# Patent

## Title
mGluR1 antagonists as therapeutic agents

## 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.

## Background
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 undesirable 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 psychosis, 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:




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;
 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 —SR12, 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;
R4 is 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;
R5 is R3 when  is a single bond and R5 is absent when  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)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), 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: when  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: when  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, CO2R2, 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: when  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: when  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-fluorophenyl; then R4 is not —NR6R7;

proviso 5: when  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;
        R5 is 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  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: when  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: when  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  is a double bond and R1 and R2 taken together are (═O) represented by formula Ia. In another embodiment, X is S (formula IIa) or O (formula IIb). In yet another embodiment, X is S (formula IIa).




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]pyrimidin-4-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.







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, 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). 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 I





Cpd
Structure







7A






 


7B






 


7C






 


7D






 


7E






 


7F






 


7G






 


7H






 


7I






 


7J






 


7K






 


7L






 


7M






 


7N






 


7O






 


7P






 


7Q






 


7R






 


7S






 


7T






 


7U






 


7V






 


7W






 


7X






 


7Y






 


7Z






 


7AA






 


7AB






 


7AC






 


7AD






 


7AE






 


7AF






 


7AG






 


7AH






 


7AI






 


7AJ






 


7AK






 


7AL






 


7AM






 


7AN






 


7AO






 


7AP






 


7AQ






 


7AR






 


7AS






 


7AT






 


7AU






 


7AV






 


7AW






 


7AX






 


7AY






 


7AZ






 


7BA






 


7BB






 


7BC






 


7BD






 


7BE






 


7BF






 


7BG






 


7BH






 


7B1






 


7BJ






 


7BK






 


7BL






 


7BM






 


7BN






 


7BO






 


7BP






 


7BQ






 


7BR






 


7BS






 


7BT






 


7BU






 


7BV






 


7BW






 


7BX






 


7BY






 


7BZ






 


7CA






 


7CB






 


7CC






 


7CD






 


7CE






 


7CF






 


7CG






 


7CH






 


7CI






 


7CJ






 


7CK






 


7CL






 


7CM






 


7CN






 


7CO






 


7CP






 


7CQ






 


7CR






 


7CS






 


7CT






 


7CU






 


7CV






 


7CW






 


7CX






 


7CY






 


7CZ






 


7DA






 


7DB






 


7DC






 


7DD






 


7DE






 


7DF






 


7DG






 


7DH






 


7DI






 


7DJ






 


7DK






 


7DL






 


7DM






 


7DN






 


7DO






 


7DP






 


7DQ






 


7DR






 


7DS






 


7DT






 


7DU






 


7DV






 


7DW






 


7DX






 


7DY






 


7DZ






 


7EA






 


7EB






 


7EC






 


11






 


12A






 


12B






 


13






 


14






 


15A






 


15B






 


15C






 


15D






 


15E






 


15F






 


15G






 


15H






 


15I






 


15J






 


15K






 


15N






 


15O






 


15P






 


15Q






 


15R






 


15S






 


15T






 


15U






 


15V






 


15W






 


15X






 


15Y






 


15Z






 


15AA






 


15AB






 


15AC






 


15AD






 


15AE






 


15AF






 


15AG






 


15AH






 


15AI






 


15AJ






 


15AK






 


19






 


25A






 


25B






 


25C






 


25D






 


26A






 


26C






 


27A






 


27B






 


27C






 


28A






 


28B






 


28C






 


28D






 


28E






 


28F






 


28G






 


28H






 


28I






 


28J






 


28K






 


28L






 


28M






 


28N






 


28O






 


28P






 


28Q






 


28R






 


28S






 


28T






 


28U






 


28V






 


28W






 


28X






 


28Y






 


28Z






 


28AA






 


28AB






 


28AC






 


28AD






 


28AE






 


28AF






 


28AG






 


28AH






 


28AI






 


28AJ






 


28AK






 


28AL






 


28AM






 


28AN






 


28AO






 


28AP






 


28AQ






 


28AR






 


28AS






 


28AT






 


28AU






 


28AV






 


28AW






 


28AX






 


28AY






 


28AZ






 


28BA






 


28BB






 


28BC






 


29A






 


29B






 


29C






 


29D






 


30A






 


30B






 


30C






 


37A






 


37B






 


37C






 


37D






 


37E






 


37F






 


37G






 


37H






 


40






 


41






 


42






 


43






 


44






 


45






 


46






 


47A






 


47B






 


48






 


49






 


50






 


51






 


52






 


55






 


58






 


59A






 


59B






 


59C






 


60A






 


60B






 


60C






 


60D






 


60E






 


60F






 


60G






 


60H






 


60I






 


60J






 


60L






 


61A






 


61B






 


62






 


63






 


64






 


65A






 


65B






 


65C






 


65D






 


65E






 


66A






 


66B






 


66C






 


66D






 


66E






 


72A






 


72B






 


72C






 


72D






 


72E






 


72F






 


72G






 


72H






 


72I






 


73A






 


73B






 


73C






 


73D






 


73E






 


73F






 


76






 


77






 


78






 


80






 


83






 


84






 


85






 


87A






 


87B






 


87C






 


95A






 


95B






 


95C






 


95D






 


95E






 


95F






 


95G






 


95H






 


95I






 


95J






 


95K






 


95L






 


95M






 


95N






 


95O






 


95P






 


95Q






 


95R






 


95S






 


95T






 


95U






 


95V






 


95W






 


95X






 


95Y






 


95Z






 


95AA






 


95AB






 


95AC






 


95AD






 


95AE






 


95AF






 


95AG






 


95AH






 


95AI






 


95AJ






 


95AK






 


95AL






 


95AM






 


95AN






 


103A






 


103B






 


103C






 


103D






 


103E






 


103F






 


104






 


105






 


106






 


113A






 


113B






 


113C






 


113D






 


113E






 


113F






 


113G






 


113H






 


113I






 


113J






 


113K






 


113L






 


113M






 


113N






 


115






 


116






 


116A






 


116B






 


116C






 


116D






 


116E






 


116F






 


116G






 


117






 


117A






 


117B






 


118






 


131A






 


131B






 


131C






 


131D






 


131E






 


131F






 


131G






 


134A






 


134B






 


134C






 


134D






 


134E






 


134F






 


134G






 


134H






 


134I






 


135A






 


136






 


137A






 


137B






 


138






 


144A






 


147A






 


148






 


149






 


150






 


151






 


152






 


P-1






 


P-2






 


P-3






 


P-4






 


P-5






 


P-6






 


P-7






 


P-8






 


P-9






 


P-10






 


P-11






 


P-12






 


P-13






 


P-14






 


P-15













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, 7 DB, 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, 131B, 131C, 131D, 131E, 131G, 136, 137A, 137B, 138, 148, 151, and 152, or a pharmaceutically 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, 131C, 131D, 131E, 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 hydrogen 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:




and the like.

“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:




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:




represents





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, Alzheimers 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.






































































































































































































































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) δ 7.22 (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, 128, 158 and 166 were prepared analogously from 119, 127, 157 and 165, respectively.



















m/z Found


Cpd
Structure
Formula
MW
(M + 1)+







120




C9H10ClN3
195.6
196.0


 


128




C8H8ClN3
181.6
182.1


 


158




C6H4ClN3O
169.6
170.1


 


166




C15H9ClN4OS
328.8
329.1









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): δ 7.97 (d, 1H), 6.28 (d, 1H), 3.93 (s, 2H), 3.70 (s, 3H), 3.18 (s, 6H).

The following compounds were prepared analogously:


















m/z calcd
m/z Found


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



















 34




C11H14N3O2S+
252.1
252.1


 









121




1H NMR (CDCl3) δ 6.13 (s, 1 H), 3.89 (s, 2 H), 3.69 (s, 3 H), 3.14 (s, 6 H), 2.29 (s, 3 H).


 











159




C9H10N3O3S+
240.04
240.09


 









162




1H NMR (CDCl3) δ 7.69 (s, 1 H), 5.99 (dd, 1 H), 4.05 (d, 1 H), 3.73-3.68 (m, 6 H), 2.10- 1.98 (m, 2 H), 1.66-1.50 (m, 4 H).









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): δ 8.41 (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




C11H14N3O2S+
252.1
252.1


 









122




1H NMR (CDCl3) δ 6.67 (br. s, 3 H), 3.82 (s, 3 H), 2.79 (s, 6 H), 2.55 (s, 3 H).


 











160




C9H10N3O3S+
240.04
240.09









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): δ 8.24 (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




C14H19N4O2S+
307.1
307.1


 


123 




C15H21N4O2S+
321.1
321.1


 


133A




C16H24N5O2+
318.2
318.2


 


133B




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 24 h. 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, 1H), 6.76 (d, 1H), 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




C18H14N4O3S
366.4
367.2


 


 7B




C17H13ClN4OS
356.8
357.1


 


 7C




C18H16N4OS
336.4
337.1


 


 7D




C17H14N4OS
322.4
323.1


 


 7E




C11H10N4OS
246.3


 


 7F




C17H13ClN4OS
356.8
357.1


 


 7G




C17H13FN4OS
340.4
341.1


 


 7H




C17H13BrN4OS
401.3
403.1


 


 7I




C18H15ClN4OS
370.9
371.2


 


 7J




C19H23N5O3S
401.5
402.1


 


 7K




C18H13N5OS
347.4
348.1


 


 7L




C17H13ClN4OS
356.8
357.2


 


 7M




C17H13IN4OS
448.3
449.1


 


 7N




C17H12ClIN4OS
482.7
483.1


 


 7O




C16H13N5OS
323.4
324.1


 


 7P




C15H18N4OS
302.4
303.1


 


 7Q




C17H20N4OS
328.4
329.1


 


 7R




C18H15ClN4OS
370.9
371.1


 


 7S




C18H14Cl2N4OS
405.3
405.1


 


 7T




C18H15ClN4O2S
386.9
387.2


 


 7U




C16H13N5OS
323.4
324.1


 


 7V




C19H17ClN4O3S
416.9
417.1


 


 7W




C16H18N4OS
314.4
315.1


 


 7X




C18H22N4OS
342.5
343.1


 


 7Y




C18H13F3N4O2S
406.4
407.1


 


 7Z




C18H14F2N4O2S
388.4
389.1


 


 7AA




C18H16N4O2S
352.4
353.1


 


 7AB




C14H14N4OS
286.4
287.2


 


 7AC




C19H16N4O3S
380.4
381.2


 


 7AD




C19H18N4O3S
382.4
383.2


 


 7AE




C19H18N4O2S
366.4
367.1


 


 7AF




C20H20N4O4S
412.5
413.1


 


 7AG




C20H20N4O2S
380.5
381.1


 


 7AH




C19H18N4OS
350.4
351.1


 


 7AI




C21H20N4OS
376.5
377.1


 


 7AJ




C19H19N5OS
365.5
366.1


 


 7AK




C17H14N4O2S
338.4
339.1


 


 7AL




C19H17N5O2S
379.4
380.1


 


 7AM




C19H15N5OS
361.4
362.1


 


 7AN




C18H14N6OS
362.4
363.1


 


 7AO




C17H13N7OS
363.4
363.1 (M+)


 


 7AP




C18H15FN4O2S
370.4
371.1


 


 7AQ




C20H20N4O2S
380.5
381.1


 


 7AR




C19H15N5O3S
393.4
394.1


 


 7AS




C18H13N5OS2
379.5
380.1


 


 7AT




C19H15N5OS2
393.5
394.1


 


 7AU




C17H14N4O3S2
386.4
387.1


 


 7AV




C17H14N4O2S
338.4
339.2


 


 7AW




C18H14N6OS
362.4
363.1


 


 7AX




C19H18N4O3S
382.4
383.1


 


 7AY




C18H16N4O2S
352.4
353.2


 


 7AZ




C18H15N5O2S
365.4
366.2


 


 7BA




C20H20N4OS
364.5
365.2


 


 7BB




C21H22N4OS
378.5
379.2


 


 7BC




C19H15N5OS
361.4
362.2


 


 7BD




C19H13F3N6OS
430.4
431.2


 


 7BE




C19H15N5O2S
377.4
378.2


 


 7BF




C18H16N4OS
336.4
337.1


 


 7BG




C18H16N4O2S
352.4
353.1


 


 7BH




C14H12N4OS
284.3
285.1


 


 7BI




C20H18N4OS
362.4
363.1


 


 7BJ




C19H18N4OS
350.4
351.1


 


 7BK




C20H20N4OS
364.5
365.1


 


 7BL




C20H16N4OS
360.4
361.1


 


 7BM




C19H14N4OS2
378.5
379.2


 


 7BN




C17H12N6OS2
380.4
381.2


 


 7BO




C19H15N5O3S
393.4
394.2


 


 7BP




C19H15N5O2S2
409.5
410.2


 


 7BQ




C18H13N5OS2
379.5
380.2


 


 7BR




C17H12N6O2S
364.4
365.1


 


 7BS




C18H13N5O2S
363.4
364.2


 


 7BT




C19H15N5O2S
377.4
378.2


 


 7BU




C19H15N5O2S
377.4
378.2


 


 7BV




C19H16N6OS
376.4
377.2


 


 7BW




C17H15N5O2S
353.4
354.2


 


 7BX




C18H14Br2N4O2S
510.2
511.1


 


 7BY




C19H14N4O2S
362.4
363.1


 


 7BZ




C17H11N5OS2
365.4
366.1


 


 7CA




C17H13FN4O2S
356.4
357.2


 


 7CB




C17H12N4O3S
352.4
353.2


 


 7CC




C18H16N4OS
336.4
337.1


 


 7CD




C16H12N4O2S
324.4
325.2


 


 7CE




C19H18N4O2S
366.4
367.1


 


 7CF




C18H17N5OS
351.4
352.2


 


 7CG




C19H16N4O2S
364.4
365.1


 


 7CH




C20H18N4O3S
394.4
395.1


 


 7CI




C19H17N5O2S
379.4
380.1


 


 7CJ




C19H18N4O2S
366.4
367.1


 


 7CK




C19H18N4OS
350.4
351.1


 


 7CL




C19H17FN4O2S
384.4
385.1


 


 7CM




C18H15ClN4OS
370.9
371.1


 


 7CN




C20H18N4O2S
378.4
379.1


 


 7CO




C19H15N5OS2
393.5
394.1


 


 7CP




C20H20N4OS
364.5
365.1


 


 7CQ




C18H16N4OS2
368.5
369.1


 


 7CR




C18H13N5OS2
379.5
380.1


 


 7CS




C18H14N6O2S
378.4
379.1


 


 7CT




C17H13FN4O2S
356.4
357.1


 


 7CU




C18H16N4OS
336.4
337.1


 


 7CV




C19H18N4OS
350.4
351.1


 


 7CW




C18H16N4OS
336.4
337.1


 


 7CX




C17H15N5OS
337.4
338.1


 


 7CY




C18H15BrN4OS
415.3
417.1 415.1


 


 7CZ




C18H22N4OS
342.5
343.2


 


 7DA




C19H18N4OS2
382.5
383.2


 


 7DB




C18H16N4OS
336.4
337.1


 


 7DC




C18H15FN4OS
354.4
355.2


 


 7DD




C17H15N5OS
337.4
338.2


 


 7DE




C17H15N5OS
337.4
338.1


 


 7DF




C17H15N5OS
337.4
338.1


 


 7DG




C18H15ClN4OS
370.9
371.1


 


 7DH




C18H15FN4OS
354.4
355.1


 


 7DI




C19H18N4O2S
366.4
367.1


 


 7DJ




C19H18N4O2S
366.4
367.1


 


 7DK




C18H15FN4O2S
370.4
371.1


 


 7DL




C17H13BrN4OS
401.3
403.1


 


 7DM




C19H15F3N4OS
404.4
405.2


 


 7DN




C18H15BrN4OS
415.3
415.1 417.1


 


 7DO




C18H13F3N4OS
390.4
391.2


 


 7DP




C19H15N5OS
361.4
462.1


 


 7DQ




C18H15BrN4OS
415.3
417.1 415.1


 


 7DR




C18H15BrN4OS
415.3
417.1 415.1


 


 7DS




C18H12BrF3N4OS
469.3
471.1


 


 7DT




C18H15BrN4O2S
431.3
433.1


 


 7DU




C17H12BrFN4OS
419.3
421.1 419.1


 


 7DV




C17H12BrFN4OS
419.3
421.1 419.1


 


 7DW




C18H15FN4OS
354.4
355.1


 


 7DX




C18H15FN4OS
354.4
355.1


 


 7DY




C18H15IN4OS
462.3
463.1


 


 7DZ




C18H15FN4OS
354.4
355.2


 


 7EA




C18H15IN4OS
462.3
463.3


 


 7EB




C18H15FN4O2S
370.4
371.2


 


 7EC




C18H15FN4O2S
370.4
371.2


 


 37A




C17H20N4OS
328.1
329.1


 


 37B




C18H13N5OS2
379.1
380.2


 


 37C




C19H16N4O3S
380.1
381.2


 


 37D




C17H14N4OS
322.1
323.1


 


 37E




C17H13ClN4OS
356.1
357.2


 


 37F




C18H16N4O2S
352.1
353.2


 


 37G




C18H15FN4O2S
370.4
371.2


 


 37H




C17H14N4O2S
338.4
339.2


 


 40




C15H10N4O2S
310.1
311.0


 


134A




C19H19N5O
333.4
334.1


 


134B




C19H19N5O2
349.4
350.1


 


134C




C19H19N5OS
365.5
366.1


 


134D




C19H17F2N5O2
385.4
386.1


 


134E




C19H16N6OS
376.4
377.1


 


134F




C18H16ClN5O
353.8
354.1


 


134G




C18H23N5O
325.4
326.1


 


134H




C26H25N5O2
439.5
440.1


 


134I




C25H23N5O2
425.5
426.1









Method G:





(refs.: (a) A. D. Dunn, R. Norrie, J. Heterocyclic Chem. 1987, 24, 85; (b) J. A. Van Allan, 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




C16H16N4OS
312.4
313.1


 


10C




C14H11N3O2
253.3
254.1


 


10D




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




C17H13ClN4O2S
372.8
373.1


 


53




C17H13ClN4O2S
372.8
373.1


 


56




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




C17H12Cl2N4OS
391.3
391.1


 


57




C18H15ClN4OS
370.9
371.2


 


78




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): δ 8.37 (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




C15H16N4OS
300.4
301.2


 


15C




C18H22N4OS
342.5
343.1


 


15D




C14H16N4O2S
304.4
305.0


 


15E




C16H18N4O2S
330.4
331.2


 


15F




C16H18N4O2S
330.4
331.1


 


15G




C16H19N5OS
329.4
330.1


 


15H




C16H14N4O2S
326.4
327.1


 


15I




C16H14N4OS2
342.4
343.1


 


15J




C15H16N4OS
300.4
301.1


 


15K




C14H14N4OS
286.4
287.0


 


15L




C14H16N4OS
288.4
289.0


 


15M




C21H28N4OS
384.5
385.2


 


15N




C17H21N5O2S
359.5
360.1


 


15O




C18H23N5OS
357.5
358.1


 


15P




C15H18N4OS
302.4
303.2


 


15Q




C19H24N4OS
356.5
357.1


 


15R




C14H11N5OS2
329.4
330.1


 


15S




C15H13N5O2S
327.4
328.1


 


15T




C17H20N4O2S
344.4
345.1


 


15U




C17H21N5OS
343.4
344.1


 


15V




C16H14N4OS2
342.4
343.1


 


15W




C14H12N6OS
312.3
313.2


 


15X




C13H10N6OS2
330.4
331.2


 


15Y




C20H18N4OS
362.4
363.1


 


15Z




C18H22N4OS
342.5
343.1


 


15AA




C15H12N4OS2
328.4
329.2


 


15AB




C15H12N4OS2
328.4
329.1


 


15AC




C17H18N6OS
354.4
355.2


 


15AD




C16H15N5O2S
341.4
342.2


 


15AE




C15H13N5O2S
327.4
328.2


 


15AF




C14H9F3N6OS2
398.4
399.1


 


15AG




C19H14N4OS2
378.5
379.1


 


15AH




C19H22N4O3S
386.5
387.2









Method L:

Compound 3 (1.0 g, 5.5 mmol), methyl glyocate (2.47 g, 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)







    (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




C16H17N3O2S
315.4
316.1


 


25B




C17H13N3O3S
399.4
340.1


 


25C




C17H13N3O2S
323.4
324.1


 


25D




C17H10N4O2S2
366.4
367.1









Method P:





    (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




C15H15N3O2S
301.4
302.1


 


 26C




C16H11N3O2S
309.3
310.0


 


111




C16H11N3O2S
309.3
310.0









Method Q:





    (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 (tt, 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




C16H14F3N3O4S2
433.4
434.1


 


 27B




C17H10F3N3O5S2
457.4
457.9


 


 27C




C17H10F3N3O4S2
441.4
441.8


 


112A




C18H12F3N3O4S2
455.4
456.0


 


112B




C17H10F3N3O4S2
441.4
441.9









Method R:





    (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 l, 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 l, 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




C19H22N4OS
354.5
355.1


 


28B




C21H19ClN4OS
410.9
411.1


 


28C




C21H26N4OS
382.5
383.1


 


28D




C21H20N4OS
376.5
377.1


 


28E




C22H22N4O2S
406.5
407.1


 


28F




C22H19F3N4O2S
460.5
461.3


 


28G




C22H16N4O2S
400.5
401.1


 


28H




C21H20N4OS
376.5
377.1


 


28I




C17H14N4O2S
338.4
339.1


 


28J




C19H24N4OS
356.5
356.1


 


28K




C21H28N4OS
384.5
385.1


 


28L




C20H24N4OS
368.5
369.1


 


28M




C19H22N4O2S
370.5
371.1


 


28N




C19H22N4O2S
370.5
371.1


 


28O




C19H22N4O2S
370.5
371.1


 


28P




C17H20N4OS
328.4
329.1


 


28Q




C18H22N4OS
342.5
343.1


 


28R




C19H24N4OS
356.5
357.1


 


28S




C18H20N4OS
340.4
341.1


 


28T




C20H24N4OS
368.5
369.1


 


28U




C19H23N5OS
369.5
370.1


 


28V




C18H20N4OS
340.4
341.1


 


28W




C19H22N4OS
354.5
355.1


 


28X




C16H18N4OS
314.4
315.2


 


28Y




C18H22N4OS
342.5
353.1


 


28Z




C19H14N4OS
346.4
347.1


 


28AA




C18H13N5OS
347.4
348.1


 


28AB




C20H16N4OS
360.4
361.1


 


28AC




C20H18N4OS
362.4
363.1


 


28AD




C20H16N4OS
360.4
361.1


 


28AE




C17H15N5OS
337.4
338.1


 


28AF




C20H24N4O2S
384.5
385.1


 


28AG




C17H20N4O2S
344.4
345.1


 


28AH




C18H22N4OS
342.5
343.1


 


28AI




C17H14N4OS
322.4
323.1


 


28AJ




C19H22N4OS
354.5
355.1


 


28AK




C19H18N4OS
350.4
351.1


 


28AL




C19H16N4O2S
364.4
365.2


 


28AM




C19H16N4O2S
364.4
365.2


 


28AN




C19H24N4OS
356.5
357.1


 


28AO




C20H20N4O2S
380.5
381.1


 


28AP




C19H16N4OS
348.4
349.1


 


28AQ




C20H20N4O2S
380.5
381.1


 


28AR




C19H18 N4O2S
366.4
367.1


 


28AS




C19H18N4OS
350.4
351.2


 


28AT




C20H20N4OS
364.5
365.2


 


28AU




C18H13F3N4OS
390.4
391.2


 


28AV




C18H16N4O2S
352.4
353.2


 


28AW




C18H13F3N4O2S
406.4
407.2


 


28AX




C20H18N4O2S
378.4
379.2


 


28AY




C20H18N4OS
362.4
363.2


 


28AZ




C19H18N4O2S
366.4
367.1


 


28BA




C20H21N5OS
379.5
380.1


 


28BB




C19H18N4O2S
366.4
367.2


 


28BC




C19H18N4O2S
366.4
367.2









Method R (Alternate):





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




C19H18N4OS
350.4
351.1


 


113B




C18H16N4OS
336.4
337.1


 


113C




C19H16N4OS
348.4
349.1


 


113D




C19H18N4OS
350.4
351.1


 


113E




C17H14N4OS
322.4
323.1


 


113F




C18H16N4OS
336.4
337.1


 


113G




C18H16N4OS
336.4
337.1


 


113H




C19H18N4OS
350.4
351.1


 


113I




C20H20N4OS
364.5
365.1


 


113J




C20H18N4OS
362.4
363.1


 


113K




C20H16N4OS
360.4
361.1


 


113L




C19H15F3N4OS
404.4
405.2


 


113M




C21H22N4OS
378.5
379.2


 


113N




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




C20H23N3OS
353.5
354.1


 


29C




C17H19N3OS
313.4
314.2


 


29D




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:


















m/z Found


Cpd
Structure
Formula
MW
(M + 1)+



















30B




C18H17N5OS
351.4
352.1


 


30C




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.


















m/z Found


Cpd
Structure
Formula
MW
(M + 1)+



















41




C17H19ClN4OS
362.9
363.1


 


42




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.
Compounds 55, 156 and 163 could be prepared analogously from compounds 54, 155 and 162 respectively:


















m/z Found


Cpd
Structure
Formula
MW
(M + 1)+



















46




C18H19N5OS
353.4
354.2


 


55




C18H12ClN5OS
381.8
382.1


 


156




C11H13N3O3
235.2
236.2


 


163




C13H15N3O4S
309.3
310.1









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.


















m/z Found


Cpd
Structure
Formula
MW
(M + 1)+



















47A




C24H23N5OS
429.5
430.2


 


47B




C23H24FN4OS
422.5
423.2









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



















m/z Found


Cpd
Structure
Formula
MW
(M + 1)+



















86A




C24H26N4OS
418.6
419.2


 


86B




C24H20N4OS
412.5
413.1


 


86C




C25H19N5OS
437.5
438  1


 


86D




C25H22N4OS
426.5
427.1


 


86E




C23H19N5OS
413.5
414.2









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.


















m/z Found


Cpd
Structure
Formula
MW
(M + 1)+



















48




C17H17N5OS
339.4
340.1


 


52




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.


















m/z Found


Cpd
Structure
Formula
MW
(M + 1)+



















59A




C23H26N6OS
434.6
435.1


 


59B




C22H24N6OS
420.5
421.1


 


59C




C22H23N5O2S
421.5
422.1


 


79A




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 materials:


















m/z Found


Cpd
Structure
Formula
MW
(M + 1)+



















60A




C16H19N5OS
329.4
330.1


 


60B




C17H15N5OS
337.4
338.1


 


60C




C18H17N5OS
351.4
352.1


 


60D




C17H21N5OS
343.4
344.2


 


60E




C18H21N5OS
355.5
356.1


 


60F




C18H23N5OS
357.5
358.1


 


60G




C17H21N5OS
343.4
344.1


 


60H




C11H11N5OS
261.3
262.1


 


60I




C15H17N5OS
315.4
316.1


 


60J




C23H19N5OS
413.5
414.1


 


60L




C16H19N5OS
329.4
330.1









The following compound can be prepared from compound 23 analogously.



















m/z Found


Cpd
Structure
Formula
MW
(M + 1)+



















60K




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:


















m/z Found


Cpd
Structure
Formula
MW
(M + 1)+







61A




C20H25N5OS
383.5
384.1


 


61B




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:




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




C14H15N5O2S
317.4
318.1


 


65B




C14H9F6N5O2S
425.3
426.1


 


65C




C18H19N5O2S
369.4
370.1


 


65D




C20H23N5O2S
397.5
398.1


 


65E




C17H15N5OS
337.4
338.1









Method AO:





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




C19H13N3O2S
347.4
348.1


 


66B




C20H15N3O2S
361.4
362.1


 


66C




C21H19N3O2S
377.5
378.2


 


66D




C19H15N3O2S
349.4
350.2


 


66E




C18H15N3O3S
353.4
354.1









Method AP:





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:




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:





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 2 h. 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:




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): δ 8.43 (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:





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




C15H15N4OS
300.4
301.2


 


72B




C18H20N4OS
340.4
341.2


 


72C




C16H12N4O2S
324.4
325.2


 


72D




C24H24N4OS
416.5
417.1


 


72E




C22H22N4OS
390.5
391.1


 


72F




C23H24N4OS
404.5
405.1


 


72G




C18H18N4OS
338.4
339.1


 


72H




C16H12N4OS
308.4
309.0


 


72I




C19H16N4OS
348.4
349.1









Method AT:





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




C18H20N4O2S
356.4
357.1


 


73B




C17H18N4O2S
342.4
343.2


 


73C




C22H20N4O2S
404.5
405.1


 


73D




C20H22N4O2S
382.5
383.1


 


73E




C20H18N4O3S
394.4
395.1


 


73F




C23H22N4O3S
434.5
435.1


 


73G




C22H19ClN4O2S
438.9
439.1









Method AU:





Compound 26C (0.020 g, 0.045 mmol) in DMF (1 mL) 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:





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:





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% formic 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) δ 8.88-8.85 (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:





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 tlc (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 tlc (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:




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):




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:




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):




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):




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):




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):





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:




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




C21H22N4OS
378.5
379.1


 


87B




C20H20N4OS
364.5
365.1


 


87C




C20H26N4OS
370.5
371.2









Method BB:





    (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:







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.
Method BD:




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




C7H7N4O
164.2
165.2


 


91B




C8H10N4O
178.2
179.2


 


91C




C7H8N4O
164.2
165.2


 


91D




C8H8N4O
176.2
177.2


 


91E




C7H5F3N4O
218.1
219.1


 


91F




C6H6N4O
150.1
151.1









Method BE:





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




C7H6N4Cl
182.6
183.1


 


92B




C8H9ClN4
196.6
197.2


 


92C




C7H7ClN4
182.6
182.1


 


92D




C8H7ClN4
194.6
195.1


 


92E




C7H4CIF3N4
236.6
237.0


 


92F




C6H5ClN4
168.6
169.1









Method BF:





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




C10H12N4O2S
252.3
253.1


 


93B




C11H14N4O2S
266.3
267.2


 


93C




C10H12N4O2S
252.3
253.2


 


93D




C11H12N4O2S
264.3
265.2


 


93E




C10H9F3N4OS
306.3
307.1


 


93F




C9H10N4O2S
238.3
239.1









Method BG:





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




C13H17N5O2S
307.4
308.1


 


94B




C14H19N5O2S
321.4
322.2


 


96A




C11H10N4O2S
262.3
263.1


 


96B




C12H10N4O2S
274.3
275.1


 


94C




C13H14F3N5O2S
361.3
362.0


 


96C




C10H8N4O2S
248.3
249.1


 


96D




C11H10N4O3S
278.3
279.1









Method F (Alternate 3):





To a mixture of 94A (200 mg, 0.649 mmoles) in toluene (2 mL) and glacial acetic acid (400 δL) 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




C17H15N5O2S
353.4
354.1


 


95B




C17H15N5OS
337.4
338.1


 


95C




C17H12N6OS2
380.4
381.1


 


95D




C16H14N6O2S
354.4
355.2


 


95E




C18H15N5O2S
365.4
366.2


 


95F




C17H15N5OS2
369.5
370.1


 


95G




C18H17N5O2S
367.4
368.1


 


95H




C18H17N5OS
351.4
352.1


 


95I




C18H14N6OS2
394.5
395.1


 


95J




C15H12N6OS
324.4
325.1


 


95K




C19H17N5O2S
379.4
380.1


 


95L




C18H17N5OS2
383.5
384.1


 


95M




C16H14N6OS
338.4
339.1


 


95N




C17H12F3N5O2S
407.4
408.1


 


95O




C16H14N6OS
338.4
339.1


 


95P




C17H15N5OS
337.4
338.1


 


95Q




C17H13F2N5O2S
389.4
390.2


 


95R




C18H14F3N5O2S
421.4
422.2


 


95S




C17H15N5O2S
353.4
354.2


 


95T




C18H15F2N5O2S
403.4
404.1


 


95U




C17H16N6OS
352.4
353.1


 


95V




C17H12F3N5O2S
407.4
408.2


 


95W




C17H13F2N5O2S
389.4
390.1


 


95X




C17H12F3N5OS
391.4
392.2


 


95Y




C18H14F3N5OS
405.4
406.2


 


95Z




C18H15N5O2S
365.4
366.1


 


95AA




C18H15N5OS
349.4
350.1


 


95AB




C16H14N6OS
338.4
339.1


 


95AC




C18H15N5O2S
365.4
366.1


 


95AD




C17H15N5OS2
369.5
370.1


 


95AE




C16H12ClN5OS
357.8
358.2


 


95AF




C16H13N5OS
323.4
324.2


 


95AG




C16H13N5O2S
339.4
340.1


 


95AH




C17H12F3N5O2S
407.4
408.2


 


95AI




C17H15N5O3S
369.4
370.2


 


95AJ




C16H12ClN5O2S
373.8
374.2


 


95AK




C17H15N5O2S
353.4
354.2


 


95AL




C16H12BrN5OS
402.3
402.2


 


95AM




C16H12FN5OS
341.4
342.1


 


95AN




C16H12FN5OS
341.4
342.1









Method BG:





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:




    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:







    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 μL, 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) δ 8.71 (s, 1H), 6.43 (bs, 2H), 4.17 (s, 2H), 3.84 (s, 3H), 3.74 (s, 3H).

Method BJ:







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:




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:





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:





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




C18H14ClN3OS
355.8
356.2


 


103B




C18H21N3OS
327.4
328.2


 


103C




C18H15N3OS
321.4
322.2


 


103D




C19H17N3OS
335.4
336.2


 


103E




C19H17N3O2S
351.4
352.2


 


103F




C19H14N4OS2
378.5
379.2









Method BN:





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:





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:





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:





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, 1H). 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




C9H11NO2S
197.3
198.2









Method BR:





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




C16H15N3O3S
329.4
330.1


 


109C




C15H13N3O2S
299.4
300.0









Method BS:





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




C18H15N3O3S
353.4
354.2


 


110C




C17H13N3O2S
323.4
324.1


 


116A




C20H20N4OS
364.5
365.2


 


116B




C21H22N4OS
378.5
379.1


 


116C




C22H24N4OS
392.5
393.1


 


116D




C19H18N4O2S
366.4
367.1


 


116E




C20H20N4O2S
380.5
381.1


 


116F




C21H22N4O2S
394.5
395.1


 


116G




C22H24N4O2S
408.5
409.2









Method BS (Alternate):





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




C19H15F3N4OS
404.4
405.1


 


117B




C19H15F3N4O2S
420.4
421.2









Method C (Alternate):





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




C17H18N4OS
326.4
327.1


 


114B




C17H18N4O2S
342.4
343.1









Method D (Alternate):





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): δ 8.42 (dd, 1H), 7.40 (d, 2H), 7.12 (d, 2H), 7.02 (s, 1H), 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




C17H18N4OS
326.4
327.1


 


115B




C17H18N4O2S
342.4
343.1









Method BT:





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





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 absorption) 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): δ 8.38 (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:




    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:




    (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:







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):





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):





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:





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




C18H16N4O2S
352.4
353.1


 


131B




C17H14N4O2S
338.4
339.1


 


131C




C18H13N5OS2
379.5
380.1


 


131D




C18H16N4OS
336.4
337.1


 


131E




C18H14N4O3S
366.4
367.1


 


131F




C19H18N4OS
350.4
351.1


 


131G




C18H15N5O2S2
397.5
397.1









Method CA:





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 chromatography 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




C13H18N4O2
262.3
263.3


 









132B




1H NMR (CDCl3): δ 8.20 (d, 1 H), 7.02 (d, 2 H), 6.69 (d, 2 H), 6.40 (d, 1 H), 5.65 (s, 2 H), 5.30 (br. s, 2 H), 3.79 (s, 3 H), 3.68 (s, 3 H), 2.87 (s, 6 H)









Method CB:





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 dichlormethane/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:





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:





    (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




C20H18N4OS
362.4
363.1









Method CE:





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:





    (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:







    (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:







    (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:







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:





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).

The following compounds were also prepared using Method CJ:



















m/z Found


Cpd
Structure
Formula
MW
(M + 1)+







144B




C19H15N3O4S
381.4
382.2


 


144C




C20H14F3N3O3S
433.4
434.2









Method CK:





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:





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:





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+).
Method Y (Alternate):




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).

Method CN:





The mixture of mucobromic acid (5.0 g, 0.019 mol), hydrazine dihydrochloride (2.13 g, 0.020 mol) and sodium acetate (3.97 g, 0.048 mol) in water (30 mL) was heated to 100° C. for 16 hours. The reaction mixture was cooled to room temperature. The precipitated solid was collected by filtration and dried over vacuum to afford the crude solid 153 (2.58 g). 1H NMR (CD3OD) δ 8.02 (s, 1H). MS m/z calcd. for C4H3Br2N2O+=254.88; found m/z=254.96.

Method CO:





The mixture of 153 (2.58 g, 0.01 mol), dihydropyran (1.4 mL, 0.015 mol), p-toluenesulfonic acid monohydrate (0.19 g, 0.001 mol) and 30 mL THF was heated to reflux for 24 hours. Additional dihydropyran (2.8 mL, 0.030 mol) was added at 16 hours. The reaction mixture was allowed to cool to room temperature and concentrated in-vacuo to an oily residue. The residue was taken up in ethyl acetate (100 mL) and washed with sodium bicarbonate solution (50 mL). The organic layer was washed with Brine (50 mL) and dried with sodium sulfate. The solvent was removed in-vacuo to give an oily residue. The residue was purified by flash chromatography eluting with 0-40% ethyl acetate/hexane to afford 154 (2.96 g). MS m/z calcd. for C9H11Br2N2O+=339.0; found m/z=338.93.

Method CP:





Compound 154 (1.5 g, 0.0044 mol) was dissolved in 10 mL methanol and cooled to OC. To this solution was added 25% sodium methoxide in methanol (1.02 mL, 0.0044 mol). The reaction mixture was allowed to stir for additional 2 hours at room temperature. The solvent was evaporated to give a residue. This residue was taken up in ethyl acetate (100 mL) washed with water (50 mL) and then brine (50 mL). The organic layer was dried with sodium sulfate and evaporated to afford the crude 155. 1H NMR (CDCl3) δ 7.75 (s, 1H), 6.04 (dd, 1H), 4.05 (d, 1H), 4.00 (s, 3H), 3.69 (t, 1H), 2.15-1.98 (m, 2H), 1.69-1.65 (m, 4H).

Method CQ:





Compound 156 (0.58 g, 0.0025 mol) and 4 mL methanol was added 6N HCl (8 mL) and heated to reflux for 1 hour. The reaction mixture was allowed to cool to room temperature. The solvent was evaporated in-vacuo. The residue was taken up in ethyl acetate (50 mL), then washed with saturated sodium bicarbonate (25 mL). The aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layer was washed with brine, dried with sodium sulfate and evaporated in-vacuo. The residue was purified by flash column eluting with 0-6% methanol/methylene chloride with 0.5% ammonia hydroxide to afford 157. 1H NMR (CD3OD) δ 8.13 (s, 1H), 4.16 (s, 3H). MS m/z calcd. for C6H6N3O2+=152.12; found m/z=152.10.

The following compound was also prepared using Method CQ:



















m/z Found


Cpd
Structure
Formula
MW
(M + 1)+







165




C15H10N4O2S
310.3
311.1









Method CR:





To a solution of 74 (0.1 g, 0.314 mmol) in con HCl (1 mL) was added anhydrous tin chloride (0.1 g, 0.527 mmol) and heated at 70° C. for one hour. The excess HCl was removed in vacuo and redissolved in DCM. The product was isolated by preparative reverse phase HPLC using acetonitrile/water as the eluent to get compound 168. 1H NMR (CDCl3): 8.8 (d, 1H), 8.67 (s, 1H), 8.60 (m, 1H), 7.7 (d, 1H), 7.39 (m, 3H), 4.8 (s, 2H), 2.35 (s, 3H). Mass Spectrum (M++1) m/z calcd. for C17H15N4OS+=323.10, found m/z=323.2

Method CS:





The 1M Br2/AcOH (17.80 mls, 17.80 mmol) was added dropwise to a stirring suspension of phenol (5.00 g, 16.20 mmol) in glacial AcOH (500 mls) at room temperature. The reaction was continued to be stirred at room temperature for 6 hrs. The AcOH was evaporated under vacuum. The solid was taken up with CH2Cl2 (2×100 mls) and evaporated each time. The product 170 was fully dried to a powder (7.07 g, 97%) (obtained as the acetic acid salt). MS (M+1)+ m/z calcd for C16H11BrN3O2S+=389.2, observed m/z=389.9

Method CT:





To a solution of 0.013 g (0.040 mmol) of compound 58 in 5 mL of 1,2-dichloroethane was added 0.3 mL (excess) of iodotrimethylsilane. The mixture was stirred at 60° C. for 5 h and cooled to room temperature. It was quenched with 5 mL of methanol and concentrated. The residue was purified by preparative TLC eluting with 7% methanol in methylene chloride to give 0.002 g of compound 172A. Calcd MS for C17H15N4O2S=353.1; found m/z=353.2. And 0.002 g of Compound 172B. Calcd MS for C16H18ClN4OS=339.1; found m/z=339.2

Method CU:





A solution of 0.11 g (0.3 mmol) of compound 51 and 0.5 mL of 28% aqueous ammonium hydroxide in 5 mL of MeCN in a sealed tube was stirred at 100° C. for 3 h, and cooled to room temperature. It was lilued with 4 mL of methanol and filtered to give 0.074 g of compound. Compound 174, Calcd MS for C15H16N5O3S=346; found m/z=346.1

Method CV:





To a suspension of 0.031 g (0.12 mmol) of compound 11 in 5 mL of acetic acid were added a solution of 0.026 g (0.1 mmol) of iodine and 0.022 g (0.1 mmol) of sodium periodate. The mixture was stirred at the same temperature for 2 days, and concentrated. The residue was purified by chromatography eluting with 1% to 3% methanol in methylene chloride to give 0.021 g of compound 175. Calcd MS for C16H12IN4OS=435.0; found m/z=435.1

Method CW:





A mixture of 0.63 g (0.18 mmol) of compound 57E and 2 g of phenol was stirred at 120° C. for 18 h and 140° C. for 4 h. It was concentrated; the residue was purified by preparative TLC eluting with 3% methanol in methylene chloride to give 0.028 g of compound 176. Calcd MS for C21H13ClN3O2S=372.2; found m/z=406.2

Method CX:





A mixture of 0.050 g (0.14 mmol) of compound 57E, 0.07 g (0.22 mmol) of 1-propargyltributyltin, and 0.06 g (0.49 mmol) of diisopropylethylamine, and 0.02 g of Pd(PPh3)4 in 3 mL of toluene and 2 mL of trifluoromethylbenzene in a sealed tube was heated at 180° C. for 40 min (in microwave, personalChemistry). It was concentrated, the residue was purified by preparative TLC eluting with 4% methanol in methylene chloride to give 0.034 g of compound 177. Calcd MS for C18H11ClN3OS=352.0; found m/z=352.2

Method CY:

A mixture of 0.24 g (0.7 mmol) of compound 57E, 0.37 g (1.1 mmol) of allylltributyltin, and 0.27 g (2.1 mmol) of diisopropylethylamine, and 0.06 g of Pd(PPh3)4 in 3 mL of toluene and 2 mL of trifluoromethylbenzene in a sealed tube was heated at 180° C. for 40 min (in microwave, personalChemistry). It was concentrated, the residue was purified by chromatography eluting with 4% methanol in methylene chloride to give 0.034 g of compound 178A. Calcd MS for C18H13ClN3OS=354.1; found m/z=354.2.

The following compounds were prepared using method CY:



















m/z Found


Cpd
Structure
Formula
MW
(M + 1)+







178A




C18H12ClN3OS
353.8
354.2


 


178B




C18H13ClN4OS
368.8
369.2









Method CZ:





To a solution of 0.1 mL (1.36 mmol) of chloroiodomethane in 3 mL of 1,2-dichloroethane was added 1 mL (1.0 mmol) of diethylzinc in ether. After 5 min, a solution of 0.03 g (0.1 mmol) of compound 178 in 2 mL of dichloroethane was added. the mixture was stirred at room temperature for 30 min, and quenched with 1 mL of methanol. It was concentrated, the residue was purified by preparative TLC eluting with 4% methanol in methylene chloride to give 0.04 g of compound 179. Calcd MS for C19H15ClN3OS=368.1; found m/z=368.2.

Method DA:





A mixture of 0.28 g (0.6 mmol) of compound 182, 0.33 g (1.1 mmol) of ethoxyvinyltributyltin, and 0.23 g (1.8 mmol) of diisopropylethylamine, and 0.04 g of Pd(PPh3)4 in 4 mL of toluene and 1 mL of trifluoromethylbenzene in a sealed tube was heated at 140° C. for 1 min (in microwave, personalChemistry). It was concentrated, the residue was purified by chromatography eluting with 1% to 4% methanol in methylene chloride plus 1% ammonium hydroxide to give 0.106 g of compound 183A. Calcd MS for C19H15ClN3O2S=384.1; found m/z=384.2. and 0.047 g of compound 183B Calcd MS for C15H9ClN3OS=314.1; found m/z=314.2.

Method DB:





A mixture of 0.1 g (0.26 mmol) of compound 183A 1 mL of conc. HCl in 8 mL of THF was stirred at reflux for 18 h and concentrated. The residue was purified by preparative TLC eluting with 5% methanol in methylene chloride to give 0.073 g of compound 184. Calcd MS for C17H11ClN3O2S=356.0; found m/z=356.2.

Method DC:





To a suspension of 0.015 g (0.04 mmol) of compound 184 in 15 mL of methanol was added 0.004 g (0.1 mmol) of sodium borohydride slowly. The reaction was monitored by TLC and quenched with 1 drop of 37% aqueous HCHO. It was concentrated; the residue was purified by preparative TLC eluting with 6% methanol in methylene chloride to give 0.011 g of compound 185. Calcd MS for C17H13ClN3O2S=358.0; found m/z=358.2

Method DD:





To a suspension of 0.03 g (0.08 mmol) of compound 184 in 3 mL of THF was added 0.4 mL (0.12 mmol) of methylmagnesiumbromide in ether at −78° C. The reaction was stirred for 20 min and quenched with 1 mL of methanol It was concentrated; the residue was purified by preparative TLC eluting with 5% methanol in methylene chloride to give 0.027 g of compound 186. Calcd MS for C18H15ClN3O2S=372.0; found m/z=372.2.

Method DE:





A mixture of 0.046 g (0.1 mmol) of compound 182, 0.1 g (0.12 mmol) of cyclopropylboronic acid, 0.036 g (0.4 mmol) of potassium fluoride dehydrate, 0.1 g (0.1 mmol) of sodium bromide and 0.1 g of Pd(PPh3)4 in 3 mL of toluene in a sealed tube was stirred at 100° C. for 3 h. It was diluted with 10 mL of methylene chloride and filtered. The filtrate was concentrated; the residue was purified by preparative TLC eluting with 5% methanol in methylene chloride to give 0.029 g of compound 187. Calcd MS for C18H13ClN3OS=354.1; found m/z=354.2.

Method DF:





To a stirred solution of 0.044 g (0.4 mmol) of 4-fluoroaniline in 5 mL of THF was added 0.25 mL (0.4 mmol) of n-BuLi in hexanes at 0° C. After 20 min, 0.068 g (0.2 mmol) of compound 93GO was added. The mixture was stirred at reflux for 4 h, and concentrated. The residue was purified preparative TLC eluting with 5% methanol in methylene chloride to give 0.01 g of compound 190A. Calcd MS for C21H15FN5O2S=420.1; found m/z=420.2 and 0.004 g of compound 191: Calcd MS for C19H19N4O3S=383.1; found m/z=383.2

The following compounds were prepared using Method DF:



















m/z Found


Cpd
Structure
Formula
MW
(M + 1)+







190A




C21H14FN5O2S
419.4
420.2


 


190B




C22H17N5O3S
431.5
432.2


 


190C




C21H13ClN4OS
404.9
405.2


 


190D




C18H12N6O2S2
408.5
408.2


 


190E




C21H14ClN5O2S
435.9
436.2


 


190F




C21H14FN5O2S
419.4
420.2


 


190G




C21H14ClN5O2S
435.9
436.2


 


190H




C20H14N6O2S
402.4
403.2


 


190I




C22H14N6O2S
426.5
427.2


 


190J




C20H14N6O2S
402.4
403.2


 


190K




C20H14N6O2S
402.4
403.2


 


190L




C22H17N5O2S
415.5
416.2


 


190M




C22H14N6O2S
426.5
427.2


 


190N




C21H14ClN5O2S
435.9
436.2


 


191




C19H18N4O3S
382.4
383.2









Method DG:





To a stirred solution of 0.018 g (0.05 mmol) of compound 148 in 4 mL of MeCN was added 0.036 g (0.1 mmol) of Selectfluor. The mixture was stirred at room temperature for 2 h and concentrated. The residue was purified preparative TLC eluting with 5% methanol in methylene chloride to give 0.002 g of compound 192. Calcd MS for C18H15FN4O2S=371.1; found m/z=371.2

The following compounds were prepared using Method DG:



















m/z Found


Cpd
Structure
Formula
MW
(M + 1)+







192




C18H15FN4O2S
370.4
371.2


 


193




C16H11ClN4OS
342.8
343.2









Method DH:





To a stirred suspension of 2.0 g (6.38 mmol) of compound 99 and 0.1 g of Pd(PPh3)4 in 40 mL of THF was added 20 mL (20 mmol) of diethylzinc in hexanes at room temperature. The mixture was stirred at reflux for 1.5 h, cooled to room temperature, and quenched with 15 mL of saturated sodium bicarbonate. It was diluted with 300 mL of methylene chloride, filtered through a pad of celite. The filtrate was concentrated; the residue was purified by chromatography eluting with 1% to 5% methanol in methylene chloride plus 1% ammonium hydroxide to give 0.7 g of compound 203. Calcd MS for C10H12N3O2S=238.1; found m/z=238.1.

Method DI:





To a solution of compound 7AK (0.143 g, 0.0004 mol) and diisopropylethylamine (0.11 mL, 0.0007 mol) in CH2Cl2 (5 mL) was added methylsulfonyl chloride (0.05 mL, 0.0006 mol) dropwise at RT. After 1 h, the mixture was transferred to a preparative TLC and Eluted using 10% acetone in dichloromethane to product. 1H NMR (CDCl3): δ 8.46 (br.s, 1H), 8.29 (s, 1H), 7.50 (m, 2H), 7.30 (m, 2H), 6.83 (br.s, 1H), 3.12 (s, 6H). Mass spectrum (M+1): 417.2

Method DJ:





To a solution of acyl chloride 146A in dichloromethane (10 mL) at RT under nitrogen atmosphere, was added dimethylamine (2 mL, 40% solution in water). After 30 min., water was added and the mixture extracted with CH2Cl2, dried (Na2SO4), filtered and evaporated under vacuum. Solid residue was then tritrated in ether and filtered to give product 205A. 1H NMR (CDCl3): δ 8.86 (s, 1H), 8.61 (s, 1H), 8.24 (s, 1H), 7.34 (d, 2H), 7.31 (d, 2H), 3.16 (s, 3H), 3.07 (s, 3H), 2.42 (s, 3H). Mass spectrum (M+1): 365.1

The following compounds were prepared using Method DJ:



















m/z Found


Cpd
Structure
Formula
MW
(M + 1)+







205A




C19H16N4O2S
364.4
365.1


 


205B




C21H19N5O2S
405.5
406.2


 


205C




C17H12N4O2S
336.4
337.1









Method DK:





Step 1: A mixture of compound 152 (1.83 g, 0.0044 mol), vinyltributyltin (1.52 g, 0.0048 mol) and tetrakis(triphenylphosphine)palladium (0.25 g, 0.00022 mol) in toluene (50 ml) was heated at reflux under a nitrogen atmosphere for 1 h. This was then cooled to room temperature, evaporated the solvent and purified by column eluted using dichloromethane/ethyl acetate to give the product 206. Mass spectrum (M+1): m/z=365.07
Step 2: To a suspension compound 206 (0.23 g, 0.6 mmol) in THF/water (2:1), was added OSO4 (0.4 mL, 4% wt in water). After 5 min., NaIO4 (0.14 g, 0.0006 mol) was added and mixture stirred at RT overnight. Added 10% Na2SO3 solution and extracted by dichloromethane (100 mL×2) dried (Na2SO4), filtered and evaporated to give product 207. Mass spectrum (M+1): m/z=366.99.

Step 3: A mixture of compound 207 (0.2 g, 0.00055 mol), cyclobutylamine (0.1 mL) and Na(OAc)3BH (0.19 g, 0.87 mmol) in dichloromethane (20 ml) was stirred at RT under a nitrogen atmosphere for 24 h. Added a NaOH solution (1M) and extracted with dichloromethane (100 mL×3), dried (Na2SO4), filtered and evaporated under vacuum. Purification prep TLC using 4% methanol in dichloromethane followed tritration in ether to give the product 208 after filtration. 1H NMR (DMSO-d6): δ 8.59 (s, 1H), 8.29 (m, 1H), 8.08 (s, 1H), 7.48 (d, 2H), 7.10 (d, 2H), 4.08 (m, 1H), 3.82 (s, 3H), 3.41 (d, 3H), 3.20 (m, 1H), 3.14 (d, 2H), 2.08 (m, 2H), 1.45-1.75 (m, 4H). Mass spectrum (M+1): m/z=422.2.

The following compounds were prepared using Method F (Alternate 1):



















m/z






Found


Cpd
Structure
Formula
MW
(M + 1)+







180




C16H10FN3O2S
327.3
328.2


 


28FR




C16H10BrN3O2S
388.2
388.2


 


28FS




C16H10ClN3O2S
343.8
344.2


 


28FT




C16H9ClFN3O2S
361.8
362.2


 


28FU




C17H12ClN3O2S
357.8
358.2


 


28FV




C16H9Cl2N3O2S
378.2
378.2


 


28FW




C18H15FN4O2S
370.4
371.1


 


28FX




C17H12FN3O3S
357.4
358.2


 


28FY




C17H11N3O4S
353.4
354.2


 


28FZ




C18H15FN4O2S
370.4
371.2









The following compounds were prepared using Method F (Alternate 2):



















m/z






Found


Cpd
Structure
Formula
MW
(M + 1)+







25E




C17H12FN3O3S
357.4
358.2


 


25F




C18H13N3O3S
351.4
352.2


 


25G




C18H15N3O2S
337.4
338.2









The following compounds were prepared using Method F (Alternate 3):



















m/z






Found


Cpd
Structure
Formula
MW
(M + 1)+







95DA




C17H12FN5OS
353.4
354.2


 


95DB




C15H10ClN5OS
343.8
344.2


 


95DC




C15H10FN5OS
327.3
328.2


 


95DD




C18H14ClN5OS
383.9
384.2


 


95DE




C19H17N5O2S
379.4
380.2


 


95DF




C18H14FN5OS
367.4
368.2


 


95DG




C17H12ClN5OS
369.8
370.1


 


95DH




C19H17N5OS
363.4
364.2


 


95DI




C17H14ClN5O2S
387.8
388.2


 


95DJ




C18H17N5O2S
367.4
368.1


 


95DK




C19H15N5O2S
377.4
378.1


 


95DL




C18H17N5O2S
367.4
368.2


 


95DM




C18H17N5O3S
383.4
384.2


 


95DN




C19H19N5O2S
381.5
382.2


 


95DO




C19H19N5O3S
397.5
398.2


 


95DP




C19H17N5OS
363.4
364.2


 


95DQ




C19H17N5O2S
379.4
380.2


 


95DR




C18H14ClN5OS
389.9
384.2


 


95DS




C18H14BrN5OS
428.3
430.2


 


95DT




C19H17N5O2S
379.4
380.2


 


95DU




C18H14ClN5OS
383.9
384.2


 


95DV




C18H14BrN5OS
428.3
430.2


 


95DW




C15H17N5O2S
331.4
332.2


 


95DX




C14H17N5O3S
335.4
336.2


 


95DY




C13H12F3N5O2S
359.3
360.2


 


95DZ




C19H17N5OS
363.4
364.2


 


95EA




C13H15N5O2S
305.4
306.2


 


95EB




C16H19N5OS
329.4
330.2


 


95EC




C14H15N5O2S
317.4
318.2


 


95ED




C17H19N5OS
341.4
342.2


 


95EE




C16H9BrF3N5OS
456.2
456.3


 


95EF




C16H9ClF3N5OS
411.8
412.2


 


95EG




C17H10ClN5OS
367.8
368.2


 


95EH




C18H13N5OS
347.4
348.2


 


95EI




C18H13N5O2S
363.4
364.2


 


95EJ




C18H12FN5O2S
381.4
382.2


 


95EK




C18H12FN5O2S
381.4
382.2


 


95EL




C18H10N6OS2
390.4
391.2


 


95EM




C18H10N6OS2
390.4
391.2


 


95EN




C19H13N5O3S
391.4
392.2


 


95EO




C18H11N5O3S
377.4
378.2


 


95EP




C19H11N5OS2
389.4
390.2


 


95EQ




C17H10BrN5OS
412.3
412.2


 


95ER




C17H10FN5OS
351.4
352.2


 


95ES




C19H11N5O2S
373.4
374.2


 


95ET




C16H13N5OS
323.4
324.2


 


95EU




C16H13N5O2S
339.4
340.1


 


95EV




C15H10ClN5OS
343.8
344.0


 


95EW




C15H10FN5OS
327.3
328.1


 


95EX




C15H11N5OS
309.3
310.2


 


95EY




C19H17N5OS
363.4
364.2


 


95EZ




C18H14ClN5OS
383.9
384.2


 


95FA




C18H14BrN5OS
428.3
430.2


 


95FB




C19H16FN5O2S
397.4
398.2


 


95FC




C19H14N6OS2
406.5
407.2


 


95FD




C19H14N6OS2
406.5
407.2


 


95FE




C20H15N5OS2
405.5
406.2


 


95FF




C20H17N5O3S
407.4
408.2


 


95FG




C18H17N5OS
351.4
352.2


 


95FH




C18H15N5OS
349.4
350.2


 


95FI




C18H14FN5OS
367.4
368.0


 


95FJ




C17H14N6OS
350.4
351.2


 


95FK




C18H14ClN5OS
383.9
384.2


 


95FL




C17H19N5OS
341.4
342.2


 


95FP




C20H21N5OS
379.5
380.2


 


95FQ




C20H19N5O2S
393.5
394.2


 


95FR




C18H17N5OS2
383.5
384.2


 


95FS




C17H14ClN5OS2
403.9
404.2


 


95FT




C19H17N5O2S
379.4
380.2


 


95FW




C21H15N5OS
385.4
386.2


 


95FX




C20H12ClN5OS
405.9
406.2


 


95FY




C21H15N5O2S
401.4
402.2


 


95FZ




C20H12FN5OS
389.4
390.2


 


95GA




C21H14FN5O2S
419.4
420.2


 


95GB




C21H14FN5OS
403.4
404.2


 


95GC




C20H13N5OS
371.4
372.2


 


95GD




C21H12N6OS2
428.5
429.2


 


95GE




C21H12N6OS2
428.5
429.2


 


95GF




C20H12BrN5OS
450.3
452.2


 


95GG




C21H13N5O3S
415.4
416.2


 


95GH




C21H14ClN5O2S
435.9
436.2


 


95GI




C21H15N5O2S
401.4
402.2


 


95GJ




C22H17N5O2S
415.5
416.2


 


95GK




C21H14FN5O2S
419.4
420.2


 


95GL




C18H15N5O2S
365.4
366.2


 


95GM




C17H15N5O2S
353.4
354.2


 


95GN




C16H13N5O2S
339.4
340.2


 


95GO




C16H12N4O3S
340.4
341.2


 


95GP




C18H15N5O2S
365.4
366.2


 


95GQ




C20H15N5O3S
405.4
406.2


 


201




C17H14N4O2S
338.4
339.2


 


202




C16H11ClN4OS
342.8
343.2









Method H (Alternate 1):





    Ref: Synthetic Communications 23 (3), 1993, 335-341.

To a mixture of 94A (2.50 g, 8.12 mmoles) in toluene (36 mL) and glacial acetic acid (9.0 mL) was added 2-fluoro-4-methoxyaniline (160 mg, 1.30 mmoles) freshly prepared from the corresponding carboxylic acid. The reaction was allowed to stir at reflux for 2 h. The reaction mixture was then poured onto water (360 ml), basified with conc. NH4OH and filtered. The crude solid was then purified via silica gel chromatography eluting with 10% acetone/CH2Cl2 to give 95AQ as an off-white solid (381 mg, 13% yield). 1H NMR (CDCl3): δ 8.58 (s, 1H), 8.5 (s, 1H), 7.36-7.31 (m, 1H), 6.89-6.82 (m, 2H), 3.88 (s, 3H), 3.49 (s, 6H), MS m/z calcd. for C17H15FN5O2S+=372.1; found m/z=372.2 (M+1)

The following compounds were prepared using Method J:





















m/z






Found


Cpd
Structure
Formula
MW
(M + 1)+







171




C16H9BrClN3OS
406.7
408.2


 


57B




C17H12ClN3O3S
373.8
374.2


 


195




C16H10ClN3O2S
343.8
344.2









The following compounds were prepared using Method K:



















m/z Found


Cpd
Structure
Formula
MW
(M + 1)+



















95AO




C18H17N5O2S
367.4
368.2


 


95AP




C18H13NF5O2S
363.4
364.2


 


95AQ




C17H14FN5O2S
371.4
372.2


 


95AR




C16H11BrFN5OS
420.3
420.2


 


95AS




C16H12ClN5OS
357.8
358.2


 


95AT




C16H12BrN5OS
402.3
404.2


 


95AU




C17H12BrN5OS
414.3
416.2


 


95AV




C19H13N5O2S
375.4
376.2


 


95AW




C19H17N5O2S
379.4
380.2


 


95AX




C17H11BrFN5OS
432.3
434.2


 


95AY




C18H14FN5O2S
383.4
384.2


 


95AZ




C18H12N6OS2
392.5
393.1


 


95BA




C18H12N6OS2
392.5
393.1


 


95BB




C17H14FN5O2S
371.4
372.2


 


95BC




C18H14FN5O2S
383.4
384.2


 


95BD




C15H10BrN5OS
388.2
388.1


 


95BE




C17H14FN5O2S
371.4
372.2


 


95BF




C16H12FN5O2S
357.4
358.2


 


95BG




C16H10N6O2S
366.4
367.2


 


95BH




C17H15N5O2S
353.4
354.2


 


95BI




C16H12FN5O2S
357.4
358.2


 


95BJ




C17H12N6O2S
380.4
381.2


 


95BK




C17H12N6O2S
380.4
381.2


 


95BL




C17H14FN5O2S
371.4
372.2


 


95BM




C18H12N6O2S
392.5
393.2


 


95BN




C18H14FN5O2S
383.4
384.2


 


95BO




C17H12BrN5OS
414.3
416.2


 


95BP




C17H12ClN5OS
369.8
370.2









The following compounds were prepared using Method R:



















m/z






Found


Cpd
Structure
Formula
MW
(M + 1)+







28BD




C19H14N4O3S
378.4
379.2


 


28BE




C20H16N4O3S
392.4
393.2


 


28BF




C20H16N4O3S
392.4
393.2


 


28BG




C19H14N4O2S
362.4
363.2


 


28BH




C18H12N4O2S
348.4
349.2


 


28BI




C20H14N4O2S
374.4
375.2


 


28BJ




C18H15FN4O2S
370.4
371.2


 


28BK




C17H13FN4O2S
356.4
357.2


 


28BL




C18H15N3O3S
353.4
354.2


 


28BM




C18H12F4N4O2S
424.4
425.2


 


28BN




C18H16N4O2S
352.4
353.2


 


28BO




C19H18N4O2S
366.4
367.2


 


28BP




C19H15F3N4O2S
420.4
421.2


 


28BQ




C19H16N4O2S
364.4
365.2


 


28BR




C18H14N4O2S
350.4
351.2


 


28BS




C20H20N4OS
364.5
365.2


 


28BT




C20H18N4OS
362.4
363.2


 


28BU




C20H16N4O2S
376.4
377.2


 


28BV




C20H20N4O2S
380.5
381.2


 


28BW




C19H17FN4OS2
384.4
385.2


 


28BX




C21H16N4O2S
388.4
389.2


 


28BY




C19H16N4O3S
380.4
381.2


 


28BZ




C18H14N4O3S
366.4
366.2


 


28CA




C18H15ClN4OS
370.9
371.2


 


28CB




C18H13ClN4OS
368.8
369.2


 


28CC




C16H11ClN4OS
342.8
343.2


 


28CD




C17H13ClN4OS
356.8
357.2


 


28CE




C20H16N4O2S
376.4
377.2


 


28CF




C20H18N4O4S
410.4
411.2


 


28CG




C20H18N4O3S
394.4
395.2


 


28CH




C20H18N4O2S
378.4
379.2


 


28CI




C20H18N4O4S
410.4
411.2


 


28CJ




C20H18N4O3S
394.4
395.2


 


28CK




C20H16N4O3S
392.4
393.2


 


28CL




C20H18N4O3S
394.4
395.2


 


28CM




C18H15FN4OS
354.4
355.2


 


28CN




C18H13FN4OS
352.4
353.2


 


28CO




C16H11FN4OS
326.3
327.2


 


28CP




C17H13FN4OS
340.4
341.2


 


28CQ




C17H13FN4OS
340.4
341.2


 


28CR




C17H13BrN4OS
401.3
403.2


 


28CS




C16H11BrN4OS
387.3
387.2


 


28CT




C20H20N4O2S
380.5
381.2


 


28CU




C20H18N4O2S
378.4
379.2


 


28CV




C20H18N4O2S
378.4
379.2


 


28CW




C20H18N4O2S
378.4
379.2


 


28CX




C19H18N4O2S
366.4
367.1


 


28CY




C20H20N4O2S
380.5
381.1


 


28CZ




C20H20N4O2S
380.5
381.1


 


28DA




C20H18N4OS
362.4
363.2


 


28DB




C18H16N4O3S
368.4
369.2


 


28DC




C19H18N4O3S
382.4
383.1


 


28DD




C19H18N4O2S
366.4
367.2


 


28DE




C22H22N4O2S
406.5
407.2


 


28DF




C22H22N4OS
390.5
391.2


 


28DG




C21H20N4O2S
392.5
393.2


 


28DH




364.4
365.2
364.4


 


28DI




384.8
385.2
384.8


 


28DJ




380.4
381.2
380.4


 


28DK




C16H13N5OS
323.4
324.1


 


28DL




C18H11ClN4OS
366.8
367.1


 


28DM




C16H12ClN5OS
357.8
358.1


 


28DN




C17H13ClN4O2S
372.8
373.2


 


28DO




C17H15N5O2S
353.4
354.2


 


28DP




C18H11BrN4OS
411.3
411.2


 


28DQ




C19H14N4O2S
362.4
363.2


 


28DR




C18H13BrN4OS
413.3
414.2


 


28DS




C19H16N4O2S
364.4
365.2


 


28DT




C19H15FN4O2S
382.4
383.2


 


28DU




C20H16N4O2S
376.4
377.2


 


28DV




C19H13BrN4OS
425.3
425.2


 


28DW




C19H13FN4O2S
380.4
381.2


 


28DX




C19H13ClN4OS
380.9
381.2


 


28DY




C18H13ClN4OS
368.8
369.2


 


28DZ




C19H15ClN4OS
382.9
383.2


 


28EA




C20H18N4O2S
378.4
379.2


 


28EB




C19H15BrN4OS
427.3
427.2


 


28EC




C18H13FN4OS
352.4
353.2


 


28ED




C17H13N5OS
335.4
336.2


 


28EE




C16H13N5OS
323.4
324.2


 


28EF




C15H11N5OS
309.3
310.2


 


28EG




C16H13N5OS
323.4
324.2


 


28EO




C20H20N4OS
364.5
365.2


 


28EP




C19H17ClN4OS
384.9
385.2


 


28EQ




C21H16N4OS2
404.5
405.2


 


28ER




C20H15ClN4OS
394.9
395.2


 


28ES




C21H22N4OS
378.5
379.2


 


28ET




C21H20N4O2S
392.5
393.2


 


28EU




C23H22N4OS
402.5
403.2


 


28EV




C19H18N4OS2
382.5
383.2


 


28EW




C20H18N4OS
362.4
363.2


 


28EX




C20H20N4O2S
380.5
381 .2


 


28EY




C19H15ClN4OS
382.9
383.2


 


28EZ




C20H16N4OS
360.4
361.2


 


28FA




C20H16N4O2S
376.4
377.2


 


28FB




C20H18N4O2S
378.4
379.2


 


28FC




C19H15BrN4OS
427.3
429.0


 


28FD




C19H15ClN4OS
382.9
384.0


 


28FE




C20H17FN4O2S
396.4
397.2


 


28FF




C21H18N4O3S
406.5
407.2


 


28FG




C20H16N4O3S
392.4
393.2


 


28FH




C21H18N4OS
374.5
375.2


 


28FI




C21H18N4O2S
390.5
391.2


 


28FP




C23H18N4O3S
430.5
431.2


 


95FV




C20H15N5OS2
405.5
406.2


 


28GA




C17H13BrN4O2S
417.3
419.1


 


28GB




C17H13ClN4O2S
372.8
373.2


 


28GC




C17H13FN4O2S
356.4
357.1


 


28GD




C18H15ClN4O2S
386.9
387.2


 


28GE




C19H17ClN4O2S
400.9
401.2


 


28GF




C19H15ClN4OS
382.9
383.2


 


28GG




C17H12FN5O2S
369.4
370.2


 


28GH




C20H17ClN4OS
396.9
397.1


 


28GI




C20H17ClN4O2S
412.9
413.2


 


28GJ




C18H13ClN4OS
368.8
369.1


 


28GK




C18H15ClN4O2S
386.9
387.1


 


28GL




C18H15FN4O2S
370.4
371.1


 


28GM




C20H17ClN4O2S
412.9
413.2


 


28GN




C19H17ClN4O2S
400.9
401.2


 


28GO




C18H15BrN4O2S
431.3
433.2


 


28GP




C18H15FN4O2S
370.4
371.2


 


28GQ




C18H15BrN4O2S
431.3
433.2


 


28GR




C19H17BrN4O2S
445.3
447.2


 


28GS




C19H17FN4O2S
384.4
385.2


 


28GT




C19H15BrN4OS
427.3
430.2


 


28GU




C19H17FN4O2S
384.4
385.2


 


28GV




C19H17BrN4O2S
445.3
447.2


 


28GW




C19H15FN4OS
366.4
367.2


 


28GX




C18H15FN4OS
354.4
355.2


 


28GY




C18H13BrN4OS
413.3
415.2


 


28GZ




C19H17BrN4O2S
445.3
447.2


 


28HA




C19H17BrN4O2S
445.3
447.2


 


28HB




C18H15BrN4O2S
431.3
431.2


 


28HC




C18H15BrN4O2S
431.3
431.2


 


28HD




C18H15BrN4OS
415.3
417.2


 


28HE




C19H15FN4O2S
382.4
383.2


 


28HF




C18H13ClN4OS
368.8
369.2


 


28HG




C18H15ClN4O2S
386.9
387.1


 


28HH




C18H15FN4O2S
370.4
371.1


 


28HI




C18H15BrN4O2S
431.3
433.1


 


28HJ




C19H18N4O3S
382.4
383.2


 


28HK




C19H18N4O3S
382.4
383.2


 


28HL




C20H20N4O3S
396.5
397.1


 


28HM




C19H17ClN4O2S
400.9
401.1


 


28HN




C19H17FN4O2S
384.4
385.1


 


28HO




C19H17BrN4O2S
445.3
447.1


 


28HP




C20H20N4O3S
396.5
397.1


 


28HQ




C19H17ClN4O3S
416.9
417.2


 


28HR




C19H17FN4O3S
400.4
401.2


 


28HS




C18H14N4O2S
350.4
351.2


 


28HT




C19H13F3N4O4S2
482.5
483.3


 


28HU




C19H17BrN4O3S
461.3
463.3


 


28HV




C20H20N4O4S
412.5
413.2


 


28HW




C19H18N4O3S
382.4
383.2


 


28HX




C20H17F3N4O5S2
514.5
515.3


 


28HY




C17H13FN4OS
340.4
341.2


 


28HZ




C17H13ClN4OS
356.8
357.2


 


28IA




C19H17FN4O2S
384.4
385.2


 


28IB




C16H11FN4OS
326.3
327.2


 


28IC




C18H15ClN4OS
370.9
371.2


 


28ID




C18H15FN4OS
354.4
355.2


 


28IE




C19H16N4O3S
380.4
381.2









The following compounds were prepared using Method T:



















m/z Found


Cpd
Structure
Formula
MW
(M + 1)+







28FK




C15H9ClN4OS
328.8
329.2


 


95FU




C15H11N5O2S
325.3
326.1









The following compounds were prepared using Method X:



















m/z Found


Cpd
Structure
Formula
MW
(M + 1)+







197




C18H15ClN4O2S
386.9
387.2


 


198




C17H13ClN4O2S
372.8
373.2


 


199




C17H12Cl2N4OS
391.3
391.2


 


200




C16H10Cl2N4OS
377.2
377.2









Method X (Alternate 1):

The following compound was prepared using Method X substituting NBS for NCS:



















m/z Found


Cpd
Structure
Formula
MW
(M + 1)+







188




C16H10BrClN4OS
421.7
423.2









The following compound was prepared using Method Y:



















m/z Found


Cpd
Structure
Formula
MW
(M + 1)+







173A




C16H11BrN4OS
387.3
387.1


 


173B




C16H11BrN4O2S
403.3
405.2


 


196




C15H8BrClN4OS
407.7
409.2









The following compounds were prepared using Method AA:



















m/z Found


Cpd
Structure
Formula
MW
(M + 1)+







189




C17H10ClN5OS
367.8
368.2


 


194




C17H11N5O2S
349.4
350.2









Method AH (Alternate 3, additional example):





A stirring mixture of n-propargyl amine tricyclic (0.035 g, 0.088 mmol) in 7N—NH3/methanol (40 mls) 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 and was analyzed by tlc (20% acetone/CH2Cl2). The solvent was concentrated under vacuum to give a solid (0.056 g). The crude product was purified by reverse-phase HPLC (C18 column). Elution with solvent gradient 5% CH3CN/H2O/0.1% formic acid to 95% CH3CN/H2O/0.1% formic acid gave 59H (0.005 g) and 59I (0.011 g). Product 59H: MS (M+1)+ m/z calcd for C16H14N5O2S+=340.1, observed m/z=340.2 Product 59I: MS (M+1)+ m/z calcd for C16H12ClN4O2S+=359.0, observed m/z=359.2

The following compounds were prepared using Method AH:



















m/z Found


Cpd
Structure
Formula
MW
(M + 1)+







28FM




C18H16BrN5OS
430.3
432.2


 


28FN




C18H15BrN4O2S
431.3
433.2


 


28FO




C21H15N5O2S
401.4
402.2


 


59F




C18H17N5O2S
367.4
368.2


 


59G




C19H17N5O2S
379.4
380.2









The following compounds were prepared using Method AJ:



















m/z Found


Cpd
Structure
Formula
MW
(M + 1)+







169A




C19H18N4OS
350.4
351.2


 


169B




C25H26N4OS
430.6
431.2









The following compounds were prepared using Method AL*:



















m/z Found


Cpd
Structure
Formula
MW
(M + 1)+







73J




C18H17N5O3S2
415.5
416.2


 


28FL




C19H19N5O3S2
429.5
430.2





*including a MeOH, NaOMe hydrolysis of a bis-sulfonylated product for compound 28FL (Method AL-Alternate-1)






The following compounds were prepared using Method AO:



















m/z Found


Cpd
Structure
Formula
MW
(M + 1)+







66F




C18H12ClN3O2S
369.8
370.2


 


66G




C18H10ClN3O2S
367.8
368.2


 


66H




C17H12ClN3O3S
373.8
374.2


 


66I




C18H10BrN3O2S
412.3
414.0


 


66J




C18H12BrN3O2S
414.3
416.0


 


66K




C19H14BrN3O2S
428.3
430.0


 


66L




C19H14BrN3O2S
428.3
430.0


 


66M




C18H12N4O2S
348.4
349.2









The following compounds were prepared using Method AS:



















m/z Found


Cpd
Structure
Formula
MW
(M + 1)+







71B




C16H14N6OS
338.4
339.2


 


71C




C19H18N6OS
378.5
379.2


 


71D




C18H15N5OS
349.4
350.1


 


71E




C16H10F3N5OS
377.3
378.2


 


71F




C15H11N5OS2
341.4
342.1









The following compounds were prepared using Method AT:



















m/z Found


Cpd
Structure
Formula
MW
(M + 1)+







73H




C18H14ClN5O2S
399.9
400.2


 


73I




C19H17N5O2S
379.4
380.2









The following compound were prepared using Method AZ:



















m/z Found


Cpd
Structure
Formula
MW
(M + 1)+







57C




C18H15ClN4O2S
386.9
387.2


 


57D




C19H15ClN4O2S
398.9
399.2









The following compounds were prepared using Method BA:



















m/z Found


Cpd
Structure
Formula
MW
(M + 1)+







29F




C19H17N3OS
335.4
336.1


 


29G




C18H15N3OS
321.4
322.2


 


29H




C19H17N3O2S
351.4
352.2


 


29I




C18H15N3O2S
337.4
338.2


 


29J




C18H14ClN3OS
355.8
356.2


 


29K




C17H12ClN3OS
341.8
342.2









The following compound was prepared using Method BB:



















m/z Found


Cpd
Structure
Formula
MW
(M + 1)+







57E




C15H7Cl2N3OS
348.2
348.2









The following compounds were prepared using Method BD:



















m/z Found


Cpd
Structure
Formula
MW
(M + 1)+







167A




C18H15N5OS
349.4
350.2


 


167B




C17H15N5OS
337.4
338.2


 


167C




C18H15N5OS
349.4
350.2


 


167D




C18H17N5O2S
367.4
368.2


 


167E




C18H12N4O2S
348.4
349.1


 


167F




C18H17N5O2S
367.4
368.2


 


167G




C17H12F3N5OS
391.4
392.2


 


167H




C16H13N5OS
323.4
324.2


 


167I




C17H15N5OS
337.4
338.1


 


167J




C18H13N5OS
347.4
348.1









The following compounds were prepared using Method BM:



















m/z Found


Cpd
Structure
Formula
MW
(M + 1)+







161A




C17H14N4O2S
338.4
339.2


 


161B




C18H13N3O4S
367.4
368.2


 


161C




C15H10N4O2S
310.3
311.2


 


164




C20H18N4O3S
394.5
395.2


 


103G




C18H14ClN3OS
355.8
356.2


 


103H




C18H14ClN3OS
355.8
356.2


 


103I




C18H13Cl2N3OS
390.3
392.2


 


103J




C18H13Cl2N3OS
390.3
392.2


 


103K




C18H13Cl2N3OS
390.3
392.2


 


103L




C18H14FN3OS
339.4
340.1


 


103M




C18H14FN3OS
339.4
340.1


 


103N




C18H14FN3OS
339.4
340.1


 


103O




C18H13F2N3OS
357.4
358.1


 


103P




C18H13F2N3OS
357.4
358.1


 


103Q




C18H13F2N3OS
357.4
358.2


 


103R




C17H12ClN3OS
341.8
342.2


 


103S




C17H11ClN2O2S
342.8
343.1


 


28EH




C16H9BrClN3O2S
422.7
424.2


 


28EI




C18H12BrClN4OS
447.7
449.2


 


28EJ




C18H20N4O3S
372.4
372.2


 


28EK




C19H21N3O4S
387.5
388.2


 


28EL




C19H14FN5O2S
395.4
396.2


 


28EM




C20H20N4O2S
380.5
381.2


 


28EN




C19H16Cl2N4OS
419.3
419.2


 


95FM




C19H15N5O2S
377.4
378.2


 


95FN




C16H12N4O2S
324.4
325.2


 


95FO




C15H9ClN4O2S
344.8
345.2









The following compound was prepared using Method BO:



















m/z Found


Cpd
Structure
Formula
MW
(M + 1)+







28FQ




C18H13N5O2S
363.4
364.2









The following compounds were prepared using Method BZ:



















m/z Found


Cpd
Structure
Formula
MW
(M + 1)+







131H




C19H15FN4O2S
382.4
383.2


 


131I




C20H18N4O2S
378.4
379.2


 


131J




C19H13N5OS2
391.5
392.2


 


131K




C19H15ClN4O2S
398.9
399.1


 


131L




C19H15FN4OS
366.4
367.2


 


131M




C19H15FN4OS
366.4
367.1


 


131N




C19H15FN4O2S
382.4
383.2









The following compound was prepared using Method CC:



















m/z Found


Cpd
Structure
Formula
MW
(M + 1)+







29E




C17H10ClN3OS
339.8
340.1









The following compounds were prepared using Method CD:



















m/z Found


Cpd
Structure
Formula
MW
(M + 1)+







137C




C20H17N5OS
375.4
376.1


 


137D




C19H17N5OS
363.4
364.1


 


137E




C20H18N4O2S
378.4
379.2


 


137F




C20H17FN4OS
380.4
381.2


 


137G




C20H17FN4OS
380.4
381.2


 


137H




C19H15N3O2S
349.4
350.2


 


137I




C21H18N4OS
374.5
375.2









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 Tables 2 and 2a 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






mGIuR




1 IC50


Cpd
(nM)
Structure







7A
A






 


7B
A






 


7C
B






 


7D
A






 


7E
D






 


7F
B






 


7G
A






 


7H
A






 


7I
D






 


7J
D






 


7K
A






 


7L
A






 


7M
D






 


7N
C






 


7O
B






 


7P
B






 


7Q
A






 


7R
C






 


7S
D






 


7T
B






 


7U
B






 


7V
D






 


7W
A






 


7X
A






 


7Y
A






 


7Z
A






 


7AA
A






 


7AB
C






 


7AC
A






 


7AD
D






 


7AE
C






 


7AF
D






 


7AG
D






 


7AH
B






 


7AI
C






 


7AJ
A






 


7AK
A






 


7AL
D






 


7AM
A






 


7AN
C






 


7AO
C






 


7AP
A






 


7AQ
D






 


7AR
D






 


7AS
A






 


7AT
D






 


7AU
D






 


7AV
A






 


7AW
B






 


7AX
A






 


7AY
A






 


7AZ
D






 


7BA
C






 


7BB
D






 


7BC
D






 


7BD
D






 


7BE
D






 


7BF
A






 


7BG
A






 


7BH
D






 


7BI
A






 


7BJ
A






 


7BK
C






 


7BL
A






 


7BM
A






 


7BN
A






 


7BO
A






 


7BP
D






 


7BQ
C






 


7BR
C






 


7BS
A






 


7BT
D






 


7BU
D






 


7BV
D






 


7BW
A






 


7BX
D






 


7BY
A






 


7BZ
A






 


7CA
A






 


7CB
A






 


7CC
A






 


7CD
A






 


7CE
A






 


7CF
A






 


7CG
A






 


7CH
C






 


7CI
C






 


7CJ
B






 


7CK
A






 


7CL
B






 


7CM
A






 


7CN
B






 


7CO
B






 


7CP
B






 


7CQ
A






 


7CR
A






 


7CS
C






 


7CT
A






 


7CU
A






 


7CV
A






 


7CW
B






 


7CX
B






 


7CY
A






 


7CZ
A






 


7DA
C






 


7DB
A






 


7DC
A






 


7DD
C






 


7DE
A






 


7DF
A






 


7DG
A






 


7DH
A






 


7DI
A






 


7DJ
A






 


7DK
A






 


7DL
A






 


7DM
C






 


7DN
B






 


7DO
A






 


7DP
B






 


7DQ
A






 


7DR
A






 


7DS
C






 


7DT
C






 


7DU
A






 


7DV
A






 


7DW
A






 


7DX
A






 


7DY
B






 


7DZ
A






 


7EA
A






 


7EB
—






 


7EC
—






 


11
D






 


12A
C






 


12B
B






 


13
C






 


14
D






 


15A
D






 


15B
C






 


15C
A






 


15D
D






 


15E
B






 


15F
C






 


15G
D






 


15H
C






 


15I
C






 


15J
B






 


15K
D






 


15L
D






 


15M
D






 


15N
D






 


15O
D






 


15P
C






 


15Q
A






 


15T
C






 


15U
C






 


15V
C






 


15W
D






 


15X
D






 


15Y
A






 


15Z
A






 


15AA
A






 


15AB
A






 


15AC
D






 


15AD
B






 


15AE
B






 


15AF
C






 


15AG
A






 


15AH
B






 


15AI
—






 


15AJ
—






 


15AK
—






 


19
C






 


25A
C






 


25B
C






 


25C
B






 


25D
C






 


26A
D






 


26C
D






 


27A
D






 


28A
D






 


28B
D






 


28C
D






 


28D
D






 


28E
D






 


28F
D






 


28G
C






 


28H
D






 


28I
A






 


28J
C






 


28K
D






 


28L
D






 


28M
D






 


28N
D






 


28O
D






 


28P
A






 


28Q
B






 


28R
C






 


28S
A






 


28T
D






 


28U
D






 


28V
C






 


28W
C






 


28X
A






 


28Y
A






 


28Z
A






 


28AA
A






 


28AB
A






 


28AC
A






 


28AD
B






 


28AE
A






 


28AF
D






 


28AG
B






 


28AH
C






 


28AI
A






 


28AJ
C






 


28AK
A






 


28AL
A






 


28AM
B






 


28AN
A






 


28AO
A






 


28AP
A






 


28AQ
B






 


28AR
A






 


28AS
A






 


28AT
A






 


28AU
A






 


28AV
A






 


28AW
A






 


28AX
C






 


28AY
C






 


28AZ
A






 


28BA
C






 


28BB
A






 


28BC
A






 


29A
C






 


29B
D






 


29C
B






 


29D
B






 


30A
D






 


30B
D






 


30C
D






 


37A
C






 


37B
C






 


37C
B






 


37D
C






 


37E
A






 


37F
B






 


37G
C






 


37H
D






 


40
D






 


41
B






 


42
B






 


43
C






 


44
A






 


45
A






 


46
A






 


47A
C






 


47B
D






 


48
C






 


49
D






 


50
C






 


51
A






 


52
C






 


53
D






 


54
C






 


55
B






 


57
—






 


58
A






 


59A
D






 


59B
D






 


59C
D






 


60A
A






 


60B
A






 


60C
A






 


60D
A






 


60E
A






 


60F
B






 


60G
A






 


60H
D






 


60I
B






 


60J
D






 


60L
C






 


61A
D






 


61B
D






 


62
D






 


63
C






 


64
D






 


65A
D






 


65B
D






 


65C
D






 


65D
D






 


65E
D






 


66A
A






 


66B
D






 


66C
D






 


66D
A






 


66E
D






 


71A
A






 


72A
A






 


72B
A






 


72C
A






 


72D
D






 


72E
D






 


72F
D






 


72G
A






 


72H
A






 


72I
A






 


73A
D






 


73B
D






 


73C
D






 


73D
D






 


73E
D






 


73F
D






 


73G
D






 


76
D






 


77
D






 


78
D






 


80
D






 


83
B






 


84
B






 


85
D






 


87A
C






 


87B
B






 


95B
A






 


95C
A






 


95D
A






 


95E
A






 


95F
A






 


95G
A






 


95H
A






 


95I
A






 


95J
C






 


95K
A






 


95L
A






 


95M
B






 


95N
A






 


95O
A






 


95P
A






 


95Q
A






 


95R
A






 


95S
A






 


95T
A






 


95U
A






 


95V
C






 


95W
A






 


95X
A






 


95Y
A






 


95Z
A






 


95AA
A






 


95AB
C






 


95AC
A






 


95AD
A






 


95AE
—






 


95AF
—






 


95AG
—






 


95AH
—






 


95AI
—






 


95AJ
—






 


95AK
—






 


95AL
—






 


95AM
—






 


95AN
—






 


103A
B






 


103B
C






 


103C
C






 


103D
B






 


103E
B






 


103F
C






 


104
D






 


105
D






 


106
—






 


113A
A






 


113B
A






 


113C
C






 


113D
A






 


113E
A






 


113F
A






 


113G
A






 


113H
A






 


113I
A






 


113J
C






 


113K
A






 


113L
C






 


113M
B






 


113N
B






 


115
D






 


116
C






 


116A
B






 


116B
C






 


116C
C






 


116D
A






 


116E
B






 


116F
C






 


116G
C






 


117
B






 


117A
C






 


117B
C






 


118
—






 


131A
A






 


131B
A






 


131C
A






 


131D
A






 


131E
A






 


131F
B






 


131G
A






 


134A
C






 


134B
C






 


134C
D






 


134D
D






 


134E
D






 


134F
C






 


134G
D






 


134H
D






 


134I
D






 


135A
D






 


136
A






 


137A
A






 


137B
A






 


138
A






 


144A
B






 


147A
C






 


148
A






 


149
D






 


150
C






 


151
A






 


152
A






 


P-1
A






 


P-2
A






 


P-3
A






 


P-4
C






 


P-5
C






 


P-6
C






 


P-7
C






 


P-8
C






 


P-9
C






 


P-10
C






 


P-11
C






 


P-12
C






 


P-13
C






 


P-14
C






 


P-15
C























TABLE 2a








IC50



Compound #
Class









166
D



168
D



171
D



174
C



175
A



176
D



177
D



179
C



180
C



184
B



185
B



186
D



187
A



188
A



189
B



191
D



192
A



193
A



194
C



195
C



196
A



197
A



198
A



199
A



200
A



201
A



202
A



204
B



208
C



103G
D



103H
D



103I
D



103J
D



103K
D



103L
D



103M
C



103N
C



103O
D



103P
C



103Q
C



103R
C



103S
C



131H
B



131I
B



131J
A



131K
D



131L
A



131M
B



131N
C



137C
B



137D
A



137E
A



137F
B



137G
A



137H
D



137I
C



144B
D



144C
D



161A
D



161B
D



161C
D



167A
C



167B
B



167C
C



167D
D



167E
D



167F
D



167G
D



167H
C



167I
C



167J
B



169A
D



169B
D



172A
A



172B
A



173A
A



173B
A



178A
B



178B
A



183A
C



183B
C



190A
D



190B
B



190C
C



190D
C



190E
C



190F
C



190G
D



190H
D



190I
C



190J
D



190K
C



190L
D



190M
D



190N
D



205A
D



205B
D



205C
C



25E
D



25F
C



25G
C



28BD
A



28BE
A



28BF
A



28BG
A



28BH
A



28BI
A



28BJ
B



28BK
A



28BL
D



28BM
B



28BN
A



28BO
A



28BP
C



28BQ
A



28BR
A



28BS
A



28BT
B



28BU
A



28BV
A



28BW
A



28BX
C



28BY
A



28BZ
A



28CA
A



28CB
B



28CC
B



28CD
A



28CE
A



28CF
A



28CG
A



28CH
A



28CI
A



28CJ
A



28CK
A



28CL
A



28CM
A



28CN
A



28CO
A



28CP
A



28CQ
A



28CR
B



28CS
B



28CT
A



28CU
D



28CV
D



28CW
D



28CX
A



28CY
A



28CZ
A



28DA
C



28DB
A



28DC
A



28DD
C



28DE
C



28DF
D



28DG
C



28DH
C



28DI
C



28DJ
B



28DK
C



28DL
A



28DM
D



28DN
A



28DO
A



28DP
A



28DQ
A



28DR
A



28DS
A



28DT
A



28DU
A



28DV
A



28DW
A



28DX
A



28DY
B



28DZ
A



28EA
A



28EB
B



28EC
A



28ED
C



28EE
C



28EF
C



28EG
C



28EH
A



28EI
C



28EJ
D



28EK
D



28EL
D



28EM
D



28EN
C



28EO
C



28EP
C



28EQ
C



28ER



28ES
D



28ET
B



28EU
C



28EV
A



28EW
A



28EX
B



28EY
A



28EZ
C



28FA
C



28FB
A



28FC
A



28FD
A



28FE
B



28FF
C



28FG
C



28FH



28FI



28FK
A



28FL
C



28FM
C



28FN
A



28FO
C



28FP
C



28FQ
B



28FR
A



28FS
A



28FT
C



28FU
D



28FV
D



28FW
C



28FX
C



28FY
D



28FZ
A



28GA
A



28GB
A



28GC
B



28GD
A



28GE
A



28GF
A



28GG
C



28GH
D



28GI
D



28GJ
B



28GK
A



28GL
A



28GM
D



28GN
A



28GO
A



28GP
A



28GQ
A



28GR
A



28GS
A



28GT
C



28GU
A



28GV
A



28GW
C



28GX
C



28GY
A



28GZ
D



28HA
C



28HB
A



28HC
B



28HD
C



28HE
A



28HF
A



28HG
A



28HH
B



28HI
A



28HJ
A



28HK
A



28HL
A



28HM
A



28HN
A



28HO
A



28HP
A



28HQ
B



28HR
C



28HS
A



28HT
D



28HU
A



28HV
A



28HW
A



28HX
C



28HY
A



28HZ
A



28IA
A



28IB
A



28IC
A



28ID
A



28IE
A



29E
A



29F
A



29G
A



29H
A



29I
A



29J
A



29K
A



57B
D



57C
A



57D
C



57E
C



59F
A



59G
A



59H
A



59I
B



66F
A



66G
A



66H
D



66I
A



66J
A



66K
C



66L
C



66M
B



71B
D



71C
D



71D
C



71E
D



71F
A



73H
C



73I
C



73J
C



95AO
A



95AP
A



95AQ
A



95AR
A



95AS
A



95AT
A



95AU
A



95AV
A



95AW
A



95AX
B



95AY
A



95AZ
A



95BA
A



95BB
A



95BC
A



95BD
A



95BE
B



95BF
A



95BG
A



95BH
A



95BI
A



95BJ
A



95BK
A



95BL
A



95BM
A



95BN
B



95BO
A



95BP
A



95DA
B



95DB
A



95DC
A



95DD
C



95DE
B



95DF
C



95DG
A



95DH
C



95DI
A



95DJ
A



95DK
A



95DL
A



95DM
A



95DN
A



95DO
A



95DP
B



95DQ
C



95DR
B



95DS
C



95DT
A



95DU
A



95DV
A



95DW
D



95DX
D



95DY
D



95DZ
A



95EA
D



95EB
A



95EC
D



95ED
B



95EE
A



95EF
A



95EG
A



95EH
A



95EI
A



95EJ
B



95EK
C



95EL
A



95EM
C



95EN
B



95EO
B



95EP
C



95EQ
A



95ER
A



95ES
A



95ET
A



95EU
C



95EV
A



95EW
B



95EX
A



95EY
A



95EZ
A



95FA
A



95FB
B



95FC
A



95FD
A



95FE
A



95FF
A



95FG
A



95FH
A



95FI
A



95FJ
C



95FK
B



95FL
A



95FM
B



95FN
C



95FO
C



95FP
D



95FQ
C



95FR
A



95FS
A



95FT
A



95FU
B



95FV
C



95FW
D



95FX
C



95FY
C



95FZ
D



95GA
D



95GB
D



95GC
D



95GD
D



95GE
D



95GF
D



95GG
D



95GH
B



95GI
C



95GJ
B



95GK
D



95GL
C



95GM
D



95GN
D



95GO
D



95GP
A



95GQ
C










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













TABLE 3








mGluR1

mGluR1



Cpd
IC50 (nM)
Cpd
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



193
0.18
28GE
0.28



95AT
0.58
28GQ
0.66



175
0.76
28GD
0.77



28DL
0.91
28DZ
1.08



28HZ
1.22
95BP
1.31



95AU
1.37
178B
1.46



95AS
1.48
95BO
1.54



28BQ
1.57
95AP
1.6



28DP
1.75
28DV
1.87



95DV
1.94
28DS
1.95



28IC
2.09
95BI
28.25

## Claims

1. A compound or a pharmaceutically acceptable salt, or ester thereof, wherein said compound is selected from the group consisting of:

2. A pharmaceutical composition comprising at least one compound of claim 1, or a pharmaceutically acceptable salt, or ester thereof and at least one pharmaceutically acceptable carrier, adjuvant or vehicle.

3. The pharmaceutical composition of claim 2, further comprising one or more additional therapeutic agents.

4. The pharmaceutical composition of claim 3, 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.

5. A compound of the formula:



or a pharmaceutically acceptable salt, or ester thereof.

6. A compound of the formula:



or a pharmaceutically acceptable salt, or ester thereof.

7. A compound of the formula:



or a pharmaceutically acceptable salt, or ester thereof.

8. A compound of the formula:



or a pharmaceutically acceptable salt, or ester thereof.

9. A compound of the formula:



or a pharmaceutically acceptable salt, or ester thereof.

10. A compound of the formula:



or a pharmaceutically acceptable salt, or ester thereof.

11. A pharmaceutical composition comprising a compound of any of claims 5, 6, 7, 8, 9, or 10.