WO2004084901A1 - Methods for treating or preventing an inflammatory or metabolic condition by inhibiting jnk - Google Patents

Methods for treating or preventing an inflammatory or metabolic condition by inhibiting jnk Download PDF

Info

Publication number
WO2004084901A1
WO2004084901A1 PCT/US2004/009208 US2004009208W WO2004084901A1 WO 2004084901 A1 WO2004084901 A1 WO 2004084901A1 US 2004009208 W US2004009208 W US 2004009208W WO 2004084901 A1 WO2004084901 A1 WO 2004084901A1
Authority
WO
WIPO (PCT)
Prior art keywords
substituted
heterocycle
aryl
alkyl
different
Prior art date
Application number
PCT/US2004/009208
Other languages
French (fr)
Inventor
Yoshitaka Satoh
Shripad S. Bhagwat
Original Assignee
Signal Pharmaceuticals, 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 Signal Pharmaceuticals, Llc filed Critical Signal Pharmaceuticals, Llc
Priority to AU2004224302A priority Critical patent/AU2004224302A1/en
Priority to JP2006509310A priority patent/JP2006521394A/en
Priority to BRPI0408784-4A priority patent/BRPI0408784A/en
Priority to EP04758138A priority patent/EP1608375A1/en
Priority to NZ543052A priority patent/NZ543052A/en
Priority to MXPA05010185A priority patent/MXPA05010185A/en
Priority to CA002520440A priority patent/CA2520440A1/en
Publication of WO2004084901A1 publication Critical patent/WO2004084901A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • 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
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • 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
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • 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
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • 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
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • A61P31/04—Antibacterial agents
    • 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
    • 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
    • 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
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • 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
    • 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
    • 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
    • C07D403/12—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 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
    • 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
    • C07D405/12—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 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
    • C07D405/14—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
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D417/02—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 two hetero rings
    • C07D417/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D417/02—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 two hetero rings
    • C07D417/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems

Definitions

  • FIELD OF THE INVENTION This invention is generally directed to Anilinopyrimidines and derivatives thereof which have utility over a wide range of indications, including activity as Jun N- terminal kinase inhibitors, and related compositions and methods. 5
  • JNK Jun N-terminal kinase pathway
  • JNK binds to the N-terminal region of c-jun and ATF-2 and phosphorylates two sites within the activation domain of each transcription 5 factor (Hibi M., Lin A., Smeal T., Minden A., Karin M. Genes Dev. 7:2135-2148, 1993; Mohit A. A., Martin M.H., and Miller CA. Neuron 14:67-75, 1995).
  • JNK enzymes have been identified as products of distinct genes (Hibi et al, supra; Mohit et al., supra).
  • Ten different isoforms of JNK have been identified. These represent alternatively spliced forms of three different genes: JNKl, JNK2 and JNK3.
  • JNKl and 2 are ubiquitously 0 expressed in human tissues, whereas JNK3 is selectively expressed in the brain, heart and testis (Dong, C, Yang, D., Wysk, M., Whitmarsh, A., Davis, R., Flavell, R. Science 270:1- 4, 1998).
  • Gene transcripts are alternatively spliced to produce four- JNKl isoforms, four- JNK2 isoforms and two-JNK3 isoforms.
  • JNKl and 2 are expressed widely in mammalian tissues, whereas JNK3 is expressed almost exclusively in the brain. Selectivity of JNK 5 signaling is achieved via specific interactions of JNK pathway components and by use of scaffold proteins that selectively bind multiple components of the signaling cascade.
  • JEP-l JNK-interactmg protein- 1 selectively binds the MAPK module, MLK - JNKK2 - JNK.12,13. It has no binding affinity for a variety of other MAPK cascade enzymes. Different scaffold proteins are likely to exist for other MAPK signaling cascades to preserve substrate specificity.
  • JNKs are activated by dual phosphorylation on Thr-183 and Tyr-185.
  • JNKKl also own as MKK-4
  • JNKK2 MKK-7
  • MKK-7 two MAPKK level enzymes
  • JNKK2 specifically phosphorylates JNK, whereas JNKKl can also phosphorylate and activate p38. Both JNKKl and JNKK2 are widely expressed in mammalian tissues. JNKKl and JNKK2 are activated by the MAPKKK enzymes, MEKK-1, MEKK-2, MEKK-3 and MLK-3 (Lange-Carter C.A., Pleiman CM., Gardner A.M., Blumer K.J., and Johnson G.L. Science 260:315-319, 1993; Yan M., Dai J.C, Deak J.C, Kyriakis J.M., Zon L.I., Woodgett J.R., and Templeton DJ.
  • MAPKKK enzymes MAPKKK enzymes, MEKK-1, MEKK-2, MEKK-3 and MLK-3 (Lange-Carter C.A., Pleiman CM., Gardner A.M., Blumer K.J., and Johnson G.L. Science 260:315-319,
  • autoimmune and inflammatory diseases arise from the over- activation of the immune system.
  • Activated immune cells express many genes encoding inflammatory molecules, including cytokines, growth factors, cell surface receptors, cell adhesion molecules and degradative enzymes. Many of these genes are regulated by the JNK pathway, through activation of the transcription factors AP-1 and ATF-2, including TNF ⁇ , LL-2, E-selectin and matrix metalloproteinases such as collagenase-1 (Manning A.M. and Mecurio F. Exp. Opin. Invest. Drugs 6: 555-567, 1997). Monocytes, tissue macrophages and tissue mast cells are key sources of TNF ⁇ production.
  • the JNK pathway regulates TNF ⁇ production in bacterial lipopolysaccharide-stimulated macrophages, and in mast cells stimulated through the FceRJJ receptor (Swantek J.L., Cobb M.H., Geppert T.D. Mol. Cell. Biol. 17:6274-6282, 1997; Ishizuka, T., Tereda N., Gerwins, P., Hamelmann E., Oshiba A., Fanger G.R., Johnson G.L., and Gelfland E.W. Proc. Nat. Acad. Sci. USA 94:6358-6363, 1997). Inhibition of JNK activation effectively modulates TNF ⁇ secretion O 2004/084901
  • JNK pathway therefore regulates production of this key pro- inflammatory cytokine.
  • International Publication No. WO 98/18782 to Celltech Therapeutics Limited discloses 4-pyridyl-pyrimidine compounds which are allegedly useful in the prophylaxis and treatment of immune diseases, allergic diseases involving mast cells or eosinophils, and diseases involving inappropriate platelet activation.
  • Matrix metalloproteinases (MMPs) promote cartilage and bone erosion in rheumatoid arthritis, and generalized tissue destruction in other autoimmune diseases.
  • MMPs including MMP-3 and MMP-9, type JJ and JV collagenases
  • JNK pathway and AP-1 Gum, R., Wang, H., Lengyel, E., Jurez, J., and Boyd, D. Oncogene 14:1481-1493, 1997.
  • AP-1 AP-1
  • JNK activation results in decreased AP-1 activation and collagenase-1 expression (Han et al., supra).
  • the JNK pathway therefore regulates MMP expression in cells involved in rheumatoid arthritis.
  • T lymphocytes Inappropriate activation of T lymphocytes initiates and perpetuates many autoimmune diseases, including asthma, inflammatory bowel disease and multiple sclerosis.
  • the JNK pathway is activated in T cells by antigen stimulation and CD28 receptor co- stimulation and regulates production of the growth factor IL-2 and cellular proliferation (Su B., Jacinto E., Hibi M., Kallunki T., Karin M., Ben-Neriah Y. Cell 11:121-136, 1994; Fans M., Kokot N., Lee L., and Nel A.E. J. Biol. Chem. 271:27366-27373, 1996).
  • T cells from mice genetically deficient in JNKKl show decreased proliferation and LL-2 production after CD28 co-stimulation and PMA /Ca2+ ionophore activation, providing important validation for the role of the JNK pathway in these cells (Nishina H., Bachmann M., Oliveria-dos-Santos A.J., et al. J. Exp. Med. 186:941-953, 1997). It is known that T cells activated by antigen receptor stimulation in the absence of accessory cell-derived co- stimulatory signals lose the capacity to synthesize IL-2, a state called clonal anergy. This is an important process by which auto-reactive T cell populations are eliminated from the peripheral circulation.
  • JNK-deficient mice revealed that the JNK pathway plays a key role in T cell activation and differentiation to T helper 1 and 2 cell types. JNKl or JNK2 l ⁇ iockout mice develop normally and are pheno typically unremarkable.
  • Activated naive CD4+ T cells from these mice fail to produce IL-2 and do not proliferate well (Sabapathy, K, Hu, Y, Kallunki, T, Schreiber, M, David, J-P, Jochum, W, Wagner, E, Karin, M. Curr Biol 9: 116-125, 1999). It is possible to induce T cell differentiation in T cells from these mice, generating Thl cells (producer of IFN-g and TNF ⁇ ) and Th2 effector
  • Cardiovascular disease accounts for nearly one quarter of total annual deaths worldwide.
  • Vascular disorders such as atherosclerosis and restenosis result from dysregulated growth of the vessel wall, restricting blood flow to vital organs.
  • the JNK pathway is activated by atherogenic stimuli and regulates local cytokine and growth factor production in vascular cells (Yang, DD, Conze, D, Whitmarsh, AJ, et al, Immunity, 9:575,
  • JNK pathway is activated by ischemia and reperfusion (Li Y., Shyy J., Li S., Lee J., Su B., Karin M., Chien S Mol. Cell. Biol. 16:5947-5954, 1996), leading to the activation of JNK- responsive genes and leukocyte-mediated tissue damage.
  • 5 JNK activation can be either pro- or anti-apoptotic.
  • JNK activation is correlated with enhanced apoptosis in cardiac tissues following ischemia and reperfusion (Pombo CM, Bonventre JV, Avruch J, Woodgett JR, Kyriakis J.M, Force T. J. Biol. Chem. 26 :26546- 26551, 1994).
  • Cancer is characterized by uncontrolled growth, proliferation and migration 0 of cells. Cancer is the second leading cause of death with 500,000 deaths and an estimated 1.3 million new cases in the United States in 1996.
  • the role of signal fransduction pathways contributing to cell transformation and cancer is a generally accepted concept.
  • the JNK pathway leading to AP-1 appears to play a critical role in cancer.
  • Expression of c-jun is altered in early lung cancer and may mediate growth factor signaling in non-small 5 cell lung cancer (Yin T., Sandhu G., Wolfgang CD., Burrier A., Webb R.L., Rigel D.F. Hai T., and Whelan J. J. Biol. Chem. 272:19943-19950, 1997).
  • JNK inhibitors may block transformation and tumor cell growth.
  • JNK insulin mediated diseases
  • Type JJ diabetes and obesity has also been confirmed (Hirosumi, J. et al Nature 420:333-336, 2002; International Publication No. WO 02/085396).
  • phosphorylation at Ser 307 of insulin receptor substrate ('TRS-1") is responsible for TNF- ⁇ -induced and FFA-induced insulin resistance (Hotamisigil, G.H. Science 271 :665-668, 1996). This was demonstrated in a cellular model of insulin resistance in liver cells where increased Ser 307 phosphorylation of IRS-1 was seen in cells treated with TNF- ⁇ (Hirosumi, J. Id.).
  • the present invention generally relates to methods for treating or preventing a condition responsive to JNK inhibition, comprising administering to a patient in need thereof an effective amount of a compound having the following formula (I):
  • R j though R 6 are as defined below, and including isomers, prodrugs and pharmaceutically acceptable salts thereof.
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof is hereinafter referred to as an "Anilinopyrimidine Derivative.”
  • the present invention is directed to methods for treating or preventing a condition responsive to inhibition of the JNK pathway, comprising administering to a patient in need thereof an effective amount of an Anilinopyrimidine Derivative.
  • Anilinopyrimidine Derivatives are useful for treating or preventing a metabolic condition including, but not limited to: diabetes (such as Type JJ diabetes, Type I diabetes, diabetes insipidus, diabetes mellitus, maturity-onset diabetes, juvenile diabetes, insulin-dependant diabetes, non-insulin dependant diabetes, malnutrition-related diabetes, ketosis-prone diabetes or keto sis-resistant diabetes); or obesity (such as hereditary obesity, dietary obesity, hormone related obesity or obesity related to the administration of medication).
  • diabetes such as Type JJ diabetes, Type I diabetes, diabetes insipidus, diabetes mellitus, maturity-onset diabetes, juvenile diabetes, insulin-dependant diabetes, non-insulin dependant diabetes, malnutrition-related diabetes, ketosis-prone diabetes or keto sis-resistant diabetes
  • obesity such as hereditary obesity, dietary obesity, hormone related obesity or obesity related to the administration of medication.
  • Anilinopyrimidine Derivatives are useful for treating or preventing an inflammatory condition including, but not limited to: hearing loss (such as that from otitis extema or acute otitis media); fibrosis related diseases (such as pulmonary interstitial fibrosis, renal fibrosis, cystic fibrosis, liver fibrosis, wound-healing or bum-healing, wherein the bum is a first- , second- or third-degree bum and/or a thermal, chemical or electrical burn); arthritis (such as rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis or gout); an allergy; allergic rhinitis; acute respiratory distress syndrome; asthma; bronchitis; an inflammatory bowel disease (such as irritable bowel syndrome, mucous colitis, ulcerative colitis, Crohn's disease, gastritis, esophagitis, pancreatitis or peritonitis); or an
  • Anilinopyrimidine Derivatives are also useful for treating or preventing a liver disease (such as hepatitis, alcohol-induced liver disease, toxin-induced liver disease, steatosis or sclerosis); a cardiovascular disease (such as atherosclerosis, restenosis following angioplasty, left ventricular hypertrophy, myocardial infarction, chronic obstructive pulmonary disease or stroke); ischemic damage (such as to the heart, kidney, liver or brain); ischemia-reperfusion injury (such as that caused by transplant, surgical trauma, hypotension, thrombosis or trauma injury); neurodegenerative disease (such as epilepsy, Alzheimer's disease, Huntington's disease, Amyotrophic laterial sclerosis, peripheral neuropathies, spinal cord damage or Parkinson's disease); or cancer (such as cancer of the head, neck, eye, mouth, throat, esophagus, chest, bone, lung, colon, rectum, stomach, prostate, breast, ovaries, testicles or other reproductive organs
  • the present methods for treating or preventing further comprise the administration of an effective amount of another therapeutic agent useful for treating or preventing the diseases or disorders disclosed herein.
  • the time in which the therapeutic effect of the other therapeutic agent is exerted overlaps with the time in which the therapeutic effect of the Anilinopyrimidine Derivative is exerted.
  • the present methods for treating or preventing a metabolic condition an inflammatory condition, a liver disease, a cardiovascular disease, ischemic damage, a neurodegenerative disease or cancer comprise inhibiting JNK in vivo.
  • inhibiting JNK in vivo comprises inhibiting TNF- ⁇ in vivo.
  • the JNK is JNKl .
  • the JNK is
  • Alkyl means a straight chain or branched, saturated or unsaturated alkyl, cyclic or non-cyclic hydrocarbon having from 1 to 10 carbon atoms, while “lower alkyl” has the same meaning but only has from 1 to 6 carbon atoms.
  • Representative saturated straight chain alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, and the like; while saturated branched alkyls include isopropyl, ⁇ ec-butyl, isobutyl, tert-butyl, isopentyl, and the like.
  • Unsaturated alkyls contain at least one double or triple bond between adjacent carbon atoms (also referred to as an "alkenyl” or “alkynyl", respectively).
  • Representative straight chain and branched alkenyls include ethylenyl, propylenyl, 1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3 -methyl- 1-butenyl, 2-methyl-2-butenyl, 2,3-dimethyl- 2-butenyl, and the like; while representative straight chain and branched alkynyls include acetylenyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3 -methyl- 1 butynyl, and the like.
  • saturated cyclic alkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like; while unsaturated cyclic alkyls include cyclopentenyl and cyclohexenyl, and the like.
  • Cycloalkyls are also referred to herein as "carbocyclic" rings systems, and include bi- and tri-cyclic ring systems having from 8 to 14 carbon atoms such as a cycloalkyl (such as cyclopentane or cyclohexane) fused to one or more aromatic (such as phenyl) or non-aromatic (such as cyclohexane) carbocyclic rings.
  • Halogen means fluorine, chlorine, bromine or iodine.
  • Aryl means an aromatic carbocyclic moiety such as-phenyl or naphthyl.
  • Arylalkyl means an alkyl having at least one alkyl hydrogen atom replaced with an aryl moiety, such as benzyl, -(CH 2 ) 2 phenyl, -(CH 2 ) 3 phenyl, -CH(phenyl) 2 , and the like.
  • Heteroaryl means an aromatic heterocycle ring of 5- to 10 members and having at least one heteroatom selected from nitrogen, oxygen and sulfur, and containing at least 1 carbon atom, including both mono- and bicyclic ring systems.
  • Representative heteroaryls are pyridyl, furyl, benzofuranyl, fhiophenyl, benzothiophenyl, quinolinyl, pyrrolyl, indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl, and quinazolinyl.
  • Heteroarylalkyl means an alkyl having at least one alkyl hydrogen atom replaced with
  • Heterocycle means a heterocyclic ring containing from 5 to 10 ring atoms
  • Heterocycle means a 5- to 7-membered monocyclic, or 7- to 10-membered bicyclic, heterocyclic ring which is either saturated, unsaturated, or aromatic, and which contains from 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and wherein the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quatemized, including bicyclic rings in which any of the above heterocycles are fused to a benzene ring.
  • the heterocycle may be attached via any heteroatom or carbon atom.
  • Heterocycles include heteroaryls as defined above.
  • heterocycles also include morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrindinyl, tetrahydroprimidinyl, tetrahydrothiophenyl, tetraliydrothiopyranyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.
  • Heterocyclealkyl means an alkyl having at least one alkyl hydrogen atom replaced with a heterocycle, such as -CH 2 morpholinyl, and the like.
  • substituted means any of the above groups (i.e., aryl, arylalkyl, heterocycle and heterocyclealkyl) wherein at least one hydrogen atom is replaced with a substituent.
  • aryl, arylalkyl, heterocycle and heterocyclealkyl wherein at least one hydrogen atom is replaced with a substituent.
  • two hydrogen atoms are replaced.
  • Haloalkyl means alkyl having one or more hydrogen atoms replaced with halogen, such as -CF 3 .
  • Hydroalkyl means alkyl having one or more hydrogen atoms replaced with hydroxy, such as -CH 2 OH
  • “Sulfonylalkyl” means -SO 2 -(alkyl);
  • Sulfmylalkyl means -SO-(alkyl);
  • Thioalkyl means -S-(alkyl);
  • Carboxyl means -COOH.
  • Alkoxy means -O-(alkyl), such as methoxy, ethoxy, n-propyloxy, iso- propyloxy, n-butyloxy, iso-butyloxy, and the like.
  • Patient means an animal, including, but not limited to, an animal such as a cow, monkey, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit, and guinea pig, and is more preferably a mammal, and most preferably a human.
  • Non-containing non-aromatic heterocycle means morpholinyl, thiomorpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, hydantoinyl, tefrahydropyrindinyl, tetrahydropyrimidinyl, oxazolidinyl, thiazolidinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl and the like.
  • an “effective amount" when used in connection with an Anilinopyrimidine Derivative is an amount effective for treating or preventing a condition, such as those described herein that can be treated or prevented by administering a JNK inhibitor.
  • a "patient” includes an animal (e.g., cow, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit or guinea pig), in one embodiment a mammal such as a non-primate and a primate (e.g., monkey and human), and in another embodiment a human.
  • the patient is an infant, child, adolescent or adult.
  • prodrug refers to any derivative of the Anilinopyrimidine Derivatives that are metabolized or otherwise converted into an active form upon introduction into the body of an animal.
  • Prodmgs are well known to those skilled in the art of pharmaceutical chemistry, and provide benefits such as increased adsorption and half-life.
  • Prodrags of this invention may be formed when, for example, hydroxy groups are esterified or alkylated, or when carboxyl groups are esterified.
  • pharmacokinetic properties of Anilinopyrimidine Derivatives maybe controlled by an appropriate choice of moieties to produce prodrug derivatives.
  • the present invention is related to methods for treating or preventing a condition responsive to JNK inhibition, comprising administering to a patient in need thereof an effective amount of a Anilinopyrimidine Derivative of formula (I):
  • R ! is aryl or heteroaryl optionally substituted with one to four substituents independently selected from R 7 ;
  • R 2 is hydrogen;
  • R 3 is hydrogen or lower alkyl
  • R 4 represents one to four optional substituents, wherein each substituent is the same or different and independently selected from halogen, hydroxy, lower alkyl and lower alkoxy;
  • R 7 is at each occurrence independently halogen, hydroxy, cyano, nitro, carboxy, alkyl, alkoxy, haloalkyl, acyloxy, thioalkyl, sulfinylalkyl, sulfonylalkyl, hydroxyalkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, heterocycle
  • R x is a substituted or unsubstituted aryl or heteroaryl with the proviso that the heteroaryl is not pyridyl.
  • R ⁇ is substituted, it is substituted with one or more substituents defined below.
  • R j is substituted with a halogen, sulfone or sulfonamide.
  • R r is substituted or unsubstituted aryl, furyl, benzofuranyl, thiophenyl, benzothiophenyl, quinolinyl, pyrrolyl, indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl or quinazolinyl.
  • stracture (I) R r is substituted or unsubstituted aryl, furyl, benzofuranyl, thiophenyl, benzothiophenyl, quinolinyl, pyrrolyl, indolyl, oxazolyl, benzoxazolyl,
  • R x is substituted or unsubstituted aryl or heteroaryl with the proviso that the heteroaryl is not imidazo[l,2a]pyrid-3-yl or pyrazolo[2,3a]pyrid-3-yl.
  • R ⁇ is substituted, it is substituted with one or more substituents defined below.
  • R ⁇ is substituted with a halogen, sulfone or sulfonamide.
  • Rj is substituted or unsubstituted aryl, preferably phenyl.
  • Rj is a substituted aryl
  • the substituents are defined below.
  • R 1 is substituted with a halogen, sulfone or sulfonamide.
  • R 5 and R 6 taken together with the nitrogen atom to which they are attached form a substituted or unsubstituted nitrogen-containing non-aromatic heterocycle, preferably piperazinyl, piperidinyl or morpholinyl.
  • R 5 and R 6 taken together with the nitrogen atom to which they are attached form substituted piperazinyl, piperadinyl or morpholinyl, the piperazinyl, piperadinyl or mo holinyl is substituted with one or more substituents defined below.
  • the substituent is alkyl, amino, alkylamino, alkylether, acyl, pyrrolidinyl or piperidinyl.
  • R 3 is hydrogen and R 4 is not present, and the compounds of this invention have the following formula (IT):
  • R t is phenyl optionally substituted with R 7 , and having the following formula (IH):
  • R 7 is at the para position relative to the pyrimidine, as represented by the following formula (IV):
  • Anilinopyrimidine Derivatives can generally be obtained using organic synthesis techniques known to those skilled in the art, as well as by the following general teclmiques and the procedures set forth in the Examples. To that end, the Anilinopyrimidine Derivatives can be made according to the following Reaction Schemes 1 through 9:
  • methylketones may be treated with a dimethylformamide acetal, such as dimethylformamide dimethylacetal or dimethylformamide diethylacetal, to afford the corresponding ⁇ -dimethylaminobutenones.
  • a dimethylformamide acetal such as dimethylformamide dimethylacetal or dimethylformamide diethylacetal
  • thiourea in the presence of a base such as sodium methoxide, followed by alkylation with an alkyl halide, such as methyl iodide, gives 4-substituted 2- alkylthiopyrimidines.
  • the Anilinopyrimidine Derivatives may be prepared from the 2- chloropyrimidine derivatives.
  • condensation of the ⁇ -dimethylaminobutenones with urea followed y the treatment with chlorinating agent such as phosphoras oxychloride gives 4-substituted 2-chloropyrimidines. Further treatment with substituted anilines affords the desired Anilinopyrimidine Derivatives.
  • the Anilinopyrimidine Derivatives can also be prepared by condensation of the ⁇ -dimethylaminobutenones with appropriately substituted guanidines.
  • the requisite guanidines may be synthesized by the reaction of the aniline with cyanamide in the presence of an acid, or with a pyrazoloamidine.
  • Acetophenones with p-alkyl- and arylthio groups may be prepared by the reaction of p-chloroacetophenone with alkyl and arylthiols.
  • Anilinopyrimidine Derivatives with the p-alkyl- and arylsulfenyl groups may be prepared by controlled oxidation of the sulfides with an oxidizing agent such as oxone. Reaction Scheme 9
  • Anilinopyrimidine Derivatives having p-alkyl- and arylsulfenyl groups may be prepared by oxidation of the sulfides with an oxidizing agent such as oxone.
  • the Anilinopyrimidine Derivatives can be in the form of a pharmaceutically acceptable salt or free base.
  • Acid addition salts of the free base can be prepared by methods well known in the art, and may be formed from organic and inorganic acids. Suitable organic acids include maleic, fumaric, benzoic, ascorbic, succinic, methanesulfonic acetic, oxalic, propionic, tartaric, salicylic, citric, gluconic, lactic, mandelic, cinnamic, aspartic, stearic, palmitic, glycolic, glutamic, and benzenesulfonic acids.
  • Suitable inorganic acids include hydrochloric, hydrobromic, sulfuric, phosphoric, and nitric acids. Additional salts include sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, -toluenesulfonate, and pamoate (i.e., l,l'-methylene-bis-(2-hydroxy-3-
  • salts can be formed by conventional and known teclmiques, such as by reacting a compound of this invention with a suitable acid as disclosed above. Such salts are typically formed in high yields at moderate temperatures, and often are prepared by merely isolating the compound from a suitable acidic wash in the final step of the synthesis.
  • the salt- forming acid may dissolved in an appropriate organic solvent, or aqueous organic solvent, such as an alkanol, ketone or ester.
  • the Anilinopyrimidine Derivative is desired in the free base form, it may be isolated from a basic final wash step, according to known techniques. For example, a typical technique for preparing hydrochlori.de salt is to dissolve the free base in a suitable solvent, and dry the solution thoroughly, as over molecular sieves, before bubbling hydrogen chloride gas through it.
  • Anilinopyrimidine Derivatives can also exist in various isomeric forms, including configurational, geometric and conformational isomers, as well as existing in various tautomeric forms, particularly those that differ in the point of attachment of a hydrogen atom.
  • the term "isomer" is intended to encompass all isomeric forms of a compound, including tautomeric forms of the compound.
  • Conditions that may be treated using an Anilinopyrimidine Derivative, or using a pharmaceutical composition containing the same, include any condition that is responsive to JNK pathway inhibition, and thereby benefit from administration of such an inhibitor.
  • the invention relates to methods for treating or preventing a metabolic condition including, but not limited to: diabetes (such as Type II diabetes, Type I diabetes, diabetes insipidus, diabetes mellitus, maturity-onset diabetes, juvenile diabetes, insulin-dependant diabetes, non-insulin dependant diabetes, malnutrition- related diabetes, ketosis-prone diabetes or ketosis-resistant diabetes); or obesity (such as hereditary obesity, dietary obesity, hormone related obesity or obesity related to the administration of medication) comprising administering to a patient in need thereof an effective amount of an Anilinopyrimidine Derivative.
  • diabetes such as Type II diabetes, Type I diabetes, diabetes insipidus, diabetes mellitus, maturity-onset diabetes, juvenile diabetes, insulin-dependant diabetes, non-insulin dependant diabetes, malnutrition- related diabetes, ketos
  • the invention relates to methods for treating or preventing an inflammatory condition including, but not limited to: hearing loss (such as that from otitis extema or acute otitis media); fibrosis related diseases (such as pulmonary interstitial fibrosis, renal fibrosis, cystic fibrosis, liver fibrosis, wound-healing or bum- healing, wherein the bum is a first- , second- or third-degree bum and/or a thermal, chemical or electrical bum); arthritis (such as rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis or gout); an allergy; allergic rhinitis; acute respiratory distress syndrome; asthma; bronchitis; an inflammatory bowel disease (such as irritable bowel syndrome, mucous colitis, ulcerative colitis, Crohn's disease, gastritis, esophagitis, pancreatitis or peritonitis); or an autoimmune disease (such as
  • the invention relates to methods for treating or preventing a liver disease (such as hepatitis, alcohol-induced liver disease, toxin-induced liver disease, steatosis or sclerosis); a cardiovascular disease (such as atherosclerosis, restenosis following angioplasty, left ventricular hypertrophy, myocardial infarction, chronic obstructive pulmonary disease or stroke); ischemic damage (such as to the heart, kidney, liver or brain); ischemia-reperfusion injury (such as that caused by transplant, surgical trauma, hypotension, thrombosis or trauma injury); neurodegenerative disease (such as epilepsy, Alzheimer's disease, Huntington's disease, Amyotrophic laterial sclerosis, peripheral neuropathies, spinal cord damage or Parkinson's disease); or cancer (such as cancer of the head, neck, eye, mouth, throat, esophagus, chest, bone, lung, colon, rectum, stomach, prostate, breast, ovaries, testicles or other reproductive organs, skin, thyroid,
  • the invention relates to methods for treating or preventing otitis extema, acute otitis media, hearing loss, pulmonary interstitial fibrosis, liver fibrosis, renal fibrosis, wound-healing or burn-healing (wherein the burn is a first-, second- or third-degree burn and/or a thermal, chemical or electrical burn), chronic obstructive pulmonary disease, allergic rhinitis, acute respiratory distress syndrome, systemic lupus erythematosus, nephropathy, pancreatitis, peritonitis, sepsis, alcohol or toxin-induced liver disease, sclerosis, steatosis or ischemia-reperfusion injury comprising administering to a patient in need thereof an effective amount of an Anilinopyrimidine Derivative.
  • the invention relates to the use of an Anilinopyrimidine Derivative for use in the manufacture of a medicament for treating or preventing a disease responsive to JNK inhibition.
  • the invention relates to the use of an Anilinopyrimidine Derivative for use in the manufacture of a medicament for treating or preventing a metabolic condition including, but not limited to: diabetes (such as Type II diabetes, Type I diabetes, diabetes insipidus, diabetes mellitus, maturity-onset diabetes, juvenile diabetes, insulin-dependant diabetes, non-insulin dependant diabetes, malnutrition- related diabetes, ketosis-prone diabetes or ketosis-resistant diabetes); or obesity (such as hereditary obesity, dietary obesity, hormone related obesity or obesity related to the administration of medication).
  • diabetes such as Type II diabetes, Type I diabetes, diabetes insipidus, diabetes mellitus, maturity-onset diabetes, juvenile diabetes, insulin-dependant diabetes, non-insulin dependant diabetes, malnutrition- related diabetes, ketosis-prone diabetes or ketosis-resistant diabetes
  • obesity such
  • the invention relates to the use of an Anilinopyrimidine Derivative for use in the manufacture of a medicament for treating or preventing an inflammatory condition including, but not limited to: hearing loss (such as that from otitis extema or acute otitis media); fibrosis related diseases (such as pulmonary interstitial fibrosis, renal fibrosis, cystic fibrosis, liver fibrosis, wound-healing or burn- healing, wherein the bum is a first- , second- or third-degree bum and/or a thermal, chemical or electrical bum); arthritis (such as rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis or gout); an allergy; allergic rhinitis; acute respiratory distress syndrome; asthma; bronchitis; an inflammatory bowel disease (such as irritable bowel syndrome, mucous colitis, ulcerative colitis, Crohn's disease, gastritis, esophagitis
  • the invention relates to the use of an Anilinopyrimidine Derivative for use in the manufacture of a medicament for treating or preventing a liver disease (such as hepatitis, alcohol-induced liver disease, toxin-induced liver disease, steatosis or sclerosis); a cardiovascular disease (such as atherosclerosis, restenosis following angioplasty, left ventricular hypertrophy, myocardial infarction, chronic obstructive pulmonary disease or stroke); ischemic damage (such as to the heart, kidney, liver or brain); ischemia-reperfusion injury (such as that caused by transplant, surgical trauma, hypotension, thrombosis or trauma injury); neurodegenerative disease (such as epilepsy, Alzheimer's disease, Huntington's disease, Amyotrophic laterial sclerosis, peripheral neuropathies, spinal cord damage or Parkinson's disease); or cancer (such as cancer of the head, neck, eye, mouth, throat, esophagus, chest, bone, lung, colon, rectum, stomach
  • the present methods for treating or preventing further comprise the administration of an effective amount of another therapeutic agent useful for treating or preventing the diseases or disorders disclosed herein, hi this embodiment, the time in which the therapeutic effect of the other therapeutic agent is exerted overlaps with the time in which the therapeutic effect of the Anilinopyrimidine Derivative is exerted, h one embodiment, the methods for treating or preventing a metabolic condition an inflammatory condition, a liver disease, a cardiovascular disease, ischemic damage, a neurodegenerative disease or cancer comprise inhibiting JNK in vivo.
  • inhibiting JNK in vivo comprises inhibiting TNF- ⁇ in vivo.
  • the JNK is JNKl. h another embodiment the JNK is JNK2. h another embodiment the JNK is JNK3. hi another embodiment of the present methods, in the Anilinopyrimidine
  • R t is a substituted or unsubstituted aryl or heteroaryl with the proviso that the heteroaryl is not pyridyl.
  • R is substituted, it is substituted with one or more substituents defined above.
  • R ⁇ is substituted with a halogen, sulfone or sulfonamide.
  • R ⁇ is substituted or unsubstituted aryl, furyl, benzofuranyl, thiophenyl, benzothiophenyl, quinolinyl, pyrrolyl, indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl or quinazolinyl.
  • the Anilinopyrimidine in the Anilinopyrimidine
  • R j is substituted or unsubstituted aryl or heteroaryl with the proviso that the heteroaryl is not imidazo[l,2a]pyrid-3-yl or pyrazolo[2,3a]pyrid-3-yl.
  • R j is substituted, it is substituted with one or more substituents defined above.
  • R t is substituted with a halogen, sulfone or sulfonamide. in another embodiment of the present methods, in the Anilinopyrimidine
  • R t is substituted or unsubstituted aryl, preferably phenyl or naphthyl.
  • R j is a substituted aryl, it is substituted with one or more substituents defined above.
  • R ⁇ is substituted with a halogen, sulfone or sulfonamide.
  • the nitrogen-containing non- aromatic heterocycle is piperazinyl, piperadinyl or morpholinyl.
  • the nitrogen- containing non-aromatic heterocycle is a substituted piperazinyl, piperadinyl or morpholinyl ring
  • the substituents are defined above.
  • the substituent is alkyl, amino, alkylamino, alkylether, acyl, pyrrolidinyl or piperidinyl.
  • the Anilinopyrimidine Derivatives of this invention can be administered as a component of a composition that optionally comprises a pharmaceutically acceptable carrier or vehicle.
  • Anilinopyrimidine Derivatives can also be used in cancer adjuvant 5 therapy in combination with a cytotoxic agent or with radiation therapy.
  • Anilinopyrimidine Derivatives can be administered to a patient orally or parenterally in conventional and well known preparations, such as capsules, microcapsules,
  • the Anilinopyrimidine Derivatives are typically formulated as a pharmaceutical composition that contains an effective dosage amount of one or more of such compounds in combination with one (or more) pharmaceutically acceptable carrier(s). Suitable formulations in this regard may be prepared by methods commonly employed using
  • additives such as an excipient (e.g., sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate or calcium carbonate), a binder (e.g., cellulose, methylcellulose, hydroxymethyl cellulose, polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic, polyethyleneglycol, sucrose or starch), a disintegrator (e.g., starch, carboxymethylcellulose,
  • hydroxypropylstarch low substituted hydroxypropylcellulose, sodium bicarbonate, calcium phosphate or calcium citrate
  • a lubricant e.g., magnesium stearate, light anhydrous sicilic acid, talc or sodium lauryl sulfate
  • a flavoring agent e.g., citric acid, menthol, glycine or orange powder
  • a preservative e.g., sodium benzoate, sodium bisulfite, methylparaben or propylparaben
  • a stabilizer e.g., citric acid, sodium citrate or acetic acid
  • agent e.g., methylcellulose, polyvinyl pyrrolidone or aluminum stearate
  • a dispersing agent e.g., hydroxypropylmethylcellulose
  • a diluent e.g., water
  • a base wax e.g., cocoa butter, white petrolatum or polyethylene glycol
  • the amount of an Anilinopyrimidine Derivative in a dosage form may differ depending on factors such as, but not limited to, the route by which it is to be administered
  • typical dosage forms of the invention comprise an Anilinopyrimidine Derivative in an amount of from about 0.10 mg to about 3500 mg, from about 1 mg to about 2500 mg, from about 10 mg to about 500 mg, from about 25 mg to about 250 mg, from about 50 mg to about 100 mg.
  • Typical dosage forms comprise an Anilinopyrimidine Derivative in an amount of about 0.1, 1, 2, 5, 7.5, 10, 12.5, 15, 17.5, 20, 25, 50, 100, 150,
  • a dosage form comprises a Pyrazoloanfhrone Derivative in an amount of about 1, 2, 5, 10, 25, 50, 100, 250 or 500 mg.
  • a dosage form comprises an amount of about 5, 10, 25 or 50 mg of an Anilinopyrimidine Derivative.
  • anilinopyrimidine Derivative can be delayed or prolonged by proper formulation.
  • a slowly soluble pellet of the Anilinopyrimidine Derivative can be delayed or prolonged by proper formulation.
  • a slowly soluble pellet of the Anilinopyrimidine Derivative can be delayed or prolonged by proper formulation.
  • Anilinopyrimidine Derivative may be prepared and incorporated in a tablet or capsule.
  • the technique may be improved by making pellets of several different dissolution rates and filling capsules with a mixture of the pellets. Tablets or capsules may be coated with a film which resists dissolution for a predictable period of time. Even the parenteral preparations may be made long-acting, by dissolving or suspending the compound in oily or emulsified vehicles which allow it to disperse only slowly in the serum.
  • the Anilinopyrimidine Derivatives can be used in combination, e.g., as an adjunct therapy, with at least one other therapeutic agent.
  • An Anilinopyrimidine Derivative and the other therapeutic agent can act additively or, more preferably, synergistically.
  • an Anilinopyrimidine Derivative is administered concurrently with the administration of another therapeutic agent, which can be part of the same composition as or in a different composition from that comprising the Anilinopyrimidine Derivative
  • an Anilinopyrimidine Derivative is administered prior or subsequent to administration of another therapeutic agent.
  • combination therapy involves alternating between administering an Anilinopyrimidine Derivative and another therapeutic agent.
  • the duration of administration of the Anilinopyrimidine Derivative or the other therapeutic agent can be, e.g., one month, three months, six months, a year, or for more extended periods, such as the patient's lifetime.
  • the other therapeutic agent when a composition of the invention is administered concurrently with another therapeutic agent that potentially produces adverse side effects including, but not limited to, toxicity, the other therapeutic agent can advantageously be administered at a dose that falls below the threshold at which the adverse side effect is elicited.
  • the other therapeutic agent can be an anti-inflammatory agent.
  • Useful anti- inflammatory agents include, but are not limited to, non-steroidal anti-inflammatory drags such as salicylic acid, acetylsalicylic acid, methyl salicylate, diflunisal, salsalate, olsalazine, sulfasalazine, acetaminophen, indomethacin, sulindac, etodolac, mefenamic acid, meclofenamate sodium, tolmetin, ketorolac, dichlofenac, ibuprofen, naproxen, naproxen sodium, fenoprofen, ketoprofen, flurbinprofen, oxaprozin, piroxicam, meloxicam, ampiroxicam, droxicam, pivoxicam, tenoxicam, nabumetome, phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine, apazone and nimesulide; leukotriene
  • the other therapeutic agent can be an anti-cancer agent.
  • Useful anti-cancer agents include, but are not limited to, nitrogen mustards, such as cyclophosphamide, Ifosfamide, trofosfamide and Chlorambucil; nitrosoureas, such as carmustine (BCNU) and Lomustine (CCNU); alkylsulphonates, such as busulfan and Treosulfan; triazenes, such as dacarbazine; platinum-containing compounds, such as Cisplatin and carboplatin; vinca alkaloids, such as vincristine, Vinblastine, Vindesine and Vinorelbine; taxoids, such as paclitaxel and Docetaxol; epipodophyllins, such as etoposide, Teniposide, Topotecan, 9- aminocamptothecin, camptoirinotecan and crisnatol; mytomycins, such as mytomycin C; DHFR inhibitors,
  • the other therapeutic agent can also be an antiobiotic (e.g., vancomycin, penicillin, amoxicillin, ampicillin, cefotaxime, ceftriaxone, cefixime, rifampin, metronidazole, doxycycline or streptomycin).
  • the other therapeutic agent can also be a PDE4 inhibitor (e.g., roflumilast or rolipram).
  • the other therapeutic agent can also be an antihistamine (e.g., cyclizine, hydroxyzine, promethazine or diphenhydramine).
  • the other therapeutic agent can also be an anti-malarial (e.g., artemisinin, artemether, artsunate, chloroquine phosphate, mefloquine hydrochloride, doxycycline hyclate, proguanil hydrochloride, atovaquone or halofantrine).
  • the other therapeutic agent can also be drotrecogin alfa.
  • Mobile Phase A, 0.1% formic acid in acetonitrile; B, 0.1 % trifluoroacetic acid in water.
  • Mobile Phase A, 0.1 %> trifluoroacetic acid in acetonitrile; B, 0.1% trifluoroacetic acid in water.
  • Acetophenone (5) was then taken up on toluene (50 mL). To this solution was added ethylene glycol (2.6 mL, 2 equiv) and -toluenesulfonic acid (0.7g). The reaction was refluxed with a Dean Stark trap for 2 - 3 h. After azeotropic removal of water, the reaction was cooled and then washed with 10% NaHCO 3 (aq, 50 mL), water (50 mL), and brine (50 mL). The organic extract was dried (MgSO 4 ), filtered, and concentrated. The crude acetal was then taken up in CH 2 CL 2 (20 mL).
  • the titled compound was prepared by the procedure of Example 10, except dimethylamine was used in place of mo ⁇ holine during the reductive amination of aldehyde (7).
  • R 1 4-c lorophenyl
  • Example 18 with the desired Rj moiety, may be modified according to the above procedures to yield further representative compounds of this invention.
  • the following compounds were made according to the above procedures.
  • ether extract was dried (MgSO 4 ), filtered and concentrated to afford crude l-[4-(4- hydroxybutylsulfanyl)phenyl]ethanone, which was used without purification.
  • l-[4-(4- hydroxybutylsulfanyl)phenyl] ethanone was taken up in dimethylformamide dimethylacetal (100 mL) and stirred at reflux for 12h. The mixture was cooled and then concentrated to about one half of the original volume. Hexane was added to precipitate 3-Dimethylamino-l-[4-(4- hydroxybutylsulfanyl)phenyl]propenone.
  • the eneamino ketone was filtered and washed with hexanes (2 x 50 mL), dried under vacuum, and then taken up in ⁇ PrOH (150 mL). To this solution was added added 4-guanidinobenzoic acid, methyl ester, hydrochloride salt (1.1 equiv, 3.7 g) and K 2 CO 3 (3 equiv, 6.4 g). The mixture was stirred at reflux for 24 h. After this time, 10% NaOH (aq, 50 mL) was added, and the mixture was stirred at reflux for another 1 h. The mixture was then cooled to RT and concentrated to about half of the original volume. The pH of the mixture was then adjusted to pH 4-5 to precipitate the acid.
  • the Anilinopyrimidine Derivatives may be assayed for their activity according to the following procedures.
  • test compound in 20% DMSO/80% dilution buffer consisting of 20 mM HEPES (pH 7.6), 0.1 mM EDTA, 2.5 mM magnesium chloride, 0.004% Triton xlOO, 2 ⁇ g/mL leupeptin, 20 mM ⁇ -glycerolphosphate, 0.1 mM sodium vanadate, and 2 mM DTT in water is added 30 ⁇ L of 50 ng His6-JNK2 in the same dilution buffer. The mixture is preincubated for 30 minutes at room temperature.
  • the precipitate is harvested onto a filter plate, diluted with 50 ⁇ L of the scintillation fluid and quantified by a counter.
  • the IC 50 values are calculated as the concentration of the test compound at which the c-Jun phosphorylation is reduced to 50% of the control value.
  • Preferred compounds of the present invention have an 1C 50 value ranging 0.01 - 10 ⁇ M in this assay.
  • test compound in 20% DMSO/80% dilution buffer consisting of 20 mM HEPES (pH 7.6), 0.1 mM EDTA, 2.5 mM magnesium chloride, 0.004% Triton xlOO, 2 ⁇ g/mL leupeptin, 20 mM ⁇ -glycerolphosphate, 0.1 mM sodium vanadate, and 2 mM DTT in water is added 30 ⁇ L of 200 ng His6-JNK3 in the same dilution buffer. The mixture is preincubated for 30 minutes at room temperature.
  • the precipitate is harvested onto a filter plate, diluted with 50 ⁇ L of the scintillation fluid and quantified by a counter.
  • the IC 50 values are calculated as the concentration of the test compound at which the c-Jun phosphorylation is reduced to 50% of the control value.
  • Preferred compounds of the present invention have an IC 50 value ranging 0.01 - 10 ⁇ M in this assay.
  • Jurkat T cells (clone E6-1) are purchased from the American Tissue Culture Collection and maintained in growth media consisting of RPMI 1640 medium containing 2 mM L-glutamine (Mediatech), with 10% fetal bovine serum (Hyclone) and penicillin/streptomycin. All cells are cultured at 37°C in 95% air and 5% CO 2 . Cells are plated at a density of 0.2 x 10 6 cells per well in 200 ⁇ L of media. Compound stock (20 mM) is diluted in growth media and added to each well as a 1 Ox concentrated solution in a volume of 25 ⁇ l, mixed, and allowed to pre-incubate with cells for 30 minutes.
  • RPMI 1640 medium containing 2 mM L-glutamine (Mediatech), with 10% fetal bovine serum (Hyclone) and penicillin/streptomycin. All cells are cultured at 37°C in 95% air and 5% CO 2 . Cells are plated at a density of
  • the compound vehicle (dimethylsulfoxide) is maintained at a final concentration of 0.5% 0 in all samples. After 30 minutes the cells are activated with PMA (phorbol myristate acetate; final concentration 50 ng/niL) and PHA (phytohemagglutinin; final concentration 2 ⁇ g/mL). PMA and PHA are added as a 1 Ox concentrated solution made up in growth media and added in a volume of 25 ⁇ L per well. Cell plates are cultured for 10 hours. Cells are pelleted by centrifugation and the media removed and stored at -20 °C. Media aliquots are analyzed by sandwich ELISA for the presence of IL-2 as per the manufacturers instructions (Endogen). The IC 50 values are calculated as the concentration of the test compound at which the 11-2 production was reduced to 50% of the control value. Preferred compounds of the present invention have an IC 50 value ranging 0.1 - 30 ⁇ M in this assay.
  • Rats procured from Charles River Laboratories at 7 weeks of age are allowed to acclimate for one week prior to use.
  • a lateral tail vein is cannulated percutaneously with a 22-gage over-the-needle catheter under brief isoflurane anesthesia.
  • Rats are administered test compound either by intravenous injection via the tail vein catheter or oral gavage 15 to 180 min prior to injection of 0.05 mg/kg LPS (E. Coli 055 :B5).
  • Catheters are flushed with 2.5 mL/kg of normal injectable saline.
  • Blood is collected via cardiac puncture 90 minutes after LPS challenge. Plasma is prepared using lithium heparin separation tubes and frozen at -80°C until analyzed.
  • TNF- ⁇ levels are determined using a rat specific TNF- ⁇ ELISA kit (Busywork).
  • the ED 50 values are calculated as the dose of the test compound at which the TNF- ⁇ production is reduced to 50% of the control value.
  • Preferred compounds of the present invention have an ED 30 value ranging 1-30 mg/kg in this assay.
  • Detection of Phosphorylated c-Jun Human umbilical vein endothelial cells are cultured to 80% confluency and then pre-treated with compound (30 ⁇ M) at a final concentration of 0.5% DMSO. After 30 minutes, cells are stimulated with TNF ⁇ (30 ng/ml) for 20 minutes. Cells are washed, scraped from the plate, lyzed with 2x Laemmli buffer and heated to 100°C for 5 minutes. Whole cell lysate (approx. 30 ⁇ g) is fractionated on Tris-glycine buffered 10% SDS-polyacrylamide gels (Novex, San Diego, CA) and transferred to nitrocellulose membrane (Amersham, Piscataway, NJ).
  • Membranes are blocked with 5% non-fat milk powder (BioRad, Hercules, CA) and incubated with antibody to phospho-cJun (1:1000 #91645) (New England Biolabs, Beverly, MA) and then donkey anti-rabbit horse radish peroxidase conjugated antibody (1 :2500) (Amersham) in phosphate buffered saline with 0.1%) Tween-20 and 5% non-fat milk powder. Immunoreactive proteins are detected with chemiluminescence and autoradiography (Amersham). Compounds are selected as inhibitors of the JNK pathway if they showed greater than 50% inhibition of cJun phosphorylation at 30 ⁇ M in this assay.
  • Anilinopyrimidine Derivatives were assayed for their ability to inhibit JNK2 by the assay set forth in Example 28.
  • preferred Anilinopyrimidine Derivatives have an IC 50 value ranging 0.01 - 10 ⁇ M in this assay.
  • Anilinopyrimidine Derivative having an IC 50 value in the JNK2 Assay of 10 ⁇ M or less include Compound Nos.
  • Preferred compounds of this invention have an IC 50 value in the JNK2 assay of 1 ⁇ M or less, and include Compound Nos. 3-2, 3-4, 3-9, 3-13, 3-14, 3-15, 3-23, 3-24, 3-25, 3-40, 17-20, 17-21, 17-22, 17-24, 17-29, 17-30, 17-31, 17-32, 17-33, 17-34, 17-37, 17-127, 17-129, 17- 137, 17-141, 17-147, 17-154, 17-169, 17-171, 17-190, 18, 20-1, 20-3, 20-4, 22-10, 22-11, and 25-52.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Urology & Nephrology (AREA)
  • Immunology (AREA)
  • Obesity (AREA)
  • Pulmonology (AREA)
  • Cardiology (AREA)
  • Endocrinology (AREA)
  • Emergency Medicine (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Child & Adolescent Psychology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Psychology (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Vascular Medicine (AREA)
  • Dermatology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

This invention generally relates to methods for treating or preventing a condition responsive to JNK inhibition, such as a metabolic condition, comprising administering to a patient in need thereof an effective amount of an Anilinopyrimidine Derivative having the following structure (I) or a pharmaceutically acceptable salt thereof, wherein R1 through R6 are as defined herein.

Description

METHODS FOR TREATING OR PREVENTING AN INFLAMMATORY OR METABOLIC CONDITION BY INHIBITING JNK
This application claims the benefit of U.S. Application No. 10/395,811, filed March 24, 2003, which is a continuation-in-part of U.S. Application No. 10/004,645 filed December 4, 2001 which claims the benefit of U.S. Provisional Application No. 60/251,904, filed December 6, 2000, each of which is incorporated by reference herein in its entirety. 0
1. FIELD OF THE INVENTION This invention is generally directed to Anilinopyrimidines and derivatives thereof which have utility over a wide range of indications, including activity as Jun N- terminal kinase inhibitors, and related compositions and methods. 5
2. BACKGROUND OF THE INVENTION The Jun N-terminal kinase (JNK) pathway is activated by exposure of cells to environment stress or by treatment of cells with pro-inflammatory cytokines. Targets of the JNK pathway include the transcription factors c-jun and ATF-2 (Whitmarsh A.J., and 0 Davis RJ. . J. Mol. Med. 74:589-607, 1996). These transcription factors are members of the basic leucine zipper (bZJP) group that bind as homo- and hetero-dimeric complexes to AP-1 and AP-1-like sites in the promoters of many genes (Karin M., Liu Z.G. and Zandi E. Curr Opin Cell Biol 9:240-246, 1997). JNK binds to the N-terminal region of c-jun and ATF-2 and phosphorylates two sites within the activation domain of each transcription 5 factor (Hibi M., Lin A., Smeal T., Minden A., Karin M. Genes Dev. 7:2135-2148, 1993; Mohit A. A., Martin M.H., and Miller CA. Neuron 14:67-75, 1995). Three JNK enzymes have been identified as products of distinct genes (Hibi et al, supra; Mohit et al., supra). Ten different isoforms of JNK have been identified. These represent alternatively spliced forms of three different genes: JNKl, JNK2 and JNK3. JNKl and 2 are ubiquitously 0 expressed in human tissues, whereas JNK3 is selectively expressed in the brain, heart and testis (Dong, C, Yang, D., Wysk, M., Whitmarsh, A., Davis, R., Flavell, R. Science 270:1- 4, 1998). Gene transcripts are alternatively spliced to produce four- JNKl isoforms, four- JNK2 isoforms and two-JNK3 isoforms. JNKl and 2 are expressed widely in mammalian tissues, whereas JNK3 is expressed almost exclusively in the brain. Selectivity of JNK 5 signaling is achieved via specific interactions of JNK pathway components and by use of scaffold proteins that selectively bind multiple components of the signaling cascade. JEP-l (JNK-interactmg protein- 1) selectively binds the MAPK module, MLK - JNKK2 - JNK.12,13. It has no binding affinity for a variety of other MAPK cascade enzymes. Different scaffold proteins are likely to exist for other MAPK signaling cascades to preserve substrate specificity.
JNKs are activated by dual phosphorylation on Thr-183 and Tyr-185. JNKKl (also own as MKK-4) and JNKK2 (MKK-7), two MAPKK level enzymes, can mediate JNK activation in cells (Lin A., Minden A., Martinetto H., Claret F.-Z., Lange- Carter C, Mercurio F., Johnson G.L., and Karin M. Science 268:286-289, 1995; Tournier C, Whitmarsh A.J., Cavanagh J., Barrett T., and Davis R.J. Proc. Nat. Acad. Sci. USA 94:7337-7342, 1997). JNKK2 specifically phosphorylates JNK, whereas JNKKl can also phosphorylate and activate p38. Both JNKKl and JNKK2 are widely expressed in mammalian tissues. JNKKl and JNKK2 are activated by the MAPKKK enzymes, MEKK-1, MEKK-2, MEKK-3 and MLK-3 (Lange-Carter C.A., Pleiman CM., Gardner A.M., Blumer K.J., and Johnson G.L. Science 260:315-319, 1993; Yan M., Dai J.C, Deak J.C, Kyriakis J.M., Zon L.I., Woodgett J.R., and Templeton DJ. Nature 372:798-781, 1994; Deacon, K. and Blank, J., J. Biol. Chem. 274:16604-16610, 1999; Teramoto, H., Coso, O., Miyata, H., Igishi, T., Miki, T. and Gutkind, S., J. Biol. Chem. 271:27225-27228, 1996). Both MEKK-1 and MEKK-2 are widely expressed in mammalian tissues. Activation of the JNK pathway has been documented in a number of disease settings, providing the rationale for targeting this pathway for drug discovery. Lti addition, molecular genetic approaches have validated the pathogenic role of this pathway in several diseases. For example, autoimmune and inflammatory diseases arise from the over- activation of the immune system. Activated immune cells express many genes encoding inflammatory molecules, including cytokines, growth factors, cell surface receptors, cell adhesion molecules and degradative enzymes. Many of these genes are regulated by the JNK pathway, through activation of the transcription factors AP-1 and ATF-2, including TNFα, LL-2, E-selectin and matrix metalloproteinases such as collagenase-1 (Manning A.M. and Mecurio F. Exp. Opin. Invest. Drugs 6: 555-567, 1997). Monocytes, tissue macrophages and tissue mast cells are key sources of TNFα production. The JNK pathway regulates TNFα production in bacterial lipopolysaccharide-stimulated macrophages, and in mast cells stimulated through the FceRJJ receptor (Swantek J.L., Cobb M.H., Geppert T.D. Mol. Cell. Biol. 17:6274-6282, 1997; Ishizuka, T., Tereda N., Gerwins, P., Hamelmann E., Oshiba A., Fanger G.R., Johnson G.L., and Gelfland E.W. Proc. Nat. Acad. Sci. USA 94:6358-6363, 1997). Inhibition of JNK activation effectively modulates TNFα secretion O 2004/084901
from these cells. The JNK pathway therefore regulates production of this key pro- inflammatory cytokine. International Publication No. WO 98/18782 to Celltech Therapeutics Limited discloses 4-pyridyl-pyrimidine compounds which are allegedly useful in the prophylaxis and treatment of immune diseases, allergic diseases involving mast cells or eosinophils, and diseases involving inappropriate platelet activation. Matrix metalloproteinases (MMPs) promote cartilage and bone erosion in rheumatoid arthritis, and generalized tissue destruction in other autoimmune diseases. Inducible expression of MMPs, including MMP-3 and MMP-9, type JJ and JV collagenases, are regulated via activation of the JNK pathway and AP-1 (Gum, R., Wang, H., Lengyel, E., Jurez, J., and Boyd, D. Oncogene 14:1481-1493, 1997). In human rheumatoid synoviocytes activated with TNFα, IL-1, or Fas ligand the JNK pathway is activated (Han Z., Boyle D.L., Aupperle K.R., Bennett B., Manning A.M., Firestein G.S. J. Pharm. Exp. Therap. 291:1-7, 1999; Okamoto K., Fujisawa K, Hasunuma T., Kobata T., Sumida T., and Nishioka K. Arth & Rheum 40: 919-92615, 1997). Inhibition of JNK activation results in decreased AP-1 activation and collagenase-1 expression (Han et al., supra). The JNK pathway therefore regulates MMP expression in cells involved in rheumatoid arthritis.
Inappropriate activation of T lymphocytes initiates and perpetuates many autoimmune diseases, including asthma, inflammatory bowel disease and multiple sclerosis. The JNK pathway is activated in T cells by antigen stimulation and CD28 receptor co- stimulation and regulates production of the growth factor IL-2 and cellular proliferation (Su B., Jacinto E., Hibi M., Kallunki T., Karin M., Ben-Neriah Y. Cell 11:121-136, 1994; Fans M., Kokot N., Lee L., and Nel A.E. J. Biol. Chem. 271:27366-27373, 1996). Peripheral T cells from mice genetically deficient in JNKKl show decreased proliferation and LL-2 production after CD28 co-stimulation and PMA /Ca2+ ionophore activation, providing important validation for the role of the JNK pathway in these cells (Nishina H., Bachmann M., Oliveria-dos-Santos A.J., et al. J. Exp. Med. 186:941-953, 1997). It is known that T cells activated by antigen receptor stimulation in the absence of accessory cell-derived co- stimulatory signals lose the capacity to synthesize IL-2, a state called clonal anergy. This is an important process by which auto-reactive T cell populations are eliminated from the peripheral circulation. Of note, anergic T cells fail to activate the JNK pathway in response to CD3- and CD28-receptor co-stimulation, even though expression of the JNK enzymes is unchanged (Li W., Whaley CD., Mondino A., and Mueller D.L. Science 111: 1272-1276, 1996). Recently, the examination of JNK-deficient mice revealed that the JNK pathway plays a key role in T cell activation and differentiation to T helper 1 and 2 cell types. JNKl or JNK2 lαiockout mice develop normally and are pheno typically unremarkable. Activated naive CD4+ T cells from these mice fail to produce IL-2 and do not proliferate well (Sabapathy, K, Hu, Y, Kallunki, T, Schreiber, M, David, J-P, Jochum, W, Wagner, E, Karin, M. Curr Biol 9: 116-125, 1999). It is possible to induce T cell differentiation in T cells from these mice, generating Thl cells (producer of IFN-g and TNFβ) and Th2 effector
5 cells (producers of IL-4, IL-5, JJ -6, EL- 10 and LL-13 ) [22,23]. Deletion of either JNKl or JNK2 in mice resulted in a selective defect in the ability of Thl effector cells to express LFNg. This suggests that JNKl and JNK2 do not have redundant functions in T cells and that they play different roles in the control of cell growth, differentiation and death. The JNK pathway therefore, is an important point for regulation of T cell responses to antigen.
10 Cardiovascular disease (CVD) accounts for nearly one quarter of total annual deaths worldwide. Vascular disorders such as atherosclerosis and restenosis result from dysregulated growth of the vessel wall, restricting blood flow to vital organs. The JNK pathway is activated by atherogenic stimuli and regulates local cytokine and growth factor production in vascular cells (Yang, DD, Conze, D, Whitmarsh, AJ, et al, Immunity, 9:575,
15 1998). hi addition, alterations in blood flow, hemodynamic forces and blood volume lead to JNK activation in vascular endothelium, leading to AP-1 activation and pro-atherosclerotic gene expression (Aspenstrom P., Lindberg U., and Hall A. Curr. Biol. 6:10-11, 1996). Ischemia and ischemia coupled with reperfusion in the heart, kidney or brain results in cell death and scar formation, which can ultimately lead to congestive heart failure, renal failure 0 or cerebral dysfunction, h organ transplantation, reperfusion of previously ischemic donor organs results in acute leukocyte-mediated tissue injury and delay of graft function. The JNK pathway is activated by ischemia and reperfusion (Li Y., Shyy J., Li S., Lee J., Su B., Karin M., Chien S Mol. Cell. Biol. 16:5947-5954, 1996), leading to the activation of JNK- responsive genes and leukocyte-mediated tissue damage. In a number of different settings 5 JNK activation can be either pro- or anti-apoptotic. JNK activation is correlated with enhanced apoptosis in cardiac tissues following ischemia and reperfusion (Pombo CM, Bonventre JV, Avruch J, Woodgett JR, Kyriakis J.M, Force T. J. Biol. Chem. 26 :26546- 26551, 1994).
Cancer is characterized by uncontrolled growth, proliferation and migration 0 of cells. Cancer is the second leading cause of death with 500,000 deaths and an estimated 1.3 million new cases in the United States in 1996. The role of signal fransduction pathways contributing to cell transformation and cancer is a generally accepted concept. The JNK pathway leading to AP-1 appears to play a critical role in cancer. Expression of c-jun is altered in early lung cancer and may mediate growth factor signaling in non-small 5 cell lung cancer (Yin T., Sandhu G., Wolfgang CD., Burrier A., Webb R.L., Rigel D.F. Hai T., and Whelan J. J. Biol. Chem. 272:19943-19950, 1997). hideed, over-expression of c-jun in cells results in transformation, and blocking c-jun activity inhibits MCF-7 colony formation (Szabo E., Riffe M., Steinberg S.M., Birrer M.J., Linnoila R.I. Cancer Res. 56:305-315, 196). DNA-damaging agents, ionizing radiation and tumor necrosis factor activate the pathway, h addition to regulating c-jun production and activity, JNK activation can regulate phosphorylation of p53, and thus can modulate cell cycle progression (Chen T.K., Smith L.M., Gebhardt D.K., Birrer M.J., Brown P.H. Mol. Carcinogenesis 15:215- 226, 1996). The oncogene BCR-Abl, associated with t(9,22) Philadelphia chromosome translocation of chronic myelogenous leukemia, activates JNK and leads to transformation of hematopoietic cells (Milne D.M., Campbell L.E., Campbell D.G., Meek D W. J. Biol. Chem. 270:5511-5518, 1995). Selective inhibition of JNK activation by naturally occurring JNK inhibitory protein, called JTP-1, blocks cellular transformation caused by BCR-Abl expression (Raitano A.B., Halpern J.R., Hambuch T.M., Sawyers CL. Proc. Nat. Acad. Sci USA 92:11746-11750, 1995). Thus, JNK inhibitors may block transformation and tumor cell growth.
The involvement of JNK in insulin mediated diseases such as Type JJ diabetes and obesity has also been confirmed (Hirosumi, J. et al Nature 420:333-336, 2002; International Publication No. WO 02/085396). Without being limited by theory, it is thought that phosphorylation at Ser 307 of insulin receptor substrate ('TRS-1") is responsible for TNF-α-induced and FFA-induced insulin resistance (Hotamisigil, G.H. Science 271 :665-668, 1996). This was demonstrated in a cellular model of insulin resistance in liver cells where increased Ser 307 phosphorylation of IRS-1 was seen in cells treated with TNF-α (Hirosumi, J. Id.). It was also shown that the TNF-α-induced Ser 307 phosphorylation was completely prevented by an inhibitor of JNK (Id.). Additional studies have demonstrated that inhibition of the JNK pathway inhibits TNF-α lipolysis which has been implicated in diseases characterized by insulin resistance (International Publication No. WO 99/53927).
Accordingly, there is a need in the art for inhibitors of the JNK pathway. In addition, there is a need for pharmaceutical compositions comprising one or more i •nhibitors, as well as to methods for treating conditions in animals which are responsive to such inhibitors. The present invention fulfills these needs, and provides further related advantages. Citation of any reference in Section 2 of this application is not an admission that the reference is prior art to the application. 3. SUMMARY OF THE INVENTION h brief, the present invention generally relates to methods for treating or preventing a condition responsive to JNK inhibition, comprising administering to a patient in need thereof an effective amount of a compound having the following formula (I):
Figure imgf000007_0001
wherein Rj though R6 are as defined below, and including isomers, prodrugs and pharmaceutically acceptable salts thereof.
A compound of formula (I), or a pharmaceutically acceptable salt thereof, is hereinafter referred to as an "Anilinopyrimidine Derivative." hi general, the present invention is directed to methods for treating or preventing a condition responsive to inhibition of the JNK pathway, comprising administering to a patient in need thereof an effective amount of an Anilinopyrimidine Derivative.
Anilinopyrimidine Derivatives are useful for treating or preventing a metabolic condition including, but not limited to: diabetes (such as Type JJ diabetes, Type I diabetes, diabetes insipidus, diabetes mellitus, maturity-onset diabetes, juvenile diabetes, insulin-dependant diabetes, non-insulin dependant diabetes, malnutrition-related diabetes, ketosis-prone diabetes or keto sis-resistant diabetes);or obesity (such as hereditary obesity, dietary obesity, hormone related obesity or obesity related to the administration of medication).
Anilinopyrimidine Derivatives are useful for treating or preventing an inflammatory condition including, but not limited to: hearing loss (such as that from otitis extema or acute otitis media); fibrosis related diseases (such as pulmonary interstitial fibrosis, renal fibrosis, cystic fibrosis, liver fibrosis, wound-healing or bum-healing, wherein the bum is a first- , second- or third-degree bum and/or a thermal, chemical or electrical burn); arthritis (such as rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis or gout); an allergy; allergic rhinitis; acute respiratory distress syndrome; asthma; bronchitis; an inflammatory bowel disease (such as irritable bowel syndrome, mucous colitis, ulcerative colitis, Crohn's disease, gastritis, esophagitis, pancreatitis or peritonitis); or an autoimmune disease (such as scleroderma, systemic lupus erythematosus, myasthenia gravis, transplant rejection, endotoxin shock, sepsis, psoriasis, eczema, dermatitis or multiple sclerosis).
Anilinopyrimidine Derivatives are also useful for treating or preventing a liver disease (such as hepatitis, alcohol-induced liver disease, toxin-induced liver disease, steatosis or sclerosis); a cardiovascular disease (such as atherosclerosis, restenosis following angioplasty, left ventricular hypertrophy, myocardial infarction, chronic obstructive pulmonary disease or stroke); ischemic damage (such as to the heart, kidney, liver or brain); ischemia-reperfusion injury (such as that caused by transplant, surgical trauma, hypotension, thrombosis or trauma injury); neurodegenerative disease (such as epilepsy, Alzheimer's disease, Huntington's disease, Amyotrophic laterial sclerosis, peripheral neuropathies, spinal cord damage or Parkinson's disease); or cancer (such as cancer of the head, neck, eye, mouth, throat, esophagus, chest, bone, lung, colon, rectum, stomach, prostate, breast, ovaries, testicles or other reproductive organs, skin, thyroid, blood, lymph nodes, kidney, liver, pancreas, and brain or central nervous system). In one embodiment, the present methods for treating or preventing further comprise the administration of an effective amount of another therapeutic agent useful for treating or preventing the diseases or disorders disclosed herein. In this embodiment, the time in which the therapeutic effect of the other therapeutic agent is exerted overlaps with the time in which the therapeutic effect of the Anilinopyrimidine Derivative is exerted. Ji one embodiment, the present methods for treating or preventing a metabolic condition an inflammatory condition, a liver disease, a cardiovascular disease, ischemic damage, a neurodegenerative disease or cancer comprise inhibiting JNK in vivo. In one embodiment, inhibiting JNK in vivo comprises inhibiting TNF-α in vivo. hi one embodiment the JNK is JNKl . In another embodiment the JNK is
JNK2. hi another embodiment the JNK is JNK3.
These and other aspects of this invention will be evident upon reference to the following detailed description and illustrative examples, which are intended to exemplify non-limiting embodiments of the invention. Certain patent and other documents are cited herein to more specifically set forth various aspects of this invention. Each of these documents are hereby incorporated by reference in their entirety. 4. DETAILED DESCRIPTION OF THE INVENTION
4.1 DEFINITIONS As used herein, the terms used above having following meaning: "Alkyl" means a straight chain or branched, saturated or unsaturated alkyl, cyclic or non-cyclic hydrocarbon having from 1 to 10 carbon atoms, while "lower alkyl" has the same meaning but only has from 1 to 6 carbon atoms. Representative saturated straight chain alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, and the like; while saturated branched alkyls include isopropyl, ^ec-butyl, isobutyl, tert-butyl, isopentyl, and the like. Unsaturated alkyls contain at least one double or triple bond between adjacent carbon atoms (also referred to as an "alkenyl" or "alkynyl", respectively). Representative straight chain and branched alkenyls include ethylenyl, propylenyl, 1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3 -methyl- 1-butenyl, 2-methyl-2-butenyl, 2,3-dimethyl- 2-butenyl, and the like; while representative straight chain and branched alkynyls include acetylenyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3 -methyl- 1 butynyl, and the like. Representative saturated cyclic alkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like; while unsaturated cyclic alkyls include cyclopentenyl and cyclohexenyl, and the like. Cycloalkyls are also referred to herein as "carbocyclic" rings systems, and include bi- and tri-cyclic ring systems having from 8 to 14 carbon atoms such as a cycloalkyl (such as cyclopentane or cyclohexane) fused to one or more aromatic (such as phenyl) or non-aromatic (such as cyclohexane) carbocyclic rings.
"Halogen" means fluorine, chlorine, bromine or iodine.
"Keto" means a carbonyl group (i.e., =O).
"Aryl" means an aromatic carbocyclic moiety such as-phenyl or naphthyl. "Arylalkyl" means an alkyl having at least one alkyl hydrogen atom replaced with an aryl moiety, such as benzyl, -(CH2)2phenyl, -(CH2)3phenyl, -CH(phenyl)2, and the like.
"Heteroaryl" means an aromatic heterocycle ring of 5- to 10 members and having at least one heteroatom selected from nitrogen, oxygen and sulfur, and containing at least 1 carbon atom, including both mono- and bicyclic ring systems. Representative heteroaryls are pyridyl, furyl, benzofuranyl, fhiophenyl, benzothiophenyl, quinolinyl, pyrrolyl, indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl, and quinazolinyl. "Heteroarylalkyl" means an alkyl having at least one alkyl hydrogen atom replaced with a heteroaryl moiety, such as -CH2pyridinyl, -CH2pyrimidinyl, and the like.
"Heterocycle" means a heterocyclic ring containing from 5 to 10 ring atoms "Heterocycle" means a 5- to 7-membered monocyclic, or 7- to 10-membered bicyclic, heterocyclic ring which is either saturated, unsaturated, or aromatic, and which contains from 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and wherein the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quatemized, including bicyclic rings in which any of the above heterocycles are fused to a benzene ring. The heterocycle may be attached via any heteroatom or carbon atom. Heterocycles include heteroaryls as defined above. Thus, in addition to the heteroaryls listed above, heterocycles also include morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrindinyl, tetrahydroprimidinyl, tetrahydrothiophenyl, tetraliydrothiopyranyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.
"Heterocyclealkyl" means an alkyl having at least one alkyl hydrogen atom replaced with a heterocycle, such as -CH2morpholinyl, and the like.
The term "substituted" as used herein means any of the above groups (i.e., aryl, arylalkyl, heterocycle and heterocyclealkyl) wherein at least one hydrogen atom is replaced with a substituent. hi the case of a keto substituent ("C(=O)") two hydrogen atoms are replaced. Substituents include halogen, hydroxy, alkyl, substituted alkyl (such as haloalkyl, mono- or di-substituted aminoalkyl, alkyloxyalkyl, and the like, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, -NRaRb, -NRaC(=O)Rb, -NRaC(=O)NRaRb, -NRaC(=O)ORb -NRaSO2Rb, -OR,, -C(=O)Ra -C(=O)ORa -C(=O)NRaRb, -OC(=O)Ra, -OC(=O)ORa, -OC(=O)NRaRb -NRaSO2Rb, or a radical of the formula -Y-Z-Ra where Y is alkanediyl, substitute alkanediyl, or a direct bond, Z is -O-, -S-, -S(=O)-, -S(=O)2-, -N(Rb)-, -C(=O)-, -C(=O)O-, -OC(=O)-, -N(Rb)C(=O)-, -C(=O)N(Rb)- or a direct bond, wherein Ra and Rb are the same or different and independently hydrogen, amino, alkyl, substituted alkyl (including halogenated alkyl), aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocylealkyl or substituted heterocyclealkyl, or wherein Ra and Rb taken together with the nitrogen atom to which they are attached form a heterocycle or substituted heterocycle.
"Haloalkyl" means alkyl having one or more hydrogen atoms replaced with halogen, such as -CF3. "Hydroxyalkyl" means alkyl having one or more hydrogen atoms replaced with hydroxy, such as -CH2OH
"Sulfonylalkyl" means -SO2-(alkyl);
"Sulfmylalkyl" means -SO-(alkyl); "Thioalkyl" means -S-(alkyl);
"Carboxyl" means -COOH.
"Alkoxy" means -O-(alkyl), such as methoxy, ethoxy, n-propyloxy, iso- propyloxy, n-butyloxy, iso-butyloxy, and the like.
"Patient" means an animal, including, but not limited to, an animal such as a cow, monkey, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit, and guinea pig, and is more preferably a mammal, and most preferably a human.
"Acyl" means alkyl(C=O).
"Nitrogen-containing non-aromatic heterocycle" means morpholinyl, thiomorpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, hydantoinyl, tefrahydropyrindinyl, tetrahydropyrimidinyl, oxazolidinyl, thiazolidinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl and the like.
An "effective amount" when used in connection with an Anilinopyrimidine Derivative is an amount effective for treating or preventing a condition, such as those described herein that can be treated or prevented by administering a JNK inhibitor.
A "patient" includes an animal (e.g., cow, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit or guinea pig), in one embodiment a mammal such as a non-primate and a primate (e.g., monkey and human), and in another embodiment a human. In certain embodiments, the patient is an infant, child, adolescent or adult.
As used herein, the term "prodrug" refers to any derivative of the Anilinopyrimidine Derivatives that are metabolized or otherwise converted into an active form upon introduction into the body of an animal. Prodmgs are well known to those skilled in the art of pharmaceutical chemistry, and provide benefits such as increased adsorption and half-life. Prodrags of this invention may be formed when, for example, hydroxy groups are esterified or alkylated, or when carboxyl groups are esterified. Those skilled in the art of drug delivery will readily appreciate that the pharmacokinetic properties of Anilinopyrimidine Derivatives maybe controlled by an appropriate choice of moieties to produce prodrug derivatives. 4.2 COMPOUNDS OF THE INVENTION As mentioned above, the present invention is related to methods for treating or preventing a condition responsive to JNK inhibition, comprising administering to a patient in need thereof an effective amount of a Anilinopyrimidine Derivative of formula (I):
Figure imgf000012_0001
w including isomers, prodrags and pharmaceutically acceptable salts thereof, wherein:
R! is aryl or heteroaryl optionally substituted with one to four substituents independently selected from R7; R2 is hydrogen;
R3 is hydrogen or lower alkyl;
R4 represents one to four optional substituents, wherein each substituent is the same or different and independently selected from halogen, hydroxy, lower alkyl and lower alkoxy; R5 and R6 are the same or different and independently -R8, -(CH2)0C(=O)R9>
-(CH2)αC(=O)OR9, -(CH2)αC(=O)NR9R10,
Figure imgf000012_0002
(CH2)flNRπC(=O)NR9R10, -(CH2)flNR9R10, -(CH2)aOR9, -(CH^SOJA, or -(CH2)flSO2NR9R10; or R5 and R6 taken together with the nitrogen atom to which they are attached to form a heterocycle or substituted heterocycle; R7 is at each occurrence independently halogen, hydroxy, cyano, nitro, carboxy, alkyl, alkoxy, haloalkyl, acyloxy, thioalkyl, sulfinylalkyl, sulfonylalkyl, hydroxyalkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, -C(=O)OR8, -OC(=O)R8, -C(=O)NR8R5, -C(=O)NR8OR9, -SOcR8, -SOcNR8R9, -NRgSOJA,,, -NR8R9, -NR8C(=O)R9, -NR8C(=O)(CH2)iOR9, -NR8C(=O)(CH2)ύR9, -O(CH2)feNR8R9, or heterocycle fused to phenyl; Rg, R9, R10 and Rn are the same or different and at each occurrence independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, aralkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl or substituted heterocyclealkyl; or R8 and R9 taken together with the atom or atoms to which they are attached to form a heterocycle or substituted heterocycle; a and b are the same or different and at each occurrence independently selected from 0, 1, 2, 3 or 4; and c is at each occurrence 0, 1 or 2. hi one embodiment of the invention, in the Anilinopyrimidine Derivatives of structure (I), Rx is a substituted or unsubstituted aryl or heteroaryl with the proviso that the heteroaryl is not pyridyl. When Rλ is substituted, it is substituted with one or more substituents defined below. Preferably, when substituted, Rj is substituted with a halogen, sulfone or sulfonamide. h another embodiment of the invention, in the Anilinopyrimidine
Derivatives of stracture (I), Rr is substituted or unsubstituted aryl, furyl, benzofuranyl, thiophenyl, benzothiophenyl, quinolinyl, pyrrolyl, indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl or quinazolinyl. In another embodiment of the invention, in the Anilinopyrimidine
Derivatives of stracture (I), Rx is substituted or unsubstituted aryl or heteroaryl with the proviso that the heteroaryl is not imidazo[l,2a]pyrid-3-yl or pyrazolo[2,3a]pyrid-3-yl. When R^ is substituted, it is substituted with one or more substituents defined below. Preferably, when substituted, R} is substituted with a halogen, sulfone or sulfonamide. hi another embodiment of the invention, in the Anilinopyrimidine
Derivatives of stracture (I), Rj is substituted or unsubstituted aryl, preferably phenyl. When Rj is a substituted aryl, the substituents are defined below. Preferably, when substituted, R1 is substituted with a halogen, sulfone or sulfonamide. hi another embodiment of the invention, in the Anilinopyrimidine Derivatives of stracture (I), R5 and R6, taken together with the nitrogen atom to which they are attached form a substituted or unsubstituted nitrogen-containing non-aromatic heterocycle, preferably piperazinyl, piperidinyl or morpholinyl.
When R5 and R6, taken together with the nitrogen atom to which they are attached form substituted piperazinyl, piperadinyl or morpholinyl, the piperazinyl, piperadinyl or mo holinyl is substituted with one or more substituents defined below. Preferably, when substituted, the substituent is alkyl, amino, alkylamino, alkylether, acyl, pyrrolidinyl or piperidinyl. hi one embodiment of the invention, in the Anilinopyrimidine Derivatives of formula (I), R3 is hydrogen and R4 is not present, and the compounds of this invention have the following formula (IT):
Figure imgf000014_0001
(π)
In a more specific embodiment of the invention, in the Anilinopyrimidine Derivatives of formula (IT), Rt is phenyl optionally substituted with R7, and having the following formula (IH):
Figure imgf000014_0002
hi still a further embodiment of the invention, in the Anilinopyrimidine Derivatives of formula (IE), R7 is at the para position relative to the pyrimidine, as represented by the following formula (IV):
Figure imgf000014_0003
4.3 PREPARATION OF COMPOUNDS OF THE INVENTION
The Anilinopyrimidine Derivatives can generally be obtained using organic synthesis techniques known to those skilled in the art, as well as by the following general teclmiques and the procedures set forth in the Examples. To that end, the Anilinopyrimidine Derivatives can be made according to the following Reaction Schemes 1 through 9:
Reaction Scheme 1
Rι
Figure imgf000015_0001
R1ΛN SR or SR
HN^ H2
Figure imgf000015_0002
(oxone, mCPBA)
Appropriately substituted methylketones may be treated with a dimethylformamide acetal, such as dimethylformamide dimethylacetal or dimethylformamide diethylacetal, to afford the corresponding β-dimethylaminobutenones. Treatment of the aminobutenones with thiourea in the presence of a base such as sodium methoxide, followed by alkylation with an alkyl halide, such as methyl iodide, gives 4-substituted 2- alkylthiopyrimidines. Oxidation of the thioether with organic and inorganic oxidizing agents, such as m-chloroperbenzoic acid or oxone, yields the sulfones which, upon condensation with >-aminocarbonylanilines, give rise to the formation of the desired anilinopyrimidine derivatives. Reaction Scheme 2
Figure imgf000016_0001
Similarly, the Anilinopyrimidine Derivatives may be prepared from the 2- chloropyrimidine derivatives. Thus, condensation of the β-dimethylaminobutenones with urea followed y the treatment with chlorinating agent such as phosphoras oxychloride gives 4-substituted 2-chloropyrimidines. Further treatment with substituted anilines affords the desired Anilinopyrimidine Derivatives.
Reaction Scheme 3
Figure imgf000016_0002
The Anilinopyrimidine Derivatives can also be prepared by condensation of the β-dimethylaminobutenones with appropriately substituted guanidines. The requisite guanidines may be synthesized by the reaction of the aniline with cyanamide in the presence of an acid, or with a pyrazoloamidine.
Reaction Scheme 4
Figure imgf000017_0001
base
Figure imgf000017_0002
Cyclization of alkoxycarbonylphenylguanidines with the b-aminoketones gives 4-substituted 2-(4-carboxyphenyl)ammopyrimidines. Condensation of the benzoic acid derivatives with appropriate amines affords the desired amides.
Reaction Scheme 5
Figure imgf000017_0003
RaCOOH EDCI, HOBT
Condensation of the benzoic acids with N-Boc-piperazine followed by deprotection of the tert-butoxycarbonyl group with an acid such as hydrochloric acid yields piperazineamides. Subsequent condensation with carboxylic acid derivatives yields bisacylpipei
Reaction Scheme 6
Figure imgf000018_0001
Similar reaction with sulfonyl chlorides gives the corresponding sulfonamides.
Reaction Scheme 7
Figure imgf000018_0002
Acetophenones with p-alkyl- and arylthio groups may be prepared by the reaction of p-chloroacetophenone with alkyl and arylthiols.
Reaction Scheme 8
Figure imgf000018_0003
Anilinopyrimidine Derivatives with the p-alkyl- and arylsulfenyl groups may be prepared by controlled oxidation of the sulfides with an oxidizing agent such as oxone. Reaction Scheme 9
Figure imgf000019_0001
Anilinopyrimidine Derivatives having p-alkyl- and arylsulfenyl groups may be prepared by oxidation of the sulfides with an oxidizing agent such as oxone.
The Anilinopyrimidine Derivatives can be in the form of a pharmaceutically acceptable salt or free base. Acid addition salts of the free base can be prepared by methods well known in the art, and may be formed from organic and inorganic acids. Suitable organic acids include maleic, fumaric, benzoic, ascorbic, succinic, methanesulfonic acetic, oxalic, propionic, tartaric, salicylic, citric, gluconic, lactic, mandelic, cinnamic, aspartic, stearic, palmitic, glycolic, glutamic, and benzenesulfonic acids. Suitable inorganic acids include hydrochloric, hydrobromic, sulfuric, phosphoric, and nitric acids. Additional salts include sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, -toluenesulfonate, and pamoate (i.e., l,l'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. The term "pharmaceutically acceptable salt" is intended to encompass any and all acceptable salt forms.
Pharmaceutically acceptable salts can be formed by conventional and known teclmiques, such as by reacting a compound of this invention with a suitable acid as disclosed above. Such salts are typically formed in high yields at moderate temperatures, and often are prepared by merely isolating the compound from a suitable acidic wash in the final step of the synthesis. The salt- forming acid may dissolved in an appropriate organic solvent, or aqueous organic solvent, such as an alkanol, ketone or ester. On the other hand, if the Anilinopyrimidine Derivative is desired in the free base form, it may be isolated from a basic final wash step, according to known techniques. For example, a typical technique for preparing hydrochlori.de salt is to dissolve the free base in a suitable solvent, and dry the solution thoroughly, as over molecular sieves, before bubbling hydrogen chloride gas through it.
The Anilinopyrimidine Derivatives can also exist in various isomeric forms, including configurational, geometric and conformational isomers, as well as existing in various tautomeric forms, particularly those that differ in the point of attachment of a hydrogen atom. As used herein, the term "isomer" is intended to encompass all isomeric forms of a compound, including tautomeric forms of the compound.
4.4 METHODS OF USE Conditions that may be treated using an Anilinopyrimidine Derivative, or using a pharmaceutical composition containing the same, include any condition that is responsive to JNK pathway inhibition, and thereby benefit from administration of such an inhibitor. hi one embodiment, the invention relates to methods for treating or preventing a metabolic condition including, but not limited to: diabetes (such as Type II diabetes, Type I diabetes, diabetes insipidus, diabetes mellitus, maturity-onset diabetes, juvenile diabetes, insulin-dependant diabetes, non-insulin dependant diabetes, malnutrition- related diabetes, ketosis-prone diabetes or ketosis-resistant diabetes); or obesity (such as hereditary obesity, dietary obesity, hormone related obesity or obesity related to the administration of medication) comprising administering to a patient in need thereof an effective amount of an Anilinopyrimidine Derivative. hi another embodiment, the invention relates to methods for treating or preventing an inflammatory condition including, but not limited to: hearing loss (such as that from otitis extema or acute otitis media); fibrosis related diseases (such as pulmonary interstitial fibrosis, renal fibrosis, cystic fibrosis, liver fibrosis, wound-healing or bum- healing, wherein the bum is a first- , second- or third-degree bum and/or a thermal, chemical or electrical bum); arthritis (such as rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis or gout); an allergy; allergic rhinitis; acute respiratory distress syndrome; asthma; bronchitis; an inflammatory bowel disease (such as irritable bowel syndrome, mucous colitis, ulcerative colitis, Crohn's disease, gastritis, esophagitis, pancreatitis or peritonitis); or an autoimmune disease (such as scleroderma, systemic lupus erythematosus, myasthenia gravis, transplant rejection, endotoxin shock, sepsis, psoriasis, eczema, dermatitis or multiple sclerosis) comprising administering to a patient in need thereof an effective amount of an Anilinopyrimidine Derivative. I another embodiment, the invention relates to methods for treating or preventing a liver disease (such as hepatitis, alcohol-induced liver disease, toxin-induced liver disease, steatosis or sclerosis); a cardiovascular disease (such as atherosclerosis, restenosis following angioplasty, left ventricular hypertrophy, myocardial infarction, chronic obstructive pulmonary disease or stroke); ischemic damage (such as to the heart, kidney, liver or brain); ischemia-reperfusion injury (such as that caused by transplant, surgical trauma, hypotension, thrombosis or trauma injury); neurodegenerative disease (such as epilepsy, Alzheimer's disease, Huntington's disease, Amyotrophic laterial sclerosis, peripheral neuropathies, spinal cord damage or Parkinson's disease); or cancer (such as cancer of the head, neck, eye, mouth, throat, esophagus, chest, bone, lung, colon, rectum, stomach, prostate, breast, ovaries, testicles or other reproductive organs, skin, thyroid, blood, lymph nodes, kidney, liver, pancreas, and brain or central nervous system) comprising administering to a patient in need thereof an effective amount of an Anilinopyrimidine Derivative. hi another embodiment, the invention relates to methods for treating or preventing otitis extema, acute otitis media, hearing loss, pulmonary interstitial fibrosis, liver fibrosis, renal fibrosis, wound-healing or burn-healing (wherein the burn is a first-, second- or third-degree burn and/or a thermal, chemical or electrical burn), chronic obstructive pulmonary disease, allergic rhinitis, acute respiratory distress syndrome, systemic lupus erythematosus, nephropathy, pancreatitis, peritonitis, sepsis, alcohol or toxin-induced liver disease, sclerosis, steatosis or ischemia-reperfusion injury comprising administering to a patient in need thereof an effective amount of an Anilinopyrimidine Derivative. h one embodiment, the invention relates to the use of an Anilinopyrimidine Derivative for use in the manufacture of a medicament for treating or preventing a disease responsive to JNK inhibition. h another embodiment, the invention relates to the use of an Anilinopyrimidine Derivative for use in the manufacture of a medicament for treating or preventing a metabolic condition including, but not limited to: diabetes (such as Type II diabetes, Type I diabetes, diabetes insipidus, diabetes mellitus, maturity-onset diabetes, juvenile diabetes, insulin-dependant diabetes, non-insulin dependant diabetes, malnutrition- related diabetes, ketosis-prone diabetes or ketosis-resistant diabetes); or obesity (such as hereditary obesity, dietary obesity, hormone related obesity or obesity related to the administration of medication).
In another embodiment, the invention relates to the use of an Anilinopyrimidine Derivative for use in the manufacture of a medicament for treating or preventing an inflammatory condition including, but not limited to: hearing loss (such as that from otitis extema or acute otitis media); fibrosis related diseases (such as pulmonary interstitial fibrosis, renal fibrosis, cystic fibrosis, liver fibrosis, wound-healing or burn- healing, wherein the bum is a first- , second- or third-degree bum and/or a thermal, chemical or electrical bum); arthritis (such as rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis or gout); an allergy; allergic rhinitis; acute respiratory distress syndrome; asthma; bronchitis; an inflammatory bowel disease (such as irritable bowel syndrome, mucous colitis, ulcerative colitis, Crohn's disease, gastritis, esophagitis, pancreatitis or peritonitis); or an autoimmune disease (such as scleroderma, systemic lupus erythematosus, myasthenia gravis, transplant rejection, endotoxin shock, sepsis, psoriasis, eczema, dermatitis or multiple sclerosis) comprising administering to a patient in need thereof an effective amount of an Anilinopyrimidine Derivative. hi another embodiment, the invention relates to the use of an Anilinopyrimidine Derivative for use in the manufacture of a medicament for treating or preventing a liver disease (such as hepatitis, alcohol-induced liver disease, toxin-induced liver disease, steatosis or sclerosis); a cardiovascular disease (such as atherosclerosis, restenosis following angioplasty, left ventricular hypertrophy, myocardial infarction, chronic obstructive pulmonary disease or stroke); ischemic damage (such as to the heart, kidney, liver or brain); ischemia-reperfusion injury (such as that caused by transplant, surgical trauma, hypotension, thrombosis or trauma injury); neurodegenerative disease (such as epilepsy, Alzheimer's disease, Huntington's disease, Amyotrophic laterial sclerosis, peripheral neuropathies, spinal cord damage or Parkinson's disease); or cancer (such as cancer of the head, neck, eye, mouth, throat, esophagus, chest, bone, lung, colon, rectum, stomach, prostate, breast, ovaries, testicles or other reproductive organs, skin, thyroid, blood, lymph nodes, kidney, liver, pancreas, and brain or central nervous system) comprising administering to a patient in need thereof an effective amount of an Anilinopyrimidine Derivative. hi one embodiment, the present methods for treating or preventing further comprise the administration of an effective amount of another therapeutic agent useful for treating or preventing the diseases or disorders disclosed herein, hi this embodiment, the time in which the therapeutic effect of the other therapeutic agent is exerted overlaps with the time in which the therapeutic effect of the Anilinopyrimidine Derivative is exerted, h one embodiment, the methods for treating or preventing a metabolic condition an inflammatory condition, a liver disease, a cardiovascular disease, ischemic damage, a neurodegenerative disease or cancer comprise inhibiting JNK in vivo. hi one embodiment, inhibiting JNK in vivo comprises inhibiting TNF-α in vivo.
In one embodiment the JNK is JNKl. h another embodiment the JNK is JNK2. h another embodiment the JNK is JNK3. hi another embodiment of the present methods, in the Anilinopyrimidine
Derivatives of structure (I), Rt is a substituted or unsubstituted aryl or heteroaryl with the proviso that the heteroaryl is not pyridyl. When R is substituted, it is substituted with one or more substituents defined above. Preferably, when substituted, Rλ is substituted with a halogen, sulfone or sulfonamide. h another embodiment of the present methods, in the Anilinopyrimidine
Derivatives of structure (I), R} is substituted or unsubstituted aryl, furyl, benzofuranyl, thiophenyl, benzothiophenyl, quinolinyl, pyrrolyl, indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl or quinazolinyl. In another embodiment of the present methods, in the Anilinopyrimidine
Derivatives of structure (I), Rj is substituted or unsubstituted aryl or heteroaryl with the proviso that the heteroaryl is not imidazo[l,2a]pyrid-3-yl or pyrazolo[2,3a]pyrid-3-yl. When Rj is substituted, it is substituted with one or more substituents defined above. Preferably, when substituted, Rt is substituted with a halogen, sulfone or sulfonamide. in another embodiment of the present methods, in the Anilinopyrimidine
Derivatives of structure (I), Rt is substituted or unsubstituted aryl, preferably phenyl or naphthyl. When Rj is a substituted aryl, it is substituted with one or more substituents defined above. Preferably, when substituted, Rλ is substituted with a halogen, sulfone or sulfonamide. l another embodiment of the present methods, in the Anilinopyrimidine
Derivatives of structure (I), R5 and R6 taken together with the nitrogen atom to which they are attached form a susbstituted or unsubstituted nitrogen containing non-aromatic heterocycle.
In another embodiment of the present methods, the nitrogen-containing non- aromatic heterocycle is piperazinyl, piperadinyl or morpholinyl. When the nitrogen- containing non-aromatic heterocycle is a substituted piperazinyl, piperadinyl or morpholinyl ring, the substituents are defined above. Preferably, when substituted, the substituent is alkyl, amino, alkylamino, alkylether, acyl, pyrrolidinyl or piperidinyl. When used in the present methods, the Anilinopyrimidine Derivatives of this invention can be administered as a component of a composition that optionally comprises a pharmaceutically acceptable carrier or vehicle.
The Anilinopyrimidine Derivatives can also be used in cancer adjuvant 5 therapy in combination with a cytotoxic agent or with radiation therapy.
4.5 ADMINISTRATION AND PHARMACEUTICAL COMPOSITIONS
The Anilinopyrimidine Derivatives can be administered to a patient orally or parenterally in conventional and well known preparations, such as capsules, microcapsules,
10 tablets, granules, powder, troches, pills, suppositories, injections, suspensions and syrups. Prior to administration, the Anilinopyrimidine Derivatives are typically formulated as a pharmaceutical composition that contains an effective dosage amount of one or more of such compounds in combination with one (or more) pharmaceutically acceptable carrier(s). Suitable formulations in this regard may be prepared by methods commonly employed using
15 conventional, organic or inorganic additives, such as an excipient (e.g., sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate or calcium carbonate), a binder (e.g., cellulose, methylcellulose, hydroxymethyl cellulose, polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic, polyethyleneglycol, sucrose or starch), a disintegrator (e.g., starch, carboxymethylcellulose,
20 hydroxypropylstarch, low substituted hydroxypropylcellulose, sodium bicarbonate, calcium phosphate or calcium citrate), a lubricant (e.g., magnesium stearate, light anhydrous sicilic acid, talc or sodium lauryl sulfate), a flavoring agent (e.g., citric acid, menthol, glycine or orange powder) a preservative (e.g., sodium benzoate, sodium bisulfite, methylparaben or propylparaben), a stabilizer (e.g., citric acid, sodium citrate or acetic acid), a suspending
25 agent (e.g., methylcellulose, polyvinyl pyrrolidone or aluminum stearate), a dispersing agent (e.g., hydroxypropylmethylcellulose), a diluent (e.g., water), and/or a base wax (e.g., cocoa butter, white petrolatum or polyethylene glycol).
The amount of an Anilinopyrimidine Derivative in a dosage form may differ depending on factors such as, but not limited to, the route by which it is to be administered
30 to patients. However, typical dosage forms of the invention comprise an Anilinopyrimidine Derivative in an amount of from about 0.10 mg to about 3500 mg, from about 1 mg to about 2500 mg, from about 10 mg to about 500 mg, from about 25 mg to about 250 mg, from about 50 mg to about 100 mg. Typical dosage forms comprise an Anilinopyrimidine Derivative in an amount of about 0.1, 1, 2, 5, 7.5, 10, 12.5, 15, 17.5, 20, 25, 50, 100, 150,
35 200, 250, 500, 750, 1000, 1500, 2000, 2500, 3000 or 3500 mg. h a particular embodiment, a dosage form comprises a Pyrazoloanfhrone Derivative in an amount of about 1, 2, 5, 10, 25, 50, 100, 250 or 500 mg. hi a specific embodiment, a dosage form comprises an amount of about 5, 10, 25 or 50 mg of an Anilinopyrimidine Derivative.
Further, the effect of the Anilinopyrimidine Derivative can be delayed or prolonged by proper formulation. For example, a slowly soluble pellet of the
Anilinopyrimidine Derivative may be prepared and incorporated in a tablet or capsule. The technique may be improved by making pellets of several different dissolution rates and filling capsules with a mixture of the pellets. Tablets or capsules may be coated with a film which resists dissolution for a predictable period of time. Even the parenteral preparations may be made long-acting, by dissolving or suspending the compound in oily or emulsified vehicles which allow it to disperse only slowly in the serum.
In certain embodiments, the Anilinopyrimidine Derivatives can be used in combination, e.g., as an adjunct therapy, with at least one other therapeutic agent. An Anilinopyrimidine Derivative and the other therapeutic agent can act additively or, more preferably, synergistically. hi a preferred embodiment, an Anilinopyrimidine Derivative is administered concurrently with the administration of another therapeutic agent, which can be part of the same composition as or in a different composition from that comprising the Anilinopyrimidine Derivative, hi another embodiment, an Anilinopyrimidine Derivative is administered prior or subsequent to administration of another therapeutic agent. As many of the disorders for which the Anilinopyrimidine Derivatives are useful in treating are chronic, in one embodiment combination therapy involves alternating between administering an Anilinopyrimidine Derivative and another therapeutic agent. The duration of administration of the Anilinopyrimidine Derivative or the other therapeutic agent can be, e.g., one month, three months, six months, a year, or for more extended periods, such as the patient's lifetime. In certain embodiments, when a composition of the invention is administered concurrently with another therapeutic agent that potentially produces adverse side effects including, but not limited to, toxicity, the other therapeutic agent can advantageously be administered at a dose that falls below the threshold at which the adverse side effect is elicited. The other therapeutic agent can be an anti-inflammatory agent. Useful anti- inflammatory agents include, but are not limited to, non-steroidal anti-inflammatory drags such as salicylic acid, acetylsalicylic acid, methyl salicylate, diflunisal, salsalate, olsalazine, sulfasalazine, acetaminophen, indomethacin, sulindac, etodolac, mefenamic acid, meclofenamate sodium, tolmetin, ketorolac, dichlofenac, ibuprofen, naproxen, naproxen sodium, fenoprofen, ketoprofen, flurbinprofen, oxaprozin, piroxicam, meloxicam, ampiroxicam, droxicam, pivoxicam, tenoxicam, nabumetome, phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine, apazone and nimesulide; leukotriene antagonists including, but not limited to, zileuton, aurothioglucose, gold sodium thiomalate and auranofin; and other anti-inflammatory agents including, but not limited to, colchicine, allopurinol, probenecid, sulfmpyrazone and benzbromarone. Anti-inflammatory agents particularly useful for treating arthritis, including rhumatiod arthritis, include enbrel, infliximab, anarkinra, celecoxib and rofecoxib.
The other therapeutic agent can be an anti-cancer agent. Useful anti-cancer agents include, but are not limited to, nitrogen mustards, such as cyclophosphamide, Ifosfamide, trofosfamide and Chlorambucil; nitrosoureas, such as carmustine (BCNU) and Lomustine (CCNU); alkylsulphonates, such as busulfan and Treosulfan; triazenes, such as Dacarbazine; platinum-containing compounds, such as Cisplatin and carboplatin; vinca alkaloids, such as vincristine, Vinblastine, Vindesine and Vinorelbine; taxoids, such as paclitaxel and Docetaxol; epipodophyllins, such as etoposide, Teniposide, Topotecan, 9- aminocamptothecin, camptoirinotecan and crisnatol; mytomycins, such as mytomycin C; DHFR inhibitors, such as methotrexate and Trimetrexate; lMP-dehydrogenase inhibitors, such as mycophenolic acid, Tiazofurin, Ribavirin and EICAR; ribonuclotide-reductase inhibitors, such as hydroxyurea and deferoxamine; uracil analogs, such as 5-fluorouracil, Floxuridine, Doxifluridine and Ratitrexed; cytosine analogs, such as cytarabine (ara C), cytosine arabinoside and fludarabine; purine analogs, such as mercaptopurine and thioguanine; anti-estrogens, such as Tamoxifen, Raloxifene and megestrol; LHRH agonists, such as goscrclin and Leuprolide acetate; anti-androgens, such as flutamide and bicalutamide; vitamin D3 analogs, such as B 1089, CB 1093 and KH 1060; photodynamic therapeutic agents, such as vertoporfm (BPD-MA), Phthalocyanine, photosensitizer Pc4 and demethoxyhypocrellin A (2BA-2-DMHA); cytokines, such as interferon-α, interferon-γ and tumor-necrosis factor; isoprenylation inhibitors, such as Lovastatin; dopaminergic neurotoxins, such as l-methyl-4-phenylpyridinium ion; cell-cycle inhibitors, such as staurosporine; actinomycins, such as Actinomycin D and Dactinomycin; bleomycins, such as bleomycin A2, Bleomycin B2 and Peplomycin; anthracyclines, such as daunorabicin, Doxorabicin (adriamycin), Idarabicin, Epirabicin, Pirarabicin, Zorabicin and Mitoxantrone; MDR inhibitors, such as verapamil; and Ca2+ATPase inhibitors, such as thapsigargin.
The other therapeutic agent can also be an antiobiotic (e.g., vancomycin, penicillin, amoxicillin, ampicillin, cefotaxime, ceftriaxone, cefixime, rifampin, metronidazole, doxycycline or streptomycin). The other therapeutic agent can also be a PDE4 inhibitor (e.g., roflumilast or rolipram). The other therapeutic agent can also be an antihistamine (e.g., cyclizine, hydroxyzine, promethazine or diphenhydramine). The other therapeutic agent can also be an anti-malarial (e.g., artemisinin, artemether, artsunate, chloroquine phosphate, mefloquine hydrochloride, doxycycline hyclate, proguanil hydrochloride, atovaquone or halofantrine). The other therapeutic agent can also be drotrecogin alfa.
The following examples are offered by way of illustration, not limitation. To this end, it should be noted that one or more hydrogen atoms may be omitted from the drawn stracture consistent with accepted shorthand notation of such organic compounds, and that one skilled in the art would readily appreciate their presence. Retention time data for the following examples was obtained by one of two methods detailed as follows: Method A
Column: YMC Pro C-18, 3.0 μ spherical silica gel, 4.0 x 50 mm, pore size 12θA. Gradient: 0-10 min, 20%A - 90%A linear binary gradient. Flow rate : 2.0 mL/min.
Mobile Phase: A, 0.1% formic acid in acetonitrile; B, 0.1 % trifluoroacetic acid in water.
Method B
Column: YMC ODS-A, 5.0 μ spherical silica gel, 4.6 x 250 mm, pore size 120A. Gradient: 0-10 min, 20% A - 90% A linear binary gradient followed by 10-25 min, 100%A. Flow rate: 1.0 mL/min.
Mobile Phase: A, 0.1 %> trifluoroacetic acid in acetonitrile; B, 0.1% trifluoroacetic acid in water.
4.6 EXAMPLES
EXAMPLE 1
SYNTHESIS OF
4- {[4-(4-CHLOROPHENYL)PYRIMIDIN-2-YL] AMINO} BENZAMIDE
Figure imgf000027_0001
f2E>3-CDimethylamino - 1 -(4-chlorophenyl ρrop-2-en-l-one
A solution of l-(4-chlorophenyl)ethan-l-one (3.0g, 19.3 mmol) and N,N, dimethylformamide diisopropylacetal (20ml) was heated at 150°C for 16 hours. The reaction mixture was cooled to 0°C and treated with hexanes (20ml). The resulting solid was collected via filtration and washed with hexanes to provide the title compound: EI-MS (m/z) 209 [M+l]+.
4-(4-ChlorophenvDpyrimidine-2-thiol
To a solution of (2E)-3-(dimethylamino)-l-(4-chlorophenyl)prop-2-en-l-one (1.5g, 7.2 mmol) in ethanol (25 ml) was added thiourea (0.60g, 7.9 mmol) and potassium carbonate (K2CO3) (1.19g. 8.63 mmol). The resulting suspension was heated to 85°C for 12 hours then cooled to ambient temperature. The resulting solid was collected and thoroughly washed with water and hexanes to provide a beige solid: EI-MS (m z) 222 [M+l]+.
4-f4-ChlorophenylV2-methylthiopyrimidine
4-(4-Chlorophenyl)pyrimidine-2-thiol (1.2 g, 5.39 mmol) was taken in 10 ml of an aqueous potassium hydroxide (0.453g, 5.39 mmol) solution. Iodomethane (503 μl, 5.39 mmol) was added at ambient temperature and the reaction mixture was allowed to stir for 30 minutes. The resulting white solid was collected via filtration and washed with minimal water and hexanes to provide the title compound: EI-MS (m/z) 237 [M+l]+.
4- 4-chlorophenyllV2- methylsulfonyl)pyrimidine
To a solution of 4-(4-chlorophenyl)-2-methylthiopyrimidine (1.1 g, 4.65 mmol) in acetone ( 30 ml) and water (10 ml) was added oxone (7.14g, 11.62 mmol). The reaction mixture was stirred for 18 hours then diluted with water and extracted into dichloromethane. The extracts were dried over magnesium sulfate, filtered and concentrated to provide a white solid: EI-MS (m/z) 269 [M+l]+.
4- {(4- (4-chlorophenyl)pyrimidin-2-yl amino|benzamide To a solution of 4-(4-chlorophenyl)-2-(methylsulfonyl)pyrimidine (0.1 Og,
0.37 mmol) and 4-aminobenzamide in 2-propanol (3 ml) was heated to 120°C in a sealed vessel for 14 hours. The crude material was concentrated and purified by preparative HPLC to provide the title compound as a beige solid: LC/MS Retention Time; 6.30 min (Method A), M+1; 325. EXAMPLE 2
ALTERNATIVE SYNTHESIS OF
4-{[4-(4-CHLOROPHENYL)PYTAMroiN-2-YL]AMlNO}BENZAMIDE
Figure imgf000029_0001
N- (f4-Aminocarbonyr)phenyl} guanidine nitrate
To a stirred suspension of 4-aminocarbonylaniline (20 g, 147 mmol) and cyanamide (14.2g, 338 mmol) in 70 mL of ethanol was added concentrated nitric acid (20 mL) dropwise. The reaction mixture was heated at reflux overnight, and cooled. Volatile matters were evaporated to give a thick oil. The residue was taken up in methylene chloride and methanol to afford yellow solid. This material was filtered, washed with ether and water and dried in vacuo at 50°C to afford the desired product (17.5 g, 66% yield): LC/MS Retention Time; 0.63 min (Method A), M+1; 179.
4-{ 4- 4-Chlorophenyl pyrimidin-2-yDamino>benzamide
To a solution of (2E)-3-(dimethylamino)-l-(4-chlorophenyl)prop-2-en-l-one (0.10 g, 0.48 mmol), 4-(amidinoamino)benzamide nitrate (0.116 g, 0.48 mmol), and potassium carbonate (0.132g, 0.96 mmol) in ethanol (10 ml) with was heated to 120°C overnight in a sealed vessel. The reaction mixture was cooled to room temperature and the resulting solid was collected then washed with ethanol, water, and diethyl ether to provide the title compound as a beige solid, identical in all respects with the compound prepared in Example 1.
EXAMPLE 3 SYNTHESIS OF REPRESENTATIVE COMPOUNDS
The compounds listed below were prepared according to the procedure of Example 2 using the appropriate methylketone as the starting material.
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
2004/0849
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0002
EXAMPLE 4
SYNTHESIS OF 4-[(4-{4-[(4-CHLOROPHENYL)SULFONYL]PHENYL}PYRLMIDΙN-2-
YL)AMΓNO]BENZAMIDE
Figure imgf000047_0001
Figure imgf000048_0001
OXONE®, acetone, H2O
Figure imgf000048_0002
•HNO3
K2CO3, EtOH, 100°C
Figure imgf000048_0003
To a stirred solution ofp-chlorobenzenefhiol (1) (3.2g, 0.022 mol) in DMF (40 mL) was added NaH (60% dispersion in mineral oil, 0.8g). After the effervescence had ceased, jt?-chlorobenzenethiol (0.011 mol, 0.55 equiv) was added. The solution was then stirred at 110°C for 3 h. Tlihe mixture was cooled to room temperature and then diluted with ether (150 L). The ethereal suspension was washed with 5% NaOH (aq, 50 mL), 3% HCl (aq, 2 x 50 mL), filtered, and concentrated to afford 2.88 g ofp- chlorophenylthioacetophenone (2) (100%). Biarylsulfide (2) was then dissolved in acetone/water (4:1, v/v, 100 mL). OXONE (13.5 g, 2.2 equiv) was added to the solution. The reaction was stirred 4 h at room temperature. After this time, the acetone was removed in vacuo. The mixture was diluted in ether (100 mL) and water (lOOmL). The mixture was shaken and the layers separated. The ether layer was dried (MgSO4 ), filtered, and concentrated to afford 2.02 g (62%) of sulfone 3. Sulfone (3) was then dissolved in dimethylformamide dimethyl acetal (15 mL) and heated to 110°C for 12 h. The reaction mixture was then concentrated to remove excess in dimethylfoπnamide dimethyl aceteal. A portion of the intermediate ene-amino ketone (0.38 g, 1.09 mmol) was taken up in ethanol (20 mL). To this solution was added K2CO3 (0.45 g, 3 equiv) and 4-guanadinobenzamide (4) (0.26 g, 1 equiv). The reaction mixture was heated in a sealed tube at 100°C for 12 h. The mixture was then cooled to room temperature, diluted with water (30 mL), and then filtered. The solid was washed with water and ethanol. A portion of the material was purified by preparatory HPLC to afford 15 mg of the desired compound, which was found to be 100% pure by analytical HPLC. LCMS (M+H=465.0 @ 6.47 min.(Method A)).
EXAMPLE 5 SYNTHESIS OF 4-( {4-[4-(4-PYRlDYLSULFONYL)PHENYL]PYRlMIDrN-2-
YL}AMINO)BENZAMIDE
Figure imgf000049_0001
The above compound was made according to the procedure of Example 4 from 2-mercaptopyridine and the appropriate thiol as the starting materials. LCMS: (M+H=432.1, @ 5.50 min.(Method B)).
O 2004 0
EXAMPLE 6
SYNTHESIS OF 4-({4-[4-(2-PYRIOYLSULFONYL)PHENYL]}PYRIMIDIN-2-
YL}AMΓNO)BENZAMΓDE
Figure imgf000050_0001
The above compound was made according to the procedure of Example 4 from 2-mercaptopyridme and the appropriate thiol as the starting materials. LCMS (M+H=432.0 @ 5.58 min.(Method B)).
EXAMPLE 7 SYNTHESIS OF 4-({4-[4-(3-PYRIDYLSULFONYL)PHENYL]PYRIMΓDΓN-2-
YL}AMΓNO)BENZAMΓDE
Figure imgf000050_0002
The above compound was made according to the procedure of Example from 3-mercaptopyridine and the appropriate thiol as the starting materials. LCMS (M+H=432.1 @ 5.55 min.(Method B)). EXAMPLE 8
SYNTHESIS OF 4-({4-[4-(3-HYDROXYPROPYLTHIO)PHENYL]PYRIMIDΙN-2-
YL}AMΓNO)BENZAMIDE
Figure imgf000051_0001
The above compound was made according to the procedure of Example 4 from 3-mercaptopropanol and the appropriate thiol as the starting materials. LCMS (M+H=381.0 @ 5.55 min.(Method B)).
EXAMPLE 9 SYNTHESIS OF 4-[(4-{4-[(3-HYOROXYPROPYL)SULFONYL]PHENYL}PYRIMΓDΓN-
2-YL)AMΓNO]BENZAMΓDE
Figure imgf000051_0002
Figure imgf000052_0001
OXONE®, acetone water
Figure imgf000052_0002
HN03
K2C03, EtOH, 100°C
Figure imgf000052_0003
To a solution of 3-mercaptopropanol (5 g, 0.054 mol) in DMF (40 mL) was added NaH (2.2 g, 60% dispersion in mineral oil). After the bubbling had ceased, p- chloroacetophenone (5.25 mL, 0.041 mol, 0.75 equiv) was added and the mixture was stirred at 100°C for 3 h. The reaction was cooled, diluted with ether (200 mL), and washed with 5% HCl (aq) (2 x 30 mL), water (2 x 50 mL), and then brine (40 mL). The ether layer was dried (MgSO4 ), filtered, and concentrated to afford thioaryl ketone (5) (6.1 g, 0.29 mol, 72%). Ketone (5) (0.72 g, 3.4 mmol) was dissolved in acetone/water (4:1 v/v, 20 mL). OXONE® (4.2 g) was added and the mixture was stirred for 2 h. The mixture was then concentrated, diluted with ether (75 mL), washed with water (3 x 50 mL), and then brine (50 mL). The ether layer was then dried (MgSO4 ), filtered, and concentrated to afford to aryl sulfone (6). The title compound was prepared as previously described in Example 4 from ketone (6) to afford 39 mg (3%) of analytically pure material. LCMS: (M+H=413.0 @ 5.04 min. (Method A)). EXAMPLE 10 SYNTHESIS OF 4-({4-[4-(3-MORPHOLIN-4-YLPROPYLTHIO)PHENYL]PYRIMIDIN-
2-YL}AMΓNO)BENZAMΓDE
Figure imgf000053_0001
Figure imgf000053_0002
Figure imgf000053_0003
Figure imgf000054_0001
Figure imgf000054_0002
Acetophenone (5) was then taken up on toluene (50 mL). To this solution was added ethylene glycol (2.6 mL, 2 equiv) and -toluenesulfonic acid (0.7g). The reaction was refluxed with a Dean Stark trap for 2 - 3 h. After azeotropic removal of water, the reaction was cooled and then washed with 10% NaHCO3 (aq, 50 mL), water (50 mL), and brine (50 mL). The organic extract was dried (MgSO4), filtered, and concentrated. The crude acetal was then taken up in CH2CL2 (20 mL). In a separate flask, (COCl)2 (2.26 mL, 26.0 mmol) was dissolved in CH2CL2 (20 mL) and cooled to -78°C. DMSO (3.7 mL, 52.0 mmol) in CH2CL2 (5 mL) was then added to the cold solution dropwise. This mixture was stirred for 2 min, after which the crude acetal was added in CH2CL2 (20 mL). After stirring 15 min, Et3N (16.5 mL, 5 equiv) was added slowly. The resulting mixture was stirred 5 min, and then let warm to room temperature over 1 h. The mixture was then poured into a separatory funnel and washed with 5% NaHCO3 (100 mL). The organic layer was then washed with brine (50 mL), dried (Na2SO4), filtered, and concentrated to afford cmde aldehyde (7). Aldehyde (7)(0.5 g) was then taken up in MeOH/AcOH (10 mL). To this solution was added morpholine (0.21 mL). The mixture was stirred 10 min, after which time NaBH3CN (0.19 g) was added. After 30 min, the reaction mixture was concentrated, basified with 3 M NaOH, and extracted with CH2CL2 (3 15 mL). The organic extracts were concentrated and then taken up in acetone/water (9: 1 v/v, 20 mL). -TsOH (0.1 g) was then added to the solution and the mixture was stirred 12 h. After this time, the mixture was concentrated, basified with 1 M NaOH, and extracted with CH2C12 (3 x 15 mL). The organic extracts were then dried (Na2SO4), filtered, and concentrated to afford crude aryl ketone (8), which was taken up in dimethylformamide dimethyl acetal (15 mL) and heated to 100°C for 12 h. The mixture was then concentrated down and taken up in EtOH (15 mL). To this solution was added K2CO3 (0.31 g) and 4-guanadinobenzamide (4) (0.14 ). The reaction mixture was heated in a sealed tube at 100°C for 12 h. The mixture was then cooled to room temperature, diluted with water (30 mL), and then filtered. The solid was washed with water and ethanol. The material was purified by preparatory HPLC to afford the titled compound (33 mg, 4%): LCMS 4.62 min. (Method A), M+H = 450.
EXAMPLE 11
SYNTHESIS OF 4-[(4-{4-[3-(DIMETHYLAMΓNO)PROPYLTHIO]
PHENYL}PYRJMIDIN-2-YL)AMrNO]BENZAMrDE
Figure imgf000056_0001
The titled compound was prepared by the procedure of Example 10, except dimethylamine was used in place of moφholine during the reductive amination of aldehyde (7). LCMS (M+H=408.0 @ 4.62 min.(Method B)).
EXAMPLE 12 SYNTHESIS OF 4-rr4-(4-r3-r4-METHYLPIPERAZINYL PROPYLTHIOl
PHENYLIPYRΓMIDΓN-2-YL^AMΓNOIBENZAMΓDE -
Figure imgf000057_0001
The titled compound was prepared by the procedure of Example 10, except N-methylpiperizine was used in place of moφholine in the reductive amination of aldehyde (7). LCMS (M+H=463.0 @ 4.47 min.(Method B)).
EXAMPLE 13
SYNTHESIS OF 4-r4-(4- (l-METHYL-4-PIPERIDYL)SULFONYLl
PHENΥLIPYTrMIDIN-2-YL AMINOlBENZAMIDE
Figure imgf000058_0001
NaH, DMF OXONE® p-chloracetophenone
Figure imgf000058_0002
Figure imgf000058_0003
Figure imgf000058_0004
4-mercaptopyridine (2.8 g, 25.0 mmol) was dissolved in DMF (25 mL). NaH (lg, 60%) dispersion in mineral oil) was then added to the solution. After the effervescence had ceased, ?-chloroacetophenone (1.4 mL, 11 mmol) was added and the mixture was heated to 110°C for 14 h. After this time, the mixture was cooled, diluted with ether (100 mL). The mixture was washed with 5% NaOH (2 x 50 mL), water (2 x 50 mL), and brine (50 mL). The ethereal extract was dried (MgSO4), filtered, and concentrated. The resulting oil was purified by flash chromatography (9:1 to 7:3 hexanes/ethyl acetate gradient). Concentration of the desired fractions afforded 1.37g (54%) of thioacetophenone (9). Sulfide (9) (1.37 g)was then dissolved in acetone/water (9:1 v/v, 35 mL). To this solution was added OXONE® (7.4 g, 2 equiv). The mixture was stirred for 2 h. The mixture was then concentrated, neutralized with 10% NaHCO3, and extracted with CH2C12 (3 x 50 mL). The organic extracts were dried (NajSO,,), filtered, and concentrated to afford diarylsulfone (10) (1.25 g, 80%). Sulfone (10) (0.53 g. 2.0 mmol) was dissolved in THF (7 mL). To this solution was added Super Hydride® (6.3 mL, 1 M in THF) at room temperature. The solution was stirred at room temperature for 1 h, followed by quenching with MeOH (0.6 mL). The mixture was then concentrated. The residue was taken up in 1 N HCl (50 mL). The aqueous mixture was extracted with ether (3 x 50 mL). The organic layers were discarded. The aqueous layer was basified and extracted with CH2C12 (3 x 15 mL). The organic layers were concentrated. The residue was taken up in AcOH/MeOH (1:1 v/v, 10 mL). CH2O (37% aq, 1 mL) and NaBH3CN (0.1 g) were added. The mixture was stirred 30 min. The mixture was then concentrated, basified with 10% NaOH (aq) and extracted with CH2C12 (3 15 mL). The organic extracts were dried
Figure imgf000059_0001
filtered, and concenfrated to afford crude ketone (11). Aryl ketone (10) was refluxed in dimethylformamide dimethyl acetal (15 mL) and heated to 100°C for 12 h. The mixture was then concentrated down and taken up in EtOH (15 mL). To this solution was added K2CO3 (0.31 g) and 4- guanadinobenzamide (4) (0.14 g). The reaction mixture was heated in a sealed tube at 100°C for 12 h. The mixture was then cooled to room temperature, diluted with water (30 mL), and then filtered. The solid was washed with water and ethanol. The material was purified by preparatory HPLC to afford 6.0 mg (0.5% from sulfone (10)) of the title compound. LCMS (M + H = 452 @ 6.13 min.(Method A)).
EXAMPLE 14
SYNTHESIS OF 4-[(4-{4-[(4-METFiΥLPlPEl^AZINYL)SULFONYL]PHENYL}
PYRIMIDIN-2-YL)AMINO]BENZAMrDE
Figure imgf000060_0001
N-Methylpiperizine (1.16 mL, 0.01 mol) was dissolved in CH2C12 (30 mL) and Et3Ν (4.4 mL, 0.033 mol). The solution was cooled to 0°C and 4-acetylbenzenesulfonyl chloride (2.29 g, 0.01 mol) was added at once. The reaction was stirred for 15 min., poured into a separatory funnel, and extracted with water (3 x 20 mL) and then brine (10 mL). The organic layer was dried (Na^O^), filtered, and concentrated to afford aryl ketone (12). Ketone (12) was carried on without purification to make the title compound as described in Example 13. An analytical sample was purified by preparatory HPLC (0.028 mg, 0.6 %): LCMS (M+H=453.2 @ 5.48 min.(Method A)). EXAMPLE 15
SYNTHESIS OF
4-{2-[(4-CARBAMOYLPHENYL)AMlNO]PYRlMIDIN-4-YL}
BENZOIC ACID
Figure imgf000061_0001
DMF-acetal
Figure imgf000061_0002
Figure imgf000061_0003
Figure imgf000061_0004
A mixture of ethyl 4-acetylbenzoate (3.00 g, 15.62 mmol) and N,N- dimethylformamide dimethyl acetal (6.2 g, 52.10 mmol) was refluxed for 18 hours, cooled and concentrated to give ethyl 4-[(2E)-3-(dimethylamino)prop-2-enoyl]benzoate quantitatively. A solution of ethyl 4-[(2E)-3-(dimethylamino)prop-2-enoyl]benzoate, potassium carbonate (3.55 g, 25.74 mmol), and 4-(amidinoamino)benzamide (3.10 g, 12.87 mmol) in ETOH (120 mL) was refluxed for 18 hours. The mixture was cooled, filtered, and washed with ETOH, water, then ether respectively to give ethyl 4-{2-[(4- carbamoylphenyl)amino]pvrimidin-4-yl}benzoate (2.60 g, 46 % yield). This compound was refluxed for 2 hours in ETOH (30 mL), water (20 mL), and NaOH (0.640 g, 16 mmol). The reaction mixture was cooled, acidified to pH 3, and filtered to give 1.00 gram (42 % yield) of the titled compound. HPLC/ES-MS (20-100% acetonitrile): R.T. 4.7 min.(Method A) • (m/z) 335 [M+ If.
EXAMPLE 16
SYNTHESIS OF
(4.{[4-(4-CHLOROPHENYL)PYRΓMΓDΓN-2-YL]AMINO}
PHENΎL)-N,N-DΓMETHYL CARBOXAMΓDE
Figure imgf000063_0001
Figure imgf000063_0002
Figure imgf000063_0003
Figure imgf000063_0004
4-Guanidino-benzoic Acid Methyl Ester
To a stirred suspension of 4-guanidino benzoic acid (20. Og, 93mmol) in methanol (600mL) was added thionyl chloride (12mL) drop wise. The reaction mixture was stirred at room temperature overnight. The reaction was concentrated in vacuo to give a white powder. The crude material was dissolved in dichloromethane and evaporated to provide the title compound as a white powder (17.95g, 100% yield): HPLC Retention Time; 1.27 min (Method A). M+1; 193.
f 2E -3-Dimethylamino- 1 -f 4-chlorophenyl)prop-2-en- 1 -one A solution of 1 -(4-chlorophenyl)ethane- 1 -one (35. Og, 226 mmol) and N, N
Dimethylformamide diisopropylacetal (35mL) was heated to reflux for 16 hours. The reaction mixture was cooled to room temperature and treated with hexanes (50mL). The resulting solid was collected via filtration and washed with hexanes to provide the title compound as a yellow solid (47.12g, 99% yield): HPLC Retention Time; 6.45 min (Method B). M+1; 209.
4-[4-(4-CholorophenylVpyrimidm-2-ylamino"lbenzoic Acid
A Solution of 4-guanidino-benzoic acid methyl ester (17.95g, 93mmol), (2E) 3-dimethylamino-l-(4-chlorophenyl)prop-2-en-l-one (19.44g, 93mmol, and potassium carbonate (38.50g, 279mmol) in 1-propanol was heated to reflux for 24 hours. The reaction mixture was cooled to room temperature. The resulting solid was collected via filtration and washed with ethanol to provide the title compound which was used without further purification. El MS(m/z) 339 [M+l]+. To a suspension of 4-[4-(4-chlorophenyl)- pyrimidin-2-ylamino]benzoic acid methyl ester in methanol (lOOmL) was added 5NNaOH (lOOmL). The reaction mixture was heated to reflux for 4 hours and then cooled to room temperature. The resulting solid was collected via filtration, washed with hexanes, and dried in vacuo to provide the title compound as a yellow solid (27.36g, 100%) yield): HPLC Retention Time; 7.29 min (Method A). M+1; 325.
(4-{[4-(4-Chlorophenyl -pyrimidin-2-yl1amino|phenyl -N,N-dimethyl carboxamide
To 4-{[4-(4-chlorophenyl)pyrimidin-2-yl]amino} benzoic acid (200 mg, 0.615 mmol) is added thionyl chloride (4 mL) along with a catalytic amount of DMF at room temperature. The resulting suspension is then refluxed for a period of 1 hour resulting in a clear pale yellow solution which was concentrated in vacuo. To the flask was then added a solution of dimethylamine (615 μL of a 2.0 M solution in THF, 1.23 mmol) and triethylamine (124 mg, 1.23 mmol) in tetrahydrofuran (4.5 mL). The solution was then stirred for 18 hours at room temperature, diluted with water (5 mL) and filtered. Purification of the remaining solid by preparative HPLC yielded the title compound. HPLC/ES-MS: RT 6.74 min.(Method A); (m/z) 353 [M+l]+.
EXAMPLE 17 SYNTHESIS OF FURTHER REPRESENTATIVE COMPOUNDS
Figure imgf000065_0001
Compounds listed below were prepared according to the above procedure:
Figure imgf000065_0002
Figure imgf000066_0001
Figure imgf000067_0001
2004/084901
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
2004/084901
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
35
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
2004/084901
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
30
35
Figure imgf000094_0001
Figure imgf000095_0001
2004/084901
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
2004/084901
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
2004/084901
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
2004/084901
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
0
5
0
5
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
35 ■■-■\ I! •■' '',l ■*""""
Figure imgf000119_0001
30
35 2004/084901
Figure imgf000120_0001
Figure imgf000121_0001
EXAMPLE 18
SYNTHESIS OF 4-{[4-(4-CHLOROPHENYL)PYRTMIDIN-2-YL]AMINO}BENZOIC
ACID PIPERAZINE AMIDE HYDROCHLORIDE
Figure imgf000122_0001
HCl
Figure imgf000122_0002
R1 = 4-c lorophenyl
Hydrogen chloride gas was bubbled slowly in a solution of tert-butyl 4~{[4- (4-chlorophenyl)pyrimidin-2-yl]amino}benzoic acid piperazine amide (3.0 g, 6.1 mmol) in acetic acid (61 L) for 20 minutes. The solution was concentrated and dried on a vacuum pump to give 2.6 g (99%) of the title compound; ES-MS, m/z 394 (M+l)+ LC/MS Retention Time, 5.84 min.(Method A).
EXAMPLE 19 SYNTHESIS OF 4-{[4-(4-CHLOROPHENYL)PYRlMIDIN-2-YL]AMINO}BENZOIC
ACID 4-ETHYL PIPERAZINE AMIDE
Figure imgf000122_0003
A solution of 4- {[4-(4-chlorophenyl)pyrimidin-2-yl] amino} phenyl piperazine ketone (0.5 g, 1.54 mmol), N-ethylpiperazine (0.18 g, 1.54 mmol), l-(3- dimethylaminopropyl)-3 -ethyl carbodiimide hydrochloride (0.44 g, 2.31 mmol) and hydroxybenzotriazole (0.31 g, 2.31 mmol) in dimethylformamide (15 mL) was stirred for 18 h. Water (50 mL) was added and the solid was filtered. The solid was purified on preparatory HPLC (C-18 column, 30%) acetonitrile to 100% acetonitrile in water-both containing 0.1 % trifluoracetic acid) to give the titled compound, 0.27 g (42%) yield; ES- MS, m/z 422 (M+l)+ LC/MS Retention Time, 5.92 min.(Method A).
EXAMPLE 20
SYNTHESIS OF 4-ACYLAMΓNOPIPERIDΓNES
Figure imgf000123_0001
Figure imgf000123_0002
4-Aminopiperidyl 4- j[4-f4-chlorophenyDpyrimidin-2-yl]amino}phenyl Ketone Hydrochloride
(tert-Butoxy)-N- { 1 -[(4- { [4-(4-chlorophenyl)pyrimidin-2- yl]amino}phenyl)carbonyl](4-piperidyl)}carboxamide (4.00g, 7.87 mmol) was stirred in 50 mL EtOH followed by addition of anhydrous HCl gas. The reaction was stirred for 30 min. then concentrated down to a residue. To this was added a small amount of EtOH followed by dilution with ether. A yellow solid formed which was filtered and dried to give 3.00 grams of 4-aminopiperidyl 4-{[4-(4-chlorophenyl)pyrimidin-2-yl]amino}phenyl ketone hydrochloride: HPLC Retention time; 5.89 min. (Method B) M+1; 408.4
N-(l-[r4-(r4-r4-ChlorophenvDpyrimidin-2-yllamino|phenyl)carbonyl]-4- piperidyl) acetamide
Stirred 4-aminopiperidyl 4-{[4-(4-chlorophenyl)pyrimidin-2- yl] amino} phenyl ketone hydrochloride (300 mg , 0.582 mmol) in 10 mL THF with triethylamine (0.293 mg , 2.91 mmol). Acetic anhydride (89 mg , 0.873 mmol) was added and the reaction was stirred for 40 minutes. The solution was concentrated down and purified by preperative HPLC to give N- { 1 - [(4- { [4-(4-chlorophenyl)pyrimidin-2- yl]amino}phenyl)carbonyl]-4-piperidyl}acetamide (0.120 g , 46 % yield): HPLC Retention time; 6.92 min. (Method B) M+1; 450.4
Compounds listed below were prepared according to the above procedure.
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
EXAMPLE 21 SYNTHESIS OF PPERAZTNEACETIC ACID AMIDES
Figure imgf000127_0001
Figure imgf000127_0002
Figure imgf000127_0003
Ethyl 2- {4-[(4- {[4f4--Chlorophenyl pyrimin-2-yl]amino|phenyl) carbonyl] piperazinyl} acetate
4-{[4-(4-chlorophenyl)pyrimidin-2-yl]amino}benzoic acid (5g, 15.3 mmol) was dissolved in dimethylformamide. The HOBT(2.82 g, 18.4 mmo)] and EDCI(3.53 g, 18.4 mmol) were then added. The reaction stirred for 15 minutes then ethyl-2- piperazinylacetate (2.14 mL, 18.4 mmol) was added. The reaction was stirred overnight at room temperature. Water (150 mL) was added. The solid was collected by filtration, and purified by silica-gel column chromatography (90% EtOAc/Hexane, Rt=0.25) to yield 4.3 g (45%o yield) of ethyl 2-{4-[(4-{[4(4-chlorophenyl)pyrimin-2- yl]amino}phenyl)carbonyl]piρerazinyl} acetate: HPLC Retention time; 9.932 min. (Method B) M+1; 480.2
2- (4- \(4- 1 [4-(4-ChlorophenvDpyrmτidin-2-yl] amino Iphenv carbonyl] piperazinyl) acetic Acid
To ethyl 2-{4-[(4-{[4(4-chlorophenyl)pyrimin-2-yl]amino}phenyl) carbonyl]piperazinyl} acetate (5.0 g, 15.3 mmol) was added ethanol (69 mL) and NaOH (1.14 g, 29.2 mmol, 4.1 eq) in 46 mL water. The reaction was heated at 75°C for 1.5 hours. The reaction was acidified to pH=3, filtered, and dried, affording 4.3g of the acid 2-{4-[(4- {[4-(4-chlorophenyl)pyrimidin-2-yl]amino}phenyl)carbonyl]piperazinyl} acetic acid (83.3%): HPLC Retention time; 9.260 min. (Method B) M+1; 452.3
2-(4- (4-{ 4-(4-ChlorophenyDpyrimidin-2-yl]amino phenvDcarbonyl]piperazinyl}N- ethylacetamide
2- {4-[(4- {[4-(4-Chlorophenyl)pyrimidin-2-yl]amino}phenyl) carbonyl]piperazinyl} acetic acid (0.200 g, 0.44 mmol) was dissolved in DMF then stirred for 15 minutes in ice-brine solution, then the HOBT (0.072 g, 0.53 mmol] then EDCI(0.102 g, 0.53 mmol) were added and stirred for another 30 minutes. Ethylamine (0.030 mL, 0.53 mmol) was added and the reaction was left to stir at room temp overnight. The reaction was quenched with 10 mL of water and a precipitate formed. The precipitate was colleted by filtration, and purified by preparative HPLC to yield 2- {4-[(4- {[4-(4- chlorophenyl)pyrimidin-2-yl]amino}phenyl)carbonyl]piperazinyl}N-ethylacetamide: HPLC Retention time; 9.508 min.(Method B) M+1; 479.2
Compounds listed below were prepared according to the above procedure. O 2004/084901
Figure imgf000129_0001
2004/084901
Figure imgf000130_0001
EXAMPLE 22 REDUCTIVE AMINATION
Figure imgf000131_0001
Figure imgf000131_0002
HCl
4- 1 [4-(4-chlorophenyl pyrimidin-2-yl] amino I phenyl 4-[(methylethyDamino]piperidyl ketone hydrochloride l-[(4-{[4-(4-chlorophenyl)pyrimidin-2yl]amino}phenyl)carbonyl]piperidin-4- one (400 mg, 0.980 mmol) was dissolved in 10 mL EtOH along with isopropylamine (58 mg , 0.980 mmol). Sodium cyanoborohydride (62 mg , 0.986 mmol) was added and the mixture was stirred at room temperature for 18 hours. The reaction was quenched with water , extracted with ethyl acetate followed by flash chromatography (EtOAc / MeOH ; 90 : 10) to give a residue. This was taken up in ETOH saturated with HCl(g) , diluted with ether, filtered to give 4- {[4-(4- chlorophenyl)pyrimidin-2-yl] amino} phenyl 4-[(methylethyl)amino]piperidyl ketone hydrochloride (0.150 g, 30 % yield): HPLC Retention time; 6.02 min. (Method B) M+1; 450.4.
Compounds listed below were prepared according to the above procedure. Compound Structure MW RT, min M+1 Number
22-1 522.905 6.02 450.4
22-2 490.0478 10.612 490.3
22-3 465.9822 9.644 466.3
22-4 465.9822 9.604 466.3
22-5 465.9822 9.52 466.4
Figure imgf000132_0001
084901
Figure imgf000133_0001
Figure imgf000134_0001
EXAMPLE 23 SYNTHESIS OF REVERSE SULFONAMIDES
Figure imgf000135_0001
Figure imgf000135_0002
NaOMe/MeOH
Figure imgf000135_0003
Figure imgf000135_0004
Figure imgf000135_0005
pyridine
Figure imgf000135_0006
(2E)- 1 -f 4-nitrophenviy 3 -dimethylamino prop-2-en- 1 -one
A mixture of 4-nitroacetophenone (20.0 g, 121 mmol) and N,N~ dimethylformamide dimethylacetal (200 ml) was refluxed for 18 hours, cooled and concentrated to give (2E)-l-(4-nitrophenyl)-3-dimethylamino)prop-2-en-l-one quantitatively.
l-Acetyl-4-r(4-(["4-f4-nitrophenyl)pyrimidin-2-yl>ammo}phenyDcarbonyl}piperazine
To a mixture of (2E)-l-(4-nitrophenyl)-3-dimethylamino)prop-2-en-l-one (250 mg, 1.14 mmol) and {4- {(4-acetylpiperazinyl)carbonyl]phenyl} aminocarboxamidine (394 mg, 1.36 mmol) in methanol (6 ml) is added 2 mL of a 2.0M solution of sodium methoxide in methanol. The reaction mixture is then refluxed for 18 hours then acidified to pH ~ 4 using IN HCl. The solid which formed at this time was then flitered and purified by column chromatography using 10% methanol in chloroform to give 320 mg (69%) of the desired product.
l-Acetyl-4-[f4-( 4- 4-aminophenvDpyrimidin-2-yl|aminolphenyl carbonyl}piperazine
To a solution of l-acetyl-4-[(4-{[4-(4-nitrophenyl)pyrimidin-2- yl}amino}phenyl)carbonyl}piperazine (150 mg, 0.34 mmol) in methanol (5mL) containing a few drops of acetic acid, is added 100 mg of 10%> Palladium-Charcoal. The solution is then hydrogenated at 50 psi for 6h at which time there remains no starting material. The solution is then filtered through a pad of Celite which gives 135 mg (95%>) of essentially pure reduced material as a brown oil.
l - A c etyl - 4 - { [" 4 - ( { 4 - [4 - (ph enyl s ulfonyl) aminophenyl ]pyrimi din- 2 - yl|ammo phenyl]carbonyl}piperazine To a solution of l-acetyl-4-[(4-{[4-(4-aminophenyl)pyrimidin-2- yl}amino}phenyl)carbonyl}piperazine (100 mg, 0.24 mmol) in pyridine (5 mL) containing a catalytic amount of DMAP is added benzenesulfonyl chloride (50 mg, 0.29 mmol) and the solution is stirred overnight at room temperature. The pyridine is removed under vacuum and the residue extracted into methylene chloride and washed with IN HCl. Evaporation of solvent provides the crude piperazine which is purified by preparative HPLC (10-60% CH3CN over 25 min.)to give an analytically pure sample as a yellow solid: M+1; 557.3. HPLC Retention Time; 9.59 min (Method B). Compounds listed below were prepared according to the above procedure.
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
O 2004/084901
23-26 623.6911 9.2 624.5
23-27 528.6342 5.92 529.3
Figure imgf000141_0001
EXAMPLE 24 SYNTHESIS OF FURTHER REPRESENTATIVE COMPOUNDS
Figure imgf000141_0002
RaCOOH EDCI, HOBT
Figure imgf000141_0003
The compounds of Example 18, with the desired Rj moiety, may be modified according to the above procedures to yield further representative compounds of this invention. For example, the following compounds were made according to the above procedures.
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0001
2004/084901
Figure imgf000147_0001
2004/084901
Figure imgf000148_0001
Figure imgf000149_0001
Figure imgf000150_0001
Figure imgf000151_0001
2004/084901
Compound Number Structure MW RT, min M+1
24-43 502.9597 7.27 503.4
24-44 533.0535 7.19 533.2
24-45 488.9329 7.09 489.4
24-46 588.4076 3.25 478.3
24-47 515.0143 7.16 515.4
Figure imgf000152_0001
EXAMPLE 25 SYNTHESIS OF SULFIDES
Figure imgf000153_0001
Figure imgf000153_0002
K2C03 , nPrOH, reflux
Figure imgf000153_0003
then NaOH (aq)
Figure imgf000153_0004
3-Dimethylamino- 1 -[4-(4-hydroxybutylsulfanyDphenyl]propenone
To a stirred solution of 4-hydroxybutanethiol (5.0g, 47 mmol) in DMF (100 mL) was added NaH (60% dispersion in mineral oil, 2.1g). After the effervescence had ceased, p- chloroacetophenone (4.3 mL, 33 mmol) was added. The solution was then stirred at 110°C for 3 h. The mixture was cooled to RT and then diluted with ether (200 mL). The ethereal suspension was washed with 5% HCl (aq, 2 x 100 mL), water (100 mL), and then brine (50 mL). The ether extract was dried (MgSO4), filtered and concentrated to afford crude l-[4-(4- hydroxybutylsulfanyl)phenyl]ethanone, which was used without purification. l-[4-(4- hydroxybutylsulfanyl)phenyl] ethanone was taken up in dimethylformamide dimethylacetal (100 mL) and stirred at reflux for 12h. The mixture was cooled and then concentrated to about one half of the original volume. Hexane was added to precipitate 3-Dimethylamino-l-[4-(4- hydroxybutylsulfanyl)phenyl]propenone. The mixture was filtered, washed with hexanes (50 mL), and dried to afford 3-Dimethylamino-l-[4-(4-hydroxy-butylsulfanyl)phenyl]propenone (6.4g, 23 mmol): HPLC Retention Time; 5.58 min. (Method B) M+1; 279.8.
4-(4-[4-(4-HvdroxybutylsulfanyDphenyllpyrimidin-2-ylaminoibenzoic Acid
3-Dimethylamino-l -[4-(4-hydroxybutylsulfanyl)-phenyl]propenone (6.4g, 23 mmol) was,then taken up in «PrOH (150 mL). To this solution was added 4-guanidinobenzoic acid, methyl ester, hydrochloride salt (1.1 equiv, 5.4 g) and K2CO3 (3 equiv, 9.5 g). The mixture was stirred at reflux for 24 h. After this time, 10% NaOH (aq, 50 mL) was added, and the mixture was stirred at reflux for another 1 h. The mixture was then cooled to RT and concentrated to about half of the original volume. The pH of the mixture was then adjusted to pH 4-5 to 4-{4-[4-(4-Hydroxybutylsulfanyl)phenyl]pyrimidin-2-ylamino}benzoic acid. The acid was immediately filtered and washed with water (50 mL), cold EtOH (50 mL), and then dried (8.6 g, 21 mmol, 88%): HPLC Retention Time; 6.37 min. (Method B) M+1; 396.0.
[4-('Furan-2-carbonyl piperazin-l-yl]-(4-{4-[4-(4-hydroxybutylsulfanyl)phenyl]pyrimidin-2- ylamino I phenyDmethanone
4-{4-[4-(4-Hydroxybutylsulfanyl)phenyl]pyrimidin-2-ylamino}benzoic acid (0.34 g, 0.86 mmol) was dissolved in THF (5 mL). To this solution was added 1- furoylpiperazine (0.170 g), EDCI (0.180 g), and HOBt (0.127 g). The mixture was stirred 12h. The mixture was then diluted with CH2C12 (20 mL) and washed with 2% NaOH (aq, 30 mL), water (30 mL), and then brine (30 mL). The organic layer was dried (TM^SO^, filtered, and concentrated. The crude solid was subjected to preparatory HPLC (30 - 80 acetonitrile/water gradient, 20 min). The desired fractions were concentrated to remove most of the acetonitrile, and then the aqueous mixture was extracted with CH2Cl2/2% NaOH (aq). The organic layer was dried (Na^O^, filtered, and concentrated to afford [4-(Furan-2-carbonyl)-piperazin-l-yl]- (4- {4-[4-(4-hydroxybutylsulfanyl)phenyl]pyrimidin-2-ylamino}phenyl)methanone (0.042 g, 9%): HPLC Retention Time; 10.07 min. (Method B) M + H = 558.3.
Compounds listed below were prepared according to the above procedure.
Figure imgf000155_0001
Figure imgf000156_0001
Figure imgf000157_0001
/084901
Figure imgf000158_0001
Figure imgf000159_0001
Figure imgf000160_0001
/084901
Figure imgf000161_0001
EXAMPLE 26 SYNTHESIS OF SULFONAMIDES
Figure imgf000162_0001
Figure imgf000162_0002
Figure imgf000162_0003
l-r4-fMo holine-4-sulfonvDphenyl]ethanone
To a suspension of 4-acetylbenzenesulfonyl chloride (5.5 g, 25 mmol) in CH2C12 (75 mL) and Et3N (2 equiv, 7.0 mL, 50 mmol) was added morpholine (1.5 equiv, 3.3 mL, 38 mmol) dropwise. The mixture was stirred at room temperature for 30 min. The mixture was then diluted with CH2C12 (100 mL) and washed with 5% HCl (2 x 50 mL), water (50 mL), and then brine (50 mL). The organic layer was dried (Na^O^, filtered, and concentrated to afford crude l-[4-(morpholine-4-sulfonyl)phenyl]ethanone (2) (4.78g, 18 mmol, 71%): HPLC Retention Time; 5.82 min. (Method B) M+1, 270.0.
4-(4-["4-(Mo holine-4-sulfonylVphenyl]-pyrimidin-2-ylamino|benzoic Acid Crude l-[4-(morpholine-4-sulfonyl)phenyl]ethanone (4.78g, 18 mmol) was suspended in dimethyformamide dimethylacetal (50 mL) and refluxed for 12 h. The reaction was allowed to cool and the mixture was concentrated to about half of the original volume. The solution was then titurated with hexanes to precipitate the eneamino ketone intermediate. The eneamino ketone was filtered and washed with hexanes (2 x 50 mL), dried under vacuum, and then taken up in πPrOH (150 mL). To this solution was added added 4-guanidinobenzoic acid, methyl ester, hydrochloride salt (1.1 equiv, 3.7 g) and K2CO3 (3 equiv, 6.4 g). The mixture was stirred at reflux for 24 h. After this time, 10% NaOH (aq, 50 mL) was added, and the mixture was stirred at reflux for another 1 h. The mixture was then cooled to RT and concentrated to about half of the original volume. The pH of the mixture was then adjusted to pH 4-5 to precipitate the acid. 4- {4-[4-(morpholine-4-sulfonyl)phenyl]pyrimidin-2-ylamino}benzoic acid was immediately filtered and washed with water (50 mL), cold EtOH (50 mL), and then dried
(4.6 g, 10.5 mmol, 68%): HPLC Retention Time; 6.6 min. (Method B) M+1, 441.0.
r4-(Furan-2-carbonyl -piperazin-l-yl](4-{4- 4-(moφholine-4-sulfonv phenyl]pyrimidin-2- ylamino I phenyPmethanone
4- {4- [4-(Morpholine-4-sulfonyl)-phenyl] -pyrimidin-2-ylamino } -benzoic acid (0.25 g, 0.57 mmol) was dissolved in THF (5 mL). To this solution was added 1- furoylpiperazine (0.123 g), EDCI (0.131 g), and HOBt (0.092 g). The mixture was stirred 12h. The mixture was then diluted with CH2C12 (20 mL) and washed with 2% NaOH (aq, 30 mL), water (30 mL), and then brine (30 mL). The organic layer was dried (Na^O^, filtered, and concentrated. The crude solid was subjected to preparatory HPLC (20 - 70 acetonitrile/water gradient, 20 min). The desired fractions were concentrated to remove most of the acetonitrile, and then the aqueous mixture was extracted with CH2Cl2/2% NaOH (aq). The organic layer was dried (Na^O^), filtered, and concentrated to afford [4-(furan-2-carbonyl)piperazin- 1 -yl] (4- {4-[4-(morpholine-4-sulfonyl)-phenyl]pyrimidin-2-ylamino}phenyl)methanone (0.177 g, 52%): HPLC Retention Time; 9.62 min. (Method B) M + H = 603.3 Compounds listed below were prepared according to the above procedure.
Figure imgf000164_0001
Figure imgf000165_0001
Figure imgf000166_0001
84901
Figure imgf000167_0001
Figure imgf000168_0001
Figure imgf000169_0001
Figure imgf000170_0001
Figure imgf000171_0001
Figure imgf000172_0001
Figure imgf000173_0001
Figure imgf000174_0001
Figure imgf000175_0001
Figure imgf000176_0001
Figure imgf000177_0001
Figure imgf000178_0001
Figure imgf000179_0001
O 2004 0
EXAMPLE 27 SYNTHESIS OF SULFONES
Figure imgf000180_0001
p-chloroacetophenone
Figure imgf000180_0002
then NaOH (aq)
Figure imgf000180_0003
l-["4- Tetrahvdropyran-4-sulfanyl phenyl]ethanone
To a stirred solution of NajS (17.4 g, 0.22 mol) in water (26 mL) was added CS2 (14.7 mL, 0.24 mol). The mixture was stirred at 60 - 70°C for 6h. To the resultant red solution of Na2CS3 was added 4-chlorotetrahydropyran (0.074 mol). The mixture was stirred for 12h at 60 - 70°C. The mixture was then cooled to ~10°C. H2SO4 (cone.) was added to the mixture dropwise with stirring until a cloudy yellow color persisted. The mixture was then extracted with CH2C12 (3 x 50 mL). The aqueous layer was discarded and the CH2C12 layer was dried (Na^O^, filtered, and concentrated. The crude thiol (47.5 mmol, -64%) was dissolved in DMF (100 mL) and treated with NaH (1.9g, 48 mmol). After the effervescence had ceased, ?-chloroacetophenone (4.3 mL, 33 mmol) was added. The solution was then stirred at 110°C for 3 h. The mixture was cooled to RT and then diluted with ether (200 mL). The ethereal suspension was washed with 5% HCl (aq, 2 x 100 mL), water (100 mL), and then brine (50 mL). The ether extract was dried (MgSO4), filtered and concentrated to afford crude l-[4-(tetrahydro-pyran-4-sulfanyl)-phenyl]-ethanone 1, which was purified by chromatography (SiO2, 9:1 hex/EtOAc) to afford pure l-[4- (tetrahydropyran-4-sulfanyl)phenyl]ethanone 1 (7.4 mmol, 16% from 4- chlorotetrahydropyran): HPLC Retention Time; 5.41 min. (Method B) M+1; 269.0.
3-Dimethylamino-l-[4-('tetrahvdropyran-4-sulfonyl phenyl]propenone l-[4-(Tetrahydro-pyran-4-sulfanyl)-phenyl]-ethanone 1 (7.4 mmol) was dissolved in acetone/water (9:1 v/v, 100 mL). Oxone® (2.1 equiv, 9.1 g) was added to the solution. The reaction was stirred at room temperature for 5h. The mixture was filtered and the majority of acetone was removed in vacuo. The solution was then diluted with water (50 mL) and extracted with CH2C12 (3 x 50 mL). The organic layer was dried (Na^SO , filtered, and concentrated to afford the intermediate tetrahydropyranyl sulfone, which was taken up in dimethylformamide dimethylacetal (100 mL) and stirred at reflux for 12h. The mixture was cooled and then concentrated to about one half of the original volume. Hexane was added to precipitate eneamino ketone intermediate. The mixture was filtered, washed with hexanes (50 mL), and dried to afford 3-dimethylamino-l-[4-(tetrahydro-pyran-4- sulfonyl)-phenyl]-propenone (2.2g, 7 mmol): HPLC Retention Time; 5.18 min. (Method B) M+1; 324.0.
4-{4-["4-(Tetrahydropyran-4-sulfonylVphenyl]pyrimidin-2-ylaminolbenzoic Acid
3-Dimethylamino-l-[4-(tetrahydro-pyran-4-sulfonyl)-phenyl]-propenone was then taken up in røPrOH (80 mL). To this solution was added 4-guanidinobenzoic acid, methyl ester, hydrochloride salt (1.1 equiv, 1.7 g) and K2CO3 (3 equiv, 2.9 g). The mixture was stirred at reflux for 24 h. After this time, 10% NaOH (aq, 50 mL) was added, and the mixture was stirred at reflux for another 1 h. The mixture was then cooled to RT and concentrated to about half of the original volume. The pH of the mixture was then adjusted to pH 4-5 to precipitate 4- {4-[4-(tetrahydro-pyran-4-sulfonyl)-phenyl]-pyrimidin-2- ylamino} -benzoic acid 4. The acid was immediately filtered and washed with water (50 mL), cold EtOH (50 mL), and then dried (2.4 g, 5.5 mmol, 79% yield): HPLC Retention Time; 6.07 min. (Method B) M+1; 593.3.
4-('3-Dimethylamino-propylVpiperazin- 1 -yl]-(4- (4-[4-ftetrahydropyran-4- sulfonvDphenyl]pyrimidin-2-ylamino } phenyDmethanone
4-{4-[4-(Tetrahydropyran-4-sulfonyl)-phenyl]pvrimidin-2-ylamino}benzoic acid 4 (0.26 g, 0.6 mmol) was dissolved in THF (5 mL). To this solution was added 1- (N,N-dimethylaminopropyl)piperazine (0.130 g), EDCI (0.136 g), and HOBt (0.096 g). The mixture was stirred 12h. The mixture was then diluted with CH2C12 (20 mL) and washed with 2% NaOH (aq, 30 mL), water (30 mL), and then brine (30 mL). The organic layer was dried (Na^O , filtered, and concentrated. The crude solid was subjected to preparative HPLC (20 - 70 acetonitrile/water gradient, 20 min). The desired fractions were concentrated to remove most of the acetonitrile, and then the aqueous mixture was extracted with CH2Cl2/2% NaOH (aq). The organic layer was dried (Na^O , filtered, and concentrated to afford [4-(3-dimethylamino-propyl)piperazin-l-yl]-(4-{4-[4- (tetrahydropyran-4-sulfonyl)phenyl]pyrimidin-2-ylamino}phenyl)methanone 5 (0.079 g, 22%): HPLC Retention Time; 7.93 min. (Method B) M + 1 = 593.3
Compounds listed below were prepared according to the above procedure.
Compound Structure MW RT, min M+1
Number
27-1 612.664 10.25 595.3
Figure imgf000182_0001
Figure imgf000183_0001
Figure imgf000184_0001
Figure imgf000185_0001
Figure imgf000186_0001
Figure imgf000187_0001
27-20 584.741 8.692 585.2
27-21 528.63 10.648 529.2
27-22 458.54 11.44 458.9
Figure imgf000188_0001
EXAMPLE 28 ASSAYS FOR MEASURING ACTIVITY OF COMPOUNDS
The Anilinopyrimidine Derivatives may be assayed for their activity according to the following procedures.
JNK2 Assay
To 10 μL of the test compound in 20% DMSO/80% dilution buffer consisting of 20 mM HEPES (pH 7.6), 0.1 mM EDTA, 2.5 mM magnesium chloride, 0.004% Triton xlOO, 2 μg/mL leupeptin, 20 mM β-glycerolphosphate, 0.1 mM sodium vanadate, and 2 mM DTT in water is added 30 μL of 50 ng His6-JNK2 in the same dilution buffer. The mixture is preincubated for 30 minutes at room temperature. Sixty microliter of 10 μg GST-c-Jun(l-79) in assay buffer consisting of 20 mM HEPES (pH 7.6), 50 mM sodium chloride, 0.1 mM EDTA, 24 mM magnesium chloride, 1 mM DTT, 25 mM PNPP, 0.05% Triton xlOO, 11 μM ATP, and 0.5 μCi γ-32P ATP in water is added and the reaction is allowed to proceed for 1 hour at room temperature. The c-Jun phosphorylation is terminated by addition of 150 μL of 12.5% trichloroacetic acid. After 30 minutes, the precipitate is harvested onto a filter plate, diluted with 50 μL of the scintillation fluid and quantified by a counter. The IC50 values are calculated as the concentration of the test compound at which the c-Jun phosphorylation is reduced to 50% of the control value. Preferred compounds of the present invention have an 1C50 value ranging 0.01 - 10 μM in this assay.
JNK3 Assay
To 10 μL of the test compound in 20% DMSO/80% dilution buffer consisting of 20 mM HEPES (pH 7.6), 0.1 mM EDTA, 2.5 mM magnesium chloride, 0.004% Triton xlOO, 2 μg/mL leupeptin, 20 mM β-glycerolphosphate, 0.1 mM sodium vanadate, and 2 mM DTT in water is added 30 μL of 200 ng His6-JNK3 in the same dilution buffer. The mixture is preincubated for 30 minutes at room temperature. Sixty microliter of 10 μg GST-c-Jun(l-79) in assay buffer consisting of 20 mM HEPES (pH 7.6), 50 mM sodium chloride, 0.1 mM EDTA, 24 mM magnesium chloride, 1 mM DTT, 25 mM PNPP, 0.05% Triton xlOO, 11 μM ATP, and 0.5 μCi γ-32P ATP in water is added and the reaction is allowed to proceed for 1 hour at room temperature. The c-Jun phosphorylation is terminated by addition of 150 μL of 12.5% trichloroacetic acid. After 30 minutes, the precipitate is harvested onto a filter plate, diluted with 50 μL of the scintillation fluid and quantified by a counter. The IC50 values are calculated as the concentration of the test compound at which the c-Jun phosphorylation is reduced to 50% of the control value. Preferred compounds of the present invention have an IC50 value ranging 0.01 - 10 μM in this assay.
Jurkat T-cell 11-2 Production Assay
Jurkat T cells (clone E6-1) are purchased from the American Tissue Culture Collection and maintained in growth media consisting of RPMI 1640 medium containing 2 mM L-glutamine (Mediatech), with 10% fetal bovine serum (Hyclone) and penicillin/streptomycin. All cells are cultured at 37°C in 95% air and 5% CO2. Cells are plated at a density of 0.2 x 106 cells per well in 200 μL of media. Compound stock (20 mM) is diluted in growth media and added to each well as a 1 Ox concentrated solution in a volume of 25 μl, mixed, and allowed to pre-incubate with cells for 30 minutes. The compound vehicle (dimethylsulfoxide) is maintained at a final concentration of 0.5%0 in all samples. After 30 minutes the cells are activated with PMA (phorbol myristate acetate; final concentration 50 ng/niL) and PHA (phytohemagglutinin; final concentration 2 μg/mL). PMA and PHA are added as a 1 Ox concentrated solution made up in growth media and added in a volume of 25 μL per well. Cell plates are cultured for 10 hours. Cells are pelleted by centrifugation and the media removed and stored at -20 °C. Media aliquots are analyzed by sandwich ELISA for the presence of IL-2 as per the manufacturers instructions (Endogen). The IC50 values are calculated as the concentration of the test compound at which the 11-2 production was reduced to 50% of the control value. Preferred compounds of the present invention have an IC50 value ranging 0.1 - 30 μM in this assay.
Rat in vivo LPS-induced TNF-α Production Assay
Male CD rats procured from Charles River Laboratories at 7 weeks of age are allowed to acclimate for one week prior to use. A lateral tail vein is cannulated percutaneously with a 22-gage over-the-needle catheter under brief isoflurane anesthesia. Rats are administered test compound either by intravenous injection via the tail vein catheter or oral gavage 15 to 180 min prior to injection of 0.05 mg/kg LPS (E. Coli 055 :B5). Catheters are flushed with 2.5 mL/kg of normal injectable saline. Blood is collected via cardiac puncture 90 minutes after LPS challenge. Plasma is prepared using lithium heparin separation tubes and frozen at -80°C until analyzed. TNF-α levels are determined using a rat specific TNF-α ELISA kit (Busywork). The ED50 values are calculated as the dose of the test compound at which the TNF-α production is reduced to 50% of the control value. Preferred compounds of the present invention have an ED30 value ranging 1-30 mg/kg in this assay.
Detection of Phosphorylated c-Jun Human umbilical vein endothelial cells (HUVEC) are cultured to 80% confluency and then pre-treated with compound (30 μM) at a final concentration of 0.5% DMSO. After 30 minutes, cells are stimulated with TNFα (30 ng/ml) for 20 minutes. Cells are washed, scraped from the plate, lyzed with 2x Laemmli buffer and heated to 100°C for 5 minutes. Whole cell lysate (approx. 30 μg) is fractionated on Tris-glycine buffered 10% SDS-polyacrylamide gels (Novex, San Diego, CA) and transferred to nitrocellulose membrane (Amersham, Piscataway, NJ). Membranes are blocked with 5% non-fat milk powder (BioRad, Hercules, CA) and incubated with antibody to phospho-cJun (1:1000 #91645) (New England Biolabs, Beverly, MA) and then donkey anti-rabbit horse radish peroxidase conjugated antibody (1 :2500) (Amersham) in phosphate buffered saline with 0.1%) Tween-20 and 5% non-fat milk powder. Immunoreactive proteins are detected with chemiluminescence and autoradiography (Amersham). Compounds are selected as inhibitors of the JNK pathway if they showed greater than 50% inhibition of cJun phosphorylation at 30 μM in this assay.
EXAMPLE 29
ACTIVITY OF REPRESENTATIVE COMPOUNDS
Representative Anilinopyrimidine Derivatives were assayed for their ability to inhibit JNK2 by the assay set forth in Example 28. As noted above, preferred Anilinopyrimidine Derivatives have an IC50 value ranging 0.01 - 10 μM in this assay. To this end, Anilinopyrimidine Derivative having an IC50 value in the JNK2 Assay of 10 μM or less include Compound Nos. 1, 3-2, 3-4, 3-9, 3-10, 3-11, 3-12, 3-13, 3-14, 3-15, 3-16, 3-17, 3- 22, 3-23, 3-24, 3-25, 3-26, 3-27, 3-29, 3-30, 3-34, 3-36, 3-37, 3-40, 17-2, 17-3, 17-6, 17-18, 17-20, 17-21, 17-22, 17-23, 17-24, 17-25, 17-26, 17-27, 17-28, 17-29, 17-30, 17-31, 17-32, 17-33, 17-34, 17-35, 17-37, 17-54, 17-86, 17-91, 17-106, 17-118, 17-119, 17-121, 17-127, 17-128, 17-129, 17-130, 17-131, 17-132, 17-133, 17-134, 17-135, 17-136, 17-137, 17-139, 17-140, 17-141, 17-142, 17-143, 17-144, 17-147, 17-148, 17-149, 17-150, 17-151, 17-152, 17-153, 17-154, 17-157, 17-158, 17-159, 17-160, 17-161, 17-162, 17-163, 17-164, 17-169, 17-171, 17-190, 17-215, 18, 20-1, 20-2, 20-3, 20-4, 20-5, 20-6, 22-10, 22-11 and 25-52. Preferred compounds of this invention have an IC50 value in the JNK2 assay of 1 μM or less, and include Compound Nos. 3-2, 3-4, 3-9, 3-13, 3-14, 3-15, 3-23, 3-24, 3-25, 3-40, 17-20, 17-21, 17-22, 17-24, 17-29, 17-30, 17-31, 17-32, 17-33, 17-34, 17-37, 17-127, 17-129, 17- 137, 17-141, 17-147, 17-154, 17-169, 17-171, 17-190, 18, 20-1, 20-3, 20-4, 22-10, 22-11, and 25-52. The present invention is not to be limited in scope by the specific embodiments disclosed in the examples which are intended as illustrations of a few aspects of the invention and any embodiments which are functionally equivalent are within the scope of this invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art and are intended to fall within the appended claims.

Claims

What is claimed is:
1. A method for using a compound having the structure:
Figure imgf000192_0001
or a pharmaceutically acceptable salt thereof, wherein:
Rj is aryl or heteroaryl optionally substituted with one to four substituents independently selected from R7; R2 and R3 are the same or different and are independently hydrogen or lower alkyl; R4 represents one to four optional substituents, wherein each substituent is the same or different and independently selected from halogen, hydroxy, lower alkyl or lower alkoxy; R5 and R6 are the same or different and independently -R8, -(CH2)αC(=O)R9,
Figure imgf000192_0002
-(CH2)αC(=O)NR9(CH2)fiC(=O)R10, -(CH2)αNR9C(=O)R105
-(CH2)αNRnC(=O)NR9R10, -(CH2)αNR9R10, -(CH2)αOR9, -(CH2)αSOcR9, or -(CH2)αSO2NR9R10; or R5 and R6 taken together with the nitrogen atom to which they are attached to form a heterocycle or substituted heterocycle; R7 is at each occurrence independently halogen, hydroxy, cyano, nitro, carboxy, alkyl, alkoxy, haloalkyl, acyloxy, thioalkyl, sulfinylakyl, sulfonylalkyl, hydroxyalkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, -C(=O)OR8, -OC(=O)R8, -C(=O)NR8R9,
Figure imgf000192_0003
-NR8Rg, -
NR8C(=O)R9, -NR8C(=O)(CH2)bOR95 -NR8C(=O)(CH2)bR9, -O(CH2)bNR8R9, or heterocycle fused to phenyl; R8, Rt,, R10 and Rπ are the same or different and at each occurrence independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, aralkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl or substituted heterocyclealkyl; or R8 and R9 taken together with the atom or atoms to which they are attached to form a heterocycle or substituted heterocycle; a and b are the same or different and at each occurrence independently selected from 0, 1, 2, 3 or 4; and c is at each occurrence 0, 1 or 2, for the manufacture of a medicament for treating or preventing a metabolic condition.
2. The method of claim 1 wherein the metabolic condition is obesity.
3. The method of claim 1 wherein the metabolic condition is hereditary obesity, dietary obesity, hormone related obesity or obesity related to the administration of medication.
4. The method of claim 1 wherein the metabolic condition is Type I diabetes, diabetes insipidus, diabetes mellitus, maturity-onset diabetes, juvenile diabetes, insulin-dependant diabetes, non-insulin dependant diabetes, malnutrition-related diabetes, ketosis-prone diabetes, ketosis-resistant diabetes.
5. The method of claim 1 wherein the metabolic condition is irritable bowel syndrome, mucous colitis, ulcerative colitis, Crohn's disease, Huntington's disease, gastritis, esophagitis, pancreatitis or nephritis.
6. A method for using a compound having the structure:
Figure imgf000193_0001
or a pharmaceutically acceptable salt thereof, wherein:
Rj is aryl or heteroaryl optionally substituted with one to four substituents independently selected from R7; R2 and R3 are the same or different and are independently hydrogen or lower alkyl; R4 represents one to four optional substituents, wherein each substituent is the same or different and independently selected from halogen, hydroxy, lower alkyl or lower alkoxy;
R5 and R6 are the same or different and independently -R8, -(CH2)αC(=O)R9, -(CH2)αC θ)OR9, -(CH2)αC θ)NR9R10, -(CH2)αC(=O)NR9(CH2)6C(=O)R10, -(CH2)αNR9C(=O)R10, -(CH2)αNRnC(=O)NR9R10, -(CH2)αNR9R10, -(CH2)αOR9, -(CH2)βSOcR9, or -(CH2)αSO2N 9R10; or R5 and R6 taken together with the nitrogen atom to which they are attached to form a heterocycle or substituted heterocycle; R7 is at each occurrence independently halogen, hydroxy, cyano, nitro, carboxy, alkyl, alkoxy, haloalkyl, acyloxy, thioalkyl, sulfinylakyl, sulfonylalkyl, hydroxyalkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, -C(=O)OR8, -OC(=O)R8, -C(=O)NR8R9, -C(=O)NR8OR5, -SOcR8, -SOcNR8R9, -NR8SOcR9, -NRgR,, - NR8C(=O)R9, -NR8C O)(CH2)bOR9, -NR8C(=O)(CH2)bR9, -O(CH2)bNR8R9, or heterocycle fused to phenyl;
R8, R9, RI0 and Rπ are the same or different and at each occurrence independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, aralkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl or substituted heterocyclealkyl; or R8 and R9 taken together with the atom or atoms to which they are attached to form a heterocycle or substituted heterocycle; a and b are the same or different and at each occurrence independently selected from 0, 1, 2, 3 or 4; and c is at each occurrence 0, 1 or 2, for the manufacture of a medicament for treating or preventing otitis externa, acute otitis media, hearing loss, pulmonary interstitial fibrosis, liver fibrosis, renal fibrosis, wound-healing, burn-healing, chronic obstructive pulmonary disease, allergy, allergic rhinitis, acute respiratory distress syndrome, systemic lupus erythematosus, nephropathy, pancreatitis, peritonitis, sepsis, alcohol or toxin-induced liver disease, sclerosis, steatosis or ischemia-reperfusion injury. A method for using a compound having the structure:
Figure imgf000195_0001
rmaceutically acceptable salt thereof, wherein:
R is aryl or heteroaryl optionally substituted with one to four substituents independently selected from R7;
R2 and R3 are the same or different and are independently hydrogen or lower alkyl;
R4 represents one to four optional substituents, wherein each substituent is the same or different and independently selected from halogen, hydroxy, lower alkyl or lower alkoxy;
R5 and R6 are the same or different and independently -R8, -(CH2)αC(=O)R9, -(CH2)αC(=O)OR9, -(CH2)αC(=O)NR9R10,
Figure imgf000195_0002
-(CH2)αNR11C(=O)NR9R10, -(CH2)αNR9R10, -(CH2)αOR9, -(CH2)αSOcR9, or -(CH2)αSO2NR9R10; or R5 and R6 taken together with the nitrogen atom to which they are attached to form a heterocycle or substituted heterocycle;
R7 is at each occurrence independently halogen, hydroxy, cyano, nitro, carboxy, alkyl, alkoxy, haloalkyl, acyloxy, thioalkyl, sulfinylakyl, sulfonylalkyl, hydroxyalkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, -C(=O)OR8, -OC(=O)R8, -C(=O)NR8R9, -C(=O)NR8OR9, -SOcR8, -SOcNR8R9, -NR8SOcR9, -NRgR,, - NR8C(=O)R9, -NR8C(=O)(CH2)bOR9, -NR8C(=O)(CH2)bR9, -O(CH2)bNR8R9, or heterocycle fused to phenyl;
R8, Rg, R10 and Ru are the same or different and at each occurrence independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, aralkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl or substituted heterocyclealkyl; or R8 and R^ taken together with the atom or atoms to which they are attached to form a heterocycle or substituted heterocycle; a and b are the same or different and at each occurrence independently selected from 0, 1, 2, 3 or 4; and c is at each occurrence 0, 1 or 2, anufacture of a medicament for treating or preventing a disease responsive on.
PCT/US2004/009208 2003-03-24 2004-03-24 Methods for treating or preventing an inflammatory or metabolic condition by inhibiting jnk WO2004084901A1 (en)

Priority Applications (7)

Application Number Priority Date Filing Date Title
AU2004224302A AU2004224302A1 (en) 2003-03-24 2004-03-24 Methods for treating or preventing an inflammatory or metabolic condition by inhibiting JNK
JP2006509310A JP2006521394A (en) 2003-03-24 2004-03-24 Method of treating or preventing inflammation or metabolic symptoms by inhibiting JNK
BRPI0408784-4A BRPI0408784A (en) 2003-03-24 2004-03-24 method to use a compound
EP04758138A EP1608375A1 (en) 2003-03-24 2004-03-24 Methods for treating or preventing an inflammatory or metabolic condition by inhibiting jnk
NZ543052A NZ543052A (en) 2003-03-24 2004-03-24 Anilinopyrimidine derivatives for treating or preventing an inflammatory or metabolic condition by inhibiting JNK
MXPA05010185A MXPA05010185A (en) 2003-03-24 2004-03-24 Methods for treating or preventing an inflammatory or metabolic condition by inhibiting jnk.
CA002520440A CA2520440A1 (en) 2003-03-24 2004-03-24 Methods for treating or preventing an inflammatory or metabolic condition by inhibiting jnk

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US10/395,811 2003-03-24
US10/395,811 US7429599B2 (en) 2000-12-06 2003-03-24 Methods for treating or preventing an inflammatory or metabolic condition or inhibiting JNK

Publications (1)

Publication Number Publication Date
WO2004084901A1 true WO2004084901A1 (en) 2004-10-07

Family

ID=33096785

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2004/009208 WO2004084901A1 (en) 2003-03-24 2004-03-24 Methods for treating or preventing an inflammatory or metabolic condition by inhibiting jnk

Country Status (12)

Country Link
US (1) US7429599B2 (en)
EP (1) EP1608375A1 (en)
JP (1) JP2006521394A (en)
KR (1) KR20060025131A (en)
CN (1) CN1791410A (en)
AU (1) AU2004224302A1 (en)
BR (1) BRPI0408784A (en)
CA (1) CA2520440A1 (en)
MX (1) MXPA05010185A (en)
NZ (1) NZ543052A (en)
WO (1) WO2004084901A1 (en)
ZA (1) ZA200507987B (en)

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008040548A2 (en) * 2006-10-04 2008-04-10 Ares Trading S.A. Treatment for non-alcoholic-steatohepatitis
FR2911139A1 (en) * 2007-01-05 2008-07-11 Sanofi Aventis Sa New 2,4-diaminopyrimidine derivatives useful for treating inflammatory diseases, diabetes or cancer
WO2010056907A2 (en) * 2008-11-12 2010-05-20 The Scripps Research Institute Compounds that induce pancreatic beta-cell expansion
US8088771B2 (en) 2008-07-28 2012-01-03 Gilead Sciences, Inc. Cycloalkylidene and heterocycloalkylidene inhibitor compounds
US8124764B2 (en) 2008-07-14 2012-02-28 Gilead Sciences, Inc. Fused heterocyclyc inhibitor compounds
US8134000B2 (en) 2008-07-14 2012-03-13 Gilead Sciences, Inc. Imidazolyl pyrimidine inhibitor compounds
US8258316B2 (en) 2009-06-08 2012-09-04 Gilead Sciences, Inc. Alkanoylamino benzamide aniline HDAC inhibitor compounds
US8283357B2 (en) 2009-06-08 2012-10-09 Gilead Sciences, Inc. Cycloalkylcarbamate benzamide aniline HDAC inhibitor compounds
US8344018B2 (en) 2008-07-14 2013-01-01 Gilead Sciences, Inc. Oxindolyl inhibitor compounds
WO2020011812A1 (en) * 2018-07-09 2020-01-16 Abivax Phenyl/pyridyl-n-phenyl/pyridyl derivatives for treating rna virus infection
US11066404B2 (en) 2018-10-11 2021-07-20 Incyte Corporation Dihydropyrido[2,3-d]pyrimidinone compounds as CDK2 inhibitors
US11384083B2 (en) 2019-02-15 2022-07-12 Incyte Corporation Substituted spiro[cyclopropane-1,5′-pyrrolo[2,3-d]pyrimidin]-6′(7′h)-ones as CDK2 inhibitors
US11427567B2 (en) 2019-08-14 2022-08-30 Incyte Corporation Imidazolyl pyrimidinylamine compounds as CDK2 inhibitors
US11440914B2 (en) 2019-05-01 2022-09-13 Incyte Corporation Tricyclic amine compounds as CDK2 inhibitors
US11447494B2 (en) 2019-05-01 2022-09-20 Incyte Corporation Tricyclic amine compounds as CDK2 inhibitors
US11472791B2 (en) 2019-03-05 2022-10-18 Incyte Corporation Pyrazolyl pyrimidinylamine compounds as CDK2 inhibitors
RU2790838C2 (en) * 2018-07-09 2023-02-28 Абивакс Phenyl/pyridyl-n-phenyl/pyridyl derivatives for the treatment of rna viral infection
US11851426B2 (en) 2019-10-11 2023-12-26 Incyte Corporation Bicyclic amines as CDK2 inhibitors
US11919904B2 (en) 2019-03-29 2024-03-05 Incyte Corporation Sulfonylamide compounds as CDK2 inhibitors
US11976073B2 (en) 2021-12-10 2024-05-07 Incyte Corporation Bicyclic amines as CDK2 inhibitors
US11981671B2 (en) 2021-06-21 2024-05-14 Incyte Corporation Bicyclic pyrazolyl amines as CDK2 inhibitors
US12084422B2 (en) 2018-07-09 2024-09-10 Abivax Phenyl-n-quinoline derivatives for treating a RNA virus infection

Families Citing this family (70)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2533474A1 (en) * 2003-07-30 2005-02-10 Shudong Wang 2-aminophenyl-4-phenylpyrimidines as kinase inhibitors
CA2544591A1 (en) * 2003-11-06 2005-05-26 Celgene Corporation Methods of using and compositions comprising a jnk inhibitor for the treatment and management of asbestos-related diseases and disorders
US20050266391A1 (en) * 2004-01-15 2005-12-01 Bennett Brydon L Methods for preserving tissue
US20060223807A1 (en) * 2005-03-29 2006-10-05 University Of Massachusetts Medical School, A Massachusetts Corporation Therapeutic methods for type I diabetes
US7803817B2 (en) * 2005-05-11 2010-09-28 Vecta, Ltd. Composition and methods for inhibiting gastric acid secretion
US7981908B2 (en) * 2005-05-11 2011-07-19 Vecta, Ltd. Compositions and methods for inhibiting gastric acid secretion
WO2007047468A2 (en) 2005-10-13 2007-04-26 Anthrogenesis Corporation Immunomodulation using placental stem cells
CN101374941A (en) 2005-12-29 2009-02-25 人类起源公司 Improved composition for collecting and preserving placental stem cells and methods of using the composition
MX2008012064A (en) * 2006-03-23 2008-12-17 Amgen Inc 1-phenylsulfonyl-diaza heterocyclic amide compounds and their uses as modulators of hydroxsteroid dehydrogenases.
WO2007125397A2 (en) * 2006-04-27 2007-11-08 Vecta, Ltd. Compositions and methods for inhibiting gastric acidity using endoperoxide bridge-containing compounds
CA2658804A1 (en) * 2006-07-25 2008-01-31 Vecta Ltd. Compositions and methods for inhibiting gastric acid secretion using derivatives of small dicarboxylic acids in combination with ppi
AR063946A1 (en) * 2006-09-11 2009-03-04 Cgi Pharmaceuticals Inc CERTAIN REPLACED PIRIMIDINS, THE USE OF THE SAME FOR THE TREATMENT OF DISEASES MEDIATED BY THE INHIBITION OF THE ACTIVITY OF BTK AND PHARMACEUTICAL COMPOSITIONS THAT UNDERSTAND THEM.
MX349225B (en) 2007-02-12 2017-07-19 Anthrogenesis Corp Treatment of inflammatory diseases using placental stem cells.
CN101687853A (en) * 2007-05-04 2010-03-31 Irm责任有限公司 Pyrimidine derivatives and compositions as C-KIT and PDGFR kinase inhibitors
RU2455288C2 (en) 2007-08-22 2012-07-10 Айрм Ллк Compounds and compositions of 5-(4-(halogenalkoxy)phenyl)pyrimidin-2-amine as kinase inhibitors
EA017392B1 (en) * 2007-08-22 2012-12-28 Айрм Ллк 2-heteroarylamino-pyrimidine derivatives as kinase inhibitors
BRPI1013366A2 (en) * 2009-03-06 2016-03-29 Novartis Ag use of pyrimidylaminobenzamide derivatives for the treatment of leucine zipper containing kinase and sterile alpha motif (zak) kinase mediated disorders.
CN101503402B (en) * 2009-03-10 2014-06-25 沈阳药科大学 2-aniline pyrimidine derivative, as well as preparation and uses thereof
WO2010144909A1 (en) 2009-06-12 2010-12-16 Novartis Ag Fused heterocyclic compounds and their uses
AU2010343102B2 (en) 2009-12-29 2016-03-24 Dana-Farber Cancer Institute, Inc. Type II Raf kinase inhibitors
AU2010339531A1 (en) * 2009-12-30 2012-08-23 Arqule, Inc. Substituted naphthalenyl-pyrimidine compounds
US9205577B2 (en) * 2010-02-05 2015-12-08 Allergan, Inc. Porogen compositions, methods of making and uses
US9138309B2 (en) 2010-02-05 2015-09-22 Allergan, Inc. Porous materials, methods of making and uses
US11202853B2 (en) * 2010-05-11 2021-12-21 Allergan, Inc. Porogen compositions, methods of making and uses
GB201012105D0 (en) 2010-07-19 2010-09-01 Domainex Ltd Novel pyrimidine compounds
AU2012340200B2 (en) * 2011-11-17 2017-10-12 Dana-Farber Cancer Institute, Inc. Inhibitors of c-Jun-N-Terminal Kinase (JNK)
JP2015517563A (en) * 2012-05-22 2015-06-22 アウトイフオンイ トヘラペウトイクス リミテッド Hydantoin derivatives as KV3 inhibitors
US10112927B2 (en) 2012-10-18 2018-10-30 Dana-Farber Cancer Institute, Inc. Inhibitors of cyclin-dependent kinase 7 (CDK7)
US10000483B2 (en) 2012-10-19 2018-06-19 Dana-Farber Cancer Institute, Inc. Bone marrow on X chromosome kinase (BMX) inhibitors and uses thereof
WO2014063061A1 (en) 2012-10-19 2014-04-24 Dana-Farber Cancer Institute, Inc. Hydrophobically tagged small molecules as inducers of protein degradation
US9227978B2 (en) 2013-03-15 2016-01-05 Araxes Pharma Llc Covalent inhibitors of Kras G12C
JP6473133B2 (en) * 2013-03-15 2019-02-20 アラクセス ファーマ エルエルシー Covalent inhibitor of KRASG12C
JO3805B1 (en) 2013-10-10 2021-01-31 Araxes Pharma Llc Inhibitors of kras g12c
CA2927917C (en) 2013-10-18 2022-08-09 Syros Pharmaceuticals, Inc. Heteroaromatic compounds useful for the treatment of proliferative diseases
US10047070B2 (en) 2013-10-18 2018-08-14 Dana-Farber Cancer Institute, Inc. Polycyclic inhibitors of cyclin-dependent kinase 7 (CDK7)
NZ715903A (en) 2014-01-30 2017-06-30 Signal Pharm Llc Solid forms of 2-(tert-butylamino)-4-((1r,3r,4r)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide, compositions thereof and methods of their use
CN106455579A (en) * 2014-04-23 2017-02-22 耳瑞思医学股份有限公司 Methods and compositions for treating and preventing tinnitus
WO2015164614A1 (en) 2014-04-23 2015-10-29 Dana-Farber Cancer Institute, Inc. Janus kinase inhibitors and uses thereof
WO2015164604A1 (en) 2014-04-23 2015-10-29 Dana-Farber Cancer Institute, Inc. Hydrophobically tagged janus kinase inhibitors and uses thereof
WO2015179436A1 (en) * 2014-05-19 2015-11-26 Sanford-Burnham Medical Research Institute Inflammation therapy using mekk3 inhibitors or blocking peptides
JP6854762B2 (en) 2014-12-23 2021-04-07 ダナ−ファーバー キャンサー インスティテュート， インコーポレイテッド Inhibitor of cyclin-dependent kinase 7 (CDK7)
EP3273966B1 (en) 2015-03-27 2023-05-03 Dana-Farber Cancer Institute, Inc. Inhibitors of cyclin-dependent kinases
CN107849022A (en) 2015-04-10 2018-03-27 亚瑞克西斯制药公司 Substituted quinazoline compound and its application method
EP3283462B1 (en) 2015-04-15 2020-12-02 Araxes Pharma LLC Fused-tricyclic inhibitors of kras and methods of use thereof
EP3307728A4 (en) 2015-06-12 2019-07-17 Dana Farber Cancer Institute, Inc. Combination therapy of transcription inhibitors and kinase inhibitors
US10144724B2 (en) 2015-07-22 2018-12-04 Araxes Pharma Llc Substituted quinazoline compounds and methods of use thereof
JP7028766B2 (en) 2015-09-09 2022-03-02 ダナ－ファーバー キャンサー インスティテュート， インコーポレイテッド Inhibitor of cyclin-dependent kinase
US10975071B2 (en) 2015-09-28 2021-04-13 Araxes Pharma Llc Inhibitors of KRAS G12C mutant proteins
WO2017058728A1 (en) 2015-09-28 2017-04-06 Araxes Pharma Llc Inhibitors of kras g12c mutant proteins
EP3356347A1 (en) 2015-09-28 2018-08-08 Araxes Pharma LLC Inhibitors of kras g12c mutant proteins
US10689356B2 (en) 2015-09-28 2020-06-23 Araxes Pharma Llc Inhibitors of KRAS G12C mutant proteins
WO2017058792A1 (en) 2015-09-28 2017-04-06 Araxes Pharma Llc Inhibitors of kras g12c mutant proteins
EP3356354A1 (en) 2015-09-28 2018-08-08 Araxes Pharma LLC Inhibitors of kras g12c mutant proteins
EP3356351A1 (en) 2015-09-28 2018-08-08 Araxes Pharma LLC Inhibitors of kras g12c mutant proteins
US10414757B2 (en) 2015-11-16 2019-09-17 Araxes Pharma Llc 2-substituted quinazoline compounds comprising a substituted heterocyclic group and methods of use thereof
US10646488B2 (en) 2016-07-13 2020-05-12 Araxes Pharma Llc Conjugates of cereblon binding compounds and G12C mutant KRAS, HRAS or NRAS protein modulating compounds and methods of use thereof
CN110036010A (en) 2016-09-29 2019-07-19 亚瑞克西斯制药公司 The inhibitor of KRAS G12C mutain
CN110312711A (en) 2016-10-07 2019-10-08 亚瑞克西斯制药公司 Heterocyclic compound and its application method as RAS inhibitor
US11358959B2 (en) 2017-01-26 2022-06-14 Araxes Pharma Llc Benzothiophene and benzothiazole compounds and methods of use thereof
US11279689B2 (en) 2017-01-26 2022-03-22 Araxes Pharma Llc 1-(3-(6-(3-hydroxynaphthalen-1-yl)benzofuran-2-yl)azetidin-1 yl)prop-2-en-1-one derivatives and similar compounds as KRAS G12C modulators for treating cancer
WO2018140512A1 (en) 2017-01-26 2018-08-02 Araxes Pharma Llc Fused bicyclic benzoheteroaromatic compounds and methods of use thereof
CN110382482A (en) 2017-01-26 2019-10-25 亚瑞克西斯制药公司 Condensed miscellaneous-Heterobicyclic compounds and its application method
EP3573970A1 (en) 2017-01-26 2019-12-04 Araxes Pharma LLC 1-(6-(3-hydroxynaphthalen-1-yl)quinazolin-2-yl)azetidin-1-yl)prop-2-en-1-one derivatives and similar compounds as kras g12c inhibitors for the treatment of cancer
TW201906832A (en) 2017-05-25 2019-02-16 美商亞瑞克西斯製藥公司 Compounds for cancer treatment and methods of use thereof
CN110869358A (en) 2017-05-25 2020-03-06 亚瑞克西斯制药公司 Covalent inhibitors of KRAS
EP3630747A1 (en) 2017-05-25 2020-04-08 Araxes Pharma LLC Quinazoline derivatives as modulators of mutant kras, hras or nras
CN111093663A (en) 2017-09-07 2020-05-01 奥古斯塔大学研究所公司 Specific AKT3 activator and application thereof
WO2020111283A1 (en) * 2018-11-26 2020-06-04 (의료)길의료재단 Novel 4-carbonylamino-4-phenylpyrimidine compound or pharmaceutically acceptable salt thereof
MX2022000278A (en) * 2019-07-19 2022-02-03 Abivax Aryl-n-aryl derivatives for treating a rna virus infection.
CN114671861B (en) * 2022-04-12 2023-11-24 安徽医科大学 Wogonin derivative and preparation method and application thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001012609A1 (en) * 1999-08-19 2001-02-22 Signal Pharmaceuticals, Inc. Pyrazoloanthrone and derivatives thereof as jnk inhibitors and their compositions
WO2002046170A2 (en) * 2000-12-06 2002-06-13 Signal Pharmaceuticals, Inc. Anilinopyrimidine derivatives as jnk pathway inhibitors and compositions and methods related thereto
WO2002085396A1 (en) * 2001-04-24 2002-10-31 President And Fellows Of Harvard College Inhibition of jun kinase

Family Cites Families (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1266763B (en) 1965-07-27 1968-04-25 Kalle Ag Process for the preparation of indole and indazole derivatives substituted in the 3-position
CH538528A (en) 1968-11-07 1973-06-30 Hoechst Ag Dyestuffs for natural and synthetic fibres
US3994890A (en) 1974-01-31 1976-11-30 Chugai Seiyaku Kabushiki Kaisha 1-Aminoalkyl, 3-phenyl indazoles
JPS57109787A (en) 1980-12-26 1982-07-08 Chugai Pharmaceut Co Ltd Pyrazoloindazole derivative
US4788195A (en) * 1986-01-13 1988-11-29 American Cyanamid Company 4,5,6-substituted-N-(substituted-phenyl)-2-pyrimidinamines
US4876252A (en) 1986-01-13 1989-10-24 American Cyanamid Company 4,5,6-substituted-N-(substituted-phenyl)-2-pyrimidinamines
ATE135699T1 (en) * 1986-01-13 1996-04-15 American Cyanamid Co 4,5,6-SUBSTITUTED 2-PYRIMIDINAMINES
JPS63184364A (en) * 1987-01-27 1988-07-29 Toshiba Corp Manufacture of semiconductor device
EP0494774A1 (en) 1991-01-11 1992-07-15 MERCK SHARP & DOHME LTD. Indazole-substituted fivemembered heteroaromatic compounds
NZ243065A (en) 1991-06-13 1995-07-26 Lundbeck & Co As H Piperidine derivatives and pharmaceutical compositions
US5516775A (en) * 1992-08-31 1996-05-14 Ciba-Geigy Corporation Further use of pyrimidine derivatives
WO1997010806A1 (en) 1995-09-19 1997-03-27 Fujisawa Pharmaceutical Co., Ltd. Aerosol compositions
GB9622363D0 (en) 1996-10-28 1997-01-08 Celltech Therapeutics Ltd Chemical compounds
JP2001518094A (en) 1997-03-31 2001-10-09 デュポン ファーマシューティカルズ カンパニー Indazole-cyclic ureas useful as HIV protease inhibitors
US6162613A (en) 1998-02-18 2000-12-19 Vertex Pharmaceuticals, Inc. Methods for designing inhibitors of serine/threonine-kinases and tyrosine kinases
ATE212552T1 (en) 1998-04-17 2002-02-15 Tufts College MAP KINASE INHIBITORS FOR THE TREATMENT OF TNF-ALPHA INDUCED LIPOLYSIS CAUSED DISEASES
GB2345486A (en) 1999-01-11 2000-07-12 Glaxo Group Ltd Heteroaromatic protein tyrosine kinase inhibitors
TWI262914B (en) 1999-07-02 2006-10-01 Agouron Pharma Compounds and pharmaceutical compositions for inhibiting protein kinases
BR0013551A (en) 1999-08-13 2003-06-17 Vertex Pharma Inhibitors of cjun (jnk) n-terminal kinases and other protein kinases

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001012609A1 (en) * 1999-08-19 2001-02-22 Signal Pharmaceuticals, Inc. Pyrazoloanthrone and derivatives thereof as jnk inhibitors and their compositions
WO2002046170A2 (en) * 2000-12-06 2002-06-13 Signal Pharmaceuticals, Inc. Anilinopyrimidine derivatives as jnk pathway inhibitors and compositions and methods related thereto
US20030220330A1 (en) * 2000-12-06 2003-11-27 Satoh Yoshitaka Anilinopyrimidine derivatives as JNK pathway inhibitors and compositions and methods related thereto
WO2002085396A1 (en) * 2001-04-24 2002-10-31 President And Fellows Of Harvard College Inhibition of jun kinase

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BENNETT B L ET AL: "JNK: A new therapeutic target for diabetes", CURRENT OPINION IN PHARMACOLOGY, ELSEVIER SCIENCE PUBLISHERS,, NL, vol. 3, no. 4, August 2003 (2003-08-01), pages 420 - 425, XP001180182, ISSN: 1471-4892 *

Cited By (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008040548A2 (en) * 2006-10-04 2008-04-10 Ares Trading S.A. Treatment for non-alcoholic-steatohepatitis
WO2008040548A3 (en) * 2006-10-04 2009-05-22 Ares Trading Sa Treatment for non-alcoholic-steatohepatitis
FR2911139A1 (en) * 2007-01-05 2008-07-11 Sanofi Aventis Sa New 2,4-diaminopyrimidine derivatives useful for treating inflammatory diseases, diabetes or cancer
WO2008099074A1 (en) * 2007-01-05 2008-08-21 Sanofi-Aventis Phenyl- (4-phenyl-pyrimidin-2-yl) - amine derivatives as ikk inhibitors, preparation thereof, and pharmaceutical compositions thereof
US8124764B2 (en) 2008-07-14 2012-02-28 Gilead Sciences, Inc. Fused heterocyclyc inhibitor compounds
US8134000B2 (en) 2008-07-14 2012-03-13 Gilead Sciences, Inc. Imidazolyl pyrimidine inhibitor compounds
US8344018B2 (en) 2008-07-14 2013-01-01 Gilead Sciences, Inc. Oxindolyl inhibitor compounds
US8088771B2 (en) 2008-07-28 2012-01-03 Gilead Sciences, Inc. Cycloalkylidene and heterocycloalkylidene inhibitor compounds
WO2010056907A2 (en) * 2008-11-12 2010-05-20 The Scripps Research Institute Compounds that induce pancreatic beta-cell expansion
WO2010056907A3 (en) * 2008-11-12 2010-07-22 The Scripps Research Institute Heterocyclic compounds that induce pancreatic beta-cell expansion
US8258316B2 (en) 2009-06-08 2012-09-04 Gilead Sciences, Inc. Alkanoylamino benzamide aniline HDAC inhibitor compounds
US8283357B2 (en) 2009-06-08 2012-10-09 Gilead Sciences, Inc. Cycloalkylcarbamate benzamide aniline HDAC inhibitor compounds
WO2020011812A1 (en) * 2018-07-09 2020-01-16 Abivax Phenyl/pyridyl-n-phenyl/pyridyl derivatives for treating rna virus infection
RU2790838C2 (en) * 2018-07-09 2023-02-28 Абивакс Phenyl/pyridyl-n-phenyl/pyridyl derivatives for the treatment of rna viral infection
US12084422B2 (en) 2018-07-09 2024-09-10 Abivax Phenyl-n-quinoline derivatives for treating a RNA virus infection
US11739073B2 (en) 2018-07-09 2023-08-29 Abivax Aryl-n-aryl derivatives for treating a RNA virus infection
US11866432B2 (en) 2018-10-11 2024-01-09 Incyte Corporation Dihydropyrido[2,3-d]pyrimidinone compounds as CDK2 inhibitors
US11066404B2 (en) 2018-10-11 2021-07-20 Incyte Corporation Dihydropyrido[2,3-d]pyrimidinone compounds as CDK2 inhibitors
US11384083B2 (en) 2019-02-15 2022-07-12 Incyte Corporation Substituted spiro[cyclopropane-1,5′-pyrrolo[2,3-d]pyrimidin]-6′(7′h)-ones as CDK2 inhibitors
US11472791B2 (en) 2019-03-05 2022-10-18 Incyte Corporation Pyrazolyl pyrimidinylamine compounds as CDK2 inhibitors
US11919904B2 (en) 2019-03-29 2024-03-05 Incyte Corporation Sulfonylamide compounds as CDK2 inhibitors
US11447494B2 (en) 2019-05-01 2022-09-20 Incyte Corporation Tricyclic amine compounds as CDK2 inhibitors
US11440914B2 (en) 2019-05-01 2022-09-13 Incyte Corporation Tricyclic amine compounds as CDK2 inhibitors
US11427567B2 (en) 2019-08-14 2022-08-30 Incyte Corporation Imidazolyl pyrimidinylamine compounds as CDK2 inhibitors
US11851426B2 (en) 2019-10-11 2023-12-26 Incyte Corporation Bicyclic amines as CDK2 inhibitors
US11981671B2 (en) 2021-06-21 2024-05-14 Incyte Corporation Bicyclic pyrazolyl amines as CDK2 inhibitors
US11976073B2 (en) 2021-12-10 2024-05-07 Incyte Corporation Bicyclic amines as CDK2 inhibitors

Also Published As

Publication number Publication date
NZ543052A (en) 2009-01-31
BRPI0408784A (en) 2006-03-28
ZA200507987B (en) 2007-12-27
JP2006521394A (en) 2006-09-21
US7429599B2 (en) 2008-09-30
MXPA05010185A (en) 2005-11-08
CN1791410A (en) 2006-06-21
KR20060025131A (en) 2006-03-20
AU2004224302A1 (en) 2004-10-07
EP1608375A1 (en) 2005-12-28
US20040106634A1 (en) 2004-06-03
CA2520440A1 (en) 2004-10-07

Similar Documents

Publication Publication Date Title
WO2004084901A1 (en) Methods for treating or preventing an inflammatory or metabolic condition by inhibiting jnk
US7129242B2 (en) Anilinopyrimidine derivatives as JNK pathway inhibitors and compositions and methods related thereto
AU2002227214A1 (en) Anilinopyrimidine derivatives as JNK pathway inhibitors and compositions and methods related thereto
JP4384408B2 (en) Anilinopyrimidine derivatives as IKK inhibitors and compositions and methods related thereto
US11806337B2 (en) Small molecule activators of nicotinamide phosphoribosyltransferase (NAMPT) and uses thereof
AU2002220195A1 (en) Anilinopyrimidine derivatives as IKK inhibitors and compositions and methods related thereto
US8697911B2 (en) Rho kinase inhibitors
JP5426543B2 (en) Pyridazinone derivatives
ES2534095T3 (en) Aminopyridine derivatives for the treatment of tumors and inflammatory diseases
KR101606945B1 (en) 2-benzylpyridazinone derivatives as met kinase inhibitors
US8088761B2 (en) Enzyme inhibitors
JP5769326B2 (en) Rho kinase inhibitor
KR101674695B1 (en) Pyridazinone derivatives
US20130029970A1 (en) CB Receptor Agonists
WO2013033862A1 (en) 4-substituted-(3-substituted-1h-pyrazole-5-amino)-pyrimidine derivatives having activity of inhibiting protein kinase and use thereof
KR101669696B1 (en) Pyridazinone derivatives
WO2024131265A1 (en) COMPOUND FOR TREATING PI3Kγ-MEDIATED DISEASES AND USE THEREOF

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

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 KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL 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: A1

Designated state(s): BW GH GM KE LS MW MZ 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 IT LU 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

DPEN Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed from 20040101)
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: PA/a/2005/010185

Country of ref document: MX

Ref document number: 1020057017981

Country of ref document: KR

WWE Wipo information: entry into national phase

Ref document number: 171088

Country of ref document: IL

WWE Wipo information: entry into national phase

Ref document number: 2520440

Country of ref document: CA

Ref document number: 2006509310

Country of ref document: JP

WWE Wipo information: entry into national phase

Ref document number: 200507987

Country of ref document: ZA

WWE Wipo information: entry into national phase

Ref document number: 2004224302

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 543052

Country of ref document: NZ

WWE Wipo information: entry into national phase

Ref document number: 2004758138

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2004224302

Country of ref document: AU

Date of ref document: 20040324

Kind code of ref document: A

WWP Wipo information: published in national office

Ref document number: 2004224302

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 20048135889

Country of ref document: CN

WWP Wipo information: published in national office

Ref document number: 2004758138

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1020057017981

Country of ref document: KR

ENP Entry into the national phase

Ref document number: PI0408784

Country of ref document: BR