WO2000043373A2 - Inhibiteurs de kinase - Google Patents

Inhibiteurs de kinase Download PDF

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Publication number
WO2000043373A2
WO2000043373A2 PCT/US2000/001581 US0001581W WO0043373A2 WO 2000043373 A2 WO2000043373 A2 WO 2000043373A2 US 0001581 W US0001581 W US 0001581W WO 0043373 A2 WO0043373 A2 WO 0043373A2
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Prior art keywords
coor
aryl
alkenyl
substituted
alkyl
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PCT/US2000/001581
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WO2000043373A3 (fr
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.
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Priority to CA002359680A priority Critical patent/CA2359680A1/fr
Priority to EP00905700A priority patent/EP1144390A2/fr
Priority to JP2000594789A priority patent/JP2002535318A/ja
Priority to AU27344/00A priority patent/AU768201B2/en
Publication of WO2000043373A2 publication Critical patent/WO2000043373A2/fr
Publication of WO2000043373A3 publication Critical patent/WO2000043373A3/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 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 ;
  • 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; haloalkyl; C1-C10 alkyl optionally substituted with 1-3 independent C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-
  • CN C(O)R 13 , C(O)NR l 3 R 13 , NHC(O)R°, or OC(O)R 13 ; or phenyl 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,
  • 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 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 haloalkyl is independently a C1-C10 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 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 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 19 , SR 19 , NR' 9 R 9 , COOR , NO2, CN;
  • 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 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 5 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 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 ; 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 ; NR R ;
  • 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 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 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-
  • 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-
  • 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 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 alkynyl; C3-C10
  • Each R is independently H; Cl -CIO 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 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
  • 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 ; 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 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- WO 00/43373 PCTVUSOO/01581
  • 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 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;
  • the invention also relates to methods of inhibiting enzyme or polypeptide activity, particularly of an enzyme or polypeptide described herein, such as a kinase, in a mammal comprising the step of administering to said mammal a compound of any of the formulae described herein or a composition comprising a compound of any of the formulae described herein.
  • the invention relates to a method of inhibiting kinase activity in a mammal comprising the step of administering to said mammal a compound, or a composition comprising a compound, of any one of the formulae described herein.
  • the mammal is a human.
  • the invention in another embodiment, relates to a method of inhibiting enzyme activity 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.
  • the invention also relates to methods of treating disease and/or disease symptoms, particularly those mediated by an enzyme or polypeptide described herein, such as kinase mediated disease or disease symptoms, in a mammal comprising the step of administering to said mammal a compound of any of the formulae described herein or a composition comprising a compound of any of the formulae described herein.
  • diseases or disease symptoms are described herein.
  • Kinase mediated disease or disease symptoms refers to disease or disease symptoms in which kinase activity is involved.
  • 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.
  • said mammal is preferably a human.
  • the inhibitors described herein are useful in inhibiting kinase activity in human cells and useful in murine and other species used as surrogates for investigating activity in vitro and in vivo in humans and against human kinases.
  • the inhibitors described herein are also useful for investigating inhibition and activity of kinases originating from species other than humans.
  • 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 described herein are useful as inhibitors of tyrosine, serine/threonine or histidine protein kinases.
  • 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.
  • transplant rejection e.g., kidney, liver, heart, lung, pancreas (islet cells), bone marrow, cornea, small bowel, skin allografts or xenografts
  • graft versus host disease osteoarthritis, rheumatoid arthritis, multiple sclerosis, diabetes, diabetic retinopathy, asthma, inflammatory bowel disease (Crohn's disease, ulcerative colitis), renal disease, cachexia, septic shock, lupus, diabetes mellitus, myasthenia gravis, psoriasis, dermatitis, eczema, seborrhea, Alzheimer's disease, Parkinson's disease, stem cell protection during chemotherapy, ex vivo selection or ex vivo purging for autologous or allogeneic bone marrow transplantation, leukemia (acute myeloid, chronic myeloid, acute lymphoblastic, etc.
  • leukemia acute myeloid, chronic myeloid, acute lymphoblastic, etc.
  • compositions and methods described herein are useful in treating or preventing rheumatoid arthritis, transplant rejection, asthma or allergy, or their symptoms.
  • Another embodiment envisioned by this invention relates to the use of the kinase inhibitory compounds described herein for use as reagents that effectively bind to kinases.
  • the compounds of this invention, and their derivatives may be derivatized to bind to a stable resin as a tethered substrate for affinity chromatography applications.
  • the compounds of this invention, and their derivatives may also be modified (e.g., radiolabelled or affinity labelled, etc.) in order to utilize them in the investigation of enzyme or polypeptide characterization, structure, and/or function.
  • 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.
  • one embodiment relates to a method of using the compounds described in the formulae herein for generating derivatives or chemical libraries comprising: 1) providing a body comprising a plurality of wells; 2) providing one or more compounds of the formulae described herein in each well; 3) providing an additional one or more chemicals in each well; 4) isolating the resulting one or more products from each well.
  • An alternate embodiment relates to a method of using the compounds described in the formulae herein for generating derivatives or chemical libraries comprising: 1) providing one or more compounds of the formulae described herein attached to a solid support; 2) treating the one or more compounds of the formulae described herein attached to a solid support with one or more additional chemicals; 3) isolating the resulting one or more products from the solid support.
  • 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.
  • the compounds of the formulae herein may be used to study the mechanism and role of proteins in biological pathways and processes involving kinases.
  • the compounds of the formulae herein may also be used as probes to identify new kinase enzymes or polypeptides with sequence homology to kinases.
  • the inhibitor compounds may be tethered to a support or modified (e.g., tagged, radiolabeled or other identifiable detection method) such that the compound may be detected and isolated in the presence of the kinase enzyme or polypeptide.
  • another embodiment relates to a method of identifying and/or isolating a kinase enzyme or polypeptide with sequence homology to a kinase enzyme sequence or subsequence, comprising, contacting a tethered or modified compound of any of the formulae herein with one or more polypeptides, isolating a polypeptide/inhibitor complex, and identifying or isolating the sequence of the polypeptide in the polypeptide/inhibitor complex.
  • the identification of the polypeptide sequence may be performed while in the polypeptide/inhibitor complex or after the polypeptide is decomplexed from the tethered or modified compound of any of the formulae herein.
  • Table 1 lists representative individual compounds of the invention and compounds employed in the compositions and methods of this invention.
  • stable refers to compounds which possess stability sufficient to allow manufacture and which maintains the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a mammal or for use in affinity chromatography applications). Typically, such compounds are stable at a temperature of 40 °C or less, in the absence of excessive moisture for at least one week.
  • the compounds of this invention including the compounds of formulae described herein, are defined to include pharmaceutically acceptable derivatives or prodrugs thereof.
  • 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.
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases.
  • suitable acid salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, palmoate, pec
  • Salts derived from appropriate bases include alkali metal (e.g., sodium), alkaline earth metal (e.g., magnesium, calcium, magnesium, calcium, magnesium, calcium, magnesium, calcium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium
  • the compounds of this invention may be synthesized using conventional techniques.
  • these compounds are conveniently synthesized from readily available starting materials.
  • the compounds of the formulae described herein are conveniently obtained via methods illustrated in General Synthetic Schemes I-IV and the Examples herein. These general schemes are also exemplified by the specific methods described in the Examples section below.
  • one embodiment relates to a method of making a compound of the formulae described herein, comprising synthesizing any one or more intermediates illustrated in the synthetic schemes herein and then converting that intermediate(s) to a compound of the formulae described herein.
  • Another embodiment relates to a method of making a compound of the formulae described herein, comprising synthesizing any one or more intermediates illustrated in the examples herein and then converting that intermediate(s) to a compound of the formulae described herein.
  • Another embodiment relates to a method of making a compound of the formulae described herein, comprising synthesizing any one or more intermediates illustrated in the synthetic schemes herein and then converting that intermediate(s) to a compound of the formulae described herein utilizing one or more of the chemical reactions described in the synthetic schemes or examples herein.
  • Nucleophilic agents are known in the art and are described in the chemical texts and treatises referred to herein.
  • the chemicals used in the aforementioned methods may include, for example, solvents, reagents, catalysts, protecting group and deprotecting group reagents and the like.
  • the methods described above may also additionally comprise steps, either before or after the steps described specifically herein, to add or remove suitable protecting groups in order to ultimately allow synthesis of the compound of the 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.
  • one embodiment relates to a method of making a compound of the formulae described herein, comprising 1) the step of reacting an aldehyde (or equivalent) with a cyanoacetate (or equivalent) and an alkylisothiouronium salt to form a pyrimidinone; 2) reacting said pyrimidinone with a nucleophilic agent (e.g., an aniline or amine) to form the compound of the formulae described herein.
  • Nucleophilic agents are known in the art and are described in the chemical texts and treatises referred to herein. Such agents may have carbon or a heteroatom (e.g, N, O, S) as the nucleophilic atom.
  • the method of making a compound of the formulae described herein comprises 1) preparation of a thio-substituted pyrimidone intermediate (as exemplified by S2, S5, SIO and S12 in the General Synthetic Schemes); and 2) reacting the pyrimidinone of step 1 with another chemical to form the compound of the formulae described herein.
  • the chemicals used in the aforementioned methods may include, for example, solvents, reagents, catalysts, protecting group and deprotecting group reagents and the like.
  • the methods described above may also additionally comprise steps, either before or after steps 1 and 2 described above, to add or remove suitable protecting groups in order to ultimately allow synthesis of the compound of the formulae described herein.
  • the compounds of this invention may be modified by appending appropriate functionalities to enhance selective biological properties.
  • modifications are known in the art and include those which increase biological penetration into a given biological compartment (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.
  • 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.
  • Such assays include any assay wherein a nucleoside or nucleotide are cofactors or substrates of the peptide of interest, and particularly any assay involving phosphofransfer in which the substrates and or cofactors are ATP, GTP, Mg, Mn, peptides or polymeric amino acids.
  • Pharmaceutical compositions of this invention comprise a compound of the formulae described herein or a pharmaceutically acceptable salt thereof; an additional agent selected from an immunosuppressant, an anticancer agent, an anti-viral agent, antiinflammatory agent, antifungal agent, antibiotic, or an anti-vascular hyperproliferation compound; and any pharmaceutically acceptable carrier, adjuvant or vehicle.
  • compositions of this invention comprise a compound of the formulae described herein or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier, adjuvant or vehicle.
  • Such compositions may optionally comprise additional therapeutic agents, including, for example, immunosuppressants, anti-cancer agents, anti-viral agents, antiinflammatory agents, antifungal agents, antibiotics, or anti-vascular hyperproliferation compounds.
  • pharmaceutically acceptable carrier or adjuvant refers to a carrier or adjuvant that may be administered to a patient, together with a compound of this invention, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound.
  • Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d- ⁇ -tocopherol polyethyleneglycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-
  • Cyclodextrins such as ⁇ -, ⁇ -, and ⁇ -cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl- ⁇ -cyclodextrins, or other solubilized derivatives may also be advantageously used to enhance delivery of compounds of the formulae described herein.
  • compositions of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir, preferably by oral administration or administration by injection.
  • the pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles.
  • the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form.
  • parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
  • the pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3- butanediol.
  • suitable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms such as emulsions and or suspensions.
  • compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions.
  • carriers which are commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried corn starch.
  • compositions of this invention may also be administered in the form of suppositories for rectal administration.
  • a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components.
  • suitable non-irritating excipient include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.
  • Topical administration of the pharmaceutical compositions of this invention is especially useful when the desired treatment involves areas or organs readily accessible by topical application.
  • the pharmaceutical composition should be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier.
  • Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water.
  • the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier with suitable emulsifying agents.
  • Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • the pharmaceutical compositions of this invention may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topically- transdermal patches are also included in this invention.
  • compositions of this invention may be administered by nasal aerosol or inhalation.
  • Such compositions are prepared according to techniques well- known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, abso ⁇ tion promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
  • Dosage levels of between about 0.01 and about 100 mg/kg body weight per day, alternatively between about 0.5 and about 75 mg kg body weight per day of the kinase inhibitory compounds described herein are useful in a monotherapy and/or in combination therapy for the prevention and treatment of kinase mediated disease.
  • the pharmaceutical compositions of this invention will be administered from about 1 to about 6 times per day or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. A typical preparation will contain from about 5% to about 95% active compound (w/w).
  • compositions of this invention comprise a combination of a kinase inhibitor of the formulae described herein and one or more additional therapeutic or prophylactic agents
  • both the kinase inhibitor and the additional agent should be present at dosage levels of between about 10 to 100%, and more preferably between about 10 to 80% of the dosage normally administered in a monotherapy regimen.
  • the additional agents may be administered separately, as part of a multiple dose regimen, from the compounds of this invention. Alternatively, those agents may be part of a single dosage form, mixed together with the compounds of this invention in a single composition.
  • the pharmaceutical compositions of this invention comprise an additional immunosuppression agent.
  • additional immunosuppression agents include, but are not limited to, cyclosporin A, FK506, rapamycin, leflunomide, deoxyspergualin, prednisone, azathioprine, mycophenolate mofetil, OKT3, ATAG, interferon and mizoribine.
  • the pharmaceutical compositions of this invention may additionally comprise cytotoxic or hormonal anti-cancer agents or combinations thereof.
  • anti-cancer agents include, but are not limited to, cis- platin, actinomycin D, doxorubicin, vincristine, vinblastine, etoposide, amsacrine, mitoxantrone, tenipaside, taxol, taxotere, colchicine, cyclosporin A, phenothiazines, interferons, thioxantheres, anti-estrogens (e.g., tamoxifen), aromatase inhibitors, anti- androgens, and LHRH antagonists.
  • anti-cancer agents include, but are not limited to, cis- platin, actinomycin D, doxorubicin, vincristine, vinblastine, etoposide, amsacrine, mitoxantrone, tenipaside, taxol, taxotere
  • compositions of this invention may additionally comprise an anti-viral agent.
  • anti-viral agents include, but are not limited to, Cytovene, Ganciclovir, trisodium phosphonoformate, Ribavirin, d4T, ddl, AZT, amprenavir and acyclovir.
  • a maintenance dose of a compound, composition or combination of this invention may be administered, if necessary.
  • the dosage or frequency of administration, or both may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level, treatment should cease.
  • Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.
  • this invention provides methods of treating, preventing, or relieving symptoms of disease in a mammal comprising the step of administrating to said mammal any of the pharmaceutical compositions and combinations described above.
  • the mammal is a human.
  • such methods may additionally comprise the step of administering to said mammal an additional therapeutic agent, such as an antiinflammatory agent, immunosuppressant, an anti-cancer agent, an anti-viral agent, or an anti-vascular hype ⁇ roliferation compound.
  • additional agent may be administered to the mammal prior to, concurrently with, or following the administration of the inhibitor composition.
  • the compounds of this invention may contain one or more asymmetric centers and thus occur as racemates and racemic mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures. All such isomeric forms of these compounds are expressly included in the present invention.
  • the compounds of this invention may also be represented in multiple tautomeric forms, for example, as illustrated below:
  • the invention expressly includes all tautomeric forms of the compounds described herein.
  • the compounds may also occur in cis- or trans- or E- or Z- double bond isomeric forms. All such isomeric forms of such compounds are expressly included in the present invention. All crystal forms of the compounds described herein are expressly included in the present invention.
  • ring moieties e.g., phenyl, thienyl, etc.
  • ring moieties may be attached to specific atoms, whereby they are intended to be fixed to that atom, or they may be drawn unattached to a specific atom (see below), whereby they are intended to be attached at any available atom that is not already substituted by an atom other than H (hydrogen).
  • a mixture of 25 mg (.09 mmol) of the product from Example 1 and 200 mg of p- chloroaniline is heated by heat gun until a homogeneous solution is obtained.
  • the reaction is heated at 170°C until such time as the solution solidifies.
  • the product is broken up and suspended in dichloromethane and filtered while washing with excess dichloromethane.
  • kinases suitable for use in the following protocol to determine kinase activity of the compounds described herein include, but are not limited to: Lck, Lyn, Src, Fyn, Syk, Zap- 70, Itk, Tec, Btk, EGFR, ErbB2, Kdr, Flt-1, Flt-3, Tek, c-Met, InsR.
  • kinases are expressed as either kinase domains or full length constructs fused to glutathione S-transferase (GST) or polyHistidine tagged fusion proteins in either E. coli or Baculovirus-High Five expression systems. They are purified to near homogeneity by affinity chromatography essentially as previously described (Lehr et al., 1996; Gish et al., 1995). In some instances, kinases are co-expressed or mixed with purified or partially purified regulatory polypeptides prior to measurement of activity.
  • Kinase activity and inhibition are measured essentially by established protocols (Braunwalder et al., 1996). Briefly, The transfer of 33 PO 4 from ATP to the synthetic substrates poly(Glu, Tyr) 4:1 or poly(Arg, Ser) 3:1 attached to the bioactive surface of microtiter plates serves as the basis to evaluate enzyme activity. After an incubation period, the amount of phosphate transferred is measured by first washing the plate with 0.5% phosphoric acid, adding liquid scintillant, and then counting in a liquid scintillation detector. The IC 50 is determined by the concentration of compound that causes a 50% reduction in the amount of 33 P inco ⁇ orated onto the substrate bound to the plate.
  • kinase activity can be measured using antibody-based methods whereby an antibody or polypeptide is used as a reagent to detect phosphorylated target polypeptide.
  • the compounds of the invention described herein are potent and selective kinase inhibitors as demonstrated by representative compounds described herein that inhibit one or more kinases with ICso values at less than about 5 ⁇ M or greater, at less than about 1 ⁇ M, or at less than about 300 nM.
  • Typical sources for cells include, but are not limited to, human bone marrow or peripheral blood lymphocytes, or their equivalents, or rodent spleen cells.
  • Transformed cell lines that have been reported as cytokine- and growth factor-dependent cells are available from standard cell banks such as The American Type Culture Collection (Bethesda, MD). Cells genetically manipulated to express a particular kinase or kinases are also suitable for use in assaying cellular activity.
  • GIBCO/BRL Gibco-BCO/BRL (Grand Island, NY) supplemented with fetal bovine serum.
  • Cellular activity may also be measured using bacterial, yeast, or virally infected mammalian cells.
  • Standard inhibitors of cell activation include mycophenolic acid (SIGMA, St. Louis, MO), staurosporine (Calbiochem, San Diego, CA), wortmannin (Calbiochem), cyclosporine, FK-506, and steroids (e.g., corticosteroids).
  • the compound(s) are tested for activity in cellular assays of T or B cell activation.
  • the receptor-induced production of cytokines and/or cell proliferation is a useful measure.
  • This assay is performed similarly to techniques described in the literature (1,2), and involves antibody-, antigen-, mitogen-, or antigen presenting cell-mediated crosslinking of the T cell or B cell receptor with or without engagement of co-stimulatory receptors.
  • 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.
  • the compound(s) are tested for activity in cellular assays of growth factor effects.
  • growth factor receptor-induced signaling in a cell leading to intracellular signaling events such as kinase autophosphorylation, phosphorylation of relevant kinase substrates, phosphorylation of MAP kinases, or induction of gene expression.
  • growth factor-induced functional events in cells such as DNA synthesis, proliferation, migration, or apoptosis.
  • the compound(s) are tested for activity in cellular assays of cytokine activation.
  • cytokine-induced intracellular signaling events and/or cell proliferation and/or cytokine production are a useful measure.
  • This assay is performed similarly to techniques described in the literature (8), and involves addition of cytokine to responsive cells followed by monitoring intracellular signaling events and/or cell proliferation and/or cytokine production.
  • JAK3 are differentially regulated by tyrosine phosphorylation. Current Biology. 7 (11): 817-826 (1997).

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.
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JP2000594789A JP2002535318A (ja) 1999-01-22 2000-01-21 キナーゼ阻害薬
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WO2001025220A1 (fr) * 1999-10-07 2001-04-12 Amgen Inc. Inhibiteurs de triazine kinase
WO2001060816A1 (fr) * 2000-02-17 2001-08-23 Amgen Inc. Inhibiteurs de kinases
US6864255B2 (en) 2001-04-11 2005-03-08 Amgen Inc. Substituted triazinyl amide derivatives and methods of use
US6881737B2 (en) 2001-04-11 2005-04-19 Amgen Inc. Substituted triazinyl acrylamide derivatives and methods of use
US7105530B2 (en) 2000-12-21 2006-09-12 Smithkline Beecham Corporation Pyrimidineamines as angiogenesis modulators
US7122544B2 (en) 2000-12-06 2006-10-17 Signal Pharmaceuticals, Llc Anilinopyrimidine derivatives as IKK inhibitors and compositions and methods related thereto
US7129242B2 (en) 2000-12-06 2006-10-31 Signal Pharmaceuticals, Llc Anilinopyrimidine derivatives as JNK pathway inhibitors and compositions and methods related thereto
WO2006099075A3 (fr) * 2005-03-10 2007-04-26 Cgi Pharmaceuticals Inc Amides substitues, procede pour les produire et procede pour les utiliser
WO2008033854A1 (fr) 2006-09-11 2008-03-20 Cgi Pharmaceuticals, Inc. Amides substitués, procédé de production et d'utilisation desdits amides
US7351729B2 (en) 2002-03-08 2008-04-01 Signal Pharmaceuticals, Llc JNK inhibitors for use in combination therapy for treating or managing proliferative disorders and cancers
US7423148B2 (en) 2002-11-21 2008-09-09 Chiron Corporation Small molecule PI 3-kinase inhibitors and methods of their use
JP2010502750A (ja) * 2006-09-11 2010-01-28 シージーアイ ファーマシューティカルズ，インコーポレイティド 特定の置換型アミド、その製造方法及び使用方法
CN102206207A (zh) * 2011-04-15 2011-10-05 南京邮电大学 4-芳基嘧啶或4-杂环芳基嘧啶化合物发光材料及其制备方法
US8173647B2 (en) 2007-02-06 2012-05-08 Gordana Atallah PI 3-kinase inhibitors and methods of their use
US8217035B2 (en) 2006-01-20 2012-07-10 Novartis Ag Pyrimidine derivatives used as PI-3-kinase inhibitors
WO2014014933A1 (fr) * 2012-07-20 2014-01-23 Merck Sharp & Dohme Corp. Dérivés de pyrimidinone amido-substituée pouvant être utilisés en vue du traitement de l'infection par le vih
US8865894B2 (en) 2012-02-24 2014-10-21 Novartis Ag Oxazolidin-2-one compounds and uses thereof
US8957068B2 (en) 2011-09-27 2015-02-17 Novartis Ag 3-pyrimidin-4-yl-oxazolidin-2-ones as inhibitors of mutant IDH
US9221840B2 (en) 2011-05-17 2015-12-29 Discoverybiomed Inc. Treating protein folding disorders with small molecule CFTR correctors
US9296733B2 (en) 2012-11-12 2016-03-29 Novartis Ag Oxazolidin-2-one-pyrimidine derivative and use thereof for the treatment of conditions, diseases and disorders dependent upon PI3 kinases
US9434719B2 (en) 2013-03-14 2016-09-06 Novartis Ag 3-pyrimidin-4-yl-oxazolidin-2-ones as inhibitors of mutant IDH
US9546176B2 (en) 2012-11-20 2017-01-17 Discoverybiomed, Inc. Small molecule bicyclic and tricyclic CFTR correctors
US9676779B2 (en) 2012-11-20 2017-06-13 Discoverybiomed, Inc. Small molecule CFTR correctors
WO2019055832A1 (fr) * 2017-09-15 2019-03-21 The Regents Of The University Of California Compositions et procédés d'inhibition de la n-smase2
KR20200061823A (ko) * 2018-11-26 2020-06-03 고려대학교 산학협력단 뇌종양 줄기세포의 세포사멸 유도 활성을 갖는 피리미딘온 유도체 화합물의 용도
WO2021046034A1 (fr) * 2019-09-05 2021-03-11 University Of Houston System Modulateurs à petites molécule du récepteur nucléaire des oxystérols et leurs utilisations

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WO2001025220A1 (fr) * 1999-10-07 2001-04-12 Amgen Inc. Inhibiteurs de triazine kinase
US7074789B2 (en) 1999-10-07 2006-07-11 Amgen Inc. Kinase inhibitors
WO2001060816A1 (fr) * 2000-02-17 2001-08-23 Amgen Inc. Inhibiteurs de kinases
US7282504B2 (en) 2000-02-17 2007-10-16 Amgen Inc. Kinase inhibitors
US7129242B2 (en) 2000-12-06 2006-10-31 Signal Pharmaceuticals, Llc Anilinopyrimidine derivatives as JNK pathway inhibitors and compositions and methods related thereto
US7442699B2 (en) 2000-12-06 2008-10-28 Signal Pharmaceuticals, Llc Anilinopyrimidine derivatives as IKK inhibitors and compositions and methods related thereto
US7122544B2 (en) 2000-12-06 2006-10-17 Signal Pharmaceuticals, Llc Anilinopyrimidine derivatives as IKK inhibitors and compositions and methods related thereto
US7105530B2 (en) 2000-12-21 2006-09-12 Smithkline Beecham Corporation Pyrimidineamines as angiogenesis modulators
US7858626B2 (en) 2000-12-21 2010-12-28 Glaxosmithkline Llc Pyrimidineamines as angiogenesis modulators
US7262203B2 (en) 2000-12-21 2007-08-28 Smithkline Beecham Corporation Pyrimidineamines as angiogenesis modulators
US8114885B2 (en) 2000-12-21 2012-02-14 Glaxosmithkline Llc Chemical compounds
US6881737B2 (en) 2001-04-11 2005-04-19 Amgen Inc. Substituted triazinyl acrylamide derivatives and methods of use
US6864255B2 (en) 2001-04-11 2005-03-08 Amgen Inc. Substituted triazinyl amide derivatives and methods of use
US7351729B2 (en) 2002-03-08 2008-04-01 Signal Pharmaceuticals, Llc JNK inhibitors for use in combination therapy for treating or managing proliferative disorders and cancers
US7423148B2 (en) 2002-11-21 2008-09-09 Chiron Corporation Small molecule PI 3-kinase inhibitors and methods of their use
US7767669B2 (en) 2002-11-21 2010-08-03 Novartis Ag Small molecule PI 3-kinase inhibitors and methods of their use
WO2006099075A3 (fr) * 2005-03-10 2007-04-26 Cgi Pharmaceuticals Inc Amides substitues, procede pour les produire et procede pour les utiliser
US7947835B2 (en) 2005-03-10 2011-05-24 Cgi Pharmaceuticals, Inc. Certain substituted amides, method of making, and method of use thereof
AU2006223409B2 (en) * 2005-03-10 2011-07-21 Gilead Connecticut, Inc. Certain substituted amides, method of making, and method of use thereof
US8563549B2 (en) 2006-01-20 2013-10-22 Novartis Ag Pyrimidine derivatives used as PI-3 kinase inhibitors
US8217035B2 (en) 2006-01-20 2012-07-10 Novartis Ag Pyrimidine derivatives used as PI-3-kinase inhibitors
WO2008033854A1 (fr) 2006-09-11 2008-03-20 Cgi Pharmaceuticals, Inc. Amides substitués, procédé de production et d'utilisation desdits amides
AU2007296559B2 (en) * 2006-09-11 2013-01-17 Gilead Connecticut, Inc. Certain substituted amides, method of making, and method of use thereof
JP2010502750A (ja) * 2006-09-11 2010-01-28 シージーアイ ファーマシューティカルズ，インコーポレイティド 特定の置換型アミド、その製造方法及び使用方法
US8058446B2 (en) 2006-09-11 2011-11-15 Gilead Connecticut, Inc. Certain substituted amides, method of making, and method of use thereof
US8173647B2 (en) 2007-02-06 2012-05-08 Gordana Atallah PI 3-kinase inhibitors and methods of their use
CN102206207A (zh) * 2011-04-15 2011-10-05 南京邮电大学 4-芳基嘧啶或4-杂环芳基嘧啶化合物发光材料及其制备方法
CN102206207B (zh) * 2011-04-15 2015-05-06 南京邮电大学 4-芳基嘧啶或4-杂环芳基嘧啶化合物发光材料及其制备方法
US9221840B2 (en) 2011-05-17 2015-12-29 Discoverybiomed Inc. Treating protein folding disorders with small molecule CFTR correctors
US8957068B2 (en) 2011-09-27 2015-02-17 Novartis Ag 3-pyrimidin-4-yl-oxazolidin-2-ones as inhibitors of mutant IDH
US9458177B2 (en) 2012-02-24 2016-10-04 Novartis Ag Oxazolidin-2-one compounds and uses thereof
US8865894B2 (en) 2012-02-24 2014-10-21 Novartis Ag Oxazolidin-2-one compounds and uses thereof
WO2014014933A1 (fr) * 2012-07-20 2014-01-23 Merck Sharp & Dohme Corp. Dérivés de pyrimidinone amido-substituée pouvant être utilisés en vue du traitement de l'infection par le vih
US9296733B2 (en) 2012-11-12 2016-03-29 Novartis Ag Oxazolidin-2-one-pyrimidine derivative and use thereof for the treatment of conditions, diseases and disorders dependent upon PI3 kinases
US10202371B2 (en) 2012-11-12 2019-02-12 Novartis Ag Oxazolidin-2-one-pyrimidine derivatives and the use thereof as phosphatidylinositol-3-kinase inhibitors
US9546176B2 (en) 2012-11-20 2017-01-17 Discoverybiomed, Inc. Small molecule bicyclic and tricyclic CFTR correctors
US9676779B2 (en) 2012-11-20 2017-06-13 Discoverybiomed, Inc. Small molecule CFTR correctors
US9434719B2 (en) 2013-03-14 2016-09-06 Novartis Ag 3-pyrimidin-4-yl-oxazolidin-2-ones as inhibitors of mutant IDH
US9688672B2 (en) 2013-03-14 2017-06-27 Novartis Ag 3-pyrimidin-4-yl-oxazolidin-2-ones as inhibitors of mutant IDH
US10112931B2 (en) 2013-03-14 2018-10-30 Novartis Ag 3-pyrimidin-4-yl-oxazolidin-2-ones as inhibitors of mutant IDH
WO2019055832A1 (fr) * 2017-09-15 2019-03-21 The Regents Of The University Of California Compositions et procédés d'inhibition de la n-smase2
KR20200061823A (ko) * 2018-11-26 2020-06-03 고려대학교 산학협력단 뇌종양 줄기세포의 세포사멸 유도 활성을 갖는 피리미딘온 유도체 화합물의 용도
KR102159277B1 (ko) * 2018-11-26 2020-09-23 고려대학교 산학협력단 뇌종양 줄기세포의 세포사멸 유도 활성을 갖는 피리미딘온 유도체 화합물의 용도
WO2021046034A1 (fr) * 2019-09-05 2021-03-11 University Of Houston System Modulateurs à petites molécule du récepteur nucléaire des oxystérols et leurs utilisations
CN114599638A (zh) * 2019-09-05 2022-06-07 休斯敦大学*** 小分子肝x受体调节剂及其用途

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