mGluR1 antagonists as therapeutic agents

Information

  • Patent Grant
  • 7485648
  • Patent Number
    7,485,648
  • Date Filed
    Tuesday, June 14, 2005
    19 years ago
  • Date Issued
    Tuesday, February 3, 2009
    15 years ago
Abstract
In its many embodiments, the present invention provides tricyclic compounds of formula I (wherein J1-J4, X, and R1—R5 are as defined herein) useful as metabotropic glutamate receptor (mGluR) antagonists, particularly as selective metabotropic glutamate receptor 1 antagonists, pharmaceutical compositions containing the compounds, and methods of treatment using the compounds and compositions to treat diseases associated with metabotropic glutamate receptor (e.g., mGluR1) such as, for example, pain, migraine, anxiety, urinary incontinence and neurodegenerative diseases such Alzheimer's disease.
Description
FIELD OF THE INVENTION

The present invention relates to tricyclic compounds useful as metabotropic glutamate receptor (mGluR) antagonists, particularly as selective metabotropic glutamate receptor 1 antagonists, pharmaceutical compositions containing the compounds, and methods of treatment using the compounds and compositions to treat diseases associated with metabotropic glutamate receptor (e.g., mGluR1) such as, for example, pain, migraine, anxiety, urinary incontinence and neurodegenerative diseases such Alzheimer's disease.


BACKGROUND OF THE INVENTION

Glutamate is an important excitatory neurotransmitter in the mammalian central nervous system. Glutamate synaptic responses in the central nervous system (CNS) are mediated via activation of two families of receptors; ligand-gated cation channels termed ionotropic glutamate receptors, and G-protein-coupled receptors known as metabotropic glutamate receptors (mGluRs). Thus far, eight mGluR subtypes, together with splice variants, have been cloned and characterized in functional studies (Schoepp et al. Neuropharmacology, 1999, 38, 1431-1476). The eight mGluRs are grouped into three classes based on structural homology, pharmacology and signal transduction mechanisms.


Group I receptors (mGluR1 and mGluR5) couple through Gq/11 proteins to the activation of phospholipase C (PLC) resulting in phosphoinositide (PI) hydrolysis, the release of calcium from intracellular stores. While group II (mGluR2 and mGluR3) and III (mGluR4, mGluR6 mGluR7 and mGluR8) are negatively coupled to adenyl cyclase (AC) through G1/Go proteins thereby inhibiting cyclic AMP (cAMP) formation (Francesconi and Duvoisin, 1998).


Glutamate and Pain


Chronic pain is an area of high unmet medical need. Current therapies are not adequate and chronic pain is often refractory to most commonly used analgesics, including opioids. Glutamate plays a major role in nociceptive processing. Glutamate receptors, including mGluRs, are expressed in relevant areas of the brain, spinal cord and periphery that are involved in pain sensation and transmission.


Chronic pain may be due to tissue injury and diseases (inflammatory pain) or of the central and peripheral nervous system (neuropathic pain) and is associated with severe chronic sensory disturbances characterized by spontaneous pain, hyperalgesia (exaggerated responsiveness to painful stimuli) and allodynia (wrong perception of non noxious stimuli as painful). Prevalent symptoms in human patients include cold hyperalgesia, mechanical allodynia and less commonly, heat hyperalgesia.


Chronic pain is a true disease. It is believed to be a result of the plasticity at synapses in nociceptive processing centers, a phenomenon referred to as “central sensitization” which consists of increased excitability of spinal cord dorsal horn neurons. Glutamate receptors have been identified for their key role in central sensitization. Plasticity at synapses involved in nociceptive processing requires activation of ionotropic glutamate receptors NMDA and this plasticity is modulated by mGluRs including mGluR1. NMDA receptor antagonists have been tested in experimental therapies for the prevention and treatment of persistent pain following injury. However there are significant undesiderable side effects associated with the use of NMDA antagonists due largely to the critical role of those receptors in normal excitatory synaptic transmission throughout the nervous system. These side effects include pyschosis, hyperactivity, fatigue, dizziness, and in the case of higher levels of NMDA antagonists, amnesia and neuronal toxicity. Drugs designed to target mGluRs responsible for persistent alterations in nociception such as antagonists at mGluR1 might have reduced effects on excitatory transmission since their role of modulators of NMDA receptor-dependent plasticity in the dorsal horn, while effectively modifying the abnormal elevation of transmission thought to underlie persistent pain states. Thus mGluR antagonists might perform well clinically in chronic pain states without the side effects inherent to NMDA receptor antagonists.


mGluR1 and Pain


A number of behavioral (Fisher et al. Neuroreport, 1998, 20, 1169-1172; Fundytus et al. Neuroreport, 1998, 9, 731-735; Bhave et al. Nature Neurosci., 2001, 4, 417-423; Dolan et al. Neuropharmacology, 2002, 43, 319-326; Dolan et al. Pain, 2003, 106, 501-512) and electrophysiological (Young et al. Neuropharmacology, 1994, 33, 141-144; and Young et al. Brain Res., 1997, 777, 161-169) studies have demonstrated a specific role for Group I mGluRs, and in particular mGluR1 receptors, in nociceptive processing in the CNS, including mechanisms of hyperalgesia and inflammation. In the spinal cord, mGluR1 appears to be localized primarily on postsynaptic elements throughout the dorsal and ventral horns. (Neugebauer, Trends Neurosci., 2001, 24, 550-552). The intrinsic activation of spinal mGluR1 in chronic nociception has been demonstrated using antagonists, antibodies and antisense oligonucleotides. Intrathecal administration of an mGluR1 antagonist produced antinociceptive effects in the second phase of formalin-induced nociceptive behavior (Neugebauer, Trends Neurosci., 2001, 24, 550-552). Behavioral studies have also addressed the role of spinal mGluR1 receptors in the spinal injury and ligation models of neuropathic pain. Expression of mGluR1 is increased in rats following spinal cord injury and this may mediate the chronic central pain induced by the injury (Mills and Hulsebosch, Neurosci. Lett., 2002, 319, 59-62). Knockdown of spinal mGluR1 by intrathecal infusion of antisense oligonucleotides attenuated cold hyperalgesia and mechanical allodynia in neuropathic rats (Fundytus et al. Br. J. Pharmacol., 2001, 132, 354-367; and Fundytus et al. Pharmacol. Biochem. Behav., 2002, 73, 401-410). Additionally, spinal administration of anti-mGluR1 IgG antibodies reduced cold hyperalgesia, but not mechanical allodynia, in neuropathic rats (Fundytus et al. Neuroreport, 1998, 9, 731-735). The critical role of spinal mGluR1 receptors in pain-related central sensitization is emphasized at the single cell level by electrophysiological in vivo studies in anesthetized animals. Intraspinal administration of an mGluR1 antagonist inhibited the responses of primate spinothalamic tract neurons to brief noxious, but not innocuous, mechanical cutaneous stimuli, as well as central sensitization in the capsaicin pain model (Neugebauer et al. J. Neurophysiol., 1999, 82, 272-282). In rats with knocked down mGluR1 expression, the responses of multireceptive dorsal horn neurons to noxious input evoked by repeated topical applications of the C-fiber irritant mustard oil were significantly reduced compared to control neurons; the responses to innocuous cutaneous stimuli were not significantly different (Young et al. J. Neurosci., 1998, 18, 10180-10188).


SUMMARY OF THE INVENTION

In its many embodiments, the present invention provides a novel class of tricyclic compounds useful as metabotropic glutamate receptor (mGluR) antagonists, particularly as selective mGluR1 antagonists, methods of preparing such compounds, pharmaceutical compositions comprising one or more such compounds, methods of preparing pharmaceutical formulations comprising one or more such compounds, and methods of treatment, prevention, inhibition or amelioration of one or more diseases associated with the mGluRs, particularly mGluR1, using such compounds or pharmaceutical compositions.


In one aspect, the present application discloses a compound of formula I:




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or a pharmaceutically acceptable salt, solvate or ester thereof, wherein:


J1, J2, J3 and J4 are independently N, N→O, or C(R), provided that 0-2 of J1, J2, J3 and J4 are N or N→O;



custom character is a single or double bond;


R is selected from the group consisting of H, halo, —NR6R7, —OR6, —SR6, —CF3, —OCF3, —OCHF2, —OCH2F, —CN, —C(O)R6, —C(O2)R6, —OC(O)R6, —C(O)NR6R7, —N(R6)C(O)R6, —OS(O2)R6, —S(O2)R6, —S(O2)NR6R7, —N(R6)S(O2)R6, —N(R6)C(O)NR6R7, alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl optionally substituted with one or more (═O) or (═S), heterocyclyl optionally substituted with one or more (═O) or (═S), cycloalkylalkyl optionally substituted with one or more (═O) or (═S), and heterocyclylalkyl optionally substituted with one or more (═O) or (═S); wherein said alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, and heterocyclylalkyl are optionally substituted with one or more substituents independently selected from halo, alkyl optionally substituted with one or more R11, aryl optionally substituted with one or more R11, cycloalkyl optionally substituted with one or more R11, heteroaryl optionally substituted with one or more R11, heterocyclyl optionally substituted with one or more R11, —CF3, —OCF3, —OCHF2, —OCH2F, —CN, —NO2, —OR6, —SR6, —NR6R7, —C(O)R6, —C(O2)R6, —OCOR6, —C(O)NR6R7, —N(R6)C(O)R6, —OS(O2)R6, —S(O2)R6, —S(O2)NR6R7, —N(R6)S(O2)R6, or —N(R6)C(O)NR6R7, or two adjacent substituents are linked to form a methylenedioxy or ethylenedioxy;


X is O, S, N(R8), C(O), or C(RaRb);


R1 is selected from the group consisting of H, —OR6, —SR6, —NR6R7, halo, alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl optionally substituted with one or more (═O) or (═S), heterocyclyl optionally substituted with one or more (═O) or (═S), cycloalkylalkyl optionally substituted with one or more (═O) or (═S), and heterocyclylalkyl optionally substituted with one or more (═O) or (═S); wherein said alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, and heterocyclylalkyl are optionally substituted with one or more substituents independently selected from halo, alkyl optionally substituted with one or more R11, aryl optionally substituted with one or more R11, cycloalkyl optionally substituted with one or more R11, heteroaryl optionally substituted with one or more R11, heterocyclyl optionally substituted with one or more R11, —CF3, —OCF3, —OCHF2, —OCH2F, —CN, —NO2, —OR6, —SR6, —NR6R7, —C(O)R6, —C(O2)R6, —OC(O)R6, —C(O)NR6R7, —N(R6)C(O)R6, —OS(O2)R6, —S(O2)R6, —S(O2)NR6R7, —N(R6)S(O2)R6, or —N(R6)C(O)NR6R7, or two adjacent substituents are linked to form a methylenedioxy or ethylenedioxy;


R2 is selected from the group consisting of H, halo, alkyl, —N(R12)2, —OR12 and —SR2, wherein said alkyl is optionally substituted with one or more substituents independently selected from halo, hydroxy or alkoxy; or R1 and R2 optionally taken together form (═O) or (═S);


R3 is selected from the group consisting of H, —NR6R7, alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl optionally substituted with one or more (═O) or (═S), heterocyclyl optionally substituted with one or more (═O) or (═S), cycloalkylalkyl optionally substituted with one or more (═O) or (═S), and heterocyclylalkyl optionally substituted with one or more (═O) or (═S); wherein said alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, and heterocyclylalkyl are optionally substituted with one or more substituents independently selected from halo, alkyl optionally substituted with one or more R11, aryl optionally substituted with one or more R11, cycloalkyl optionally substituted with one or more R11, heteroaryl optionally substituted with one or more R11, heterocyclyl optionally substituted with one or more R11, —CF3, —OCF3, —OCHF2, —OCH2F, —CN, —NO2, —OR6, —SR6, —NR6R7, —C(O)R6, —C(O2)R6, —OC(O)R6, —C(O)NR6R7, —N(R6)C(O)R6, —OS(O2)R6, —S(O2)R6, —S(O2)NR6R7, —N(R6)S(O2)R6, or —N(R6)C(O)NR6R7, or two adjacent substituents are linked to form a methylenedioxy or ethylenedioxy;


R4is selected from the group consisting of H, —OR6, (═O), (═S), —SR6, —NR6R7, halo, alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl optionally substituted with one or more (═O) or (═S), heterocyclyl optionally substituted with one or more (═O) or (═S), cycloalkylalkyl optionally substituted with one or more (═O) or (═S), and heterocyclylalkyl optionally substituted with one or more (═O) or (═S); wherein said alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, and heterocyclylalkyl are optionally substituted with one or more substituents independently selected from halo, alkyl optionally substituted with one or more R11, aryl optionally substituted with one or more R11, cycloalkyl optionally substituted with one or more R11, heteroaryl optionally substituted with one or more R11, heterocyclyl optionally substituted with one or more R11, —CF3, —OCF3, —OCHF2, —OCH2F, —CN, —NO2, —OR6, —SR6, —NR6R7, —C(O)R6, —C(O2)R6, —OC(O)R6, —C(O)NR6R7, —N(R6)C(O)R6, —OS(O2)R6, —S(O2)R6, —S(O2)NR6R7, —N(R6)S(O2)R6, or —N(R6)C(O)NR6R7, or two adjacent substituents are linked to form a methylenedioxy or ethylenedioxy; or R3 and R4 optionally taken together with intervening atoms form a 5-8 membered heterocyclic ring having 0-3 heteroatoms independently selected from O, N or S in addition to the intervening nitrogen;


R5is R3 whencustom character is a single bond and R5is absent whencustom character is a double bond;


R6 and R7 are independently selected from the group consisting of H, alkyl, alkoxyalkyl, aryloxyalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl optionally substituted with one or more (═O) or (═S), heterocyclyl optionally substituted with one or more (═O) or (═S), cycloalkylalkyl optionally substituted with one or more (═O) or (═S), and heterocyclylalkyl optionally substituted with one or more (═O) or (═S); wherein each member of R6 and R7 except H is optionally substituted with one or more substituents independently selected from halo, alkyl optionally substituted with one or more R11, aryl optionally substituted with one or more R11, cycloalkyl optionally substituted with one or more R11, heteroaryl optionally substituted with one or more R11, heterocyclyl optionally substituted with one or more R11, —CF3, —OCF3, —OCHF2, —OCH2F, —CN, —NO2, —OR10, —SR10, —NR9R10, —C(O)R10, —C(O2)R10, —OC(O)R10, —C(O)NR9R10, —N(R9)C(O)R10, —OS(O2)R10, —S(O2)R10, —S(O2)NR9R10, —N(R9)S(O2)R10, or —N(R9)C(O)NR9R10, or two adjacent substituents are linked to form a methylenedioxy or ethylenedioxy; or R6 and R7, when attached to the same nitrogen atom, optionally taken together with the nitrogen atom form a 3-7 membered heterocyclic ring containing 0-3 heteroatoms independently selected from O, N or S in addition to said nitrogen atom;


Ra is selected from the group consisting of H, halo, alkyl, hydroxyalkyl, alkoxyalkyl, and N(R12)2;


Rb is selected from the group consisting of H, halo, alkyl, hydroxyalkyl, and alkoxyalkyl;


R8 is selected from the group consisting of H, alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl optionally substituted with one or more (═O) or (═S), heterocyclyl optionally substituted with one or more (═O) or (═S), cycloalkylalkyl optionally substituted with one or more (═O) or (═S), and heterocyclylalkyl optionally substituted with one or more (═O) or (═S); wherein each member of R8 except H is optionally substituted with one or more substituents independently selected from halo, alkyl optionally substituted with one or more R11, aryl optionally substituted with one or more R11, cycloalkyl optionally substituted with one or more R11, heteroaryl optionally substituted with one or more R11, heterocyclyl optionally substituted with one or more R11, —CF3, —OCF3, —OCHF2, —OCH2F, —CN, —NO2, —OR10, —SR10, —NR10R10, —C(O)R10, —C(O2)R10, —OC(O)R10, —C(O)NR9R10, —N(R9)C(O)R10, —OS(O2)R10, —S(O2)R10, —S(O2)NR9R10, —N(R9)S(O2)R10, or —N(R9)C(O)NR9R10, or two adjacent substituents are linked to form a methylenedioxy or ethylenedioxy;


R9 is H or alkyl;


R10 is selected from H, alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl optionally substituted with one or more (═O) or (═S), heterocyclyl optionally substituted with one or more (═O) or (═S), cycloalkylalkyl optionally substituted with one or more (═O) or (═S), heterocyclylalkyl optionally substituted with one or more (═O) or (═S); wherein each member of R11 except H is optionally substituted with one or more substituents independently selected from halo, alkyl optionally substituted with one or more R11, aryl optionally substituted with one or more R11, cycloalkyl optionally substituted with one or more R11, heteroaryl optionally substituted with one or more R11, heterocyclyl optionally substituted with one or more R11, —CF3, —OCHF2, —OCH2F, —OCF3, —CN, —NO2, —OR12, —SR12, —N(R12)(R12), —C(O)R12, —C(O2)R12, —OC(O)R2, —C(O)N(R12)(R12) —N(R12)C(O)R12, —OS(O2)R12, —S(O2)R12, —S(O2)N(R12)(R12), —N(R12)S(O2)R12, or —N(R12)C(O)N(R12)(R12), or two adjacent substituents are linked to form a methylenedioxy or ethylenedioxy; or R9 and R10, when attached to the same nitrogen atom, optionally taken together with the attached nitrogen atom form a 3-7 membered heterocyclic ring containing 0-3 heteroatoms independently selected from O, N or S in addition to the attached nitrogen; and two R12s attached to the same nitrogen atom optionally taken together with the attached nitrogen atom form a 3-7 membered heterocyclic ring having 0-3 heteroatoms independently selected from O, N or S in addition to the attached nitrogen;


R11 is halo, —CF3, —OCF3, —OCHF2, —OCH2F, —CN, —NO2, —OR12, —SR12, —N(R12)(R12), —C(O)R12, —C(O2)R12, —OC(O)R12, —C(O)N(R12)(R12), —N(R12)C(O)R12, —OS(O2)R12, —S(O2)R12, —S(O2)N(R12)(R12), —N(R12)S(O2)R12, or —N(R12)C(O)N(R12)(R12); and


R12 is H or alkyl.


The compounds of formula I are useful as selective metabotropic glutamate receptor 1 antagonists and thus are useful in the treatment and prevention of pain (neurotropic or inflammatory), migraine, anxiety, urinary incontinence and neurodegenerative diseases such Alzheimer's disease.







DETAILED DESCRIPTION

In one embodiment, the present invention discloses tricyclic compounds which are represented by structural formula I or a pharmaceutically acceptable salt, solvate or ester thereof, wherein the various moieties are as described above.


In another embodiment, the present invention discloses tricyclic compounds of formula I or a pharmaceutically acceptable salt, solvate or ester thereof, wherein the various moieties are as described above with one of the following provisos 1-11: proviso 1: whencustom character is a double bond; R5 is absent; R1 and R2 taken together are (═O); X is O, S or NR12; then R3 is not H; proviso 2: whencustom character is a double bond; R5 is absent; R1 and R2 taken together are (═O); then


either (a) J1, J2, J3 and J4 are each C(H);

    • X is S or O;
    • R3 is 3-(3-hydroxypiperidin-2-yl)-2-oxo-propyl; and
    • R4 is not H;


or (b) J1, J2, J3 and J4 are each C(H);

    • X is NH;
    • R3 is C1-C3 alkyl or NH2; and
    • R4 is not H, —(CH2)4—N-(optionally substituted piperazine) or —S—(CH2)3—N-(optionally substituted piperazine);


or (c) J1, J2, J3 and J4 are each C(H);

    • X is NH,
    • R3 is —NH2, —(CH2)2-3—OH, —(CH2)2-3-halo or —(CH2)2-3—N-(optionally substituted piperazine); and
    • R4 is not H or C1-C3 alkyl;


or (d)(i) J1 is N, J2 and J3 are each C(H), and J4 is C(N(CH3)2);

    • X is S;
    • R4 is H; and
    • R3 is not benzyl, phenyl, p-chlorophenyl, p-methylphenyl, or p-methoxyphenyl;


or (d)(ii) J1 is N, J2 is C(CH3) or C(NH2), J3 is C(H), C(NO2) or C(C(O)CH3) and J4 is C(CH3)or C(optionally substituted phenyl);

    • X is S;
    • R4 is H or CH3; and
    • R3 is not benzyl, phenyl, p-chlorophenyl, p-methylphenyl, p-methoxyphenyl, or 2-methyl-4-nitrophenyl;


or (e) J1 is N and J2, J3 and J4 are each C(R13), wherein R13 is H, CF3, C1-C3 alkyl, —CONH(C1-C6 alkyl), —CO2Et, optionally substituted phenyl or benzyl;

    • X is O or S;
    • R4 is H, halo, —NR6R7, C1-C4 alkyl, or phenyl; and
    • R3 is not —NH2, —NH(phenyl), or C1-C4 alkyl optionally substituted with halo, OH, pyridyl, —NR6R7, CO2R12, COR12, —S—(CH2)2-3OH, —SH, or —S(CH2)2-3CO2R12;


or (f) J4 is N and J1, J2 and J3 are each C(R12);

    • X is S;
    • R3 is C1-C4 alkyl, NH2, or NH-(phenyl); and
    • R4 is not H, C1-C4 alkyl, or NH2;


or (g) J1 and J2 are each N and J3 and J4 are each C(phenyl) or C(2-furanyl);

    • X is S;
    • R3 is NH2, optionally substituted phenyl, or C1-C4 alkyl optionally substituted with CN or C(O)-phenyl; and
    • R4 is not H, methyl, or —NR6R7;


or (h) J2 is C(R) and J4 is C(H);

    • X is S;
    • R4 is H, C1-C3 alkyl, NH2, N(CH3)2, NH-(phenyl); and J1 and J3 are not both N;


      proviso 3: whencustom character is a double bond; R5 is absent; R1 and R2 taken together are (═S); J1 is N; J2 is C(H), C(CH3) or C(phenyl); J3 is C(H), and J4 is C(CH3) or C(N(CH3)2); X is S; and R4 is H or CH3; then R3 is not H, NH2, phenyl, halo substituted phenyl, or C1-C6 alkyl optionally substituted with N(C1-C3 alkyl)2 or OH; proviso 4: whencustom character is a double bond; R5 is absent; R1 is —CH2CO2Et or —CH2CN; R2 is H; J1 and J2 are N and J3 and J4 are C(phenyl); X is S; and R3 is phenyl or p-flurophenyl; then R4 is not —NR6R7; proviso 5: whencustom character is a single bond; R4 is (═O); and R1 and R2 taken together are (═O); then


either (a) X is O, S or N(R8); and

    • R3 is not alkyl substituted with N-3a,4-dihydrobenzopyrano [3,4-c]pyrrolidine or N-3a,4-dihydrobenzopyrano[3,4-c]piperidine, N-1,2,3,4,4a,5-hexahydropyrazino[2,1-c][1,4]benzoxazine, or N-(2-phenyl)pyrrolidine, wherein said benzo or phenyl is optionally substituted;


or (b) J1, J2, J3 and J4 are each C(R14), wherein R14 is H, halo, alkoxy, NO2, NHSO2-alkyl, or NH2;

    • X is O, S, N(H), N(CH3) or N-(optionally substituted benzyl); and
    • R3 and R5 are not both H, OH or alkyl;


or (c) J1, J2, J3 and J4 are each C(H) or C(halo);

    • X is S, N(CH3) or N(benzyl);
    • R5 is H or halo substituted benzyl; and R3 is not —CH2CO2R12; or R5 is H or —CH2CO2R12 and R3 is not benzyl or halo substituted benzyl;


or (d) J1, J2, J3 and J4 are each C(H);

    • X is NH, N(CH3) or S;
    • R5is H or CH3; and
    • R3 is not —(CH2)2-3—N-(optionally substituted piperazine), —(CH2)2-3—N(C1-C3 alkyl)2, —(CH2)2-3—N-pyrrolidine, —(CH2)2-3—N-piperidine, or —(CH2)2-3—N-morpholine;


or (e) J1 is N and J2, J3 and J4 are each C(R);

    • X is S;
    • R5 is H; and
    • R3 is not NH2, optionally substituted phenyl, —(CH2)2NH(CH2)2NH2, alkyl optionally substituted with halo, hydroxy or amino;


or (f) J1, J2 and J3 are each CH and J4 is N;

    • X is S;
    • R5 is H; and
    • R3 is not alkyl substituted with N-1,3,3a,4,5,9b-hexahydro-2H-benzo[e]isoindole wherein benzo is optionally substituted;


or (g) J1 and J2 are each N and J3 and J4 are each C(2-furanyl);

    • X is S;
    • R3 is phenyl; and
    • R5 is not H;


or (h) J1 and J4 are each N and J2 and J3 are each C(H);

    • X is S;


R3 and R5 are not both H;


proviso 6: when custom character is a single bond; R4 is (═O); R1 is optionally substituted phenyl; R2 is H; and X is CO; then R3 and R5 are not both H; proviso 7: whencustom character is a single bond; R1 and R2 taken together are (═O); J1 and J2 are each N and J3 and J4 are each C(phenyl); X is S; and R4 is optionally substituted phenyl; then R3 and R5 are not both H; proviso 8: whencustom character is a single bond; R4 is (═S); R1 and R2 taken together are (═O) or (═S); X is S; R5 is H; and (i) J1 and J3 are N or (ii) J1 is N, J2 is C(R15), J3 is C(R16) or N, and J4 is C(CH3) or C(optionally substituted phenyl), wherein R15 is CH3, NH2, phenyl or 2-thienyl and R16 is H, —CN, —C(O)CH3 or —CO2Et; then R3 is not H or phenyl; proviso 9: when J1, J2, J3 and J4 are each C(H); R1 and R2 taken together are (═O); X is NH or S; and R4 is (═S) or —SR6; then R3 is not —NH2; proviso 10: when J1 is N, J3 is C(H), J4 is C(CH3) or C(phenyl) and J2 is C(CH3), C(optionally substituted phenyl) or C(2-thienyl); X is S; and R4 is H, (═S) or —SR6; then R3 is not NH2, C1-C4 alkyl, —CH2CO2Et, or optionally substituted phenyl; and proviso 11: when J1, J2, J3 and J4 are each C(H); and R3 and R4 form a ring with the intervening atoms; then X is not NH or S.


In one embodiment, X is O, S, or NR8.


In another embodiment, at least one of J1-J4 is N or N→O.


In another embodiment, one of J1-J4 is N or N→O and R1 is selected from the group consisting of H, —OR6, —SR6, halo, alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl optionally substituted with one or more (═O) or (═S), heterocyclyl optionally substituted with one or more (═O) or (═S), cycloalkylalkyl optionally substituted with one or more (═O) or (═S), and heterocyclylalkyl optionally substituted with one or more (═O) or (═S); wherein said alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, and heterocyclylalkyl are optionally substituted with one or more substituents independently selected from halo, alkyl optionally substituted with one or more R11, aryl optionally substituted with one or more R11, cycloalkyl optionally substituted with one or more R11, heteroaryl optionally substituted with one or more R11, heterocyclyl optionally substituted with one or more R11, —CF3, —OCF3, —OCHF2, —OCH2F, —CN, —NO2, —OR6, —SR6, —NR6R7, —C(O)R6, —C(O2)R6, —OCOR6, —C(O)NR6R7, —N(R6)C(O)R6, —OS(O2)R6, —S(O2)R6, —S(O2)NR6R7, —N(R6)S(O2)R6, or —N(R6)C(O)NR6R7, or two adjacent substituents are linked to form a methylenedioxy or ethylenedioxy.


In another embodiment, R1 and R2 are taken together to form (═O) or (═S).


In another embodiment, custom character is a double bond and R1 and R2 taken together are (═O) representated by formula Ia. In another embodiment, X is S (formula IIa) or O (formula IIb). In yet another embodiment, X is S (formula IIa).




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In another embodiment, J1 is N or N→O and j2, J3 and J4 are each C(R).


In another embodiment, the present compounds are pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin4-ones represented by formula IIIa.


In yet another embodiment, the present compounds are represented by formula IVa, formula Va or formula Vb (in both formulae Va and Vb, R15 is a suitable substituent of the phenyl ring as defined herein).


In another embodiment, J2 is N or N? O and J1, J3 and J4 are each C(R).


In another embodiment, the present compounds are pyrido[4′,5′:4,5]thieno[3,2-d]pyrimidin-4-ones represented by formula IIIb.


In another embodiment, J3 is N or N? O and J1, J2 and J4 are each C(R).


In another embodiment, the present compounds are pyrido[5′,4′:4,5]thieno[3,2-d]pyrimidin-4-ones represented by formula IIIc.


In another embodiment, J4 is N or N? O and J1, J2 and J3 are each C(R).


In another embodiment, the present compounds are pyrido[2′,3′:4,5]thieno[3,2-d]pyrimidin-4-ones represented by formula IIId.


In another embodiment, J1 and J4 are each N and J2 and J3 are each C(R).


In another embodiment, the present compounds are pyrazino[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-ones represented by formula IIIe.


In another embodiment, J1 and J2 are each N and J3 and J4 are each C(R).


In another embodiment, the present compounds are pyridazino[4′,3′:4,5]thieno[3,2-d]pyrimidin-4-ones represented by formula IIIf.


In another embodiment, J1 and J3 are each N and J2 and J4 are each C(R).


In another embodiment, the present compounds are pyrimido[5′,4′:4,5]thieno[3,2-d]pyrimidin-4-ones represented by formula IIIg.


In another embodiment, J2 and J4 are each N and J1 and J3 are each C(R).


In another embodiment, the present compounds are pyrimido[4′,5′:4,5]thieno[3,2-d]pyrimidin-4-ones represented by formula IIIh.




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In yet another embodiment, J2 and J3 are C(H) or C(halo).


In another embodiment, R4 is H.


In another embodiment, R is H, halo, alkyl, alkoxy, cycloalkyl, heteroaryl, —OSO2R6, or —NR6R7 wherein R6 and R7 optionally taken together with the nitrogen atom form a 4-7 membered heterocyclic ring having 0-1 heteroatoms independently selected from O or N in addition to said nitrogen atom.


In another embodiment, R is H, —N(C1-C6 alkyl)2, —NH(C1-C6 alkyl), halo, —C1-C6 alkoxy, —OSO2CF3, —NH—(C3-C6 cycloalkyl), —NH-phenyl, N-piperidinyl, N-morpholinyl, C1-C6 alkyl, C3-C6 cycloalkyl, N-pyrrolyl, N-pyrazolyl, N-piperazinyl, or N-pyrrolidinyl optionally substituted with hydroxy or (═O).


In another embodiment, the (C1-C6 alkyl) of said —NH(C1-C6 alkyl) is optionally substituted with —OH or —CF3.


In another embodiment, R3 is alkyl, alkoxyalkyl, cycloalkyl, heteroaryl, heteroaralkyl, cycloalkylalkyl, aralkyl, aryl, heterocyclyl or heterocyclylalkyl; wherein each member of R3 is optionally substituted with one or more substituents independently selected from halo, —CN, —OR12, alkyl, alkoxy, —OCF3, —OCHF2, amino, alkylamino, dialkylamino, hydroxyalkyl, —NR12C(O)R12, —C(O)N(R12)2, cyanoalkyl, —CO2R12, —CF3, or two adjacent substituents are linked to form a methylenedioxy or ethylenedioxy; and said heterocyclyl is additionally and optionally substituted by (═O).


In another embodiment, R3 is C1-C6 alkyl, C3-C7 monocyclic cycloalkyl, 9-membered cycloalkylaryl, 9-membered cycloalkenylaryl, 6-membered monocyclic heteroaryl or heterocyclyl, 9- to 10-membered bicyclic heteroaryl or heterocyclyl, C6 cycloalkyl(C1-C6)alkyl, ar(C1-C6)alkyl, or aryl; wherein said aryl is optionally substituted with one or more substituents independently selected from halo, —CN, —OH, C1-C6 alkyl, C1-C6 alkoxy, —OCF3, —OCHF2, amino, C1-C6 alkylamino, di(C1-C6)alkylamino, hydroxy(C1-C6)alkyl, or two adjacent substituents of said aryl are linked to form a methylenedioxy or ethylenedioxy. In another embodiment, aryl of R3 is p-substituted.


In yet another embodiment, R3 is cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, benzyl, a-phenethyl, pyridyl, n-butyl, indolyl, benzothiazolyl, benzoimidazolyl, benzooxazolyl, cyclohexylmethyl, pyrano, indanyl, indenyl, phenyl, or 3,4-dihydrobenzo[1,4]oxazinyl; wherein said phenyl is optionally substituted with halo, —CN, —OMe, —OCF3, —OCHF2, —NMe2, —OH, —CH2OH, methyl, ethyl or two adjacent substituents of said phenyl are linked to form a methylenedioxy or ethylenedioxy; and said 3,4-dihydrobenzo[1,4]oxazinyl is optionally substituted with (═O). In another embodiment, phenyl of R3 is p-substituted.


A list of representative compounds of the present invention is shown in Table 1 below.










TABLE 1





Cpd
Structure







 7A


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 7B


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 7C


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 7D


embedded image







 7E


embedded image







 7F


embedded image







 7G


embedded image







 7H


embedded image







 7I


embedded image







 7J


embedded image







 7K


embedded image







 7L


embedded image







 7M


embedded image







 7N


embedded image







7O


embedded image







7P


embedded image







7Q


embedded image







7R


embedded image







7S


embedded image







7T


embedded image







7U


embedded image







7V


embedded image







7W


embedded image







7X


embedded image







7Y


embedded image







7Z


embedded image







7AA


embedded image







7AB


embedded image







7AC


embedded image







7AD


embedded image







7AE


embedded image







7AF


embedded image







7AG


embedded image







7AH


embedded image







7AI


embedded image







7AJ


embedded image







7AK


embedded image







7AL


embedded image







7AM


embedded image







7AN


embedded image







7AO


embedded image







7AP


embedded image







7AQ


embedded image







7AR


embedded image







7AS


embedded image







7AT


embedded image







7AU


embedded image







7AV


embedded image







7AW


embedded image







7AX


embedded image







7AY


embedded image







7AZ


embedded image







7BA


embedded image







7BB


embedded image







7BC


embedded image







7BD


embedded image







7BE


embedded image







7BF


embedded image







7BG


embedded image







7BH


embedded image







7BI


embedded image







7BJ


embedded image







7BK


embedded image







7BL


embedded image







7BM


embedded image







7BN


embedded image







7BO


embedded image







7BP


embedded image







7BQ


embedded image







7BR


embedded image







7BS


embedded image







7BT


embedded image







7BU


embedded image







7BV


embedded image







7BW


embedded image







7BX


embedded image







7BY


embedded image







7BZ


embedded image







7CA


embedded image







7CB


embedded image







7CC


embedded image







7CD


embedded image







 7CE


embedded image







 7CF


embedded image







 7CG


embedded image







 7CH


embedded image







 7CI


embedded image







 7CJ


embedded image







 7CK


embedded image







 7CL


embedded image







 7CM


embedded image







 7CN


embedded image







 7CO


embedded image







 7CP


embedded image







 7CQ


embedded image







 7CR


embedded image







 7CS


embedded image







 7CT


embedded image







 7CU


embedded image







 7CV


embedded image







 7CW


embedded image







 7CX


embedded image







 7CY


embedded image







 7CZ


embedded image







 7DA


embedded image







 7DB


embedded image







 7DC


embedded image







 7DD


embedded image







 7DE


embedded image







 7DF


embedded image







 7DG


embedded image







 7DH


embedded image







 7DI


embedded image







 7DJ


embedded image







 7DK


embedded image







 7DL


embedded image







 7DM


embedded image







 7DN


embedded image







 7DO


embedded image







 7DP


embedded image







 7DQ


embedded image







 7DR


embedded image







 7DS


embedded image







 7DT


embedded image







 7DU


embedded image







 7DV


embedded image







 7DW


embedded image







 7DX


embedded image







 7DY


embedded image







 7DZ


embedded image







 7EA


embedded image







 7EB


embedded image







 7EC


embedded image







11


embedded image







12A


embedded image







12B


embedded image







13


embedded image







14


embedded image







15A


embedded image







15B


embedded image







15C


embedded image







15D


embedded image







15E


embedded image







15F


embedded image







15G


embedded image







15H


embedded image







15I


embedded image







15J


embedded image







15K


embedded image







15N


embedded image







15O


embedded image







15P


embedded image







15Q


embedded image







15R


embedded image







15S


embedded image







15T


embedded image







15U


embedded image







15V


embedded image







15W


embedded image







15X


embedded image







15Y


embedded image







15Z


embedded image







15AA


embedded image







15AB


embedded image







15AC


embedded image







15AD


embedded image







15AE


embedded image







15AF


embedded image







15AG


embedded image







15AH


embedded image







15AI


embedded image







15AJ


embedded image







15AK


embedded image







19


embedded image







25A


embedded image







25B


embedded image







25C


embedded image







25D


embedded image







26A


embedded image







26C


embedded image







27A


embedded image







27B


embedded image







27C


embedded image







28A


embedded image







28B


embedded image







28C


embedded image







28D


embedded image







28E


embedded image







28F


embedded image







28G


embedded image







28H


embedded image







28I


embedded image







28J


embedded image







28K


embedded image







28L


embedded image







28M


embedded image







28N


embedded image







28O


embedded image







28P


embedded image







28Q


embedded image







28R


embedded image







28S


embedded image







28T


embedded image







28U


embedded image







28V


embedded image







28W


embedded image







28X


embedded image







28Y


embedded image







28Z


embedded image







28AA


embedded image







28AB


embedded image







28AC


embedded image







28AD


embedded image







28AE


embedded image







28AF


embedded image







28AG


embedded image







28AH


embedded image







28AI


embedded image







28AJ


embedded image







28AK


embedded image







28AL


embedded image







28AM


embedded image







28AN


embedded image







28AO


embedded image







28AP


embedded image







28AQ


embedded image







28AR


embedded image







28AS


embedded image







28AT


embedded image







28AU


embedded image







28AV


embedded image







2BAW


embedded image







28AX


embedded image







28AY


embedded image







28AZ


embedded image







28BA


embedded image







28BB


embedded image







28BC


embedded image







29A


embedded image







29B


embedded image







29C


embedded image







29D


embedded image







30A


embedded image







30B


embedded image







30C


embedded image







37A


embedded image







37B


embedded image







37C


embedded image







37D


embedded image







37E


embedded image







37F


embedded image







37G


embedded image







37H


embedded image







40


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41


embedded image







42


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43


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44


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45


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46


embedded image







47A


embedded image







47B


embedded image







48


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49


embedded image







50


embedded image







51


embedded image







52


embedded image







55


embedded image







58


embedded image







59A


embedded image







59B


embedded image







59C


embedded image







60A


embedded image







60B


embedded image







60C


embedded image







60D


embedded image







60E


embedded image







60F


embedded image







60G


embedded image




60H


embedded image




60I


embedded image







60J


embedded image







60L


embedded image




61A


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61B


embedded image







62


embedded image







63


embedded image







64


embedded image







65A


embedded image







65B


embedded image







65C


embedded image







65D


embedded image







65E


embedded image







66A


embedded image







66B


embedded image







66C


embedded image







66D


embedded image







66E


embedded image







72A


embedded image







72B


embedded image







72C


embedded image







72D


embedded image







72E


embedded image







72F


embedded image







72G


embedded image







72H


embedded image







72I


embedded image







73A


embedded image







73B


embedded image







73C


embedded image







73D


embedded image







73E


embedded image







73F


embedded image







76


embedded image







77


embedded image







78


embedded image







80


embedded image







83


embedded image







84


embedded image







85


embedded image







87A


embedded image







87B


embedded image







87C


embedded image







95A


embedded image







95B


embedded image







95C


embedded image







95D


embedded image







95E


embedded image







95F


embedded image







95G


embedded image







95H


embedded image







95I


embedded image







95J


embedded image







95K


embedded image







95L


embedded image







95M


embedded image







95N


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Cpd
Structure







95O


embedded image







95P


embedded image







95Q


embedded image







95R


embedded image







95S


embedded image







95T


embedded image







95U


embedded image







95V


embedded image







95W


embedded image







95X


embedded image







95Y


embedded image







95Z


embedded image







95AA


embedded image







95AB


embedded image







95AC


embedded image







95AD


embedded image







95AE


embedded image







95AF


embedded image







95AG


embedded image







95AH


embedded image







95AI


embedded image







95AJ


embedded image







95AK


embedded image







95AL


embedded image







95AM


embedded image







95AN


embedded image







103A


embedded image







103B


embedded image







103C


embedded image







103D


embedded image







103E


embedded image







103F


embedded image







104


embedded image







105


embedded image







106


embedded image







113A


embedded image







113B


embedded image







113C


embedded image







113D


embedded image







113E


embedded image







113F


embedded image







113G


embedded image







113H


embedded image







113I


embedded image







113J


embedded image







113K


embedded image







113L


embedded image







113M


embedded image







113N


embedded image







115


embedded image







116


embedded image







116A


embedded image







116B


embedded image







116C


embedded image







116D


embedded image







116E


embedded image







116F


embedded image







116G


embedded image







117


embedded image







117A


embedded image







117B


embedded image







118


embedded image







131A


embedded image







131B


embedded image







131C


embedded image







131D


embedded image







131E


embedded image







131F


embedded image







131G


embedded image







134A


embedded image







134B


embedded image







134C


embedded image







134D


embedded image







134E


embedded image







134F


embedded image







134G


embedded image







134H


embedded image







134I


embedded image







135A


embedded image







136


embedded image







137A


embedded image







137B


embedded image







138


embedded image







144A


embedded image







147A


embedded image







148


embedded image







149


embedded image







150


embedded image







151


embedded image







152


embedded image







P-1


embedded image







P-2


embedded image







P-3


embedded image







P-4


embedded image







P-5


embedded image







P-6


embedded image







P-7


embedded image







P-8


embedded image







P-9


embedded image







P-10


embedded image







P-11


embedded image







P-12


embedded image







P-13


embedded image







P-14


embedded image







P-15


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or a pharmaceutically acceptable salt, solvate or ester thereof.






Preferred compounds include 7A, 7B, 7D, 7G, 7H, 7K, 7L, 7Q, 7W, 7X, 7Y, 7Z, 7AA, 7AC, 7AJ, 7AK, 7AM, 7AP, 7AS, 7AV, 7AX, 7AY, 7BF, 7BG, 7BI, 7BJ, 7BL, 7BM, 7BN, 7BO, 7BS, 7BW, 7BY, 7BZ, 7CA, 7CB, 7CC, 7CD, 7CE, 7CF, 7CG, 7CK, 7CM, 7CQ, 7CR, 7CT, 7CU, 7CV, 7CY, 7CZ, 7DB, 7DC, 7DE, 7DF, 7DG, 7DH, 7DI, 7DJ, 7DK, 7DL, 7DO,-7DQ, 7DR, 7DU, 7DV, 7DW, 7DX, 7DZ, 7EA, 15C, 15Q, 15Y, 15Z, 15AA, 15AB, 15AG, 28I, 28P, 28S, 28X, 28Y, 28Z, 28AA, 28AB, 28AC, 28AE, 28AI, 28AK, 28AL, 28AN, 28AO, 28AP, 28AR, 28AS, 28AT, 28AU, 28AV, 28AW, 28AZ, 28BB, 28BC, 37E, 37F, 45, 46, 51, 58, 60A, 60B, 60C, 60D, 60E, 60G, 66A, 66D, 71A, 72A, 72B, 72C, 72G, 72H, 72I, 95A, 95B, 96C, 95D, 95E, 95F, 95G, 95H, 95I, 95K, 95L, 95N, 95O, 95P, 95Q, 95R, 95S, 95T, 95U, 95W, 95X, 95Y, 95Z, 95AA, 95AC, 95AD, 113A, 113B, 113D, 113E, 113F, 113G, 113H, 113I, 113K, 116D, 131A, 131 B, 131C, 131D, 131E, 131G, 136, 137A, 137B, 138, 148, 151, and 152, or a pharamaceutically acceptable salt, solvate or ester thereof.


More preferred compounds include 7A, 7B, 7H, 7L, 7Q, 7AC, 7AP, 7AS, 7BI, 7BJ, 7BL, 7BM, 7BS, 7BY, 7CC, 7CE, 7CG, 7CQ, 7CR, 7CT, 7CU, 7CV, 7CY, 7DG, 7DH, 7DK, 7DL, 7DR, 7DU, 7DV, 7DW, 15Q, 15Z, 15AA, 15AG, 28X, 28Y, 28Z, 28AA, 28AE, 28AI, 28AK, 28AL, 37E, 37F, 60A, 60D, 60E, 71A, 72G, 72H, 95A, 95B, 95C, 95E, 95F, 95G, 95H, 95K, 95L, 95P, 95Q, 95S, 95T, 95Z, 95AA, 95AC, 131 C, 131 D, 131 E, 136, 148, and 152, or a pharmaceutically acceptable salt, solvate or ester thereof.


As used above, and throughout the specification, the following terms, unless otherwise indicated, shall be understood to have the following meanings:


“Patient” includes both human and animals.


“Mammal” means humans and other mammalian animals.


“Alkyl” means an aliphatic hydrocarbon group which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain. “Lower alkyl” means a group having about 1 to about 6 carbon atoms in the chain which may be straight or branched. The term “substituted alkyl” means that the alkyl group may be substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, —NH(alkyl), —NH(cycloalkyl), —N(alkyl)2, carboxy, —C(O)O-alkyl and —S(alkyl). Non-limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, heptyl, nonyl, decyl, fluoromethyl, trifluoromethyl and cyclopropylmethyl.


“Alkenyl” means an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkenyl chain. “Lower alkenyl” means about 2 to about 6 carbon atoms in the chain which may be straight or branched. The term “substituted alkenyl” means that the alkenyl group may be substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl. aryl, cycloalkyl, cyano, alkoxy and —S(alkyl). Non-limiting examples of suitable alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl.


“Alkynyl” means an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkynyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkynyl chain. “Lower alkynyl” means about 2 to about 6 carbon atoms in the chain which may be straight or branched. Non-limiting examples of suitable alkynyl groups include ethynyl, propynyl, 2-butynyl, 3-methylbutynyl, n-pentynyl, and decynyl. The term “substituted alkynyl” means that the alkynyl group may be substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of alkyl. aryl and cycloalkyl.


“Alkylene” means a difunctional group obtained by removal of a hydrogen atom from an alkyl group that is defined above. Non-limiting examples of alkylene include methylene, ethylene and propylene.


“Aryl” (sometimes abbreviated “ar”) means an aromatic monocyclic or multicyclic ring system comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms. The aryl group can be optionally substituted with one or more “ring system substituents” which may be the same or different, and are as defined herein. Non-limiting examples of suitable aryl groups include phenyl and naphthyl.


“Heteroaryl” means an aromatic monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. Preferred heteroaryls contain about 5 to about 6 ring atoms. The “heteroaryl” can be optionally substituted by one or more “ring system substituents” which may be the same or different, and are as defined herein. The prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom. A nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide. Non-limiting examples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,2,4-triazinyl, benzothiazolyl and the like.


“Aralkyl” or “arylalkyl” means an aryl-alkyl-group in which the aryl and alkyl are as previously described. Preferred aralkyls comprise a lower alkyl group. Non-limiting examples of suitable aralkyl groups include benzyl, 2-phenethyl and naphthalenylmethyl. The bond to the parent moiety is through the alkyl.


“Alkylaryl” means an alkyl-aryl-group in which the alkyl and aryl are as previously described. Preferred alkylaryls comprise a lower alkyl group. Non-limiting examples of suitable alkylaryl groups include o-tolyl, p-tolyl and xylyl. The bond to the parent moiety is through the aryl.


“Cycloalkyl” means a non-aromatic mono- or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7 ring atoms. The cycloalkyl can be optionally substituted with one or more “ring system substituents” which may be the same or different, and are as defined above. Non-limiting examples of suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Non-limiting examples of suitable multicyclic cycloalkyls include 1-decalin, norbornyl, adamantyl and the like. “Cycloalkyl” includes “arylcycloalkyl” and “cycloalkylaryl” as defined below.


“Halo” means fluoro, chloro, bromo, or iodo groups. Preferred are fluoro, chloro or bromo, and more preferred are fluoro and chloro.


“Halogen” means fluorine, chlorine, bromine, or iodine. Preferred are fluorine, chlorine and bromine.


“Haloalkyl” means an alkyl as defined above wherein one or more hydrogen atoms on the alkyl is replaced by a halo group defined above.


“cyanoalkyl” means an alkyl as defined above wherein one or more hygrogen atoms on the alkyl is replaced by a cyano group.


“oxo” means (═O) and “thioxo” means (═S).


“Ring system substituent” means a substituent attached to an aromatic or non-aromatic ring system which, for example, replaces an available hydrogen on the ring system. Ring system substituents may be the same or different, each being independently selected from the group consisting of alkyl, aryl, heteroaryl, aralkyl, alkylaryl, aralkenyl, heteroaralkyl, alkylheteroaryl, heteroaralkenyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, Y1Y2N—, Y1Y2N-alkyl-, Y1Y2NC(O)— and Y1Y2NSO2—, wherein Y1 and Y2 may be the same or different and are independently selected from the group consisting of hydrogen, alkyl, aryl, and aralkyl. “Ring system substituent” also means a cyclic ring of 3 to 7 ring atoms of which 1-2 may be a heteroatom, attached to an aryl, heteroaryl, heterocyclyl or heterocyclenyl ring by simultaneously substituting two ring hydrogen atoms on said aryl, heteroaryl, heterocyclyl or heterocyclenyl ring. Non-limiting examples include:




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“Cycloalkenyl” means a non-aromatic mono or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms which contains at least one carbon-carbon double bond. Preferred cycloalkenyl rings contain about 5 to about 7 ring atoms. The cycloalkenyl can be optionally substituted with one or more “ring system substituents” which may be the same or different, and are as defined above. Non-limiting examples of suitable monocyclic cycloalkenyls include cyclopentenyl, cyclohexenyl, cycloheptenyl, and the like. Non-limiting example of a suitable multicyclic cycloalkenyl is norbornylenyl. “Cycloalkenyl” includes “arylcycloalkenyl” and “cycloalkenylaryl” as defined below.


“Heterocyclenyl” means a non-aromatic monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur atom, alone or in combination, and which contains at least one carbon-carbon double bond or carbon-nitrogen double bond. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heterocyclenyl rings contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclenyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The heterocyclenyl can be optionally substituted by one or more ring system substituents, wherein “ring system substituent” is as defined above. The nitrogen or sulfur atom of the heterocyclenyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting examples of suitable monocyclic azaheterocyclenyl groups include 1,2,3,4-tetrahydropyridine, 1,2-dihydropyridyl, 1,4-dihydropyridyl, 1,2,3,6-tetrahydropyridine, 1,4,5,6-tetrahydropyrimidine, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, and the like. Non-limiting examples of suitable oxaheterocyclenyl groups include 3,4-dihydro-2H-pyran, dihydrofuranyl, fluorodihydrofuranyl, and the like. Non-limiting example of a suitable multicyclic oxaheterocyclenyl group is 7-oxabicyclo[2.2.1]heptenyl. Non-limiting examples of suitable monocyclic thiaheterocyclenyl rings include dihydrothiophenyl, dihydrothiopyranyl, and the like.


“Heterocyclyl” (or heterocycloalkyl) means a non-aromatic saturated monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heterocyclyls contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The heterocyclyl can be optionally substituted by one or more “ring system substituents” which may be the same or different, and are as defined herein. The nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting examples of suitable monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like. “Heterocyclyl” includes “heteroarylcycloalkyl” and “cycloalkylheteroaryl” as defined below.


“Arylcycloalkenyl” means a group derived from a fused aryl and cycloalkenyl as defined herein by removal of a hydrogen atom from the cycloalkenyl portion. Preferred arylcycloalkenyls are those wherein aryl is phenyl and the cycloalkenyl consists of about 5 to about 6 ring atoms. The arylcycloalkenyl can be optionally substituted by one or more ring system substituents, wherein “ring system substituent” is as defined above. Non-limiting examples of suitable arylcycloalkenyls include 1,2-dihydronaphthalene, indene, and the like. The bond to the parent moiety is through a non-aromatic carbon atom.


“Cycloalkenylaryl” means a group derived from a fused arylcycloalkenyl as defined herein by removal of hydrogen atom from the aryl portion. Non-limiting examples of suitable cycloalkenylaryls are as described herein for a arylcycloalkenyl, except that the bond to the parent moiety is through an aromatic carbon atom.


“Arylcycloalkyl” means a group derived from a fused aryl and cycloalkyl as defined herein by removal of a hydrogen atom from the cycloalkyl portion. Preferred arylcycloalkyls are those wherein aryl is phenyl and the cycloalkyl consists of about 5 to about 6 ring atoms. The arylcycloalkyl can be optionally substituted by one or more ring system substituents, wherein “ring system substituent” is as defined above. Non-limiting examples of suitable arylcycloalkyls include 1,2,3,4-tetrahydronaphthyl, and the like. The bond to the parent moiety is through a non-aromatic carbon atom.


“Cycloalkylaryl” means a group derived from a fused arylcycloalkyl as defined herein by removal of a hydrogen atom from the aryl portion. Non-limiting examples of suitable cycloalkylaryls are as described herein for an arylcycloalkyl group, except that the bond to the parent moiety is through an aromatic carbon atom.


“Heteroarylcycloalkyl” means a group derived from a fused heteroaryl and cycloalkyl as defined herein by removal of a hydrogen atom from the cycloalkyl portion. Preferred heteroarylcycloalkyls are those wherein the heteroaryl thereof consists of about 5 to about 6 ring atoms and the cycloalkyl consists of about 5 to about 6 ring atoms. The prefix aza, oxa or thia before heteroaryl means that at least a nitrogen, oxygen or sulfur atom is present respectively as a ring atom. The heteroarylcycloalkyl can be optionally substituted by one or more ring system substituents, wherein “ring system substituent” is as defined above. The nitrogen atom of the heteroaryl portion of the heteroarylcycloalkyl can be optionally oxidized to the corresponding N-oxide. Non-limiting examples of suitable heteroarylcycloalkyls include 5,6,7,8-tetrahydroquinolinyl, 5,6,7,8-tetrahydroisoquinolyl, 5,6,7,8-tetrahydroquinoxalinyl, 5,6,7,8-tetrahydroquinazolyl, 4,5,6,7-tetrahydro-1H-benzimidazolyl, 4,5,6,7-tetrahydrobenzoxazolyl, 1H-4-oxa-1,5-diazanaphthalen-2-onyl, 1,3-dihydroimidizole-[4,5]-pyridin-2-onyl, and the like. The bond to the parent moiety is through a non-aromatic carbon atom.


“Cycloalkylheteroaryl” means a group derived from a fused beteroarylcycloalkyl as defined herein by removal of a hydrogen atom from the heteroaryl portion. Non-limiting examples of suitable cycloalkylheteroaryls are as described herein for heteroarylcycloalkyl, except that the bond to the parent moiety is through an aromatic carbon atom.


“Aralkenyl” means an aryl-alkenyl-group in which the aryl and alkenyl are as previously described. Preferred aralkenyls contain a lower alkenyl group. Non-limiting examples of suitable aralkenyl groups include 2-phenethenyl and 2-naphthylethenyl. The bond to the parent moiety is through the alkenyl.


“Aralkynyl” means an aryl-alkynyl-group in which the aryl and alkynyl are as previously described. Preferred aralkynyls contain a lower alkynyl group. The bond to the parent moiety is through the alkynyl. Non-limiting examples of suitable aralkynyl groups include phenacetylenyl and naphthylacetylenyl.


“Heteroaralkyl” means a heteroaryl-alkyl-group in which the heteroaryl and alkyl are as previously described. Preferred heteroaralkyls contain a lower alkyl group. Non-limiting examples of suitable aralkyl groups include pyridylmethyl, 2-(furan-3-yl)ethyl and quinolin-3-ylmethyl. The bond to the parent moiety is through the alkyl.


“Heteroaralkenyl” means an heteroaryl-alkenyl-group in which the heteroaryl and alkenyl are as previously described. Preferred heteroaralkenyls contain a lower alkenyl group. Non-limiting examples of suitable heteroaralkenyl groups include 2-(pyrid-3-yl)ethenyl and 2-(quinolin-3-yl)ethenyl. The bond to the parent moiety is through the alkenyl.


“Heteroaralkynyl” means an heteroaryl-alkynyl-group in which the heteroaryl and alkynyl are as previously described. Preferred heteroaralkynyls contain a lower alkynyl group. Non-limiting examples of suitable heteroaralkynyl groups include pyrid-3-ylacetylenyl and quinolin-3-ylacetylenyl. The bond to the parent moiety is through the alkynyl.


“Hydroxyalkyl” means a HO-alkyl-group in which alkyl is as previously defined. Preferred hydroxyalkyls contain lower alkyl. Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl.


“Acyl” means an H—C(O)—, alkyl-C(O)—, alkenyl-C(O)—, Alkynyl-C(O)—, cycloalkyl-C(O)—, cycloalkenyl-C(O)—, or cycloalkynyl-C(O)— group in which the various groups are as previously described. The bond to the parent moiety is through the carbonyl. Preferred acyls contain a lower alkyl. Non-limiting examples of suitable acyl groups include formyl, acetyl, propanoyl, 2-methylpropanoyl, butanoyl and cyclohexanoyl.


“Aroyl” means an aryl-C(O)— group in which the aryl group is as previously described. The bond to the parent moiety is through the carbonyl. Non-limiting examples of suitable groups include benzoyl and 1- and 2-naphthoyl.


“Heteroaroyl” means a heteroaryl-C(O)— group in which the heteroaryl group is as previously described. Non-limiting examples of suitable groups include nicotinoyl and pyrrol-2-ylcarbonyl. The bond to the parent moiety is through the carbonyl.


“Alkoxy” means an alkyl-O— group in which the alkyl group is as previously described. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and heptoxy. The bond to the parent moiety is through the ether oxygen.


“Aryloxy” means an aryl-O— group in which the aryl group is as previously described. Non-limiting examples of suitable aryloxy groups include phenoxy and naphthoxy. The bond to the parent moiety is through the ether oxygen.


“Aralkyloxy” means an aralkyl-O— group in which the aralkyl groups is as previously described. Non-limiting examples of suitable aralkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy. The bond to the parent moiety is through the ether oxygen.


“Alkylamino” means an —NH2 or —NH3+ group in which one or more of the hydrogen atoms on the nitrogen is replaced by an alkyl group as defined above.


“Arylamino” means an —NH2 or —NH3+ group in which one or more of the hydrogen atoms on the nitrogen is replaced by an aryl group as defined above.


“Alkylthio” means an alkyl-S— group in which the alkyl group is as previously described. Non-limiting examples of suitable alkylthio groups include methylthio, ethylthio, i-propylthio and heptylthio. The bond to the parent moiety is through the sulfur.


“Arylthio” means an aryl-S— group in which the aryl group is as previously described. Non-limiting examples of suitable arylthio groups include phenylthio and naphthylthio. The bond to the parent moiety is through the sulfur.


“Aralkylthio” means an aralkyl-S— group in which the aralkyl group is as previously described. Non-limiting example of a suitable aralkylthio group is benzylthio. The bond to the parent moiety is through the sulfur.


“Alkoxycarbonyl” means an alkyl-O—CO— group. Non-limiting examples of suitable alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl. The bond to the parent moiety is through the carbonyl.


“Aryloxycarbonyl” means an aryl-O—C(O)— group. Non-limiting examples of suitable aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl. The bond to the parent moiety is through the carbonyl.


“Aralkoxycarbonyl” means an aralkyl-O—C(O)— group. Non-limiting example of a suitable aralkoxycarbonyl group is benzyloxycarbonyl. The bond to the parent moiety is through the carbonyl.


“Alkylsulfonyl” means an alkyl-S(O2)— group. Preferred groups are those in which the alkyl group is lower alkyl. The bond to the parent moiety is through the sulfonyl.


“Alkylsulfinyl” means an alkyl-S(O)— group. Preferred groups are those in which the alkyl group is lower alkyl. The bond to the parent moiety is through the sulfinyl.


“Arylsulfonyl” means an aryl-S(O2)— group. The bond to the parent moiety is through the sulfonyl.


“Arylsulfinyl” means an aryl-S(O)— group. The bond to the parent moiety is through the sulfinyl.


The term “optionally substituted” means optional substitution with the specified groups, radicals or moieties, in available position or positions.


With reference to the number of moieties (e.g., substituents, groups or rings) in a compound, unless otherwise defined, the phrases “one or more” and “at least one” mean that there can be as many moieties as chemically permitted, and the determination of the maximum number of such moieties is well within the knowledge of those skilled in the art.


As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.


Lines drawn into the ring systems, such as, for example:




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indicate that the indicated line (bond) may be attached to any of the substitutable ring carbon atoms.


As well known in the art, a bond drawn from a particular atom wherein no moiety is depicted at the terminal end of the bond indicates a methyl group bound through that bond to the atom, unless stated otherwise. For example:




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It should also be noted that any carbon or heteroatom with unsatisfied valences in the text, schemes, examples, structural formulae, and any Tables herein is assumed to have the hydrogen atom or atoms to satisfy the valences.


Prodrugs and solvates of the compounds of the invention are also contemplated herein. The term “prodrug”, as employed herein, denotes a compound that is a drug precursor which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of formula I or a salt and/or solvate thereof. A discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) Volume 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press, both of which are incorporated herein by reference thereto.


“Solvate” means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. “Solvate” encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. “Hydrate” is a solvate wherein the solvent molecule is H2O.


“Effective amount” or “therapeutically effective amount” is meant to describe an amount of a compound or a composition of the present invention effective in antagonizing mGluRs, in particular mGluR1, and thus producing the desired therapeutic, ameliorative, inhibitory or preventative effect in a suitable patient.


The compounds of formula I form salts which are also within the scope of this invention. Reference to a compound of formula I herein is understood to include reference to salts thereof, unless otherwise indicated. The term “salt(s)”, as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases. In addition, when a compound of formula I contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions (“inner salts”) may be formed and are included within the term “salt(s)” as used herein. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful. Salts of the compounds of the formula I may be formed, for example, by reacting a compound of formula I with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization. Acids (and bases) which are generally considered suitable for the formation of pharmaceutically useful salts from basic (or acidic) pharmaceutical compounds are discussed, for example, by S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; in The Orange Book (Food & Drug Administration, Washington, D.C. on their website); and P. Heinrich Stahl, Camille G. Wermuth (Eds.), Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (2002) Int'l. Union of Pure and Applied Chemistry, pp. 330-331. These disclosures are incorporated herein by reference thereto.


Exemplary acid addition salts include acetates, adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates, methanesulfonates, methyl sulfates, 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pamoates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates, sulfonates (such as those mentioned herein), tartarates, thiocyanates, toluenesulfonates (also known as tosylates,) undecanoates, and the like.


Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, aluminum salts, zinc salts, salts with organic bases (for example, organic amines) such as benzathines, diethylamine, dicyclohexylamines, hydrabamines (formed with N,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamines, N-methyl-D-glucamides, t-butyl amines, piperazine, phenylcyclohexylamine, choline, tromethamine, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups may be quarternized with agents such as lower alkyl halides (e.g. methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g. decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others.


All such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention.


Compounds of formula I, and salts, solvates and prodrugs thereof, may exist in their tautomeric form (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present invention.


All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates and prodrugs of the compounds as well as the salts and solvates of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention. Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms “salt”, “solvate” “prodrug” and the like, is intended to equally apply to the salt, solvate and prodrug of enantiomers, stereoisomers, rotamers, tautomers, racemates or prodrugs of the present compounds.


Polymorphic forms of the compounds of formula I, and of the salts, solvates and prodrugs of the compounds of formula I, are intended to be included in the present invention.


The compounds according to the invention have pharmacological properties; in particular, the compounds of formula I can be mGluR (metabotropic glutamate receptor) antagonists, more particularly, selective mGluR1 antagonists. Accordingly, the present compounds are useful in the treatment or prevention of conditions that are treatable or preventable by inhibiting mGluR, more particularly, mGluR1 function. Such conditions include a variety of acute and chronic neurological disorders associated with excessive or inappropriate stimulation of excitatory amino acid transmission as well as conditions which lead to glutamate-deficient functions.


Examples of treatable or preventable acute neurological disorders include, but are not limited to, cerebral deficits subsequent to cardiac bypass surgery and grafting, cerebral ischemia, stroke (ischemic or hemorrhagic), spinal cord injuries (due to trauma, infarction/ischemia or inflammation), head trauma, perinatal hypoxia, cardiac arrest and hypoglycemic neuronal damage. Examples of treatable or preventable chronic neurological disorders include, but are not limited to, Alzheimer's disease, Huntington's Chorea, amyotrophic lateral sclerosis (ALS), AIDS-induced dementia, inherited ataxias, ocular damage and retinopathy, cognitive disorders, and idiopathic and drug-induced Parkinson's. Other conditions associated with glutamate dysfunctions treatable or preventable by compounds of formula I include, but are not limited to, muscle spasms, convulsions (e.g., epilepsy), spasticity, migraine (including menstrual migraine), psychoses (e.g., schizophrenia and bipolar disorder), urinary incontinence, anxiety and related disorders (e.g. panic attack), emesis, brain edema, tardive dyskinesia, depression, drug tolerance and withdrawal (e.g., opiates, benzodiazepines, nicotine, cocaine, or ethanol), and smoking cessation.


The compounds of formula I are also useful for treating or preventing pain which may be neuropathic (nerve damage) or inflammatory (tissue damage). These compounds are particularly useful for treating or preventing neuropathic pain. Neuropathic pain used herein refers to an abnormal state of pain sensation, in which a reduction of pain threshold and the like are continued, due to functional abnormalities accompanying damage or degeneration of a nerve, plexus or perineural soft tissue, which is caused by wound, compression, infection, cancer, ischemia and the like, or metabolic disorders such as diabetes mellitus and the like. Neuropathic pain includes pain caused by either central or peripheral nerve damage. It also includes the pain caused by either mononeuropathy or polyneuropathy. In some embodiments, the neuropathic pain is induced by diabetes. In other embodiments, the neuropathic pain is induced by compression of nerves.


Examples of neuropathic pain treatable or preventable by the present compounds include, but are not limited to, allodynia (a pain sensation induced by mechanical or thermal stimulus that does not normally provoke pain), hyperalgesia (an excessive response to a stimulus that is normally painful), hyperesthesia (an excessive response to a contact stimulus), diabetic polyneuropathy, entrapment neuropathy, cancer pain, central pain, labor pain, myocardial infarction pain, post-stroke pain, pancreatic pain, colic pain, muscle pain, post-operative pain, pain associated with intensive care, pain associated with a periodontal disease (including gingivitis and periodontitis), menstrual pain, migraine pain, persistent headaches (e.g., cluster headache or chronic tension headache), persistent pain states (e.g., fibromyalgia or myofascial pain), trigeminal neuralgia, postherpetic neuralgia, arthritic pain (e.g., pain due to osteoarthritis or rheumatoid arthritis), bursitis, pain associated with AIDS, visceral pain (e.g., interstitial cystitis and irritable bowel syndrome (IBS)), pain due to spinal trauma and/or degeneration, burn pain, referred pain, enhanced memory of pain and neuronal mechanisms involved in coping with pain. The compounds of the present invention are particularly useful for treating or preventing allodynia and hyperalgesia.


Compounds of formula I are also useful for treating or preventing pain associated with inflammation or an inflammatory disease in a mammal. The pain associated with inflammation or an inflammatory disease treatable or preventable by the present compounds may arise where there is an inflammation of the body tissue which may be a local inflammatory response and/or a systemic inflammation. For example, the present compounds can be used to treat or prevent pain associated with inflammatory diseases including, but not limited to, organ transplant rejection; reoxygenation injury resulting from organ transplantation including transplantation of the heart, lung, liver, or kidney; chronic inflammatory diseases of the joints, including arthritis, rheumatoid arthritis, osteoarthritis and bone diseases associated with increased bone resorption; inflammatory lung diseases, such as asthma, adult respiratory distress syndrome, and chronic obstructive airway disease; inflammatory diseases of the eye, including corneal dystrophy, trachoma, onchocerciasis, uveitis, sympathetic ophthalmitis and endophthalmitis; chronic inflammatory diseases of the gum, including gingivitis and periodontitis; tuberculosis; leprosy; inflammatory diseases of the kidney, including uremic complications, glomerulonephritis and nephrosis; inflammatory diseases of the skin, including sclerodermatitis, psoriasis and eczema; inflammatory diseases of the central nervous system, including chronic demyelinating diseases of the nervous system, multiple sclerosis, AIDS-related neurodegeneration and Alzheimer's disease, infectious meningitis, encephalomyelitis, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and viral or autoimmune encephalitis; autoimmune diseases, including Type I and Type II diabetes mellitus; diabetic complications, including diabetic cataract, glaucoma, retinopathy, nephropathy (such as microaluminuria and progressive diabetic nephropathy), polyneuropathy, mononeuropathies, autonomic neuropathy, gangrene of the feet, atherosclerotic coronary arterial disease, peripheral arterial disease, nonketotic hyperglycemic-hyperosmolar coma, foot ulcers, joint problems, and a skin or mucous membrane complication (such as an infection, a shin spot, a candidal infection and necrobiosis lipoidica diabeticorum); immune-complex vasculitis, and systemic lupus erythematosus (SLE); inflammatory diseases of the heart, such as cardiomyopathy, ischemic heart disease hypercholesterolemia, and atherosclerosis; as well as various other diseases that can have significant inflammatory components, including preeclampsia, chronic liver failure, brain and spinal cord trauma, and cancer.


The present compounds can also be used for treating or preventing pain associated with an inflammatory disease that involves a systemic inflammation of the body, such as gram-positive or gram negative shock, hemorrhagic or anaphylactic shock, shock induced by cancer chemotherapy in response to pro-inflammatory cytokines (e.g., shock associated with pro-inflammatory cytokines), and shock induced by a chemotherapeutic agent that is administered as a treatment for cancer.


One aspect of this invention relates to a method of selectively antagonizing mGluR1 in a cell in need thereof, comprising contacting said cell with at least one compound of formula I or a pharmaceutically acceptable salt or solvate thereof.


The term “antagonist of metabatropic glutamate receptor (e.g., mGluR1)” refers to a compound that binds to the metabatropic glutamate receptor (e.g., mGluR1) but fails to elicit a response thereby blocking agonist action, i.e, inhibiting a function of mGluRs (e.g., mGluR1). Accordingly, mGluR (e.g., mGluR1) mediated processes and responses can be inhibited with an antagonist of mGluR (e.g., mGluR1). Preferably, an antagonist selectively antagonizes group I mGluRs. More preferably, an antagonist of the present invention is a selective antagonist of mGluR1. A selective antagonist of mGluR1 is one that antagonizes mGluR1, but antagonizes other mGluRs only weakly or substantially not at all, or at least antagonizes other mGluRs with an IC50 at least 10 or even 100 or 1000 times greater than the IC50 at which it antagonizes mGluR1. Most preferred antagonists are those which can selectively antagonize mGluR1 at low concentrations, for example, those that cause a level of antagonism of 50% or greater at a concentration of 100 nM or less.


Another aspect of this invention relates to a method of treating or preventing a disease or condition associated with mGluR1 in a mammal (e.g., human) in need thereof comprising administering a therapeutically effective amount of at least one compound of formula I or a pharmaceutically acceptable salt or solvate thereof to said mammal.


A preferred dosage is about 0.001 to 500 mg/kg of body weight/day of the compound of formula III. An especially preferred dosage is about 0.01 to 25 mg/kg of body weight/day of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof.


The compounds of this invention may also be useful in combination (administered together or sequentially) with one or more additional therapeutic agents for the treatment of the above disorders or conditions. Such additional therapeutic agents may be a pain management agent, including non-opioid analgesics such as acetylsalicylic acid, choline magnesium trisalicylate, acetaminophen, ibuprofen, fenoprofen, diflusinal, and naproxen; and opioid analgesics, such as morphine, hydromorphone, methadone, levorphanol, fentanyl, oxycodone, and oxymorphone. Other such therapeutic agents may be a non-steroid anti-inflammatory agent, an antimigraine agent, a Cox-II inhibitor, an antiemetic, a β-adrenergic blocker, an anticonvulsant, an antidepressant, a Ca2+-channel blocker, an anticancer agent, an agent for treating or preventing UI, an agent for treating Alzheimer's disease, an agent for treating or preventing IBD, an agent for treating or preventing IBS, an agent for treating Parkinson's disease and parkinsonism, an agent for treating anxiety, an agent for treating epilepsy, an agent for treating a stroke, an agent for treating psychosis, an agent for treating Huntington's chorea, an agent for treating ALS, an agent for treating vomiting, an agent for treating dyskinesia, or an agent for treating depression, and mixtures thereof.


If formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range described herein and the other pharmaceutically active agent or treatment within its dosage range. Compounds of formula I may also be administered sequentially with known therapeutic agents when a combination formulation is inappropriate. The invention is not limited in the sequence of administration; compounds of formula I may be administered either prior to or after administration of the known therapeutic agent. Such techniques are within the skills of persons skilled in the art as well as attending physicians.


Accordingly, in one aspect, this invention includes combinations comprising an amount of at least one compound of formula I or a pharmaceutically acceptable salt or solvate thereof, and an amount of one or more additional therapeutic agents listed above wherein the amounts of the compounds/treatments result in desired therapeutic effect.


The pharmacological properties of the compounds of this invention may be confirmed by a number of pharmacological assays. The selective antagonistic activity of the present compounds towards the metabotropic glutamate receptor 1 (mGluR1) may be assayed by methods known in the art, for example, by using the methods as described in the examples.


The actions of the compounds of formula I for the treatment or prevention of pain may be assessed by various animal models, for example, by the following tests:


Formalin test: Mice are gently restrained and 30 μl of formalin solution (1.5% in saline) is injected subcutaneously into the plantar surface of the right hind paw of the mouse, using a microsyringe with a 27 gauge needle. After the formalin injection, the mouse is immediately put back into the Plexiglas observation chamber (30×20×20 cm) and the nociceptive response of the animal to formalin injection is observed for a period of 60 min. The duration of licking and flinching of the injected paw is recorded and quantified every 5 min for the total observation period. The recording of the early phase (first phase) starts immediately and lasts for 5 min. The late phase (second phase) starts about 10-15 min after formalin injection.


L5 and L6 spinal nerve ligation of the sciatic nerve (neuropathic pain model): The peripheral neuropathy is produced by ligating the L5 and L6 spinal nerves of the right sciatic nerve, according to the method previously described by Kim and Chung (1992) except for small changes. Briefly, rats are anaesthetized with chloral hydrate (400 mg/kg, i.p.), placed in a prone position and the right paraspinal muscles separated from the spinous processes at the L4-S2 levels. The L5 transverse process is carefully removed with a small rongeur to identify the L4-L5 spinal nerves. The right L5 and L6 spinal nerves are isolated and tightly ligated with 7/0 silk thread. A complete hemostasis is confirmed and the wound sutured.


Chronic constriction injury (CCI) of the sciatic nerve (neuropathic pain model): Surgery is performed according to the method described by Bennett & Xie (1987). Rats are anaesthetized with chloral hydrate (400 mg/kg, i.p.) and the common sciatic nerve is exposed at the level of the mid-thigh. Proximally, at about 1 cm from the nerve trifurcation, four loose ligatures (4/0 silk) spaced 1 mm are tied around the nerve. The ligature delays, but does not arrest, circulation through the superficial epineural vasculature. The same procedure is performed except for ligature placement (sham surgery) in a second group of animals.


Carrageenan (inflammatory pain model): The right hind paw of each animal is injected at subplantar level with 0.1 mL of carrageenan (25 GA needle). Pre-tests are determined prior to carrageenan or drug administration. In POST-TREATMENT protocol, rats are tested 3 hours after carrageenan treatment to establish the presence of hyperalgesia and then at different times after drug administration. In PRE-TREATMENT protocol, one hour after drug administration, rats are treated with carrageenan and they are tested starting from 3 hours later.


Freund's adjuvant-induced arthritic model (inflammatory pain model): Animals receive a single subplantar injection of 100 mL of a 500 mg dose of heat-killed and dried Mycobacterium tuberculosis (H37 Ra, Difco Laboratories, Detroit, Mich., USA) in a mixture of paraffin oil and an emulsifying agent, mannide monooleate (complete Freund's adjuvant). Control animals are injected with 0.1 mL mineral oil (incomplete Freund's adjuvant).


Measurement of tactile allodynia (behavioural test): Behavioral tests are conducted by observer blinded to the treatment during the light cycle to avoid circadian rhythm fluctuation. Tactile sensitivity is evaluated using a series of calibrated Semmes-Weinstein (Stoelting, Ill.) von Frey filaments, bending force ranging from 0.25 to 15 g. Rats are placed in a transparent plastic box endowed with a metal mesh floor and are habituated to this environment before experiment initiation. The von Frey filaments are applied perpendicularly to the midplantar surface of the ipsilateral hind paws and the mechanical allodynia is determined by sequentially increasing and decreasing the stimulus strength (“up-down” paradigm of the filament presentation). Data are analysed with a Dixon non-parametric test (Chaplan et al. 1994). Paw licking or vigorously shaking after stimulation is considered pain-like responses.


Thermal hyperalgesia (behavioural test): Thermal hyperalgesia to radiant heat is assessed by measuring the withdrawal latency as an index of thermal nociception (Hargreaves et al., 1998). The plantar test (Basile, Comerio, Italy) is chosen because of its sensitivity to hyperalgesia. Briefly, the test consists of a movable infrared source placed below a glass plane onto which the rat is placed. Three individual perspex boxes allow three rats to be tested simultaneously. The infrared source is placed directly below the plantar surface of the hind paw and the paw withdrawal latency (PWL) is defined as the time taken by the rat to remove its hind paw from the heat source. PWLs are taken three times for both hind paws of each rat and the mean value for each paw represented the thermal pain threshold of rat. The radiant heat source is adjusted to result in baseline latencies of 10-12 sec. The instrument cut-off is fixed at 21 sec to prevent tissue damage.


Weight bearing (behavioural test): An incapacitance tester is employed for determination of hind paw weight distribution. Rats are placed in an angled plexiglass chamber positioned so that each hind paw rested on a separate force plate. The weight bearing test represents a direct measure of the pathological condition of the arthritic rats without applying any stress or stimulus, thus this test measures a spontaneous pain behaviour of the animals.


While it is possible for the active ingredient to be administered alone, it is preferable to present it as a pharmaceutical composition. The compositions of the present invention comprise at least one active ingredient, as defined above, together with one or more acceptable carriers, adjuvants or vehicles thereof and optionally other therapeutic agents. Each carrier, adjuvant or vehicle must be acceptable in the sense of being compatible with the other ingredients of the composition and not injurious to the mammal in need of treatment.


Accordingly, this invention also relates to pharmaceutical compositions comprising at least one compound of formula I, or a pharmaceutically acceptable salt, solvate or ester thereof and at least one pharmaceutically acceptable carrier, adjuvant or vehicle.


For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may be comprised of from about 5 to about 95 percent active ingredient. Suitable solid carriers are known in the art, e.g., magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co., Easton, Pa.


Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.


Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g. nitrogen.


Also included are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.


The compounds of the invention may also be deliverable transdermally. The transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.


The compounds of this invention may also be delivered subcutaneously.


Preferably the compound is administered orally.


Preferably, the pharmaceutical preparation is in a unit dosage form. In such form, the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.


The quantity of active compound in a unit dose of preparation may be varied or adjusted from about 1 mg to about 100 mg, preferably from about 1 mg to about 50 mg, more preferably from about 1 mg to about 25 mg, according to the particular application.


The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required.


The amount and frequency of administration of the compounds of the invention and/or the pharmaceutically acceptable salts, solvates or esters thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated. A typical recommended daily dosage regimen for oral administration can range from about 1 mg/day to about 500 mg/day, preferably 1 mg/day to 200 mg/day, in two to four divided doses.


Another aspect of this invention is a kit comprising a therapeutically effective amount of at least one compound of formula I or a pharmaceutically acceptable salt, solvate, or ester thereof and at least one pharmaceutically acceptable carrier, adjuvant or vehicle.


Yet another aspect of this invention is a kit comprising an amount of at least one compound of formula I or a pharmaceutically acceptable salt, solvate or ester thereof and an amount of at least one additional therapeutic agent listed above, wherein the amounts of the two or more ingredients result in desired therapeutic effect.


The invention disclosed herein is exemplified by the following preparations and examples which should not be construed to limit the scope of the disclosure. Alternative mechanistic pathways and analogous structures will be apparent to those skilled in the art.


EXAMPLES

In general, the compounds of this invention may be prepared from known or readily prepared starting materials, following methods known to one skilled in the art and those illustrated below. All stereoisomers and tautomeric forms of the compounds are contemplated.




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Experimental Procedures


Method A: (Ref: H. Zipse and L.-H. Wang, Liebigs Ann. 1996, 1501-1509.)


A mixture of cyanoacetamide (8.4 g, 0.1 mol) and dimethylacetamide dimethylacetal (14.6 mL, 0.1 mol) was heated under reflux in dry ethanol (150 mL) for 2.5 h under a nitrogen atmosphere. The resulting white crystals of 2-cyano-3-(dimethylamino)-2-butenamide (10.0 g, 0.068 mol) were filtered, washed with ethanol and dried under vacuum. To this, was added N,N-dimethyl-formamide dimethylacetal (8.1 g, 0.068 mol) and the mixture heated under reflux in dry toluene (100 mL) for 1 h before evaporating the solvent under reduced pressure. The residue was heated neat at 150° C. for 30 min, cooled, washed twice with acetone and dried under vacuum to give compound 2. 1H NMR (DMSO-d6) δ7.22 (d, 1H), 5.86 (d,1H), 3.13 (s, 6H); Mass Spectrum (M+1): m/z calcd. for C8H10N3O+=164.1, found m/z=164.2.


Alternatively, the intermediate 2-cyano-3-(dimethylamino)-2-butenamide (2.5 g, 0.0163 mol) (intermediate from above) and dimethylacetamide dimethyl acetal (2.2 ml, 0.0163 mol) was heated under reflux in dry toluene (25 ml) for 2.5 h under a nitrogen atmosphere before evaporating the solvent under reduced pressure. The residue was then heated neat at 150° C. for 30 minutes, cooled and washed twice with acetone and dried under vacuum to give compound 119. 1H NMR (DMSO-d6) δ 11.12 (br. s, 1H), 5.74 (s, 1H), 3.10 (s,6H), 2.14 (s, 3H).


Method B: (Ref.: M. Yu. Yakovlev, O. B. Romanova, S. I. Grizik, A. V. Kadushkin, and V. G. Granik, Khimiko-Farmatsevticheskii Zhurmal, 1997, 31(11), 44-47.)


To compound 2 (9.34 g, 0.057 mol) was added phosphorous oxychloride (95 mL, 1.02 mol) and to the mixture was added triethylamine (4 mL, 0.029 mol) dropwise. The resultant mixture was heated at reflux for a period of 3 h, cooled to room temperature and quenched with ice-water. The mixture was then basified using 40% sodium hydroxide solution and the resulting precipitate filtered, washed with water until neutral and dried in a vacuum oven to give chloropyridine compound 3. 1H NMR (CDCl3): δ


7.95 (d, 1H), 6.48 (d, 1H), 3.20 (s, 6H).


The following compounds 120 and 128 could also be prepared analogously from 119, and 127, respectively.




















m/z Found


Cpd
Structure
Formula
MW
(M + 1)+







120


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C9H10ClN3
195.6
196.0





128


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C8H8ClN3
181.6
182.1










Method C: (Ref.: M. Yu. Yakovlev, O. B. Romanova, S. I. Grizik, A. V. Kadushkin, and V. G. Granik, Khimiko-Farmatsevticheskii Zhurmal, 1997, 31(11), 44-47.)


A solution of compound 3 (6.02 g, 0.033 mol), methyl thioglycolate (7.05 g, 0.066 mol) and potassium carbonate (6.88 g, 0.050 mol) in DMF (50 mL) was stirred for a period of 5 h at room temperature under a nitrogen atmosphere. Water (200 mL) was added, and the resulting precipitate filtered and dried in a vacuum oven to give ester 4. 1H NMR (CDCl3): δ7.97 (d, 1H), 6.28 (d, 1H), 3.93 (s, 2H), 3.70 (s, 3H), 3.18 (s, 6H).


The following compound were prepared analogously:



















m/z calcd
m/z Found


Cpd
Structure
Formula
(M + 1)+
(M + 1)+



















34


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C11H14N3O2S+
252.1
252.1












121


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1H NMR (CDCl3) δ6.13 (s, 1H), 3.89 (s, 2H), 3.69 (s, 3H), 3.14(s, 6H), 2.29 (s, 3H).











Method D:


A solution of compound 4 (8.33 g, 0.033 mol) and sodium methoxide (3.77 g, 0.070 mol) in methanol was heated at reflux for 3 h under a nitrogen atmosphere. The reaction was cooled to room temperature, water was added and the product isolated by extraction with dichloromethane (150 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give the desired product 5. 1H NMR (CDCl3): δ8.41 (d,1H), 6.81 (d, 1H), 6.70 (br.s, 2H), 3.82 (s, 3H), 2.81 (s, 6H). Mass Spectrum (M+1): m/z calcd. for C11H14N3O2S+=252.1, found m/z=252.1.


The following compounds were prepared analogously:



















m/z calcd
m/z Found


Cpd
Structure
Formula
(M + 1)+
(M + 1)+



















35


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C11H14N3O2S+
252.1
252.1












122


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1H NMR (CDCl3) δ6.67 (br. s, 3H), 3.82 (s, 3H), 2.79 (s, 6H),2.55 (s, 3H).











Method E: (Ref.: N. P. Solov'eva, A. V. Kadushkin, and V. G. Granik, Khimiko-Farmatsevticheskii Zhurmal, 1993, 27(3), 40-43.)


To bicyclic ester 5 (7.24 g, 0.029 mol) was added N,N-dimethylformamide dimethylacetal (7.7 mL, 0.058 mol) and mixture heated in toluene under reflux for a period of 5-24 h under a nitrogen atmosphere. The solvent was evaporated under reduced pressure to give amidine product 6 by proton NMR and mass spectrum. 1H NMR (CDCl3): δ8.24 (d, 1H), 7.35 (s, 1H), 6.54 (d, 1H), 3.76 (s, 3H), 3.11 (s, 3H), 3.01 (s, 3H), 2.92 (s, 6H).


The following compounds were prepared analogously:



















m/z calcd
m/z Found


Cpd
Structure
Formula
(M + 1)+
(M + 1)+







 36


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C14H19N4O2S+
307.1
307.1





123


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C15H21N4O2S+
321.1
321.1





133A


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C16H24N5O2+
318.2
318.2





133B


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C22H27N5O3
409.5
410.2










Method F: (Ref: N. P. Solov'eva, A. V. Kadushkin, and V. G. Granik, Khimiko-Farmatsevticheskii Zhurmal, 1993, 27(3), 40-43.)


Amidine 6 (0.22 g, 0.7 mmol) and 3,4-(methylenedioxy)aniline (0.20 g, 1.4 mmol) was heated in 10% acetic acid in toluene or 100% acetic acid at 80-100° C. for a period of 30 minutes to 24h. The reaction was cooled to room temperature, ice-water was added. The mixture was made basic with saturated sodium bicarbonate or concentrated ammonium hydroxide solutions, and the resultant solid filtered. The solid was dissolved in dichloromethane, dried with sodium sulfate, filtered, and concentrate under reduced pressure. Trituration of the residue with diethyl ether, ethyl acetate, or hexane/ethyl acetate affords the desired compound 7A. 1H NMR (CDCl3): δ


8.40 (d, 1H), 8.22 (s, 1H), 6.91 (d, 2H), 6.82 (dd,1 H), 6.76 (d,1 H), 6.04 (s, 2H), 3.11 (s, 6H). Mass spectrum (M+1)+: m/z calcd. for C18H15N4O3S+=367.1, found m/z=367.2.


Alternatively, the basic aqueous mixture was extracted with dichloromethane, dried with sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via preparative TLC or column chromatography on silica gel with dichloromethane/ethyl acetate to afford the desired compound.


The following compounds were prepared analogously.




















m/z Found


Cpd
Structure
Formula
MW
(M + 1)+







7A


embedded image


C18H14N4O3S
366.4
367.2





7B


embedded image


C17H13ClN4OS
356.8
357.1





7C


embedded image


C18H16N4OS
336.4
337.1





7D


embedded image


C17H14N4OS
322.4
323.1





7E


embedded image


C11H10N4OS
246.3





7F


embedded image


C17H13ClN4OS
356.8
357.1





7G


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C17H13FN4OS
340.4
341.1





7H


embedded image


C17H13BrN4OS
401.3
403.1





7I


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C18H15ClN4OS
370.9
371.2





7J


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C19H23ClN4OS
401.5
402.1





7K


embedded image


C18H13N5O3S
347.4
348.1





7L


embedded image


C17H13ClN4OS
356.8
357.2





7M


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C17H13IN4OS
448.3
449.1





7N


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C17H12ClIN4OS
482.7
483.1





7O


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C16H13N5OS
323.4
324.1





7P


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C15H18N4OS
302.4
303.1





7Q


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C17H20N4OS
328.4
329.1





7R


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C18H15ClN4OS
370.9
371.1





7S


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C18H14Cl2N4OS
405.3
405.1





7T


embedded image


C18H15ClN4O2S
386.9
387.2





7U


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C16H13N5OS
323.4
324.1





7V


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C19H17ClN4O3S
416.9
417.1





7W


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C16H18N4OS
314.4
315.1





7X


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C18H22N4OS
342.5
343.1





7Y


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C18H13F3N4O2S
406.4
407.1





7Z


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C18H14F2N4O2S
388.4
389.1





7AA


embedded image


C18H16N4O2S
352.4
353.1





7AB


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C14H14N4OS
286.4
287.2





7AC


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C19H16N4O3S
380.4
381.2





7AD


embedded image


C19H18N4O3S
382.4
383.2





7AE


embedded image


C19H18N4O2S
366.4
367.1





7AF


embedded image


C20H20N4O4S
412.5
413.1





7AG


embedded image


C20H20N4O2S
380.5
381.1





7AH


embedded image


C19H18N4OS
350.4
351.1





7AI


embedded image


C21H20N4OS
376.5
377.1





7AJ


embedded image


C19H19N5OS
365.5
366.1





7AK


embedded image


C17H14N4O2S
338.4
339.1





7AL


embedded image


C19H17N5O2S
379.4
380.1





7AM


embedded image


C19H15N5OS
361.4
362.1





7AN


embedded image


C18H14N6OS
362.4
363.1





7AO


embedded image


C17H13N7OS
363.4
363.1(M+)





7AP


embedded image


C18H15FN4O2S
370.4
371.1





7AQ


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C20H20N4O2S
380.5
381.1





7AR


embedded image


C19H15N5O3S
393.4
394.1





7AS


embedded image


C18H13N5OS2
379.5
380.1





7AT


embedded image


C19H15N5OS2
393.5
394.1





7AU


embedded image


C17H14N4O3S2
386.4
387.1





7AV


embedded image


C17H14N4O2S
338.4
339.2





7AW


embedded image


C18H14N6OS
362.4
363.1





7AX


embedded image


C19H18N4O3S
382.4
383.1





7AY


embedded image


C18H16N4O2S
352.4
353.2





7AZ


embedded image


C18H15N5O2S
365.4
366.2





7BA


embedded image


C20H20N4OS
364.5
365.2





7BB


embedded image


C21H22N4OS
378.5
379.2





7BC


embedded image


C19H15N5OS
361.4
362.2





7BD


embedded image


C19H13F3N6OS
430.4
431.2





7BE


embedded image


C19H15N5O2S
377.4
378.2





7BF


embedded image


C18H16N4OS
336.4
337.1





7BG


embedded image


C18H16N4O2S
352.4
353.1





7BH


embedded image


C14H12N4OS
284.3
285.1





7BI


embedded image


C20H18N4OS
362.4
363.1





7BJ


embedded image


C19H18N4OS
350.4
351.1





7BK


embedded image


C20H20N4OS
364.5
365.1





7BL


embedded image


C20H16N4OS
360.4
361.1





7BM


embedded image


C19H14N4OS2
378.5
379.2





7BN


embedded image


C17H12N6OS2
380.4
381.2





7BO


embedded image


C19H15N5O3S
393.4
394.2





7BP


embedded image


C19H15N5O2S2
409.5
410.2





7BQ


embedded image


C18H13N5OS2
379.5
380.2





7BR


embedded image


C17H12N6O2S
364.4
365.1





7BS


embedded image


C18H13N5O2S
363.4
364.2





7BT


embedded image


C19H15N5O2S
377.4
378.2





7BU


embedded image


C19H15N5O2S
377.4
378.2





7BV


embedded image


C19H16N6OS
376.4
377.2





7BW


embedded image


C17H15N5O2S
353.4
354.2





7BX


embedded image


C18H14Br2N4O2S
510.2
511.1





7BY


embedded image


C19H14N4O2S
362.4
363.1





7BZ


embedded image


C17H11N5OS2
365.4
366.1





7CA


embedded image


C17H13FN4O2S
356.4
357.2





7CB


embedded image


C17H12N4O3S
352.4
353.2





7CC


embedded image


C18H16N4OS
336.4
337.1





7CD


embedded image


C16H12N4O2S
324.4
325.2





7CE


embedded image


C19H18N4O2S
366.4
367.1





7CF


embedded image


C18H17N5OS
351.4
352.2





7CG


embedded image


C19H16N4O2S
364.4
365.1





7CH


embedded image


C20H18N4O3S
394.4
395.1





7CI


embedded image


C19H17N5O2S
379.4
380.1





7CJ


embedded image


C19H18N4O2S
366.4
367.1





7CK


embedded image


C19H18N4OS
350.4
351.1





7CL


embedded image


C19H17FN4O2S
384.4
385.1





7CM


embedded image


C18H15ClN4OS
370.9
371.1





7CN


embedded image


C20H18N4O2S
378.4
379.1





7CO


embedded image


C19H15N5OS2
393.5
394.1





7CP


embedded image


C20H20N4OS
364.5
365.1





7CQ


embedded image


C18H16N4OS2
368.5
369.1





7CR


embedded image


C18H13N5OS2
379.5
380.1





7CS


embedded image


C18H14N6O2S
378.4
379.1





7CT


embedded image


C17H13FN4O2S
356.4
357.1





7CU


embedded image


C18H16N4OS
336.4
337.1





7CV


embedded image


C19H18N4OS
350.4
351.1





7CW


embedded image


C18H16N4OS
336.4
337.1





7CX


embedded image


C17H15N5OS
337.4
338.1





7CY


embedded image


C18H15BrN4OS
415.3
417.1415.1





7CZ


embedded image


C18H22N4OS
342.5
343.2





7DA


embedded image


C19H18N4OS2
382.5
383.2





7DB


embedded image


C18H16N4OS
336.4
337.1





7DC


embedded image


C18H15FN4OS
354.4
355.2





7DD


embedded image


C17H15N5OS
337.4
338.2





7DE


embedded image


C17H15N5OS
337.4
338.1





7DF


embedded image


C17H15N5OS
337.4
338.1





7DG


embedded image


C18H15ClN4OS
370.9
371.1





7DH


embedded image


C18H15FN4OS
354.4
355.1





7DI


embedded image


C19H18N4O2S
366.4
367.1





7DJ


embedded image


C19H18N4O2S
366.4
367.1





7DK


embedded image


C18H15FN4O2S
370.4
371.1





7DL


embedded image


C17H13BrN4OS
401.3
403.1





7DM


embedded image


C19H15F3N4OS
404.4
405.2





7DN


embedded image


C18H15BrN4OS
415.3
415.1417.1





7DO


embedded image


C18H13F3N4OS
390.4
391.2





7DP


embedded image


C19H15N5OS
361.4
462.1





7DQ


embedded image


C18H15BrN4OS
415.3
417.1415.1





7DR


embedded image


C18H15BrN4OS
415.3
417.1415.1





7DS


embedded image


C18H12BrF3N4OS
469.3
471.1





7DT


embedded image


C18H15BrN4O2S
431.3
433.1





7DU


embedded image


C17H12BrFN4OS
419.3
421.1419.1





7DV


embedded image


C17H12BrFN4OS
419.3
421.1419.1





7DW


embedded image


C18H15FN4OS
354.4
355.1





7DX


embedded image


C18H15FN4OS
354.4
355.1





7DY


embedded image


C18H15IN4OS
462.3
463.1





7DZ


embedded image


C18H15FN4OS
354.4
355.2





7EA


embedded image


C18H15IN4OS
462.3
463.3





7EB


embedded image


C18H15FN4O2S
370.4
371.2





7EC


embedded image


C18H15FN4O2S
370.4
371.2





37A


embedded image


C17H20N4OS
328.1
329.1





37B


embedded image


C18H13N5OS2
379.1
380.2





37C


embedded image


C19H16N4O3S
380.1
381.2





37D


embedded image


C17H14N4OS
322.1
323.1





37E


embedded image


C17H13ClN4OS
356.1
357.2





37F


embedded image


C18H16N4O2S
352.1
353.2





37G


embedded image


C18H15FN4O2S
370.4
371.2





37H


embedded image


C17H14N4O2S
338.4
339.2





40


embedded image


C15H10N4O2S
310.1
311.0





134A


embedded image


C19H19N5O
333.4
334.1





134B


embedded image


C19H19N5O2
349.4
350.1





134C


embedded image


C19H19N5OS
365.5
366.1





134D


embedded image


C19H17F2N5O2
385.4
386.1





134E


embedded image


C19H16N6OS
376.4
377.1





134F


embedded image


C18H16ClN5O
353.8
354.1





134G


embedded image


C18H23N5O
325.4
326.1





134H


embedded image


C26H25N5O2
439.5
440.1





134I


embedded image


C25H23N5O2
425.5
426.1










Method G:




embedded image



(Refs.: (a) A. D. Dunn, R. Norrie, J. Heterocyclic Chem. 1987, 24, 85; (b) J. A. VanAllan, J. Amer. Chem. Soc. 1947, 69, 2914.)


To 5.00 g (36.1 mmol) of 2-chloro-3-pyridine carbonitrile (8) in 75 mL of DMF was added 6.04 g of thiol 9 (36.1 mmol) followed by the addition of 1.95 g of sodium methoxide (36.1 mmol). The reaction mixture was allowed to stir at room temperature for 1 hour and subsequently poured onto H2O (300 mL). The resulting suspension was filtered and the yellow solids recrystallized from absolute ethanol to yield 5.30 g of 10A as a yellow solid. 1H NMR (DMSO-d6) δ


9.44 (s, 1H), 8.66 (dd, 1H), 8.49 (dd, 1H), 7.69 (d, 1H), 7.67 (d, 1H), 7.46 (dd, 1H), 7.38 (bs, 2H), 7.30 (dd, 2H), 7.06 (t, 1H). MS m/z calcd. for C14H12N3OS+=270.1; found m/z=270.1.


The following compounds were prepared analogously.




















m/z Found


Cpd
Structure
Formula
MW
(M + 1)+







10B


embedded image


C16H16N4OS
312.4
313.1





10C


embedded image


C14H11N3O2
253.3
254.1





10D


embedded image


C20H22N4OS
366.5
367.2










Method H:


To compound 10A (5.00 g, 18.5 mmol) was added trimethylorthoformate (116 mL). The resulting mixture was heated to reflux and stirred overnight. The reaction was then cooled and the solvents removed in vacuo. The crude solid was purified via silica gel chromatography eluting with 5% acetone/dichloro-methane to give 2.52 g of tricycle 11 as a yellow solid. 1H NMR (CDCl3) δ


8.82 (dd, 1H), 8.59 (dd, 1H), 8.29 (s,1H), 7.62-7.50 (m, 4H), 7.47 (d, 2H). MS m/z calcd. for C15H10N3OS+=280.1; found m/z=280.1.


Method I:


To a stirred solution of compound 11 (1.42 g, 5.07 mmol) in dichloro-methane (34 mL) was added MCPBA (70%) (1.88 g, 7.61 mmol) at 0° C. The reaction mixture was stirred at 0° C. and allowed to warm to room temperature overnight. The mixture was washed with NaHCO3 (sat. aq.) (50 mL). The organic layer was separated, dried over MgSO4 and the solvents removed in vacuo. The crude off-white solid was purified via silica chromatography eluting with 10% methanol/dichloromethane to afford 902 mg of pure 12A as a white solid. 1H NMR (DMSO-d6) δ


8.71 (d, 1H), 8.71 (s, 1H), 8.26 (d, 1H), 7.89-7.86 (m, 1H), 7.72 (dd, 1H), 7.61-7.50 (m, 4H). MS m/z calcd for C14H12N3O2S+=296.1; found m/z=296.1.


The following compound was prepared analogously.




















m/z Found


Cpd
Structure
Formula
MW
(M + 1)+







12B


embedded image


C17H13ClN4O2S
372.8
373.1





53


embedded image


C17H13ClN4O2S
372.8
373.1





56


embedded image


C18H16N4O2S
352.4
?????










Method J:


To compound 12 (902 mg, 3.04 mmol) was added POCl3 (30 mL). The reaction mixture was stirred at reflux for 4 h. The solvents were then removed in vacuo, the residue taken up in dichloromethane (50 mL) and washed with 20% NaOH (50 mL). The organic layer was separated, dried over MgSO4 and concentrated in vacuo. The resulting residue was chromatographed on silica gel eluting with 5% acetone/dichloromethane to provide a white solid product containing a mixture of 2 and 4 chlorinated pyridines (13, 14). 1H NMR (CDCl3) (13) δ 8.51 (d, 1H), 8.29 (s, 1H), 7.62-7.51 (m, 4H), 7.48-7.43 (m, 2H). MS m/z calcd. for C15H9ClN3OS+=314.0; found m/z=314.1. 1H NMR (CDCl3) (14) & 8.67 (bs, 1H), 8.36 (s, 1H), 7.64-7.50 (m, 4H), 7.50-7.43 (m, 2H). MS m/z calcd. for C15H9ClN3OS+=314.0; found m/z=314.1.


The following analogs can be prepared similarly:




















m/z Found


Cpd
Structure
Formula
MW
(M + 1)+







54


embedded image


C17H12Cl2N4OS
391.3
391.1





57


embedded image


C18H15ClN4OS
370.9
371.2





78


embedded image


C16H16ClN3O2S
349.8
350.1










Method K:


Compound 6 (0.150 g, 0.49 mmol) and ethanolamine (0.120 g, 1.96 mmol) in 10% acetic acid in toluene or 100% acetic acid (˜0.20 M) were combined and irradiated in a 300 W power microwave oven at 160° C. for 10 minutes. The mixture was concentrated in vacuo, diluted with ice-water, basified with concentrated NH4OH (aq.). The resultant solid was collected by filtration. The solid was then dissolved in dichloromethane, dried with MgSO4, filtered and concentrated in vacuo. The residue was triturate d with Et2O. The resulting solid was collected by filtration, washed with Et2O, and dried to afford the compound 15A as a solid. 1H NMR (CDCl3): δ8.37 (d, 1H), 8.23 (s, 1H), 6.74 (d, 1H), 4.23 (t, 2H), 4.00 (q, 2H), 3.09 (s, 6H), 2.29 (t, 1H). MS m/z calcd. for C13H15N4O2S+=291.1; found m/z =291.1.


Alternatively, the basic aqueous mixture was extracted with dichloro-methane, dried with MgSO4, filtered, and concentrated in vacuo. Purification via preparative TLC or column chromatography on silica gel with dichloromethane/ethyl acetate (1:1) or methanol/dichloromethane (1:10) afforded the desired compound.


The following compounds were prepared analogously:




















m/z Found


Cpd
Structure
Formula
MW
(M + 1)+







15B


embedded image


C15H16N4OS
300.4
301.2





15C


embedded image


C18H22N4OS
342.5
343.1





15D


embedded image


C14H16N4O2S
304.4
305.0





15E


embedded image


C16H18N4O2S
330.4
331.2





15F


embedded image


C16H18N4O2S
330.4
331.1





15G


embedded image


C16H19N5OS
329.4
330.1





15H


embedded image


C16H14N4O2S
326.4
327.1





15I


embedded image


C16H14N4OS2
342.4
343.1





15J


embedded image


C15H16N4OS
300.4
301.1





15K


embedded image


C14H14N4OS
286.4
287.0





15L


embedded image


C14H16N4OS
288.4
289.0





15M


embedded image


C21H28N4OS
384.5
385.2





15N


embedded image


C17H21N5O2S
359.5
360.1





15O


embedded image


C18H23N5OS
357.5
358.1





15P


embedded image


C15H18N4OS
302.4
303.2





15Q


embedded image


C19H24N4OS
356.5
357.1





15R


embedded image


C14H11N5OS2
329.4
330.1





15S


embedded image


C15H13N5O2S
327.4
328.1





15T


embedded image


C17H20N4O2S
344.4
345.1





15U


embedded image


C17H21N5OS
343.4
344.1





15V


embedded image


C16H14N4OS2
342.4
343.1





15W


embedded image


C14H12N6OS
312.3
313.2





15X


embedded image


C13H10N6OS2
330.4
331.2





15Y


embedded image


C20H18N4OS
362.4
363.1





15Z


embedded image


C18H22N4OS
342.5
343.1





15AA


embedded image


C15H12N4OS2
328.4
329.2





15AB


embedded image


C15H12N4OS2
328.4
329.1





15AC


embedded image


C17H18N6OS
354.4
355.2





15AD


embedded image


C16H15N5O2S
341.4
342.2





15AE


embedded image


C15H13N5O2S
327.4
328.2





15AF


embedded image


C14H9F3N6OS2
398.4
399.1





15AG


embedded image


C19H14N4OS2
378.5
379.1





15AH


embedded image


C19H22N4O3S
386.5
387.2










Method L:


Compound 3 (1.0 g, 5.5 mmol), methyl glyocate (2.479, 0.028 mol) and sodium hydride (1.10 g, 0.028 mol of 60% in mineral oil) in ethylene glycol dimethyl ether (20 mL) were heated at 60° C. for 4 h under a nitrogen atmosphere. The reaction was cooled to room temperature and added ice-water, extracted by dichloromethane, dried using sodium sulfate, filtered and evaporated under reduced pressure to give the desired ester 16. 1H NMR (CDCl3): & 7.71 (d, 1H), 6.21 (d, 1H), 4.87 (s, 2H), 3.70 (s, 3H), 3.20 (s, 6H). MS m/z calcd. for C11H14N3O3+=236.1; found m/z=236.1.


Method M:


A solution of 16 (1.00 g, 0.004 mol) and sodium methoxide (2.30 g, 0.043 mol) in methanol was heated under reflux for 3 h under a nitrogen atmosphere. The reaction was cooled to room temperature, partitioned between water and dichloromethane (150 mL). The dichloromethane layer was dried using anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give the desired bicyclic ester 17. 1H NMR (CDCl3): δ


8.17 (d, 1H), 6.56 (d, 1H), 5.21 (br.s, 2H), 3.89 (s, 3H), 2.94 (s, 6H).


Method E: (Alternate)


To compound 17 (0.04 g, 0.20 mmol) was added N,N-dimethylformamide dimethyl acetal (0.20 g, 1.7 mmol) and the mixture was heated in toluene (10 mL) under reflux for a period of 11/2 h under a nitrogen atmosphere. The solvent was then evaporated under reduced pressure to give product 18 which was used without purification. MS m/z calcd. for C14H19N4O3+=291.1; found m/z=291.1.


Method F: (Alternate 1)


Compound 18 (0.049 g, 0.2 mmol) and 4-chloroaniline (0.033 g, 2.6 mmol) were heated in acetic acid (3 mL) at 80° C. for a period of 5 h. The reaction was cooled to room temperature, ice-water was added and the mixture was basified using concentrated ammonium hydroxide solution. The mixture was then extracted by dichloromethane, dried using sodium sulfate, filtered and evaporated under reduced pressure. Purification using preparative TLC on silica gel using dichloromethane/ethyl acetate (9:1) led to product 19. 1H NMR (CDCl3): δ 8.17 (d, 1H), 8.08 (s, 1H), 7.50 (d, 2H), 7.36 (d, 2H), 6.49 (d, 1H), 3.37 (s, 6H). MS m/z calcd. for C17H14ClN4O2+=341.1; found m/z=341.1.


Method N:


Refs.: (a) S. Yano, T. Ohno, K. Ogawa, Heterocycles 1993, 36, 145. (b) M. Mittelbach, G. Kastner, H. Junek, Arch. Pharm. 1985, 318, 481.


(1-Ethoxyethylidene)malononitrile (20) (40.0 g, 294 mmol) and N,N-dimethylformamide dimethyl acetal (63.0 ml, 470 mmol) were reacted according to Mittelbach and Yano's procedures to give 23.5 g of 21 as a yellow-orange solid. 1H NMR (DMSO-d6) δ 12.12 (bs, 1H), 7.77 (d, 1H), 6.33 (d, 1H), 3.95 (s, 3H).


Method B: (Alternate)


To compound 21 (23.5 g, 157 mmol) was added POCl3 (300 mL) and Et3N (15 mL). The reaction mixture was stirred at reflux for 2 h and the solvents removed in vacuo. The resulting brown solid was quenched dropwise with water and basified with 40% aq. NaOH. The aqueous suspension was extracted with three 100 mL portions of dichloromethane, dried over MgSO4 and concentrated in vacuo to provide 23.9 g of compound 22 as a brown solid. 1H NMR (CDCl3) δ 8.42 (d, 1H), 6.89 (d, 1H), 4.03 (s, 3H).


Method O:


To a solution of compound 22 (10.0 g, 59.2 mmol) in 200 mL of DMF was added methylthioglycolate (7.15 mL, 65.0 mmol) and sodium methoxide (3.60 g, 65.0 mmol). The reaction was allowed to stir at room temperature for 2 h and poured onto 500 mL of water. The solid was filtered off and recrystallized from ethanol to give 10.0 g of compound 23 as a yellow solid. 1H NMR (CDCl3) δ 8.37 (d, 1H), 6.64 (d, 1H), 4.02 (s, 2H), 3.97 (s, 3H), 3.74 (s, 3H).


Method E: (Alternate 2) (Ref.: N. P. Solov'eva, A. V. Kadushkin, and V. G. Granik, Khimiko-Farmatsevticheskii Zhurmal, 1993, 27(3), 40-43.)


A solution of compound 23 (10.0 g, 42.0 mmol), and N,N-dimethyl-formamide dimethyl acetal (25.0 mL, 187 mmol) in abs. ethanol (36 mL) was allowed to stir at reflux for 3 h. The solvent was removed in vacuo and the resulting solid was recrystallized from ethanol to give 7.50 g of compound 24 as a yellow solid. 1H NMR (CDCl3) δ 8.46 (d, 1H), 7.55 (s, 1H), 6.65 (d, 1H), 3.94 (s, 3H), 3.82 (s, 3H), 3.10 (bd, 6H).


Method F: (Alternate 2)




embedded image



(Ref.: N. P. Solov'eva, A. V. Kadushkin, and V. G. Granik, Khimiko-Farmatsevticheskii Zhurmal, 1993, 27(3), 40-43.)


To a mixture of compound 24 (3.00 g, 10.2 mmol) in glacial acetic acid (11 mL) was added cyclohexylamine (2.40 mL, 20.5 mmol). The reaction was allowed to stir at 80° C. overnight. The reaction mixture was then poured onto water (100 mL), basified with conc. NH4OH and extracted with 3-25 mL portions of dichloromethane. The organic layer was separated, dried over MgSO4 and concentrated in vacuo. The crude solid was then purified via silica gel chromatography eluting with 10% acetone/dichloromethane to give 2.07 g of compound 25A as a white solid. 1H NMR (CDCl3) δ 8.62 (d, 1H), 8.34 (s, 1H), 6.91 (d, 1H), 4.90 (tt, 1H), 4.16 (s, 3H), 2.06 (d, 2H), 1.96 (d, 2H), 1.81 (d, 1H), 1.69-1.47 (m, 5H), 1.34-1.21 (m, 1H). C16H18N3O2S+=316.1; found m/z=316.1.


The following compound were prepared analogously:




















m/z Found


Cpd
Structure
Formula
MW
(M + 1)+







25A


embedded image


C16H17N3O2S
315.4
316.1





25B


embedded image


C17H13N3O3S
399.4
340.1





25C


embedded image


C17H13N3O2S
323.4
324.1





25D


embedded image


C17H10N4O2S2
366.4
367.1










Method P:




embedded image



(Ref.: C. L. Cywin, Z. Chen, J. Emeigh, R. W. Fleck, M. Hao, E. Hickey, W. Liu, D. R. Marshall, T. Morwick, P. Nemoto, R. J. Sorcek, S. Sun, J. Wu, PCT Int. Appl. WO 03/103661 (2003)).


To compound 25A (2.07 g, 6.55 mmol) was added 33% HBr in acetic acid (26.0 mL). The reaction mixture was stirred at 100° C. in a sealed tube for 2 h, cooled to room temperature, filtered and washed with water. The resulting white solid was dried in vacuo overnight to give 1.90 g of 26A as a white solid. 1H NMR (CD3OD) δ 8.70 (s, 1H), 8.69 (d, 1H), 7.22 (d, 1H), 4.80 (tt, 1H), 2.08-1.75 (m, 7H), 1.62-1.49 (m, 2H), 1.43-1.30 (m, 1H). MS m/z calcd. for C15H16N3O2S+=302.1; found m/z=302.1.


The following compounds were prepared analogously:




















m/z Found


Cpd
Structure
Formula
MW
(M + 1)+







26A


embedded image


C15H15N3O2S
301.4
302.1





26C


embedded image


C16H11N3O2S
309.3
310.0





111


embedded image


C16H11N3O2S
309.3
310.0










Method Q:




embedded image



(Ref.: C. L. Cywin, Z. Chen, J. Emeigh, R. W. Fleck, M. Hao, E. Hickey, W. Liu, D. R. Marshall, T. Morwick, P. Nemoto, R. J. Sorcek, S. Sun, J. Wu, PCT Int. Appl. WO 03/103661 (2003)).


To a solution of compound 26A (1.90 g, 6.30 mmol) in 1,4-dioxane (17 mL) was added N,N-diisopropylethylamine (1.91 mL, 10.9 mmol) and N-phenyltrifluoromethane sulfonimide (3.79 g, 10.6 mmol). The reaction was allowed to stir at room temperature overnight and diluted with ethyl acetate (50 mL). The mixture was then washed with 50 mL of water, 50 mL of saturated aqueous NH4Cl, and 50 mL of saturated aqueous NaHCO3. The organic layer was separated, dried over MgSO4, and concentrated in vacuo. The resulting crude off-white solid was purified via silica gel chromatography eluting with 5% acetone/dichloromethane to yield 1.20 g of compound 27A as a white solid. 1H NMR (CDCl3) δ 8.84 (d, 1H), 8.35 (s, 1H), 7.35 (d, 1H), 4.89 (t, 1H), 2.09 (d, 2H), 1.98 (d, 2H), 1.82 (d, 1H), 1.71-1.68 (m, 2H), 1.62-1.47 (m, 2H), 1.34-1.21 (m, 1H). MS m/z calcd. for C16H15F3N3O4S2+=434.1; found m/z=434.1.


The following compounds were prepared analogously:




















m/z Found


Cpd
Structure
Formula
MW
(M + 1)+







27A


embedded image


C16H14F3N3O4S2
433.4
434.1





27B


embedded image


C17H10F3N3O5S2
457.4
457.9





27C


embedded image


C17H10F3N3O4S2
441.4
441.8





112A


embedded image


C18H12F3N3O4S2
455.4
456.0





112B


embedded image


C17H10F3N3O4S2
441.4
441.9










Method R:




embedded image



(Ref: C. L. Cywin, Z. Chen, J. Emeigh, R. W. Fleck, M. Hao, E. Hickey, W. Liu, D. R. Marshall, T. Morwick, P. Nemoto, R. J. Sorcek, S. Sun, J. Wu, PCT Int. Appl. WO 03/103661 (2003)).


To a solution of compound 27A (100 mg, 0.231 mmol) in 3 mL of THF was added pyrrolidine (95 δ


I, 1.15 mmol). The reaction mixture was allowed to stir at 60° C. for 1 h. Upon completion (as indicated by TLC) the reaction was diluted with 20 mL of ethyl acetate and washed with four 25 mL portions of water. The organic layer was separated, dried over MgSO4, and concentrated in vacuo. The resulting crude white solid was applied to a 2000 micron silica gel prep plate that was developed twice in 10% acetone/dichloromethane. The band was eluted with 50% acetone/dichloromethane to yield 26 mg of product 28A as a white solid. 1H NMR (CDCl3) δ


8.26 (d, 1H), 8.19 (s, 1H), 6.58 (d, 1H), 4.89 (tt, 1H), 3.73 (t, 4H), 2.13-1.99 (m, 6H), 1.95 (d, 2H), 1.81 (d, 1H), 1.73-1.46 (m, 4H), 1.33-1.19 (m, 1H). MS m/z calcd. for C19H23N4OS+ m/z=355.2; found m/z=355.1.


Analogously, To a solution of compound 27C (300 mg, 0.680 mmol) in 9 mL of THF was added ethanolamine (90 δ


I, 1.36 mmol). The reaction mixture was allowed to stir at reflux for 3 h. Upon completion (as indicated by TLC) the solvents were removed in vacuo. The resulting residue was purified via silica gel chromatography eluting with 10% methanol/dichloromethane to yield 180 mg of product 28AV as a white solid. 1H NMR (CDCl3) δ 8.11 (bs, 1H), 8.10 (s, 1H), 7.95 (bt, 1H), 7.24 (d, 2H), 7.22 (d, 2H), 6.39 (d, 1H), 3.95 (t, 2H), 3.52 (q, 2H), 2.39 (s, 3H). MS m/z calcd. for C18H16N4O2S+ m/z=353.1; found m/z=353.2.


The following additional compounds were prepared analogously:




















m/z Found


Cpd
Structure
Formula
MW
(M + 1)+







28A


embedded image


C19H22N4OS
354.5
355.1





28B


embedded image


C21H19ClN4OS
410.9
411.1





28C


embedded image


C21H26N4OS
382.5
383.1





28D


embedded image


C21H20N4OS
376.5
377.1





28E


embedded image


C22H22N4O2S
406.5
407.1





28F


embedded image


C22H19F3N4O2S
460.5
461.3





28G


embedded image


C22H16N4O2S
400.5
401.1





28H


embedded image


C21H20N4OS
376.5
377.1





28I


embedded image


C17H14N4O2S
338.4
339.1





28J


embedded image


C19H24N4OS
356.5
356.1





28K


embedded image


C21H28N4OS
384.5
385.1





28L


embedded image


C20H24N4OS
368.5
369.1





28M


embedded image


C19H22N4O2S
370.5
371.1





28N


embedded image


C19H22N4O2S
370.5
371.1





28O


embedded image


C19H22N4O2S
370.5
371.1





28P


embedded image


C17H20N4OS
328.4
329.1





28Q


embedded image


C18H22N4OS
342.5
343.1





28R


embedded image


C19H24N4OS
356.5
357.1





28S


embedded image


C18H20N4OS
340.5
341.1





28T


embedded image


C20H24N4OS
368.5
369.1





28U


embedded image


C19H23N5OS
369.5
370.1





28V


embedded image


C18H20N4OS
340.4
341.1





28W


embedded image


C19H22N4OS
354.5
355.1





28X


embedded image


C16H18N4OS
314.4
315.2





28Y


embedded image


C18H22N4OS
342.5
353.1





28Z


embedded image


C19H14N4OS
346.4
347.1





28AA


embedded image


C18H13N5OS
347.4
348.1





28AB


embedded image


C20H16N4OS
360.4
361.1





28AC


embedded image


C20H18N4OS
362.4
363.1





28AD


embedded image


C20H16N4OS
360.4
361.1





28AE


embedded image


C17H15N5OS
337.4
338.1





28AF


embedded image


C20H24N4O2S
384.5
385.1





28AG


embedded image


C17H20N4O2S
344.4
345.1





28AH


embedded image


C18H22N4OS
342.5
343.1





28AI


embedded image


C17H14N4OS
322.4
323.1





28AJ


embedded image


C19H22N4OS
354.5
355.1





28AK


embedded image


C19H18N4OS
350.4
351.1





28AL


embedded image


C19H16N4O2S
364.4
365.2





28AM


embedded image


C19H16N4O2S
364.4
365.2





28AN


embedded image


C19H24N4OS
356.5
357.1





28AO


embedded image


C20H20N4O2S
380.5
381.1





28AP


embedded image


C19H16N4OS
348.4
349.1





28AQ


embedded image


C20H20N4O2S
380.5
381.1





28AR


embedded image


C19H18N4O2S
366.4
367.1





28AS


embedded image


C19H18N4OS
350.4
351.2





28AT


embedded image


C20H20N4OS
364.5
365.2





28AU


embedded image


C18H13F3N4OS
390.4
391.2





28AV


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C18H16N4O2S
352.4
353.2





28AW


embedded image


C18H13F3N4O2S
406.4
407.2





28AX


embedded image


C20H18N4O2S
378.4
379.2





28AY


embedded image


C20H18N4OS
362.4
363.2





28AZ


embedded image


C19H18N4O2S
366.4
367.1





28BA


embedded image


C20H21N5OS
379.5
380.1





28BB


embedded image


C19H18N4O2S
366.4
367.2





28BC


embedded image


C19H18N4O2S
366.4
367.2










Method R (Alternate):




embedded image


To a solution of compound 112A (50 mg, 0.11 mmol) in 1.4 mL of THF was added 2 M dimethyl amine in THF (0.55 mL, 1.1 mmol). The reaction mixture was stirred and refluxed for 11/2 h. Upon completion (as indicated by TLC) the reaction mixture was concentrated in vacuo. The resultant yellow oil was purified via preparative silica gel TLC with 11% acetone/methylene chloride to afford 36 mg of compound 113A as a white foam. 1H NMR (CDCl3): δ 8.37 (d, 1H), 7.33 (d, 2H), 7.12 (d, 2H), 6.72 (d, 1H), 3.14 (s, 6H), 2.41 (s, 3H), 2.30 (s, 3H). MS m/z calcd. for C19H19N4OS+=351.1; found m/z=351.1.


The following compounds were prepared analogously:




















m/z Found


Cpd
Structure
Formula
MW
(M + 1)+







113A


embedded image


C19H18N4OS
350.4
351.1





113B


embedded image


C18H16N4OS
336.4
337.1





113C


embedded image


C19H16N4OS
348.4
349.1





113D


embedded image


C19H18N4OS
350.4
351.1





113E


embedded image


C17H14N4OS
322.4
323.1





113F


embedded image


C18H16N4OS
336.4
337.1





113G


embedded image


C18H16N4OS
336.4
337.1





113H


embedded image


C19H18N4OS
350.4
351.1





113I


embedded image


C20H20N4OS
364.5
365.1





113J


embedded image


C20H18N4OS
362.4
363.1





113K


embedded image


C20H16N4OS
360.4
361.1





113L


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C19H15F3N4OS
404.4
405.2





113M


embedded image


C21H22N4OS
378.5
379.2





113N


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C19H18N4O2S
366.4
367.2










Method S:


To a suspension of 0.063 g (0.2 mmol) of compound 25A in 4 mL of toluene was added 0.2 mL (0.4 mmol) of isopropylmagnesium bromide at room temperature. After being stirred for 2 h, it was quenched with 30 mL of water, and extracted with two 30 mL portions of dichloromethane. The combined organic extracts were washed with 15 mL of brine and concentrated. The residue was purified by preparative TLC eluting with 5% methanol in dichloromethane to give 0.019 g of compound 29A. MS m/z calcd. for C19H22N3OS+ m/z=328.1; found m/z=328.1.


The following compounds were prepared analogously:




















m/z Found


Cpd
Structure
Formula
MW
(M + 1)+







29B


embedded image


C20H23N3OS
353.5
354.1





29C


embedded image


C17H19N3OS
313.4
314.2





29D


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C16H17N3OS
299.4
300.1










Method T:


To a solution of 0.04 g (0.6 mmol) of pyrrole in 3 mL of THF was added 0.38 mL (0.6 mmol) of n-BuLi at 0° C. After being stirred for 15 min., 0.063 g of compound 25A (0.2 mmol) was added as a solid. The mixture was stirred at room temperature for 2 h and at reflux for 18 h, then cooled to room temperature. It was quenched with 0.2 mL of water, and concentrated. The residue was purified by preparative TLC eluting with 4% methanol in dichloromethane containing 0.2% NH4OH to give 0.038 g of compound 30A. MS m/z calcd. for C19H19N4OS+ m/z=351.1; found m/z=351.1.


The following compound were prepared analogously:
















Cpd
Structure
Formula
MW
m/z Found (M + 1)+







30B


embedded image


C18H17N5OS
351.4
352.1





30C


embedded image


C19H20N4O2S
368.5
369.2










Method U:


To a solution of 5.21 g (37.2 mmol) of diisopropylamine in 10 mL of THF was added 23.1 mL (37 mmol) of n-BuLi in hexanes at 0° C. After 30 min, it was diluted with 30 mL of THF and cooled to −78° C. To this solution was added a solution of 5.00 g (33.8 mmol) of 3,5-dichloropyridine in 60 mL of THF. After 1 h, a solution of 3.14 mL (50.7 mmol) of N,N-dimethyl formate in 15 mL of THF was added dropwise over 30 min. The reaction was stirred at −78° C. for 2 hrs and poured into 400 mL of sodium bicarbonate. The mixture was stirred vigorously and portioned with 600-700 mL of ethyl acetate. The combined organic extracts were washed with two 100 mL portions of sodium bicarbonate, 100 mL of brine and dried over. magnesium sulfate. It was filtered and the filtrate was concentrated. The residue was chromatographed over SiO2 eluting with 10% ethyl acetate in hexanes to give 4.81 g (81%) of product 31. 1H NMR(CDCl3) δ 0.42 (s, 1H), 8.61 (s, 2H).


Method V:


A mixture of 4.71 g (26.8 mmol) of the aldehyde 31, 20 mL of formic acid, 2.42 g (34.8 mmol) of hydroxylamine hydrochloride and 2-3 drops of conc. sulfuric acid was heated at reflux for 4 hrs. The reaction was cooled to room temperature and the formic acid was evaporated under vacuum. The residue was partitioned between 80 mL of ether and 40 mL of water. The organic layer was washed with two 50 mL portions of saturated sodium bicarbonate and 40 mL of brine. It was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give 4.48 g (96%) of compound 32. 1H NMR(CDCl3) δ


8.70 (s, 2H).


Method W:


A sealed tube containing 6-8 mL of dimethylamine and 4.18 g (24.2 mmol) of compound 32 was warmed from −78° C. to room temperature over 1 h and then heated at 50° C. for an additional 1 h. The reaction mixture was cooled to 0° C. and partitioned between 20 mL of water and 50 mL of ethyl acetate. The organic layer was washed with 10 mL of water, 20 mL of brine, and dried over sodium sulfate. It was filtered and the filtrate was concentrated to give 4.37 g (98%) of compound 33. MS calcd for C8H9ClN3=182.1;.found=182.1.


Method X:


To a solution of 0.13 g (0.40 mmol) of compound 7Q in 5 mL of acetonitrile was added 0.10 g (0.8 mmol) of N-Chlorosuccinimide (NCS). The mixture was stirred at reflux for 18 h and concentrated. The residue was purified by chromatography eluting with 1 to 3% methanol in methylene chloride plus 1% ammonium hydroxide to give 0.11 g of compound 41. Calcd MS for C17H20ClN4OS=363.1; found m/z=363.1.


Compound 42 was prepared analogously. MS calcd for C16H18ClN4OS=349.1; found m/z=349.2.
















Cpd
Structure
Formula
MW
m/z Found (M + 1)+







41


embedded image


C17H19ClN4OS
362.9
363.1





42


embedded image


C16H17ClN4OS
348.8
349.2










Method Y:


To a solution of 0.16 g (0.5 mmol) of compound 7Q in 4 mL of THF was added 0.086 g (0.3 mmol) of 1,3-dibromohydantoin. The mixture was stirred at room temperature for 30 min, quenched with 20 mL of saturated sodium bicarbonate. It was extracted with two 30 mL portions of methylene chloride. The combined organic extracts were washed with 10 mL of brine, then concentrated. The residue was purified by preparative TLC eluting with 3% methanol in methylene chloride to give 0.060 g of compound 43 and 0.022 g of compound 44. Compound 43, MS calcd for C76H20BrN4OS=409.1; found m/z=409.2. Compound 44, MS calcd for C16H18BrN4OS=395.1; found m/z=395.2.


Method Z:


To a stirred solution of 0.10 g (0.25 mmol) of compound 43 in 4 mL of ether was added 0.25 mL (0.4 mmol) of n-BuLi at −78° C. After 1 h, a solution of 0.1 mL of DMF in 1 mL of ether was introduced. The mixture was stirred for 3 h and quenched with 30 mL of water. It was extracted with two 30 mL portions of ethyl acetate. The combined organic extracts were washed 20 mL of brine, and concentrated. The residue was purified by preparative TLC eluting with 7% methanol in methylene chloride to give 0.03 g of compound 45. MS calcd for C18H21N4O2S=357.1; found m/z=357.2.


Method AA:


A mixture of 0.285 g (0.7 mmol) of compound 43, 0.082 g (0.7 mmol) of zinc cyanide and 0.025 g (0.021 mmol) of Pd(PPh3)4 in 5 mL of DMF was heated at 120° C. using microwave irradiation (PersonalChemistry) for 5 min., and concentrated. The residue was purified by chromatography eluting with 1 to 4% methanol in methylene chloride plus 1% ammonium hydroxide to give 0.225 g of compound 46. MS calcd for C18H20N5OS=354.1; found m/z=354.2.


Compound 55 could be prepared analogously from compound 54:
















Cpd
Structure
Formula
MW
m/z Found (M + 1)+







46


embedded image


C18H19N5OS
353.4
354.2





55


embedded image


C18H12ClN5OS
381.8
382.1










Method AB:


A mixture of 0.04 g (0.1 mmol) of compound 43, 0.02 g (0.135 mmol) of 3-cyanophenylboronic acid, 0.015 g (cat.) of Pd (PPh3)4 in 4 mL of toluene-methanol (1:1) and 0.2 mL of 2N sodium carbonate in a sealed tube was heated at 120° C. for 5 min. using microwave irradiation (Personalchemistry). It was diluted with 25 mL of methanol and filtered. The filtrate was concentrated; the residue was purified by preparative TLC eluting with 5% methanol in methylene chloride to give 0.036 g of compound 47A. MS calcd for C24H24N5OS=430.2; found m/z=430.2.


Compound 47B was prepared analogously.
















Cpd
Structure
Formula
MW
m/z Found (M + 1)+







47A


embedded image


C24H23N5OS
429.5
430.2





47B


embedded image


C23H24FN4OS
422.5
423.2









The following compounds were prepared analogously from compounds 57 or 83.
















Cpd
Structure
Formula
MW
m/z Found (M + 1)+



















86A


embedded image


C24H26N4OS
418.6
419.2





86B


embedded image


C24H20N4OS
412.5
413.1





86C


embedded image


C25H19N5OS
437.5
4381





86D


embedded image


C25H22N4OS
426.5
427.1





86E


embedded image


C23H19N5OS
413.5
414.1










Method AC:


To a solution of 0.042 g (0.12 mmol) of Compound 46 in 4 mL of acetonitrile was added a solution of 0.023 g (0.13 mmol) of N-bromosuccinimide (NBS). The mixture was stirred at the same temperature for 3 h, and concentrated. The residue was purified by preparative TLC eluting with 4% methanol in methylene chloride to give 0.03 g of compound 48. MS calcd for C17H18N5OS=340.1; found m/z=340.1.


Compound 52 was prepared from compound 51 analogously. MS calcd for C16H18N5O3S=360.1; found m/z=360.1.
















Cpd
Structure
Formula
MW
m/z Found (M + 1)+







48


embedded image


C17H17N5OS
339.4
340.1





52


embedded image


C16H17N4O3S
422.5
423.2










Method AD:


A solution of 0.036 g (0.1 mmol) of compound 46 in 1.5 mL of concentrated sulfuric acid was stirred at 60° C. for 18 h, and poured into-40 mL of water. It was basified with sodium bicarbonate, and extracted with two 40 mL portions of methylene chloride. The combined organic extracts were washed with 20 mL of brine, and concentrated. The residue was purified by preparative TLC eluting with 7% methanol in methylene chloride to give 0.021 g of compound 49. MS calcd for C18H22N5O2S=372.2; found m/z=372.2.


Method AE:


A solution of 0.039 g (0.11 mmol) of compound 46 and 0.5 mL (1 mmol) of ethylamine (2.0M THF solution) in 2 mL of acetonitrile in a sealed tube was heated at 80° C. for 18 h and 120° C. for 16 h, and concentrated. The residue was purified by preparative TLC eluting with 4% methanol in methylene chloride to give 0.030 g of compound 50. MS calcd for C18H20N5OS=354.1; found m/z=354.2.


Method AF:


To a solution of 0.066 g (0.2 mmol) of compound 7Q in 2 mL of concentrated sulfuric acid was added 0.2 mL of concentrated nitric acid at 0° C. The mixture was stirred at room temperature for 1 h, and poured into 20 mL of ice-water. It was basified with sodium carbonate, and extracted with two 30 mL portions of methylene chloride. The combined organic extracts were washed with 20 mL of brine, and concentrated. The residue was purified by preparative TLC eluting with 4% methanol in methylene chloride to give 0.021 g of compound 51. MS calcd for C17H20N5O3S=374.1; found m/z=374.1.


Method AG:


A mixture of 0.075 g (0.2 mmol) of compound 57, 0.11 g (2 mmol) of sodium methoxide in 3 mL of methanol in a sealed tube was heated at 80° C. for 50 h and cooled to room temperature. It was quenched with 30 mL of 95% methanol and concentrated. The residue was purified by preparative TLC eluting with 4% methanol in methylene chloride to give 0.05 g of compound 58. MS calcd for C19H19N4O2S=367.1; found m/z=367.1.


Method AH:


A mixture of 0.022 g (0.06 mmol) of compound 57, 0.02 g (0.2 mmol) of 1-methylpiperazine in 3 mL of ethanol in a sealed tube was heated at 120° C. for 90 h and cooled to room temperature. It was concentrated; the residue was purified by preparative TLC eluting with 10% methanol in methylene chloride plus 1% ammonium hydroxide to give 0.027 g of compound 59A. Calcd MS for C23H27N6OS=435.2; found m/z=435.1.


Compounds 59B and 59C can be prepared analogously. Compounds 79 can be prepared analogously starting with chloropyridine 78.
















Cpd
Structure
Formula
MW
m/z Found (M + 1)+







59A


embedded image


C23H26N6OS
434.6
435.1





59B


embedded image


C22H24N6OS
420.5
421.1





59C


embedded image


C22H23N5O2S
421.5
422.1





79A


embedded image


C18H22N4O2S
358.5
359.1










Method AI:


A mixture of 0.092 g (0.3 mmol) of compound C18, 0.04 g (0.2 mmol) of 1-aminopiperidine and 0.1 mL of acetic acid in 5 mL of toluene was heated at reflux for 2 h and cooled to room temperature. It was concentrated; the residue was purified by preparative TLC eluting with 5% methanol in methylene chloride plus 1% ammonium hydroxide to give 0.083 g of compound 60A. MS calcd for C16H20N5OS=330.1; found m/z=330.1.


The following compounds can be prepared analogously from the appropriate starting materialss:
















Cpd
Structure
Formula
MW
m/z Found (M + 1)+







60A


embedded image


C16H19N5OS
329.4
330.1





60B


embedded image


C17H15N5OS
337.4
338.1





60C


embedded image


C18H17N5OS
351.4
352.1





60D


embedded image


C17H21N5OS
343.4
344.2





60E


embedded image


C18H21N5OS
355.5
356.1





60F


embedded image


C18H23N5OS
357.5
358.1





60G


embedded image


C17H21N5OS
343.4
344.1





60H


embedded image


C11H11N5OS
261.3
262.1





60I


embedded image


C15H17N5OS
315.4
316.1





60J


embedded image


C23H19N5OS
413.5
414.1





60L


embedded image


C16H19N5OS
329.4
330.1









The following compound can be prepared from compound 23 analogously.
















Cpd
Structure
Formula
MW
m/z Found (M + 1)+







60K


embedded image


C15H17N4O2S
337.4
338.1










Method AJ:


A mixture of 0.037 g (0.1 mmol) of compound 28U, 0.1 mL of 37% formaldehyde and 0.05 g (0.23 mmol) of sodium triacetoxyborohydride in 2.5 mL of methylene chloride was stirred at room temperature for 18 h. It was purified by chromatography eluting with 1 to 7% methanol in methylene chloride plus 1% ammonium hydroxide to give 0.039 g of compound 61A. Calcd MS for C20H26N5OS=384.2; found m/z=384.1.


Compound 61B could be prepared analogously:
















Cpd
Structure
Formula
MW
m/z Found (M + 1)+







61A


embedded image


C20H25N5OS
383.5
384.1





61B


embedded image


C23H29N5O2S
423.6
424.1










Method AK:


A mixture of 0.037 g (0.1 mmol) of compound 28U, 0.02 g (0.2 mmol) of acetic anhydride and 0.05 g (0.5 mmol) of triethylamine in 2 mL of methylene chloride was stirred at room temperature for 70 h. It was purified by chromatography eluting with 1 to 7% methanol in methylene chloride plus 1% ammonium hydroxide to give 0.037 g of compound 62. MS calcd for C21H26N5O2S=412.2; found m/z=412.2.


Method AL:


A mixture of 0.037 g (0.1 mmol) of compound 28U, 0.028 g (0.2 mmol) of methanesulfonyl chloride and 0.05 g (0.5 mmol) of triethylamine in 2 mL of methylene chloride was stirred at room temperature for 70 h. It was purified by chromatography eluting with 1 to 6% methanol in methylene chloride plus 1% ammonium hydroxide to give 0.036 g of compound 63. Calcd MS for C20H26N5O3S2=448.2; found m/z=448.2.


Method AM:


A mixture of 0.037 g (0.1 mmol) of compound 28U, 0.027 g (0.2 mmol) of N,N-diethylaminocarbonyl chloride and 0.05 g (0.5 mmol) of triethylamine in 2 mL of methylene chloride was stirred at room temperature for 70 h. It was purified by chromatography eluting with 1 to 6% methanol in methylene chloride plus 1% ammonium hydroxide to give 0.036 g of compound 64. MS calcd for C24H33N6O2S=469.2; found m/z=469.3.


Method AN:




embedded image


To a solution of 5 (0.2 g, 0.796 mmol) in ethanol (2 mL) was added hydrazine hydrate (0.5 mL, excess) and the mixture was heated at 100° C. in a sealed tube for 16 hours. The reaction mixture was cooled to room temperature and the precipitated hydrazide was isolated by filtration. The product was washed several times with pentane to intermediate hydrazide. 1H NMR (CDCl3): δ


8.45 (d, 1H), 6.88 (d, 1H), 6.87 (s, 2H), 6.8 (s, 1H), 4.03 (s, 1H), 2.87 (s, 6H). MS calcd for C10H14N5OS+ m/z=252.09, found m/z=252.1


The hydrazide (0.1 g, 0.398 mmol) was dissolved in glacial acetic acid (10 mL) and heated at 100° C. for 48 h. The solvent was removed in vacuo and the product was isolated by column chromatography using 0-5% methanol in dichloromethane as eluent to afford compound 65A. 1H NMR (CDCl3): δ


8.83 (s, 1H), 8.35 (d, 1H), 6.74 (d, 1H), 3.18 (s, 6H), 2.64 (s, 3H), 2.30 (s, 3H). MS calcd for C14H16N5O2S+=318.1, found m/z=318.1


The following compounds could be prepared analogously:




















m/z Found


Cpd
Structure
Formula
MW
(M + 1)+







65A


embedded image


C14H15N5O2S
317.4
318.1





65B


embedded image


C14H9F6N5O2S
425.3
426.1





65C


embedded image


C18H19N5O2S
369.4
370.1





65D


embedded image


C20H23N5O2S
397.5
398.1





65E


embedded image


C17H15N5OS
337.4
338.1










Method AO:




embedded image


Hydroxy pyridine 26C (0.05 g, 0.16 mmol) was dissolved in DMF (2 mL) and treated with K2CO3 (0.05 g, 0.36 mmol) followed by propargyl chloride (0.05 g, 0.67 mmol) and the reaction mixture was stirred at room temperature overnight. Water was added and the mixture was extracted with dichloromethane. The organic layer was dried and concentrated in vacuo. The product was isolated by silica gel chromatography eluting with 0-10% methanol in dichloromethane to give compound 66A. 1H NMR (CDCl3): δ 8.68 (d, 1H), 8.34 (s, 1H), 7.33 (m, 4H), 7.11 (d, 1H), 5.10 (s, 2H), 2.65 (s, 1H), 2.45 (s, 3H). MS calcd. for C19H14N3O2S+=348.1, found m/z=348.1


The following compounds could be prepared analogously:




















m/z Found


Cpd
Structure
Formula
MW
(M + 1)+







66A


embedded image


C19H13N3O2S
347.4
348.1





66B


embedded image


C20H15N3O2S
361.4
362.1





66C


embedded image


C21H19N3O2S
377.5
378.2





66D


embedded image


C19H15N3O2S
349.4
350.2





66E


embedded image


C18H15N3O3S
353.4
354.1










Method AP:




embedded image


To a solution of p-toluidine (2.5 g, 0.0233 mol) in toluene (50 mL) was added trimethyl aluminum (2 M in THF, 12 mL) at 0° C. and the reaction was stirred for 10 minutes. Compound 67 (5 g, 0.0219 mol) was introduced to the above solution and the contents were heated at 120° C. for 16 h. The reaction mixture was cooled to room temperature and quenched by the addition of water (5 mL) and extracted several times with dichloromethane and ethyl acetate. The combined extracts were washed with Rochelle salt, dried and the solvents were removed in vacuo. The residue 68A was used for the next step without further purification.



1H NMR (CDCl3): δ 7.32 (d, 2H), 7.11 (d, 2H), 6.82 (s, 1H), 6.00 (s, 2H), 2.63 (s, 3H), 2.30 (s, 3H). MS calcd. for C14H14N3OS2+=304.06, found m/z=304.1


Method AQ:




embedded image


Solid 68A was suspended in triethyl orthoformate (50 mL) and treated with acetic anhydride (10 mL). The contents were heated at 100° C. for 7 hours. The solvent was removed in vacuo and the product was isolated by column chromatography using 0-5% MeOH/dichloromethane as eluent to give compound 69A. 1H NMR (CDCl3): δ 8.52 (s, 1H), 7.40 (m, 4H), 2.87 (s, 3H), 2.39 (s, 3H). MS calcd. for C15H12N3OS2+=314.04, found m/z=314.2


Method AR:




embedded image


Compound 69A (2.5 g, 7.98 mmol) was dissolved in glacial acetic acid (50 mL) and treated with 10 mL 30% hydrogen peroxide. The reaction mixture was heated at 100° C. for 2h. The reaction mixture was cooled to 0° C. and the precipitated sulfone 70A was washed several times with water and ether.



1H NMR (CDCl3): δ 8.70 (s, 1H), 7.42 (m, 4H), 3.66 (s, 3H), 2.40 (s, 3H). MS calcd. for C15H12N3O3S2+=346.03, found m/z=346.1


Method AS:




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A solution of compound 70A (0.05 g, 0.1449 mmol) and guanidine hydrochloride (0.02 g, 0.2 mmol) in DMF was heated at 100° C. for 16 h. The solvent was removed in vacuo and the product was isolated by reverse phase HPLC using CH3CN/H2O as eluent to give compound 71A. 1H NMR (CDCl3): δ8.43 (s, 1H), 7.62 (s, 1H), 7.34 (d, 2H), 7.29 (d, 2H), 6.9 (s, 1H), 6.76 (s, 1H), 2.33 (s, 3H). MS calcd. for C15H13N6OS+=325.09, found m/z=325.1


Alternate Method T:




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To compound 25A (0.60 g, 0.0019 mol) was added ammonium acetate (5 g) and the contents were heated in a sealed tube at 150° C. for 16 hours. The reaction mixture was cooled to room temperature and water was added (50 mL). The precipitated solid was collected by filtration and dried over vacuum. The crude solid was purified by silica gel column chromatography using 5% methanol in dichloromethane as eluent to afford compound 72A. 1H NMR (CD3OD) δ 8.56 (s, 1H), 8.11 (d, 1H), 6.64 (d, 1H), 3.31-3.29 (m, 3H), 1.99-1.36(m, 10H). MS m/z calcd. for C15H16N4OS+=301.4; found m/z=301.2.


The following compounds could be prepared analogously:




















m/z Found


Cpd
Structure
Formula
MW
(M + 1)+







72A


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C15H15N4OS
300.4
301.2





72B


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C18H20N4OS
340.4
341.2





72C


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C16H12N4O2S
324.4
325.2





72D


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C24H24N4OS
416.5
417.1





72E


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C22H22N4OS
390.5
391.1





72F


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C23H24N4OS
404.5
405.1





72G


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C18H18N4OS
338.4
339.1





72H


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C16H12N4OS
308.4
309.0





72I


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C19H16N4OS
348.4
349.1










Method AT:




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Compound 72A (0.010 g, 0.033 mmol) in dichloroethane (1 mL) was treated with triethylamine (0.025 mL, 0.018 mmol) and propionyl chloride (0.040 mL, 0.46 mmol) and allowed to stir at room temperature for 3 hours. The solvent was evaporated in vacuo and the resulting residue was purified by preparative TLC eluting with 5% methanol/94.5%dichloromethane/0.5% ammonia hydroxide to give compound 73A.



1H NMR (CDCl3) δ


8.61(d, 1H), 8.51 (d, 1H), 8.30 (s, 1H), 2.62-2.11(q, 2H), 2.11-2.09(d, 2H), 2.00-1.95(d, 2H), 1.80-1.82(d, 1H), 1.55-1.68 (m, 5H), 1.36-1.32(t, 3H). MS m/z calcd. for C18H20N4O2S+=357.4; found m/z=357.1.


The following compounds were prepared analogously:




















m/z Found


Cpd
Structure
Formula
MW
(M + 1)+







73A


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C18H20N4O2S
356.4
357.1





73B


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C17H18N4O2S
342.4
343.2





73C


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C22H20N4O2S
404.5
405.1





73D


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C20H22N4O2S
382.5
383.1





73E


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C20H18N4O3S
394.4
395.1





73F


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C23H22N4O3S
434.5
435.1





73G


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C22H19ClN4O2S
438.9
439.1










Method AU:




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Compound 26C (0.020 g, 0.045 mmol) in DMF (1mL) was treated with zinc cyanide(0.005 g, 0.043 mmol), dppf (0.005 g, 0.009 mmol), water (5 μL) followed by tris(dibenzylideneacetone)dipalladium(0) (0.004 g, 0.0044 mmol) under nitrogen atmosphere and the contents were heated in a sealed tube at 130° C. for 3 hours. The reaction mixture was passed through a short pad of celite and all the solvent was evaporated under reduced pressure. The residue was redissolved in dichloromethane (10 mL) and washed with water (10 mL). The organic layer was dried with sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by preparative TLC eluting with dichloromethane to give compound 74A. 1H NMR (CDCl3) δ 8.94(d, 1H), 8.40 (s, 1H), 7.80 (d, 1H), 7.38-7.26(m, 4H), 2.47(s, 3H). MS m/z calcd. for C17H10N4OS+=319.4; found m/z=319.1.


Method AV:




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Compound 74A (0.025 g, 0.079 mmol) was suspended in methanol (10 mL) and HCl gas was bubbled for 5 minutes at 0° C. The reaction mixture was allowed to stir at room temperature for 20 minutes and then heated under reflux for 10 minutes. The reaction mixture was cooled and the solvent was removed in vacuo. The residue was redissolved in dichloromethane (20 mL) and washed with sodium bicarbonate solution (10 mL). The organic layer was dried with sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by preparative TLC eluting with 2% methanol/97.5% dichloromethane/0.5% ammonia hydroxide to give compound 75A. 1H NMR (CDCl3) δ 8.82(s, 1H), 8.20 (s, 1H), 7.47 (d, 1H), 7.33-7.26(m, 4H), 4.02(s, 3H), 2.41(s, 3H).MS m/z calcd. for C18H13N3O3S+=352.4; found m/z=352.1.


Method AW:




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To compound 74A (0.038 g, 0.11 mmol) was added PPA (0.25 mL) and heated at 130° C. for 3 hours. The reaction mixture was cooled to room temperature and diluted with water (30 mL). The white precipitate was collected by filtration and dried under vacuum. The solid was dissolved in 1 mL of 60% DMSO/30% MeCN/10% formic acid and purified by BHK alpha C-18 column ramping from 95% water/5% MeCN/0.1% fromic acid to 5% water/95% MeCN/0.1% formic acid over 12 minutes at flow rate of 20 mL/min to give compounds 76 and 77. Compound 76 1H NMR (DMSO) δ8.88-8.85(m, 1H), 8.60 (d, 1H), 7.65-7.62 (m, 1H), 7.47-7.37(m, 4H), 2.48 (s, 3H). MS m/z calcd. for C17H12N4O2S+=337.4; found m/z=337.1. Compound 77 1H NMR (DMSO) δ 8.88-8.85(m, 1H), 8.60 (d, 1H), 7.66-7.62 (m, 1H), 7.47-7.37(m, 4H), 2.48 (s, 3H). MS m/z calcd. for C17H11N3O3S+=338.4; found m/z=338.1.


Method AX:




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A stirring mixture of the compound 78 (0.400 g, 1.21 mmol) in acetic anhydride (5.00 mL) was heated at 130 to 135° C. for 3 hrs. The reaction was monitored by quenching a sample with saturated sodium bicarbonate and extracting with ethyl acetate. The ethyl acetate was analyzed by tic (5% acetone/dichloromethane). Upon completion, the reaction was added in portions to a stirring ice cold saturated sodium bicarbonate solution (200 mL). The aqueous phase was partitioned with dichloromethane (150 mL). The organic extract was washed with saturated sodium bicarbonate (100 mL) and brine (50 mL). The dichloromethane was dried over anhydrous sodium sulfate and evaporated to a solid (0.440 g). This material was purified by flash column chromatography on silica gel (20 g) eluting with a solvent gradient 1% acetone/dichloromethane to 5% acetone/dichloromethane yielded the resulting acetoxy analog as a solid (0.174 g, 40%). A stirring suspension of the acetate (0.100 g, 0.268 mmol) in MeOH (15 mL) at room temperature was treated with 1N-NaOH (1 mL) to give a solution. The solution was continued to be stirred for 20 min and was analyzed by tic (5% acetone/dichloromethane). 1N-HCl (1 mL) was added dropwise to yield a precipitate. This was followed by the addition of saturated sodium bicarbonate until weakly basic (pH 8). The material was collected by vacuum filtration and was washed with water (1-2 mLi). The hydroxyl product was dried under vacuum to give compound 80 as a solid (0.075 g, 85%). MS m/z calcd. for C16H18N3O3S+=332.1; found m/z=332.1.


Method AY:




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A solution of the methoxy compound 78 (0.101 g, 0.286 mmol) in dichloromethane (10 mL) at room temperature was treated with the dropwise addition of 1M boron tribromide in dichloromethane (1.15 mL, 1.15 mmol). The reaction was stirred at room temperature for 20 hrs. It was cooled to 0° C. and methanol (1 mL) was added dropwise. The solution was then stirred at room temperature for 20 min and then heated to reflux for 1 hr. The reaction was cooled and was concentrated under vacuum. The solid was stirred with water (3 mL) and made basic with saturated sodium bicarbonate. The solid was stirred and collected by filtration. This material was washed with water and dried under vacuum to give the hydroxyl product 81 as a powder (0.082 g, 85%). MS m/z calcd. for C15H15ClN3O2S+=336.0 (M+1)+; found m/z=336.0.


Method Q (Alternate 1):




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A stirring mixture of the hydroxyl compound 81 (0.050 g, 0.149 mmol) and triethylamine (0.030 g, 0.298 mmol) in dichloromethane (1.50 mL) was treated with the dropwise addition of triflic anhydride (0.084 g, 0.298 mmol) at room temperature. The reaction was stirred at room temperature for 4 hrs. The reaction was diluted with dichloromethane (5 mL) and was washed with saturated sodium bicarbonate (3 mL). The layers were separated and the water was washed with dichloromethane (5 mL). The combined dichloromethane extracts were dried over anhydrous sodium sulfate, filtered and evaporated to a semi-solid (0.097 g). This material was purified by flash column on silica gel (5 g) eluting with 100% dichloromethane to give the triflate 82 as a solid (0.059 g, 84%). MS m/z calcd. for C16H14ClF3N3O4S2+=468.0 (M+1)+; found m/z=467.9.


Method AZ:




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The 2M-dimethylamine/MeOH (0.555 mL, 1.11 mmol) was added to a stirring mixture of the triflate 82 (0.400 g, 0.855 mmol) in methanol (6 mL) at room temperature. The suspension was continued to be stirred at room temperature for 3 hrs. The methanol was evaporated under vacuum and the solid residue was partitioned between dichloromethane (70 mL) and saturated sodium bicarbonate (15 mL). The organic phase was washed with water (15 mL) and brine (15 mL). The dichloromethane solution was dried over anhydrous sodium sulfate and evaporated to a solid, which was purified by flash column chromatography on silica gel (10 g) eluting with a solvent gradient from 100% dichloromethane to 2% acetone/dichloromethane yielded the dimethylamino product 83 as a solid (0.200 g, 65%). MS calcd for C17H20ClN4OS+ m/z=363.1, found m/z=363.1.


Method AA (Alternate 1):




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The chloro compound 83 (0.010 g, 0.028 mmol), zinc cyanide (0.0033 g, 0.028 mmol) and tetrakis (triphenylphosphine) palladium (0) (0.005 g, 0.0043 mmol) in DMF (1.50 mL) were subjected to microwave conditions at 180° C. for 10 min. The DMF was evaporated under vacuum. The solid residue obtained was washed several times with dichloromethane. The combined washings were evaporated to a solid (0.018 g). This crude product was purified by flash column chromatography on silica gel (1 g) eluting with 1% acetone/dichloromethane gave the cyano product 84 as a solid (0.009 g, 90%). MS calcd for C18H20N5OS+ m/z=354.1, found m/z=354.1.


Method AH (Alternate 1):




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A stirring mixture of the chloro compound 83 (0.010 g, 0.028 mmol) and pyrrolidine (0.100 g, 1.41 mmol) in methanol (0.80 mL) was heated in an oil bath at 100° C. for 1.50 hrs. The reaction was cooled and concentrated under vacuum to give an oily residue (0.013 g). This material was purified by flash column chromatography on silica gel (1 g) eluting with a solvent gradient from 1% acetone/dichloromethane to 4% acetone/dichloromethane to give the pyrrolidinyl product 85 (0.009 g, 81%). MS calcd for C21H28N5OS+ m/z=398.2, found m/z=398.2.


Method AH (Alternate 2):




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A stirring mixture of the chloro compound 57 (0.020 g, 0.054 mmol) in MeOH (1 mL)/2M methylamine in methanol (2.50 mL) was subjected to microwave conditions at 140° C. for 1 hr. The solvent was evaporated under vacuum. The residue was purified by flash column chromatography on silica gel (2 g) eluting with a solvent gradient from 100% dichloromethane to 8% acetone/dichloromethane to give the methylamino product 59D as a solid (0.014 g, 70%). MS calcd for C19H20N5OS+ m/z=366.1, found m/z=366.2.


Method AH (Alternate 3):




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A stirring mixture of the chloro compound 57 (0.250 g, 0.674 mmol) in 7N ammonia in methanol (50 mL) was sealed in a Parr steel reaction vessel and was heated in an oil bath at 180-185° C. for 20 hrs. The reaction was cooled to room temperature concentrated under vacuum to a solid (0.269 g). The solid was purified by flash column chromatography on silica gel (25 g) eluting with a solvent gradient from 100% dichloromethane to 2% methanol in dichloromethane to give 59E as a solid (0.101 g, 43%). MS calcd for C18H18N5OS+ m/z=352.1, found m/z=352.1.


Method BA:




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The chloro compound 57 (0.015 g, 0.040 mmol) was dissolved in THF (2 mL) containing NMP (0.20 mL) at room temperature. The iron (III) acetylacetonate (1.4 mg, 0.004 mmol) was added. An orange-red solution was obtained. The 2M isopropyl magnesium chloride in THF (0.034 mL, 0.068 mmol) was added dropwise. The reaction was stirred at room temperature for 40 min. The reaction was quenched with saturated sodium bicarbonate (1-2 mL) and was diluted with water (3-4 mL). It was extracted with ethyl acetate (15 mL). The ethyl acetate extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate and evaporated to an oil. The crude material was purified by flash column chromatography on silica gel (10 g) eluting with a solvent gradient from 100% dichloromethane to 3% acetone in dichloromethane to give the isopropyl derivative 87A as a solid (0.003 g, 20%).


The following compounds could be prepared analogously starting with 57 or with 83:




















m/z Found


Cpd
Structure
Formula
MW
(M + 1)+







87A


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C21H22N4OS
378.5
379.1





87B


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C20H20N4OS
364.5
365.1





87C


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C20H26N4OS
370.5
371.2










Method BB:




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(Ref: A. Gomtsyan, S. Didomenico, C-H. Lee, M. A. Matulenko, K. Kim, E. A. Kowaluk, C. T. Wismer, J. Mikusa, H. Yu, K. Kohlhass, M. F. Jarvis, S. S. Bhagwat; J. Med. Chem., 2002, 45, 3639-3648.)


A mixture of DMF (32 mL) and POCl3 (100 mL) at 0° C. was stirred for 1 h, treated with 4,6-dihydroxypyrimidine (25.0 g, 223 mmol), and stirred for 0.5 h at room temperature. The heterogeneous mixture was then heated to refluxed and stirred for 3 h. The reaction was cooled to room temperature and the resulting viscous, black liquid was poured onto ice water and extracted with diethyl ether (6×100 mL). The organic phase was subsequently washed with NaHCO3, and water, dried over MgSO4, and concentrated to give 89 as a yellow solid (20.0 g, 57% yield). 1H NMR (CDCl3) δ 10.41 (s, 1H), 8.85 (s, 1H).


Method BC:




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Step 1: (ref: A. A. Santilli, D. H. Kim, and S. V. Wanser; J. Heterocyclic Chem., 1971, 8, 445-453) Aldehyde 89 (29.0 g, 164 mmoles) and hydroxylamine hydrochloride were dissolved in AcOH (0.83 M, 198 mL) by heating to reflux. The reaction was allowed to stir at reflux for 0.5 h and then cooled to room temperature. The solvents were removed in vacuo. The resulting yellow solids were taken up in H2O and the product filtered off. The solid product was then dried under vacuum overnight to provide the oxime as a yellow solid which was dried under vacuum and used crude in the next step.


Step 2: (ref: A. A. Santilli, D. H. Kim, and S. V. Wanser; J. Heterocyclic Chem., 1971, 8, 445-453) A solution of the above oxime (5.00 g, 26.0 mmol) in thionyl chloride (104 mL) was allowed to stir at reflux for 3 h. The reaction was cooled to room temperature and the solvents removed in vacuo. The resulting yellow-brown solid was dried under vacuum overnight to yield 90 (3.90 g, 96% yield). 13C NMR (DMSO-d6) δ 164.7, 159.5, 152.3, 117.4, 102.2.




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To a solution of compound 90 (3.00 g, 19.2 mmoles) in THF (65 mL) was added dimethyl amine (2.0 M in THF, 11.5 mL). The reaction mixture was stirred at reflux for 3 h and subsequently cooled to room temperature. The solvents were then removed in vacuo to provide 91A as a yellow-brown solid (3.0 g, 95% yield). Mass Spectrum (M+1): m/z calcd. for C7H8N4O+=165.1, found m/z=165.2.


The following compounds were prepared analogously:




















m/z Found


Cpd
Structure
Formula
MW
(M + 1)+







91A


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C7H7N4O
164.2
165.2





91B


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C8H10N4O
178.2
179.2





91C


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C7H8N4O
164.2
165.2





91D


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C8H8N4O
176.2
177.2





91E


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C7H5F3N4O
218.1
219.1





91F


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C6H6N4O
150.1
151.1










Method BE:




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To compound 91A (3.00 g, 18.2 mmoles) was added POCl3 (35.2 mL) and Et3N (2.0 mL). The reaction mixture was stirred at reflux for 3 h and the solvents removed in vacuo. The resulting brown solid was quenched dropwise with water and basified with 40% aq. NaOH. The aqueous suspension was extracted with dichloromethane (100 ml×3), dried over MgSO4 and concentrated in vacuo to provide 2.50 g of 92A as a brown solid. Mass Spectrum (M+1): m/z calcd. for C7H7N4Cl+=183.1, found m/z=183.1.


The following compounds were prepared analogously:




















m/z Found


Cpd
Structure
Formula
MW
(M + 1)+







92A


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C7H6N4Cl
182.6
183.1





92B


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C8H9ClN4
196.6
197.2





92C


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C7H7ClN4
182.6
182.1





92D


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C8H7ClN4
194.6
195.1





92E


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C7H4ClF3N4
236.6
237.0





92F


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C6H5ClN4
168.6
169.1










Method BF:




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To a solution of 92A (2.50 g, 13.7 mmoles) in ethanol (70 mL) was added methylthioglycolate (1.65 mL, 15.0 mmoles) and sodium carbonate (2.20 g, 20.5 mmoles). The reaction was allowed to stir at reflux for 3 h and cooled to room temperature. The solvents were removed in vacuo. The resulting solids were taken up in H2O and filtered to yield 93A as a yellow solid (3.10 g, 90% yield). 1H NMR (CDCl3) δ


8.56 (s, 1H), 6.23 (bs, 2H), 3.83 (s, 3H), 3.03 (s, 6H).


The following compounds were prepared analogously:




















m/z Found


Cpd
Structure
Formula
MW
(M + 1)+







93A


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C10H12N4O2S
252.3
253.1





93B


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C11H14N4O2S
266.3
267.2





93C


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C10H12N4O2S
252.3
253.2





93D


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C11H12N4O2S
264.3
265.2





93E


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C10H9F3N4OS
306.3
307.1





93F


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C9H10N4O2S
238.3
239.1










Method BG:




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A solution of 93A (3.10 g, 12.3 mmoles), and N,N-dimethylformamide dimethyl acetal (8.21 mL, 61.3 mmoles) in abs. EtOH (13 ml) was allowed to stir at reflux for 3 h. The solvents were removed in vacuo and the resulting solids triturated with boiling ethanol to give 94A as a yellow solid (2.0 g, 53% yield). 1H NMR (CDCl3) δ 8.38 (s, 1H), 7.35 (s, 1H), 3.74 (s, 3H), 3.17 (s, 6H), 3.10 (s, 3H), 3.02 (s, 3H).


The following compounds were prepared analogously from compounds 93:




















m/z Found


Cpd
Structure
Formula
MW
(M + 1)+







94A


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C13H17N5O2S
307.4
308.1





94B


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C14H19N5O2S
321.4
322.2





96A


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C11H10N4O2S
262.3
263.1





96B


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C12H10N4O2S
274.3
275.1





94C


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C13H14F3N5O2S
361.3
362.0





96C


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C10H8N4O2S
248.3
249.1





96D


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C11H10N4O3S
278.3
279.1










Method F (Alternate 3):




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To a mixture of 94A (200 mg, 0.649 mmoles) in toluene (2 mL) and glacial acetic acid (400 δ L) was added p-anisidine (160 mg, 1.30 mmoles). The reaction was allowed to stir at 80° C. for 1 h. The reaction mixture was then poured onto water (100 ml), basified with conc. NH4OH and extracted with dichloromethane (25 ml×3). The organic layer was separated, dried over MgSO4 and concentrated in vacuo. The crude solid was then purified via silica gel chromatography eluting with 10% acetone/dichloromethane to give 95A as a white solid (77.6 mg, 34% yield). Mass Spectrum (M+1): m/z calcd. for C17H16N5O2S+=354.1, found m/z=354.1


The following compounds could be prepared analogously from either 94 or 96




















m/z Found


Cpd
Structure
Formula
MW
(M + 1)+







95A


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C17H15N5O2S
353.4
354.1





95B


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C17H15N5OS
337.4
338.1





95C


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C17H12N6OS2
380.4
381.1





95D


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C16H14N6O2S
354.4
355.2





95E


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C18H15N5O2S
365.4
366.2





95F


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C17H15N5OS2
369.5
370.1





95G


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C18H17N5O2S
367.4
368.1





95H


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C18H17N5OS
351.4
352.1





95I


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C18H14N6OS2
394.5
395.1





95J


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C15H12N6OS
324.4
325.1





95K


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C19H17N5O2S
379.4
380.1





95L


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C18H17N5OS2
383.5
384.1





95M


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C16H14N6OS
338.4
339.1





95N


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C17H12F3N5O2S
407.4
408.1





95O


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C16H14N6OS
338.4
339.1





95P


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C17H15N5OS
337.4
338.1





95Q


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C17H13F2N5O2S
389.4
390.2





95R


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C18H14F3N5O2S
421.4
422.2





95S


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C17H15N5O2S
353.4
354.2





95T


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C18H15F2N5O2S
403.4
404.1





95U


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C17H16N6OS
352.4
353.1





95V


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C17H12F3N5O2S
407.4
408.2





95W


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C17H13F2N5O2S
389.4
390.1





95X


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C17H12F3N5OS
391.4
392.2





95Y


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C18H14F3N5OS
405.4
406.2





95Z


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C18H15N5O2S
365.4
366.1





95AA


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C18H15N5OS
349.4
350.1





95AB


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C16H14N6OS
338.4
339.1





95AC


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C18H15N5O2S
365.4
366.1





95AD


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C17H15N5OS2
369.5
370.1





95AE


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C16H12ClN5OS
357.8
358.2





95AF


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C16H13N5OS
323.4
324.2





95AG


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C16H13N5O2S
339.4
340.1





95AH


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C17H12F3N5O2S
407.4
408.2





95AI


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C17H15N5O3S
369.4
370.2





95AJ


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C16H12ClN5O2S
373.8
374.2





95AK


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C17H15N5O2S
353.4
354.2





95AL


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C16H12BrN5OS
402.3
402.2





95AM


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C16H12FN5OS
341.4
342.1





95AN


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C16H12FN5OS
341.4
342.1










Method BG:




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To compound 90 (2.50 g, 16.0 mmoles) was added POCl3 (31 mL) and Et3N (2.0 mL). The reaction mixture was stirred at reflux for 3 h and the solvents removed in vacuo. The resulting brown solid was quenched dropwise with water and basified with 40% aq. NaOH. The aqueous suspension was extracted with dichloromethane (100 ml×3), dried over MgSO4 and concentrated in vacuo to provide 2.64 g of 97 as a brown solid. Mass Spectrum (M+1): m/z calcd. for C7H7N4Cl+=183.1, found m/z=183.1.


Method BH:




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Ref: J. Clark, M. S. Shahhet, D. Korakas, G. Varvounis; J. Heterocyclic Chem., 1993, 30, 1065-1072


To compound 97 (100 mg, 0.58 mmols) and methyl thioglycolate (127 □L, 1.16 mmols) in THF (2.5 mL) was added Et3N (162 δ L, 1.16 mmols). The reaction immediately formed yellow precipitate and was allowed to stir for 10 min. at room temperature. The solvents were subsequently removed in vacuo and the resulting yellow solid taken up in a minimum amount of H2O. The aqueous suspension was stirred for 5 min. and room temperature and filtered to yield 150 mg of 98 as a yellow solid. Mass Spectrum (M+1): m/z calcd. for C11H11N3O4S2+=314.0, found m/z=314.0.


Method BI:




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Ref: J. Clark, M. S. Shahhet, D. Korakas, G. Varvounis; J. Heterocyclic Chem., 1993, 30, 1065-1072


To compound 98 (156 mg, 0.50 mmols) in toluene (3.1 mL) was added Et3N (80 □L, 0.55 mmols). The reaction was stirred at reflux for 4 hours. The mixture was subsequently cooled to room temperature and the solvents removed in vacuo to provide 150 mg of 99 as a yellow solid. 1H NMR (CDCl3) δ8.71 (s, 1H), 6.43 (bs, 2H), 4.17 (s, 2H), 3.84 (s, 3H), 3.74 (s, 3H).


Method BJ:




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To compound 99 (1.34 g, 4.27 mmols) in methanol (14.5 mL) was added ethanol amine (7.0 mL, 113 mmols). The reaction was stirred at reflux for 0.5 h. The mixture was cooled to room temperature and the solvents removed in vacuo. The resulting residue was taken up in 1:1 dichloromethane:water (50 mL). The aqueous layer was extracted with dichloromethane (3×25 mL). The organic layers were combined, dried with MgSO4, and the solvents removed in vacuo to yield 1.0 g of 93G as a yellow solid. Mass Spectrum (M+1): m/z calcd. for C10H12N4O3S+=269.1, found m/z=269.1


Method BK:




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To compound 100 (9.5 g, 0.0578 mol) in DMF (100 mL) was added K2CO3 (10 g, 0.0723 mol) at room temperature. Methylthioglycolate (5.5 mL, 0.0615 mol) was added to the above solution and heated at 70° C. for 48 hours. The reaction mixture was poured into 500 mL ice water and extracted with ethyl acetate. The solvent was removed in vacuo to give 101 which was used for the next step without further purification. 1H NMR (CDCl3): δ 7.32 (t, 1H), 6.94 (d, 1H), 6.78 (d, 1H), 3.72 (s, 3H), 3.71 (s, 2H), 3.01 (s, 6H). Mass Spectrum (M+1): m/z calcd. for C12H14N2O2S+=251.1, found m/z=251.0.


Method BL:




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The above oil 101 was dissolved in methanol (200 mL) and treated with a 25% solution of sodium methoxide in methanol (50 mL) and the contents were heated at 80° C. for 1 hour. The solvent was removed in vacuo and the precipitate was washed several times with water to afford compound 102 as white solid. 1H NMR (CDCl3): δ


7.34 (d, 1H), 7.28 (t, 1H), 6.99 (d, 1H), 3.78 (s, 3H), 2.68 (s, 6H). Mass Spectrum (M+1): m/z calcd. for C12H14N2O2S+=251.08, found m/z=251.0.


Method BM:




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Compound 102 (0.1 g, 0.399 mmol) was dissolved in 1 mL triethyl orthoformate and treated with acetic acid (0.1 mL) and 4-chloroaniline (0.15 g, 1.17 mmol). The contents were heated in a sealed tube at 150° C. for 16 h. The solvent was removed in vacuo and the product was isolated by preparative TLC using 5% methanol in dichloromethane to afford compound 103A as off white solid. 1H NMR (CDCl3): δ 7.30 (s, 1H), 7.50 (m, 6H), 7.05 (d, 1H), 3.01 (s, 6H). Mass Spectrum (M+1): m/z calcd. for C18H15ClN3OS+=356.1, found m/z=356.2.


The following compounds were prepared analogously:




















m/z Found


Cpd
Structure
Formula
MW
(M + 1)+







103A


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C18H14ClN3OS
355.8
356.2





103B


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C18H21N3OS
327.4
328.2





103C


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C18H15N3OS
321.4
322.2





103D


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C19H17N3OS
335.4
336.2





103E


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C19H17N3O2S
351.4
352.2





103F


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C19H14N4OS2
378.5
379.2










Method BN:




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Compound 103B (0.05 g, 0.152 mmol) was dissolved in acetonitrile (2 mL) and treated with NBS (0.03 g, 0.168 mmol) and the reaction mixture was stirred at room temperature for 1 hour. The solvent was removed in vacuo and the product was isolated by preparative TLC using 4% methanol in dichloromethane to give compound 104 as an off-white solid. 1H NMR (CDCl3): δ 8.36 (s, 1H), 7.55 (d, 1H), 6.91 (d, 1H), 4.92 (m, 1H), 2.99 (s, 6H), 2.09-1.25 (m, 10H). Mass Spectrum (M+1): m/z calcd. for C18H21BrN3OS+=406.1, found m/z=406.2.


Method BO:




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Compound 104 (0.023 g, 0.0567 mmol) was dissolved in DMF (2 mL) and treated with Zn(CN)2 (0.01 g, 0.0851 mmol) followed by Pd (PPh3)4 (0.01 g, 0.0086 mmol). The contents were heated at 180° C. in a microwave oven for 10 minutes. The solvent was removed in vacuo and the product was isolated by preparative TLC to get compound 105. 1H NMR (CDCl3): δ 8.33 (s, 1H), 7.72 (d, 1H), 6.97 (d, 1H), 4.91 (m, 1H), 3.10 (s, 6H), 2.09-1.25 (m, 10H). Mass Spectrum (M+1): m/z calcd. for C19H21N4OS+=353.1, found m/z=353.2.


Method BP:




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Compound 103B (0.2 g, 0.61 mmol) was dissolved in formic acid (3 mL) and treated with conc. HNO3 (0.05 mL, 1.25 eq) at 0° C. Stirred at 0° C. for 30 minutes and warmed to room temperature. The reaction mixture was stirred at rt for 2 hours. The solvent was removed in vacuo and the product was isolated by preparative TLC using 50% ethyl acetate-hexane as eluent to afford compound 106. 1H NMR (CDCl3): δ 8.45 (d, 1H), 8.31 (s, 1H), 6.97 (d, 1H), 4.91 (m, 1H), 3.18 (s, 6H), 2.10-1.26 (m, 10H). Mass Spectrum (M+1): m/z calcd. for C18H21N4O3S+=373.1, found m/z=373.1.


Method BQ:




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Thioglycolic acid (20 g, 217 mmol) and p-toluidine (23.26 g, 217 mmol) and benzene (110 mL) were combined in a one neck round bottom flask fitted with a Dean Stark apparatus, a reflux condenser, and a N2 inlet line. The mixture was stirred and heated under reflux for 7 h and then cooled to RT and stored under N2 for 48 h. The resultant solid was quickly collected via vacuum filtration and immediately washed with a 110 mL of benzene (acidified with several drops of conc. HCl). Next, the solid was quickly transferred to a flask containing 250 mL of water (acidified to pH=3 with conc. HCl). The flask was sealed with a glass stopper and stored at RT for 1 week. The resultant white crystals were collected via vacuum filtration, washed with water (acidified to pH=3 with conc. HCl), and dried to afford 13.56 g of 108A which was stored in a dark glass bottle sealed under N2. 1H NMR (CDCl3) δ 8.40 (bs, 1H), 7.38 (d, 2H), 7.10 (d, 2H), 3.35 (d, 2H), 2.28 (s, 3H), 1.97 (t, 1 H). MS m/z calcd.for C9H12NOS+=182.0; found m/z=182.0.


The following compound was prepared analogously.




















m/z Found


Cpd
Structure
Formula
MW
(M + 1)+







108B


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C9H11NO2S
197.3
198.2










Method BR:




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Compound 22 (1.0 g, 5.92 mmol), compound 108A (1.18 g, 6.51 mmol), potassium carbonate (1.23 g, 8.89 mmol), and DMF (23 mL) were combined, stirred under N2, and heated at ˜80° C. for 2 h. The reaction mixture was poured into ice water and stirred vigorously. The resultant solid was collected via vacuum filtration, washed with water, and dried under vacuum to afford 1.75 g of a pale pink solid which was combined with sodium methoxide (0.408 g, 7.55 mmol) and methanol (87 mL), stirred under N2, refluxed for 2 h, and then stirred overnight at RT. The mixture was concentrated in vacuo and mixed vigorously with ice water. The resultant solid was collected via vacuum filtration, washed with water, and dried in a vacuum oven at 40° C. to afford 1.59 g of compound 109A as a pale yellow solid. 1H NMR (CDCl3): δ 8.45 (d, 1H), 7.39 (d, 2H), 7.12 (d, 2H), 6.99 (s, 1H), 6.82 (bs, H), 6.67 (d, 1H), 4.01 (s, 3H), 2.29 (s, 3H). Mass Spectrum (M+1): m/z calcd. for C16H16N3O2S+=314.1, found m/z=314.1.


The following compounds were prepared analogously.




















m/z Found


Cpd
Structure
Formula
MW
(M + 1)+







109B


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C16H15N3O3S
329.4
330.1





109C


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C15H13N3O2S
299.4
300.0










Scheme BS:




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Compound 109A (1.0 g, 3.20 mmol), triethyl orthoacetate (11.2 mL), and acetic anhydride (5.60 mL) were combined, stirred, and irradiated in a 300 W power microwave oven at 180° C. for 20 minutes. The mixture was concentrated in vacuo, diluted with ice water, basified with concentrated NH4OH (aq.), and stirred vigorously overnight. The resultant solid was collected by filtration, washed with water, and dried to afford 1.05 g of compound 110A as a light tan solid. 1H NMR (CDCl3): δ 8.58 (d, 1H), 7.33 (d, 2H), 7.11 (d, 2H), 6.86 (d, 1H), 4.11 (s, 3H), 2.41 (s, 3H), 2.33 (s, 3H). MS m/z calcd. for C18H16N3O2S+=338.1; found m/z=338.1.


The following compounds were prepared analogously.




















m/z Found


Cpd
Structure
Formula
MW
(M + 1)+







110B


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C18H15N3O3S
353.4
354.2





110C


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C17H13N3O2S
323.4
324.1





116A


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C20H20N4OS
364.5
365.2





116B


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C21H22N4OS
378.5
379.1





116C


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C22H24N4OS
392.5
393.1





116D


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C19H18N4O2S
366.4
367.1





116E


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C20H20N4O2S
380.5
381.1





116F


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C21H22N4O2S
394.5
395.1





116G


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C22H24N4O2S
408.5
409.2










Method BS (Alternate):




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Compound 115A (50 mg, 0.15 mmol), trifluoroacetic anhydride (0.25 mL), and toluene (1 mL) were combined, stirred, and irradiated in a 300 W power microwave oven at 150° C. for 15 minutes. The mixture was concentrated in vacuo, diluted with ice water, basified with concentrated NH4OH (aq.), and stirred vigorously overnight. The resultant solid was collected by filtration, washed with water, and dried in a vacuum oven at 40° C. to afford 30 mg of compound 117A as a pale yellow solid. 1H NMR (CDCl3): δ 8.38 (d, 1H), 7.31 (d, 2H), 7.16 (d, 2H), 6.73 (d, 1H), 3.17 (s, 6H), 2.42 (s, 3H). MS m/z calcd. for C19H16F3N4OS+=405.1; found m/z=405.1.


The following compounds were prepared by this method:




















m/z Found


Cpd
Structure
Formula
MW
(M + 1)+







117A


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C19H15F3N4OS
404.4
405.1





117B


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C19H15F3N4O2S
420.4
421.2










Method C (Alternate):




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Compound 3 (1.5 g, 8.26 mmol), compound 108A (1.65 g, 9.09 mmol), potassium carbonate (1.71 g, 12.4 mmol), and DMF (20 mL) were combined, stirred under N2, and heated for 3 h at 65° C. The reaction mixture was poured into ice water and stirred vigorously. The resultant solid was collected via vacuum filtration, washed with water, and dried in a vacuum oven at 40° C. to afford 2.62 g of compound 114A as a light yellow solid. 1H NMR (CDCl3): δ 9.65 (bs, 1H), 8.09 (d, 1H), 7.29 (d, 2H), 7.04 (d, 2H), 6.39 (d, 1H), 3.86 (s, 2H), 3.23 (s, 6H), 2.24 (s, 3H). MS m/z calcd. for C17H19N4OS+=327.1; found m/z=327.1.


The following compound was prepared analogously.




















m/z Found


Cpd
Structure
Formula
MW
(M + 1)+







114A


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C17H18N4OS
326.4
327.1





114B


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C17H18N4O2S
342.4
343.1










Method D (Alternate):




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Compound 114A (2.62 g, 8.03 mmol), sodium methoxide (0.59 g, 10.8 mmol), and methanol (125 mL) were combined, stirred under N2, heated under reflux for 21/2 h, and then stirred overnight at RT. The mixture was concentrated in vacuo and mixed vigorously with ice water. The resultant solid was collected via vacuum filtration, washed with water, and dried in a vacuum oven at 40° C. to afford 2.53 g of compound 115A as a pale yellow solid. 1H NMR (CDCl3): δ8.42 (dd, 1H), 7.40 (d, 2H), 7.12 (d, 2H), 7.02 (s, 1 Hz, 6.96 (bs, 2H), 6.86 (d, 1H), 2.84 (s, 6H), 2.30 (s, 3H). MS m/z calcd. for C17H19N4OS+=327.1; found m/z=327.1.


The following compound was prepared analogously.




















m/z Found


Cpd
Structure
Formula
MW
(M + 1)+







115A


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C17H18N4OS
326.4
327.1





115B


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C17H18N4O2S
342.4
343.1










Method BT:




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To compound 15AH (780 mg, 2.02 mmol) in methanol (35 mL) was added 6 N HCl(aq) (7 mL) at RT. The reaction mixture was stirred under N2 and heated at 90° C. for 18 h after which time the reaction was ˜50% complete (as indicated by TLC). Consequently, refluxing at 110° C. was continued for another 6 h after which time the reaction was ˜90% complete (as indicated by TLC). Additional 6 N HCl(aq) (1.5 mL) was added to the reaction mixture and refluxing at 110° C. was continued for another 15 h. After cooling to RT, water (3 mL) was added to the reaction mixture and the MeOH was removed in vacuo at=25° C. The residue was partitioned between dichloromethane and saturated NaHCO3. The organic layer was removed and the aqueous layer was re-extracted with dichloromethane. The organics were combined, washed with saturated NaCl, dried over MgSO4, filtered, and concentrated in vacuo to afford 656 mg of compound 15AI as an off white solid. 1H NMR (CDCl3): δ 8.38 (d, 1H), 8.21 (s, 1H), 6.75 (d, 1H), 5.37 (m, 1H), 3.09 (s, 6H), 2.69-2.13 (m, 8H). MS m/z calcd. for C17H19N4O2S+=343.1; found m/z=343.1.


Method BU




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Compound 15AI (70 mg, 0.21 mmol), DAST (0.08 mL, 0.62 mmol), and dichloroethane (1.5 mL) were combined, stirred, and irradiated in a 300 W power microwave oven at 100° C. (high absorbtion) for 10 minutes. The reaction mixture was partitioned between dichloromethane and 1N NaOH. The organic layer was removed and the aqueous layer was re-extracted with dichloromethane. The organics were combined, washed with saturated NaCl, dried over MgSO4, filtered, and concentrated in vacuo to afford a tan residue which was purified via preparative silica gel TLC with 5% methanol/dichloromethane to afford 35 mg of a ˜1:1 mixture of compounds a16 and a17, along with other minor impurities, as a pale yellow foam. Crystallization from ethyl acetate/hexane afforded 25 mg of an analytically pure, 1:1 mixture of compounds 15AJ and 15AK as a pale yellow solid. 15AJ 1H NMR (CDCl3): δ


8.39 (d, 1H), 8.24 (s, 1H), 6.75 (d, 1H), 5.15 (m, 1H), 3.09 (s, 6H), 2.35-1.95 (m, 8H). MS m/z calcd. for C17H19F2N4OS+=365.1; found m/z=365.1. 15AK 1H NMR (CDCl3): δ8.38 (d, 1H), 8.23 (s, 1H), 6.74 (d, 1H), 5.28 (m, 1H), 5.06 (m, 1H), 3.09 (s, 6H), 2.65-2.20 (m, 6H). MS m/z calcd. for C17H18FN4OS+=345.1; found m/z=345.1.


Method BV:




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Ref.: M. D. Meyer, I. Drizin, R. J. Altenbach, et. al., J. Med. Chem. 2000, 43, 1586-1603.


To a mixture of compound 115A (100 mg, 0.31 mmol) and Et3N (69 mg, 0.68 mmol) in dichloromethane (2.5 mL), cooled to −78° C. under N2, was added 1.9 M phosgene in toluene (0.16 mL, 0.31 mmol). The mixture was stirred at −78° C. for 2 h and then at RT for 48 h. After concentrating the reaction mixture in vacuo, the residue was suspended in THF (2 mL), treated with 1M KOtBu in THF (0.37 mL), and stirred under N2 at RT for 4 days. Insoluble material was removed from the reaction mixture via filtration and washed with dichloromethane. The filtrate was concentrated in vacuo and purified via preparative silica gel TLC with 40% ethyl acetate/dichloromethane to afford 22 mg of compound 118 as a yellow-orange solid. This solid was repurified via preparative silica gel TLC with 40% ethyl acetate/dichloromethane to afford 3.3 mg of compound 118 as a yellow solid. 1H NMR (CDCl3): δ 9.28 (bs, 1H), 8.57 (d, 1H), 7.30 (d, 2H), 7.17 (d, 2H), 7.01 (d, 1H), 2.88 (s, 6H), 2.38 (s, 3H). MS m/z calcd. for C18H17N4O2S+=353.1; found m/z=353.1.


Method BW:




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(Ref: Chemistry of Heterocyclic Compounds, 39 (3), 2003, 328-334)


A mixture of 2-cyano-3-(dimethylamino)-2-butenamide (5 g, 0.0327 mol) (intermediate from method A) and ethylamine (49 ml of 2.0 M solution in THF) in ethanol (40 ml) was stirred at room temperature for a period of 22 h. The precipitate was filtered to give the product 125 as white crystals. 1H NMR (DMSO-d6): δ 6.63 (br. s, 2H), 3.31 (q, 2H), 2.15 (s, 3H), 1.11 (t, 3H).


Methods BX and BY:




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Compound 125 (5.0 g, 0.0327) and N, N-dimethylformamide dimethyl acetal (26.1 ml,) in ethanol (33 ml) were heated at reflux under a nitrogen atmosphere for 30 minutes. The reaction mixture was concentrated under reduced pressure to give compound 126. Compound 126 (7.12 g, 0.0327 mol) was heated under reflux with 5% sodium hydroxide solution (130 ml) for 1 h, cooled to room temperature and then acidified with dilute hydrochloric acid to pH 6-7 and the product 127 was isolated by filtration. After drying in a vacuum oven, 127 was used without further purification.



1H NMR (DMSO-d6) δ 11.04 (br. s, 1H), 7.31 (br. s, 2H), 5.86 (m, 1H), 3.26 (m, 2H), 1.08 (t, 3H).


Method D (Alternate 2):




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Compound 128 (1.42 g, 0.0079 mol), thiol (1.41 ml, 0.0157 mol) and potassium carbonate (1.63 g, 0.0118 mol) in DMF (20 ml) were stirred at room temperature. Water was then added and the resulting precipitate filtered. The precipitate was then dried in a vacuum oven to provide product 129 which was used in subsequent reactions without purification. 1H NMR (CDCl3) δ 8.09 (d, 1H), 6.80 (br. s, 3H), 6.44 (d, 1H), 3.74 (s, 3H), 3.25 (q, 2H), 1.20 (t, 3H).


Method BG (Alternate 1):




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Compound 129 (1.44 g, 0.0057 mol) and N, N-dimethylformamide dimethyl acetal (1.53 ml, 0.0114 mol) in toluene (15 ml) were heated at reflux for 2 h. The reaction was cooled to room temperature and product 130 which precipitated was collected by filtration. 1H NMR (CDCl3): δ 8.36 (d, 1H), 7.58 (s, 1H), 6.32 (d, 1H), 3.88 (s, 3H), 3.75 (q, 2H), 1.37 (t, 3H). MS m/z calcd. for C12H12N3O2S+=262.1; found m/z=262.1 (M+1).


Method BZ:




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A mixture of p-anisidine (0.26 g, 0.0021 mol) and sodium hydride (0.132 g, 0.0033 mol of 60% slurry in mineral oil) in THF (10 ml) were stirred at room temperature for 30 minutes before adding compound 130 (0.145 g, 0.00055 mol). The resultant mixture was heated at reflux for 3 h, cooled to room temperature and ice-water was added. The precipitate was collected by filtration, dissolved in dichloromethane, dried (Na2SO4) and evaporated to give the desired product 131A. 1H NMR (CDCl3): δ 8.27 (d, 1H), 8.16 (s, 1H), 7.60 (br. s, 1H), 7.31 (d, 2H), 7.02 (d, 2H), 6.42 (d, 1H), 3.84 (s, 3H), 3.37 (q, 2H), 1.36 (t, 3H). MS m/z calcd. for C18H17N4O2S+=353.1; found m/z=353.1 (M+1).


The following compounds were prepared analogously:




















m/z Found


Cpd
Structure
Formula
MW
(M + 1)+







131A


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C18H16N4O2S
352.4
353.1





131B


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C17H14N4O2S
338.4
339.1





131C


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C18H13N5OS2
379.5
380.1





131D


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C18H16N4OS
336.4
337.1





131E


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C18H14N4O3S
366.4
367.1





131F


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C19H18N4OS
350.4
351.1





131G


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C18H15N5O2S2
397.5
397.1










Method CA:




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Compound 3 (4.89 g, 0.0269 mol), N-methylglycine ethyl ester (8.25 g, 0.0537 mol) and potassium carbonate (11.14 g, 0.0806 mol) in NMP (50 mL) were heated at 135° C. overnight under a nitrogen atmosphere. The reaction was cooled to room temperature and ice-water was added. It was extracted by ethyl acetate (100 mL×3) combined fractions washed with water and dried using sodium sulfate, filtered and evaporated under reduced pressure. Purification by column chramotography on silica gel using dichloromethane/ethyl acetate (9:1 to 4:1) led to product 132A. 1H NMR (CDCl3): δ 8.17 (d, 1H), 6.36 (d, 1H), 5.28 (br. s, 2H), 4.35 (q, 2H), 3.91 (s, 3H), 2.87 (s, 6H), 1.37 (t, 3H). MS m/z calcd. for C13H19N4O2+=263.2; found m/z=263.3 (M+1).


The following compounds were prepared analogously:




















m/z Found


Cpd
Structure
Formula
MW
(M + 1)+







132A


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C13H18N4O2
262.3
263.3












132B


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1H NMR (CDCl3): δ8.20 (d, 1H), 7.02 (d, 2H), 6.69 (d, 2H), 6.40(d, 1H), 5.65 (s, 2H), 5.30 (br. s, 2H), 3.79 (s,3H), 3.68 (s, 3H), 2.87 (s, 6H)











Method CB:




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A solution of compound 134H (0.017 g, 0.00004 mol) in trifluoroacetic acid (1.5 ml) was stirred in a microwave oven at 120° C. for 2 h. After the evaporation of the solvent, the residue was transferred to a preparative TLC and eluted using dichlomethane/ethyl acetate (4:1) to give the product 135A. 1H NMR (CDCl3): δ 8.33 (br. s, 1H), 8.03 (s, 1H), 7.31 (m, 4H), 6.40 (d, 1H), (s, 6H), 2.41 (s, 3H). MS m/z calcd. for C18H18N5O+=320.2; found m/z=320.2 (M+1).


Method CC:




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A mixture of compound 7H (0.12 g, 0.3 mmol), vinyltributyltin (0.099 g, 0.31 mmol) and tetrakis(triphenylphosphine) palladium (0.017 g, 0.015 mmol) in toluene (10 mL) was heated at reflux under a nitrogen atmosphere for 16 h. The reaction mixture was cooled to room temperature and transferred to a prep TLC and eluted using dichloromethane/ethyl acetate (9:1) several times to give the product 136. 1H NMR (CDCl3): δ 8.40 (d, 1H), 8.25 (s, 1H), 7.55 (d, 2H), 7.39 (d, 2H), 6.76 (d, 1H), 6.74 (dd, 1H), 5.81 (d, 1H), 5.34 (d, 1H), 3.12 (s, 6H). MS m/z calcd. for C19H17N4OS+=349.1; found m/z=349.1 (M+1).


Method CD:




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(Ref: Tetrahedron Lett. 43, 2002, 6987-6990)


To a suspension of bromide 7H (0.40 g, 0.99 mmol), cyclopropyl boronic acid (0.11 g, 1.3 mmol), potassium phosphate (0.74 g, 0.0035 mol), and tricyclohexylphosphine (0.028 g, 0.99 mmol) in toluene (5 mL) and water (200 □L) under a nitrogen atmosphere was added palladium acetate (0.011 g, 0.05 mmol). The mixture was heated at 100° C. for 3 h and then cooled to room temperature. The reaction was transferred to a prep TLC and eluted using dichloromethane/ethyl acetate (9:1) to give the product 137A. 1H NMR (CDCl3): δ 8.39 (d, 1H), 8.23 (s, 1H), 7.29 (d, 2H), 7.19 (d, 2H), 6.76 (d, 1H), 3.13 (s, 6H), 1.94 (m, 1H), 1.02 (m, 2H), 0.73 (m, 2H). MS m/z calcd. for C20H19N4OS+=363.1; found m/z=363.1 (M+1).


The following compound was prepared analogously:




















m/z Found


Cpd
Structure
Formula
MW
(M + 1)+







137B


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C20H18N4OS
362.4
363.1










Method CE:




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Compound 7AK (0.056 g, 0.17 mmol) was heated at reflux in acetic anhydride (3 mL) for 15 minutes. The reaction was cooled to room temperature and transferred to a preparative TLC. Elution using dichloromethane/ethyl acetate (9:1) led to product 138. 1H NMR (CDCl3): δ 8.40 (d, 1H), 8.25 (s, 1H), 7.45 (d, 2H), 7.26 (d, 2H), 6.77 (d, 1H), 3.13 (s, 6H), 2.31 (s, 3H). MS m/z calcd. for C19H17N4O3S+=381.1; found m/z=381.1 (M+1).


Method CF:




embedded image



(Ref: Tetrahedron 59, 2003, 341-352)


To a solution of compound 139 (10.54 g, 0.0752 mol) in dry DMF (60 mL) at 0° C., was added phosphorous oxychloride (14 ml, 0.150 mol) and mixture heated at 90° C. for 1 h. The solvent was evaporated under reduced pressure and ice-water was added. Product 140 was obtained by extracting the aqueous solution several times using dichloromethane, dried (Na2SO4) and concentration. 1H NMR (CDCl3): δ 9.99 (s, 1H), 8.02 (s, 1H), 3.49 (s, 3H), 3.45 (s, 3H).


Method CG:




embedded image



(Ref: J. Org. Chem. 1981, 46, 3949-3953)


To a solution of NaOEt in ethanol, prepared by slowly adding sodium (4.78 g) to dry ethanol (600 mL), was added aldehyde 140 (10.59 g, 0.063 mol) and cyanoacetamide (17.50 g, 0.208 mol). The mixture was then heated at reflux for a period of 2 h before evaporating solvent under reduced pressure. Water was then added to the residue and acidified by slow addition of conc. HCl until crystals started forming. This mixture was cooled in ice and filtered to give product 141. 1H NMR (DMSO-d6): δ 8.41 (d, 1H), 8.27 (d, 1H), 4.19 (q, 2H), 1.22 (t, 3H).


Method CH:




embedded image



(Ref: Pharmaceutical Chemistry Journal 31(11), 1997, 615-618)


A solution of 141 (6.75 g, 0.0352 mol) in phosphorous oxychloride (40 mL) was heated at reflux for 1 h, and excess solvent was evaporated under reduced pressure. Water was then added and the pH adjusted to pH˜7.5 using a 1N sodium hydroxide solution. The resulting precipitate 142 was collected, washed with water and dried under vacuum. 1H NMR (CDCl3): δ 9.11 (d, 1H), 8.54 (d, 1H), 4.22 (q, 2H), 1.39 (t, 3H).


Method CI:




embedded image


A mixture of 2-chloro-3-pyridine carbonitrile derivative 142 (1.97 g, 0.0094 mol), thiol derivative 108A (1.95 g, 0.0108 mol) and potassium carbonate (1.94 g, 0.014 mol) in DMF (30 mL) was stirred at 60° C. for 2 h. The reaction was cooled to room temperature before adding ice-water. The precipitate 143 was collected by filtration, washed with water and dried in a vacuum oven. 1H NMR (CDCl3): δ 9.22 (d, 1H), 8.55 (d, 1H), 7.41 (d, 2H), 7.14 (d, 2H), 7.13 (s, 1H), 6.24 (s, 2H), 4.43 (q, 2H), 2.30 (s, 3H), 1.41 (t, 3H). MS m/z calcd. for C18H18N3O3S+=356.1; found m/z=356.1 (M+1).


Method CJ:




embedded image


A mixture of compound 143A (3.06 g, 0.0086 mol) and triethylorthoformate (7.2 ml, 0.0431 mol) in 1% solution of acetic acid in toluene (30 mL) was heated at reflux overnight. The reaction was cooled to room temperature, diluted with ether and the solid precipitate was filtered. The solid was washed with more ether and dried under vacuum to give the desired product 144A. 1H NMR (CDCl3): δ 9.37 (d, 1H), 9.15 (d, 1H), 8.27 (s, 1H), 7.26-7.34 (m, 4H), 4.45 (q, 2H), 2.42 (s, 3H), 1.43 (t, 3H). MS m/z calcd. for C19H16N3O3S+=366.1; found m/z=366.1 (M+1).


Method CK:




embedded image


Compound 144A (1.02 g, 0.00279 mol) and potassium hydroxide (0.25 g, 0.0062 mol) were heated in refluxing ethanol for 1 h. Evaporated the solvent under vacuum and then quenched with water. The resulting solution was acidified with conc. HCl and the precipitate was filtered, washed with water and dried in a vacuum oven to give the desired acid 145A. 1H NMR (CDCl3): δ 9.24 (d, 1H), 8.91 (d, 1H), 8.63 (s, 1H), 7.42 (d, 2H), 7.34 (d, 2H), 2.35 (s, 3H). MS m/z calcd. for C17H12N3O3S+=338.1; found m/z=338.0 (M+1).


Method CL:




embedded image


Compound 145A (0.656 g, 0.00195 mol) was heated under reflux in thionyl chloride (10 mL) for a period of 2 h. The solvent was evaporated under reduced pressure and the residue was used in subsequent reactions without purification. 1H NMR (CDCl3): δ 9.34 (d, 1H), 9.22 (d, 1H), 8.27 (s, 1H), 7.33 (d, 2H), 7.28 (d, 2H), 2.40 (s, 3H). MS m/z calcd. for C17H11ClN3O2S+=356.0; found m/z=356.0 (M+1).


Method CM:




embedded image


Compound 146A (0.692 g, 0.00195 mol) and sodium azide (0.127 g, 0.00195 mol) were heated in a mixture of toluene and DMF (1:1) at 90° C. under a nitrogen atmosphere for 2 h. The solvent was then evaporated under reduced pressure leaving a solid residue. To this was added 8N hydrochloric acid (15 ml) and the mixture heated at reflux for 1 h. The reaction was cooled to room temperature and filtered. The filtrate was basified using concentrated ammonium hydroxide and extracted with dichloromethane. The organic layer was dried (Na2SO4) and evaporated in vacuo. Purification by preparative TLC using dichloromethane/acetone (9:1) led to product 147A.



1H NMR (DMSO-d6): δ 8.47 (s, 1H), 8.23 (d, 1H); 7.61 (d, 1H), 7.39 (d, 2H), 7.32 (d, 2H), 5.72 (s, 2H), 2.34 (s, 3H). MS m/z calcd. for C16H13N4OS+=309.1; found m/z=309.1 (M+1).


Method Y (Alternate):




embedded image


To a solution of compound 148 (4.70 g, 0.0134 mol) in acetic acid (60 mL) was added bromine (1.4 mL, 0.0267 mol) and the mixture heated at reflux overnight. The solvent was then evaporated under reduced pressure leaving a solid residue to which was added water. This mixture was basified using concentrated ammonium hydroxide and extracted with dichloromethane, dried (Na2SO4), filtered and evaporated under reduced pressure. Purification by column chromatography on silica gel followed by preparative TLC led to the isolation of compounds 149-152. Compound 149: 1H NMR (CDCl3): δ 8.60 (s, 1H), 8.19 (s, 1H), 7.62 (d, 1H), 7.37 (dd, 1H), 7.02 (d, 1H), 3.94 (s, 3H), 3.20 (s, 6H). Compound 150: 1H NMR (CDCl3): δ 8.51 (d, 1H), 8.31 (s, 1H), 7.69 (d, 1H), 7.33 (d, 2H), 7.03 (d, 2H), 3.85 (s, 3H). Compound 151: 1H NMR (CDCl3): δ 8.60 (s, 1H), 8.22 (s, 1H), 7.33 (d, 2H), 7.02 (d, 2H), 3.84 (s, 3H), 3.21 (s, 6H). MS m/z calcd. for C18H16BrN4O2S+=433.0; found m/z=433.1 (M+1). Compound 41: 1H NMR (DMSO-d6): δ 8.58 (s, 1H), 8.38 (s, 1H), 8.30 (m, 1H), 7.44 (d, 2H), 7.06 (d, 2H), 3.78 (s, 3H), 3.38 (d, 3H). MS m/z calcd. for C17H14BrN4O2S+=419.0; found m/z=419.1 (M+1).


IC50 Determination


A CHO cell line stably expressing hmGluR1 receptor was established. One day prior to assay, cells were split in growth media at concentration of 50,000 cells/well in a volume of 100 μl and seeded into black clear-bottom 96-well plates. After two to six hours, when cells were well attached to the plate, growth medium was replaced with assay medium (100 μL) consisting of DMEM high glucose, supplemented with GPT (1 U/mL) and Sodium pyruvate, 1 mM. Following overnight incubation, medium was discarded and cells were loaded for 2 h with dye from the Calcium 3 Assay Reagent Kit (Molecular Devices, # R8033), prepared according to manufacturers' instructions. A 96-tip pipettor/fluorometric imaging plate reader (FLIPR 384; Molecular Devices) was used and intracellular calcium mobilization was measured by increases in fluorescence upon agonist Quisqualate stimulation following 6 sec-baseline measurement. Test compounds were added 10 minutes before Quisqualate. IC50 determinations for tested compounds were generated against Quisqualate 1 μM corresponding to EC80 value in a standard dose response curve.


IC50s for representative compounds are shown in Table 2 below. Compounds with IC50 values greater than 1000 nM are designated as D class compounds. Compounds with IC50 values between 150 nM and 1000 nM are designated as C class compounds. Compounds with IC50 values between 50 nM and 150 nM are designated as B class compounds. Compounds with IC50 values less than 50 nM are designated as A class compounds.











TABLE 2






mGluR1




IC50


Cpd
(nM)
Structure







7A
A


embedded image







7B
A


embedded image







7C
B


embedded image







7D
A


embedded image







7E
D


embedded image







7F
B


embedded image







7G
A


embedded image







7H
A


embedded image







7I
D


embedded image







7J
D


embedded image







7K
A


embedded image







7L
A


embedded image







7M
D


embedded image







7N
C


embedded image







7O
B


embedded image







7P
B


embedded image







7Q
A


embedded image







7R
C


embedded image







7S
D


embedded image







7T
B


embedded image







7U
B


embedded image







7V
D


embedded image







7W
A


embedded image







7X
A


embedded image







7Y
A


embedded image







7Z
A


embedded image







7AA
A


embedded image







7AB
C


embedded image







7AC
A


embedded image







7AD
D


embedded image







7AE
C


embedded image







7AF
D


embedded image







7AG
D


embedded image







7AH
B


embedded image







7AI
C


embedded image







7AJ
A


embedded image







7AK
A


embedded image







7AL
D


embedded image







7AM
A


embedded image







7AN
C


embedded image







7AO
C


embedded image







7AP
A


embedded image







7AQ
D


embedded image







7AR
D


embedded image







7AS
A


embedded image







7AT
D


embedded image







7AU
D


embedded image







7AV
A


embedded image







7AW
B


embedded image







7AX
A


embedded image







7AY
A


embedded image







7AZ
D


embedded image







7BA
C


embedded image







7BB
D


embedded image







7BC
D


embedded image







7BD
D


embedded image







7BE
D


embedded image







7BF
A


embedded image







7BG
A


embedded image







7BH
D


embedded image







7BI
A


embedded image







7BJ
A


embedded image







7BK
C


embedded image







7BL
A


embedded image







7BM
A


embedded image







7BN
A


embedded image







7BO
A


embedded image







7BP
D


embedded image







7BQ
C


embedded image







7BR
C


embedded image







7BS
A


embedded image







7BT
D


embedded image







7BU
D


embedded image







7BV
D


embedded image







7BW
A


embedded image







7BX
D


embedded image







7BY
A


embedded image







7BZ
A


embedded image







7CA
A


embedded image







7CB
A


embedded image







7CC
A


embedded image







7CD
A


embedded image







7CE
A


embedded image







7CF
A


embedded image







7CG
A


embedded image







7CH
C


embedded image







7CI
C


embedded image







7CJ
B


embedded image







7CK
A


embedded image







7CL
B


embedded image







7CM
A


embedded image







7CN
B


embedded image







7CO
B


embedded image







7CP
B


embedded image







7CQ
A


embedded image







7CR
A


embedded image







7CS
C


embedded image







7CT
A


embedded image







7CU
A


embedded image







7CV
A


embedded image







7CW
B


embedded image







7CX
B


embedded image







7CY
A


embedded image







7CZ
A


embedded image







7DA
C


embedded image







7DB
A


embedded image







7DC
A


embedded image







7DD
C


embedded image







7DE
A


embedded image







7DF
A


embedded image







7DG
A


embedded image







7DH
A


embedded image







7DI
A


embedded image







7DJ
A


embedded image







7DK
A


embedded image







7DL
A


embedded image







7DM
C


embedded image







7DN
B


embedded image







7DO
A


embedded image







7DP
B


embedded image







7DQ
A


embedded image







7DR
A


embedded image







7DS
C


embedded image







7DT
C


embedded image







7DU
A


embedded image







7DV
A


embedded image







7DW
A


embedded image







7DX
A


embedded image







7DY
B


embedded image







7DZ
A


embedded image







7EA
A


embedded image







7EB



embedded image







7EC



embedded image







11
D


embedded image







12A
C


embedded image







12B
B


embedded image







13
C


embedded image







14
D


embedded image







15A
D


embedded image







15B
C


embedded image







15C
A


embedded image







15D
D


embedded image







15E
B


embedded image







15F
C


embedded image







15G
D


embedded image







15H
C


embedded image







15I
C


embedded image







15J
B


embedded image







15K
D


embedded image







15L
D


embedded image







15M
D


embedded image







15N
D


embedded image







15O
D


embedded image







15P
C


embedded image







15Q
A


embedded image







15T
C


embedded image







15U
C


embedded image







15V
C


embedded image







15W
D


embedded image







15X
D


embedded image







15Y
A


embedded image







15Z
A


embedded image







15AA
A


embedded image







15AB
A


embedded image







15AC
D


embedded image







15AD
B


embedded image







15AE
B


embedded image







15AF
C


embedded image







15AG
A


embedded image







15AH
B


embedded image







15AI



embedded image







15AJ



embedded image







15AK



embedded image







19
C


embedded image







25A
C


embedded image







25B
C


embedded image







25C
B


embedded image







25D
C


embedded image







26A
D


embedded image







26C
D


embedded image







27A
D


embedded image







28A
D


embedded image







28B
D


embedded image







28C
D


embedded image







28D
D


embedded image







28E
D


embedded image







28F
D


embedded image







28G
C


embedded image







28H
D


embedded image







28I
A


embedded image







28J
C


embedded image







28K
D


embedded image







28L
D


embedded image







28M
D


embedded image







28N
D


embedded image







28O
D


embedded image







28P
A


embedded image







28Q
B


embedded image







28R
C


embedded image







28S
A


embedded image







28T
D


embedded image







28U
D


embedded image







28V
C


embedded image
























mGluR1




IC50


Cpd
(nM)
Structure







28W
C


embedded image







28X
A


embedded image







28Y
A


embedded image







28Z
A


embedded image







28AA
A


embedded image







28AB
A


embedded image







28AC
A


embedded image







28AD
B


embedded image







28AE
A


embedded image







28AF
D


embedded image







28AG
B


embedded image







28AH
C


embedded image







28AI
A


embedded image







28AJ
C


embedded image







28AK
A


embedded image







28AL
A


embedded image







28AM
B


embedded image







28AN
A


embedded image







28AO
A


embedded image







28AP
A


embedded image







28AQ
B


embedded image







28AR
A


embedded image







28AS
A


embedded image







28AT
A


embedded image







28AU
A


embedded image







28AV
A


embedded image







28AW
A


embedded image







28AX
C


embedded image







28AY
C


embedded image







28AZ
A


embedded image







28BA
C


embedded image







28BB
A


embedded image







28BC
A


embedded image







29A
C


embedded image







29B
D


embedded image







29C
B


embedded image







29D
B


embedded image







30A
D


embedded image







30B
D


embedded image







30C
D


embedded image







37A
C


embedded image







37B
C


embedded image







37C
B


embedded image







37D
C


embedded image







37E
A


embedded image







37F
B


embedded image







37G
C


embedded image







37H
D


embedded image







40
D


embedded image







41
B


embedded image







42
B


embedded image







43
C


embedded image







44
A


embedded image







45
A


embedded image







46
A


embedded image







47A
C


embedded image







47B
D


embedded image







48
C


embedded image







49
D


embedded image







50
C


embedded image







51
A


embedded image







52
C


embedded image







53
D


embedded image







54
C


embedded image







55
B


embedded image







57



embedded image







58
A


embedded image







59A
D


embedded image







59B
D


embedded image







59C
D


embedded image







60A
A


embedded image







60B
A


embedded image







60C
A


embedded image







60D
A


embedded image







60E
A


embedded image







60F
B


embedded image







60G
A


embedded image







60H
D


embedded image







60I
B


embedded image







60J
D


embedded image







60L
C


embedded image







61A
D


embedded image







61B
D


embedded image







62
D


embedded image







63
C


embedded image







64
D


embedded image







65A
D


embedded image







65B
D


embedded image







65C
D


embedded image







65D
D


embedded image







65E
D


embedded image







66A
A


embedded image







66B
D


embedded image







66C
D


embedded image







66D
A


embedded image







66E
D


embedded image







71A
A


embedded image







72A
A


embedded image







72B
A


embedded image







72C
A


embedded image







72D
D


embedded image







72E
D


embedded image







72F
D


embedded image







72G
A


embedded image







72H
A


embedded image







72I
A


embedded image







73A
D


embedded image







73B
D


embedded image







73C
D


embedded image







73D
D


embedded image







73E
D


embedded image







73F
D


embedded image







73G
D


embedded image







76
D


embedded image







77
D


embedded image







78
D


embedded image







80
D


embedded image







83
B


embedded image







84
B


embedded image







85
D


embedded image







87A
C


embedded image







87B
B


embedded image







95B
A


embedded image







95C
A


embedded image







95D
A


embedded image







95E
A


embedded image







95F
A


embedded image







95G
A


embedded image







95H
A


embedded image







95I
A


embedded image







95J
C


embedded image







95K
A


embedded image







95L
A


embedded image







95M
B


embedded image







95N
A


embedded image







95O
A


embedded image







95P
A


embedded image







95Q
A


embedded image







95R
A


embedded image







95S
A


embedded image







95T
A


embedded image







95U
A


embedded image







95V
C


embedded image







95W
A


embedded image







95X
A


embedded image







95Y
A


embedded image







95Z
A


embedded image







95AA
A


embedded image







95AB
C


embedded image







95AC
A


embedded image







95AD
A


embedded image







95AE



embedded image







95AF



embedded image







95AG



embedded image







95AH



embedded image







95AI



embedded image







95AJ



embedded image







95AK



embedded image







95AL



embedded image







95AM



embedded image







95AN



embedded image







103A
B


embedded image







103B
C


embedded image







103C
C


embedded image







103D
B


embedded image







103E
B


embedded image







103F
C


embedded image







104
D


embedded image







105
D


embedded image







106



embedded image







113A
A


embedded image







113B
A


embedded image







113C
C


embedded image







113D
A


embedded image







113E
A


embedded image







113F
A


embedded image







113G
A


embedded image







113H
A


embedded image







113I
A


embedded image







113J
C


embedded image







113K
A


embedded image







113L
C


embedded image







113M
B


embedded image







113N
B


embedded image







115
D


embedded image







116
C


embedded image







116A
B


embedded image







116B
C


embedded image







116C
C


embedded image







116D
A


embedded image







116E
B


embedded image







116F
C


embedded image







116G
C


embedded image







117
B


embedded image







117A
C


embedded image







117B
C


embedded image







118



embedded image







131A
A


embedded image







131B
A


embedded image







131C
A


embedded image







131D
A


embedded image







131E
A


embedded image







131F
B


embedded image







131G
A


embedded image







134A
C


embedded image







134B
C


embedded image







134C
D


embedded image







134D
D


embedded image







134E
D


embedded image







134F
C


embedded image







134G
D


embedded image







134H
D


embedded image







134I
D


embedded image







135A
D


embedded image







136
A


embedded image







137A
A


embedded image







137B
A


embedded image







138
A


embedded image







144A
B


embedded image







147A
C


embedded image







148
A


embedded image







149
D


embedded image







150
C


embedded image







151
A


embedded image







152
A


embedded image







P-1
A


embedded image







P-2
A


embedded image







P-3
A


embedded image







P-4
C


embedded image







P-5
C


embedded image







P-6
C


embedded image







P-7
C


embedded image







P-8
C


embedded image







P-9
C


embedded image







P-10
C


embedded image







P-11
C


embedded image







P-12
C


embedded image







P-13
C


embedded image







P-14
C


embedded image







P-15
C


embedded image











Representative preferred compounds have IC50 values as shown in Table 3.














TABLE 3







Cpd
mGluR1 IC50 (nM)
Cpd
mGluR1 IC50 (nM)





















7Q
0.35
95A
1.68



7X
0.68
7DV
1.71



95B
1
7DR
1.73



28AI
1.27
28AA
1.81



28Z
1.47
7AC
1.84



7BM
1.48
7DH
2.02









Claims
  • 1. A compound of formula I:
  • 2. The compound of claim 1, wherein R1 and R2 are taken together to form (═O) or (═S).
  • 3. The compound of claim 1 represented by formula Ia:
  • 4. The compound of claim 3, wherein X is S.
  • 5. The compound of claim 4, wherein J1 and J3 are each N and J2 and J4 are each C(R).
  • 6. The compound of claim 4, wherein J2 and J3 are C(H) or C(halo).
  • 7. The compound of any one of claims 4, wherein R4is H.
  • 8. The compound of claim 7, wherein R is H, halo, alkyl, alkoxy, cycloalkyl, heteroaryl, —OSO2R6, or —NR6R7 wherein R6 and R7 are optionally taken together with the nitrogen atom form a 4-7 membered heterocyclic ring having 0-1 heteroatoms independently selected from O or N in addition to said nitrogen atom.
  • 9. The compound of claim 8, wherein R is H, —N(C1-C6 alkyl)2, —NH(C1-C6 alkyl), halo, —C1-C6 alkoxy, —OSO2CF3, —NH—(C3-C6 cycloalkyl), —NH-phenyl, N-piperidinyl, N-morpholinyl, C1-C6 alkyl, C3-C6 cycloalkyl, N-pyrrolyl, N-pyrazolyl, N-piperazinyl, or N-pyrrolidinyl optionally substituted with hydroxy or (═O).
  • 10. The compound of claim 9, wherein the (C1-C6 alkyl) of said —NH(C1-C6 alkyl) is optionally substituted with —OH or —CF3.
  • 11. The compound of claim 3, wherein R3 is alkyl, alkoxyalkyl, cycloalkyl, heteroaryl, heteroaralkyl, cycloalkylalkyl, aralkyl, aryl, heterocyclyl or heterocyclylalkyl; wherein each member of R3 is optionally substituted with one or more substituents independently selected from halo, —CN, —OR12, alkyl, alkoxy, —OCF3, —OCHF2, amino, alkylamino, dialkylamino, hydroxyalkyl, —NR12C(O)R12, —C(O)N(R12)2, cyanoalkyl, —CO2R12, —CF3, or two adjacent substituent form a methylenedioxy or ethylenedioxy; and said heterocyclyl is additionally and optionally substituted by (═O).
  • 12. The compound of claim 11, wherein R3 is C1-C6 alkyl, C3-C7 monocyclic cycloalkyl, 9-membered cycloalkylaryl, 9-membered cycloalkenylaryl, 6-membered monocyclic heteroaryl or heterocyclyl, 9- to 10-membered bicyclic heteroaryl or heterocyclyl, C6 cycloalkyl(C1-C6)alkyl, ar(C1-C6)alkyl, or aryl; wherein said aryl is optionally substituted with one or more substituents independently selected from halo, —CN, —OH, C1-C6 alkyl, C1-C6 alkoxy, —OCF3, —OCHF2, amino, C1-C6 alkylamino, di(C1-C6)alkylamino, hydroxy(C1-C6)alkyl, or two adjacent substituents of said aryl are linked to form a methylenedioxy or ethylenedioxy.
  • 13. The compound of claim 12, wherein R3 is cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, benzyl, α-phenethyl, pyridyl, n-butyl, indolyl, benzothiazolyl, benzoimidazolyl, benzooxazolyl, cyclohexylmethyl, pyrano, indanyl, indenyl, phenyl, or 3,4-dihydrobenzo[1,4]oxazinyl; wherein said phenyl is optionally substituted with halo, —CN, —OMe, —OCF3, —OCHF2, —NMe2, —OH, —CH2OH, methyl, ethyl or two adjacent substituents of said phenyl are linked to form a methylenedioxy or ethylenedioxy; and said 3,4-dihydrobenzo[1,4]oxazinyl is optionally substituted with (═O).
  • 14. The compound of claim 12, wherein said aryl or phenyl is p-substituted.
  • 15. A compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
  • 16. The compound of claim 15, wherein the compound is selected from the group consisting of 95A, 95B, 96C, 95D, 95E, 95F, 95G, 95H, 95I, 95K, 95L, 95N, 95O, 95P, 95Q, 95R, 95S, 95T, 95U, 95W, 95X, 95Y, 95Z, 95AA, 95AC, and 95AD, or a pharmaceutically acceptable salt thereof.
  • 17. The compound of claim 16, selected from the group consisting of 95A, 95B, 95C, 95E, 95F, 95G, 95H, 95K, 95L, 95P, 95Q, 95S, 95T, 95Z, 95AA, and 95AC or pharmaceutically acceptable salt thereof.
  • 18. A pharmaceutical composition comprising at least one compound of claim 1 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier, adjuvant or vehicle.
  • 19. The pharmaceutical composition of claim 18, further comprising one or more additional therapeutic agents.
  • 20. The pharmaceutical composition of claim 19, wherein said additional therapeutic agents are selected from the group consisting of therapeutic agents suitable for pain management, anti-anxiety agents, anti-migraine agents, and therapeutic agents suitable for treating urinary incontinence.
CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority of U.S. Provisional application Ser. No. 60/579,920, filed Jun. 15, 2004.

US Referenced Citations (4)
Number Name Date Kind
6232320 Stewart et al. May 2001 B1
20020151544 Masahiko et al. Oct 2002 A1
20060167029 Matasi et al. Jul 2006 A1
20060189639 Stewart et al. Aug 2006 A1
Foreign Referenced Citations (3)
Number Date Country
WO 0132632 May 2001 WO
WO 02062803 Aug 2002 WO
WO 2006081072 Aug 2006 WO
Related Publications (1)
Number Date Country
20060009477 A1 Jan 2006 US
Provisional Applications (1)
Number Date Country
60579920 Jun 2004 US