyl) -IH-pyrazol-3 catmLiiiinnee;;
N N--eetthhyl-5- (3 -methylphenyl) -4- (4 -pyridinyl) -lH-pyrazol-3- aammiinnee ;;
N,N-diethyl-5- (3 -methylphenyl) -4- (4 -pyridinyl) -IH- pyrazol-3 -amine ;
5- (4-chlorophenyl) - N,N-diethyl-4- (4-pyridinyl) -IH-
SUBSmUTE8HEEr(RϋLE2β) pyrazol-3 -amine ; 270 4- [5- (4 -chlorophenyl) -4- (4-pyridinyl) -lH-pyrazol-3- yl] morpholine;
5- (4 -chlorophenyl) -N-propyl-4- (4 -pyridinyl) -lH-pyrazol-3- amine ;
5- (4-chlorophenyl) -N- (phenylmethyl) -4- ( -pyridinyl) -1H- 275 pyrazol-3 -amine hydrate (2:1);
5- (4 -chlorophenyl) -N- (2-methoxyethyl) -4- (4 -pyridinyl) -IH- pyrazol-3 -amine monohydrate;
1, l-dimethylethyl-4- [5- (4 -chlorophenyl) -4- (4-pyridinyl) -
IH-pyrazol-3 -yl] -1-piperazinecarboxylate ; 280 1- [5- ( -chlorophenyl) -4- (4-pyridinyl) -lH-pyrazol-3- vyTl1] pii npeerraazziinnee ttrriihhvyddrroocchhlloorriiddee,:
1- [5- (4-chlorophenyl) -4- (4-pyridinyl) -lH-pyrazol-3-yl] -4- methylpiperazine;
1, 1-dimethylethyl 4- [5- (4-fluorophenyl) -4- (4 -pyridinyl) - 285 lH-pyrazol-3-yl] -1-piperazinecarboxylate;
1- [5- (4-fluorophenyl) -4- (4-pyridinyl) -lH-pyrazol-3- yl] piperazine trihydrochloride ;
1- [5- (4-chlorophenyl) -4- (4 -pyridinyl) -lH-pyrazol-3- yl] piperazine ; 290 N- [5- (4 -chlorophenyl) -4- [2- (phenylmethyl) amino] -4- pyridinyl] -IH-pyrazol-3 -yl] -1, 3 -propanediamine , trihydrochloride ;
1- [5- (4-chlorophenyl) -4- (4-pyridinyl) -lH-pyrazol-3-yl] -4*
(phenylmethyl) piperazine; 295 4- [3- (4-fluorophenyl) -5- (1-piperazinyl) -lH-pyrazol-4- yl] pyrimidine , dihydrochloride ;
1, 1-dimethylethyl [3- [ [5- (4-chlorophenyl) -4- (4- pyridinyl) -IH-pyrazol-3 -yl] amino] propyl] carbamate;
N- [5- [4 -chlorophenyl) -4- (4-pyridinyl) -lH-pyrazol-3-yl] - 300 1, 3 -propanediamine, trihydrochloride monohydrate;
1, 1-dimethylethyl [2- [ [5- (4-chlorophenyl) -4- (4- pyridinyl) -IH-pyrazol-3 -yl] amino] ethyl] carbamate;
1, 1-dimethylethyl 4- [5- (4-chlorophenyl) -1- (2- hydroxyethy1) -4- (4-pyridinyl) -IH-pyrazol-3 -yl] -1-
8UBOTUTESHEET(RULE26) 305 piperazinecarboxylate;
1, 1-dimethylethyl 4- [5- (4-fluorophenyl) -4- (4- pyrimidinyl) -lH-pyrazol-3-yl] -1-piperazinecarboxylate;
1, 1-dimethylethyl [3- [ [5- (4 -chlorophenyl) -4- (2-fluoro-4- pyridinyl) -lH-pyrazol-3-yl] amino] propyl] carbamate; 310 1- [5- (4 -chlorophenyl) -4- (4-pyridinyl) -lH-pyrazol-3-yl] -4- ethylpiperazine ;
N- [5- (4 -chlorophenyl) -4- (4-pyridinyl) -lH-pyrazol-3-yl] -
1, 2-ethanediamine;
4- [3- (2, 6 -difluorophenyl) -5-methyl-IH-pyrazol-4- 315 yl] pyridine ;
4- [3- (3 -ethyIpheny1) -5-methyl-lH-pyrazol-4-yl] pyridine;
4- [3- (3 -chlorophenyl) -5-ethyl-lH-pyrazol-4-yl] pyridine;
4- [3-ethyl-5- (3-ethylphenyl) -lH-pyrazol-4-yl] pyridine;
4- [3- (4 -chlorophenyl) -5- (1-methylethyl) -lH-pyrazol-4- 320 yl] pyridine;
4- [3-cyclopropyl-5- (4-fluorophenyl) -lH-pyrazol-4- yl] pyridine;
4- [3- (4-fluorophenyl) -5- (trifluoromethyl) -lH-pyrazol-4- yl] pyridine; 325 4- [5- (cyclopropyl-3- (4- (fluorophenyl) -1-methyl-lH- pyrazol-4 -y1] pyridine ;
5-cyclopropyl-3- (4-fluorophenyl) -4- ( -pyridinyl) -1H- pyrazole-1-ethanol ;
3- (4-fluorophenyl) -5- (2 -methoxy-4 -pyridinyl) -4- (4- 330 pyridinyl) -lH-pyrazole-1-ethanol;
4- [3- (4-fluorophenyl) - 1- (2 -hydroxyethyl) -4- (4 -pyridinyl)
IH-pyrazol-5-yl] -2 (IH) -pyridinone; l-acetyl-4- [3- (4-fluorophenyl) -1- (2-hydroxyethyl) -4- (4- pyridinyl) -IH-pyrazol-5-yl] -2 (IH) -pyridinone; 335 Ethyl 2- [3- (4-fluorophenyl) -1- (2-hydroxyethyl) -4- (4- pyridinyl) -lH-pyrazol-5-yl] cyclopropanecarboxylate;
2- [3- (4-fluorophenyl) -1- (2-hydroxyethyl) -4- (4 -pyridinyl) lH-pyrazol-5-yl] cyclopropanecarboxylic acid;
3- (4-fluorophenyl) -5- (4 -imidazolyl) -4- (4-pyridinyl) -1H- 340 pyrazole-1-ethanol;
SUBSmUTE8t«Er(R JE26) 4- [3- (4-chloro-3-methylphenyl) -lH-pyrazol-4-yl] pyridine
5- (4-fluorophenyl) -4- (4-pyridinyl) -lH-pyrazole-3- carboxylic acid;
5- (4-fluorophenyl) -4- (4-pyridinyl) -lH-pyrazole-3- 345 methanol;
1- t [5- (4-fluorophenyl) -4- (4-pyridinyl) -lH-pyrazol-3- yl] carbonyl] piperazine;
1, 1-dimethylethyl 4- [ [5- (4-fluorophenyl) -4- (4-pyridinyl) - lH-pyrazol-3-yl] carbonyl] -1-piperazinecarboxylate; 350 4- (1, 5-dimethyl-3-phenyl-lH-pyrazol-4-yl)pyridine;
4- (1, 3-dimethyl-5-phenyl-lH-pyrazol-4-yl] yridine;
4- [3- (4 -chlorophenyl) -1, 5-dimethyl-lH-pyrazol-4- yl] pyridine;
4- [5- (4 -chlorophenyl) -1, 3-dimethyl-lH-pyrazol-4- 355 yl] pyridine;
4- [5-ethyl-1-methyl-3- (3 -methylphenyl) -IH-pyrazol-4- yl] pyridine;
4- [3 -ethyl-1-methyl-5- (3 -methylphenyl) -lH-pyrazol-4- yl] pyridine; 360 4- [3- (4-chlorophenyl) -l-ethyl-5-methyl-lH-pyrazol-4- yl] pyridine;
4- [3- (4-chlorophenyl) -2-ethyl-5-methyl-IH-pyrazol-4- yl] pyridine;
4- [3- (4-fluorophenyl) -lH-pyrazol-4-yl] pyridine; 365 4- [3- (2-chlorophenyl) -IH-pyrazol-4-yl] pyridine;
3- (4-fluorophenyl) -4- (4-pyridinyl) -lH-pyrazole-1-ethanol;
3- (4-fluorophenyl) -4- (4 -pyrimidinyl) -lH-pyrazole-1- ethanol ;
4- [3- (4-fluorophenyl) -l-methyl-lH-pyrazol-4-yl] pyridine; 370 2- t [4- [3- (4-fluorophenyl) -lH-pyrazol-4-yl] -2- pyridinyl] amino] -1-butanol;
4- [5-bromo-3- (4-fluorophenyl) -l-methyl-lH-pyrazol-4- yl] pyridine;
4- [3- (4-fluorophenyl) -lH-pyrazol-4-yl] -2- 375 pyridinecarbonitrile;
4- [2- [3- (4-fluorophenyl) -4- (4-pyridinyl) -IH-pyrazol-1-
8UBOTFtfrESHEET(RUlEfi8) yl] ethyl] morpholine;
3- (4-fluorophenyl) -l-methyl-α-phenyl-4- (4-pyridinyl) -1H- pyrazole-5-methanol ; 380 N- [5- (4-fluorophenyl) -4- (4-pyridinyl) -lH-pyrazol-3-yl] -4- morpholineethanamine ;
4- [3- (3 -chlorophenyl) -lH-pyrazol-4-yl] -2 (IH) -pyridinone hydrazone ;
4- [3- (3 -chlorophenyl) -lH-pyrazol-4-yl] -N- (phenylmethyl) - 385 2 -pyridinamine;
4- [3- (3 -chlorophenyl) -lH-pyrazol-4-yl] -N- (phenylethyl) -2- pyridinamine ;
4- [3- (3 -chlorophenyl) -lH-pyrazol-4-yl] -N-ethyl-2- pyridinamine ; 390 4- [3- (4 -fluorophenyl) -lH-pyrazol-4-yl] -2- pyridinecarboxamide ;
Methyl 4- [3- (4-fluorophenyl) -lH-pyrazol-4-yl] -2- pyridinecarboxylate ;
4- [3- (4-fluorophenyl) -lH-pyrazol-4-yl] -N-methyl-2- 395 pyridinecarboxamide ;
4- [3- (4-fluorophenyl) -lH-pyrazol-4-yl] -2- pyridinecarboxylic acid;
4- [3- (3-fluorophenyl) -IH-pyrazol-4-yl] pyridine;
4- [3- (1, 3-benzodioxol-5-yl) -lH-pyrazol-4-yl] pyridine; 400 4- [3- (3-fluorophenyl) -l-methyl-lH-pyrazol-4-yl] pyridine;
4- [3- (4-chlorophenyl) -lH-pyrazol-4-yl] pyridine;
4- [3- (1, 3-benzodioxol-5-y) -l-methyl-lH-pyrazol-4-yl] pyrid ine;
4- [3- (4-chlorophenyl) -l-methyl-lH-pyrazol-4-yl] pyridine; 405 4- [3- (3 -chlorophenyl) -1-methyl-IH-pyrazol-4-yl] -2-methylp yridine; 4- [5- (3 -chlorophenyl) -1-methyl-IH-pyrazol-4 -yl] -2-methylpyridine;
4- [3- (3 -chlorophenyl) -l-methyl-lH-pyrazol-4-yl] pyridine;
4- [5- (3 -chlorophenyl) -l-methyl-lH-pyrazol-4-yl] pyridine; 410 2-methyl-4- [l-methyl-3- (3 -methylphenyl) -lH-pyrazol-4 -yl] pyridine; 2-methyl-4- [l-methyl-5- (3 -methylphenyl) -lH-pyrazol-4
SϋrømUTESi«Er(fWLE26) -yl] pyridine ;
4 - (3 -phenyl-IH-pyrazol-4 -yl) pyridine ; 4- [3- [3- (trifluoromethyl) phenyl] -lH-pyrazol-4-yl] pyridine
/
4- [l-methyl-3- [3- (trifluoromethyl) phenyl] -lH-pyrazol-4-yl
] yridine ;
4- [3- (3 , 4 -difluorophenyl) -lH-pyrazol-4-yl] pyridine; 4- [3- (4 -chlorophenyl) -lH-pyrazol-4-yl] -2-fluoropyridme;
4- [3- (4 -bromophenyl) -lH-pyrazol-4yl] pyridine;
4- [3- (3 , 4 -difluorophenyl) -l-methyl-lH-pyrazol-4-yl] pyridi ne;
4- [3- (4 -bromophenyl) -1-methyl-IH-pyrazol-4-yl] pyridine; (E) -4- [3- (4 -fluorophenyl) -lH-pyrazol-4-yl] -2- (2-phenyleth enyl) pyridine ;
(S) -4- [3- (4 -chlorophenyl) -lH-pyrazol-4-yl] -N- (2-methylbut yl) - 2 -pyridinamine;
4- [3- (4 -chlorophenyl) -lH-pyrazol-4-yl] -N- [ (4-methoxy- phenyl) methyl] - 2 -pyridinamine ;
N- [4- [3- (4 -chlorophenyl) -lH-pyrazol-4-yl] -2-pyridinyl] -
2 -pyridinemethanamine ;
N- [4- [3- (4-fluorophenyl) -lH-pyrazol-4-yl] -2-pyridinyl] -
2 -pyridinemethanamine; 2-fluoro-4- [3- (4-fluorophenyl) -lH-pyrazol-4-yl] yridine ;
4- [3- (4-iodophenyl) -lH-pyrazol-4-yl] pyridine;
4- [3- (4-iodophenyl) -l-methyl-lH-pyrazol-4-yl] pyridine;
4- [l-methyl-3- [4- (trifluoromethyl) phenyl] -lH-pyrazol-4-yl
] pyridine ; N- [1- (4-fluorophenyl) ethyl] -4- [3- (4-fluorophenyl) -IH-pyra zol-4-yl] -2-pyridinamine;
N- [ (3 -fluorophenyl) methyl] -4- [3- (4-fluorophenyl) -IH-pyraz ol-4-yl] -2-pyridinamine ;
4- [3- (4-fluorophenyl) -l-methyl-lH-pyrazol-4-yl] -2- (1- methylhydrazino) pyridine ;
2-fluoro-4- [3- (4-fluorophenyl) -1-methyl-IH-pyrazol-4 -yl] p yridine ;
[3- (3, 4-difluorophenyl) -lH-pyrazol-4-yl] -2-fluoro-
SϋKmuτE8HEET(RϋL£26) pyridine ; 450 4- [3- (4-fluorophenyl) -lH-pyrazol-4-yl] -3-methylpyridine;
4- [3- (4-fluorophenyl) -l-methyl-lH-pyrazol-4-yl] -3-methyl- pyridine ;
4- [3- (3, 4 -difluorophenyl) -l-methyl-lH-pyrazol-4-yl] -2-flu oropyridine ; 455 3- (4-fluorophenyl) -N,N-dimethyl-4- (4-pyridinyl) -IH-pyrazo le-1-ethanamine ;
2- [2- (4-fluorophenyl) ethyl] -4- [3- (4-fluorophenyl) -1- methyl-lH-pyrazol-4-yl] pyridine;
4- [3- (4-fluorophenyl) -lH-pyrazol-4-yl] -N- [1- 460 (phenylmethyl) -4 -piperidinyl] -2 -pyridinamine;
N' - [4- [3- (4 -fluorophenyl) -lH-pyrazol-4-yl] -2-pyridinyl] -
N, N-dimethyl-1,2 -ethanediamine ;
2 , 4-bis [3- (4-fluorophenyl) -lH-pyrazol-4-yl] pyridine;
N- [4- [3- (4-fluorophenyl) -lH-pyrazol-4-yl] -2-pyridinyl] -4- 465 morpholineethanamine;
3- (4-fluorophenyl) -4- (2-fluoro-4 -pyridinyl) -lH-pyrazole-
1-ethanol;
4- [3- (4-fluorophenyl) -lH-pyrazol-4-yl] -N- [2- (lH-imidazol-
1-yl) ethyl] -2 -pyridinamine; 470 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] -lH-pyrazole-1-ethanol;
3- (4-fluorophenyl) -4- (2-fluoro-4 -pyridinyl) -N,N-dimethyl- 475 lH-pyrazole-1-ethanamine;
3- (4-fluorophenyl) -4- [2- [2- (4-fluorophenyl) ethyl] -4- pyridinyl] -lH-pyrazole-1-ethanol ;
4- [1- [2- (dimethylamino) ethyl] -3- (4-fluorophenyl) -IH- pyrazol-4-yl] -N,N-dimetnyl-2-pyridinamine; 480 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-lH-pyrazole-l-ethanamine;
N- [ (4-fluorophenyl) methyl] -4- [3 (or 5) - (4-fluorophenyl) -1-
eUBSmUTESHEET(RULE26) 485 [ [2- (4 -morpholinyl) ethyl] -lH-pyrazol-4-yl] -2- pyridinamine ;
4- [3- (4-fluorophenyl) -lH-pyrazol-4-yl] -N-4-piperadinyl-2- pyridinamine ;
N,N-diethyl-3- (4-fluorophenyl) -4- (2-fluoro-4-pyridinyl) - 490 lH-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) -lH-pyrazol-4-yl] -2- pyridinyl] amino] ethanol ; 495 2- [ [4- [3- (4 -fluorophenyl) -l-methyl-lH-pyrazol-4-yl] -2- pyridinyl] amino] ethanol;
3- [ [4- [3- (4-fluorophenyl) -lH-pyrazol-4-yl] -2- pyridinyl] amino] -1-propanol;
3- (4-fluorophenyl) -4- [2- [ [ (4-fluorophenyl) methyl] amino] - 500 4 -pyridinyl] -lH-pyrazole-1-ethanol;
5- (4-fluorophenyl) -4- [2- [ [ (4-fluorophenyl) ethyl] amino] -
4-pyridinyl] -lH-pyrazole-1-ethanol;
N,N-diethyl-3- (4-fluorophenyl) -4- (4-pyridinyl) -1H- pyrazole-1-ethanamine ; 505 N- [ (4 -fluorophenyl) methyl] -4- [3- (4-fluorophenyl) -1- [2- (4- morpholinyl) ethyl] -lH-pyrazol-4-yl] -2 -pyridinamine;
N- [5- (4-fluorophenyl) -4- (4-pyridinyl) -lH-pyrazol-3-yl] -4- morpholinepropanamine ;
N' - [5- (4-fluorophenyl) -4- (4-pyridinyl) -lH-pyrazol-3-yl] - 510 N,N-dimethyl-l, 3 -propanediamine ;
5- (4-fluorophenyl) -N-2-propynyl-4- (4-pyridinyl) -IH- pyrazol-3 -amine ;
3- (4-fluorophenyl) -4- [2- [ [ (4-fluorophenyl) methyl] amino] - -pyridinyl] -lH-pyrazole-1-ethanol; 515 5- (4-fluorophenyl) -4- [2- [ [ (4-fluorophenyl) methyl] amino] -
4-pyridinyl] -lH-pyrazole-1-ethanol;
4- [3- [ (4-fluorophenyl) -lH-pyrazol-4-yl] quinoline;
N- [5- (4-fluorophenyl) -4- (4-pyridinyl) -lH-pyrazol-3- yl] glycine methyl ester; 520 N- [5- (4-fluorophenyl) -4- (4-pyridinyl) -lH-pyrazol-3-
yl] glycine;
4- [3- (4-fluorophenyl) -1- (2-propynyl) -lH-pyrazol-4- yl] pyridine;
4- [5- (4-fluorophenyl) -1- (2-propynyl) -lH-pyrazol-4- 525 yl] pyridine ;
4,4'- (lH-pyrazole-3, 4-diyl) bis [pyridine] ;
4- [3- (3, 4-dichlorophenyl) -lH-pyrazol-4-yl] pyridine;
N- [5- (4 -chlorophenyl) -4- (4-pyridinyl) -lH-pyrazol-3-yl] -4- piperidinamine ; 530 2-Chloro-4- [3- (4-fluorophenyl) -lH-pyrazol-4- yl] pyrimidine ;
4- [3- (4-fluorophenyl) -lH-pyrazol-4-yl] -2 (IH) -pyrimidinone hydrazone;
4- [3- (4-fluorophenyl) -lH-pyrazol-4-yl] -N,N-dimethyl-2- 535 pyrimidinamine;
4- [3- (4-fluorophenyl) -lH-pyrazol-4-yl] -N-methyl-2- pyrimidinamine ;
4- [3- (4-fluorophenyl) -lH-pyrazol-4-yl] -N- (phenylmethyl) -
2-pyrimidinamine ; 540 N-cyclopropyl-4- [3- (4-fluorophenyl) -lH-pyrazol-4-yl] -2- pyrimidinamine ;
4- [3- (4-fluorophenyl) -lH-pyrazol-4-yl] -N- [ (4- methoxyphenyl) methyl] -2-pyrimidinamine;
4- [3- (4-fluorophenyl) -IH-pyrazol-4-yl] -2-pyrimidinamine ; 545 N- [4- [3- (4-fluorophenyl) -lH-pyrazol-4-yl] -2-pyrimidinyl] -
N- (phenylmethyl) acetamide;
Ethyl [4- [3- (4-fluorophenyl) -lH-pyrazol-4-yl] -2- pyrimidinyl] carbamate;
4- [3- (3 -methylphenyl) -IH-pyrazol-4-yl] pyrimidine; 550 4- [3- (4 -chlorophenyl) -lH-pyrazol-4-yl] pyrimidine;
4- [3- (3-fluorophenyl) -IH-pyrazol-4-yl] pyrimidine; and
4- [3- (4-fluorophenyl) -lH-pyrazol-4-yl] pyrimidine.
SUBSTmjTESHEEr(RUUE2S)
70. A compound of Claim 1 selected from compounds, their tautomers and their pharmaceutically acceptable salts, of the group consisting of
SUBSnTUFESHEETCRUlE&Q
SUESTrrU7ESHEEr(RULE26)
SUBSΠTIΠESHEET-CI
SUSSTmrrESHEET(RULE26)
sυssπτuτESHE F £2tø
8UBSΠΠΠESHEEΓ(RUIJE26)
SUB8mUTESHEET(RULE26)
-3ϋBST17iπESHEET(RULE26)
SUBSTmrcSH£Er(RUlE26)
71. A compound of claim 1 that is 4-[5-(4- fluorophenyl) -1- (2-propynyl) -lH-pyrazol-4-yl] pyridine or a pharmaceutically-acceptable salt or a tautomer thereof.
72. A compound of claim 1 that is 4- [3- (4- fluorophenyl) -1- (2-propynyl) -lH-pyrazol-4-yl] pyridine or a pharmaceutically-acceptable salt or a tautomer thereof.
73. A compound of claim 1 that is 3- (4- fluorophenyl) -4- (4-pyridinyl) -lH-pyrazole-1-ethanol or a pharmaceutically-acceptable salt or a tautomer thereof.
74. A compound of claim 1 that is 4- [3- (4- fluorophenyl) -l-methyl-lH-pyrazol-4-yl] -2- (1- methylhydrazino) pyridine or a pharmaceutically-acceptable salt or a tautomer thereof .
75. A compound of claim 1 that is 1- [5- (4- chlorophenyl) -4- (4-pyridinyl) -lH-pyrazol-3-yl] piperazine or a pharmaceutically-acceptable salt or a tautomer thereof .
76. A compound of claim 1 that is 4- [3-cyclopropyl- 5- (4-fluorophenyl) -lH-pyrazol-4-yl] yridine or a pharmaceutically-acceptable salt or a tautomer thereof.
77. A compound of claim 1 that is 4- [3- (4- fluorophenyl) -lH-pyrazol-4-yl] pyridine or a pharmaceutically-acceptable salt or a tautomer thereof.
78. A compound of claim 1 that is 1- [5- (4- chlorophenyl) -4- (4-pyridinyl) -lH-pyrazol-3-yl] -4- methylpiperazine or a pharmaceutically-acceptable salt or a tautomer thereof .
SϋBSmϋTESHEEr(RUl£2β)
79. A compound of claim 1 that is 4- [3- (4- fluorophenyl) -lH-pyrazol-4-yl] pyrimidine or a pharmaceutically-acceptable salt or a tautomer thereof.
80. A compound of claim 1 that is 2-fluoro-4- [3- (4-fluorophenyl) -lH-pyrazol-4-yl] pyridine or a pharmaceutically-acceptable salt or a tautomer thereof.
81. A compound of claim 1 that is
4- [3- (3 , 4-diflurophenyl) -1-methyl-IH-pyrazol-4
-yl] pyridine or a pharmaceutically-acceptable salt or a tautomer thereof .
82. A compound of claim 1 that is
4- [3- (4-bromophenyl) -lH-pyrazol-4yl] pyridine or a pharmaceutically-acceptable salt or a tautomer thereof.
83. A compound of claim 1 that is
4- [3- (4 -chlorophenyl) IH-pyrazol-4-yl] -2-fluoropyridine or a pharmaceutically-acceptable salt or a tautomer thereof.
84. A compound of claim 1 that is 4- [3 - (1,3 -benzodioxol
5-y) -l-methyl-lH-pyrazol-4-yl] pyridine or a pharmaceutically-acceptable salt or a tautomer thereof.
85. A compound of claim 1 that is
4- [3- (3-fluorophenyl) 1-methyl-IH-pyrazol-4-yl] pyridine or a pharmaceutically-acceptable salt or a tautomer thereof.
86. A compound of claim 1 that is 4- [3- (3- fluorophenyl) -l-methyl-pyrazol-4-yl] pyridine or a pharmaceutically-acceptable salt or a tautomer thereof.
SUBOTTUTESH£Er(RmE26)
87. A compound of claim 1 that is 5- (4- fluorophenyl) -N-2 -propynyl-4- (4-pyridinyl) -lH-pyrazol-3- amine or a pharmaceutically-acceptable salt or a tautomer thereof .
88. A substituted pyrazole that specifically binds to an ATP binding site of p38 kinase.
89. A compound of claim 88 having the formula:
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
SUBSTΓRΠESHEEΓ(RULE26) methylsulfonylphenyl; or a pharmaceutically-acceptable salt or tautomer thereof.
90. A compound of claim 89 wherein R2 is a hydrocarbyl, heterosubstituted hydrocarbyl or heterocyclyl radical that 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 .
91. A compound of claim 89 wherein 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.
92. A compound of claim 89 wherein R1 is a hydrocarbyl, heterosubstituted hydrocarbyl or heterocyclyl radical having a molecular weight less than about 250 atomic mass units.
93. A compound of claim 89 wherein R4 is a hydrocarbyl, heterosubstituted hydrocarbyl or heterocyclyl radical having a molecular weight less than about 250 atomic mass units.
94. A compound of claim 89 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, eu84, Leu101, and Thr103 sidechains
SUBSTTFUirESH££r(RULE26) 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.
95. A compound of claim 94 wherein R1 and R4 are independently selected from hydrocarbyl, heterosubstituted hydrocarbyl and heterocyclyl radicals and have a combined molecular weight less than about 360 atomic mass units.
96. A pharmaceutical composition comprising a therapeutically-effective amount of a compound, said compound selected from the compounds of Claims 1; or a pharmaceutically acceptable salt thereof.
97. A pharmaceutical composition of Claim 96 wherein said compound is selected from the compounds of Claim 3; or a pharmaceutically acceptable salt thereof.
98. A pharmaceutical composition of Claim 96 wherein said compound is selected from the compounds of Claim 4 ; or a pharmaceutically acceptable salt thereof.
99. A pharmaceutical composition of Claim 96 wherein said compound is selected from the compounds of Claim 5 ; or a pharmaceutically acceptable salt thereof .
100. A pharmaceutical composition of Claim 96
SUBSπTϋTE8HEEr(Rϋl£2β) wherein said compound is selected from the compounds of Claim 6; or a pharmaceutically acceptable salt thereof.
101. A pharmaceutical composition comprising a therapeutically-effective amount of a compound, said compound selected from the compounds of Claim 24; or a pharmaceutically acceptable salt thereof.
102. A pharmaceutical composition of Claim 101 wherein said compound is selected from the compounds of Claim 25; or a pharmaceutically acceptable salt thereof.
103. A pharmaceutical composition comprising a therapeutically-effective amount of a compound, said compound selected from the compounds of Claim 25; or a pharmaceutically acceptable salt thereof.
104. A pharmaceutical composition of Claim 103 wherein said compound is selected from the compounds of Claim 36; or a pharmaceutically acceptable salt thereof.
105. A pharmaceutical composition comprising a therapeutically-effective amount of a compound, said compound selected from the compounds of Claim 44 ; or a pharmaceutically acceptable salt thereof.
106. A pharmaceutical composition of Claim 105 wherein said compound is selected from the compounds of Claim 45; or a pharmaceutically acceptable salt thereof
107. A pharmaceutical composition comprising a therapeutically-effective amount of a compound, said compound selected from the compounds of Claim 53; or a pharmaceutically acceptable salt thereof.
108. A pharmaceutical composition of Claim 107
SUBOTrUTESH£ET(RUlEfiβ) wherein said compound is selected from the compounds of Claim 54; or a pharmaceutically acceptable salt thereof.
109. A pharmaceutical composition comprising a therapeutically-effective amount of a compound, said compound selected from the of compounds of Claim 66; or a pharmaceutically acceptable salt thereof.
110. A pharmaceutical composition comprising a therapeutically-effective amount of a compound, said compound selected from the compounds of Claims 69; or a pharmaceutically salt thereof.
111. A pharmaceutical composition of Claim 110 wherein said compound is 4- [3- (4-fluorophenyl) -IH- pyrazol-4-yl] pyridine or a pharmaceutically-acceptable salt or a tautomer thereof .
112. 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 of Formula I
wherein
R1 is selected from hydrido, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, cycloalkylalkylene, cycloalkenylalkylene, heterocyclylalkylene, haloalkyl, haloalkenyl,
sιrørmπE8i«Er( JE2β) 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 , alkylammoalkylene , 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
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
syBsrπϋTESt εri ϋiESβ) 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 , alkylammoalkylene , 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,
SUB8πmjmSHEET(RUiJE26) alkoxy, keto, amino, nitro, and cyano; or 80 R27 is -CHR28R29 wherein R28 is alkoxycarbonyl, and R29 is selected from aralkyl, aralkoxyalkylene, heterocyclylalkylene, alkylheterocyclylalkylene , alkoxycarbonylalkylene, alkylthioalkylene, and aralkylthioalkylene; wherein said aralkyl and 85 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 90 heterocycle is optionally substituted with one or more radicals independently selected from alkyl, aryl, heterocyclyl , heterocyclylalkylene, alkylheterocyclylalkylene , aryloxyalkylene , alkoxyarylene, alkylaryloxyalkylene, alkylcarbonyl, 95 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;
100 and
R2 is selected from hydrido, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, haloalkyl, hydroxyalkyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, alkylamino, alkenylamino, alkynylamino, arylamino,
105 heterocyclylamino, heterocyclylalkylamino, aralkylamino, aminoalkyl, aminoaryl, aminoalkylamino, arylaminoalkylene, alkylammoalkylene, arylammoarylene , alkylaminoarylene, alkylaminoalkylamino, cycloalkyl, cycloalkenyl, alkoxy, heterocyclyloxy, alkylthio,
110 arylthio, heterocyclylthio, carboxy, carboxyalkyl, carboxycycloalkyl , carboxycycloalkenyl , carboxyalkylamino, alkoxycarbonyl, heterocyclylcarbonyl, alkoxycarbonylalkyl, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonyl , alkoxyalkylamino,
st SrrnJTE8HEET(R £20) 115 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,
120 aryl, heterocyclyl, aralkyl, heterocyclylalkyl, epoxyalkyl, amino (hydroxyalkyl) carboxy, alkoxy, aryloxy, aralkoxy, haloalkyl, alkylamino, alkynylamino, alkylaminoalkylamino, heterocyclylalkylamino, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl,
125 arylsulfonyl, and aralkylsulfonyl; or R2 has the formula :
R30 R32 c— CCH23 • I
R31
(III)
wherein: j is an integer from 0 to 8; and
130 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
135 R32 is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl , alkylaminoalkyl , arylaminoalkyl , alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene;
140 R33 is selected from hydrogen, alkyl, -C(0)R35,
-C(0)OR35, -S02R36, -C(0)NR37R38, and -S02NR39R40, wherein R35, R36, R37, R38, R39 and R40 are independently selected from hydrocarbon, heterosubstituted hydrocarbon and heterocyclyl; and
145 R34 is selected from hydrogen, alkyl, aminocarbonyl, alkylaminocarbonyl, and arylaminocarbonyl ; or
SUBSTΠUTESHEEΓ(RULE26) R2 is -CR41R42 wherein R41 is aryl, and R42 is hydroxy; and
R3 is selected from pyridinyl, pyrimidinyl, quinolinyl, purinyl,
(IV) (V) wherein R43 is selected from hydrogen, alkyl, aminoalkyl , alkoxyalkyl , alkenoxyalkyl , and aryloxyalkyl ; and
155 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,
160 alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, aralkoxy, heterocyclylalkoxy, amino, alkylamino, alkenylamino, alkynylamino, cycloalkylamino, cycloalkenylamino, arylamino, heterocyclylamino, aminocarbonyl, cyano, hydroxy, hydroxyalkyl,
165 alkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl, alkoxycarbonylamino, alkoxyaralkylamino, aminosulfinyl, aminosulfonyl, alkylaminoalkylamino, hydroxyalkylamino, aralkylamino, heterocyclylalkylamino, aralkylheterocyclylamino, nitro, alkylaminocarbonyl,
170 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,
175 cycloalkyl, cycloalkenyl, aryl, and heterocyclyl, wherein R4 is optionally substituted with one or more radicals
SUBSmUIESHEET(RULE&e) independently selected from halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylthio, arylthio, alkylthioalkylene, arylthioalkylene, alkylsulfinyl,
180 alkylsulfinylalkylene, arylsulfinylalkylene, alkylsulfonyl , alkylsulfonylalkylene , arylsulfonylalkylene, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, cyano,
185 nitro, alkylamino, arylamino, alkylammoalkylene, 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,
190 unsubstituted cycloalkyl and cycloalkenyl when R4 is hydrido; and further provided R4 is not methylsulfonylphenyl; or a pharmaceutically-acceptable salt or tautomer thereof .
113. 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 of 5 Formula I
wherein
R1 is selected from hydrido, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl,
SUBS UTE8HEET(RULE2e) 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 , alkylammoalkylene , 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 ■
wherein: i is an integer from 0 to 9;
R25 is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl , alkylaminoalkyl , arylaminoalkyl ,
sυ88muresHEEr(RuiE2β) 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 , alkylammoalkylene, 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
SUBSnTrUTESHEET(RULE£6) are optionally substituted with one or more radicals independently selected from alkyl, halo, haloalkyl, 80 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 85 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 90 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 , 95 alkoxyarylene, alkylaryloxyalkylene, alkylcarbonyl, alkoxycarbonyl, aralkoxycarbonyl , alkylamino and alkoxycarbonylamino; wherein said aryl, heterocyclylalkylene and aryloxyalkylene radicals are optionally substituted with one or more radicals
100 independently selected from halogen, alkyl and alkoxy; and
R2 is selected from hydrido, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, haloalkyl, hydroxyalkyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl,
105 alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, heterocyclylalkylamino, aralkylamino, aminoalkyl, aminoaryl, aminoalkylamino, arylaminoalkylene, alkylammoalkylene , arylammoarylene, alkylaminoarylene, alkylaminoalkylamino, cycloalkyl,
110 cycloalkenyl, alkoxy, heterocyclyloxy, alkylthio, arylthio, heterocyclylthio, carboxy, carboxyalkyl, carboxycycloalkyl , carboxycycloalkenyl, carboxyalkylamino, alkoxycarbonyl, heterocyclylcarbonyl,
SUBSffnireSH£Er(RULE26> alkoxycarbonylalkyl , alkoxycarbonylheterocyclyl , 115 alkoxycarbonylheterocyclylcarbonyl, alkoxyalkylamino, alkoxycarbonylaminoalkylamino, and heterocyclylsulfonyl; wherein the aryl, heterocyclyl, heterocyclylalkyl, cycloalkyl and cycloalkenyl groups are optionally substituted with one or more radicals independently 120 selected from halo, keto, amino, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, aralkyl, heterocyclylalkyl, epoxyalkyl, amino (hydroxyalkyl) carboxy, alkoxy, aryloxy, aralkoxy, haloalkyl, alkylamino, alkynylamino, alkylaminoalkylamino, heterocyclylalkylamino, 125 alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, and aralkylsulfonyl; or R2 has the formula :
, 30 R 3 2
- C H pD
2 j j
3 1 ' R
( III )
wherein: 130 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 , 135 alkoxyalkyl, and alkylcarbonyloxyalkyl; and
R32 is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl , alkylaminoalkyl , arylaminoalkyl , alkylcarbonylalkylene, arylcarbonylalkylene, and 140 heterocyclylcarbonylaminoalkylene;
R33 is selected from hydrogen, alkyl, -C(0)R35, -C(0)OR35, -S02R36, -C(0)NR37R38, and -S02NR39R40, wherein R35, R3S, R37, R38, R39 and R40 are independently selected from hydrocarbon, heterosubstituted hydrocarbon and 145 heterocyclyl; and
OϋBSπTϋTESHEErCϋLESβ) 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, 150 quinolinyl, purinyl,
(IV) (V) wherein R43 is selected from hydrogen, alkyl, aminoalkyl, alkoxyalkyl, alkenoxyalkyl, and aryloxyalkyl;
155 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,
160 carboxyalkyl, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, aralkoxy, heterocyclylalkoxy, amino, alkylamino, alkenylamino, alkynylamino, cycloalkylamino, cycloalkenylamino, arylamino, heterocyclylamino,
165 aminocarbonyl, cyano, hydroxy, hydroxyalkyl, alkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl, alkoxycarbonylamino, alkoxyaralkylamino, aminosulfinyl, aminosulfonyl, alkylaminoalkylamino, hydroxyalkylamino, aralkylamino, heterocyclylalkylamino,
170 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
175 R4 is selected from hydrido, alkyl, alkenyl, alkynyl,
Sl STrTUrrEStCEr(RULE26) 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,
180 alkylthioalkylene, arylthioalkylene, alkylsulfinyl, alkylsulfinylalkylene , arylsulfinylalkylene , alkylsulfonyl , alkylsulfonylalkylene , arylsulfonylalkylene, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl ,
185 alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, cyano, nitro, alkylamino, arylamino, alkylammoalkylene, 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;
190 further provided R2 is selected from aryl, heterocyclyl, unsubstituted cycloalkyl and cycloalkenyl when R4 is hydrido; and further provided R4 is not methy1sulfonyIpheny1; or a pharmaceutically-acceptable salt or tautomer
195 thereof.
114. A method of treating inflammation, said method comprising treating the subject having or susceptible to inflammation with a therapeutically-effective amount of a compound of Formula I
wherein
R1 is selected from hydrido, alkyl, cycloalkyl,
8UBSnTUTESHEET(RULE26) 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 , alkylammoalkylene , 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
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 , alkylammoalkylene , 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,
SUBSTmJTESHEET(RULE26) 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
80 R27 is -CHR28R29 wherein R28 is alkoxycarbonyl, and R29 is selected from aralkyl, aralkoxyalkylene, heterocyclylalkylene , alkylheterocyclylalkylene , alkoxycarbonylalkylene, alkylthioalkylene, and aralkylthioalkylene; wherein said aralkyl and
85 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
90 heterocycle is optionally substituted with one or more radicals independently selected from alkyl, aryl, heterocyclyl , heterocyclylalkylene , alkylheterocyclylalkylene , aryloxyalkylene , alkoxyarylene, alkylaryloxyalkylene, alkylcarbonyl,
95 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; 100 and
R2 is selected from hydrido, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, haloalkyl, hydroxyalkyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, 105 heterocyclylamino, heterocyclylalkylamino, aralkylamino, aminoalkyl, aminoaryl, aminoalkylamino, arylaminoalkylene, alkylammoalkylene, arylammoarylene, alkylaminoarylene, alkylaminoalkylamino, cycloalkyl, cycloalkenyl, alkoxy, heterocyclyloxy, alkylthio, 110 arylthio, heterocyclylthio, carboxy, carboxyalkyl, carboxycycloalkyl , carboxycycloalkenyl ,
carboxyalkylamino, alkoxycarbonyl, heterocyclylcarbonyl, alkoxycarbonylalkyl , alkoxycarbonylheterocyclyl , alkoxycarbonylheterocyclylcarbonyl , alkoxyalkylamino,
115 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,
120 aryl, heterocyclyl, aralkyl, heterocyclylalkyl, epoxyalkyl, amino (hydroxyalkyl) carboxy, alkoxy, aryloxy, aralkoxy, haloalkyl, alkylamino, alkynylamino, alkylaminoalkylamino, heterocyclylalkylamino, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl,
125 arylsulfonyl, and aralkylsulfonyl; or R2 has the formula:
,30 R 32
-CCH2: -N y
2Jj
(III)
wherein: j is an integer from 0 to 8; and
130 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
135 R32 is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl , alkylaminoalkyl , arylaminoalkyl , alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene;
140 R33 is selected from hydrogen, alkyl, -C(0)R35,
-C(0)OR35, -S02R36, -C(0)NR37R38, and -S02NR39R40, wherein R35, R36, R37, R38, R39 and R40 are independently selected from hydrocarbon, heterosubstituted hydrocarbon and
SUBSmtnESHEET(RULE2e) heterocyclyl; and 145 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,
(IV) (V) wherein R43 is selected from hydrogen, alkyl, aminoalkyl , alkoxyalkyl , alkenoxyalkyl , and aryloxyalkyl ; and
155 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,
160 alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, aralkoxy, heterocyclylalkoxy, amino, alkylamino, alkenylamino, alkynylamino, cycloalkylamino, cycloalkenylamino, arylamino, heterocyclylamino, aminocarbonyl, cyano, hydroxy, hydroxyalkyl,
165 alkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl, alkoxycarbonylamino, alkoxyaralkylamino, aminosulfinyl, aminosulfonyl, alkylaminoalkylamino, hydroxyalkylamino, aralkylamino, heterocyclylalkylamino, aralkylheterocyclylamino, nitro, alkylaminocarbonyl,
170 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,
175 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,
180 alkylsulfinylalkylene, arylsulfinylalkylene, alkylsulfonyl , alkylsulfonylalkylene, arylsulfonylalkylene, alkoxy, aryloxy, aralkoxy, aminocarbonyl , alkylaminocarbonyl , arylaminocarbonyl , alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, cyano,
185 nitro, alkylamino, arylamino, alkylammoalkylene, 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,
190 unsubstituted cycloalkyl and cycloalkenyl when R4 is hydrido; and further provided R4 is not methylsulfonylphenyl; or a pharmaceutically-acceptable salt or tautomer thereof .
115. A method of treating arthritis, said method comprising treating the subject having or susceptible to arthritis with a therapeutically-effective amount of a compound of Formula I
8UBSrmJTE8HEET(RuLE26) 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 , alkylammoalkylene, 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
( I I )
wherein : i is an integer from 0 to 9 ;
SUBSrrninESHEET(RULE26) 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 , alkylammoalkylene, 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 ,
SUBSTmπESHEET(RULE26) aryloxycarbonylarylene, arylcarbonylarylene ,
75 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
80 R27 is -CHR28R29 wherein R28 is alkoxycarbonyl, and R29 is selected from aralkyl, aralkoxyalkylene, heterocyclylalkylene , alkylheterocyclylalkylene , alkoxycarbonylalkylene, alkylthioalkylene, and aralkylthioalkylene; wherein said aralkyl and
85 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
90 heterocycle is optionally substituted with one or more radicals independently selected from alkyl, aryl, heterocyclyl , heterocyclylalkylene, alkylheterocyclylalkylene, aryloxyalkylene, alkoxyarylene, alkylaryloxyalkylene , alkylcarbonyl,
95 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; 100 and
R2 is selected from hydrido, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, haloalkyl, hydroxyalkyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, 105 heterocyclylamino, heterocyclylalkylamino, aralkylamino, aminoalkyl, aminoaryl, aminoalkylamino, arylaminoalkylene, alkylammoalkylene, arylammoarylene , alkylaminoarylene, alkylaminoalkylamino, cycloalkyl, cycloalkenyl, alkoxy, heterocyclyloxy, alkylthio,
110 arylthio, heterocyclylthio, carboxy, carboxyalkyl, carboxycycloalkyl , carboxycycloalkenyl , carboxyalkylamino, alkoxycarbonyl, heterocyclylcarbonyl, alkoxycarbonylalkyl , alkoxycarbonylheterocyclyl , alkoxycarbonylheterocyclylcarbonyl , alkoxyalkylamino,
115 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,
120 aryl, heterocyclyl, aralkyl, heterocyclylalkyl, epoxyalkyl, amino (hydroxyalkyl) carboxy, alkoxy, aryloxy, aralkoxy, haloalkyl, alkylamino, alkynylamino, alkylaminoalkylamino, heterocyclylalkylamino, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl,
125 arylsulfonyl, and aralkylsulfonyl; or R2 has the formula:
in : j s an integer fro m 0 to i and
130 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
135 R32 is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene;
140 R33 is selected from hydrogen, alkyl, -C(0)R35,
-C(0)OR35, -S02R36, -C(0)NR37R38, and -S02NR39R40, wherein R35,
8UBSπnjrcsHEεr<FUUi«& R36, R37, R38, R39 and R40 are independently selected from hydrocarbon, heterosubstituted hydrocarbon and heterocyclyl; and 145 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,
(IV) (V) wherein R43 is selected from hydrogen, alkyl, aminoalkyl, alkoxyalkyl, alkenoxyalkyl, and aryloxyalkyl; and
155 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,
160 alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, aralkoxy, heterocyclylalkoxy, amino, alkylamino, alkenylamino, alkynylamino, cycloalkylamino, cycloalkenylamino, arylamino, heterocyclylamino, aminocarbonyl, cyano, hydroxy, hydroxyalkyl,
165 alkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl, alkoxycarbonylamino, alkoxyaralkylamino, aminosulfinyl, aminosulfonyl, alkylaminoalkylamino, hydroxyalkylamino, aralkylamino, heterocyclylalkylamino, aralkylheterocyclylamino, nitro, alkylaminocarbonyl,
170 alkylcarbonylamino, halosulfonyl, aminoalkyl, haloalkyl, alkylcarbonyl, hydrazinyl, alkylhydrazinyl,
SUBOTTUTESHEEr(RULE2 arylhydrazinyl, or -NR44R45 wherein R44 is alkylcarbonyl or amino, and R45 is alkyl or aralkyl; and
R4 is selected from hydrido, alkyl, alkenyl, alkynyl,
175 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,
180 alkylsulfinylalkylene, arylsulfinylalkylene, alkylsulfonyl , alkylsulfonylalkylene, arylsulfonylalkylene, alkoxy, aryloxy, aralkoxy, aminocarbonyl , alkylaminocarbonyl , arylaminocarbonyl , alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, cyano,
185 nitro, alkylamino, arylamino, alkylammoalkylene, 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,
190 unsubstituted cycloalkyl and cycloalkenyl when R4 is hydrido; and further provided R4 is not methylsulfonylphenyl; or a pharmaceutically-acceptable salt or tautomer thereof .
116. 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 of 5 Formula I
SϋBSrm TESHEEr( ϋlE2flϊ
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 .
117. The method of Claim 112 wherein the TNF 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.
118. The method of Claim 112 wherein the TNF mediated disorder is inflammation.
119. The method of Claim 112 wherein the TNF mediated disease is arthritis.
120. The method of Claim 112 wherein the TNF mediated disorder is asthma.
121. The method of claim 112 wherein the compound is 4- [3- (4-fluorophenyl) -lH-pyrazol-4-yl] pyridine or a pharmaceutically-acceptable salt or a tautomer thereof.
122. The method of claim 112 wherein the compound is 1- [5- (4 -chlorophenyl) -4- (4-pyridinyl) -lH-pyrazol-3-yl] -4- methylpiperazine or a pharmaceutically-acceptable salt or a tautomer thereof .
123. The method of Claim 113 wherein the disorder is a p38α kinase mediated disorder.
124. The method of Claim 113 wherein the p38 kinase mediated disorder is selected from the group 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.
125. The method of Claim 113 wherein the p38 kinase mediated disorder is inflammation.
126. The method of Claim 113 wherein the p38 kinase
$UBSnrπUlESHEET(ROE2e) mediated disorder is arthritis.
127. The method of Claim 113 wherein the p38 kinase mediated disorder is asthma.
128. The method of Claim 116 wherein the disorder is a p38α kinase mediated disorder.
129. The method of Claim 116 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.
130. The method of Claim 116 wherein the p38 kinase mediated disorder is inflammation.
131. The method of Claim 116 wherein the p38 kinase mediated disorder is arthritis.
132. The method of Claim 116 wherein the p38 kinase mediated disorder is asthma.
133. A method of preparing pyrazoles of Formula I
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 , alkylammoalkylene , 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
« " 0 n 26
- C H pD C- N
, 27
(ID
wherein : i is an integer from 0 to 9 ;
SUBSπ IE8HEEr(RUiJE26) 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 , alkylammoalkylene, 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
75 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,
80 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
85 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,
90 alkylheterocyclylalkylene, aryloxyalkylene, alkoxyarylene, alkylaryloxyalkylene, alkylcarbonyl, alkoxycarbonyl, aralkoxycarbonyl , alkylamino and alkoxycarbonylamino; wherein said aryl, heterocyclylalkylene and aryloxyalkylene radicals are
95 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, 100 aralkyl, alkylheterocyclyl, heterocyclylalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, heterocyclylalkylamino, aralkylamino, aminoalkyl, aminoaryl, aminoalkylamino, arylaminoalkylene, alkylammoalkylene, arylammoarylene , 105 alkylaminoarylene, alkylaminoalkylamino, cycloalkyl, cycloalkenyl, alkoxy, heterocyclyloxy, alkylthio,
arylthio, heterocyclylthio, carboxy, carboxyalkyl, carboxycycloalkyl , carboxycycloalkenyl , carboxyalkylamino, alkoxycarbonyl, heterocyclylcarbonyl,
110 alkoxycarbonylalkyl, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonyl , alkoxyalkylamino, alkoxycarbonylaminoalkylamino, and heterocyclylsulfonyl ; wherein the aryl, heterocyclyl, heterocyclylalkyl, cycloalkyl and cycloalkenyl groups are optionally
115 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,
120 alkylaminoalkylamino, heterocyclylalkylamino, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, and aralkylsulfonyl; or R2 has the formula:
125 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, 130 aminoalkyl, alkylaminoalkyl, aminocarbonylalkyl , alkoxyalkyl, and alkylcarbonyloxyalkyl; and
R32 is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl , 135 alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene;
R33 is selected from hydrogen, alkyl, -C(0)R35, -C(0)OR35, -S02R36, -C(0)NR37R38, and -S02NR39R40, wherein R35,
Sl®STπUTESHEET(RϋLEai) R36, R37, R38, R39 and R40 are independently selected from 140 hydrocarbon, heterosubstituted hydrocarbon and heterocyclyl; and
R34 is selected from hydrogen, alkyl, aminocarbonyl, alkylaminocarbonyl, and arylaminocarbonyl ; or
R2 is -CR1R42 wherein R41 is aryl, and R42 is hydroxy; and 145 R3 is selected from pyridinyl, pyrimidinyl, quinolinyl, purinyl,
(IV) (V) wherein R43 is selected from hydrogen, alkyl,
150 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,
155 aralkyl, aralkenyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, aralkoxy, heterocyclylalkoxy, amino, alkylamino, alkenylamino, alkynylamino, cycloalkylamino,
160 cycloalkenylamino, arylamino, heterocyclylamino, aminocarbonyl, cyano, hydroxy, hydroxyalkyl, alkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl, alkoxycarbonylamino, alkoxyaralkylamino, aminosulfinyl, aminosulfonyl, alkylaminoalkylamino, hydroxyalkylamino,
165 aralkylamino, heterocyclylalkylamino, aralkylheterocyclylamino, nitro, alkylaminocarbonyl, alkylcarbonylamino, halosulfonyl, aminoalkyl, haloalkyl, alkylcarbonyl, hydrazinyl, alkylhydrazinyl,
SlffiSTπUTESHEEr(RULE26) arylhydrazinyl, or -NR44R45 wherein R44 is alkylcarbonyl or
170 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,
175 alkynyl, aryl, heterocyclyl, alkylthio, arylthio, alkylthioalkylene, arylthioalkylene, alkylsulfinyl, alkylsulfinylalkylene , arylsulfinylalkylene , alkylsulfonyl , alkylsulfonylalkylene , arylsulfonylalkylene, alkoxy, aryloxy, aralkoxy,
180 aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl , alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, cyano, nitro, alkylamino, arylamino, alkylammoalkylene, arylaminoalkylene, aminoalkylamino, and hydroxy; or a pharmaceutically-acceptable salt or tautomer
185 thereof, said method comprising the steps of forming an acyl hydrazone and condensing to form the substituted pyrazole .
134. The process of Claim 133 wherein the acyl hydrazone is formed by reaction of a ketone with an acyl hydrazide .
135. The process of Claim 133 wherein the condensation is performed at a temperature from about 25 °C to about 200 °C.
136. A method of preparing pyrazoles of Formula I
8l 8TrTUTE8S«Er( iL£2 )
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 , alkylammoalkylene, alkylsulfonylalkylene, acyl, acyloxycarbonyl , alkoxycarbonylalkylene, aryloxycarbonylalkylene, heterocyclyloxycarbonylalkylene , alkoxycarbonylarylene , aryloxycarbonylarylene, heterocyclyloxycarbonylarylene , alkylcarbonylalkylene , arylcarbonylalkylene, heterocyclylcarbonylalkylene, alkylcarbonylarylene , arylcarbonylarylene, heterocyclylcarbonylarylene , alkylcarbonyloxyalkylene , arylcarbonyloxyalkylene, heterocyclylcarbonyloxyalkylene , alkylcarbonyloxyarylene, arylcarbonyloxyarylene, and
suBsrrrrtπESHEEr(RULE26) heterocyclylcarbonyloxyarylene; or R1 has the formula
R 5 , 26
I
— C — C C H 2 D , - C- N
\ 27
H R ( II ]
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 , alkylammoalkylene , arylaminocarbonylalkylene, alkoxyarylammocarbonylalkylene , ammocarbonylalkylene , 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
SUBST17U7ESHEET(RULi2e) R2 is selected from hydrido, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, haloalkyl, hydroxyalkyl,
100 aralkyl, alkylheterocyclyl, heterocyclylalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, heterocyclylalkylamino, aralkylamino, aminoalkyl, aminoaryl, aminoalkylamino, arylaminoalkylene, alkylammoalkylene, arylammoarylene,
105 alkylaminoarylene, alkylaminoalkylamino, cycloalkyl, cycloalkenyl, alkoxy, heterocyclyloxy, alkylthio, arylthio, heterocyclylthio, carboxy, carboxyalkyl, carboxycycloalkyl , carboxycycloalkenyl , carboxyalkylamino, alkoxycarbonyl, heterocyclylcarbonyl,
110 alkoxycarbonylalkyl, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonyl , alkoxyalkylamino, alkoxycarbonylaminoalkylamino, and heterocyclylsulfonyl; wherein the aryl, heterocyclyl, heterocyclylalkyl, cycloalkyl and cycloalkenyl groups are optionally
115 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,
120 alkylaminoalkylamino, heterocyclylalkylamino, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, and aralkylsulfonyl; or R2 has the formula:
125 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,
130 aminoalkyl, alkylaminoalkyl, aminocarbonylalkyl, alkoxyalkyl, and alkylcarbonyloxyalkyl; and
R32 is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, 135 alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene;
R33 is selected from hydrogen, alkyl, -C(0)R35, -C(0)OR35, -S02R36, -C(0)NR37R38, and -S02NR39R40, wherein R35, R36, R37, R38, R39 and R40 are independently selected from
140 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 145 R3 is selected from pyridinyl, pyrimidinyl, quinolinyl, purinyl,
(IV) (V) wherein R43 is selected from hydrogen, alkyl, 150 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, 155 aralkyl, aralkenyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, aralkoxy, heterocyclylalkoxy, amino, alkylamino, alkenylamino, alkynylamino, cycloalkylamino,
SuBSmUTESHEET(RUL£26) 160 cycloalkenylamino, arylamino, heterocyclylamino, aminocarbonyl, cyano, hydroxy, hydroxyalkyl, alkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl, alkoxycarbonylamino, alkoxyaralkylamino, aminosulfinyl, aminosulfonyl, alkylaminoalkylamino, hydroxyalkylamino,
165 aralkylamino, heterocyclylalkylamino, aralkylheterocyclylamino, nitro, alkylaminocarbonyl, alkylcarbonylamino, halosulfonyl, aminoalkyl, haloalkyl, alkylcarbonyl, hydrazinyl, alkylhydrazinyl, arylhydrazinyl, or -NR44R45 wherein R44 is alkylcarbonyl or
170 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,
175 alkynyl, aryl, heterocyclyl, alkylthio, arylthio, alkylthioalkylene, arylthioalkylene, alkylsulfinyl, alkylsulfinylalkylene , arylsulfinylalkylene , alkylsulfonyl , alkylsulfonylalkylene , arylsulfonylalkylene, alkoxy, aryloxy, aralkoxy,
180 aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, cyano, nitro, alkylamino, arylamino, alkylammoalkylene, arylaminoalkylene, aminoalkylamino, and hydroxy; or a pharmaceutically-acceptable salt or tautomer
185 thereof, said method comprising the steps of treating a substituted ketone with an acyl hydrazide to give the pyrazole .
137. The process of Claim 136 wherein it is carried out in an acidic solvent.
138. The process of Claim 137 wherein the acidic solvent is acetic acid.
SlrømUTE r(RϋLE26}
139. The process of Claim 137 wherein the acidic solvent is an organic solvent containing an acid.
SUBSmUTESHEEURULEO)
AU75883/98A 1997-05-22 1998-05-22 Substituted pyrazoles as p38 kinase inhibitors Ceased AU754830C (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US4757097P 1997-05-22 1997-05-22
US60/047570 1997-05-22
PCT/US1998/010436 WO1998052940A1 (en) 1997-05-22 1998-05-22 SUBSTITUTED PYRAZOLES AS p38 KINASE INHIBITORS

Related Child Applications (1)

Application Number Title Priority Date Filing Date
AU2003200580A Division AU2003200580A1 (en) 1997-05-22 2003-02-17 Substituted pyrazoles as P38 kinase inhibitors

Publications (3)

Publication Number Publication Date
AU7588398A AU7588398A (en) 1998-12-11
AU754830B2 AU754830B2 (en) 2002-11-28
AU754830C true AU754830C (en) 2004-02-12

Family

ID=21949743

Family Applications (1)

Application Number Title Priority Date Filing Date
AU75883/98A Ceased AU754830C (en) 1997-05-22 1998-05-22 Substituted pyrazoles as p38 kinase inhibitors

Country Status (24)

Country Link
EP (1) EP1000055A1 (en)
JP (1) JP2002508754A (en)
KR (1) KR20010012854A (en)
CN (1) CN1264377A (en)
AP (1) AP1246A (en)
AU (1) AU754830C (en)
BG (1) BG64313B1 (en)
BR (1) BR9809147A (en)
CA (1) CA2291115A1 (en)
EA (1) EA003925B1 (en)
EE (1) EE9900527A (en)
GE (1) GEP20033053B (en)
HU (1) HUP0001880A3 (en)
ID (1) ID22982A (en)
IL (1) IL132991A (en)
IS (1) IS5257A (en)
NO (1) NO995695L (en)
NZ (1) NZ501112A (en)
OA (1) OA12981A (en)
PL (1) PL337020A1 (en)
SK (1) SK157899A3 (en)
TR (1) TR200000235T2 (en)
WO (1) WO1998052940A1 (en)
ZA (1) ZA984358B (en)

Families Citing this family (77)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TW289752B (en) * 1994-03-11 1996-11-01 Ciba Geigy Ag
US5559137A (en) * 1994-05-16 1996-09-24 Smithkline Beecham Corp. Compounds
US6514977B1 (en) 1997-05-22 2003-02-04 G.D. Searle & Company Substituted pyrazoles as p38 kinase inhibitors
WO1998052941A1 (en) 1997-05-22 1998-11-26 G.D. Searle And Co. PYRAZOLE DERIVATIVES AS p38 KINASE INHIBITORS
US6979686B1 (en) 2001-12-07 2005-12-27 Pharmacia Corporation Substituted pyrazoles as p38 kinase inhibitors
EP1023066A4 (en) 1997-06-13 2001-05-23 Smithkline Beecham Corp Novel pyrazole and pyrazoline substituted compounds
US7301021B2 (en) 1997-07-02 2007-11-27 Smithkline Beecham Corporation Substituted imidazole compounds
US6184226B1 (en) 1998-08-28 2001-02-06 Scios Inc. Quinazoline derivatives as inhibitors of P-38 α
US6649617B1 (en) 1998-10-07 2003-11-18 Smithkline Beecham Corporation Treatment for stroke management
EP1140916B1 (en) 1998-12-16 2002-11-13 Aventis Pharma Limited Heteroaryl-cyclic acetals
US6191147B1 (en) 1998-12-24 2001-02-20 Ppd Discovery, Inc. Pyrazole compounds and uses thereof
EP1142890B1 (en) * 1998-12-25 2005-08-03 Teikoku Hormone Mfg. Co., Ltd. Aminopyrazole derivatives
CZ20013435A3 (en) 1999-03-26 2002-04-17 Euro-Celtique S. A. Aryl substituted pyrazoles, imidazoles, oxazoles, thiazoles and pyrroles as well as use thereof
ATE296820T1 (en) 1999-06-03 2005-06-15 Teikoku Hormone Mfg Co Ltd SUBSTITUTED PYRAZOLE DERIVATIVES
US7122666B2 (en) 1999-07-21 2006-10-17 Sankyo Company, Limited Heteroaryl-substituted pyrrole derivatives, their preparation and their therapeutic uses
AR032130A1 (en) * 1999-08-13 2003-10-29 Vertex Pharma AN INHIBITOR COMPOUND OF PROTEIN KINASES, A PHARMACEUTICAL COMPOSITION THAT INCLUDES IT, AND A METHOD TO TREAT AFFECTIONS WITH SUCH COMPOUND
WO2001030154A2 (en) * 1999-10-25 2001-05-03 Basf Aktiengesellschaft Agrochemical compositions containing pyrazoles and use thereof as fungicidal plant protection agents
DE19952147A1 (en) 1999-10-29 2001-05-03 Boehringer Ingelheim Pharma New cyclopropanes, pharmaceutical compositions containing these compounds and process for their preparation
US7053099B1 (en) 1999-11-23 2006-05-30 Smithkline Beecham Corporation 3,4-dihydro-(1H)quinazolin-2-one compounds as CSBP/p38 kinase inhibitors
CA2419550A1 (en) 2000-08-14 2002-02-21 Ortho-Mcneil Pharmaceutical, Inc. Substituted pyrazoles
GB0102687D0 (en) 2001-02-02 2001-03-21 Pharmacia & Upjohn Spa Oxazolyl-pyrazole derivatives active as kinase inhibitors,process for their preparation and pharmaceutical compositions comprising them
WO2002062792A1 (en) * 2001-02-02 2002-08-15 Takeda Chemical Industries, Ltd. Jnk inhibitor
EP2048142A3 (en) 2001-04-26 2009-04-22 Eisai R&D Management Co., Ltd. Nitrogen-containing condensed cyclic compound having a pyrazolyl group as a substituent group and pharmaceutical composition thereof
UA76461C2 (en) 2001-05-24 2006-08-15 Lilly Co Eli Pyrrazole derivatives as pharmaceutical agents, use thereof, a pharmaceutical composition on their basis
BR0212812A (en) 2001-09-25 2004-08-03 Pharmacia Corp Processes for the manufacture of substituted pyrazoles and pharmaceutical composition comprising the same
US7057049B2 (en) 2001-09-25 2006-06-06 Pharmacia Corporation Process for making substituted pyrazoles
US20040082551A1 (en) * 2002-06-05 2004-04-29 Benson Alan G. Novel pyrazoles and their use as p38 kinase inhibitors
GB0215844D0 (en) 2002-07-09 2002-08-14 Novartis Ag Organic compounds
CA2492033A1 (en) 2002-07-09 2004-01-15 Boehringer Ingelheim Pharma Gmbh & Co. Kg Pharmaceutical compositions of anticholinergics and p38 kinase inhibitors in the treatment of respiratory diseases
GB0217786D0 (en) * 2002-07-31 2002-09-11 Glaxo Group Ltd Compounds
WO2004016592A1 (en) 2002-08-14 2004-02-26 Ppd Discovery, Inc. Prenylation inhibitors and methods of their synthesis and use
US6649638B1 (en) 2002-08-14 2003-11-18 Ppd Discovery, Inc. Prenylation inhibitors and methods of their synthesis and use
WO2004026302A1 (en) * 2002-09-19 2004-04-01 Eli Lilly And Company Methods of inhibiting tgf beta with substituted pyrazoles
GB0229618D0 (en) 2002-12-19 2003-01-22 Cancer Rec Tech Ltd Pyrazole compounds
CA2515119A1 (en) 2003-02-07 2004-08-19 Daiichi Pharmaceutical Co., Ltd. Pyrazole derivative
US20060035893A1 (en) 2004-08-07 2006-02-16 Boehringer Ingelheim International Gmbh Pharmaceutical compositions for treatment of respiratory and gastrointestinal disorders
EP1778686B9 (en) 2004-08-12 2009-07-08 Pfizer Limited Triazolopyridinylsulfanyl derivatives as p38 map kinase inhibitors
PE20060777A1 (en) 2004-12-24 2006-10-06 Boehringer Ingelheim Int INDOLINONE DERIVATIVES FOR THE TREATMENT OR PREVENTION OF FIBROTIC DISEASES
EP1832584B1 (en) 2004-12-28 2011-12-21 ASKA Pharmaceutical Co., Ltd. Pyrimidinylisoxazole derivative
CA2643066A1 (en) * 2006-03-16 2007-09-20 Pfizer Products Inc. Pyrazole compounds
KR20090031721A (en) * 2006-06-28 2009-03-27 아스카 세이야쿠 가부시키가이샤 Treatment agent for inflammatory bowel disease
CN101472921B (en) 2006-06-28 2012-10-10 Aska制药株式会社 Pyridylisoxazole derivative
KR101434706B1 (en) 2007-02-16 2014-08-26 아스카 세이야쿠 가부시키가이샤 Pharmaceutical composition containing fine particle oil-based suspension
EP1992344A1 (en) 2007-05-18 2008-11-19 Institut Curie P38 alpha as a therapeutic target in pathologies linked to FGFR3 mutation
EP2181110A2 (en) * 2007-07-13 2010-05-05 ADDEX Pharma S.A. Novel heteroaromatic derivatives and their use as positive allosteric modulators of metabotropic glutamate receptors
EP2220048B1 (en) 2007-11-16 2017-01-25 Boehringer Ingelheim International GmbH Aryl- and heteroarylcarbonyl derivatives of benzomorphanes and related scaffolds, medicaments containing such compounds and their use
CL2009000904A1 (en) 2008-04-21 2010-04-30 Shionogi & Co Compounds derived from cyclohexyl sulfonamides having antagonist activity at the npy y5 receptor, pharmaceutical composition and pharmaceutical formulation comprising them.
US8765780B2 (en) 2008-05-13 2014-07-01 Boehringer Ingelheim International Gmbh Alicyclic carboxylic acid derivatives of benzomorphans and related scaffolds, medicaments containing such compounds and their use
CA2731146C (en) 2008-07-24 2016-05-03 Nerviano Medical Sciences S.R.L. 3,4-diarylpyrazoles as protein kinase inhibitors
EP2318403B1 (en) * 2008-08-25 2015-12-23 Boehringer Ingelheim International GmbH Aryl- and heteroarylcarbonyl derivatives of substituted nortropanes, medicaments containing such compounds and their use
CN102177138A (en) * 2008-10-23 2011-09-07 隆萨有限公司 Process for the synthesis of substituted pyrazoles
JP5621148B2 (en) * 2008-11-21 2014-11-05 ラクオリア創薬株式会社 Novel pyrazole-3-carboxamide derivatives having 5-HT2B receptor antagonistic activity
JP5670440B2 (en) 2009-06-02 2015-02-18 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Cyclic inhibitor of 11β-hydroxysteroid dehydrogenase 1
WO2011011123A1 (en) 2009-06-11 2011-01-27 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1 based on the 1,3 -oxazinan- 2 -one structure
EA201200321A1 (en) * 2009-08-26 2012-09-28 Новартис Аг TETRA-SUBSTITUTED HETEROARRYL COMPOUNDS AND THEIR USE AS MDM2 AND / OR MDM4 MODULATORS
AR077975A1 (en) 2009-08-28 2011-10-05 Irm Llc PIRAZOL PYRIMIDINE DERIVATIVES AND COMPOSITIONS AS PROTEIN KINASE INHIBITORS
EP2308866A1 (en) * 2009-10-09 2011-04-13 Bayer CropScience AG Phenylpyri(mi)dinylpyrazoles and their use as fungicides
JP2013514970A (en) 2009-12-21 2013-05-02 バイエル・クロップサイエンス・アーゲー Thienylpyri (mi) dinylazoles and their use for controlling phytopathogenic fungi
US8791265B2 (en) 2010-01-27 2014-07-29 Nerviano Medical Sciences S.R.L. Sulfonamido derivatives of 3,4-diarylpyrazoles as protein kinase inhibitors
AR081810A1 (en) 2010-04-07 2012-10-24 Bayer Cropscience Ag BICYCLE PIRIDINYL PIRAZOLS
US8933072B2 (en) 2010-06-16 2015-01-13 Vitae Pharmaceuticals, Inc. Substituted 5-,6- and 7-membered heterocycles, medicaments containing such compounds, and their use
CN103153980B (en) 2010-08-03 2015-12-16 内尔维安诺医学科学有限公司 The derivative of pyrazolo phenyl benzenesulfonamides compound and the purposes as antitumour drug thereof
JP5684923B2 (en) * 2010-12-20 2015-03-18 ファイザー・インク Novel condensed pyridine compounds as casein kinase inhibitors
AR086992A1 (en) 2011-06-20 2014-02-05 Bayer Ip Gmbh TIENILPIRI (MI) DINILPIRAZOLES
JP2014524438A (en) 2011-08-17 2014-09-22 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Indenopyridine derivatives
PL2763987T3 (en) 2011-10-06 2019-01-31 Bayer Cropscience Ag Heterocyclylpyri(mi)dinylpyrazole as fungicidals
MX351460B (en) 2011-10-06 2017-10-16 Bayer Ip Gmbh Heterocyclylpyri(mi)dinylpyrazole.
DE102011115525A1 (en) 2011-10-11 2013-04-11 Boehringer Ingelheim International Gmbh Two-part bottle packaging device for containing pharmaceutical tablets or capsules, has bottle body and bottle base, where bottle is closed with pressure lock or with pressure lock injected at bottle body or with separate rotary lock
CN108542906A (en) 2011-11-11 2018-09-18 诺华股份有限公司 The method for treating proliferative disease
EP3449911A1 (en) 2011-11-23 2019-03-06 Array Biopharma, Inc. Pharmaceutical formulations
JP6579623B2 (en) 2013-03-15 2019-09-25 ザ・スクリップス・リサーチ・インスティテュート Compounds and methods for inducing cartilage formation
BR112016012482B1 (en) * 2013-12-12 2020-07-21 Sumitomo Chemical Company, Limited aromatic compound, its use, agent and method of pest control
CN104829536B (en) * 2015-05-04 2017-12-29 陕西科技大学 A kind of Phenylpyrazole carboxylic acid compound and its synthetic method for having antitumor activity
WO2016189877A1 (en) * 2015-05-27 2016-12-01 Kyorin Pharmaceutical Co., Ltd. Urea derivative or pharmacologically acceptable salt thereof
CN109748873B (en) * 2017-11-08 2021-02-02 北京嘉林药业股份有限公司 Compounds and their use for treating cancer
CA3121202A1 (en) 2018-11-30 2020-06-04 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof
EP4085056A1 (en) 2020-01-03 2022-11-09 Berg LLC Polycyclic amides as ube2k modulators for treating cancer

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5559137A (en) * 1994-05-16 1996-09-24 Smithkline Beecham Corp. Compounds

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2753659B2 (en) * 1990-09-03 1998-05-20 株式会社大塚製薬工場 Pyrazole derivatives
US5593992A (en) * 1993-07-16 1997-01-14 Smithkline Beecham Corporation Compounds
US5486534A (en) * 1994-07-21 1996-01-23 G. D. Searle & Co. 3,4-substituted pyrazoles for the treatment of inflammation
JP3734180B2 (en) * 1994-12-28 2006-01-11 エーザイ株式会社 New pyrazole derivatives

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5559137A (en) * 1994-05-16 1996-09-24 Smithkline Beecham Corp. Compounds

Also Published As

Publication number Publication date
JP2002508754A (en) 2002-03-19
BG64313B1 (en) 2004-09-30
EA199900953A1 (en) 2000-10-30
AU754830B2 (en) 2002-11-28
ID22982A (en) 1999-12-23
BG103964A (en) 2000-08-31
EE9900527A (en) 2000-06-15
IL132991A0 (en) 2001-03-19
IS5257A (en) 1999-11-19
EP1000055A1 (en) 2000-05-17
NO995695D0 (en) 1999-11-19
CN1264377A (en) 2000-08-23
BR9809147A (en) 2000-08-01
GEP20033053B (en) 2003-08-25
HUP0001880A2 (en) 2001-03-28
SK157899A3 (en) 2000-08-14
AU7588398A (en) 1998-12-11
HUP0001880A3 (en) 2002-03-28
AP1246A (en) 2004-02-07
EA003925B1 (en) 2003-10-30
CA2291115A1 (en) 1998-11-26
NZ501112A (en) 2002-10-25
ZA984358B (en) 1999-05-24
OA12981A (en) 2006-10-13
TR200000235T2 (en) 2000-05-22
IL132991A (en) 2005-11-20
KR20010012854A (en) 2001-02-26
PL337020A1 (en) 2000-07-31
WO1998052940A1 (en) 1998-11-26
AP9901715A0 (en) 1999-12-31
NO995695L (en) 2000-01-21

Similar Documents

Publication Publication Date Title
AU754830C (en) Substituted pyrazoles as p38 kinase inhibitors
US6423713B1 (en) Substituted pyrazoles as p38 kinase inhibitors
US6979686B1 (en) Substituted pyrazoles as p38 kinase inhibitors
US20020086869A1 (en) 3 (5) -heteroaryl substituted pyrazoles as p38 kinase inhibitors
US20080113967A1 (en) Enzyme modulators and treatments
AU7698198A (en) 3(5)-heteroaryl substituted pyrazoles as p38 kinase inhibitors
EP1077971A1 (en) 1,5-DIARYL SUBSTITUTED PYRAZOLES AS p38 KINASE INHIBITORS
CZ411899A3 (en) Substituted pyrazoles functioning as inhibitors of p38 kinase, process of their preparation and pharmaceutical composition

Legal Events

Date Code Title Description
FGA Letters patent sealed or granted (standard patent)
DA2 Applications for amendment section 104

Free format text: THE NATURE OF THE PROPOSED AMENDMENT IS AS SHOWN IN THE STATEMENT(S) FILED 20021115

HB Alteration of name in register

Owner name: G.D. SEARLE LLC

Free format text: FORMER NAME WAS: G.D. SEARLE AND CO.

DA3 Amendments made section 104

Free format text: THE NATURE OF THE AMENDMENT IS AS WAS NOTIFIED IN THE OFFICIAL JOURNAL DATED 20030626