EP1144390A2 - Inhibiteurs de kinase - Google Patents

Inhibiteurs de kinase

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Publication number
EP1144390A2
EP1144390A2 EP00905700A EP00905700A EP1144390A2 EP 1144390 A2 EP1144390 A2 EP 1144390A2 EP 00905700 A EP00905700 A EP 00905700A EP 00905700 A EP00905700 A EP 00905700A EP 1144390 A2 EP1144390 A2 EP 1144390A2
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EP
European Patent Office
Prior art keywords
coor
aryl
alkenyl
substituted
alkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP00905700A
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German (de)
English (en)
Inventor
David M. Armistead
Jean E. Bemis
Daniel Elbaum
Gregory Habgood
Perry M. Novak
Joseph J. Nunes
Leticia M. Toledo-Sherman
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Amgen Inc
Original Assignee
Amgen Inc
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Publication date
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Publication of EP1144390A2 publication Critical patent/EP1144390A2/fr
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Definitions

  • the invention relates to inhibitors of kinases, compositions comprising the inhibitors, and methods of using the inhibitors and inhibitor compositions.
  • the inhibitors and compositions comprising them are useful for treating or modulating disease in which kinases may be involved, symptoms of such disease, or the effect of other physiological events mediated by kinases.
  • the invention also provides for methods of making kinase inhibitor compounds and methods for treating diseases in which kinase activity is involved.
  • the protein kinases constitute a large family of structurally related enzymes that are responsible for the control of a wide variety of signal transduction processes within the cell. (See, Hardie, G. and Hanks, S. (1995) The Protein Kinase Facts Book, I and II, Academic Press, San Diego, CA).
  • Protein kinases are thought to have evolved from a common ancestral gene due to the conservation of their structure and catalytic function. Almost all kinases contain a similar 250-300 amino acid catalytic domain. The kinases may be categorized into families by the substrates they phosphorylate (e.g., protein- tyrosine, protein-serine/threonine, lipids, etc.).
  • cAPK cAMP-dependent protein kinase
  • the N-terminal portion forms the small lobe (including subdomains I-IV) whose architecture is composed of an antiparallel five-strand ⁇ -sheet and one ⁇ -helix, while the lower C- terminal domain forms another lobe (including subdomains VIA - XI) containing mostly -helical architecture.
  • Subdomain V spans the two lobes.
  • the N-terminal domain is thought to participate in orienting the nucleotide (or other binding entity), while the C- terminal domain is thought to be responsible for binding peptide substrate and initiating phosphotransfer to the hydroxyl group of a serine, threonine, or tyrosine residue.
  • the N- and C-terminal domains are connected through a single peptide strand, to which the adenine moiety of ATP binds via an eleven membered hydrogen bond cycle, involving the NI and the N6 amino group, and the backbone carbonyl and NH functions of two nonconsecutive residues.
  • This linker acts as a hinge about which the domains can rotate with respect to each other without disruption of the secondary architecture of the kinase. Several torsion angle changes in the linker backbone allow this movement to occur.
  • the ribose group of ATP is anchored to the enzyme via hydrogen bonds with residues within the ribose-binding pocket.
  • the triphosphate group is held in position via various polar interactions with several variable residues form the glycine rich loop, the conserved DFG motive and the catalytic loop.
  • Protein kinases may be characterized by their regulation mechanisms. It must be noted, however, that an individual protein kinase may be regulated by more than one mechanism. These mechanisms include, for example, autophosphorylation, transphosphorylation by other kinases, protein-protein interactions, protein-lipid interactions, and protein-polynucleotide interactions.
  • Kinases regulate many different cell processes including, but not limited to, proliferation, differentiation, apoptosis, motility, transcription, translation and other signaling processes, by adding phosphate groups to target proteins. These phosphorylation events act as molecular on/off switches that can modulate or regulate the target protein biological function. Phosphorylation of target proteins occurs in response to a variety of extracellular signals (hormones, neurotransmitters, growth and differentiation factors, etc.), cell cycle events, environmental or nutritional stresses, etc.
  • the appropriate protein kinase functions in signaling pathways to activate or inactivate (either directly or indirectly), for example, a metabolic enzyme, regulatory protein, receptor, cytoskeletal protein, ion channel or pump, or transcription factor.
  • Uncontrolled signaling due to defective control of protein phosphorylation has been implicated in a number of diseases, including, for example, inflammation, cancer, allergy/asthma, disease and conditions of the immune system, disease and conditions of the central nervous system, and angiogenesis.
  • Initial interest in protein kinases as pharmacological targets was stimulated by the findings that many viral oncogenes encode structurally modified cellular protein kinases with constitutive enzyme activity. These findings pointed to the potential involvement of proto-oncogene encoded protein kinases in human proliferative disorders.
  • deregulated protein kinase activity resulting from a variety of more subtle mechanisms, has been implicated in the pathophysiology of a number of important human disorders including cancer and immunologically related diseases.
  • the development of selective protein kinase inhibitors that can block the disease pathologies and/or symptoms resulting from aberrant protein kinase activity has therefore generated much interest.
  • the invention relates to compounds of the formula:
  • R 1 is H; CN; COOR 5 ; C(O)NRV; halo; C1-C10 alkyl; C1-C10 alkenyl;
  • X is O or S; and the remaining groups are as defined herein.
  • the invention also relates to compositions comprising these compounds, methods of making these compounds, methods of inhibiting enzyme activity, particularly kinase activity, through use of these compounds, and methods of treating disease or disease symptoms in a mammal, particularly where modulation of enzyme activity, and more particularly kinase activity, can affect disease outcome.
  • the invention provides compounds useful in inhibiting kinase activity and inhibiting kinases or other polypeptides having sequences or subsequences homologous to kinase sequences or subsequences.
  • the inhibitory compound has the
  • R 1 is H; CN; COOR 5 ; C(O)NR 5 R 5 ; halo; C1-C10 alkyl; C1-C10 alkenyl; C1-C10 alkyl substituted with 1-3 independent NR R , NR R , SR or OR ; or C1-C10
  • R is phenyl substituted with 1-3 independent R ; R ; COOR ; or C1-C10
  • Each R is independently selected from H, C1-C10 alkyl; C2-C10 alkenyl;
  • NR 5 (COOR 5 ); NR 5 C(O)R 8 ; NR 5 S(O)2NR 5 R 5 ; NR 5 S(O)2R 5 ; NR 5 S(O)2R 8 ;
  • R or C1-C10 alkenyl substituted with aryl, R or R ;
  • Each R is independently H; C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R ; C1-C10 alkyl substituted
  • Each R is independently C(O)R , COOR , or S(O)2 R ;
  • Each R is independently halo, CF3, SR , OR , OC(O)R , NR R ,
  • Each R is independently a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system comprising 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, which may be saturated or unsaturated, and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substiruent independently selected from Cl- C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R ; halo; sulfur; oxygen; CF3; haloalkyl; SR ; OR ; OC(O)R ; NR R ; NR R ;
  • NR 6 R 6 COOR 5 ; NO2; CN; C(O)R 5 ; C(O)NR 5 R 5 ; C1-C10 alkyl substituted with 1-3
  • Each R is independently a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system comprising 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, which may be saturated or unsaturated, and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent independently selected from Cl- C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; halo; sulfur; oxygen; CF3; haloalkyl; SR ; OR ; NR R ; NR R ; NR R ; NR R ;
  • Each R is independently H, Cl-ClO alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; haloalkyl; Cl-ClO alkyl optionally substituted with 1-3 independent Cl-ClO alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3- C10 cycloalkyl, C4-C10 cycloalkenyl, halo, CF3, OR 13 , SR°, NR B R 13 , COOR* 3 , NO2, CN, C(O)R' , C(O)NR R , NHC(O)R 3 , or OC(O)R 3 ; or phenyl optionally substituted with 1-3 independent Cl-ClO alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalky
  • Each R is independently C(O)R , COOR , or S(O)2R ;
  • Each R is independently H, Cl-ClO alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, or phenyl optionally substituted with
  • Each R is independently H; Cl-ClO alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; Cl-ClO alkyl optionally substituted with halo, CF3, OR , SR , NR R , COOR , NO2, CN; or phenyl optionally substituted with halo, CF3, OR , SR , NR R , COOR , NO2, CN;
  • Each R 15 is independently Cl-ClO alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R ; Cl-ClO alkyl substituted
  • Each R is independently Cl-ClO alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; R ; Cl-ClO alkyl substituted with 1-3
  • Each R is independently H; Cl-ClO alkyl; C3-C10 cycloalkyl or phenyl;
  • Each haloalkyl is independently a Cl-ClO alkyl substituted with one or more halogen atoms, selected from F, Cl, Br, or I, wherein the number of halogen atoms may not exceed that number that results in a perhaloalkyl group; and
  • Each aryl is independently a 6-carbon monocyclic or 10-carbon bicyclic aromatic ring system optionally substituted with 1-3 independent Cl-ClO alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; R 9 ; halo; haloalkyl CF3; OR 12 ; SR 12 ; NR 12 R 12 ; COOR 12 ; NO2; CN; C(O)R 12 ; C(O)C(O)R 12 ; C(O)NR'V 2 S(O)2R 12 ; N(R l2 )C(O)R
  • R 1 is H; COOR 5 ; C(O)NR 5 R 5 ; halo; C2-C10 alkyl; Cl-ClO alkenyl; Cl- CIO alkyl substituted with NR R , NR R , SR or OR ; or Cl-ClO alkenyl substituted with NR R , NR R , SR or OR ;
  • R is phenyl substituted with 1-3 independent R ; R ; COOR ; or Cl-ClO
  • Each R is independently selected from H, Cl-ClO alkyl; C2-C10 alkenyl
  • Each R 5 is independently H; Cl-ClO alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R ; Cl-ClO alkyl substituted
  • Each R is independently C(O)R , COOR , or S(O)2 R ;
  • Each R is independently a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system comprising 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, which may be saturated or unsaturated, and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent independently selected from Cl- C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R ; halo; sulfur; oxygen; CF3; haloalkyl; SR ; OR ; OC(O)R ; NR R ; NR R ;
  • R is independently a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system comprising 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, which may be saturated or unsaturated, and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent independently selected from Cl- C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl;
  • Each R is independently H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, or phenyl optionally substituted with 1-3 independent C 1 -C 10 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, C3 -C 10 cycloalkyl, C4-
  • Each R is independently H; C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; C1-C10 alkyl optionally substituted with halo, CF3, OR , SR , NR R , COOR , NO2, CN; or phenyl optionally substituted with halo, CF3, OR , SR , NR R , COOR , NO2, CN;
  • Each R is independently C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R ; C1-C10 alkyl substituted
  • Each R 1 is independently Cl-ClO alkyl; C2-C10 alkenyl; C2-C10
  • Each R is independently H; C1 -CIO alkyl; C3-C 10 cycloalkyl or phenyl;
  • Each aryl is independently a 6-carbon monocyclic or 10-carbon bicyclic aromatic ring system optionally substituted with 1-3 independent C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; R ; halo; haloalkyl CF3; OR 12 ; SR 12 ; NR 12 R 12 ; COOR 12 ; NO2; CN; C(O)R 12 ; C(O)C(O)R 12 ; C(O)NR' 2 R 12 S(O)2R 12 ; N(R l2 )C(O)R 12 ; N(R I2 )(COOR 12 ); N(R' 2 )S(O)2R 12 ; S(O)2NR* 2 R' 2 OC(O)R 12 ; NR l 2 C(O)NR 12 R 12 ; NR 12 C(O)C
  • R 1 is CN
  • X is O or S
  • Each R is independently selected from H, Cl-ClO alkyl; C2-C10 alkenyl C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R ; halo; haloalkyl CF3; SR 5 ; OR 5 ; NR 5 R 5 ; NRV; COOR 5 ; NO2; CN; C(O)R 5 ; C(O)C(O)R 5 ; C(O)NR 5 R 5 OC(O)R 5 ; S(O)2R 5 ; S(O)2NR 5 R 5 ; NR 5 C(O)NR 5 R 5 ; NR 5 C(O)C(O)R 5 ; NR 5 C(O)R " NR 5 (COOR 5 ); NR 5 C(O)R 8 ; NR 5 S(O)2NR 5 R 5 ; NR $ S(O)2R 5 ; NR
  • Each R is independently H; Cl-ClO alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R ; Cl-ClO alkyl substituted
  • Each R 6 is independently C(O)R , COOR , or S(O)2 R 5 ;
  • Each R is independently halo, CF3, SR , OR , OC(O)R , NR R , NR'V ', NR 1 R 11 , COOR 10 , NO2, CN, C(O)R'°, or C(O)NR 10 R 10 ;
  • Each R is independently a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system comprising 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, which may be saturated or unsaturated, and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent independently selected from Cl- C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R ; halo; sulfur; oxygen; CF3; haloalkyl; SR ; OR ; OC(O)R ; NR R ; NR R ;
  • Each R is independently a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system comprising 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, which may be saturated or unsaturated, and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent independently selected from Cl- CIO alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl;
  • Each R is independently H, C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; haloalkyl; C1-C10 alkyl optionally substituted with 1-3 independent C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3- C10 cycloalkyl, C4-C10 cycloalkenyl, halo, CF3, OR , SR , NR R , COOR , NO2, CN, C(O)R , C(O)NR R , NHC(O)R , or OC(O)R ; or phenyl optionally substituted with 1-3 independent C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10
  • Each R is independently C(O)R , COOR , or S(O)2R ;
  • Each R 12 is independently H, Cl-ClO alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, or phenyl optionally substituted with
  • Each R is independently H; Cl-ClO alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; Cl-ClO alkyl optionally substituted
  • Each R is each independently selected from Cl-ClO alkyl; C2-C10
  • Each R 15 is independently Cl-ClO alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R ; Cl-ClO alkyl substituted
  • Each R is independently Cl-ClO alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; R ; Cl-ClO alkyl substituted with one
  • Each R is independently selected from H, Cl-ClO alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R ; halo; haloalkyl; CF3; SR 5 ; OR 5 ; NR 5 R 5 ; NR 5 R 6 ; COOR 5 ; NO2; CN; C(O)R 5 ; C(O)C(O)R 5 ; C(O)NR 5 R 5 ; OC(O)R 5 ; S(O)2R 5 ; S(O)2NR 5 R 5 ; NR 5 C(O)NR 5 R 5 ; NR 5 C(O)C(O)R 5 ; NR 5 C(O)R 5 ; NR 5 (COOR 5 ); NR $ C(O)R 8 ; NR 5 S(O)2NR 5 R 5 ; NR 5 S(
  • Each R is independently H; C 1 -C 10 alkyl; C3-C 10 cycloalkyl or phenyl;
  • Each haloalkyl is independently a Cl-ClO alkyl substituted with one or more halogen atoms, selected from F, Cl, Br, or I, wherein the number of halogen atoms may not exceed that number that results in a perhaloalkyl group;
  • Each aryl is independently a 6-carbon monocyclic or 10-carbon bicyclic aromatic ring system optionally substituted with 1-3 independent Cl-ClO alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; R ; halo; haloalkyl
  • R may not be Me, Cl, or OMe
  • each R is independently selected from C2-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R 8 ; I; Br; F; CF 3 ; SR 5 ; OR 25 ; NR 5 R 5 ; NR 5 R 6 ; COOR 5 ; NO 2 ; CN; C(O)R 5 ; C(O)C(O)R 5 ; C(O)NR 5 R 5 ; S(O) 2 NR 5 R 5 ; NR 5 C(O)NR 5 R 5 ; NR 5 C(O)C(O)R 5 ; NR 5 C(O)R 8 ; NR 5 S(O) 2 NR 5 R 5 ; NR 5 S(O) 2 R 5 ; NR 5 S(O) 2 R 5 ; NR 5 S(O) 2 R 5 ; NR 5 S(O) 2 R 5
  • the compound has the formula directly above wherein each R is independently selected from NR 5 R 5 ; NRV; NR C(O)NR R 5 ; NR 5 C(O)C(O)R 5 ; NR 5 C(O)R 5 ; NR 5 (COOR 5 ); NR 5 C(O)R 8 ; NR 5 S(O)2NR 5 R 5 ; NR 5 S(O)2R 5 ; NR 5 S(O)2R 8 ; NR C(O)C(O)NR R ; or NR C(O)C(O)NR R .
  • the compound is independently selected from NR 5 R 5 ; NRV; NR C(O)NR R 5 ; NR 5 C(O)C(O)R 5 ; NR 5 C(O)R 5 ; NR 5 (COOR 5 ); NR 5 C(O)R 8 ; NR 5 S(O)2NR 5 R 5 ; NR 5 S(O)2R 5 ; NR
  • 4 17 is of any of the formulae above, wherein at least two of R and or R are independently H. Preferred compounds of these embodiments are also those wherein X is O. In an alternate embodiment, the inhibitory compound has the formula:
  • R is CN
  • X is O or S
  • Each R is independently selected from H, Cl-ClO alkyl; C2-C10 alkenyl C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R ; halo; haloalkyl CF3; SR 5 ; OR 5 ; NR 5 R 5 ; NR 5 R 6 ; COOR 5 ; NO2; CN; C(O)R 5 ; C(O)C(O)R 5 ; C(O)NR 5 R 5 OC(O)R 5 ; S(O)2R 5 ; S(O)2NR 5 R 5 ; NR 5 C(O)NR 5 R 5 ; NR 5 C(O)C(O)R 5 ; NR 5 C(O)R 5 ; NR 5 (COOR 5 ); NR 5 C(O)R 8 ; NR 5 S(O)2NR 5 R 5 ; NR 5 S(O)2R
  • R or Cl-ClO alkenyl substituted with aryl, R or R ;
  • Each R is independently H; Cl-ClO alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R ; Cl-ClO alkyl substituted
  • Each R is independently C(O)R , COOR , or S(O)2 R ;
  • Each R is independently halo, CF3, SR , OR , OC(O)R , NR R ,
  • NR R NR R , COOR , NO2, CN, C(O)R , or C(O)NR R ;
  • Each R is independently a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system comprising 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, which may be saturated or unsaturated, and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent independently selected from Cl- C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R ; halo; sulfur; oxygen; CF3; haloalkyl; SR ; OR ; OC(O)R ; NR R ; NR R ; NR 6 R 6 ; COOR 5 ; NO2; CN; C(O)R 5 ; C(O)
  • Each R is independently a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system comprising 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, which may be saturated or unsaturated, and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent independently selected from Cl- C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; halo; sulfur; oxygen; CF3; haloalkyl; SR ; OR ; NR R ; NR R ; NR R ; COOR 10 ; NO2; CN; C(O)R 10 ; or C(O)NR 10 R'°; Each R is independently H, Cl-Cl
  • Each R is independently C(O)R , COOR , or S(O)2R ;
  • Each R is independently H, Cl-ClO alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, or phenyl optionally substituted with 1-3 independent Cl-ClO alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4- C10 cycloalkenyl, halo, CF3, OR 13 , SR B , NR' 3 , COOR 13 , NO2, CN, C(O)R°, C(O)NR 13 R 13 , NHC(O)R 13 , or OC(O)R 13 ;
  • Each R is independently H; Cl-ClO alkyl; C2-C10 alkenyl; C2-C10 alkynyl
  • Each R is independently selected from Cl-ClO alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R ; halo; haloalkyl; CF3; SR 5 ; OR 5 ; NR 5 R 5 ; NRV; COOR 5 ; NO2; CN; C(O)R 5 ; C(O)C(O)R 5 ; C(O)NR 5 R 5 ; OC(O)R 5 ; S(O)2R 5 ; S(O)2NR 5 R 5 ; NR 5 C(O)NR 5 R 5 ; NR 5 C(O)C(O)R 5 ; NR 5 C(O)R 5 ; NR 5 (COOR 5 ); NR 5 C(O)R 8 ; NR 5 S(O)2NR 5 R 5 ; NR 5 S(O)2R 5
  • Each R is independently Cl-ClO alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R ; Cl-ClO alkyl substituted
  • Each R is independently Cl-ClO alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; R ; Cl-ClO alkyl substituted with one
  • Each R is independently H; Cl-ClO alkyl; C3-C10 cycloalkyl or phenyl;
  • Each haloalkyl is independently a Cl-ClO alkyl substituted with one or more halogen atoms, selected from F, Cl, Br, or I, wherein the number of halogen atoms may not exceed that number that results in a perhaloalkyl group;
  • Each aryl is independently a 6-carbon monocyclic or 10-carbon bicyclic aromatic ring system optionally substituted with 1-3 independent Cl-ClO alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; R ; halo; haloalkyl;
  • R 9 halo, CF3, OR 12 , SR 12 , NR' 2 , COOR 12 , NO2, CN, C(O)R 12 , C(O)NR 12 R 12 ,
  • NHC(O)R 12 NH(COOR 12 ), S(O)2NR 12 R 12 , OC(O)R 12 ; C2-C10 alkenyl substituted with
  • each R 14 is independently selected from C2-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R 8 ; halo; CF 3 ; SR 5 ; OR 25 ; NR 5 R 5 ; NR 5 R 6 ; COOR 5 ; NO 2 ; CN; C(O)R 5 ; C(O)C(O)R 5 ; C(O)NR 5 R 5 ; S(O) 2 NR 5 R 5 ; NR 5 C(O)NR 5 R 5 ; NR 5 C(O)C(O)R 5 ; NR 5 C(O)R 8 ; NR 5 S(O) 2 NR 5 R 5 ; NR 5 C(O)NR 5 R 5 ; NR 5 C(O)C(O)R 5 ; NR 5 C(O)R 8 ; NR 5 S(O) 2
  • each R 25 is independently H; C2-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R 9 ; Cl-ClO alkyl substituted with one or two
  • each R is independently selected from NRV; NR 5 R 6 ; NR 5 C(O)NRV; NR 5 C(O)C(O)R 5 ; NR 5 C(O)R 5 ; NR 5 (COOR 5 ); NR 5 C(O)R 8 ; NR 5 S(O)2NRV; NR 5 S(O)2R 5 ; NR 5 S(O)2R 8 ;
  • the inhibitory compound has the formula
  • R is CN
  • X is O or S
  • Each R is independently selected from H, Cl-ClO alkyl; C2-C10 alkenyl
  • Each R is independently H; Cl-ClO alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R ; Cl-ClO alkyl substituted
  • Each R is independently C(O)R , COOR , or S(O)2 R ;
  • Each R is independently halo, CF3, SR , OR , OC(O)R , NR R ,
  • Each R is independently a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system comprising 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, which may be saturated or unsaturated, and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent independently selected from Cl- C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R ; halo; sulfur; oxygen; CF3; haloalkyl; SR ; OR ; OC(O)R ; NR R ; NR R ;
  • Each R is independently a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system comprising 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, which may be saturated or unsaturated, and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent independently selected from Cl- CIO alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; 10 10 10 10 10 10 11 1 1 1 1 1 halo; sulfur; oxygen; CF3; haloalkyl; SR ; OR ; NR R ; NR R ; NR R ; COOR 10 ; NO2; CN; C(O)R'°; or C(O)NR" V°
  • Each R is independently H, C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; haloalkyl; C1-C10 alkyl optionally substituted with 1-3 independent C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3- C10 cycloalkyl, C4-C10 cycloalkenyl, halo, CF3, OR , SR , NR R , COOR , NO2, CN, C(O)R , C(O)NR R , NHC(O)R , or OC(O)R ; or phenyl optionally substituted with 1-3 independent C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10
  • Each R is independently C(O)R , COOR , or S(O)2R ;
  • Each R is independently H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, or phenyl optionally substituted with 1-3 independent C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4- CIO cycloalkenyl, halo, CF3, OR 13 , SR 13 , NR 13 R 13 , COOR 13 , NO2, CN, C(O)R 13 , C(O)NR ,3 R 13 , NHC(O)R 13 , or OC(O)R 13 ;
  • Each R is independently selected from C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R ; halo; haloalkyl; CF3; SR 5 ; OR 5 ; NR 5 R 5 ; NRV; COOR 5 ; NO2; CN; C(O)R 5 ; C(O)C(O)R 5 ; C(O)NR 5 R 5 ; OC(O)R 5 ; S(O)2R 5 ; S(O)2NR 5 R 5 ; NR 5 C(O)NR 5 R 5 ; NR 5 C(O)C(O)R 5 ; NR 5 C(O)R 5 ; NR 5 (COOR 5 ); NR 5 C(O)R 8 ; NR 5 S(O)2NR 5 R 5 ; NR 5 S(O)2R 5
  • Each R is independently C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R ; C1-C10 alkyl substituted 7 9 with one or two independent aryl, R or R groups; or Cl-ClO alkenyl substituted with
  • Each R is independently H; Cl-ClO alkyl; C2-C10 alkenyl; C2-C10
  • Each R is independently selected from H, Cl-ClO alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R ; halo haloalkyl; CF3; SR 5 ; OR 5 ; NR 5 R 5 ; NRV; COOR 5 ; NO2; CN; C(O)R 5 ; C(O)C(O)R 5 C(O)NR 5 R 5 ; OC(O)R 5 ; S(O)2R 5 ; S(O)2NR 5 R 5 ; NR 5 C(O)NR 5 R 5 ; NR 5 C(O)C(O)R 5 NR 5 C(O)R 5 ; NR 5 (COOR 5 ); NR 5 C(O)R 8 ; NR 5 S(O)2NR 5 R 5 ; NR 5 S(O)2R 5 ;
  • Each R is independently H; Cl-ClO alkyl; C3-C10 cycloalkyl or phenyl;
  • Each haloalkyl is independently a Cl-ClO alkyl substituted with one or more halogen atoms, selected from F, Cl, Br, or I, wherein the number of halogen atoms may not exceed that number that results in a perhaloalkyl group;
  • Each aryl is independently a 6-carbon monocyclic or 10-carbon bicyclic aromatic ring system optionally substituted with 1-3 independent Cl-ClO alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; R ; halo; haloalkyl;
  • Preferred compounds of this embodiment are also those wherein X is O.
  • the compound has the formula directly above wherein each R 17 is independently selected from from H, Cl-ClO alkyl C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R 8 ; I; Br; F; CF 3 ; SR 5 ; OR 5 ; NR 5 R 5 ; NR 5 R 6 ; COOR 5 ; NO 2 ; CN; C(O)R 5 ; C(O)C(O)R C(O)NR 5 R 5 ; S(O) 2 NR 5 R 5 ; NR 5 C(O)NR 5 R 5 ; NR 5 C(O)C(O)R 5 ; NR 5 C(O)R !
  • each R is independently selected from NR R ; NR R ; NR C(O)NR R 5 ; NR C(O)C(O)R ;
  • NR 5 C(O)R 5 NR 5 (COOR 5 ); NR 5 C(O)R 8 ; NR 5 S(O)2NR 5 R 5 ; NR 5 S(O)2R 5 ; NR 5 S(O)2R 8 ; NR C(O)C(O)NR R ; or NR C(O)C(O)NR R .
  • 4 17 is of any of the formulae above, wherein at least two of R and or R are independently H. Preferred compounds of these embodiments are also those wherein X is O. In another embodiment, the inhibitory compound has the formula,
  • R is CN
  • NR -NR C(O)NR R NR -NR R ; NR -NR R ; Cl-ClO alkyl substituted with aryl, R , halo, CF3, SR 5 , OR 5 , OC(O)R 5 , NR 5 R 5 , NR 5 R 6 , COOR 5 , NO2, CN, C(O)R 5 ,
  • R is R ; COOR ; or Cl-ClO alkyl substituted with R , R , or phenyl substituted with 1-3 independent Cl-ClO alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3- C10 cycloalkyl, C4-C10 cycloalkenyl, R 9 , halo, CF3, OR 12 , SR 12 , NR I 2 R 12 , COOR* 2 , NO2, CN, C(O)R 12 , C(O)NR 12 R 12 , NHC(O)R 12 , NH(COOR 12 ), S(O)2NR l 2 R 12 , OC(O)R 12 , Cl-ClO alkyl substituted with R 9 , halo, CF3, OR 12 , SR 12 , NR 12 R 12 , COOR 12 , NO2, CN, C(O)R 12 , C(O)NR 12 R 12 , N
  • R is not unsubstituted furanyl, unsubstituted thienyl or unsubstituted pyridyl;
  • X is O or S;
  • Each R is independently H; Cl-ClO alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R ; Cl-ClO alkyl substituted
  • Each R is independently C(O)R , COOR , or S(O)2 R ;
  • Each R is independently halo, CF3, SR , OR , OC(O)R , NR R ,
  • Each R is independently a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system comprising 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, which may be saturated or unsaturated, and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent independently selected from Cl- C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; halo; sulfur; oxygen; CF3; haloalkyl; SR ; OR ; NR R ; NR R ; NR R ; NR R ;
  • Each R is independently C(O)R , COOR , or S(O)2R ;
  • Each R is independently H; C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; C1-C10 alkyl optionally substituted with halo, CF3, OR , SR , NR R , COOR , NO2, CN; or phenyl optionally
  • Each R 1 is independently Cl-ClO alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10
  • Each aryl is independently a 6-carbon monocyclic or 10-carbon bicyclic aromatic ring system optionally substituted with 1-3 independent Cl-ClO alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; R ; halo; haloalkyl CF3; OR* 2 ; SR 12 ; NR' 2 ; COOR 12 ; NO2; CN; C(O)R 12 ; C(O)C(O)R 12 ; C(O)NR 12 R 12 S(O)2R 12 ; N(R 12 )C(O)R 12 ; N(R 12 )(COOR 12 ); N(R 12 )S(O)2R 12 ; S(O)2NR 12 R i 2 OC(O)R 12 ; NR l2 C(O)NR 12 R 12 ; NR l C(O)C(O)R
  • R is R that is attached by a nitrogen atom in the R ring system.
  • Preferred compounds of these embodiments are also those wherein X is O.
  • the inhibitory compound has the formula,
  • R is one, two, or three substituents, each independently selected from H,
  • Each R 5 is independently H; Cl-ClO alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R ; Cl-ClO alkyl substituted
  • Each R is independently C(O)R , COOR , or S(O)2 R ; 7 10 10 10 10 10
  • NR R NR R , COOR , NO2, CN, C(O)R , or C(O)NR R ;
  • Each R is independently a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system comprising 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, which may be saturated or unsaturated, and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent independently selected from Cl- C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R ; halo; sulfur; oxygen; CF3; haloalkyl; SR ; OR ; OC(O)R ; NR R ; NR R ; NRV; COOR 5 ; NO2; CN; C(O)R 5 ; C(O)NR 5 R
  • Each R is independently a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system comprising 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, which may be saturated or unsaturated, and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent independently selected from Cl-
  • Each R 10 is independently H, C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; haloalkyl; C1-C10 alkyl optionally substituted with 1-3 independent C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3- C10 cycloalkyl, C4-C10 cycloalkenyl, halo, CF3, OR* 3 , SR 13 , NR' 3 , COOR 13 , NO2, CN, C(O)R , C(O)NR R , NHC(O)R , or OC(O)R ; or phenyl optionally substituted with 1-3 independent C1-C10 alkyl, C2-C10 alken
  • Each R is independently C(O)R , COOR , or S(O)2R ;
  • Each R 1 is independently H; Cl-ClO alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; Cl-ClO alkyl optionally substituted
  • Each R is independently Cl-ClO alkyl or both R may be taken together
  • Each haloalkyl is independently a Cl-ClO alkyl substituted with one or more halogen atoms, selected from F, Cl, Br, or I, wherein the number of halogen atoms may not exceed that number that results in a perhaloalkyl group;
  • this invention relates to a method of treating disease or disease symptoms, particularly kinase mediated disease or disease symptoms, in a mammal comprising the step of administering to said mammal a compound, or a composition comprising a compound, of any of the formulae described herein.
  • a mammal is a human.
  • this invention relates to a method of treating disease or disease symptoms in a mammal comprising the step of administering to said mammal a compound, or a composition comprising a compound, of any of the formulae described herein.
  • the mammal is a human.
  • halo refers to any radical of fluorine, chlorine, bromine or iodine.
  • alkyl alkenyl
  • alkynyl hydrocarbon chains that may be straight-chain or branched-chain, containing the indicated number of carbon atoms.
  • Cl-ClO indicates the group may have from 1 to 10 (inclusive) carbon atoms in it.
  • ring and “ring system” refer to a ring comprising the delineated number of atoms, said atoms being carbon or, where indicated, a heteroatom such as nitrogen, oxygen or sulfur. The ring itself, as well as any substitutents thereon, may be attached at any atom that allows a stable compound to be formed.
  • Kinases include, for example, protein kinases, lipid kinases (e.g., phosphatidylinositol kinases PI-3, PI-4) and carbohydrate kinases. Further information relating to kinase structure, function and and their role in disease or disease symptoms is available at the Protein Kinase Resource web site (http : //www . sdsc . edu/Kinases/pk home . tml ) . Kinases may be of prokaryotic, eukaryotic, bacterial, viral, fungal or archaea origin.
  • the compounds and compositions of the invention are therefore also particularly suited for treatment of diseases and disease symptoms that involve one or more of the aforementioned protein kinases.
  • the compounds, compositions or methods of this invention are particularly suited for inhibition of or treatment of disease or disease symptoms mediated by LCK, ZAP, LYN, EGFR, ERB-B2, KDR, ITK, BTK, or SYK.
  • the compounds, compositions or methods of this invention are particularly suited for inhibition of or treatment of disease or disease symptoms mediated by src-family kinases.
  • the compounds, compositions or methods of this invention are particularly suited for inhibition of or treatment of disease or disease symptoms mediated by kinases in one of the kinase families defined by Hardie & Hanks, ed. supra.
  • the compounds and compositions are also suited for regulating or modulating signal transduction in signal transduction pathways that involve one or more kinases, thus affecting events in a cell, and are therefor useful in methods for regulating or modulating signal transduction.
  • the inhibitors described herein are also useful for inhibiting the biological activity of any enzyme comprising greater than 90%, alternatively greater than 85%, or alternatively greater than 70% sequence homology with a kinase sequence, including the kinases mentioned herein.
  • the inhibitors described herein are also useful for inhibiting the biological activity of any enzyme comprising a subsequence, or variant thereof, of any enzyme that comprises greater than 90%, alternatively greater than 85%, or alternatively greater than 70% sequence homology with a kinase subsequence, including subsequences of the kinases mentioned herein.
  • Such subsequence preferably comprises greater than 90%, alternatively greater than 85%, or alternatively greater than 70% sequence homology with the sequence of an active site or subdomain of a kinase enzyme.
  • the subsequences, or variants thereof comprise at least about 300, or alternatively at least about 200, amino acids.
  • the inhibitors described herein are useful for inhibiting the biological activity of any enzyme that binds ATP and thus for treating disease or disease symptoms mediated by any enzyme that binds ATP.
  • the inhibitors described herein are also useful for inhibiting the biological activity of any enzyme that is involved in phosphofransfer and thus for treating disease or disease symptoms mediated by any enzyme that is involved in phosphotransfer.
  • the inhibitors described herein are also useful for inhibiting the biological activity of a polypeptide or enzyme having sequence homology with a kinase sequence and thus for treating disease or disease symptoms mediated by such polypeptide or enzyme.
  • polypeptides or enzymes may be identified by comparison of their sequence with kinase sequences and kinase catalytic domain sequences. For example, one method of comparison involves the database PROSITE (http://expasy.hcuge.ch), containing "signatures” or sequence patterns (or motifs) or profiles of protein families or domains.
  • inhibitors described herein are useful for inhibiting the biological activity of a polypeptide or enzyme comprising a sequence that comprises a "signature" or sequence pattern or profile derived for, and identified in PROSITE as relating to kinases, and for treating disease or disease symptoms mediated by such polypeptide or enzyme.
  • PROSITE motifs or consensus patterns identified as relating to kinases include PS00107, PS00108, PS00109, PS50011, PS00915, and PS00916.
  • kinase mediated diseases are those wherein a protein kinase is involved in signaling, mediation, modulation, or regulation of the disease process.
  • Kinase mediated diseases are exemplified by the following disease classes: cancer, autoimmunological, metabolic, inflammatory, infection (bacterial, viral, yeast, fungal, etc.), diseases of the central nervous system, degenerative neural disease, allergy/asthma, angiogenesis, neovascularization, vasculogenesis, cardiovascular, and the like.
  • the inhibitors described herein are useful for crystallizing or co-crystallizing with a protein kinase.
  • Such crystals or crystal complexes may additionally comprise additional peptides and or metal ions.
  • the crystals or crystal complexes may be used for investigation and determination of enzyme characteristics including, for example, structure of the kinase enzyme, enzyme active site domains, and inhibitor-enzyme interactions. This information is useful in developing inhibitor compounds with modified characteristics and for understanding structure-function relationships of the enzymes and their enzyme-inhibitor interactions.
  • the inhibitory compounds described herein may be used as platforms or scaffolds which may be utilized in combinatorial chemistry techniques for preparation of derivatives and/or chemical libraries of compounds.
  • Such derivatives and libraries of compounds have kinase inhibitory activity and are useful for identifying and designing compounds possessing kinase inhibitory activity.
  • Combinatorial techniques suitable for utilizing the compounds described herein are known in the art as exemplified by Obrecht, D.
  • tags or identifier or labeling moieties may be attached to and/or detached from the compounds of the formulae herein or their derivatives, to facilitate tracking, identification or isolation of the desired products or their intermediates.
  • moieties are known in the art.
  • the chemicals used in the aforementioned methods may include, for example, solvents, reagents, catalysts, protecting group and deprotecting group reagents and the like. Examples of such chemicals are those that appear in the various synthetic and protecting group chemistry texts and treatises referenced herein.
  • a "pharmaceutically acceptable derivative or prodrug” means any pharmaceutically acceptable salt, ester, salt of an ester, or other derivative of a compound of this invention which, upon administration to a recipient, is capable of providing (directly or indirectly) a compound of this invention.
  • Particularly favored derivatives and prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a mammal (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) relative to the parent species.
  • Preferred prodrugs include derivatives where a group which enhances aqueous solubility or active transport through the gut membrane is appended to the structure of formulae described herein.
  • an appropriate benzaldehyde (SI) is converted to pyrimidinone S2 by reaction with an appropriate cyanoacetate (or equivalent) S- methylisothiouronium sulphate.
  • Pyrimidinone S2 may be reacted with a substituted aniline or amine to form pyrimidinone S3.
  • a protected benzaldehyde (S4) may be reacted under the same conditions to provide pyrimidinone S5.
  • Pyrimidinone S5 can be subsequently reacted with an aniline, amine or other appropriate heteroatom nucleophile to provide pyrimidinone S6.
  • novel compounds of the present invention are excellent ligands for protein kinases, subsequences thereof, and homologous polypeptides. Accordingly, these compounds are capable of targeting and inhibiting kinase enzyme and subsequences thereof. Inhibition can be measured by various methods, including, for example, those methods illustrated in the examples below.
  • the compounds described herein may be used in assays, including radiolabelled, antibody detection and fluorometric, for the isolation, identification, or structural or functional characterization of enzymes, peptides or polypeptides.
  • the compound(s) are tested for activity in cellular assays of allergic mediator release.
  • the receptor-induced degranulation in mast cells or basophils leading to histamine release and the production of cytokines is a useful measure.
  • This assay is performed similarly to techniques described in the literature (3), and involves crosslinking of antigen-specific IgE on cells leading to degranulation and or cytokine production.

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Abstract

Cette invention concerne des inhibiteurs de kinases, des compositions renfermant ces inhibiteurs et des procédés d'utilisation desdits inhibiteurs et desdites compositions. Ces inhibiteurs et les compositions qui les renferment conviennent pour le traitement de pathologies et de leurs symptômes. L'invention concerne également des procédés de fabrication de composés inhibiteurs de kinases, des méthodes permettant d'inhiber l'activité kinase et des méthodes de traitement de pathologies et de leurs symptômes.
EP00905700A 1999-01-22 2000-01-21 Inhibiteurs de kinase Withdrawn EP1144390A2 (fr)

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PCT/US2000/001581 WO2000043373A2 (fr) 1999-01-22 2000-01-21 Inhibiteurs de kinase

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AU2734400A (en) 2000-08-07
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