Title of Invention

QUINAZOLINES USEFUL AS MODULATORS OF ION CHANNELS

Abstract The present invention relates to quinazoline compounds of formula (I) useful us inhibitors of voltage-gated sidium channels and calcium channels. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders, or a pharmaceutically acceptable derivative thereof, wherein Rl, X. R3, x, and ring A are as defined in the present application.
Full Text OUTNAZOLINES USEFUL AS MODULATORS OF ION CHANNELS
PRIORITY INFORMATION
[0001] The present application claims priority under 35 U.S.C. §119 to U.S. Provisional
Application numbers: 60/451,458 filed March 3, 2003, entitled "Compositions Useful as
Inhibitors of Voltage-Gated Sodium Channels", and 60/463,797, filed April 18, 2003, entitled
"Compositions Useful as Inhibitors of Voltage-Gated Sodium Channels", and the entire
contents of each of these applications is hereby incorporated by reference.
TECHNICAL FIELD OF THE INVENTION
[0002] The present invention relates to compounds useful as inhibitors of ion channels.
The invention also provides pharmaceutically acceptable compositions comprising the
compounds of the invention and methods of using the compositions in the treatment of
various disorders.
BACKGROUND OF THE INVENTION
[0003] Na channels are central to the generation of action potentials in all excitable cells
such as neurons and myocytes. They play key roles in excitable tissue including brain,
smooth muscles of the gastrointestinal tract, skeletal muscle, the peripheral nervous system,
spinal cord and airway. As such they play key roles in a variety of disease states such as
epilepsy (See, Moulard, B. and D. Bertrand (2002) "Epilepsy and sodium channel blockers"
Expert Qpin. Ther. Patents 12(1): 85-91)), pain (See, Waxman, S. G., S. Dib-Hajj, et al.
(1999) "Sodium channels and pain" Proc Natl Acad Sci U S A 96(14): 7635-9 and Waxman,
S. G., T. R. Cummins, et al. (2000) "Voltage-gated sodium channels and the molecular
pathogenesis of pain: a review" J Rehabil Res Dev 37(5): 517-28), myotonia (See, Meola, G.
and V. Sansone (2000) "Therapy in myotonic disorders and in muscle channelopathies"
Neurol Sci 21(5): S953-61 and Mankodi, A. and C. A. Thornton (2002) "Myotonic
syndromes" Curr Qpin Neurol 15(5): 545-52), ataxia (See. Meisler, M. H., J. A. Kearney, et
al. (2002) "Mutations of voltage-gated sodium channels in movement disorders and epilepsy"
Novartis Found Svmp 241: 72-81), multiple sclerosis (See, Black, J. A., S. Dib-Hajj, et al.
(2000) "Sensory neuron-specific sodium channel SNS is abnormally expressed in the brains
of mice with experimental allergic encephalomyelitis and humans with multiple sclerosis"
Proc Natl Acad Sci USA 97(21): 11598-602, and Renganathan, M., M. Gelderblom, et al.
(2003) "Expression of Na(v)1.8 sodium channels perturbs the firing patterns of cerebellar
purkinje cells" Brain Res 959(2): 235-42), irritable bowel (See. Su, X., R. E. Wachtel, et al.
(1999) "Capsaicin sensitivity and voltage-gated sodium currents in colon sensory neurons
from rat dorsal root ganglia" Am J Physiol 277(6 Pt 1): G1180-8, and Laird, J. M., V.
Souslova, et al. (2002) "Deficits in visceral pain and referred hyperalgesia in Navl.8
(SNS/PN3)- null mice" J Neurosci 22(19): 8352-6), urinary incontinence and visceral pain
(See.Yoshimura, N., S. Seki, et al. (2001) "The involvement of the tetrodotoxin-resistant
sodium channel Na(v)1.8 (PN3/SNS) in a rat model of visceral pain" J Neurosci 21(21):
8690-6), as well as an array of psychiatry dysfunctions such as anxiety and depression (See.
Hurley, S. C. (2002) "Lamotrigine update and its use in mood disorders" Ann Pharmacother
36(5): 860-73).
[0004] Voltage gated Na channels comprise a gene family consisting of 9 different
subtypes (NaVl.l-NaV1.9). As shown in Table 1, these subtypes show tissue specific
localization and functional differences (See, Goldin, A. L. (2001) "Resurgence of sodium
channel research" Annu Rev Physiol 63: 871-94). Three members of the gene family
(NaVl.8, 1.9, 1.5) are resistant to block by the well-known Na channel blocker TTX,
demonstrating subtype specificity within this gene family. Mutational analysis has identified
glutamate 387 as a critical residue for TTX binding (See, Noda, M., H. Suzuki, et al. (1989)
"A single point mutation confers tetrodotoxin and saxitoxin insensitivity on the sodium
channel H" FEES Lett 259(1): 213-6).
[0005] Table 1 (Abbreviations: CNS = central nervous system, PNS = peripheral nervous
sytem, DRG = dorsal root ganglion, TG = Trigeminal ganglion):
[0006] In general, voltage-gated sodium channels (NaVs) are responsible for initiating
the rapid upstroke of action potentials in excitable tissue in nervous system, which transmit
the electrical signals that compose and encode normal and aberrant pain sensations.
Antagonists of NaV channels can attenuate these pain signals and are useful for treating a
variety of pain conditions, including but not limited to acute, chronic, inflammatory, and
neuropathic pain. Known NaV antagonists, such as TTX, lidocaine (See, Mao, J. and L. L.
Chen (2000) "Systemic lidocaine for neuropathic pain relief Pain 87(1): 7-17.) bupivacaine,
phenytoin (See, Jensen, T. S. (2002) "Anticonvulsants in neuropathic pain: rationale and
clinical evidence" Eur J Pain 6 (Suppl A): 61-8), lamotrigine (See, Rozen, T. D. (2001)
"Antiepileptic drugs in the management of cluster headache and trigeminal neuralgia"
Headache 41 Suppl 1: S25-32 and Jensen, T. S. (2002) "Anticonvulsants in neuropathic pain:
rationale and clinical evidence" Eur J Pain 6 (Suppl A): 61-8.), and carbamazepine (See,
Backonja, M. M. (2002) "Use of anticonvulsants for treatment of neuropathic pain"
Neurology 59(5 Suppl 2): S14-7), have been shown to be useful attenuating pain in humans
and animal models.
[0007] Hyperalgesia (extreme sensitivity to something painful) that develops in the
presence of tissue injury or inflammation reflects, at least in part, an increase in the
excitability of high-threshold primary afferent neurons innervating the site of injury. Voltage
sensitive sodium channels activation is critical for the generation and propagation of neuronal
action potentials. There is a growing body of evidence indicating that modulation of NaV
currents is an endogenous mechanism used to control neuronal excitability (See, Goldin, A.
L. (2001) "Resurgence of sodium channel research" Annu Rev Physiol 63: 871-94.). Several
kinetically and pharmacologically distinct voltage-gated sodium channels are found in dorsal
root ganglion (DRG) neurons. The TTX-resistant current is insensitive to micromolar
concentrations of tetrodotoxin, and displays slow activation and inactivation kinetics and a
more depolarized activation threshold when compared to other voltage-gated sodium
channels. TTX-resistant sodium currents are primarily restricted to a subpopulation of
sensory neurons likely to be involved in nociception. Specifically, TTX-resistant sodium
currents are expressed almost exclusively in neurons that have a small cell-body diameter;
and give rise to small-diameter slow-conducting axons and that are responsive to capsaicin. A
large body of experimental evidence demonstrates that TTX-resistant sodium channels are
expressed on C-fibers and are important in the transmission of nociceptive information to the
spinal cord.
[0008] Intrathecal administration of antisense oligo-deoxynucleotides targeting a unique
region of the TTX-resistant sodium channel (NaV1.8) resulted in a significant reduction in
PGE2-induced hyperalgesia (See. Khasar, S. G., M. S. Gold, et al. (1998) "A tetrodotoxin-
resistant sodium current mediates inflammatory pain in the rat" Neurosci Lett 256(1): 17-20).
More recently, a knockout mouse line was generated by Wood and colleagues, which lacks
functional NaV1.8. The mutation has an analgesic effect in tests assessing the animal's
response to the inflammatory agent carrageenan (See. Akopian, A. N., V. Souslova, et al.
(1999) 'The tetrodotoxin-resistant sodium channel SNS has a specialized function in pain
pathways" Nat Neurosci 2(6): 541-8.). In addition, deficit in both mechano- and
thermoreception were observed in these animals. The analgesia shown by the Navl.8
knockout mutants is consistent with observations about the role of TTX-resistant currents in
nociception.
[0009] Immunohistochemical, in-situ hybridization and in-vitro electrophysiology
experiments have all shown that the sodium channel NaV1.8 is selectively localized to the
small sensory neurons of the dorsal root ganglion and trigeminal ganglion (See, Akopian, A.
N., L. Sivilotti, et al. (1996) "A tetrodotoxin-resistant voltage-gated sodium channel
expressed by sensory neurons" Nature 379(6562): 257-62.). The primary role of these
neurons is the detection and transmission of nociceptive stimuli. Antisense and
immunohistochemical evidence also supports a role for NaV1.8 in neuropathic pain (See, Lai,
J., M. S. Gold, et al. (2002) "Inhibition of neuropathic pain by decreased expression of the
tetrodotoxin-resistant sodium channel, NaV1.8" Pain 95(1-2): 143-52, and Lai, J., J. C.
Hunter, et al. (2000) "Blockade of neuropathic pain by antisense targeting of tetrodotoxin-
resistant sodium channels in sensory neurons" Methods Enzvmol 314: 201-13.). NaV1.8
protein is upregulated along uninjured C-fibers adjacent to the nerve injury. Antisense
treatment prevents the redistribution of NaV1.8 along the nerve and reverses neuropathic
pain. Taken together the gene-knockout and antisense data support a role for NaV1.8 in the
detection and transmission of inflammatory and neuropathic pain.
[0010] In neuropathic pain states there is a remodeling of Na channel distribution and
subtype. In the injured nerve, expression of NaV1.8 and NaV1.9 are greatly reduced whereas
expression of the TTX sensitive subunit NaV1.3 is 5-10 fold upregulated (See, Dib-Hajj, S.
D., J. Fjell, et al. (1999) "Plasticity of sodium channel expression in DRG neurons in the
chronic constriction injury model of neuropathic pain." Pain 83(3): 591-600.) The
timecourse of the increase in NaV1.3 parallels the appearance of allodynia in animal models
subsequent to nerve injury. The biophysics of the NaV1.3 channel is distinctive in that it
shows very fast repriming after inactivation following an action potential. This allows for
sustained rates of high firing as is often seen in the injured nerve (See, Cummins, T. R., F.
Aglieco, et al. (2001) "Navl.3 sodium channels: rapid repriming and slow closed-state
inactivation display quantitative differences after expression in a mammalian cell line and in
spinal sensory neurons" J Neurosci 21(16): 5952-61.). NaV1.3 is expressed in the central and
peripheral systems of man. NaV1.9 is similar to NaV1.8 as it is selectively localized to
small sensory neurons of the dorsal root ganglion and trigeminal ganglion (See, Fang, X., L.
Djouhri, et al. (2002). "The presence and role of the tetrodotoxin-resistant sodium channel
Na(v)1.9 (NaN) in nociceptive primary afferent neurons." J Neurosci 22(17): 7425-33.). It
has a slow rate of inactivation and left-shifted voltage dependence for activation (See, Dib-
Hajj, S., J. A. Black, et al. (2002) "NaN/Navl.9: a sodium channel with unique properties"
Trends Neurosci 25(5): 253-9.). These two biophysical properties allow NaV1.9 to play a
role in establishing the resting membrane potential of nociceptive neurons. The resting
membrane potential of NaV1.9 expressing cells is in the -55 to -50mV range compared to -
65mV for most other peripheral and central neurons. This persistent depolarization is in large
part due to the sustained low-level activation of NaV1.9 channels. This depolarization
allows the neurons to more easily reach the threshold for firing action potentials in response
to nociceptive stimuli. Compounds that block the NaV1.9 channel may play an important
role in establishing the set point for detection of painful stimuli. In chronic pain.states, nerve
and nerve ending can become swollen and hypersensitive exhibiting high frequency action
potential firing with mild or even no stimulation. These pathologic nerve swellings are
termed neuromas and the primary Na channels expressed in them are NaV1.8 and NaV1.7
(See, Kretschmer, T., L. T. Happel, et al. (2002) "Accumulation of PN1 and PN3 sodium
channels in painful human neuroma- evidence from immunocytochemistry" Acta Neurochir
(Wien) 144(8): 803-10; discussion 810.). NaV1.6 and NaV1.7 are also expressed in dorsal
root ganglion neurons and contribute to the small TTX sensitive component seen in these
cells. NaV1.7 in particular my therefore be a potential pain target in addition to it's role in
neuroendocrine excitability (See, Klugbauer, N., L. Lacinova, et al. (1995) "Structure and
functional expression of a new member of the tetrodotoxin- sensitive voltage-activated
sodium channel family from human neuroendocrine cells" Embo J 14(6): 1084-90).
[0011] NaVl.l (See. Sugawara, T., E. Mazaki-Miyazaki, et al. (2001) "Navl.l mutations
cause febrile seizures associated with afebrile partial seizures." Neurology 57(4): 703-5.) and
NaV1.2 (See. Sugawara, T., Y. Tsurubuchi, et al. (2001) "A missense mutation of the Na+
channel alpha n subunit gene Na(v)1.2 in a patient with febrile and afebrile seizures causes
channel dysfunction" Proc Natl Acad Sci U S A 98(11): 6384-9) have been linked to epilepsy
conditions including febrile seizures. There are over 9 genetic mutations in NaVl.l
associated with febrile seizures (See. Meisler, M. H., J. A. Kearney, et al. (2002) "Mutations
of voltage-gated sodium channels in movement disorders and epilepsy" Novartis Found
Symp. 241: 72-81)
[0012] Antagonists for NaV1.5 have been developed and used to treat cardiac
arrhythmias. A gene defect in NaV1.5 that produces a larger noninactivating component to
the current has been linked to long QT in man and the orally available local anesthetic
mexilitine has been used to treat this condition (See. Wang, D. W., K. Yazawa, et al. (1997)
"Pharmacological targeting of long QT mutant sodium channels." J Clin Invest 99(7): 1714-
20).
[0013] Several Na channel blockers are currently used or being tested in the clinic to treat
epilepsy (See, Moulard, B. and D. Bertrand (2002) "Epilepsy and sodium channel blockers"
Expert Opin. Ther. Patents 12(1): 85-91.); acute (See, Wiffen, P., S. Collins, et al. (2000)
"Anticonvulsant drugs for acute and chronic pain" Cochrane Database Svst Rev 3), chronic
(See, Wiffen, P., S. Collins, et al. (2000) "Anticonvulsant drugs for acute and chronic pain"
Cochrane Database Syst Rev 3, and Guay, D. R. (2001) "Adjunctive agents in the
management of chronic pain" Pharmacotherapy 21(9): 1070-81), inflammatory (See. Gold,
M. S. (1999) "Tetrodotoxin-resistant Na+ currents and inflammatory hyperalgesia." Proc Natl
Acad Sci U S A 96(14): 7645-9), and neuropathic pain (See, Strichartz, G. R., Z. Zhou, et al.
(2002) "Therapeutic concentrations of local anaesthetics unveil the potential role of sodium
channels in neuropathic pain" Novartis Found Symp 241: 189-201, and Sandner-Kiesling, A.,
G. Rumpold Seitlinger, et al. (2002) "Lamotrigine monotherapy for control of neuralgia after
nerve section" Acta Anaesthesiol Scand 46(10): 1261-4); cardiac arrhythmias (See, An, R.
H., R. Bangalore, et al. (1996) "Lidocaine block of LQT-3 mutant human Na+ channels" Circ
Res 79(1): 103-8, and Wang, D. W., K. Yazawa, et al. (1997) "Pharmacological targeting of
long QT mutant sodium channels" J Clin Invest 99(7): 1714-20); neuroprotection (See.
Taylor, C. P. and L. S. Narasimhan (1997) "Sodium channels and therapy of central nervous
system diseases" Adv Pharmacol 39: 47-98) and as anesthetics (See^Strichartz, G. R., Z.
Zhou, et al. (2002) "Therapeutic concentrations of local anaesthetics unveil the potential role
of sodium channels in neuropathic pain." Novartis Found Symp 241: 189-201)
[0014] Calcium channels are membrane-spanning, multi-subunit proteins that allow Ca
entry from the external milieu and concurrent depolarization of the cell's membrane
potential. Traditionally calcium channels have been classified based on their functional
characteristics such as low voltage or high voltage activated and their kinetics (L,T,N,P,Q).
The ability to clone and express the calcium channel subunits has lead to an increased
understanding of the channel composition that produces these functional responses. There
are three primary subunit types that make up calcium channels - al, a2d, and p. The al is
the subunit containing the channel pore and voltage sensor, a2 is primarily extracellular and
is disulfide linked to the transmembrane d subunit, ß is nonglycosylated subunit found bound
to the cytoplasmic region of the al subunit of the Ca channel. Currently the various calcium
channel subtypes are believed to made up of the following specific subunits:
• L-type, comprising subunits a1caida1f, or a1S, a2d and ß3a
• N-Type, comprising subunits a1b, a2d, ß1b
o P-Type, comprising subunits a1A, a2d, ß4a
• Q-Type, comprising subunits a1A (splice variant) a2ß, ß4a
• R-Type, comprising subunits a1E, a2d, ß1b
• T-Type, comprising subunits a1G, a1H, or a1I
[0015] Calcium channels play a central role in neurotransmitter release. Ca influx into
the presynaptic terminal of a nerve process binds to and produces a cascade of protein-protein
interactions (syntaxin 1A, SNAP-25 and synaptotagmin) that ultimately ends with the.fusion
of a synaptic vesical and release of the neurotransmitter packet. Blockade of the presynaptic
calcium channels reduces the influx of Ca and produces a cubic X3 decrease in
neurotransmitter release.
[0016] The N type Ca channel (CaV2.2) is highly expressed at the presynaptic nerve
terminals of the dorsal root ganglion as it forms a synapse with the dorsal horn neurons in
lamina I and II. These neurons in turn have large numbers of N type Ca channels at their
presynaptic terminals as they synapse onto second and third order neurons. This pathway is
very important in relaying pain information to the brain.
[0017] Pain can be roughly divided into three different types: acute, inflammatory, and
neuropathic. Acute pain serves an important protective function in keeping the organism safe
from stimuli that may produce tissue damage. Severe thermal, mechanical, or chemical
inputs have the potential to cause severe damage to the organism if unheeded. Acute pain
serves to quickly remove the individual from the damaging environment. Acute pain by its
very nature generally is short lasting and intense. Inflammatory pain on the other had may
last for much longer periods of time and it's intensity is more graded. Inflammation may
occur for many reasons including tissue damage, autoimmune response, and pathogen
invasion. Inflammatory pain is mediated by an "inflammatory soup" that consists of
substance P, histamines, acid, prostaglandin, bradykinin, CGRP, cytokines, ATP, and
neurotransmitter release. The third class of pain is neuropathic and involves nerve damage
that results in reorganization of neuronal proteins and circuits yielding a pathologic
"sensitized" state that can produce chronic pain lasting for years. This type of pain provides
no adaptive benefit and is particularly difficult to treat with existing therapies.
[0018] Pain, particularly neuropathic and intractable pain is a large unmet medical need.
Millions of individuals suffer from severe pain that is not well controlled by current
therapeutics. The current drugs used to treat pain include NSAIDS, COX2 inhibitors,
opioids, tricyclic antidepressants, and anticonvulsants. Neuropathic pain has been
particularly difficult to treat as it does not respond well to opiods until high doses are
reached. Gabapentin is currently the favored therapeutic for the treatment of neuropathic
pain although it works in only 60% of patients where it shows modest efficacy. The drug is
however very safe and side effects are generally tolerable although sedation is an issue at
higher doses.
[0019] The N type Ca channel has been validated in man by intrathecal infusion of the
toxin Ziconotide for the treatment of intractable pain, cancer pain, opioid resistant pain, and
neuropathic and severe pain. The toxin has an 85% success rate for the treatment of pain in
humans with a greater potency than morphine. An orally available N type Ca channel
antagonist would garner a much larger share of the pain market. Ziconotide causes mast cell
degranulation and produces dose-dependent central side effects. These include dizziness,
nystagmus, agitation, and dysmetria. There is also orthostatic hypotension in some patients at
high doses. The primary risk for this target involves the CNS side effects seen with
Ziconotide at high dosing. These include dizziness, nystagmus, agitation, and dysmetria.
There is also orthostatic hypotension in some patients at high doses. It is believed that this
may be due to Ziconotide induced mast cell degranulation and/or its effects on the
sympathetic ganglion that like the dorsal root ganglion also expresses the N type Ca channel.
Use-dependent compounds that block preferentially in the higher frequency range >10Hz
should be helpful in minimizing these potential side-effect issues. The firing rate in man of
the sympathetic efferents is in the 0.3 Hz range. CNS neurons can fire at high frequencies
but generally only do so in short bursts of action potentials. Even with the selectivity
imparted by use-dependence intrinsic selectivity against the L type calcium channel is still
necessary as it is involved in cardiac and vascular smooth muscle contraction.
[0020] Unfortunately, as described above, the efficacy of currently used sodium channel
blockers and calcium channel blockers for the disease states described above has been to a
large extent limited by a number of side effects. These side effects include various CNS
disturbances such as blurred vision, dizziness, nausea, and sedation as well more potentially
life threatening cardiac arrhythmias and cardiac failure. Accordingly, there remains a need to
develop additional Na channel and Ca channel antagonists, preferably those with higher
potency and fewer side effects.
SUMMARY OF THE INVENTION
[0021] It has now been found that compounds of this invention, and pharmaceutically
acceptable compositions thereof, are useful as inhibitors of voltage-gated sodium channels
and calcium channels. These compounds have the general formula I:

or a pharmaceutically acceptable derivative thereof, wherein R1, X, R3, x, and ring A
are as defined below.
[0022] These compounds and pharmaceutically acceptable compositions are useful for
treating or lessening the severity of a variety of diseases, disorders, or conditions, including,
but not limited to, acute, chronic, neuropathic, or inflammatory pain, arthritis, migrane,
cluster headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, epilepsy or
epilepsy conditions, neurodegenerative disorders, psychiatric disorders such as anxiety and
depression, myotonia, arrythmia, movement disorders, neuroendocrine disorders, ataxia,
multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritis pain,
postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, head or neck
pain, severe or intractable pain, nociceptive pain, breakthrough pain, postsurgical pain, or
cancer pain.
DETAILED DESCRIPTION OF THE INVENTION
[0023] /. General Description of Compounds of the Invention:
[0024] The present invention relates to compounds of formula I useful as inhibitors of
voltage-gated sodium channels and calcium channels:

or a pharmaceutically acceptable salt thereof, wherein:
X is O or NR2;
wherein R1 and R2 are each independently an optionally substituted group selected
from hydrogen, C1-6aliphatic, or Cy1, wherein Cyl is a 5-7-membered monocyclic aryl ring or
an 8-10-membered bicyclic aryl ring having 0-3 heteroatoms independently selected from
nitrogen, oxygen, or sulfur, or is a 3-12-membered saturated, or partially unsaturated
monocyclic or bicyclic ring having 0-3 heteroatoms independently selected from nitrogen,
oxygen, or sulfur, wherein Cy1 is bonded directly to the nitrogen atom or is bonded through
an optionally substituted C1-4 aliphatic group, wherein one or more methylene units in the C1-4
aliphatic group are optionally replaced with -NR-, -O-, -COO, -OCO-, -NRCO-, -CONR-, -
SO2NR-, or -NRSO2-; or R1 and R2, taken together with the nitrogen atom to which they are
bound, form an optionally substituted 3-12-membered monocyclic or bicyclic saturated,
partially unsaturated, or fully unsaturated ring having 0-3 additional heteroatoms
independently selected from nitrogen, sulfur, or oxygen; wherein R1 and R2, or the ring
formed by R1 and R2 taken together, are each optionally and independently substituted at one
or more substitutable carbon, nitrogen, or sulfur atoms with z independent occurrences of -
R4, wherein z is 0-5;
Ring A is a 5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl
ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or is a
3-12-membered monocyclic or bicyclic saturated or partially unsaturated monocyclic ring
having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein ring
A is optionally substituted with y independent occurrences of-R5, wherein y is 0-5, and is
additionally optionally substituted with q independent occurrences of R5a, wherein q is 0-2;
x is 0-4;
each occurrence of R3, R4, and R5 is independently Q-Rx; wherein Q is a bond or is a
C1-C6 alkylidene chain wherein up to two non-adjacent methylene units of Q are optionally
and independently replaced by -NR-, -S-, -O-, -CS-, -CO2-, -OCO-, -CO-, -COCO-, -CONR-,
-NRCO-, -NRCO2-, -SO2NR-, -NRSO2-, -CONRNR-, -NRCONR-, -OCONR-, -NRNR-, -
NRSO2NR-, -SO-, -SO2-, -PO-, -PO2-, -OP(O)(OR)-, or -POR-; and each occurrence of Rx is
independently selected from -R', =O, =NR', halogen, -NO2, -CN, -OR', -SR', -N(R')2, -
NR'COR', -NR'CON(R')2, -NR'CO2R, -COR', -CO2R', -OCOR', -CON(R')2) -
OCON(R')2) -SOR', -SO2R', -SO2N(R')2, -NR'SO2R', -NR'SO2N(R')2, -COCOR', -
COCH2COR', -OP(O)(OR')2, -P(O)(OR')2, -OP(O)2OR', -P(O)2OR', -PO(R')2, or -
OPO(R')2;
each occurrence of R5a is independently an optionally substituted C1-C6aliphatic
group, halogen, -OR', -SR', -N(R')2, -NR'COR', -NR'CON(R')2, -NR'CO2R', -COR', -
CO2R', -OCOR', -CON(R')2, -OCON(R')2, -SOR', -SO2R', -SO2N(R')2, -NR'SO2R', -
NR'SO2N(R')2, -COCOR', -COCH2COR', -OP(O)(OR')2, -P(O)(OR')2, -OP(O)2OR', -
P(O)2OR', -PO(R')2, or -OPO(R')2; and
each occurrence of R is independently hydrogen or an optionally substituted C1-6
aliphatic group; and each occurrence of R is independently hydrogen or an optionally
substituted C1-6 aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully
unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen,
oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated
bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen,
or sulfur; or R and R, two occurrences of R, or two occurrences of R, are taken together with
the atom(s) to which they are bound to form an optionally substituted 3-12 membered
saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4
heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[0025] In certain embodiments for compounds described directly above:
*********i) when x is 1 and R3 is optionally substituted 6-phenyl or 6-pyridyl, and R1 is
hydrogen, then R2 is not Cy*;and
ii)PiperazineJ-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4(2-furanylcarbonyl)-
monohydrochlorideandPiperazine,l-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4[(2,3-
dihydro-l,4-benzodioxin-2-yl)carbonyI]- are excluded.
[0026] 2. Compounds and Definitions:
[0027] Compounds of this invention include those described generally above, and are
further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the
following definitions shall apply unless otherwise indicated. For purposes of this invention,
the chemical elements are identified in accordance with the Periodic Table of the Elements,
CAS version, Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles
of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University
Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5th Ed., Ed.:
Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of
which are hereby incorporated by reference.
[0028] As described herein, compounds of the invention may optionally be substituted
with one or more substituents, such as are illustrated generally above, or as exemplified by
particular classes, subclasses, and species of the invention. It will be appreciated that the
phrase "optionally substituted" is used interchangeably with the phrase "substituted or
unsubstituted." In general, the term "substituted", whether preceded by the term "optionally"
or not, refers to the replacement of hydrogen radicals in a given structure with the radical of a
specified substituent. Unless otherwise indicated, an optionally substituted group may have a
substituent at each substitutable position of the group, and when more than one position in
any given structure may be substituted with more than one substituent selected from a
specified group, the substituent may be either the same or different at every position.
Combinations of substituents envisioned by this invention are preferably those that result in
the formation of stable or chemically feasible compounds. The term "stable", as used herein,
refers to compounds that are not substantially altered when subjected to conditions to allow
for their production, detection, and preferably their recovery, purification, and use for one or
more of the purposes disclosed herein. In some embodiments, a stable compound or
chemically feasible compound is one that is not substantially altered when kept at a
temperature of 40°C or less, in the absence of moisture or other chemically reactive
conditions, for at least a week.
[0029] The term "aliphatic" or "aliphatic group", as used herein, means a straight-chain
(i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is
completely saturated or that contains one or more units of unsaturation, or a monocyclic
hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more
units of unsaturation, but which is not aromatic (also referred to herein as "carbocycle"
"cycloaliphatic" or "cycloalkyl"), that has a single point of attachment to the rest of the
molecule. Unless otherwise specified, aliphatic groups contain 1-20 aliphatic carbon atoms.
In some embodiments, aliphatic groups contain 1-10 aliphatic carbon atoms. In other
embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms. In still other
embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms, and in yet other
embodiments aliphatic groups contain 1-4 aliphatic carbon atoms. In some embodiments,
"cycloaliphatic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic C3-C8 hydrocarbon
or bicyclic C8-C12 hydrocarbon that is completely saturated or that contains one or more units
of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of
the molecule wherein any individual ring in said bicyclic ring system has 3-7 members.
Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or
unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl,
(cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
[0030] The term "heteroaliphatic", as used herein, means aliphatic groups wherein one or
two carbon atoms are independently replaced by one or more of oxygen, sulfur, nitrogen,
phosphorus, or silicon. Heteroaliphatic groups may be substituted or unsubstituted, branched
or unbranched, cyclic or acyclic, and include "heterocycle", "heterocyclyl",
"heterocycloaliphatic", or "heterocyclic" groups.
[0031] The term "heterocycle", "heterocyclyl", "heterocycloaliphatic", or "heterocyclic"
as used herein means non-aromatic, monocyclic, bicyclic, or tricyclic ring systems in which
one or more ring members are an independently selected heteroatom. In some embodiments,
the "heterocycle", "heterocyclyl", "heterocycloaliphatic", or "heterocyclic" group has three to
fourteen ring members in which one or more ring members is a heteroatom independently
selected from oxygen, sulfur, nitrogen, or phosphorus, and each ring in the system contains 3
to 7 ring members.
[0032] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen,
phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or
silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a
heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or
NR+ (as in N-substituted pyrrolidinyl)).
[0033] The term "unsaturated", as used herein, means that a moiety has one or more units
of unsaturation.
[0034] The term "alkoxy", or "thioalkyl", as used herein, refers to an alkyl group, as
previously defined, attached to the principal carbon chain through an oxygen ("alkoxy") or
sulfur ("thioalkyl") atom.
[0035] The terms "haloalkyl", "haloalkenyl" and "haloalkoxy" means alkyl, alkenyl or
alkoxy, as the case may be, substituted with one or more halogen atoms. The term "halogen"
means F, Cl, Br, or I.
[0036]. The term "aryl" used alone or as part of a larger moiety as in "aralkyl",
"aralkoxy", or "aryloxyalkyl", refers to monocyclic, bicyclic, and tricyclic ring systems
having a total of five to fourteen ring members, wherein at least one ring in the system is
aromatic and wherein each ring in the system contains 3 to 7 ring members. The term "aryl"
may be used interchangeably with the term "aryl ring". The term "aryl" also refers to
heteroaryl ring systems as defined hereinbelow.
[0037] The term "heteroaryl", used alone or as part of a larger moiety as in
"heteroaralkyl" or "heteroarylalkoxy", refers to monocyclic, bicyclic, and tricyclic ring
systems having a total of five to fourteen ring members, wherein at least one ring in the
system is aromatic, at least one ring in the system contains one or more heteroatoms, and
wherein each ring in the system contains 3 to 7 ring members. The term "heteroaryl" may be
used interchangeably with the term "heteroaryl ring" or the term "heteroaromatic".
[0038] An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like) or heteroaryl
(including heteroaralkyl and heteroarylalkoxy and the like) group may contain one or more
substituents and thus may be "optionally substituted". Unless otherwise defined above and
herein, suitable substituents on the unsaturated carbon atom of an aryl or heteroaryl group are
generally selected from halogen; -R°; -OR°; -SR°; phenyl (Ph) optionally substituted with R°;
-O(Ph) optionally substituted with R°; -(CH2)1-2(Ph), optionally substituted with R°; -
CH=CH(Ph), optionally substituted with R°; -NO2; -CN; -N(R°)2; -NR°C(O)R°; -
NR°C(S)R°; -NR°C(O)N(R°)2; -NR°C(S)N(R°)2; -NR°CO2R°; -NR°NR°C(O)R°;
-NR°NR°C(O)N(R°)2; -NR°NR°CO2R°; -C(O)C(O)R°; -C(O)CH2C(O)R°; -CO2R°; -
C(O)R°; -C(S)R°; -C(O)N(R°)2; -C(S)N(R°)2; -OC(O)N(R°)2; -OC(O)R°; -C(O)N(OR°) R°;
-C(NOR°) R°; -S(O)2R°; -S(O)3R°; -SO2N(R°)2; -S(O)R°; -NR°SO2N(R°)2; -NR°SO2R°;
-N(OR°)R°; -C(=NH)-N(R°)2; -P(O)2R°; -PO(R°)2; -OPO(R°)2; -(CH2)0-2NHC(O)R°; phenyl
(Ph) optionally substituted with R°; -O(Ph) optionally substituted with R°; -(CH2)1-2(Ph),
optionally substituted with R°; or -CH=CH(Ph), optionally substituted with R°; wherein each
independent occurrence of R° is selected from hydrogen, optionally substituted C1-6 aliphatic,
an unsubstituted 5-6 membered heteroaryl or heterocyclic ring, phenyl, -O(Ph), or -CH2(Ph),
or, notwithstanding the definition above, two independent occurrences of R°, on the same
substituent or different substituents, taken together with the atom(s) to which each R° group
is bound, to form an optionally substituted 3-12 membered saturated, partially unsaturated, or
fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected
from nitrogen, oxygen, or sulfur.
[0039] Optional substituents on the aliphatic group of R° are selected from NH2,
NH(C1-4aliphatic), N(C1-4aliphatic)2, halogen, C1-4aliphatic, OH, O(C1-4aliphatic), NO2, CN,
CO2H, CO2(C1-4aliphatic), O(haloC1-4 aliphatic), or haloC1-4aliphatic, wherein each of the
foregoing C1-4aliphatic groups of R° is unsubstituted.
[0040] An aliphatic or heteroaliphatic group, or a non-aromatic heterocyclic ring may
contain one or more substituents and thus may be "optionally substituted". Unless otherwise
defined above and herein, suitable substituents on the saturated carbon of an aliphatic or
heteroaliphatic group, or of a non-aromatic heterocyclic ring are selected from those listed
above for the unsaturated carbon of an aryl or heteroaryl group and additionally include the
following: =O, =S, =NNHR*, =NN(R*)2, =NNHC(O)R*, =NNHCO2(alkyl),
=NNHSO2(alkyl), or =NR*, where each R* is independently selected from hydrogen or an
optionally substituted C1-6 aliphatic group.
[0041] Unless otherwise defined above and herein, optional substituents on the nitrogen
of a non-aromatic heterocyclic ring are generally selected from -R+, -N(R+)2, -C(O)R+,
-CO2R+, -C(O)C(O)R+, -C(O)CH2C(O)R+, -SO2R+, -SO2N(R+)2, -C(=S)N(R+1)2, -C(=NH)-
N(R+)2, or -NR+SO2R+; wherein R+ is hydrogen, an optionally substituted C1-6 aliphatic,
optionally substituted phenyl, optionally substituted -O(Ph), optionally substituted -CH2(Ph),
optionally substituted -(CH2)1-2(Ph); optionally substituted -CH=CH(Ph); or an unsubstituted
5-6 membered heteroaryl or heterocyclic ring having one to four heteroatoms independently
selected from oxygen, nitrogen, or sulfur, or, notwithstanding the definition above, two
independent occurrences of R+, on the same substituent or different substituents, taken
together with the atom(s) to which each R+ group is bound, form an optionally substituted 3-
12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic
ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[0042] Optional substituents on the aliphatic group or the phenyl ring of R+ are selected
from -NH2, -NH(C1-4 aliphatic), -N(C1-4 aliphatic)2, halogen, C1-4 aliphatic, -OH, -O(C1-4
aliphatic), -NO2, -CN, -CO2H, -CO2(CM aliphatic), -O(halo C1-4 aliphatic), or halo(C1-4
aliphatic), wherein each of the foregoing C1-4aliphatic groups of R+ is unsubstituted.
[0043] The term "alkylidene chain" refers to a straight or branched carbon chain that may
be fully saturated or have one or more units of unsaturation and has two points of attachment
to the rest of the molecule.
[0044] As detailed above, in some embodiments, two independent occurrences of R° (or
R+, R, R' or any other variable similarly defined herein), are taken together with the atom(s)
to which they are bound to form an optionally substituted 3-12 membered saturated, partially
unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms
independently selected from nitrogen, oxygen, or sulfur.
[0045] Exemplary rings that are formed when two independent occurrences of R° (or R+,
R, R' or any other variable similarly defined herein), are taken together with the atom(s) to
which each variable is bound include, but are not limited to the following: a) two
independent occurrences of R° (or R+, R, R' or any other variable similarly defined herein)
that are bound to the same atom and are taken together with that atom to form a ring, for
example, N(R°)2, where both occurrences of R° are taken together with the nitrogen atom to
form a piperidin-1-yl, piperazin-1-yl, or morpholin-4-yl group; and b) two independent
occurrences of R° (or R+, R, R' or any other variable similarly defined herein) that are bound
to different atoms and are taken together with both of those atoms to form a ring, for example
where a phenyl group is substituted with two occurrences of OR° these two
occurrences of R° are taken together with the oxygen atoms to which they are bound to form
a fused 6-membered oxygen containing ring: It will be appreciated that a
variety of other rings can be formed when two independent occurrences of R° (or R+, R, R' or
any other variable similarly defined herein) are taken together with the atom(s) to which each
variable is bound and that the examples detailed above are not intended to be limiting.
Unless otherwise stated, structures depicted herein are also meant to include all isomeric
(e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the
structure; for example, the R and S configurations for each asymmetric center, (Z) and (E)
double bond isomers, and (Z) and (E) conformational isomers. Therefore, single
stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or
conformational) mixtures of the present compounds are within the scope of the invention.
Unless otherwise stated, all tautomeric forms of the compounds of the invention are within
the scope of the invention. Additionally, unless otherwise stated, structures depicted herein
are also meant to include compounds that differ only in the presence of one or more
isotopically enriched atoms. For example, compounds having the present structures except
for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a
13C- or 14C-enriched carbon are within the scope of this invention. Such compounds are
useful, for example, as analytical tools or probes in biological assays.
[0046] 3. Description of Exemplary Compounds:
[0047] As described generally above, for compounds of the invention, X is O or NR".
Accordingly, in certain embodiments, X is NR2, and compounds have the structure of
formula I-A:
[0048] In other embodiments, X is O, and compounds have the structure of formula I-B:

[0049] In certain embodiments for compounds of general formula I-A, one of R1 or R2 is
hydrogen, and the other of R1 and R2 is selected from an optionally substituted C1-4aliphatic
group, wherein one or more methylene units in the C1-4aliphatic group are optionally replaced
with -NR-, -O-, -COO, -OCO-, -NRCO-, -CONR-, -SO2NR-, or -NRSO2-, or is Cy1, wherein
Cy1 is a 5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ring having
0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or is a 3-12-
membered saturated, or partially unsaturated monocyclic or bicyclic ring having 0-3
heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Cy1 is bonded
directly to the nitrogen atom or is bonded through an optionally substituted C1-4aliphatic
group, wherein one or more methylene units in the C1-4aliphatic group are optionally replaced
with -NR-, -O-, -COO, -OCO-, -NRCO-, -CONR-, -SO2NR-, or -NRSO2-.
[0050] In still other embodiments, R1 and R2 are each independently selected from Cy1,
wherein Cy1 is a 5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ring
having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or is a 3-12-
membered saturated, or partially unsaturated monocyclic or bicyclic ring having 0-3
heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Cy1 is bonded
directly to the nitrogen atom or is bonded through an optionally substituted C1-4aliphatic
group, wherein one or more methylene units in the C1-4aliphatic group are optionally replaced
with -NR-, -O-, -COO, -OCO-, -NRCO-, -CONR-, -SO2NR-, or -NRSO2-; or from an
optionally substituted C1-4aliphatic group, wherein one or more methylene units in the C1-4
aliphatic group are optionally replaced with -NR-, -O-, -COO-, -OCO-, -NRCO-, -CONR-, -
SO2NR-, or -NRSO2-.
[0051] In other embodiments, for compounds of formula I-A, one of R1 or R2 is
hydrogen, and the other of R1 or R2 is an optionally substituted C1-4aliphatic group, wherein
one or more methylene units in the C1-4aliphatic group are optionally replaced with -NR-, -O-, -COO-, -OCO-, -NRCO-, -CONR-, -SO2NR-, or -NRSO2-. In still other embodiments, the
optionally substituted C1-4aliphatic group is substituted with Cy1, wherein Cy1 is 5-7-
membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3
heteroatoms independently selected from nitrogen, oxygen, or sulfur, or is a 3-12 membered
saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms independently
selected from nitrogen, oxygen, or sulfur, wherein Cy1 is optionally substituted with 0-5
independent occurrences of -R5. In yet other embodiments, one of R1 or R2 is hydrogen or
C1-C4alkyl, and the other of R1 or R2 is -CH2-Cy1.
[0052] In yet other embodiments, for compounds of formula I-B, R1 is an optionally
substituted C1-4aliphatic group, wherein one or more methylene units in the C1-4aliphatic
group are optionally replaced with -NR-, -O-, -COO-, -OCO, -NRCO-, -CONR-, -SO2NR-,
or -NRSO2-.
[0053] In still other embodiments, for compounds of formula I-A, neither R1 nor R2 is
hydrogen, and R1 and R2 are each independently selected from Cy1, wherein Cy1 is a 5-7-
membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3
heteroatoms independently selected from nitrogen, oxygen, or sulfur, or is a 3-12-membered
saturated, or partially unsaturated monocyclic or bicyclic ring having 0-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur, wherein Cy1 is bonded directly to
the nitrogen atom or is bonded through an optionally substituted C1-4aliphatic group, wherein
one or more methylene units in the C1-4aliphatic group are optionally replaced with -NR-, -O-, -COO, -OCO-, -NRCO-, -CONR-, -SO2NR-, or -NRSO2-; or from an optionally substituted
C1-4aliphatic group, wherein one or more methylene units in the C1-4aliphatic group are
optionally replaced with -NR-, -O-, -COO-, -OCO-, -NRCO-, -CONR-, SO2NR-, or -NRSO2._
In other embodiments, both R1 and R2 are an optionally substituted C1-4aliphatic group,
wherein one or more methylene units in the C1-4ahphatic group are optionally replaced with -
NR-, -O-, -COO-, -OCO-, -NRCO-, -CONR-, -SO2NR-, or -NRSO2..
[0054] In some embodiments, for compounds of formula I, I-A or I-B, Cy1 is selected
from:
wherein R4 is previously defined and z is 0-4. Other exemplary rings include those
shown below in Table 2.
[0055] In yet other embodiments, for compounds of formula I, I-A, and I-B, exemplary
R1 and R2 groups are optionally substituted methyl, ethyl, cyclopropyl, n-propyl, propenyl,
cyclobutyl, (CO)OCH2CH3, (CH2)2OCH3, CH2(CO)OCH2CH3, CH2(CO)OCH3,
CH(CH3)CH2CH3, or n-butyl. Other exemplary R1 and R2 groups include those shown below
in Table 2.
[0056] In still other embodiments, for compounds of formula I-A, R1 and R", taken
together with the nitrogen atom to which they are bound, form an optionally substituted 3-12
membered heterocyclyl ring having 1-3 heteroatoms independently selected from nitrogen,
sulfur, or oxygen. In certain preferred embodiments, R1 and R2 are taken together with the
nitrogen atom to which they are bound and form a group selected from:
wherein the ring formed by R1 and R2 taken together, is optionally substituted at one
or more substitutable carbon, nitrogen, or sulfur atoms with z independent occurrences of -
R4, and z is 0-5.
[0057] In other embodiments, for compounds of formula I-A, R1 and R2 taken together
are optionally substituted azetidin-1-yl (jj), pyrrolidin-1-yl (ff), piperidinl-yl (dd), piperazin-
1-yl (cc), or morpholin-4-yl (ee). In other embodiments, for compounds of formula I-A, R1
and R2 taken together are optionally substituted azetidin-1-yl (jj), pyrrolidin-1-yl (ff),
piperidinl-yl (dd), or piperazin-1-yl (cc). In yet other embodiments, for compounds of
formula I-A, R1 and R2, taken together is optionally substituted azetidm-1-yl (jj). In yet other
embodiments, for compounds of formula I-A, R1 and R2, taken together is optionally
substituted pyrrolidin-1-yl (ff). In still other embodiments, for compounds of formula I-A, R1
and R2, taken together is optionally substituted piperidinl-yl (dd). In yet other embodiments,
for compounds of formula I-A, R1 and R2, taken together is optionally substituted piperazin-
1-yl (cc).
[0058] In certain embodiments, z is 0-2. In other embodiments, z is 0 and the ring is
unsubstituted. Preferred R4 groups, when present, are each independently halogen, CN, NO2,
-N(R')2, -CH2N(R')2, -OR', -CH2OR', -SR', -CH2SR', -COOR', -NRCOR', -CON(R')2, -
OCON(R')2, COR', -NHCOOR', -SO2R', -SO2N(R')2, or an optionally substituted group
selected from C1.C6aliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC1-
C6alkyl, heteroarylC1-C6alkyl, cycloaliphaticC1-C6alkyl, or heterocycloaliphaticC1-C6alkyl.
Other exemplary R4 groups are CI, Br, F, CF3, CH3, -CH2CH3, CN, -COOH, -N(CH3)2, -
N(Et)2, -N(iPr)2, -O(CH2)2OCH3, -CONH2, -COOCH3, -OH, -CH2OH, -NHCOCH3, -
SO2NH2, -SO2(CH2)3CH3, -SO2CH(CH3)2, -SO2N(CH3)2, -SO2CH2CH3)
C(O)OCH2CH(CH3)2, -C(O)NHCH2CH(CH3)2, -NHCOOCH3, -C(O)C(CH3)3, -
COO(CH2)2CH3, -C(O)NHCH(CH3)2, -C(O)CH2CH3, or an optionally substituted group
selected from -piperidinyl, piperizinyl, morpholino, C1-4alkoxy, phenyl, phenyloxy, benzyl,
benzyloxy, -CH2cyclohexyl, pyridyl, -CH2pyridyl, or -CH2thiazolyl. Still other exemplary R4
groups include those shown below in Table 2.
[0059] In certain embodiments, for compounds of formula I-A, R1 and R2, taken together
is optionally substituted azetidin-1-yl (jj), wherein z is 1 or 2 and at least one occurrence of
R4 is -NRSO2R', -NRCOOR', or -NRCOR'. In certain other embodiments, for compounds
of formula I-A, R1 and R2, taken together is optionally substituted azetidin-1-yl (jj), wherein
2 is 1 and R4 is -NRSO2R', In other embodiments, for compounds of formula I-A, R1 and
R2, taken together is optionally substituted azetidin-1-yl (jj), wherein z is 1 and R4 is -
NRCOOR'. In certain other embodiments, for compounds of formula I-A, R1 and R2, taken
together is optionally substituted azetidin-1-yl (jj), wherein z is 1 and R4 is -NRCOR'. In yet
other embodiments, for compounds of formula I-A, R1 and R2, taken together is optionally
substituted pyrrolidin-1-yl (ff), wherein z is 1 or 2 and R4 is C1, Br, F, CF3, CH3, -CH2CH3, -
OR', or -CH2OR'. In still other embodiments, for compounds of formula I-A, R1 and R2,
taken together is optionally substituted piperidin-1-yl (dd), wherein z is 1 or 2 and at least
one occurrence of R4 is CI, Br, F, CF3, CH3, -CH2CH3, -OR', or -CH2OR', -NRSO2R', -
NRCOOR', or -OCON(R')2. In certain other embodiments, for compounds of formula I-A,
R1 and R2, taken together is optionally substituted piperidin-1-yl (dd), wherein z is 1 and R4
is F, CF3, CH3, -CH2CH3, -OR', or -CH2OR', In other embodiments, for compounds of
formula I-A, R1 and R2, taken together is optionally substituted piperidin-1-yl (dd), wherein z
is 1 and R4 is — NRSO2R',. In certain other embodiments, for compounds of formula I-A, R1
and R2, taken together is optionally substituted piperidin-1-yl (dd), wherein z is 1 and R4 is -
NRCOOR'. In yet other embodiments, for compounds of formula I-A, R1 and R2, taken
together is optionally substituted piperazin-1-yl (cc), wherein z is 1 or 2 and at least one
occurrence of R4 is -SOR', -CON(R')2, -SO2N(R)2, -COR', or -COOR'. In certain other
embodiments, for compounds of formula I-A, R1 and R2, taken together is optionally
substituted piperazin-1-yl (cc), wherein z is 1 and R4 is -SOR'. In certain other
embodiments, for compounds of formula I-A, R1 and R2, taken together is optionally
substituted piperazin-1-yl (cc), wherein z is 1 and R4 is -COOR'. In certain other
embodiments, for compounds of formula I-A, R1 and R2, taken together is optionally
substituted piperazin-1-yl (cc), wherein z is 1 and R4 is -CON(R')2. In certain other
embodiments, for compounds of formula I-A, R1 and R2, taken together is optionally
substituted piperazin-1-yl (cc), wherein z is 1 and R4 is -SO2N(R')2. In certain other
embodiments, for compounds of formula I-A, R1 and R2, taken together is optionally
substituted piperazin-1-yl (cc), wherein z is 1 and R4 is -COR'.
[0060] As described generally above, for compounds of formulas I, I-A, or I-B, the
quinazoline ring can be substituted with up to four independent occurrences of R3. In certain
embodiments, x is 0-2. In other embodiments, x is 1 or 2. In still other embodiments x is 1
and R3 is substituted at the 6- or 7-position of the quinazoline ring. When the quinazoline
ring is substituted (x is 1-4), R3 groups are halogen, CN, NO2, -N(R')2, -CH2N(R')2, -OR', -
CH2OR', -SR', -CH2SR', -COOR', -NRCOR', -CON(R')2, -OCON(R')2, COR', -
NHCOQR', -SO2R', -SO2N(R')2, or an optionally substituted group selected from C1-C6
altphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC1-C6alkyl,
heteroarylC1-C6alkyl, cycloaliphaticC1-C6alkyl, or heterocycloaliphaticC1-C6alkyl. In still
other embodiments, each occurrence of R3 is independently Cl, Br, F, CF3, -OCF3, Me, Et,
CN, -COOH, -NH2, -N(CH3)2, -N(Et)2, -N(iPr)2, -O(CH2)2OCH3, -CONH2, -COOCH3, -OH,
-OCH3, -OCH2CH3, -CH2OH, -NHCOCH3, -NHCOCH(CH3)2, -SO2NH2, -
CONH(cyclopropyl), -CONHCH3, -CONHCH2CH3, or an optionally substituted group
selected from -piperidinyl, piperizinyl, morpholino, phenyl, phenyloxy, benzyl, or benzyloxy.
In still other embodiments, x is 1 or 2 and each R3 group is independently halogen, CN,
optionally substituted C1-C6alkyl, OR', N(R')2, CON(R')2, or NRCOR'. In yet other
embodiments, x is 1 or 2, and each R3 group is -CI, -CH3, -CH2CH3, -F, -CF3, -OCF3, -
CONHCH3, -CONHCH2CH3, -CONH(cyclopropyl), -OCH3, -NH2, -OCH2CH3, or -CN. In
still other embodiments, x is 1 and R3 is at the 6-position of the quinazoline ring and is -CI, -
CH3, -CH2CH3, -F, -CF3, -OCF3; -CONHCH3, -CONHCH2CH3, -CONH(cyclopropyl), -
OCH3, -NH2, -OCH2CH3, or -CN. IN yet other embodiments, x is 1 and R3 is at the 7-
position of the quinazoline ring and is -CI, -CH3, -CH2CH3, -F, -CF3, -OCF3, -CONHCH3, -
CONHCH2CH3, -CONH(cyclopropyl), -OCH3, -NH2, -OCH2CH3, or -CN. In other
embodiments, x is 1 and R3 is at the 6-position of the quinazoline ring and is -CI, -CH3, -
CH2CH3, -F, -CF3, -OCF3, -OCH3, or -OCH2CH3. In still other embodiments, x is 1 and R3 is
at the 7-position of the quinazoline ring and is -CI, -CH3, -CH2CH3, -F, -CF3, -OCF3, -OCH3,
or -OCH2CH3. In other embodiments, x is 1 and R3 is at the 6-position of the quinazoline
ring and is -CON(R')2, or NRCOR'. In yet other embodiments, x is 1 and R3 is at the 7-
position of the quinazoline ring and is -CON(R')2, or NRCOR'. Other exemplary R3 groups
include those shown below in Table 2.
[0061] As described generally above, for compounds of formula I, I-A, or I-B, Ring A is
a 5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3
heteroatoms independently selected from nitrogen, oxygen, or sulfur, or is a 3-12-membered
saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms independently
selected from nitrogen, oxygen, or sulfur, wherein ring A is optionally substituted with y
independent occurrences of -R5, wherein y is 0-5, and is additionally optionally substituted
with q independent occurrences of R5a, wherein q is 0-2.
[0062] In certain embodiments, ring A is selected from:
[0063] In certain other embodiments, ring A is selected from optionally substituted
phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl, or pyrrol-1-yl.
[0064] In some embodiments, y is 0-5, q is 0-2, and Rs and R5a groups, when present, are
each independently halogen, CN, NO2, -N(R')2, -CH2N(R')2, -OR', -CH2OR', -SR', -
CH2SR', - -NRCOR', -CON(R')2, -S(O)2N(R')2, -OCOR', -COR', -CO2R', -OCON(R')2, -
NR'SO2R', -OP(O)(OR')2, -P(O)(OR')2, -OP(O)2OR', -P(O)2OR', -PO(R')2, -OPO(R')2, or
an optionally substituted group selected from Ci.Cealiphatic, aryl, heteroaryl, cycloaliphatic,
heterocycloaliphatic, arylC1-C6alkyl, heteroarylC1-C6alkyl, cycloaliphaticC1-C6alkyl, or
heterocycloaliphaticC1-6alkyl.
[0065] In yet other embodiments, y is 0-5, and q is 1 or 2, and each occurrence of R5a is
independently Cl, Br, F, CF3, Me, Et, CN, -COOH, -NH2, -N(CH3)2, -N(Et)2, -N(iPr)2, -
O(CH2)2OCH3, -CONH2, -COOCH3, -OH, -OCH3, -OCH2CH3, -CH2OH, -NHCOCH3, -
SO2NH2, -SO2NHC(CH3)2, -OCOC(CH3)3, -OCOCH2C(CH3)3, -O(CH2)2N(CH3)2, 4-CH3-
piperazin-1-yl, OCOCH(CH3)2, OCO(cyclopentyl), -COCH3, optionally substituted phenoxy,
or optionally substituted benzyloxy.
[0066] In still other embodiments, y is 0, and q is 1 and RSa is F. In yet other
embodiments, y is 0, q is 1, and R5a is OR'. In still other embodiments, y is 0, q is 1 and R5a
is OH. In yet other embodiments, y is 0, q is 2 and one occurrence of R5a is OR' and the
other occurrence of R5a is F. In yet other embodiments, y is 0, q is 2 and one occurrence of
R5a is OH and the other occurrence of R5a is F.
[0067] In still other embodiments, ring A is phenyl, y is 0, and q is 1 and R5a is F
substituted at the 2-position of the phenyl ring. In yet other embodiments, ring A is phenyl, y
is 0, q is 1, and R5a is OR' substituted at the 2-position of the phenyl ring. In still other
embodiments, ring A is phenyl, y is 0, q is 1 and R5a is OH substituted at the 2-position of the
phenyl ring. In yet other embodiments, ring A is phenyl, y is 0, q is 2 and one occurrence of
R5a is OR' and the other occurrence of R5a is F, wherein OR' is substituted at the 2-position
of the phenyl ring and F is substituted at the 6-position of the phenyl ring. In yet other
embodiments, ring A is phenyl, y is 0, q is 2 and one occurrence of R5a is OH and the other
occurrence of R5a is F, wherein OH is substituted at the 2-position of the phenyl ring and F is
substituted at the 6-position of the phenyl ring.
[0068] Other exemplary R5 and R5a groups include those shown below in Table 2.
[0069] For compounds described in this section above, in general, compounds are useful
as inhibitors of ion channels, preferably voltage gated sodium channels and N-type calcium
channels. In certain exemplary embodiments, compounds of the invention are useful as
inhibitors of NaV1.8. In other embodiments, compounds of the invention are useful as
inhibitors of NaV1.8 and CaV2.2. In still other embodiments, compounds of the invention
are useful as inhibitors of CaV2.2. In yet other embodiments, compounds of the invention
are useful as dual inhibitors of NaV1.8 and a TTX-sensitive ion channel such as NaV1.3 or
NaV1.7.
[0070] Certain additional embodiments of compounds described generally above are
described in more detail below. For example:
[0071] I. Compounds of formula IA:

or a pharmaceutically acceptable salt thereof, wherein:
R1 and R2, taken together with the nitrogen atom to which they are bound, form an
optionally substituted 3-12-membered monocyclic or bicyclic saturated, partially unsaturated,
or fully unsaturated ring having 0-3 additional heteroatoms independently selected from
nitrogen, sulfur, or oxygen; wherein the ring formed by R1 and R2 taken together, is
optionally substituted at one or more substitutable carbon, nitrogen, or sulfur atoms with z
independent occurrences of-R4, wherein z is 0-5;
Ring A is a 5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl
ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or is a
3-12-membered saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur, wherein ring A is optionally
substituted with y independent occurrences of-R5, wherein y is 0-5, and is additionally
optionally substituted with q independent occurrences of R5a, wherein q is 0-2;
x is 0-4;
each occurrence of R3, R4, and R5 is independently Q-Rx; wherein Q is a bond or is a
C1-C6 alkylidene chain wherein up to two non-adjacent methylene units of Q are optionally
and independently replaced by -NR-, -S-, -O-, -CS-, -CO2-, -OCO-, -CO-, -COCO-, -CONR-,
-NRCO-, -NRCO2-, -SO2NR-, -NRSO2-, -CONRNR-, -NRCONR-, -OCONR-, -NRNR-, -
NRSO2NR-, -SO-, -SO2-, -PO-, -P02-, -OP(O)(OR)-, or -POR- and each occurrence of Rx is
independently selected from -R', halogen, =O, =NR', -NO2, -CN, -OR', -SR', -N(R')2, -
NR'COR', -NR'CON(R')2, -NR'CO2R', -COR', -CO2R', -OCOR', -CON(R')2, -
OCON(R')2, -SOR', -SO2R', -SO2N(R')2, -NR'SO2R', -NR'SO2N(R')2, -COCOR', -
COCH2COR', -OP(O)(OR')2, -P(O)(OR')2, -OP(O)2OR', -P(O)2OR', -PO(R')2, or -
OPO(R')2;
each occurrence of R5a is independently an optionally substituted C1-C6aliphatic
group, halogen, -OR', -SR', -N(R')2, -NR'COR', -NR'CON(R')2, -NR'CO2R', -COR', -
CO2R', -OCOR', -CON(R')2, -OCON(R')2, -SOR', -SO2R', -SO2N(R')2, -NR'SO2R', -
NR'SO2N(R')2, -COCOR', -COCH2COR', -OP(O)(OR')2, -P(O)(OR')2, -OP(O)2OR', -
P(O)2OR', -PO(R')2, or -OPO(R')2; and
each occurrence of R is independently hydrogen or an optionally substituted C1-6
aliphatic group; and each occurrence of R is independently hydrogen or an optionally
substituted Q_6 aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully
unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen,
oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated
bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen,
or sulfur; or R and R, two occurrences of R, or two occurrences of R, are taken together with
the atom(s) to which they are bound to form an optionally substituted 3-12 membered
saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4
heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[0072] In certain embodiments, for compounds described directly above:
a. when R1 and R2, taken together with the nitrogen atom to which they are bound,
form an optionally substituted 4-membered monocyclic saturated or partially unsaturated ring
having 0-3 additional heteroatoms independently selected from nitrogen, sulfur, or oxygen;
then 2-Oxazolidinone, 3-[(3R,4R)-2-oxo-l-(2-phenyl-4-quinazolinyl)-4-[2-(3-
pyridinyl)ethenyl]-3-azetidinyl]-4-phenyl-, (4S)- is excluded;
b. when R1 and R2, taken together with the nitrogen atom to which they are bound, form
an optionally substituted 5-membered monocyclic saturated or partially unsaturated ring
having 0-3 additional heteroatoms independently selected from nitrogen, sulfur, or oxygen;
then:
i. ring A is not optionally substituted hexahydro-lH-l,4-diazepin-l-yl; and
ii. Benzenesulfonamide, 2-methoxy-5-[2-[[l-(2-phenyl-4-quinazolinyl)-3-
pyrrolidinyl]amino]ethyl]-, (R)-, bis(trifluoroacetate), and Benzenesulfonamide, 2-methoxy-
5-[2-[[l-(2-phenyl-4-quinazolinyl)-3-pyrrolidinyl]amino]ethyl]-, (S)-,bis(trifluoroacetate)
are excluded;
iii. 3-PyrroIidinamine, l-(2-phenyl-4-quinazolinyl)-, and (R)- 3-Pyrrolidinamine, 1-
(2-phenyl-4-quinazolinyl)-, (S)- are excluded;
iv. when R1 and R2, taken together are unsubstituted pyrrolidin-1-yl, ring A is
unsubstituted phenyl, and x is 1, then R3 is not 6-OMe or 6-OH;
v. when R1 and R2, taken together are unsubstituted pyrrolidin-1-yl, ring A is
unsubstituted phenyl, and x is 2, then the two R3 groups are not 6-OMe and 7-OMe;
vi. when R1 and R2, taken together are unsubstituted pyrrolidin-1-yl, then ring A is
not unsubstituted pyrrolidin-1-yl, optionally substituted piperazin-1-yl, unsubstituted
morpholin-1-yl; or unsubstituted piperidin-1-yl;
vii. when R1 and R2, taken together are pyrrolidin-1-yl, x is 0 and ring A is
unsubstituted phenyl, then the pyrrolidin-1-yl group is not substituted at the 3-position with -
OH or 2-methoxy-phenoxy;
viii. when R1 and R2, taken together are unsubstituted pyrrolidin-1 -yl, and x is 0,
then ring A is not 2,3-xylyl, 3-methylphenyl, unsubstituted phenyl, 4-bromo-phenyl, 4-
chloro-phenyl, 3-nitro-phenyl, unsubstituted pyrid-3-yl, 2,4-dichlorophenyl, 3,4-
dichlorophenyl, 4-propoxyphenyl, 3-methylphenyl, 3,4,5-trimethoxyphenyl, 2-chlorophenyl,
unsubstituted pyrid-4-yl, 2-hydroxyphenyl, or 4-(l,l-dimethylethyl)phenyl;
c. when R1 and R2, taken together with the nitrogen atom to which they are bound, form
an optionally substituted 6-membered monocyclic or bicyclic saturated or partially
unsaturated ring having 0-3 additional heteroatoms independently selected from nitrogen,
sulfur, or oxygen; then:
i. when R1 and R2, taken together form an unsubstituted morpholino ring, and ring A
is unsubstituted phenyl, then x is not 0, or if x is 1 or 2, then R3 is not: 6-fluoro, 6,7-
dimethoxy, 6-nitro, 6-AcHN-, 6-methox, 6-NH2, 6-OCHN-, 6-OH, 6-AcMeN-, 6-TsHN-, 6-
Me2N-, 7-OH, 6-amino-thiazol-2-yl, 6-NHCOCOOEt, or 6-(4-phenyl-amino-thiazol-2-yl);
ii. when R1 and R2, taken together form an unsubstituted morpholino ring, and ring A
is unsubstituted cyclohexyl, unsubstituted pyrid-3-yl, unsubstituted 2-furyl, 2-fluorophenyl,
3-thienyI, benzofuran, pyridazine, phenyl substituted in one or more of the 3,4, or 5-position
of the phenyl ring, and x is 1 or 2, then R3 is not 6-NH2, 6-OHCHN-, 6-OH, 7-OH, 6-MsHN-,
6-AcHN-, 6-fluoro, or 6-OMe;
iii. when R1 and R2, taken together, form a piperid-4-one, piperid-4-ol, or
thiomorpholino, or a dimethyl substituted morpholino ring, ring A is unsubstituted phenyl,
and x is 1, then R3 is not 6-OH;
iv. when x is 0 and A is unsubstituted phenyl, 3,4,5-trimethoxyphenyl, or 3,4-
dimethoxyphenyl, then R1 and R2, taken together is not optionally substituted piperidinyl or
optionally substituted piperazinyl;
v. when x is 2 or 3, and R3 is 6,7-diOMe, or 6,7,8-triOMe, then R1 and R2, taken
together is not optionally substituted piperidin-1-yl, piperazin-1-yl, or morpholin-1-yl;
vi. when x is 0 and ring A is unsubstituted phenyl, then R1 and R2, taken together is
not optionally substituted or fused piperazinyl;
vii. when x is 0 and ring A is phenyl optionally substituted in one or more of the 3-,4-,or 5-positions of the phenyl ring, then R1 and R2, taken together is not optionally substituted
piperazin-1-yl, or morpholin-1-yl;
viii. when x is 0 and ring A is 2-F-phenyl, then R1 and R2, taken together is not 4-(2-
Cl-phenyl)-piperazin-l-yl, 4-(3-Cl-phenyl)-piperazin-l-yl, or unsubstituted morpholin-1-yl;
ix. when x is 0 and ring A is 2-Cl-phenyl, then R1 and R2, taken together is not
unsubstituted morpholin-1-yl, 4-Me-piperazin-l-yl, 4-Et-piperazin-l-yl, 4-phenyl-piperazin-
1-yl, or 4-CH2Ph2-piperazin-l-yl;
x. when x is 0 and ring A is 2-OH-phenyl, then Rl and R2, taken together is not
unsubstituted morpholin-1-yl, 4-(2-OMe-phenyl)-piperazin-l-yl, 4-CH2Ph-piperazin-l-yl, 4-
Et-piperazin-1-yl, or 4-Me-piperasin-l-yl;
xi. when x is 0, x is 1 and R3 is 6-Br, or x is 2 and R3 is 6-7-diOMe, and ring A is
optionally substituted 2- or 3-thienyl, then R1 and R2, taken together is not 4-Ph-piperazin-l-
yl, 4-(3-CF3-phenyl)-piperazin-l-yl, 4-(2-OEt-phenyl)-piperazin-l-yl, 4-Me-piperazinyl, or
unsubstituted morpholin-1-yl;
xii when x is 0, and ring A is unsubstituted pyrid-3-yl or pyrid-4-yl, then R1 and R",
taken together is not optionally substituted morpholin-1-yl, or optionally substituted
piperazin-1-yl;
xiii. when x is 0, and ring A is optionally substituted lH-imidazol-2-yl or 1H-
imidazol-1-yl, then R1 and R2 taken together is not unsubstituted morpholin-1-yl, 4-Me-
piperazin-l-yl, or 4-CH2CH2OH-piperazin-l-yl;
xiv. when x is 0 and ring A is 5-NC>2-thiazol-2-yl, then R1 and R2, taken together is
not 4-Me-piperazin-l-yl;
xv. when x is 0 and ring A is 5-NC>2-2-furanyl, then R1 and R2, taken together is not 4-
CH2CH20H-piperazin-l-yl, 4-Me-piperazin-l-yl, or unsubstituted morpholin-1-yl;
xvi. when x is 1, R3 is 6-OH and ring A is unsubstituted phenyl, then R1 and R2,
taken together is not unsubstituted morpholin-1-yl, or 4-Me-piperazin-l-yl;
xvii. when x is 0 and R1 and R2, taken together is unsubstituted piperidinyl, then
ring A is not 2-OH-phenyl, 4-OMe-phenyl, 4-F-phenyl, 4-NO2-phenyl, pyrid-3-yl, pyrid-4-yl,
2-Cl-phenyl, 4-OnPr-phenyl, 3,4-dichlorophenyl, 2-F-phenyl, 4-Br-phenyl, 4-Cl-phenyl, 3-
NO2-phenyl, or 2,4-dichlorophenyl;
xviii. when x is 0, ring A is 4-Br-phenyl, 2-F-phenyl, 2-Cl-phenyl, 4-Cl-phenyl, 4-
OnPr-phenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 4-Me-phenyl, 3-Me-phenyl, pyrid-3-
yl, pyrid-4-yl, 2-OH-phenyl, 4-NO2-phenyl, 4-tBu-phenyl, then R1 andR2, taken together is
not 2-Me-piperidin-l-yl, 4-CH2-Ph-piperidin-l-yl, 4-Me-piperidin-l-yl, 3-COOEt-piperidin-
1-yl, 4-COOEt-piperidin-l-yl, 2-Et-piperidin-l-yl, 3-Me-piperidin-l-yl, 3,5-diMe-piperidin-
1-yl, 4-CONH2-piperidin-l-yl, (4-piperidinyl, 4-carboxamide)-piperidin-l-yl, l,4-dioxa-8-
azaspiro[4.5]decane, 3,4-dihydro-2(lH)-isoquinolinyl,orpiperidin-4-one;
xix. when x is 1, R3 is 6-Br, 6-C1, 6-OH, 6-OMe, or 6-Me and ring A is 4-
bromophenyl, 4-CH2P(O)(OH)(OEt)phenyl, or unsubstituted phenyl, then R1 and R2, taken
together, is not optionally substituted piperidinyl;
xx.when x is 2, and R3 is 6,7-dimethoxy, and A is unsubstituted phenyl, then R1 and
R2, taken together is not l,4-dioxa-8-azaspiro[4.5]decane or 3,4-dihydro-2(lH)-isoquinolinyl;
xxi. when x is 3, and the three occurrences of R3 are 5-OAc, 6-OAc, and 8-
piperidinyl, and ring A is unsubstituted phenyl, then R1 and R2, taken together is not an
unsubstituted piperidinyl ring;
xxii. when x is 3 and the three occurrences of R3 are 6-Me, 7-COOEt, and 8-Me,
and ring A is 2-Cl-phenyl, then R1 and R2, taken together, is not 4-phenyl-piperidin-l-yl, 4-
(4-Cl-phenyl)-piperazin-l-yl, unsubstituted piperazin-1-yl, 4-CH2Ph-piperazin-l-yl, 4(2-Cl-
phenyl)piperazin-l-yl, or 4-COOEt-piperazin-l-yl;
c. when R1 and R2, taken together with the nitrogen atom to which they are bound, form
an optionally substituted 7-membered monocyclic or bicyclic saturated or partially
unsaturated ring having 0-3 additional heteroatoms independently selected from nitrogen,
sulfur, or oxygen; then:
i. Benzenesulfonamide, 2-methoxy-5-[2-[5-(2-phenyl-4-quinazolinyl)-2,5-
diazabicyclo[2.2.1]hept-2-yl]ethyl]-, and bis(trifluoroacetate) 2,5-
Diazabicyclo[2.2.1]heptane, 2-(2-phenyl-4-quinazolinyl)- are excluded;
ii. when x is 2 and both occurrences of R3 are OMe, and ring A is 4-Cl-phenyl,
then R1 and R2, taken together is not unsubstituted hexahydro-lH-azepin-1-yl;
iii. when x is 0 and R1 and R2, taken together is unsubstituted hexahydro-lH-
azepin-1-yl, then ring A is not unsubstituted phenyl, 4-F-phenyl, 4-NO2-phenyl, pyrid-4-yl,
3,4-diCl-phenyl, 2-Cl-phenyl, 2,4-diCl-phenyl, 2,4-diCl-phenyl, 3-NO2-phenyl, 4-Cl-phenyl,
4-OnPr-phenyl, 3-Me-phenyl, 3,4-OMe-phenyl, 3,4,5-OMe-phenyl, pyrid-3-yl, or 2-OH-
phenyl;
d. when R1 and R2, taken together with the nitrogen atom to which they are bound, form
an optionally substituted 8-membered monocyclic or bicyclic saturated or partially
unsaturated ring having 0-3 additional heteroatoms independently selected from nitrogen,
sulfur, or oxygen; then:
i. Benzenesulfonamide, 2-methoxy-5-[2-[8-(2-phenyl-4-quinazolinyl)-3,8-
diazabicyclo[3.2.1]oct-3-yl]ethyl]-, bis(trifluoroacetate) 3,8-Diazabicyclo[3.2.1]octane, 3-
(phenylmethyl)-8-(2-phenyl-4-quinazolinyl)- 3,8-Diazabicyclo[3.2.l]octane, 8-(2-phenyI-4-
quinazolinyl)-; Quinazoline, 2-(3-methylphenyl)-4-(l,3,3-trimethyl-6-azabicyclo[3.2.1]oct-6-
yl)-, monohydrochloride; Quinazoline, 2-(4-nitrophenyl)-4-(l,3,3-trimethyl-6-
azabicyclo[3.2.1]oct-6-yl)-, monohydrochloride; Quinazoline, 2-(3-methylphenyl)-4-( 1,3,3-
trimethyl-6-azabicyclo[3.2. l]oct-6-yl)-; Quinazoline, 2-(4-methylphenyl)-4-(l,3,3-trimethyl-
6-azabicyclo[3.2.1]oct-6-yl)-; and Quinazoline, 2-(4-nitrophenyl)-4-(l,3,3-trimethyl-6-
azabicyclo[3.2.1]oct-6-yl)-are excluded; and
e. when R1 and R2, taken together with the nitrogen atom to which they are bound, form
an optionally substituted 9-membered monocyclic or bicyclic saturated or partially
unsaturated ring having 0-3 additional heteroatoms independently selected from nitrogen,
sulfur, or oxygen; then:
Piperazine, l-[4-(l,3-dihydro-l,3-dioxo-2H-isoindol-2-yl)-6,7-dimefhoxy-2-
quinazolinyl]-4-(2-furanylcarbonyl)- is excluded.
[0073] In other embodiments, for compounds described directly above, the ring formed
by R1 and R2 taken together is selected from:

wherein the ring formed by R1 and R2 taken together, is optionally substituted at one
or more substitutable carbon, nitrogen, or sulfur atoms with z independent occurrences of -
R4, and z is 0-5.
[0074] In other embodiments, for compounds of formula I-A, Rl and R2 taken together
are optionally substituted azetidin-1-yl (jj), pyrrolidin-1-yl (ff), piperidinl-yl (dd), piperazin-
1-yl (cc), or morpholin-4-yl (ee). In other embodiments, for compounds of formula I-A, R1
and R2 taken together are optionally substituted azetidin-1-yl (jj), pyrrolidin-1-yl (ff),
piperidinl-yl (dd), or piperazin-1-yl (cc). In yet other embodiments, for compounds of
formula I-A, R1 and R2, taken together is optionally substituted azetidin-1-yl (jj). In yet other
embodiments, for compounds of formula I-A, R1 and R, taken together is optionally
substituted pyrrolidin-1-yl (ff). In still other embodiments, for compounds of formula I-A, R1
and R2, taken together is optionally substituted piperidinl-yl (dd). In yet other embodiments,
for compounds of formula I-A, R1 and R2, taken together is optionally substituted piperazin-
1-yl (cc).
[0075] For compounds described directly above, z is 0-5, and R4 groups, when present,
are each independently halogen, CN, NO2, -N(R')2, -CH2N(R')2, -OR', -CH2OR', -SR', -
CH2SR', -COOR', -NRCOR', -CON(R')2, -OCON(R')2, COR', -NHCOOR', -SO2R', -
SO2N(R')2, or an optionally substituted group selected from Ci.Cealiphatic, aryl, heteroaryl,
cycloaliphatic, heterocycloaliphatic, arylC1-C6alkyl, heteroarylC1-C6alkyl, cycloaliphaticCi-
Cealkyl, or heterocycloaliphaticC1-C6alkyl.
[0076] In still other embodiments, z is 0-5 and R4 groups are each independently CI, Br,
F, CF3, CH3, -CH2CH3, CN, -COOH, -N(CH3)2, -N(Et)2, -N(iPr)2, -O(CH2)2OCH3, -CONH2,
-COOCH3, -OH, -CH2OH, -NHCOCH3, -SO2NH2, -SO2(CH2)3CH3, -SO2CH(CH3)2, -
SO2N(CH3)2) -SO2CH2CH3, -C(O)OCH2CH(CH3)2) -C(O)NHCH2CH(CH3)2, -NHCOOCH3) -
C(O)C(CH3)3, -COO(CH2)2CH3, -C(O)NHCH(CH3)2, -C(O)CH2CH3, or an optionally
substituted group selected from -piperidinyl, piperizinyl, morpholino, C1-4alkoxy, phenyl,
phenyloxy, benzyl, benzyloxy, -CH2cyclohexyl, pyridyl, -CH2pyridyl, or -CH2thiazolyl.
[0077] In certain embodiments, for compounds of formula I-A, R1 and R2, taken together
is optionally substituted azetidin-1-yl (jj), wherein z is 1 or 2 and at least one occurrence of
R4 is -NRSO2R', -NRCOOR', or -NRCOR'. In certain other embodiments, for compounds
of formula I-A, R1 and R2, taken together is optionally substituted azetidin-1-yl (jj), wherein
z is 1 and R4 is -NRSO2R'. In other embodiments, for compounds of formula I-A, R1 and
R", taken together is optionally substituted azetidin-1-yl (jj), wherein z is 1 and R4 is -
NRCOOR'. hi certain other embodiments, for compounds of formula I-A, R1 and R2, taken
together is optionally substituted azetidin-1-yl (jj), wherein z is 1 and R4 is-NRCOR'. In yet
other embodiments, for compounds of formula I-A, R1 and R2, taken together is optionally
substituted pyrrolidin-1-yl (ff), wherein z is 1 or 2 and R4 is CI, Br, F, CF3, CH3, -CH2CH3, -
OR', or -CH2OR'. In still other embodiments, for compounds of formula I-A, R1 and R2,
taken together is optionally substituted piperidin-1-yl (dd), wherein z is 1 or 2 and at least
one occurrence of R4 is CI, Br, F, CF3, CH3, -CH2CH3, -OR', or -CH2OR', -NRSO2R', -
NRCOOR', or -OCON(R')2. In certain other embodiments, for compounds of formula I-A,
R1 and R2, taken together is optionally substituted piperidin-1-yl (dd), wherein z is 1 and R4
is F, CF3, CH3, -CH2CH3, -OR', or -CH2OR'. In other embodiments, for compounds of
formula I-A, R1 and R2, taken together is optionally substituted piperidin-1-yl (dd), wherein z
is 1 and R4 is —NRSO2R',. In certain other embodiments, for compounds of formula I-A, R1
and R2, taken together is optionally substituted piperidin-1-yl (dd), wherein z is 1 and R4 is -
NRCOOR'. In yet other embodiments, for compounds of formula I-A, R1 and R2, taken
together is optionally substituted piperazin-1-yl (cc), wherein z is 1 or 2 and at least one
occurrence of R4 is -SOR', -CON(R')2) -SO2N(R')2, -COR', or -COOR'. In certain other
embodiments, for compounds of formula I-A, R1 and R2, taken together is optionally
substituted piperazin-1-yl (cc), wherein z is 1 and R4 is -SOR'. In certain other
embodiments, for compounds of formula I-A, R1 and R2, taken together is optionally
substituted piperazin-1-yl (cc), wherein z is 1 and R4 is -COOR'. In certain other
embodiments, for compounds of formula I-A, R1 and R2, taken together is optionally
substituted piperazin-1-yl (cc), wherein z is 1 and R4 is -CON(R')2- In certain other
embodiments, for compounds of formula I-A, R1 and R2, taken together is optionally
substituted piperazin-1-yl (cc), wherein z is 1 and R4 is -SO2N(R')2. In certain other
embodiments, for compounds of formula I-A, R1 and R2, taken together is optionally
substituted piperazin-1-yl (cc), wherein z is 1 and R4 is -COR'.
[0078] For compounds described directly above, in some embodiments, x is 0-4, and R3
groups, when present, are each independently halogen, CN, NO2, -N(R')2, -CH2N(R')2, -OR',
-CH2OR', -SR', -CH2SR', -COOR', -NRCOR', -CON(R')2, -OCON(R')2, COR', -
NHCOOR', -SO2R', -SO2N(R')2, or an optionally substituted group selected from Q.
C6aliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC1-C6alkyl,
heteroarylCi-Cgalkyl, cycloaliphaticC1-C6alkyl, or heterocycloaliphaticC1-C6alkyl.
[0079] In yet other embodiments, x is 1 or 2, and each occurrence of R3 is independently
CI, Br, F, CF3, -OCF3, Me, Et, CN, -COOH, -NH2, -N(CH3)2, -N(Et)2, -N(iPr)2) -
0(CH2)2OCH3, -CONH2, -COOCH3, -OH, -OCH3, -OCH2CH3, -CH2OH, -NHCOCH3, -
NHCOCH(CH3)2, -SO2NH2, -CONH(cyclopropyl), -CONHCH3, -CONHCH2CH3, or an
optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, phenyl,
phenyloxy, benzyl, or benzyloxy.
[0080] In still other embodiments, x is 1 or 2 and each R3 group is independently
halogen, CN, optionally substituted C1-C6alkyl, OR', N(R')2, CON(R')2, or NRCOR'.
[0081] In yet other embodiments, x is 1 or 2, and each R3 group is -CI, -CH3, -CH2CH3, -
F, -CF3, -OCF3, -CONHCH3, -CONHCH2CH3, -CONH(cyclopropyl), -OCH3, -NH2, -
OCH2CH3, or -CN.
[0082] In still other embodiments, x is 1 and R3 is at the 6-position of the quinazoline
ring and is -CI, -CH3, -CH2CH3, -F, -CF3, -OCF3, -CONHCH3, -CONHCH2CH3, -
CONH(cyclopropyl), -OCH3, -NH2, -OCH2CH3, or -CN.
[0083] In yet other embodiments, x is 1 and R3 is at the 7-position of the quinazoline ring
and is -CI, -CH3, -CH2CH3, -F, -CF3, -OCF3, -CONHCH3, -CONHCH2CH3, -
CONH(cyclopropyl), -OCH3, -NH2, -OCH2CH3, or -CN.
[0084] In still other embodiments, x is 1 and R3 is at the 6-position of the quinazoline
ring and is -CI, -CH3, -CH2CH3, -F, -CF3, -OCF3, -OCH3, or -OCH2CH3.
[0085] In yet other embodiments, x is 1 and R3 is at the 7-position of the quinazoline ring
and is -CI, -CH3, -CH2CH3, -F, -CF3, -OCF3, -OCH3, or -OCH2CH3.
[0086] In still other embodiments, x is 1 and R3 is at the 6-position of the quinazoline
ring and is -CON(R')2) or NRCOR'.
[0087] In yet other embodiments, x is 1 and R3 is at the 7-position of the quinazoline ring
and is -CI, -CH3, -CH2CH3, -F, -CF3, -OCF3, -OCH3, or -OCH2CH3.
[0088] For compounds described directly above, in certain embodiments, ring A is a
group selected from:
[0089] In other embodiments, ring A is optionally substituted phenyl, 2-pyridyl, 3-
pyridyl, or 4-pyridyl, or pyrrol-1-yl.
[0090] For compounds described directly above, in some embodiments, y is 0-5, q is 0-2,
and R5 and R5a groups, when present, are each independently halogen, CN, NO2, -N(R')2, -
CH2N(R')2, -OR', -CH2OR', -SR', -CH2SR', - -NRCOR', -CON(R')2) -S(O)2N(R')2, -
OCOR', -COR', -CO2R', -OCON(R')2, -NR'SO2R', -OP(O)(OR')2, -P(O)(OR')2, -
OP(O)2OR', -P(O)2OR', -PO(R')2, -OPO(R')2, or an optionally substituted group selected
from Ci.Cealiphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC1-C6alkyl,
heteroarylC1-C6alkyl, cycIoaliphaticC1-C6alkyl, or heterocycloaliphaticC1-C6alkyl.
[0091] In still other embodiments, y is 0-5, and q is 1 or 2, and each occurrence of R5a is
independently CI, Br, F, CF3, Me, Et, CN, -COOH, -NH2, -N(CH3)2, -N(Et)2, -N(iPr)2, -
0(CH2)2OCH3, -CONH2, -COOCH3, -OH, -OCH3, -OCH2CH3, -CH2OH, -NHCOCH3, -
SO2NH2, -SO2NHC(CH3)2, -OCOC(CH3)3, -OCOCH2C(CH3)3) -O(CH2)2N(CH3)2, 4-CH3-
piperazin-1-yl, OCOCH(CH3)2, OCO(cyclopentyl), -COCH3, optionally substituted phenoxy,
or optionally substituted benzyloxy.
[0092] In still other embodiments, y is 0, and q is 1 and R5a is F. In yet other
embodiments, y is 0, q is 1, and R5a is OR'. In still other embodiments, y is 0, q is 1 and R5a
is OH. In yet other embodiments, y is 0, q is 2 and one occurrence of RSa is OR' and the
other occurrence of R5a is F. In yet other embodiments, y is 0, q is 2 and one occurrence of
R5a is OH and the other occurrence of R5a is F.
[0093] In yet other embodiments, ring A is optionally substituted phenyl and compounds
have the structure lA-i:
wherein:
y is 0-5;
q is 0-2; and
each occurrence of R5a is independently an optionally substituted Ci-Cgaliphatic
group, halogen, -OR', -SR', -N(R')2, -NR'COR', -NR'CON(R')2, -NR'CO2R', -COR', -
CO2R', -OCOR', -CON(R')2, -OCON(R')2, -SOR', -SO2R', -SO2N(R')2, -NR'SO2R', -
NR'SO2N(R')2, -COCOR', -COCH2COR', -OP(O)(OR')2, -P(O)(OR')2, -OP(O)2OR', -
P(O)2OR', -PO(R')2, or -OPO(R')2.
[0094] In certain exemplary embodiments, the ring formed by R1 and R2 taken together is
selected from:
wherein the ring formed by R1 and R2 taken together, is optionally substituted at one
or more substitutable carbon, nitrogen, or sulfur atoms with z independent occurrences of -
R4, and z is 0-5.
[0095] In other embodiments, for compounds of formula IA-i, R1 and R2 taken together
are optionally substituted azetidin-1-yl (jj), pyrrolidin-1-yl (ff), piperidinl-yl (dd), piperazin-
1-yl (cc), or morpholin-4-yl (ee). In other embodiments, for compounds of formula I-A, R1
and R2 taken together are optionally substituted azetidin-1-yl (jj), pyrrolidin-1-yl (ff),
piperidinl-yl (dd), or piperazin-1-yl (cc). In yet other embodiments, for compounds of
formula IA-i, R1 and R2, taken together is optionally substituted azetidin-1-yl (jj). In yet
other embodiments, for compounds of formula IA-i, R1 and R2, taken together is optionally
substituted pyrrolidin-1-yl (ff). In still other embodiments, for compounds of formula IA-i,
R1 and R2, taken together is optionally substituted piperidinl-yl (dd). In yet other
embodiments, for compounds of formula IA-i, R1 and R2, taken together is optionally
substituted piperazin-1-yl (cc).
[0096] For compounds of formula IA-i, z is 0-5, and R4 groups, when present, are each
independently halogen, CN, NO2, -N(R')2, -CHzNCR'h, -OR', -CH2OR', -SR', -CH2SR', -
COOR', -NRCOR', -CON(R')2, -OCON(R')2, COR', -NHCOOR', -SO2R', -SO2N(R')2, or
an optionally substituted group selected from Ci.Cealiphatic, aryl, heteroaryl, cycloaliphatic,
heterocycloaliphatic, arylC1-C6alkyl, heteroarylC1-C6alkyl, cycloaliphaticC1-C6alkyl, or
heterocycloaliphaticC1-C6alkyl. In other embodiments, z is 0-5 and R4 groups are each
independently CI, Br, F, CF3, CH3, -CH2CH3, CN, -COOH, -N(CH3)2, -N(Et)2, -N(iPr)2, -
0(CH2)2OCH3, -CONH2, -COOCH3, -OH, -CH2OH, -NHCOCH3, -SO2NH2, -SO2(CH2)3CH3,
-SO2CH(CH3)2, -SO2N(CH3)2, -SO2CH2CH3, -C(O)OCH2CH(CH3)2,
C(O)NHCH2CH(CH3)2, -NHCOOCH3, -C(O)C(CH3)3) -COO(CH2)2CH3,
C(O)NHCH(CH3)2, -C(O)CH2CH3l or an optionally substituted group selected from -
piperidinyl, piperizinyl, morpholino, C^alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, -
CH2cyclohexyl, pyridyl, -CH2pyridyl, or -CH2thiazolyl.
[0097] In certain embodiments, for compounds of formula IA-i, R1 and R2, taken together
is optionally substituted azetidin-1-yl (jj), wherein z is 1 or 2 and at least one occurrence of
R4 is -NRSO2R', -NRCOOR', or -NRCOR'. In certain other embodiments, for compounds
of formula IA-i, R1 and R2, taken together is optionally substituted azetidin-1-yl (jj), wherein
z is 1 and R4 is -NRSO2R', In other embodiments, for compounds of formula IA-i, R1 and
R2, taken together is optionally substituted azetidin-1-yl (jj), wherein z is 1 and R4 is -
NRCOOR'. In certain other embodiments, for compounds of formula IA-i, R1 and R2, taken
together is optionally substituted azetidin-1-yl (jj), wherein z is 1 and R4 is -NRCOR'. In yet
other embodiments, for compounds of formula IA-i, R1 and R2, taken together is optionally
substituted pyrrolidin-1-yl (ff), wherein z is 1 or 2 and R4 is CI, Br, F, CF3, CH3, -CH2CH3, -
OR', or -CH2OR'. In still other embodiments, for compounds of formula IA-i, R1 and R2,
taken together is optionally substituted piperidin-1-yl (dd), wherein z is 1 or 2 and at least
one occurrence of R4 is CI, Br, F, CF3, CH3, -CH2CH3, -OR', or -CH2OR', -NRSO2R', -
NRCOOR', or -OCON(R')2. In certain other embodiments, for compounds of formula IA-i,
R1 and R2, taken together is optionally substituted piperidin-1-yl (dd), wherein z is 1 and R4
is F, CF3, CH3, -CH2CH3, -OR', or -CH2OR'. In other embodiments, for compounds of
formula IA-i, R1 and R2, taken together is optionally substituted piperidin-1-yl (dd), wherein
z is 1 and R4 is —NRSO2R',. In certain other embodiments, for compounds of formula IA-i,
R1 and R2, taken together is optionally substituted piperidin-1-yl (dd), wherein z is 1 and R4
is -NRCOOR'. In yet other embodiments, for compounds of formula IA-i, R1 and R2, taken
together is optionally substituted piperazin-1-yl (cc), wherein 2 is 1 or 2 and at least one
occurrence of R4 is -SOR', -CON(R')2, -SO2N(R')2, -COR', or -COOR'. In certain other
embodiments, for compounds of formula IA-i, R1 and R2, taken together is optionally
substituted piperazin-1-yl (cc), wherein z is 1 and R4 is -SOR'. In certain other
embodiments, for compounds of formula IA-i, Rl and R2, taken together is optionally
substituted piperazin-1-yl (cc), wherein z is 1 and R4 is -COOR'. In certain other
embodiments, for compounds of formula IA-i, R1 and R2, taken together is optionally
substituted piperazin-1-yl (cc), wherein z is 1 and R4 is -CON(R')2. In certain other
embodiments, for compounds of formula IA-i, R1 and R2, taken together is optionally
substituted piperazin-1-yl (cc), wherein z is 1 and R4 is -SO2N(R')2. In certain other
embodiments, for compounds of formula IA-i, R1 and R2, taken together is optionally
substituted piperazin-1-yl (cc), wherein z is 1 and R4 is -COR'.
[0098] In some embodiments for compounds of formula IA-i, x is 0-4, and R3 groups,
when present, are each independently halogen, CN, NO2, -N(R')2, -CH2N(R')2, -OR', -
CH2OR', -SR', -CH2SR', -COOR', -NRCOR', -CON(R')2, -OCON(R')2, COR', -
NHCOOR', -SO2R', -SO2N(R')2, or an optionally substituted group selected from Ci-
Cgaliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC1-C6alkyl,
heteroarylCrC6alkyl, cycloaliphaticCi-Cgalkyl, or heterocycloaliphaticC1-C6alkyl.
[0099] In still other embodiments, x is 1 or 2, and each occurrence of R3 is independently
CI, Br, F, CF3, -OCF3, Me, Et, CN, -COOH, -NH2, -N(CH3)2, -N(Et)2, -M(iPr)2, -
0(CH2)2OCH3, -CONH2, -COOCH3, -OH, -OCH3, -OCH2CH3, -CH2OH, -NHCOCH3, -
NHCOCH(CH3)2, -SO2NH2, -CONH(cyclopropyl), -CONHCH3, -CONHCH2CH3, or an
optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, phenyl,
phenyloxy, benzyl, or benzyloxy.
[00100] In yet other embodiments, x is 1 or 2 and each R3 group is independently halogen,
CN, optionally substituted CrC6alkyl, OR', N(R')2, CON(R')2, or NRCOR'.
[00101] In still other embodiments, x is 1 or 2, and each R3 group is -CI, -CH3, -CH2CH3, -
F, -CF3, -OCF3, -CONHCH3, -CONHCH2CH3, -CONH(cyclopropyl), -OCH3, -NH2, -
OCH2CH3,or-CN.
[00102] In yet other embodiments x is 1 and R3 is at the 6-position of the quinazoline ring
and is -CI, -CH3, -CH2CH3, -F, -CF3, -OCF3, -CONHCH3, -CONHCH2CH3, -
CONH(cyclopropyl), -OCH3, -NH2, -OCH2CH3, or -CN.
[00103] In still other embodimenst, x is 1 and R3 is at the 7-position of the quinazoline
ring and is -CI, -CH3> -CH2CH3) -F, -CF3, -OCF3> -CONHCH3, -CONHCH2CH3) -
CONH(cyclopropyl), -OCH3, -NH2, -OCH2CH3, or -CN.
[00104] In yet other embodiments, x is 1 and R3 is at the 6-position of the quinazoline ring
and is -CI, -CH3, -CH2CH3, -F, -CF3, -OCF3, -OCH3, or -OCH2CH3.
[00105] In still other embodiments, x is 1 and R3 is at the 7-position of the quinazoline
ring and is -CI, -CH3, -CH2CH3, -F, -CF3, -OCF3, -OCH3, or -OCH2CH3.
[00106] In yet other embodiments, x is 1 and R3 is at the 6-position of the quinazoline ring
and is -CON(R')2, or NRCOR'.
[00107] In still other embodiments, x is 1 and R3 is at the 7-position of the quinazoline
ring and is -CON(R')2) or NRCOR'.
[00108] In some embodiments for compounds of formula IA-i, y is 0-5, q is 0-2, and R5
and R5a groups, when present, are each independently halogen, CN, NO2, -N(R')2, -
CH2N(R')2, -OR', -CH2OR', -SR', -CH2SR', - -NRCOR', -CON(R')2, -S(O)2N(R')2, -
OCOR', -COR', -CO2R', -OCON(R')2, -NR'SO2R', -OP(O)(OR')2, -P(O)(0R')2, -
OP(O)2OR', -P(O)2OR', -PO(R')2, -OPO(R')2, or an optionally substituted group selected
from Ci.Cealiphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC1-C6alkyl,
heteroarylC1-C6alkyl, cycloaliphaticC1-C6alkyl, or heterocycloaliphaticC1-C6alkyl.
[00109] In yet other embodiments, y is 0-5, and q is 1 or 2, and each occurrence of R5a is
independently CI, Br, F, CF3, Me, Et, CN, -COOH, -NH2, -N(CH3)2, -N(Et)2, -N(iPr)2, -
0(CH2)2OCH3, -CONH2, -COOCH3, -OH, -OCH3, -OCH2CH3, -CH2OH, -NHCOCH3, -
SO2NH2, -SO2NHC(CH3)2, -OCOC(CH3)3) -OCOCH2C(CH3)3, -O(CH2)2N(CH3)2, 4-CH3-
piperazin-1-yl, OCOCH(CH3)2, OCO(cyclopentyl), -COCH3, optionally substituted phenoxy,
or optionally substituted benzyloxy.
[00110] In still other embodiments, when ring A is phenyl, y is 0, and q is 1 and R5a is F
substituted at the 2-position of the phenyl ring. In yet other embodiments, when ring A is
phenyl, y is 0, q is 1, and R5a is OR' substituted at the 2-position of the phenyl ring. In still
other embodiments, when ring A is phenyl, y is 0, q is 1 and R5a is OH substituted at the 2-
position of the phenyl ring. In yet other embodiments, when ring A is phenyl, y is 0, q is 2
and one occurrence of R5a is OR' and the other occurrence of R5a is F, wherein OR' is
substituted at the 2-position of the phenyl ring and F is substituted at the 6-position of the
phenyl ring. In yet other embodiments, when ring A is phenyl, y is 0, q is 2 and one
occurrence of RSa is OH and the other occurrence of R5a is F, wherein OH is substituted at the
2-position of the phenyl ring and F is substituted at the 6-position of the phenyl ring.
b) wherein z is 0-5, and R4 groups, when present, are each independently halogen,
CN, NO2, -N(R')2, -CH2N(R')2, -OR', -CH2OR', -SR', -CH2SR', -COOR', -NRCOR', -
CON(R')2, -OCON(R')2, COR', -NHCOOR', -SO2R', -SO2N(R')2) or an optionally
substituted group selected from Ci.C6aliphatic, aryl, heteroaryl, cycloaliphatic,
heterocycloaUphatic, arylCi-Cgalkyl, heteroarylC1-C6alkyl, cycloaliphaticCi-Csalkyl, or
heterocycloaliphaticC1-C6alkyl.
c) wherein x is 0-4, and R3 groups, when present, are each independently halogen,
CN, NO2, -N(R')2, -CH2N(R')2, -OR', -CH2OR', -SR', -CH2SR', -COOR', -NRCOR', -
CON(R')2, -OCON(R')2, COR', -NHCOOR', -SO2R', -SO2N(R')2, or an optionally
substituted group selected from Ci.Cealiphatic, aryl, heteroaryl, cycloaliphatic,
heterocycloaliphatic, arylQ-Cealkyl, heteroarylC1-C6alkyl, cycloaliphaticC1-C6alkyl, or
heterocycloaliphaticC1-C6alkyl.
d) wherein y is 0-5, and R5 groups, when present, are each independently halogen,
CN, NO2, -N(R')2, -CH2N(R')2, -OR', -CH2OR', -SR', -CH2SR', - -NRCOR', -CON(R')2, -
S(O)2N(R')2, -OCOR', -COR', -CO2R', -OCON(R')2, -NR'SO2R', -OP(O)(OR')2, -
P(O)(OR')2, -OP(O)2OR', -P(O)2OR', -PO(R')2, -OPO(R')2, or an optionally substituted
group selected from Ci_C6aliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic,
arylC1-C6alkyl, heteroarylCi-Cgalkyl, cycloaliphaticC1-C6alkyl, or heterocycloaliphaticCi-
Cealkyl; and
e) R5a is CI, Br, F, CF3, Me, Et, CN, -COOH, -NH2, -N(CH3)2, -N(Et)2, -N(iPr)2, -
0(CH2)2OCH3, -CONH2, -COOCH3, -OH, -OCH3> -OCH2CH3; -CH2OH, -NHCOCH3, -
SO2NH2, -SO2NHC(CH3)2, -OCOC(CH3)3, -OCOCH2C(CH3)3, -O(CH2)2N(CH3)2, 4-CH3-
piperazin-1-yl, OCOCH(CH3)2, OCO(cyclopentyl), -COCH3, optionally substituted phenoxy,
or optionally substituted benzyloxy.
[00112] In still other embodiments, for compounds of formula IA-ii: q is 1 and R5a is at the
2-position of the phenyl ring, and compounds have the structure IA-ii:
wherein:
a) R1 and R2 taken together is an optionally substituted ring selected from azetidin-1-
yl (jj). pyrrolidin-1-yl (ff), piperidinl-yl (dd), or piperazin-1-yl (cc);
b) z is 0-5 and R4 groups are each independently CI, Br, F, CF3, CH3, -CH2CH3, CN, -
COOH, -N(CH3)2, -N(Et)2, -N(iPr)2) -O(CH2)2OCH3, -CONH2, -COOCH3l -OH, -CH2OH, -
NHCOCH3, -SOzNHz, -SO2(CH2)3CH3, -SO2CH(CH3)2, -SO2N(CH3)2, -SO2CH2CH3) -
C(O)OCH2CH(CH3)2) -C(O)NHCH2CH(CH3)2) -NHCOOCH3, -C(O)C(CH3)3, -
COO(CH2)2CH3, -C(O)NHCH(CH3)2, -C(O)CH2CH3, or an optionally substituted group
selected from -piperidinyl, piperizinyl, morpholino, Q^alkoxy, phenyl, phenyloxy, benzyl,
benzyloxy, -CH2cyclohexyl, pyridyl, -CH2pyridyl, or -CH2thiazolyl;
c) x is 1 or 2, and each occurrence of R3 is independently CI, Br, F, CF3, -OCF3, Me,
Et, CN, -COOH, -NH2, -N(CH3)2, -N(Et)2, -N(iPr)2, -O(CH2)2OCH3, -CONH2, -COOCH3, -
OH, -OCH3, -OCH2CH3, -CH2OH, -NHCOCH3, -NHCOCH(CH3)2, -SO2NH2, -
CONH(cyclopropyl), -CONHCH3, -CONHCH2CH3, or an optionally substituted group
selected from -piperidinyl, piperizinyl, morpholino, phenyl, phenyloxy, benzyl, or benzyloxy;
d) wherein y is 0-4, and R5 groups, when present, are each independently CI, Br, F,
CF3, Me, Et, CN, -COOH, -NH2, -N(CH3)2, -N(Et)2, -N(iPr)2, -O(CH2)2OCH3, -CONH2, -
COOCH3, -OH, -OCH3, -OCH2CH3, -CH2OH, -NHCOCH3, -SO2NH2, -SO2NHC(CH3)2, -
OCOC(CH3)3, -OCOCH2C(CH3)3, -O(CH2)2N(CH3)2, 4-CH3-piperazin-l-yl, OCOCH(CH3)2,
OCO(cyclopentyl), -COCH3, optionally substituted phenoxy, or optionally substituted
benzyloxy; and
e) R5a is CI, F, CF3, Me, Et, -OH, -OCH3, -OCH2CH3, -CH2OH, -SO2NH2, -
SO2NHC(CH3)2, -OCOC(CH3)3, -OCOCH2C(CH3)3, -O(CH2)2N(CH3)2, 4-CH3-piperazin-l-
yl, OCOCH(CH3)2, OCO(cyclopentyl), or -COCH3.
[00113] In still other embodiments, for compounds of formula IA-ii x is 1 and R3 is at the
6-position of the quinazoline ring and is -CI, -CH3, -CH2CH3, -F, -CF3, -OCF3, -CONHCH3) -
CONHCH2CH3, -CONH(cyclopropyl), -OCH3, -NH2, -OCH2CH3, or -CN. In yet other
embodiments, x is 1 and R3 is at the 7-position of the quinazoline ring and is -CI, -CH3, -
CH2CH3, -F, -CF3, -OCF3, -CONHCH3, -CONHCH2CH3, -CONH(cyclopropyl), -OCH3, -
NH2, -OCH2CH3, or -CN. In still other embodiments, x is 1 and R3 is at the 6-position of the
quinazoline ring and is -CI, -CH3, -CH2CH3, -F, -CF3, -OCF3, -OCH3, or -OCH2CH3. In yet
other embodiments, x is 1 and R3 is at the 7-position of the quinazoline ring and is -CI, -CH3,
-CH2CH3> -F, -CF3, -OCF3, -OCH3, or -OCH2CH3. In still other embodiments, x is 1 and R3
is at the 6-position of the quinazoline ring and is -CON(R')2, or NRCOR'.
[00114] In yet other embodiments, x is 1 and R3 is at the 7-position of the quinazoline ring
and is -CON(R'>2, or NRCOR'.
[00115] In still other embodiments, R5a is CI, F, CF3, Me, Et, OR'.-OH, -OCH3, -
OCH2CH3.
[00116] In yet other embodiments, R5a is OR'. In still other embodiments, R5a is F.
[00117] In still other exemplary embodiments compounds have formula IA-ii:
wherein:
a) R1 and R2 taken together is an optionally substituted ring selected from azetidin-1-
yl (jj), pyrrolidin-1-yl (ff), piperidinl-yl (dd), or piperazin-1-yl (cc);
b) z is 0-5 and R4 groups are each independently CI, Br, F, CF3, CH3, -CH2CH3, CN, -
COOH, -N(CH3)2, -N(Et)2, -N(iPr)2, -O(CH2)2OCH3, -CONH2, -COOCH3, -OH, -CH2OH, -
NHCOCH3, -SO2NH2, -SO2(CH2)3CH3, -SO2CH(CH3)2, -SO2N(CH3)2, -SO2CH2CH3, -
C(O)OCH2CH(CH3)2, -C(O)NHCH2CH(CH3)2, -NHCOOCH3, -C(O)C(CH3)3,
COO(CH2)2CH3, -C(O)NHCH(CH3)2, -C(O)CH2CH3, or an optionally substituted group
selected from -piperidinyl, piperizinyl, morpholino, C1-4alkoxy, phenyl, phenyloxy, benzyl,
benzyloxy, -CH2cyclohexyl, pyridyl, -CH2pyridyl, or -CH2thiazolyl;
c) x is 1, and each occurrence of R3 is independently CI, Br, F, CF3, -OCF3, Me, Et,
CN, -COOH, -OH, or -OCH3;
d) y is 0 or 1, and R5 groups, when present, are each independently CI, Br, F, CF3,
Me, -OH, -OCH3, -OCH2CH3, -CH2OH, -NHCOCH3, -SO2NH2, -SO2NHC(CH3)2; and
e) R5a is F, -OR', or NHSO2R',
[00118] In some embodiments for compounds described directly above, x is 1 and R3 is at
the 6-position of the quinazoline ring and is -CI, -CH3, -CH2CH3, -F, -CF3, -OCF3, -
CONHCH3, -CONHCH2CH3, -CONH(cyclopropyl), -OCH3, -NH2, -OCH2CH3, or -CN. In
still other embodiments, x is 1 and R3 is at the 7-position of the quinazoline ring and is -CI, -
CH3, -CH2CH3, -F, -CF3, -OCF3, -CONHCH3, -CONHCH2CH3, -CONH(cyclopropyl), -
OCH3, -NH2, -OCH2CH3, or -CN. In yet other embodiments, x is 1 and R3 is at the 6-
position of the quinazoline ring and is -CI, -CH3, -CH2CH3, -F, -CF3l -OCF3, -OCH3, or -
OCH2CH3. In still other embodiments, x is 1 and R3 is at the 7-position of the quinazoline
ring and is -CI, -CH3, -CH2CH3, -F, -CF3, -OCF3, -OCH3, or -OCH2CH3. In yet other
embodiments, x is 1 and R3 is at the 6-position of the quinazoline ring and is -CON(R')2, or
NRCOR'. In still other embodiments, x is 1 and R3 is at the 7-position of the quinazoline
ring and is -CON(R')2, or NRCOR'.
[00119] In yet other embodiments, R5a is OR' and x is 1 and R3 is at the 6-position of the
quinazoline ring and is -CI, -CH3, -CH2CH3, -F, -CF3, -OCF3, -OCH3, or -OCH2CH3. In yet
other embodiments, R5a is OR' and x is 1 and R3 is at the 7-position of the quinazoline ring
and is -CI, -CH3, -CH2CH3, -F, -CF3, -OCF3) -OCH3, or -OCH2CH3.
[00120] In yet other embodiments, R5a is OH and x is 1 and R3 is at the 6-position of the
quinazoline ring and is -CI, -CH3, -CH2CH3, -F, -CF3, -OCF3, -OCH3, or -OCH2CH3. In yet
other embodiments, R5a is OH and x is 1 and R3 is at the 7-position of the quinazoline ring
and is -CI, -CH3, -CH2CH3) -F, -CF3, -OCF3, -OCH3, or -OCH2CH3.
[00121] In yet other embodiments, R5a is F and x is 1 and R3 is at the 6-position of the
quinazoline ring and is -CI, -CH3, -CH2CH3, -F, -CF3, -OCF3, -OCH3, or -OCH2CH3. In yet
other embodiments, R5a is F and x is 1 and R3 is at the 7-position of the quinazoline ring and
is -CI, -CH3, -CH2CH3, -F, -CF3, -OCF3, -OCH3, or -OCH2CH3.
[00122] In still other embodiments, for compounds of formula IA-ii, R1 and R2, taken
together is optionally substituted azetidin-1-yl (jj). In yet other embodiments, for compounds
of formula IA-ii, R1 and R2, taken together is optionally substituted pyrrolidin-1-yl (if). In
still other embodiments, for compounds of formula IA-ii, R1 and R2, taken together is
optionally substituted piperidinl-yl (dd). In yet other embodiments, for compounds of
formula IA-ii, R1 and R2, taken together is optionally substituted piperazin-1-yl (cc).
[00123] In certain embodiments, for compounds of formula IA-ii, R1 and R2, taken
together is optionally substituted azetidin-1-yl (jj), wherein z is 1 or 2 and at least one
occurrence of R4 is -NRSO2R', -NRCQOR', or -NRCOR'. In certain other embodiments, for
compounds of formula IA-ii, R1 and R2, taken together is optionally substituted azetidin-1-yl
(jj), wherein z is 1 and R is -NRSO2R', In other embodiments, for compounds of formula
IA-ii, R1 and R2, taken together is optionally substituted azetidin-1-yl (jj), wherein z is 1 and
R4 is -NRCOOR'. In certain other embodiments, for compounds of formula IA-ii, R1 and R2,
taken together is optionally substituted azetidin-1-yl (jj), wherein z is 1 and R4 is -NRCOR'.
In yet other embodiments, for compounds of formula IA-ii, R1 and R2, taken together is
optionally substituted pyrrolidin-1-yl (ff), wherein z is 1 or 2 and R4 is CI, Br, F, CF3, CH3, -
CH2CH3, -OR', or -CH2OR'. In still other embodiments, for compounds of formula IA-ii, R1
and R2, taken together is optionally substituted piperidin-1-yl (dd), wherein z is 1 or 2 and at
least one occurrence of R4 is CI, Br, F, CF3, CH3, -CH2CH3, -OR', or -CH2OR', -NRSO2R', -
NRCOOR', or -OCON(R')2. In certain other embodiments, for compounds of formula IA-ii,
R1 and R2, taken together is optionally substituted piperidin-1-yl (dd), wherein z is 1 and R4
is F, CF3, CH3, -CH2CH3, -OR', or -CH2OR'. In other embodiments, for compounds of
formula IA-ii, R1 and R2, taken together is optionally substituted piperidin-1-yl (dd), wherein
z is 1 and R4 is —NRSO2R',. In certain other embodiments, for compounds of formula IA-ii,
R1 and R2, taken together is optionally substituted piperidin-1-yl (dd), wherein z is 1 and R4
is -NRCOOR'. In yet other embodiments, for compounds of formula IA-ii, R1 and R2, taken
together is optionally substituted piperazin-1-yl (cc), wherein z is 1 or 2 and at least one
occurrence of R4 is -SOR', -CON(R')2) -SO2N(R')2, -COR', or -COOR'. In certain other
embodiments, for compounds of formula IA-ii, R1 and R2, taken together is optionally
substituted piperazin-1-yl (cc), wherein z is 1 and R4 is -SOR'. In certain other
embodiments, for compounds of formula IA-ii, R1 and R2, taken together is optionally
substituted piperazin-1-yl (cc), wherein z is 1 and R4 is -COOR'. In certain other
embodiments, for compounds of formula IA-ii, R1 and R2, taken together is optionally
substituted piperazin-1-yl (cc), wherein z is 1 and R4 is -CON(R')2. In certain other
embodiments, for compounds of formula IA-ii, R1 and R2, taken together is optionally
substituted piperazin-1-yl (cc), wherein s is 1 and R4 is -SO2N(R')2. In certain other
embodiments, for compounds of formula IA-ii, R1 and R2, taken together is optionally
substituted piperazin-1-yl (cc), wherein z is 1 and R4 is -COR'.
[00124] For compounds described in this section above, in general, compounds are useful
as inhibitors of ion channels, preferably voltage gated sodium channels and N-type calcium
channels. In certain exemplary embodiments, compounds of the invention are useful as
inhibitors of NaVl.8. In other embodiments, compounds of the invention are useful as
inhibitors of NaV1.8 and CaV2.2. In still other embodiments, compounds of the invention
are useful as inhibitors of CaV2.2. In yet other embodiments, compounds of the invention
are useful as dual inhibitors of NaV1.8 and a TTX-sensitive ion channel such as NaV1.3 or
NaV1.7.
[00125] II. Compounds of formula IA-ii:
wherein R1 and R2 are each independently an optionally substituted group selected
from Ci-6aliphatic, Cy1, wherein Cy1 is a 5-7-membered monocyclic aryl ring or an 8-10-
membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen,
oxygen, or sulfur, or is a 3-12-membered saturated or partially unsaturated monocyclic ring
having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Cy1
is bonded directly to the nitrogen atom or is bonded through an optionally substituted Ci_
4aliphatic group, wherein one or more methylene units in the C1-4aliphatic group are
optionally replaced with -NR-, -O-, -COO, -OCO-, -NRCO-, -CONR-, -SO2NR-, or -
NRSO2-; wherein R1 and R2 are each optionally and independently substituted at one or more
substitutable carbon, nitrogen, or sulfur atoms with z independent occurrences of -R4,
wherein z is 0-5;
x is 0-4;
y is 0-4;
each occurrence of R3, R4, and R5 is independently Q-Rx; wherein Q is a bond or is a
C1-C6 alkylidene chain wherein up to two non-adjacent methylene units of Q are optionally
and independently replaced by -NR-, -S-, -O-, -CS-, -CO2-, -OCO-, -CO-, -COCO-, -CONR-,
-NRCO-, -NRCO2-, -SO2NR-, -NRSO2-, -CONRNR-, -NRCONR-, -OCONR-, -NRNR-, -
NRSO2NR-, -SO-, -SO2-, -PO-, -PO2-, -OP(O)(OR)-, or -POR-; and each occurrence of Rx is
independently selected from -R', =O, =NR', halogen, -NO2, -CN, -OR', -SR', -N(R')2, -
NR'COR', -NR'CON(R')2, -NR'CO2R', -COR', -CO2R', -OCOR', -CON(R')2, -
OCON(R')2, -SOR', -SO2R', -SO2N(R')2, -NR'SO2R', -NR'SO2N(R')2, -COCOR', -
COCH2COR', -OP(O)(OR')2, -P(O)(OR')2, -OP(O)2OR',-P(O)2OR', -PO(R')2, or -
OPO(R')2;
R5a is an optionally substituted Ci-Cgaliphatic group, halogen, -OR', -SR', -N(R')2, -
NR'COR', -NR'CON(R')2, -NR'CO2R', -COR', -CO2R', -OCOR', -CON(R')2, -
OCON(R')2, -SOR', -SO2R', -SO2N(R')2, -NR'SO2R', -NR'SO2N(R')2, -COCOR', -
COCH2COR', -OP(O)(OR')2, -P(O)(OR')2, -OP(O)2OR', -P(O)2OR', -PO(R')2, or -
OPO(R')2; and
each occurrence of R is independently hydrogen or an optionally substituted C1-4
aliphatic group; and each occurrence of R is independently hydrogen or an optionally
substituted Cj.6 aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully
unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen,
oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated
bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen,
or sulfur; or R and R, two occurrences of R, or two occurrences of R, are taken together with
the atom(s) to which they are bound to form an optionally substituted 3-12 membered
saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4
heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[00126] In certain embodiments, for compounds described directly above,
a. when x is 0, R1 is hydrogen, and R5a is CI, Me, CF3, Br, or F, then R2 is not -
(CH2)2-4-Cy\ -SO2CH2Cy\ or -CH2SO2Cy\ wherein Cy1 is a 5-7-membered monocyclic
aryl ring or an 8-10-membered bicyclic aryl ring having 0-3 heteroatoms independently
selected from nitrogen, oxygen, or sulfur, or is a 3-8-membered saturated or partially
unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen,
oxygen, or sulfur;
b. when x is 0, and R5a is CI, Me, NO2, or OH, then:
i. when R1 is hydrogen, R2 is not Me, iBu, nBu, -COCH3, -CH2COOEt, -
CH2COOMe, -CH2CH2OH, iPr, -CH2-pyridyl, -CH2Ph, -(CH2)3NH2, -
(CH2)2-moropholinyl, or -CH2CH2Ph;
ii. R1 and R2 are not simultaneously Et or Me; and
iii. when R1 is Et, then R2 is not 4-Me-phenyl, 4-OMe-phenyl, or 2-Me-
phenyl;
c. when x is 1 and R3 is 6-C1, or 7-F, or x is 0 and Rsa is -OPrn or CI, then when
R1 is hydrogen, R2 is not -(CH2)2-morpholino, or -CH2(benzofuran); and
d. when x is 2 and one occurrence of R3 is 6-OMe and the other occurrence of R3
is 7-OMe, and R5a is F, then when R1 is hydrogen, R2 is not -(CH2)3N(CH3)2;
[00127] In certain other embodiments, for compounds described directly above,
a) one of R1 or R2 is hydrogen, and the other of R1 and R2 is selected from:
i) Cy1 wherein Cy1 is bonded directly to the nitrogen atom or is bonded
through an optionally substituted C1-4aliph.atic group, wherein one or more methylene
units in the C1-4aliphatic group are optionally replaced with -NR-, -O-, -COO, -OCO-,
-NRCO-, -CONR-, -SO2NR-, or -NRSO2-; or
ii) an optionally substituted C1-4aliphatic group, wherein one or more
methylene units in the C1-4aliphatic group are optionally replaced with -NR-, -O-, -
COO, -OCO-, -NRCO-, -CONR-, -SO2NR-, or -NRSO2-; or
b) R1 and R2 are each independently selected from Cy1, wherein Cy1 is bonded
directly to the nitrogen atom or is bonded through an optionally substituted Ci-
4aliphatic group, wherein one or more methylene units in the C1-4aliphatic group are
optionally replaced with -NR-, -O-, -COO, -OCO-, -NRCO-, -CONR-, -SO2NR-, or -
NRSO2-; or an optionally substituted C1-4aliphatic group, wherein one or more
methylene units in the C1-4aliphatic group are optionally replaced with -NR-, -O-, -
COO-, -OCO-, -NRCO-, -CONR-, -SOzNR-, or -NRSO2-.
[00128] In other embodiments Cy1 is:

[00129] In still other embodiments, for compounds described directly above, R1 is
hydrogen or an optionally substituted Ci-C4aliphatic group and R2 is -CHR-Cy1, wherein R is
hydrogen or Ci-C4alkyl, and Cy1 is:
[00130] In yet other embodiments, R1 and R2 groups are each independently an optionally
substituted Ci-4aliphatic group and are each independently selected from optionally
substituted methyl, ethyl, cyclopropyl, n-propyl, propenyl, cyclobutyl, (CO)OCH2CH3,
(CH2)2OCH3, CH2CO)OCH2CH3, CH2(CO)OCH3, CH(CH3)CH2CH3, or n-butyl.
[00131] For compounds described directly above, z is 0-5, and R4 groups, when present,
are each independently halogen, CN, NO2, -N(R')2, -CH2N(R')2, -OR', -CH2OR', -SR', -
CH2SR', -COOR', -NRCOR', -CON(R')2, -OCON(R')2, COR', -NHCOOR', -SO2R', -
SO2N(R')2, or an optionally substituted group selected from CuCealiphatic, aryl, heteroaryl,
cycloaliphatic, heterocycloaliphatic, arylC1-C6alkyl, heteroarylC1-C6alkyl, cycloaliphaticCr
Cealkyl, or heterocycloaliphaticC1-C6alkyl.
[00132] In other embodiments, z is 0-5 and R4 groups are each independently CI, Br, F,
CF3) CH3, -CH2CH3, CN, -COOH, -N(CH3)2, -N(Et)2, -N(iPr)2, -O(CH2)2OCH3, -CONH2, -
COOCH3, -OH, -CH2OH, -NHCOCH3, -SO2NH2, -SO2(CH2)3CH3, -SO2CH(CH3)2, -
SO2N(CH3)2, -SO2CH2CH3) -C(O)OCH2CH(CH3)2, -C(O)NHCH2CH(CH3)2, -NHCOOCH3, -
C(O)C(CH3)3, -COO(CH2)2CH3, -C(O)NHCH(CH3)2, -C(O)CH2CH3, or an optionally
substituted group selected from -piperidinyl, piperizinyl, morpholino, C1-4alkoxy, phenyl,
phenyloxy, benzyl, benzyloxy, -CH2cyclohexyl, pyridyl, -CH2pyridyl, or -CH2thiazolyl.
[00133] In still other embodiments, for compounds described directly above, x is 0-4, and
R3 groups, when present, are each independently halogen, CN, NO2, -N(R')2, -CH2N(R')2, -
OR', -CH2OR', -SR', -CH2SR', -COOR', -NRCOR', -CON(R')2, -OCON(R')2, COR', -
NHCOOR', -SO2R', -SO2N(R')2, or an optionally substituted group selected from Q.
Cealiphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC1-C6alkyl,
heteroarylC1-C6alkyl, cycloaliphaticC1-C6alkyl, or heterocycloaliphaticC1-C6alkyl.
[00134] In yet other embodients, for compounds described directly above, x is 1 or 2, and
each occurrence of R3 is independently CI, Br, F, CF3, -OCF3, Me, Et, CN, -COOH, -NH2, -
N(CH3)2, -N(Et)2, -N(iPr)2, -O(CH2)2OCH3, -CONH2, -COOCH3, -OH, -OCH3, -OCH2CH3, -
CH2OH, -NHCOCH3, -NHCOCH(CH3)2, -SO2NH2> -CONH(cyclopropyl), -CONHCH3, -
CONHCH2CH3, or an optionally substituted group selected from -piperidinyl, piperizinyl,
morpholino, phenyl, phenyloxy, benzyl, or benzyloxy.
[00135] In still other embodiments, x is 1 or 2 and each R3 group is independently
halogen, CN, optionally substituted C1-C6alkyl, OR', N(R')2, CON(R')2, or NRCOR'.
[00136] In yet other embodiments, x is 1 or 2, and each R3 group is -CI, -CH3, -CH2CH3, -
F, -CF3, -OCF3, -CONHCH3, -CONHCH2CH3, -CONH(cyclopropyl), -OCH3, -NH2, -
OCH2CH3, or -CN.
[00137] In still other embodiments, x is 1 and R3 is at the 6-position of the quinazoline
ring and is -CI, -CH3, -CH2CH3, -F, -CF3, -OCF3, -CONHCH3, -CONHCH2CH3, -
CONH(cyclopropyl), -OCH3, -NH2, -OCH2CH3, or -CN.
[00138] In yet other embodiments, x is 1 and R3 is at the 7-position of the quinazoline ring
and is -CI, -CH3, -CH2CH3, -F, -CF3, -OCF3, -CONHCH3, -CONHCH2CH3, -
CONH(cyclopropyl), -OCH3, -NH2, -OCH2CH3, or -CN.
[00139] In still other embodiments, x is 1 and R3 is at the 6-position of the quinazoline
ring and is -CI, -CH3, -CH2CH3, -F, -CF3, -OCF3, -OCH3, or -OCH2CH3.
[00140] In other embodiments, x is 1 and R3 is at the 7-position of the quinazoline ring and
is -CI, -CH3, -CH2CH3, -F, -CF3, -OCF3, -OCH3, or -OCH2CH3.
[00141] In yet other embodiments, R3 is at the 6-position of the quinazoline ring and is -
CON(R')2, or NRCOR'.
[00142] In still other embodiments, x is 1 and R3 is at the 7-position of the quinazoline
ring and is -CON(R')2, or NRCOR'.
[00143] For compounds described directly above, y is 0-4, q is 0-2, and R5 and R5a groups,
when present, are each independently halogen, CN, NO2, -N(R')2. -CH2N(R')2, -OR', -
CH2OR', -SR', -CH2SR', - -NRCOR', -CON(R')2, -S(O)2N(R')2, -OCOR', -COR', -CO2R', -
OCON(R')2, -NR'SO2R', -OP(O)(OR')2, -P(O)(OR')2, -OP(O)2OR', -P(O)2OR', -PO(R')2, -
OPO(R')2, or an optionally substituted group selected from C1-C6aliphatic, aryl, heteroaryl,
cycloaliphatic, heterocycloaliphatic, arylCt-Cealkyl, heteroarylC1-C6alkyl, cycloaliphaticCi-
Csalkyl, or heterocycloaliphaticC1-C6alkyl.
[00144] In other embodiments, y is 0-4, and q is 1 or 2, and each occurrence of R5a is
independently CI, Br, F, CF3, Me, Et, CN, -COOH, -NH2, -N(CH3)2) -N(Et)2) -N(iPr)2, -
0(CH2)2OCH3> -CONH2, -COOCH3, -OH, -OCH3, -OCH2CH3, -CH2OH, -NHCOCH3, -
SO2NH2, -SO2NHC(CH3)2, -OCOC(CH3)3; -OCOCH2C(CH3)3, -O(CH2)2N(CH3)2, 4-CH3-
piperazin-1-yl, OCOCH(CH3)2, OCO(cyclopentyl), -COCH3, optionally substituted phenoxy,
or optionally substituted benzyloxy.
[00145] In still other embodiments, y is 0, and R5a is F. In yet other embodimentsy is 0, q
is 1, and R5a is OR'. In still other embodiments, y is 0, q is 1 and R5a is OH. In yet other
embodiments, y is 1, R5a is OR' and R5 is F, wherein OR' is substituted at the 2-position of
the phenyl ring and F is substituted at the 6-position of the phenyl ring. In yet other
embodiments, y is 1, R5a is OH and R5 is F, wherein OH is substituted at the 2-position of the
phenyl ring and F is substituted at the 6-position of the phenyl ring.
[00146] In still other embodiments for compounds of formula IA-ii described directly
above:
a) one of R1 or R2 is hydrogen, and the other of R1 and R2 is selected from Cy1,
wherein Cy is bonded directly to the nitrogen atom or is bonded through an optionally
substituted C1-4aliphatic group, wherein one or more methylene units in the C1-4aliphatic
group are optionally replaced with -NR-, -O-, -COO, -OCO-, -NRCO-, -CONR-, -SO2NR-, or
-NRSO2-, or an optionally substituted Q^aliphatic group, wherein one or more methylene
units in the C1-4aliphatic group are optionally replaced with -NR-, -O-, -COO, -OCO-, -
NRCO-, -CONR-, -SO2NR-, or -NRSO2-; or R1 and R2 are each independently selected from
an optionally substituted C1-4aliphatic group, wherein one or more methylene units in the Ci_
4aliphatic group are optionally replaced with -NR-, -O-, -COO, -OCO-, -NRCO-, -CONR-, -
SO2NR-, or -NRSO2-; or Cy1 wherein Cy1 is bonded to the nitrogen atom directly or is
bonded through an optionally substituted C1-4aliphatic group, wherein one or more methylene
units in the Q^aliphatic group are optionally replaced with -NR-, -O-, -COO, -OCO-, -
NRCO-, -CONR-, -SO2NR-, or -NRSO2-;
b) z is 0-5 and R4 groups are each independently CI, Br, F, CF3, CH3, -CH2CH3, CN, -
COOH, -N(CH3)2, -N(Et)2, -N(iPr)2) -O(CH2)20CH3, -CONH2) -COOCH3, -OH, -CH2OH, -
NHCOCH3, -SO2NH2, -SO2(CH2)3CH3, -SO2CH(CH3)2, -SO2N(CH3)2, -SO2CH2CH3, -
C(O)OCH2CH(CH3)2: -C(O)NHCH2CH(CH3)2, -NHCOOCH3: -C(O)C(CH3)3, -
CO0(CH2)2CH3, -C(O)NHCH(CH3)2, -C(O)CH2CH3, or an optionally substituted group
selected from -piperidinyl, piperizinyl, morpholino, CMalkoxy, phenyl, phenyloxy, benzyl,
benzyloxy, -CH2cyclohexyl, pyridyl, -CH2pyridyl, or -CH2thiazolyl;
c) x is 0, 1, or 2, and each occurrence of R3 is independently CI, Br, F, CF3, -OCF3,
Me, Et, CN, -COOH, ~NH2, -N(CH3)2, -N(Et)2, -N(iPr)2, -O(CH2)20CH3, -CONH2, -
COOCH3, -OH, -OCH3, -OCH2CH3, -CH2OH, -NHCOCH3, -NHCOCH(CH3)2, -SO2NH2, -
CONH(cyclopropyl), -CONHCH3, -CONHCH2CH3, or an optionally substituted group
selected from -piperidinyl, piperizinyl, morpholino, phenyl, phenyloxy, benzyl, or benzyloxy;
d) wherein y is 0-4, and R5 groups, when present, are each independently CI, Br, F,
CF3, Me, Et, CN, -COOH, -NH2, -N(CH3)2, -N(Et)2, -N(iPr)2, -O(CH2)2OCH3, -CONH2, -
COOCH3, -OH, -OCH3, -OCH2CH3, -CH2OH, -NHCOCH3, -SQ2NH2, -SO2NHC(CH3)2, -
OCOC(CH3)3, -OCOCH2C(CH3)3, -O(CH2)2N(CH3)2, 4-CH3-piperazin-l-yl, OCOCH(CH3)2,
OCO(cyclopentyl), -COCH3, optionally substituted phenoxy, or optionally substituted
bensyloxy; and
e) R5a is CI, F, CF3, Me, Et, -OH, -OCH3) -OCH2CH3, -CH2OH, -SO2NH2, -
SO2NHC(CH3)2, -OCOC(CH3)3, -OCOCH2C(CH3)3, -O(CH2)2N(CH3)2, 4-CH3-piperazin-l-
yl, 0COCH(CH3)2, OCO(cyclopentyl), or -COCH3.
[00147] In other embodiments, for compounds described directly above, x is 1 and R3 is at
the 6-position of the quinazoline ring and is -CI, -CH3, -CH2CH3, -F, -CF3, -OCF3, -
CONHCH3, -CONHCH2CH3, -CONH(cyclopropyl), -OCH3, -NH2, -OCH2CH3, or -CN. In
yet other embodiments, x is 1 and R3 is at the 7-position of the quinazoline ring and is -CI, -
CH3, -CH2CH3, -F, -CF3, -OCF3, -CONHCH3, -CONHCH2CH3, -CONH(cyclopropyl), -
OCH3, -NH2, -OCH2CH3, or -CN. In still other embodiments, x is 1 and R3 is at the 6-
position of the quinazoline ring and is -CI, -CH3, -CH2CH3, -F, -CF3, -OCF3, -OCH3, or -
OCH2CH3. In still other embodiments, x is 1 and R3 is at the 7-position of the quinazoline
ring and is -CI, -CH3, -CH2CH3, -F, -CF3, -OCF3, -OCH3, or -OCH2CH3. In yet other
embodiments, x is 1 and R3 is at the 6-position of the quinazoline ring and is -CON(R')2, or
NRCOR'.
[00148] In still other embodiments, x is 1 and R3 is at the 7-position of the quinazoline
ring and is -CON(R')2, or NRCOR'.
[00149] In yet other embodiments, R5a is CI, F, CF3, Me, Et, -OH, -OCH3, -OCH2CH3.
[00150] In still other embodiments, y is 0, and R5a is F. In yet other embodimentsy is 0, q
is 1, and R5a is OR'. In still other embodiments, y is 0, q is 1 and R5a is OH. In yet other
embodiments, y is 1, R5a is OR' and R5 is F, wherein OR' is substituted at the 2-position of
the phenyl ring and F is substituted at the 6-position of the phenyl ring. In yet other
embodiments, y is 1, R5a is OH and Rs is F, wherein OH is substituted at the 2-position of the
phenyl ring and F is substituted at the 6-position of the phenyl ring.
[00151] In still other embodiments for compounds of formula IA-ii described above:
a): one of R1 or R2 is hydrogen, and the other of R1 and R2 is selected from Cyl,
wherein Cyl is bonded directly to the nitrogen atom or is bonded through an optionally
substituted C1-4aliphatic group, wherein one or more methylene units in the C1-4aliphatic
group are optionally replaced with -NR-, -O-, -COO, -OCO-, -NRCO-, -CONR-, -SO2NR-, or
-NRSO2-, or an optionally substituted C1-4aliphatic group, wherein one or more methylene
units in the C1-4aliphatic group are optionally replaced with -NR-, -O-, -COO, -OCO-, -
NRCO-, -CONR-, -SO2NR-, or -NRSO2-; or R1 and R2 are each independently selected from
an optionally substituted C1-4aliphatic group, wherein one or more methylene units in the Ci_
4aliphatic group are optionally replaced with -NR-, -O-, -COO, -OCO-, -NRCO-, -CONR-, -
SO2NR-, or -NRSO2-; or Cy1 wherein Cy1 is bonded to the nitrogen atom directly or is
bonded through an optionally substituted C1-4aliphatic group, wherein one or more methylene
units in the C1-4aliphatic group are optionally replaced with -NR-, -O-, -COO, -OCO-, -
NRCO-, -CONR-, -SO2NR-, or -NRSOz-; and Cy1 is selected from:


or R1 and R2 are each independently an optionally substituted Ci-4aliphatic group and are
each independently selected from optionally substituted methyl, ethyl, cyclopropyl, n-propyl,
propenyl, cyclobutyl, (CO)OCH2CH3, (CH2)2OCH3, CH2CO)OCH2CH3, CH2(CO)OCH3,
CH(CH3)CH2CH3> or n-butyl;
b) z is 0-5 and R4 groups are each independently CI, Br, F, CF3, CH3, -CH2CH3, CN, -
COOH, -N(CH3)2, -N(Et)2, -N(iPr)2, -O(CH2)2OCH3, -CONH2, -COOCH3, -OH, -CH2OH, -
NHCOCH3, -SO2NH2, -SO2(CH2)3CH3, -SO2CH(CH3)2, -SO2N(CH3)2, -SO2CH2CH3, -
C(O)OCH2CH(CH3)2l -C(O)NHCH2CH(CH3)2) -NHCOOCH3) -C(O)C(CH3)3, -
COO(CH2)2CH3, -C(O)NHCH(CH3)2, -C(O)CH2CH3, or an optionally substituted group
selected from -piperidinyl, piperizinyl, morpholino, C1-4alkoxy, phenyl, phenyloxy, benzyl,
benzyloxy, -CH2cyclohexyl, pyridyl, -CH2pyridyl, or -CH2thiazolyl;
c) x is 0, 1, or 2, and each occurrence of R3 is independently CI, Br, F, CF3, -OCF3,
Me, Et, CN, -COOH, -NH2, -N(CH3)2, -N(Et)2, -N(iPr)2, -O(CH2)2OCH3, -CONH2, -
COOCH3, -OH, -OCH3, -OCH2CH3, -CH2OH, -NHCOCH3, -NHCOCH(CH3)2, -SO2NH2, -
CONH(cyclopropyl), -CONHCH3> -CONHCH2CH3, or an optionally substituted group
selected from -piperidinyl, piperizinyl, morpholino, phenyl, phenyloxy, benzyl, or benzyloxy;
d) wherein y is 0-4, and R5 groups, when present, are each independently CI, Br, F,
CF3, Me, Et, CN, -COOH, -NH2, -N(CH3)2, -N(Et)2, -N(iPr)2, -O(CH2)2OCH3, -CONH2, -
COOCH3, -OH, -OCH3, -OCH2CH3, -CH2OH, -NHCOCH3, -SO2NH2> -SO2NHC(CH3)2, -
0COC(CH3)3, -OCOCH2C(CH3)3; -O(CH2)2N(CH3)2, 4-CH3-piperazin-l-yl, 0COCH(CH3)2,
OCO(cyclopentyl), -COCH3, optionally substituted phenoxy, or optionally substituted
benzyloxy; and
e) R5a is CI, F, CF3, Me, Et, -OH, -OCH3, -OCH2CH3, -CH2OH, -SO2NH2, -
SO2NHC(CH3)2, -OCOC(CH3)3, -OCOCH2C(CH3)3) -O(CH2)2N(CH3)2> 4-CH3-piperazin-l-
yl, OCOCH(CH3)2lOCO(cyclopentyl), or -COCH3.
[00152] In yet other embodiments for compounds described directly above, x is 1 and R3 is
at the 6-position of the quinazoline ring and is -CI, -CH3, -CH2CH3, -F, -CF3, -OCF3, -
CONHCH3, -CONHCH2CH3, -CONH(cyclopropyl), -OCH3, -NH2, -OCH2CH3, or -CN. In
still other embodiments, x is 1 and R3 is at the 7-position of the quinazoline ring and is -CI, -
CH3, -CH2CH3, -F, -CF3, -OCF3, -CONHCH3, -CONHCH2CH3, -CONH(cyclopropyl), -
OCH3, -NH2, -OCH2CH3, or -CN. In still other embodiments, x is 1 and R3 is at the 6-
position of the quinazoline ring and is -CI, -CH3, -CH2CH3, -F, -CF3, -OCF3, -OCH3, or -
OCH2CH3. In yet other embodiments, x is 1 and R3 is at the 7-position of the quinazoline
ring and is -CI, -CH3, -CH2CH3, -F, -CF3, -OCF3, -OCH3, or -OCH2CH3. In still other
embodiments, x is 1 and R3 is at the 6-position of the quinazoline ring and is -CON(R')2, or
NRCOR'. In yet other embodiments, x is 1 and R3 is at the 7-position of the quinazoline ring
and is -CON(R')2, or NRCOR'. In still other embodiments, R5a is CI, F, CF3, Me, Et, -OH, -
OCH3, -OCH2CH3.
[00153] In still other embodiments, y is 0, and R3a is F. In yet other embodimentsy is 0, q
is 1, and R5a is OR'. In still other embodiments, y is 0, q is 1 and R5a is OH. In yet other
embodiments, y is 1, R5a is OR' and R5 is F, wherein OR' is substituted at the 2-position of
the phenyl ring and F is substituted at the 6-position of the phenyl ring. In yet other
embodiments, y is 1, R5a is OH and R5 is F, wherein OH is substituted at the 2-position of the
phenyl ring and F is substituted at the 6-position of the phenyl ring.
[00154] For compounds described in this section above, in general, compounds are useful
as inhibitors of ion channels, preferably voltage gated sodium channels and N-type calcium
channels. In certain exemplary embodiments, compounds of the invention are useful as
inhibitors of NaV1.8. In other embodiments, compounds of the invention are useful as
inhibitors of NaV1.8 and. CaV2.2. In still other embodiments, compounds of the invention
are useful as inhibitors of CaV2.2. In yet other embodiments, compounds of the invention
are useful as dual inhibitors of NaVl.S and a TTX-sensitive ion channel such as NaV1.3 or
NaV1.7.

or a pharmaceutically acceptable salt thereof,
wherein R1 and R2 are each independently an optionally substituted group selected
from C1-6aliphatic, Cy1, wherein Cy1 is a 5-7-membered monocyclic aryl ring or an 8-10-
membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen,
oxygen, or sulfur, or is a 3-12-membered saturated or partially unsaturated monocyclic ring
having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Cy1
is bonded directly to the nitrogen atom or is bonded through an optionally substituted Ci.
4aliphatic group, wherein one or more methylene units in the C1-4aliphatic group are
optionally replaced with -NR-, -O-, -COO, -OCO-, -NRCO-, -CONR-, -SO2NR-, or -NRSO2-
; wherein R1 and R2, are each optionally and independently substituted at one or more
substitutable carbon, nitrogen, or sulfur atoms with z independent occurrences of -R4,
wherein z is 0-5;
x is 1 and R3 is substituted at either the 6- or 7-position of the quinazoline ring;
y is 0-4;
q is 0, 1 or 2;
each occurrence of R3, R4, and R5 is independently Q-R ; wherein Q is a bond or is a
C1-C6 alkylidene chain wherein up to two non-adjacent methylene units of Q are optionally
and independently replaced by -NR-, -S-, -O-, -CS-, -CO2-, -OCO-, -CO-, -COCO-, -CONR-,
-NRCO-, -NRCO2-, -SO2NR-, -NRSO2-, -CONRNR-, -NRCONR-, -OCONR-, -NRNR-, -
NRSO2NR-, -SO-, -SO2-, -PO-, -PO2-, -OP(O)(OR)-, or -POR-; and each occurrence of Rx is
independently selected from -R', =O, =NR', halogen, -NO2, -CN, -OR', -SR', -N(R')2, -
NR'COR', -NR'CON(R')2> -NR'CO2R', -COR', -CO2R', -OCOR', -CON(R')2, -
OCON(R')2, -SOR', -SO2R', -SO2N(R')2, -NR'SO2R', -NR'SO2N(R')2, -COCOR', -
COCH2COR', -OP(O)(OR')2, -P(O)(OR')2, -OP(O)2OR', -P(O)2OR', -PO(R')2, or -
OPO(R')2;
each occurrence of R5a is independently an optionally substituted C1-C6aliphatic
group, halogen, -OR', -SR', -N(R')2, -NR'COR', -NR'CON(R')2, -NR'CO2R', -COR', -
CO2R', -OCOR', -CON(R')2, -OCON(R')2, -SOR', -SO2R', -SO2N(R')2) -NR'SO2R', -
NR'SO2N(R')2, -COCOR', -COCH2COR', -OP(O)(OR')2, -P(O)(OR')2, -OP(O)2OR', -
P(O)2OR', -PO(R')2, or -OPO(R')2; and
each occurrence of R is independently hydrogen or an optionally substituted Ci-g
aliphatic group; and each occurrence of R is independently hydrogen or an optionally
substituted Q-6 aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully
unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen,
oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated
bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen,
or sulfur; or R and R, two occurrences of R, or two occurrences of R, are taken together with
the atom(s) to which they are bound to form an optionally substituted 3-12 membered
saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4
heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[00156] In certain embodiments, for compounds described directly above:
a) when R3 is at the 7-position of the quinazoline ring then:
i) when R3 is CI or Me, ring A is unsubstituted naphthyl, and R1 is hydrogen,
then R2 is not -(CH2)3NMe2;
ii) when R3 is CI, the sum of q and y is 1 and the phenyl ring is substituted at
the 4-position with Br, and R1 is hydrogen, then R2 is not Cy1, wherein Cy1 is bonded to the
nitrogen atom through an optionally substituted C^aliphatic group, wherein one or more
methylene units in the Ci„4aliphatic group are optionally replaced with -NR-, -O-, -COO, -
OCO-, -NRCO-, -CONR-, -SOzNR-, or -NRSO2-;
iii) when R3 is CI or OMe, the sum of q and y is 1 and the phenyl ring is
substituted at the 4-position with either OMe or CI, and R1 is hydrogen, then R2 is not -
CH(CH3)(CH2)3N(Et)2;
iv) when R3 is Me, OMe, or NO2, and q and y are 0, then R1 and R2 are not
both methyl;
v) when R3 is OMe, q and y are 0, and R1 is hydrogen, then R2 is not -SO2(4-
Me-phenyl);
vi) when R3 is F, the sum of q and y is 1 and the phenyl ring is substituted at
the 2-position with CI, and R1 is hydrogen, then R2 is not -(CH2)morpholino; and
b) a) when R3 is at the 6-position of the quinazoline ring then:
i) when R3 is NH2, Me, CI, Br, -NHAc, the sum of q and y is 1 and the phenyl
ring is substituted at the 4-position with F, or ring A is naphthyl, and R1 is hydrogen, then R2
is not -(CH3)3-4N(R')2;
ii) when R3 is -OCH2Ph, or OH, and q and y are 0, then when R1 is hydrogen,
R2 is not Me, nBu, or -(CH2)2morpholino, or R1 and R2 are not simultaneously Me or Et;
iii) when R3 is Me or CI, and the sum of q and y are 1, then the phenyl ring is
not substituted in the 4-position with Br;
iv) when R3 is CI, q and y are 0, and R1 is hydrogen, then R2 is not -SO2(4-
Me-phenyl);
v) when R3 is OMe, and q and y are 0, and R1 is hydrogen, then R2 is not -
CH2CH2OH or -CH2CH2pyn-oUdinyl;
vi) when R3 is CI or Br, the sum of q and y is 1, and the phenyl ring is
substituted in the 4-position with -CH2PO(OR')2, then R1 is not hydrogen when R2 is -Me, or
R1 and R2 are not simultaneously Me or Et;
vii) when R3 is OH and q and y are 0, then R1 and R2 are not simultaneously -
CH2CH2OMe;
viii) when R3 is CI, the sum of q and y is 1 and the phenyl ring is substituted in
the 2-position with OnPr, and R1 is hydrogen, then R2 is not -CH2(l,3-benzodioxol);
ix) when R3 is OMe, OH, Br, CI, NO2, Me, and q and y are 0, then when R1 is
hydrogen, R2 is not Me, -CH2CH2COOMe, -CH2COOMe, or -(CH2)3CH3, or R1 and R2 are
not simultaneously Me; and
x) when R is CI, the sum of q and y is 1 and the phenyl ring is substituted in
the 4-position with CI, then R1 and R2 are not simultaneously Me or iPr.
[00157] In certain other embodiments, for compounds described directly above:
a) one of R1 or R2 is hydrogen, and the other of R1 and R2 is selected from:
i) Cy1 wherein Cy1 is bonded directly to the nitrogen atom or is bonded
through an optionally substituted C^aliphatic group, wherein one or more methylene
units in the C1-4aliphatic group are optionally replaced with -NR-, -O-, -COO, -OCO-,
-NRCO-, -CONR-, -SO2NR-, or -NRSO2-; or
ii) an optionally substituted C1-4aliphatic group, wherein one or more
methylene units in the C^aliphatic group are optionally replaced with -NR-, -O-, -
COO, -OCO-, -NRCO-, -CONR-, -SO2NR-, or -NRSO2-; or
b) Rl and R2 are each independently selected from Cy1, wherein Cy1 is bonded
directly to the nitrogen atom or is bonded through an optionally substituted Cu
4aliphatic group, wherein one or more methylene units in the C1-4aliphatic group are
optionally replaced with -NR-, -O-, -COO, -OCO-, -NRCO-, -CONR-, -SO2NR-, or -
NRSO2-; or an optionally substituted C1-4aliphatic group, wherein one or more
methylene units in the C1-4aliphatic group are optionally replaced with -MR-, -O-, -
COO-, -OCO-, -NRCO-, -CONR-, -SO2NR-, or -NRSO2-.
[00158] In still other embodiments, Cy1 is:


[00160] In yet other embodiments, R1 and R" groups are each independently an optionally
substituted Ci-4aliphatic group and are each independently selected from optionally
substituted methyl, ethyl, cyclopropyl, n-propyl, propenyl, cyclobutyl, (CO)OCH2CH3,
(CH2)2OCH3, CH2CO)OCH2CH3, CH2(CO)OCH3, CH(CH3)CH2CH3, or n-butyl.
[00161] In still other embodiments, for compounds described directly above, z is 0-5, and
R4 groups, when present, are each independently halogen, CN, NO2, -N(R')2, -CH2N(R')2, -
OR', -CH2OR', -SR', -CH2SR', -COOR', -NRCOR', -CON(R')2, -OCON(R')2, COR', -
NHCOOR', -SO2R', -SO2N(R')2, or an optionally substituted group selected from Cx.
Cealiphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylCj-Coalkyl,
heteroarylCi-Cgalkyl, cycloaliphaticC1-C6alkyl, or heterocycloaliphaticCi-Qalkyl.
[00162] In yet other embodiments, z is 0-5 and R4 groups are each independently CI, Br, F,
CF3, CH3, -CH2CH3, CN, -COOH, -N(CH3)2, -N(Et)2, -N(iPr)2, -O(CH2)2OCH3, -CONH2, -
COOCH3, -OH, -CH2OH, -NHCOCH3, -SO2NH2, -SO2(CH2)3CH3, -SO2CH(CH3)2, -
SO2N(CH3)2, -SO2CH2CH3, -C(O)0CH2CH(CH3)2, -C(O)NHCH2CH(CH3)2, -NHCOOCH3, -
C(O)C(CH3)3, -COO(CH2)2CH3, -C(O)NHCH(CH3)2, -C(O)CH2CH3, or an optionally
substituted group selected from -piperidinyl, piperizinyl, morpholino, C1-4alkoxy, phenyl,
phenyloxy, benzyl, benzyloxy, -CHacyclohexyl, pyridyl, -CH2pyridyl, or -CH2thiazolyl.
[00163] In still other embodiments, for compounds described directly above, R3 is
halogen, CN, NO2, -N(R')2, -CH2N(R')2, -OR', -CH2OR', -SR', -CH2SR', -COOR', -
NRCOR', -CON(R')2, -OCON(R')2, COR', -NHCOOR', -SO2R', -SO2N(R')2, or an
optionally substituted group selected from Ci-Cgaliphatic, aryl, heteroaryl, cycloaliphatic,
heterocycloaliphatic, arylC1-C6alkyl, heteroarylCrC6alkyl, cycloaliphaticC1-C6alkyl, or
heterocycloaliphaticC i -Cgalkyl.
[00164] In yet other embodiments, R3 is CI, Br, F, CF3, -OCF3, Me, Et, CN, -COOH, -
NH2, -N(CH3)2, -N(Et)2, -N(iPr)2, -O(CH2)2OCH3, -CONH2, -COOCH3, -OH, -OCH3, -
OCH2CH3, -CH2OH, -NHCOCH3, -NHCOCH(CH3)2, -SO2NH2, -CONH(cycIopropyl), -
CONHCH3, -CONHCH2CH3, or an optionally substituted group selected from -piperidinyl,
piperizinyl, morpholino, phenyl, phenyloxy, benzyl, or benzyloxy.
[00165] In still other embodiments, R3 is halogen, CN, optionally substituted C1-C6alkyl,
OR', N(R')2, CON(R')2, or NRCOR'. In yet other embodiments, R3 is -CI, -CH3, -CH2CH3, -
F, -CF3, -OCF3, -CONHCH3, -CONHCH2CH3, -CONH(cyclopropyl), -OCH3, -NH2, -
OCH2CH3, or -CN. In still other embodiments. R3 is at the 6-position of the quinazoline ring
and is -CI, -CH3, -CH2CH3, -F, -CF3, -OCF3, -CONHCH3, -CONHCH2CH3, -
CONH(cyclopropyl), -OCH3, -NH2, -OCH2CH3, or -CN. In yet other embodiments, R3 is at
the 7-position of the quinazoline ring and is -CI, -CH3, -CH2CH3, -F, -CF3, -OCF3; -
CONHCH3, -CONHCH2CH3, -CONH(cyclopropyl), -OCH3, -NH2, -OCH2CH3, or -CN. In
still other embodiments, R3 is at the 6-position of the quinazoline ring and is -CI, -CH3, -
CH2CH3, -F, -CF3, -OCF3, -OCH3, or -OCH2CH3. In yet other embodiments, R3 is at the 7-
position of the quinazoline ring and is -CI, -CH3, -CH2CH3, -F, -CF3, -OCF3, -OCH3, or -
OCH2CH3. In still other embodiments, R3 is at the 6-position of the quinazoline ring and is -
CON(R')2, or NRCOR'. In still other embodiments, R3 is at the 7-position of the quinazoline
ring and is -CON(R')2, or NRCOR'.
[00166] In still other embodiments for compounds described directly above, y is 0-5, q is
0-2, and R5 and R5a groups, when present, are each independently halogen, CN, NO2, -
N(R')2, -CH2N(R')2, -OR', -CH2OR', -SR', -CH2SR', - -NRCOR', -CON(R')2, ~S(O)2N(R')2,
-OCOR', -COR', -CO2R', -OCON(R')2) -NR'SO2R', -OP(O)(OR')2> -P(O)(OR')2, -
OP(O)2OR', -P(O)2OR', -PO(R')2, -OPO(R')2, or an optionally substituted group selected
from Ci.Cealiphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylCi-Cgalkyl,
heteroarylC1-C6alkyl, cycloaliphaticCi-C5alkyl, or heterocycloaliphaticC1-C6alkyl.
[00167] In yet other embodiments, y is 0-5, and q is 1 or 2, and each occurrence of R5a is
independently CI, Br, F, CF3, Me, Et, CN, -COOH, -NH2) -N(CH3)2, -N(Et)2, -N(iPr)2, -
0(CH2)2OCH3, -CONH2, -COOCH3, -OH, -OCH3, -OCH2CH3, -CH2OH, -NHCOCH3, -
SO2NH2, -SO2NHC(CH3)2, -OCOC(CH3)3, -OCOCH2C(CH3)3, -O(CH2)2N(CH3)2, 4-CH3-
piperazin-1-yi, OCOCH(CH3)2, OCO(cyclopentyl), -COCH3, optionally substituted phenoxy,
or optionally substituted benzyloxy.
[00168] In still other embodiments, y is 0, and R5a is F. In yet other embodiments y is 0, q
is 1, and R5a is OR'. In still other embodiments, y is 0, q is 1 and R5a is OH. In yet other
embodiments, y is 1, R5a is OR' and R5 is F, wherein OR' is substituted at the 2-position of
the phenyl ring and F is substituted at the 6-position of the phenyl ring. In yet other
embodiments, y is 1, R5a is OH and R5 is F, wherein OH is substituted at the 2-position of the
phenyl ring and F is substituted at the 6-position of the phenyl ring.
[00169] In still other embodiments, R3 is substituted at the 6-position of the quinazoline
ring, q is 1, and y is 0, and compounds have formula III:

[00170] In certain embodiments, for compounds described above,
a) R1 and R2 are each independently an optionally substituted group selected from Ci_
6aliphatic, Cy1, wherein Cy1 is a 5-7-membered monocyclic aryl ring or an 8-10-membered
bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or
sulfur, or is a 3-12-membered saturated or partially unsaturated monocyclic ring having 0-3
heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Cy1 is bonded
directly to the nitrogen atom or is bonded through an optionally substituted C1-4aliphatic
group, wherein one or more methylene units in the C1-4aliphatic group are optionally replaced
with -NR-, -O-, -COO, -OCO-, -NRCO-, -CONR-, -SOzNR-, or -NRSO2-; wherein R1 and
R2, are each optionally and independently substituted at one or more substitutable carbon,
nitrogen, or sulfur atoms with z independent occurrences of-R, wherein z is 0-5;
b) z is 0-5 and R4 groups are each independently CI, Br, F, CF3, CH3, -CH2CH3, CN, -
COOH, -N(CH3)2) -N(Et)2, -N(iPr)2, -O(CH2)2OCH3, -CONH2l -COOCH3, -OH, -CH2OH, -
NHCOCH3, -SO2NH2, -SO2(CH2)3CH3, -SO2CH(CH3)2, -SO2N(CH3)2, -SO2CH2CH3, -
C(O)OCH2CH(CH3)2, -C(O)NHCH2CH(CH3)2, -NHCOOCH3, -C(O)C(CH3)3, -
COO(CH2)2CH3, -C(O)NHCH(CH3)2, -C(O)CH2CH3, or an optionally substituted group
selected from -piperidinyl, piperizinyl, morpholino, C1-4alkoxy, phenyl, phenyloxy, benzyl,
benzyloxy, -CH2cyclohexyl, pyridyl, -CH2pyridyl, or -CH2thiazolyl;
c) R3 is CI, Br, F, CF3, -OCF3, Me, Et, CN, -COOH, -NH2, -N(CH3)2, -N(Et)2, -
N(iPr)2, -O(CH2)2OCH3( -CONH2, -COOCH3, -OH, -OCH3, -OCH2CH3, -CH2OH, -
NHCOCH3, -NHCOCH(CH3)2, -SO2NH2, -CONH(cyclopropyl), -CONHCH3, -
CONHCH2CH3, or an optionally substituted group selected from -piperidinyl, piperizinyl,
morpholino, phenyl, phenyloxy, benzyl, or benzyloxy; and
d) R5a is CI, F, CF3, Me, Et, -OH, -OCH3, -OCH2CH3s -CH2OH, -SO2NH2, -
SO2NHC(CH3)2, -OCOC(CH3)3, -OCOCH2C(CH3)3, -O(CH2)2N(CH3)2, 4-CH3-piperazin-l-
yl, 0COCH(CH3)2, OCO(cyclopentyl), or -COCH3.
[00171] In certain other embodiments, for compounds described directly above R3 is -CI, -
CH3, -CH2CH3, -F, -CF3, -OCF3, -CONHCH3, -CONHCH2CH3, -CONH(cyclopropyl), -
OCH3, -NH2, -OCH2CH3, or -CN. In still other embodiments, R3 is -CI, -CH3, -CH2CH3, -F,
-CF3, -OCF3, -OCH3, or -OCH2CH3. In yet other embodiments, R3 is is -COM(R')2, or
NRCOR'. In still other embodiments, R5a is CI, F, CF3, Me, Et, -OH, -OCH3, -OCH2CH3.
[00172] In still other embodiments, y is 0, and R5a is F. In yet other embodimentsy is 0, q
is 1, and R5a is OR'. In still other embodiments, y is 0, q is 1 and R5a is OH.
[00173] In certain other embodiments, for compounds described directly above:


or R1and R2 are each independently an optionally substituted C1-4aliphatic group and are
each independently selected from optionally substituted methyl, ethyl, cyclopropyl, n-propyl,
propenyl, cyclobutyl, (CO)OCH2CH3, (CH2)20CH3> CH2CO)OCH2CH3, CH2(CO)OCH3,
CH(CH3)CH2CH3, orn-butyl;
b) z is 0-5 and R4 groups are each independently CI, Br, F, CF3, CH3, -CH2CH3, CN, -
COOH, -N(CH3)2, -N(Et)2, -N(iPr)2, -O(CH2)2OCH3, -CONH2, -COOCH3, -OH, -CH2OH, -
NHCOCH3, -SO2NH2, -SO2(CH2)3CH3, -SO2CH(CH3)2, -SO2N(CH3)2) -SO2CH2CH3, -
C(O)OCH2CH(CH3)2) -C(O)NHCH2CH(CH3)2, -NHCOOCH3> -C(O)C(CH3)3, -
COO(CH2)2CH3, -C(O)NHCH(CH3)2) -C(O)CH2CH3, or an optionally substituted group
selected from -piperidinyl, piperizinyl, morpholino, C1-4alkoxy, phenyl, phenyloxy, benzyl,
benzyloxy, -CH2cyclohexyl, pyridyl, -CH2pyridyl, or -CH2thiazolyl;
c) R3 is CI, Br, F, CF3, -OCF3, Me, Et, CN, -COOH, -NH2, -N(CH3)2, -N(Et)2, -
N(iPr)2, -O(CH2)2OCH3, -CONH2, -COOCH3, -OH, -OCH3, -OCH2CH3, -CH2OH, -
NHCOCH3, -NHCOCH(CH3)2, -SO2NH2, -CONH(cyclopropyl), -CONHCH3, -
CONHCH2CH3, or an optionally substituted group selected from -piperidinyl, piperizinyl,
morpholino, phenyl, phenyloxy, benzyl, or benzyloxy; and
d) R5a is CI, F, CF3, Me, Et, -OH, -OCH3, -OCH2CH3, -CH2OH, -SO2NH2, -
SO2NHC(CH3)2, -OCOC(CH3)3, -OCOCH2C(CH3)3, -O(CH2)2N(CH3)2, 4-CH3-piperazin-l-
yl, OCOCH(CH3)2,OCO(cyclopentyl), or -COCH3.
[00174] In certain embodiments, for compounds described directly above R3 is -CI, -CH3, -
CH2CH3, -F, -CF3, -OCF3, -CONHCH3, -CONHCH2CH3, -CONH(cyclopropyl), -OCH3, -
NH2, -OCH2CH3, or -CN. In other embodiments, R3 is -CI, -CH3, -CH2CH3, -F, -CF3, -OCF3,
-OCH3, or -OCH9CH3. In still other embodiments, R3 is-CON(R')2, or NRCOR'. In yet
other embodiments, R5a is CI, F, CF3, Me, Et, -OH, -OCH3, -OCH2CH3. In still other
embodiments, y is 0, and R5a is F. In yet other embodiments y is 0, q is 1, and R5a is OR'. In
still other embodiments, y is 0, q is 1 and Rja is OH.
[001753 In yet other embodiments, R3 is substituted at the 7-position of the quinazoline
ring, q is 1, and y is 0, and. compounds have formula IV:

a) wherein R1 and R2 are each independently an optionally substituted group selected
from Ct.6aliphatic, Cy1, wherein Cy1 is a 5-7-membered monocyclic aryl ring or an 8-10-
membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen,
oxygen, or sulfur, or is a 3-12-membered saturated or partially unsaturated monocyclic ring
having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Cy1
is bonded directly to the nitrogen atom or is bonded through an optionally substituted Q.
4aliphatic group, wherein one or more methylene units in the Cj^aliphatic group are
optionally replaced with -MR-, -O-, -COO, -OCO-, -NRCO-, -CONR-, -SO2NR-, or -NRSO2-
; wherein R1 and R2, are each optionally and independently substituted at one or more
substitutable carbon, nitrogen, or sulfur atoms with z independent occurrences of -R4,
wherein z is 0-5;
b) z is 0-5 and R4 groups are each independently CI, Br, F, CF3, CH3, -CH2CH3, CN, -
COOH, -N(CH3)2, -N(Et)2, -N(iPr)2, -O(CH2)2OCH3; -CONH2, -COOCH3, -OH, -CH2OH, -
NHCOCH3, -SO2NH2, -SO2(CH2)3CH3, -SO2CH(CH3)2, -SO2N(CH3)2, -SO2CH2CH3, -
C(O)0CH2CH(CH3)2, -C(O)NHCH2CH(CH3)2, -NHCOOCH3, -C(O)C(CH3)3) -
CO0(CH2)2CH3, -C(O)NHCH(CH3)2, -C(O)CH2CH3, or an optionally substituted group
selected from -piperidinyl, piperizinyl, morpholino, C1-4alkoxy, phenyl, phenyloxy, benzyl,
benzyloxy, -CH2cyclohexyl, pyridyl, -CH2pyridyl, or -CH2thiazolyl;
c) R3 is CI, Br, F, CF3, -OCF3, Me, Et, CN, -COOH, -NH2, -N(CH3)2, -N(Et)2, -
N(iPr)2> -O(CH2)2OCH3, -CONH2, -COOCH3, -OH, -OCH3, -OCH2CH3, -CH2OH, -
NHCOCH3, -NHCOCH(CH3)2, -SO2NH2, -COMH(cyclopropyl), -CONHCH3, -
CONHCH2CH3, or an optionally substituted group selected from -piperidinyl, piperizinyl,
morpholino, phenyl, phenyloxy, benzyl, or benzyloxy; and
d) R5a is CI, F, CF3, Me, Et, -OH, -OCH3, -OCH2CH3> -CH2OH, -SO2NH2, -
SO2NHC(CH3)2, -OCOC(CH3)3, -OCOCH2C(CH3)3, -O(CH2)2N(CH3)2, 4-CH3-piperazin-l-
yl, OCOCH(CH3)2, OCO(cyclopentyl), or -COCH3.
[00176] In certain embodiments, for compounds described directly above, R3 is -CI, -CH3,
-CH2CH3, -F, -CF3, -OCF3, -CONHCH3, -CONHCH2CH3> -CONH(cyclopropyl), -OCH3, -
NH2, -OCH2CH3, or -CN. In other embodiments, R3 is -CI, -CH3, -CH2CH3, -F, -CF3, -
OCF3, -OCH3, or -OCH2CH3. In still other embodiments, R3 is is -CON(R')2, or NRCOR'.
In yet other embodiments, R5a is CI, F, CF3, Me, Et, -OH, -OCH3, -OCH2CH3. In still other
embodiments, y is 0, and R5a is F. In yet other embodiments y is 0, q is 1, and R5a is OR'. In
still other embodiments, y is 0, q is 1 and R5a is OH.
[00177] In certain other embodiments, for compounds described directly above:
a) Cy1 is:
or R1 and R2 are each independently an optionally substituted C1-4aliphatic group and are
each independently selected from optionally substituted methyl, ethyl, cyclopropyl, n-propyl,
propenyl, cyclobutyl, (CO)OCH2CH3, (CH2)20CH3) CH2CO)OCH2CH3, CH2(CO)OCH3,
CH(CH3)CH2CH3, or n-butyl;
b) z is 0-5 and R4 groups are each independently CI, Br, F, CF3, CH3, -CH2CH3, CN, -
COOH, -N(CH3)2, -N(Et)2, -N(iPr)2) -O(CH2)2OCH3, -CONH2, -COOCH3, -OH, -CH2OH, -
NHCOCH3, -SO2NH2, -SO2(CH2)3CH3, -SO2CH(CH3)2, -SO2N(CH3)2, -SO2CH2CH3> -
C(O)OCH2CH(CH3)2, -C(O)NHCH2CH(CH3)2, -NHCOOCH3, -C(O)C(CH3)3> -
COO(CH2)2CH3, -C(O)NHCH(CH3)2, -C(O)CH2CH3, or an optionally substituted group
selected from -piperidinyl, piperizinyl, morpholino, C1-4alkoxy, phenyl, phenyloxy, benzyl,
benzyloxy, -CH2cyclohexyl, pyridyl. -CH2pyridyl, or -CH2thiazolyl;
c) R3 is CI, Br, F, CF3) -OCF3, Me, Et, CN, -COOH, -NH2, -N(CH3)2, -N(Et)2, -
N(iPr)2, -O(CH2)2OCH3, -CONH2, -COOCH3, -OH, -OCH3, -OCH2CH3, -CH2OH, -
NHCOCH3, -NHCOCH(CH3)2, -SO2NH2, -CONH(cyclopropyl), -CONHCH3, -
CONHCH2CH3, or an optionally substituted group selected from -piperidinyl, piperizinyl,
morpholino, phenyl, phenyloxy, benzyl, or benzyloxy; and
d) R5a is CI, F, CF3, Me, Et, -OH, -OCH3, -OCH2CH3, -CH2OH, -SO2NH2, -
SO2MHC(CH3)2, -OCOC(CH3)3, -OCOCH2C(CH3)3, -O(CH2)2N(CH3)2, 4-CH3-piperazin-l-
yl, OCOCH(CH3)2,OCO(cyclopentyl), or -COCH3.
[00178] In certain other embodiments, for compounds described directly above R3 is -CI, -
CH3, -CH2CH3s -F, -CF3, -OCF3, -CONHCH3, -CONHCH2CH3, -CONH(cyclopropyl), -
OCH3, -NH2, -OCH2CH3, or -CN. In other embodiments, R3 is -CI, -CH3, -CH2CH3, -F, -
CF3, -OCF3, -OCH3, or -OCH2CH3. In still other embodiments, R3 is-CON(R')2, or
NRCOR'. In yet other embodiments, RSa is CI, F, CF3, Me, Et, -OH, -OCH3, or -OCH2CH3.
In still other embodiments, y is 0, and R3a is F. In yet other embodiments y is 0, q is 1, and
R5a is OR'. In still other embodiments, y is 0, q is 1 and R5a is OH.
[00179] For compounds described in this section above, in general, compounds are useful
as inhibitors of ion channels, preferably voltage gated sodium channels and N-type calcium
channels. In certain exemplary embodiments, compounds of the invention are useful as
inhibitors of NaV1.8. In other embodiments, compounds of the invention are useful as
inhibitors of NaV1.8 and CaV2.2. In still other embodiments, compounds of the invention
are useful as inhibitors of CaV2.2. In yet other embodiments, compounds of the invention
are useful as dual inhibitors of NaV1.8 and a TTX-sensitive ion channel such as NaV1.3 or
NaV1.7.

wherein R1 and R2 are each independently an optionally substituted group selected
from C1-6aliphatic, Cy1, wherein Cy1 is a 5-7-membered monocychc aryl ring or an 8-10-
membered bicyclic aryl ring having 0-3 heteroatoras independently selected from nitrogen,
oxygen, or sulfur, or is a 3-12-membered saturated or partially unsaturated monocyclic ring
having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Cy1
is bonded directly to the nitrogen atom or is bonded through an optionally substituted C\.
4aliphatic group, wherein one or more methylene units in the C1-4aliphatic group are
optionally replaced with -NR-, -O-, -COO, -OCO-, -NRCO-, -CONR-, -SO2NR-, or -
NRSO2-; or R1 and R2, taken together with the nitrogen atom to which they are bound, form
an optionally substituted. 3-12-membered monocyclic or bicyclic saturated or partially
unsaturated ring having 0-3 additional heteroatoms independently selected from nitrogen,
sulfur, or oxygen; wherein R1 and R2, or the ring formed by R1 and R2 taken together, are
each optionally and independently substituted at one or more substitutable carbon, nitrogen,
or sulfur atoms with z independent occurrences of -R4, wherein z is 0-5;
x is 0-4;
y is 0-2;
each occurrence of R3, R4, and RD is independently Q-Rx; wherein Q is a bond or is a
C1-C6 alkylidene chain wherein up to two non-adjacent methylene units of Q are optionally
and independently replaced by -NR-, -S-, -O-, -CS-, -CO2-, -OCO-, -CO-, -COCO-, -CONR-,
-NRCO-, -NRCO2-, -SO2NR-, -NRSO2-( -CONRNR-, -NRCONR-, -OCONR-, -NRNR-, -
NRSO2NR-, -SO-, -SO2-, -PO-, -PO2-, -OP(O)(OR)-, or -POR-; and each occurrence of Rx is
independently selected from -R', =O, =NR', halogen, -NO2, -CN, -OR', -SR', -N(R')2, -
NR'COR', -NR'CON(R')2, -NR'CO2R', -COR', -CO2R', -OCOR', -CON(R')2, -
OCON(R')2, -SOR', -SO2R', -SO2N(R')2, -NR'SO2R', -NR'SO2N(R')2, -COCOR', -
COCH2COR', -OP(O)(OR')2, -P(O)(OR')2, -OP(O)2OR', -P(O)2OR', -PO(R')2, or -
OPO(R')2;
R5a is an optionally substituted C1-C6aliphatic group, halogen, -OR', -SR', -N(R')2, -
NR'COR', -NR'CON(R')2, -NR'CO2R', -COR', -CO2R', -OCOR', -CON(R')2, -
OCON(R')2, -SOR', -SO2R', -SO2N(R')2, -NR'SO2R', -NR'SO2N(R')2, -COCOR', -
COCH2COR', -OP(O)(OR')2, -P(O)(OR')2) -OP(O)2OR', -P(O)2OR', -PO(R')2, or -
OPO(R')2; and
each occurrence of R is independently hydrogen or an optionally substituted Ci-g
aliphatic group; and each occurrence of R is independently hydrogen or an optionally
substituted Q-6 aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully
unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen,
oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated
bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen,
or sulfur; or R and R, two occurrences of R, or two occurrences of R, are taken together with
the atom(s) to which they are bound to form an optionally substituted 3-12 membered
saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4
heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[00181] In certain embodiments, for compounds described directly above, when x is 1 and
R3 is 6-OMe, R1 is hydrogen, and y and q are both 0, then R2 is not -CH2CH2OCH2CH2OH
or the monomethanesulfonate salt.
[00182] In certain other embodiments, for compounds described directly above,
a) one of R1 or R2 is hydrogen, and the other of R1 and R2 is selected from:
i) Cy1 wherein Cy1 is bonded directly to the nitrogen atom or is bonded
through an optionally substituted C^aliphatic group, wherein one or more methylene
units in the C1-4aliphatic group are optionally replaced with -NR-, -O-, -COO, -OCO-,
-NRCO-, -CONR-, -SO2NR-, or -NRSO2-; or
ii) an optionally substituted C1-4aliphatic group, wherein one or more
methylene units in the C1-4aliphatic group are optionally replaced with -NR-, -O-, -
COO, -OCO-, -NRCO-, -CONR-, -SO2NR-, or -NRSO2-; or
b) R and R2 are each independently selected from Cy1, wherein Cy1 is bonded
directly to the nitrogen atom or is bonded through an optionally substituted Ci.
4aliphatic group, wherein one or more methylene units in the ^aliphatic group are
optionally replaced with -NR-, -O-, -COO, -OCO-, -NRCO-, -CONR-, -SO2NR-, or -
NRSO2-; or an optionally substituted C1-4aliphatic group, wherein one or more
methylene units in the C1-4aliphatic group are optionally replaced with -NR-, -O-, -
COO-, -OCO-, -NRCO-, -CONR-, -SO2NR-, or -NRSO2-.
[00185] In still other embodiments, R1 and R2 groups are each independently an optionally
substituted C1-4aliphatic group and are each independently selected from optionally
substituted methyl, ethyl, cyclopropyl, n-propyl, propenyl, cyclobutyl, (CO)OCH2CH3,
(CH2)2OCH3, CH2CO)OCH2CH3, CH2(CO)OCH3, CH(CH3)CH2CH3, or n-butyl.
[00186] In yet other embodiments for compounds described directly above, R1 and R2,
taken together with the nitrogen atom to which they are bound, form an optionally substituted
3-12 membered heterocyclyl ring having 1-3 heteroatoms independently selected from
nitrogen or oxygen and form a 3-12 membered heterocyclyl group selected from:


wherein the ring formed by R1 and R2 taken together, is optionally substituted at one
or more substitutable carbon, nitrogen, or sulfur atoms with z independent occurrences of -
R4, and z is 0-5.
[00187] In other embodiments, for compounds of formula I-A, R1 and R2 taken together
are optionally substituted azetidin-1-yl (jj), pyrrolidin-1-yl (ff), piperidinl-yl (dd), piperazin-
1-yl (cc), or morpholin-4-yl (ee). In other embodiments, for compounds of formula I-A, R1
and R2 taken together are optionally substituted azetidin-1-yl (jj), pyrrolidin-1-yl (ff),
piperidinl-yl (dd), or piperazin-1-yl (cc). In yet other embodiments, for compounds of
formula I-A, R1 and R2, taken together is optionally substituted azetidin-1-yl (jj). In yet other
embodiments, for compounds of formula I-A, R1 and R2, taken together is optionally
substituted pyrrolidin-1-yl (ff). In still other embodiments, for compounds of formula I-A, R1
and R2, taken together is optionally substituted piperidinl-yl (dd). In yet other embodiments,
for compounds of formula I-A, R1 and R", taken together is optionally substituted piperazin-
1-yl («).
[00188] In still other embodiments, for compounds described directly above, z is 0-5, and
R4 groups, when present, are each independently halogen, CN, NO2, -N(R')2, -CH2N(R')2, -
OR', -CH2OR', -SR', -CH2SR', -COOR', -NRCOR', -CON(R')2, -OCON(R')2, COR', -
NHCOOR', -SO2R', -SO2N(R')2, or an optionally substituted group selected from Ci.
Cealiphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC1-C6alkyl,
heteroarylC1-C6alkyl, cycloaliphaticC1-C6alkyl, or heterocycloaliphaticC1-C6alkyl.
[00189] In yet other embodiments, z is 0-5 and R4 groups are each independently CI, Br, F,
CF3, CH3, -CH2CH3, CN, -COOH, -N(CH3)2, -N(Et)2, -N(iPr)2, -O(CH2)2OCH3, -CONH2l -
COOCH3, -OH, -CH2OH, -NHCOCH3, -SO2NH2, -SO2(CH2)3CH3, -SO2CH(CH3)2, -
SO2N(CH3)2, -SO2CH2CH3, -C(O)OCH2CH(CH3)2, -C(O)NHCH2CH(CH3)2, -NHCOOCH3, -
C(O)C(CH3)3, -COO(CH2)2CH3, -C(O)NHCH(CH3)2, -C(O)CH2CH3, or an optionally
substituted group selected from -piperidinyl, piperizinyl, morpholino, Ci-4alkoxy, phenyl,
phenyloxy, benzyl, benzyloxy, -CH2cyclohexyl, pyridyl, -CH2pyridyl, or -CH2thiazolyl.
[00190] In certain embodiments, for compounds of formula I-A, R1 and R2, taken together
is optionally substituted azetidin-1-yl (jj), wherein z is 1 or 2 and at least one occurrence of
R4 is -NRSO2R', -NRCOOR', or -NRCOR'. In certain other embodiments, for compounds
of formula I-A, R1 and R2, taken together is optionally substituted azetidin-1-yl (jj), wherein
z is 1 and R4 is -NRSO2R'. In other embodiments, for compounds of formula I-A, R1 and
R2, taken together is optionally substituted azetidin-1-yl (jj), wherein z is 1 and R is -
NRCOOR'. In certain other embodiments, for compounds of formula I-A, R1 and R2, taken
together is optionally substituted azetidin-1-yl (jj), wherein z is 1 and R4 is -NRCOR'. In yet
other embodiments, for compounds of formula I-A, R1 and R2, taken together is optionally
substituted pyrrolidin-1-yl (ff), wherein z is 1 or 2 and R4 is CI, Br, F, CF3, CH3, -CH2CH3, -
OR', or -CH2OR'. In still other embodiments, for compounds of formula I-A, R1 and R",
taken together is optionally substituted piperidin-1-yl (dd), wherein z is 1 or 2 and at least
one occurrence of R4 is CI, Br, F, CF3, CH3, -CH2CH3, -OR', or -CH2OR', -NRSO2R', -
NRCOOR', or -OCON(R')2. In certain other embodiments, for compounds of formula I-A,
Rl and R2, taken together is optionally substituted piperidin-1-yl (dd), wherein 2 is 1 and R4
is F, CF3, CH3; -CH2CH3, -OR', or -CH2OR', In other embodiments, for compounds of
formula I-A, R1 and R2, taken together is optionally substituted piperidin-1-yl (dd), wherein z
is 1 and R4 is —NRSO2R',. In certain other embodiments, for compounds of formula I-A, R1
and R2, taken together is optionally substituted piperidin-1-yl (dd), wherein z is 1 and R4 is -
NRCOOR'. In yet other embodiments, for compounds of formula I-A, R1 and R2, taken
together is optionally substituted piperazin-1-yl (cc), wherein z is 1 or 2 and at least one
occurrence of R4 is -SOR', -CON(R')2, -SO2N(R')2, -COR', or -COOR'. In ceitain other
embodiments, for compounds of formula I-A, R1 and R2, taken together is optionally
substituted piperazin-1-yl (cc), wherein z is 1 and R4 is -SOR'. In certain other
embodiments, for compounds of formula I-A, R1 and R2, taken together is optionally
substituted piperazin-1-yl (cc), wherein z is 1 and R4 is -COOR'. In certain other
embodiments, for compounds of formula I-A, R1 and R2, taken together is optionally
substituted piperazin-1-yl (cc), wherein z is 1 and R4 is -CON(R')2. In certain other
embodiments, for compounds of formula I-A, Rl and R2, taken together is optionally
substituted piperazin-1-yl (cc), wherein z is 1 and R4 is -SO2N(R')2. In certain other
embodiments, for compounds of formula I-A, R1 and R2, taken together is optionally
substituted piperazin-1-yl (cc), wherein z is 1 and R4 is -COR'.
[00191] In still other embodiments, x is 0-4, and R3 groups, when present, are each
independently halogen, CN, NO2, -N(R')2, -CH2N(R')2, -OR', -CH2OR', -SR', -CH2SR', -
COOR', -NRCOR', -CON(R')2, -OCON(R')2, COR', -NHCOOR', -SO2R', -SO2N(R')2, or
an optionally substituted group selected from Ci.C6aliphatic, aryl, heteroaryl, cycloaliphatic,
heterocycloaliphatic, arylCj-Cealkyl, heteroarylC1-C6alkyl, cycloaliphaticC1-C6alkyl, or
heterocycloaliphaticC1-C6alkyl. In yet other embodiments, x is 1 or 2, and each occurrence
of R3 is independently CI, Br, F, CF3, -OCF3) Me, Et, CN, -COOH, -NH2, -N(CH3)2, -N(Et)2,
-N(iPr)2, -O(CH2)2OCH3, -CONH2, -COOCH3, -OH, -OCH3, -OCH2CH3, -CH2OH, -
NHCOCH3, -NHCOCH(CH3)2, -SOzNHz, -CONH(cyclopropyl), -CONHCH3, -
CONHCH2CH3, or an optionally substituted group selected from -piperidinyl, piperizinyl,
morphohno, phenyl, phenyloxy, benzyl, or benzyloxy.
[00192] In still other embodiments, x is 1 or 2 and each R3 group is independently
halogen, CN, optionally substituted C1-C6alkyl, OR', N(R')2, CON(R')2, or NRCOR'. In yet
other embodiments, x is 1 or 2, and each R3 group is -CI, -CH3, -CH2CH3, -F, -CF3, -OCF3, -
CONHCH3, -CONHCH2CH3, -CONH(cyclopropyl), -OCH3, -NH2, -OCH2CH3, or -CN. In
still other embodiments, x is 1 and R3 is at the 6-position of the quinazoline ring and is -CI, -
CH3, -CH2CH3, -F: -CF3, -OCF3, -CONHCH3, -CONHCH2CH3, -CONH(cyclopropyl), -
OCH3, -NH2, -OCH2CH3, or -CN. In yet other embodiments, x is 1 and R3 is at the 7-
position of the quinazoline ring and is -CI, -CH3, -CH2CH3, -F, -CF3, -OCF3, -CONHCH3, -
CONHCH2CH3, -CONH(cyclopropyl), -OCH3, -NH2, -OCH2CH3, or -CN. In still other
embodiments, x is 1 and R3 is at the 6-position of the quinazoline ring and is -CI, -CH3, -
CH2CH3, -F, -CF3, -OCF3, -OCH3, or -OCH2CH3. In yet other embodiments, x is 1 and R3 is
at the 7-position of the quinazoline ring and is -CI, -CH3, -CH2CH3, -F, -CF3, -OCF3, -OCH3,
or -OCH2CH3. In still other embodiments, x is 1 and R3 is at the 6-position of the quinazoline
ring and is -CON(R')2, or NRCOR'. In yet other embodiments, x is 1 and R3 is at the 7-
position of the quinazoline ring and is -CON(R')2, or NRCOR'.
[00193] In still other embodiments for compounds described directly above, y is 0-2, q is
0-2, and R5 and R5a groups, when present, are each independently halogen, CN, NO2, -
N(R')2, -CH2N(R')2, -OR', -CH2OR', -SR', -CH2SR', - -NRCOR', -CON(R')2, -S(O)2N(R')2,
-OCOR', -COR', -CO2R', -OCON(R')2, -NR'SO2R', -OP(O)(OR')2, -P(O)(OR')2, -
OP(O)2OR', -P(O)2OR', -PO(R')2, -OPO(R')2, or an optionally substituted group selected
from Ci.Cealiphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC1-C6alkyl,
heteroarylC1-C6alkyl, cycloaliphaticC1-C6alkyl, or heterocycloaliphaticC1-C6alkyl.
[00194] In yet other embodiments, y is 0-2, and q is 1 or 2, and each occurrence of R5a is
independently CI, Br, F, CF3, Me, Et, CN, -COOH, -NH2, -N(CH3)2, -N(Et)2, -N(iPr)2, -
0(CH2)2OCH3, -CONH2, -COOCH3, -OH, -OCH3, -OCH2CH3, -CH2OH, -NHCOCH3, -
SO2NH2, -SO2NHC(CH3)2) -OCOC(CH3)3, -OCOCH2C(CH3)3, -O(CH2)2N(CH3)2, 4-CH3-
piperazin-1-yl, OCOCH(CH3)2, OCO(cyclopentyl), -COCH3, optionally substituted phenoxy,
or optionally substituted benzyloxy.
[00195] In still other embodiments, y is 0, and q is 1 and R5a is F. In yet other
embodiments, y is 0, q is 1, and R5a is OR'. In still other embodiments, y is 0, q is 1 and R5a
is OH. In yet other embodiments, y is 0, q is 2 and one occurrence of R5a is OR' and the
other occurrence of R5a is F. In yet other embodiments, y is 0, q is 2 and one occurrence of
R5a is OH and the other occurrence of R5a is F.
[00196] In still other embodiments:
a) R1 and R2 taken together is an optionally substituted ring selected from azetidin-1-
yl C)J). pyrrolidin-1-yl (ff), piperidinl-yl (dd), or piperazin-1-yl (cc); one of R1 or R2 is
hydrogen, and the other of R1 and R2 is selected from Cy1, wherein Cy1 is bonded directly to
the nitrogen atom or is bonded through an optionally substituted C1-4aliphatic group, wherein
one or more methylene units in the Ci-4aliphatic group are optionally replaced with -NR-, -O-, -COO, -OCO-, -NRCO-, -CONR-, -SO2NR-, or -NRSO2-, or an optionally substituted Ci-
4aliphatic group, wherein one or more methylene units in the C1-4aliph.atic group are
optionally replaced with -NR-, -O-, -COO, -OCO-, -NRCO-, -CONR-, -302NR-, or -
MRSO2-; or R1 and R2 are each independently selected from an optionally substituted Q.
4aliphatic group, wherein one or more methylene units in the C^aliphatic group are
optionally replaced with -NR-, -O-, -COO, -OCO-, -NRCO-, -CONR-, -SO2NR-, or -
NRSO2-; or Cy1 wherein Cy1 is bonded to the nitrogen atom directly or is bonded through an
optionally substituted C1-4aliphatic group, wherein one or more methylene units in the Q.
4aliphatic group are optionally replaced with -NR-, -O-, -COO, -OCO-, -NRCO-, -CONR-, -
SO2NR-, or -NRSO2-;
b) z is 0-5 and R4 groups are each independently CI, Br, F, CF3, CH3, -CH2CH3, CN, -
COOH, -N(CH3)2, -N(Et)2, -N(iPr)2, -O(CH2)2OCH3, -CONH2, -COOCH3, -OH, -CH2OH, -
NHCOCH3, -SO2NH2, -SO2(CH2)3CH3, -SO2CH(CH3)2, -SO2N(CH3)2, -SO2CH2CH3, -
C(O)0CH2CH(CH3)2, -C(O)NHCH2CH(CH3)2, -NHCOOCH3, -C(O)C(CH3)3, -
COO(CH2)2CH3, -C(O)NHCH(CH3)2, -C(O)CH2CH3, or an optionally substituted group
selected from -piperidinyl, piperizinyl, morpholino, CMaIkoxy, phenyl, phenyloxy, benzyl,
benzyloxy, -CH2cyclohexyl, pyridyl, -CH2pyridyl, or -CH2thiazolyl;
c) x is 0, 1, or 2, and each occurrence of R3 is independently CI, Br, F, CF3, -OCF3,
Me, Et, CN, -COOH, -NH2, -N(CH3)2, -N(Et)2, -N(iPr)2, -O(CH2)2OCH3, -CONH2, -
COOCH3, -OH, -OCH3, -OCH2CH3, -CH2OH, -NHCOCH3, -NHCOCH(CH3)2, -SO2NH2, -
CONH(cyclopropyl), -CONHCH3, -CONHCH2CH3, or an optionally substituted group
selected from -piperidinyl, piperizinyl, morpholino, phenyl, phenyloxy, benzyl, or benzyloxy;
d) wherein y is 0-2, and R5 groups, when present, are each independently CI, Br, F,
CF3, Me, Et, CN, -COOH, -NH2) • -N(CH3)2, -N(Et)2, -N(iPr)2, -O(CH2)2OCH3, -CONH2) -
COOCH3, -OH, -OCH3, -OCH2CH3, -CH2OH, -NHCOCH3, -SO2NH2, -SO2NHC(CH3)2, -
OCOC(CH3)3, -OCOCH2C(CH3)3, -O(CH2)2N(CH3)2, 4-CH3-piperazin-l-yl, OCOCH(CH3)2>
OCO(cyclopentyl), -COCH3, optionally substituted phenoxy, or optionally substituted
benzyloxy; and
e) R5a is CI, F, CF3, Me, Et, -OH, -OCH3, -OCH2CH3, -CH2OH, -SO2NH2, -
SO2NHC(CH3)2, -OCOC(CH3)3, -OCOCH2C(CH3)3, -O(CH2)2N(CH3)2, 4-CH3-piperazin-l-
yl, 0COCH(CH3)2, OCO(cyclopentyl), or -COCH3.
[00197] In yet other embodiments, for compounds of formula I-A, R1 and R2, taken
together is optionally substituted azetidin-1-yl (jj). In yet other embodiments, for compounds
of formula I-A, R! and R2, taken together is optionally substituted pyrrolidin-1-yl (ff). In still
other embodiments, for compounds of formula I-A, R1 and R2, taken together is optionally
substituted piperidinl-yl (dd). In yet other embodiments, for compounds of formula I-A, R1
and R2, taken together is optionally substituted piperazin-1-yl (cc).
[00198] In certain embodiments, for compounds of formula I-A, R1 and R2, taken together
is optionally substituted azetidin-1-yl (jj), wherein z is 1 or 2 and at least one occurrence of
R4 is -NRSO2R', -NRCOOR', or -NRCOR'. In certain other embodiments, for compounds
of formula I-A, R1 and R2, taken together is optionally substituted azetidin-1-yl (jj), wherein
z is 1 and R4 is -NRSO2R'. In other embodiments, for compounds of formula I-A, R1 and
R2, taken together is optionally substituted azetidin-1-yl (jj), wherein z is 1 and R4 is -
NRCOOR'. In certain other embodiments, for compounds of formula I-A, R1 and R2, taken
together is optionally substituted azetidin-1-yl (jj), wherein z is 1 andR4 is -NRCOR'. In yet
other embodiments, for compounds of formula I-A, R1 and R2, taken together is optionally
substituted pyrrolidin-1-yl (ff), wherein z is 1 or 2 and R4 is CI, Br, F, CF3, CH3, -CH2CH3, -
OR', or -CH2OR', In still other embodiments, for compounds of formula I-A, R1 and R2,
taken together is optionally substituted piperidin-1-yl (dd), wherein z is 1 or 2 and at least
one occurrence of R4 is CI, Br, F, CF3, CH3, -CH2CH3, -OR', or -CH2OR', -NRSO2R', -
NRCOOR', or -OCON(R')2. In certain other embodiments, for compounds of formula I-A,
R1 and R2, taken together, is optionally substituted piperidin-1-yl (dd), wherein z is 1 and R4
is F, CF3, CH3) -CH2CH3, -OR', or -CH2OR'. In other embodiments, for compounds of
formula I-A, R1 and R2, taken together is optionally substituted piperidin-1-yl (dd), wherein z
is 1 and R4 is —NRSO2R',. In certain other embodiments, for compounds of formula I-A, R1
and R2, taken together is optionally substituted piperidin-1-yl (dd), wherein z is 1 and R is -
NRCOOR'. In yet other embodiments, for compounds of formula I-A, R1 and R2, taken
together is optionally substituted piperazin-1-yl (cc), wherein z is 1 or 2 and at least one
occurrence of R4 is -SOR', -CON(R')2, -SO2N(R')2, -COR', or -COOR'. In certain other
embodiments, for compounds of formula I-A, R1 and R2, taken together is optionally
substituted piperazin-1-yl (cc), wherein z is 1 and R4 is -SOR'. In certain other
embodiments, for compounds of formula I-A, R1 and R", taken together is optionally
substituted piperazin-1-yl (cc), wherein z is 1 and R4 is -COOR'. In certain other
embodiments, for compounds of formula I-A, R1 and R2, taken together is optionally
substituted piperazin-1-yl (cc), wherein z is 1 and R4 is -CON(R')2. In certain other
embodiments, for compounds of formula I-A, R1 and R2, taken together is optionally
substituted piperazin-1-yl (cc), wherein z is 1 and R4 is -SO2N(R')2- In certain other
embodiments, for compounds of formula I-A, R1 and R2, taken together is optionally
substituted piperasin-l-yl (cc), v/herein z is 1 and R4 is -COR'.
[00199] In yet other embodiments for compounds described directly above, x is 1 and R3 is
at the 6-position of the quinazoline ring and is -CI, -CH3, -CH2CH3, -F, -CF3, -OCF3, -
CONHCH3, -CONHCH2CH3, -CONH(cyclopropyl), -OCH3, -NH2, -OCH2CH3, or -CN. In
still other embodiments, x is 1 and R3 is at the 7-position of the quinazoline ring and is -CI, -
CH3, -CH2CH3, -F, -CF3, -OCF3, -CONHCH3, -CONHCH2CH3, -CONH(cyclopropyl), -
OCH3, -NH2, -OCH2CH3, or -CN. In yet other embodiments, x is 1 and R3 is at the 6-
position of the quinazoline ring and is -CI, -CH3, -CH2CH3, -F, -CF3, -OCF3, -OCH3, or -
OCH2CH3. In still other embodiments, x is 1 and R3 is at the 7-position of the quinazoline
ring and is -CI, -CH3, -CH2CH3, -F, -CF3, -OCF3, -OCH3, or -OCH2CH3. In yet other
embodiments, x is 1 and R3 is at the 6-position of the quinazoline ring and is -CON(R')2, or
NRCOR'. In yet other embodiments, x is 1 and R3 is at the 7-position of the quinazoline ring
and is -CON(R')2, or NRCOR'. In yet other embodiments, R5a is CI, F, CF3, Me, Et, -OH, -
OCH3, -OCH2CH3. In still other embodiments, y is 0, and q is 1 and R5a is F. In yet other
embodiments, y is 0, q is 1, and R5a is OR'. In still other embodiments, y is 0, q is 1 and R5a
is OH. In yet other embodiments, y is 0, q is 2 and one occurrence of R5a is OR' and the
other occurrence of R5a is F. In yet other embodiments, y is 0, q is 2 and one occurrence of
R5a is OH and the other occurrence of R5a is F.

or R1 and R2 are each independently an optionally substituted C1-4aliphatic group and are
each independently selected from optionally substituted methyl, ethyl, cyclopropyl, n-propyl,
propenyl, cyclobutyl, (CO)OCH2CH3, (CH2)2OCH3, CH2CO)OCH2CH3, CH2(CO)OCH3,
CH(CH3)CH2CH3, or n-butyl;
b) z is 0-5 and R4 groups are each independently CI, Br, F, CF3, CH3, -CH2CH3) CN, -
COOH, -N(CH3)2, -N(Et)2, -N(iPr)2, -O(CH2)2OCH3, -CONH2, -COOCH3, -OH, -CH2OH, -
NHCOCH3, -SO2NH2, -SO2(CH2)3CH3, -SO2CH(CH3)2) -SO2N(CH3)2, -SO2CH2CH3, -
C(O)OCH2CH(CH3)2, -C(O)NHCH2CH(CH3)2, -NHCOOCH3, -C(O)C(CH3)3,
COO(CH2)2CH3, -C(O)NHCH(CH3)2, -C(O)CH2CH3, or an optionally substituted group
selected from -piperidinyl, piperizinyl, morphohno, C1-4alkoxy, phenyl, phenyloxy, benzyl,
benzyloxy, -CH2cyclohexyl, pyridyl, -CH2pyridyL or -CH2thiaii;olyl;
c) x is 0, 1, or 2, and each occurrence of R3 is independently CI, Br, F, CF3, -OCF3,
Me, Et, CN, -COOH, -NH2, -N(CH3)2, -N(Et)2, -N(iPr)2, -O(CH2)2OCH3, -CONH2, -
COOCH3, -OH, -OCH3, -OCH2CH3, -CH2OH, -NHCOCH3, -NHCOCH(CH3)2, -SO2NH2, -
CONH(cyclopropyl), -CONHCH3, -CONHCH2CH3, or an optionally substituted group
selected from -piperidinyl, piperizinyl, morpholino, phenyl, phenyloxy, benzyl, or benzyloxy;
d) wherein y is 0-5, and R5 groups, when present, are each independently CI, Br, F,
CF3, Me, Et, CN, -COOH, -NH2, -N(CH3)2, -N(Et)2, -N(iPr)2, -O(CH2)2OCH3, -CONH2, -
COOCH3, -OH, -OCH3, -OCH2CH3, -CH2OH, -NHCOCH3, -SO2NH2, -SO2NHC(CH3)2, - -
OCOC(CH3)3, -OCOCH2C(CH3)3, -O(CH2)2N(CH3)2, 4-CH3-piperazin-l-yl, 0COCH(CH3)2,
OCO(cyclopentyl), -COCH3, optionally substituted phenoxy, or optionally substituted
benzyloxy; and
e) R5a is CI, F, CF3, Me, Et, -OH, -OCH3, -OCH2CH3, -CH2OH, -SO2NH2, -
SO2NHC(CH3)2, -OCOC(CH3)3, -OCOCH2C(CH3)3) -O(CH2)2N(CH3)2, 4-CH3-piperazin-l-
yl, OCOCH(CH3)2,OCO(cyclopentyl), or -COCH3.
[00201] In yet other embodiments for compounds described directly above, x is 1 and R3 is
at the 6-position of the quinazoline ring and is -CI, -CH3, -CH2CH3, -F, -CF3, -OCF3, -
CONHCH3, -CONHCH2CH3, -CONH(cyclopropyl), -OCH3, -NH2, -OCH2CH3> or -CN. In
still other embodiments, x is 1 and R3 is at the 7-position of the quinazoline ring and is -CI, -
CH3, -CH2CH3, -F, -CF3, -OCF3, -CONHCH3, -CONHCH2CH3, -CONH(cyclopropyl), -
OCH3, -NH2, -OCH2CH3, or -CN. In yet other embodiments, x is 1 and R3 is at the 6-
position of the quinazoline ring and is -CI, -CH3, -CH2CH3, -F, -CF3, -OCF3, -OCH3, or -
OCH2CH3. In still other embodiments, x is 1 and R3 is at the 7-position of the quinazoline
ring and is -CI, -CH3, -CH2CH3, -F, -CF3, -OCF3, -OCH3, or -OCH2CH3. In yet other
embodiments, x is 1 and R3 is at the 6-position of the quinazoline ring and is -CON(R')2, or
NRCOR'. In yet other embodiments, x is 1 and R3 is at the 7-position of the quinazoline ring
and is -CON(R')2, or NRCOR'. In yet other embodiments, R5a is CI, F, CF3, Me, Et, -OH, -
OCH3, -OCH2CH3. In still other embodiments, y is 0, and q is 1 and R5a is F. In yet other
embodiments, y is 0, q is 1, and R5a is OR'. In still other embodiments, y is 0, q is 1 and R5a
is OH. In yet other embodiments, y is 0, q is 2 and one occurrence of R3a is OR' and the
other occurrence of R3a is F. In yet other embodiments, y is 0, q is 2 and one occurrence of
R5a is OH and the other occurrence of R311 is F.
[00202] For compounds described in this section above, in general, compounds are useful
as inhibitors of ion channels, preferably voltage gated sodium channels and N-type calcium
channels. In certain exemplary embodiments, compounds of the invention are useful as
inhibitors of NaV1.8. In other embodiments, compounds of the invention are useful as
inhibitors of NaVl.8 and CaV2.2. In still other embodiments, compounds of the invention
are useful as inhibitors of CaV2.2. In yet other embodiments, compounds of the invention
are useful as dual inhibitors of NaV1.8 and a TTX-sensitive ion channel such as NaVI.3 or
NaV1.7.
[00203] V. Compounds of formula I-B-i:

or a pharmaceutically acceptable salt thereof,
wherein R1 is selected from Ci-6aliphatic, Cy1, wherein Cy1 is a 5-7-membered
monocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur, or is a 3-12-membered saturated or
partially unsaturated monocyclic ring having 0-3 heteroatoms independently selected from
nitrogen, oxygen, or sulfur, wherein Cy1 is bonded directly to the nitrogen atom or is bonded
through an optionally substituted C1-4alipb.atic group, wherein one or more methylene units in
the C1-4aliphatic group are optionally replaced with -NR-, -O-, -COO, -OCO-, -NRCO-, -
CONR-, -SO2NR-, or -NRSO2-; wherein R1 is optionally substituted at one or more
substitutable carbon, nitrogen, or sulfur atoms with z independent occurrences of -R4,
wherein z is 0-5;
x is 0-4;
y is 0-4;
each occurrence of R3, R4, and R5 is independently Q-Rx; wherein Q is a bond or is a
C1-CO alkylidene chain wherein up to tv/o non-adjacent methylene units of Q are optionally
and independently replaced by -NR-, -S-, -O-, -CS-, -CG2-, -OCO-, -CO-, -COCO-, -CONR-,
-NRCO-, -NRCO2-, -SO2NR-, -NRSO2-, -CONRNR-, -NRCONR-, -OCONR-, -NRNR-, -
NRSO2NR-, -SO-, -SO2-, -PO-, -PO2-, -OP(O)(OR)-, or -POR-; and each occurrence of Rx is
independently selected from -R', =O, =NR', halogen, -NO2, -CN, -OR', -SR', -N(R')2, -
NR'COR', -NR'CON(R')2, -NR'CO2R', -COR', -CO2R', -OCOR', -CON(R')2, -
OCON(R')2> -SOR', -SO2R', -SO2N(R')2, -NR'SO2R', -NR'SO2N(R')2, -COCOR', -
COCH2COR', -OP(O)(OR')2, -P(O)(OR')2, -OP(O)2OR', -P(O)2OR', -PO(R')2, or -
OPO(R')2;
each occurrence of RSa is independently an optionally substituted C1-C6aliphatic
group, halogen, -OR', -SR', -N(R')2, -NR'COR', -NR'CON(R')2, -NR'CO2R', -COR', -
CO2R', -OCOR', -CON(R')2, -OCON(R')2, -SOR', -SO2R', -SO2N(R')2, -NR'SO2R', -
NR'SO2N(R')2, -COCOR', -COCH2COR', -OP(O)(OR')2> -P(O)(OR')2, -OP(O)2OR', -
P(O)2OR', -PO(R')2, or-OPO(R')2; and
each occurrence of R is independently hydrogen or an optionally substituted C1-6
aliphatic group; and each occurrence of R is independently hydrogen or an optionally
substituted C1-6 aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully
unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen,
oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated
bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen,
or sulfur; or R and R, two occurrences of R, or two occurrences of R, are taken together with
the atom(s) to which they are bound to form an optionally substituted 3-12 membered
saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4
heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[00204] For compounds described directly above, in certain embodiments,
a) when R5a is Me, CI, or OMe, and x is 0, then R1 is not Et or Me;
b) when R5a is CI, x is 3, and the three occurrences of R3 are 6-Me, 7-COOEt, and 8-
Me, then R1 is not -(CEfe^piperidin-l-yl;
c) when R5a is Me, x is 1 and R3 is NO2 or NH2, then R1 is not Et;
d) when R5a is OH, NHMe, or N(NO)Me, and x is 0, then R1 is not Et, Me or -
CH2CH=CH2",
e) when R5a is NH2, and x is 0, then R1 is not -COCH3;
f) when R5a is CI or Me, and y is 0 or 1 and when y is 1, R5 is 4-C1, and x is 0, then R1
is not 4-CN-phenyl, 4-Me-phenyl, 4-OMe-phenyl, 4-Cl-phenyl, 4-NO2-phenyl, -
CH2CH2NHMe, Et, Me, 4-COOMe-phenyl, -CH2Ph, iPr, 2-Me-phenyI, 4-phenyl-phenyl, or-
CH2CH=CH2.
[00205] For compounds described directly above, in certain other embodiments,
a) R1 is selected from:
i) Cy1 wherein Cy is bonded directly to the nitrogen atom or is bonded
through an optionally substituted C1-4aliphatic group, wherein one or more methylene
units in the C1-4aliphatic group are optionally replaced with -NR-, -O-, -COO, -OCO-,
-NRCO-, -CONR-, -SO2NR-, or -NRSO2-; or
ii) an optionally substituted C1-4aliphatic group, wherein one or more
methylene units in the C1-4aliphatic group are optionally replaced with -NR-, -O-, -
COO, -OCO-, -NRCO-, -CONR-, -SO2NR-, or -NRSO2-.
[00206] For compounds described directly above, in certain embodiments Cy1 is,
y z aa bb
[00208] In still other embodiments, R1 is an optionally substituted CMaliphatic group and
are each independently selected from optionally substituted methyl, ethyl, cyclopropyl, n-
propyl, propenyl, cyclobutyl, (CO)OCH2CH3) (CH2)2OCH3, CH2CO)OCH2CH3>
CH2(CO)OCH3, CH(CH3)CH2CH3, or n-butyl.
[00209] In yet other embodiments, z is 0-5, and R4 groups, when present, are each
independently halogen, CN, NO2, -N(R')2> -CH2N(R')2, -OR', -CH2OR', -SR', -CH2SR', -
COOR', -NRCOR', -CON(R')2, -OCON(R')2, COR', -NHCOOR', -SO2R', -SO2N(R')2, or
an optionally substituted group selected from Q.Cgaliphatic, aryl, heteroaryl, cycloaliphatic,
heterocycloaliphatic, arylC1-C6alkyl, heteroarylCi-Cgalkyl, cycloaliphaticCi-Cfialkyl, or
heterocycloaliphaticC1-C6alkyl.
[00210] In still other embodiments, z is 0-5 and R4 groups are each independently CI, Br,
F, CF3, CH3, -CH2CH3, CN, -COOH, -N(CH3)2, -N(Et)2, -N(iPr)2, -O(CH2)2OCH3, -CONH2,
-COOCH3, -OH, -CH2OH, -NHCOCH3l -SO2NH2, -SO2(CH2)3CH3, -SO2CH(CH3)2) -
SO2N(CH3)2, -SO2CH2CH3) -C(O)OCH2CH(CH3)2, -C(O)NHCH2CH(CH3)2) -NHCOOCH3, -
C(O)C(CH3)3l -COO(CH2)2CH3; -C(O)NHCH(CH3)2, -C(O)CH2CH3, or an optionally
substituted group selected from -piperidinyl, piperizinyl, morpholino, C^alkoxy, phenyl,
phenyloxy, benzyl, benzyloxy, -CH2cyclohexyl, pyridyl, -CH2pyridyl, or -CH2thiazolyl.
[00211] In yet other embodiments, R3 is halogen, CN, NO2, -N(R')2, -CH2N(R')2, -OR', -
CH2OR', -SR', -CH2SR', -COOR', -NRCOR', -CON(R')2, -OCON(R')2, COR', -
NHCOOR', -SO2R', -SO2N(R')2, or an optionally substituted group selected from Ci-
Ccaliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylCi-Csalkyl,
heteroarylCi-Cgalkyl, cycloaliphaticC1-C6alkyl, or heterocycloaliphaticC1-C6alkyl.
[00212] In still other embodiments, R3 is CI, Br, F, CF3, -OCF3, Me, Et, CN, -COOH, -
NH2, -N(CH3)2, -N(Et)2:, -N(iPr)2, -O(CH2)2OCH3, -CONH2, -COOCH3, -OH, -OCH3, -
OCH2CH3, -CH2OH, -NHCOCH3, -NHCOCH(CH3)2, -SO2NH2, -CONH(cyclopropyl), -
CONHCH3, -CONHCH2CH3, or an optionally substituted group selected from -piperidinyl,
piperizinyl, morpholino, phenyl, phenyloxy, benzyl, or benzyloxy.
[00213] In yet other embodiments, R3 is halogen, CN, optionally substituted CrC6alkyl,
OR', N(R')2, CON(R')2, or NRCOR'. In still other embodiments, R3 is -CI, -CH3> -CH2CH3,
-F, -CF3, -OCF3, -CONHCH3, -CONHCH2CH3, -CONH(cyclopropyl), -OCH3, -NH2, -
OCH2CH3, or -CN. In yet other embodiments, R3 is at the 6-position of the quinazoline ring
and is -CI, -CH3, -CH2CH3, -F, -CF3, -OCF3, -CONHCH3, -CONHCH2CH3, -
CONH(cyclopropyl), -OCH3, -NH2, -OCH2CH3, or -CN. In still other embodiments, R3 is at
the 7-position of the quinazoline ring and is -CI, -CH3, -CH2CH3, -F, -CF3, -OCF3, -
CONHCH3, -CONHCH2CH3, -CONH(cyclopropyl), -OCH3, -NH2, -OCH2CH3, or -CN. In
yet other embodiments, R3 is at the 6-position of the quinazoline ring and is -CI, -CH3, -
CH2CH3, -F, -CF3, -OCF3, -OCH3, or -OCH2CH3. In still other embodiments, R3 is at the 7-
position of the quinazoline ring and is -CI, -CH3, -CH2CH3, -F, -CF3, -OCF3, -OCH3, or -
OCH2CH3. In other embodiments, R3 is at the 6-position of the quinazoline ring and is -
CON(R')2, or NRCOR'. In yet other embodiments, R3 is at the 7-position of the quinazoline
ring and is -CON(R')2, or NRCOR'.
[00214] In yet other embodiments, for compounds described directly above, y is 0-5, q is
0-2, and R5 and R5a groups, when present, are each independently halogen, CN, NO2, -
N(R')2, -CH2N(R')2, -OR', -CH2OR', -SR', -CH2SR', - -NRCOR', -CON(R')2, -S(O)2N(R')2,
-OCOR', -COR', -CO2R', -OCON(R')2, -NR'SO2R', -OP(O)(OR')2, -P(O)(OR')2, -
OP(O)2OR', -P(O)2OR', -PO(R')2, -OPO(R')2, or an optionally substituted group selected
from Ci.Cealiphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylCj-Cealkyl,
heteroarylC1-C6alkyl, cycloaliphaticC1-C6alkyl, or heterocycloaliphaticC1-C6alkyl.
[00215] In still other embodiments, y is 0-5, and q is 1 or 2, and each occurrence of R5a is
independently CI, Br, F, CF3, Me, Et, CN, -COOH, -NH2, -N(CH3)2, -N(Et)2, -N(iPr)2, -
0(CH2)2OCH3, -CONH2, -COOCH3, -OH, -OCH3, -OCH2CH3, -CH2OH, -NHCOCH3, -
SO2NH2, -SO2NHC(CH3)2, -OCOC(CH3)3, -OCOCH2C(CH3)3> -O(CH2)2N(CH3)2, 4-CH3-
piperazin-1-yl, OCOCH(CH3)2, OCO(cyclopentyl), -COCH3, optionally substituted phenoxy,
or optionally substituted benzyloxy.
[00216] In still other embodiments, y is 0, and R3a is F. In yet other embodimentsy is 0, q
is 1, and R5a is OR'. In still other embodiments, y is 0, q is 1 and R5a is OH. In yet other
embodiments, y is 1, R3a is OR' and R5 is F, wherein OR' is substituted at the 2-position of
the phenyl ring and F is substituted at the 6-position of the phenyl ring. In yet other
embodiments, y is 1, R5a is OH and R5 is F, wherein OH is substituted at the 2-position of the
phenyl ring and F is substituted at the 6-position of the phenyl ring.
[00217] For compounds described in this section above, in general, compounds are useful
as inhibitors of ion channels, preferably voltage gated sodium channels and N-type calcium
channels. In certain exemplary embodiments, compounds of the invention are useful as
inhibitors of NaV1.8. In other embodiments, compounds of the invention are useful as
inhibitors of NaV1.8 and CaV2.2. In still other embodiments, compounds of the invention
are useful as inhibitors of CaV2.2. In yet other embodiments, compounds of the invention
are useful as dual inhibitors of NaV1.8 and a TTX-sensitive ion channel such as NaV1.3 or
NaV1.7.
[00218] Representative examples of compounds as described above and herein are set
forth below in Table 2.
[00219] Table 2. Examples of Compounds of Formula I:
[00220] 4. General Synthetic Methodology:
[00221] The compounds of this invention may be prepared in general by methods known to
those skilled in the art for analogous compounds, as illustrated by the general scheme below, and
the preparative examples that follow.
[00222] Scheme A below depicts general conditions for the synthesis of compounds of
formula IA where X is NR. In general, the useful intermediate iii can be obtained by
condensing a benzoylchloride with an anthranilamide.
[00223] Scheme A:

[00224] Reaction of i and ii (step a) using K2CO3 and ether under reflux conditions, and
subsequent treatment with 5% aq. NaOH under reflux conditions yields intermediate iii.
Reaction of intermediate iii with POCl3 to generate the 4-chloro compound, and subsequent
reaction with i) N,N-dimethylaniline in benzene under reflux conditions; ii) BBr3, CH2Cl2, -78
°C; and iii) R1R2NH, in THF/CH2C12 at room temperature yields the desired product IA.
[00225] Scheme B: Scheme B depicts an alternative synthesis for compounds of formula IA:
[00226] Reaction of i and ii (step a) using triethylamine and 1,4-Dioxane under ambient
conditions yields intermediate iii. Reaction of intermediate iii (step b) with 0.5M solution of
ammonia in 1,4-Dioxane, triethylamine and BOP reagent was stirred at ambient temperature for
16h to yield intermediate iv. Treatment of iv with 5% aq. NaOH under reflux conditions yields
intermediate v. Treatment of v with POCI3 to generate the 4-chloro compound, and subsequent
reaction with i) N,N-dimethylaniline in benzene under reflux conditions; ii) BBr3, CH2Cl2, -78
°C; and iii) R1R2NH, in THF/CH2C12 at room temperature yields the desired product IA.
[00227] Scheme C:

[00228] Reaction of i and ii (step a) using pyridine yields intermediate iii. Treatment of iii
with 5% aq. NaOH under reflux conditions yields intermediate iv. Reaction of intermediate iv
with POCl3 to generate the 4-chloro compound, and subsequent reaction with i) N,N-
dimethylaniline in benzene under reflux conditions; ii) BBr3, CH2Cl2, -78 °C; and iii) R1R2NH,
in THF/CH2Cl2 at room temperature yields the desired product IA.
[00229] Schemes D and E below depict the synthesis of a variety of useful anthranilimides:

[00231] Reaction of i (step a) with chloral hydrate in the presence of hydroxylamine
hydrochloride yields isatin ii. Treatment of ii with basic hydrogen peroxide gives iii (step b),
useful as shown in Scheme D.

[00233] Reaction of i (step a) with Boc anhydride yields ii. Subsequent metalation of ii with
butyl lithium at low temperature and reaction with CO2 yields the N-protected anthranilic acid
(step b). Boc removal with TFA yields the anthranilic acid iii, useful as shown in Scheme E.

[00235] Reaction of isatoic anhydrides i (step a) with aqueous ammonium hydroxide yields ii,
useful as shown in Scheme F.

[00237] (step a) i) Traeatment of i in water with AcOH and KOCN 0°C to room temperature
for 24h, and subsequent reaction with ii) NaOH followed by acidification with HC1 yields
intermediate ii. (step b) Treatment of ii with POQ3 and triethylamine under reflux conditions
yields intermediate iii. (step c) Treatment of iii with R1R2NH, in THF/CH2C12 0°C to room
temperature yields intermediate iv.
[00238] Scheme H:

[00239] Reaction of intermediate i (step a) with POCl3 generates the 2,4-dichloro compound
ii. Reaction of intermediate ii (step b) with R1-NH-R2, and Et3N, in CH2C12 yields amine iii.
Reaction of intermediate iii (step c) with an NH containing heterocycle, NaH, and THF generates
iv. Reaction of intermediate iii (step d) with LiHMDS, Pd2(dba)3, 2-
(dicyclohexyl)phosphinobiphenyl, and THF yields diamine v. Reaction of intermediate v (step
e) with a substituted 2,5-dimethoxytetrahydrofuran, in AcOH generates vi. Reaction of
intermediate v (step f) with ClCO-CH2-(CH2)n-CH2-Cl, Et3N, and p-dioxane generates vii.
Reaction of intermediate iii (step g) with a cyclic anhydride, and p-dioxane generates viii.
[00241] Reaction of intermediate i (step a) with POCl3 and subsequent treatment with BBr3,
CH2Cl2, at -78 °C generates the 4-chloro compound ii. Reaction of intermediate ii (step b) with
R'-NH-R2-X(R"')H, and Et3N, in CH2C12 yields iii. Reaction of intermediate iii (step c) with
R'N(R")X-SO2C1, and Et3N, in CH2Cl2 generates iv. Reaction of intermediate iii (step d) with
R'-SO2Cl, and Et3N, in CH2Cl2 generates v. Reaction of intermediate iii (step e) with R'-CO2Cl,
and Et3N, in CH2Cl2 or with phosgene, and R'(R")XH generates vi. Reaction of intermediate iii
(step f) with R'COCl, Et3N, in CH2Cl2 generates vi. Reaction of intermediate iii (step g) with
electrophiles in the presence of Et3N (organic halide electrophiles) or NaBH(OAc)3 (aldehyde
and ketone electrophiles) yields viii.
[00258] Reaction of i with iia or iib (step a), treatment with triethylamine in THF/CH2Cl2 at
room temperature yields compounds iii and v respectively. Treatment of iii (step b) with i) NaH
in THF 0°C, then reaction with electrophiles at 0°C to room temperature yields compound iv.
[00259] Although certain exemplary embodiments are depicted and described above and
herein, it will be appreciated that a compounds of the invention can be prepared according to the
methods described generally above using appropriate starting materials, and according to
methods known in the art. For example, in certain embodiments, compounds as described herein
wherein R1 is hydrogen, and R2 is pyrazolyl, exemplary procedures and compounds can be found
in WO02/22607, WO 02/22604, WO 02/066461, WO 02/22601, WO 02/22603, WO 02/22608,
WO 02/022605, or WO 02/22602.
[00260] 5. Uses, Formulation and Administration
[00261] Pharmaceuticaly acceptable compositions
[00262] As discussed above, the present invention provides compounds that are inhibitors of
voltage-gated sodium ion channels and/or calcium channels, and thus the present compounds are
useful for the treatment of diseases, disorders, and conditions including, but not limited to acute,
chronic, neuropathic, or inflammatory pain, arthritis, migrane, cluster headaches, trigeminal
neuralgia, herpetic neuralgia, general neuralgias, epilepsy or epilepsy conditions,
neurodegenerative disorders, psychiatric disorders such as anxiety and depression, myotonia,
arrythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable
bowel syndrome, and incontinence. Accordingly, in another aspect of the present invention,
pharmaceutically acceptable compositions are provided, wherein these compositions comprise
any of the compounds as described herein, and optionally comprise a pharmaceutically
acceptable carrier, adjuvant or vehicle. In certain embodiments, these compositions optionally
further comprise one or more additional therapeutic agents.
[00263] It will also be appreciated that certain of the compounds of present invention can exist
in free form for treatment, or where appropriate, as a pharmaceutically acceptable derivative
thereof. According to the present invention, a pharmaceutically acceptable derivative includes,
but is not limited to, pharmaceutically acceptable salts, esters, salts of such esters, or any other
adduct or derivative which upon administration to a patient in need is capable of providing,
directly or indirectly, a compound as otherwise described herein, or a metabolite or residue
thereof.
[00264] As used herein, the term "pharmaceutically acceptable salt" refers to those salts which
are, within the scope of sound medical judgement, suitable for use in contact with the tissues of
humans and lower animals without undue toxicity, irritation, allergic response and the like, and
are commensurate with a reasonable benefit/risk ratio. A "pharmaceutically acceptable salt"
means any non-toxic salt or salt of an ester of a compound of this invention that, upon
administration to a recipient, is capable of providing, either directly or indirectly, a compound of
this invention or an inhibitorily active metabolite or residue thereof. As used herein, the term
"inhibitorily active metabolite or residue thereof" means that a metabolite or residue thereof is
also an inhibitor of a voltage-gated sodium ion channel or calcium channel.
[00265] Pharmaceutically acceptable salts are well known in the art. For example, S. M.
Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences,
\911, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the
compounds of this invention, include those derived from suitable inorganic and organic acids and
bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an
amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid,
phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid,
oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other
methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include
adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,
camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate,
ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate,
heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate,
lauryl sulfate, malate, maleate, rnalonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate,
nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate,
picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate,
undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali
metal, alkaline earth metal, ammonium and N+(C1-4alkyl)4 salts. This invention also envisions
the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein.
Water or oil-soluble or dispersable products may be obtained by such quaternization.
Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium,
magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate,
nontoxic ammonium, quaternary ammonium, and amine cations formed using counterfoils such
as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl
sulfonate.
[00266] As described above, the pharmaceutically acceptable compositions of the present
invention additionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle,
which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion
or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents,
preservatives, solid binders, lubricants and the like, as suited to the particular dosage form
desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack
Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating
pharmaceutically acceptable compositions and known techniques for the preparation thereof.
Except insofar as any conventional carrier medium is incompatible with the compounds of the
invention, such as by producing any undesirable biological effect or otherwise interacting in a
deleterious manner with any other component(s) of the pharmaceutically acceptable
composition, its use is contemplated to be within the scope of this invention. Some examples of
materials which can serve as pharmaceutically acceptable carriers include, but are not limited to,
ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum
albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial
glyceride mixtures of saturated vegetable fatty, acids, water, salts or electrolytes, such as
protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium
chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates,
waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose
and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as
sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth;
malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil,
cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a
propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar;
buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-
free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as
well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium
stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and
perfuming agents, preservatives and antioxidants can also be present in the composition,
according to the judgment of the formulator.
[00267] Uses of Compounds and Pharmaceutically Acceptable Compositions
[00268] In yet another aspect, a method for the treatment or lessening the severity of acute,
chronic, neuropathic, or inflammatory pain, arthritis, migrane, cluster headaches, trigeminal
neuralgia, herpetic neuralgia, general neuralgias, epilepsy or epilepsy conditions,
neurodegenerative disorders, psychiatric disorders such as anxiety and depression, myotonia,
arrythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable
bowel syndrome, incontinence, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic
neuropathy, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain,
nociceptive pain, breakthrough pain, postsurgical pain, or cancer pain is provided comprising
administering an effective amount of a compound, or a pharmaceutically acceptable composition
comprising a compound to a subject in need thereof. In certain embodiments, a method for the
treatment or lessening the severity of acute, chronic, neuropathic, or inflammatory pain is
provided comprising administering an effective amount of a compound or a pharmaceutically
acceptable composition to a subject in need thereof. In certain other embodiments, a method for
the treatment or lessening the severity of radicular pain, sciatica, back pain, head pain, or neck
pain is provided comprising administering an effective amount of a compound or a
pharmaceutically acceptable composition to a subject in need thereof. In still other
embodiments, a method for the treatment or lessening the severity of severe or intractable pain,
acute pain, postsurgical pain, back pain, or cancer pain is provided comprising administering an
effective amount of a compound or a pharmaceutically acceptable composition to a subject in
need thereof.
[00269] In certain embodiments of the present invention an "effective amount" of the
compound or pharmaceutically acceptable composition is that amount effective for treating or
lessening the severity of one or more of acute, chronic, neuropathic, or inflammatory pain,
arthritis, migrane, cluster headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias,
epilepsy or epilepsy conditions, neurodegenerative disorders, psychiatric disorders such as
anxiety and depression, myotonia, arrythmia, movement disorders, neuroendocrine disorders,
ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritis
pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, head or neck
pain, severe or intractable pain, nociceptive pain, breakthrough pain, postsurgical pain, or cancer
pain.
[00270] The compounds and compositions, according to the method of the present invention,
may be administered using any amount and any route of administration effective for treating or
lessening the severity of one or more of acute, chronic, neuropathic, or inflammatory pain,
arthritis, migrane, cluster headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias,
epilepsy or epilepsy conditions, neurodegenerative disorders, psychiatric disorders such as
anxiety and depression, myotonia, arrythmia, movement disorders, neuroendocrine disorders,
ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritis
pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, head or neck
pain, severe or intractable pain, nociceptive pain, breakthrough pain, postsurgical pain, or cancer
pain. The exact amount required will vary from subject to subject, depending on the species,
age, and general condition of the subject, the severity of the infection, the particular agent, its
mode of administration, and the like. The compounds of the invention are preferably formulated
in dosage unit form for ease of administration and uniformity of dosage. The expression "dosage
unit form" as used herein refers to a physically discrete unit of agent appropriate for the patient
to be treated. It will be understood, however, that the total daily usage of the compounds and
compositions of the present invention will be decided by the attending physician within the scope
of sound medical judgment. The specific effective dose level for any particular patient or
organism will depend upon a variety of factors including the disorder being treated and the
severity of the disorder; the activity of the specific compound employed; the specific
composition employed; the age, body weight, general health, sex and diet of the patient; the time
of administration, route of administration, and rate of excretion of the specific compound
employed; the duration of the treatment; drugs used in combination or coincidental with the
specific compound employed, and like factors well known in the medical arts. The term
"patient", as used herein, means an animal, preferably a mammal, and most preferably a human.
[00271] The pharmaceutically acceptable compositions of this invention can be administered
to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally,
intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal
spray, or the like, depending on the severity of the infection being treated. In certain
embodiments, the compounds of the invention may be administered orally or parenterally at
dosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to
about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired
therapeutic effect.
[00272] Liquid dosage forms for oral administration include, but are not limited to,
pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and
elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents
commonly used in the art such as, for example, water or other solvents, solubilizing agents and
emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl
alcohol, benzyl benzoate, propylene glycol, 1,3-butyIene glycol, dimethylformamide, oils (in
particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol,
tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures
thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting
agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
[00273] Injectable preparations, for example, sterile injectable aqueous or oleaginous
suspensions may be formulated according to the known art using suitable dispersing or wetting
agents and suspending agents. The sterile injectable preparation may also be a sterile injectable
solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for
example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may
be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In
addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For
this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In
addition, fatty acids such as oleic acid are used in the preparation of injectables.
[00274] The injectable formulations can be sterilized, for example, by filtration through a
bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid
compositions which can be dissolved or dispersed in sterile water or other sterile injectable
medium prior to use.
[00275] In order to prolong the effect of a compound of the present invention, it is often
desirable to slow the absorption of the compound from subcutaneous or intramuscular injection.
This may be accomplished by the use of a liquid suspension of crystalline or amorphous material
with poor water solubility. The rate of absorption of the compound then depends upon its rate of
dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively,
delayed absorption of a parenterally administered compound form is accomplished by dissolving
or suspending the compound in an oil vehicle. Injectable depot forms are made by forming
microencapsule matrices of the compound in biodegradable polymers such as polylactide-
polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular
polymer employed, the rate of compound release can be controlled. Examples of other
biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable
formulations are also prepared by entrapping the compound in liposomes or microemulsions that
are compatible with body tissues.
[00276] Compositions for rectal or vaginal administration are preferably suppositories which
can be prepared by mixing the compounds of this invention with suitable non-irritating
excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are
solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or
vaginal cavity and release the active compound.
[00277] Solid dosage forms for oral administration include capsules, tablets, pills, powders,
and granules. In such solid dosage forms, the active compound is mixed with at least one inert,
pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate
and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic
acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin,
polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating
agents such as agar--agar, calcium carbonate, potato or tapioca starch, alginic acid, certain
silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption
accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example,
cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i)
lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium
lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form
may also comprise buffering agents.
[00278] Solid compositions of a similar type may also be employed as fillers in soft and hard-
filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular
weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules,
pills, and granules can be prepared with coatings and shells such as enteric coatings and other
coatings well known in the pharmaceutical formulating art. They may optionally contain
opacifying agents and can also be of a composition that they release the active ingredient(s) only,
or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
Examples of embedding compositions that can be used include polymeric substances and waxes.
Solid compositions of a similar type may also be employed as fillers in soft and hard-filled
gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight
polethylene glycols and the like.
[00279] The active compounds can also be in microencapsulated form with one or more
excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and
granules can be prepared with coatings and shells such as enteric coatings, release controlling
coatings and other coatings well known in the pharmaceutical formulating art. In such solid
dosage forms the active compound may be admixed with at least one inert diluent such as
sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice,
additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids
such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and
pills, the dosage forms may also comprise buffering agents. They may optionally contain
opacifying agents and can also be of a composition that they release the active ingredient(s) only,
or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
Examples of embedding compositions that can be used include polymeric substances and waxes.
[00280] Dosage forms for topical or transdermal administration of a compound of this
invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants
or patches. The active component is admixed under sterile conditions with a pharmaceutically
acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic
formulation, eardrops, and eye drops are also contemplated as being within the scope of this
invention. Additionally, the present invention contemplates the use of transdermal patches,
which have the added advantage of providing controlled delivery of a compound to the body.
Such dosage forms are prepared by dissolving or dispensing the compound in the proper
medium. Absorption enhancers can also be used to increase the flux of the compound across the
skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing
the compound in a polymer matrix or gel.
[002S1] As described generally above, the compounds of the invention are useful as inhibitors
of voltage-gated sodium ion channels or calcium channels, preferably N-type calcium channels.
In one embodiment, the compounds and compositions of the invention are inhibitors of one or
more of NaVl.l, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, NaV1.9, or
CaV2.2, and thus, without wishing to be bound by any particular theory, the compounds and
compositions are particularly useful for treating or lessening the severity of a disease, condition,
or disorder where activation or hyperactivity of one or more of NaVl.l, NaV1.2, NaV1.3,
NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, NaV1.9, or CaV2.2 is implicated in the disease,
condition, or disorder. When activation or hyperactivity of NaVl.l, NaV1.2, NaV1.3, NaV1.4,
NaV1.5, NaV1.6, NaV1.7, NaV1.8, NaV1.9, or CaV2.2, is implicated in a particular disease,
condition, or disorder, the disease, condition, or disorder may also be referred to as a "NaVl.l,
NaV1.2, NaV1.3, NaV1.4, NaVl.5, NaV1.6, NaV1.7, NaV1.8 or NaV1.9-mediated disease,
condition or disorder" or a "CaV2.2-mediated condition or disorder". Accordingly, in another
aspect, the present invention provides a method for treating or lessening the severity of a disease,
condition, or disorder where activation or hyperactivity of one or more of NaVl.l, NaV1.2,
NaVl.3, NaV1.4, NaVl.5, NaV1.6, NaV1.7, NaV1.8, NaV1.9, or CaV2.2 is implicated in the
disease state.
[00282] The activity of a compound utilized in this invention as an inhibitor of NaVl.l,
NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaVl.8, NaV1.9, or CaV2.2 may be
assayed according to methods described generally in the Examples herein, or according to
methods available to one of ordinary skill in the art.
[00283] In certain exemplary embodiments, compounds of the invention are useful as
inhibitors of NaV1.8. In other embodiments, compounds of the invention are useful as inhibitors
of NaV1.8 and CaV2.2. In still other embodiments, compounds of the invention are useful as
inhibitors of CaV2.2. In yet other embodiments, compounds of the invention are useful as dual
inhibitors of NaV1.8 and a TTX-sensitive ion channel such as NaV1.3 or NaV1.7.
[00284] It will also be appreciated that the compounds and pharmaceutically acceptable
compositions of the present invention can be employed in combination therapies, that is, the
compounds and pharmaceutically acceptable compositions can be administered concurrently
with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures.
The particular combination of therapies (therapeutics or procedures) to employ in a combination
regimen will take into account compatibility of the desired therapeutics and/or procedures and
the desired therapeutic effect to be achieved. It will also be appreciated that the therapies
employed may achieve a desired effect for the same disorder (for example, an inventive
compound may be administered concurrently with another agent used to treat the same disorder),
or they may achieve different effects (e.g., control of any adverse effects). As used herein,
additional therapeutic agents that are normally administered to treat or prevent a particular
disease, or condition, are known as "appropriate for the disease, or condition, being treated". For
example, exemplary additional therapeutic agents include, but are not limited to: nonopioid
analgesics (indoles such as Etodolac, Indomethacin, Sulindac, Tolmetin; naphthylalkanones such
sa Nabumetone; oxicams such as Piroxicam; para-aminophenol derivatives, such as
Acetaminophen; propionic acids such as Fenoprofen, Flurbiprofen, Ibuprofen, Ketoprofen,
Naproxen, Naproxen sodium, Oxaprozin; salicylates such as Asprin, Choline magnesium
trisalicylate, Diflunisal; fenamates such as meclofenamic acid, Mefenamic acid; and pyrazoles
such as Phenylbutazone); or opioid (narcotic) agonists (such as Codeine, Fentanyl,
Hydromorphone, Levorphanol, Meperidine, Methadone, Morphine, Oxycodone, Oxymorphone,
Propoxyphene, Buprenorphine, Butorphanol, Dezocine, Nalbuphine, and Pentazocine).
Additionally, nondrug analgesic approaches may be utilized in conjunction with administration
of one or more compounds of the invention. For example, anesthesiologic (intraspinal infusion,
neural blocade), neurosurgical (neurolysis of CNS pathways), neurostimulatory (transcutaneous
electrical nerve stimulation, dorsal column stimulation), physiatric (physical therapy, orthotic
devices, diathermy), or psychologic (cognitive methods-hypnosis, biofeedback, or behavioral
methods) approaches may also be utilized. Additional appropriate therapeutic agents or
approaches are described generally in The Merck Manual, Seventeenth Edition, Ed. Mark H.
Beers and Robert Berkow, Merck Research Laboratories, 1999, and the Food and Drug
Administration website, www.fda.gov. the entire contents of which are hereby incorporated by
reference.
[002S5] The amount of additional therapeutic agent present in the compositions of this
invention will be no more than the amount that would normally be administered in a composition
comprising that therapeutic agent as the only active agent. Preferably the amount of additional
therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of
the amount normally present in a composition comprising that agent as the only therapeutically
active agent.
[002G6] The compounds of this invention or pharmaceutically acceptable compositions
thereof may also be incorporated into compositions for coating an implantable medical device,
such as prostheses, artificial valves, vascular grafts, stents and catheters. Accordingly, the
present invention, in another aspect, includes a composition for coating an implantable device
comprising a compound of the present invention as described generally above, and in classes and
subclasses herein, and a carrier suitable for coating said implantable device. In still another
aspect, the present invention includes an implantable device coated with a composition
comprising a compound of the present invention as described generally above, and in classes and
subclasses herein, and a carrier suitable for coating said implantable device. Suitable coatings
and the general preparation of coated implantable devices are described in US Patents 6,099,562;
5,886,026; and 5,304,121. The coatings are typically biocompatible polymeric materials such as
a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic
acid, ethylene vinyl acetate, and mixtures thereof. The coatings may optionally be further
covered by a suitable topcoat of fluorosilicone, polysaccarides, polyethylene glycol,
phospholipids or combinations thereof to impart controlled release characteristics in the
composition.
[00287] Another aspect of the invention relates to inhibiting one or more of NaVl.l, NaV1.2,
NaVl.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaVl.8, NaV1.9, or CaV2.2 activity in a biological
sample or a patient, which method comprises administering to the patient, or contacting said
biological sample with a compound of formula I or a composition comprising said compound.
The term "biological sample", as used herein, includes, without limitation, cell cultures or
extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood,
saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.
[00288] Inhibition of one or more of NaVl.l, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6,
NaV1.7, NaV1.8, NaV1.9, or CaV2.2 activity in a biological sample is useful for a variety of
purposes that are known to one of skill in the art. Examples of such purposes include, but are not
limited to, the study of sodium ion channels in biological and pathological phenomena; and the
comparative evaluation of new sodium ion channel inhibitors.
[00289] In order that the invention described herein may be more fully understood, the
following examples are set forth. It should be understood that these examples are for illustrative
purposes only and are not to be construed as limiting this invention in any manner.
EXAMPLES
[00290] SYNTHESIS OF EXEMPLARY COMPOUNDS OF THE INVENTION:
[00291] Example 1:
[00292] In a 2L three-necked round-bottomed flask equipped with an overhead stirrer and
reflux condenser, anthranilamide 1 (20.0g, 147 mmol) and potassium carbonate (28.4g, 206
mmol) was suspended in 1L dry ether and heated to reflux. o-Anisoyl chloride (32.5g, 191
mmol) was added slowly to the refluxing mixture. After 3 hours at reflux, the reaction mixture
was allowed to cool to room temperature, the ether was removed under reduced pressure, and the
resulting residue was filtered and washed with water. The resulting solid was then suspended in
600 mL of 5% aq. NaOH solution and boiled for one hour. The reaction was allowed to cool to
room temperature, then neutralized with acetic acid, upon which quinazilinone 2 was
precipitated. Product 2 was collected by filtration, washed with water, and dried overnight in
vacuo to yield 27g (73%) of pure 2.
[00293] LC/MS(10-99%) M/Z 253.0 retention time 3.22 min; JH NMR (DMSO) 53.86 (s,
3H), 57.09 (t, 1H), 5 7.18 (d, 1H), 6 7.53 (m, 2H), 5 7.70 (m, 2H), 5 7.80 (m, 1H), 5 8.14 (d, 1H),
5 12.11 (s, 1H); 13C NMR (DMSO) 5 55.75, 5 111.86, 5 120.89, 5 120.97, 5 122.74, 5 125.75, 5
126.45, 5 127.26, 5 130.41, 5 132.13, 5 134.32, 5 148.97, 5 152.48, 5 157.12, 5 161.35

[00294] Quinazolinone 2 (20.0g, 79.3mmol) was suspended in 500 mL dry benzene inal L
round-bottomed flask equipped with a reflux condenser. N,N-Dimethylanaline (14.4g, 119
mmol) was added and the reaction was refluxed for 30 minutes under nitrogen. Upon cooling to
room temperature, phosphorus oxychloride (12.2 g, 79.3 mmol) was added and the reaction
mixture was then refluxed for an additional 3 hours under nitrogen. The mixture was cooled to
room temperature, poured over ice, and neutralized with saturated aqueous sodium bicarbonate.
The solution was then extracted four times with toluene and the combined organic layers dried
over magnesium sulfate, filtered, and concentrated in vacuo to a reddish-brown solid. The
resulting 4-chloroquinazoline 3 was purified via flash chromatography (40% hexanes, 60%
dichloromethane) to afford 20 g (93%) 3 as a yellow solid.
[00295] LC/MS (40-99%) M/Z 271.4 retention time 2.49min; 1H NMR (CDC13) 53.89 (s, 3H),
57.06 (d, 1H), 5 7.09 (d, 1H), 5 7.45 (m, 1H), 5 7.71 (m, 1H), 5 7.80 (m, 1H), 5 7.95 (m, 1H), 5
8.17 (d, 1H), 5 8.30 (d, 1H); 13C NMR (CDC13) 5 56.3 (d), 5 112.15 (d), 5 121.0 (s), 5 122.29 (s),
5 125.97 (s), 5 126.76 (s), 8 127.25 (d), 8 128.71 (d), 5 132.10 (m), 5 135.26 (s), S 151.16 (s), 5
158.19 (s), 5 161.02 (s), 8 162.58 (s).

[00296] A 500 mL two-necked round-bottomed flask equipped with an addition funnel was
charged with 4-Chloroquinazoline 3 (5.00 g, 18.5 mmol) and 80 mL dry dichloromethane under
nitrogen. The mixture was cooled to -78 °C and 92 mL of 1M boron tribromide in
dichloromethane was added dropwise via the addition funnel. The cooling bath was removed
and the reaction allowed to stir for three hours at room temperature. The mixture was then
cooled to 0 °C and slowly neutralized with saturated aqueous sodium bicarbonate, extracted 3
times with dichloromethane, and the combined organic solutions dried over magnesium sulfate,
filtered, and concentrated in vacuo to a yellow solid. The residue was promptly dissolved in 30
mL of 2:1 dry THF/CH2C12, then treated with 2 M dimefhlyamine in THF (46.3 mL, 92.5 mmol).
After 30 min the solvent was removed under reduced pressure, the residue partitioned between
dichloromethane and water, and the aqueous solution extracted 4 times with dichloromethane.
The combined organic solutions were dried over magnesium sulfate, filtered, and concentrated in
vacuo to an orange solid. Recrystallization from ethanol gave 2.61g (53 %) yellow crystalline 4.
[00297] LC/MS (10-99%) M/Z 266.0 retention time 2.59min; 1H NMR (DMSO) 83.32 (s,),
83.45 (s, 6H), 8 6.93 (m, 2H), 8 7.35 (m, 1H), 8 7.46 (m, 1H), 8 7.78 (m, 2H), S 8.21 (d, 1H), 8
8.43 (d, 1H); 13C NMR (DMSO) 8 41.62, 113.77, 117.18, 118.25, 118.97, 124.75, 126.15,
126.51, 128.96, 132.36, 133.11, 149.09, 159.22, 160.74, 161.69.
[00298] HC1 salt:

[00299] A 250 mL round-bottomed flask was charged with quinazoline 4 (1.0 g, 3.8 mmol),
l00mL dry ether, 11 mL dry methanol, then sealed with a septum and placed in a sonicator with
the bath temperature at 43 °C. Upon complete dissolution of 4, 2 M ethereal HC1 solution was
added (1.9 mL, 3.8 mmol), causing immediate precipitation of 5. The solvent was removed in
vacuo, and the salt twice re-suspended in dry ether, concentrated, and dried in vacuo. After
drying overnight under vacuum, 1.13 g (98 %) 5 was obtained as a pale yellow solid.
[00300] M/Z 266.0 retention time 2.59 rnin; 1H NMR (DMSO) 53.59 (s, 6H), 5 7.02 (m, 1H),
5 7.19 (d, 1H), 5 7.49 (m, 1H), 5 7.64 (m, 1H), 8 7.96 (m, 1H), 8 8.05 (d, 1H), 8 8.20 (d, 1H), 8
8.35 (d, 1H); 13C NMR (DMSO) 8 42.37, 112.07, 117.19,119.23, 121.09, 126.15, 127.48,
130.45, 134.01, 134.67, 155.37, 158.61, 160.97.
[00301] Example 2: Synthesis of 2-(2-Methoxv-phenvl)-7-rrifluoromethvl-3ff-quinazolin-4-
one

[00302] 2-(2-Methoxy-benzoyIamino)-4-trifluoromethyl-benzoic acid 2-Amino-4-trifluoro-
benzoic acid (3.84g,18.73mmol) was dissolved in 30rnl dry 1,4-Dioxane followed by the slow
addition of O-Anisoyl chloride (3.3ml, 24.35mmol), then triethylamine (7.85ml, 56.19mmol) and
stirred under a nitrogen atmosphere at room temperature for 2 hours. Solvent was remove under
reduced pressure and organic was partitioned between water and EtOAc and the pH was adjusted
to 3 with HCI. Organic layer was separated, dried over MgSO4, filtered and concentrated to an
off white solid. Recovered 6.35g 100% yield. LC/MS (10-99%) M/Z 339.9, retention time 3.58
minutes.

[00303] 2-(2-Methoxy-benzoyIamino)-4-trifluoromethyI-benzamide 2-(2-Methoxy-
benzoylamino)-4-trifluoromethyl-benzoic acid (7.04g, 20.77mmol) was suspended in 0.5M
solution of ammonia in 1,4-Dioxane (125ml, 62.31mmoI), followed by the addition of
triethylamine (5.78ml, 41.54mmol) then BOP reagent (12g, 27.0mmol) and stirred at room
temperature for 16 hours. The product was collected by vacuum filtration and washed with
water. The desired product was dried on the lyophilizer for 24h. Recovered 3.8g as a white
solid. LC/MS (10-99%) M/Z 339.1, retention time 2.93 minutes.

[00304] 2-(2-Methoxy-phenyl)-7-trifluoromethyl-3J?-quinazolin-4-one 2-(2-Methoxy-
benzoylamino)-4-trifluoromethyl-benzamide (3.8g, 11.24mmol) was suspended in 145ml 5%
aqueous NaOH solution then refluxed fro three hours at 120°C. The reaction was cooled to room
temperature and adjusted to pH 4 causing the desired product to precipitate from solution. Solid
was collected by vacuum filtration as a white solid and dried on the lyophilizer for 24h. White
solid 2.7g, 75% yield. LC/MS (10-99%) M/Z 321.1, retention time 3.25 minutes.
[00305] Synthesis of 2-(2-Methoxy-phenyl)-7-methyl-3H-quinazolin-4-one

[00306] N-(2-Cyano-5-methyI-phenyI)-2-methoxy-benzamide 2-Amino-4-methyl
anthronitrile (50.0g, 378.3mmol) was dissolved in 1L dry pyridine and cooled to 0°C. O-Anisoyl
chloride (63.0ml, 453.96mmol) was added dropwise over a 40 minute period and the reaction
was allowed to warm to room temperature and stirred under a nitrogen atmosphere for 16 hours.
The reaction was poured over 2L of ice and the product formed a precipitate. The product was
collected by vacuum filtration and dried for 3 days to produce the desired product a fluffy tan
solid. Recovered 92.0g 91% yield. LC/MS (10-99%) M/Z 267.2, retention time 3.34 minutes.

[00307] 2-(2-Methoxy-phenyI)-7-methyI-3H-quinazoIin-4-one N-(2-Cyano-5-methyl-
phenyl)-2-methoxy-benzamide (47.0g, 176.5mmol) was suspended in 1L of ethanol followed by
the addition of a 6M aqueous NaOH solution (326ml), then a 30% solution of H2O2 (100ml). The
reaction was refluxed for 3 hours, cooled to room temperature and poured over an equal volume
of ice. The solution was adjusted to pH3.5 and the product precipitated from solution. Desired
product was collected by vacuum filtration and dried on the lyophilizer for 24h. 22.4g, 48%
yield. LC/MS (10-99%) M/Z 267.0, retention time 2.54 minutes.
5-Fluoro-4-methyl~anthranilic acid
[00308] 2-Amino-5-fIuoro-4-methyl-benzoic acid. Chloral hydrate (76 g) was dissolved in 1
L water and subsequently 1 kg Na2SO4) 94.1 g H2NOH-HCl, and 51.3 g 4-fluoro-3-methyl
aniline in 250 ml 5% aq. HC1 were added. The suspension was heated to boiling and kept boiling
for 1 minute. After cooling down to room temperature, the solid was filtered off and washed
twice with warm water (40°C). Yield after drying overnight at 60°C under vacuum was 275 g,
which was used without further purification or drying. The 275 g of crude product was slowly
poured in 500 ml of concentrated H2SO4 at 50°C, such that the temperature was kept below 75°C.
After completion of addition, the dark/purple solution was heated to 85°C for 15 minutes. After
cooling down to room temperature, the solution was poured in 2 L of ice water and was left
standing for an half hour. The red solid was filtered and washed twice with cold water.
Subsequently, the solid was dried under vacuum at 70°C. Yield: 69.9 g (quantitatively from 4-
fluoro-3-methyl aniline) of a mixture of tworegio isomers: 5-fluoro and 3-fluoro 3-methyl-isatin
in a ratio of about 55:45. The mixture of isatins (69.4g) was dissolved in 1L IN aq. NaOH and
subsequently 100 ml of 30% aq. H2O2 was added drop wise, keeping the temperature below
30°C. After completion of addition, the mixture was heated to 45°C until evolution of gas ceased.
The solution was cooled to room temperature, filtered and acidified with glacial acetic acid. The
precipitate formed was filtered off, washed twice with water and air-dried 45°C. Yield: 29.4 g of
5-fluoro-4-methyl-anthranilic acid iii.

[00309] 2-Amino-5-trifluoromethyl-benzoic acid. 4-(trifluoromethyl)aniline (25 g, 0. 15
mol) was dissolved in THF (275 mL), then treated with Boc anhydride (41 g, 0.19 mol), ET3N
(19 g, 0.19 mol), and 4-(dimethylamino)pyridine (0.1 g, 0.8 mmol). The mixture was refluxed
for 3 hours, the solvents removed in vacuo, and the organic residue dissolved in EtOAc, washed
with 1 M NaOH, then 1 M HC1, then dried and concentrated. The resulting product was
recrystallized from heptane yielding 39 g final product as a white solid. The solid (0.15 mol)
was dissolved in THF (350 mL) and cooled to -78 °C under nitrogen, then treated dropwise with
BuLi (1.6 M in hexane, 282 mL, 0.45 mol). After 1 h, the solution was warmed to 0 °C and held
for 1.5 h. The mixture was poured onto excess solid CO2 and stirred overnight at RT. After
partitioning against 1 M HC1, the THF layer was evaporated and the residue dissolved in EtOAc,
washed with 1 M HC1, then dried and concentrated. The solid product was triturated with hexan
to yield the final product as a white solid (15.8 g). LC/MS retention time 2.70 min, m/z (obs, M-
H) = 304.1. Finally the Boc anthranilate (11.3 g) was dissolved in CH2CL2 (26 mL) and treated
with TFA (21 mL). After stirring at RT for 2 h, the solution was dried in vacuo, the resulting
residue dissolved in toluene (100 mL), concentrated to dryness, and the dissolution / drying
process repeated twice more, yielding the desired product as a white solid (10.8 g), LC/MS
retention time 1.2 min, m/z (obs, M-H) = 204.0.

[00310] 2-Amino-5-bromo-benzamide. The isatoic anhydride (15 g, 0.062 mol) was
combined with 1 M aq. NH4OH (340 mL) and stirred for 2 d at RT. The solid product was
collected by filtration and dried in vacuo (6.6 g). LC/MS retention time 2.47 min, m/z obs =
215.2.

[00311] To a stirring suspension of benzoyleneurea 1 (l0.0g, 61.7 mmol) and phosphorus
oxychloride (20 ml) in a 500 mL three-necked round-bottomed flask equipped with a magnetic
stirrer and reflux condenser, was added N, N-dimethylaniline (7.80 ml, 61.7 mmol) in a single
portion. The suspension was heated at reflux for 3 hours and slowly formed a light red solution.
The solution was concentrated under reduced pressure and the residue was poured onto ice (100
g). The solution was basified to pH = 9.0 using concentrated aqueous sodium bicarbonate
solution. The mixture was partitioned between CH2Cl2 and H2O. The organic portion was dried
(MgSCO4) and evaporated to dryness under reduced pressure. The residue was dissolved in
anhydrous THF (75 ml) and cooled to 0 °C. Dimethylaniline (67.7 mL, 135 mmol, 2.0 M in
THF) was added dropwise, with stirring, over a period of 30 minutes. The solution was then
stirred at 0 °C for 1 hour. The solution was concentrated under reduced pressure and the residue
was purified by silica gel chromatography using (70% hexanes, 30% ethyl acetate) to obtain 2
(7.90 g, 38.1 mmol, 62% yield) as a white solid.
[00312] . 'H NMR (CDCl3) 53.43 (s, 6H), 7.40 (t, 1H), 7.69 (t, 1H), 7.78 (d, 1H), 8.02 (d, 1H);
M+l (obs) = 208.0; Rt = 2.26.

[00313] A 5 mL microwave reaction vessel was charged with a mixture of 2 (100 mg, 0.48
mmol), 2-methoxyphenylboronic acid (96 mg, 0.63 mmol),
tetrakis(triphenylphosphine)palladium(O) (55 mg, 0.048 mmol), sodium carbonate ( 1.20 mL,
0.48 mmol, 0.40 M aqueous solution), and acetonitrile (1.20 mL). The vessel was sealed and
heated, with stirring, at 170 °C for 10 minutes via microwave irradiation. The organic portion
was concentrated under reduced pressure and the residue was purified by silica gel
chromatography using (80% hexanes, 20% ethyl acetate) to obtain 3 (120 mg, 0.43 mmol, 89%
yield) as a white solid.
[00314] 1H NMR(CDC13) S3.32 (s, 6H),. 3.8.i(s, 3H), 6.89-7.02 (m, 2H), 7.28-7.34 (m, 2H),
7.62 (t, 1H), 7.75 (d, 1H), 7.89 (d, 1H), 7.95 (d, 1H); M+l (obs) = 280.2; Rt = 2.46.

[00315] 2-ChIoro-4-dimethylaminoquinazoIine-7-carboxylic acid methyl ester. A stirring
suspension of 2,4-dioxo-l,2,3,4-tetrahydro-quinazoline-7-carboxylic acid methyl ester (12.2 g,
55.4 mmol), N,N-dimethylaniline (14.0 mL, 110.8 mmol), and POCl3 (25 mL), under N2, was
heated at 100 °C for 15 minutes. The solution was evaporated to dryness under reduced pressure
and the residual oil was poured into ice-water (800 mL). The mixture was made strongly basic
by the addition of 50% aqueous NaOH solution at 0°C. The mixture v/as partitioned between
CH2Cl2 and H2O and the organic portion was evaporated to dryness under reduced pressure. The
residue was purified by silica gel chromatography using 70% hexanes/30%EtOAc to obtain the
intermediate chloride as a white solid (5.1 g, 19.8 mmol). The obtained intermediate was
dissolved in CH2Cl2 (100 mL). The solution was cooled to 0 °C followed by the addition of Et3N
(5.5 mL, 39.6 mmol) and dimethylamine hydrochloride (1.6 g, 19.8 mmol). The mixture was
then stirred at 0 °C for 30 minutes. The mixture was evaporated to dryness and the obtained
residue was purified via silica gel chromatography using 70% hexanes/30%EtOAc to obtain the
desired amine as a white solid (3.3 g, 12.4 mmol, 11% yield). LC/MS (10-99%) M/Z 268.0
retention time 2.85 min.

[00316] 6-Fluoro-N4,N4-dimethylquinazoline-2,4-diamine. A stirring mixture of (2-
chloro-6-fluoro-quinazolin-4-yl)-dimethylamine (50 mg, 0.22 mmol), lithium
bis(trimethylsilyl)amide (260 µL, 0.26 mmol, 1.0 M in hexanes), Pd2(dba)3 (20 mg, 0.022
mmol), 2-(dicyclohexyI)phosphinobiphenyl (19 mg, 0,053 mmol), and THF (1.0 mL) was heated
in a sealed tube via microwave irradiation at 65 °C for 1.5 hours. 1.0 N aqueous HC1 solution
(3.0 mL) was added and the mixture was stirred at room temperature for 30 minutes. The
mixture was partitioned between H2O and EtOAc. The organic portion was evaporated to
dryness under reduced pressure. The obtained residue was purified via silica gel
chromatography using 95% CH2Cl2/5%MeOH to obtain the desired amine as a tan solid (40 mg,
19.4 mmol, 88% yield). LC/MS (10-99%) M/Z 206.9 retention time 1.18 min.

[00317] l-(4-Dimethylamino-6-fluoroquinazolin-2-yl)-pyrrolidine-2,5-dione. A stirring
mixture of 6-fluoro-N4,N4-dimethylquinazoline-2,4-diamine (30.0 mg, 0.13 mmol), succinic
anhydride (12 mg, 0.12 mmol), and p-dioxane (500 µL) was heated in a sealed tube via
microwave irradiation at 170 °C for 20 minutes. The mixture was purified via HPLC to obtain
the desired succinate as a TFA salt (40 mg, 0.10 mmol, 76% yield). LC/MS (10-99%) M/Z
289.3 retention time 2.01 min.

[00318] l-(6-FIuoro-4-pyrrolidin-l-yl-quinazolin-2-yl)-pyrrolidlu-2-one. A stirring
mixture of 6-fluoro-4-pyrrolidin-l-yl-quinazolin-2-ylamine (30.0 mg, 0.14 mmol), 4-
chlorobutyryl chloride (17 µL, 0.15 mmol), Et3N (42 fxL, 0.30 mmol), and p-dioxane (500 µL
was heated in a sealed tube via microwave irradiation at 170 °C for 20 minutes. The mixture was
purified via HPLC to obtain the desired lactam as a TFA salt (45 mg, 0.11 mmol, 81% yield).
LC/MS (10-99%) M/Z 301.2 retention time 2.24 min.

[00319] l-(4-Dimethylamino-6-fluoro-quinazolin-2-yl)-lH-pyrrole-3-carbaldehyde. A
stirring mixture of 6-fluoro-N4,N4-dimethylquinazoline-2,4-diamine (20.0 mg, 0.10 mmol), 2,5-
dimethyoxy-3-tetrahydrofurancarboxaldehyde (43 µL, 0.30 mmol), and AcOH (500 µL) was
heated at 90 °C for 30 minutes. The mixture was evaporated to dryness and the obtained residue
was purified via silica gel chromatography using 70% hexanes/30%EtOAc to obtain the desired
aldehyde as a white solid (15 mg, 0.05 mmol, 50% yield). LC/MS (10-99%) M/Z 285.1
retention time 3.23 min.
[00320] (6-Methoxy-2-pyrrol-l-yl-quinazolin-4-yl)-dimethyl-ainine. To a stirring solution
pyrrole (310 mg, 4.6 mmol) and DMF (5.0 mL), under N2, was added NaH (170 mg, 4.2 mmol,
60% in mineral oil). The mixture was stirred at room temperature for 10 minutes. To this
solution was added (2-chloro-6-methoxyquinazolin-4-yl)dimethylamine (1.0 g, 4.2 mmol). The
mixture was heated in a sealed tube via microwave irradiation at 220 °C for 20 minutes. The
mixture was evaporated to dryness and the obtained residue was purified via silica gel
chromatography using 70% hexanes/30%EtOAc to obtain the desired aldehyde as a white solid
(15 mg, 0.05 mmol, 50% yield). LC/MS (10-99%) M/Z 269.0 retention time 2.39 min.

[00321] [2-(2-Chloro-pyrrol-l-yl)-6-methoxyquinazoIin-4-yl]dimethyl-amine. To a
stirring solution of (6-methoxy-2-pyrrol-l-yl-quinazolin-4-yl)dimethyl-amine (25 mg, 0.09
mmol) and THF (2.0 mL), under N2, was added N-chlorosuccinimide (13 mg, 0.09 mmol). The
solution was stirred at room temperature for 17 hours. The mixture was purified via HPLC to
obtain the desired chloropyrrole as a TFA salt (23 mg, 0.06 mmol, 62% yield). LC/MS (10-
99%) M/Z 303.0 retention time 2.71 min.

[00322] 2-[4-(4-Aminopiperidin-l-yI)-7-methylquinazolin-2-yI]-phenoI. To a stirring
solution of 2-(4-Chloro-7-methylquinazolin-2-yl)-phenol (100 mg, 0.35 mmol), Et3N (72 µL,
0.52 mmol), and CH2Cl2 (300 µL) under N2, was added 4-aminopiperidine (54 µL, 0.52 mmol).
The mixture was stirred at room temperature for 2 hours. The mixture was evaporated to dryness
under reduced pressure. The residue was purified by silica gel chromatography using 98%
CH2Cl2/2%MeOH to obtain the desired amine as a white solid (11 mg, 0.31 mmol, 89% yield).
LC/MS (10-99%) M/Z 349.3 retention time 2.22 min.

[00323] Ethanesulfonic acid {l-[2-(2-hydroxyphenyl)-7-methylquinazoIin-4-yI]-
piperidin-4-yI}-amide. To a stirring solution of 2-[4-(4-Aminopiperidin-l-yl)-7-
methylquinazolin-2-yl]-phenol (30 mg, 0.09 mmol), Et3N (25 µL, 0.18 mmol), and CH2C12 (500
µL) under N2, was added ethanesulfonyl chloride (10 µL, 0.09 mmol). The mixture was stirred
at room temperature for 3 hours. The mixture was purified via HPLC to obtain the desired
sulfonamide as a TFA salt (33 mg, 0.06 mmol, 68% yield). LC/MS (10-99%) M/Z 427.3
retention time 2.80 min.
[00324] 3-{l-[2-(2-Hydroxyphenyl)-7-methyIquinazolin-4-yl]-piperidin-4-yl}-l,l-
dimethylsulfonylurea. To a stirring solution of 2-[4-(4-Aminopiperidin-l-yl)-7-
methylquinazolin-2-yl]-phenol (35 mg, 0.11 mmol), Et3N (30 µL, 0.22 mmol), and CH2C12 (300
µL) under N2, was added dimethylsulfamoyl chloride (12 µL, 0.11 mmol). The mixture was
stirred at room temperature for 17 hours. The mixture was purified via HPLC to obtain the
desired sulfonylurea as a TFA salt (44 mg, 0.08 mmol, 71% yield). LC/MS (10-99%) M/Z 442.4
retention time 2.84 min.
[00325] {l-[2-(2-Hydroxyphenyl)-7-methylquinazolin-4-yl]-piperidin-4-yl}-carbamic acid
isobutyl ester. To a stirring solution of 2-[4-(4-Aminopiperidin-l-yl)-7-methylquinazolin-2-yl]-
phenol (30 mg, 0.09 mmol), Et3N (25 µL, 0.18 mmol), and CH2C12 (300 µL) under N2, was
added isobutylchloroformate (12 µL, 0.09 mmol). The mixture was stirred at room temperature
for 1 hour. The mixture was purified via HPLC to obtain the desired carbamate as a TFA salt
(27 mg, 0.05 mmol, 58% yield). LC/MS (10-99%) M/Z 435.2 retention time 3.21 min.
[00326] Isobutylcarbamic acid l-[2-(2-hydroxyphenyI)-7-methyIquinazolin-4-yI]-
piperidin-4-yl ester. To a stirring solution of l-[2-(2-Methoxyphenyl)-7-methylquinazolin-4-
yl]-piperidin-4-ol (100 mg, 0.30 mmol) and THF (500 µL) under N2, was added phosgene (317
µL, 0.60 mmol, 20% in toluene). The mixture was stirred at room temperature for 15 minutes.
Isobutylamine (300 µL, 3.0 mmol) was added drop wise over a 2 minute period followed by
stirring at room temperature for 1 hour. The mixture was evaporated to dryness and the obtained
residue was purified via silica gel chromatography using 97% CH2Cl2/3%MeOH to obtain the
desired carbamate intermediate as a clear oil (90 mg, 0.20 mmol). To a stirring solution of the
carbamate intermediate (90 mg, 0.20 mmol) and CH2Cl2 (15 mL), under N2, at -78 °C, was
added BBr3 (0.60 mL, 0.60 mmol, 1.0 M in CH2Cl2) dropwise over a period of 2 minutes. The
mixture was then allowed to warm to room temperature and was then heated at 50 °C for 15
minutes. The mixture was poured into a saturated aqueous NaHCO3 solution (80 mL) and the
organic portion was evaporated to dryness. The residue was purified via HPLC to obtain the
desired carbamate as a TFA salt (66 mg, 0.12 mmol, 39% yield). LC/MS (10-99%) M/Z 435.3
retention time 3.08 min.
[00327] N-{l-[2-(2-Hydroxy-phenyl)-7-methylquinazolin-4-yI]-piperidin-4-yI}-3-
methylbutyramide. To a stinting solution of 2-[4-(4-Aminopiperidin-l-yl)-7-methylquinazolin-
2-yl]-phenol (35 mg, 0.11 mmol), Et3N (30 µL, 0.22 mmol), and CH2C12 (300 µL) under N2, was
added isovaleryl chloride (14 µL, 0.11 mmol). The mixture was stirred at room temperature for
17 hours. The mixture was purified via HPLC to obtain the desired sulfonamide as a TFA salt
(37 mg, 0.07 mmol, 59% yield). LC/MS (10-99%) M/Z 419.3 retention time 2.77 min.
[00328] Synthesis of 2-( 4-Ethoxy-quinazolin-2-yl)-phenol

[00329] 2-(4-Ethoxy-quinazoIin-2-yl)-phenol. 2-(4-ChIoro-quinazolin-2-yl)-phenol (50mg,
0.196mmol) was placed in a microwave tube charged with a stir bar and dissolved 0.5ml dry
dichloromethane, followed by the addition of 2ml dry ethanol. Tube was sealed with a cap and
heated at 160 to 200°C for one hour in CEM microwave. Solvent was removed under reduced
pressure, reconstituted organic in DMSO and purified by Gilson HPLC. The desired compound
was concentrated to a white solid as the TFA salt. LC/MS (10-99%) M/Z 267.2, retention time
2.57 minutes.

[00331] [2-(2-Methoxy-3-methyI-phenyI)-quinazolin-4-yl]-dimethyl-amine To a stirring
solution of [2-(2-Methoxy-phenyl)-quinazolin-4-yl]-dimethyl-amine (200mg, 0.72mmol) in dry
THF under an argon atmosphere at -78°C was added dropwise a 1.6M solution of nBuLi in
hexanes (0.671ml, 1.074mmol). After 10 minutes Mel (0.076ml, 1.22mmol) was added and the
reaction was allowed to warm to room temperature. After 10 minutes at room temperature the
reaction was quenched with a saturated aqueous solution of NH4CI and partitioned between
aqueous and EtOAc. Organic phase was separated, dried over MgSCO4, filtered and concentrated
to a yellow oil. Purified by flash chromatograpy 10% EtOAc/ 90% hexanes to afford product as a
white solid. Recovered 146mg 50% yield. LC/MS (10-99%) M/Z 294.0, retention time
3.23minutes.

[00332] 2-(4-Dimethylamino-quinazolin-2-yI)-6-methyl-phenol To a stirring solution of [2-
(2-Methoxy-phenyl)-quinazolin-4-yl]-dimethyl-amine (54mg, 0.184mmol) in CH2Cl2 at -78°C
under a nitrogen atmosphere was added BBr3 (0.92ml, 0.92mmol). The reaction was allowed to
warm to room temperature and the heated at 45°C for 4 hours. The reaction was allowed to cool
to room temperature and then quenched with an aqueous solution of NaHCO3 until pH8. Organic
layer was separated, dried over MgSO4, filtered, and concentreated to a yellow solid. Purified by
Gilson HPLC and desired product was isolated as the TFA salt. LC/MS (10-99%) M/Z 280.2,
retention time 2.55minutes.

[00334] [2-(2-Methoxy-5-morpholin-4-yI-phenyl)-quinazolin-4-yl]-dimethyl-aniine To a
tube charged with a stirbar was added Pd2(dba)3 (51.1mg, 0.0558mmol), biphenyl-2-yl-di-tert-
butyl-phosphane (67mg, 0.223mmol), NaOtBu (80mg, 0.837mmol) in 2ml dry toluene was
added 4-Bromo-2-(4-dimethylamino-quinazolin-2-yl)-phenol(200mg,0.558mmol) and
morpholine (0.073ml, 0.837mmol). The reaction was sealed with a screw cap and heated at
100°C in an oil bath for 16h. Purified by flash chromatograpy 30%-60% EtOAc/ hexanes to
afford product as a white solid. Recovered 100mg 49% yield. LC/MS (10-99%) M/Z 365.0,
retention time 2.07minutes.

[00335] 2-(4-Dimethylamino-quinazoIin-2-yI)-4-raorphoIin-4-yl-phenol To a stirring
solution of [2-(2-Methoxy-5-morpholin-4-yl-phenyl)-quinazolin-4-yl]-dimethyl-amine (109mg,
0.299mmol)in CH2C12 at -78°C under a nitrogen atmosphere was added BBr3 (1.5ml, 1.5mmol).
The reaction was allowed to warm to room temperature and was heated at 40°C for 2 hours. The
reaction was quenched with an aqueous solution of NaHCC>3 until pH8. Organic layer was
separated, dried over MgSC>4, filtered, and concentreated to a yellow solid. Purified by Gilson
HPLC and desired product was isolated as the TFA salt. LC/MS (10-99%) M/Z 351.4, retention
time 1.89minutes.
[00336] Synthesis of 2-(4-Dimethylamino-quinazolin-2-yl)-4-methyl-phenoI

[00337] [2-(2-Methoxy-5-melhyl-phenyI)-quinazolin-4-y]]-dimethyl-amine To a stirring
solution of [[2-(5-Bromo-2-methoxy-phenyl)-quinazolin-4-yl]-dimethyl-amine (200mg,
0.558mmol) in dry THF under an argon atmosphere at -78°C was added dropwise a 1.6M
solution of nBuLi in hexanes (0.76ml, 1.23mmol). After 10 minutes Mel (0.054ml, 1.23mmol)
was added and the reaction was allowed to warm to room temperature. After 10 minutes at room
temperature the reaction was quenched with a saturated aqueous solution of NH4Cl and
partitioned between aqueous and EtOAc. Organic phase was separated, dried over MgSO4,
filtered and concentrated to a yellow oil. Purified by flash chromatograpy 30% EtOAc/ 70%
hexanes to afford product as a white solid. Recovered 146mg 89% yield. LC/MS (10-99%) M/Z
294.4, retention time 2.64minutes.

[00338] 2-(4-Dimethylamino-quinazoIin-2-yI)-4-raethyl-phenolTo a stirring solution of [2-
(2-Methoxy-5-methyl-phenyl)-quinazolin-4-yl]-dimethyl-amine (146mg, 0.498mmol) in CH2C12
at -78°C under a nitrogen atmosphere was added BBr3 (2.49ml, 2.49mmol). The reaction was
allowed to warm to room temperature and was complete after 2 hours. The reaction was
quenched with an aqueous solution of NaHCO3 until pH8. Organic layer was separated, dried
over MgSO4, filtered, and concentreated to a yellow solid. Purified by Gilson HPLC and desired
product was isolated as the TFA salt. LC/MS (10-99%) M/Z 280.2, retention time 2.65minutes.
[00339] Synthesis of 2-(2-methylsulfonylphenyl)-4-dimuethylaminoquinazoline

[00340] 2-(2'-methylsulfonylphenyl)-4-dimethylaminoquinazoline. A 2 mL Personal
Chemistry Microwave reaction vessel with a stir bar was charged with 2-(2'-bromophenyl)-4-
dimethylaminoquinazoline (0.020 g, 61 mmol), copper (I) iodide (0.017 g, 91 mmol), sodium
methanesulfinate (0.010 g, 97 mmol), and 0.5 mL of DMF.1 This mixture was irradiated at
180°C for 10 min. After cooling, water and ether were added, and an extraction was performed.
The ether layer was then filtered through celite and then extracted once again, using
approximately 20% NH4OH to remove additional copper. After concentrating, the product was
redissolved in a 50/50 solution of DMSO/MeOH. Purification was conducted on LC/MS to
provide the TFA salt. LC/MS(10-99%) M/Z 328.3, retention time 3.03 min.
[00341] Synthesis of 2-(2'-anilino)-4-dimethylaminoquinazoIine
[00342] 2-(2'-anilino)-4-dimethylaminoqninazoline. Zinc powder (1.18 g, 18.0 mmol) was
added to a solution of 2-(2'-nitrophenyl)-4-dimethylaminoquinazoIine (0.530 g, 1.80 mmol) in
acetic acid (10.9 mL, 190 mmol) at 0°C. The reaction mixture solidified, but then began to stir
again after the ice bath was removed.3,4 The reaction mixture was stirred for three hours at room
temperature. Deionized water (approximately10 mL) was men added, and a solution formed,
followed by formation of a precipitate. This solution was then taken slightly basic with
NaHCO3(aq). The product was extracted three times with ethyl acetate, dried with MgSO4,
filtered, and concentrated. Approximately 20 mg of the product was redissolved in a 50/50
solution of DMSO/MeOH and purified by LC/MS to provide the bis-TFA salt. LC/MS (10-
99%) M/Z 265.0, retention time 2.81 min.
[00343] Synthesis of 2-(2'-ethylsulfanylphenyI)-4-dimethylaminoquinazoline

[00344] 2-(2'-ethylsulfanyIphenyl)-4-dimethylaminoquinazoIine. Potassium carbonate
(0.052g, 0.374 mmol) and ethanethiol (0.055 mL, 0.748 mmol) were added to a solution of 2-(2'-
fluorophenyl)-4-dimethylaminoquinazoline (0.020 g, 0.0748 mmol) in JV,iV-dimethylforrnamide
(1 mL) in a microwave reaction vessel with a stir bar. This mixture was irradiated in the
microwave at 135°C for 1.5 hours. The resulting mixture was filtered and then purified by
LC/MS to provide the TFA salt. LC/MS (10-99%) M/Z 310.2, retention time 3.27 min.
[00345] Synthesis of 2-(2'-cyanophenyI)-4-dimethylaminoquinazoline
[00346] 2-(2'-cyanophenyl)-4-dimethylaminoquinazoline. A round bottom flask was
charged with 2-(2'-bromophenyl)-4-dimethylaminoquinazoline (0.010 g, 0.0305 mmol),
potassium cyanide (0.0040 g, 0.0609 mmol), tetrakis(triphenylphosphine)palladium(O) (0.0018 g,
0.00152 mmol), copper(I)iodide (0.00058 g, 0.00305 mmol), and acetonitrile (0.50 mL) and
heated to reflux overnight.5 After cooling to room temperature, ethyl acetate was added and
filtered through celite. An extraction was then performed, using ammonium hydroxide
(approximately 20%) to remove additional copper. After being concentrated, the product was
redissolved in a 50/50 solution of DMSO/MeOH and purified by LC/MS to provide the TFA salt.
LC/MS (10-99%) M/Z 275.2, retention time 2.85 min.
[00347] Synthesis of 2-(2'-isopropenylphenyI)-4-dimethylaminoquinazoline

[00348] 2-(2'-isopropenyIphenyI)-4-dimethylaminoquinazoIine. A 0.5 M solution of
isopropenyl magnesium bromide (0.898 mL, 0.449 mmol) was added to a solution of 2-(2'-
fluorophenyl)-4-dimethylaminoquinazoline (0.040g, 0.150 mmol) in ethylene glycol dimethyl
ether (lmL) in a microwave vessel with a stir bar. The sample was irradiated in the microwave
for 5 min at 170°C. Deionized water (approximately 2 mL) was then added. An extraction was
then performed with ether. After being concentrated, the product was redissolved in a 50/50
solution of DMSO/MeOH and purified by LC/MS to provide the TFA salt. LC/MS (10-99%)
M/Z 289.8, retention time 3.23 min.
[00349] Synthesis of 2-(2'-hydroxyphenyl)-4-dimethylamino-6-methoxyquinazoline
[00350] 2-(2'-hydroxyphenyl)-4-dimethylamino-6-methoxyquinazoline. A microwave
reaction vessel with a stir bar was charged with 2-(2'-acetoxyphenyl)-4-dimethylamino-6-
bromoquinazoline (0.100 g, 0.259 mmol), copper(I)iodide (0.0245 g, 0.129 mmol), N,N-
dimethylformamide (0.90 mL), and a 0.5 M solution of sodium methoxide ( 1.04 mL, 0.518
mmol) in methanol. The sample was irradiated in the microwave for 20 min at 150°C. After
cooling, the sample was diluted with ether and then filtered through celite. Next, an extraction
was performed, using ammonium hydroxide (approximately 20%) to remove additional copper.
After being concentrated, the product was redissolved in a 50/50 solution of DMSO/MeOH and
purified by LC/MS (20-99%) to provide the TFA salt. Approximate yield = 60% (by LC/MS).
LC/MS (10-99%) M/Z 296.4, retention time 2.31 min.
[00351] Synthesis of 4-Fhioro-3-(4,4,5,5-tetramethyl-[l,3,2]dioxaboroIan-2-yl)-benzoic
acid methyl ester

[00352] 3-Bromo-4-iluoro-benzoic acid methyl ester. 3-Bromo-4-fluoro-benzoic acid
(2.5g, 11.42mmol) was placed in a 100ml round bottom flask charged with a stir bar, sealed with
a septum and placed under a nitrogen atmosphere and dissolved in 9ml dry THF and 3ml dry
MeOH. A 2.0M solution of TMSdiazomethane in ether (6.28ml, 12.56mmol) was added
dropwise to the stirring solution of the acid. Conversion of the acid to the ester was complete
after twenty minutes according to LC/MS analysis. The solvent was removed under reduced
pressure and product was used without further purification. Recovered a light oil (2.66g, 100%
yield) LC/MS (10-99%) M/Z 234, retention time 3.09minutes.

[00353] 4-FIuoro-3-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yI)-benzoic acid methyl
ester. To a round bottom flask charged with a stir bar was added 3-Bromo-4-fluoro-benzoic acid
methyl ester (1.66g, 7.12mmol), Bis(pinacolato)diboron (2.2g, 8.5mmol), potassium acetate
(2.1g, 21.3mmol), and (0.35g, 0.43mmol) [1,1'-
Bis(diphenylphosphino)ferrocene]dichloropalladium (11), complex with dichloromethane (1:1).
The reaction was sealed with a septum, evacuated and the placed under a nitrogen atmosphere,
followed by the addition of 20ml of dry DMSO. The reaction was heated at 80°C in an oil bath
for two hours. The reaction was allowed to cool to room temperature and partitioned between
ethyl acetate and water. Organic layer was separated, and the aqueous layer was extracted two
more times. All organics were combined, dried over MgSO4, filtered and concentrated under
reduced pressure to a black oil. The product was purified by flash chromatography using a
gradient of EtOAc/ Hexanes 0 to 60%, to afford the desired product as a white solid (1.48g, 74%
yield). LC/MS (10-99%) M/Z 281.4, retention time 2.73 minutes.

[00354] The quinazoline 1 (1.5 g, 3.0 mmol) was dissolved in THF (150 mL). After cooling
to -78°C, r-BuLi (1.7 M in heptane, 1.76 mL) was added dropwise. After stirring for 10 min at -
78°C, CO2 (crushed) was added to the solution, then warmed up to RT and stirred for 30 min.
Quenched the reaction with H2O (100 mL), diluted with EtOAc (100 mL), The organic layer was
dried, concentrated, purified by flash chromatography (1%-10% MeOH/DCM) to obtain 2 (600
mg, 43% yield).
[00355] Synthesis of 2-(2'-hydroxyphenyI)-4-dimethylamino-6-morpholinoquinazoline

[00356] 2-(2'-hydroxyphenyl)-4-dimethylamino-6-morphoIinoquinazoline. A dry
reaction tube with a septa screw cap under N2 was charged with
tris(dibenzylideneacetone)dipalladium(0) (0.012 g, 13.0 mmol), 2,2'-bis(diphenylphosphino)-
l,r-binapthyl (0.024 g, 38.8 mrnol), cesium carbonate (0.097 g, 298 mmol), toluene (0.25 mL),
2-(2'-acetoxyphenyl)-4-dimethylamino-6-bromoquinazoline (0.050 g, 129 mmol), and
morpholine (23 µL, 259 mmol), in that order.2 This mixture was then heated to 80°C for 24
hours. After cooling, the mixture was diluted with ether, filtered through celite and silica gel,
and concentrated. The product was redissolved in a 50/50 solution of DMSO/MeOH and
purified by LC/MS to provide the bis-TFA salt. LC/MS (10-99%) M/Z 351.0, retention time
2.75 min.
[00357] The quinazoline 1 (0.2 g, 0.62 mmol) was dissolved in CH3CN (5 mL). After cooling
to -10°C (ice/NaCl), CC14, DBEA and DMAP were added. After stirring for 10 min, a solution of
dibenzyl phosphite in CH3CN (2 mL) was slowly added over 10 min. Stirring was continued at -
10°C for 2 h, then at RT for 24 h. Quenched by addition of 0.5 M K2HPO4, diluted with water
(15 mL), extracted with DCM (30 mL), dried, concentrated, purified by flash chromatography
(100% DCM) to obtain 2 (168 mg, 47% yield) as a colorless oil. LC/MS(10-99%) M/Z 586.0
retention time 2.54 min.

[00358] To a solution of the quinazoline 2 (0.168 g, 0.29 mmol) in DCM (1.5 mL) was added
TMSBr (0.079 mL, 0.61 mmol) at 0°C. The reaction was stirred for 1 h at 0°C, then for 1 h at
RT. The reaction was quenched with water (3 mL) and stirred for 15 min. The aqueous layer
was washed with EtOAc (5 mL), and dried with lyophilizer overnight to give desired product 3
as white foam (0.14 g, 100% yield). LC/MS(10-99%) M/Z 406.0 retention time 3.32 min.

[00359] To a solution of the quinazoline 3 (0.14 g, 0.36 mmol) in MeOH (3 mL) was added
NaOMe (1.44 mL, 0.72 mmol) at RT. The reaction was stirred overnight at RT. The reaction
mixture was concentrated using rotavap (25°C), then the residue was taken up with water (75
mL) and washed with EtOAc (3 x 50 mL). The aqueous phase was dried with lyophilizer to give
final product 4 (0.14 g, 98% yield) as solid. LC/MS(10-99%) M/Z 406.0 retention time 3.32
rain.
[00360] 2-{7-Methyl-4-[metliyl-(5-methyl-[l,3,4]oxadiazoI-2-yImethyl)-araino]-
quinazoIin-2-yI}-phenoI

[00361] [2-(2-Methoxy-phenyl)-7-methyl-quinazolin-4-yl]-(5-methyl-[l,3,4]oxadiazol-2-
ylraethyl)-amine 4-ChIoro-2-(2-methoxy-phenyI)-7-methyl-quinazoline (400mg, 1.48mmol)
was dissolved in 10ml dry DMF followed by the addition of C-(5-Methyl-[l,3,4]oxadiazol-2yl)-
methylamine oxalate (234mg, 1.48mmol) then triethylamine (413jxl, 2.96mmol). After 6 hours
the reaction was complete, partitioned between EtOAc and water. The organic phase was
separated, dried over MgSO4, filtered and concentrated to an oil. Purified by flash
chromatography 60% EtOAc/ 40% hexanes to afford the desired product a white solid.
Recovered 290mg 56% yleld. LC/MS (10-99%) M/Z 348.4, retention time 2.17minutes.

[00362] [2-(2-Methoxy-phenyl)-7-methyl-quinagoIin-4-yl]-methyl-(5-methyl-
[l,3,4]oxadiazoI-2-ylmethyl)-amiiie To a stirring suspension of freshly washed sodium hydride
(42mg, 1.04mmol) in dry DMF at 0°C under a nitrogen atmosphere was added the [2-(2-
Methoxy-phenyl)-7-methyl-quinazolin-4-yl]-(5-methyl-[l,3,4]oxadiazol-2-ylmethyl)-amine
(180mg, 0.518mmol, in 5ml DMF). After 30 minutes at 0°C, Mel (74µl, 1.19mmol) was added
and the reaction was allowed to warm to room temperature. After one hour the reaction was
quenched with water and extracted 3 times with EtOAc. Organics were combined, dried over
MgSO4, filtered and concentrated to a yellow oil. Purified by flash chromatography 50/ 50
EtOAc/ hexanes to afford the desired product as a clear oil. 128mg, 66% yleld. LC/MS (10-99%)
M/Z 376.1, retention time 2.06 minutes.

[00363] 2-{7-Methyl-4-[methyl-(5-methyl-[l,3,4]oxadiazol-2-ylmethyl)-amino]-
quinazoIin-2-yl}-phenol To a stirring solution of [2-(2-Methoxy-phenyl)-7-methyl-quinazolin-
4-yl]-methyl-(5-methyl-[l,3,4]oxadiazol-2-ylmethyl)-amine (128mg, 0.341mmol) in 7ml dry
CH2Cl2 at -78°C under a nitrogen atmosphere was added BBr3 (1.71ml, 1.71mmol) dropwise.
The reaction was allowed to warm to room temperature and after three hours the reaction was
quenched with a saturated aqueous solution of NaHCO3 until pH8. The organic was separated,
dried over MgSO4, filtered and concentrated to a light yellow oil. Purified by Gilson HPLC and
compound was isolated as the TFA salt. LC/MS (10-99%) M/Z 362.3, retention time 2.12
minutes.

[00364] To a solution of the quinazoline (187 mg, 0.63 mmol) in CH2C12 (5 mL) was added
pyridine (0.11 mL, 1.36 mmol) at RT. After cooling to 0 °C a solution of acetyl chloride (50 µL,
0.70 mmol) in CH2C12 (5 mL) was added, stirring was continued for 45 Min at RT and the
solvent was removed in vacuo. Chromatography over silica (hexanes / EtOAc / NEt3: 2:1:0.05)
afforded compound 1 as a white solid (90 mg, 42%). Compound 1: LC/MS (10-99%): m/z = 338
[M+H]+, Rt: 3.28 min.
[00365] Other compounds of general formula I have been prepared by methods substantially
similar to those described above. The characterization data for these compounds is summarized
in Table 3 below, and compound numbers correspond to the compounds depicted in Table 2.

[00367] Methods:
[00368] (A) Micromass MUX LCT 4 channel LC/MS, Waters 60F pump, Gilson 215 4
probe autosampler, Gilson 849 injection module, 1.5 mL/min/column flow rate, 10-99% CH3CN
(0.035 % TFA) / H2O (0.05 % TFA) gradient, Phenomenex Luna 5u C18 columns (50 x 4.60
mm), Waters MUX UV-2488 UV detector, Cedex 75 ELSD detectors.
[00369] (B) PESciex API-150-EX LC/MS, Shimadzu LC-8A pumps, Gilson 215
autosampler, Gilson 819 injection module, 3.0 mL/min flow rate, 10-99% CH3CN (0.035 %
TFA) / H2O (0.05 % TFA) gradient, Phenomenex Luna 5u C18 column (50 x 4.60 mm),
Shimadzu SPD-10A UV/Vis detector, Cedex 75 ELSD detector.
[00370] (C) PESciex API-150-EX LC/MS, Shimadzu LC-8A pumps, Gilson 215
autosampler, Gilson 819 injection module, 3.0 mL/min flow rate, 40-99% CH3CN (0.035 %
TFA) / H2O (0.05 % TFA) gradient, Phenomenex Luna 5u C18 column (50 x 4.60 mm),
Shimadzu SPD-10A UV/Vis detector, Cedex 75 ELSD detector.
[00371] ASSAYS FOR DETECTING AND MEASURING NaV INHIBITION
PROPERTIES OF COMPOUNDS
[00372] A) Optical methods for assaylng NaV inhibition properties of compounds:
[00373] Compounds of the invention are useful as antagonists of voltage-gated sodium ion
channels. Antagonist properties of test compounds were assessed as follows. Cells expressing
the NaV of interest were placed into microtiter plates. After an incubation period, the cells were
stained with fluorescent dyes sensitive to the transmembrane potential. The test compounds
were added to the microtiter plate. The cells were stimulated with either a chemical or electrical
means to evoke a NaV dependent membrane potential change from unblocked channels, which
was detected and measured with trans-membrane potential-sensitive dyes. Antagonists were
detected as a decreased membrane potential response to the stimulus. The optical membrane
potential assay utilized voltage-sensitive FRET sensors described by Gonzalez and Tsien (See,
Gonzalez, J. E. and R. Y. Tsien (1995) "Voltage sensing by fluorescence resonance energy
transfer in single cells" Biophvs J 69(4): 1272-80, and Gonzalez, J. E. and R. Y. Tsien (1997)
"Improved indicators of cell membrane potential that use fluorescence resonance energy
transfer" Chem Biol 4(4): 269-77) in combination with instrumentation for measuring
fluorescence changes such as the Voltage/Ion Probe Reader (VIPR®) (See, Gonzalez, J. E., K.
Oades, et al. (1999) "Cell-based assays and instrumentation for screening ion-channel targets"
Drug Discov Today 4(9): 431-439).
[00374] B) VIPR® optical membrane potential assay method with chemical stimulation
[00375] Cell Handling and Dye Loading
[00376] 24 hours before the assay on VIPR, CHO cells endogenously expressing a NaV1.2
type voltage-gated NaV are seeded in 96-well poly-lysine coated plates at 60,000 cells per well.
Other subtypes are performed in an analogous mode in a cell line expressing the NaV of interest.
1) On the day of the assay, medium is aspirated and cells are washed twice with 225 µL of Bath
Solution #2 (BS#2).
2) A 15 uM CC2-DMPE solution is prepared by mixing 5 mM coumarin stock solution with
10% Pluronic 127 1:1 and then dissolving the mix in the appropriate volume of BS#2.
3) After bath solution is removed from the 96-well plates, the cells are loaded with 80 µL of the
CC2-DMPE solution. Plates are incubated in the dark for 30 minutes at room temperature.
4) While the cells are being stained with coumarin, a 15 µL oxonol solution in BS#2 is
prepared. In addition to DiSBAC2(3), this solution should contain 0.75 mM ABSC1 and 30
µL veratridine (prepared from 10 mM EtOH stock, Sigma #V-5754).
5) After 30 minutes, CC2-DMPE is removed and the cells are washed twice with 225 µL of
BS#2. As before, the residual volume should be 40 µL.
6) Upon removing the bath, the cells are loaded with 80 µL of the DiSBAC2(3) solution, after
which test compound, dissolved in DMSO, is added to achieve the desired test concentration
to each well from the drug addition plate and mixed thoroughly. The volume in the well
should be roughly 121 µL. The cells are then incubated for 20-30 minutes.
7) Once the incubation is complete, the cells are ready to be assayed on VIPR® with a sodium
addback protocol. 120 µL of Bath solution #1 is added to stimulate the NaV dependent
depolarization. 200 µL tetracaine was used as an antagonist positive control for block of the
NaV channel.
[00377] Analysis of VEPR® Data:
[00378] Data are analyzed and reported as normalized ratios of background-subtracted
emission intensities measured in the 460 nm and 580 nm channels. Background intensities are
then subtracted from each assay channel. Background intensities are obtained by measuring the
emission intensities during the same time periods from identically treated assay wells in which
there are no cells. The response as a function of time is then reported as the ratios obtained
using the following formula:

[00379] The data is further reduced by calculating the initial (Rj) and final (Rf) ratios. These
are the average ratio values during part or all of the pre-stimulation period, and during sample
points during the stimulation period. The response to the stimulus R = Rf/R, is then calculated.
For the Na+ addback analysis time windows, baseline is 2-7 sec and final response is sampled at
15-24 sec.
[00330] Control responses are obtained by performing assays in the presence of a compound
with the desired properties (positive control), such as tetracaine, and in the absence of
pharmacological agents (negative control). Responses to the negative (N) and positive (P)
controls are calculated as above. The compound antagonist activity A is defined as:
where R is the ratio response of the test compound
Solutions [mM]
Bath Solution #1: NaCl 160, KC1 4.5, CaCl2 2, MgCl2 1, HEPES 10, pH 7.4 with NaOH
Bath Solution #2 TMA-C1 160, CaCl2 0.1, MgCl2 1, HEPES 10, pH 7.4 with KOH (final K
concentration - 5 mM)
CC2-DMPE: prepared as a 5 mM stock solution in DMSO and stored at -20°C
DiSBAC2(3): prepared as a 12 mM stock in DMSO and stored at -20°C
ABSC1: prepared as a 200 mM stock in distilled H2O and stored at room
temperature
[00381] Cell Culture
[00382] CHO cells are grown in DMEM (Dulbecco's Modified Eagle Medium; GibcoBRL
#10569-O10) supplemented with 10% FBS (Fetal Bovine Serum, qualified; GibcoBRL #16140-
071) and 1% Pen-Strep (Penicillin-Streptomycin; GibcoBRL #15140-122). Cells are grown in
vented cap flasks, in 90% humidity and 10% CO2, to 100% confluence. They are usually split by
trypsinization 1:10 or 1:20, depending on scheduling needs, and grown for 2-3 days before the
next split.
[00383] C) VIPR® optical membrane potential assay method with electrical stimulation
[00384] The following is an example of how NaV1.3 inhibition activity is measured using the
optical membrane potential method#2. Other subtypes are performed in an analogous mode in a
cell line expressing the NaV of interest.
[00385] HEK293 cells stably expressing NaV1.3 are plated into 96-well microliter plates.
After an appropriate incubation period, the cells are stained with the voltage sensitive dyes CC2-
DMPE/DiSBAC2(3) as follows.
[00386] Reagents:
100 mg/mL Pluronic F-127 (Sigma #P2443), in dry DMSO
10 mM DiSBAC2(3) (Aurora #00-100-O10) in dry DMSO
10 mM CC2-DMPE (Aurora #00-100-O08) in dry DMSO
200 mM ABSCl in H2O
Hank's Balanced Salt Solution (Hyclone #SH30268.02) supplemented with 10 mM HEPES
(Gibco #15630-O80)
[00387] Loading protocol:
[00388] 2X CC2-DMPE = 20 µL CC2-DMPE: 10 mM CC2-DMPE is vortexed with an
equivalent volume of 10% pluronic, followed by vortexing in required amount of BBSS
containing 10 mM HEPES. Each cell plate will require 5 mL of 2X CC2-DMPE. 50 µL of 2X
CC2-DMPE is to wells containing washed cells, resulting in a 10 µL final staining
concentration. The cells are stained for 30 minutes in the dark at RT.
[00389] 2X DISBAC2(3) with ABSC1 = 6µM DISBAC2(3) and 1 mM ABSC1: The
required amount of 10 mM DISBAC2(3) is added to a 50 ml conical tube and mixed with 1 µL
10% pluronic for each mL of solution to be made and vortexed together. Then HBSS/HEPES
is added to make up 2X solution. Finally, the ABSC1 is added .
[00390] The 2X DiSBAC2(3) solution can be used to solvate compound plates. Note that
compound plates are made at 2X drug concentration. Wash stained plate again, leaving residual
volume of 50 µL. Add 50 uL/well of the 2X DiSBAC2(3) w/ ABSC1. Stain for 30 minutes in
the dark at RT.
[00391] The electrical stimulation instrument and methods of use are described in ION
Channel Assay Methods PCT/USO1/21652, herein incorporated by reference. The instrument
comprises a microtiter plate handler, an optical system for exciting the coumarin dye while
simultaneously recording the coumarin and oxonol emissions, a waveform generator, a current-
or voltage-controlled amplifier, and a device for inserting electrodes in well. Under integrated
computer control, this instrument passes user-programmed electrical stimulus protocols to cells
within the wells of the microtiter plate.
[00392] Reagents
[00393] Assay buffer #1
140 mM NaCl, 4.5 mM KC1, 2 mM CaCl2, 1 mM MgCl2, 10 mM HEPES, 10 mM glucose, pH
7.40, 330 mOsm
Pluronic stock (1000X): 100 mg/mL pluronic 127 in dry DMSO
Oxonol stock (3333X): 10 mM DiSBAC2(3) in dry DMSO
Coumarin stock (1000X): 10 mM CC2-DMPE in dry DMSO
ABSC1 stock (400X): 200mM ABSC1 in water
[00394] Assay Protocol
1. Insert or use electrodes into each well to be assayed.
2. Use the current-controlled amplifier to deliver stimulation wave pulses for 3 s. Two
seconds of pre-stimulus recording are performed to obtain the un-stimulated intensities.
Five seconds of post-stimulation recording are performed to examine the relaxation to the
resting state.
[00395] Data Analysis
[00396] Data are analyzed and reported as normalized ratios of background-subtracted
emission intensities measured in the 460 nm and 580 run channels. Background intensities are
then subtracted from each assay channel. Background intensities are obtained by measuring the
emission intensities during the same time periods from identically treated assay wells in which
there are no cells. The response as a function of time is then reported as the ratios obtained
using the following formula:

[00397] The data is further reduced by calculating the initial (R1) and final (Rf) ratios. These
are the average ratio values during part or all of the pre-stimulation period, and during sample
points during the stimulation period. The response to the stimulus R = Rf/Ri is then calculated.
[00398] Control responses are obtained by performing assays in the presence of a compound
with the desired properties (positive control), such as tetracaine, and in the absence of
pharmacological agents (negative control). Responses to the negative (N) and positive (P)
controls are calculated as above. The compound antagonist activity A is defined as:
where R is the ratio response of the test compound.
[00399] ELECTRQPHYSIOLOGY ASSAYS FOR NaV ACTIVITY AND INHBITION OF
TEST COMPOUNDS
[00400] Patch clamp electrophysiology was used to assess the efficacy and selectivity of
sodium channel blockers in dorsal root ganglion neurons. Rat neurons were isolated from the
dorsal root ganglions and maintained in culture for 2 to 10 days in the presence of NGF (50
ng/ml) (culture media consisted of NeurobasalA supplemented with B27, glutamine and
antibiotics). Small diameter neurons (nociceptors, 8-12 µm in diameter) have been visually
identified and probed with fine tip glass electrodes connected to an amplifier (Axon
Instruments). The "voltage clamp" mode has been used to assess the compound's IC50 holding
the cells at - 60 mV. In addition, the "current clamp" mode has been employed to test the
efficacy of the compounds in blocking action potential generation in response to current
injections. The results of these experiments have contributed to the definition of the efficacy
profile of the compounds.
[00401] VOLTAGE-CLAMP assay in DRG neurons
[00402] TTX-resistant sodium currents were recorded from DRG somata using the whole-cell
variation of the patch clamp technique. Recordings were made at room temperature (~22° C)
with thick walled borosilicate glass electrodes (WPI; resistance 3-4 MO) using an Axopatch
200B amplifier (Axon Instruments). After establishing the whole-cell configuration,
approximately 15 minutes were allowed for the pipette solution to equilibrate within the cell
before beginning recording. Currents were lowpass filtered between 2-5 kHz and digitally
sampled at 10 kHz. Series resistance was compensated 60-70% and was monitored continuously
throughout the experiment. The liquid junction potential (-7 mV) between the intracellular
pipette solution and the external recording solution was not accounted for in the data analysis.
Test solutions were applied to the cells with a gravity driven fast perfusion system (SF-77;
Warner Instruments).
[00403] Dose-response relationships were determined in voltage clamp mode by repeatedly
depolarizing the cell from the experiment specific holding potential to a test potential of +10mV
once every 60 seconds. Blocking effects were allowed to plateau before proceeding to the next
test concentration.
[00404] Solutions
[00405] Intracellular solution (in mM): Cs-F (130), NaCl (10), MgCl2 (1), EGTA (1.5),
CaCl2 (0.1), HEPES (10), glucose (2), pH = 7.42, 290 mOsm.
[00406] Extracellular solution (in mM): NaCl (138), CaCl2 (1.26), KC1 (5.33), KH2PO4
(0.44), MgCl2 (0.5), MgSO4 (0.41), NaHCO3 (4), Na2HPO4 (0.3), glucose (5.6), HEPES (10),
CdC12 (0.4 ), NiC12 (0.1), TTX (0.25 x 10-3).
[00407] CURRENT-CLAMP assay for NaV channel inhibition activity of compounds
[00408] Cells were current-clamped in whole-cell configuration with a Multiplamp 700A
amplifier (Axon Inst). Borosilicate pipettes (4-5 MOhm) were filled with (in mM):150 K-
gluconate, 10 NaCl, 0.1 EGTA, 10 Hepes, 2 MgCl2, (buffered to pH 7.34 with KOH). Cells were
bathed in (in mM): 140 NaCl, 3 KC1, 1 MgCl, 1 CaCl, and 10 Hepes). Pipette potential was
zeroed before seal formation; liquid junction potentials were not corrected during acquisition.
Recordings were made at room temperature.
[00409] Following these procedures, representative compounds of the present invention were
found to possess desired voltage gated sodium channel activity and selectivity.
[00410] ASSAYS FOR DETECTING AND MEASURING CaV INHIBITION PROPERTIES
OF COMPOUNDS
[00411] A) Optical methods for assaylng CaV inhibition properties of compounds:
[00412] Compounds of the invention are useful as antagonists of voltage-gated calcium ion
channels. Antagonist properties of test compounds were assessed as follows. Cells expressing
the CaV of interest were placed into microtiter plates. After an incubation period, the cells were
stained with fluorescent dyes sensitive to the transmembrane potential. The test compounds
were added to the microtiter plate. The cells were stimulated with electrical means to evoke a
CaV dependent membrane potential change from unblocked channels, which was detected and
measured with trans-membrane potential-sensitive dyes. Antagonists were detected as a
decreased membrane potential response to the stimulus. The optical membrane potential assay
utilized voltage-sensitive FRET sensors described by Gonzalez and Tsien (See, Gonzalez, J. E.
and R. Y. Tsien (1995) "Voltage sensing by fluorescence resonance energy transfer in single
cells" Biophvs J 69(4): 1272-80, and Gonzalez, J. E. and R. Y. Tsien (1997) "Improved
indicators of cell membrane potential that use fluorescence resonance energy transfer" Chem
Biol 4(4): 269-77) in combination with instrumentation for measuring fluorescence changes such
as the Voltage/Ion Probe Reader (VIPR®) (See, Gonzalez, J. E., K. Oades, et al. (1999) "Cell-
based assays and instrumentation for screening ion-channel targets" Drug Discov Today 4(9):
431-439).
[00413] VIPR optical membrane potential assay method with electrical stimulation
[00414] The following is an example of how CaV2.2 inhibition activity is measured using the
optical membrane potential method. Other subtypes are performed in an analogous mode in a
cell line expressing the CaV of interest.
[00415] HEK293 cells stably expressing CaV2.2 are plated into 96-well microliter plates.
After an appropriate incubation period, the cells are stained with the voltage sensitive dyes CC2-
DMPE/DiSBAC2(3) as follows.
Reagents:
100 mg/mL Pluronic F-127 (Sigma #P2443), in dry DMSO
10 mM DiSBAC6(3) (Aurora #00-100-O10) in dry DMSO
10 mM CC2-DMPE (Aurora #00-100-O08) in dry DMSO
200 mM Acid Yellow 17 (Aurora #VABSC) in H2O
370mM Barium Chloride (Sigma Cat# B6394) in H2O
Bath X
160mM NaCl (Sigma Cat# S-9383)
4.5mM KCI (Sigma Cat# P-5405)
ImM MgC12 (Fluka Cat# 63064)
10mM HEPES (Sigma Cat# H-4034)
pH 7.4 using NaOH
[00416] Loading rotocol:
[00417] 2X CC2-DMPE = 20 µL CC2-DMPE: 10 mM CC2-DMPE is vortexed with an
equivalent volume of 10% pluronic, followed by vortexing in required amount of HBSS
containing 10 mM HEPES. Each cell plate will require 5 mL of 2X CC2-DMPE. 50 µL of 2X
CC2-DMPE is added to wells containing washed cells, resulting in a 10 µM final staining
concentration. The cells are stained for 30 minutes in the dark at RT.
[00418] 2X CC2DMPE & DISBAC6(3) = 8 µM CC2DMPE & 2. 5 µM DISBAC6(3):
Vortex together both dyes with an equivalent volume of 10% pluronic (in DMSO). Vortex in
required amount of Bath X with beta-cyclodextrin. Each 96well cell plate will require 5 ml of
2XCC2DMPE. Wash plate with ELx405 with Bath X, leaving a residual volume of 50 µL/well.
Add 50 µL of 2XCC2DMPE & DISBAC6(3) to each well. Stain for 30 minutes in the dark at
RT.
[00419] 1. 5X AY17 = 750 µM AY17 with 15mM BaCl2: Add Acid Yellow 17 to vessel
containing Bath X. Mix well. Allow solution to sit for 10 minutes. Slowly mix in 370mM
BaCl2. This solution can be used to solvate compound plates. Note that compound plates are
made at 1.5X drug concentration and not the usual 2X. Wash CC2 stained plate, again, leaving
residual volume of 50 µL. Add 100 uL/well of the AY17 solution. Stain forl5 minutes in the
dark at RT. Run plate on the optical reader.
[00420] The electrical stimulation instrument and methods of use are described in ION
Channel Assay Methods PCT/USO1/21652, herein incorporated by reference. The instrument
comprises a microtiter plate handler, an optical system for exciting the coumarin dye while
simultaneously recording the coumarin and oxonol emissions, a waveform generator, a current-
or voltage-controlled amplifier, and a device for inserting electrodes in well. Under integrated
computer control, this instrument passes user-programmed electrical stimulus protocols to cells
within the wells of the microtiter plate.
[00421] Assay Protocol
[00422] 'Insert or use electrodes into each well to be assayed.
[00423] Use the current-controlled amplifier to deliver stimulation wave pulses for 3-5 s.
Two seconds of pre-stimulus recording are performed to obtain the un-stimulated intensities.
Five seconds of post-stimulation recording are performed to examine the relaxation to the resting
state.
[00424] Data Analysis
[00425] Data are analyzed and reported as normalized ratios of background-subtracted
emission intensities measured in the 460 nm and 580 nm channels. Background intensities are
then subtracted from each assay channel. Background intensities are obtained by measuring the
emission intensities during the same time periods from identically treated assay wells in which
there are no cells. The response as a function of time is then reported as the ratios obtained
using the following formula:

[00426] The data is further reduced by calculating the initial (Ri) and final (Rf) ratios. These
are the average ratio values during part or all of the pre-stimulation period, and during sample
points during the stimulation period. The response to the stimulus R = Rf/Ri is then calculated.
[00427] Control responses are obtained by performing assays in the presence of a compound
with the desired properties (positive control), such as mibefradil, and in the absence of
pharmacological agents (negative control). Responses to the negative (N) and positive (P)
controls are calculated as above. The compound antagonist activity A is defined as:
where R is the ratio response of the test compound.
[00428] ELECTROPHYSIOLOGY ASSAYS FOR CaV ACTIVITY AND INHBITION OF
TEST COMPOUNDS
[00429] Patch clamp electrophysiology was used to assess the efficacy of calcium channel
blockers expressed in HEK293 cells. HEK293 cells expressing CaV2.2 have been visually
identified and probed with fine tip glass electrodes connected to an amplifier (Axon
Instruments). The "voltage clamp" mode has been used to assess the compound's IC50 holding
the cells at - 100 mV. The results of these experiments have contributed to the definition of the
efficacy profile of the compounds.
[00430] VOLTAGE-CLAMP assay in HEK293 cells expressing CaV2.2
[00431] CaV2.2 calcium currents were recorded from HEK293 cells using the whole-cell
variation of the patch clamp technique. Recordings were made at room temperature (-22° C)
with thick walled borosilicate glass electrodes (WPI; resistance 3-4 MO) using an Axopatch
200B amplifier (Axon Instruments). After establishing the whole-cell configuration,
approximately 15 minutes were allowed for the pipette solution to equilibrate within the cell
before beginning recording. Currents were lowpass filtered between 2-5 kHz and digitally
sampled at 10 kHz. Series resistance was compensated 60-70% and was monitored continuously
throughout the experiment. The liquid junction potential (-7 mV) between the intracellular
pipette solution and the external recording solution was not accounted for in the data analysis.
Test solutions were applied to the cells with a gravity driven fast perfusion system (SF-77;
Warner Instruments).
[00432] Dose-response relationships were determined in voltage clamp mode by repeatedly
depolarizing the cell from the experiment specific holding potential to a test potential of +20mV
for 50ms at frequencies of 0.1,1, 5, 10, 15, and 20 Hz. Blocking effects were allowed to plateau
before proceeding to the next test concentration.
[00433] Solutions
[00434] Intracellular solution (in mM): Cs-F (130), NaCl (10), MgCl2 (1), EGTA (1.5),
CaCl2 (0.1), HEPES (10), glucose (2), pH = 7.42,290 mOsm.
[00435] Extracellular solution (in mM): Nad (138), BaCl2 (10), KC1 (5.33), KH2PO4 (0.44),
MgCl2 (0.5), MgSO4 (0.41), NaHCO3 (4), Na2HPO4 (0.3), glucose (5.6), HEPES (10).
[00436] Following these procedures, representative compounds of the present invention were
found to possess desired N-type calcium channel modulation activity and selectivity.
WE CLAIM:
1. A compound of formula IA-ii:

or a pharmaceutically acceptable salt thereof, wherein:
a) the ring formed by R1 and R2 taken together is selected from:

and the ring formed by R1 and R2 taken together, is optionally substituted at one or more
substitutable carbon, nitrogen, or sulfur atoms with z independent occurrences of -R, and z is 0-
5;
b) wherein z is 0-5, and R groups, when present, are each independently halogen. CN,
NO2, -N(R')2, -CH2N(R')2, -OR', -CH2OR', -SR', -CH2SR', -COOR'. -NRCOR', -CON(R')2, -
OCON(R')2, COR', -NHCOOR', -SO2R', -SO2N(R')2, or an optionally substituted group
selected from C1-C6aliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC1-
C6alkyl, heteroarylC1-C6alkyl, cycloaliphaticC1-C6alkyl, or heterocycloaliphaticC1-C6alkyl;
c) wherein x is 1 or 2 and each R group is independently halogen, CN, optionally
substituted C1-C6alkyl, -N(R')2, -OR', -NRCOR' or -CON(R')2;
d) wherein y is 0-5, and R groups, when present, are each independently halogen, CN,
NO2, -N(R')2, -CH2N(R')2, -OR', -CH2OR', -SR', -CH2SR', - -NRCOR', -CON(R')2, -
S(O)2N(R')2, -OCOR', -COR', -CO2R', -OCON(R')2, -NR'SO2R', -OP(O)(OR')2, -P(O)(OR')2,
-OP(O)2OR', -P(O)2OR', -PO(R')2, -OPO(R')2, or an optionally substituted group selected from
C1-C6aliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC1-C6alkyl,
heteroarylC1-C6alkyl, cycloaliphaticC1-C6alkyl, or heterocycloaliphaticC1-C6alkyl; and
e) R5a is CI. Br, F, CF3, Me, Et, CN, -COOH, -NH2, -N(CH3)2, -N(Et)2, -N(iPr)2,
-O(CH2)2OCH3, -CONH2, -COOCH3, -OH, -OCH3, -OCH2CH3, -CH2OH, -NHCOCH3,
-SO2NH2, -SO2NHC(CH3)3, -OCOC(CH3)3, -OCOCH2C(CH3)3, -O(CH2)2N(CH3)2,
4-CH3-piperazin-l-yl, OCOCH(CH3)2, OCO(cyclopentyl), -COCH3, optionally substituted
phenoxy, or optionally substituted benzyloxy and
each occurrence of R is independently hydrogen or an optionally substituted C1-6 aliphatic
group; and each occurrence of R is independently hydrogen or an optionally substituted C1-6
aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic
ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12
membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5
heteroatoms independently selected from nitrogen, oxygen, or sulfur; or R and R, two
occurrences of R, or two occurrences of R, are taken together with the atom(s) to which they are
bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully
unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from
nitrogen, oxygen, or sulfur;
provided that:
(a) when x is 2, and R3 is 6,7-diOMe, then R1 and R2, taken together is not optionally
substituted piperidin-1-yl or piperazin-1-yl.
2. The compound as claimed in claim 1, wherein z is 0-5 and R groups are each
independently Cl, Br, F, CF3, CH3, -CH2CH3, CN, -COOH, -N(CH3)2, -N(Et)2, -N(iPr)2, -
O(CH2)2OCH3, -CONH2, -COOCH3, -OH, -CH2OH, -NHCOCH3, -SO2NH2, -SO2(CH2)3CH3, -
SO2CH(CH3)3, -SO2N(CH3)2, -SO2CH2CH3, -C(O)0CH2CH(CH3)2, -C(O)NHCH2CH(CH3)2, -
NHCOOCH3, -C(O)C(CH3)3, -COO(CH2)2CH3, -C(O)NHCH(CH3)2, -C(O)CH2CH3, or an
optionally substituted group selected from -piperidinyl, piperazinyl, morpholino, C1-4alkoxy,
phenyl, phenyloxy, benzyl, benzyloxy, -CH2cyclohexyl, pyridyl, -CH2pyridyl, or -CH2thiazolyl.
3. The compound as claimed in claim 1, wherein x is 1 or 2, and each R group is -Cl, -CH3,
-CH2CH3, -F, -CF3, -OCF3, -CONHCH3, -CONHCH2CH3, -CONH(cyclopropyl), -OCH3, -NH2,
-OCH2CH3, or -CN.
4. The compound as claimed in any one of claims 1-4, wherein R is substituted at the 6-
position of the quinazoline ring, q is 1, and y is 0, and compounds have formula III:

5. The compound as claimed in any one of claims 1-3, wherein R3 is substituted at the 7-
position of the quinazoline ring, q is 1, and y is 0, and compounds have formula IV:

6. The compound as claimed in claim 1, wherein x is 1 and R3 is at the 6-position of the
quinazoline ring and is -Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -CONHCH3, -CONHCH2CH3,
-CONH(cyclopropyl), -OCH3, -NH2, -OCH2CH3, or -CN.
7. The compound as claimed in claim 1, wherein x is 1 and R3 is at the 7-position of the
quinazoline ring and is -Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -CONHCH3. -CONHCH2CH3,
-CONH(cyclopropyl), -OCH3, -NH2, -OCH2CH3, or -CN.
8. The compound as claimed in claim 6, wherein x is 1 and R3 is at the 6-position of the
quinazoline ring and is -Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -OCH3, or -OCH2CH3.
9. The compound as claimed in claim 7, wherein x is 1 and R3 is at the 7-position of the
quinazoline ring and is -Cl, -CH3, ~CH2CH3, -F, -CF3, -OCF3, -OCH3, or -OCH2CH3.
10. The compound as claimed in claim 1, wherein x is 1 and R is at the 6-position of the
quinazoline ring and is -CON(R')2, or -NRCOR'.
11. The compound as claimed in claim 1, wherein:
a) R and R taken together is an optionally substituted ring selected from azetidin-1-yl
(jj), pyrrolidin-1-yl (ff), piperidinl-yl (dd), or piperazin-1-yl (cc);
b) z is 0-5 and R4 groups are each independently ClI, Br, F, CF3, CH3, -CH2CH3. CN,
-COOH, -N(CH3)2, -N(Et)2, -N(iPr)2, -O(CH2)2OCH3, -CONH2, -COOCH3, -OH, -CH2OH,
-NHCOCH3, -SO2NH2, -SO2(CH2)3CH3, -SO2CH(CH3)2, -SO2N(CH3)2, -SO2CH2CH3,
-C(O)OCH2CH(CH3)2, -C(O)NHCH2CH(CH3)2, -NHCOOCH3, -C(O)C(CH3)3,
-COO(CH2)2CH3, -C(O)NHCH(CH3)2, -C(O)CH2CH3, or an optionally substituted group
selected from piperidinyl, piperazinyl, morpholino, C1-4alkoxy, phenyl, phenyloxy, benzyl,
benzyloxy, -CH2cyclohexyl, pyridyl, -CH2pyridyl, or -CH2thiazolyl;
c) wherein x is 1 or 2 and each R group is independently halogen, CN, optionally
substituted C1.C6alkyl, -N(R')2, -OR', -NRCOR' or -CON(R')2;
d) wherein y is 0-4, and R groups, when present, are each independently Cl, Br, F, CF3.
Me, Et, CN, -COOH, -NH2, -N(CH3)2, -N(Et)2, -N(iPr)2, -O(CH2)2OCH3, -CONH2, -COOCH3,
-OH, -OCH3, -OCH2CH3, -CH2OH, -NHCOCH3, -SO2NH2, -SO2NHC(CH3)3, -OCOC(CH3)3,
-OCOCH2C(CH3)3, -O(CH2)2N(CH3)2, 4-CH3-piperazin-l-yl, -OCOCH(CH3)2,
-OCO(cyclopentyl), -COCH3, optionally substituted phenoxy, or optionally substituted
benzyloxy; and
e) R5a is Cl, F, CF3, Me, Et, -OH, -OCH3, -OCH2CH3, -CH2OH, -SO2NH2,
-SO2NHC(CH3)3, -OCOC(CH3)3, -OCOCH2C(CH3)3, -O(CH2)2N(CH3)2, 4-CH3-piperazin-l-yl,
-OCOCH(CH3)2, -OCO(cyclopentyl), or -COCH3.
12. The compound as claimed in claim 1, wherein R a is Cl, F, CF3. Me, Et, -OH, -OCH3 or -
OCH2CH3.
13. The compound as claimed in claim 1, wherein:
a) R1 and R2 taken together is an optionally substituted ring selected from azetidin-1-yl
(jj), pyrrolidin-1-yl (ff), piperidinl-yl (dd), or piperazin-1-yl (cc);
b) z is 0-5 and R4 groups are each independently Cl, Br, F, CF3, CH3, -CH2CH3, CN,
-COOH, -N(CH3)2, -N(Et)2, -N(iPr)2, -O(CH2)2OCH3, -CONH2, -COOCH3, -OH, -CH2OH,
-NHCOCH3, -SO2NH2, -SO2(CH2)3CH3, -SO2CH(CH3)2, -SO2N(CH3)2, -SO2CH2CH3,
-C(O)OCH2CH(CH3)2, -C(O)NHCH2CH(CH3)2, -NHCOOCH3, -C(O)C(CH3)3,
COO(CH2)2CH3, -C(O)NHCH(CH3)2, -C(O)CH2CH3, or an optionally substituted group selected
from piperidinyl, piperazinyl, morpholino, C^alkoxy, phenyl, phenyloxy, benzyl, benzyloxy,
-CH2cyclohexyl, pyridyl, -CH2pyridyl, or -CH2thiazolyl;
c) x is 1, and each occurrence of R3 is independently Cl, Br, F, CF3, -OCF3, Me, Et, CN,
-COOH, -OH, or -OCH3;
d) y is 0 or 1, and R groups, when present, are each independently Cl, Br, F, CF3, Me,
-OH, -OCH3, -OCH2CH3, -CH2OH, -NHCOCH3, -SO2NH2, -SO2NHC(CH3)3; and
e) R5a is F, -OR', or NHSO2R'.
14. The compound as claimed in claim 1, wherein R5a is OR' and x is 1 and R is at the 6-
position of the quinazoline ring and is -Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -OCH3, or -
OCH2CH3.
15. The compound as claimed in claim 1, wherein R5a is OR' and x is 1 and R is at the 7-
position of the quinazoline ring and is -Cl, -CH3, -CH2CH3, -F, -CF3, -OCF3, -OCH3, or -
OCH2CH3.
16. The compound as claimed in claim 1, wherein said compound is selected from Table 2.
17. A composition comprising a compound as claimed in any one of claims 1-16; and a
pharmaceutically acceptable carrier, vehicle, or diluent.
18. A composition for treating or lessening the severity of a disease, disorder, or condition
selected from acute, chronic, neuropathic, or inflammatory pain, arthritis, migrane, cluster
headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, epilepsy or epilepsy
conditions, neurodegenerative disorders, psychiatric disorders such as anxiety and depression,
myotonia, arrythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis,
irritable bowel syndrome, incontinence, visceral pain, osteoarthritis pain, postherpetic neuralgia,
diabetic neuropathy, radicular pain, sciatica, back pain, head or neck pain, severe or intractable
pain, nociceptive pain, breakthrough pain, postsurgical pain, or cancer pain comprising the step
of administering to said patient an effective amount of a compound of formula IIA-ii as claimed
in claim 1.
19. A composition as claimed in claim 18, wherein the disease, condition, or disorder is
implicated in the activation or hyperactivity of voltage-gated sodium channels.
20. A composition as claimed in claim 18, wherein the disease, condition, or disorder is
implicated in the activation or hyperactivity of calcium channels.
21. A composition as claimed in claim 18, wherein the disease, condition, or disorder is
acute, chronic, neuropathic, or inflammatory pain.
22. A composition as claimed in claim 18, wherein the disease, condition, or disorder is
radicular pain, sciatica, back pain, head or neck pain.
23. A composition as claimed in claim 18, wherein the disease, condition, or disorder is
severe or intractable pain, acute pain, postsurgical pain, back pain or cancer pain.
24. A method of inhibiting one or more of NaVl.l, NaV1.2, NaV1.3, NaV1.4, NaV1.5,
NaV1.6, NaV1.7, NaV1.8, NaV1.9, or CaV2.2 activity in a biological sample comprising the
step of contacting said biological sample with a compound of formula IIA-ii as claimed in claim
1.
25. A composition as claimed in claim 1 for inhibiting one or more of NaVl.l, NaV1.2,
NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, NaV1.9, or CaV2.2 activity in a patient.

The present invention relates to quinazoline compounds of formula (I) useful us inhibitors of voltage-gated sidium
channels and calcium channels. The invention also provides pharmaceutically acceptable compositions comprising the compounds
of the invention and methods of using the compositions in the treatment of various disorders, or a pharmaceutically acceptable
derivative thereof, wherein Rl, X. R3, x, and ring A are as defined in the present application.

Documents:

01955-kolnp-2005-abstract.pdf

01955-kolnp-2005-claims.pdf

01955-kolnp-2005-description complete.pdf

01955-kolnp-2005-form 1.pdf

01955-kolnp-2005-form 3.pdf

01955-kolnp-2005-form 5.pdf

01955-kolnp-2005-international publication.pdf

1955-kolnp-05-granted-description (complete).pdf

1955-KOLNP-2005-FORM-27.pdf

1955-kolnp-2005-granted-abstract.pdf

1955-kolnp-2005-granted-assignment.pdf

1955-kolnp-2005-granted-claims.pdf

1955-kolnp-2005-granted-correspondence.pdf

1955-kolnp-2005-granted-examination report.pdf

1955-kolnp-2005-granted-form 1.pdf

1955-kolnp-2005-granted-form 13.pdf

1955-kolnp-2005-granted-form 18.pdf

1955-kolnp-2005-granted-form 3.pdf

1955-kolnp-2005-granted-form 5.pdf

1955-kolnp-2005-granted-gpa.pdf

1955-kolnp-2005-granted-reply to examination report.pdf

1955-kolnp-2005-granted-specification.pdf


Patent Number 239547
Indian Patent Application Number 1955/KOLNP/2005
PG Journal Number 13/2010
Publication Date 26-Mar-2010
Grant Date 24-Mar-2010
Date of Filing 03-Oct-2005
Name of Patentee VERTEX PHARMACEUTICALS INCORPORATED
Applicant Address 130 WAVERLY STREET, CAMBRIDGE, MA 02139
Inventors:
# Inventor's Name Inventor's Address
1 WILSON DEAN MITCHELL 9317 PIPILO STREET, SAN DIEGO, CA 92129
2 GONZALES JESUS E., III 12442 CARMEL CAPE, SAN DIEGO, CA 92130
3 TERMIN ANDREAS PETER 2080 WANDERING ROAD, ENCINITAS, CA 92024
4 GROOTENHUIS PETER DIEDERIK JAN 4801 RIDING RIDGE ROAD, SAN DIEGO, CA 92130
5 ZHANG YULIAN 7809 PALMILLA DRIVE, #1301, SAN DIEGO, CA 92122
6 PETZOLDT BENJAMIN JOHN 7309 EADS AVENUE, LA JOLLA, CA 92037
7 FANNING LEV TYLER DEWEY 5175 LUIGI TERRACE, #25, SAN DIEGO, CA 921222
8 NEUBERT TIMOTHY DONALD 10721 BALLYSTOCK COURT, SAN DIEGO, CA 92131
9 TUNG ROGER D 14015 CAMINITO PACIFICA TRAIL, SAN DIEGO, CA 92130
10 MARTINBOROUGH ESTHER 11128 PORTOBELO DRIVE, SAN DIEGO, CA 92124
11 ZIMMERMANN NICOLE 11568 COMPASS POINT DRIVE NORTH, APT. 54, SAN DIEGO, CA 92126
PCT International Classification Number C07D 239/94
PCT International Application Number PCT/US2004/006451
PCT International Filing date 2004-03-03
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/451,458 2003-03-03 U.S.A.
2 60/463,797 2003-04-18 U.S.A.