WO2006026754B1 - Bicyclic heteroaryl pde4b inhibitors - Google Patents

Bicyclic heteroaryl pde4b inhibitors

Info

Publication number
WO2006026754B1
WO2006026754B1 PCT/US2005/031322 US2005031322W WO2006026754B1 WO 2006026754 B1 WO2006026754 B1 WO 2006026754B1 US 2005031322 W US2005031322 W US 2005031322W WO 2006026754 B1 WO2006026754 B1 WO 2006026754B1
Authority
WO
WIPO (PCT)
Prior art keywords
optionally substituted
compound
bound
substituted lower
alkynyl
Prior art date
Application number
PCT/US2005/031322
Other languages
French (fr)
Other versions
WO2006026754A9 (en
WO2006026754A2 (en
WO2006026754A3 (en
Inventor
Prabham L Ibrahim
Ryan E Bremer
Samuel J Gillette
Hanna Cho
Marika Nespi
Shumeye Mamo
Chao Zhang
Dean R Artis
Byunghun Lee
Rebecca L Zuckerman
Original Assignee
Plexxikon Inc
Prabham L Ibrahim
Ryan E Bremer
Samuel J Gillette
Hanna Cho
Marika Nespi
Shumeye Mamo
Chao Zhang
Dean R Artis
Byunghun Lee
Rebecca L Zuckerman
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 Plexxikon Inc, Prabham L Ibrahim, Ryan E Bremer, Samuel J Gillette, Hanna Cho, Marika Nespi, Shumeye Mamo, Chao Zhang, Dean R Artis, Byunghun Lee, Rebecca L Zuckerman filed Critical Plexxikon Inc
Priority to CA002583428A priority Critical patent/CA2583428A1/en
Priority to EP05816059A priority patent/EP1786813A2/en
Priority to JP2007530399A priority patent/JP2008512380A/en
Priority to AU2005279795A priority patent/AU2005279795A1/en
Publication of WO2006026754A2 publication Critical patent/WO2006026754A2/en
Publication of WO2006026754A9 publication Critical patent/WO2006026754A9/en
Publication of WO2006026754A3 publication Critical patent/WO2006026754A3/en
Publication of WO2006026754B1 publication Critical patent/WO2006026754B1/en

Links

Classifications

    • 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
    • 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
    • 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
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/06—Antiabortive agents; Labour repressants
    • 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
    • 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
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • A61P37/08—Antiallergic agents
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/12—Radicals substituted by oxygen atoms
    • 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
    • C07D401/12—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 linked by a chain containing hetero atoms as chain links
    • 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
    • C07D405/02—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 two hetero rings
    • C07D405/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
    • G16B15/00—ICT specially adapted for analysing two-dimensional or three-dimensional molecular structures, e.g. structural or functional relations or structure alignment
    • G16B15/30—Drug targeting using structural data; Docking or binding prediction
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16C—COMPUTATIONAL CHEMISTRY; CHEMOINFORMATICS; COMPUTATIONAL MATERIALS SCIENCE
    • G16C20/00—Chemoinformatics, i.e. ICT specially adapted for the handling of physicochemical or structural data of chemical particles, elements, compounds or mixtures
    • G16C20/50—Molecular design, e.g. of drugs
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
    • G16B15/00—ICT specially adapted for analysing two-dimensional or three-dimensional molecular structures, e.g. structural or functional relations or structure alignment

Abstract

Compounds are described that are active on PDE4. Also described are crystal structures of PDE4B determined using X-ray crystallography, the use of PDE4B crystals and stractural information for identifying molecular scaffolds, for developing ligands that bind to and modulate PDE4B, and for identifying improved ligands based on known ligands.

Claims

AMENDED CLAIMS
[Received by the International Bureau on 04 Januaiy 2007 (04.01.2007)]
What is claimed is:
1, A compound having the chemical structure
Figure imgf000003_0001
all salts, prodrugs, tautomers and isomers thereof, wherein: k is selected from the group consisting of -CR6R7R19, -C(Z)R8, -C(Z)NR12R13, -S(O)2NR12R13, and -S(O)2R14;
Z is O, S, or NR9; t is CH; y is N or CH; v, w and x are CH;
A has a structure selected from the group consisting of
Figure imgf000003_0002
Figure imgf000004_0001
R6 and R7 are independently selected from tine group consisting of hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylakyl, optionally substituted aryl, optionally substituted araJkyl, optionally substituted heteroaryl- and optionally substituted heteroaralkyl;
R8 at each occurrence is independently selected from the group consisting of -OR9, Optionally substituted lower alkyl, optionally substituted lower alkenyl, provided, however, that when R8 is alkenyl, no alkene carbon thereof is bound to C(Z), optionally substituted lower alkynyl, provided, however, that when R8 is alkynyl, no alkyne carbon thereof is bound to C(Z), optionally substituted cyeloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, and optionally substituted heteroaralkyl;
R9 at each occurrence is independently selected from the group consisting of hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, provided, however, that when R9 is alkenyl, no alkene carbon thereof is bound to O, N or S, optionally substituted lower alkynyl, provided, however, that when R9 is alkynyl, no alkyne carbon thereof is bound to O, N or S, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl. optionally substituted aryl. optionally substituted aralkyl, optionally substituted heteroaryl, and optionally substituted heteroaralkyl;
R10 and R1 1 at each occurrence are independently selected from the group consisting of hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, provided, however, that when R10 and/or R11 are alkenyl, no alkene carbon thereof is bound to nitrogen, optionally substituted lower alkynyl, provided, however, that when R10 and/or R11 are alkynyl, no alkyne carbon thereof is bound to nitrogen, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, -C(Z)R8, -C(Z)NR12R13, -S(O)2NR12R13, and -S(O)2R14J or
R10 and R11 together with the nitrogen to which they are attached form a 5-7 merabered optionally substituted heterocycloalkyl or optionally substituted heteroaryl ring;
R12 and R13 at each occurrence are independently selected from the group consisting of hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, provided, however, that when R12 and/or R13 are alkenyl, no alkene carbon thereof is bound to nitrogen, optionally substituted lower alkynyl, provided, however, that when R12 and/or R13 are alkynyl, no alkyne carbon thereof is bound to nitrogen, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heteroeycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, and optionally substituted heteroaralkyl; or
R12 and R13 together with the nitrogen to which they are attached form a 5-7 membered optionally substituted heterocycloalkyl or optionally substituted heteroaryl ring;
R14 at each occurrence is independently selected from the group consisting of optionally substituted lower alkyl, optionally substituted lower alkenyl, provided, however, that when R14 is alkenyl, no alkene carbon thereof is bound to -S(O)2-, optionally ' substituted lower alkynyl, provided, however, that when R14 is alkynyl, no alkyne carbon thereof is bound to -S(O)2-, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, and optionally substituted heteroaralkyl;
R15 at each occurrence is independently selected from the group consisting of optionally substituted lower alkyl, optionally substituted lower alkenyl, provided, however, that when R15 is alkenyl, no alkene carbon thereof is bound to oxygen, optionally substituted lower alkynyl, provided, however, that when R15 is alkynyl, no alkyne carbon thereof is bound to oxygen, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted beteroaryl, optionally substituted heteroaralkyl, -C(Z)R8, and -C(Z)NR12R13; or each R15, along with the oxygens to which they are bound, combine to form a S-I membered optionally substituted heterocycloalkyl ring fused to the phenyl ring;
R16 is selected from the group consisting of optionally substituted lower alkyl, optionally substituted lower alkenyl provided, however, that when R16 is alkenyl, no alkene carbon thereof is bound to oxygen, optionally substituted lower alkynyl provided, however, that when R16 is alkynyl, no alkyne carbon thereof is bound to oxygen, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, -C(Z)R8, and -C(Z)NR12R13;
R17 is selected from the group consisting of optionally substituted lower alkyl, optionally substituted lower alkenyl provided, however, that when R17 is alkenyl, no alkene carbon thereof is bound to N, O, or S, optionally substituted lower alkynyl, provided, however, that when R17 is alkynyl, no alkyne carbon thereof is bound to N, O, or S, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, and optionally substituted heteroaralkyl;
R18 is selected from the group consisting of optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, -C(Z)R8, -OR9, -SR9, -NR10R11, -C(Z)NR12R13, -S(O)2NR12R13, and -S(O)2R14; and
R19 is selected from the group consisting of optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalk ylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterooycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, and optionally substituted heteroaralkyl; provided, however that the compound is not
Figure imgf000007_0001
2. The compound of claim 1, wherein y is CH.
3. The compound of claim 1, wherein y is N.
4. The compound of either of claims 3 or 99, wherein k is selected from the group consisting of -CH2R19, -C(Z)R8, -C(Z)NR12R13,
-S(O)2NR12R13, and -S(O)2R14; and wherein R8, R12, R13, R14, and R19 are selected from, the group consisting of optionally substituted lower alkyl, aryl and heteroaryl, wherein aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the group consisting of halogen, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted lower thioalkyl, optionally substituted aryloxy, optionally substituted hetero aryloxy, optionally substituted amino, optionally substituted carboxyl, optionally substituted alkylsulfonylarnino, cyano and nitro.
5. The compound of claim 3 or 99, wherein A has the structure
Figure imgf000008_0001
The compound of claim 5 having the structure
Figure imgf000008_0002
The compound of claim 5 having the structure
Figure imgf000008_0003
8. The compound of claim 5 having the structure
Figure imgf000008_0004
9. The compound of claim 8, wherein k is selected from the group consisting of -CH2R19, -C(Z)R8, -C(Z)NR12R13,
-S(O)2NR12R13, and -S(O)2R14; and wherein R8, R12, R13, R14, and R19 are selected from the group consisting of optionally substituted lower aϊkyϊ, aryl and heteroaryl, wherein aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the group consisting of halogen, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted lower thioalkyl, optionally substituted aryloxy, optionally substituted heteroaiyloxy, optionally substituted amino, optionally substituted carboxyl, optionally substituted alkylsulfonylamino, cyano and nitro.
10. The compound of claim 9, wherein each occurrence of R15 is independently selected from the group consisting of optionally substituted lower alkyl, optionally substituted cyeloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, or each R15, along with the oxygens to which they are bound, combine to form a 5-7 membered optionally substituted heterocycloalkyl ring fused to the phenyl ring.
11. The compound of claim 10, wherein when R15 is optionally substituted lower alkyl, the lower alkyl is optionally substituted with 1-3 substituents selected from the group consisting of fluoro, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl.
12. A composition comprising: a compound according to any of claims 1-11, 96-98 or 99; and a pharmaceutially acceptable carrier.
13. A method for treating a subject suffering from or at risk of a disease or condition for which PDE4B modulation provides a therapeutic benefit, comprising: administering to said subject an effective amount of a compound having a chemical structure of
Figure imgf000010_0001
wherein: k is selected from the group consisting of -CR6R7R19, -C(Z)R8, -C(Z)NR12R13, -S(O)2NR12R13, and -S(O)2R14;
Z is O, S, or NR9; t, u, v, w, x, and y are each independently N or CR1, provided, however, that no more than 1 of u and t axe N, and no more than 2 of v, w, x and y are N;
R1 at each occurrence is independently selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylaϊkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylakyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, -C(Z)R8, -OR9, -SR9, -NR10R11, -C(Z)NR12R13, -S(O)2NR12R13, -S(O)2R14, and A, provided, however, that at least one R1 is A;
A is selected from the group consisting of substituted aryl and substituted heteroaryl;
R6 and R7 are independently selected from the group consisting of hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylakyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl. and optionally substituted heteroaralkyl;
R8 at each occurrence is independently selected from the group consisting of -OR9, optionally substituted lower alkyl, optionally substituted lower alkenyl, provided, however, that when R8 is alkenyl, no alkene carbon thereof is bound to C(Z), optionally substituted lower alkynyl, provided, however, that when R8 is alkynyl, no alkyne carbon thereof is bound to C(Z), optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted atyl, optionally substituted aralkyl, optionally substituted heteroaryl, and optionally substituted heteroaralkyl;
R9 at each occurrence is independently selected from the group consisting of hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, provided, however, that when R9 is alkenyl, no alkene carbon thereof is bound to O, N or S, optionally substituted lower alkynyl, provided, however, that when R9 is alkynyl, no alkyne carbon thereof is bound to O, N or S, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted axyl, optionally substituted aralkyl, optionally substituted heteroaryl, and optionally substituted heteroaralkyl;
R10 and R11 are independently selected from the gtoup consisting of hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, provided, however, that when R10 and/or R11 are alkenyl, no alkene carbon thereof is bound to nitrogen, optionally substituted lower alkynyl, provided, however, that when R10 and/or R11 are alkynyl, no alkyne carbon thereof is bound to nitrogen, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted axyl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, -C(Z)R8, -C(Z)NR12R13, -S(O)2NR12R13, and -S(O)2R14; or
R1 and R11 together with the nitrogen to which they are attached form a 5-7 membered optionally substituted heterocycloalkyl or optionally substituted heteroaryl ring;
R12 and R13 at each occurrence are independently selected from the group consisting of hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, provided, however, that when R12 and/or R13 are alkenyl, no alkene carbon thereof is bound to nitrogen, optionally substituted lower alkynyl, provided, however, that' when R12 and/or R13 are alkynyl, no alkyne carbon thereof is bound to nitrogen, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, and optionally substituted heteroaralkyl; or
R12 and R13 together with the nitrogen to which they are attached form a 5-7 rnembered optionally substituted heterocycloalkyl or optionally substituted heteroaryl ring; R14 at each occurrence is independently selected from the group consisting of optionally substituted lower alkyl, optionally substituted lower alkenyl, provided, however, that when R14 is alkenyl, no alkene carbon thereof is bound to -S (0)2-, optionally substituted lower alkynyl, provided, however, that when R14 is alkynyl no alkyne carbon thereof is bound to -S(O)2-, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, and optionally substituted heteroaralkyl; and
R19 is selected from the group consisting of optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl., optionally substituted aryl: optionally substituted aralkyl, optionally substituted heteroaryl, and optionally substituted heteroaralkyl,
14, The method of claim 13, wherein A has a structure selected from the group consisting of
■
Figure imgf000012_0001
Figure imgf000013_0001
wherein;
R13 at each occurrence is independently selected from the group consisting of optionally substituted lower alkyl, optionally substituted lower alkenyl, provided, however, that when R15 is alkenyl, no alkene carbon thereof is bound to oxygen, optionally substituted lower alkynyl, provided, however, that when R15 is alkynyl, no alkyne carbon thereof is bound to oxygen, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl optionally substituted hetei'ocycloalkylallcyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, -C(Z)R8, and -C(Z)NR12R13; or each R15, along with the oxygens to which they are bound, combine to form a 5-7 membered optionally substituted heterocycloalkyl ring fused to the phenyl ring;
R16 at each occurrence is independently selected from the group consisting of optionally substituted lower alkyl, optionally substituted lower alkenyl provided, however that when R16 is alkenyl, no alkene carbon thereof is bound to oxygen, optionally substituted lower alkynyl provided, however, that when R16 is alkynyl, no alkyrie carbon thereof is bound to oxygen, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, -C(Z)R8, and -C(Z)NR12R13;
R17 at each occurrence is independently selected from the group consisting of optionally substituted lower alkyl, optionally substituted lower alkenyl provided, however, that when R17 is alkenyl, no alkene carbon thereof is bound to N, O, or S, optionally substituted lower alkynyl, provided, however, that when R17 is alkynyl, no alkyne carbon thereof is bound to N, O, or S, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, and optionally substituted heteroaralkyl; and R18 is selected from the group consisting of optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, -C(Z)R8, -OR9, -SR9, -NR10R11, -C(Z)NR12R13, -S(O)2NR12R13, and -S(O)2R14.
15. The method of claim 14, wherein A has the structure
Figure imgf000014_0001
16. The method of claim 15, wherein no more than one oft, u, v, w, x, and y is N.
17. The method of claim 16, wherein t is CH, y is N, one of u, v, w, and x is C-A and the others of u, v, w and x are CH,
18. The method of claim 17, wherein the compound has the structure
Figure imgf000014_0002
19- The method of claim 13, wherein said compound is approved for administration to a human,
20. The method of claim 19, wherein said disease or condition is a PDE4B- mediated disease or condition,
21. The method of claim 19, wherein said disease or condition is selected from the group consisting of asthma, bronchitis, allergic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, idiopathic pulmonary fibrosis, sarcoidosis, pulmonaryry hypertension, allergic bronchitis, emphysema, Alzheimer's disease, Parkinson's disease, Huntington's chorea, multiple sclerosis, rheumatoid arthritis, Crohn's disease, cerebral ischemia , inflammatory bowel disease, ulcerative colitis, atopic dermatitis, osteoporosis, osteopetrosis, Paget's disease, diffuse large-cell B cell lymphoma, chronic lymphocytic leukemia, acute lymphoblastic leukemia. Severe Acute Respiratory Syndrome, and pre-teim labor.
22. A kit comprising a composition of claim 12.
23. The kit of claim 22, further comprising a written indication that said composition is approved for administering to a human,
24. The kit of claim 23, wherein said composition is approved for an indication selected from the group consisting of asthma, bronchitis, allergic bronchitis, chronic . obstructive pulmonary disease, cystic fibrosis, idiopathic pulmonary fibrosis, sarcoidosis, pulmonary hypertension, allergic bronchitis, emphysema, Alzheimer's disease, Parkinson's disease, Huntington's chorea, multiple sclerosis, rheumatoid arthritis, Crohn's disease, cerebral ischemia , inflammatory bowel disease, ulcerative colitis, atopic dermatitis, osteoporosis, osteopetrosis, Paget's disease, diffuse large-cell B cell lymphoma, chronic lymphocytic leukemia, acute lymphoblastic leukemia, Severe Acute Respiratory Syndrome, and pre-term labor.
25. A method for developing an improved modulator active on PDE4, comprising: determining whether any of a plurality of test compounds according to Formula provides an improvement in one or more desired pharmacologic properties relative to a reference compound active on PDE4; and selecting those compounds that have an improvement in said desired pharmacologic property, thereby providing an improved modulator.
26. The method of claim 25, wherein said desired pharmacologic property is at least 10-fold greater activity on PDE4B than on PDE4D. • .
27- The method of claim 25, wherein said desired pharmacologic property is an IC50 of less than 0.10 //M.
28. The method of claim 25, wherein said reference compound is a compound of Formula I.
29. The method of claim 25, wherein at least one derivative of said improved modulator is used as a test compound and said determining and selecting are repeated,
30. A method for developing ligands with improved specificity for PDE4B, comprising: identifying a compound that binds to a plurality of phosphodiesterases; and determining whether a derivative of said compound has greater specificity for PDE4B than said compound, thereby providing ligands with improved specificity for PDE4B.
31. The method of claim 30, wherein said compound binds to PDE4B with an affinity at least 10-fold greater than for binding to any of said plurality of phosphodiesterases,
32. The method of claim 30, wherein said compound interacts with at least one conserved PDE4B active site residue.
33. The method of claim 30, wherein said compound binds weakly to said plurality of phosphodiesterases.
34. The method of claim 30, wherein said plurality of phosphodiesterases comprises PDE4B and PDE4D.
35. The method of claim 30, wherein said plurality of phosphodiesterases comprises PDE4B and PDE5A.
36. The method of claim 30, wherein said compound is a compound of Formula I.
37. A crystal comprising a crystalline form of PDE4B phosphodiesterase domain, having coordinates as described in Table 1 or 2.
38. The crystal of claim 37, comprising one more heavy metal atoms,
39. The crystal of claim 37, wherein said crystalline form comprises a co-crystal of PDE4B with a binding compound.
40. The crystalline form of claim 39, wherein said binding compound interacts with at least one conserved PDE4B active site residue.
41. The crystalline form of claim 39, wherein said co-crystal is in an X-ray beam.
42. The crystalline form of claim 37, wherein said crystal is in an X-ray beam.
43. A method for obtaining a crystal of PDE4B, comprising: subjecting PDE4B protein at 5-20 mg/ml to crystallization condition substantially equivalent to 30% PEG 400, 0.2M MgCl2, 0.1M Tris pH 8,5, 1 mM binding compound, at 4 °C; or 20% PEG 3000, 0.2M Ca(OAc)2, 0. IM Tris pH 7.0, 1 mM binding compound, 15,9 mg/ml protein at 4 °C; or 1 ,8M -2.0M ammonium sulphate, 0.1 M CAPS pH 10,0 - 10.5, 0.2M lithium sulphate.
44. The method of claim 43, further comprising optimizing said crystallization conditions,
45. A co-crystal of PDE4B and a PDE4B binding compound, wherein said binding compound comprises a compound of Formula 1.
46. The co-crystal of claim 45, wherein said co-crystal is in an X-ray beam.
47. A method for determining a structure of a phosphodiesterase, comprising: creating a homology model from an electronic representation of a PDE4B structure, wherein said PDE4B structure represents the atomic coordinates of Table 1 or 2; and equating said homology model with said stucture of a phosphodiesterase.
48. The method of claim 47, wherein said creating comprises: identifying conserved amino acid residues between PDE4B and said phosphodiesterase; transferring the atomic coordinates of a plurality of conserved amino acids in said PDE4B structure to the corresponding amino acids of said phosphodiesterase to provide a rough structure of said phosphodiesterase; and constructing structures representing the remainder of said phosphodiesterase using electronic representations of the structures of the remaining amino acid residues in said phosphodiesterase.
49. The method of claim 48, further comprising fitting said homology model to low resolution x-ray diffraction data from one or more crystals of said phosphodiesterase,
50. The method of claim 48, wherein the coordinates of conserved residues from Table 1 or 2 are utilized.
51. The method of claim 48, wherein said phosphodiesterase is PDE5 A.
52. An electronic representation of a crystal structure of PDE4B, containing atomic coordinate representations corresponding to the coordinates listed in Table 1 or 2,
53. The electronic representation of claim 52, comprising a schematic representation.
54. The electronic representation of claim 52, wherein said PDE4B consists essentially of a PDE4B phosphodiesterase domain.
55. An electronic representation of a PDE4B-based homology model for a phosphodiesterase, wherein said homology model utilizes conserved residue atomic coordinates of Table 1 or 2.
56. A method for developing a biological agent, comprising: analyzing a PDE4B crystal structure and identifying at least one sub-structure for forming said biological agent,
57. The method of claim 56, wherein said substructure comprises an epitope, and said method further comprises developing antibodies against said epitope,
58. The method of claim 56, wherein said sub-structure comprises a mutation site expected to provide altered activity, and said method further comprises creating a mutation at said site thereby providing a modified PDE4B.
59. The method of claim 56, wherein said sub-structure comprises an attachment point for attaching a separate moiety.
60. The method of claim 56, wherein said separate moiety is selected from the group consisting of a peptide, a polypeptide, a solid phase material, a linker, and a label.
61. The method of claim 56, further comprising attaching said separate moiety.
62. A method for identifying compounds with, the potential to bind PDE4B, comprising: fitting at least one electronic representation of a compound in an electronic representation of a PDE4B binding site, wherein said binding site includes electronic representations of coordinates of conserved binding site residues from Table 4.
63. The method of claim 62, wherein said electronic representation further comprises an electronic representation of a binding compoxπid complexed in said binding site,
64. The method of claim 63, comprising: removing a computer representation of a compound complexed with PDE4B and. fitting a computer representation of a compound from a computer database with a computer representation of the active site of PDE4B; and identifying compounds that best fit said active site based on favorable geometric fit and energetically favorable complementary interactions as potential binding compounds.
65. The method of claim 63, comprising: modifying a computer representation of a compound complexed with PDE4B by the deletion or addition or both of one or more chemical grcmps; fitting a computer representation of a compound from a computer database with a computer representation of the active site of PDE4B; and identifying compounds that best fit said active site based on favorable geometric fit, and energetically favorable complementary interactions as potential binding compounds.
66. The method of claim 63, comprising: removing a computer representation of a compound complexed with PDE4B; and searching a database for compounds having structural similarity to said compound using a compound searching computer program or replacing portions of said compound with similar chemical structures using a compound construction computer program.
67. The method of claim 63, wherein said compound coinplexed with PDE4B is non-hydrolyzable cGMP analog.
68. The method of claim 62, wherein said fitting comprises deteπnining whether said compounds will interact with one or more of conserved PDE4B active site residues.
69. A method for attaching a PDE4B binding compound or derivative thereof to an attachment component so as to maintain substantial PDE4B binding of said PDE4B binding compound, comprising: ; attaching said PDE4B binding compound or derivative thereof to said attachment component at an energetically allowed site for attachment.
70. The method of claim 69, wherein said attachment component is a linker for attachment to a solid phase medium, and said method further comprises attaching said compound or derivative to a solid phase medium through a linker attached at said energetically allowed site,
71. The method of claim 69, wherein said phosphodiesterase comprises conserved residues matching at least one conserved PDE4B active site residues,
72. The method of claim 70, wherein said linker is a traceless linker.
73. The method of claim 70, wherein said phosphodiesterase binding compound or derivative thereof is synthesized on said linker attached to said solid phase medium.
74. The method of claim 73, wherein a plurality of said compounds or derivatives are synthesized in combinatorial synthesis.
75. The method of claim 70, wherein attachment of said compound to said solid phase medium provides an affinity medium.
16. The method of claim 69, wherein said attachment component comprises a label.
77. The method of claim 76, wherein said label comprises a fluorophore.
78. A modified compound, comprising a PDE4B binding compound, with a" linker moiety attached thereto at an energetically allowed site for binding of said modified compound to PDE4B,
79. The compound of claim 78, wherein said linker is attached to a solid phase,
80. The compound of claim 78, wherein said linker comprises or is attached to a label
81. The compound of claim 78, wherein said linker is a traceless linker.
82. The compound of claim 78, wherein said binding compound is a compound for Formula I.
83. A method for developing a ligand for a phosphodiesterase, said phosphodiesterase comprising conserved residues matching one or more conserved PDE4B active site residues, comprising: determining whether a PDE4B binding compound which binds to said phosphodiesterase interacts with said one or more conserved PDE4B active site residues in a crystal structure.
84. The method of claim S3, wherein said phosphodiesterase comprises conserved residues matching at least two conserved PDE4B active site residues.
85. The method of claim 83, further comprising determining whether said compound modulates said phosphodiesterase,
86. The method of claim 83, wherein said determining comprises computer fitting said compound in a binding site of said phosphodiesterase.
87. The method of claim 83, further comprising forming a co-crystal of said phosphodiesterase and said compound.
88, The method of claim 83, further comprising determining the binding orientation of said compound with said phosphodiesterase.
89, The method of claim 83, wherein said binding compound is a compound of Formula I,
90, A method for identifying a compound having selectivity between PDB4B and PDE4D, comprising: analyzing whether a compound differentially interacts in PDE4B and PDE4D in at least one differential site, wherein a differential interaction is indicative of said selectivity.
91. The method of claim 90, wherein, said analyzing comprises: fitting an electronic representation of said compound in electronic representations of binding sites of PDE4B and PDE4D; and determining whether said compound differentially interacts based on said fitting.
92. The method of claim 90, comprising: fitting an electronic representation of an initial compound to electronic representations of binding sites of PDE4B and PDE4D, wherein said initial compound binds both PDE4B and PDE4D; modifying said electronic representation of said initial compound with at least one moiety that interacts with at least differential site; and determining whether the modified compound differentially binds to PDE4B and PDE4D,
93. The method of claim 92. wherein said modified compound binds differentially to a greater extent than does said initial compound.
94. The method of claim 90, further comprising assaying a compound that differentially interacts for differential activity on PDE4B and PDE4D.
95. The method of claim 90, wherein said compound is a compound of Formula I.
96. A compound having the chemical structure
Figure imgf000022_0001
all salts, prodrugs, tautomers and isomers thereof, wherein: k is selected from Hie group consisting of -CR6R7R19, -C(Z)R8, -C(Z)NR12R13, -S(O)2NR12R13, and -S(O)2R14; Z is O, S, orNR9; t is N or CH; y is N or CH, provided that both t and y are not N;
V, w and x are CH;
A has a structure selected from the group consisting of
Figure imgf000023_0001
R5 and R7 are independently selected from the group consisting of hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylakyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, and optionally substituted heteroaralkyl; R8 at each occurrence is independently selected -from the group consisting of -OR9, optionally substituted lower alkyl, optionally substituted lower alkenyl, provided, however, that when R8 is alkenyl, no alkene carbon thereof is bound to C(Z), optionally substituted lower alkynyl, provided, however, that when R8 is alkynyl, no alkyne carbon thereof is bound to C(Z), optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl., optionally substituted heterocycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, and optionally substituted heteroaralkyl;
R9 at each occurrence is independently selected from the group consisting of hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, provided, however, that when R9 is alkenyl, no alkene carbon thereof is bound to O, N or S, optionally substituted lower alkynyl, provided, however, that when R9 is alkynyl, no alkyne carbon thereof is bound to O, N or S, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, and optionally substituted heteroaralkyl;
R10 and Ru at each occurrence are independently selected from the group consisting of hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, provided, however, that when R10 and/or R.11 are alkenyl, no alkene carbon thereof is bound to nitrogen, optionally substituted lower alkynyl, provided, however, that when. Ri0 and/or R11 are alkynyl, no alkyne carbon thereof is bound to nitrogen, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, -C(Z)R8, -C(Z)NR12R13, -S(O)2NR12R13, and -S(O)2R14; or
R10 and R11 together with the nitrogen to which they are attached form a 5-7 membered optionally substituted heterocycloalkyl or optionally substituted heteroaryl ring;
R12 and R13 at each occurrence are independently selected from the group consisting of hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, provided, however, that when R12 and/or R13 are alkenyl, no alkene carbon thereof is bound to nitrogen, optionally substituted lower alkynyl, provided, however, that when R12 and/or R13 are alkynyl, no alkyne carbon thereof is bound to nitrogen, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkylj optionally substituted heterocycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl., and optionally substituted heteroaxalkyl; or
R12 and R13 together with the nitrogen to which they are attached form a 5-7 membered optionally substituted heterocycloalkyl or optionally substituted heteroaryl ring;
R14 at each occurrence is independently selected from the group consisting of optionally substituted lower alkyl, optionally substituted lower alkenyl., provided, however, that when R14 is alkenyl- no alkene carbon thereof is bound to -S(O)2-, optionally substituted lower alkynyl, provided, however, that when R14 is alkynyl, no alkyne carbon thereof is bound to -S (0)2-, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, and optionally substituted heteroaralkyl;
R15 at each occurrence is independently selected from the group consisting of optionally substituted lower alkyl, optionally substituted lower alkenyl, provided, however, that when R15 is alkenyl, no alkene carbon thereof is bound to oxygen, optionally substituted lower alkynyl, provided, however, that when R15 is alkynyl, no alkyne carbon thereof is bound to oxygen, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted aryl, optionally substituted axalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, -C(Z)R8, and -C(Z)NR12R13; or each R15, along with the oxygens to which they are bound, combine to form a 5-7 membered optionally substituted heterocycloalkyl ring fused to the phenyl ring;
R16 is selected from the group consisting of optionally substituted lower alkyl, optionally substituted lower alkenyl provided, however, that when R16 is alkenyl, no alkene carbon thereof is bound to oxygen, optionally substituted lower alkynyl provided, however, that when R16 is alkynyl, no alkyne carbon thereof is bound to oxygen, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, -C(Z)R8, and -C(Z)NR12R13; R17 is selected from the group consisting of optionally substituted lower alkyl, optionally substituted lower alkenyl provided, however, that when R17 is alkenyl, no alkene carbon thereof is bound to N, O, or S, optionally substituted lower alkynyl., provided, however, that when R17 is alkynyl, no alkyne carbon thereof is bound to N, O, or S, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryi, and optionally substituted heteroaralkyl;
R18 is selected from the group consisting of optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted lieterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryi, optionally substituted heteroaralkyl, -C(Z)R8, -OR9, -SR9, -NR10R11, -C(Z)NR12R13, -S(O)2NR12R13, and -S(O)2R14; and
R19 is selected from the group consisting of optionally substituted lower alky], optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryi, and optionally substituted heteroaralkyl; provided, however that the compound is not
Figure imgf000026_0001
97, A compound having the chemical structure selected from the group consisting of
Figure imgf000027_0001
all salts, prodrugs, tautomers and isomers thereof, wherein: k is selected from the group consisting of -CR6R7R19, -C(Z)R8, -C(Z)NR12R13, -S(O)2NR12R13, and -S(O)2R14;
Z is O, S, Or NR9; t is N or CH; y is N or CH, provided that both t and y are not N;
U, v, w and x are CH;
A has a structure selected from the group consisting of
Figure imgf000027_0002
Figure imgf000028_0001
R6 and R7 are independently selected from the group consisting of hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylakyl., optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaiyl, and optionally substituted heteroaralkyl;
R8 at each occurrence is independently selected from the group consisting of -OR9, optionally substituted lower alkyl, optionally substituted lower alkenyl, provided, however, that when R8 is alkenyl, no alkene carbon thereof is bound to C(Z), optionally substituted lower alkynyl, provided, however, that when R8 is alkynyl, no alkyne carbon thereof is bound to C(Z), optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, and optionally substituted heteroaralkyl;
R9 at each occurrence is independently selected from the group consisting of hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, provided, however, that when R9 is alkenyl, no alkene carbon thereof is bound to O, N or S, optionally substituted lower alkynyl, provided, however, that when R9 is alkynyl, no alkyne carbon thereof is bound to O, N or S, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocyσloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl., optionally substituted heteroaryl, and optionally substituted heteroaralkyl;
R1 and R11 at each occurrence are independently selected from the group consisting of hydrogen, optionally substituted lower alkyl, optionally substituted lower allcenyl, provided, however, that when R10 and/or R11 are alkenyl, no alkene carbon thereof is bound to nitrogen, optionally substituted lower alkynyl, provided, however, that when R10 and/or R11 are alkyny], no alkyne carbon thereof is bound to nitrogen, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, -C(Z)R8, -C(Z)NR12R13, -S(O)2NR12R13, and -S(O)2R14; or
R10 and R11 together with the nitrogen to which they are attached form a 5-7 membered optionally substituted heterocycloalkyl or optionally substituted heteroaryl ring;
R12 and R13 at each occurrence are independently selected from the group consisting of hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, provided, however, that when R12 and/or R13 are alkenyl, no alkene carbon thereof is bound to nitrogen, optionally substituted lower alkynyl, provided, however, that when R12 and/or R13 are alkynyl, no alkyne carbon thereof is bound to nitrogen, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, and optionally substituted heteroaralkyl; or
R12 and R13 together with the nitrogen to which they are attached form a 5-7 membered optionally substituted heterocycloalkyl or optionally substituted heteroaryl ring;
R14 at each occurrence is independently selected from the group consisting of optionally substituted lower alkyl, optionally substituted lower alkenyl, provided, however, that when R14 is alkenyl, no alkene carbon thereof is bound to -S (0)2-, optionally substituted lower alkynyl, provided, however, that when R14 is alkynyl, no alkyne carbon thereof is bound to -S(0)2-, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclo alkyl , optionally substituted heterocycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl , optionally substituted heteroaryl, and optionally substituted heteroaralkyi;
R15 at each occurrence is independently selected from the group consisting of optionally substituted lower alkyl, optionally substituted lower alkenyl., provided, however, that when R19 is alken yl, no alkene carbon thereof is bound to oxygen, optionally substituted lower alkynyl, provided, however, that when R15 is alkynyl, no alkyae carbon thereof is bound to oxygen, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl. optionally substituted heterocycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, -C(Z)R8, and -C(Z)NR12R13; or each R15, along with the oxygens to which they are bound, combine to form a 5-7 membered optionally substituted heterocycloalkyl ring fused to the phenyl ring;
R16 is selected froni the group consisting of optionally substituted lower alkyl, optionally substituted lower alkenyl provided, however, that when R16 is alkenyl, no alkene carbon thereof is bound to oxygen, optionally substituted lower alkynyl provided, however, that when R16 is alkynyl, no alkyne carbon thereof is bound to oxygen^ optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl optionally substituted heterocycloalkylalkyl, optionally substituted aτyl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, -C(Z)R8, and -C(Z)NR12R13;
R17 is selected from the group consisting of optionally substituted lower alkyl, optionally substituted lower alkenyl provided, however, that when R17 is alkenyl, no alkene carbon thereof is bound to N, O, or S, optionally substituted lower alkynyl, provided, however, that when R17 is alkynyl, no alkyne carbon thereof is bound to N, O, or S, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl; and optionally substituted heteroaralkyi;
R18 is selected from the group consisting of optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, -C(Z)R8, -OR9, -SR9, -NR10R1 , -C(Z)NR12R13, -S(O)2NR12R13, and -S(O)2R14; and is selected from the group consisting of optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, and optionally substituted heteroaralkyl.
98, The compound of claim 97, wherein t and y are CH.
99. The compound of claim 97, wherein t is CH and y is N,
PCT/US2005/031322 2004-09-03 2005-09-02 Bicyclic heteroaryl pde4b inhibitors WO2006026754A2 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
CA002583428A CA2583428A1 (en) 2004-09-03 2005-09-02 Bicyclic heteroaryl pde4b inhibitors
EP05816059A EP1786813A2 (en) 2004-09-03 2005-09-02 Bicyclic heteroaryl pde4b inhibitors
JP2007530399A JP2008512380A (en) 2004-09-03 2005-09-02 PDE4B inhibitor
AU2005279795A AU2005279795A1 (en) 2004-09-03 2005-09-02 Bicyclic heteroaryl PDE4B inhibitors

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US60740704P 2004-09-03 2004-09-03
US60/607,407 2004-09-03

Publications (4)

Publication Number Publication Date
WO2006026754A2 WO2006026754A2 (en) 2006-03-09
WO2006026754A9 WO2006026754A9 (en) 2006-04-20
WO2006026754A3 WO2006026754A3 (en) 2007-01-11
WO2006026754B1 true WO2006026754B1 (en) 2007-02-22

Family

ID=36000749

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2005/031322 WO2006026754A2 (en) 2004-09-03 2005-09-02 Bicyclic heteroaryl pde4b inhibitors

Country Status (7)

Country Link
US (1) US7605168B2 (en)
EP (1) EP1786813A2 (en)
JP (1) JP2008512380A (en)
CN (1) CN101048407A (en)
AU (1) AU2005279795A1 (en)
CA (1) CA2583428A1 (en)
WO (1) WO2006026754A2 (en)

Families Citing this family (72)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6663602B2 (en) 2000-06-16 2003-12-16 Novo Nordisk A/S Injection device
WO2006045526A1 (en) 2004-10-21 2006-05-04 Novo Nordisk A/S Dial-down mechanism for wind-up pen
US8921376B2 (en) * 2005-05-20 2014-12-30 Vertex Pharmaceuticals Incorporated Pyrrolopyridines useful as inhibitors of protein kinase
US7572807B2 (en) 2005-06-09 2009-08-11 Bristol-Myers Squibb Company Heteroaryl 11-beta-hydroxysteroid dehydrogenase type I inhibitors
US7579360B2 (en) 2005-06-09 2009-08-25 Bristol-Myers Squibb Company Triazolopyridine 11-beta hydroxysteroid dehydrogenase type I inhibitors
KR101468830B1 (en) 2005-06-24 2014-12-03 바이엘 크롭사이언스 엔.브이. Methods for altering the reactivity of plant cell walls
DE102006012617A1 (en) * 2006-03-20 2007-09-27 Merck Patent Gmbh 4- (pyrrolopyridinyl) -pyrimidinyl-2-amine derivatives
JP5253387B2 (en) 2006-05-18 2013-07-31 ノボ・ノルデイスク・エー／エス Injection device with mode locking means
US8097699B2 (en) 2006-08-30 2012-01-17 Rsr Limited Crystal structure of thyroid stimulating hormone receptor
WO2008063888A2 (en) 2006-11-22 2008-05-29 Plexxikon, Inc. Compounds modulating c-fms and/or c-kit activity and uses therefor
GB0702456D0 (en) 2007-02-08 2007-03-21 Astrazeneca Ab New combination
MX2010000617A (en) 2007-07-17 2010-05-17 Plexxikon Inc Compounds and methods for kinase modulation, and indications therefor.
US8119658B2 (en) 2007-10-01 2012-02-21 Bristol-Myers Squibb Company Triazolopyridine 11-beta hydroxysteroid dehydrogenase type I inhibitors
WO2009067597A1 (en) * 2007-11-21 2009-05-28 Decode Genetics Ehf 4- (or 5-) substituted catechol derivatives
NZ586106A (en) 2007-12-20 2012-09-28 Astrazeneca Ab Device, typically for medicament powder, for deaggregating powder by passing air stream along flat region with recess of brick shape where eddy is generated
WO2009143018A2 (en) 2008-05-19 2009-11-26 Plexxikon, Inc. Compounds and methods for kinase modulation, and indications therefor
TW201036957A (en) 2009-02-20 2010-10-16 Astrazeneca Ab Novel salt 628
RU2536826C2 (en) 2009-07-01 2014-12-27 Астразенека Аб Delivery device and method for increasing powder supply into air flow
PE20121335A1 (en) 2009-11-18 2012-10-12 Plexxikon Inc AMIDA-DERIVED COMPOUNDS AS RAF KINASES INHIBITORS
WO2011073662A1 (en) 2009-12-17 2011-06-23 Astrazeneca Ab Combination of a benzoxazinone and a further agent for treating respiratory diseases
WO2011079133A2 (en) 2009-12-23 2011-06-30 Plexxikon, Inc. Compounds and methods for kinase modulation, and indications therefor
MX2012008906A (en) 2010-02-10 2012-08-15 Astrazeneca Uk Ltd Process for providing a filled canister for an inhaler.
TWI510487B (en) 2010-04-21 2015-12-01 Plexxikon Inc Compounds and methods for kinase modulation, and indications therefor
JO3131B1 (en) 2010-04-27 2017-09-20 Glaxosmithkline Llc Chemical Compounds
EP2593453B1 (en) 2010-07-15 2014-09-17 Bristol-Myers Squibb Company Azaindazole compounds
BR112013001266A2 (en) 2010-07-21 2019-09-24 Astrazeneca Ab inhaler
WO2012010877A2 (en) 2010-07-21 2012-01-26 Astrazeneca Ab New device
JP5941069B2 (en) 2011-02-07 2016-06-29 プレキシコン インコーポレーテッドＰｌｅｘｘｉｋｏｎ Ｉｎｃ． Compounds and methods for kinase regulation and indications therefor
EP2487159A1 (en) 2011-02-11 2012-08-15 MSD Oss B.V. RorgammaT inhibitors
RU2631487C2 (en) 2011-05-17 2017-09-22 Плексксикон Инк. Kinases modulation and indications for its use
ES2624984T3 (en) * 2011-07-15 2017-07-18 Viiv Healthcare Uk Limited 2- (Pyrrolo [2,3-b] pyridin-5-yl) -2- (t-butoxy) -acetic acid derivatives as inhibitors of HIV replication for the treatment of AIDS
GB201115874D0 (en) 2011-09-14 2011-10-26 Astrazeneca Ab Inhaler
US9533106B2 (en) 2011-12-29 2017-01-03 Novo Nordisk A/S Torsion-spring based wind-up auto injector pen with dial-up/dial-down mechanism
US9358235B2 (en) 2012-03-19 2016-06-07 Plexxikon Inc. Kinase modulation, and indications therefor
US9951335B2 (en) 2012-04-10 2018-04-24 Georgia State University Research Foundation, Inc. Compositions and methods for treating otitis media and other conditions with inhibitors of CYLD
WO2014026330A1 (en) 2012-08-15 2014-02-20 Merck Sharp & Dohme Corp. 3-AMINOCYCLOALKYL COMPOUNDS AS RORgammaT INHIBITORS AND USES THEREOF
WO2014026327A1 (en) 2012-08-15 2014-02-20 Merck Sharp & Dohme Corp. 4-heteroaryl substituted benzoic acid compounds as rorgammat inhibitors and uses thereof
WO2014026329A1 (en) 2012-08-15 2014-02-20 Merck Sharp & Dohme Corp. N-alkylated indole and indazole compounds as rorgammat inhibitors and uses thereof
EP2892534B8 (en) 2012-09-06 2021-09-15 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
CN105308036B (en) 2012-12-21 2019-06-21 普莱希科公司 The Compounds and methods for and its indication adjusted for kinases
WO2014128585A1 (en) 2013-02-19 2014-08-28 Pfizer Inc. Azabenzimidazole compounds as inhibitors of pde4 isozymes for the treatment of cns and other disorders
HUE039380T2 (en) 2013-03-15 2018-12-28 Plexxikon Inc Heterocyclic compounds and uses thereof
US20140303121A1 (en) 2013-03-15 2014-10-09 Plexxikon Inc. Heterocyclic compounds and uses thereof
MX2015015966A (en) 2013-05-30 2016-04-13 Plexxikon Inc Compounds for kinase modulation, and indications therefor.
WO2015134536A1 (en) 2014-03-04 2015-09-11 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US10131669B2 (en) 2014-07-24 2018-11-20 Pfizer Inc. Pyrazolopyrimidine compounds
DK3177624T3 (en) 2014-08-06 2019-07-01 Pfizer IMIDAZOPYRIDAZINE COMPOUNDS
US9856259B2 (en) 2014-09-15 2018-01-02 Plexxikon Inc. Heterocyclic compounds and uses thereof
US10221142B2 (en) 2015-02-11 2019-03-05 Merck Sharp & Dohme Corp. Substituted pyrazole compounds as RORgammaT inhibitors and uses thereof
US10160755B2 (en) 2015-04-08 2018-12-25 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
EP3757104A1 (en) 2015-05-06 2020-12-30 Plexxikon Inc. Solid forms of a compound modulating kinases
HUE047657T2 (en) 2015-05-06 2020-05-28 Plexxikon Inc Synthesis of 1h-pyrrolo[2,3-b]pyridin derivatives that modulate kinases
US10829484B2 (en) 2015-07-28 2020-11-10 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
KR20180052757A (en) 2015-09-21 2018-05-18 플렉시콘 인코퍼레이티드 Heterocyclic compounds and uses thereof
KR20180070697A (en) 2015-10-27 2018-06-26 머크 샤프 앤드 돔 코포레이션 Substituted indazole compounds as ROR gamma T inhibitors and uses thereof
US10344000B2 (en) 2015-10-27 2019-07-09 Merck Sharp & Dohme Corp. Substituted bicyclic pyrazole compounds as RORgammaT inhibitors and uses thereof
US10584121B2 (en) 2015-10-27 2020-03-10 Merck Sharp & Dohme Corp. Heteroaryl substituted benzoic acids as RORgammaT inhibitors and uses thereof
RU2018123825A (en) 2015-12-07 2020-01-15 Плексксикон Инк. COMPOUNDS AND METHODS FOR MODULATION OF KINASES, AND INDICATIONS FOR THIS
AU2017232610B2 (en) 2016-03-16 2021-07-22 Plexxikon Inc. Compounds and methods for kinase modulation and indications therefore
WO2017205459A1 (en) 2016-05-26 2017-11-30 Kalyra Pharmaceuticals, Inc. Egfr inhibitor compounds
TW201815766A (en) 2016-09-22 2018-05-01 美商普雷辛肯公司 Compounds and methods for IDO and TDO modulation, and indications therefor
WO2018136202A2 (en) 2016-12-23 2018-07-26 Plexxikon Inc. Compounds and methods for cdk8 modulation and indications therefor
WO2018175311A1 (en) 2017-03-20 2018-09-27 Plexxikon Inc. Crystalline forms of 4-(1-(1,1-di(pyridin-2-yl)ethyl)-6-(3,5-dimethylisoxazol-4-yl)-1h- pyrrolo[3,2-b]pyridin-3-yl)benzoic acid that inhibits bromodomain
US10428067B2 (en) 2017-06-07 2019-10-01 Plexxikon Inc. Compounds and methods for kinase modulation
CN110944670B (en) 2017-07-25 2023-03-10 普莱希科公司 Formulations of compounds for modulating kinases
EP3694855A1 (en) 2017-10-13 2020-08-19 Plexxikon Inc. Solid forms of a compound for modulating kinases
JP7175309B2 (en) 2017-10-27 2022-11-18 プレキシコン インコーポレーテッド Formulations of compounds that modulate kinases
CN112119072A (en) 2018-03-20 2020-12-22 普莱希科公司 Compounds and methods for IDO and TDO modulation, and indications thereof
US11446287B2 (en) 2019-04-09 2022-09-20 Opna Immuno-Oncology Sa Compounds and methods for EP300 or CBP modulation and indications therefor
TW202206422A (en) 2020-04-23 2022-02-16 美商普雷辛肯公司 Compounds and methods for cd73 modulation and indications therefor
CN116322690A (en) 2020-08-21 2023-06-23 奥普纳生物有限公司 Combination pharmaceutical anticancer therapies
CN113754796B (en) * 2021-10-18 2022-09-30 中国石油大学(华东) Naphthalene-modified crosslinked beta-cyclodextrin gel, preparation method and application

Family Cites Families (77)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US587707A (en) * 1897-08-10 Tension device for sewing-machine binders
GB1573212A (en) * 1976-04-15 1980-08-20 Technicon Instr Immunoassay for gentamicin
US4568649A (en) * 1983-02-22 1986-02-04 Immunex Corporation Immediate ligand detection assay
US4626513A (en) * 1983-11-10 1986-12-02 Massachusetts General Hospital Method and apparatus for ligand detection
DE3483099D1 (en) 1984-03-15 1990-10-04 Immunex Corp TEST FOR IMMEDIATELY DETECTING LIGANDS, TEST SET AND ITS PRODUCTION.
US5688655A (en) 1988-02-10 1997-11-18 Ict Pharmaceuticals, Inc. Method of screening for protein inhibitors and activators
US5700637A (en) * 1988-05-03 1997-12-23 Isis Innovation Limited Apparatus and method for analyzing polynucleotide sequences and method of generating oligonucleotide arrays
US6054270A (en) * 1988-05-03 2000-04-25 Oxford Gene Technology Limited Analying polynucleotide sequences
US5658775A (en) * 1988-05-17 1997-08-19 Sloan-Kettering Institute For Cancer Research Double copy retroviral vector
US4861891A (en) * 1988-08-31 1989-08-29 Pfizer Inc. Antidepressant N-substituted nicotinamide compounds
JP3082204B2 (en) * 1988-09-01 2000-08-28 ホワイトヘッド・インスティチュート・フォー・バイオメディカル・リサーチ Recombinant retrovirus with an amphotropic and ecotropic host range
US5703055A (en) * 1989-03-21 1997-12-30 Wisconsin Alumni Research Foundation Generation of antibodies through lipid mediated DNA delivery
US5744101A (en) * 1989-06-07 1998-04-28 Affymax Technologies N.V. Photolabile nucleoside protecting groups
US5527681A (en) * 1989-06-07 1996-06-18 Affymax Technologies N.V. Immobilized molecular synthesis of systematically substituted compounds
US5143854A (en) * 1989-06-07 1992-09-01 Affymax Technologies N.V. Large scale photolithographic solid phase synthesis of polypeptides and receptor binding screening thereof
US5800992A (en) * 1989-06-07 1998-09-01 Fodor; Stephen P.A. Method of detecting nucleic acids
WO1991018088A1 (en) * 1990-05-23 1991-11-28 The United States Of America, Represented By The Secretary, United States Department Of Commerce Adeno-associated virus (aav)-based eucaryotic vectors
EP0659209A1 (en) * 1991-07-26 1995-06-28 The University Of Rochester Cancer therapy utilizing malignant cells
US5632957A (en) * 1993-11-01 1997-05-27 Nanogen Molecular biological diagnostic systems including electrodes
JPH05236997A (en) * 1992-02-28 1993-09-17 Hitachi Ltd Chip for catching polynucleotide
US5840485A (en) * 1993-05-27 1998-11-24 Selectide Corporation Topologically segregated, encoded solid phase libraries
ATE366741T1 (en) * 1993-05-27 2007-08-15 Aventis Pharma Inc TOPOLOGICALLY SEPARATE, SOLID-PHASE CODING LIBRARIES
US5631236A (en) * 1993-08-26 1997-05-20 Baylor College Of Medicine Gene therapy for solid tumors, using a DNA sequence encoding HSV-Tk or VZV-Tk
US5426039A (en) * 1993-09-08 1995-06-20 Bio-Rad Laboratories, Inc. Direct molecular cloning of primer extended DNA containing an alkane diol
US6045996A (en) * 1993-10-26 2000-04-04 Affymetrix, Inc. Hybridization assays on oligonucleotide arrays
US6468742B2 (en) * 1993-11-01 2002-10-22 Nanogen, Inc. Methods for determination of single nucleic acid polymorphisms using bioelectronic microchip
US5965452A (en) * 1996-07-09 1999-10-12 Nanogen, Inc. Multiplexed active biologic array
JP2928079B2 (en) * 1994-02-14 1999-07-28 永信薬品工業股▲ふん▼有限公司 1- (Substituted benzyl) -3- (substituted aryl) condensed pyrazoles, their production and use
US5807522A (en) * 1994-06-17 1998-09-15 The Board Of Trustees Of The Leland Stanford Junior University Methods for fabricating microarrays of biological samples
US5763198A (en) * 1994-07-22 1998-06-09 Sugen, Inc. Screening assays for compounds
US5556752A (en) * 1994-10-24 1996-09-17 Affymetrix, Inc. Surface-bound, unimolecular, double-stranded DNA
US5830645A (en) * 1994-12-09 1998-11-03 The Regents Of The University Of California Comparative fluorescence hybridization to nucleic acid arrays
US5837815A (en) 1994-12-15 1998-11-17 Sugen, Inc. PYK2 related polypeptide products
US5959098A (en) * 1996-04-17 1999-09-28 Affymetrix, Inc. Substrate preparation process
US6117681A (en) * 1995-03-29 2000-09-12 Bavarian Nordic Research Inst. A/S Pseudotyped retroviral particles
US6110456A (en) * 1995-06-07 2000-08-29 Yale University Oral delivery or adeno-associated viral vectors
US5856174A (en) * 1995-06-29 1999-01-05 Affymetrix, Inc. Integrated nucleic acid diagnostic device
US5866411A (en) * 1995-09-08 1999-02-02 Pedersen; Finn Skou Retroviral vector, a replication system for said vector and avian or mammalian cells transfected with said vector
US5747276A (en) * 1995-09-15 1998-05-05 The Scripps Research Institute Screening methods for the identification of novel antibiotics
WO1997016533A1 (en) * 1995-10-31 1997-05-09 The Regents Of The University Of California Mammalian artificial chromosomes and methods of using same
US6022963A (en) * 1995-12-15 2000-02-08 Affymetrix, Inc. Synthesis of oligonucleotide arrays using photocleavable protecting groups
US6013440A (en) * 1996-03-11 2000-01-11 Affymetrix, Inc. Nucleic acid affinity columns
US6025155A (en) * 1996-04-10 2000-02-15 Chromos Molecular Systems, Inc. Artificial chromosomes, uses thereof and methods for preparing artificial chromosomes
WO1997046313A1 (en) 1996-06-07 1997-12-11 Eos Biotechnology, Inc. Immobilised linear oligonucleotide arrays
US5922557A (en) * 1997-01-09 1999-07-13 Merck & Co., Inc. System for stably expressing a high-affinity camp phosphodiesterase and use thereof
US6294330B1 (en) * 1997-01-31 2001-09-25 Odyssey Pharmaceuticals Inc. Protein fragment complementation assays for the detection of biological or drug interactions
WO1998039471A1 (en) * 1997-03-07 1998-09-11 Tropix, Inc. Protease inhibtor assay
TR199902432T2 (en) 1997-04-04 2000-01-21 Prizer Products Inc. Nicotinamide is highly valued.
CA2238283C (en) * 1997-05-30 2002-08-20 Cell Pathways, Inc. Method for identifying compounds for inhibition of neoplastic lesions, pharmaceutical compositions from such compounds and uses of such compounds and compositions for treating neoplastic lesions
US6096718A (en) * 1997-06-05 2000-08-01 Gene Targeting Corp. Tissue specific adenovirus vectors for breast cancer treatment
US6826296B2 (en) * 1997-07-25 2004-11-30 Affymetrix, Inc. Method and system for providing a probe array chip design database
WO1999009217A1 (en) 1997-08-15 1999-02-25 Hyseq, Inc. Methods and compositions for detection or quantification of nucleic acid species
WO1999013313A1 (en) * 1997-09-11 1999-03-18 Genovations, Inc. Method of making high density arrays
US6178384B1 (en) * 1997-09-29 2001-01-23 The Trustees Of Columbia University In The City Of New York Method and apparatus for selecting a molecule based on conformational free energy
US6465178B2 (en) * 1997-09-30 2002-10-15 Surmodics, Inc. Target molecule attachment to surfaces
MA24682A1 (en) 1997-10-23 1999-07-01 Smithkline Beecham Corp NEW POLYMORPHIC FORMS OF CIPAMFYLLINE, PROCESS FOR THEIR PREPARATION AND COMPOSITIONS CONTAINING THEM
TR200001081T2 (en) 1997-10-27 2000-10-23 Agouron Pharmaceuticals, Inc. 4-amino thiazole-2-yl compounds substituted as CDKS inhibitors
IL138668A0 (en) 1998-04-03 2001-10-31 Phylos Inc Addressable protein arrays
US6048695A (en) * 1998-05-04 2000-04-11 Baylor College Of Medicine Chemically modified nucleic acids and methods for coupling nucleic acids to solid support
WO1999063929A2 (en) * 1998-06-08 1999-12-16 Advanced Medicine, Inc. Multibinding inhibitors of microsomal triglyceride transferase protein
US6113913A (en) * 1998-06-26 2000-09-05 Genvec, Inc. Recombinant adenovirus
US6277628B1 (en) * 1998-10-02 2001-08-21 Incyte Genomics, Inc. Linear microarrays
US20020009764A1 (en) * 1999-10-08 2002-01-24 W. Joseph Thompson Methods for identifying compounds for inhibition of neoplastic lesions, and pharmaceutical compositions containing such compounds
US6277489B1 (en) * 1998-12-04 2001-08-21 The Regents Of The University Of California Support for high performance affinity chromatography and other uses
US6221653B1 (en) * 1999-04-27 2001-04-24 Agilent Technologies, Inc. Method of performing array-based hybridization assays using thermal inkjet deposition of sample fluids
PE20010306A1 (en) 1999-07-02 2001-03-29 Agouron Pharma INDAZOLE COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM USEFUL FOR THE INHIBITION OF PROTEIN KINASE
US6653151B2 (en) * 1999-07-30 2003-11-25 Large Scale Proteomics Corporation Dry deposition of materials for microarrays using matrix displacement
US20010008765A1 (en) * 1999-12-06 2001-07-19 Fuji Photo Film Co., Ltd. DNA chip and reactive solid carrier
US6387942B2 (en) * 2000-06-19 2002-05-14 Yung Shin Pharmaceutical Ind. Co. Ltd Method of treating disorders related to protease-activated receptors-induced cell activation
US20020165237A1 (en) * 2000-08-11 2002-11-07 Fryburg David Albert Treatment of the insulin resistance syndrome
TWI262920B (en) * 2000-10-27 2006-10-01 Elbion Ag New 7-azaindoles, their use as inhibitors of phosphodiesterase 4, and a method for synthesizing them
US6849644B2 (en) * 2000-11-21 2005-02-01 Smithkline Beecham P.L.C. Isoquinoline derivatives useful in the treatment of CNS disorders
US6774134B2 (en) * 2000-12-20 2004-08-10 Bristol-Myers Squibb Company Heterocyclic substituted 2-methyl-benzimidazole antiviral agents
KR20030072614A (en) * 2001-01-31 2003-09-15 화이자 프로덕츠 인크. Thiazolyl-, Oxazolyl-, Pyrrolyl-, and Imidazolyl-Acid Amide Derivatives Useful as Inhibitors of PDE4 Isozymes
GB0111186D0 (en) * 2001-05-08 2001-06-27 Smithkline Beecham Plc Novel compounds
FR2828693B1 (en) * 2001-08-14 2004-06-18 Exonhit Therapeutics Sa NEW MOLECULAR TARGET OF NEUROTOXICITY
GB0319037D0 (en) * 2003-08-13 2003-09-17 Glaxo Group Ltd 7-Azaindole Derivatives

Also Published As

Publication number Publication date
US7605168B2 (en) 2009-10-20
AU2005279795A1 (en) 2006-03-09
CA2583428A1 (en) 2006-03-09
CN101048407A (en) 2007-10-03
JP2008512380A (en) 2008-04-24
EP1786813A2 (en) 2007-05-23
US20060100218A1 (en) 2006-05-11
WO2006026754A9 (en) 2006-04-20
WO2006026754A2 (en) 2006-03-09
WO2006026754A3 (en) 2007-01-11

Similar Documents

Publication Publication Date Title
WO2006026754B1 (en) Bicyclic heteroaryl pde4b inhibitors
Appelt et al. Design of enzyme inhibitors using iterative protein crystallographic analysis
Tian et al. Targeting the entrance channel of NNIBP: Discovery of diarylnicotinamide 1, 4-disubstituted 1, 2, 3-triazoles as novel HIV-1 NNRTIs with high potency against wild-type and E138K mutant virus
Hurley et al. Regulation of an enzyme by phosphorylation at the active site
Bruno et al. IsoStar: a library of information about nonbonded interactions
He et al. Inhibition of the Mycobacterium tuberculosis enoyl acyl carrier protein reductase InhA by arylamides
WO2005062795B1 (en) Compounds and methods for development of ret modulators
Pan et al. Time‐Dependent Diaryl Ether Inhibitors of InhA: Structure–Activity Relationship Studies of Enzyme Inhibition, Antibacterial Activity, and in vivo Efficacy
Evison et al. A small molecule inhibitor of PCSK9 that antagonizes LDL receptor binding via interaction with a cryptic PCSK9 binding groove
EP0407342A2 (en) Pyrimidine derivatives
KR20020032537A (en) Carboxylic acid amides, medicaments containing these compounds and the use and production thereof
R Helgren et al. Advances in bacterial methionine aminopeptidase inhibition
Varga et al. Selectivity of kinases on the activation of tenofovir, an anti-HIV agent
Johnson et al. Fluorescence studies of the interaction of calmodulin with myosin light chain kinase.
Zhao et al. Direct targeting of the Ras GTPase superfamily through structure-based design
CN108368060A (en) A kind of novel pyridine derivatives kinase inhibitor
Zhang et al. Design, synthesis and preliminary SAR studies of novel N-arylmethyl substituted piperidine-linked aniline derivatives as potent HIV-1 NNRTIs
Janes et al. Role of the charged groups of glutathione disulfide in the catalysis of glutathione reductase: crystallographic and kinetic studies with synthetic analogs
Lodhi et al. 3D-QSAR CoMFA studies on bis-coumarine analogues as urease inhibitors: A strategic design in anti-urease agents
Schwartz et al. . alpha.-Fluoro Acid and. alpha.-Fluoro Amide Analogs of Acetyl-CoA as Inhibitors of Citrate Synthase: Effect of pKa Matching on Binding Affinity and Hydrogen Bond Length
Chen et al. Elucidating inhibitory models of the inhibitors of epidermal growth factor receptor by docking and 3D-QSAR
Suthagar et al. Synthesis of sulfamide analogues of deoxthymidine monophosphate as potential inhibitors of mycobacterial cell wall biosynthesis
Pajkert et al. Synthesis of novel α-CF3-trifluoroalanine derivatives containing N-(diethoxyphosphoryl) difluoroacetyl group
Tian et al. Mechanism of adenylate kinase. Histidine-36 is not directly involved in catalysis, but protects cysteine-25 and stabilizes the tertiary structure
Brewer et al. Significance of the enzymatic properties of yeast S39A enolase to the catalytic mechanism

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KM KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NG NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SM SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LT LU LV MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

COP Corrected version of pamphlet

Free format text: PAGE 1/2-2/2, DRAWINGS, REPLACED BY A NEW PAGE 1/2-2/2; DUE TO LATE TRANSMITTAL BY THE RECEIVING OFFICE

COP Corrected version of pamphlet

Free format text: PAGE 396, DESCRIPTION, REPLACED BY CORRECT PAGE 396

WWE Wipo information: entry into national phase

Ref document number: 2583428

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 2005816059

Country of ref document: EP

Ref document number: 2007530399

Country of ref document: JP

WWE Wipo information: entry into national phase

Ref document number: 2005279795

Country of ref document: AU

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2005279795

Country of ref document: AU

Date of ref document: 20050902

Kind code of ref document: A

WWP Wipo information: published in national office

Ref document number: 2005279795

Country of ref document: AU

121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 200580036980.X

Country of ref document: CN

WWP Wipo information: published in national office

Ref document number: 2005816059

Country of ref document: EP