WO2001081340A2 - Heterocycles that are inhibitors of impdh enzyme - Google Patents

Heterocycles that are inhibitors of impdh enzyme Download PDF

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WO2001081340A2
WO2001081340A2 PCT/US2001/012900 US0112900W WO0181340A2 WO 2001081340 A2 WO2001081340 A2 WO 2001081340A2 US 0112900 W US0112900 W US 0112900W WO 0181340 A2 WO0181340 A2 WO 0181340A2
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hydrogen
substituted
compound
formula
alkyl
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PCT/US2001/012900
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French (fr)
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WO2001081340A3 (en
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Edwin J. Iwanowicz
Scott H. Watterson
T. G. Murali Dhar
William J. Pitts
Henry H. Gu
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Bristol-Myers Squibb Company
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Priority to AU5553801A priority Critical patent/AU5553801A/en
Priority to JP2001578430A priority patent/JP2003531205A/en
Priority to AU2001255538A priority patent/AU2001255538B2/en
Priority to EP01928708A priority patent/EP1276739A2/en
Priority to CA002407370A priority patent/CA2407370A1/en
Publication of WO2001081340A2 publication Critical patent/WO2001081340A2/en
Publication of WO2001081340A3 publication Critical patent/WO2001081340A3/en

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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P35/02—Antineoplastic agents specific for leukemia
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    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to novel compounds which inhibit IMPDH, and to methods of making such compounds.
  • the invention also encompasses pharmaceutical compositions containing these compounds.
  • the compounds and pharmaceutical compositions of the invention are particularly well suited for inhibiting IMPDH enzyme activity and, consequently, can be advantageously used as therapeutic agents for IMPDH-associated disorders.
  • This invention also relates to methods for inhibiting the activity of IMPDH using the compounds of this invention alone or in combination with other pharmaceutically active agents .
  • Inosine monophosphate dehydrogenase has been shown to be a key enzyme in the regulation of cell proliferation and differentiation. Nucleotides are required for cells to divide and replicate. In mammals, nucleotides may be synthesized through one of two pathways : the de novo synthesis pathway or the salvage pathway. The extent of utilization of each pathway is dependent on the cell type. This selectivity has ramifications with regard to therapeutic utility as described below.
  • IMPDH is involved in the de novo synthesis of guanosine nucleotides.
  • IMPDH catalyzes the irreversible NAD-dependent oxidation of inosine-5 ' -monophosphate ("IMP") to xanthosine-5' -monophosphate ("XMP"), Jackson et al., Nature 256:331-333 (1975).
  • IMPDH is ubiquitous in eukaryotes, bacteria and protozoa. The prokaryotic forms share 30-40% sequence identity with the human enzyme.
  • IMPDH type I and type II Two distinct cDNA's encoding IMPDH have been identified and isolated. These transcripts are labeled type I and type II and are of identical size (514 amino acids). Collart et al . , J. Biol. Chem. 263:15769-15772 (1988); Natsu eda et al . , J. Biol. Chem. 265:5292-5295 (1990); and U.S. Patent 5,665,583 to Collart et al . These isoforms share 84% sequence identity. IMPDH type I and type II form tetramers in solution, the enzymatically active unit.
  • B and T-lymphocytes depend on the de novo, rather than salvage pathway, to generate sufficient levels of nucleotides necessary to initiate a proliferative response to mitogen or antigen. Due to the B and T cell's unique reliance on the de novo pathway, IMPDH is an attractive target for selectively inhibiting the immune system without also inhibiting the proliferation of other cells.
  • Immunosuppression has been achieved by inhibiting a variety of enzymes .
  • examples include phosphatase calcineurin (inhibited by cyclosporin and FK-506) ; dihydroorotate dehydrogenase (DHODase) , an enzyme involved in the biosynthesis of pyrimidines (inhibited by leflunomide and brequinar) ; the kinase FRAP (inhibited by rapamycin) ; and the heat shock protein hsp70 (inhibited by deoxyspergualin) .
  • Inhibitors of IMPDH have also been described in the art.
  • WO 97/40028 and U.S. Patent 5,807,876 describe a class of urea derivatives that possess a common urea backbone.
  • WO 98/40381 describes a series of heterocyclic substituted anilines as inhibitors of IMPDH.
  • MPA mycophenolic acid
  • WO 94/01105 and WO 94/12184 describe mycophenolic acid (“MPA”) and some of its derivatives as potent, uncompetitive, reversible inhibitors of human IMPDH type I and type II. MPA has been demonstrated to block the response of B and T-cells to mitogen or antigen.
  • Immunosuppressants such as MPA and derivatives of MPA, are useful drugs in the treatment of transplant rejection and autoimmune disorders, psoriasis, inflammatory diseases, including, rheumatoid arthritis, tumors and for the treatment of allograft rejection. These are described in U.S. Pat. Nos. 4,686,234,
  • cyclic AMP agonists such as Rolipram (Schering AG) , a Type 4 Phosphodiesterase Inhibitor (PDE4) and immunomodulator, synergized with IMPDH inhibitor MPA by a cAMP- and IMPDH-dependent dependent mechanism.
  • Rolipram Schering AG
  • PDE4 Type 4 Phosphodiesterase Inhibitor
  • immunomodulator synergized with IMPDH inhibitor MPA by a cAMP- and IMPDH-dependent dependent mechanism.
  • Rolipram [4- [3- (cyclopentyloxy) -4-methoxy-phenyl] -2- pyrrolidinone] .
  • cyclic AMP agonists such as the PDE4 inhibitor Rolipram (Rol)
  • Rolipram PDE4 inhibitor
  • the potential for a very low concentration of Rol (10 ⁇ 7 M, approximate ICio) to synergize with a variety of immunosuppressive agents used for the prevention and/or treatment of allograft rejection was defined.
  • MPA is a selective, uncompetitive, and reversible inhibitor of IMPDH, a key enzyme in the purine salvage pathway, the potential for cAMP-mediated crosstalk at this locus was further investigated. It was found that gene expression for IMPDH types I and II (assessed by RT-PCR) remained unaffected by the administration of rolipram, MPA, or both at low and high concentrations. However, functional reversal of the synergistic effect was demonstrated with the use of deoxyguanosine, a specific antagonist of MPA on IMPDH (% inhibition of proliferation 81 ⁇ 16 vs. 35 ⁇ 12, p ⁇ 0.05).
  • Mycophenolate mofetil sold under the trade name CELLCEPT, is a prodrug which liberates MPA in vivo . It is approved for use in preventing acute renal allograft rejection following kidney transplantation. The side effect profile limits the therapeutic potential of this drug.
  • MPA is rapidly metabolized to the inactive glucuronide in vivo . In humans, the blood levels of glucuronide exceed that of MPA. The glucuronide undergoes enterohepatic recycling causing accumulation of MPA in the bile and subsequently in the gastrointestinal tract. This together with the production of the inactive glucuronide effectively lowers the drug's in vivo potency, while increasing its undesirable gastrointestinal side effects.
  • type II mRNA is preferentially upregulated in human leukemic cell lines K562 and H -60. Weber, J. Biol. Chem. 266: 506-509 (1991).
  • cells from human ovarian tumors and leukemic cells from patients with chronic granulocytic, lymphocytic and acute myeloid leukemias also display an up regulation type II mRNA. This disproportionate increase in IMPDH activity in malignant cells may be addressed through the use of an appropriate IMPDH inhibitor.
  • IMPDH has also been shown to play a role in the proliferation of smooth muscle cells, indicating that inhibitors of IMPDH may be useful in preventing restenosis or other hyperproliferative vascular diseases.
  • IMPDH has been shown to play a role in viral replication in some viral cell lines. Carr, J. Biol. Chem. 268:27286-27290 (1993).
  • the IMPDH inhibitor VX- 497 is currently being evaluated for the treatment of hepatitis C virus in humans . Ribavirin has also been used in the treatment of hepatitis C and B viruses and when used in combination with interferon an enhancement in activity was observed.
  • the IMPDH inhibitor ribavirin is limited by its lack of a sustained response in monotherapy and broad cellular toxicity.
  • inhibitors of IMPDH with improved pharmacological properties, physical properties and fewer side effects.
  • Such inhibitors would have therapeutic potential as immunosuppressants, anti-cancer agents, anti-vascular hyperproliferative agents, antiinflammatory agents, antifungal agents, antipsoriatic and anti-viral agents.
  • the compounds of the present invention are effective inhibitors of IMPDH.
  • X 2 is CR 3 or N;
  • X 3 is-NH-, -0-, or -S-;
  • X 4 is CR 4 or N
  • X 5 is CR 5 or N
  • X 6 is CR 6 or N;
  • R 1 is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, NR 8 R 9 , SR 20 , cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycloalkyl, or heteroaryl;
  • R 2 is halogen, cyano, nitro, hydroxy, oxo (double bond is no longer present between CR 2 and X 6 ), SR 7 , S(0)R 7 , S0 2 R 7 , S0 2 NR 8 R 9 , C0 2 R 7 , C(0)NR 8 R 9 , or heteroaryl;
  • R 3 is hydrogen, hydroxy, halogen, cyano, C0R 7 , NR 8 R 9 , alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycloalkyl or heteroaryl;
  • R 4 , R 5 , and R 6 are independently selected from the group consisting of hydrogen, halogen, nitro, cyano, O-R 7 , NR 8 R 9 , SR 7 , S(0)R 7 , S0 2 R 7 , S0 3 R 7 , S0 2 NR 8 R 9 , C0 2 R 7 , C(0)NR 8 R 9 , C(O) lkyl, C (0) substituted alkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl and substituted alkynyl;
  • R 7 , R 10 , and R 11 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, cycloalkyl, substituted cycloalkyl, C(0) alkyl, C (0) substituted alkyl, C (O) cycloalkyl, C(0) substituted cycloalkyl, C(0)aryl, C (O) substituted aryl, C(0) Oalkyl, C (0) Osubstituted alkyl, C (O) heterocycloalkyl, C (0) heteroaryl, aryl, substituted aryl, heterocycloalkyl and heteroaryl ;
  • R 8 and R 9 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, alkynyl, C(O) alkyl, C (0) substituted alkyl, C (0) cycloalkyl, C
  • R 20 is alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl or heterocycloalkyl;
  • R 3 and R 1 may be taken together with the carbon atoms to which they are attached to form a monocyclic or substituted monocyclic ring system of 5 or 6 carbon atoms;
  • R 4 and R 5 may be joined together by the chain -O-CH 2 -O- or -0-CH 2 -CH 2 -0- .
  • the present invention provides a method of treating inosine monophosphate dehydrogenase associated disorders comprising: administering a therapeutically effective amount of a compound of formula (I)
  • X 2 is CR 3 or N
  • X 3 is-NH-, -0-, or -S-;
  • X 4 is CR 4 or N
  • X 5 is CR 5 or N
  • X 6 is CR 6 or N
  • R 1 is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, NR 8 R 9 , SR 20 , cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycloalkyl, or heteroaryl;
  • R 2 is halogen, cyano, nitro, hydroxy, oxo (double bond is no longer present between CR 2 and X 6 ), SR 7 , S(0)R 7 , S0 2 R 7 , S0 2 NR 8 R 9 , C0 2 R 7 , C(0)NR 8 R 9 , or heteroaryl;
  • R 3 is hydrogen, hydroxy, halogen, cyano, C0 2 R 7 , NR 8 R 9 , alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycloalkyl or heteroaryl;
  • R 4 , R 5 , and R 6 are independently selected from the group consisting of hydrogen, halogen, nitro, cyano, O-R 7 , NR 8 R 9 , SR 7 , S(0)R 7 , S0 2 R 7 , S0 3 R 7 , S0 2 NR 8 R 9 , C0 2 R 7 , C(0)NR 8 R 9 , C(0) lkyl, C (0) substituted alkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl and substituted alkynyl;
  • R 7 , R 10 , and R 11 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, cycloalkyl, substituted cycloalkyl, C(O) alkyl, C (0) substituted alkyl, C (O) cycloalkyl, C(0) substituted cycloalkyl, C(0)aryl, C (0) substituted aryl, C(0)0alkyl, C (0) Osubstituted alkyl, C (O) heterocycloalkyl , C (0) heteroaryl, aryl, substituted aryl, heterocycloalkyl and heteroaryl;
  • R 8 and R 9 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, alkynyl, C(0) alkyl, C (0) substituted alkyl, C (0) cycloalkyl, C (0) substituted cycloalkyl, C(0)aryl, C (0) substituted aryl, C(0)0alkyl, C (0) Osubstituted alkyl, C (0) heterocycloalkyl, C (0) heteroaryl, aryl, substituted aryl, heterocycloalkyl, and heteroaryl or R 8 and R 9 taken together with the nitrogen atom to which they are attached complete a heterocycloalkyl or heteroaryl ring;
  • R 20 is alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl or heterocycloalkyl;
  • R 3 and R 1 may be taken together with the carbon atoms to which they are attached to form a monocyclic or substituted monocyclic ring system of 5 or 6 carbon atoms;
  • R 4 and R 5 may be joined together by the chain -0-CH 2 -0- or -O-CH2-CH 2 -O- .
  • the present invention provides a method of treating inosine monophosphate dehydrogenase associated disorders comprising: administering a therapeutically effective amount of a compound of formula (II)
  • R 2 is a monocyclic substituted or unsubstituted heteroaryl group .
  • the present invention provides a method of treating inosine monophosphate dehydrogenase associated disorders comprising: administering a therapeutically effective amount of a compound of formula (III)
  • R 2 is 4-oxazolyl, substituted 4-oxazolyl, 5-oxazolyl, or substituted 5-oxazolyl;
  • R 3 is hydrogen, hydroxy, NR 8 R 9 , alkyl of 1 to 4 carbons, alkenyl of 2 to 4 carbons, alkynyl of 2 to 4 carbons, substituted alkyl of 1 to 4 carbons, phenyl, substituted phenyl, cycloalkyl of 5 to 7 carbons, substituted cycloalkyl of 5 to 7 carbons, monocyclic heterocycloalkyl and monocyclic heteroaryl;
  • R 4 is hydrogen, halogen, nitro, hydroxy, alkyl of 1 to 4 carbons, cyano, CF 3 , OCF 3 , OCH 3 , SCH 3 , S(0)CH 3 , or S(0) 2 CH 3 ;
  • R 6 is hydrogen, halogen, nitro, hydroxy, alkyl of 1 to 4 carbons, cyano, CF 3 , 0CH 3 , 0CF 3 , SCH 3 , S(0)CH 3 , and S(0) 2 CH 3 .
  • the present invention provides a method of treating inosine monophosphate dehydrogenase associated disorders comprising: administering a therapeutically effective amount of a compound including isomers, enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, prodrugs and solvates wherein: R 2 is 4-oxazolyl, substituted 4-oxazolyl, 5-oxazolyl, substituted 5-oxazolyl or heteroaryl;
  • R 3 is hydrogen, hydroxy, halogen, methyl or NR 8 R 9 ;
  • R 4 is hydrogen;
  • R 5 is halogen, methyl, ethyl, substituted alkenyl, alkyne, OMe or 0CF 3 ; and R 5 is hydrogen.
  • the present invention provides a method of treating inosine monophosphate dehydrogenase associated disorders comprising: administering a therapeutically effective amount of a compound including isomers, enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, prodrugs and solvates wherein: R 2 is 4-oxazolyl, substituted 4-oxazolyl, 5-oxazolyl or substituted 5-oxazolyl;
  • R 3 is hydrogen, hydroxy, halogen or methyl
  • R 4 is hydrogen;
  • R 5 is halogen, methyl or OMe;
  • R 6 is hydrogen
  • the present invention provides a method of treating inosine monophosphate dehydrogenase associated disorders comprising: administering a therapeutically effective amount of a phosphodiesterase Type 4 inhibitor and a compound of formula (X) :
  • X 2 is CR 3 or N;
  • X 3 is-NH-, -0-, or -S-;
  • X 4 is CR 4 or N;
  • X 5 is CR 5 or N;
  • X 6 is CR 6 or N;
  • R 1 is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, NR 8 R 9 , SR 20 , cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycloalkyl, or heteroaryl;
  • R 2 is halogen, cyano, nitro, hydroxy, oxo (double bond is no longer present between CR 2 and X 6 ), SR 7 , S(0)R 7 , S0 2 R 7 , S0 2 NR 8 R 9 , C0 2 R 7 , C(0)NR 8 R 9 , or heteroaryl;
  • R 3 is hydrogen, hydroxy, halogen, cyano, C0 2 R 7 , NR 8 R 9 , alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted
  • R 4 , R 5 , and R ⁇ are independently selected from the group consisting of hydrogen, halogen, nitro, cyano, O-R 7 , NR 8 R 9 , SR 7 , S(0)R 7 , S0 2 R 7 , S0 3 R 7 , S0 2 NR 8 R 9 , C0 2 R 7 , C(0)NR 8 R 9 , C(O) alkyl, C (0) substituted alkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl and substituted alkynyl;
  • R 7 , R 10 , and R 11 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, cycloalkyl, substituted cycloalkyl, C(O) alkyl, C (0) substituted alkyl, C (0) cycloalkyl, C(0) substituted cycloalkyl, C(0)aryl, C (0) substituted aryl, C(0)0alkyl, C (0) Osubstituted alkyl, C (0) heterocycloalkyl, C (0) heteroaryl, aryl, substituted aryl, heterocycloalkyl and heteroaryl;
  • R 8 and R 9 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, alkynyl, C(O) alkyl, C (0) substituted alkyl, C (0) cycloalkyl, C (0)
  • R 20 is alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl or heterocycloalkyl;
  • R 3 and R 1 may be taken together with the carbon atoms to which they are attached to form a monocyclic or substituted monocyclic ring system of 5 or 6 carbon atoms; and R 4 and R 5 may be joined together by the chain -O-CH2-O- or -O-CH2-CH2-O-.
  • the present invention provides a method for the treatment or prevention of allograft rejection comprising: administering a therapeutically effective amount of a phosphodiesterase Type 4 inhibitor and a compound of formula (X) :
  • X 2 is CR 3 or N
  • X 3 is-NH-, -0-, or -S-;
  • X 4 is CR 4 or N
  • X 5 is CR 5 or N
  • X 6 is CR 6 or N
  • R 1 is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, NR 8 R 9 , SR 20 , cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycloalkyl, or heteroaryl;
  • R 2 is halogen, cyano, nitro, hydroxy, oxo (double bond is no longer present between CR 2 and X 6 ), SR 7 , S(0)R 7 , S0 2 R 7 , S0 2 NR 8 R 9 , C0 2 R 7 , C(0)NR 8 R 9 , or heteroaryl;
  • R 3 is hydrogen, hydroxy, halogen, cyano, C0 2 R 7 , NR 8 R 9 , alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycloalkyl or heteroaryl;
  • R 4 , R 5 , and R 6 are independently selected from the group consisting of hydrogen, halogen, nitro, cyano, 0-R 7 , NR 8 R 9 , SR 7 , S(0)R 7 , S0 2 R 7 , S0 3 R 7 , S0 2 NR 8 R 9 , C0 2 R 7 , C(0)NR 8 R 9 , C(O) alkyl, C (0) substituted alkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl and substituted alkynyl;
  • R 7 , R 10 , and R 11 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, cycloalkyl, substituted cycloalkyl, C(0)alkyl, C (0) ubstituted alkyl , C (0) cycloalkyl, C(O) substituted cycloalkyl, C(0)aryl, C (O) substituted aryl, C(0)0alkyl, C (0) Osubstituted alkyl, C (0) heterocycloalkyl , C (0) heteroaryl, aryl, substituted aryl, heterocycloalkyl and heteroaryl;
  • R 8 and R 9 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, alkynyl, C(0)alkyl, C (0) substituted alkyl , C (0) cyclo
  • R 20 is alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl or heterocycloalkyl;
  • R 3 and R 1 may be taken together with the carbon atoms to which they are attached to form a monocyclic or substituted monocyclic ring system of 5 or 6 carbon atoms;
  • R 4 and R 5 may be joined together by the chain -0-CHa-O- or -O-CH2-CH2-O- .
  • the phosphodiesterase Type 4 inhibitor is Rolipram.
  • the phosphodiesterase Type 4 inhibitor is [4- [3- (cyclopentyloxy) -4-methoxy-phenyl] -2-pyrrolidinone] .
  • the present invention provides a novel compound, comprising: a compound of formula (I)
  • X 2 is CR 3 or N
  • X 3 is-NH-, -0-, or -S-;
  • X 4 is CR 4 or N
  • X 5 is CR 5 or N
  • X 6 is CR 6 or N
  • R 1 is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycloalkyl, or heteroaryl;
  • R 2 is cyano, hydroxy, oxo (double bond is no longer present between CR 2 and X 6 ), SR 7 , S(0)R 7 , S0 2 R 7 , S0 2 NR 8 R 9 , C0 2 R 7 , C(0)NR 8 R 9 , or heteroaryl;
  • R 3 is hydrogen, hydroxy, halogen, cyano, C0 2 R 7 , NR 8 R 9 , alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycloalkyl or heteroaryl;
  • R 4 , R 5 , and R 6 are independently selected from the group consisting of hydrogen, halogen, nitro, cyano, 0-R 7 , NR 8 R 9 , SR 7 , S(0)R 7 , S0 2 R 7 , S0 3 R 7 , S0 2 NR 8 R 9 , C0 2 R 7 , C(0)NR 8 R 9 , C(O) alkyl, C (0) substituted alkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl and substituted alkynyl;
  • R 7 , R 10 , and R 11 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, cycloalkyl, substituted cycloalkyl, C(0) alkyl, C (0) substituted alkyl, C (0) cycloalkyl, C(0) substituted cycloalkyl, C(0)aryl, C (O) substituted aryl, C(0)0alkyl, C (0) Osubstituted alkyl, C (O) heterocycloalkyl, C (O) heteroaryl, aryl, substituted aryl, heterocycloalkyl and heteroaryl;
  • R 8 and R 9 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, alkynyl, C(0)alkyl, C (0) substituted alkyl , C (O) cycloalkyl, C (
  • R 3 and R 1 may be taken together with the carbon atoms to which they are attached to form a monocyclic or substituted monocyclic ring system of 5 or 6 carbon atoms ;
  • R 4 and R 5 may be joined together by the chain -O-CH2-O- or -O-CH 2 -CH 2 -O-;
  • Y is CH 2 , O or S, m and n are each greater than 1, and the sum of m and n is between 3 and 6 ;
  • the present invention provides a compound of formula (II)
  • R 2 is a monocyclic substituted or unsubstituted heteroaryl group.
  • R 2 is 4-oxazolyl, substituted 4-oxazolyl, 5-oxazolyl, or substituted 5-oxazolyl;
  • R 3 is hydrogen, hydroxy, NR 8 R 9 , alkyl of 1 to 4 carbons, alkenyl of 2 to 4 carbons, alkynyl of 2 to 4 carbons, substituted alkyl of 1 to 4 carbons, phenyl, substituted phenyl, cycloalkyl of 5 to 7 carbons, substituted cycloalkyl of 5 to 7 carbons, monocyclic heterocycloalkyl and monocyclic heteroaryl;
  • R 4 is hydrogen, halogen, nitro, hydroxy, alkyl of 1 to 4 carbons, cyano, CF 3 , OCF 3 , OCH 3 , SCH 3 , S(0)CH 3 , or
  • R 6 is hydrogen, halogen, nitro, hydroxy, alkyl of 1 to 4 carbons, cyano, CF 3 , 0CH 3 , OCF 3 , SCH 3 , S(0)CH 3 , and S(0) 2 CH 3 .
  • the present invention provides a compound including isomers, enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, prodrugs and solvates wherein :
  • R 2 is 4-oxazolyl, substituted 4-oxazolyl, 5-oxazolyl, substituted 5-oxazolyl or heteroaryl;
  • R 3 is hydrogen, hydroxy, halogen, methyl or NR 8 R 9 ;
  • R 4 is hydrogen
  • R 5 is halogen, methyl, ethyl, substituted alkenyl, alkyne, OMe or OCF 3 ; and R 6 is hydrogen.
  • the present invention provides a compound including isomers, enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, prodrugs and solvates wherein:
  • R 2 is 4-oxazolyl, substituted 4-oxazolyl, 5-oxazolyl or substituted 5-oxazolyl;
  • R 3 is hydrogen, hydroxy, halogen or methyl
  • R 4 is hydrogen;
  • R 5 is halogen, methyl or OMe;
  • R 6 is hydrogen
  • the present invention provides a compound of formula (V)
  • R 3 is hydrogen
  • R is hydrogen
  • R is hydrogen
  • R 1 is CH 3 and R 3 is hydrogen
  • R is CH 3 ;
  • R 3 is hydrogen
  • R is hydrogen
  • R 3 is hydrogen
  • R is hydrogen
  • R is hydrogen
  • R- 1 - is
  • R is hydrogen
  • R is hydrogen
  • R is hydrogen
  • R is hydrogen
  • R is hydrogen
  • R is hydrogen
  • R is hydrogen
  • R is hydrogen
  • R is hydrogen
  • R 3 is hydrogen
  • R is hydrogen
  • R is hydrogen
  • R is hydrogen
  • R is hydrogen
  • R is hydrogen
  • R is Br
  • R is hydrogen
  • R is hydrogen
  • R 3 is hydrogen
  • R 3 is hydrogen
  • R 3 is hydrogen
  • R ,3 is hydrogen
  • R is hydrogen
  • R is hydrogen
  • R 3 is hydrogen
  • R is hydrogen
  • R 3 is hydrogen
  • R is hydrogen
  • R is hydrogen
  • R is hydrogen
  • R is hydrogen
  • R is hydrogen
  • R is hydrogen
  • R is hydrogen
  • R is hydrogen
  • R is hydrogen
  • R 3 is hydrogen
  • R is hydrogen
  • R 3 is hydrogen
  • R is hydrogen
  • R is hydrogen
  • R is hydrogen
  • R is hydrogen
  • R 3 is hydrogen
  • R is hydrogen
  • R ,3 is hydrogen
  • R is hydrogen
  • R is hydrogen
  • R 3 is hydrogen
  • R 3 is hydrogen
  • R is hydrogen
  • R is hydrogen
  • R is hydrogen
  • R is hydrogen
  • R is hydrogen
  • R is hydrogen
  • R is hydrogen
  • R is hydrogen
  • R is hydrogen
  • R 3 is hydrogen
  • R 3 is hydrogen
  • R is hydrogen
  • R is hydrogen
  • R is hydrogen
  • R 3 is hydrogen
  • R is hydrogen
  • R is hydrogen
  • R 3 is hydrogen
  • R is hydrogen
  • R is hydrogen
  • R is hydrogen
  • R is hydrogen
  • R 3 is hydrogen
  • R is hydrogen
  • R is hydrogen
  • R 3 is hydrogen
  • R is hydrogen
  • the present invention provides a compound including isomers, enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, prodrugs and solvates thereof selected from:
  • the present invention provides a pharmaceutical composition comprising: a compound of the invention and a pharmaceutically acceptable carrier.
  • the present invention provides a method of treating inosine monophosphate dehydrogenase associated disorders comprising: administering an effective amount of the pharmaceutical composition of the invention.
  • the present invention provides a method of treating inosine monophosphate dehydrogenase associated disorders comprising: administering an effective amount of the pharmaceutical composition of the invention and another agent known to be useful in treatment of such disorders .
  • the present invention provides a method of treating inosine monophosphate dehydrogenase associated disorders comprising: administering a therapeutically effective amount of the pharmaceutical composition of the invention and a phosphodiesterase Type 4 inhibitor.
  • the present invention provides a method for the treatment or prevention of allograft rejection comprising: administering a therapeutically effective amount of the pharmaceutical composition of the invention and a phosphodiesterase Type 4 inhibitor.
  • alkyl refers to straight or branched chain hydrocarbon groups having 1 to 12 carbons atoms , preferably 1 to 8 carbon atoms, and most preferably 1 to 4 carbon atoms .
  • substituted alkyl refers to an alkyl group as defined above having one, two, or three substituents selected from the group consisting of halo, cyano, O-R 7 , S-R 7 , NR 8 R 9 , nitro, cycloalkyl, substituted cycloalkyl, oxo, aryl, substituted aryl, heterocycloalkyl, heteroaryl, C0 2 R 7 , S(0)R 7 , S0 2 R 7 , S0 3 R 7 , S0NR 8 R 9 , C(0)NR 8 R 9 , C(O) alkyl, and C(0)H.
  • alkenyl refers to straight or branched chain hydrocarbon groups having 2 to 12 carbon atoms and one, two or three double bonds, preferably 2 to 6 carbon atoms and one double bond.
  • substituted alkenyl refers to an alkenyl group as defined above having one, two, or three substituents selected from the group consisting of halo, cyano, O-R 7 , S-R 7 , NR 8 R 9 , nitro, cycloalkyl, substituted cycloalkyl, oxo, aryl, substituted aryl, heterocycloalkyl, heteroaryl, C0 2 R 7 , S(0)R 7 , S0 2 R 7 , S0 3 R 7 , S0 2 NR 8 R 9 , C(0)NR 8 R 9 , C(O) alkyl, and C(0)H.
  • alkynyl refers to straight or branched chain hydrocarbon group having 2 to 12 carbon atoms and one, two or three triple bonds, preferably 2 to 6 carbon atoms and one triple bond.
  • substituted alkynyl refers to an alkynyl group as defined above having one, two or three substituents selected from the group consisting of halo, cyano, O-R 7 , S-R 7 , NR 8 R 9 , nitro, cycloalkyl, substituted cycloalkyl, oxo, aryl, substituted aryl, heterocycloalkyl, heteroaryl, C0 2 R 7 , S(0)R 7 , S0 2 R 7 , S0 3 R 7 , S0 2 NR 8 R 9 , C(0)NR 8 R 9 , C(O) alkyl, and C(0)H.
  • halo refers to chloro, bromo, fluoro, and iodo.
  • cycloalkyl refers to fully saturated and partially unsaturated monocyclic hydrocarbon rings of 3 to 9, preferably 3 to 7 carbon atoms. Also included in this definition are bicyclic rings where the cycloalkyl ring as defined above has a fused aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, or heteroaryl ring provided that the point of attachment is in the cycloalkyl ring, i.e.
  • a cycloalkyl ring as defined above having a two or three carbon bridge or a spirocycloalkyl in which a carbon atom of the cycloallkyl ring has a carbon atom in common with a second cycloalkyl, substituted cycloalkyl, or heterocycloalkyl ring again provided that the point of attachment is in the
  • substituted cycloalkyl refers to such cycloalkyl group as defined above having one, two or three substituents selected from the group consisting of halogen, nitro, alkyl, substituted alkyl, alkenyl, cyano, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycloalkyl, heteroaryl, oxo, OR 7 , CO 2 R 7 , C(0)NR 8 R 9 , OC(0)R 7 , OC(0)OR 7 , OC(0)NR 8 R 9 , OCH 2 C0 2 R 7 , C(0)R 7 , NR 8 R 9 , NR 10 C(O)R 7 , NR 10 C(O)OR 7 , NR 10 C (O) C (0) OR 7 , NR 10 C(O)C(O)NR 8 R 9 , NR 10 C (0) C (0) alkyl, NR 10 C (NCN) OR 7 ,
  • aryl refers to the phenyl, 1-naphthyl, and 2-naphthyl, preferably phenyl, as well as an aryl ring having a fused cycloalkyl, substituted cycloalkyl, heterocycloalkyl, or heteroaryl ring provided that the point of attachment is in the aryl ring, i.e.
  • substituted aryl refers to such aryl groups as defined above having one, two, or three substituents selected from the group consisting of halogen, nitro, alkyl, substituted alkyl, alkenyl, cyano, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycloalkyl, heteroaryl, OR 7 , C0 2 R 7 , C(0)NR 8 R 9 , 0C(0)R 7 , 0C(0)0R 7 , OC(0)NR 8 R 9 , OCH 2 C0 2 R 7 , C(0)R 7 , NR 8 R 9 , NR 10 C(O)R 7 , NR 10 C(O)OR 7 , NR 10 C (O) C (0) OR 7 , NR 10 C (0) C (0) NR 8 R 9 , NR 10 C(O)C(O) alkyl, NR 10 C (NCN) OR 7 , NR 10 C (O) C (0) OR
  • NR 10 C( NC) (CR 12 R 13 )rR 7 , NR 10 CO (CR 12 R 13 ) rNR 8 R 9 , NR 10 (CR 12 R 13 )mOR 7 , NR 10 ( CR 12 R 13 ) rC0 R 7 , NR 10 ( CR 12 R 13 ) mNR 8 R 9 , NR 10 ( CR 12 R 13 ) nS0 2 ( CR 14 R 15 ) qR 7 , CONR 10 ( CR 1 R 13 ) nS0 2 ( CR 14 R 15 ) qR 7 , S0 2 NR 10 ( CR 12 R 13 ) nCO ( CR 14 R 15 ) qR 7 , and S0 2 NR 10 ( CR 12 R 13 ) mOR 7 as well as pentaf luorophenyl .
  • substituted monocyclic ring system of 5 or 6 carbon atoms refers to one, two or three substituents selected from the group consisting of halogen, nitro, alkyl, substituted alkyl, alkenyl, cyano, oxo, OR 7 , cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycloalkyl, heteroaryl, C0 2 R 7 , C(0)NR 8 R 9 , OC(0)R 7 , OC(0)OR 7 , OC(0)NR 8 R 9 , OCH 2 C0 R 7 , C(0)R 7 , NR 8 R 9 ,
  • heterocycloalkyl refers to substituted and unsubstituted saturated or partially saturated monocyclic rings of 3 to 7 members and bicyclic rings of 7 to 11 members having one or two 0 or S atoms and/or one to four N atoms provided that the total number of heteroatoms is four or less and that the heterocycloalkyl ring contains at least one carbon atom.
  • the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen atoms may optionally be quaternized.
  • the bicyclic heterocycloalkyl ring may also contain a two or three carbon bridge between available carbon or nitrogen atoms .
  • the bicyclic heterocycloalkyl rings may also have a cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycloalkyl, or heteroaryl ring fused to the monocyclic ring provided that the point of attachment is through an available carbon or nitrogen atom of the heterocycloalkyl ring. Also included are spiroheterocycloalkyl rings wherein a carbon atom of the heterocycloalkyl ring is in common with a second heterocycloalkyl ring, a cycloalkyl ring, or a substituted cycloalkyl ring again provided that the point of attachment is through an available carbon or nitrogen atom of the heterocycloalkyl ring.
  • the heterocycloalkyl ring can have one, two or three substituents on available carbon or nitrogen atoms selected from the group consisting of halogen, nitro, alkyl, substituted alkyl, alkenyl, cyano, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycloalkyl, heteroaryl, oxo, OR 7 , C0 2 R 7 , C(0)NR 8 R 9 , OC(0)R 7 , OC(0)OR 7 , OC(0)NR 8 R 9 , OCH 2 C0 2 R 7 , C(0)R 7 , NR 8 R 9 , NR 10 C(0)R 7 , NR 10 C(O)OR 7 , NR 10 C (0) C (0) C (0) OR 7 , NR 10 C(O)C(O)NR 8 R 9 , NR 10 C (0) C (0) alkyl , NR 10 C (NCN) OR 7 , NR 10 C(O)NR
  • Exemplary monocyclic heterocycloalkyl groups include pyrrolidinyl, pyrrolinyl, pyrazolinyl, pyrazolidinyl , oxetanyl, imidazolinyl , imidazolidinyl, oxazolidinyl, isothiazolidinyl, isoxazolinyl, thiazolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, tetrahydrothiopyranyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, tetrahydrothiopyranylsulfone, 1, 3-dioxolanyl, tetrahydro-1, 1-dioxothienyl, dioxanyl, thietanyl, thiiranyl,
  • Exemplary bicyclic heterocycloalkyl groups include indolinyl, quinuclidinyl, tetrahydroisoquinolinyl, benzimidazolinyl, chromanyl, dihydrobenzofuran, dihydrofuro [3 , 4-b] pyridinyl, dihydroisoindolyl, dihydroquinazolinyl (such as 3 , 4-dihydro-4-oxo- quinazolinyl) , benzofurazanyl, benzotriazolinyl, dihydrobenzofuryl , dihydrobenzothienyl , dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, dihydrobenzopyranyl, isoindolinyl, isochromanyl, benzodioxolyl, tetrahydroquinolinyl, etc.
  • Exemplary spirocyclic heterocycloalkyl groups include 1-aza [4.5] spirodecane, 2-aza [4.5] spirodecane, 1- aza [5.5] spiroundecane, 2-aza [5.5] spiroundecane, 3- aza [5.5] spiroundecane, etc.
  • heteroaryl refers to substituted and unsubstituted aromatic 5 or 6 membered monocyclic groups and 9 or 10 membered bicyclic groups which have at least one heteroatom (0,S or N) in at least one of rings.
  • Each ring of the heteroaryl groups containing a heteroatom can contain one or two 0 and S atoms and/or from one to four N atoms provided that the total number of heteroatoms in each ring is four or less.
  • the bicyclic heteroaryl rings are formed by fusing a cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycloalkyl, or heteroaryl group to the monocyclic heteroaryl ring as defined above.
  • the heteroaryl group is attached via an available carbon or nitrogen in the aromatic heteroaryl ring.
  • the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atoms may optionally be quaternized.
  • the heteroaryl ring system may be substituted at an available carbon or nitrogen by one, two, or three substituents selected from the group consisting of halogen, nitro, alkyl, substituted alkyl, alkenyl, cyano, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycloalkyl, heteroaryl, OR 7 , C0 2 R 7 , C(0)NR 8 R 9 , OC(0)R 7 , OC(0)OR 7 , OC(0)NR 8 R 9 , OCH 2 C0 2 R 7 , C(0)R 7 , NR 8 R 9 , NR 10 C(O)R 7 , NR 10 C (0) OR 7 , NR 10 C (0) C (0) OR 7 , NR 10 C (0) C (0) OR 7 , NR 10 C(O)C(O)NR 8 R 9 , NR 10 C (0) C (0) alkyl, NR 10 C (NCN) OR 7 , NR 10
  • NR 10 NR 8 R 9 N(COR 7 )OR 10 , N (C0 2 R 7 ) OR 10 , C (0) NR 10 (CR 12 R 13 ) r R 7 , CO ( CR 12 R 13 ) pO ( CR 1 R 15 ) qC0 2 R 7 , CO ( CR 12 R 13 ) rOR 7 , CO ( CR 12 R 13 ) pO ( CR 14 R 15 ) qR 7 , CO ( CR 12 R 13 ).
  • NR 10 C( NC) (CR 12 R 13 )rR 7 , NR 10 CO (CR 12 R 13 ) rNR 8 R 9 , NR 10 (CR 12 R 13 )mOR 7 , NR 10 (CR 12 R 13 ) rC0 2 R 7 , NR 10 (CR 12 R 13 ) mNR 8 R ,
  • Exemplary monocyclic heteroaryl groups include pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, furyl, thienyl, oxadiazolyl, 2-oxazepinyl, azepinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, etc.
  • Exemplary bicyclic heteroaryl groups include benzothiazolyl, benzoxazolyl, benzothienyl, benzofuryl, quinolinyl, quinolinyl-N-oxide, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, cinnolinyl, quinoxalinyl , indazolyl, pyrrolopyridyl, furopyridinyl (such as furo [2 , 3-c] pyridinyl, furo [3 , 1-b] pyridinyl or furo [2 , 3-b] yridinyl) , benzisothiazolyl, benzisoxazolyl, benzodiazinyl, benzothiopyranyl, benzotriazolyl , benzpyrazolyl, naphthyridinyl , phthalazinyl, purinyl, pyridopyridy
  • R 12 and R 14 are independently selected from hydrogen and alkyl of 1 to 4 carbons .
  • R 13 and R 15 are independently selected from hydrogen, alkyl of 1 to 4 carbons, and substituted alkyl of 1 to 4 carbons .
  • n is zero or an integer from 1 to 4.
  • m is an integer from 2 to 6.
  • p is an integer from 1 to 3.
  • q is zero or an integer from 1 to 3.
  • r is zero or an integer from 1 to 6.
  • IMPDH-associated disorders refers to any disorder or disease state in which inhibition of the enzyme IMPDH (inosine monophosphate dehydrogenase, ECl.1.1.205, of which there are presently two known isozymes referred to as IMPDH type 1 and IMPDH type 2 ) would modulate the activity of cells (such as lymphocytes or other cells) and thereby ameliorate or reduce the symptoms or modify the underlying cause (s) of that disorder or disease. There may or may not be present in the disorder or disease an abnormality associated directly with the IMPDH enzyme.
  • IMPDH inosine monophosphate dehydrogenase
  • IMPDH-associated disorders include transplant rejection and autoimmune disorders, such as rheumatoid arthritis, multiple sclerosis, juvenile diabetes, asthma, and inflammatory bowel disease, as well as inflammatory disorders, cancer and tumor disorders, T- cell mediated hypersensitivity diseases, ischemic or reperfusion injury, viral replication diseases, proliferative disorders and vascular diseases.
  • treating includes prophylactic and therapeutic uses, and refers to the alleviation of symptoms of a particular disorder in a patient, the improvement of an ascertainable measurement associated with a particular disorder, or the prevention of a particular immune response (such as transplant rejection) .
  • patient refers to a mammal, preferably a human.
  • the compounds of this invention may contain one or more asymmetric carbon atoms and thus may occur as racemates and racemic mixtures, .single enantiomers, diastereomeric mixtures and individual diastereomers. All such isomers of the compounds disclosed herein are expressly included within the scope of the present invention.
  • Each stereogenic carbon may be of the R or S configuration.
  • stable refers to compounds which possess stability sufficient to allow manufacture and which maintain their integrity for a sufficient period of time to be useful as a therapeutic or diagnostic agent.
  • the compounds of this invention are defined to include pharmaceutically acceptable derivatives and prodrugs thereof.
  • a "pharmaceutically acceptable derivative or prodrug” includes any pharmaceutically acceptable salt, ester, salt of an ester, or other derivative of a compound of the present invention which, upon administration to a subject, is capable of providing (directly or indirectly) a compound of the invention.
  • Particularly favored derivatives and prodrugs are those that increase the bioavailability of the compounds of the present invention when such compound is administered to a subject (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 that enhances aqueous solubility or active transport through the gut membrane is appended to a compound of the present invention.
  • Pharmaceutically acceptable salts of the compounds disclosed herein include those derived from pharmaceutically acceptable inorganic and organic acids and bases known to those skilled in the art.
  • suitable acid salts include, but are not limited to, the following: 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
  • Salts derived from appropriate bases include, but are not limited to, the following: alkali metal (e.g., sodium), alkaline earth metal (e.g., magnesium), ammonium and N-(C ] __4 alkyl ) ⁇ + salts.
  • alkali metal e.g., sodium
  • alkaline earth metal e.g., magnesium
  • ammonium e.g., ammonium
  • the present invention also envisions the quaternization of any basic nitrogen- containing groups of the compounds disclosed herein. Water- or oil-soluble or dispersible products may be obtained by such quaternization.
  • the compounds of the present invention may be synthesized using conventional techniques known in the art. Advantageously, these compounds are conveniently synthesized from readily available starting materials. Following are general synthetic schemes for manufacturing compounds of the present invention. These, schemes are illustrative and are not meant to limit the possible techniques one skilled in the art may use to manufacture compounds disclosed herein. Different methods will be evident to those skilled in the art. Additionally, the various steps in the synthesis may be performed in an alternate sequence or order to give the desired compound (s) . All documents cited herein are incorporated herein by reference in their entirety.
  • a general method for the synthesis of the anilines such as (la.4) useful in this invention can be perfomed by metal catalyzed cross coupling methods known in the literature.
  • the simplest case is a Suzuki type cross coupling (Miyaura, N. , Yanagi, T. Suzuki, A., Synth. Comm. 11(7) :513-519 (1981); A. Suzuki et. al . , J. Am. Chem. Soc. 111:513 (1989); and V. N. Kalinin, Russ. Chem. Rev.
  • the product may be deprotected by treatment with aqueous potassium hydroxide at a concentration of 0.5N to 5 N at room temperature to 100 °C for a period between 0.5h and 24h.
  • aqueous potassium hydroxide at a concentration of 0.5N to 5 N at room temperature to 100 °C for a period between 0.5h and 24h.
  • aryl boronic acid (la.5) may react with the known 5-bromothiazole (la.6) in the presence of tetrakis (triphenylphosphine) palladium (0), to provide (la.7) which may be deprotected by an appropriate method.
  • HET a 5 or 6 membered ring containing at least one O, N, S atom with an unsaturated bond directly attached to the bromine
  • P 1 alkyl, O-benzyl, O-ferfbutyl, ect.
  • aryl boronic acid (la.5) may react with oxazolone (la.8) in the presence of copper (II) acetate in the presence of an amine base such as pyridine to provide intermediate (la.9) which may be deprotected by an appropriate method
  • aryl boronic acids and esters lb.3, where X is not Br or I, may be prepared as shown in Scheme lb, from the corresponding arylbromide (lb.l) by treatment with a palladium catalyst such as [1,1'- Bis (diphenylphosphino) -ferrocene] dichloropalladium (II) and bis (pinacolato) diboron, (lb.2) , as reported by Ishayama et al .
  • a palladium catalyst such as [1,1'- Bis (diphenylphosphino) -ferrocene] dichloropalladium (II) and bis (pinacolato) diboron, (lb
  • Aryl boronic esters may be converted to the corresponding boronic acid by several methods including treatment with aqueous HCI.
  • the nitrogen may be masked as a nitro group and later reduced by several means including metal reductions, such as by treatment with tin chloride in HCI or by refluxing the nitro compound with zinc in the presence of CaCl 2 in a solvent such as ethanol, or in certain cases the nitro group may be reduced by catalytic hydrogenation in the presence of catalysts such as palladium on carbon.
  • the conditions for the reduction of nitro groups are detailed in several references including Hudlicky, M.
  • X H, OMe, Cl, etc.
  • P1 alkyl Obenzyl, Otertbutyl, etc.
  • a general method for the synthesis of 5-membered heterocycles includes the 1,3-dipolar cycloaddition reaction, which is well known to one skilled in the art of organic chemistry and is described by Padwa, Albert, Editor in ⁇ 1,3-Dipolar Cycloaddition Chemistry, Vol. 2" (1984) John Wiley and Sons, New York, N. Y. ; and Padwa, Albert; Editor. in "1,3-Dipolar Cycloaddition Chemistry, Vol. 1" (1984) John Wiley and Sons, New York, N. Y.
  • oxazoles may be prepared by 1,3 dipolar cycloaddtion of the corrosponding aldehyde (lc.l) and (p- tolylsulfonyl) ethyl isocyanate (TOSMIC) (lc.2) as shown in scheme Ic .
  • the aldehyde may be commercially available or prepared from the corresponding methyl group by oxidation with reagents such as Cr0 3 , Mn0 2 , and ammonium cerium (IV) nitrate by methods well known to one skilled in the art of organic chemistry and is described in Hudlicky, M. , "Oxidations in Organic Chemistry", ACS Monograph 186 (1990) , American Chemical Society, Washington, DC.
  • the nitro group in intermediate (lc.3), is reduced to an amine (lc.4), as discussed above.
  • Halonitrobenzenes are either commercially available or readily prepared by methods known to one skilled in the art of organic synthesis. Displacement with a variety of nucleophiles produce compounds of structure (Id.2). In one example heating (Id.3) with a nucleophilic heterocycle such as triazole with or without the addition of a base provides the intermediate nitro compound which may be reduced as previously described to provide amines (Id.4). Alternatively simple organic nucleophiles such as cyanide can be reacted with halonitrobenzene (Id.5) to provide an intermediate nitrocompound which can be reduced by many methods to an amine (Id.6) . Scheme Id
  • bromination of anilines may be accomplished in many cases by simply dissolving the aniline, such as (la.4) and (lc.4), in a suitable solvent such as methylene chloride, chloroform, acetic acid or hydrochloric acid, and treating with one equivalent of bromine, at a temperature from -78 to 40°C to provide aniline (le.l and le.2) .
  • the aniline may be protected with a group such as acetate.
  • the bromination can often be accomplished by the addition of a Lewis acid catalyst such as iron, or FeBr .
  • lodination can be effected in a manner analogous to that described for bromine, but may also benefit from the addition of silver salts such as silver benzoate, silver triflate, silver trifluoroacetate, or periodic acid, to provide aniline (le.3) and (le.4).
  • silver salts such as silver benzoate, silver triflate, silver trifluoroacetate, or periodic acid, to provide aniline (le.3) and (le.4).
  • X H, OMe, Cl, CH 3 , CF3,etc.
  • aniline (2a.1) (of which anilines (la.4) and (lc.4) are examples) is heated in an inert solvent such as toluene, xylene, or diphenylether at a temperature up to the boiling point of the solvent with a ⁇ -ketoester (2a.2) to provide quinolone (2a.3).
  • an inert solvent such as toluene, xylene, or diphenylether
  • a ⁇ -ketoester (2a.2) to provide quinolone (2a.3).
  • This method of quinolone synthesis has been described in the literature, for example see Kuo et al . in J. Med. Chem 1993, 36, 1146-1156.
  • this cyclization can be aided by the use of an acid such as polyphosphoric acid or sulfuric acid to facilitate the intramolecular Friedel-Crafts acylation.
  • isomereric cyclization products may be formed. In general these may be separated by flash column
  • This can be cyclized to the quinolone by heating in an inert solvent such as xylene at a temperature between 150-300°C.
  • an acid catalyst may be added to aid in the intramolecular Friedel-Crafts acylation.
  • 2a.3 ⁇ -ketoesters such as (IIa.2) useful for this invention are either commercially available or readily prepared from the corresponding carboxylic acids or esters by several means including, that reported by Clay, R.J., et al., in Synthesis, 1993, 290-292, and those outlined in chapter 2 of . "Advanced Organic Chemistry” 3 rd edition (1990) by Carey, F. A., and Sundberg R. J. , Plenum Press, New York, N. Y.
  • the aniline (le.3) is heated between 60-160°C in the presence of an acetylene (2d.l) and 0.1- 5 mol% of a palladium catalyst such as tetrakistriphenylphosphine palladium ( 0 ) , dichlorobis (triphenylphosphine) palladium (II), or dichloro [1, 1 ' -bis (diphenylphosphino) ferrocene palladium ( II ) , in an atmosphere of carbon monoxide (3-40 atmospheres) in a steel autoclave.
  • a palladium catalyst such as tetrakistriphenylphosphine palladium ( 0 ) , dichlorobis (triphenylphosphine) palladium (II), or dichloro [1, 1 ' -bis (diphenylphosphino) ferrocene palladium ( II )
  • Acetylenes 2d.l are either commercially available or may be prepared by several methods including, palladium catalyzed coupling with an aryl or vinyl bromide or iodide with trimethylsilylacetylene as initially described by Takahashi, S. et . al . in Synthesis 1980, 627.
  • the trimethylsilyl protecting group may be removed by treatment with aqueous base or with a fluoride source such as tetrabutylammonium fluoride.
  • An alternative sythesis of terminal acetylenes is commonly known as the Corey-Fuchs sythesis, for examples see Wang,Z. et al . J.Org.
  • aldehydes useful for this invention are either commercially available or readily prepared by oxidation of an alcohol by many methods as described by Hudlicky, M. "Oxidations in Organic Chemistry", ACS Monograph 186, 1990, American Chemical Society, Washington, DC.
  • Acids (2c.1) useful for this invention in their own right or for the preparation of beta ketoesters such as (2a.2) are either commercially available or readily prepared by a number of methods known to one skilled in the art of orgainic chemistry including, oxidation of an alcohol or hydrolysis of an ester. Transformations that produce acids from commercially available reagents are described by Larock, R.C. in "Comprehensive Organic Transformations: a Guide to Functional Group Preparations.” 1989, VCH Publishers, N.Y. , N.Y..
  • the compounds of the present invention may be modified by appending appropriate functionalities to enhance selective biological properties . Such 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.
  • the compounds of the present invention inhibit IMPDH enzyme, and are thus useful in the treatment, including prevention and therapy of disorders which are mediated or effected by cells which are sensitive to IMPDH inhibition, as described previously.
  • the present invention thus provides methods for the treatment of IMPDH-associated disorders, comprising the step of administering to a subject in need thereof at least one compound of the formula I, preferably at least one compound represented by formulas II and/or III, in an amount effective therefor.
  • Other therapeutic agents such as those described below, may be employed with the inventive compounds in the present methods .
  • such other therapeutic agent (s) may be administered prior to, simultaneously with or following the administration of the compound (s) of the present invention.
  • the compounds of the present invention can be used in treating a range of disorders exemplified by, but not limited to, disorders such as: the treatment of transplant rejection (e.g., kidney, liver, heart, lung, pancreas (e.g., islet cells), bone marrow, cornea, small bowel, skin allografts, skin homografts (such as employed in burn treatment), heart valve xenografts, serum sickness, and graft vs.
  • transplant rejection e.g., kidney, liver, heart, lung, pancreas (e.g., islet cells), bone marrow, cornea, small bowel, skin allografts, skin homografts (such as employed in burn treatment), heart valve xenografts, serum sickness, and graft vs.
  • transplant rejection e.g., kidney, liver, heart, lung, pancreas (e.g., islet cells), bone marrow, cornea, small bowel, skin allografts, skin homograf
  • autoimmune diseases such as rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, juvenile diabetes, asthma, inflammatory bowel disease (such as Crohn's disease and ulcerative colitus) , pyoderma gangrenum, lupus (systemic lupus erythematosis) , myasthenia gravis, psoriasis, dermatitis, dermatomyositis; eczema, seborrhoea, pulmonary inflammation, eye uveitis, hepatitis, Grave's disease, Hashimoto's thyroiditis, autoimmune thyroiditis, Behcet's or Sjorgen's syndrome (dry eyes /mouth) , pernicious or immunohaemolytic anaemia, Addison's disease (autoimmune disease of the adrenal glands) , idiopathic adrenal insufficiency, autoimmune polyglandular disease (also known as autoimmune polyglandular disease (also known
  • HSV-1 herpes simplex type 1
  • HSV-2 herpes simplex type 2
  • hepatitis including hepatitis B and hepatitis C
  • cytomegalovirus Epstein-Barr
  • HMV human immunodeficiency virus
  • IMPDH is also known to be present in bacteria and thus may regulate bacterial growth.
  • the IMPDH-inhibitor compounds of- the present invention may be useful in treatment or prevention of bacterial infection, alone or in combination with other antibiotic agents .
  • the compounds of the present invention are useful for the treatment of the aforementioned exemplary disorders irrespective of their etiology, for example, for the treatment of transplant rejection, rheumatoid arthritis, inflammatory bowel disease, and viral infections.
  • the present invention also provides pharmaceutical compositions comprising at least one of the compounds of formula I, preferably at least one of the compounds of formulas II and/or III, or a salt thereof, capable of treating an IMPDH-associated disorder in an amount effective therefor, alone or in combination with at least one additional therapeutic agent, and any pharmaceutically acceptable carrier, adjuvant or vehicle.
  • Additional therapeutic agents encompasses, but is not limited to, an agent or agents selected from the group consisting of an immunosuppressant , an anti-cancer agent, an anti-viral agent, an anti-inflammatory agent, an anti- fungal agent, an antibiotic, or an anti-vascular hyperproliferation compound.
  • pharmaceutically acceptable carrier, adjuvant or vehicle refers to a carrier, adjuvant or vehicle that may be administered to a subject, together with a compound of the present invention, and which does not destroy the pharmacological activity thereof.
  • Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of the present invention include, but are not limited to, the following: 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
  • 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 used to enhance delivery of the compounds of the present invention.
  • the compositions of the present invention may contain other therapeutic agents as described below, and may be formulated, for example, by employing conventional solid or liquid vehicles or diluents, as well as pharmaceutical additives of a type appropriate to the mode of desired administration (for example, excipients, binders, preservatives, stabilizers, flavors, etc.) according to techniques such as those well known in the art of pharmaceutical formulation.
  • the compounds of the formula I may be administered by any suitable means, for example, orally, such as in the form of tablets, capsules, granules or powders; sublingually; buccally; parenterally, such as by subcutaneous, intravenous, intramuscular, or intrasternal injection or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions) ; nasally such as by inhalation spray; topically, such as in the form of a cream or ointment; or rectally such as in the form of suppositories; in dosage unit formulations containing non-toxic, pharmaceutically acceptable vehicles or diluents.
  • suitable means for example, orally, such as in the form of tablets, capsules, granules or powders; sublingually; buccally; parenterally, such as by subcutaneous, intravenous, intramuscular, or intrasternal injection or infusion techniques (e.g., as sterile injectable aqueous
  • the present compounds may, for example, be administered in a form suitable for immediate release or extended release. Immediate release or extended release may be achieved by the use of suitable pharmaceutical compositions comprising the present compounds, or, particularly in the case of extended release, by the use of devices such as subcutaneous implants or osmotic pumps.
  • the present compounds may also be administered liposomally.
  • compositions for oral administration include suspensions which may contain, for example, microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners or flavoring agents such as those known in the art; and immediate release tablets which may contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and/or lactose and/or other excipients, binders, extenders, disintegrants , diluents and lubricants such as those known in the art.
  • the present compounds may also be delivered through the oral cavity by sublingual and/or buccal administration.
  • Molded tablets, compressed tablets or freeze-dried tablets are exemplary forms which may be used.
  • Exemplary compositions include those formulating the present compound (s) with fast dissolving diluents such as mannitol, lactose, sucrose and/or cyclodextrins .
  • Also included in such formulations may be high molecular weight excipients such as celluloses (avicel) or polyethylene glycols (PEG) .
  • Such formulations may also include an excipient to aid mucosal adhesion such as hydroxy propyl cellulose (HPC) , hydroxy propyl methyl cellulose (HPMC) , sodium carboxy methyl cellulose (SCMC) , aleic anhydride copolymer (e.g., Gantrez) , and agents to control release such as polyacrylic copolymer (e.g., Carbopol 934).
  • HPC hydroxy propyl cellulose
  • HPMC hydroxy propyl methyl cellulose
  • SCMC sodium carboxy methyl cellulose
  • aleic anhydride copolymer e.g., Gantrez
  • agents to control release such as polyacrylic copolymer (e.g., Carbopol 934).
  • Lubricants, glidants, flavors, coloring agents and stabilizers may also be added for ease of fabrication and use.
  • compositions for nasal aerosol or inhalation administration include solutions in saline which may contain, for example, benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, and/or other solubilizing or dispersing agents such as those known in the art.
  • compositions for parenteral administration include injectable solutions or suspensions which may contain, for example, suitable non-toxic, parenterally acceptable diluents or solvents, such as mannitol, 1,3- butanediol, water, Ringer's solution, an isotonic sodium chloride solution, or other suitable dispersing or wetting and suspending agents, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.
  • suitable non-toxic, parenterally acceptable diluents or solvents such as mannitol, 1,3- butanediol, water, Ringer's solution, an isotonic sodium chloride solution, or other suitable dispersing or wetting and suspending agents, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.
  • parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal , intrathecal
  • compositions for rectal administration include suppositories which may contain, for example, a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquify and/or dissolve in the rectal cavity to release the drug.
  • a suitable non-irritating excipient such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquify and/or dissolve in the rectal cavity to release the drug.
  • compositions for topical administration include a topical carrier such as Plastibase (mineral oil gelled with polyethylene) .
  • a topical carrier such as Plastibase (mineral oil gelled with polyethylene) .
  • the effective amount of a compound of the present invention may be determined by one of ordinary skill in the art, and includes exemplary dosage amounts for an adult human of from about 0.1 to 500 mg/kg of body weight of active compound per day, which may be administered in a single dose or in the form of individual divided doses, such as from 1 to 5 times per day. It will be understood that the specific dose level and frequency of dosage for any particular subject may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the species, age, body weight, general health, sex and diet of the subject, the mode and time of administration, rate of excretion, drug combination, and severity of the particular condition.
  • Preferred subjects for treatment include animals, most preferably mammalian species such as humans, and domestic animals such as dogs, cats and the like, subject to IMPDH-associated disorders.
  • the compounds of the present invention may be employed alone or in combination with each other and/or other suitable therapeutic agents useful in the treatment of IMPDH-associated disorders, such as IMPDH inhibitors other than those of the present invention, immunosuppressants, anti-cancer agents, anti-viral agents, anti-inflammatory agents, anti-fungal agents, antibiotics, or anti-vascular hyperproliferation agents.
  • cyclosporins e.g., cyclosporin A
  • CTLA4-Ig antibodies such as anti-ICAM-3, anti-IL-2 receptor (Anti- Tac) , anti-CD45RB, anti-CD2, anti-CD3 (OKT-3), anti-CD4, anti-CD80, anti-CD86, monoclonal antibody OKT3
  • agents blocking the interaction between CD40 and CD154 a.k.a. "gp39"
  • CDl54/gp39 e.g., CD40Ig and CD8gp39
  • inhibitors such as nuclear translocation inhibitors, of NF-kappa B function, such as deoxyspergualin (DSG) , non-steroidal antiinflammatory drugs (NSAIDs) such as ibuprofen, celecoxib and rofecoxib, steroids such as prednisone or dexamethasone, gold compounds, antiviral agents such as abacavir, antiproliferative agents such as methotrexate, leflunomide, FK506 (tacrolimus, Prograf ) , cytotoxic drugs such as azathiprine and cyclophosphamide, TNF- ⁇ inhibitors such as tenidap, anti-TNF antibodies or soluble TNF receptor, and rapamycin (sirolimus or Rapamune) or derivatives thereof.
  • DSG deoxyspergualin
  • NSAIDs non-steroidal antiinflammatory drugs
  • the compounds disclosed herein are capable of targeting and inhibiting IMPDH enzyme. Inhibition can be measured by various methods, including, for example, IMP dehydrogenase HPLC assays (measuring enzymatic production of XMP and NADH from IMP and NAD) and IMP dehydrogenase spectrophotometric assays (measuring enzymatic production of NADH from NAD) . See, e.g., Montero et al . , Clinica Chimica Acta 238:169-178 (1995). Additional assays known in the art can be used in ascertaining the degree of activity of a compound ("test compound”) as an IMPDH inhibitor.
  • the inventors used the following assay to determine the degree of activity of the compounds disclosed herein as IMPDH inhibitors: Activity of IMPDH I and IMPDH II was measured following an adaptation of the method described in WO 97/40028.
  • the reaction mixture was prepared containing 0.1M Tris pH 8.0, 0.1 M KCl, 3 mM EDTA, 2 mM DTT, 0.4 mM IMP and 40 nM enzyme (IMPDH I or IMPDH II) .
  • the reaction was started by the addition of NAD to a final concentration of 0.4 mM.
  • the enzymatic reaction was followed by measuring the increase in absorbance at 340 nM that results from the formation of NADH.
  • the compounds disclosed herein are capable of inhibiting the enzyme IMPDH at a measurable level, under the above-described assay or an assay which can determine an effect of inhibition of the enzyme IMPDH.
  • 9A was prepared from 3A by a route analogous to that used for the preparation of 3B, except in the purification step: the reaction mixture was concentrated in vacuo and carried to the next step without further purification.
  • Example 11 Part D 2- (2 , 3-Dihydro-3-methoxy-lH-inden-5- yl) -7-methoxy-6- (5-oxazolyl) -4 (IH) -quinolinone 4A , 0.15 g (0.47 mmol), 0.163 g (0.94 mmol) of 11D, 0.02 g (0.028mmol) of bis ( triphenylphosphine ) palladium ( II ) dichloride and diethylamine (5 L) were reacted in a similar manner were reacted in a similar manner to Example 5, part D to yield the title compound as a solid (0.04 g, 21%) .
  • Examples 12 to 103 are prepared by several routes .
  • the method to prepare a specific example is noted in table 1.
  • Examples prepared in a manner analogous to Example 1 starting with aniline ID and an appropriate j eta-ketoester are designated as method Al .
  • Examples prepared in a manner analogous to Example 2 starting with aniline ID and a appropriate jbeta-ketoester, which may be obtained from commercially available acid chlorides, are designated as method A2.
  • Example prepared from esters, which are readily converted to an acid by hydrolysis, or acids, followed by reaction of the acid with carbonyldiimidazole, and reacted with potassium ethyl malonate as described in Example 6, part A are designated as method A3.
  • Compounds prepared in a manner analogous to Example 9 are designated as method B2
  • Compounds prepared in a manner analogous to Example 7 are designated as method Dl .
  • Compounds prepared in a manner analogous to Example 8 are designated as method D2.
  • the compounds of these examples have structures outlined in Table 1 below.
  • Example 104 Part A, 6-Bromo-2 , 3-dihydro-N-methyl-lH- inden-1-amine
  • Example 104 Part C, [2 , 3-Dihydro-6- [ (trimethylsilyl) ethynyl] -lH-inden-l-yl]methylcarbamic acid phenylmethyl ester
  • Example 104 Part D, (6-Ethynyl-2 , 3-dihydro-lH-inden-l- yl)methylcarbamic acid phenylmethyl ester
  • Example 104 Part F, [6- [1 , 4-Dihydro-7-methoxy-6- (5- oxazolyl ) -4-oxo-2-quinolinyl] -2 , 3-dihydro-lH-inden-1- yl]methylcarbamic acid phenylmethyl ester
  • Example 106 Part A, 1- (6-Bromo-2 , 3-dihydro-lH-inden-l- yl ) yrrolidine
  • 6-bromoindanol (0.3 g, 1.39 mmol) was subjected to the same conditions as 104, part A by substituting methylamine with pyrrolidine (1.16 mL, 14 mmol) to yield the title compound (0.195 g, 52%).
  • 1 H NMR (CDC1 3 ) 7.4 (s, IH) , 7.25 (d, IH) , 7.0 (d, IH) , 4.1 (t, IH) , 2.9 (m, IH) , 2.6 (m, IH) , 2.55 (m, 4H) , 2.1 (m, 2H) , 1.7 (brs, 4H) .
  • 6-bromoindanol (0.3 g, 1.39 mmol) was subjected to the same conditions as 104, part A by substituting methylamine with morpholine (4.0 mL) in toluene (5 mL) to yield the title compound (0.35 g, 89%).
  • 1 H NMR (CDC1 3 ) 7.5 (s, IH) , 7.3 (d, IH) , 7.0 (d, IH) , 4.2 (t, IH) , 3.7 (brs, 4H) , 2.8 (m, IH) , 2.7 (m, IH) , 2.4 (m, 4H) , 2.1 (m, 2H) .
  • 6-bromoindanol (0.3 g, 1.39 mmol) was subjected to the same conditions as 104, part A by substituting methylamine with azetidine (0.9 mL 13.9 mmol) in toluene (5 mL) to yield the title compound (0.167 g, 47%).
  • 1 H NMR (CDC1 3 ) 7.3 (s, IH) , 7.2 (d, IH) , 7.0 (d, IH) , 3.8 (m, IH), 3.2 (m, 4H) , 3.0 (m, IH) , 2.8 (m, IH) , 2.0 (m, 3H) , 1.8 (m, IH) .
  • HOB Compound 110A (0.485g, 2.14 mmol) was subjected to the same conditions as 104, part B and C to yield the title compound (0.35 g, 95%).
  • X H NMR (CDC1 3 ) D 7.5 (s, IH) , 7.3 (d, IH) , 7.0 (d, IH) , 4.7 (m, IH) , 3.3 (s, 3H) , 3.0 (m, IH) , 2.9 (s, IH) , 2.7 (m, IH) , 2.3 (m, IH) , 2.0 (m, IH) .

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Abstract

Compounds of formula (I) wherein X1 is C(O), -S(O)-, or -S(O)¿2?-; X?2 is CR3¿ or N; X3 is -NH-, -O-, or -S-; X?4 is CR4¿ or N; X?5 is CR5¿ or N; and X?6 is CR6¿ or N are useful as inhibitors of IMPDH enzyme. Thus, these compounds can be used as therapeutic agents for IMPDH- associated disorders.

Description

Heterocycles That Are Inhibitors Of IMPDH Enzyme
Field of the Invention
The present invention relates to novel compounds which inhibit IMPDH, and to methods of making such compounds. The invention also encompasses pharmaceutical compositions containing these compounds. The compounds and pharmaceutical compositions of the invention are particularly well suited for inhibiting IMPDH enzyme activity and, consequently, can be advantageously used as therapeutic agents for IMPDH-associated disorders. This invention also relates to methods for inhibiting the activity of IMPDH using the compounds of this invention alone or in combination with other pharmaceutically active agents .
Background of the Invention
Inosine monophosphate dehydrogenase (IMPDH) has been shown to be a key enzyme in the regulation of cell proliferation and differentiation. Nucleotides are required for cells to divide and replicate. In mammals, nucleotides may be synthesized through one of two pathways : the de novo synthesis pathway or the salvage pathway. The extent of utilization of each pathway is dependent on the cell type. This selectivity has ramifications with regard to therapeutic utility as described below.
IMPDH is involved in the de novo synthesis of guanosine nucleotides. IMPDH catalyzes the irreversible NAD-dependent oxidation of inosine-5 ' -monophosphate ("IMP") to xanthosine-5' -monophosphate ("XMP"), Jackson et al., Nature 256:331-333 (1975). IMPDH is ubiquitous in eukaryotes, bacteria and protozoa. The prokaryotic forms share 30-40% sequence identity with the human enzyme.
Two distinct cDNA's encoding IMPDH have been identified and isolated. These transcripts are labeled type I and type II and are of identical size (514 amino acids). Collart et al . , J. Biol. Chem. 263:15769-15772 (1988); Natsu eda et al . , J. Biol. Chem. 265:5292-5295 (1990); and U.S. Patent 5,665,583 to Collart et al . These isoforms share 84% sequence identity. IMPDH type I and type II form tetramers in solution, the enzymatically active unit.
B and T-lymphocytes depend on the de novo, rather than salvage pathway, to generate sufficient levels of nucleotides necessary to initiate a proliferative response to mitogen or antigen. Due to the B and T cell's unique reliance on the de novo pathway, IMPDH is an attractive target for selectively inhibiting the immune system without also inhibiting the proliferation of other cells.
Immunosuppression has been achieved by inhibiting a variety of enzymes . Examples include : phosphatase calcineurin (inhibited by cyclosporin and FK-506) ; dihydroorotate dehydrogenase (DHODase) , an enzyme involved in the biosynthesis of pyrimidines (inhibited by leflunomide and brequinar) ; the kinase FRAP (inhibited by rapamycin) ; and the heat shock protein hsp70 (inhibited by deoxyspergualin) .
Inhibitors of IMPDH have also been described in the art. WO 97/40028 and U.S. Patent 5,807,876 describe a class of urea derivatives that possess a common urea backbone. WO 98/40381 describes a series of heterocyclic substituted anilines as inhibitors of IMPDH.
United States patents 5,380,879 and 5,444,072 and PCT publications WO 94/01105 and WO 94/12184 describe mycophenolic acid ("MPA") and some of its derivatives as potent, uncompetitive, reversible inhibitors of human IMPDH type I and type II. MPA has been demonstrated to block the response of B and T-cells to mitogen or antigen. Immunosuppressants, such as MPA and derivatives of MPA, are useful drugs in the treatment of transplant rejection and autoimmune disorders, psoriasis, inflammatory diseases, including, rheumatoid arthritis, tumors and for the treatment of allograft rejection. These are described in U.S. Pat. Nos. 4,686,234,
4,725,622, 4,727,069, 4,753,935, 4,786,637, 4,808,592, 4,861,776, 4,868,153, 4,948,793, 4,952,579, 4,959,387, 4,992,467, and 5 , 247 , 083.
The combination of agents for prevention and/or treatment of IMPDH-associated disorders, especially allograft rejection, has been investigated. In one study, it was observed that cyclic AMP agonists, such as Rolipram (Schering AG) , a Type 4 Phosphodiesterase Inhibitor (PDE4) and immunomodulator, synergized with IMPDH inhibitor MPA by a cAMP- and IMPDH-dependent dependent mechanism. (P. . Canelos, L.M. Lichtenstein, S.K. Huang, D.M. Essayan, J. Allergy and Clinical Immunology, 107:593 (2001)). The chemical structure of Rolipram is [4- [3- (cyclopentyloxy) -4-methoxy-phenyl] -2- pyrrolidinone] . The investigators found that cyclic AMP agonists, such as the PDE4 inhibitor Rolipram (Rol) , markedly downregulated antigen-specific T lymphocyte responses through their effects on a variety of signaling pathways . In the study, the potential for a very low concentration of Rol (10~7 M, approximate ICio) to synergize with a variety of immunosuppressive agents used for the prevention and/or treatment of allograft rejection was defined. While little or no synergistic effect on inhibition of antigen-induced proliferation (assessed by 3H Thymidine incorporation) could be demonstrated with calcineurin antagonists (cyclosporine and tacrolimus) , sirolimus, or corticosteroids, a marked synergistic effect was demonstrated with MPA, the active metabolite of mycophenolate mofetil (CellCept, Roche) . This effect was statistically significant over 4 orders of magnitude (10~6 to 10"9 M) . This synergism was recapitulated with dibuteryl-cAMP (2 x 10~6 M, approximate ICio) and inhibited with the use of H-9, suggesting a mechanism involving both cAMP and protein kinase A. Since MPA is a selective, uncompetitive, and reversible inhibitor of IMPDH, a key enzyme in the purine salvage pathway, the potential for cAMP-mediated crosstalk at this locus was further investigated. It was found that gene expression for IMPDH types I and II (assessed by RT-PCR) remained unaffected by the administration of rolipram, MPA, or both at low and high concentrations. However, functional reversal of the synergistic effect was demonstrated with the use of deoxyguanosine, a specific antagonist of MPA on IMPDH (% inhibition of proliferation 81±16 vs. 35±12, p<0.05). Finally, despite a marked synergistic effect on inhibition of proliferation, no significant downregulation in the generation of proinflammatory cytokines (IL-2, IL-4, and IFN , each assessed by RT- PCR) , could be detected with the administration of Rol
10"7 M, MPA 10"8 M, or the combination. It was concluded that Rol demonstrates marked synergy with MPA by a cAMP- and IMPDH-dependent mechanism. The utility of this combination of agents for the induction of T cell tolerance was suggested by the specificity of the observed effect for proliferation, without the abrogation of cytokine generation and early signaling processes . Tiazofurin, ribavirin and mizoribine also inhibit IMPDH. These nucleoside analogs are competitive inhibitors of IMPDH; however, these agents inhibit other NAD dependent enzymes . This low level of selectivity for IMPDH limits the therapeutic application of tiazofurin, ribavirin and mizoribine. Thus, new agents which have improved selectivity for IMPDH would represent a significant improvement over the nucleoside analogs . Mycophenolate mofetil, sold under the trade name CELLCEPT, is a prodrug which liberates MPA in vivo . It is approved for use in preventing acute renal allograft rejection following kidney transplantation. The side effect profile limits the therapeutic potential of this drug. MPA is rapidly metabolized to the inactive glucuronide in vivo . In humans, the blood levels of glucuronide exceed that of MPA. The glucuronide undergoes enterohepatic recycling causing accumulation of MPA in the bile and subsequently in the gastrointestinal tract. This together with the production of the inactive glucuronide effectively lowers the drug's in vivo potency, while increasing its undesirable gastrointestinal side effects.
Unlike type I, type II mRNA is preferentially upregulated in human leukemic cell lines K562 and H -60. Weber, J. Biol. Chem. 266: 506-509 (1991). In addition, cells from human ovarian tumors and leukemic cells from patients with chronic granulocytic, lymphocytic and acute myeloid leukemias also display an up regulation type II mRNA. This disproportionate increase in IMPDH activity in malignant cells may be addressed through the use of an appropriate IMPDH inhibitor. IMPDH has also been shown to play a role in the proliferation of smooth muscle cells, indicating that inhibitors of IMPDH may be useful in preventing restenosis or other hyperproliferative vascular diseases. IMPDH has been shown to play a role in viral replication in some viral cell lines. Carr, J. Biol. Chem. 268:27286-27290 (1993). The IMPDH inhibitor VX- 497, is currently being evaluated for the treatment of hepatitis C virus in humans . Ribavirin has also been used in the treatment of hepatitis C and B viruses and when used in combination with interferon an enhancement in activity was observed. The IMPDH inhibitor ribavirin is limited by its lack of a sustained response in monotherapy and broad cellular toxicity.
There remains a need for potent selective inhibitors of IMPDH with improved pharmacological properties, physical properties and fewer side effects. Such inhibitors would have therapeutic potential as immunosuppressants, anti-cancer agents, anti-vascular hyperproliferative agents, antiinflammatory agents, antifungal agents, antipsoriatic and anti-viral agents. The compounds of the present invention are effective inhibitors of IMPDH.
Summary of the Invention
It is an object of the present invention to provide heterocyclic compounds of the following formula (I), their enantiomers, diastereomers, tautomers and pharmaceutically acceptable salts, prodrugs and solvates thereof, for use as IMPDH inhibitors:
Figure imgf000007_0001
(I) including iso ers, enantiomers, diastereomers, tauto ers, pharmaceutically acceptable salts, prodrugs and solvates thereof wherein:
X1 is C=0, -S(0)-, or -S(0)2-; X2 is CR3 or N;
X3 is-NH-, -0-, or -S-;
X4 is CR4 or N;
X5 is CR5 or N;
X6 is CR6 or N; R1 is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, NR8R9, SR20, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycloalkyl, or heteroaryl;
R2 is halogen, cyano, nitro, hydroxy, oxo (double bond is no longer present between CR2 and X6), SR7, S(0)R7, S02R7, S02NR8R9, C02R7, C(0)NR8R9, or heteroaryl;
R3 is hydrogen, hydroxy, halogen, cyano, C0R7, NR8R9, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycloalkyl or heteroaryl;
R4, R5, and R6 are independently selected from the group consisting of hydrogen, halogen, nitro, cyano, O-R7, NR8R9, SR7, S(0)R7, S02R7, S03R7, S02NR8R9, C02R7, C(0)NR8R9, C(O) lkyl, C (0) substituted alkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl and substituted alkynyl;
R7, R10, and R11, are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, cycloalkyl, substituted cycloalkyl, C(0) alkyl, C (0) substituted alkyl, C (O) cycloalkyl, C(0) substituted cycloalkyl, C(0)aryl, C (O) substituted aryl, C(0) Oalkyl, C (0) Osubstituted alkyl, C (O) heterocycloalkyl, C (0) heteroaryl, aryl, substituted aryl, heterocycloalkyl and heteroaryl ; R8 and R9 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, alkynyl, C(O) alkyl, C (0) substituted alkyl, C (0) cycloalkyl, C (0) substituted cycloalkyl, C(0)aryl, C (0) substituted aryl, C(0)0alkyl, C (0) Osubstituted alkyl, C (0) heterocycloalkyl, C (O)heeroaryl, aryl, substituted aryl, heterocycloalkyl, and heteroaryl or R8 and R9 taken together with the nitrogen atom to which they are attached complete a heterocycloalkyl or heteroaryl ring;
R20 is alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl or heterocycloalkyl;
R3 and R1 may be taken together with the carbon atoms to which they are attached to form a monocyclic or substituted monocyclic ring system of 5 or 6 carbon atoms; and
R4 and R5 may be joined together by the chain -O-CH2-O- or -0-CH2-CH2-0- .
It is another object of the present invention to provide pharmaceutical compositions containing the IMPDH inhibitor compounds of the invention.
It is yet another object of the present invention to provide methods for treating inosine monophosphate dehydrogenase associated disorders using the IMPDH inhibitor compounds of the invention. It is a further object of the present invention to provide methods for treating treating inosine monophosphate dehydrogenase associated disorders and preventing or treating allograft rejection using the IMPDH inhibitor compounds of the invention and phosphodiesterase Type 4 inhibitors.
Detailed Description Of The Invention
[1] Thus in a first embodiment, the present invention provides a method of treating inosine monophosphate dehydrogenase associated disorders comprising: administering a therapeutically effective amount of a compound of formula (I)
Figure imgf000010_0001
(I)
including isomers, enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, prodrugs and solvates thereof wherein: X1 is C=0, -S(O)-, or -S(0)2-;
X2 is CR3 or N;
X3 is-NH-, -0-, or -S-;
X4 is CR4 or N;
X5 is CR5 or N; X6 is CR6 or N;
R1 is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, NR8R9, SR20, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycloalkyl, or heteroaryl; R2 is halogen, cyano, nitro, hydroxy, oxo (double bond is no longer present between CR2 and X6), SR7, S(0)R7, S02R7, S02NR8R9, C02R7, C(0)NR8R9, or heteroaryl;
R3 is hydrogen, hydroxy, halogen, cyano, C02R7, NR8R9, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycloalkyl or heteroaryl;
R4, R5, and R6 are independently selected from the group consisting of hydrogen, halogen, nitro, cyano, O-R7, NR8R9, SR7, S(0)R7, S02R7, S03R7, S02NR8R9, C02R7, C(0)NR8R9, C(0) lkyl, C (0) substituted alkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl and substituted alkynyl;
R7, R10, and R11, are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, cycloalkyl, substituted cycloalkyl, C(O) alkyl, C (0) substituted alkyl, C (O) cycloalkyl, C(0) substituted cycloalkyl, C(0)aryl, C (0) substituted aryl, C(0)0alkyl, C (0) Osubstituted alkyl, C (O) heterocycloalkyl , C (0) heteroaryl, aryl, substituted aryl, heterocycloalkyl and heteroaryl;
R8 and R9 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, alkynyl, C(0) alkyl, C (0) substituted alkyl, C (0) cycloalkyl, C (0) substituted cycloalkyl, C(0)aryl, C (0) substituted aryl, C(0)0alkyl, C (0) Osubstituted alkyl, C (0) heterocycloalkyl, C (0) heteroaryl, aryl, substituted aryl, heterocycloalkyl, and heteroaryl or R8 and R9 taken together with the nitrogen atom to which they are attached complete a heterocycloalkyl or heteroaryl ring;
R20 is alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl or heterocycloalkyl;
R3 and R1 may be taken together with the carbon atoms to which they are attached to form a monocyclic or substituted monocyclic ring system of 5 or 6 carbon atoms; and
R4 and R5 may be joined together by the chain -0-CH2-0- or -O-CH2-CH2-O- .
[2] In a preferred embodiment, the present invention provides a method of treating inosine monophosphate dehydrogenase associated disorders comprising: administering a therapeutically effective amount of a compound of formula (II)
Figure imgf000012_0001
H di :
including isomers, enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, prodrugs and solvates thereof wherein:
R2 is a monocyclic substituted or unsubstituted heteroaryl group .
[3] In another preferred embodiment, the present invention provides a method of treating inosine monophosphate dehydrogenase associated disorders comprising: administering a therapeutically effective amount of a compound of formula (III)
Figure imgf000012_0002
( II)
including isomers, enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, prodrugs and solvates thereof wherein:
R2 is 4-oxazolyl, substituted 4-oxazolyl, 5-oxazolyl, or substituted 5-oxazolyl;
R3 is hydrogen, hydroxy, NR8R9, alkyl of 1 to 4 carbons, alkenyl of 2 to 4 carbons, alkynyl of 2 to 4 carbons, substituted alkyl of 1 to 4 carbons, phenyl, substituted phenyl, cycloalkyl of 5 to 7 carbons, substituted cycloalkyl of 5 to 7 carbons, monocyclic heterocycloalkyl and monocyclic heteroaryl;
R4 is hydrogen, halogen, nitro, hydroxy, alkyl of 1 to 4 carbons, cyano, CF3, OCF3, OCH3, SCH3, S(0)CH3, or S(0)2CH3;
R5 is hydrogen, halogen, nitro, hydroxy, alkyl of 1 to 4 carbons, cyano, vinyl, CF3, CF2CF3, CH=CF2, OCH3 , 0CF3, 0CHF2, SCH3, S(O) CH3, or S(0)2CH3; and
R6 is hydrogen, halogen, nitro, hydroxy, alkyl of 1 to 4 carbons, cyano, CF3, 0CH3, 0CF3, SCH3, S(0)CH3, and S(0)2CH3.
[4] In another preferred embodiment, the present invention provides a method of treating inosine monophosphate dehydrogenase associated disorders comprising: administering a therapeutically effective amount of a compound including isomers, enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, prodrugs and solvates wherein: R2 is 4-oxazolyl, substituted 4-oxazolyl, 5-oxazolyl, substituted 5-oxazolyl or heteroaryl;
R3 is hydrogen, hydroxy, halogen, methyl or NR8R9; R4 is hydrogen;
R5 is halogen, methyl, ethyl, substituted alkenyl, alkyne, OMe or 0CF3; and R5 is hydrogen.
[5] In another preferred embodiment, the present invention provides a method of treating inosine monophosphate dehydrogenase associated disorders comprising: administering a therapeutically effective amount of a compound including isomers, enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, prodrugs and solvates wherein: R2 is 4-oxazolyl, substituted 4-oxazolyl, 5-oxazolyl or substituted 5-oxazolyl;
R3 is hydrogen, hydroxy, halogen or methyl;
R4 is hydrogen; R5 is halogen, methyl or OMe; and
R6 is hydrogen.
[6] In an even more preferred embodiment, the present invention provides a method of treating inosine monophosphate dehydrogenase associated disorders comprising: administering a therapeutically effective amount of a phosphodiesterase Type 4 inhibitor and a compound of formula (X) :
Figure imgf000014_0001
(*>
including isomers, enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, prodrugs and solvates thereof wherein: X1 is C=0, -S(O)-, or -S(0)2-; X2 is CR3 or N; X3 is-NH-, -0-, or -S-; X4 is CR4 or N; X5 is CR5 or N; X6 is CR6 or N;
R1 is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, NR8R9, SR20, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycloalkyl, or heteroaryl; R2 is halogen, cyano, nitro, hydroxy, oxo (double bond is no longer present between CR2 and X6), SR7, S(0)R7, S02R7, S02NR8R9, C02R7, C(0)NR8R9, or heteroaryl; R3 is hydrogen, hydroxy, halogen, cyano, C02R7, NR8R9, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycloalkyl or heteroaryl;
R4, R5, and Rδ are independently selected from the group consisting of hydrogen, halogen, nitro, cyano, O-R7, NR8R9, SR7, S(0)R7, S02R7, S03R7, S02NR8R9, C02R7, C(0)NR8R9, C(O) alkyl, C (0) substituted alkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl and substituted alkynyl;
R7, R10, and R11, are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, cycloalkyl, substituted cycloalkyl, C(O) alkyl, C (0) substituted alkyl, C (0) cycloalkyl, C(0) substituted cycloalkyl, C(0)aryl, C (0) substituted aryl, C(0)0alkyl, C (0) Osubstituted alkyl, C (0) heterocycloalkyl, C (0) heteroaryl, aryl, substituted aryl, heterocycloalkyl and heteroaryl; R8 and R9 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, alkynyl, C(O) alkyl, C (0) substituted alkyl, C (0) cycloalkyl, C (0) substituted cycloalkyl, C(0)aryl, C (0) substituted aryl, C(0)0alkyl, C (0) Osubstituted alkyl,
C (O) eterocycloalkyl, C (0) heteroaryl, aryl, substituted aryl, heterocycloalkyl, and heteroaryl or R8 and R9 taken together with the nitrogen atom to which they are attached complete a heterocycloalkyl or heteroaryl ring; R20 is alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl or heterocycloalkyl;
R3 and R1 may be taken together with the carbon atoms to which they are attached to form a monocyclic or substituted monocyclic ring system of 5 or 6 carbon atoms; and R4 and R5 may be joined together by the chain -O-CH2-O- or -O-CH2-CH2-O-.
[7] In another even more preferred embodiment, the present invention provides a method for the treatment or prevention of allograft rejection comprising: administering a therapeutically effective amount of a phosphodiesterase Type 4 inhibitor and a compound of formula (X) :
Figure imgf000016_0001
(X)
including isomers, enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, prodrugs and solvates thereof wherein:
X1 is C=0, -S(O)-, or -S(0)2-;
X2 is CR3 or N;
X3 is-NH-, -0-, or -S-;
X4 is CR4 or N; X5 is CR5 or N;
X6 is CR6 or N;
R1 is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, NR8R9, SR20, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycloalkyl, or heteroaryl;
R2 is halogen, cyano, nitro, hydroxy, oxo (double bond is no longer present between CR2 and X6), SR7, S(0)R7, S02R7, S02NR8R9, C02R7, C(0)NR8R9, or heteroaryl;
R3 is hydrogen, hydroxy, halogen, cyano, C02R7, NR8R9, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycloalkyl or heteroaryl; R4, R5, and R6 are independently selected from the group consisting of hydrogen, halogen, nitro, cyano, 0-R7, NR8R9, SR7, S(0)R7, S02R7, S03R7, S02NR8R9, C02R7, C(0)NR8R9, C(O) alkyl, C (0) substituted alkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl and substituted alkynyl;
R7, R10, and R11, are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, cycloalkyl, substituted cycloalkyl, C(0)alkyl, C (0) ubstituted alkyl , C (0) cycloalkyl, C(O) substituted cycloalkyl, C(0)aryl, C (O) substituted aryl, C(0)0alkyl, C (0) Osubstituted alkyl, C (0) heterocycloalkyl , C (0) heteroaryl, aryl, substituted aryl, heterocycloalkyl and heteroaryl; R8 and R9 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, alkynyl, C(0)alkyl, C (0) substituted alkyl , C (0) cycloalkyl, C (0) substituted cycloalkyl, C(0)aryl, C (0) substituted aryl, C(0)0alkyl, C (0) Osubstituted alkyl,
C (0) heterocycloalkyl, C (O) heteroaryl , aryl, substituted aryl, heterocycloalkyl, and heteroaryl or R8 and R9 taken together with the nitrogen atom to which they are attached complete a heterocycloalkyl or heteroaryl ring; R20 is alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl or heterocycloalkyl;
R3 and R1 may be taken together with the carbon atoms to which they are attached to form a monocyclic or substituted monocyclic ring system of 5 or 6 carbon atoms; and
R4 and R5 may be joined together by the chain -0-CHa-O- or -O-CH2-CH2-O- .
[8] In another- even more preferred embodiment, the phosphodiesterase Type 4 inhibitor is Rolipram. [9] In another even more preferred embodiment, the phosphodiesterase Type 4 inhibitor is [4- [3- (cyclopentyloxy) -4-methoxy-phenyl] -2-pyrrolidinone] .
[10] In a second embodiment, the present invention provides a novel compound, comprising: a compound of formula (I)
Figure imgf000018_0001
:D
including isomers, enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, prodrugs and solvates thereof wherein: X1 is C=0, -S(O)-, or -S(0)2-;
X2 is CR3 or N;
X3 is-NH-, -0-, or -S-;
X4 is CR4 or N;
X5 is CR5 or N; X6 is CR6 or N;
R1 is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycloalkyl, or heteroaryl; R2 is cyano, hydroxy, oxo (double bond is no longer present between CR2 and X6), SR7, S(0)R7, S02R7, S02NR8R9, C02R7, C(0)NR8R9, or heteroaryl;
R3 is hydrogen, hydroxy, halogen, cyano, C02R7, NR8R9, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycloalkyl or heteroaryl; R4, R5, and R6 are independently selected from the group consisting of hydrogen, halogen, nitro, cyano, 0-R7, NR8R9, SR7, S(0)R7, S02R7, S03R7, S02NR8R9, C02R7, C(0)NR8R9, C(O) alkyl, C (0) substituted alkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl and substituted alkynyl;
R7, R10, and R11, are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, cycloalkyl, substituted cycloalkyl, C(0) alkyl, C (0) substituted alkyl, C (0) cycloalkyl, C(0) substituted cycloalkyl, C(0)aryl, C (O) substituted aryl, C(0)0alkyl, C (0) Osubstituted alkyl, C (O) heterocycloalkyl, C (O) heteroaryl, aryl, substituted aryl, heterocycloalkyl and heteroaryl; R8 and R9 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, alkynyl, C(0)alkyl, C (0) substituted alkyl , C (O) cycloalkyl, C (O) substituted cycloalkyl, C(0)aryl, C (0) substituted aryl, C(0)0alkyl, C(0) Osubstituted alkyl,
C (O) heterocycloalkyl, C (0) heteroaryl, aryl, substituted aryl, heterocycloalkyl, and heteroaryl or R8 and R9 taken together with the nitrogen atom to which they are attached complete a heterocycloalkyl or heteroaryl ring; R3 and R1 may be taken together with the carbon atoms to which they are attached to form a monocyclic or substituted monocyclic ring system of 5 or 6 carbon atoms ; and
R4 and R5 may be joined together by the chain -O-CH2-O- or -O-CH2-CH2-O-;
with the following provisos:
(a) when X1 is C=0, X2 is CR3, X3 is NH, X4 is CR4, X5 is CR5, X6 is CR6, R1 is substituted or meta unsubstituted phenyl, R3 is H, R4 is H, R5 is H and R6 is H, then R2 is not PhCONH,
Figure imgf000020_0001
(b) when X1 is C=0, X2 is CR3, X3 is NH, X4 is CR4, X5 is CR5, X5 is CR6, R1 is phenyl substituted with H, F, Cl, Br, I, CH3 , CF3 , OH, OCH3 , OCF3 , OCH2CH3, NH2, NHCH3, N(CH3)2, O-benzyl , -C (=0) -R0, or -C (=0) -ORo and Ro is a lower alkyl group, R3 is H, R4 is H, R5 is H and R6 is H, then R2 is not
Figure imgf000020_0002
where Y is CH2, O or S, m and n are each greater than 1, and the sum of m and n is between 3 and 6 ; and
(c) when R2 is heteroaryl, at least one of the heteroatoms must be 0;
[11] In a preferred embodiment, the present invention provides a compound of formula (II)
Figure imgf000020_0003
H di:
including isomers, enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, prodrugs and solvates thereof wherein:
R2 is a monocyclic substituted or unsubstituted heteroaryl group. [12] In a more preferred embodiment, the present invention provides a compound of formula (III)
Figure imgf000021_0001
(I") including isomers, enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, prodrugs and solvates thereof wherein:
R2 is 4-oxazolyl, substituted 4-oxazolyl, 5-oxazolyl, or substituted 5-oxazolyl;
R3 is hydrogen, hydroxy, NR8R9, alkyl of 1 to 4 carbons, alkenyl of 2 to 4 carbons, alkynyl of 2 to 4 carbons, substituted alkyl of 1 to 4 carbons, phenyl, substituted phenyl, cycloalkyl of 5 to 7 carbons, substituted cycloalkyl of 5 to 7 carbons, monocyclic heterocycloalkyl and monocyclic heteroaryl;
R4 is hydrogen, halogen, nitro, hydroxy, alkyl of 1 to 4 carbons, cyano, CF3, OCF3, OCH3, SCH3, S(0)CH3, or
S(0)2CH3; R5 is hydrogen, halogen, nitro, hydroxy, alkyl of 1 to 4 carbons, cyano, vinyl, CF3, CF2CF3, CH=CF2, OCH3 ,
OCF3, OCHF2, SCH3, S(0)CH3, or S(0)2CH3; and
R6 is hydrogen, halogen, nitro, hydroxy, alkyl of 1 to 4 carbons, cyano, CF3, 0CH3, OCF3, SCH3, S(0)CH3, and S(0)2CH3.
[13] In an even more preferred embodiment, the present invention provides a compound including isomers, enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, prodrugs and solvates wherein :
R2 is 4-oxazolyl, substituted 4-oxazolyl, 5-oxazolyl, substituted 5-oxazolyl or heteroaryl;
R3 is hydrogen, hydroxy, halogen, methyl or NR8R9;
R4 is hydrogen;
R5 is halogen, methyl, ethyl, substituted alkenyl, alkyne, OMe or OCF3; and R6 is hydrogen.
[14] In another even more preferred embodiment, the present invention provides a compound including isomers, enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, prodrugs and solvates wherein:
R2 is 4-oxazolyl, substituted 4-oxazolyl, 5-oxazolyl or substituted 5-oxazolyl;
R3 is hydrogen, hydroxy, halogen or methyl;
R4 is hydrogen; R5 is halogen, methyl or OMe; and
R6 is hydrogen.
[15] In another even more preferred embodiment, the present invention provides a compound of formula (V)
Figure imgf000022_0001
(V) including isomers, enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, prodrugs and solvates selected from: a compound of formula (V) wherein:
R is
Figure imgf000023_0001
and R3 is hydrogen;
a compound of formula (V) wherein: R1 is
Figure imgf000023_0002
and R is hydrogen;
a compound of formula (V) wherein:
Figure imgf000023_0003
and R is hydrogen;
a compound of formula (V) wherein:
R1 is CH3 and R3 is hydrogen;
a compound of formula (V) wherein: R1 is
Figure imgf000024_0001
and R is CH3;
a compound of formula (V) wherein:
R1 is
Figure imgf000024_0002
and R3 is hydrogen;
a compound of formula (V) wherein: R1 is
Figure imgf000024_0003
and R is hydrogen;
a compound of formula (V) wherein:
R is
Figure imgf000025_0001
and R3 is hydrogen;
a compound of formula (V) wherein:
R is
Figure imgf000025_0002
and R is hydrogen;
a compound of formula (V) wherein:
R1 is
Figure imgf000025_0003
and R is hydrogen;
a compound of formula (V) wherein:
R-1- is
Figure imgf000025_0004
and R is hydrogen;
a compound of formula (V) wherein: R1 is
Figure imgf000026_0001
and R is hydrogen;
a compound of formula (V) wherein:
R1 is
Figure imgf000026_0002
and R is hydrogen;
a compound of formula (V) wherein:
R1 is
Figure imgf000026_0003
and R is hydrogen;
a compound of formula (V) wherein:
R1 is
Figure imgf000026_0004
and R is hydrogen;
a compound of formula (V) wherein:
Figure imgf000027_0001
and R is hydrogen;
a compound of formula (V) wherein:
R is
Figure imgf000027_0002
and R is hydrogen;
a compound of formula (V) wherein:
R is
Figure imgf000027_0003
and R is hydrogen;
a compound of formula (V) wherein:
R is
Figure imgf000027_0004
and R is hydrogen;
a compound of formula (V) wherein: R1 is
Figure imgf000028_0001
and R is hydrogen;
a compound of formula (V) wherein: R1 is
Figure imgf000028_0002
and R3 is hydrogen;
a compound of formula (V) wherein:
R1 is
Figure imgf000028_0003
and R is hydrogen;
a compound of formula (V) wherein:
R1 is
Figure imgf000028_0004
and R is hydrogen;
a compound of formula (V) wherein: R is
Figure imgf000029_0001
and R is hydrogen;
a compound of formula (V) wherein:
R is
Figure imgf000029_0002
and R is hydrogen;
a compound of formula (V) wherein:
R1 is
Figure imgf000029_0003
and R is hydrogen;
a compound of formula (V) wherein: R1 is
Figure imgf000029_0004
and R is Br;
a compound of formula (V) wherein: R1 is
Figure imgf000029_0005
and R is hydrogen;
a compound of formula (V) wherein:
R1 is
Figure imgf000030_0001
and R is hydrogen;
a compound of formula (V) wherein:
R1 is
Figure imgf000030_0002
and R3 is hydrogen;
a compound of formula (V) wherein:
R-1 IS
Figure imgf000030_0003
and R3 is hydrogen;
a compound of formula (V) wherein: R1 is
Figure imgf000030_0004
and R3 is hydrogen;
a compound of formula (V) wherein:
Figure imgf000031_0001
and R ,3 is hydrogen;
a compound of formula (V) wherein:
Figure imgf000031_0002
and R is hydrogen;
a compound of formula (V) wherein:
R1 is
Figure imgf000031_0003
and R is hydrogen;
a compound of formula (V) wherein:
RJ IS
Figure imgf000031_0004
and R3 is hydrogen;
a compound of formula (V) wherein: R is
Figure imgf000032_0001
and R is hydrogen;
a compound of formula (V) wherein:
Figure imgf000032_0002
and R3 is hydrogen;
a compound of formula (V) wherein:
R1 is
Figure imgf000032_0003
and R is hydrogen;
a compound of formula (V) wherein:
R is
Figure imgf000032_0004
and R is hydrogen;
a compound of formula (V) wherein:
Figure imgf000033_0001
and R is hydrogen;
a compound of formula (V) wherein:
R1 is
Figure imgf000033_0002
and R is hydrogen;
a compound of formula (V) wherein:
R1 IS
and R is hydrogen;
a compound of formula (V) wherein:
Figure imgf000033_0004
and R is hydrogen;
a compound of formula (V) wherein:
R1 is
Figure imgf000033_0005
and R is hydrogen;
a compound of formula (V) wherein:
R1 is
Figure imgf000034_0001
and R is hydrogen;
a compound of formula (V) wherein:
R1 is
Figure imgf000034_0002
and R is hydrogen;
a compound of formula (V) wherein:
R1 is
Figure imgf000034_0003
and R is hydrogen;
a compound of formula (V) wherein :
Br is
Figure imgf000034_0004
and R3 is hydrogen;
a compound of formula (V) wherein: R1 is
Figure imgf000035_0001
and R is hydrogen;
a compound of formula (V) wherein:
R is
Figure imgf000035_0002
and R3 is hydrogen;
a compound of formula (V) wherein:
R1 is
Figure imgf000035_0003
and R is hydrogen;
a compound of formula (V) wherein:
R is
Figure imgf000035_0004
and R is hydrogen;
a compound of formula (V) wherein: Rx is
Figure imgf000036_0001
and R is hydrogen;
a compound of formula (V) wherein:
IT is
Figure imgf000036_0002
and R is hydrogen;
a compound of formula (V) wherein:
R1 is
Figure imgf000036_0003
and R3 is hydrogen;
a compound of formula (V) wherein:
R1 is
Figure imgf000036_0004
and R is hydrogen;
a compound of formula (V) wherein: R is Ha
Figure imgf000037_0001
and R ,3 is hydrogen;
a compound of formula (V) wherein:
Rx IS
Figure imgf000037_0002
and R is hydrogen;
a compound of formula (V) wherein:
R1 is
Figure imgf000037_0003
and R is hydrogen;
a compound of formula (V) wherein:
Rα is
Figure imgf000037_0004
and R3 is hydrogen;
a compound of formula (V) wherein: R1 is
Figure imgf000038_0001
and R3 is hydrogen;
a compound of formula (V) wherein:
R1 is
Figure imgf000038_0002
and R is hydrogen;
a compound of formula (V) wherein:
Figure imgf000038_0003
and R is hydrogen;
a compound of formula (V) wherein:
Figure imgf000038_0004
and R is hydrogen;
a compound of formula (V) wherein: R1 is
Figure imgf000039_0001
and R is hydrogen;
a compound of formula (V) wherein:
Figure imgf000039_0002
and R is hydrogen;
a compound of formula (V) wherein :
R1 is
Figure imgf000039_0003
and R is hydrogen;
a compound of formula (V) wherein:
R1 is
Figure imgf000039_0004
and R is hydrogen;
a compound of formula (V) wherein: R1 is
Figure imgf000040_0001
and R is hydrogen;
a compound of formula (V) wherein:
R1 is
Figure imgf000040_0002
and R is hydrogen;
a compound of formula (V) wherein:
R1 is
Figure imgf000040_0003
and R3 is hydrogen;
a compound of formula (V) wherein:
R1 is
Figure imgf000040_0004
and R3 is hydrogen;
a compound of formula (V) wherein:
Figure imgf000041_0001
and R3 is hydrogen;
a compound of formula (V) wherein : R1 is
Figure imgf000041_0002
and R is hydrogen;
a compound of formula (V) wherein ;
R1 is
Figure imgf000041_0003
and R is hydrogen;
a compound of formula (V) wherein;
R is
Figure imgf000041_0004
and R is hydrogen;
a compound of formula (V) wherein: R1 is
Figure imgf000042_0001
and R3 is hydrogen;
a compound of formula (V) wherein:
R is
Figure imgf000042_0002
and R is hydrogen;
a compound of formula (V) wherein:
Rx IS
Figure imgf000042_0003
and R is hydrogen;
a compound of formula (V) wherein:
Rx is
Figure imgf000042_0004
and R3 is hydrogen;
a compound of formula (V) wherein: Rx is
Figure imgf000043_0001
and R is hydrogen;
a compound of formula (V) wherein:
R1 is
Figure imgf000043_0002
and R is hydrogen;
a compound of formula (V) wherein: R1 is
Figure imgf000043_0003
and R is hydrogen;
a compound of formula (V) wherein:
R is
Figure imgf000043_0004
and R is hydrogen;
a compound of formula (V) wherein:
R is
Figure imgf000043_0005
and R3 is hydrogen;
a compound of formula (V) wherein: R1 is
Figure imgf000044_0001
and R is hydrogen;
a compound of formula (V) wherein:
Rx is
Figure imgf000044_0002
and R is hydrogen;
a compound of formula (V) wherein:
Rx IS
Figure imgf000044_0003
and R is hydrogen; a compound of formula (V) wherein:
R1 is
Figure imgf000044_0004
and R3 is hydrogen;
a compound of formula (V) wherein: R1 is
Figure imgf000045_0001
and R is hydrogen;
and a compound of formula (V) wherein:
Figure imgf000045_0002
and R is hydrogen.
[16] In another even more preferred embodiment, the present invention provides a compound including isomers, enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, prodrugs and solvates thereof selected from:
Figure imgf000045_0003
Figure imgf000045_0004
Figure imgf000046_0001
Figure imgf000046_0002
10
Figure imgf000046_0003
Figure imgf000046_0004
15
Figure imgf000046_0005
20
Figure imgf000047_0001
Figure imgf000047_0002
10
Figure imgf000047_0003
15
Figure imgf000047_0004
20
Figure imgf000047_0005
25
Figure imgf000048_0001
Figure imgf000048_0002
10
Figure imgf000048_0003
15
Figure imgf000048_0004
20
Figure imgf000048_0005
Figure imgf000049_0001
Figure imgf000049_0002
10
Figure imgf000049_0003
15
Figure imgf000049_0004
Figure imgf000049_0005
Figure imgf000050_0001
Figure imgf000050_0002
10
Figure imgf000050_0003
20
Figure imgf000050_0004
25
Figure imgf000050_0005
Figure imgf000051_0001
Figure imgf000051_0002
Figure imgf000051_0003
Figure imgf000051_0004
20
Figure imgf000051_0005
Figure imgf000052_0001
Figure imgf000052_0002
15
Figure imgf000052_0003
Figure imgf000052_0004
20
Figure imgf000052_0005
Figure imgf000053_0001
Figure imgf000053_0002
Figure imgf000053_0003
Figure imgf000053_0004
Figure imgf000054_0001
Figure imgf000054_0002
10
Figure imgf000054_0003
15
Figure imgf000054_0004
Figure imgf000055_0001
Figure imgf000055_0002
10
Figure imgf000055_0003
15
20
25
Figure imgf000055_0004
Figure imgf000056_0001
Figure imgf000056_0002
Figure imgf000056_0003
Figure imgf000056_0004
Figure imgf000056_0005
Figure imgf000057_0001
Figure imgf000057_0002
Figure imgf000057_0003
Figure imgf000057_0004
25
Figure imgf000057_0005
Figure imgf000058_0001
Figure imgf000058_0002
Figure imgf000058_0003
Figure imgf000058_0004
25
Figure imgf000058_0005
Figure imgf000059_0001
Figure imgf000059_0002
Figure imgf000059_0003
Figure imgf000059_0004
25
Figure imgf000059_0005
Figure imgf000060_0001
Figure imgf000060_0002
Figure imgf000060_0003
Figure imgf000060_0004
25
Figure imgf000061_0001
Figure imgf000061_0002
10
Figure imgf000061_0003
15
Figure imgf000061_0004
20
Figure imgf000061_0005
25
Figure imgf000062_0001
Figure imgf000062_0002
Figure imgf000062_0003
and
Figure imgf000062_0004
[17] In a third preferred embodiment, the present invention provides a pharmaceutical composition comprising: a compound of the invention and a pharmaceutically acceptable carrier. [18] In another preferred embodiment, the present invention provides a method of treating inosine monophosphate dehydrogenase associated disorders comprising: administering an effective amount of the pharmaceutical composition of the invention.
[19] In another preferred embodiment, the present invention provides a method of treating inosine monophosphate dehydrogenase associated disorders comprising: administering an effective amount of the pharmaceutical composition of the invention and another agent known to be useful in treatment of such disorders .
[20] In another preferred embodiment, the present invention provides a method of treating inosine monophosphate dehydrogenase associated disorders comprising: administering a therapeutically effective amount of the pharmaceutical composition of the invention and a phosphodiesterase Type 4 inhibitor.
[21] In a another preferred embodiment, the present invention provides a method for the treatment or prevention of allograft rejection comprising: administering a therapeutically effective amount of the pharmaceutical composition of the invention and a phosphodiesterase Type 4 inhibitor.
The following are definitions of the terms as used throughout this specification and claims. The initial definition provided for a group or term herein applies to that group or term throughout the present specification, individually or as part of another group, unless otherwise indicated.
The term "alkyl" refers to straight or branched chain hydrocarbon groups having 1 to 12 carbons atoms , preferably 1 to 8 carbon atoms, and most preferably 1 to 4 carbon atoms .
The term "substituted alkyl" refers to an alkyl group as defined above having one, two, or three substituents selected from the group consisting of halo, cyano, O-R7, S-R7, NR8R9, nitro, cycloalkyl, substituted cycloalkyl, oxo, aryl, substituted aryl, heterocycloalkyl, heteroaryl, C02R7, S(0)R7, S02R7, S03R7, S0NR8R9, C(0)NR8R9, C(O) alkyl, and C(0)H. The term "alkenyl" refers to straight or branched chain hydrocarbon groups having 2 to 12 carbon atoms and one, two or three double bonds, preferably 2 to 6 carbon atoms and one double bond.
The term "substituted alkenyl" refers to an alkenyl group as defined above having one, two, or three substituents selected from the group consisting of halo, cyano, O-R7, S-R7, NR8R9, nitro, cycloalkyl, substituted cycloalkyl, oxo, aryl, substituted aryl, heterocycloalkyl, heteroaryl, C02R7, S(0)R7, S02R7, S03R7, S02NR8R9, C(0)NR8R9, C(O) alkyl, and C(0)H.
The term' "alkynyl" refers to straight or branched chain hydrocarbon group having 2 to 12 carbon atoms and one, two or three triple bonds, preferably 2 to 6 carbon atoms and one triple bond. The term "substituted alkynyl" refers to an alkynyl group as defined above having one, two or three substituents selected from the group consisting of halo, cyano, O-R7, S-R7, NR8R9, nitro, cycloalkyl, substituted cycloalkyl, oxo, aryl, substituted aryl, heterocycloalkyl, heteroaryl, C02R7, S(0)R7, S02R7, S03R7, S02NR8R9, C(0)NR8R9, C(O) alkyl, and C(0)H.
The term "halo" refers to chloro, bromo, fluoro, and iodo.
The term "cycloalkyl" refers to fully saturated and partially unsaturated monocyclic hydrocarbon rings of 3 to 9, preferably 3 to 7 carbon atoms. Also included in this definition are bicyclic rings where the cycloalkyl ring as defined above has a fused aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, or heteroaryl ring provided that the point of attachment is in the cycloalkyl ring, i.e.
Figure imgf000065_0001
etc., as well as a cycloalkyl ring as defined above having a two or three carbon bridge or a spirocycloalkyl in which a carbon atom of the cycloallkyl ring has a carbon atom in common with a second cycloalkyl, substituted cycloalkyl, or heterocycloalkyl ring again provided that the point of attachment is in the
cycloalkyl ring, i.e.
Figure imgf000065_0002
etc,
The term "substituted cycloalkyl" refers to such cycloalkyl group as defined above having one, two or three substituents selected from the group consisting of halogen, nitro, alkyl, substituted alkyl, alkenyl, cyano, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycloalkyl, heteroaryl, oxo, OR7, CO2R7, C(0)NR8R9, OC(0)R7, OC(0)OR7, OC(0)NR8R9, OCH2C02R7, C(0)R7, NR8R9, NR10C(O)R7, NR10C(O)OR7, NR10C (O) C (0) OR7, NR10C(O)C(O)NR8R9, NR10C (0) C (0) alkyl, NR10C (NCN) OR7,
NR10C(O)NR8R9, NR10C(NCN)NR8R9, NR10C (NR11) NR8R9, NR10SO2NR8R9 , NR10SO2R7, SR7, S(0)R7, S02R7, S03R7, S02NR8R9, NHOR7, NR10NR8R9, N(COR7)OR10, N (C02R7) OR10, C ( 0 ) NR10 ( CR12R13 ) rR? , CO ( CR12R13 ) pO ( CR14R15 ) qC02 7 , CO ( CR12R13 ) rOR7 , CO(CR12R13)pO(CR14R15)qR7, CO (CR12R13) rNR8R9,
OC(0)0(CR1 R13)mNR8R9, OC (0) N (CR12R13) rR7, 0 ( CR12R13 ) NR8R9 , NR10C(O) (CR12R13)rR7, NR10C(O) (CR12R13) rOR7 ,
NR10C(=NC) (CR12R13)rR7, NR10CO (CR12R13) rNR8R9, NR10 (CR12R13) mOR7 , NR10 ( CR12R13 ) rC02R7 , NR10 ( CR12R13 ) mNR8R9 ,
NR10 ( CR12R13 ) nS02 ( CR1 R15 ) qR7 , CONR10 ( CR12R13 ) nS02 ( CR14R15 ) qR7 , SO2NR10(CR12R13)nCO(CR14R15)qR7, and S02NR10 (CR12R13)mOR7.
The term "aryl" refers to the phenyl, 1-naphthyl, and 2-naphthyl, preferably phenyl, as well as an aryl ring having a fused cycloalkyl, substituted cycloalkyl, heterocycloalkyl, or heteroaryl ring provided that the point of attachment is in the aryl ring, i.e.
Figure imgf000066_0001
The term "substituted aryl" refers to such aryl groups as defined above having one, two, or three substituents selected from the group consisting of halogen, nitro, alkyl, substituted alkyl, alkenyl, cyano, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycloalkyl, heteroaryl, OR7, C02R7, C(0)NR8R9, 0C(0)R7, 0C(0)0R7, OC(0)NR8R9, OCH2C02R7, C(0)R7, NR8R9 , NR10C(O)R7, NR10C(O)OR7, NR10C (O) C (0) OR7, NR10C (0) C (0) NR8R9, NR10C(O)C(O) alkyl, NR10C (NCN) OR7, NR10C (0)NR8R9,
NR10C(NCN)NR8R9, NR10C (NR11) NR8R9, NR10SO2NR8R9, NR10SO2R7, SR7, S(0)R7, S02R7, S03R7, S02NR8R9, NHOR7, NR10NR8R9, N(COR7)OR10, N ( C02R7 ) OR10 , C ( 0 ) NR10 ( CR12R13 ) rR7 , CO ( CR12R13 ) pO ( CR14R15 ) qC02R7 , CO(CR12R13)rOR7, CO (CR12R13)pO (CR1 R15) qR7, CO (CR12R13) rNR8R9, OC(0)0(CR12R13)mNR8R9, OC (0)N(CR12R13) rR7, 0 ( CR12R13 ) mNR8R9 , NR10C(O) (CR12R13)rR7, NR10C(O) (CR12R13) rOR7 ,
NR10C(=NC) (CR12R13)rR7, NR10CO (CR12R13) rNR8R9, NR10 (CR12R13)mOR7, NR10 ( CR12R13 ) rC0 R7 , NR10 ( CR12R13 ) mNR8R9 , NR10 ( CR12R13 ) nS02 ( CR14R15 ) qR7 , CONR10 ( CR1 R13 ) nS02 ( CR14R15 ) qR7 , S02NR10 ( CR12R13 ) nCO ( CR14R15 ) qR7 , and S02NR10 ( CR12R13 ) mOR7 as well as pentaf luorophenyl .
The term "substituted monocyclic ring system of 5 or 6 carbon atoms" refers to one, two or three substituents selected from the group consisting of halogen, nitro, alkyl, substituted alkyl, alkenyl, cyano, oxo, OR7, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycloalkyl, heteroaryl, C02R7, C(0)NR8R9, OC(0)R7, OC(0)OR7, OC(0)NR8R9, OCH2C0 R7, C(0)R7, NR8R9,
NR10C(O)R7, NR10C(O)OR7, NR10C (O) C (0) OR7, NR10C (0) C (0) NR8R9, NR10C(0)C(0) alkyl, NR10C (NCN) OR7, NR10C (0)NR8R9, NR10C(NCN)NR8R9, NR10C (NR11) NR8R9, NR10SO2NR8R9 , NR10SO2R7, SR7 , S(0)R7, S02R7, S03R7, S02NR8R9, NHOR7, NR10NR8R9, N(COR7)OR10, N(C02R7)OR10, C(O)NR10(CR12R13)rR7, CO (CR12R13) pO (CR14R15) qC02R7 , CO(CR12R13)rOR7, CO (CR12R13)pO (CR14R15) qR7, CO (CR12R13) rNR8R9 , OC(O)0(CR1 R13)mNR8R9, OC (0) N (CR12R13) rR7, 0 ( CR12R13 ) mNR8R9 , NR10C ( 0 ) ( CR12R13 ) rR7 , NR10C ( 0 ) ( CR12R13 ) rOR7 , NR10C(=NC) (CR12R13)rR7, NR10CO (CR12R13) rNR8R9, NR10 (CR12R13) mOR7, NR10(CR12R13)rCO2R7, NR10 ( CR12R13 ) mNR8R9 ,
NR10 ( CR12R13 ) nS02 ( CR14R15 ) qR7 , CONR10 ( CR12R13 ) nS02 ( CR 4R15 ) qR7 , Sθ2NR10(CR12R13)nCO(CR14R15)qR7, and S02NR10 (CR12R13) mOR7.
The term "heterocycloalkyl" refers to substituted and unsubstituted saturated or partially saturated monocyclic rings of 3 to 7 members and bicyclic rings of 7 to 11 members having one or two 0 or S atoms and/or one to four N atoms provided that the total number of heteroatoms is four or less and that the heterocycloalkyl ring contains at least one carbon atom. The nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen atoms may optionally be quaternized. The bicyclic heterocycloalkyl ring may also contain a two or three carbon bridge between available carbon or nitrogen atoms . The bicyclic heterocycloalkyl rings may also have a cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycloalkyl, or heteroaryl ring fused to the monocyclic ring provided that the point of attachment is through an available carbon or nitrogen atom of the heterocycloalkyl ring. Also included are spiroheterocycloalkyl rings wherein a carbon atom of the heterocycloalkyl ring is in common with a second heterocycloalkyl ring, a cycloalkyl ring, or a substituted cycloalkyl ring again provided that the point of attachment is through an available carbon or nitrogen atom of the heterocycloalkyl ring. The heterocycloalkyl ring can have one, two or three substituents on available carbon or nitrogen atoms selected from the group consisting of halogen, nitro, alkyl, substituted alkyl, alkenyl, cyano, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycloalkyl, heteroaryl, oxo, OR7, C02R7, C(0)NR8R9, OC(0)R7, OC(0)OR7, OC(0)NR8R9, OCH2C02R7, C(0)R7, NR8R9, NR10C(0)R7, NR10C(O)OR7, NR10C (0) C (0) OR7, NR10C(O)C(O)NR8R9, NR10C (0) C (0) alkyl , NR10C (NCN) OR7, NR10C(O)NR8R9, NR10C(NCN)NR8R9, NR10C (NR11) NR8R9, NR10SO2NR8R9 , NR10SO2R7, SR7, S(0)R7, S02R7 , S03R7, S02NR8R9, NH0R7,
NR10NR8R9, N(COR7)OR10, N (C02R7) OR10, C (0) NR10 (CR12R13) rR7 , CO ( CR12R13 ) pO ( CR14R15 ) qC02R7 , CO ( CR12R13 ) rOR7 , CO ( CR12R13 ) p0 ( CR14R15 ) qR7 , CO ( CR12R13 ) rNR8R9 , OC(0)0(CR12R13)mNR8R9, OC (0) N (CR12R13) rR7 , 0 ( CR12R13 ) mNR8R9 , NR10C(O) (CR12R13)rR7, NR10C (0) (CR12R13) rOR7,
NR10C(=NC) (CR12R13)rR7, NR10CO (CR12R13) rNR8R9, NR10 (CR12R13) mOR7, NR10 (CR12R13 ) rC02R7 , NR10 (CR12R13) mNR8R9 ,
NR10 (CR12R13 ) nS02 (CR14R15) qR7 , CONR10 (CR12R13 ) nS02 (CR14R15) qR7, S02NR10 (CR12R13 ) nCO (CR1R15) qR7 , and S02NR10 (CR12R13 ) mOR7. Exemplary monocyclic heterocycloalkyl groups include pyrrolidinyl, pyrrolinyl, pyrazolinyl, pyrazolidinyl , oxetanyl, imidazolinyl , imidazolidinyl, oxazolidinyl, isothiazolidinyl, isoxazolinyl, thiazolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, tetrahydrothiopyranyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, tetrahydrothiopyranylsulfone, 1, 3-dioxolanyl, tetrahydro-1, 1-dioxothienyl, dioxanyl, thietanyl, thiiranyl, triazolinyl, triazolidinyl, etc. Exemplary bicyclic heterocycloalkyl groups include indolinyl, quinuclidinyl, tetrahydroisoquinolinyl, benzimidazolinyl, chromanyl, dihydrobenzofuran, dihydrofuro [3 , 4-b] pyridinyl, dihydroisoindolyl, dihydroquinazolinyl (such as 3 , 4-dihydro-4-oxo- quinazolinyl) , benzofurazanyl, benzotriazolinyl, dihydrobenzofuryl , dihydrobenzothienyl , dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, dihydrobenzopyranyl, isoindolinyl, isochromanyl, benzodioxolyl, tetrahydroquinolinyl, etc.
Exemplary spirocyclic heterocycloalkyl groups include 1-aza [4.5] spirodecane, 2-aza [4.5] spirodecane, 1- aza [5.5] spiroundecane, 2-aza [5.5] spiroundecane, 3- aza [5.5] spiroundecane, etc. The term "heteroaryl" refers to substituted and unsubstituted aromatic 5 or 6 membered monocyclic groups and 9 or 10 membered bicyclic groups which have at least one heteroatom (0,S or N) in at least one of rings. Each ring of the heteroaryl groups containing a heteroatom can contain one or two 0 and S atoms and/or from one to four N atoms provided that the total number of heteroatoms in each ring is four or less. The bicyclic heteroaryl rings are formed by fusing a cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycloalkyl, or heteroaryl group to the monocyclic heteroaryl ring as defined above. The heteroaryl group is attached via an available carbon or nitrogen in the aromatic heteroaryl ring. The nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atoms may optionally be quaternized. The heteroaryl ring system may be substituted at an available carbon or nitrogen by one, two, or three substituents selected from the group consisting of halogen, nitro, alkyl, substituted alkyl, alkenyl, cyano, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycloalkyl, heteroaryl, OR7, C02R7, C(0)NR8R9, OC(0)R7, OC(0)OR7, OC(0)NR8R9, OCH2C02R7, C(0)R7, NR8R9, NR10C(O)R7, NR10C (0) OR7, NR10C (0) C (0) OR7, NR10C(O)C(O)NR8R9, NR10C (0) C (0) alkyl, NR10C (NCN) OR7, NR10C(O)NR8R9, NR10C(NCN)NR8R9, NR10C (NRlx)NR8R9, NR10SO2NR8R9 , NR10SO2R7, SR7, S(0)R7, S02R7, S03R7, S02NR8R9 , NHOR7,
NR10NR8R9, N(COR7)OR10, N (C02R7) OR10, C (0) NR10 (CR12R13) rR7 , CO ( CR12R13 ) pO ( CR1 R15 ) qC02R7 , CO ( CR12R13 ) rOR7 , CO ( CR12R13 ) pO ( CR14R15 ) qR7 , CO ( CR12R13 ). rNR8R9 , OC(0)0(CR12R13)mNR8R9, OC (0) N (CR12R13) rR7, O (CR12R13)mNR8R9, NR10C(O) (CR12R13)rR7, NR10C(O) (CR12R13) rOR7,
NR10C(=NC) (CR12R13)rR7, NR10CO (CR12R13) rNR8R9, NR10 (CR12R13)mOR7 , NR10 (CR12R13) rC02R7 , NR10 (CR12R13 ) mNR8R ,
NR10 (CR12R13 ) nS02 (CR14R15 ) qR7 , CONR10 (CR12R13) nS02 (CR14R15) qR7, SO2NR10(CR12R13)nCO(CR14R15)qR7, and S02NR10 (CR12R13)mOR7. Exemplary monocyclic heteroaryl groups include pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, furyl, thienyl, oxadiazolyl, 2-oxazepinyl, azepinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, etc. Exemplary bicyclic heteroaryl groups include benzothiazolyl, benzoxazolyl, benzothienyl, benzofuryl, quinolinyl, quinolinyl-N-oxide, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, cinnolinyl, quinoxalinyl , indazolyl, pyrrolopyridyl, furopyridinyl (such as furo [2 , 3-c] pyridinyl, furo [3 , 1-b] pyridinyl or furo [2 , 3-b] yridinyl) , benzisothiazolyl, benzisoxazolyl, benzodiazinyl, benzothiopyranyl, benzotriazolyl , benzpyrazolyl, naphthyridinyl , phthalazinyl, purinyl, pyridopyridyl, quinazolinyl, thienofuryl, thienopyridyl, thienothienyl, etc.
R12 and R14 are independently selected from hydrogen and alkyl of 1 to 4 carbons .
R13 and R15 are independently selected from hydrogen, alkyl of 1 to 4 carbons, and substituted alkyl of 1 to 4 carbons . n is zero or an integer from 1 to 4. m is an integer from 2 to 6. p is an integer from 1 to 3. q is zero or an integer from 1 to 3. r is zero or an integer from 1 to 6.
"IMPDH-associated disorders" refers to any disorder or disease state in which inhibition of the enzyme IMPDH (inosine monophosphate dehydrogenase, ECl.1.1.205, of which there are presently two known isozymes referred to as IMPDH type 1 and IMPDH type 2 ) would modulate the activity of cells (such as lymphocytes or other cells) and thereby ameliorate or reduce the symptoms or modify the underlying cause (s) of that disorder or disease. There may or may not be present in the disorder or disease an abnormality associated directly with the IMPDH enzyme. Examples of IMPDH-associated disorders include transplant rejection and autoimmune disorders, such as rheumatoid arthritis, multiple sclerosis, juvenile diabetes, asthma, and inflammatory bowel disease, as well as inflammatory disorders, cancer and tumor disorders, T- cell mediated hypersensitivity diseases, ischemic or reperfusion injury, viral replication diseases, proliferative disorders and vascular diseases. As used herein the term "treating" includes prophylactic and therapeutic uses, and refers to the alleviation of symptoms of a particular disorder in a patient, the improvement of an ascertainable measurement associated with a particular disorder, or the prevention of a particular immune response (such as transplant rejection) . The term "patient" refers to a mammal, preferably a human.
The compounds of this invention may contain one or more asymmetric carbon atoms and thus may occur as racemates and racemic mixtures, .single enantiomers, diastereomeric mixtures and individual diastereomers. All such isomers of the compounds disclosed herein are expressly included within the scope of the present invention. Each stereogenic carbon may be of the R or S configuration.
Combinations of substituents and variables thereof that result in stable compounds are also contemplated within the present invention. The term "stable" as used herein refers to compounds which possess stability sufficient to allow manufacture and which maintain their integrity for a sufficient period of time to be useful as a therapeutic or diagnostic agent.
As used herein, the compounds of this invention are defined to include pharmaceutically acceptable derivatives and prodrugs thereof. A "pharmaceutically acceptable derivative or prodrug" includes any pharmaceutically acceptable salt, ester, salt of an ester, or other derivative of a compound of the present invention which, upon administration to a subject, is capable of providing (directly or indirectly) a compound of the invention. Particularly favored derivatives and prodrugs are those that increase the bioavailability of the compounds of the present invention when such compound is administered to a subject (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 that enhances aqueous solubility or active transport through the gut membrane is appended to a compound of the present invention.
Pharmaceutically acceptable salts of the compounds disclosed herein include those derived from pharmaceutically acceptable inorganic and organic acids and bases known to those skilled in the art. Examples of suitable acid salts include, but are not limited to, the following: 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, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, trifluoroacetic, tosylate and undecanoate. Other acids, for example oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the present invention and their pharmaceutically acceptable acid additional salts.
Salts derived from appropriate bases include, but are not limited to, the following: alkali metal (e.g., sodium), alkaline earth metal (e.g., magnesium), ammonium and N-(C]__4 alkyl ) ^+ salts. The present invention also envisions the quaternization of any basic nitrogen- containing groups of the compounds disclosed herein. Water- or oil-soluble or dispersible products may be obtained by such quaternization.
Methods of Preparation
The compounds of the present invention may be synthesized using conventional techniques known in the art. Advantageously, these compounds are conveniently synthesized from readily available starting materials. Following are general synthetic schemes for manufacturing compounds of the present invention. These, schemes are illustrative and are not meant to limit the possible techniques one skilled in the art may use to manufacture compounds disclosed herein. Different methods will be evident to those skilled in the art. Additionally, the various steps in the synthesis may be performed in an alternate sequence or order to give the desired compound (s) . All documents cited herein are incorporated herein by reference in their entirety.
Compounds of the present invention can be made by many methods, which will be known to one skilled in the art of organic chemistry. In general, the time taken to complete a reaction procedure will be judged by the person performing the procedure, preferably with the aid of information obtained by monitoring the reaction by methods such as HP C or TLC . A reaction does not have to go to completion to be useful to this invention. The preparation of heterocycles useful to this invention are described in the series of books: "Comprehensive Heterocyclic Chemistry, The Structure, Reactions, Synthesis and Uses, of Heterocyclic Compounds" Katritzky, A.R., Rees, C.W. Eds Pergamon Press New York, First edition 1984, and "Comprehensive Heterocyclic Chemistry II, A Review of the Literature 1982-1995. The Structure, Reactions, Synthesis and Uses, of Heterocyclic Compounds" Katritzky, A.R., Rees, C.W. and Scriven, E., F. Eds Pergamon Press New York, 1996. Amines such as anilines or heterocyclic amines, useful for the preparation of compounds useful to this invention may be commercially available or readily prepared by many methods known to one skilled in the art of organic chemistry, and are described in "Comprehensive Organic Transformations A Guide to Functional Group Preparation" pp 385-439. Richard C. Larock 1989 VCH Publishers, Inc. Examples include but are not limited to reduction of a nitro group, and reduction of an azide. Methods for the production of amines useful to this invention are outlined in Schemes la-lf .
A general method for the synthesis of the anilines such as (la.4) useful in this invention can be perfomed by metal catalyzed cross coupling methods known in the literature. The simplest case is a Suzuki type cross coupling (Miyaura, N. , Yanagi, T. Suzuki, A., Synth. Comm. 11(7) :513-519 (1981); A. Suzuki et. al . , J. Am. Chem. Soc. 111:513 (1989); and V. N. Kalinin, Russ. Chem. Rev. 60:173 (1991)) of an aryl boronic acid or ester (la.l) (as shown below) with an appropriate bromoheterocycle in the presence of a suitable catalyst such as tetrakis (triphenylphosphine) palladium. After the cross coupling has been performed the product may be deprotected. The choice of protecting group and its method of removal will be readily apparent to one skilled in the art of organic chemistry. Such considerations and methods are,t for example, described by Greene, Theodora W. and Wuts, Peter G. M. in "Protective Groups in Organic Synthesis." 2nd Ed., (1991) Publisher: (John Wiley and Sons, Inc., New York, N.Y. For example, if the protecting group is acetyl the product may be deprotected by treatment with aqueous potassium hydroxide at a concentration of 0.5N to 5 N at room temperature to 100 °C for a period between 0.5h and 24h. For example aryl boronic acid (la.5) may react with the known 5-bromothiazole (la.6) in the presence of tetrakis (triphenylphosphine) palladium (0), to provide (la.7) which may be deprotected by an appropriate method. Scheme la
Figure imgf000076_0001
X= H, OMe, etc.
HET = a 5 or 6 membered ring containing at least one O, N, S atom with an unsaturated bond directly attached to the bromine P1 = alkyl, O-benzyl, O-ferfbutyl, ect.
Figure imgf000076_0002
Copper has been recently been shown to be an effective catalyst for cross coupling of aryl boronic acids to N-unsubstituted heterocycles as described by
Chan et al . , Tetrahed. Lett. 39:2933-2936 (1998); and Lam et al., Tetrahed. Lett. 39:2941-2944 (1998). This results in compounds in which the heterocycle is attached to the aryl ring through nitrogen rather than carbon. For example aryl boronic acid (la.5) may react with oxazolone (la.8) in the presence of copper (II) acetate in the presence of an amine base such as pyridine to provide intermediate (la.9) which may be deprotected by an appropriate method In general aryl boronic acids and esters, lb.3, where X is not Br or I, may be prepared as shown in Scheme lb, from the corresponding arylbromide (lb.l) by treatment with a palladium catalyst such as [1,1'- Bis (diphenylphosphino) -ferrocene] dichloropalladium (II) and bis (pinacolato) diboron, (lb.2) , as reported by Ishayama et al . , J. Org. Chem., (1995) 7508-7510. Aryl boronic esters may be converted to the corresponding boronic acid by several methods including treatment with aqueous HCI. In a variation of the synthesis, the nitrogen may be masked as a nitro group and later reduced by several means including metal reductions, such as by treatment with tin chloride in HCI or by refluxing the nitro compound with zinc in the presence of CaCl2 in a solvent such as ethanol, or in certain cases the nitro group may be reduced by catalytic hydrogenation in the presence of catalysts such as palladium on carbon. The conditions for the reduction of nitro groups are detailed in several references including Hudlicky, M. , "Reductions in Organic Chemistry", 2nd Ed., ACS Monograph 188, 1996, pp 91-101, American Chemical Society, Washington, DC. A second variation of the synthesis allows the aryl bromide to remain through the entire synthesis and elaborated to the boronic acid at the end. This may eliminate the need for a protecting group. Scheme lb
Figure imgf000077_0001
Catalytic PdCI2(dppf)
Figure imgf000077_0003
Figure imgf000077_0002
X= H, OMe, Cl, etc. P1 = alkyl Obenzyl, Otertbutyl, etc.
In certain cases it may be more expedient to construct the heterocyclic ring by other methods. A general method for the synthesis of 5-membered heterocycles includes the 1,3-dipolar cycloaddition reaction, which is well known to one skilled in the art of organic chemistry and is described by Padwa, Albert, Editor in λ1,3-Dipolar Cycloaddition Chemistry, Vol. 2" (1984) John Wiley and Sons, New York, N. Y. ; and Padwa, Albert; Editor. in "1,3-Dipolar Cycloaddition Chemistry, Vol. 1" (1984) John Wiley and Sons, New York, N. Y. For example oxazoles may be prepared by 1,3 dipolar cycloaddtion of the corrosponding aldehyde (lc.l) and (p- tolylsulfonyl) ethyl isocyanate (TOSMIC) (lc.2) as shown in scheme Ic . The aldehyde may be commercially available or prepared from the corresponding methyl group by oxidation with reagents such as Cr03, Mn02, and ammonium cerium (IV) nitrate by methods well known to one skilled in the art of organic chemistry and is described in Hudlicky, M. , "Oxidations in Organic Chemistry", ACS Monograph 186 (1990) , American Chemical Society, Washington, DC. The nitro group in intermediate (lc.3), is reduced to an amine (lc.4), as discussed above.
Scheme lc
Figure imgf000079_0001
Base, heat
Figure imgf000079_0002
Figure imgf000079_0003
1c.1 1c.3
Figure imgf000079_0004
An alternative method of producing amines useful to this invention is by nucleophilic attack on an electron deficient ring system as outlined in Scheme Id.
Halonitrobenzenes (ld.l), are either commercially available or readily prepared by methods known to one skilled in the art of organic synthesis. Displacement with a variety of nucleophiles produce compounds of structure (Id.2). In one example heating (Id.3) with a nucleophilic heterocycle such as triazole with or without the addition of a base provides the intermediate nitro compound which may be reduced as previously described to provide amines (Id.4). Alternatively simple organic nucleophiles such as cyanide can be reacted with halonitrobenzene (Id.5) to provide an intermediate nitrocompound which can be reduced by many methods to an amine (Id.6) . Scheme Id
Figure imgf000080_0001
In some cases it will be useful to have an ortho- bromo or ortho-iodo aniline as an intermediate for the synthesis of heterocycles useful for this invention as described in scheme Ie. Bromination of anilines may be accomplished in many cases by simply dissolving the aniline, such as (la.4) and (lc.4), in a suitable solvent such as methylene chloride, chloroform, acetic acid or hydrochloric acid, and treating with one equivalent of bromine, at a temperature from -78 to 40°C to provide aniline (le.l and le.2) . In some cases the aniline may be protected with a group such as acetate. In this case the bromination can often be accomplished by the addition of a Lewis acid catalyst such as iron, or FeBr . lodination can be effected in a manner analogous to that described for bromine, but may also benefit from the addition of silver salts such as silver benzoate, silver triflate, silver trifluoroacetate, or periodic acid, to provide aniline (le.3) and (le.4). Scheme le
Figure imgf000081_0001
1c.4 1e.2
l2, Silver salt
Figure imgf000081_0002
1 a.4
Figure imgf000081_0004
Figure imgf000081_0003
1c.4 1e.4
X= H, OMe, Cl, CH3, CF3,etc.
The synthesis of useful aniline intermediates which contain an ortho keto group (If.3) is depicted in Scheme If. They may be prepared from anilines (le.l) and (le.2, shown) by palladium mediated couping with an appropriate alkoxyvinyl stannane (lf.l) to produce the enol-ether (If .2) . Hydrolysis of the enol-ether with dilute acid provides the ketone (If.3)
Scheme If
Figure imgf000082_0001
X= H, OMe, Cl, CH3, CF3,etc. R= Me, Et...
Figure imgf000082_0002
1f.3
In the case where the compounds useful; for this invention are quinolines they may be conveniently prepared from the corresponding anilines via several methods including those outlined in Scheme 2a, through 2c.
In scheme 2a, aniline (2a.1), (of which anilines (la.4) and (lc.4) are examples) is heated in an inert solvent such as toluene, xylene, or diphenylether at a temperature up to the boiling point of the solvent with a β-ketoester (2a.2) to provide quinolone (2a.3). This method of quinolone synthesis has been described in the literature, for example see Kuo et al . in J. Med. Chem 1993, 36, 1146-1156. In some cases this cyclization can be aided by the use of an acid such as polyphosphoric acid or sulfuric acid to facilitate the intramolecular Friedel-Crafts acylation. In some cases isomereric cyclization products may be formed. In general these may be separated by flash column chromatography or high performance liquid chromatography.
A modification of the above the synthesis has been reported by Toda, J. et al . in Heterocycles 1994, 38, 2091-2097. In this method the beta keto ester (2a.2) is converted to an enamine (2a.4) by refluxing with an amine such as methylamine in an alcoholic solvent in the presence of acetic acid. The enamine (2a.4) is then reacted with an aniline such as (2a.1) in an inert solvent such as benzene, methylene chloride, or carbon tetrachloride in the presence of an equivalent of pyridinium p-toluenesulfonate (PPTS) to effect an N-N exchange reaction to produce enamine (2a.5) . This can be cyclized to the quinolone by heating in an inert solvent such as xylene at a temperature between 150-300°C. In some cases, as mentioned above, an acid catalyst may be added to aid in the intramolecular Friedel-Crafts acylation.
Scheme 2a
t
Figure imgf000083_0001
mediated
Figure imgf000083_0002
Friedle Crafts
2a.1 2a.2 cyclization 2a.3
P= Me, Et, Pr ,Bn.
Figure imgf000083_0003
2a.1 2a.5
Figure imgf000083_0004
2a.3 β-ketoesters such as (IIa.2) useful for this invention are either commercially available or readily prepared from the corresponding carboxylic acids or esters by several means including, that reported by Clay, R.J., et al., in Synthesis, 1993, 290-292, and those outlined in chapter 2 of . "Advanced Organic Chemistry" 3rd edition (1990) by Carey, F. A., and Sundberg R. J. , Plenum Press, New York, N. Y.
An alternative quinolone synthesis starting from aniline (le.3) (of which aniline le.4 is an example) is depicted in Scheme 2b. This method of quinolone synthesis has been described in the literature, for example see Kalinin, V.N. , et. al . Tetrahedron Lett. 1992, 33, 373- 376, and Torii, S., et . al . in Tetrahedron 1993, 42, 6773-6784. The aniline (le.3) is heated between 60-160°C in the presence of an acetylene (2d.l) and 0.1- 5 mol% of a palladium catalyst such as tetrakistriphenylphosphine palladium ( 0 ) , dichlorobis (triphenylphosphine) palladium (II), or dichloro [1, 1 ' -bis (diphenylphosphino) ferrocene palladium ( II ) , in an atmosphere of carbon monoxide (3-40 atmospheres) in a steel autoclave.
Scheme 2b
Figure imgf000084_0001
1e.3
2d.1 2d.2
Acetylenes 2d.l are either commercially available or may be prepared by several methods including, palladium catalyzed coupling with an aryl or vinyl bromide or iodide with trimethylsilylacetylene as initially described by Takahashi, S. et . al . in Synthesis 1980, 627. The trimethylsilyl protecting group may be removed by treatment with aqueous base or with a fluoride source such as tetrabutylammonium fluoride. An alternative sythesis of terminal acetylenes is commonly known as the Corey-Fuchs sythesis, for examples see Wang,Z. et al . J.Org. Chem.2000, 65, 1889 - 91, and references contained therein. The Corey-Fuchs syntheses and its modifications start with an appropriately substituted aldehyde. The aldehydes useful for this invention are either commercially available or readily prepared by oxidation of an alcohol by many methods as described by Hudlicky, M. "Oxidations in Organic Chemistry", ACS Monograph 186, 1990, American Chemical Society, Washington, DC.
Another alternative synthesis of quinolones has been reported in the literature for example see, Li, L., et al. in J. Med. Chem. 1994, 37, 3400-3407, and is depicted in Scheme 2c. Aniline (If .3) is coupled with an carboxylic- acid (2c.1) to form an amide (2c.2). The coupling is carried out using any of the many methods for the formation of amide bonds known to one skilled in the art of organic synthesis. These methods include but are not limited to conversion of the acid to the corresponding acid chloride, or use of standard coupling procedures such as the azide method, mixed carbonic acid anhydride (isobutyl chloroformate) method, carbodiimide (dieyelohexylcarbodiimide, diisopropylcarbodiimide, or water-soluble carbodiimides) method, active ester (p- nitrophenyl ester, N-hydroxysuccinic imido ester) method, carbonyldiimidazole method, phosphorus reagents such as BOP-C1. Some of these methods (especially the carbodiimide) can be enhanced by the addition of 1- hydroxybenzotriazole. The amide (2c.2) is then treated with a base such as potassium tert-butoxide to effect cyclization to the quinolone (2c.3). Scheme 2 c
Figure imgf000086_0001
2c.3
Scheme 3 a
Figure imgf000086_0002
The the synthesis of dioxides of benzothiazines (3a.2) has been reported in the literature, for example see, Florio at al . in J. Chem. Soc. Perkin Trans. I. 1984, 1899-1903. This chemistry is depicted in scheme 3a. Scheme 3b
Figure imgf000086_0003
An alternative synthesis of benzothiazines (3b.3) and benzothiadiazines (3b.5) has been reported in the literature, for example, Vysokov et al . in Russian J. of Org . Chem. 1998 , 34 , 428-433 . This chemistry is depicted in scheme 3b .
Scheme 4a
Figure imgf000087_0001
The synthesis of substituted-3 -hydroxy quinolinones (4a.3) has been reported in the literature, for example, Hradil et al . J. Heterocyclic Chem. 1999, 36, 141-144. This chemistry is depicted in scheme 4a.
Scheme 4b
Figure imgf000087_0002
An alternative synthesis of substituted-3 -hydroxy quinolinones (4b.4) has been reported in the literature, for example, Sui et al . Eur. J. Chem. 1999, 34 , 381-387. This chemistry is depicted in scheme 4b. A direct conversion of 4-quinolones into 3-hydroxy-4-quinolones has been reported in the liturature, for example, Behrman et al, J. Chem Research 1995, 164-165. Scheme 5a
Figure imgf000088_0001
A versatile synthesis of quinolones was reported in the literature, by Chen et al, Synthesis, 1987, 482-483. The chemistry is shown in scheme 5a. Examples described herein such as Example 160 were prepared by a similar route.
Acids (2c.1) useful for this invention in their own right or for the preparation of beta ketoesters such as (2a.2) are either commercially available or readily prepared by a number of methods known to one skilled in the art of orgainic chemistry including, oxidation of an alcohol or hydrolysis of an ester. Transformations that produce acids from commercially available reagents are described by Larock, R.C. in "Comprehensive Organic Transformations: a Guide to Functional Group Preparations." 1989, VCH Publishers, N.Y. , N.Y.. The compounds of the present invention may be modified by appending appropriate functionalities to enhance selective biological properties . Such 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.
Utility
The compounds of the present invention inhibit IMPDH enzyme, and are thus useful in the treatment, including prevention and therapy of disorders which are mediated or effected by cells which are sensitive to IMPDH inhibition, as described previously. The present invention thus provides methods for the treatment of IMPDH-associated disorders, comprising the step of administering to a subject in need thereof at least one compound of the formula I, preferably at least one compound represented by formulas II and/or III, in an amount effective therefor. Other therapeutic agents, such as those described below, may be employed with the inventive compounds in the present methods . In the methods of the present invention, such other therapeutic agent (s) may be administered prior to, simultaneously with or following the administration of the compound (s) of the present invention.
The compounds of the present invention can be used in treating a range of disorders exemplified by, but not limited to, disorders such as: the treatment of transplant rejection (e.g., kidney, liver, heart, lung, pancreas (e.g., islet cells), bone marrow, cornea, small bowel, skin allografts, skin homografts (such as employed in burn treatment), heart valve xenografts, serum sickness, and graft vs. host disease, in the treatment of autoimmune diseases, such as rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, juvenile diabetes, asthma, inflammatory bowel disease (such as Crohn's disease and ulcerative colitus) , pyoderma gangrenum, lupus (systemic lupus erythematosis) , myasthenia gravis, psoriasis, dermatitis, dermatomyositis; eczema, seborrhoea, pulmonary inflammation, eye uveitis, hepatitis, Grave's disease, Hashimoto's thyroiditis, autoimmune thyroiditis, Behcet's or Sjorgen's syndrome (dry eyes /mouth) , pernicious or immunohaemolytic anaemia, Addison's disease (autoimmune disease of the adrenal glands) , idiopathic adrenal insufficiency, autoimmune polyglandular disease (also known as autoimmune polyglandular syndrome) , glomerulonephritis, scleroderma, morphea, lichen planus, viteligo (depigmentation of the skin) , alopecia areata, autoimmune alopecia, autoimmune hypopituatarism, Guillain-Barre syndrome, and alveolitis; in the treatment of T-cell mediated hypersensitivity diseases, including contact hypersensitivity, delayed-type hypersensitivity, contact dermatitis (including that due to poison ivy) , uticaria, skin allergies, respiratory allergies (hayfever, allergic rhinitis) and gluten-sensitive enteropathy (Celiac disease) ; in the treatment of inflammatory diseases such as osteoarthritis, acute pancreatitis, chronic pancreatitis, asthma, acute respiratory distress syndrome, Sezary's syndrome and vascular diseases which have an inflammatory and or a proliferatory component such as restenosis, stenosis and artherosclerosis; in the treatment of cancer and' tumor disorders, such as solid tumors, lymphomas and leukemia; in the treatment of fungal infections such as mycosis fungoides; in protection from ischemic or reperfusion injury such as ischemic or reperfusion injury that may have been incurred during organ transplantation,
■ myocardial infarction, stroke or other causes; and in the treatment of DNA and RNA viral replication diseases, such herpes simplex type 1 (HSV-1) , herpes simplex type 2 (HSV-2), hepatitis (including hepatitis B and hepatitis C) , cytomegalovirus, Epstein-Barr, and human immunodeficiency virus (HIV) .
Additionally, IMPDH is also known to be present in bacteria and thus may regulate bacterial growth. As such, the IMPDH-inhibitor compounds of- the present invention may be useful in treatment or prevention of bacterial infection, alone or in combination with other antibiotic agents .
In a particular embodiment, the compounds of the present invention are useful for the treatment of the aforementioned exemplary disorders irrespective of their etiology, for example, for the treatment of transplant rejection, rheumatoid arthritis, inflammatory bowel disease, and viral infections. The present invention also provides pharmaceutical compositions comprising at least one of the compounds of formula I, preferably at least one of the compounds of formulas II and/or III, or a salt thereof, capable of treating an IMPDH-associated disorder in an amount effective therefor, alone or in combination with at least one additional therapeutic agent, and any pharmaceutically acceptable carrier, adjuvant or vehicle. "Additional therapeutic agents" encompasses, but is not limited to, an agent or agents selected from the group consisting of an immunosuppressant , an anti-cancer agent, an anti-viral agent, an anti-inflammatory agent, an anti- fungal agent, an antibiotic, or an anti-vascular hyperproliferation compound.
The term "pharmaceutically acceptable carrier, adjuvant or vehicle" refers to a carrier, adjuvant or vehicle that may be administered to a subject, together with a compound of the present invention, and which does not destroy the pharmacological activity thereof. Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of the present invention include, but are not limited to, the following: 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-polyoxypropylene-block polymers , polyethylene glycol and wool fat. Cyclodextrins such as α- , β- and γ-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-β-cyclodextrins, or other solubilized derivatives may also be used to enhance delivery of the compounds of the present invention. The compositions of the present invention may contain other therapeutic agents as described below, and may be formulated, for example, by employing conventional solid or liquid vehicles or diluents, as well as pharmaceutical additives of a type appropriate to the mode of desired administration (for example, excipients, binders, preservatives, stabilizers, flavors, etc.) according to techniques such as those well known in the art of pharmaceutical formulation.
The compounds of the formula I may be administered by any suitable means, for example, orally, such as in the form of tablets, capsules, granules or powders; sublingually; buccally; parenterally, such as by subcutaneous, intravenous, intramuscular, or intrasternal injection or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions) ; nasally such as by inhalation spray; topically, such as in the form of a cream or ointment; or rectally such as in the form of suppositories; in dosage unit formulations containing non-toxic, pharmaceutically acceptable vehicles or diluents. The present compounds may, for example, be administered in a form suitable for immediate release or extended release. Immediate release or extended release may be achieved by the use of suitable pharmaceutical compositions comprising the present compounds, or, particularly in the case of extended release, by the use of devices such as subcutaneous implants or osmotic pumps. The present compounds may also be administered liposomally.
Exemplary compositions for oral administration include suspensions which may contain, for example, microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners or flavoring agents such as those known in the art; and immediate release tablets which may contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and/or lactose and/or other excipients, binders, extenders, disintegrants , diluents and lubricants such as those known in the art. The present compounds may also be delivered through the oral cavity by sublingual and/or buccal administration. Molded tablets, compressed tablets or freeze-dried tablets are exemplary forms which may be used. Exemplary compositions include those formulating the present compound (s) with fast dissolving diluents such as mannitol, lactose, sucrose and/or cyclodextrins . Also included in such formulations may be high molecular weight excipients such as celluloses (avicel) or polyethylene glycols (PEG) . Such formulations may also include an excipient to aid mucosal adhesion such as hydroxy propyl cellulose (HPC) , hydroxy propyl methyl cellulose (HPMC) , sodium carboxy methyl cellulose (SCMC) , aleic anhydride copolymer (e.g., Gantrez) , and agents to control release such as polyacrylic copolymer (e.g., Carbopol 934). Lubricants, glidants, flavors, coloring agents and stabilizers may also be added for ease of fabrication and use.
Exemplary compositions for nasal aerosol or inhalation administration include solutions in saline which may contain, for example, benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, and/or other solubilizing or dispersing agents such as those known in the art.
Exemplary compositions for parenteral administration include injectable solutions or suspensions which may contain, for example, suitable non-toxic, parenterally acceptable diluents or solvents, such as mannitol, 1,3- butanediol, water, Ringer's solution, an isotonic sodium chloride solution, or other suitable dispersing or wetting and suspending agents, including synthetic mono- or diglycerides, and fatty acids, including oleic acid. The term "parenteral" as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal , intrathecal, intralesional and intracranial injection or infusion techniques.
Exemplary compositions for rectal administration include suppositories which may contain, for example, a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquify and/or dissolve in the rectal cavity to release the drug.
Exemplary compositions for topical administration include a topical carrier such as Plastibase (mineral oil gelled with polyethylene) .
The effective amount of a compound of the present invention may be determined by one of ordinary skill in the art, and includes exemplary dosage amounts for an adult human of from about 0.1 to 500 mg/kg of body weight of active compound per day, which may be administered in a single dose or in the form of individual divided doses, such as from 1 to 5 times per day. It will be understood that the specific dose level and frequency of dosage for any particular subject may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the species, age, body weight, general health, sex and diet of the subject, the mode and time of administration, rate of excretion, drug combination, and severity of the particular condition. Preferred subjects for treatment include animals, most preferably mammalian species such as humans, and domestic animals such as dogs, cats and the like, subject to IMPDH-associated disorders. The compounds of the present invention may be employed alone or in combination with each other and/or other suitable therapeutic agents useful in the treatment of IMPDH-associated disorders, such as IMPDH inhibitors other than those of the present invention, immunosuppressants, anti-cancer agents, anti-viral agents, anti-inflammatory agents, anti-fungal agents, antibiotics, or anti-vascular hyperproliferation agents. Exemplary such other therapeutic agents include the following: cyclosporins (e.g., cyclosporin A), CTLA4-Ig, antibodies such as anti-ICAM-3, anti-IL-2 receptor (Anti- Tac) , anti-CD45RB, anti-CD2, anti-CD3 (OKT-3), anti-CD4, anti-CD80, anti-CD86, monoclonal antibody OKT3 , agents blocking the interaction between CD40 and CD154 (a.k.a. "gp39"), such as antibodies specific for CD40 and/or CD154, fusion proteins constructed from CD40 and/or
CDl54/gp39 (e.g., CD40Ig and CD8gp39), inhibitors, such as nuclear translocation inhibitors, of NF-kappa B function, such as deoxyspergualin (DSG) , non-steroidal antiinflammatory drugs (NSAIDs) such as ibuprofen, celecoxib and rofecoxib, steroids such as prednisone or dexamethasone, gold compounds, antiviral agents such as abacavir, antiproliferative agents such as methotrexate, leflunomide, FK506 (tacrolimus, Prograf ) , cytotoxic drugs such as azathiprine and cyclophosphamide, TNF-α inhibitors such as tenidap, anti-TNF antibodies or soluble TNF receptor, and rapamycin (sirolimus or Rapamune) or derivatives thereof.
The above other therapeutic agents, when employed in combination with the compounds of the present invention, may be used, for example, in those amounts indicated in the Physicians' Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art.
The compounds disclosed herein are capable of targeting and inhibiting IMPDH enzyme. Inhibition can be measured by various methods, including, for example, IMP dehydrogenase HPLC assays (measuring enzymatic production of XMP and NADH from IMP and NAD) and IMP dehydrogenase spectrophotometric assays (measuring enzymatic production of NADH from NAD) . See, e.g., Montero et al . , Clinica Chimica Acta 238:169-178 (1995). Additional assays known in the art can be used in ascertaining the degree of activity of a compound ("test compound") as an IMPDH inhibitor. The inventors used the following assay to determine the degree of activity of the compounds disclosed herein as IMPDH inhibitors: Activity of IMPDH I and IMPDH II was measured following an adaptation of the method described in WO 97/40028. The reaction mixture was prepared containing 0.1M Tris pH 8.0, 0.1 M KCl, 3 mM EDTA, 2 mM DTT, 0.4 mM IMP and 40 nM enzyme (IMPDH I or IMPDH II) . The reaction was started by the addition of NAD to a final concentration of 0.4 mM. The enzymatic reaction was followed by measuring the increase in absorbance at 340 nM that results from the formation of NADH. For the analysis of potential inhibitors of the enzyme, compounds were dissolved in DMSO to a final concentration of 10 mM and added to the assay mixture such that the final concentration of DMSO was 2.5%. The assay was carried out in a 96-well plate format, with a final reaction volume of 200 DI.
The compounds disclosed herein are capable of inhibiting the enzyme IMPDH at a measurable level, under the above-described assay or an assay which can determine an effect of inhibition of the enzyme IMPDH.
The following examples illustrate preferred embodiments of the present invention and do not limit the scope of the present invention which is defined in the claims . Abbreviations employed in the Examples are defined below. Compounds of the Examples are identified by the example and step in which they are prepared (e.g., "1A" denotes the title compound of step A of Example 1) , or by the example only where the compound is the title compound of the example (for example, "2" denotes the title compound of Example 2) . Abbreviations
Ac Acetyl
AcOH Acetic acid aq. Aqueous
CDI Carbonyldiimidazole
Bn Benzyl
Boc tert-butoxycarbonyl
DMAP Dimethylaminopyridine
DMF dimethylformamide
DMSO Dimethylsulfoxide
EDC 1- (3-Dimethylaminopropyl) -3- ethylcarbodiimide hydrochloride
EtOAc Ethyl acetate
Et Ethyl
EtOH Ethanol h Hours i iso
HPLC High pressure liquid chromatography
HOAc Acetic acid
THF Tetrahydrofuran
Lawesson' s Reagent [2 , 4-bis (4-methoxyphenyl) -1, 3-dithia
2 , 4-diphosphetane-2-4-disufide
LC liquid chromatography
Me Methyl
MeOH Methanol min. Minutes
M+ (M+H)+
M+1 (M+H) +
MS Mass spectrometry n normal
Pd/C Palladium on carbon
Ph Phenyl
PPTS Pyridinium p-toluenesulfonate
Pr Propyl p-TsOH para-Toluenesulonic acid Ret Time Retention time rt or RT Room temperature sat . Saturated
TFA Trifluoroacetic acid
THF Tetrahydrofuran
TOSMIC Tosylmethyl isocyanide
YMC YMC Inc, Wilmington, NC 28403
Example 1
7-Methoxy-6- (5-oxazolyl) -2-phenyl-4 (1H) -quinolinone
Figure imgf000100_0001
1
Example 1 Part A, 4-Nitro-2-methoxy- ( , bisacetoxy) toluene
Figure imgf000100_0002
1A
To a 5 L three necked round bottom flask equipped with a mechanical stirrer was added 4-nitro-2-methoxytoluene
(150.0 g, 0.8973 mol), HOAc (900 mL) and Ac20 (900 mL) .
The mixture was stirred and cooled to 8° C with an acetone/ice bath. Concentrated H2S04 (136 mL) was carefully added while keeping the reaction temperature below 19 °C. After cooling to 0 °C, Cr03 (252.6 g, 2.526 mol, 2.815 equiv. ) was added portion-wise over 1 hour while maintaining the reaction temperature between 0-10 °C . After the addition, the mixture was stirred at 0 °C for 30 minutes at which time the reaction was complete.
The reaction mixture was then carefully poured into ice
(1.5 kg) with stirring to give a slurry. The remaining black gummy residue was rinsed with HOAc (3 x 100 mL) , and the washes were added to the slurry. After stirring for 10 minutes, the slurry was filtered. The cake was washed with water (3 x 400 mL) and suction dried for 17 hours to 1A (129.0 g, 51%). XH NMR (CDC13) D 8.02 (s, 1H) , 7.89 (d, J =8.4 Hz, 1H) , 7.77 (s, 1H) , (d, 8.4 Hz, 1H) , 3.98 (s, 3H) , 2.16 (s, 6H) . Example 1, Part B. 4-Nitro-2-methoxybenzaldehyde
Figure imgf000101_0001
IB
To a 2 L rounded bottom flask equipped with a condenser and a mechanical stirrer was placed 1A (250.7 g, 0.8851 mol), dioxane (300 mL) and concentrated HCI (60 mL) . The reaction mixture was heated to reflux and stirred under N2 for 20 hours. Water (250 mL) was added dropwise while maintaining the reaction mixture at reflux. After cooling to 0 °C with an ice/water bath, the resulting slurry was stirred for 30 minutes and then filtered. The cake was washed with water (4 x 200 mL) and suction dried for 17 hours to give IB (146.3 g, 91%) as a yellow solid. E NMR (CDC13) D 10.54 (s, 1H) , 8.00 (d, J = 8.3 Hz, 1H) , 7.91 (s, 1H) , 7.89 (d, J = 8.3 Hz, 1H) , 4.08 (s, 3H) .
Example 1 Part C. 5- (4-Nitro-2-methoxyphenyl) oxazole
Figure imgf000101_0002
1C
To a 5 L three necked round bottom flask equipped with a condenser and a mechanical stirrer was placed IB
(146.3 g, 0.8076 mol), TOSMIC (157.7 g, 0.8077 mol), K2C03
(116.6 g, 0.8075 mol) and MeOH (2.5 L) . The mixture was heated to reflux under N and stirred for 3 hours . Water
(1.25 L) was added drop-wise while maintaining the pot temperature between 59-69 °C . The resulting slurry was cooled to room temperature, and then to 5 °C with an ice- water bath. After stirring for 30 minutes at 5 °C, the slurry was filtered. The resulting cake was washed with water (3 x 400 mL) and dried in a vacuum oven at 45°C for 20 hours to 1C (148.5 g, 84%) as a yellow-reddish solid. XH NMR (CDC13) D 8.02 (s, 1H) , 7.97 (d, J = 2 Hz, 1H) , 7.95 (d, J = 2 Hz, 1H) , 7.86 (s, 1H) , 7.78 (s, 1H) , 4.11 (s, 3H) .
Example 1, Part D. 5- (4-Amino-2-methoxyphenyl) oxazole,
Figure imgf000102_0001
ID
In a 2 L hydrogenation flask was placed 1C (130.0 g, 0.6131mol), Pd/C (10 %, 26.2 g) and absolute EtOH (1280 mL) . The mixture was hydrogenated at 35-45psi H2 until the reaction was complete. The mixture was filtered over a pad of celite (20 g) and the cake was washed with EtOH (3 x 100 mL) . The filtrate was concentrated to a volume of 350 mL. Heptane (500 mL) was added to the resulting slurry. After stirring for 2 hours at room temperature, the slurry was filtered. The cake was washed with heptane (3 x 100 mL) and air-dried to give ID (80.0 g) . A second portion of product (30.2 g) was recovered from the mother liquor affording a total yield of 95%. 1H NMR (CDCI3) D 7.88 (s, 1H) , 7.60 (d, J = 8.4 Hz, 1H) , 7.41 (s, 1H) , 6.41 (dd, J = 8.4, 2.1 Hz, 1H) , 3.34 (d, J = 2.1 Hz, 1H) , 3.98 (bs, 2H) , 3.94 (s, 3H) .
Example 1, Part E, 3- [3-methoxy-4- (5- oxazolyl ) phenyl] amino] -3-phenyl-2-propenoic acid Ethyl ester
Figure imgf000103_0001
IE
A mixture of 3-methoxy-4- (5-oxazolyl) aniline, ID,
(1.00 g; 5.26 mmol), ethyl benzoylacetate (0.91 mL; 5.26 mmol), and p-toluenesulfonic acid (0.10 g; 0.526 mmol) in 55 mL of dry toluene was heated at reflux in a Dean-Stark apparatus overnight. During this time a precipitate formed. The reaction mixture was cooled to room temperature and filtered to give IF and small amount of p-toluenesulfonic acid. The filtrate was concentrated under reduced pressure, diluted with dichloromethane, and washed with water. The organic layer was collected and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica chromatography to provide 0.487g of IE as a pale yellow semi-solid. Analytical HPLC retention time = 4.08 min. (Column: YMC S5 ODS 4.6 x 50 mm Ballistic; Solvent A = 10% MeOH, 90% H20, 0.2% H3P0 ; Solvent B = 90% MeOH, 10% H20, 0.2% H3P04) with a LC/MS M+1 = 365.23.
Example 1, Part F, 7-Methoxy-6- (5-oxazolyl) -2-phenyl- 4 (1H) -quinolinone IE was heated in 4 mL of xylene in a sealed tube at 250°C overnight. During this time, a precipitate was formed. The reaction mixture was cooled to room temperature, and the precipitate was collected by vacuum filtration, washed with dichloromethane, and dried thoroughly to give 281 mg of IF as a white solid. The filtrate contained additional amounts of the product and starting material IE. The product was 99% pure by analytical HPLC with a retention time = 2.71 min. (Column: YMC S5 ODS 4.6 x 50 mm Ballistic; Solvent A =
10% MeOH, 90% H20, 0.2% H3P04; Solvent B = 90% MeOH, 10%
H20, 0.2% H3P0 ) and a LC/MS M+1 = 319.14. XH-NMR (400 mHz, DMSO) D 4.05 (s, 3H) , 6.34 (s, 1H)., 7.38 (s, 1H) , 7.59-7.61 (m, 4H) , 7.84-7.85 (m, 2H) , 8.40 (s, 1H) , 8.50
(s, 1H) , and 11.72 (s, 1H) .
Example 2
2- (3-Bromophenyl) -7-methoxy-6- (5-oxazolyl) -4 (1H) - quinolinone
Figure imgf000104_0001
2 Example 2 Part A, 3- (3-Bromophenyl) -3-oxopropanoic acid ethyl ester o o
B*γγJ Λ0E.
2A
To potassium ethyl malonate (3.25 g, 19.13 mmol) in acetonitrile (50 mL) was sequentially added triethyl amine (4.1 mL, 29.16 mmol) and magnesium chloride (2.16 g, 22.78 mmol) at room temperature. After stirring the reaction mixture at room temperature for 2 hours, 3- bromobenzoyl chloride (2.0 g, 9.11 mmol) was added and the mixture was heated at 60 °C for 18 hours, concentrated under reduced pressure and partitioned between ethyl acetate (100 mL) and IN HCI (25 mL) . The ethyl acetate layer was dried over sodium sulfate and concentrated under reduced pressure to yield the title compound (2.45 g, 99 %) . XH NMR (CDC13) : δ 8.1 (s, 1H) , 7.85 (d, 1H) , 7.7 (d, 1H) , 7.35 (t, 1H) , 4.3 (m, 2H) , 3.4 (s, 1H) , 1.3 (m, 3H) . Example 2 Part B, 3- (3-Bromophenyl) -3- (methylamino) -2- propenoic acid ethyl ester
Figure imgf000105_0001
To a solution of 2A (2.5 g, 9.22 mmol) in ethyl alcohol (15 mL) was added methyl amine (2.0M in methyl alcohol, 23 mL, 46.12 mmol) and acetic acid (2.63 L, 46.12 mmol). The reaction mixture was heated under reflux for three hours, cooled to room temperature and partitioned between ethyl acetate (50 L) and water (100 mL) . The ethyl acetate layer was dried over sodium sulfate and concentrated under reduced pressure to yield the title compound (2.45 g, 93%) as an oil. ^Η NMR (CDC13) : δ 8.4 (brs, 1H) , 7.4 (m, 2H) , 7.2 (m, 2H) , 4.6 (s, 1H) , 4.2 (q, 2H) , 2.8 (d, 3H) , 1.2 (t, 3H) .
Example 2, Part C, 3- [3-methoxy-4- (5- oxazolyl ) phenyl] amino] -3-phenyl-2-propenoic acid ethyl ester
Figure imgf000105_0002
2C To a solution of 2B (2.45 g, 8.68 mmol) in dichloromethane (50 mL) was added anilinelD (1.5 g, 7.89 mmol) and pyridinium para-toluenesulfonate (2.2 g, 8.68 mmol) . The reaction mixture was heated under reflux for 24 hours and stirred at room temperature for 40 hours. The solid that separates out was filtered and washed with dichloromethane (20 mL) . The filtrate was concentrated under reduced pressure and purified by flash column chromatography employing hexane-ethyl acetate (6:4) as the eluent, to yield the title compound as a syrup (3.0 g, 85.7%). XH NMR (CDCl3): δ 10.3 (s, IH) , 7.8 (s, IH) , 7.6 (s, IH) , 7.5 (m, 2H) , 7.4 (s, IH) , 7.25 (IH) , 7.2 ( , IH) , 6.3 (d, IH) , 6.2 (s, IH) , 5.1 (s, IH) , 4.3 (q, 2H) , 3.65 (s, 3H) , 1.2 (t, 3H) .
Example 2, Part D, 2- (3-Bromophenyl) -7-methoxy-6- (5- oxazolyl) -4 (IH) -quinolinone
A solution of 2C (3.0 g, 6.77 mmol) in ortho-xylene
(25 mL) was heated to 240 °C in a sealed tube for three hours . The reaction mixture was cooled to room temperature and the solid that separates out was filtered, washed with ethyl acetate (60 mL) and dried to yield the title compound as a solid (2.1 g, 78.1%) . """H
NMR (DMSO) : δ 8.6 (s, IH) < 8.5 (s, IH) , 8.1 (s, IH) , 7.9
(d, IH) , 7.8 (d, IH) , 7.6 (s, IH) , 7.5 (t, IH) , 7.4 (m,lH), 6.6 (s, IH) 4.1 (s, 3H) . LC/MS (retention time =
3.11 min.; M+ 398. Column: YMC ODSA S5 C18 4.6 x 50 mm (4 min. gradient. Solvent A = 10% MeOH, 90% H20, 0.1%
TFA; Solvent B = 90% MeOH, 10% H20, 0.1% TFA).
Example 3
7-Methoxy-2- [3- (1-pyrrolidinyl) phenyl] -6- (5-oxazolyl) -
4 (IH) - uinolinone
Figure imgf000107_0001
3A
Quinolone 2 (0.3 g, 0.75 mmol) in dimethylformamide
(10 L) was cooled to 0 °C and sodium hydride (0.023 g,
0.90 mmol) was added over a three minute period. The reaction mixture was stirred at 0 °C for twenty minutes and heated at 80 °C for twenty minutes. The mixture was bought to room temperature and chloromethyl methyl ether
(68 μL, 0.90 mmol) was added over three minutes. The reaction mixture was heated at 80 °C for ten minutes and concentrated under reduced pressure. To the residue that was obtained, water (20 mL) was cautiously added and the solid that separates out was filtered and dried (0.33 g, 100%). LC/MS (retention time = 3.03 min.; M+ 441.21. Column: YMC ODSA S5 C18 4.6 x 50 mm (4 min. gradient. Solvent A = 10% MeOH, 90% H20, 0.1% TFA; Solvent B = 90% MeOH, 10% H20, 0.1% TFA). Example 3 Part B, 2- [3- (1-pyrrolidinyl) henyl] -7-methoxy- 4-methoxymethoxy-6- (5-oxazolyl) quinoline
Figure imgf000108_0001
3B
To a solution of 3A. (0.125 g, 0.28 mmol) in toluene
(2 mL) was sequentially added tris (dibenzylideneacetone) dipalladium(O) (1 mg) , S(- )BINAP (2 mg) , cesium carbonate (0.129 g, 0.396 mmol) and pyrrolidine (71 μL, 0.85 mmol). The reaction mixture was heated at 100 °C for eighteen hours, cooled to room temperature, filtered over celite and the celite pad was washed with ethyl acetate (30 mL) . The filtrate was concentrated under reduced pressure and purified by flash column chromatography using hexane-ethyl acetate (2:3) as the eluent to yield the title compound as an oil (0.04g,
36.5%). XH NMR (CDC13): δ 8.6 (s, IH) , 8.0 (s, IH) , 7.7
(s, IH) , 7.5 (s, IH) , 7.2-7.4 (m, 4H) , 6.8 (d, IH) , 5.5
(s, 2H) , 4.1 (s, 3H) , 3.6 (s, 3H) , 3.4 (m, 4H) , 2.1 ( , 4H) .
Example 3 Part C, 7-Methoxy-2- [3- (1-pyrrolidinyl) phenyl] - 6- (5-oxazolyl) -4 (IH) -quinolinone To a solution of 3B (0.04g, 0.1 mmol) in dichloromethane (1 mL) was added five drops of 4N HCI in dioxane. The reaction mixture was heated at 45 °C for thirty minutes, concentrated under reduced pressure and kept on the high vacuum pump for thirty minutes to yield the title compound as a solid (0.038 g) . 41 NMR (CDC13) : δ 8.6 (s, IH) , 8.5 (s, IH) , 8.1 (s, IH) , 7.8 (s, IH) , 7.5 (t, 2H) , 7.3 (s, IH) , 7.1 ( , 2H) , 6.8 (d, 2H) , 4.1 (s, 3H) , 3.4 (m, 4H) , 2.0 (m, 4H) . LC/MS (retention time = 3.56 min.; M+ 388.15. Column: YMC ODS-A S5 C18 4.6 x 50 mm (4 min. gradient. Solvent A = 10% MeOH, 90% H0, 0.1% TFA; Solvent B = 90% MeOH, 10% H20, 0.1% TFA).
Example 4
7-Methoxy-2- (4-methylphenyl) -6- (5-oxazolyl) -4 (IH) - quinolinone
Figure imgf000109_0001
4
Example 4 , Part A 5- ( 4-Amino-5-iodo-2- methoxyphenyl ) oxazole
Figure imgf000109_0002
4A
To a solution of ID (l.Og, 5.26mmol) in CH2C12 in a round bottom flask was placed in an ice water bath. Pyridine (0.44ml, 5.44 mmol), iodine (1.38g, 5.42 mmol) and AgS03CF3 (1.39g, 5.43 mmol) were added to the reaction mixture, which was stirred overnight at room temperature. The solid was removed with filtration and the solution was washed with two 30ml potions of water, 30ml of NaHS03, 30ml of water, 30ml of Brine, dried over Na2S04. Filtration and removal of solvent afforded the title compound (1.20g, 72%). NMR (CD30D) : D 8.16 (IH, s), 7.94 (IH, s), 7.32 (IH, 2), 6.60 (IH, s) , 3.95 (3H, s) ; HPLC: 98%; LC-MS: m/z 317.04 (M+H)+ Example 4, Part A 7-Methoxy-2- (4-methylphenyl) -6- (5- oxazolyl) -4 (IH) -quinolinone
A small stainless steel bomb was charged with 4A, (lOOmg, 0.3mmmol) dissolved in 2.5ml of diethylamine .
Hereto was added p-methyl-phenylaσetylene
(81.7μL,0.6mmol) and PdCl2(PPh3)2 (19mg, 5%). The stainless steel bomb was sealed and charged with carbon monoxide. The reaction was stirred for 4 hours at 119°C with an internal pressure of ~ 40psi. The reaction was cooled to room temperature and the reaction mixture transferred to a round bottom flask by dissolving it in methylene chloride. The mixture was evaporated in vacuo and the residue washed with warm methanol, and filtered. The filtrate was passed through a cation exchange plug, and the solvent was removed in vacuo to afford 25.4mg of the desired product MW 332.36, yield 25.4%. The HPLC retention Time was 2.957 min (YMC S5 ODS 4.6x50mm Ballistic; Solvent A = 10% MeOH, 90% H20, 0.2% H3P0 ; Solvent B = 90% MeOH, 10% H20, 0.2% H3P04) with a LC/MS [M+H]+ = 333.
Example 5
3- [1, 4-Dihydro-7-methoxy-6- (5-oxazaolyl) -4-oxo-2- quinolinyljbenzeneacetic acid
Figure imgf000110_0001
Example 5, Part A, 3-Bromophenylacetic acid methyl ester
Figure imgf000111_0001
5A
To a solution of 3-bromophenylacetic acid (l.Og, 4.65mmol), 1, 3-dicyclohexylcarbodiimide (1.44g, 6.98mmol) and MeOH (149mg, 4.65mmol) in dichloromethane (40ml) was added 4-dimethylaminopyridine (57mg, 0.465mmol). The reaction mixture was stirred at RT for lhr. The white solid was precipitated out which was removed with filtration. The reaction solution was concentrated to give a crude product which was purified on silica gel column with dichloromethane. The product was collected which contain a little amount of DCU (1.36g). NMR (CDC13) : D 7.20-7.46 (4H, m) , 3.72 (3H, s), 3.621(2H, s) .
Example 5, Part B, 3- (Trimethylsilylethynly)phenylacetic acid methyl ester
Figure imgf000111_0002
A mixture of 5A (1.36g, 5.52mmol), (trimethylsilyl) cetylene (0.90g, 9.15mmol), bis (triphenylphosphine) palladium (II) acetate (0.40g, 0.539mmol) and triethylamine (20ml) in toluene (20ml) was heated to 90-100°C for 2 hrs. The catalyst was removed with filtration. The reaction mixture was concentrated to give a crude product which was dissolved in 150ml of EtOAc. It was washed with 50ml of NaHC03 , 50ml of brine, dried over Na2S04. Filtration and removal of solvent afforded a crude product which was purified by flash chromatography (silica, Hexane/CH2C1 20/1) to give the title compound (0.88g, 65%). NMR (CDC13) : □ 6.96-7.22 (4H, m) , 3.47 (3H, d, J=5.5Hz), 3.37 (2H, d, J=2.9Hz).
Example 5, Part C, 3-Ethynlyphenylacetic acid
Figure imgf000112_0001
5C
A solution of 5B (0.88g, 3.84mmol) in THF (40 mL) was treated with Bu4NF (4.5 mL 1M in THF) at ice water bath. The reaction mixture was warmed up to RT and stirred for 20 minutes which was concentrated to yield a crude product. It was dissolved in 150ml of ethyl acetate was washed with 50ml of water, 50ml of brine, dried over K2COs. Filtration and removal of solvent afforded a crude product which was dissolved in MeOH (40ml) and water (15 mL) . To this solution was added LiOH*H20 (200mg, 4.76mmol) and stirred at RT for 1 hr. Filtration and removal of solvent afforded a crude product which was added water
(50ml) . It was acidified with IN HCI solution until PH<3. The water phase was extracted with three 50ml portions of dichloromethane. The combined organic phase was washed with water (50ml), brine (50ml) and then dried over MgS04. Filtration and removal of solvent afforded a crude product which was purified by flash chromatography (silica, CH2Cl2/MeOH 20/1) to give the title compound (0.474g, 77%). NMR (CDCI3) : □ 7.08-7.34 (4H, m) , 3.52 (IH, s) , 3.51 (2H, d) .
Example 5, Part D, 3- [1, 4-Dihydro-7-methoxy-6- (5- oxazaolyl) -4-oxo-2-quinolinyl]benzeneacetic acid
A mixture of above 5C (96mg, 0.6mmol), 4A (lOOmg, 0.3mmol), diethylamine (2.5ml) and bis (triphenylphosphine) palladium (II) chloride (13mg, 0.019mmol) in a stainless steel pressure reaction vessel was assembled and hooked up to a carbon monoxide tank. It was charged CO about 40psi and heated to 120°C for 20 minutes. The reaction mixture was added MeOH (20ml) . Filtration and removal of solvent afforded a crude product which was purified by flash prep-TLC plate
(silica, 25% methanol in CHC1 ) to give the title compound (36mg, 32%). NMR (CD3OD) : D 8.67 (IH, s) , 8.34
(IH, s) , 7.76 (IH, 2), 7.58-7.66 (2H, m) , 7.44-7.55 (2H, m) , 7.33 (IH, s) , 6.57 (IH, s) , 4.15 (3H, s) , 3.61 (2H, s) ; HPLC: 96.9%; LC-MS: m/z 377.12 (M+H)+ .
Example 6
3- [ 1 , 4-Dihydro-7-methoxy-6- (5-oxazaolyl ) ~4-oxo~2- quinolinyl] benzoic acid methyl ester
Figure imgf000114_0001
Example 6 Part A, 3- (3-methoxycarbonylphenyl] oxopropanoic acid ethyl ester
Figure imgf000114_0002
6A
Monomethyl isophathalate (2.0 g, 11.1 mmol) was dissolved in a 1:3 mixture of tetrahydrofuran and dichloromethane. Carbonyldiimidazole (1.89 g, 11.7 mmol) was added slowly. The mixture was then stirred under nitrogen for 1 hr at room temperature. In a separate flask, ethyl malonate, potassium salt (3.96 g, 23.3 mmol) was dissolved in acetonitrile and magnesium chloride (2.64 g, 27.8 mmol) and triethylamine (4.95 ml, 35.5 mmol) was added to result in a heterogeneous suspension, which was stirred at room temperature for 1 h. The two reaction mixtures were mixed, and the resulting suspension was stirred @80°C for 8 hours. 100 ml of a 2N aqueous HCI solution was added to the reaction mixture, which was subsequently extracted with dichloromethane.
The organic layer was washed with 2N HCl twice and twice with water, dried (MgS0 ) and evaporated in vacuo to afford 4.0 g of an oil. Purification on silica gel using Biotage® eluting with 20% EtOAc in Hexanes , recovered 1.5 g of 6A as a clear oil. LC/MS: Retention Time = 1.38 min (YMC S5 Turbopack 4.6x33mm, 2 min gradient; Solvent A = 10% MeOH, 90% H20, 0.1% TFA; Solvent B = 90% MeOH, 10% H20, 0.1% TFA) with a (M+H)+ = 251.13. XH-NMR (Joel
500Hz/ CDC13) (1:2 mixture of enol and keto form) Keto: δ 1.17-1.21 (t, 3H, J=8.8 Hz), 3.89 (s, 3H) , 3.96 (s, 2H) , 4.12-4.18 (q, 2H, J=8.8 Hz) 5.67(s, IH) ; 7.50-7.54 (t, IH, J=9.3 Hz), 8.07-8.09 (d, IH, J=9.9 Hz), 8.19-8.21 (d, IH, J=9.9 Hz), 8.5 (d,lH, J=2.2Hz)
Example 6 Part B, 3- (3-Methoxycarbonylphenyl) -3-
(methylamino) -2-propenoic acid ethyl ester
Figure imgf000115_0001
6B
A mixture of 6A (0.730 g, 2.92 mmol), methylamine
(7.29 mL, 14.6 mmol of a 2.0 M solution in methanol), and acetic acid (0.84 mL, 14.6 mmol) in 14 mL of ethanol was heated a approximately 80° overnight. The solvent was removed under reduced pressure, and the residue was dissolved in dichloromethane and washed three times with a saturated aqueous brine solution. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 0.766 g (99%) of 6B. XH-NMR (400 mHz, CDCl3) D 1.26-1.30 (m, 3H) , 2.75-2.77 (m, 2H) , 3.94 (s, 3H) , 4.12- 4.18 (m, 2H) , 4.60 (s, IH) , 7.49 (t, IH, J=7.6 Hz), 7.55 (d, IH, J=7.6 Hz), 8.04 (s, IH) , 8.08 (d, IH, J=7.6 Hz), and 8.48 (brs, IH) . Example 6, Part C, 3- [3-Methoxy-4- (5- oxazolyl) phenyl] amino] -3- (3-methoxycarbonylphenyl) -2- propenoic acid ethyl ester
Figure imgf000116_0001
6C
A mixture of the ID (0.496 g, 2.61 mmol), 6B (0.756 g, 2.87 mmol), and pyridinium p-toluenesulfonate (0.722 g, 2.87 mmol) in 22 mL of dry dichloromethane was heated at reflux overnight. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel chromatography to give 0.783 g (71%) of the 6C as a pale yellow semi-solid. The product had an analytical HPLC retention time = 3.92 min. (Column: YMC S5 ODS 4.6 x 50 mm Ballistic; Solvent A = 10% MeOH, 90% H20, 0.2% H3P04; Solvent B *= 90% MeOH, 10% H20, 0.2% H3P04) and a LC/MS (M+l)+ *= 423.26.
Example 6, Part D, 3- [1, 4-Dihydro-7-methoxy-6- (5- oxazaolyl) -4-oxo-2-quinolinyl]benzoic acid methyl ester
A solution of 6C (0.783 g, 1.85 mmol) in approximately 10 mL of xylene was divided between two sealed tubes. The reaction mixtures were heated at 250°C overnight. The resulting precipitate was collected via vacuum filtration to give 0.334g (48%) of the 6 as a white solid. The filtrate was concentrated to provide recovered 6Calong with some additional quinolone 6. The product was 100% pure by analytical HPLC with a retention time = 2.92 min. (Column: YMC S5 ODS 4.6 x 50 mm Ballistic; Solvent A = 10% MeOH, 90% H20, 0.2% H3P04; Solvent B = 90% MeOH, 10% H20, 0.2% H3P04) and a LC/MS M+1 = 377.28. ^Ϊ-NMR (400 mHz, DMSO) D 3.93 (s, 3H) , 4.06 (s, 3H) , 6.37 (s, IH) , 7.39 (s, IH) , 7.61 (s, IH) , 7.73-7.77 (m, IH) , 8.12-8.16 (m, 2H) , 8.41 (s, 2H) , 8.49 (s, IH) , and 11.85 (s, IH) .
Example 7
2- [3- (Hydroxymethyl) phenyl] -7-methoxy-6- (5-oxazaolyl) 4 (IH) -quinolinone
Figure imgf000117_0001
7
To 6 (0.100 g, 0.266 mmol) in 20 mL of anhydrous tetrahydrofuran and 20 mL of 1,4-dioxane was added lithium aluminum hydride (0.80mL of a 1.0 M solution in tetrahydrofuran, 0.798 mmol) at room temperature. The reaction mixture was stirred for 1 h. To the mixture was added water (31.0 DL) , followed by 15% aqueous sodium hydroxide (31.0 DL) , and finally, additional water (93.0 DL) . The mixture was stirred for 1 h. The solvent was removed under reduced pressure, and the residue was purified by silica gel chromatography to give 85 mg (91%) of the product as an off-white solid. The product was 100% pure by analytical HPLC with a retention time = 2.52 min. (Column: YMC S5 ODS 4.6 x 50 mm Ballistic; Solvent A = 10% MeOH, 90% H20, 0.2% H3P04; Solvent B = 90% MeOH, 10% H20, 0.2% H3P0 ) and a LC/MS M+1 = 349.16. Example 8
2- [3- (1-Hydroxy-l-methylethyl) phenyl] -7-methoxy-6- (5-oxazaolyl) -4 (IH) -quinolinone
Figure imgf000118_0001
8
To 6 (0.015 g, 0.040 mmol) in 14 mL of anhydrous tetrahydrofuran at room temperature was added methyl magnesium bromide (80.0 mL of a 3.0 M solution in tetrahydrofuran, 0.239 mmol). The reaction mixture was stirred for 30 min. and then quenched with a small amount of a saturated aqueous solution of ammonium chloride. The mixture was filtered, and the solvent was removed under reduced pressure. The resulting crude product was purified by preparative HPLC to afford 6.0 mg of the product as a off-white solid. The product was 96% pure by analytical HPLC with a retention time = 2.77 min. (Column: YMC S5 ODS 4.6 x 50 mm Ballistic; Solvent A = 10% MeOH, 90% H20, 0.2% H3P04; Solvent B = 90% MeOH, 10% H20, 0.2% H3P04) and a LC/MS M+1 = 377.22.
Example 9
7-Methoxy-2- [3- (4-methyl-l-piperazinyl)phenyl] -6- (5- oxazaolyl) -4 (IH) -quinolinone
Figure imgf000118_0002
Example 9, Part A, 2- [3- (4-methyl-l-piperazinyl) phenyl] 7-methoxy-4-methoxymethoxy-6- (5-oxazolyl) quinoline
Figure imgf000119_0001
9A
9A was prepared from 3A by a route analogous to that used for the preparation of 3B, except in the purification step: the reaction mixture was concentrated in vacuo and carried to the next step without further purification.
Example 9, Part B, 7-Methoxy-2- [3- (4-methyl-l- piperazinyl) phenyl] -6- (5-oxazaolyl) -4 (IH) -quinolinone
To a solution of crude 9A (43 mg, 0.098 mmol) in dichloromethane (0.4 mL) was added 1 mL TFA dropwise and stirred at room temperature for 30 minutes. The reaction mixture was then concentrated in vacuo and subject to preparative HPLC (Preparative HPLC Conditions: YMC S5 ODS 20x100 mm column, start %B = 0 , final %B = 100, gradient time = 10 min, wavelength = 254, solvent A = 10% MeOH, 90% H20, 0.1% TFA, solvent B = 90% MeOH, 10% H20, 0.1% TFA). to give 12 mg of 9 as yellow solid (TFA salt). LC/MS (retention time = 2.393 min.; M+ 417. Column: YMC ODS-A S5 C18 4.6 x 50 mm (4 min. gradient. Solvent A = 10% MeOH, 90% H0, 0.1% TFA; Solvent B = 90% MeOH, 10% H20, 0.1% TFA). Example 10
2- [2 , 3-Dihydro-3- (dimethylamino) -lH-inden-5-yl] -7- methoxy-6- (5-oxazolyl) -4 (IH) -quinolinone
Figure imgf000120_0001
10
Example 10 Part A, 6-Bromo-2 , 3-dihydro-lH-inden-l-ol
Figure imgf000120_0002
10A To a solution of 6-bromo-l-indanone (prepared as described by Cornelius, Lyndon A. M. and Combs, Donald W. Synth. Commun. (1994), 24(19), 2777-88) (1.4 g, 6.57 mmol) in 20 mL of methanol was added sodium borohydride (0.087 g, 2.3 mmol) over a period of five minutes at room temperature. The reaction mixture was stirred for two hours at room temperature, concentrated under pressure and partitioned between ethyl acetate (50 mL) and IN HCl (20 mL) . The ethyl acetate layer was dried over sodium sulfate and concentrated under reduced pressure to yield the title compound as a solid (1.4 g, 99%) . 1H NMR
(CDC13) : δ 7.45 (s, IH) , 7.3 (d, IH) , 7.0 (d, IH) , 5.2 (t, IH) , 2.9 (m, IH) , 2.7 (m, IH) , 2.4 (m, IH) , 1.9 (m, 2H) . Example 10 Part B , 6-Bromo-l- (dimethylamino) -2 , 3-dihydro- lH-indene
Figure imgf000121_0001
10B To a solution of 10A (0.767 g, 3.56 mmol) in anhydrous toluene (10 mL) was added thionyl chloride (0.4 mL, 5.34 mmol) at room temperature. The reaction mixture was stirred at room temperature for twenty minutes and heated at 50 °C for one hour. The reaction mixture was concentrated under reduced pressure and partitioned between dichloromethane (20 mL) and water (20 mL) . The dichloromethane layer is dried over sodium sulfate and concentrated under reduced pressure to yield a liquid (0.641 g) , which was used as such for the subsequent step without further purification.
To the liquid obtained above (0.641 g) was added dimethylamine (2 mL of a 33% solution in ethyl alcohol) and the contents were heated in a sealed tube at 90 °C for eighteen hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure and purified by flash column chromatography using dichloromethane-methanol (18:1) as the eluent to yield the title compound as an oil (0.362 g, 42% over two steps). H NMR (CDC13): δ 7.45 (s, IH) , 7.3 (d, IH) , 7.0 (d, IH) , 4.2 (t, IH) , 2.9 (m, IH) , 2.8 (m, IH) , 2.2 (s, 6H) , 1.95 (m, 2H) . Example 10, Part C, 1- (Dimethylamino) -2 , 3-dihydro-6- [ ( trimethylsilyl) ethynyl] -lH-indene
Figure imgf000122_0001
IOC To 10B (0.29 g, 1.21 mmol), under a nitrogen atmosphere was sequentially added triethylamine (0.37 mL, 2.66 mmol), copper (I) iodide (0.018 g, 0.0968 mmol), bis (triphenylphosphine) palladium (II) dichloride (0.034 g, 0.0484 mmol) and trimethylsilyl acetylene (0.2 L, 1.45 mmol) . The reaction mixture was heated at 80 °C for two hours . The reaction mixture was cooled to room temperature, dichloromethane (20 mL) was added and the contents filtered over a thin pad of celite. The filtrate is concentrated under reduced pressure and purified by flash column chromatography using dichloromethane-methanol (18:1) as the eluent to yield the title compound as an oil (0.300 g, 96%). XH NMR (CDC13) : δ 7.5 (s, IH) , 7.3 (d, IH) , 7.1 (d, IH) , 4.3 (t, IH) , 2.9 (m, IH) , 2.8 (m, IH) , 2.2 (s, 6H) , 2.1 (m, 2H) , 0.2 (s, 9H) .
Example 10, Part D, 1- (Dimethylamino) -6-ethynyl-2 , 3- dihydro-lH-indene
Figure imgf000122_0002
10D
To a solution of XC (0.3 g, 1.16 mmol) in anhydrous THF (5 mL) was added tetrabutylammonium fluoride (1.4 mL, 1.39 mmol of a 1.0M solution in THF) at room temperature. The reaction mixture was stirred at room temperature for two hours, concentrated under reduced pressure and purified by flash column chromatography using dichloromethane-methanol (18:1) as the eluent to yield the title compound as an oil (0.18g, 83%) . 1H NMR (CDC13) : δ 7.45 (s, IH) , 7.3 (d, IH) , 7.1 (d, IH) , 4.2 (t, IH) , 2.95 (s, IH) , 2.9 (m, IH) , 2.8 (m, IH) , 2.2 (s, 6H) , 2.0 (m, 2H) .
Example 10, Part E, 2- [2 , 3-Dihydro-3- (dimethylamino) -1H- inden-5-yl] -7-methoxy-6- (5-oxazolyl) -4 (IH) -quinolinone
4A 0.15 g (0.47 mmol), 0.18 g (0.94 mmol) of 10D, 0.02 g (0.028mmol) of bis ( triphenylphosphine) palladium ( II ) dichloride and diethylamine (5 L) were reacted in a similar manner to Example 5, part D. The reaction was conducted at 120 °C for 30 minutes and then cooled to room temperature. Methanol (60 mL) was added and the contents filtered. The residue was concentrated under reduced pressure and purified by flash column chromatography using dichloromethane-methanol (7:3) as the eluent to yield the title compound as a solid (0.135 g, 71%). LC/MS (retention time = 2.31 min.; M+ 402.24. Column: YMC ODSA 5u C18 4.6 x 50 mm (4 min. gradient. Solvent A = 10% MeOH, 90% H20, 0.1% TFA; Solvent B = 90% MeOH, 10% H20, 0.1% TFA) .
Example 11
2- ( 2 , 3-Dihydro-3-methoxy-lH-inden-5-yl ) -7-methoxy-6- ( 5- oxazolyl) -4 ( IH) -quinolinone
Figure imgf000124_0001
11
Example 11 , Part A, 6-Bromo-2 , 3-dihydro-l-methoxy-lH- indene
Figure imgf000124_0002
IIA
To a solution of 10A (0.51 g, 2.4 mmol) in 10 mL of anhydrous THF was added sodium hydride (0.097 g, 3.84 mmol) over a period of 5 minutes at room temperature. After stirring the reaction mixture for fifteen minutes at room temperature, methyl iodide (0.22 mL, 3.6 mmol) was added and the contents stirred at room temperature for thirty minutes. The reaction mixture was concentrated and partitioned between ethyl acetate (20 mL) and water (20 mL) . The ethyl acetate layer was washed with IN HCI (20 mL) , brine (20 mL) , dried over sodium sulfate and concentrated to yield the title compound as a liquid (0.485 g, 89%). ^Η NMR (CDCI3) : δ 7.45 (s, IH) , 7.3 (d, IH) , 7.0 (d, IH) , 4.7 (m, IH) , 3.3 (s, 3H) , 2.9 (m, IH) , 2.8 (m, IH) , 2.3 (m, IH) , 2.0 (m, IH) . Example 11 , Part B 2 , 3 -Dihydro-l-methoxy- 6- [ ( trimethylsilyl ) ethynyl ] -lH-indene
Figure imgf000125_0001
IIB IIA 0.485 g (2.14 mmol), 0.36 mL (2.56 mmol) of trimethylsilyl acetylene, 0.06g (0.085 mmol) of bis (triphenylphosphine) palladium (II) dichloride, 0.032 g (0.171 mmol) of copper (I) iodide and 0.65 mL (4.7 mmol) of triethylamine were reacted in a similar manner to Example 10, part C, to yield the title compound as an oil (0.5 g, 96%). NMR (CDCI3) : δ 7.3 (s, IH) , 7.2 (d, IH) , 7.0 (d, IH) , 4.6 (m, IH) , 3.2 (s, 3H) , 2.9 (m, IH) , 2.6 (m, IH) , 2.2 (m, IH) , 1.95 (m, IH) . 0.1 (s, 3H) .
Example 11 , Part C 6-Ethynyl-2 , 3 -dihydro-l-methoxy-lH- indene
Figure imgf000125_0002
11c
IIB, 0.5 g (2.05 mmol) and 2.46 mL (2.46 mmol of 1.0M solution in THF) of tetrabutylammonium flouride were reacted in a similar manner to example 10, part D, to yield the title compound as an oil (0.5 g, 99%) . """H NMR (CDCI3) : δ 7.45 (s, IH) , 7.3 (d, IH) , 7.1 (d, IH) , 4.8 (m, IH) , 3.3 (s, 3H) , 3.0 (m, 2H) , 2.75 (m, IH) , 2.25 (m, IH) , 2.0 (m, IH) .
Example 11, Part D 2- (2 , 3-Dihydro-3-methoxy-lH-inden-5- yl) -7-methoxy-6- (5-oxazolyl) -4 (IH) -quinolinone 4A , 0.15 g (0.47 mmol), 0.163 g (0.94 mmol) of 11D, 0.02 g (0.028mmol) of bis ( triphenylphosphine ) palladium ( II ) dichloride and diethylamine (5 L) were reacted in a similar manner were reacted in a similar manner to Example 5, part D to yield the title compound as a solid (0.04 g, 21%) . XH NMR (CDC13) : δ 11.8 (s, IH) , 8.5 (s, IH) , 8.4 (s, IH) , 7.8 (s, IH) , 7.75 (d, IH) , 7.6 (s, IH) , 7.4 (d, IH) , 7.35 (s, IH) , 6.3 (s, IH) , 4.9 (m, IH) , 4.1 (s, 3H) , 3.3 (s, 3H) , 3.0 (m, IH) , 2.85 (m, IH) , 2.4 (m, IH) , 2.0 (m, IH) .
Examples 12 to 103
Examples 12 to 103 are prepared by several routes . The method to prepare a specific example is noted in table 1. Examples prepared in a manner analogous to Example 1 starting with aniline ID and an appropriate j eta-ketoester are designated as method Al . Examples prepared in a manner analogous to Example 2 starting with aniline ID and a appropriate jbeta-ketoester, which may be obtained from commercially available acid chlorides, are designated as method A2. Example prepared from esters, which are readily converted to an acid by hydrolysis, or acids, followed by reaction of the acid with carbonyldiimidazole, and reacted with potassium ethyl malonate as described in Example 6, part A, are designated as method A3. Examples which starting with intermediate 3A, and react in a manner analogous to example 3, are designated as method Bl . Compounds prepared in a manner analogous to Example 9 are designated as method B2 Examples which starting with intermediate 4A, and react it with a commercially available terminal alkyne, prepared in a manner analogous to example 4, are designated as method Cl . Examples which starting with intermediate 4A, and react it with a terminal alkyne, which is prepared from a commercially available aryl halide and trimethylsilylacetylene as described in Example 5, Part B and Part C, and then reacted to form a quinolone in a manner analogous to example 4, are designated as method C2. Compounds prepared in a manner analogous to Example 7 are designated as method Dl . Compounds prepared in a manner analogous to Example 8 are designated as method D2. The compounds of these examples have structures outlined in Table 1 below.
Column conditions A: YMC ODSA S5 C18 4.6 x 50 mm (4 min. gradient. Solvent A = 10% MeOH, 90% H20, 0.1% TFA; Solvent B = 90% MeOH, 10% H20, 0.1% TFA).
Column conditions B: Column: YMC S5 Turbopack Pro 4.6 x 33 mm (2 min. gradient. Solvent A = 10% MeOH, 90% H20, 0.1% TFA; Solvent B = 90% MeOH, 10% H20, 0.1% TFA).
Column conditions C: YMC ODSA 5μ C18 4.6 x 50 mm (4 min. gradient. Solvent A = 10% MeOH, 90% H20, 0.1% TFA; Solvent B = 90% MeOH, 10% H20, 0.1% TFA).
Column conditions D: YMC S5 CombiScreen 4.6X50 mm; Gradient time: 4 min; Flow rate = 4 ml/min; Solvent A = 10% MeOH, 90% Water, 0.2% H3P04; Solvent B = 90% MeOH, 10% water, 0.2% H3P04 Start % B = 0; Final % B = 100;
Column conditions E: YMC S5 ODS 4.6X50 mm; Gradient time: 4 min; Flow rate = 4 ml/min; Solvent A = 10% MeOH, 90% Water, 0.2% H3P04; Solvent B = 90% MeOH, 10% water, 0.2% H3P0 Start % B = 0; Final % B = 100; Column condition F: YMC PRO S5 4.6 x 33 mm; Gradient time: 2 min; Flow rate = 4 mL/min; Solvent A = 10% MeOH, 90% H20, 0.1% TFA; Solvent B = 90% MeOH, 10% H20, 0.1% TFA; Start % B = 0 ; Final % B = 100.
Figure imgf000128_0001
Figure imgf000128_0002
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Example 104
[6- [1, 4-Dihydro-7 -methoxy-6- (5-oxazolyl) -4-oxo-2- quinolinyl] -2 , 3-dihydro-lH-inden-l-yl]methylcarbamic acid phenylmethyl ester
Figure imgf000140_0001
Example 104, Part A, 6-Bromo-2 , 3-dihydro-N-methyl-lH- inden-1-amine
Figure imgf000140_0002
104Λ
To a solution of 6-bromoindanol (0.65 g, 3.02 mmol) in toluene (10 L) was added thionyl chloride (0.34 mL, 4.53 mmol) and the contents heated at 50 °C for one hour. The reaction mixture was cooled to room temperature and partitioned between dichloromethane (20 mL) and water (20 mL) . The dichlromethane layer was dried over sodium sulfate and concentrated under reduced pressure to yield a liquid (0.63 g) which was used as such for the subsequent step without further purification.
To 6-bromo-l-chloroindane obtained in the previous step was added methylamine (6 mL of a 33% solution in ethanol) and the contents heated in a sealed tube at 90 °C for eighteen hours . The reaction mixture was concentrated under reduced pressure and purified by silica gel flash chromatography using dichloromethane/methanol to yield the title compound (0.251 g, 37%). XH NMR (CDCI3) : □ 7.45 (s, IH) , 7.25 (d, IH) , 7.0 (d, IH) , 4.1 (t, IH) , 2.9 (m, IH) , 2.7 ( , IH) , 2.5 (brs, IH) , 2.4 (s, 3H) , 2.3 (m, IH) , 1.8 (m, IH) . Example 104, Part B, (6-Bromo-2 , 3-dihydro-lH-inden-l- yl)methylcarbamic acid phenylmethyl ester
Figure imgf000141_0001
104B
To a solution of 104A (0.251 g, 1.11 mmol) in dioxane/water (10:5 mL) was added sodium carbonate (0.294 g, 2.77 mmol) followed by benzyloxycarbonyl chloride (0.19 mL, 1.33 mmol) at room temperature. The reaction mixture was stirred at room temperature for one hour and partitioned between ethyl acetate (2 x 20 mL) and water (20 mL) . The ethyl acetate layer is dried over sodium sulfate and concentrated under reduced pressure to yield the title compound (0.392 g, 98%). 1H NMR (CDC13, mixture of rotomers) : D (7.3 , 7H) , 7.0 (m, IH) , 5.8, 5.7 (t,
IH) , 5.1 (s, 2H) , 2.9 (s, IH) , 2.8 (s, IH) , 2.6, 2.55 (s, 3H) , 2.3 (m, IH) , 1.9 (m, IH) .
Example 104, Part C, [2 , 3-Dihydro-6- [ (trimethylsilyl) ethynyl] -lH-inden-l-yl]methylcarbamic acid phenylmethyl ester
Figure imgf000141_0002
104C
A mixture of 104B (0.392g, 1.08mmol), (trimethylsilyl) acetylene (0.18 mL, 1.3 mmol), bis (triphenylphosphine) palladium (II) chloride (0.030g, 0.04mmol), copper (I) iodide (0.016g, 0.08mmol) and triethylamine (0.33 mL, 2.4 mmol) in toluene was heated to 80 °C for 2 hrs. The reaction mixture was filtered over celite. The filtrate was concentrated under reduced pressure and purified by silica gel flash chromatography employing dichloromethane/methanol to give the title compound (0.375g, 91%). LC-MS: Column A, retention time
= 4.5 minutes, m/z 378.17 (M+H)+ .
Example 104, Part D, (6-Ethynyl-2 , 3-dihydro-lH-inden-l- yl)methylcarbamic acid phenylmethyl ester
Figure imgf000142_0001
Compound 104C (0.375 g, 0.99 mmol) was subjected to the same conditions as outlined in C2 (example 4) to yield the title compound (0.285 g, 94%). LC-MS: Column A, retention time = 3.86 minutes, m/z 306.14 (M+H)+ .
Example 104, Part F, [6- [1 , 4-Dihydro-7-methoxy-6- (5- oxazolyl ) -4-oxo-2-quinolinyl] -2 , 3-dihydro-lH-inden-1- yl]methylcarbamic acid phenylmethyl ester
Figure imgf000142_0002
Compound 104D (0.285 g, 0.94 mmol) was subjected to the same conditions as outlined in C2 (example 4) to yield the title compound (0.145 g, 94%). LC-MS: Column C, retention time = 3.45 minutes, m/z 522.26 (M+H)+ . Example 105
2- [2, 3-Dihydro-3- (methylamino) -lH-inden-5-yl] -7-methoxy- 6- (5-oxazolyl) -4 (IH) -quinolinone
Figure imgf000143_0001
To 104 (0.14 g, 0.26 mmol) in 20 mL of methanol was added 10% Palladium on carbon (0.09g) and the contents hydrogenated at 40 psi for six hours. The reaction mixture was filtered and the filtrate concentrated to yield the title compound (0.063 g, 61%). LC-MS: Column
A, retention time = 2.46 minutes, m/z 388.12 (M+H)+ .
Example 106
2- [2 , 3-Dihydro-3- (1-pyrrolidinyl) -lH-inden-5-yl] -7- methoxy-6- (5-oxazolyl) -4 (IH) -quinolinone
Figure imgf000143_0002
Example 106, Part A, 1- (6-Bromo-2 , 3-dihydro-lH-inden-l- yl ) yrrolidine
Figure imgf000144_0001
106A
6-bromoindanol (0.3 g, 1.39 mmol) was subjected to the same conditions as 104, part A by substituting methylamine with pyrrolidine (1.16 mL, 14 mmol) to yield the title compound (0.195 g, 52%). 1H NMR (CDC13) : 7.4 (s, IH) , 7.25 (d, IH) , 7.0 (d, IH) , 4.1 (t, IH) , 2.9 (m, IH) , 2.6 (m, IH) , 2.55 (m, 4H) , 2.1 (m, 2H) , 1.7 (brs, 4H) .
Example 106 Part B, 1- (6-Ethynyl-2 , 3-dihydro-lH-inden-l- yl ) pyrrolidine
Figure imgf000144_0002
106B Compound 106A (0.195 g, 0.73 mmol) was subjected to the same conditions as 104, part B and C to yield the title compound (0.130 g, 84%). LC-MS: Column A, retention time = 1.85 minutes, m/z 212.17 (M+H)+ . Example 106, Part C, 2- [2 , 3-Dihydro-3- (1-pyrrolidinyl) - lH-inden-5-yl] -7-methoxy-6- (5-oxazolyl) -4 (IH) -quinolinone
Figure imgf000145_0001
Compound B (0.13 g, 0.63 mmol) was subjected to the same conditions as outlined in C2 (example 4) to yield the title compound (0.007 g) . LC-MS: Column C, retention time = 2.36 minutes, m/z 428.24 (M+H)+ .
Example 107
2- [2, 3-Dihydro-3- (4-morpholinyl) -lH-inden-5-yl] -7- methoxy-6- (5-oxazolyl) -4 (IH) -quinolinone
Figure imgf000145_0002
Example 107, Part A, 1- (6-Bromo-2 , 3-dihydro-lH-inden-l- yl) morpholine
Figure imgf000145_0003
107A
6-bromoindanol (0.3 g, 1.39 mmol) was subjected to the same conditions as 104, part A by substituting methylamine with morpholine (4.0 mL) in toluene (5 mL) to yield the title compound (0.35 g, 89%). 1H NMR (CDC13) : 7.5 (s, IH) , 7.3 (d, IH) , 7.0 (d, IH) , 4.2 (t, IH) , 3.7 (brs, 4H) , 2.8 (m, IH) , 2.7 (m, IH) , 2.4 (m, 4H) , 2.1 (m, 2H) .
Example 107, Part B, 4- (6-Ethynyl-2 , 3-dihydro-lH-inden-l- yl ) morpholine
Figure imgf000146_0001
107B Compound 107A (0.35g, 1.24 mmol) was subjected to the same conditions as 104, part B and C to yield the title compound (0.243 g, 86%). LC-MS: Column A, retention time = 1.73 minutes, m/z 228.14 (M+H)+ .
Example 107, Part C, 2- [2 , 3-Dihydro-3- (4-morpholinyl) -1H- inden-5-yl] -7-methoxy-6- (5-oxazolyl) -4 (IH) -quinolinone
Figure imgf000146_0002
Compound 104B (0.233 g, 1.04 mmol) was subjected to the same conditions as outlined in C2 (example 4) to yield the title compound (0.045 g) . LC-MS: Column C, retention time = 2.34 minutes, m/z 444.25 (M+H)+ . Example 108
2- [3- (1-Azetidinyl) -2 , 3-dihydro-lH-inden-5-yl] -7-methoxy- 6- (5-oxazolyl) -4 (IH) -quinolinone
Figure imgf000147_0001
6-bromoindanol (0.3 g, 1.39 mmol) was subjected to the same conditions as 104, part A by substituting methylamine with azetidine (0.9 mL 13.9 mmol) in toluene (5 mL) to yield the title compound (0.167 g, 47%). 1H NMR (CDC13) : 7.3 (s, IH) , 7.2 (d, IH) , 7.0 (d, IH) , 3.8 (m, IH), 3.2 (m, 4H) , 3.0 (m, IH) , 2.8 (m, IH) , 2.0 (m, 3H) , 1.8 (m, IH) .
Example 108, Part B, 1- (6-Ethynyl-2 , 3-dihydro-lH-inden-l- yl) azetidine
Figure imgf000147_0002
108B Compound 108A (0.167 g, 0.66 mmol) was subjected to the same conditions as 104, part B and C to yield the title compound (0.075 g, 57%). LC-MS: Column A, retention time = 1.67 minutes, m/z 198.11 (M+H)+ . Example 108, Part C, 2- [3- (1-Azetidinyl) -2 , 3-dihydro-lH- inden-5-yl] -7-methoxy-6- (5-oxazolyl) -4 (IH) -quinolinone
Figure imgf000148_0001
Compound 108B (0.0.075 g, 0.391 mmol) was subjected to the same conditions as outlined in C2 (example 4) to yield the title compound (0.015 g) . LC-MS: Column C, retention time = 2.32 minutes, m/z 414.26 (M+H)+ .
Example 109
7-Methoxy-2- [ (3-methylphenyl) methyl] -6- (5-oxazolyl)
4 (IH) -quinolinone
Figure imgf000148_0002
Example 109, Part A, 3-Methyl-b-oxobenzenebutanoic acid ethyl ester
Figure imgf000148_0003
m-tolylacetic acid (2.0 g, 13.33 mmol) was subjected to the same conditions as outlined in method A3 (example 3) to yield the title compound (2.7 g, 92%). XH NMR (CDCI3) • D 7.25 (m, IH) , 7.1 (d, IH) , 7.0 (m, 2H) , 4.2 (q, 2H) , 3.8 (s, 2H) , 3.4 (s, 2H) , 2.4 (s, 3H) , 1.2 (t, 3H) . Example 109, Part B, 3- [ [3-Methoxy-4- (5- oxazolyl) phenyl] amino] -4- (3-methylphenyl) -2-propenoic acid ethyl ester
Figure imgf000149_0001
Compound 109A (1.0 g, 4.54 mmol) was subjected to the same conditions as outlined in method A3 (example 3) to yield the title compound (1.2 g, 67%).
Example 109, Part C, 7-Methoxy-2- [ (3- methylphenyl) ethyl] -6- (5-oxazolyl) -4 (IH) -quinolinone
Figure imgf000149_0002
Compound 109B (0.075 g, 0.391 mmol) was subjected to the same conditions as outlined in A3 (example 4) to yield the title compound (0.6 g, 68%). LC-MS: Column A, retention time = 3.21 minutes, m/z 347.05 (M+H)+ .
Example 110
2- (2 , 3-Dihydro-3-methoxy-lH-inden-5-yl) -7-methoxy-6- (5- oxazolyl) -4 ( IH) -quinolinone
Figure imgf000150_0001
Example 110, Part A, 6-Bromo-2 , 3-dihydro-l-methoxy-lH- indene
Figure imgf000150_0002
110A To a solution of 6-bromoindanol (0.51 g, 2.4 mmol) in anhydrous tetrahydrofuran (10 mL) , was added sodium hydride (0.097 g, 3.84 mmol) over a period of five minutes at room temperature . The reaction mixture was stirred at room temperature for fifteen minutes and iodomethane (0.22 mL, 3.6 mmol) was added. After thirty minutes at room temperature, the reaction mixture was partitioned between ethyl acetate (20 mL) and water (20 mL) . The ethyl acetate layer was washed with brine (20 mL) , dried over sodium sulfate and concentrated to yield the title compound (0.485 g, 89%). XH NMR (CDC13) : D 7.5 (s, IH) , 7.3 (d, IH) , 7.0 (d, IH) , 4.7 (m, IH) , 3.3 (s, 3H) , 3.0 (m, IH) , 2.7 (m, IH) , 2.3 (m, IH) , 2.0 (m, IH) . Example 110, Part B, 6-Ethynyl-2 , 3-dihydro-1-methoxy-1H- indene
Figure imgf000151_0001
HOB Compound 110A (0.485g, 2.14 mmol) was subjected to the same conditions as 104, part B and C to yield the title compound (0.35 g, 95%). XH NMR (CDC13) : D 7.5 (s, IH) , 7.3 (d, IH) , 7.0 (d, IH) , 4.7 (m, IH) , 3.3 (s, 3H) , 3.0 (m, IH) , 2.9 (s, IH) , 2.7 (m, IH) , 2.3 (m, IH) , 2.0 (m, IH) .
Example 110, Part C, 2- (2 , 3-Dihydro-3-methoxy-lH-inden-5- yl) -7-methoxy-6- (5-oxazolyl) -4 (IH) -quinolinone
Figure imgf000151_0002
Compound HOB (0.163 g, 0.94 mmol) was subjected to the same conditions as outlined in C2 (example 4) to yield the title compound (0.05 g, 27%). LC-MS: Column A, retention time = 3.17 minutes, m/z 389.11 (M+H)+ .
Example 111
2- (2 , 3-Dihydro-l-methyl-lH-isoindol-5-yl ) -7-methoxy-6- ( 5- oxazolyl ) -4 ( IH) -quinolinone
Figure imgf000152_0001
Example 111, Part A, 6-Ethynyl-2 , 3-dihydro-2-methyl-lH- isoindole
Figure imgf000152_0002
111A
5-bromo-2- (N-methyl) isoindoline (prepared in a similar manner to 5-bromoisoindoline, as reported in EP0343560) (0.1.1 g, 5.18 mmol) was subjected to the same conditions as 104, part B and C to yield the title compound (0.298 g, 22%) . LC-MS: Column A, retention time = 1.05 minutes, m/z 158.04 (M+H)+ .
Example 111, Part B, 2- (2 , 3-Dihydro-l-methyl-lH-isoindol- 5-yl) -7-methoxy-6- (5-oxazolyl) -4 (IH) -quinolinone
Figure imgf000152_0003
111B
Compound DDDDD (0.298 g ) was subjected to the same conditions as outlined in C2 (example 4) to yield the title compound (0.05 g ) . LC-MS: Column A, retention time = 2.18 minutes, m/z 374.16 (M+H)+ .
Example 112 7-Methoxy-2- [3- [ (4-methoxyphenyl) methoxy] phenyl] -6- (5- oxazolyl) -4 (IH) -quinolinone
Figure imgf000153_0001
Example 112, Part A, 3- [ (4-Methoxyphenyl)methoxy]benzoic acid methyl ester
Figure imgf000153_0002
112A
To a solution of methyl-3 -hydroxybenzoate (5.0 g, 32.8 mmol) in acetone (30 mL) was added potassium carbonate (6.82 g, 49.2 mmol) and p-methoxybenzyl chloride (4.5 mL, 32.8 mmol) . The contents are heated under reflux for forty eight hours, concentrated under pressure and partitioned between ethyl acetate (100 mL) and water (100 mL) . The ethyl acetate layer was dried over sodium sulfate and concentrated to yield the title compound (8.87 g, 99%). NMR (CDC13) : □ 7.8 (m, 2H) , 7.4 (m, 3H) , 7.15 (m, IH) , 6.9 (d, 2H) , 5.1 (s, 2H) , 3.9 (s, 3H) , 3.8 (s, 3H) . Example 112, Part B, 3- [ (4-Methoxyphenyl) methoxy]benzoic acid
Figure imgf000154_0001
112B
To compound 112A (8.87 g, 32.61 mmol) in amixture of dioxane and water (15:10 mL) was added lithium hydroxide
(2.73 g, 65.22 mmol) and the contents heated under reflux for two hours . The reaction mixture was concentrated and partitioned between ethyl acetate (2 x 300 mL) and water
(600 mL) . The aqueous layer was made acidic using IN hydrochloric acid (aqueous) and extracted into ethyl acetate (2 x 300 mL) . The ethyl acetate layer was dried over sodium sulfate and concentrated to yield the title compound (8.2 g, 97%). XH NMR (DMSO-d6): D 11.0 (s, IH) , 7.6 (m, 2H) , 7.4 (m, 3H) , 7.2 (m, IH) , 6.9 (d, 2H) , 5.1
(s, 2H) , 3.9 (s, 3H) , 3.8 (s, 3H) .
Example 112, Part C, 3- [ (4-Methoxyphenyl) methoxy] -b- oxobenzenepropanoic acid ethyl ester
Figure imgf000154_0002
112C Compound 112B (8.1 g, 31.39 mmol) was subjected to the same conditions as outlined in method A3 (example 3) to yield the title compound (9.8 g, 95%). 1H NMR (CDC13): D 7.6 (brs, IH) , 7.5 (d, IH) , 7.4 (m, 3H) , 7.2 (m, IH) , 6.9 (d, 2H) , 5.0 (s, 2H) , 4.2 (q, 2H) , 3.9 (s, 2H) , 3.8 (s, 3H) , 1.2 (t, 3H) . Example 112, Part D, 3- [ [3-Methoxy-4- (5- oxazolyl) phenyl] mino] -3- [3- [ (4- methoxyphenyl) methoxy] phenyl] -2-propenoic acid ethyl ester
Figure imgf000155_0001
112D Compound 112C (5.0 g, 15.24 mmol) was subjected to the same conditions as outlined in method A3 (example 3) to yield the title compound (5.5 g, 72%) .
Example 112, Part E, 7-Methoxy-2- [3- [ (4- methoxyphenyl) methoxy] phenyl] -6- (5-oxazolyl) -4 (IH) quinolinone
Figure imgf000155_0002
112E Compound 112D (5.3 g, 10.6 mmol) was subjected to the same conditions as outlined in A3 (example 4) to yield the title compound (2.8 g, 58%). LC-MS: Column A, retention time = 3.54 minutes, m/z 455.10 (M+H)+ . Example 113
2- (3-Hydroxyphenyl ) -7-methoxy-6- (5-oxazolyl) -4 (IH) -
Figure imgf000156_0001
To compound 112 (0.2 g, 0.44 mmol) was added trifluoroacetic acid (2 mL) and the contents stirred at room temperature for thirty minutes . The reaction mixture was concentrated and azeotroped twice with toluene. To the residue was added a mixture of methanol and ether (7:3 mL) and the solid that separates out is filtered and dried to yield the title compound (0.14 g, 95%). LC-MS: Column A, retention time = 2.8 minutes, m/z 335.10 (M+H)+ .
Example 114
2- [3- [2- (Dimethylamino) ethoxy] phenyl] -7-methoxy-6- (5- oxazolyl) -4 (IH) -quinolinone
Figure imgf000156_0002
Example 114, Part A, 7-Methoxy-2- [3- [ (4- ethoxyphenyl) methoxy] phenyl] -6- (5-oxazolyl) -4- (phenyImethoxy) quinoline
Figure imgf000157_0001
114A
To a solution of compound 112 (0.4 g, 0.88 mmol) in anhydrous dimethylformamide (10 mL) was added sodium hydride (0.027 g, 1.056 mmol) over a two minute period. The reaction mixture was heated for ten minutes at 80 °C followed by the addition of benzyl bromide (0.13 mL, 1.056 mmol) at that temperature. The reaction mixture was heated for a further ten minutes and concentrated under reduced pressure. To the residue was added water (20 mL) and the solid that separates out is filtered and dried to yield the title compound (0.475 g, 99%). LC-MS: Column A, retention time = 3.69 minutes, m/z 545.12 (M+H)+
Example 114, Part B, 3- [7-Methoxy-6- (5-oxazolyl) -4- (phenyl ethoxy) -2-quinolinyl] phenol
Figure imgf000157_0002
114B To compound 114A obtained above (0.475 g, 0.87 mmol) was added trifluoroacetic acid (6 mL) and the contents stirred at room temperature for forty minutes. The reaction mixture was concentrated and made basic by the slow addition of saturated aqueous sodium bicarbonate. The solid that separates out was extracted into ethyl acetate (110 mL) , dried over sodium sulfate and concentrated to yield the title compound (0.36 g, 97%). LC-MS: Column A, retention time = 3.24 minutes, m/z 425.08 (M+H)+ .
Example 114, Part C, 2- [3- [7-Methoxy-6- (5-oxazolyl) -4- (phenylmethoxy) -2-quinolinyl]phenoxy] -N,N- dimethylethanamine
Figure imgf000158_0001
114C
To a solution of compound 114B (0.275 g, 0.65 mmol) in anhydrous dimethyformamide (10 mL) was added potassium carbonate (0.134 g, 0.975 mmol) and the contents heated to 80 °C for two minutes. l-chloro-2-dimethylaminoethane
(0.78 mL, 0.78 mmol of a 1.0M solution in chlorobenzene) was added and the contents heated at 80 °C for two hours.
Additional potassium carbonate (2 x 0.134g) and 1-chloro- 2-dimethylaminoethane (2 x 0.78 mL, 0.78 mmol of a 1.0M solution in chlorobenzene) was added in one hour intervals at 80 °C . The reaction mixture was concentrated and partitoned between dichloromethane (20 mL) and water (20 L) . The dichloromethane layer was dried over sodium sulfate, concentrated and column purified using silica gel flash column chromatography (dichloromethane/methanol as eluent) to yield the title compound (0.155 g, 48%). LC-MS: Column C, retention time = 2.74 minutes, m/z 496.22 (M+H)+ .
Example 114, Part D, 2- [3- [2- (Dimethylamino) ethoxy] phenyl] -7-methoxy-6- (5-oxazolyl) - 4 (IH) -quinolinone
Figure imgf000159_0001
To a solution of compound 114C in methanol (0.155 g, 0.31 mmol) was added 10% palladium on carbon (0.07 g) and the contents hydrogenated at 20 psi for two hours. The reaction mixture was filtered and the filter pad washed with methanol (3 x 10 mL) . The filtrate was concentrated under reduced pressure to yield the title compound (0.119 g, 94%) . LC-MS: Column A, retention time = 2.23 minutes, m/z 406.37 (M+H)+ .
Example 115
7-Methoxy-2- [3- [2- (4-morpholinyl) ethoxy] phenyl] -6- (5- oxazolyl) -4 (IH) -quinolinone
Figure imgf000159_0002
The title compound was made in a manner similar to 114 employing 2-chloroethylmorpholine in place of 1-chloro- 2dimethylaminoethane in step C. LC-MS: Column A, retention time = 2.29 minutes, m/z 448 (M+H)+ .
Example 116 6-Methoxy-7- (5-oxazolyl) -3-phenyl-2H-1, 4-benzothiazine
1, 1-dioxide
Figure imgf000160_0001
Example 116, Part A, [ [2-Amino-4-methoxy-5- (5- oxazolyl) phenyl] thio] carbonitrile
Figure imgf000160_0002
116A
To a solution of ID (2.0 g, 10.52 mmol) in methanol (20 mL) was added ammonium thiocyanate (1.6 g, 21.04 mmol). The contents were cooled to -5 °C and bromine (0.34 mL, 6.62 mmol) was added dropwise. The reaction mixture was stirred at -.5 °C for 10 minutes and at room temperature for twenty minutes . The solid that separates out was washed with water ( 2 x 20 mL) , ethanol (2 x 10 mL) and dried to yield the title compound (1.4 g, 54%) . XH NMR (DMS0-d6) : 8.32 (s, IH) , 7.67 (s, IH) , 7.28 (s, IH) , 6.56 (s, IH) , 6.3 (brs, 2H) , 3.88 (s, 3H) . Example 116, Part B, N- [5-Methoxy-4- (5-oxazolyl) -2- ( thiocyanato) phenyl ] acetamide
Figure imgf000161_0001
116B To a solution of 116A (0.4 g, 1.62 mmol) in dichloromethane (10 mL) was added triethylamine (0.22 mL, 1.62 mmol) and the contents cooled to 0 °C . Acetyl chloride (0.11 mL, 1.62 mmol) was added and the contents stirred at room temperature for one hour. The reaction mixture was filtered and the solid washed with dichloromethane (2 x 10 mL) and dried to yield the title compound (0.436 g, 93%). LC-MS: Column A, retention time = 2.06 minutes, m/z 290.3 (M+H)+ .
Example 116, Part C, N- [5-Methoxy-4- (5-oxazolyl) -2- [ (2- oxo-2-phenylethyl) thio] phenyl] acetamide
Figure imgf000161_0002
To a solution of 116B (0.396 g, 1.37 mmol) in a mixture of ethanol and dimethylformamide (10:3 mL) , at 0 °C was added sodium borohydride (0.104 g, 2.74 mmol) in one lot. After five minutes, acetone (5 mL) was added and the reaction mixture stirred at room temperature for one minute. 2-bromoacetophenone (0.272 g, 1.37 mmol) was added in one lot and the contents stirred at room temperature for forty five minutes. The reaction mixture was concentrated under reduced pressure. To the residue that is obtained was added ethyl acetate (10 mL) . The solid that is thrown out (0.035 g) was filtered and dried to yield the title compound. The filtrate was concentrated and subjected to silica gel flash column chromatography (dichloromethane/ethyl acetate as eluent) to yield another batch of the title compound (combined yield: 0.120 g, 23%). LC-MS: Column A, retention time = 3.14 minutes, m/z 383.08 (M+H)+ .
Example 116, Part D, N- [5-Methoxy-4- (5-oxazolyl) -2- [ (2- oxo-2-phenylethyl) sulfonyl] phenyl] acetamide
Figure imgf000162_0001
116D
To a solution of 116C (0.12 g, 0.31 mmol) in acetic acid (5 mL) was added a few crystals of sodium tungstate followed by hydrogen peroxide (30% aqueous solution, 0.1 mL, 0.93 mmol) at room temperature. The raction mixture was stirred at room temperature for eighteen hours and the solid that is thrown out was filtered, washed with water and dried to yield the title compound (0.105 g, 81%). LC-MS: Column A, retention time = 2.96 minutes, m/z 415.03 (M+H)+ . Example 116, Part E, 6-Methoxy-7- (5-oxazolyl) -3-phenyl- 2H-1, 4-benzothiazine 1,1-dioxide
Figure imgf000163_0001
A solution of 116D (0.105 g, 0.25 mmol) in 4N aqueous hydrochloric acid (3 mL) was heated at 110 °C for one hour. The reaction mixture was cooled to room temperature and the solid that separates out was filtered, washed with water (3 x 10 mL) and dried to yield the title compound (0.055g, 61%). LC-MS: Column A, retention time = 2.94 minutes, m/z 355.07 (M+H)
Example 117
6-Methoxy-3- (4-methoxyphenyl) -7- (5-oxazolyl) -2H-1, 4- benzothiazine 1,1-dioxide
Figure imgf000163_0002
The title compound was made in a manner similar to 116 employing 2-bromo-4 'methoxyacetophenone in place of 2- bromoacetophenone in step 116C. LC-MS: Column A, retention time = 3.09 minutes, m/z 384.97 (M+H)+ . Example 118
3-Hydroxy-7-methoxy-6- ( 5-oxazolyl ) -2-phenyl-4 ( IH) - quinolinone
Figure imgf000164_0001
Example 118, Part A, 2-Amino-4-methoxy-5- (5- oxazolyl)benzoic acid methyl ester
Figure imgf000164_0002
118A
A steel bomb was charged with iodo aniline (1.18 g, 3.73 mmol) DMF (15 ml) bis (triphenylphosphine) palladium (II) dichloride (135 mg, 0.19 mmol), triethylamine (1.56 ml, 11.4 mmol), and methanol (20 ml) . The reaction mixture was heated at 120 °C under a carbon monoxide atmosphere for eighteen hours, cooled to room temperature, concentrated under reduced pressure and purified by silica gel flash column chromatography employing ethyl acetate/hexane (2 : 3) to yield the title compound (706 mg, 76 %) . XH NMR (CDC13) δ 3.81 (s, 3H) , 3.86 (s, 3H) , 6.10 (s, IH) , 7.37 (s, IH) , 7.80 (s, IH) , 8.20 (s, IH) .
Example 118, Part B, 2-Amino-4-methoxy-5- (5- oxazolyl)benzoic acid
Figure imgf000164_0003
To the methyl ester (706 mg, 2.85 mmol) was added lithium hydroxide (251 mg, 5.97 mmol), water (5 ml) THF (20 ml) and MeOH (20 ml) . The reaction mixture was heated under reflux for eighteen hours and concentrated under reduced pressure. The pH of the reaction was adjusted to 4-5 employing 1 N HCI . The solid that separates out was filtered rinsed with water and dried to yield the title compound (630 mg, 94 %) . 1H NMR (DMSO) δ 3.89 (s, 3H) , 6.45 (s, IH) , 7.0 (br, 2H) , 7.26 (s, IH) , 8.06 (s, IH) , 8.29 (s, IH) , 12.0 (broad, IH) .
118B
Example 118, Part C, 2 -Amino-4-methoxy-5- (5- oxazolyl)benzoic acid 2-oxo-2-phenylethyl ester
Figure imgf000165_0001
118C To a solution of acid 118B (0.279 g, 1.19 mmol) in acetone (10 ml) was added potassium carbonate (0.215 g, 1.19 mmol) and the contents stirred at room temperature for 30 min. Then 2-bromoacetophenone (0.236 g, 1.19 mmol) was added and the reaction mixture was heated under reflux for eighteen hours . The reaction mixture was concentrated under reduced pressure and partitioned between dichloromethane (20 mL) and water (20 mL) . The dichloromethane layer was dried over sodium sulfate and concentrated under reduced pressure to yield the title compound (0.410 g, 97 %) . LC-MS: Column A, retention time = 3.25 minutes, m/z 353.09 (M+H)+ . Example 118, Part C, 3-Hydroxy-7-methoxy-6- (5-oxazolyl) - 2-phenyl-4 (IH) -quinolinone
Figure imgf000166_0001
To phosphorous pentoxide (0.073 g, 0.51 mmol) in 1,2- dichlorobenzene (2 mL) was added hexamethyldisiloxane (0.43 mL, 2.04 mmol) and the contents heated at 150 °C for thirty minutes . To the clear solution was added 118B (0.06 g, 0.17 mmol) and the contents heated at 150 °C for 2.5 hours. The reaction mixture was cooled to room temperature and filtered. The solid is washed with ethyl acetate (5 x 10 mL) , water (10 mL) , saturated aqueous sodium bicarbonate (10 mL) , water (10 mL) and dried to yield the title compound (0.035 g, 61%). LC-MS: Column A, retention time = 2.88 minutes, m/z 335.38 (M+H)+ .
Example 119
3-Hydroxy-7-methoxy-2- (2-methylphenyl) -6- (5-oxazolyl) - 4 ( IH) -quinolinone
Figure imgf000166_0002
The title compound was made in a manner similar to 118 employing 2-bromo-2' methylacetophenone in place of 2- bromoacetophenone in step 118A. LC-MS: Column C, retention time = 2.82 minutes, m/z 349.12 (M+H)+ . Example 120
3-Hydroxy-7-methoxy-2- (3-methylphenyl) -6- (5-oxazolyl) -
4 (IH) -quinolinone
Figure imgf000167_0001
The title compound was made in a manner similar to 118 employing 2-bromo-3' methylacetophenone in place of 2- bromoacetophenone in step 118A. LC-MS: Column A, retention time = 3.04 minutes, m/z 349.18 (M+H)+ .
Example 121
3 -Hydroxy-7-methoxy-2- (4-methylphenyl) -6- (5-oxazolyl)
4 (IH) -quinolinone
Figure imgf000167_0002
The title compound was made in a manner similar to 118 employing 2-bromo-4' methylacetophenone in place of 2- bromoacetophenone in step 118A. LC-MS: Column A, retention time = 3.13 minutes, m/z 349.37 (M+H)+ . Example 122
2- (3 , 4-Dimethylphenyl) -3-hydroxy-7-methoxy-6- (5- oxazolyl) -4 (IH) -quinolinone
Figure imgf000168_0001
The title compound was made in a manner similar to 118 employing 2-bromo-3 ' , 4 ' methylacetophenone in place of 2- bromoacetophenone in step 118A. LC-MS: Column A, retention time = 3.26 minutes, m/z 363.18 (M+H)+ .
Example 123
3-Hydroxy-7-methoxy-2- (4-methoxyphenyl) -6- (5-oxazolyl) -
4 (IH) -quinolinone
Figure imgf000168_0002
The ,title compound was made in a manner similar to 118 employing 2-bromo-4' methoxyacetophenone in place of 2- bromoacetophenone in step 118A. LC-MS: Column A, retention time = 2.89 minutes, m/z 365.13 (M+H)+ . Example 124
2- (4-Chloro-3-methylphenyl) -3-hydroxy-7-methoxy-6- (5- oxazolyl) -4 (IH) -quinolinone
Figure imgf000169_0001
Example 124, Part A, 2~Amino-4-methoxy-5~ (5- oxazolyl)benzoic acid 2- (4-chloro-3-methylphenyl) -2- oxoethyl ester
Figure imgf000169_0002
124A The title compound was made in a manner similar to 118 employing 2-bromo-4' chloro-3 ' methylacetophenone in place of 2-bromoacetophenone in step 118A.
Example 124, Part B, 2- (4-Chloro-3-methylphenyl) -3- hydroxy-7-methoxy-6- (5-oxazolyl) -4 (IH) -quinolinone
Figure imgf000169_0003
To a solution of 124A (0.06 g, 0.15 mmol) in aceti-c acid (1.5 mL) was added ammonium acetate (0.044 g, 2.25 mmol) and the contents heated at 120 °C for eighteen hours. The reaction mixture was concentrated and partitioned between dichloromethane/methanol (8:2, 20 mL) and water (20 mL) . The dichloromethane/methanol layer was dried over sodium sulfate and concentrated. To the residue was added methanol and the solid that separates out was filtered. The filtrate was concentrated under reduced pressure and purified by preparative HPLC to yield the title compound (0.005 g) as the trifluoroacetic acid salt. LC-MS: Column A, retention time = 3.44 minutes, m/z 383 (M+H)+ .
Example 125
2 - ( 2 , 3-Dihydro-3 -me thoxy- lH-inden-5-yl ) -3-hydroxy-7- methoxy-6- ( 5-oxazolyl ) -4 ( IH) -quinolinone
Figure imgf000170_0001
Example 125, Part A, 2-Bromo-l- (2 , 3-dihydro-3-methoxy-lH- inden-5-yl) ethanone
Figure imgf000170_0002
125A
To a solution of 110A (0.525 g, 2.31 mmol) in anhydrous dioxane (10 mL) was sequentially added tributyl(l- ethoxyvinyl) tin (0.82 mL, 2.42 mmol) and bis (triphenylphosphine) palladium (II) dichloride (0.081 g, 0.11 mmol) . The reaction mixture was heated at 100 °C for eighteen hours, cooled to room temperature and filtered. To the filtrate was added water (10 mL) followed by N- bromosuccinamide (0.452 g, 2.54 mmol) and the contents stirred at room temperature for one hour. The reaction mixture was partitioned between ethyl acetate (2 x 20 mL) and water (10 mL) . The ethyl acetate layer was washed with brine, dried over sodium sulfate, concentrated and purified by silica gel flash chromatography (hexane/ethyl acetate, 9:1 as eluent) to yield the title compound (0.495 g, 79%). XH NMR (CDC13) : D 7.93 (s, IH) , 7.85 (d, IH) , 7.3 (d, IH) , 4.8 (m, IH) , 4.4 (m, 2H) , 3.4 (s, IH) , 3.1 (m, IH) , 2.85 ( , IH) , 2.4 (m, IH) , 2.1 (m, IH) .
Example 125, Part B, 2- (2 , 3-Dihydro-3-methoxy-lH-inden-5- yl) -3-hydroxy-7-methoxy-6- (5-oxazolyl) -4 (IH) -quinolinone
Figure imgf000171_0001
The title compound was made in a manner similar to 118 employing 125A in place of 2-bromoacetophenone in step A. LC-MS: Column A, retention time = 3.01 minutes, m/z 405.17 (M+H)+ .
Example 126
3-Hydroxy-7-methoxy-2- [2- (methylsulfonyl) phenyl] -6- (5- oxazolyl) -4 (IH) -quinolinone
Figure imgf000171_0002
To 118A (125 mg. 0.35 mmol) was added Eaton's reagent (4.5 ml) and the contents heated at 100 °C for 2.5 hr, The reaction mixture was poured into crushed ice and extracted with dichloromethane. The dichloromethane layer is successively washed with sat. aqueous sodium bicarbonate, brine, dried over sodium sulfate, concentrated and purified by silica gel flash chromatography (100 % Ethyl acetate as eluent) to give the title compound (10 mg) . LC-MS: Column A, retention time = 3.04 minutes, m/z 413.04 (M+H)+ .
Example 127
2- [1- (Dimethylamino) -2 , 3-dihydro-lH-inden-5-yl] -7- methoxy-6- (5-oxazolyl) -4 (IH) -quinolinone
Figure imgf000172_0001
Example 127, Part A, 5-Bromo-2 , 3-dihydro-N,N-dimethyl-lH- inden-1-amine
Figure imgf000172_0002
127A
To a solution of 5-bromo-l-chloro-indane (542 mg, 2.35 mmol) in toluene (9 ml) was added dimethylamine (3 ml) and resulting mixture was heated at 90 °C for 1.5 hr. The reaction mixture is concentrated under reduced pressure to yield the title compound (300 mg, 53%) . 1H NMR (CDC13) : 2.06 (m, 2H) , 2.24 (s, 6H) , 2.81-2.93 (m, 2H) , 4.27 (t, IH) , 7.22 (d, IH) , 7.33 (d IH) , 7.36 (s, IH) .
Example 127, Part B, 2- [1- (Dimethylamino) -2 , 3-dihydro-lH- inden-5-yl] -7-methoxy-6- (5-oxazolyl) -4 (IH) -quinolinone
Figure imgf000173_0001
Compound 127A was subjected to the conditions outlined in C2 to yield the title compound. LC-MS: Column A, retention time = 2.41 minutes, m/z 402.15 (M+H)+ .
Example 128
2- (2 , 3-Dihydro-3-methoxy-2 , 2-dimethyl-lH-inden-5-yl) -7- methoxy-6- (5-oxazolyl) -4 (IH) -quinolinone
Figure imgf000173_0002
This compound was prepared using conditions outlined in C2 and using 5-Bromo-2 , 2-dimethyl-l-hydroxy-indane. LC- MS: Column A, retention time = 3.50 minutes, m/z 417.13 (M+H)+ .
Example 129
2 - ( 2 , 3 -Dihydro-3 -methoxy-l , l-dimethyl-lH-inden-5-yl ) -7 - methoxy-6- ( 5-oxazolyl ) -4 ( IH) -quinolinone
Figure imgf000174_0001
Example 129 , Part A, 5-Bromo-2 , 3 -dihydro- 3 -me thoxy- 1 , 1- dimethyl-lH-indene
Figure imgf000174_0002
129A
To a solution of 5-Bromo-3 , 3-dimethyl-1-hydroxy-indane
(200 mg, 0.83 mmol) in' THF was added sodium hydride (32 mg, 1.33 mmol) and resulting mixture was stirred for 15 min. Iodomethane was added dropwise and stirring continued for 1 hr. The reaction mixture was concentrated under reduced pressure, extracted into ethyl acetate, washed with H0, dried over Na2S04, concentrated and purified using silica gel flash chromatography (EtOAc
/Hex, 1:5 as eluent) to yield the title compound (105 mg) . R NMR(CDC13) : D 1.14 (s, 3H) , 1.28 (s, 3H) , 1.85
(s, IH) , 2.18 (s, IH) , 3.34 (s, 3H) , 4.70 (t, IH) , 6.98
(s, IH) , 7.222 (d, IH) , 7.41 (s, IH) . Example 129, Part B, 2- (2 , 3-Dihydro-3-methoxy-l, 1- dimethyl-lH-inden-5-yl) -7-methoxy-6- (5-oxazolyl) -4 (IH) - quinolinone
Figure imgf000175_0001
Compound 129A was subjected to the conditions outlined in C2 to yield the title compound. LC-MS: Column A, retention time = 3.41 minutes, m/z 417.13 (M+H)+ .
Example 130 trans-2- [3- (Dimethylamino) -2, 3-dihydro-2-methoxy-lH- inden-5-yl] -7-methoxy-6- (5-oxazolyl) -4 (IH) -quinolinone
Figure imgf000175_0002
Example 130, Part A, trans-6-Bromo-2 , 3-dihydro-2-hydroxy- N, N-dimethyl-IH-inden-1-amine
Figure imgf000175_0003
130A
A mixture of 5-bromoindene (608 mg, 3.12 mmol) and m- CPBA (804 mg, 3.27 mmol) in CH2C12 was stirred at room temperature for eighteen hours . The solid that separated out was filtered. The filtrate was concentrated under reduced pressure and subjected to silica gel flash chromatography (EtOAc/Hex 1: 8 as eluent) to give the epoxide (350 mg, 53 %) which was used as such for the subsequent step.
To the epoxide obtained above (350 mg, 1.66 mmol), dimethylamine (5.6 M in ethanol, 3 ml) was added and the contents heated in a sealed tube at 100 °C for eighteen hours . The reaction mixture was concentrated under reduced pressure and the residue partitioned between ethyl acetate (30 mL) and IN HCI (15 ml) . The HCI layer was basified with 1 N NaOH and extracted into EtOAc, washed with brine, dried over Na2S04 and concentrated to yield the title compound (420 mg, 95 %) . H NMR (CDC13) : □ 2.37 (s, 6H) , 2.70 (q, IH) , 3.15 (q, IH) , 4.06 (d, IH) , 4.60 (q, IH) , 7.02 (d, IH) , 7.29 (d, IH) , 7.42 (s, IH) .
Example 130 , Part B , trans- 6-Bromo-2 , 3 -dih.ydro-2~meth.oxy- N, N-dimethyl-lH-inden-1-amine
Figure imgf000177_0001
130C
Compound 130A was methylated analogous to 129 (part A) to yield the title compound.
Example 130, Part C, trans-2- [3- (Dimethylamino) -2 , 3- dihydro-2-methoxy-lH-inden-5-yl] -7-methoxy-6- (5- oxazolyl) -4 (IH) -quinolinone
Figure imgf000177_0002
Compound 130B was subjected to the conditions outlined in C2 to yield the title compound. LC-MS: Column A, retention time = 2.69 minutes, m/z 432.09(M+H)
Example 131 trans-2- [ 3- (Dimethylamino ) -2 , 3 -dihydro- 2 -hydroxy- 1H- inden-5-yl ] -7-methoxy-6- ( 5-oxazolyl ) -4 ( IH) -quinolinone
Figure imgf000178_0001
Compound 130 was subjected to the conditions outlined in C2 to yield the title compound. LC-MS: Column A, retention time = 2.40 minutes, m/z 418.07 (M+H)+ .
Example 132 trans-6- [1 , 4-Dihydro-7-methoxy-6- (5-oxazolyl) -4-oxo-2- quinolinyl] -1- (dimethylamino) -2, 3-dihydro-lH-inden-2-ol methylcarbamate
Figure imgf000178_0002
A mixture of 131 (50 mg, 0.12 mmol), methyl isocyanate (15 mg, 0.14 mmol) in pyridine (1 ml) was heated at 65 °C for 2 hr. The reaction mixture was concentrated under reduced pressure and to the residue was added ethyl acetate. The solid that separates out is filtered and dried to yield the title compound (15 mg) . LC-MS: Column
A, retention time = 2.59 minutes, m/z 475.16 (M+H)+ . Example 133
Ethylcarbamic acid trans-6- [1, 4-dihydro~7-methoxy-6- (5- oxazolyl) -4-oxo-2-quinolinyl] -1- (dimethylamino) -2 , 3- dihydro-lH-inden-2-yl ester
Figure imgf000179_0001
This compound was prepared analogous to 132 using ethyl isocyanate. LC-MS: Column A, retention time = 2.76 minutes, m/z 489.16 (M+H)+ .
Example 134
(1-Methylethyl) carbamic acid trans-6- [1, 4-dihydro-7- methoxy-6- (5-oxazolyl) -4-oxo-2-quinolinyl] -1-
( dimethylamino) -2 , 3-dihydro-lH-inden-2-yl ester
Figure imgf000179_0002
This compound was prepared analogous to 132 using isopropyl isocyanate. LC-MS: Column A, retention time = 2.46 minutes, m/z 503.17 (M+H)+ . Example 135
(2-Chloroethyl) carbamic acid trans-6- [1, 4-dihydro-7- methoxy-6- (5-oxazolyl) -4-oxo-2-quinolinyl] -1-
(dimethylamino) -2 , 3-dihydro-lH-inden-2-yl ester
Figure imgf000180_0001
This compound was prepared analogous to 132 using 2- chloroethyl isocyanate. LC-MS: Column A, retention time = 2.79 minutes, m/z 523.07 (M+H)+ .
Example 136
Imidodicarbonic acid trans-6- [1, 4-dihydro-7-methoxy-6- (5- oxazolyl) -4-oxo-2-quinolinyl] -1- (dimethylamino) -2 , 3- dihydro-lH-inden-2-yl methyl ester
Figure imgf000180_0002
This compound was prepared analogous to 132 using methyl isocyanatoformate. LC-MS: Column A, retention time = 2.61 minutes, m/z 519.12 (M+H)+ . Example 137
7-Methoxy-2- [4-methyl-3- (phenylmethoxy) phenyl] -6- (5- oxazolyl) -4 (IH) -quinolinone
Figure imgf000181_0001
Example 137, Part A, 4-Methyl-b-oxo-3- (phenylmethoxy)benzenepropanoic acid ethyl ester
Figure imgf000181_0002
Compound 137A was prepared from 3-benzyl-4-methylbenzoic acid in an analogous way to Method A3 (Example 3) . HPLC retention time: 1.770 min.; Column conditions B.
Example 2, Part B, 7-Methoxy-2- [4-methyl-3-
(phenylmethoxy) phenyl] -6- (5-oxazolyl) -4 (IH) -quinolinone
137 was prepared from 137A in a similar method to Method A2 (Example 2) with pyridinium p-toluenesulfonate used for the H+ source and diphenyl ether replacing xylene in the cyclization step. HPLC retention time: 1.814 min.; Column conditions B; 439+ (M+H)+.
Example 138
2- (3-Hydroxy-4-methylphenyl) -7-methoxy-6- (5-oxazolyl) -
4 (IH) -quinolinone
Figure imgf000182_0001
Example 138, Part A, 7-Methoxy-4- (methoxymethoxy) -2- [4- methyl-3- (phenylmethoxy) phenyl] -6- (5-oxazolyl) quinoline
Figure imgf000182_0002
138A
Compound 138A was prepared from 137 in an analogous method to the first step in Method Bl (Example 3) with the reaction being run at 70°C. HPLC retention time: 1.711 min.; Column conditions B.
Example 138, Part B: 2- (3-Hydroxy-4-methylphenyl) -7- methoxy-6- (5-oxazolyl) -4 (IH) -quinolinone
138 was prepared from 138A through hydrogenation using palladium on activated carbon (10%) , H2, and MeOH/THF (12.5:1 ratio) as solvent. HPLC retention time: 2.886 min.; Column conditions: YMC S5 ODS 4.6 x 50 mm; Gradient time: 4 min.; Flow rate = 4 ml/min.; Solvent A = 10% MeOH, 90% H20, 0.1% TFA; Solvent B = 90% MeOH, 10% H20, 0.1% TFA; Start % B = 0; Final % B = 100; 349+ (M+H)+. Example 139
7-Methoxy-2- [3- (2-methoxyethoxy) -4-methylphenyl] -6- (5- oxazolyl) -4 (IH) -quinolinone
Figure imgf000183_0001
Example 139, Part A, 5- [7-Methoxy-4- (methoxymethoxy) -6- (5-oxazolyl) -2-quinolinyl] -2-methylphenol
Figure imgf000183_0002
139A
139A was prepared from 138A through hydrogenation using palladium on activated carbon (10%) , H2, and MeOH/THF (12.5:1 ratio) as solvent. HPLC retention time: 1.458 min.; Column conditions B.
Example 139, Part B, 7-Methoxy-2- [3- (2-methoxyethoxy) -4- methylphenyl] -6- (5-oxazolyl) -4 (IH) -quinolinone
139 was prepared by coupling 138A with 2-chloroethyl methyl ether using KC03 in DMF at 80°C. Aqueous work up done before compounds were deprotected using TFA in CH2C1 . Products then purified by Prep HPLC. HPLC retention time: 1.58 min.; column conditions B; (M+H) + 407. Example 140
7-Methoxy-2- [4-mβthyl-3- [ (1-methyl-3- piperidinyl) methoxy] phenyl] -6- (5-oxazolyl) -4 (IH) - quinolinone
Figure imgf000184_0001
140 was prepared by coupling 138A with the respective 3- chloromethyl-1-methyl piperdine using K2C03 in DMF at 80°C. Aqueous work up done before compounds were deprotected using TFA in CH2C12. Products then purified by Prep HPLC. HPLC retention time: 1.41 min.; column conditions B; (M+H) + 460.
Examples 141-149
Examples 141-149 were prepared using 138A, the respective alcohols, diethyl azodicarboxylate, and triphenylphosphine in THF. Compounds were purified by normal phase silica gel column before being deprotected with TFA in CH2CI2 - Compounds then purified by either normal phase silica gel column or by Prep HPLC. Table 2
Figure imgf000185_0001
Figure imgf000185_0002
Figure imgf000186_0002
Example 150
6- [ 1 , 4-Dihydro-7-methoxy-6- ( 5-oxazolyl ) -4-oxo-2- quinolinyl ] -2 , 3-dihydro-N, N, N-trimethyl-lH-inden-1- aminium
Figure imgf000186_0001
150 was prepared by methylating 10 using K2C03 and methyl iodide in acetone refluxing at 48°C. Compound was purified by Prep HPLC. HPLC retention time: 1.20 min.; column condition B; (M+H)+ 417+ .
Example 151
2- [3- (Dimethylamino) -2 , 3-dihydro-lH-inden-5-yl] -3- hydroxy-7-methoxy-6- (5-oxazolyl) -4 (IH) -quinolinone
Figure imgf000187_0001
Example 151, Part A, 6- (Bromoacetyl) -2 , 3-dihydro-N, N- dimethyl-IH-inden-1-amine
Figure imgf000187_0002
151A
151A was prepared from 10A by an analogous method described for the preparation of 110A.
Example 151, Part B, 2-Amino-4-methoxy-5- (5- oxazolyDbenzoic acid 2- [2 , 3 -dihydro-3- (dimethylamino) lH-inden-5-yl] -2-oxoethyl ester
Figure imgf000187_0003
151B A mixture of 118B (58 mg, 0.246 mmol) and potassium carbonate (75 mg, 0.542 mmol) in dry DMF (1.0 mL) was heated to 90°C for 1 hr, then cooled to 0°C. A solution of Compound lb (69 mg, 0.246 mmol) in 1.0 mL of dry DMF was added and the mixture was stirred at ambient temperature for 2.0 hr. The reaction mixture partitioned between ethyl acetate and ice water, extracted with ethyl acetate (2X) . The combined organic extracts were washed once with 10% LiCl aq. solution, dried over anhydrous Na2S04. Concentration in vacuo followed by flash chromatography (CH2Cl2-MeOH: 95:5) on silica gel afforded 50 mg of 151B as a colorless oil.
Example 151, Part C, 2- [3- (Dimethylamino) -2 , 3-dihydro-lH- inden-5-yl] -3-hydroxy-7-methoxy-6- (5-oxazolyl) -4 (IH) - ■ quinolinone
A mixture of Compound 151B (27 mg, 0.062 mmol), p-TsOH monohydrate (24 mg, 0.124 mmol) and propionic acid (92 mg, 1.24 mmol) in 2 mL of dry toluene was heated to reflux for 4.0 hr. After the solvent was removed under reduced pressure, the residue was taken into CH2C12 and washed with pH 7.0 buffer solution. The organic layer was dried over anhydrous Na2S0 . Concentration in vacuo followed by flash chromatography (CH2Cl2-MeOH-NH4θH: 90:10:0 to 90:10:1) on silica gel afforded 23.8 mg of the target compound as a yellow solid. HPLC retention time: 2.289 min (Column conditions C) . LC-MS: 418+ (M+H) +. Example 152
1, 4-Dihydro-3-hydroxy-7-methoxy-2- (4-methylphenyl) -4-oxo-
6-quinolinecarbonitrile
Figure imgf000189_0001
Example 152, Part A, 2-Amino-5-cyano-4-methoxybenzoic acid
Figure imgf000189_0002
152A
Compound 152A was prepared by an analogous method as that of 118B starting from 3-methoxy-4-cyanoaniline.
Example 152, Part B, 2-Amino-5-cyano-4-methoxybenzoic acid 2- (4-methylphenyl) -2-oxoethyl ester
Figure imgf000189_0003
152B was prepared by an analogous method as that of 151B starting from Compound 152A. Example 152, Part C, 1, 4-Dihydro-3-hydroxy-7-methoxy-2~ (4-methylphenyl) -4-oxo-6-quinolinecarbonitrile
152 was prepared by an analogous method described for the preparation of 151. HPLC retention time: 2.836 min (Column conditions C) . LC-MS: 307+ (M+H) +.
Example 153
1, 4-Dihydro-3-hydroxy-7-methoxy-2- (3 -methylphenyl) -4-oxo- 6-quinolinecarbonitrile
Figure imgf000190_0001
153 was prepared by an analogous method as that of Compound 152. HPLC retention time: 2.806 min (Column conditions C) . LC-MS: 307+ (M+H) +.
Example 154
7-Methoxy-6- (5-oxazolyl) -4 (IH) -quinolinone
Figure imgf000190_0002
Example 154, Part A, 5- [ [ [3-Methoxy-4- (5- oxazolyl) phenyl] amino] methylene] -2 , 2-dimethyl-l, 3- dioxane-4, 6-dione
Figure imgf000191_0001
154A
To ID (500 mg, 2.6 mmol) in MeOH (5 mL) at room temperature was added 5- (Methoxymethylene) -2 , 2-dimethyl- 1, 3-dioxane-4, 6-dione (490 mg, 2.6 mmol). The mixture was stirred at room temperature for 15 min then cooled in an ice bath and the solid filtered with cold MeOH rinse to give 880 mg (97 %) of a yellow solid solid.
Example 154, Part B, 7-Methoxy-6- (5-oxazolyl) -4 (IH) - quinolinone
154A (820 mg, 2.38 mmol) in diphenylether (10 L) was heated in a 200°C bath for 2.5h. The reaction was then cooled to room temperature and 10 mL hexane was added. The solid was filtered to give 545 mg (95 %) of the title compound as an off white solid. HPLC Ret. Time: 2.756 min (Method A). Mass Spec: 243 (M+H+) .
Example 155
7-Methoxy-2- (methylthio) -6- (5-oxazolyl) -4 (IH) -quinolinone
Figure imgf000191_0002
To ID (500 mg, 2.63 mmol) in diphenylether (5 mL) was added 5- [Bis (methylthio) methylene] -2 , 2-dimethyl-l, 3- dioxane-4, 6-dione (653 mg, 2.63 mmol) and the mixture heated to 120°C for 2h. The reaction was then heated to 200°C for 15min then cooled to room temperature. Hexane was added to the mixture and the solid was filtered to give 675 mg (89%) of the title compound as a yellow solid. HPLC Ret. Time: 2.316 min (Method A). Mass Spec: 289 (M+H+)
Example 156
2- (2, 3-Dihydro-3-hydroxy-lH-inden-5-yl) -7-methoxy-6- (5- oxazolyl) -4 (IH) -quinolinone
Figure imgf000192_0001
Example 156, Part A, 6-Bromo-2 , 3-dihydro-l- [ [tris (1- methylethyl) silyl] oxy] -lH-indene
Figure imgf000192_0002
156A
To 6-Bromo-2,3-dihydro-lH-inden-l-ol (300 mg, 1.41 mmol) in CH2C12 (4 mL) was added 2,6-lutidine (151 μL, 1.4 lmmol) followed by triisopropylsilyltriflate (378 μL, 1.41 mmol) at room temperature. The reaction was stirred for 30min then added to IN HCI and extracted. The organic layer was washed with saturated sodium bicarbonate then brine and dried over MgS04. The solvent was removed in vacuo and the crude material purified by column chromatography.
Example 156, Part B, 2 , 2-Dimethyl-5- [ (methylthio) [3- [ [tris (1-methylethyl) silyl] oxy] -lH-inden-5-yl]methylene] - 1 , 3-dioxane-4, 6-dione
Figure imgf000193_0001
156B
To 156A (843 mg, 1.72 mmol) in THF (lOmL) with magnesium (83 mg, 3.43 mmol) at 50°C was added catalytic dibromoethane . The reaction was cooled to room temperature then transferred via canula to 5- [Bis (methylthio) methylene] -2 , 2-dimethyl-1 , 3-dioxane-4 , 6- dione (380 mg, 1.53 mmol) in THF (10 mL) . The reaction was quenched with IN HCI and extracted with Et20. The organic layer was washed with brine, dried over MgS04, filtered and the solvent removed in vacuo . The crude product was used as is in the next step.
Example 156, Part C, 7-Methoxy-6- (5-oxazolyl) -2- [3- [ [tris (1-methylethyl) silyl] oxy] -lH-inden-5-yl] -4 (IH) - quinolinone
Figure imgf000194_0001
156C
To crude 156B (1.5 mmol) in diphenylether (10 mL) was added ID (290 mg, 1.52 mmol) and the reaction was heated to 140°C for 6h then heated to 200°C for 15 min. The reaction was cooled to room temperature and hexane was added, then the solid filtered and rinsed with hexane to give 539 mg 156C.
Example 156, Part D, 2- (2 , 3-Dihydro-3-hydroxy-lH-inden-5- yl) -7-methoxy-6- (5-oxazolyl) -4 (IH) -quinolinone
To 156C (100 mg, 0.19 mmol) in MeOH (30 mL) was added IN HCI (7 mL) and the reaction stirred at room temperature for 18h. The solvent was then removed in vacuo and water was added. The solid precipitate was filtered with water rinse followed by Et20 rinse to give 67 mg (95 %) of the title compound as a off white solid. HPLC retention time: 2.749 min (Method A). Mass Spec: 375 (M+H+) . Example 157
2- (3 , 4-Dimethoxyphenyl) -7-methoxy-6- (5-oxazolyl) -4 (IH) - quinolinone
Figure imgf000195_0001
Example 157, Part A, 5- [ (3 , 4-Dimethoxyphenyl) [ [3-methoxy- 4- (5-oxazolyl) phenyl] amino] methylene] -2 , 2-dimethyl-1, 3- dioxane-4, 6-dione
Figure imgf000195_0002
157A
157A was prepared from 4-bromoveratrole (100 mg, 0.46 mmol) and 5- [Bis (methylthio) methylene] -2 , 2-dimethyl- 1, 3-dioxane-4, 6-dione (76 mg, 0.3 mmol) using the same procedure as 156B to give 80 mg (78 %) .
Example 157, Part B, 5- [ [5- [ (Dimethylamino) methyl] -3- thienyl] (methylthio) methylene] -2 , 2-dimethyl-1, 3-dioxane- 4, 6-dione
Figure imgf000196_0001
157B
To 157A (60 mg, 0.17 mmol) in EtOH (2 mL) was added ID (34 mg, 0.17 mmol) and the reaction was heated to reflux for 12h. The reaction was cooled in ice and the solid filtered with cold EtOH rinse to give 48 mg of 157B.
Example 157, Part C, 2- (3 , 4-Dimethoxyphenyl) -7-methoxy-6- ( 5-oxazolyl) -4 (IH) -quinolinone
157B (40 mg, 0.083 mmol) in diphenylether (700 μL) was heated to 200°C for lh then cooled to room temperature. Hexane was added to the mixture and the solid filtered with hexane rinse to give 28 mg (87%) of the title compound. HPLC retention time: 2.756 min (Method A) . Mass Spec: 379 (M+H+) .
Example 158
2- [5- [ (Dimethylamino) methyl] -3-thienyl] -7-methoxy-6- (5- oxazolyl) -4 (IH) -quinolinone
Figure imgf000196_0002
Example 158, Part A, 5- [ [5- [ (Dimethylamino) methyl] -3- thienyl] (methylthio) methylene] -2 , 2-dimethyl-1, 3-dioxane- 4 , 6-dione
Figure imgf000197_0001
To 4-Bromo-N,N-dimethyl-2-thiophenemethanamine (130 mg, 0.59 mmol) in THF (2 mL) cooled to -78°C was added n- BuLi (230 μL, 0.59 mmol) dropwise. The reaction was stirred at -78°C for 15min then the reaction was rapidly tranfered via canula to 5- [Bis (methylthio) methylene] -2 , 2- dimethyl-1, 3 -dioxane-4 , 6-dione (125 mg, 0.50 mmol) in THF (2 mL) stirring at room temperature. The reaction was quenched with IN HCI and extracted with CH2CI2 and saturated sodium bicarbonate. The crude reaction residue was purified by column chromatography to give 74 mg of 158A.
Example 158, Part B, 2- [5- [ (Dimethylamino) methyl] -3- thienyl] -7-methoxy-6- (5-oxazolyl) -4 (IH) -quinolinone
To 158A (74 mg, 0.21 mmol) in diphenylether (2 mL) was added ID (41 mg, 0.21 mmol) and the reaction was heated to 120°C for 6h. The reaction was heated to 200°C for lOmin then cooled to room temperature. Hexane was added to the reaction and the solid was filtered with hexane rinse to give 54 mg (67 %) of the title compound. HPLC retention time: 2.033 min (Method A). Mass Spec: 382 (M+H+) .
Example 159 2- [3- (Dimethylamino) -2 , 3-dihydro-lH-inden-5-yl] -7- methoxy-6- (5-oxazolyl) -4 (IH) -quinolinone enantiomer A; 2- [3- (Dimethylamino) -2 , 3-dihydro-lH-inden-5-yl] -7- methoxy-6- (5-oxazolyl) -4 (IH) -quinolinone enantiomer B
Figure imgf000198_0001
Example 159, Part A, 5- [ [3- (Dimethylamino) -2 , 3-dihydro- lH-inden-5-ylj (methylthio) methylene] -2 , 2-dimethyl-l, 3- dioxane-4 , 6-dione
Figure imgf000198_0002
159A
159A was prepared from 10B (1.1 g, 4.58 mmol) and 5- [Bis (methylthio) ethylene] -2 , 2-dimethyl-l , 3-dioxane-4 , 6- dione (755 mg, 3.04 mmol) using the same procedure as 156B to give 1.2g (72%) .
Example 159, Part B,
159 was prepared from 159A (1.2g, 3.32mmol) and ID (630mg, 3.32mmol) using the same procedure as 158 to give l.Og (75%). HPLC retention time: 2.22 min. (Method A). Mass Spec: 402 (M+H+) .
The two enantiomers were separated on a chiral preperative AS HPLC column eluted with 15% EtOH/Hexane with 0.12% Et3N. The analytical chiral HPLC retention time for the first enantioner A is 11.5 min on a chiral AS analytical column eluted with 14% EtOH/Hexane with 0.12% EtN at 2 mL/min on a 35 min run time. The second enantiomer B has a retention time on the analytical chiral AS column of 16.1 min using the same conditions .
Both enantiomers gave identical retention times with method A and identical Mass Spectra as given above.
Example 160
7-Methoxy-2- (methylamino) -6- (5-oxazolyl) -4 (IH) - quinolinone
Figure imgf000199_0001
Example 160, Part A, 5- [ [ [3-Methoxy-4- (5- oxazolyl) phenyl] amino] (methylthio) methylene] -2,2- dimethyl-1, 3-dioxane-4, 6-dione
Figure imgf000199_0002
160A To ID (316 mg, 1.66 mmol) in MeOH (3 mL) was added 5- [Bis (methylthio)methylene] -2 , 2-dimethyl-l, 3-dioxane- 4, 6-dione (412.5 mg, 1.66 mmol) and stirred at room temperature for 5h. The reaction was cooled in an ice bath and filtered to give 620 mg (96 %)of the title compound, as a yellow solid.
Example 160, Part B, 5- [ [ [3-Methoxy-4- (5- oxazolyl) phenyl] amino] (methylamino) methylene] -2,2- dimethyl-1, 3-dioxane-4 , 6-dione
Figure imgf000200_0001
160B
To 160A (60 mg, 0.154 mmol) in THF (2 mL) was added dimethylamine (ImL, M in H0) followed by HgCl2 (41.8 mg, 0.154 mmol) at room temperature. The reaction was stirred for 2h at room temperature then filtered. Water was added and the mixture extracted 3 times with CH2CI2. The organic layer was washed with brine and dried over MgS04. After the solvent was removed the residue was purified by column chromatography to give 51.6 mg 160B.
Example 160, Part C, 7-Methoxy-2- (methylamino) -6- (5- oxazolyl ) -4 ( IH) -quinolinone
160B (51.6 mg, 0.14 mmol) in diphenylether (2 mL) was heated to 250°C for 2h. The reaction was cooled to room temperature and hexane was added. The solid was filtered and washed with hexane to give 29 mg (77 %) of the title compound. HPLC retention time: 2.289 min (Method A) . MassSpec: 272 (M+H+) .
Example 161 2- (Dimethylamino) -7-methoxy-6- (5-oxazolyl) -4 (IH) - quinolinone
Figure imgf000201_0001
Example 161, Part A, 5- [ (Dimethylamino) [ [3-methoxy-4- (5- oxazolyl) phenyl] amino] methylene] -2 , 2-dimethyl-l, 3- dioxane-4, 6-dione
Figure imgf000201_0002
161A
161A was prepared from 160A (60 mg, 0.154 mmol) and dimethylamine (2 mL, M in EtOH) using the same procedure as 160B to give 35 mg.
Example 161, Part B, 2- (Dimethylamino) -7-methoxy-6- (5- oxazolyl) -4 (IH) -quinolinone
161 was prepared from 161A (35 mg, 0.09 mmol) and diphenylether (ImL) using the same procedure as 160 to give 16 mg (62%) of the title compound. HPLC retention • time: 2.276 min (Method A). Mass Spec 286 (M+H+) .
Example 162
[6- [1, 4-Dihydro-7-methoxy-6- (5-oxazolyl) -4-oxo-2- quinolinyl] -2, 3-dihydro-lH-inden-l-yl]methylcarbamic acid
1, 1-dimethylethyl ester
Figure imgf000202_0001
Example 162, Part A, ( 6-Bromo-2 , 3-dihydro-lH-inden-l- yl)methylcarbamic acid 1, 1-dimethylethyl ester
Figure imgf000202_0002
162A
To 104A (650 mg, 2.86 mmol) in MeOH (2 mL) was added di-tertbutyldicarbonate (722 mg, 3.44 mmol) and triethylamine (220 μL) . The reaction was heated to reflux for lh then the solvent removed in vacuo and the residue was dissolved in Et20 and washed with water then brine. The organic layer was dried over MgS04, filtered and the solvent removed in vacuo to give 782 mg of 162A. Example 162, Part B, [6- [ (2 , 2-Dimethyl-4, 6-dioxo-l, 3- dioxan-5-ylidene) (methylthio) methyl] -2, 3-dihydro-lH- inden-1-yl] methylcarbamic acid 1 , 1-dimethylethyl ester
Figure imgf000203_0001
162B
162B was prepared from 162A (682 mg, 2.1 mmol) and 5- [Bis (methylthio) methylene] -2 , 2-dimethyl-l, 3-dioxane- 4,6-dione (495 mg, 2.1 mmol) using the same procedure as 156B to give 538 mg (57%) .
Example 162, Part C, [6- [1, 4-Dihydro-7-methoxy-6- (5- oxazolyl) -4-oxo-2-quinolinyl] -2 , 3-dihydro-lH-inden-l- yl]methylcarbamic acid 1, 1-dimethylethyl ester
162 was prepared from 162B (538 mg, 1.2 mmol) and ID (247 mg, 1.2 mmol) using the same procedure as 156C to give 269 mg (46%) of the title compound. HPLC retention time: 3.466 min (Method A). Mass spec: 488 (M+Hτ++\
Example 163
N- [6- [1, 4-Dihydro-7-methoxy-6- (5-oxazolyl) -4-oxo-2- quinolinyl] -2, 3-dihydro-lH-inden-l-yl] -N-methylacetamide
Figure imgf000203_0002
Example 163, Part A, 2- [2 , 3-Dihydro-3- (methylamino) -1H- inden-5-yl] -7-methoxy-6- (5-oxazolyl) -4 (IH) -quinolinone
Figure imgf000204_0001
163A
To 162 (269 mg, 0.55 mmol) was added TFA (lOmL) and the mixture was stirred at room temperature for 3h. The TFA was removed in vacuo and IN HCI was added. The solid formed was filtered rinsed with IN HCI and dried under vacuum to give 164.5 mg (70.5%) of 163A as an HCI salt.
Example 163, Part B, N- [6- [1, 4-Dihydro-7-methoxy-6- (5- oxazolyl) -4-oxo-2-quinolinyl] -2 , 3 -dihydro-lH-inden-1-yl] - N-methylacetamide
To 163A (20 mg, 0.052 mmol) in DMF (1.5 mL) with Et3N (18 μL, 0.13 mmol) cooled in a -10°C bath was slowly added acetylchloride (3.7 μL, 0.052 mmol) dissolved in CH2C12 (0.5 mL) . The reaction was stirred at -10°C for Ih then the solvent was removed in vacuo and the residue dissolved in CH2CI2 and washed with water and brine. The organic phase was dried over MgS04 filtered and the solvent removed in vacuo to give 6.5 mg. HPLC retention time: 2.769 min (Method A) . Mass spec: 430 (M+H+) . Example 164
N- [6- [1, 4-Dihydro-7-methoxy-6- (5-oxazolyl) -4-oxo-2- quinolinyl] -2 , 3-dihydro-lH-inden-1-yl] -2-methoxy-N- methylacetamide
Figure imgf000205_0001
164 was prepared from 163A (20 mg, 0.052 mmol) and methoxy acetylchloride (4.7 μL, 0.052 mmol) using the same procedure as 163 to give 20.4 mg of the title compound. HPLC retention time: 2.75*2 min (Method A). Mass spec: 460 (M+H+) .
Example 165
N- [6- [1, 4-Dihydro-7-methoxy-6- (5-oxazolyl) -4-oxo-2- quinolinyl] -2 , 3-dihydro-lH-inden-l-yl] -N-methyl-lH- imidazole-1-acetamide
Figure imgf000205_0002
To 163A (20 mg, 0.052 mmol) in DMF (1.5 mL) with Et3N
(18 μL, 0.13 mmol) cooled in a -10°C bath was slowly added chloroacetylchloride (4.1 μL, 0.052mmol) dissolved in
CH2C12 (0.5mL). The reaction was stirred at -10°C for lh then imidazole (7 mg, 0.1 mmol) and KC03 (21.5 mg, 0.156 mmol) and the reaction was heated to 60°C for lh. The solvent was removed in vacuo and the residue purified by preparative chromatography to give 3.8 mg of the title compound. HPLC retention time: 2.539 min (Method A). Mass spec: 496 (M+H+) .
Example 166
N- [6- [1, 4-Dihydro-7-methoxy-6- (5-oxazolyl) -4-oxo-2- quinolinyl] -2 , 3-dihydro-lH-inden-l-yl] -N-methyl-4- morpholineacetamide
Figure imgf000206_0001
166 was prepared from 163A (20 mg, 0.052 mmol) and morpholine (10.8 μL, 0.1 mmol) using the same procedure as 165 to give 0.9 mg of the title compound. HPLC retention time: 2.526 min (Method A). Mass spec: 515 (M+H+) .
Example 167
N- [6- [1, 4-Dihydro-7-methoxy-6- (5-oxazolyl) -4-oxo-2- quinolinyl] -2 , 3-dihydro-lH-inden-l-yl j -N-methyl-2H-l, 2 , 3- triazole-2-acetamide
Figure imgf000206_0002
157 was prepared from 163A (39.7 mg, 0.102 mmol) and triazole (17.7 mg, 0.256 mmol) using the same procedure as 165 to give 7.8 mg of the title compound. HPLC retention time: 2.726 min (Method A) . Mass spec: 497 (M+H+) .
Example 168 N- [6- [1, 4-Dihydro-7-methoxy-6- (5-oxazolyl) -4-oxo-2- quinolinyl] -2 , 3-dihydro-lH-inden-l-yl] -N-methyl-lH-1 ,2,3- triazole-1-acetamide
Figure imgf000207_0001
168 was prepared from 163A (39.7 mg, 0.102 mmol) and triazole (17.7 mg, 0.256 mmol) using the same procedure as 165 to give 15.4 mg of the title compound. HPLC retention time: 2.659 min (Method A). Mass spec: 497 (M+H+) .
Example 169
[6- [1, 4-Dihydro-7-methoxy-6- (5-oxazolyl) -4-oxo-2- quinolinyl] -2, 3-dihydro-lH-inden-l-yl]methylcarbamic acid ethyl ester
Figure imgf000207_0002
169 was prepared from 163A (25 mg, 0.059 mmol) and ethylchloroformate (5.6 μL, 0.059 mmol) using the same procedure as 164 to give 2.8 mg of the title compound. HPLC retention time: 3.202 min (Method A) . Mass spec: 460 (M+H+) .
Example 170 Dimethylcarbamic acid 6- [1, 4-dihydro-7-methoxy-6- (5- oxazolyl) -4-oxo-2-quinolinyl] -2 , 3-dihydro-lH-inden-l-yl ester
Figure imgf000208_0001
To 163A (15 mg, 0.04 mmol) in DMF (1 mL) was added NaH (2.4 mg, 0.1 mmol) at room temperature. The mixture was stirred for 10 min then cooled in -78°C bath and dimethylcarbamyl chloride (3.7 μL, 0.04 mmol) in DMF (1 mL) was added. The reaction was slowly brought to room temperature and stirred for 18h. The reaction was quenched with 1 drop of acetic acid and the solvent removed in vacuo . Water was added and the precipitate filtered and rinsed with water to give 11.3 mg. HPLC retention time: 3.108 min (Method A). Mass spec: 446 (M+H+) . Example 171
2- [2 , 3-Dihydro-l- (1-pyrrolidinyl) -lH-inden-5-yl] -7- methoxy-6- (5-oxazolyl) -4 (IH) -quinolinone
Figure imgf000209_0001
This compound was prepared analogous to 127 starting from 5-bromo-l-chloro-indane and using pyrrolidine instead of dimethylamine. LC-MS: HPLC conditions A, retention time = 2.53 minutes, m/z 428.15 (M+H)+ .
Example 172
4-Acetyl-6- [1, 4-dihydro-7-methoxy-6- (5-oxazolyl) -4-oxo-2- quinolinyl] -3 , 4-dihydro-2H-l, 4-benzoxazine
Figure imgf000209_0002
This compound was prepared in an analogous fashion to method C2. LC-MS: HPLC conditions E, retention time = 2.72 minutes, m/z 418.12 (M+H)+ .
Example 173
1,2,3, 4-Tetrahydro-6-methoxy-7- (5-oxazolyl) -9H- cyclopenta [b] quinolin-9-one
Figure imgf000210_0001
This compound was prepared in an analogous fashion to method A2. LC-MS: HPLC conditions E, retention time - 2.25 minutes, m/z 283.15 (M+H)+.
Example 174
7-Methoxy-2- [4- ( 4-morpholinylmethyl) phenyl] -6- (5- oxazolyl) - (IH) -quinolinone
Figure imgf000210_0002
This compound was prepared in an analogous fashion to method A3. LC-MS: HPLC conditions E, retention time = 1.86 minutes, m/z 418.23 (M+H)+ .
Obviously, numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described herein.

Claims

WHAT IS CLAIMED IS ;
1. A method of treating inosine monophosphate dehydrogenase associated disorders comprising: administering a therapeutically effective amount of a compound of formula (I)
Figure imgf000211_0001
(I)
including isomers, enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, prodrugs and solvates thereof wherein:
X1 is C=0, -S(O)-, or -S(0)2-; X2 is CR3 or N; X3 is-NH-, -0-, or -S-; X4 is CR4 or N; X5 is CR5 or N; X6 is CR6 or N;
• R1 is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, NR8R9, SR20, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycloalkyl, or heteroaryl;
R2 is halogen, cyano, nitro, hydroxy, oxo (double bond is no longer present between CR2 and X6), SR7, S(0)R7, S02R7, S02NR8R9, C02R7, C(0)NR8R9, or heteroaryl;
R3 is hydrogen, hydroxy, halogen, cyano, C02R7, NR8R9 , alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycloalkyl or heteroaryl; R4, R5, and R6 are independently selected from the group consisting of hydrogen, halogen, nitro, cyano, O-R7, NR8R9, SR7, S(0)R7, S02R7, S03R7, S02NR8R9, C02R7, C(0)NR8R9, C(O) alkyl, C (0) substituted alkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl and substituted alkynyl;
R7, R10, and R11, are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, cycloalkyl, substituted cycloalkyl, C(O) alkyl, C (O) substituted alkyl, C (0) cycloalkyl, C(0) substituted cycloalkyl, C(0)aryl, C (0) substituted aryl, C(0)0alkyl, C (0) Osubstituted alkyl, C (O) heterocycloalkyl, C (O) heteroaryl, aryl, substituted aryl, heterocycloalkyl and heteroaryl ; R8 and R9 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, alkynyl, C(0) alkyl, C (0) substituted alkyl, C (0) cycloalkyl, C (O) substituted cycloalkyl, C(0)aryl, C (0) substituted aryl, C(0)0alkyl, C (0) Osubstituted alkyl,
C (O) heterocycloalkyl, C (0) heteroaryl, aryl, substituted aryl, heterocycloalkyl, and heteroaryl or R8 and R9 taken together with the nitrogen atom to which they are attached complete a heterocycloalkyl or heteroaryl ring; R20 is alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl or heterocycloalkyl;
R3 and R1 may be taken together with the carbon atoms to which they are attached to form a monocyclic or substituted monocyclic ring system of 5 or 6 carbon atoms; and
R4 and R5 may be joined together by the chain -O-CH2-O- or -O-CH2-CH2-O- .
2. A method of claim 1 comprising: administering a . therapeutically effective amount of a compound of formula (ID
Figure imgf000213_0001
H
(II)
including isomers, enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, prodrugs and solvates thereof wherein:
R2 is a monocyclic substituted or unsubstituted heteroaryl group.
3. A method of claim 2 comprising: administering a therapeutically effective amount of a compound of formula (III)
Figure imgf000213_0002
(III)
including isomers, enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, prodrugs and solvates thereof wherein:
R2 is 4-oxazolyl, substituted 4-oxazolyl, 5-oxazolyl, or substituted 5-oxazolyl;
R3 is hydrogen, hydroxy, NR8R9, alkyl of 1 to 4 carbons, alkenyl of 2 to 4 carbons, alkynyl of 2 to 4 carbons, substituted alkyl of 1 to 4 carbons, phenyl, substituted phenyl, cycloalkyl of 5 to 7 carbons, substituted cycloalkyl of 5 to 7 carbons, monocyclic heterocycloalkyl and monocyclic heteroaryl; R4 is hydrogen, halogen, nitro, hydroxy, alkyl of 1 to 4 carbons, cyano, CF3, OCF3, OCH3, SCH3, S(0)CH3, or S(0)2CH3;
R5 is hydrogen, halogen, nitro, hydroxy, alkyl of 1 to 4 carbons, cyano, vinyl, CF3, CF2CF3, CH=CF2, 0CH3 , 0CF3, 0CHF2, SCH3, S(0)CH3, or S(0)2CH3; and
R6 is hydrogen, halogen, nitro, hydroxy, alkyl of 1 to 4 carbons, cyano, CF3, 0CH3, 0CF3, SCH3, S(0)CH3, and S(0)2CH3.
4. A method of Claim 3 comprising: administering a therapeutically effective amount of a compound including isomers, enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, prodrugs and solvates wherein : R2 is 4-oxazolyl, substituted 4-oxazolyl, 5-oxazolyl, substituted 5-oxazolyl or heteroaryl;
R3 is hydrogen, hydroxy, halogen, methyl or NR8R9; R4 is hydrogen;
R5 is halogen, methyl, ethyl, substituted alkenyl, alkyne, OMe or OCF3; and R6 is hydrogen.
5. A method of Claim 4 comprising: administering a therapeutically effective amount of a compound including isomers, enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, prodrugs and solvates wherein :
R2 is 4-oxazolyl, substituted 4-oxazolyl, 5-oxazolyl or substituted 5-oxazolyl; R3 is hydrogen, hydroxy, halogen or methyl; R4 is hydrogen;
R5 is halogen, methyl or OMe; and
R6 is hydrogen.
6. A method of treating inosine monophosphate dehydrogenase associated disorders comprising: administering a therapeutically effective amount of a phosphodiesterase Type 4 inhibitor and a compound of formula (X) :
Figure imgf000215_0001
(X)
including isomers, enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, prodrugs and solvates thereof wherein:
X1 is C=0, -S(O)-, or -S(0)2-; X2 is CR3 or N; X3 is-NH-, -0-, or -S-; X4 is CR4 or N; X5 is CR5 or N; X6 is CR6 or N;
R1 is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, NR8R9, SR20, cycloalkyl, substituted cycloalkyl, aryl, substituted' aryl, heterocycloalkyl, or heteroaryl;
R2 is halogen, cyano, nitro, hydroxy, oxo (double bond is no longer present between CR2 and X6), SR7, S(0)R7, S02R7, S02NR8R9, C02R7, C(0)NR8R9, or heteroaryl;
R3 is hydrogen, hydroxy, halogen, cyano, C02R7, NR8R9, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycloalkyl or heteroaryl;
R4, R5, and R6 are independently selected from the group consisting of hydrogen, halogen, nitro, cyano, O-R7, NR8R9, SR7, S(0)R7, S02R7, S03R7, S0NR8R9, C02R7, C(0)NR8R9, C(O) alkyl, C (0) substituted alkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl and substituted alkynyl;
R7, R10, and R11, are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, cycloalkyl, substituted cycloalkyl, C(0) alkyl, C (0) substituted alkyl, C (0) cycloalkyl, C(0) substituted cycloalkyl, C(0)aryl, C (0) substituted aryl,C(0)Oalkyl, C (0) Osubstituted alkyl, C (0) heterocycloalkyl, C (0) heteroaryl, aryl, substituted aryl, heterocycloalkyl and heteroaryl;
R8 and R9 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, alkynyl, C(0) alkyl, C (0) substituted alkyl, C (0) cycloalkyl,
C (0) substituted cycloalkyl, C(0)aryl, C (0) substituted aryl, C(0)0alkyl, C (0) Osubstituted alkyl, C (0) heterocycloalkyl, C (0) heteroaryl, aryl, substituted aryl, heterocycloalkyl, and heteroaryl or R8 and R9 taken together with the nitrogen atom to which they are attached complete a heterocycloalkyl or heteroaryl ring;
R20 is alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl or heterocycloalkyl;
R3 and R1 may be taken together with the carbon atoms to which they are attached to form a monocyclic or substituted monocyclic ring system of 5 or 6 carbon atoms ; and
R4 and R5 may be joined together by the chain -O-CH2-O- or -O-CH2-CH2-O-.
7. A method for the treatment or prevention of allograft rejection comprising: administering a therapeutically effective amount of a phosphodiesterase Type 4 inhibitor and a compound of formula (X) :
Figure imgf000217_0001
(X)
including isomers, enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, prodrugs and solvates thereof wherein:
X1 is C=0, -S(0)-, or -S(0)2~; X2 is CR3 or N; X3 is-NH-, -0-, or -S-; X4 is CR4 or N; X5 is CR5 or N; X6 is CR6 or N;
R1 is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, NR8R9, SR20, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycloalkyl, or heteroaryl;
R2 is halogen, cyano, nitro, hydroxy, oxo (double bond is no longer present between CR2 and X6), SR7, S(0)R7, S02R7, S02NR8R9, C02R7, C(0)NR8R9, or heteroaryl;
R3 is hydrogen, hydroxy, halogen, cyano, C02R7, NR8R9, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycloalkyl or heteroaryl ;
R4, R5, and R6 are independently selected from the group consisting of hydrogen, halogen, nitro, cyano, O-R7, NR8R9, SR7, S(0)R7, S0R7, S03R7, S02NR8R9, C02R7, C(0)NR8R9, C(O) alkyl, C (0) substituted alkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl and substituted alkynyl; R7, R10, and R11, are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, cycloalkyl, substituted cycloalkyl, C(0) alkyl, C (0) substituted alkyl, C (0) cycloalkyl, C(0) substituted cycloalkyl, C(0)aryl, C (0) substituted aryl, C(0)Oalkyl, C (0) Osubstituted alkyl, C (0) heterocycloalkyl, C (0) heteroaryl, aryl, substituted aryl, heterocycloalkyl and heteroaryl;
R8 and R9 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, alkynyl, C(0)alkyl, C (0) substituted alkyl , C (0) cycloalkyl, C (0) substituted cycloalkyl, C(0)aryl, C (0) substituted aryl, C(0)0alkyl, C (0) Osubstituted alkyl, C (0) heterocycloalkyl, C (0) heteroaryl, aryl, substituted aryl, heterocycloalkyl, and heteroaryl or R8 and R9 taken together with the nitrogen atom to which they are attached complete a heterocycloalkyl or heteroaryl ring;
R20 is alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl or heterocycloalkyl; R3 and R1 may be taken together with the carbon atoms to which they are attached to form a monocyclic or substituted monocyclic ring system of 5 or 6 carbon atoms ; and
R4 and R5 may be joined together by the chain -O-CH2-O- or -O-CH2-CH2-O- .
8. A method of Claims 6 or 7 wherein: the phosphodiesterase Type 4 inhibitor is Rolipram.
9. A method of Claims 6 or 7 wherein: the phosphodiesterase Type 4 inhibitor is [4- [3- (cyclopentyloxy) -4-methoxy-phenyl] -2-pyrrolidinone] .
10. A compound of formula (I)
Figure imgf000219_0001
(I)
including isomers, enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, prodrugs and solvates thereof wherein:
X1 is C=0, -S(O)-, or -S(0)2-; X2 is CR3 or N; X3 is-NH-, -0-, or -S-; X4 is CR4 or N; X5 is CR5 or N; X6 is CR6 or N;
R1 is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycloalkyl, or heteroaryl;
R2 is cyano, hydroxy, oxo (double bond is no longer present between CR2 and X6), SR7, S(0)R7, S02R7, S02NR8R9, C02R7, C(0)NR8R9, or heteroaryl; R3 is hydrogen, hydroxy, halogen, cyano, CO2R7, NR8R9, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycloalkyl or heteroaryl; R4, R5, and R6 are independently selected from the group consisting of hydrogen, halogen, nitro, cyano, O-R7, NR8R9, SR7, S(0)R7, S02R7, S03R7, S0NR8R9, C02R7, C(0)NR8R9, C(O) alkyl, C (0) substituted alkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl and substituted alkynyl; R7, R10, and R11, are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, cycloalkyl, substituted cycloalkyl, C(O) alkyl, C (0) substituted alkyl, C (0) cycloalkyl, C(0) substituted cycloalkyl, C(0)aryl, C (0) substituted aryl, C(0)0alkyl, C (0) Osubstituted alkyl, C (0) heterocycloalkyl, C (0) heteroaryl, aryl, substituted aryl, heterocycloalkyl and heteroaryl;
R8 and R9 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, alkynyl, C(0) alkyl, C (0) substituted alkyl, C (0) cycloalkyl, C (0) substituted cycloalkyl, C(0)aryl, C (0) substituted aryl, C(0)0alkyl, C(0) Osubstituted alkyl, C (0) heterocycloalkyl, C (0) heteroaryl, aryl, substituted aryl, heterocycloalkyl, and heteroaryl or R8 and R9 taken together with the nitrogen atom to which they are attached complete a heterocycloalkyl or heteroaryl ring;
R3 and R1 may be taken together with the carbon atoms to which they are attached to form a monocyclic or substituted monocyclic ring system of 5 or 6 carbon atoms; and
R4 and R5 may be joined together by the chain -O-CH2-O- or -O-CH2-CH2-O-;
with the following provisos :
(c) when X1 is C=0, X2 is CR3, X3 is NH, X4 is CR4, X is CR5, X6 is CR6, R1 is substituted or meta unsubstituted phenyl, R3 is H, R4 is H, R5 is H and R6 is H, then R2 is not PhCONH,
Figure imgf000221_0001
when X1 is C=0, X2 is CR3, X3 is NH, X4 is CR4, X5 is CR5, X6 is CR6, R1 is phenyl substituted with H, F, Cl, Br, I, CH3, CF3, OH, OCH3, OCF3, OCH2CH3, NH2, NHCH3, N(CH3)2, O-benzyl, -C(=O)-R0, or -C(*=O)-OR0 and R0 is a lower alkyl group, R3 is H, R4 is H, R5 is H and Rs is H, then R2 is not
Figure imgf000221_0002
where Y is CH2, 0 or S, m and n are each greater than 1, and the sum of and n is between 3 and 6 ; and
[c) when R2 is heteroaryl, at least one of the heteroatoms must be 0;
11. A compound of Claim 10 of formula (II)
Figure imgf000221_0003
(II)
including isomers, enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, prodrugs and solvates thereof wherein:
R2 is a monocyclic substituted or unsubstituted heteroaryl group.
12. A compound of Claim 11 of formula (III)
Figure imgf000222_0001
(III)
including isomers, enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, prodrugs and solvates thereof wherein:
R2 is 4-oxazolyl, substituted 4-oxazolyl, 5-oxazolyl, or substituted 5-oxazolyl; R3 is hydrogen, hydroxy, NR8R9, alkyl of 1 to 4 carbons, alkenyl of 2 to 4 carbons, alkynyl of 2 to 4 carbons, substituted alkyl of 1 to 4 carbons, phenyl, substituted phenyl, cycloalkyl of 5 to 7 carbons, substituted cycloalkyl of 5 to 7 carbons, monocyclic heterocycloalkyl and monocyclic heteroaryl;
R4 is hydrogen, halogen, nitro, hydroxy, alkyl of 1 to 4 carbons, cyano, CF3, OCF3, OCH3, SCH3, S(0)CH3, or S(0)2CH3;
R5 is hydrogen, halogen, nitro, hydroxy, alkyl of 1 to 4 carbons, cyano, vinyl, CF3, CF2CF3 , CH=CF2, 0CH3 , OCF3, OCHF2, SCH3, S(0)CH3, or S(0)2CH3; and
R5 is hydrogen, halogen, nitro, hydroxy, alkyl of 1 to 4 carbons, cyano, CF3, OCH3, 0CF3, SCH3, S(0)CH3, and S(0)2CH3.
13. A compound of Claim 12 including isomers, enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, prodrugs and solvates wherein: R2 is 4-oxazolyl, substituted 4-oxazolyl, 5-oxazolyl, substituted 5-oxazolyl or heteroaryl;
R3 is hydrogen, hydroxy, halogen, methyl or NR8R9;
R4 is hydrogen; R5 is halogen, methyl, ethyl, substituted alkenyl, alkyne, OMe or OCF3; and
R6 is hydrogen.
14. A compound of Claim 13 including isomers, enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, prodrugs and solvates wherein:
R2 is 4-oxazolyl, substituted 4-oxazolyl, 5-oxazolyl or substituted 5-oxazolyl;
R3 is hydrogen, hydroxy, halogen or methyl; R4 is hydrogen;
R5 is halogen, methyl or OMe; and R6 is hydrogen.
15. A compound of Claim 10 of formula (V)
Figure imgf000223_0001
(V) including isomers, enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, prodrugs and solvates selected from:
a compound of formula (V) wherein: R1 is
Figure imgf000223_0002
and R is hydrogen;
a compound of formula (V) wherein:
R1 is
Figure imgf000224_0001
and R3 is hydrogen;
a compound of formula (V) wherein:
R1 is
Figure imgf000224_0002
and R is hydrogen;
a compound of formula (V) wherein: R1 is CH3 and R3 is hydrogen;
a compound of formula (V) wherein: R1 is
Figure imgf000224_0003
and R3 is CH3;
a compound of formula (V) wherein:
Figure imgf000224_0004
and R is hydrogen; a compound of formula (V) wherein:
R1 is
Figure imgf000225_0001
and R3 is hydrogen;
a compound of formula (V) wherein:
R1 is
Figure imgf000225_0002
and R is hydrogen;
a compound of formula (V) wherein:
R is
Figure imgf000225_0003
and R is hydrogen;
a compound of formula (V) wherein:
Figure imgf000225_0004
and R is hydrogen;
a compound of formula (V) wherein: R1 is
Figure imgf000226_0001
and R is hydrogen;
a compound of formula (V) wherein:
R I S
Figure imgf000226_0002
and R3 is hydrogen;
a compound of formula (V) wherein :
R1 is
Figure imgf000226_0003
and R is hydrogen;
a compound of formula (V) wherein:
Figure imgf000226_0004
and R3 is hydrogen;
a compound of formula (V) wherein: R1 is
Figure imgf000227_0001
and R is hydrogen;
a compound of formula (V) wherein:
R is
Figure imgf000227_0002
and R is hydrogen;
a compound of formula (V) wherein:
Figure imgf000227_0003
and R is hydrogen;
a compound of formula (V) wherein:
R is
Figure imgf000227_0004
and R is hydrogen;
a compound of formula (V) wherein: Rx is
Figure imgf000228_0001
and R is hydrogen;
a compound of formula (V) wherein:
R is
Figure imgf000228_0002
and R is hydrogen;
a compound of formula (V) wherein;
Figure imgf000228_0003
and R is hydrogen;
a compound of formula (V) wherein:
R1 is
Figure imgf000228_0004
and R is hydrogen;
a compound of formula (V) wherein: R I S
Figure imgf000229_0001
and R is hydrogen;
a compound of formula (V) wherein:
Figure imgf000229_0002
and R3 is hydrogen;
a compound of formula (V) wherein:
R1 is
Figure imgf000229_0003
and R3 is hydrogen;
a compound of formula (V) wherein: R1 is
Figure imgf000229_0004
and R is hydrogen;
a compound of formula (V) wherein: R1 is
Figure imgf000229_0005
and R is Br ;
a compound of formula (V) wherein: R1 is
Figure imgf000230_0001
and R3 is hydrogen;
a compound of formula (V) wherein: R1 is
Figure imgf000230_0002
and R is hydrogen;
a compound of formula (V) wherein: R1 is
Figure imgf000230_0003
and R is hydrogen;
a compound of formula (V) wherein:
R1 is
Figure imgf000230_0004
and R3 is hydrogen;
a compound of formula (V) wherein: R1 is
Figure imgf000231_0001
and R is hydrogen;
a compound of formula (V) wherein:
R is
Figure imgf000231_0002
and R is hydrogen;
a compound of formula (V) wherein:
Figure imgf000231_0003
and R is hydrogen;
a compound of formula (V) wherein:
R1 is
Figure imgf000231_0004
and R is hydrogen;
a compound of formula (V) wherein: R1 is
Figure imgf000232_0001
and R is hydrogen;
a compound of formula (V) wherein:
Figure imgf000232_0002
and R is hydrogen;
a compound of formula (V) wherein:
R is
Figure imgf000232_0003
and R is hydrogen;
a compound of formula (V) wherein:
R1 is
Figure imgf000232_0004
and R is hydrogen;
a compound of formula (V) wherein: R is
Figure imgf000233_0001
and R is hydrogen;
a compound of formula (V) wherein: R1 is
Figure imgf000233_0002
and R3 is hydrogen;
a compound of formula (V) wherein: R1 is
Figure imgf000233_0003
and R is hydrogen;
a compound of formula (V) wherein:
R is
Figure imgf000233_0004
and R is hydrogen;
a compound of formula (V) wherein: R1 is
Figure imgf000234_0001
and R3 is hydrogen;
a compound of formula (V) wherein:
R1 is
Figure imgf000234_0002
and R is hydrogen;
a compound of formula (V) wherein:
R1 is
Figure imgf000234_0003
and R is hydrogen;
a compound of formula (V) wherein:
R1 is
Figure imgf000234_0004
and R3 is hydrogen;
a compound of formula (V) wherein:
R1 is
Figure imgf000234_0005
and R is hydrogen;
a compound of formula (V) wherein:
R is
Figure imgf000235_0001
and R is hydrogen;
a compound of formula (V) wherein:
RΛ IS
Figure imgf000235_0002
and R is hydrogen;
a compound of formula (V) wherein:
Rx IS
Figure imgf000235_0003
and R is hydrogen;
a compound of formula (V) wherein:
R1 is
Figure imgf000235_0004
and R is hydrogen;
a compound of formula (V) wherein: Rx I S
Figure imgf000236_0001
and R is hydrogen;
a compound of formula (V) wherein:
R is
Figure imgf000236_0002
and R3 is hydrogen;
a compound of formula (V) wherein: Rα is
Figure imgf000236_0003
and R3 is hydrogen;
a compound of formula (V) wherein: R1 is
Figure imgf000236_0004
and R3 is hydrogen;
a compound of formula (V) wherein: R1 is
Figure imgf000237_0001
and R is hydrogen;
a compound of formula (V) wherein: R1 is
H3C.-, .CH3
Figure imgf000237_0002
and R is hydrogen;
a compound of formula (V) wherein:
R1 is
Figure imgf000237_0003
and R is hydrogen;
a compound of formula (V) wherein:
R1 is
Figure imgf000237_0004
and R3 is hydrogen;
a compound of formula (V) wherein: R1 is
Figure imgf000238_0001
and R3 is hydrogen;
a compound of formula (V) wherein: R1 is
Figure imgf000238_0002
and R is hydrogen;
a compound of formula (V) wherein:
Figure imgf000238_0003
and R is hydrogen;
a compound of formula (V) wherein:
Figure imgf000238_0004
and R is hydrogen;
a compound of formula (V) wherein: R is
Figure imgf000239_0001
and R3 is hydrogen;
a compound of formula (V) wherein:
R IS
Figure imgf000239_0002
and R3 is hydrogen;
a compound of formula (V) wherein:
Figure imgf000239_0003
and R3 is hydrogen ;
a compound of formula (V) wherein : R1 is
Figure imgf000239_0004
and R3 is hydrogen;
a compound of formula (V) wherein: R1 is
Figure imgf000240_0001
and RJ is hydrogen;
a compound of formula (V) wherein:
R is
Figure imgf000240_0002
and Rά is hydrogen;
a compound of formula (V) wherein:
Rx is
Figure imgf000240_0003
and RJ is hydrogen;
a compound of formula (V) wherein:
R is
Figure imgf000240_0004
and R3 is hydrogen;
a compound of formula (V) wherein: R is
Figure imgf000241_0001
and R3 is hydrogen;
a compound of formula (V) wherein:
R is
Figure imgf000241_0002
and R is hydrogen;
a compound of formula (V) wherein: R1 is
Figure imgf000241_0003
and R is hydrogen;
a compound of formula (V) wherein:
R is
Figure imgf000241_0004
and R3 is hydrogen;
a compound of formula (V) wherein: R1 is
Figure imgf000242_0001
and R is hydrogen;
a compound of formula (V) wherein:
R1 is
Figure imgf000242_0002
and R is hydrogen;
a compound of formula (V) wherein:
Rx is
Figure imgf000242_0003
and R is hydrogen;
a compound of formula (V) wherein:
R1 is
Figure imgf000242_0004
and R is hydrogen;
a compound of formula (V) wherein: 3
Figure imgf000243_0001
and R3 is hydrogen;
a compound of formula (V) wherein:
Rx I S
Figure imgf000243_0002
and R is hydrogen;
a compound of formula (V) wherein :
Rx is
Figure imgf000243_0003
and R is hydrogen;
a compound of formula (V) wherein:
Rx is
Figure imgf000243_0004
and R is hydrogen;
a compound of formula (V) wherein:
R1 is
Figure imgf000243_0005
and R is hydrogen;
a compound of formula (V) wherein:
R1 is
Figure imgf000244_0001
and R is hydrogen;
a compound of formula (V) wherein:
R is
Figure imgf000244_0002
and R is hydrogen;
a compound of formula (V) wherein: R1 is
Figure imgf000244_0003
and R is hydrogen;
a compound of formula (V) wherein:
Rx is
Figure imgf000244_0004
and R3 is hydrogen; a compound of formula (V) wherein: R1 is
Figure imgf000245_0001
and R is hydrogen;
a compound of formula (V) wherein:
Figure imgf000245_0002
and R is hydrogen;
and a compound of formula (V) wherein:
R1 is
Figure imgf000245_0003
and R3 is hydrogen.
16. A compound of Claim 10 including isomers, enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, prodrugs and solvates thereof selected from:
Figure imgf000245_0004
Figure imgf000246_0001
Figure imgf000246_0002
10
Figure imgf000246_0003
15
Figure imgf000246_0004
Figure imgf000246_0005
Figure imgf000247_0001
Figure imgf000247_0002
10
Figure imgf000247_0003
15
Figure imgf000247_0004
20
Figure imgf000247_0005
25
Figure imgf000248_0001
Figure imgf000248_0002
10
Figure imgf000248_0003
15
Figure imgf000248_0004
20
Figure imgf000248_0005
25
Figure imgf000249_0001
Figure imgf000249_0002
10
Figure imgf000249_0003
15
Figure imgf000249_0004
20
25
Figure imgf000249_0005
Figure imgf000250_0001
Figure imgf000250_0002
Figure imgf000250_0003
Figure imgf000250_0004
25
Figure imgf000250_0005
Figure imgf000251_0001
Figure imgf000251_0002
Figure imgf000251_0003
Figure imgf000251_0004
Figure imgf000251_0005
Figure imgf000252_0001
Figure imgf000252_0002
Figure imgf000252_0003
Figure imgf000252_0004
Figure imgf000253_0001
Figure imgf000253_0002
Figure imgf000253_0003
15
Figure imgf000253_0004
Figure imgf000253_0005
Figure imgf000254_0001
Figure imgf000254_0002
Figure imgf000254_0003
20
Figure imgf000254_0004
Figure imgf000255_0001
Figure imgf000255_0002
Figure imgf000255_0003
15
20
25
30
Figure imgf000256_0001
Figure imgf000256_0002
10
Figure imgf000256_0003
15
Figure imgf000256_0004
20
Figure imgf000256_0005
25
Figure imgf000257_0001
Figure imgf000257_0002
10
Figure imgf000257_0003
15
Figure imgf000257_0004
20
Figure imgf000257_0005
25
Figure imgf000258_0002
10
Figure imgf000258_0003
15
Figure imgf000258_0004
20
Figure imgf000258_0005
25
Figure imgf000259_0001
Figure imgf000259_0002
10
Figure imgf000259_0003
15
Figure imgf000259_0004
20
Figure imgf000259_0005
25
Figure imgf000260_0001
Figure imgf000260_0002
10
Figure imgf000260_0003
15
Figure imgf000260_0004
20
Figure imgf000260_0005
25
Figure imgf000261_0001
Figure imgf000261_0002
10
Figure imgf000261_0003
15
Figure imgf000261_0004
20
Figure imgf000261_0005
25
Figure imgf000262_0001
Figure imgf000262_0002
Figure imgf000262_0003
and
Figure imgf000262_0004
17. A pharmaceutical composition comprising a compound of Claims 10, 11, 12, 13, 14, 15 and 16 and a pharmaceutically acceptable carrier.
18. A method of treating inosine monophosphate dehydrogenase associated disorders comprising: administering an therapeutically effective amount of the composition of Claim 17.
19. A method of treating inosine monophosphate dehydrogenase associated disorders comprising: administering a therapeutically effective amount of the composition of Claim 17 and another agent known to be useful in treatment of such disorders .
20. A method of treating inosine monophosphate dehydrogenase associated disorders comprising: administering a therapeutically effective amount of the pharmaceutical composition of Claim 17 and a phosphodiesterase Type 4 inhibitor.
21. A method for the treatment or prevention of allograft rejection comprising: administering a therapeutically effective amount of the pharmaceutical composition of Claim 17 and a phosphodiesterase Type 4 inhibitor.
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