# Patent

## Title
Azaspiro[4.5] decane derivatives and use thereof

## Abstract

The invention provides azaspiro[4.5]decane derivatives of Formula (A): and pharmaceutically acceptable salts, solvates, hydrates, N-oxides, and diastereomers thereof, wherein A1, X, A2, Rr, R2′, W1, R3′, R4′, a, and b are defined in the disclosure. The invention also provides compounds of Formulae I, and B-G, and pharmaceutically acceptable salts, solvates, hydrates, N-oxides, and diastereomers thereof. Further, the invention provides use of the compounds of Formulae A-G and I, and the pharmaceutically acceptable salts, solvates, hydrates, N-oxides, and diastereomers thereof, to treat pain. In certain embodiments, Compounds of the Disclosure are useful for treating a disorder responsive to blockade of one or more sodium channels.

## Background
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is the U.S. national phase, pursuant to 35 U.S.C. § 371, of PCT International Application Ser. No. PCT/US2014/050549, filed Aug. 11, 2014, designating the United States and published in English on Mar. 5, 2015 as publication WO 2015/031036 A1, which claims priority to U.S. Provisional Application Ser. No. 61/987,727, filed May 2, 2014; and U.S. Provisional Application Ser. No. 61/869,941, filed Aug. 26, 2013. The contents of the afore-mentioned patent applications are incorporated herein by their entirety.


BACKGROUND OF THE INVENTION
Voltage-gated sodium channels (VGSCs) are found in all excitable cells. In neuronal cells of the central nervous system (CNS) and peripheral nervous system (PNS) sodium channels are primarily responsible for generating the rapid upstroke of the action potential. In this manner sodium channels are essential to the initiation and propagation of electrical signals in the nervous system. Proper function of sodium channels is therefore necessary for normal function of the neuron. Consequently, aberrant sodium channel function is thought to underlie a variety of medical disorders (See Hubner et al., Hum. Mol. Genet. 11:2435-2445 (2002) for a general review of inherited ion channel disorders) including epilepsy (Yogeeswari et al, Curr. Drug Target 5:589-602 (2004)), arrhythmia (Noble, Proc. Natl. Acad. Sci. USA 99:5755-5756 (2002)), myotonia (Cannon, Kidney Int. 57:772-779 (2000)), and pain (Wood et al., J. Neurobiol., 61:55-71 (2004)).
VGSCs are composed of one α-subunit, which forms the core of the channel and is responsible for voltage-dependent gating and ion permeation, and several auxiliary β-subunits (see, e.g., Chahine et al., CNS & Neurological Disorders-Drug Targets 7:144-158 (2008) and Kyle and Ilyin, J. Med. Chem. 50:2583-2588 (2007)). α-Subunits are large proteins composed of four homologous domains. Each domain contains six α-helical transmembrane spanning segments. There are currently nine known members of the family of voltage-gated sodium channel α-subunits. Names for this family include SCNx, SCNAx, and Navx.x (see TABLE 1, below). The VGSC family has been phylogenetically divided into two subfamilies Nav1.x (all but SCN6A) and Nav2.x (SCN6A). The Nav1.x subfamily can be functionally subdivided into two groups, those which are sensitive to blocking by tetrodotoxin (TTX-sensitive or TTX-s) and those which are resistant to blocking by tetrodotoxin (TTX-resistant or TTX-r).
There are three members of the subgroup of TTX-resistant sodium channels. The SCN5A gene product (Nav1.5, H1) is almost exclusively expressed in cardiac tissue and has been shown to underlie a variety of cardiac arrhythmias and other conduction disorders (Liu et al., Am. J. Pharmacogenomics 3:173-179 (2003)). Consequently, blockers of Nav1.5 have found clinical utility in treatment of such disorders (Srivatsa et al., Curr. Cardiol. Rep. 4:401-410 (2002)). The remaining TTX-resistant sodium channels, Nav1.8 (SCN10A, PN3, SNS) and Nav1.9 (SCN11A, NaN, SNS2) are expressed in the peripheral nervous system and show preferential expression in primary nociceptive neurons. Human genetic variants of these channels have not been associated with any inherited clinical disorder. However, aberrant expression of Nav1.8 has been found in the CNS of human multiple sclerosis (MS) patients and also in a rodent model of MS (Black et al., Proc. Natl. Acad. Sci. USA 97:11598-115602 (2000)). Evidence for involvement in nociception is both associative (preferential expression in nociceptive neurons) and direct (genetic knockout). Nav1.8-null mice exhibited typical nociceptive behavior in response to acute noxious stimulation but had significant deficits in referred pain and hyperalgesia (Laird et al., J. Neurosci. 22:8352-8356 (2002)).







TABLE 1







Voltage-gated sodium channel gene family













Gene
Tissue
TTX IC50
Disease



Type
Symbol
Distribution
(nM)
Association
Indications















Nav1.1
SCN1A
CNS/PNS
10
Epilepsy
Pain, seizures,







neurodegeneration


Nav1.2
SCN2A
CNS
10
Epilepsy
Epilepsy,







neurodegeneration


Nav1.3
SCN3A
CNS
15
—
Pain


Nav1.4
SCN4A
Skeletal muscle
25
Myotonia
Myotonia


Nav1.5
SCN5A
Heart muscle
2,000
Arrhythmia
Arrhythmia


Nav1.6
SCN8A
CNS/PNS
6
—
Pain, movement







disorders


Nav1.7
SCN9A
PNS
25
Erythermalgia
Pain


Nav1.8
SCN10A
PNS
50,000
—
Pain


Nav1.9
SCN11A
PNS
1,000
—
Pain









The Nav1.7 (PN1, SCN9A) VGSC is sensitive to blocking by tetrodotoxin and is preferentially expressed in peripheral sympathetic and sensory neurons. The SCN9A gene has been cloned from a number of species, including human, rat, and rabbit and shows  ̃90% amino acid identity between the human and rat genes (Toledo-Aral et al., Proc. Natl. Acad. Sci. USA 94:1527-1532 (1997)).
An increasing body of evidence suggests that Nav1.7 plays a key role in various pain states, including acute, inflammatory and/or neuropathic pain. Deletion of the SCN9A gene in nociceptive neurons of mice led to an increase in mechanical and thermal pain thresholds and reduction or abolition of inflammatory pain responses (Nassar et al., Proc. Natl. Acad. Sci. USA 101:12706-12711 (2004)).
Sodium channel-blocking agents have been reported to be effective in the treatment of various disease states, and have found particular use as local anesthetics, e.g., lidocaine and bupivacaine, and in the treatment of cardiac arrhythmias, e.g., propafenone and amiodarone, and epilepsy, e.g., lamotrigine, phenytoin and carbamazepine (see Clare et al., Drug Discovery Today 5:506-510 (2000); Lai et al., Annu. Rev. Pharmacol. Toxicol. 44:371-397 (2004); Anger et al., J. Med. Chem. 44:115-137 (2001), and Catterall, Trends Pharmacol. Sci. 8:57-65 (1987)). Each of these agents is believed to act by interfering with the rapid influx of sodium ions.
Other sodium channel blockers such as BW619C89 and lifarizine have been shown to be neuroprotective in animal models of global and focal ischemia (Graham et al., J. Pharmacol. Exp. Ther. 269:854-859 (1994); Brown et al., British J. Pharmacol. 115:1425-1432 (1995)).
It has also been reported that sodium channel-blocking agents can be useful in the treatment of pain, including acute, chronic, inflammatory, neuropathic, and other types of pain such as rectal, ocular, and submandibular pain typically associated with paroxysmal extreme pain disorder; see, for example, Kyle and Ilyin., J. Med. Chem. 50:2583-2588 (2007); Wood et al., J. Neurobiol. 61:55-71 (2004); Baker et al., TRENDS in Pharmacological Sciences 22:27-31 (2001); and Lai et al., Current Opinion in Neurobiology 13:291-297 (2003); the treatment of neurological disorders such as epilepsy, seizures, epilepsy with febrile seizures, epilepsy with benign familial neonatal infantile seizures, inherited pain disorders, e.g., primary erthermalgia and paroxysmal extreme pain disorder, familial hemiplegic migraine, and movement disorder; and the treatment of other psychiatric disorders such as autism, cerebellar atrophy, ataxia, and mental retardation; see, for example, Chahine et al., CNS & Neurological Disorders-Drug Targets 7:144-158 (2008) and Meisler and Kearney, J. Clin. Invest. 115:2010-2017 (2005). In addition to the above-mentioned clinical uses, carbamazepine, lidocaine and phenytoin are used to treat neuropathic pain, such as from trigeminal neuralgia, diabetic neuropathy and other forms of nerve damage (Taylor and Meldrum, Trends Pharmacol. Sci. 16:309-316 (1995)). Furthermore, based on a number of similarities between chronic pain and tinnitus, (Moller, Am. J. Otol. 18:577-585 (1997); Tonndorf, Hear. Res. 28:271-275 (1987)) it has been proposed that tinnitus should be viewed as a form of chronic pain sensation (Simpson, et al., Tip. 20:12-18 (1999)). Indeed, lidocaine and carbamazepine have been shown to be efficacious in treating tinnitus (Majumdar, B. et al., Clin. Otolaryngol. 8:175-180 (1983); Donaldson, Laryngol. Otol. 95:947-951 (1981)).
Many patients with either acute or chronic pain disorders respond poorly to current pain therapies, and the development of resistance or insensitivity to opiates is common. In addition, many of the currently available treatments have undesirable side effects.
In view of the limited efficacy and/or unacceptable side-effects of the currently available agents, there is a pressing need for more effective and safer analgesics that work by blocking sodium channels.
BRIEF SUMMARY OF THE INVENTION
In one aspect, the present disclosure provides novel compounds represented by Formula I or A, provided below, and pharmaceutically acceptable salts, solvates, hydrates, N-oxides, and diastereomers thereof, collectively referred to herein as “Compounds of the Disclosure.”
In another aspect, the present disclosure provides a method for treating pain (e.g., acute pain, chronic pain, which includes but is not limited to, neuropathic pain, postoperative pain, and inflammatory pain, or surgical pain), comprising administering an effective amount of a Compound of the Disclosure to a mammal in need of such treatment. Specifically, the present disclosure provides a method for preemptive or palliative treatment of pain by administering an effective amount of a Compound of the Disclosure to a mammal in need of such treatment.
In another aspect, the present disclosure provides Compounds of the Disclosure for use in treating pain in a mammal, e.g., acute pain, chronic pain, which includes, but is not limited to, neuropathic pain, postoperative pain, inflammatory pain, or surgical pain.
In another aspect, the present disclosure provides a method for treating stroke, neuronal damage resulting from head trauma, epilepsy, seizures, general epilepsy with febrile seizures, severe myoclonic epilepsy in infancy, neuronal loss following global and focal ischemia, migraine, familial primary erythromelalgia, paroxysmal extreme pain disorder, cerebellar atrophy, ataxia, dystonia, tremor, mental retardation, autism, a neurodegenerative disorder (e.g., Alzheimer's disease, amyotrophic lateral sclerosis (ALS), or Parkinson's disease), manic depression, tinnitus, myotonia, a movement disorder, or cardiac arrhythmia, or providing local anesthesia, comprising administering an effective amount of a Compound of the Disclosure to a mammal in need of such treatment.
In another aspect, the present disclosure provides the use of Compounds of the Disclosure as blockers of one or more sodium (Na+) channels.
In another aspect, the present disclosure provides compounds as synthetic intermediates that can be used to prepare blockers of one or more sodium (Na+) channels.
In another aspect, the present disclosure provides a method for treating a disorder responsive to blockade of one or more sodium channels in a mammal, comprising administering to the mammal an effective amount of a Compound of the Disclosure.
In yet another aspect, the present disclosure provides a pharmaceutical composition comprising a Compound of the Disclosure and one or more pharmaceutically acceptable carriers.
The present disclosure further provides a pharmaceutical composition for treating a disorder responsive to blockade of one or more sodium ion channels, wherein the pharmaceutical composition comprises an effective amount of a Compound of the Disclosure in a mixture with one or more pharmaceutically acceptable carriers.
Another aspect of the present disclosure provides a method of modulating one or more sodium channels in a mammal, comprising administering to the mammal an effective amount of at least one Compound of the Disclosure.
In another aspect, the present disclosure provides a radiolabeled Compound of the Disclosure and the use of such compounds as radioligands in any appropriately selected competitive binding assays and screening methodologies. Thus, the present disclosure further provides a method for screening a candidate compound for its ability to bind to a sodium channel or sodium channel subunit using a radiolabeled Compound of the Disclosure. In certain embodiments, the compound is radiolabeled with 3H, 11C, or 14C. This competitive binding assay can be conducted using any appropriately selected methodology. In one embodiment, the screening method comprises: i) introducing a fixed concentration of the radiolabeled compound to an in vitro preparation comprising a soluble or membrane-associated sodium channel, subunit or fragment under conditions that permit the radiolabeled compound to bind to the channel, subunit or fragment, respectively, to form a conjugate; ii) titrating the conjugate with a candidate compound; and iii) determining the ability of the candidate compound to displace the radiolabeled compound from said channel, subunit or fragment.
In another aspect, the present disclosure provides a Compound of the Disclosure for use in the manufacture of a medicament for treating pain in a mammal. In one embodiment, the present disclosure provides the use of a Compound of the Disclosure in the manufacture of a medicament for palliative or preemptive treatment of pain, such as acute pain, chronic pain, or surgical pain.
In another aspect, the present disclosure provides a Compound of the Disclosure for use in the manufacture of a medicament for treating stroke, neuronal damage resulting from head trauma, epilepsy, seizures, general epilepsy with febrile seizures, severe myoclonic epilepsy in infancy, neuronal loss following global and focal ischemia, migraine, familial primary erythromelalgia, paroxysmal extreme pain disorder, cerebellar atrophy, ataxia, dystonia, tremor, mental retardation, autism, a neurodegenerative disorder (e.g., Alzheimer's disease, amyotrophic lateral sclerosis (ALS), or Parkinson's disease), manic depression, tinnitus, myotonia, a movement disorder, or cardiac arrhythmia, or providing local anesthesia, in a mammal.
Additional embodiments and advantages of the disclosure will be set forth, in part, in the description that follows, and will flow from the description, or can be learned by practice of the disclosure. The embodiments and advantages of the disclosure will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims.
It is understood that both the foregoing summary and the following detailed description are exemplary and explanatory only, and are not restrictive of the invention as claimed.


DETAILED DESCRIPTION OF THE INVENTION
One aspect of the invention is based on discovery of compounds delineated herein (referred to as “Compounds of the Disclosure”) that are useful for treating pain in a subject (e.g., a mammal).
In certain embodiments, the Compounds of the Disclosure are useful as blockers of one or more sodium (Na+) channels. It is thus believed that the Compounds of the Disclosure are useful for treating disorders responsive to the blockade of one or more sodium ion channels. Another aspect of the invention is based on the use of Compounds of the Disclosure as synthetic intermediates useful for preparing sodium channel blockers.
In one embodiment, Compounds of the Disclosure are compounds represented by Formula I:




and pharmaceutically acceptable salts and solvates thereof,
wherein:
R1 is selected from the group consisting of:




R2a and R2b are each independently selected from the group consisting of: (a) hydrogen; (b) halo; (c) nitro; (d) cyano; (e) hydroxy; (f) amino; (g) alkylamino; (h) dialkylamino; (i) alkyl; (j) haloalkyl; (k) hydroxyalkyl; (l) alkoxy; (m) haloalkoxy; and (n) alkoxyalkyl;
R2c and R2d are each independently selected from the group consisting of: (a) hydrogen; (b) halo; (c) nitro; (d) cyano; (e) hydroxy; (f) amino; (g) alkylamino; (h) dialkylamino; (i) alkyl; (j) haloalkyl; (k) hydroxyalkyl; (l) alkoxy; (m) haloalkoxy; and (n) alkoxyalkyl;
 is a single bond or a double bond;
X1 is selected from the group consisting of 0 and NR3;
X2 is selected from the group consisting of CH2 and C═O;
R3 is selected from the group consisting of hydrogen and alkyl;
R4a is selected from the group consisting of hydrogen and alkyl;
R4b and R4c are each independently selected from the group consisting of hydrogen, alkyl, and optionally substituted aryl;
R5a is selected from the group consisting of: (a) hydrogen; (b) halo; (c) nitro; (d) cyano; (e) hydroxy; (f) amino; (g) alkylamino; (h) dialkylamino; (i) haloalkyl; (j) hydroxyalkyl; (k) alkoxy; (l) haloalkoxy; (m) alkoxyalkyl; and (n) —Z—R9;
R5b is selected from the group consisting of: (a) hydrogen; (b) halo; (c) nitro; (d) cyano; (e) hydroxy; (f) amino; (g) alkylamino; (h) dialkylamino; (i) haloalkyl; (j) hydroxyalkyl; (k) alkoxy; (l) haloalkoxy; and (m) alkoxyalkyl;
E is selected from the group consisting of: (a) hydroxy; (b) alkoxy; and (c) —NR6R7;
R6 is selected from the group consisting of: (a) hydrogen; (b) alkyl; (c) aralkyl; (d) (heterocyclo)alkyl; (e) (heteroaryl)alkyl; (f) (amino)alkyl; (g) (alkylamino)alkyl; (h) (dialkylamino)alkyl; (i) (carboxamido)alkyl; (j) (cyano)alkyl; (k) alkoxyalkyl; (l) hydroxyalkyl; and (m) heteroalkyl;
R7 is selected from the group consisting of hydrogen and alkyl; or
R6 and R7 taken together with the nitrogen atom to which they are attached form a 3- to 8-membered optionally substituted heterocyclo;
Z is selected from the group consisting of —NR8— and —O—;
R8 is selected from the group consisting of: (a) hydrogen; (b) alkyl; and (c) hydroxyalkyl;
R9 is selected from the group consisting of:




and

(c) hydroxyalkyl; or
R8 and R9 taken together with the nitrogen atom to which they are attached form a 3- to 8-membered optionally substituted heterocyclo;
R10 is selected from the group consisting of: (a) hydrogen; (b) optionally substituted alkyl; (c) aralkyl; (d) (heterocyclo)alkyl; (e) (heteroaryl)alkyl; (f) (amino)alkyl; (g) (alkylamino)alkyl; (h) (dialkylamino)alkyl; (i) (carboxamido)alkyl; (j) (cyano)alkyl; (k) alkoxyalkyl; (l) hydroxyalkyl; (m) heteroalkyl; (n) optionally substituted cycloalkyl; (o) optionally substituted aryl; (p) optionally substituted heterocyclo; and (q) optionally substituted heteroaryl;
R11 is selected from the group consisting of: (a) hydroxy; (b) alkoxy; and (c) —NR13aR13b;
R13a is selected from the group consisting of: (a) hydrogen; (b) alkyl; (c) aralkyl; (d) (heterocyclo)alkyl; (e) (heteroaryl)alkyl; (f) (amino)alkyl; (g) (alkylamino)alkyl; (h) (dialkylamino)alkyl; (i) (carboxamido)alkyl; (j) (cyano)alkyl; (k) alkoxyalkyl; (l) hydroxyalkyl; and (m) heteroalkyl;
R13b is selected from the group consisting of hydrogen and alkyl; or
R13a and R13b taken together with the nitrogen atom to which they are attached form a 3- to 8-membered optionally substituted heterocyclo;
R12 is selected from the group consisting of hydrogen and alkyl; and
s is 1, 2, or 3.
Further, the invention also includes hydrates, N-oxides, and diastereomers thereof of compounds represented by Formula I.
In a separate aspect, the invention provides a compound of Formula A, or a pharmaceutically acceptable salt, solvate, hydrate, N-oxide, or diastereomer thereof:




Wherein

a and b, each independently, are 0, 1, or 2, provided that at least one of a and b is a value other than 0;
n is 0, 1, or 2;
o is 0 or 1;
m, each independently, is 0, 1, or 2;
W1 is —(CR5′R6′)n—U—;
W2 is —(CR7′R8′)o-G-;
U is absent, N(R1a′) or O, provided that when n is 0, then U is N(R1a′) or O;
G is absent, N(R1b′) or O, provided that when o is 0, then G is N(R1b′) or O;
R1′ and R2′, each independently, are H, optionally-substituted alkyl, alkoxy, cyano, alkenyl, carboxamido, and nitro; or R1′ and R2′, taken with the carbon atom they are attached to, form a carbonyl group;
R3′ and R4′, each independently, are H, optionally-substituted alkyl, alkoxy, cyano, alkenyl, carboxamido, and nitro; or R3′ and R4′, taken with the carbon atom they are attached to, form a carbonyl group;
R5′ and R6′, each independently, are H, alkyl, haloalkyl, —S(O)m—R9′, alkoxy, haloalkoxy, amino, (alkyl)amino, (dialkyl)amino, carboxamido, cyano, (hydroxy)alkyl, (dihydroxy)alkyl, nitro, or sulfonamido;

    
    
        or R5′ and R6′, taken together with the carbon atom to which they are both directly attached, form carbonyl, 3- to 8-membered optionally-substituted heterocyclo, or 3- to 8-membered optionally-substituted cycloalkyl;
        or R1′ and R5′, together with carbon atoms to which they are respectively attached, are fused to form a carbon-carbon double bond;
        or R1′, R2′, one R5′, and one R6′, together with carbon atoms to which they are respectively attached, are fused to form optionally-substituted aryl or optionally-substituted 5- to 6-membered heteroaryl;
        or one R5′, one R6′, R3′ and R4′, together with carbon atoms to which they are respectively attached, are fused to form optionally-substituted aryl or optionally-substituted 5- to 6-membered heteroaryl, wherein said one R5′ and said one R6′ are attached to a same carbon atom;
    
    


R1a′ is H, optionally-substituted alkyl, optionally-substituted aryl, optionally-substituted cycloalkyl, optionally-substituted (alkoxy)carbonyl, carboxamido, optionally-substituted ((amino)alkyl)carbonyl, or optionally-substituted (alkyl)carbonyl; or R1a′ and R1′, taken together with the bonds they are attached to, form a 5- to 8-membered optionally-substituted heterocyclo;
R7′ and R8′, each independently, are H, alkyl, haloalkyl, —S(O)m—R9′, alkoxy, haloalkoxy, amino, (alkyl)amino, (dialkyl)amino, carboxamido, cyano, (hydroxy)alkyl, (dihydroxy)alkyl, nitro, or sulfonamido;

    
    
        or R7′ and R8′, taken together with the carbon atom to which they are attached, form 3- to 8-membered optionally substituted heterocyclo, or a 3- to 8-membered optionally-substituted cycloalkyl;
        or R3′ and R7′, together with carbon atoms to which they are respectively attached, are fused to form a carbon-carbon double bond;
        or R3′, R4′, one R7′, and one R8′, together with carbon atoms to which they are respectively attached, are fused to form optionally-substituted aryl or optionally-substituted 5- to 6-membered heteroaryl, wherein said one R7′ and said one R8′ are attached to a same carbon atom;
    
    


R1b′ is H, optionally-substituted alkyl, optionally-substituted aryl, optionally-substituted cycloalkyl, optionally-substituted (alkoxy)carbonyl, carboxamido, optionally-substituted ((amino)alkyl)carbonyl, or optionally-substituted (alkyl)carbonyl; or R1b′ and R3′, taken together with the bonds they are attached to, form a 5- to 8-membered optionally-substituted heterocyclo;
A1 is selected from the group consisting of:

    
    
        a) optionally-substituted 3- to 8-membered heterocyclo;
        b) optionally-substituted aryl; and
        c) optionally-substituted 6-membered heteroaryl;
    
    


A2 is selected from the group consisting of:

    
    
        i) absent;
        ii) optionally-substituted 3- to 8-membered heterocyclo;
        iii) optionally-substituted aryl; and
        iv) optionally-substituted 6-membered heteroaryl;
    
    


X is absent, —O—, —N(R10′)—, —SO2N(R11′)—, or —C(O)O—, provided that when A2 is absent, then X is absent or —C(O)O—;
R9′ is optionally-substituted alkyl, optionally-substituted cycloalkyl, optionally-substituted heteroaryl, or optionally-substituted heterocyclo;
R10′ and R11′, each independently, are H or optionally-substituted alkyl.
In one embodiment of Formula A, a is 1. In another embodiment of Formula A, b is 1. A separate embodiment provides that both of a and b are 1 in Formula A.
One embodiment of Formula A provides that A2 is optionally-substituted aryl (e.g., phenyl, naphthyl, etc).
In another embodiment of Formula A, A2 is optionally-substituted 6-membered heteroaryl (e.g., pyridyl, diazinyl, triazinyl, etc). Non-limiting diazinyl groups include pyrimidyl (i.e., 1,3-diazinyl), pyrazinyl (i.e., 1,4-diazinyl), and pyridazyl (i.e., 1,2-diazinyl). Non-limiting triazinyl groups include 1,2,3-triazinyl, 1,2,4-triazinyl, and 1,3,5-triazinyl.
In certain embodiments of compounds of Formula A and pharmaceutically acceptable salts, solvates, hydrates, N-oxides, and diastereomers thereof, A2 is selected from the group consisting of phenyl, pyridyl, pyrimidyl, and triazinyl, each of which is optionally substituted, e.g., by one, two, three, or four substituents independently selected from the group of optional substituents suitable for aryl and/or heteroaryl groups as discussed infra.
In one embodiment of Formula A, R1a′ is R4b as defined in Formula I; that is, R1a′ is hydrogen, alkyl, or optionally-substituted aryl. A separate embodiment of Formula A provides that R1b′ is R4c as defined in Formula I; that is, R1b′ is hydrogen, alkyl, or optionally-substituted aryl.
In another embodiment of Formula A, R1a′ is R4a as defined in Formula I; that is, R1a′ is hydrogen or alkyl. A separate embodiment of Formula A provides that R1b′ is phenyl substituted by R2c and R2d, wherein R2c and R2d are defined in Formula I.
In another embodiment, the invention provides a compound of Formula B, or a pharmaceutically acceptable salt, solvate, hydrate, N-oxide, or diastereomer thereof:




Wherein

Q1, Q2, and Q3, each independently, are CH or N;
X is absent, —O—, or —N(R10′)—;
A1 is optionally-substituted aryl or optionally-substituted 6-membered heteroaryl;
W1 is —(CR5′R6′)n—U—;
W2 is —(CR7′R8′)o-G-;
n is 0 or 1;
o is 0 or 1;
U is absent, N(R1a′) or O, provided that when n is 0, then U is N(R1a′) or O; G is absent, N(R1b′) or O, provided that when o is 0, then G is N(R1b′) or O;
R1′ and R2′, each independently, are H, optionally-substituted alkyl, alkoxy, cyano, alkenyl, carboxamido, or nitro; or R1′ and R2′, taken with the carbon atom they are attached to, form a carbonyl group;
R3′ and R4′, each independently, are H, optionally-substituted alkyl, alkoxy, cyano, alkenyl, carboxamido, or nitro; or R3′ and R4′, taken with the carbon atom they are attached to, form a carbonyl group;
R5′ and R6′, each independently, are H, alkyl, haloalkyl, alkoxy, haloalkoxy, amino, (alkyl)amino, (dialkyl)amino, carboxamido, cyano, (hydroxy)alkyl, (dihydroxy)alkyl, or sulfonamido; or R5′ and R6′, taken together with the carbon atom to which they are attached, form a 3- to 8-membered optionally substituted heterocyclo or a 3- to 8-membered optionally-substituted cycloalkyl;
R1a′ is H, optionally-substituted alkyl, optionally-substituted aryl, optionally-substituted (alkoxy)carbonyl, or carboxamido; or R1a′ and R1′, taken together with the bonds they are attached to, form a 5- to 8-membered optionally-substituted heterocyclo;
R7′ and R8′, each independently, are H, alkyl, haloalkyl, alkoxy, haloalkoxy, amino, (alkyl)amino, (dialkyl)amino, carboxamido, cyano, (hydroxy)alkyl, (dihydroxy)alkyl, or sulfonamido; or R7′ and R8′, taken together with the carbon atom to which they are attached, form a 3- to 8-membered optionally substituted heterocyclo or a 3- to 8-membered optionally-substituted cycloalkyl;
R1b′ is H, optionally-substituted alkyl, optionally-substituted aryl, optionally-substituted (alkoxy)carbonyl, or carboxamido; or R1b′ and R3′, taken together with the bonds they are attached to, form a 5- to 8-membered optionally-substituted heterocyclo;
R10′ is H or optionally-substituted alkyl;
j is 0, 1, 2, or 3;
Rd each independently is selected from the group consisting of:

    
    
        a) hydrogen;
        b) halo;
        c) nitro;
        d) cyano;
        e) hydroxy;
        f) amino;
        g) alkylamino;
        h) dialkylamino;
        i) optionally-substituted (heterocyclo)amino;
        j) haloalkyl;
        k) hydroxyalkyl;
        l) alkoxy;
        m) haloalkoxy;
        n) alkoxyalkyl;
        o) carboxamido;
        p) optionally-substituted (heterocyclo)alkyl;
        q) optionally-substituted (cycloalkyl)alkyl;
        r) (alkoxy)carbonyl;
        s) —COOH;
        t) (carboxamido)(hydroxy)alkyl; and
        u) optionally-substituted ((heterocyclo)amino)alkyl.
    
    


One embodiment in accordance with Formula A or B provides that W1 is —(CR5′R6′)n—U—, and n is 0. Accordingly, W1 is —U—, and U is N(R1a′) or O. In one embodiment, W1 is —U—, U is N(R1a′), and R1a′ is H. In another embodiment, W1 is —U—, U is N(R1a′), and R1a′ is optionally-substituted aryl (e.g., phenyl). In another embodiment, W1 is —U—, and U is O.
Another embodiment of Formula A or B provides that W2 is —(CR7′R8′)o-G-, and o is 0. Accordingly, W2 is -G-, and G is N(R1b′) or O. In one embodiment, W2 is -G-, G is N(R1b′), and R1b′ is H. In another embodiment, W2 is -G-, G is N(R1b′), and R1b′ is optionally-substituted aryl (e.g., phenyl). In another embodiment, W2 is -G-, and G is O.
In another embodiment, Compounds of the Disclosure are compounds represented by Formula A or B, and the pharmaceutically acceptable salts, solvates, hydrates, N-oxides, or diastereomers thereof, wherein R1′ and R2′, taken with the carbon atom they are attached to, form a carbonyl group.
In one embodiment, Compounds of the Disclosure are compounds represented by Formula A or B, and the pharmaceutically acceptable salts, solvates, hydrates, N-oxides, or diastereomers thereof, wherein R3′ and R4′ are both H. In another embodiment, Compounds of the Disclosure are compounds represented by Formula A or B, and the pharmaceutically acceptable salts, solvates, hydrates, N-oxides, or diastereomers thereof, wherein R3′ and R4′, taken with the carbon atom they are both attached to, form a carbonyl group.
One embodiment of Formula B provides that at least one of Q1, Q2 and Q3 is CH. For example, all of Q1, Q2 and Q3 are CH. Alternatively, two of Q1, Q2 and Q3 are CH, and the other is N. Further alternatively, one of Q1, Q2 and Q3 is CH, and the other two are N.
One embodiment of Formula A or B provides that A1 is phenyl, which is further optionally substituted by one, two, three, or four substituents independently selected from those discussed below (including the optional substituents suitable for an aryl group as defined infra.). In another embodiment of Formula A or B, A1 is 6-membered heteroaryl, which is further optionally substituted by one, two, three, or four substituents independently selected from those discussed below (including the optional substituents for a heteroaryl group as defined infra.).
In yet another embodiment, the present disclosure provides a compound of Formula C, or a pharmaceutically acceptable salt, solvate, hydrate, N-oxide, or diastereomer thereof:




Wherein

Q3 is CH or N;
X is absent or —O—;
U is N(R1a′) or O;
G is N(R1b′) or O;
R1a′ is H, alkyl, or aryl, wherein each of said alkyl and said aryl is optionally substituted by one to three substituents independently selected from the group of halogen, hydroxy, carboxamido, amino, alkylamino, (heterocyclo)amino, alkoxy, haloalkoxy, and haloalkyl;
R1b′ is H, alkyl, or aryl, wherein each of said alkyl and said aryl is optionally substituted by one to three substituents independently selected from the group of halogen, hydroxy, carboxamido, amino, alkylamino, (heterocyclo)amino, alkoxy, haloalkoxy, and haloalkyl;
Rd is selected from the group consisting of:

    
    
        a) hydrogen;
        b) halo;
        c) amino;
        d) alkylamino;
        e) dialkylamino;
        f) optionally-substituted (heterocyclo)amino;
        g) haloalkyl;
        h) hydroxyalkyl;
        i) alkoxy;
        j) haloalkoxy;
        k) alkoxyalkyl;
        l) carboxamido;
        m) optionally-substituted (heterocyclo)alkyl;
        n) (carboxamido)(hydroxy)alkyl; and
        o) optionally-substituted ((heterocyclo)amino)alkyl;
    
    


Re and Rf independently are selected from the group consisting of:

    
    
        a) hydrogen;
        b) halo;
        c) hydroxy;
        d) amino;
        e) alkylamino;
        f) dialkylamino;
        g) optionally-substituted (heterocyclo)amino;
        h) haloalkyl;
        j) hydroxyalkyl;
        k) alkoxy;
        l) haloalkoxy;
        m) carboxamido; and
        o) optionally-substituted (heterocyclo)alkyl.
    
    


In one embodiment of Formula C, Rd is H. Another embodiment provides that Rd is carboxamido. Another embodiment of Formula C provides that Rd is hydroxyalkyl. Under certain circumstances, hydroxyalkyl includes, e.g., (monohydroxy)alkyl or (hydroxy)alkyl, (dihydroxy)alkyl, and (multihydroxy)alkyl.
A separate embodiment of Formula C provides that Re is H, and Rf is selected from the group consisting of a) halo; b) amino; c) alkylamino; d) dialkylamino; e) (heterocyclo)amino optionally substituted by one to two substituents independently selected from the group of halo, alkyl, haloalkyl, alkoxy, haloalkoxy, and carboxamido; f) haloalkyl; g) hydroxyalkyl; h) alkoxy; i) haloalkoxy; j) carboxamido; and k) (heterocyclo)alkyl optionally substituted by one to two substituents independently selected from the group of halo, alkyl, haloalkyl, alkoxy, haloalkoxy, and carboxamido.
In one embodiment of the compounds of Formula C or pharmaceutically acceptable salts, solvates, hydrates, N-oxides, or diastereomers thereof, X is absent. Another embodiment provides that X is —O—.
Further, the present disclosure provides a compound of Formula D, or a pharmaceutically acceptable salt, solvate, hydrate, N-oxide, or diastereomer thereof:




wherein U, G, Q3, and Rf are defined above (e.g., those defined in any one of Formulae A to C respectively).

In still another embodiment, the present disclosure provides a compound of Formula E, or a pharmaceutically acceptable salt, solvate, hydrate, N-oxide, or diastereomer thereof:




Wherein U, G, Q3, and Rf are defined above (e.g., those defined in any one of Formulae A to C respectively).

In one embodiment of Formula A, B, C, D, or E, U is N(R1a′). In another embodiment of Formula A, B, C, D, or E, G is N(R1b′). A separate embodiment provides compounds of Formula A, B, C, D, or E, or pharmaceutically acceptable salts, solvates, hydrates, N-oxides, or diastereomers thereof, U is N(R1a′) and G is N(R1b′). One embodiment provides that U is N(R1a′) and G is N(R1b′), wherein R1a′ is H, and R1b′ is H.
Still further, one embodiment in accordance with Formula A provides that A2 is absent. In one embodiment of Formula A, X is absent. One embodiment of Formula A provides that both of A2 and X are absent. Another embodiment provides that A1 is 6-membered heteroaryl, which is optionally substituted. For example, A1 is 6-membered heteroaryl optionally substituted by one to three substituents independently selected from the group of optional substituents independently selected from those discussed below, including, such as, the optional substituents suitable for heteroaryl (as defined infra.). Also, in certain embodiments, the optional substituents to the 6-membered heteroaryl are selected from the group consisting of R5a, R5b, and —C(O)E as those defined in Formula I. For example, the optional substituents to the 6-membered heteroaryl can be selected from the group consisting of: a) hydrogen; b) halo; c) nitro; d) cyano; e) hydroxy; f) amino; g) alkylamino; h) dialkylamino; i) haloalkyl; j) hydroxyalkyl; k) alkoxy; l) haloalkoxy; m) alkoxyalkyl; n) —C(O)E (wherein E is hydroxy, alkoxy, or —NR6R7); and p) —Z—R9; wherein R6, R7, Z, and R9 are those as defined in Formula I.
One embodiment of Formula A provides that both of A2 and X are absent, A1 is pyrimidyl substituted by R5a, R5b, and —C(O)E, wherein R5a, R5b, and E are defined in Formula I.
In a further embodiment of Formulae I or A, a compound of the present disclosure is a compound of Formula F or a pharmaceutically acceptable salt, solvate, hydrate, N-oxide, or diastereomer thereof:




Wherein R4b, R4c, E, R5a, and R5b are those as defined in Formula I.

Certain embodiments of Formula F provide that
R4b and R4c, each independently, are selected from the group consisting of hydrogen, alkyl, and optionally substituted aryl (e.g., phenyl);
R5a is selected from the group consisting of a) hydrogen; b) halo; c) nitro; d) cyano; e) hydroxy; f) amino; g) alkylamino; h) dialkylamino; i) haloalkyl; j) hydroxyalkyl; k) alkoxy; 1) haloalkoxy; m) alkoxyalkyl; and n) —Z—R9;
R5b is selected from the group consisting of: a) hydrogen; b) halo; c) nitro; d) cyano; e) hydroxy; f) amino; g) alkylamino; h) dialkylamino; i) haloalkyl; j) hydroxyalkyl; k) alkoxy; l) haloalkoxy; and m) alkoxyalkyl;
E is selected from the group consisting of: a) hydroxy; b) alkoxy; and c) —NR6R7;
R6 is selected from the group consisting of: a) hydrogen; b) alkyl; c) aralkyl; d) (heterocyclo)alkyl; e) (heteroaryl)alkyl; f) (amino)alkyl; g) (alkylamino)alkyl; h) (dialkylamino)alkyl; i) (carboxamido)alkyl; j) (cyano)alkyl; k) alkoxyalkyl; l) hydroxyalkyl; and m) heteroalkyl;
R7 is hydrogen or alkyl; or
R6 and R7 taken together with the nitrogen atom to which they are attached form a 3- to 8-membered optionally substituted heterocyclo;
Z is selected from the group consisting of —NR8— and —O—;
R8 is selected from the group consisting of: a) hydrogen; b) alkyl; and c) hydroxyalkyl;
R9 is selected from the group consisting of:




and

    
    
        c) hydroxyalkyl; or
    
    


R8 and R9 taken together with the nitrogen atom to which they are attached form a 3- to 8-membered optionally substituted heterocyclo;
R10 is selected from the group consisting of: a) hydrogen; b) optionally substituted alkyl; c) aralkyl; d) (heterocyclo)alkyl; e) (heteroaryl)alkyl; f) (amino)alkyl; g) (alkylamino)alkyl; h) (dialkylamino)alkyl; i) (carboxamido)alkyl; j) (cyano)alkyl; k) alkoxyalkyl; l) hydroxyalkyl; m) heteroalkyl; n) optionally substituted cycloalkyl; o) optionally substituted aryl; p) optionally substituted heterocyclo; and q) optionally substituted heteroaryl;
R11 is selected from the group consisting of: a) hydroxy; b) alkoxy; and c) —NR13aR13b;
R13a is selected from the group consisting of: a) hydrogen; b) alkyl; c) aralkyl; d) (heterocyclo)alkyl; e) (heteroaryl)alkyl; f) (amino) alkyl; g) (alkylamino)alkyl; h) (dialkylamino)alkyl; i) (carboxamido)alkyl; j) (cyano)alkyl; k) alkoxyalkyl; l) hydroxyalkyl; and m) heteroalkyl;
R13b is hydrogen or alkyl; or
R13a and R13b taken together with the nitrogen atom to which they are attached form a 3- to 8-membered optionally substituted heterocyclo;
R12 is selected from the group consisting of hydrogen and alkyl; and
s is 1, 2, or 3.
In another embodiment of Formulae I or A, a compound of the present disclosure is a compound of Formula G, or a pharmaceutically acceptable salt, solvate, hydrate, N-oxide, or diastereomer thereof:




Wherein R2c, R2d, R4a, E, R5a, and R5b are those as above defined in Formula I.

For example, the invention provides a compound of Formula G, or a pharmaceutically acceptable salt, solvate, hydrate, N-oxide, or diastereomer thereof, wherein
R2c and R2d are each independently selected from the group consisting of: a) hydrogen; b) halo; c) nitro; d) cyano; e) hydroxy; f) amino; g) alkylamino; h) dialkylamino; i) alkyl; j) haloalkyl; k) hydroxyalkyl; l) alkoxy; m) haloalkoxy; and n) alkoxyalkyl;
R4a is hydrogen or alkyl;
R5a is selected from the group consisting of a) hydrogen; b) halo; c) nitro; d) cyano; e) hydroxy; f) amino; g) alkylamino; h) dialkylamino; i) haloalkyl; j) hydroxyalkyl; k) alkoxy; 1) haloalkoxy; m) alkoxyalkyl; and n) —Z—R9;
R5b is selected from the group consisting of: a) hydrogen; b) halo; c) nitro; d) cyano; e) hydroxy; f) amino; g) alkylamino; h) dialkylamino; i) haloalkyl; j) hydroxyalkyl; k) alkoxy; l) haloalkoxy; and m) alkoxyalkyl;
E is selected from the group consisting of: a) hydroxy; b) alkoxy; and c) —NR6R7;
R6 is selected from the group consisting of: a) hydrogen; b) alkyl; c) aralkyl; d) (heterocyclo)alkyl; e) (heteroaryl)alkyl; f) (amino)alkyl; g) (alkylamino) alkyl; h) (dialkylamino)alkyl; i) (carboxamido)alkyl; j) (cyano)alkyl; k) alkoxyalkyl; l) hydroxyalkyl; and m) heteroalkyl;
R7 is hydrogen or alkyl; or
R6 and R7 taken together with the nitrogen atom to which they are attached form a 3- to 8-membered optionally substituted heterocyclo;
Z is selected from the group consisting of —NR8— and —O—;
R8 is selected from the group consisting of: a) hydrogen; b) alkyl; and c) hydroxyalkyl;
R9 is selected from the group consisting of:




and

    
    
        c) hydroxyalkyl; or
    
    


R8 and R9 taken together with the nitrogen atom to which they are attached form a 3- to 8-membered optionally substituted heterocyclo;
R10 is selected from the group consisting of: a) hydrogen; b) optionally substituted alkyl; c) aralkyl; d) (heterocyclo)alkyl; e) (heteroaryl)alkyl; f) (amino)alkyl; g) (alkylamino)alkyl; h) (dialkylamino)alkyl; i) (carboxamido)alkyl; j) (cyano)alkyl; k) alkoxyalkyl; l) hydroxyalkyl; m) heteroalkyl; n) optionally substituted cycloalkyl; o) optionally substituted aryl; p) optionally substituted heterocyclo; and q) optionally substituted heteroaryl;
R11 is selected from the group consisting of: a) hydroxy; b) alkoxy; and c) —NR13aR13b;
R13a is selected from the group consisting of: a) hydrogen; b) alkyl; c) aralkyl; d) (heterocyclo)alkyl; e) (heteroaryl)alkyl; f) (amino)alkyl; g) (alkylamino)alkyl; h) (dialkylamino)alkyl; i) (carboxamido)alkyl; j) (cyano)alkyl; k) alkoxyalkyl; l) hydroxyalkyl; and m) heteroalkyl;
R13b is hydrogen or alkyl; or
R13a and R13b taken together with the nitrogen atom to which they are attached form a 3- to 8-membered optionally substituted heterocyclo;
R12 is selected from the group consisting of hydrogen and alkyl; and
s is 1, 2, or 3.
In one embodiment, Compounds of the Disclosure are compounds represented by Formula I, F, or G, and the pharmaceutically acceptable salts and solvates thereof, wherein R5b is hydrogen.
In another embodiment, Compounds of the Disclosure are compounds represented by Formula I, F, or G, and the pharmaceutically acceptable salts and solvates thereof, wherein R5a is —Z—R9, and R5b is hydrogen. One embodiment provides that Z is —NR8—, and R9 is




In another embodiment, Compounds of the Disclosure are compounds represented by any one of Formulae I, F, and G, and the pharmaceutically acceptable salts and solvates thereof, wherein R5a is hydroxyalkyl, R5b is hydrogen.
In another embodiment, Compounds of the Disclosure are compounds represented by any one of Formulae I, F, and G, and the pharmaceutically acceptable salts and solvates thereof, wherein E is —NH2.
In another embodiment, Compounds of the Disclosure are compounds represented by any one of Formulae I, F, and G, and the pharmaceutically acceptable salts and solvates thereof, wherein R5a is —Z—R9, Z is —NH— or —O—, R9 is




and R11 is —NH2. In one embodiment, R5b is hydrogen. In another embodiment, R5b is hydrogen and E is NH2.

In another embodiment, Compounds of the Disclosure are compounds represented by any one of Formulae I, F, and G, and the pharmaceutically acceptable salts and solvates thereof, wherein R5a is —Z—R9, Z is —NH— or —O— and R9 is




In one embodiment, R5b is hydrogen. In another embodiment, R5b is hydrogen and E is NH2.

In still another embodiment, Compounds of the Disclosure are compounds represented by any one of Formulae I, F, and G, and the pharmaceutically acceptable salts and solvates thereof, wherein R5a is —Z—R9, R9 is selected from the group consisting of:




and R10 is C1-C4 alkyl. In one embodiment, R5b is hydrogen. In another embodiment, R5b is hydrogen and E is NH2.

In another embodiment, Compounds of the Disclosure are compounds represented by any one of Formulae I, F, and G, and the pharmaceutically acceptable salts and solvates thereof, wherein R5a is R9 is selected from the group consisting of:




R10 is C1-C4 alkyl, and Z is —NH—. In another embodiment, R5b is hydrogen. In another embodiment, R5b is hydrogen and E is NH2.

In one embodiment, Compounds of the Disclosure are compounds represented by any one of Formulae I, F, and G, and the pharmaceutically acceptable salts and solvates thereof, wherein R5a is —Z—R9, and R9 is selected from the group consisting of:




In another embodiment, R5b is hydrogen. In another embodiment, R5b is hydrogen and E is NH2.

In yet another embodiment, Compounds of the Disclosure are compounds represented by any one of Formulae I, F, and G, and the pharmaceutically acceptable salts and solvates thereof, wherein R5a is —Z—R9, R9 is selected from the group consisting of:




and Z is —NH—. In one embodiment, R5b is hydrogen. In another embodiment, R5b is hydrogen and E is NH2.

Further, Compounds of the Disclosure includes compounds represented by Formula I, and the pharmaceutically acceptable salts and solvates thereof, wherein R1 is R1—I, and R2a, R2b, R5a, R5b, and E are as defined in connection with Formula I. In one embodiment, R2a and R2b are hydrogen. In another embodiment,  is a double bond. In another embodiment, R5a is —Z—R9. In another embodiment, R5a is —Z—R9 and R5b is hydrogen. In another embodiment, R5a is —Z—R9. R5b is hydrogen, and E is —NH2.
In another embodiment, Compounds of the Disclosure are compounds represented by Formula I, and the pharmaceutically acceptable salts and solvates thereof, wherein R1 is R1—II, and R2a, R2b, X1, R5a, R5b, and E are as defined in connection with Formula I. In one embodiment, R2a and R2b are hydrogen. In another embodiment, X1 is oxygen. In another embodiment, R5a is —Z—R9. In another embodiment, R5a is —Z—R9 and R5b is hydrogen. In another embodiment, R5a is —Z—R9, R5b is hydrogen, and E is —NH2.
In another embodiment, Compounds of the Disclosure are compounds represented by Formula I, and the pharmaceutically acceptable salts and solvates thereof, wherein R1 is R1—III, and R2a, R2b, R5a, R5b, and E are as defined in connection with Formula I. In one embodiment, R2a and R2b are hydrogen. In another embodiment, X1 is oxygen. In another embodiment, R5a is —Z—R9. In another embodiment, R5a is —Z—R9 and R5b is hydrogen. In another embodiment, R5a is —Z—R9, R5b is hydrogen, and E is —NH2.
In another embodiment, Compounds of the Disclosure are compounds represented by Formula I, and the pharmaceutically acceptable salts and solvates thereof, wherein R1 is R1—IV, and R2a, R2b, X1, R5a, R5b, and E are as defined in connection with Formula I. In one embodiment, R2a and R2b are hydrogen. In another embodiment, X1 is oxygen. In another embodiment, R5a is —Z—R9. In another embodiment, R5a is —Z—R9 and R5b is hydrogen. In another embodiment, R5a is —Z—R9, R5b is hydrogen, and E is —NH2.
In another embodiment, Compounds of the Disclosure are compounds represented by Formula I, and the pharmaceutically acceptable salts and solvates thereof, wherein R1 is R1—V, and R2c, R2d, R4a, R5a, R5b, and E are as defined in connection with Formula I. In one embodiment, R2c and R2d are hydrogen. In another embodiment, R4a is hydrogen. In another embodiment, R5a is —Z—R9. In another embodiment, R5a is —Z—R9 and R5b is hydrogen. In another embodiment, R5a is —Z—R9, R5b is hydrogen, and E is —NH2.
In another embodiment, Compounds of the Disclosure are compounds represented by Formula I, and the pharmaceutically acceptable salts and solvates thereof, wherein R1 is R1—VI, and R2a, R2b, X2, R5a, R5b and E are as defined in connection with Formula I. In one embodiment, R2a and R2b are hydrogen. In another embodiment, X2 is C═O. In another embodiment, X2 is CH2. In another embodiment, R5a is —Z—R9. In another embodiment, R5a is —Z—R9 and R5b is hydrogen. In another embodiment, R5a is —Z—R9, R5b is hydrogen, and E is —NH2.
In another embodiment, Compounds of the Disclosure are compounds represented by Formula I, and the pharmaceutically acceptable salts and solvates thereof, wherein R1 is R1—VII, and R4b, R4c, R5a, R5b, and E are as defined in connection with Formula I. In one embodiment, R5a is —Z—R9. In another embodiment, R5a is —Z—R9 and R5b is hydrogen. In another embodiment, R5a is —Z—R9, R5b is hydrogen, and E is —NH2.
In one embodiment, Compounds of the Disclosure are compounds of TABLE 2, and the pharmaceutically acceptable salts, solvates, hydrates, N-oxides, and diastereomers thereof.









TABLE 2





Cpd. No.
Structure
Name

















8




(S)-6-((2-oxopyrrolidin-3-yl)amino)- 2-(3H-spiro[isobenzofuran-1,4′- piperidin]-1′-yl)pyrimidine-4- carboxamide


 


9




(S)-6-((2-oxopyrrolidin-3- yl)amino)-2-(spiro[indene-1,4′- piperidin]-1′-yl)pyrimidine-4- carboxamide


 


10




(S)-2-(3-oxo-3H-spiro [isobenzofuran-1,4′-piperidin]-1′- yl)-6-((2-oxopyrrolidin-3- yl)amino)pyrimidine-4- carboxamide


 


11




(S)-2-(4-oxo-1-phenyl-1,3,8- triazaspiro[4.5]decan-8-yl)-6-((2- oxopyrrolidin-3- yl)amino)pyrimidine-4- carboxamide









Further, the present disclosure also provides compounds presented in TABLE 2A, and pharmaceutically acceptable salts, solvates, hydrates, N-oxides, and diastereomers thereof.









TABLE 2A





Cpd. No.
Structure
Name







12




8-(4-(4-fluorophenoxy)phenyl)- 1,3,8-triazaspiro[4.5]decane-2,4- dione


 


13




8-(4-(3-fluorophenoxy)phenyl)- 1,3,8-triazaspiro[4.5]decane-2,4- dione


 


14




8-(4-(3-(trifluoromethyl)phenoxy)- phenyl)-1,3,8-triazaspiro[4.5]decan- 2,4-dione


 


15




8-(4-(4-(trifluoromethoxy)phenyl)- pyridin-2-yl)-1,3,8- triazaspiro[4.5]decane-2,4-dione


 


16




8-(5-(4-fluorophenoxy)pyridin-2- yl)-1,3,8-triazaspiro[4.5]decane-2,4- dione


 


17




8-(5-(4-(trifluoromethyl)phenoxy)- pyridin-2-yl)-1,3,8- triazaspiro[4.5]decane-2,4-dione


 


18




8-(5-(3-(trifluoromethyl)phenoxy)- pyridin-2-yl)-1,3,8- triazaspiro[4.5]decane-2,4-dione


 


19




8-(4-(4-(trifluoromethyl)phenoxy)- phenyl)-1,3,8-triazaspiro- [4.5]decane-2,4-dione


 


20




8-(3-(4-fluorophenoxy)pyridin-2- yl)-1,3,8-triazaspiro[4.5]decane-2,4- dione


 


21




8-(4-(3-(trifluoromethoxy)- phenyl)pyridin-2-yl)-1,3,8- triazaspiro[4.5]decane-2,4-dione









As used herein, the term “alkyl” as used by itself or as part of another group refers to a straight- or branched-chain aliphatic hydrocarbon containing one to twelve carbon atoms (i.e., C1-12 alkyl) or the number of carbon atoms designated (i.e., a C1 alkyl (such as, methyl), a C2 alkyl (such as, ethyl), a C3 alkyl (such as, propyl or isopropyl, etc.). In one embodiment, the alkyl group is chosen from a straight chain C1-10 alkyl group. In another embodiment, the alkyl group is chosen from a branched chain C3-10 alkyl group. In another embodiment, the alkyl group is chosen from a straight chain C1-6 alkyl group. In another embodiment, the alkyl group is chosen from a branched chain C3-6 alkyl group. In another embodiment, the alkyl group is chosen from a straight chain C1-4 alkyl group. In another embodiment, the alkyl group is chosen from a branched chain C3-4 alkyl group. In another embodiment, the alkyl group is chosen from a straight or branched chain C3-4 alkyl group. Non-limiting exemplary C1-10 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, iso-butyl, 3-pentyl, hexyl, heptyl, octyl, nonyl, decyl, and the like. Non-limiting exemplary C1-4 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, and iso-butyl.
As used herein, the term “optionally substituted alkyl” as used by itself or as part of another group means that the alkyl as defined above is either unsubstituted or substituted with one, two, or three substituents independently chosen from amino, nitro, hydroxy, haloalkoxy, heterocyclo, aryloxy, aralkyloxy, alkylthio, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, cycloalkyl, carboxamido, and the like. In one embodiment, the optionally substituted alkyl is substituted with two substituents. In another embodiment, the optionally substituted alkyl is substituted with one substituent. Non-limiting exemplary optionally substituted alkyl groups include —NH2, —COOH, —OH, —CH2CH2NO2, —CH2CH2CO2H, —CH2CH2SO2CH3, —CH2CH2COPh, —CH2C6H11, —CONH2, and the like.
As used herein, the term “cycloalkyl” as used by itself or as part of another group refers to saturated and partially unsaturated (containing one or two double bonds) cyclic aliphatic hydrocarbons containing one to three rings having from three to twelve carbon atoms (i.e., C3-12 cycloalkyl) or the number of carbons designated. In one embodiment, the cycloalkyl group is saturated. In one embodiment, the cycloalkyl group has two rings. In one embodiment, the cycloalkyl group has one ring. In another embodiment, the cycloalkyl group is chosen from a C3-8 cycloalkyl group. In another embodiment, the cycloalkyl group is chosen from a C3-6 cycloalkyl group. Non-limiting exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decalin, adamantyl, cyclohexenyl, and the like.
As used herein, the term “optionally substituted cycloalkyl” as used by itself or as part of another group means that the cycloalkyl as defined above is either unsubstituted or substituted with one, two, or three substituents independently chosen from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, and (heteroaryl)alkyl. In one embodiment, the optionally substituted cycloalkyl is substituted with two substituents. In another embodiment, the optionally substituted cycloalkyl is substituted with one substituent. Non-limiting exemplary optionally substituted cycloalkyl groups include:




As used herein, the term “alkenyl” as used by itself or as part of another group refers to an alkyl group as defined above containing one, two or three carbon-to-carbon double bonds. In one embodiment, the alkenyl group is chosen from a C2-6 alkenyl group. In another embodiment, the alkenyl group is chosen from a C2-4 alkenyl group. Non-limiting exemplary alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, sec-butenyl, pentenyl, and hexenyl.
As used herein, the term “optionally substituted alkenyl” as used herein by itself or as part of another group means the alkenyl as defined above is either unsubstituted or substituted with one, two or three substituents independently chosen from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclo.
As used herein, the term “alkynyl” as used by itself or as part of another group refers to an alkyl group as defined above containing one to three carbon-to-carbon triple bonds. In one embodiment, the alkynyl has one carbon-to-carbon triple bond. In one embodiment, the alkynyl group is chosen from a C2-6 alkynyl group. In another embodiment, the alkynyl group is chosen from a C2-4 alkynyl group. Non-limiting exemplary alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl, pentynyl, and hexynyl groups.
As used herein, the term “optionally substituted alkynyl” as used herein by itself or as part of another group means the alkynyl as defined above is either unsubstituted or substituted with one, two or three substituents independently chosen from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclo.
As used herein, the term “haloalkyl” as used by itself or as part of another group refers to an alkyl group substituted by one or more fluorine, chlorine, bromine and/or iodine atoms. In one embodiment, the alkyl group is substituted by one, two, or three fluorine and/or chlorine atoms. In another embodiment, the haloalkyl group is chosen from a C1-4 haloalkyl group. Non-limiting exemplary haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, and trichloromethyl groups.
As used herein, the term “hydroxyalkyl” as used by itself or as part of another group refers to an alkyl group substituted with one or more, e.g., one, two, or three, hydroxy groups. In one embodiment, the hydroxyalkyl group refers to a monohydroxyalkyl group, i.e., substituted with one hydroxy group. However, the hydroxyalkyl group as used in the present disclosure may also refer to an alkyl group substituted by two or more hydroxy groups. That is, the hydroxyalkyl group used herein includes a dihydroxyalkyl group, i.e., substituted with two hydroxy groups. In one embodiment, the hydroxyalkyl group is chosen from a C1-4 hydroxyalkyl group. Non-limiting exemplary hydroxyalkyl groups include hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxybutyl groups, such as 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 3-hydroxybutyl, 4-hydroxybutyl, 2-hydroxy-1-methylpropyl, and 1,3-dihydroxyprop-2-yl.
As used herein, the term “(carboxamido)(hydroxy)alkyl” as used by itself or as part of another group refers to an alkyl group that is substituted with one or more hydroxy groups, and also with a carboxamido group. Non-limiting exemplary (carboxamido)(hydroxy)alkyl groups include —CH(OH)C(O)NH2, —CH2CH(OH)C(O)NH2, —CH(OH)CH(OH)C(O)NH2, and the like.
As used herein, the term “alkoxy” as used by itself or as part of another group refers to an optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl or optionally substituted alkynyl attached to a terminal oxygen atom. In one embodiment, the alkoxy group is chosen from a C1-4 alkoxy group. In another embodiment, the alkoxy group is chosen from a C1-4 alkyl attached to a terminal oxygen atom, e.g., methoxy, ethoxy, and tert-butoxy.
As used herein, the term “alkylthio” as used by itself or as part of another group refers to a sulfur atom substituted by an optionally substituted alkyl group. In one embodiment, the alkylthio group is chosen from a C1-4 alkylthio group. Non-limiting exemplary alkylthio groups include —SCH3, and —SCH2CH3.
As used herein, the term “alkoxyalkyl” as used by itself or as part of another group refers to an alkyl group substituted with an alkoxy group. Non-limiting exemplary alkoxyalkyl groups include methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, propoxymethyl, iso-propoxymethyl, propoxyethyl, propoxypropyl, butoxymethyl, tert-butoxymethyl, isobutoxymethyl, sec-butoxymethyl, and pentyloxymethyl.
As used herein, the term “heteroalkyl” as used by itself or part of another group refers to a stable straight or branched chain hydrocarbon radical containing 1 to 10 carbon atoms and at least two heteroatoms, which can be the same or different, selected from O, N, or S, wherein: 1) the nitrogen atom(s) and sulfur atom(s) can optionally be oxidized; and/or 2) the nitrogen atom(s) can optionally be quaternized. The heteroatoms can be placed at any interior position of the heteroalkyl group or at a position at which the heteroalkyl group is attached to the remainder of the molecule. In one embodiment, the heteroalkyl group contains two oxygen atoms. Non-limiting exemplary heteroalkyl groups include —CH2OCH2CH2OCH3, —OCH2CH2OCH2CH2OCH3, —CH2NHCH2CH2OCH2, —OCH2CH2NH2, and —NHCH2CH2N(H)CH3.
As used herein, the term “haloalkoxy” as used by itself or as part of another group refers to a haloalkyl attached to a terminal oxygen atom. Non-limiting exemplary haloalkoxy groups include fluoromethoxy, difluoromethoxy, trifluoromethoxy, and 2,2,2-trifluoroethoxy.
As used herein, the term “aryl” as used by itself or as part of another group refers to a monocyclic or bicyclic aromatic ring system having from six to fourteen carbon atoms (i.e., C6-C14 aryl). Non-limiting exemplary aryl groups include phenyl (abbreviated as “Ph”), naphthyl, phenanthryl, anthracyl, indenyl, azulenyl, biphenyl, biphenylenyl, and fluorenyl groups. In one embodiment, the aryl group is chosen from phenyl or naphthyl.
As used herein, the term “optionally substituted aryl” as used herein by itself or as part of another group means that the aryl as defined above is either unsubstituted or substituted with one to five substituents independently chosen from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, heteroaryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, (cycloalkylamino)alkyl, (C1-C4 haloalkoxy)alkyl, or (heteroaryl)alkyl. In one embodiment, the optionally substituted aryl is an optionally substituted phenyl. In one embodiment, the optionally substituted phenyl has four substituents. In another embodiment, the optionally substituted phenyl has three substituents. In another embodiment, the optionally substituted phenyl has two substituents. In another embodiment, the optionally substituted phenyl has one substituent. Non-limiting exemplary substituted aryl groups include 2-methylphenyl, 2-methoxyphenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 3-methylphenyl, 3-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 4-methylphenyl, 4-ethylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 2,6-di-fluorophenyl, 2,6-di-chlorophenyl, 2-methyl, 3-methoxyphenyl, 2-ethyl, 3-methoxyphenyl, 3,4-di-methoxyphenyl, 3,5-di-fluorophenyl 3,5-di-methylphenyl, 3,5-dimethoxy, 4-methylphenyl, 2-fluoro-3-chlorophenyl, and 3-chloro-4-fluorophenyl. The term optionally substituted aryl is meant to include groups having fused optionally substituted cycloalkyl and fused optionally substituted heterocyclo rings. Examples include:




As used herein, the term “aryloxy” as used by itself or as part of another group refers to an optionally substituted aryl attached to a terminal oxygen atom. A non-limiting exemplary aryloxy group is PhO—.
As used herein, the term “heteroaryloxy” as used by itself or as part of another group refers to an optionally substituted heteroaryl attached to a terminal oxygen atom. Non-limiting exemplary heteroaryloxy groups include:




As used herein, the term “aralkyloxy” as used by itself or as part of another group refers to an aralkyl group attached to a terminal oxygen atom. A non-limiting exemplary aralkyloxy group is PhCH2O—.
As used herein, the term “heteroaryl” or “heteroaromatic” refers to monocyclic and bicyclic aromatic ring systems having 5 to 14 ring atoms (i.e., C5-C14 heteroaryl) and 1, 2, 3, or 4 heteroatoms independently chosen from oxygen, nitrogen and sulfur. In one embodiment, the heteroaryl has three heteroatoms. In another embodiment, the heteroaryl has two heteroatoms. In another embodiment, the heteroaryl has one heteroatom. In one embodiment, the heteroaryl is a C5 heteroaryl. In another embodiment, the heteroaryl is a C6 heteroaryl. Non-limiting exemplary heteroaryl groups include thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, benzofuryl, pyranyl, isobenzofuranyl, benzooxazonyl, chromenyl, xanthenyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, cinnolinyl, quinazolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, thiazolyl, isothiazolyl, phenothiazolyl, isoxazolyl, furazanyl, and phenoxazinyl. In one embodiment, the heteroaryl is chosen from thienyl (e.g., thien-2-yl and thien-3-yl), furyl (e.g., 2-furyl and 3-furyl), pyrrolyl (e.g., 1H-pyrrol-2-yl and 1H-pyrrol-3-yl), imidazolyl (e.g., 2H-imidazol-2-yl and 2H-imidazol-4-yl), pyrazolyl (e.g., 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, and 1H-pyrazol-5-yl), pyridyl (e.g., pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl), pyrimidinyl (e.g., pyrimidin-2-yl, pyrimidin-4-yl, and pyrimidin-5-yl), thiazolyl (e.g., thiazol-2-yl, thiazol-4-yl, and thiazol-5-yl), isothiazolyl (e.g., isothiazol-3-yl, isothiazol-4-yl, and isothiazol-5-yl), oxazolyl (e.g., oxazol-2-yl, oxazol-4-yl, and oxazol-5-yl) and isoxazolyl (e.g., isoxazol-3-yl, isoxazol-4-yl, and isoxazol-5-yl). The term “heteroaryl” is also meant to include possible N-oxides. Exemplary N-oxides include pyridyl N-oxide and the like.
As used herein, the term “optionally substituted heteroaryl” as used by itself or as part of another group means that the heteroaryl as defined above is either unsubstituted or substituted with one to four substituents, e.g., one or two substituents, independently chosen from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, and (heteroaryl)alkyl. In one embodiment, the optionally substituted heteroaryl has one substituent. In one embodiment, the optionally substituted is an optionally substituted pyridyl, i.e., 2-, 3-, or 4-pyridyl. Any available carbon or nitrogen atom can be substituted. In another embodiment, the optionally substituted heteroaryl is an optionally substituted indole.
As used herein, the term “heterocycle” or “heterocyclo” as used by itself or as part of another group refers to saturated and partially unsaturated (e.g., containing one or two double bonds) cyclic groups containing one, two, or three rings having from three to fourteen ring members (i.e., a 3- to 14-membered heterocyclo) and at least one heteroatom. Each heteroatom is independently selected from the group consisting of oxygen, sulfur, including sulfoxide and sulfone, and/or nitrogen atoms, which can be quaternized. The term “heterocyclo” is meant to include cyclic ureido groups such as 2-imidazolidinone and cyclic amide groups such as β-lactam, γ-lactam, δ-lactam and ε-lactam. The term “heterocyclo” is also meant to include groups having fused optionally substituted aryl groups, e.g., indolinyl. In one embodiment, the heterocyclo group is chosen from a 5- or 6-membered cyclic group containing one ring and one or two oxygen and/or nitrogen atoms. The heterocyclo can be optionally linked to the rest of the molecule through a carbon or nitrogen atom. Non-limiting exemplary heterocyclo groups include 2-oxopyrrolidin-3-yl, 2-imidazolidinone, piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl, and indolinyl.
As used herein, the term “optionally substituted heterocyclo” as used herein by itself or part of another group means the heterocyclo as defined above is either unsubstituted or substituted with one to four substituents independently selected from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, (heteroaryl)alkyl, and the like. Substitution may occur on any available carbon or nitrogen atom, and may form a spirocycle. Non-limiting exemplary optionally substituted heterocyclo groups include:







As used herein, the term “amino” as used by itself or as part of another group refers to —NH2.
As used herein, the term “alkylamino” as used by itself or as part of another group refers to —NHR15, wherein R15 is alkyl.
As used herein, the term “dialkylamino” as used by itself or as part of another group refers to —NR16aR16b wherein R16a and R16b are each independently alkyl or R16a and R16b are taken together to form a 3- to 8-membered optionally substituted heterocyclo.
As used herein, the term “hydroxyalkylamino” as used by itself or as part of another group refers to —NHR17, wherein R17 is hydroxyalkyl.
As used herein, the term “cycloalkylamino” as used by itself or as part of another group refers to —NR19aR19b wherein R19a is optionally substituted cycloalkyl and R19b is hydrogen or alkyl.
As used herein, the term “(amino)alkyl” as used by itself or as part of another group refers to an alkyl group substituted with an amino group. Non-limiting exemplary amino alkyl groups include —CH2CH2NH2, —CH2CH2CH2NH2, —CH2CH2CH2CH2NH2 and the like.
As used herein, the term “(alkylamino)alkyl” as used by itself or as part of another group refers to an alkyl group substituted with an alkylamino group. A non-limiting exemplary (alkylamino)alkyl group is —CH2CH2N(H)CH3.
As used herein, the term “(dialkylamino)alkyl” as used by itself or as part of another group refers to an alkyl group substituted by a dialkylamino group. A non-limiting exemplary (dialkylamino)alkyl group is —CH2CH2N(CH3)2.
As used herein, the term “(cycloalkylamino)alkyl” as used by itself or as part of another group refers to an alkyl group substituted by a cycloalkylamino group. Non-limiting exemplary (cycloalkylamino)alkyl groups include —CH2N(H)cyclopropyl, CH2N(H)cyclobutyl, —CH2N(H)cyclohexyl, and the like.
As used herein, the term “((amino)alkyl)carbonyl” as used by itself or as part of another group refers to an (alkyl)carbonyl group (i.e., —C(O)alkyl) substituted by an amino group (at the alkyl part). Further, the term “optionally-substituted ((amino)alkyl)carbonyl” refers to an ((amino)alkyl)carbonyl group carrying one or more optional substituents that are attached to the alkyl part or to the amino part, or both. Suitable substituents include, such as, the above-defined suitable substituents for an alkyl group, and the above-defined suitable substituents for an amino group. Non-limiting exemplary optionally-substituted ((amino)alkyl)carbonyl groups include




and the like.

As used herein, the term “(C1-C4 haloalkoxy)alkyl” as used by itself or as part of another group refers to an alkyl group substituted by a C1-C4 haloalkoxy group. Non-limiting exemplary (C1-C4 haloalkoxy)alkyl groups include —CH2OCH2CF3 and —CH2OCF3.
As used herein, the term “(cyano)alkyl” as used by itself or as part of another group refers to an alkyl group substituted with one or more cyano, e.g., —CN, groups. Non-limiting exemplary (cyano)alkyl groups include —CH2CH2CN, —CH2CH2CH2CN, and —CH2CH2CH2CH2CN.
As used herein, the term “carboxamido” as used by itself or as part of another group refers to a radical of formula —C(═O)NR24aR24b, wherein R24a and R24b are each independently hydrogen, optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl, or R24a and R24b taken together with the nitrogen to which they are attached form a 3- to 8-membered heterocyclo group. In one embodiment, R24a and R24b are each independently hydrogen or optionally substituted alkyl. Non-limiting exemplary carboxamido groups include —CONH2, —CON(H)CH3, CON(CH3)2, and CON(H)Ph.
As used herein, the term “(carboxamido)alkyl” as used by itself or as part of another group refers to an alkyl group substituted with a carboxamido group. Non-limiting exemplary (carboxamido)alkyl groups include —CH2CONH2, —C(H)CH3—CONH2, and —CH2CON(H)CH3.
As used herein, the term “sulfonamido” as used by itself or as part of another group refers to a radical of the formula —SO2NR23aR23b, wherein R23a and R23b are each independently hydrogen, optionally substituted alkyl, or optionally substituted aryl, or R23a and R23b taken together with the nitrogen to which they are attached form a 3- to 8-membered heterocyclo group. Non-limiting exemplary sulfonamido groups include —SO2NH2, —SO2N(H)CH3, and —SO2N(H)Ph.
As used herein, the term “alkylcarbonyl” as used by itself or as part of another group refers to a carbonyl group, i.e., —C(═O)—, substituted by an alkyl group. A non-limiting exemplary alkylcarbonyl group is —COCH3.
As used herein, the term “arylcarbonyl” as used by itself or as part of another group refers to a carbonyl group, i.e., —C(═O)—, substituted by an optionally substituted aryl group. A non-limiting exemplary arylcarbonyl group is —COPh.
As used herein, the term “alkylsulfonyl” as used by itself or as part of another group refers to a sulfonyl group, i.e., —SO2—, substituted by any of the above-mentioned optionally substituted alkyl groups. A non-limiting exemplary alkylsulfonyl group is —SO2CH3.
As used herein, the term “arylsulfonyl” as used by itself or as part of another group refers to a sulfonyl group, i.e., —SO2—, substituted by any of the above-mentioned optionally substituted aryl groups. A non-limiting exemplary arylsulfonyl group is —SO2Ph.
As used herein, the term “mercaptoalkyl” as used by itself or as part of another group refers to any of the above-mentioned alkyl groups substituted by a —SH group.
As used herein, the term “carboxy” as used by itself or as part of another group refers to a radical of the formula —COOH.
As used herein, the term “carboxyalkyl” as used by itself or as part of another group refers to any of the above-mentioned alkyl groups substituted with a —COOH. A non-limiting exemplary carboxyalkyl group is —CH2CO2H.
As used herein, the term “aralkyl” as used by itself or as part of another group refers to an alkyl group substituted with one, two, or three optionally substituted aryl groups. In one embodiment, the aralkyl group is a C1-4 alkyl substituted with one optionally substituted aryl group. Non-limiting exemplary aralkyl groups include benzyl, phenethyl, —CHPh2, and —CH(4-F-Ph)2.
As used herein, the term “ureido” as used by itself or as part of another group refers to a radical of the formula —NR22a—C(═O)—NR22bR22c, wherein R22a is hydrogen, alkyl, or optionally substituted aryl, and R22b and R22C are each independently hydrogen, alkyl, or optionally substituted aryl, or R22b and R22C taken together with the nitrogen to which they are attached form a 4- to 8-membered heterocyclo group. Non-limiting exemplary ureido groups include —NH—C(C═O)—NH2 and —NH—C(C═O)—NHCH3.
As used herein, the term “guanidino” as used by itself or as part of another group refers to a radical of the formula —NR25a—C(═NR14)—NR25bR25c, wherein R25a, R25b, and R25c are each independently hydrogen, alkyl, or optionally substituted aryl, and R14 is hydrogen, alkyl, cyano, alkylsulfonyl, alkylcarbonyl, carboxamido, or sulfonamido. Non-limiting exemplary guanidino groups include —NH—C(C═NH)—NH2, —NH—C(C═NCN)—NH2, —NH—C(C═NH)—NHCH3 and the like.
As used herein, the term “(heterocyclo)alkyl” as used by itself or as part of another group refers to an alkyl group substituted with one, two, or three optionally substituted heterocyclo groups. In one embodiment, the (heterocyclo)alkyl is a C1-4 alkyl substituted with one optionally substituted heterocyclo group. Non-limiting exemplary (heterocyclo)alkyl groups include:




As used herein, the term “(heteroaryl)alkyl” as used by itself or as part of another group refers to an alkyl group substituted with one, two, or three optionally substituted heteroaryl groups. In one embodiment, the (heteroaryl)alkyl group is a C1-4 alkyl substituted with one optionally substituted heteroaryl group. Non-limiting exemplary (heteroaryl)alkyl groups include:




Further, the present disclosure encompasses any of the Compounds of the Disclosure being isotopically-labelled (i.e., radiolabeled) by having one or more atoms replaced by an atom having a different atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2H, 3H, 11C, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, and 36Cl, respectively, e.g., 3H, 11C, and 14C. Isotopically-labeled Compounds of the Disclosure can be prepared by methods known in the art.
The present disclosure encompasses 3H, 11C, or 14C radiolabeled Compounds of the Disclosure and the use of any such compounds as radioligands for their ability to bind to the sodium channel. For example, one use of the labeled compounds of the present disclosure is the characterization of specific receptor binding. Another use of a labeled Compound of the Disclosure is an alternative to animal testing for the evaluation of structure-activity relationships. For example, the receptor assay can be performed at a fixed concentration of a labeled Compound of the Disclosure and at increasing concentrations of a test compound in a competition assay. For example, a tritiated Compound of the Disclosure can be prepared by introducing tritium into the particular compound, for example, by catalytic dehalogenation with tritium. This method may include reacting a suitably halogen-substituted precursor of the compound with tritium gas in the presence of a suitable catalyst, for example, Pd/C, in the presence or absence of a base. Other suitable methods for preparing tritiated compounds can be found in Filer, Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987). 14C-labeled compounds can be prepared by employing starting materials having a 14C carbon.
Some of the Compounds of the Disclosure may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms. The present disclosure is meant to encompass the use of all such possible forms, as well as their racemic and resolved forms and mixtures thereof. The individual enantiomers can be separated according to methods known in the art in view of the present disclosure. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that they include both E and Z geometric isomers. All tautomers are intended to be encompassed by the present disclosure as well.
As used herein, the term “stereoisomers” is a general term for all isomers of individual molecules that differ only in the orientation of their atoms in space. It includes enantiomers and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereomers).
The term “chiral center” refers to a carbon atom to which four different groups are attached.
The terms “enantiomer” and “enantiomeric” refer to a molecule that cannot be superimposed on its mirror image and hence is optically active wherein the enantiomer rotates the plane of polarized light in one direction and its mirror image compound rotates the plane of polarized light in the opposite direction.
The term “racemic” refers to a mixture of equal parts of enantiomers and which mixture is optically inactive.
The term “resolution” refers to the separation or concentration or depletion of one of the two enantiomeric forms of a molecule.
The terms “a” and “an” refer to one or more.
The term “treat,” “treating” or “treatment” is meant to encompass administering to a subject a compound of the present disclosure for the purposes of amelioration or cure, including preemptive and palliative treatment. In one embodiment, the term “treat,” “treating” or “treatment” is meant to encompass administering to a subject a compound of the present disclosure for the purposes of amelioration or cure.
The term “about,” as used herein in connection with a measured quantity, refers to the normal variations in that measured quantity, as expected by the skilled artisan making the measurement and exercising a level of care commensurate with the objective of measurement and the precision of the measuring equipment.
The present disclosure encompasses the preparation and use of salts of the Compounds of the Disclosure, including non-toxic pharmaceutically acceptable salts. Examples of pharmaceutically acceptable addition salts include inorganic and organic acid addition salts and basic salts. The pharmaceutically acceptable salts include, but are not limited to, metal salts such as sodium salt, potassium salt, cesium salt and the like; alkaline earth metals such as calcium salt, magnesium salt and the like; organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt and the like; inorganic acid salts such as hydrochloride, hydrobromide, phosphate, sulphate and the like; organic acid salts such as citrate, lactate, tartrate, maleate, fumarate, mandelate, acetate, dichloroacetate, trifluoroacetate, oxalate, formate and the like; sulfonates such as methanesulfonate, benzenesulfonate, p-toluenesulfonate and the like; and amino acid salts such as arginate, asparginate, glutamate and the like.
Acid addition salts can be formed by mixing a solution of the particular Compound of the Disclosure with a solution of a pharmaceutically acceptable non-toxic acid such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid, dichloroacetic acid, or the like. Basic salts can be formed by mixing a solution of the compound of the present disclosure with a solution of a pharmaceutically acceptable non-toxic base such as sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate and the like.
The present disclosure encompasses the preparation and use of solvates of Compounds of the Disclosure. Solvates typically do not significantly alter the physiological activity or toxicity of the compounds, and as such may function as pharmacological equivalents. The term “solvate” as used herein is a combination, physical association and/or solvation of a compound of the present disclosure with a solvent molecule such as, e.g. a disolvate, monosolvate or hemisolvate, where the ratio of solvent molecule to compound of the present disclosure is about 2:1, about 1:1 or about 1:2, respectively. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances, the solvate can be isolated, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. Thus, “solvate” encompasses both solution-phase and isolatable solvates. Compounds of the Disclosure can be present as solvated forms with a pharmaceutically acceptable solvent, such as water, methanol, ethanol, and the like, and it is intended that the disclosure includes both solvated and unsolvated forms of Compounds of the Disclosure. One type of solvate is a hydrate. A “hydrate” relates to a particular subgroup of solvates where the solvent molecule is water. Solvates typically can function as pharmacological equivalents. Preparation of solvates is known in the art. See, for example, M. Caira et al, J. Pharmaceut. Sci., 93(3):601-611 (2004), which describes the preparation of solvates of fluconazole with ethyl acetate and with water. Similar preparation of solvates, hemisolvates, hydrates, and the like are described by E. C. van Tonder et al., AAPS Pharm. Sci. Tech., 5(1):Article 12 (2004), and A. L. Bingham et al., Chem. Commun. 603-604 (2001). A typical, non-limiting, process of preparing a solvate would involve dissolving a Compound of the Disclosure in a desired solvent (organic, water, or a mixture thereof) at temperatures above 20° C. to about 25° C., then cooling the solution at a rate sufficient to form crystals, and isolating the crystals by known methods, e.g., filtration. Analytical techniques such as infrared spectroscopy can be used to confirm the presence of the solvent in a crystal of the solvate.
Since Compounds of the Disclosure are blockers of sodium (Na+) channels, a number of diseases and conditions mediated by sodium ion influx can be treated by employing these compounds. The present disclosure is thus directed generally to a method for treating a disorder responsive to the blockade of sodium channels in an animal suffering from, or at risk of suffering from, said disorder, said method comprising administering to the animal an effective amount of one or more Compounds of the Disclosure.
The present disclosure is further directed to a method of modulating sodium channels in an animal in need thereof, said method comprising administering to the animal a modulating-effective amount of at least one Compound of the Disclosure.
More specifically, the present disclosure provides a method of treating stroke, neuronal damage resulting from head trauma, epilepsy, neuronal loss following global and focal ischemia, pain (e.g., acute pain, chronic pain, which includes but is not limited to neuropathic pain, postoperative pain, and inflammatory pain, or surgical pain), a neurodegenerative disorder (e.g., Alzheimer's disease, amyotrophic lateral sclerosis (ALS), or Parkinson's disease), migraine, manic depression, tinnitus, myotonia, a movement disorder, or cardiac arrhythmia, or providing local anesthesia. In one embodiment, the disclosure provides a method of treating pain. In another embodiment, the type of pain is chronic pain. In another embodiment, the type of pain is neuropathic pain. In another embodiment, the type of pain is postoperative pain. In another embodiment, the type of pain is inflammatory pain. In another embodiment, the type of pain is surgical pain. In another embodiment, the type of pain is acute pain. In another embodiment, the treatment of pain (e.g., chronic pain, such as neuropathic pain, postoperative pain, or inflammatory pain, acute pain or surgical pain) is preemptive. In another embodiment, the treatment of pain is palliative. In each instance, such method of treatment requires administering to an animal in need of such treatment an amount of a Compound of the Disclosure that is therapeutically effective in achieving said treatment. In one embodiment, the amount of such compound is the amount that is effective to block sodium channels in vitro. In one embodiment, the amount of such compound is the amount that is effective to block sodium channels in vivo.
Chronic pain includes, but is not limited to, inflammatory pain, postoperative pain, cancer pain, osteoarthritis pain associated with metastatic cancer, trigeminal neuralgia, acute herpetic and postherpetic neuralgia, diabetic neuropathy, causalgia, brachial plexus avulsion, occipital neuralgia, reflex sympathetic dystrophy, fibromyalgia, gout, phantom limb pain, burn pain, and other forms of neuralgia, neuropathic, and idiopathic pain syndromes.
Chronic somatic pain generally results from inflammatory responses to tissue injury such as nerve entrapment, surgical procedures, cancer or arthritis (Brower, Nature Biotechnology 18:387-391 (2000)).
The inflammatory process is a complex series of biochemical and cellular events activated in response to tissue injury or the presence of foreign substances (Levine, Inflammatory Pain, In: Textbook of Pain, Wall and Melzack eds., 3rd ed., 1994). Inflammation often occurs at the site of injured tissue, or foreign material, and contributes to the process of tissue repair and healing. The cardinal signs of inflammation include erythema (redness), heat, edema (swelling), pain and loss of function (ibid.). The majority of patients with inflammatory pain do not experience pain continually, but rather experience enhanced pain when the inflamed site is moved or touched. Inflammatory pain includes, but is not limited to, that associated with osteoarthritis and rheumatoid arthritis.
Chronic neuropathic pain is a heterogeneous disease state with an unclear etiology. In chronic neuropathic pain, the pain can be mediated by multiple mechanisms. This type of pain generally arises from injury to the peripheral or central nervous tissue. The syndromes include pain associated with spinal cord injury, multiple sclerosis, post-herpetic neuralgia, trigeminal neuralgia, phantom pain, causalgia, and reflex sympathetic dystrophy and lower back pain. Chronic pain is different from acute pain in that patients suffer the abnormal pain sensations that can be described as spontaneous pain, continuous superficial burning and/or deep aching pain. The pain can be evoked by heat-, cold-, and mechano-hyperalgesia or by heat-, cold-, or mechano-allodynia.
Neuropathic pain can be caused by injury or infection of peripheral sensory nerves. It includes, but is not limited to, pain from peripheral nerve trauma, herpes virus infection, diabetes mellitus, causalgia, plexus avulsion, neuroma, limb amputation, and vasculitis. Neuropathic pain is also caused by nerve damage from chronic alcoholism, human immunodeficiency virus infection, hypothyroidism, uremia, or vitamin deficiencies. Stroke (spinal or brain) and spinal cord injury can also induce neuropathic pain. Cancer-related neuropathic pain results from tumor growth compression of adjacent nerves, brain, or spinal cord. In addition, cancer treatments, including chemotherapy and radiation therapy, can also cause nerve injury. Neuropathic pain includes but is not limited to pain caused by nerve injury such as, for example, the pain from which diabetics suffer.
The present disclosure is also directed to the use of a Compound of the Disclosure in the manufacture of a medicament for treating a disorder responsive to the blockade of sodium channels (e.g., any of the disorders listed above) in an animal suffering from said disorder.
General Synthesis of Compounds
Compounds of the Disclosure are prepared using methods known to those skilled in the art in view of this disclosure, or by the illustrative method shown in the General Schemes below. In General Schemes 1-3, R1, R5b, R6, R7, R9, and/or Z of Formulae AA-LL are as defined in connection with Formula I, unless otherwise indicated. In General Schemes 4 and 5, R1, R5b, and E of Formulae M-T are as defined in connection with Formula I, unless otherwise indicated.




Compound AA is converted to Compound CC by coupling with a suitable amine (such as, Compound BB) in the presence of a suitable coupling reagent (such as, HATU) and a suitable base (such as, DIPEA) in a suitable solvent (such as, DMF).
In the alternative, conversion of Compound AA to an acid chloride with a suitable reagent such as POCl3 followed by reaction with Compound BB in the presence of a suitable base (such as, DIPEA) in a suitable solvent (such as, DCM or Et2O) gives Compound CC. Compound CC is converted to Compound EE by reaction with Compound DD in the presence of a suitable base (such as, DIPEA) in a suitable solvent (such as, CAN). Compound EE is converted to Compound GG by reaction with Compound FF in the presence of a suitable base (such as, K2CO3) in a suitable solvent (such as, DMF).




In a manner similar to that described in General Scheme 1, Compound AA is converted to Compound KK by coupling with a suitable alcohol such as Compound HH (wherein R is an alkyl group) followed by coupling with Compound DD and Compound FF.




Compound KK is converted to Compound LL by treatment with a suitable base (such as, NaOH) in a suitable solvent (such as, aq. MeOH).




Compound M is converted to Compound O by coupling with a suitable boron reagent (such as, Compound N, wherein R is hydroxy, alkoxy, or amino) in the presence of a suitable catalyst (such as, Pd(dppf)Cl2) in a suitable solvent (such as, THF). Compound O is converted to Compound P by reaction with Compound FF in the presence of a suitable base (such as, K2CO3) in a suitable solvent (such as, DMF).
Compound P is then converted to Compound Q by reacting with a suitable oxidizing agent (such as, OsO4) with or without a co-oxidant (such as, NMO) in a suitable solvent (such as, aqueous acetone or alcohol). Such oxidation can be effected in a chiral fashion by reaction of Compound P with a suitable chiral oxidizing agent (such as, AD-mix-alpha or beta) in a suitable solvent (such as, aqueous acetone or alcohol).
Compound P can also be converted to Compound R by reaction with a suitable reagent (such as, borane) in a suitable solvent (such as, THF) followed by reaction with a suitable oxidizing reagent (such as, hydrogen peroxide) in the presence of a suitable base (such as, NaOH) in a suitable solvent (such as, water).




Compound P is converted to Compound S by reaction with a suitable oxidizing agent (such as, OsO4) in the presence of a suitable co-oxidant (such as, sodium periodate) in a suitable solvent (such as, aqueous THF).
Compound S can also be prepared from Compound Q by oxidation with a suitable reagent (such as, sodium periodate) in a suitable solvent (such as, aqueous THF). Compound S is converted to Compound T by reaction with a suitable reducing agent (such as, NaBH4) in a suitable solvent (such as, MeOH).




Compound U is converted to Compound W according to literature procedures (e.g., J. Med. Chem. 2008, 51, 2845) by reaction with Compound V using a suitable reagent (such as, 2,2,6,6-tetramethyl-3,5-heptanedione) in the presence of a suitable base (such as, Cs2CO3) in the presence of a suitable Lewis acid, such as, copper (I) chloride (CuCl), in a suitable solvent (such as, NMP).




Compound Y is converted to Compound Z according to literature procedures described in WO 2009044160 A1 by reaction with a suitable boron reagent (such as, Compound X) in the presence of a suitable base (such as, TEA) in a suitable solvent (such as, DCM).




Compound AA′ is converted to Compound AB according to literature procedures (as those described in Bioorganic & Medicinal Chemistry Letters, 2013, 23(24), 6777-6783) by reaction with a suitable boron reagent (such as, Compound X) in the presence of a suitable catalyst (such as, Pd(Ph3P)2Cl2) in the presence of a suitable base (such as, TEA) in a suitable solvent (such as, DMF).




Compound AC is converted to Compound AE by reaction with Compound AD in the presence of a suitable alcohol (such as, t-BuOH) in a suitable solvent (such as, toluene). Removal of the protecting group in Compound AE is achieved according to literature procedure (e.g. Greene, T. W. “Protective Groups in Organic Synthesis”, J. Wiley & Sons, NY, 1981) to give Compound AF, which is further treated with a suitable base (such as, ammonium carbonate) in a suitable solvent (such as, EtOH) followed by treatment with potassium cyanide and water to afford Compound AG.
Testing of Compounds
Compounds of the Disclosure were assessed by sodium mobilization and/or electrophysiological assays for sodium channel blocker activity. One aspect of the present disclosure is based on the use of the Compounds of the Disclosure as sodium channel blockers. Based upon this property, Compounds of the Disclosure are considered useful in treating a condition or disorder responsive to the blockade of sodium ion channels, e.g., stroke, neuronal damage resulting from head trauma, epilepsy, seizures, general epilepsy with febrile seizures, severe myoclonic epilepsy in infancy, neuronal loss following global and focal ischemia, migraine, familial primary erythromelalgia, paroxysmal extreme pain disorder, cerebellar atrophy, ataxia, dystonia, tremor, mental retardation, autism, a neurodegenerative disorder (e.g., Alzheimer's disease, amyotrophic lateral sclerosis (ALS), or Parkinson's disease), manic depression, tinnitus, myotonia, a movement disorder, cardiac arrhythmia, or providing local anesthesia. Compounds of the Disclosure are also expected to be effective in treating pain, e.g., acute pain, chronic pain, which includes but is not limited to, neuropathic pain, postoperative pain, and inflammatory pain, or surgical pain.
More specifically, the present disclosure is directed to Compounds of the Disclosure that are blockers of sodium channels. According to the present disclosure, those compounds having useful sodium channel blocking properties exhibit an IC50 for Nav1.1, Nav1.2, Nav1.3, Nav1.4, Nav1.5, Nav1.6, Nav1.7, Nav1.8, and/or Nav1.9 of about 100 μM or less, e.g., about 50 μM or less, about 25 μM or less, about 10 μM or less, about 5 μM or less, or about 1 μM or less, in sodium mobilization and/or electrophysiological assays. In certain embodiments, Compounds of the Disclosure exhibit an IC50 for Nav1.7 of 100 μM or less, about 50 μM or less, about 25 μM or less, about 10 μM or less, about 5 μM or less, about 1 μM or less, about 0.5 μM or less, about 0.1 μM or less, about 0.05 μM or less, or about 0.01 μM or less. Compounds of the Disclosure can be tested for their Na+ channel blocking activity using methods known in the art and by the following fluorescence imaging and electrophysiological in vitro assays and/or in vivo assays.
In one embodiment, Compounds of the Disclosure demonstrate substantially no penetration across the CNS blood-brain barrier in a mammal Such compounds are referred to as “peripherally restricted” as a means to designate their PNS versus CNS tissue selectivity.
In one embodiment, the PNS:CNS concentration ratio of a peripherally restricted Compound of the Disclosure is about 5:1, about 10:1, about 20:1, about 30:1; about 50:1; about 100:1, about 250:1, about 500:1, about 1000:1, about 5,000:1, about 10,000:1, or more. Compounds of the Disclosure can be tested for their ability to penetrate the central nervous system using in vitro and in vivo methods known in the art.
In Vitro Assay Protocols
FLIPR® Assays
Recombinant Nav1.7 Cell Line:
In vitro assays were performed in a recombinant cell line expressing cDNA encoding the alpha subunit (Nav1.7, SCN9a, PN1, NE) of human Nav1.7 (Accession No. NM_002977). The cell line was provided by investigators at Yale University (Cummins et al, J. Neurosci. 18(23): 9607-9619 (1998)). For dominant selection of the Nav1.7-expressing clones, the expression plasmid co-expressed the neomycin resistance gene. The cell line was constructed in the human embryonic kidney cell line, HEK293, under the influence of the CMV major late promoter, and stable clones were selected using limiting dilution cloning and antibiotic selection using the neomycin analogue, G418. Recombinant beta and gamma subunits were not introduced into this cell line. Additional cell lines expressing recombinant Nav1.7 cloned from other species can also be used, alone or in combination with various beta subunits, gamma subunits or chaperones.
Non-Recombinant Cell Lines Expressing Native Nav1.7:
Alternatively, in vitro assays can be performed in a cell line expressing native, non-recombinant Nav1.7, such as the ND7 mouse neuroblastoma X rat dorsal root ganglion (DRG) hybrid cell line ND7/23, available from the European Cell Culture Collection (Cat. No. 92090903, Salisbury, Wiltshire, United Kingdom). The assays can also be performed in other cell lines expressing native, non-recombinant Nav1.7, from various species, or in cultures of fresh or preserved sensory neurons, such as dorsal root ganglion (DRG) cells, isolated from various species. Primary screens or counter-screens of other voltage-gated sodium channels can also be performed, and the cell lines can be constructed using methods known in the art, purchased from collaborators or commercial establishments, and they can express either recombinant or native channels. The primary counter-screen is for one of the central neuronal sodium channels, Nav1.2 (rBIIa), expressed in HEK293 host cells (Ilyin et al., Br. J. Pharmacol. 144:801-812 (2005)). Pharmacological profiling for these counter-screens is carried out under conditions similar to the primary or alternative Nav1.7 assays described below.
Cell Maintenance:
Unless otherwise noted, cell culture reagents were purchased from Mediatech of Herndon, Va. The recombinant Nav1.7/HEK293 cells were routinely cultured in growth medium consisting of Dulbecco's minimum essential medium containing 10% fetal bovine serum (FBS, Hyclone, Thermo Fisher Scientific, Logan, Utah), 100 U/mL penicillin, 100 μg/mL streptomycin, 2-4 mM L-glutamine, and 500 mg/mL G418. For natural, non-recombinant cell lines, the selective antibiotic was omitted, and additional media formulations can be applied as needed.
Assay Buffer:
The assay buffer was formulated by removing 120 mL from a 1 L bottle of fresh, sterile dH2O (Mediatech, Herndon, Va.) and adding 100 mL of 10×HBSS that does not contain Ca++ or Mg++ (Gibco, Invitrogen, Grand Island, N.Y.) followed by 20 mL of 1.0 M Hepes, pH 7.3 (Fisher Scientific, BP299-100). The final buffer consisted of 20 mM Hepes, pH 7.3, 1.261 mM CaCl2, 0.493 mM MgCl2, 0.407 mM Mg(SO)4, 5.33 mM KCl, 0.441 mM KH2PO4, 137 mM NaCl, 0.336 mM Na2HPO4 and 0.556 mM D-glucose (Hanks et al., Proc. Soc. Exp. Biol. Med. 71:196 (1949)), and the simple formulation was typically the basic buffer throughout the assay (i.e., all wash and addition steps).
CoroNaTM Green AM Na+ Dye for Primary Fluorescence Assay:
The fluorescence indicator used in the primary fluorescence assay was the cell permeant version of CoroNaTM Green (Invitrogen, Molecular Probes, Eugene, Oreg.), a dye that emits light in the fluorescence range (Harootunian et al., J. Biol. Chem. 264(32):19458-19467 (1989)). The intensity of this emission, but not the wavelength range, is increased when the dye is exposed to Na+ ions, which it can bind with partial selectivity. Cells expressing Nav1.7 or other sodium channels were loaded with the CoroNaTM Green dye immediately in advance of the fluorescence assay, and then, after agonist stimulation, the mobilization of Na+ ions was detected as the Na+ ions flowed from the extracellular fluid into the cytoplasm through the activated sodium channel pores. The dye was stored in the dark as a lyophilized powder, and then an aliquot was dissolved immediately before the cell loading procedure, according to the instructions of the manufacturer, to a stock concentration of 10 mM in DMSO. It was then diluted in the assay buffer to a 4× concentrated working solution, so that the final concentration of dye in the cell loading buffer was 5 μM.
Membrane Potential Dye for Alternative Fluorescence Assays:
A fluorescence indicator that can be used in alternative fluorescence assays is the blue version membrane potential dye (MDS, Molecular Devices, Sunnyvale, Calif.), a dye that detects changes in molecules following a change in membrane potential. An increase in fluorescence is expected if agonist stimulation provokes a change in membrane potential. Cells expressing Nav1.7 or other sodium channels are incubated with the membrane potential dye 30-60 minutes before the fluorescence assay. In the case of the KCl pre-stimulation version of the assay, the dye and all other components are washed out immediately before the assay, and the dye is then replaced. In the version lacking KCl pre-stimulation, the dye remains on the cells and is not washed out or replaced. The dye is stored in the dark as a lyophilized powder, and then an aliquot dissolved in assay buffer to form a 20×-concentrated stock solution that can be used for several weeks.
Agonists:
In the fluorescence assays, two agonists were used in combination, namely 1) veratridine; and 2) the venom from the yellow scorpion, Leiurus quinquestriatus hebraeus. Veratridine is an alkaloid small molecule that facilitates the capture of channel openings by inhibiting inactivation, and the scorpion venom is a natural preparation that includes peptide toxins selective for different subsets of voltage-gated sodium channels. These scorpion toxins inhibit the fast inactivation of their cognate target channels. Stock solutions of the agonists were prepared to 40 mM in DMSO (veratridine) and 1 mg/mL in dH2O (scorpion venom), and then diluted to make a 4× or 2× stock (depending on the particular assay) in assay buffer, the final concentration being 100 μM (veratridine) and 10 μg/mL (scorpion venom). Both of the agonists were purchased from Sigma Aldrich, St. Louis, Mo.
Test Compounds:
Test compounds were dissolved in DMSO to yield 10 mM stock solutions. The stock solutions were further diluted using DMSO in 1:3 serial dilution steps with 10 points (10,000 μM, 3.333 μM, 1.111 μM, 370 μM, 123 μM, 41 μM, 14 μM, 4.6 μM, 1.5 μM and 0.5 μM). The stock solutions were further diluted in assay buffer (1:125) as 4× stock serial dilutions with a DMSO concentration of 0.8% (final [DMSO], in the assay, from the compounds component=0.2%), so that the compounds' final concentrations in the assay were 20 μM, 6.7 μM, 2.2 μM, 0.74 μM, 0.25 μM and 0.08 μM, 0.03 μM, 0.01 μM, 0.003 μM and 0.001 μM. If a particular test article appeared to be especially potent, then the concentration curve was adjusted, e.g., to 10-fold lower concentrations, in order to perform the dose-response in a more relevant concentration range. Compound dilutions were added during the dye-loading and pre-stimulation step, and then again during the fluorescence assay, early in the kinetic read. Compound dilutions were added in duplicate rows across the middle 80 wells of the 96-well plate, whereas the fully stimulated and the fully inhibited controls (positive and negative) were located in the top 4 side wells and the bottom 4 side wells, respectively, on the left and right sides of the assay plate.
Data Analysis:
The data were analyzed according to methods known to those skilled in the art or using the GraphPad® Prism Program, version 4.0 or higher (available from GraphPad Software, San Diego, Calif.) to determine the IC50 value for the test article. At least one standard reference compound was evaluated during each experiment.
FLIPR® or FLIPRTETRA® Sodium Dye Assay with KCl and Test Article Pre-Incubation:
Cells were prepared by plating the recombinant HEK293 cells or other host cells expressing either recombinant or non-recombinant, native, Nav1.7 alpha subunit, alone or in combination with various beta and gamma subunits at a density of  ̃40,000 cells/well into a 96-well black, clear-bottom, PDL-coated plate. The assay can be adapted to 384-well or 1,536-well format, if desired, using proportionately fewer cells and less media. The plate was then incubated in growth media, with or without selective antibiotic, overnight at 37° C. at 5% CO2, 95% humidity, in preparation for the assay. For counter-screens of other voltage-gated sodium channels, the procedure was very similar, though optimal densities of cells, media and subsequent assay components can be fine-tuned for the particular cell line or isoform.
The next day, at the start of the assay, the media was flicked from the cells and the wells were washed once with 50 μl/well assay buffer (1× Hank's balanced salt solution without sodium bicarbonate or phenol red, 20 mM Hepes, pH 7.3) and then pre-incubated with the test articles, CoroNaTM Green AM sodium dye (for cell loading) and KCl for re-polarization and synchronization of the channels in the entire population of cells. For this dye-loading and pre-stimulation step, the components were added as follows, immediately after the wash step: 1) first, the compound dilutions and controls were added as 4× concentrates in assay buffer at 50 μL/well; 2) CoroNaTM Green AM dye was diluted from the stock solution to 20 μM in assay buffer (4× concentrate) and added to the plate at 50 μL/well; and 3) finally, a solution of 180 mM KCl (2×) was prepared by diluting a 2M stock solution into assay buffer and the solution was added to the cells at 100 μl/well. The cells were incubated at 25° C. in the dark for 30 min. before their fluorescence was measured.
The plates containing dye-loaded cells were then flicked to remove the pre-incubation components and washed once with 100 μL/well assay buffer. A 100 μL/well aliquot of assay buffer was added back to the plate, and the real-time assay was commenced. The fluorescence of cells was measured using a fluorescence plate reader (FLIPRTETRA® or FLIPR384®, MDS, Molecular Devices, Sunnyvale, Calif.) Samples were excited by either a laser or a PMT light source (Excitation wavelength=470-495 nM) and the emissions are filtered (Emission wavelength=515-575 nM). The additions of compound and the channel activators in this cell-based, medium-to-high throughput assay were performed on the fluorescence plate reader and the results (expressed as relative fluorescence units) were captured by means of camera shots every 1-3 sec., then displayed in real-time and stored. Generally, there was a 15 sec. base line, with camera shots taken every 1.5 sec., then the test compounds were added, then another 120 sec. baseline was conducted, with camera shots taken every 3 sec.; and finally, the agonist solution (containing veratridine and scorpion venom) was added. The amplitude of fluorescence increase, resulting from the binding of Na+ ions to the CoroNaTM Green dye, was captured for  ̃180 sec. thereafter. Results were expressed in relative fluorescence units (RFU) and can be determined by using the maximum signal during the latter part of the stimulation; or the maximum minus the minimum during the whole agonist stimulation period; or by taking the area under the curve for the whole stimulation period.
The assay can be performed as a screening assay as well with the test articles present in standard amounts (e.g., 10 μM) in only one or two wells of a multi-well plate during the primary screen. Hits in this screen were typically profiled more exhaustively (multiple times), subjected to dose-response or competition assays and tested in counter screens against other voltage-gated sodium channels or other biologically relevant target molecules.
FLIPR® or FLIPRTETRA® membrane potential assay with KCl and test article pre-incubation: Cells are prepared by plating the recombinant HEK293 cells or other host cells expressing either recombinant or non-recombinant, native, Nav1.7 alpha subunit, alone or in combination with various beta and gamma subunits at a density of  ̃40,000 cells/well into a 96-well black, clear-bottom, PDL-coated plate. The assay can be adapted to 384-well or 1,536-well format, if desired, using proportionately less cells and media. The plate is then incubated in growth media, with or without selective antibiotic, overnight at 37° C. at 5% CO2, 95% humidity, in preparation for the assay (see, e.g., Benjamin et. al., J. Biomol. Screen 10(4):365-373 (2005)). For screens and counter-screens of other voltage-gated sodium channels, the assay protocol is similar, though optimal densities of cells, media and subsequent assay components can be fine-tuned for the particular cell line or sodium channel isoform being tested.
The next day, at the start of the assay, the media is flicked from the cells and the wells are washed once with 50 μL/well assay buffer (1× Hank's balanced salt solution without sodium bicarbonate or phenol red, 20 mM Hepes, pH 7.3) and then pre-incubated with the test articles, the membrane potential dye (for cell loading), and the KCl for re-polarization and synchronization of the channels in the entire population of cells. For this dye-loading and pre-stimulation step, the components are added as follows, immediately after the wash step: 1) first, the compound dilutions and controls are added as 4× concentrates in assay buffer at 50 μL/well; 2) membrane potential dye is diluted from the stock solution in assay buffer (4× concentrate) and added to the plate at 50 μL/well; and 3) finally, a solution of 180 mM KCl (2×) is prepared by diluting a 2M stock solution into assay buffer and the solution added to the cells at 100 μL/well. The cells are incubated at 37° C. in the dark for 30-60 min before their fluorescence is measured.
The plates containing dye-loaded cells are then flicked to remove the pre-incubation components and washed once with 50 μL/well assay buffer. A 50 μL/well aliquot of membrane potential dye is added back to the plate, and the real-time assay is commenced. The fluorescence of cells is measured using a fluorescence plate reader (FLIPRTETRA® or FLIPR384®, MDS, Molecular Devices, Sunnyvale, Calif.). Samples are excited by either a laser or a PMT light source (Excitation wavelength=510-545 nM) and the emissions are filtered (Emission wavelength=565-625 nM). The additions of the compounds (first) and then the channel activators (later) in this are performed on the fluorescence plate reader and the results, expressed as relative fluorescence units (RFU), are captured by means of camera shots every 1-3 sec., then displayed in real-time and stored. Generally, there is a 15 sec. base line, with camera shots taken every 1.5 sec., then the test compounds are added, then another 120 sec. baseline is conducted, with camera shots taken every 3 sec.; and finally, the agonist solution (containing veratridine and scorpion venom) is added. The amplitude of fluorescence increase, resulting from the detection of membrane potential change, is captured for  ̃120 sec. thereafter. Results are expressed in relative fluorescence units (RFU) and can be determined by using the maximum signal during the latter part of the stimulation; or the maximum minus the minimum during the whole stimulation period; or by taking the area under the curve for the whole stimulation period.
The assay can be performed as a screening assay as well with the test articles present in standard amounts (e.g., 10 μM) in only one or two wells of a multi-well plate during the primary screen. Hits in this screen are typically profiled more exhaustively (multiple times), subjected to dose-response or competition assays and tested in counter screens against other voltage-gate sodium channels or other biologically relevant target molecules.
FLIPR® or FLIPRTETRA® Sodium Dye Assay without KCl and Test Article Pre-Incubation:
Cells are prepared by plating the recombinant HEK293 cells or other host cells expressing either recombinant or non-recombinant, native, Nav1.7 alpha subunit, alone or in combination with various beta and gamma subunits at a density of  ̃40,000 cells/well into a 96-well black, clear-bottom, PDL-coated plate. The assay can be adapted to 384-well or 1,536-well format, if desired, using proportionately less cells and media. The plate is then incubated in growth media, with or without selective antibiotic, overnight at 37° C. at 5% CO2, 95% humidity, in preparation for the assay. For counter-screens of other voltage-gated sodium channels, the procedure is very similar, though optimal densities of cells, media and subsequent assay components can be fine-tuned for the particular cell line or isoform.
The next day, at the start of the assay, the media is flicked from the cells and the wells washed once with 50 μL/well assay buffer (1× Hank's balanced salt solution without sodium bicarbonate or phenol red, 20 mM Hepes, pH 7.3). Membrane potential dye is then added to each well of the 96-well plate (50 μL/well), from a freshly diluted sample of the stock (now at 4× concentration) in the assay buffer. The cells are incubated at 37° C. in the dark for 30-60 min. before their fluorescence is measured.
In this standard membrane potential assay, the 96-well plate containing dye-loaded cells is then loaded directly onto the plate reader without aspirating the dye solution and without any further washing of the cells. The fluorescence of cells is measured using a fluorescence plate reader (FLIPRTETRA® or FLIPR384®, MDS, Molecular Devices, Sunnyvale, Calif.). Samples are excited by either a laser or a PMT light source (Excitation wavelength=510-545 nM) and the emissions are filtered (Emission wavelength=565-625 nM). The additions of the compounds (first, 50 μL/well from a 4× stock plate) and then the channel activators (later, 100 μL/well from a 2× stock solution) in this kinetic assay are performed on the fluorescence plate reader and the results, expressed as relative fluorescence units (RFU), are captured by means of camera shots every 1-3 sec., then displayed in real-time and stored. Generally, there is a 15 sec. base line, with camera shots taken every 1.5 sec., then the test compounds are added, then another 120 sec. baseline is conducted, with camera shots taken every 3 sec.; and finally, the agonist solution (containing veratridine and scorpion venom) is added. The amplitude of fluorescence increase, resulting from the detection of membrane potential change, is captured for  ̃120 sec. thereafter. Results are expressed in relative fluorescence units (RFU) and can be determined by using the maximum signal during the latter part of the stimulation; or the maximum minus the minimum during the whole stimulation period; or by taking the area under the curve for the whole stimulation period.
The assay can be performed as a screening assay as well, with the test articles present in standard amounts (e.g. 10 μM) in only one or two wells of a multi-well plate during the primary screen. Hits in this screen are typically profiled more exhaustively (multiple times), subjected to dose-response or competition assays and tested in counter screens against other voltage-gate sodium channels or other biologically relevant target molecules.
Electrophysiology Assay
Cells Manual Electrophysiology:
The hNav1.7 expressing HEK-293 cells are plated on 35 mm culture dishes pre-coated with poly-D-lysine in standard DMEM culture media (Mediatech, Inc., Herndon, Va.) and incubated in a 5% CO2 incubator at 37° C. Cultured cells are used approximately 12-48 hours after plating.
Cells Automated Electrophysiology:
The hNav1.7 expressing HEK-293 cells are plated on tissue culture flasks in standard DMEM culture media (Mediatech, Inc.) and incubated in a 5% CO2 incubator at 37° C. Cultured cells are used approximately 12-48 hours after plating.
Manual Electrophysiology:
On the day of experimentation, the 35 mm dish is placed on the stage of an inverted microscope equipped with a perfusion system that continuously perfuses the culture dish with fresh recording media. A gravity driven superfusion system is used to apply test solutions directly to the cell under evaluation. This “shooter” system consists of an array of glass pipettes connected to a motorized horizontal translator. The outlet of the shooter is positioned approximately 100 μm from the cell of interest.
Whole cell currents are recorded using the whole-cell patch clamp configuration using an Axopatch 200B amplifier (Axon Instruments, Foster City Calif.), 1322A A/D converter (Axon Instruments) and pClamp software (v. 8; Axon Instruments) and stored on a personal computer. Gigaseals are formed and the whole-cell configuration is established in voltage clamp mode, and membrane currents generated by hNav1.7 channels are recorded. Borosilicate glass pipettes with resistance values between 1.5 and 2.0 MΩ when filled with pipette solution are used and series resistance (<5 MΩ) is compensated by 75-80%. Signals are sampled at 50 kHz and low pass filtered at 3 kHz.
Automated Electrophysiology:
On the day of experimentation, cells are prepared by removing media and digesting with appropriate enzymes to suspend cells in external solution.
Whole cell currents are recorded using the whole-cell patch clamp configuration using an Patchliner (Nanion Technologies, Munich Germany), EPC 10 quadro amplifiers (HEKA, Bellmore, N.Y.) and PatchControl HT 10905 (Nanion Technologies) and PatchMaster v2x73 software (HEKA) and stored on a personal computer. Gigaseals are formed and the whole-cell configuration is established in voltage clamp mode, and membrane currents generated by hNav1.7 are recorded. NPC-16 chips have resistance values between 1.0 and 2.0 M52 when filled with pipette solution and series resistance (<5 Me). Signals are sampled at 25 kHz and low pass filtered at 3 kHz.
Voltage Protocols Manual Electrophysiology:
After establishing the whole-cell configuration in voltage clamp mode, voltage protocols are run to establish the 1) test potential (Vmax), 2) holding potential (Vh), and 3) the conditioning potential for each cell.
After establishing the whole-cell configuration in voltage clamp mode, a standard I-V protocol is run to determine the potential at which the maximal current (Imax) is elicited. This potential is the test potential (Vt). To determine a conditioning potential at which 100% of channels are in the inactivated state, a standard steady-state inactivation (SSIN) protocol is run using a series of fifteen 100 ms-long depolarizing prepulses, incrementing in 10 mV steps, immediately followed by a 5 ms testing pulse to Vmax. This protocol also permits determination of the holding potential at which all channels are in the resting state.
For compounds causing significant retardation of recovery from inactivation, an estimate of the affinity for the inactivated state of the channel (Ki) is generated using the following protocol. From the negative, no residual inactivation, holding potential, the cell is depolarized to the conditioning voltage for 2-5 seconds, returned to the negative holding potential for 10-20 ms to relieve fast inactivation and then depolarized to the test potential for  ̃15 ms. This voltage protocol is repeated every 10-15 seconds, first to establish a baseline in the absence of the test compound, then in the presence of the test compound.
After a stable baseline is established, the test compound is applied and block of the current elicited by the test pulse assessed. In some cases, multiple cumulative concentrations are applied to identify a concentration that blocked between 40-60% of this current. Washout of the compound is attempted by superfusing with control solution once steady-state block is observed. An estimate of the Ki is calculated as follows:

Ki=[drug]*{FR/(1−FR)},  Eq. 1

where [drug] is the concentration of a drug, and

FR=I(after drug)/I(control),  Eq. 2

where I is the peak current amplitude. If multiple concentrations were used, Ki is determined from the fit of a logistic equation to FRs plotted against corresponding drug concentrations.

In the alternative, the voltage clamp protocol to examine hNav1.7 currents is as follows. After establishing the whole-cell configuration in voltage clamp mode, two voltage protocols were run to establish: 1) the holding potential; and 2) the test potential for each cell.
Resting Block:
To determine a membrane potential at which the majority of channels are in the resting state, a standard steady-state inactivation (SSIN) protocol is run using 100 ms prepulses×10 mV depolarizing steps. The holding potential for testing resting block (Vh1) is typically 20 mV more hyperpolarized than the first potential where inactivation is observed with the inactivation protocol.
From this holding potential a standard I-V protocol is run to determine the potential at which the maximal current is elicited (Vmax). This potential is the test potential (Vt).
The compound testing protocol is a series of 10 ms depolarizations from the Vh1 (determined from the SSIN) to the Vt (determined from the I-V protocol) repeated every 10-15 seconds. After a stable baseline is established, a high concentration of a test compound (highest concentration solubility permits or that which provides  ̃50% block) is applied and block of the current assessed. Washout of the compound is attempted by superfusing with control solution once steady-state block was observed. The affinity for the resting state of the channels is calculated as follows:

Kr=[drug]*{FR/(1−FR)},  Eq. 3

where [drug] is the concentration of a drug, and

FR=I(after drug)/I(control),  Eq. 2

where I is the peak current amplitude and was used for estimating resting block dissociation constant, Kr.
Block of Inactivated Channels:
To assess the block of inactivated channels the holding potential is depolarized such that 20-50% of the current amplitude is reduced when pulsed to the same Vt as above. This is the second holding potential (Vh2). The magnitude of this depolarization depends upon the initial current amplitude and the rate of current loss due to slow inactivation. The current reduction is recorded to determine the fraction of available channels at this potential (h).

h=I@Vh2/Imax.  Eq. 4

At this membrane voltage a proportion of channels are in the inactivated state, and thus inhibition by a blocker includes interaction with both resting and inactivated channels.
To determine the potency of the test compound on inactivated channels, a series of currents are elicited by 10 ms voltage steps from Vh2 to Vt every 10-15 seconds. After establishing a stable baseline, the low concentration of the compound is applied. In some cases, multiple cumulative concentrations will have to be applied to identify a concentration that blocks between 40-60% of the current. Washout is attempted to re-establish baseline. Fractional responses are measured with respect to a projected baseline to determine Kapp.

Kapp=[drug]*{FR/(1−FR)},  Eq. 5

where [drug] is the concentration of a drug.

This Kapp value, along with the calculated Kr and h values, are used to calculate the affinity of the compound for the inactivated channels (Ki) using the following equation:

Ki=(1−h)/((1/Kapp)−(h/Kr)).  Eq. 6

Voltage protocols Automated Electrophysiology:
Similar voltage protocols are used as described above, however the test potential (Vt) is set to a predetermined voltage. Kapp is determined as described above.
Solutions and Chemicals:
For electrophysiological recordings the external solution is either standard, HBSS supplemented with 10 mM HEPES (pH adjusted to 7.34 with NaOH and the osmolarity adjusted to 320) or Tyrodes salt solution (Sigma, USA) supplemented with 10 mM HEPES (pH adjusted to 7.4 with NaOH; osmolarity=320). The internal pipette solution contains (in mM): NaCl (10), CsF (140), CaCl2 (1), MgCl2 (5), EGTA (11), HEPES (10: pH 7.4, 305 mOsm). Compounds are prepared first as series of stock solutions in DMSO and then dissolved in external solution; DMSO content in final dilutions did not exceed 0.3%. At this concentration, DMSO does not affect sodium currents. Vehicle solution used to establish base line also contains 0.3% DMSO.
Data Analysis Manual Electrophysiology:
Data is analyzed off-line using Clampfit software (pClamp, v.8; Axon Instruments) and graphed using GraphPad Prizm (v. 4.0) software.
Data Analysis Automated Electrophysiology:
Data is analyzed off-line using Igor Pro (v 6.2.2.2; Wave Metrics, Inc., Lake Oswego, Oreg.) and Microsoft XL (Microsoft Office 2010, v14x, Microsoft, Renton Wash.).
In Vivo Assay for Pain
Compounds of the Disclosure can be tested for their antinociceptive activity in the formalin model as described in Hunskaar et al., J. Neurosci. Methods 14: 69-76 (1985). Male Swiss Webster NIH mice (20-30 g; Harlan, San Diego, Calif.) can be used in all experiments. Food is withdrawn on the day of the experiment. Mice are placed in Plexiglass jars for at least 1 hour to acclimate to the environment. Following the acclimation period, mice are weighed and given either the compound of interest administered i.p. or p.o., or the appropriate volume of vehicle (for example, 10% Tween-80 or 0.9% saline, and other pharmaceutically acceptable vehicles) as control. Fifteen minutes after the i.p. dosing, and 30 minutes after the p.o. dosing mice are injected with formalin (20 μL of 5% formaldehyde solution in saline) into the dorsal surface of the right hind paw. Mice are transferred to the Plexiglass jars and monitored for the amount of time spent licking or biting the injected paw. Periods of licking and biting are recorded in 5-minute intervals for 1 hour after the formalin injection. All experiments are done in a blinded manner during the light cycle. The early phase of the formalin response is measured as licking/biting between 0-5 minutes, and the late phase is measured from 15-50 minutes. Differences between vehicle and drug treated groups can be analyzed by one-way analysis of variance (ANOVA). A P value <0.05 is considered significant. Compounds are considered to be efficacious for treating acute and chronic pain if they have activity in blocking both the early and second phase of formalin-induced paw-licking activity.
In Vivo Assays for Inflammatory or Neuropathic Pain
Test Animals:
Each experiment uses rats weighing between 200-260 g at the start of the experiment. The rats are group-housed and have free access to food and water at all times, except prior to oral administration of a test compound when food is removed for 16 h before dosing. A control group acts as a comparison to rats treated with a Compound of the Disclosure. The control group is administered the carrier as used for the test compound. The volume of carrier administered to the control group is the same as the volume of carrier and test compound administered to the test group.
Inflammatory Pain:
To assess the actions of Compounds of the Disclosure on the treatment of inflammatory pain, the Freund's complete adjuvant (“FCA”) model of inflammatory pain is used. FCA-induced inflammation of the rat hind paw is associated with the development of persistent inflammatory mechanical and thermal hyperalgesia and provides reliable prediction of the anti-hyperalgesic action of clinically useful analgesic drugs (Bartho et al., Naunyn-Schmiedeberg's Archives of Pharmacol. 342:666-670 (1990)). Prior to the injury, the animal is assessed for response to noxious mechanical stimuli by determining the paw withdrawal threshold (PWT), or to noxious thermal stimuli by determining paw withdrawal latency (PWL), as described below (baseline PWT or PWL). Then, the left hind paw of each animal is administered a 50 μL intraplantar injection of 50% FCA. 24 hour post injection, the PWT or PWL is again assessed (pre-administration PWT or PWL). Rats are then administered a single injection of either a test compound or 30 mg/Kg of a positive control compound (e.g., indomethacin). Responses to noxious mechanical or thermal stimuli are then determined 1, 3, 5 and 24 hours post administration (post-administration PWT or PWL). Percentage reversal of hyperalgesia for each animal is defined as:




  
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    ×
    100
  




Neuropathic Pain:
To assess the actions of the test compounds for the treatment of neuropathic pain the Seltzer model or the Chung model can be used.
In the Seltzer model, the partial sciatic nerve ligation model of neuropathic pain is used to produce neuropathic hyperalgesia in rats (Seltzer et al., Pain 43:205-218 (1990)). Partial ligation of the left sciatic nerve is performed under isoflurane/O2 inhalation anesthesia. Following induction of anesthesia, the left thigh of the rat is shaved and the sciatic nerve exposed at high thigh level through a small incision and is carefully cleared of surrounding connective tissues at a site near the trocanther just distal to the point at which the posterior biceps semitendinosus nerve branches off of the common sciatic nerve. A 7-0 silk suture is inserted into the nerve with a 3⁄8 curved, reversed-cutting mini-needle and tightly ligated so that the dorsal 1⁄3 to 1⁄2 of the nerve thickness is held within the ligature. The wound is closed with a single muscle suture (4-0 nylon (Vicryl)) and vetbond tissue glue. Following surgery, the wound area is dusted with antibiotic powder. Sham-treated rats undergo an identical surgical procedure except that the sciatic nerve is not manipulated. Following surgery, animals are weighed and placed on a warm pad until they recover from anesthesia. Animals are then returned to their home cages until behavioral testing begins. The animals are assessed for response to noxious mechanical stimuli by determining PWT, as described below, prior to surgery (baseline), then immediately prior to and 1, 3, and 5 hours after administration of either drug or vehicle, for the ipsilateral (injured side) rear paw of the animal. Percentage reversal of neuropathic hyperalgesia is defined as:




  
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    ⁢
    
      
    
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    ×
    100
  




In the Chung model, the spinal nerve ligation (SNL) model of neuropathic pain is used to produce mechanical hyperalgesia, thermal hyperalgesia, and tactile allodynia in rats. Surgery is performed under isoflurane/O2 inhalation anesthesia. Following induction of anesthesia a 3 cm incision is made and the left paraspinal muscles are separated from the spinous process at the L4-S2 levels. The L6 transverse process is carefully removed with a pair of small rongeurs to identify visually the L4-L6 spinal nerves. The left L5 (or L5 and L6) spinal nerve(s) is (are) isolated and tightly ligated with silk thread. A complete hemostasis is confirmed and the wound is sutured using non-absorbable sutures, such as nylon sutures or stainless steel staples. Sham-treated rats undergo an identical surgical procedure except that the spinal nerve(s) is (are) not manipulated. Following surgery animals are weighed, administered a subcutaneous (s.c.) injection of saline or ringers lactate, the wound area is dusted with antibiotic powder and they are kept on a warm pad until they recover from the anesthesia. Animals are then returned to their home cages until behavioral testing begins. The animals are assessed for response to noxious mechanical stimuli by determining PWT, as described below, prior to surgery (baseline), then immediately prior to and 1, 3, and 5 hours after being administered a Compound of the Disclosure or vehicle, for the left rear paw of the animal. The animals can also be assessed for response to noxious thermal stimuli or for tactile allodynia, as described below. The Chung model for neuropathic pain is described in Kim et al., Pain 50(3):355-363 (1992).
Tactile Allodynia:
Sensitivity to non-noxious mechanical stimuli can be measured in animals to assess tactile allodynia. Rats are transferred to an elevated testing cage with a wire mesh floor and allowed to acclimate for five to ten minutes. A series of von Frey monofilaments are applied to the plantar surface of the hindpaw to determine the animal's withdrawal threshold. The first filament used possesses a buckling weight of 9.1 gms (0.96 log value) and is applied up to five times to see if it elicits a withdrawal response. If the animal has a withdrawal response, then the next lightest filament in the series would be applied up to five times to determine if it also could elicit a response. This procedure is repeated with subsequent lesser filaments until there is no response and the identity of the lightest filament that elicits a response is recorded. If the animal does not have a withdrawal response from the initial 9.1 gms filament, then subsequent filaments of increased weight are applied until a filament elicits a response and the identity of this filament is recorded. For each animal, three measurements are made at every time point to produce an average withdrawal threshold determination. Tests can be performed prior to, and at 1, 2, 4 and 24 hours post drug administration.
Mechanical Hyperalgesia:
Representative Compounds of the Disclosure can be tested in the SNL-induced mechanical hyperalgesia model in rats. Sensitivity to noxious mechanical stimuli are measured in animals using the paw pressure test to assess mechanical hyperalgesia. In rats, hind paw withdrawal thresholds (“PWT”), measured in grams, in response to a noxious mechanical stimulus are determined using an analgesymeter (Model 7200, commercially available from Ugo Basile of Italy), as described in Stein (Biochemistry & Behavior 31: 451-455 (1988)). The rat's paw is placed on a small platform, and a punctate weight was applied in a graded manner up to a maximum of 250 grams. The endpoint is taken as the weight at which the paw is completely withdrawn. PWT is determined once for each rat at each time point. PWT can be measured only in the injured paw, or in both the injured and non-injured paw. Rats are tested prior to surgery to determine a baseline, or normal, PWT. Rats are tested again 2 to 3 weeks post-surgery, prior to, and at different times after (e.g. 1, 3, 5 and 24 hr) drug administration. An increase in PWT following drug administration indicates that the test compound reduces mechanical hyperalgesia.
In Vivo Assay for Anticonvulsant Activity
Compounds of the Disclosure can be tested for in vivo anticonvulsant activity after i.v., p.o., or i.p. injection using any of a number of anticonvulsant tests in mice or rats, including the maximum electroshock seizure test (MES). Maximum electroshock seizures are induced in male NSA mice weighing between 15-20 g and in male Sprague-Dawley rats weighing between 200-225 g by application of current (for mice: 50 mA, 60 pulses/sec, 0.8 msec pulse width, 1 sec duration, D.C.; for rats: 99 mA, 125 pulses/sec, 0.8 msec pulse width, 2 sec duration, D.C.) using a Ugo Basile ECT device (Model 7801). Mice are restrained by gripping the loose skin on their dorsal surface and saline-coated corneal electrodes are held lightly against the two corneae. Rats are allowed free movement on the bench top and ear-clip electrodes are used. Current is applied and animals are observed for a period of up to 30 seconds for the occurrence of a tonic hindlimb extensor response. A tonic seizure is defined as a hindlimb extension in excess of 90 degrees from the plane of the body. Results can be treated in a quantal manner.
Pharmaceutical Compositions
Compounds of the Disclosure can be administered to a mammal in the form of a raw chemical without any other components present. Compounds of the Disclosure can also be administered to a mammal as part of a pharmaceutical composition containing the compound combined with a suitable pharmaceutically acceptable carrier. Such a carrier can be selected from pharmaceutically acceptable excipients and auxiliaries.
Pharmaceutical compositions within the scope of the present disclosure include all compositions where a Compound of the Disclosure is combined with one or more pharmaceutically acceptable carriers. In one embodiment, the Compound of the Disclosure is present in the composition in an amount that is effective to achieve its intended therapeutic purpose. While individual needs may vary, a determination of optimal ranges of effective amounts of each compound is within the skill of the art. Typically, a Compound of the Disclosure can be administered to a mammal, e.g., a human, orally at a dose of from about 0.0025 to about 1500 mg per kg body weight of the mammal, or an equivalent amount of a pharmaceutically acceptable salt or solvate thereof, per day to treat the particular disorder. A useful oral dose of a Compound of the Disclosure administered to a mammal is from about 0.0025 to about 50 mg per kg body weight of the mammal, or an equivalent amount of the pharmaceutically acceptable salt or solvate thereof. For intramuscular injection, the dose is typically about one-half of the oral dose.
A unit oral dose may comprise from about 0.01 mg to about 1 g of the Compound of the Disclosure, e.g., about 0.01 mg to about 500 mg, about 0.01 mg to about 250 mg, about 0.01 mg to about 100 mg, 0.01 mg to about 50 mg, e.g., about 0.1 mg to about 10 mg, of the compound. The unit dose can be administered one or more times daily, e.g., as one or more tablets or capsules, each containing from about 0.01 mg to about 1 g of the compound, or an equivalent amount of a pharmaceutically acceptable salt or solvate thereof.
A pharmaceutical composition of the present disclosure can be administered to any animal that may experience the beneficial effects of a Compound of the Disclosure. Foremost among such animals are mammals, e.g., humans and companion animals, although the disclosure is not intended to be so limited.
A pharmaceutical composition of the present disclosure can be administered by any means that achieves its intended purpose. For example, administration can be by the oral, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, intranasal, transmucosal, rectal, intravaginal or buccal route, or by inhalation. The dosage administered and route of administration will vary, depending upon the circumstances of the particular subject, and taking into account such factors as age, gender, health, and weight of the recipient, condition or disorder to be treated, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired.
In one embodiment, a pharmaceutical composition of the present disclosure can be administered orally and is formulated into tablets, dragees, capsules or an oral liquid preparation. In one embodiment, the oral formulation comprises extruded multiparticulates comprising the Compound of the Disclosure.
Alternatively, a pharmaceutical composition of the present disclosure can be administered rectally, and is formulated in suppositories.
Alternatively, a pharmaceutical composition of the present disclosure can be administered by injection.
Alternatively, a pharmaceutical composition of the present disclosure can be administered transdermally.
Alternatively, a pharmaceutical composition of the present disclosure can be administered by inhalation or by intranasal or transmucosal administration.
Alternatively, a pharmaceutical composition of the present disclosure can be administered by the intravaginal route.
A pharmaceutical composition of the present disclosure can contain from about 0.01 to 99 percent by weight, and preferably from about 0.25 to 75 percent by weight, of active compound(s).
A method of the present disclosure, such as a method for treating a disorder responsive to the blockade of sodium channels in an animal in need thereof, can further comprise administering a second therapeutic agent to the animal in combination with a Compound of the Disclosure. In one embodiment, the other therapeutic agent is administered in an effective amount.
Effective amounts of the other therapeutic agents are known to those skilled in the art. However, it is well within the skilled artisan's purview to determine the other therapeutic agent's optimal effective-amount range.
Compounds of the Disclosure (i.e., the first therapeutic agent) and the second therapeutic agent can act additively or, in one embodiment, synergistically. Alternatively, the second therapeutic agent can be used to treat a disorder or condition that is different from the disorder or condition for which the first therapeutic agent is being administered, and which disorder or condition may or may not be a condition or disorder as defined herein. In one embodiment, a Compound of the Disclosure is administered concurrently with a second therapeutic agent; for example, a single composition comprising both an effective amount of a Compound of the Disclosure and an effective amount of the second therapeutic agent can be administered. Accordingly, the present disclosure further provides a pharmaceutical composition comprising a combination of a Compound of the Disclosure, the second therapeutic agent, and a pharmaceutically acceptable carrier. Alternatively, a first pharmaceutical composition comprising an effective amount of a Compound of the Disclosure and a second pharmaceutical composition comprising an effective amount of the second therapeutic agent can be concurrently administered. In another embodiment, an effective amount of a Compound of the Disclosure is administered prior or subsequent to administration of an effective amount of the second therapeutic agent. In this embodiment, the Compound of the Disclosure is administered while the second therapeutic agent exerts its therapeutic effect, or the second therapeutic agent is administered while the Compound of the Disclosure exerts its therapeutic effect for treating a disorder or condition.
The second therapeutic agent can be an opioid agonist, a non-opioid analgesic, a non-steroidal anti-inflammatory agent, an antimigraine agent, a Cox-II inhibitor, a β-adrenergic blocker, an anticonvulsant, an antidepressant, an anticancer agent, an agent for treating addictive disorder, an agent for treating Parkinson's disease and parkinsonism, an agent for treating anxiety, an agent for treating epilepsy, an agent for treating a seizure, an agent for treating a stroke, an agent for treating a pruritic condition, an agent for treating psychosis, an agent for treating ALS, an agent for treating a cognitive disorder, an agent for treating a migraine, an agent for treating vomiting, an agent for treating dyskinesia, or an agent for treating depression, or a mixture thereof.
A pharmaceutical composition of the present disclosure is manufactured in a manner which itself will be known in view of the instant disclosure, for example, by means of conventional mixing, granulating, dragee-making, dissolving, extrusion, or lyophilizing processes. Thus, pharmaceutical compositions for oral use can be obtained by combining the active compound with solid excipients, optionally grinding the resulting mixture and processing the mixture of granules, after adding suitable auxiliaries, if desired or necessary, to obtain tablets or dragee cores.
Suitable excipients include fillers such as saccharides (for example, lactose, sucrose, mannitol or sorbitol), cellulose preparations, calcium phosphates (for example, tricalcium phosphate or calcium hydrogen phosphate), as well as binders such as starch paste (using, for example, maize starch, wheat starch, rice starch, or potato starch), gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone. If desired, one or more disintegrating agents can be added, such as the above-mentioned starches and also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate.
Auxiliaries are typically flow-regulating agents and lubricants such as, for example, silica, talc, stearic acid or salts thereof (e.g., magnesium stearate or calcium stearate), and polyethylene glycol. Dragee cores are provided with suitable coatings that are resistant to gastric juices. For this purpose, concentrated saccharide solutions can be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. In order to produce coatings resistant to gastric juices, solutions of suitable cellulose preparations such as acetylcellulose phthalate or hydroxypropylmethyl-cellulose phthalate can be used. Dye stuffs or pigments can be added to the tablets or dragee coatings, for example, for identification or in order to characterize combinations of active compound doses.
Examples of other pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin, or soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. The push-fit capsules can contain a compound in the form of granules, which can be mixed with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers, or in the form of extruded multiparticulates. In soft capsules, the active compounds are preferably dissolved or suspended in suitable liquids, such as fatty oils or liquid paraffin. In addition, stabilizers can be added.
Possible pharmaceutical preparations for rectal administration include, for example, suppositories, which consist of a combination of one or more active compounds with a suppository base. Suitable suppository bases include natural and synthetic triglycerides, and paraffin hydrocarbons, among others. It is also possible to use gelatin rectal capsules consisting of a combination of active compound with a base material such as, for example, a liquid triglyceride, polyethylene glycol, or paraffin hydrocarbon.
Suitable formulations for parenteral administration include aqueous solutions of the active compound in a water-soluble form such as, for example, a water-soluble salt, alkaline solution, or acidic solution. Alternatively, a suspension of the active compound can be prepared as an oily suspension. Suitable lipophilic solvents or vehicles for such as suspension may include fatty oils (for example, sesame oil), synthetic fatty acid esters (for example, ethyl oleate), triglycerides, or a polyethylene glycol such as polyethylene glycol-400 (PEG-400). An aqueous suspension may contain one or more substances to increase the viscosity of the suspension, including, for example, sodium carboxymethyl cellulose, sorbitol, and/or dextran. The suspension may optionally contain stabilizers.
The following examples are illustrative, but not limiting, of the compounds, compositions, and methods of the present disclosure. Suitable modifications and adaptations of the variety of conditions and parameters normally encountered in clinical therapy and which are obvious to those skilled in the art in view of this disclosure are within the spirit and scope of the disclosure.
EXAMPLES
Example 1
Synthesis of 2,6-dichloropyrimidine-4-carboxamide (Compound 3)




A mixture of orotic acid mono hydrate (Compound 1) (34.828 g, 0.200 mol, Aldrich), phosphorus oxychloride (100 mL, 1.092 mol) and 20 drops of DMF were heated at 110° C. overnight. After cooling the dark mixture was diluted with 500 mL hexanes and vigorously stirred. The hexane layer was decanted and quickly washed with water (1×100 mL) and brine (1×100 mL), and dried over MgSO4. The organics were filtered and carefully evaporated in vacuo to give Compound 2 as a light yellow liquid (26.13 g). Yield: 62%. 1H NMR (400 MHz, CDCl3): δ 7.93 (s, 1H).
To a solution of Compound 2 (26.13 g, 123.6 mmol) in Et2O (500 mL) was added a mixture of 0.5 M ammonia in dioxane (250 mL, 125 mmol) and DIPEA (22 mL, 126 mmol) dropwise over 50 min. After stirring at room temperature (RT) overnight the reaction mixture was concentrated in vacuo to give a residue that was purified by flash chromatography (SiO2, 10-50% EtOAc/hexanes). The product fractions were evaporated in vacuo, and the resulting solid residue was triturated with 10 mL 10% EtOAc/hexanes and filtered to give Compound 3 as an orange crystalline solid (9.743 g). Yield: 41%. 1H NMR (400 MHz, DMSO-d6): δ 8.40 (br s, 1H), 8.16 (br s, 1H), 8.10 (s, 1H). LC/MS: m/z=192.2 [M+H]+ (Calc: 191.4).
Example 2
Synthesis of Compounds 5 and 6




To a solution of Compound 3 (4.80 g, 25.0 mmol) in ACN (100 mL) was added (S)-3-aminopyrrolidin-2-one (Compound 4) (2.55 g, 25.54 mmol, Aldrich) and DIPEA (9.60 mL, 55.11 mmol). The mixture was heated at 50° C. overnight then concentrated in vacuo. The residue was purified by flash chromatography (SiO2, 20-60% acetone/hexanes) to give Compound 5 as a tan solid (4.79 g). Yield: 75%. LC/MS: m/z=256.2 [M+f1]+ (Calc: 255.4).
In a similar manner, Compound 6 was prepared.




LC/MS: m/z=244.2 [M+H]+ (Calc: 243.4).
Example 3
Synthesis of Compound 8




To a solution of Compound 5 (0.15 g, 0.59 mmol) and Compound 7 (0.145 g, 0.65 mmol, Aldrich) in DMF (2.3 mL) was added K2CO3 (0.203 g, 1.467 mmol). The reaction mixture was heated at 80° C. for 2 h, cooled to RT, and added dropwise into cold water with rapid stirring. The resulting solid was collected by filtration, washed with water, dissolved in DCM, dried over Na2SO4, and purified by flash chromatography (SiO2, 0-5% MeOH/DCM) to give Compound 8 as a light yellow solid (0.040 g). Yield: 17%. 1H NMR (400 MHz, CDCl3): δ 7.68 (d, J=5.23 Hz, 1H), 7.30-7.22 (m, 3H) 7.09 (d, J=5.92 Hz, 1H), 6.60 (s, 1H), 6.03-5.99 (bs, 1H), 5.62-5.56 (bs, 1H), 5.53-5.50 (d, 1H), 5.13 (s, 2H), 4.75-4.68 (d, J=13.60 Hz, 2H), 4.53-4.42 (bs, 1H), 3.46-3.41 (m, 2H), 3.39-3.29 (t, J=13.15 Hz, 2H), 2.89-2.80 (m, 1H), 2.12-2.00 (quin, J=9.87 Hz, 1H), 1.95-1.84 (m, 2H), 1.82 (s, 1H), 1.79 (s, 1H). LC/MS: m/z=409.2 [M+H]+ (Calc: 408.4).
In a similar manner, the following compounds were prepared: Compound 9: 1H NMR (400 MHz, DMSO-d6): δ 7.69 (d, J=4.16 Hz, 1H), 7.35 (t, J=9.87 Hz, 2H) 7.29-7.18 (m, 2H), 6.95 (d, J=5.48 Hz, 1H), 6.83 (d, J=5.48 Hz, 1H), 6.09 (d, J=14.25 Hz, 2H), 5.63 (d, J=4.38 Hz, 1H), 5.57 (d, J=5.04 Hz, 1H), 4.78 (d, J=13.37 Hz, 2H), 4.54-4.45 (bs, 1H), 3.46-3.40 (m, 2H), 3.30 (t, J=12.50 Hz, 2H), 2.89-2.80 (m, 1H), 2.14-2.02 (m, 3H), 1.43 (d, J=13.37 Hz, 2H). LC/MS: m/z=405.1 [M+H]+ (Calc: 404.5).
Compound 10: 1H NMR (400 MHz, CD3OD): δ 7.89 (d, J=8.55 Hz, 1H), 7.76 (t, J=7.67 Hz, 1H) 7.61 (t, J=6.36 Hz, 2H), 6.58 (s, 1H), 4.98-4.91 (m, 2H), 4.57 (t, 1H), 3.45-3.36 (m, 4H), 2.56-2.46 (m, 1H), 2.36-2.19 (m, 3H), 1.79-1.69 (m, 2H). LC/MS: m/z=423.1 [M+H]+ (Calc: 422.4).
Compound 11: 1H NMR (400 MHz, CD3OD): δ 7.11 (t, J=8.77 Hz, 2H), 6.73 (t, J=7.45 Hz, 1H), 6.64 (d, J=7.89 Hz, 2H), 6.60 (s, 1H), 4.72 (s, 2H), 4.72-4.64 (m, 2H), 4.54 (t, J=10.09 Hz, 1H), 3.67 (t, J=12.06 Hz, 2H), 3.41-3.34 (m, 2H), 2.69-2.55 (m, 2H), 2.53-2.44 (m, 1H), 2.31-2.18 (m, 1H), 1.75-1.66 (m, 2H). LC/MS: m/z=451.2 [M+H]+ (Calc: 450.5).
Example 4
The following compounds were prepared according to literature procedures (including those provided infra.).




1-Bromo-4-(4-fluorophenoxy)benzene (Compound 22), 1-(4-bromophenoxy)-3-fluorobenzene (Compound 23), 1-bromo-4-(4-(trifluoromethyl)phenoxy)benzene (Compound 24) and 1-(4-bromophenoxy)-3-(trifluoromethyl)benzene (Compound 25) were prepared through procedures as those described in J. Med. Chem. 2008, 51, 2845.
2-Chloro-5-(4-fluorophenoxy)pyridine (Compound 26) was prepared in the way as those described in WO 2009044160 A1.
2-Chloro-4-(4-(trifluoromethoxy)phenyl)pyridine (Compound 27) and 2-chloro-4-(3-(trifluoromethoxy)phenyl)pyridine (Compound 28) were prepared in accordance with procedures as those described in Bioorganic & Medicinal Chemistry Letters, 2013, 23(24), 6777-6783.
Example 5
2-Chloro-5-(4-(trifluoromethyl)phenoxy)pyridine (Compound 31)




A mixture of 2-chloro-5-hydroxypyridine (Compound 29) (1.7 g, 0.013 mol, Aldrich), 4-trifluoromethylphenyl boronic acid (Compound 30) (5.0 g, 0.026 mol, Aldrich), and copper (II) acetate monohydrate (3.9 g, 0.020 mol) was stirred at RT in DCM (60 mL). TEA (8 mL) and 4A molecular sieves (20 g) were added. The suspension was stirred under air at RT for 3 days and DCM (50 mL) was then added. The reaction mixture was stirred at RT for 25 min and filtered through Celite. The filtrate was washed with water (1×100 mL), brine (1×100 mL) and dried over MgSO4. The organics were filtered and evaporated in vacuo. The residue was purified by flash chromatography (SiO2, 0-70% EtOAc/hexanes) to give Compound 31 as a white solid (932 g, yield 26%): LC/MS: m/z=274 [M+H]+ (Calc: 273.6).
In a similar manner, the following compounds were prepared:




2-Chloro-5-(3-(trifluoromethyl)phenoxy)pyridine (Compound 32): LC/MS: m/z=274 [M+H]+ (Calc: 273.6).
2-Chloro-3-(4-fluorophenoxy)pyridine (Compound 33): LC/MS: m/z=224 [M+H]+ (Calc: 223.6).
Example 6
Synthesis of 8-(5-(4-(trifluoromethyl)phenoxy)pyridin-2-yl)-1,3,8-triazaspiro[4.5]decane-2,4-dione (Compound 17)




A mixture of 2-Chloro-5-[4-(trifluoromethyl)phenoxy]pyridine (Compound 31) (925 mg, 3.38 mmol), 1,4-dioxa-8-azaspiro[4.5]decane (Compound 34) (484 mg, 3.38 mmol, Aldrich) and t-BuOH (757 mg, 6.76 mmol) were suspended in toluene (20 mL). To the suspension was added Pd2(dba)3 (72 mg, 0.068 mmol) and followed by BINAP (105 mg, 0.169 mmol). The reaction mixture was heated at 100° C. in a microwave for 6 h. The reaction mixture was poured into EtOAc and filtered through Celite. The filtrate was evaporated in vacuo and the residue purified by flash chromatography (SiO2, 0-50% EtOAc/hexanes) to give Compound 35 (811 mg). Yield 63%
To a solution of Compound 35 (805 mg, 2.11 mmol) in THF (15 mL) was added 2N HCl (10 mL). The mixture was refluxed overnight, cooled to RT, and extracted with EtOAc (2×20 mL). The combined extracts were washed with brine, dried over Na2SO4, and filtered through Celite. The filtrate was evaporated in vacuo and the residue purified by flash chromatography (SiO2, 0-50% EtOAc/hexanes) to give Compound 36 (639 mg). Yield 90% LC/MS: m/z=337 [M+H]+ (Calc: 336.3).
To a suspension of Compound 36 in EtOH (15 mL) stirred at room temperature was added ammonium carbonate (1.43 g, 14.89 mmol). The mixture was treated with a suspension of potassium cyanide (254 mg, 3.91 mmol) in water (10 mL). The resulting mixture was heated at 80° C. for 16 h. The reaction mixture was cooled to RT and the EtOH removed under reduced pressure. Water (20 mL) and EtOAc (20 mL) was added. The organic phase was separated and the aqueous phase was extracted with EtOAc (20 mL). The combined extracts were washed with brine, dried over Na2SO4, and filtered through Celite. The filtrate was evaporated in vacuo and the residue purified by recrystallization from a mixture of EtOAc and hexane to give Compound 17 as a white solid (635 mg): 1H NMR (400 MHz, DMSO-d6): δ 10.71 (s, 1H), 8.60 (s, 1H), 8.05 (d, J=3.08 Hz, 1H), 7.70 (m, J=8.58 Hz, 2H), 7.46 (dd, J=9.13, 2.97 Hz, 1H), 7.09 (m, J=8.58 Hz, 2H), 6.99 (d, J=9.24 Hz, 1H), 4.07-4.21 (m, 2H), 3.23-3.36 (m, 3H), 2.48-2.53 (m, 1H), 1.77-1.90 (m, 2H), 1.61 (d, J=13.20 Hz, 2H). LC/MS: m/z=407.1 [M+H]+ (Calc: 406.4).
In a similar manner, the following compounds were prepared.







8-(4-(4-Fluorophenoxy)phenyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione (Compound 12)
1H NMR (400 MHz, DMSO-d6): δ 10.69 (s, 2H), 8.53 (s, 2H), 7.08-7.27 (m, 4H), 6.89-7.02 (m, 10H) 3.48-3.64 (m, 4H), 3.32 (s, 4H), 2.96-3.11 (m, 4H), 2.48-2.55 (m, 9H), 1.83-2.02 (m, 4H), 1.63 (d, J=13.42 Hz, 4H). LC/MS: m/z=356.1 [M+H]+ (Calc: 355.4).
8-(4-(3-Fluorophenoxy)phenyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione (Compound 13)
1H NMR (400 MHz, DMSO-d6): δ 10.69 (s, 1H), 8.54 (s, 1H), 7.26-7.44 (m, 1H), 6.94-7.07 (m, 4H), 6.89 (t, J=8.62 Hz, 1H), 6.68-6.79 (m, 2H), 3.50-3.67 (m, 2H), 3.32 (s, 1H), 2.97-3.15 (m, 2H), 2.48-2.54 (m, 4H), 1.87-2.00 (m, 2H), 1.64 (d, J=13.20 Hz, 2H). LC/MS: m/z=356.1 [M+H]+ (Calc: 355.4).
8-(4-(3-(Trifluoromethyl)phenoxy)phenyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione (Compound 14)
1H NMR (400 MHz, DMSO-d6): δ 10.68 (br. s., 1H) 8.51 (s, 1H), 7.58 (t, J=7.92 Hz, 1H), 7.41 (d, J=7.70 Hz, 1H), 7.13-7.26 (m, 2H), 6.95-7.10 (m, 4H), 3.46-3.71 (m, 2H), 3.32 (s, 2H), 3.06 (t, J=10.78 Hz, 2H), 2.48-2.54 (m, 4H), 1.87-2.10 (m, 2H), 1.63 (d, J=13.20 Hz, 2H). LC/MS: m/z=406.0 [M+H]+ (Calc: 405.4).
8-(4-(4-(trifluoromethoxy)phenyl)pyridin-2-yl)-1,3,8-triazaspiro[4.5]decane-2,4-dione (Compound 15)
1H NMR (400 MHz, DMSO-d6): δ 10.70 (s, 1H), 8.59 (s, 1H), 8.19 (d, J=5.28 Hz, 1H), 7.82-7.98 (m, 2H), 7.48 (d, J=8.14 Hz, 2H), 7.13 (s, 1H), 6.95 (dd, J=5.17, 1.21 Hz, 1H), 4.19-4.46 (m, 2H), 3.31-3.38 (m, 3H), 2.48-2.54 (m, 6H), 1.74-1.91 (m, 2H), 1.59 (d, J=13.42 Hz, 2H). LC/MS: m/z=407.1 [M+H]+ (Calc: 406.3).
8-(5-(4-Fluorophenoxy)pyridin-2-yl)-1,3,8-triazaspiro[4.5]decane-2,4-dione (Compound 16)
1H NMR (400 MHz, DMSO-d6): δ 10.70 (s, 1H), 8.59 (s, 1H), 8.19 (d, J=5.28 Hz, 1H), 7.82-7.98 (m, 2H), 7.48 (d, J=8.14 Hz, 2H), 7.13 (s, 1H), 6.95 (dd, J=5.17, 1.21 Hz, 1H), 4.19-4.46 (m, 2H), 3.31-3.38 (m, 3H), 2.48-2.54 (m, 6H), 1.74-1.91 (m, 2H), 1.59 (d, J=13.42 Hz, 2H). LC/MS: m/z=357.1 [M+H]+ (Calc: 356.4).
8-(5-(3-(Trifluoromethyl)phenoxy)pyridin-2-yl)-1,3,8-triazaspho[4.5]decane-2,4-dione (Compound 18)
1H NMR (400 MHz, DMSO-d6): δ 10.71 (s, 1H), 8.59 (s, 1H), 8.05 (d, J=2.86 Hz, 1H), 7.58 (t, J=7.86 Hz, 1H), 7.38-7.51 (m, 2H), 7.23 (s, 1H), 7.22 (d, J=7.43 Hz, 2H), 6.99 (d, J=9.24 Hz, 1H), 4.06-4.21 (m, 2H), 3.24-3.34 (m, 4H), 2.49-2.53 (m, 3H), 1.74-1.93 (m, 2H), 1.60 (d, J=13.20 Hz, 2H). LC/MS: m/z=407.1 [M+H]+ (Calc: 406.4).
8-(4-(4-(trifluoromethyl)phenoxy)phenyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione (Compound 19)
1H NMR (400 MHz, DMSO-d6): δ 10.63 (s, 1H), 8.48 (s, 1H), 7.63 (d, J=8.80 Hz, 2H), 6.93-7.02 (m, 6H), 3.48-3.61 (m, 2H), 3.26 (s, 2H), 2.93-3.08 (m, 2H), 2.42-2.46 (m, 1H), 1.80-1.93 (m, 2H), 1.57 (d, J=13.20 Hz, 2H). LC/MS: m/z=406.0 [M+H]+ (Calc: 405.4).
8-(3-(4-Fluorophenoxy)pyridin-2-yl)-1,3,8-triazaspiro[4.5]decane-2,4-dione (Compound 20)
1H NMR (400 MHz, DMSO-d6): δ 10.65 (s, 1H), 8.54 (s, 1H), 8.05 (dd, J=4.73, 1.43 Hz, 1H), 7.16-7.28 (m, 3H), 6.88-6.97 (m, 3H), 3.84-3.96 (m, 2H), 3.33 (s, 1H), 3.18 (t, J=11.33 Hz, 2H), 2.48-2.53 (m, 1H), 1.69-1.83 (m, 2H), 1.52 (d, J=13.20 Hz, 2H). LC/MS: m/z=357.1 [M+H]+ (Calc: 356.4).
8-(4-(3-(Trifluoromethoxy)phenyl)pyridin-2-yl)-1,3,8-triazaspiro[4.5]decane-2,4-dione (Compound 21)
1H NMR (400 MHz, DMSO-d6): δ 10.70 (s, 1H), 8.60 (s, 1H), 8.20 (d, J=5.28 Hz, 1H), 7.82 (d, J=7.46 Hz, 1H), 7.79 (s, 1H), 7.63 (t, J=8.03 Hz, 1H), 7.45 (d, J=7.52 Hz, 1H), 7.17 (s, 1H), 6.97 (dd, J=5.28, 1.10 Hz, 1H), 4.22-4.35 (m, 2H), 3.31-3.40 (m, 3H), 2.48-2.53 (m, 1H), 1.78-1.99 (m, 2H), 1.60 (d, J=13.42 Hz, 2H). LC/MS: m/z=407.1 [M+H]+ (Calc: 406.4).
Example 7
Representative Compounds of the Disclosure have been tested in the FLIPR® or FLIPRTETRA® assays and/or EP assays for sodium channel blocking activity (as described above). Representative values obtained from CoroNaTM Green AM Na+ Dye for Primary Fluorescence Assay and/or EP assays are presented in TABLE 3, and representative values from membrane potential dye for alternative fluorescence assays and/or EP assays for are presented in TABLE 4.







TABLE 3







Evaluation of compounds as sodium channel (Nav) blockers










Compound
Nav1.7 Activity (μM)



No.
FLIPR assay IC50














8
3.918 ± 0.466



9
1.304 ± 0.124



10
3.860 ± 0.390



11
>20

















TABLE 4







Evaluation of compounds as sodium channel (Nav) blockers










Compound
Nav1.7(MP) Activity (μM)



No.
FLIPR assay IC50







12
>20



13
1.536 ± 0.223



14
1.268 ± 0.380



15
0.872 ± 0.117



16
4.479 ± 1.040



17
1.730 ± 0.649



18
1.435 ± 0.492



19
>20



20
>20



21
1.979 ± 0.309










Having now fully described this disclosure, it will be understood by those of ordinary skill in the art that the same can be performed within a wide and equivalent range of conditions, formulations and other parameters without affecting the scope of the disclosure or any embodiment thereof.
Other embodiments of the disclosure will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.
All patents and publications cited herein are fully incorporated by reference in their entirety.

## Claims

1. A compound having Formula I:



or a pharmaceutically acceptable salt or solvate thereof,
wherein:
R1 is selected from the group consisting of:




R2a and R2b are each independently selected from the group consisting of:
a) hydrogen;
b) halo;
c) nitro;
d) cyano;
e) hydroxy;
f) amino;
g) alkylamino;
h) dialkylamino;
i) alkyl;
j) haloalkyl;
k) hydroxyalkyl;
l) alkoxy;
m) haloalkoxy; and
n) alkoxyalkyl;

 is a single bond or a double bond;
X1 is selected from the group consisting of O and NR3;
R3 is selected from the group consisting of hydrogen and alkyl;
R5a is selected from the group consisting of:
a) hydrogen;
b) halo;
c) nitro;
d) cyano;
e) hydroxy;
f) amino;
g) alkylamino;
h) dialkylamino;
i) haloalkyl;
j) hydroxyalkyl;
k) alkoxy;
l) haloalkoxy;
m) alkoxyalkyl; and
n) —Z—R9;

R5b is selected from the group consisting of:
a) hydrogen;
b) halo;
c) nitro;
d) cyano;
e) hydroxy;
f) amino;
g) alkylamino;
h) dialkylamino;
i) haloalkyl;
j) hydroxyalkyl;
k) alkoxy;
l) haloalkoxy; and
m) alkoxyalkyl;

E is selected from the group consisting of:
a) hydroxy;
b) alkoxy; and
c) —NR6R7;
R6 is selected from the group consisting of:
a) hydrogen;
b) alkyl;
c) aralkyl;
d) (heterocyclo)alkyl;
e) (heteroaryl)alkyl;
f) (amino)alkyl;
g) (alkylamino)alkyl;
h) (dialkylamino)alkyl;
i) (carboxamido)alkyl;
j) (cyano)alkyl;
k) alkoxyalkyl;
l) hydroxyalkyl; and
m) heteroalkyl;

R7 is selected from the group consisting of hydrogen and alkyl; or
R6 and R7 taken together with the nitrogen atom to which they are attached form a 3- to 8-membered optionally substituted heterocyclo;
Z is selected from the group consisting of —NR8— and —O—;
R8 is selected from the group consisting of:
a) hydrogen
b) alkyl; and
c) hydroxyalkyl;

R9 is selected from the group consisting of:






 and
c) hydroxyalkyl; or

R8 and R9 taken together with the nitrogen atom to which they are attached form a 3- to 8-membered optionally substituted heterocyclo;
R10 is selected from the group consisting of:
a) hydrogen;
b) optionally substituted alkyl;
c) aralkyl;
d) (heterocyclo)alkyl;
e) (heteroaryl)alkyl;
f) (amino)alkyl;
g) (alkylamino)alkyl;
h) (dialkylamino)alkyl;
i) (carboxamido)alkyl;
j) (cyano)alkyl;
k) alkoxyalkyl;
l) hydroxyalkyl;
m) heteroalkyl;
n) optionally substituted cycloalkyl;
o) optionally substituted aryl;
p) optionally substituted heterocyclo; and
q) optionally substituted heteroaryl;

R11 is selected from the group consisting of:
a) hydroxy;
b) alkoxy; and
c) —NR13aR13b;

R13a is selected from the group consisting of:
a) hydrogen;
b) alkyl;
c) aralkyl;
d) (heterocyclo)alkyl;
e) (heteroaryl)alkyl;
f) (amino)alkyl;
g) (alkylamino)alkyl;
h) (dialkylamino)alkyl;
i) (carboxamido)alkyl;
j) (cyano)alkyl;
k) alkoxyalkyl;
l) hydroxyalkyl; and
m) heteroalkyl;

R13b is selected from the group consisting of hydrogen and alkyl; or
R13a and R13b taken together with the nitrogen atom to which they are attached form a 3- to 8-membered optionally substituted heterocyclo;
R12 is selected from the group consisting of hydrogen and alkyl; and
s is 1, 2, or 3.

2. The compound of claim 1, wherein:
R5a is —Z—R9;
Z is —NH— or —O—;
R9 is




 and
R11 is —NH2, or a pharmaceutically acceptable salt or solvate thereof.

3. The compound of claim 1, wherein:
R5a is —Z—R9;
Z is —NH— or —O—; and
R9 is




or a pharmaceutically acceptable salt or solvate thereof.

4. The compound of claim 3, wherein R9 is selected from the group consisting of:



wherein Z is —NH—,
or a pharmaceutically acceptable salt or solvate thereof.

5. The compound of claim 1, wherein R1 is R1—I, R1—II, R1—III, or R1—IV, or a pharmaceutically acceptable salt or solvate thereof.

6. The compound of claim 1 selected from the group consisting of:
(S)-6-((2-oxopyrrolidin-3-yl)amino)-2-(3H-spiro[isobenzofuran-1,4′-piperidin]-1′-yl)pyrimidine-4-carboxamide;
(S)-6-((2-oxopyrrolidin-3-yl)amino)-2-(spiro[indene-1,4′-piperidin]-1′-yl)pyrimidine-4-carboxamide; and
(S)-2-(3-oxo-3H-spiro[isobenzofuran-1,4′-piperidin]-1′-yl)-6-((2-oxopyrrolidin-3-yl)amino)pyrimidine-4-carboxamide;

or a pharmaceutically acceptable salt, or solvate thereof.

7. A pharmaceutical composition, comprising the compound of claim 1, or a pharmaceutically acceptable salt, or solvate thereof, and a pharmaceutically acceptable carrier.

8. A method of modulating Nav1.7 sodium channels in a mammal, comprising administering to the mammal at least one compound as claimed in claim 1, or a pharmaceutically acceptable salt, or solvate thereof.

9. The compound of claim 1, wherein
R5a is —Z—R9; and
R5b is hydrogen,

or a pharmaceutically acceptable salt or solvate thereof.

10. The compound of claim 1, wherein
R5a is hydroxyalkyl; and
R5b is hydrogen,

or a pharmaceutically acceptable salt or solvate thereof.

11. The compound of claim 1, wherein E is —NH2, or a pharmaceutically acceptable salt or solvate thereof.

12. The compound of claim 2, wherein R9 is selected from the group consisting of:




and
R19 is a C1-C4 alkyl, or a pharmaceutically acceptable salt or solvate thereof.

13. The compound of claim 12, wherein Z is —NH—, or a pharmaceutically acceptable salt or solvate thereof.

14. The compound of claim 1, wherein
Z is —NR8—, and R9 is




or a pharmaceutically acceptable salt or solvate thereof.

15. The compound of claim 1, wherein R1 is R1—I, and  is a double bond, or a pharmaceutically acceptable salt or solvate thereof.

16. The compound of claim 15, wherein R2a and R2b are both hydrogen, or a pharmaceutically acceptable salt or solvate thereof.

17. The compound of claim 1, wherein R1 is R′—II, R2a and R2b are hydrogen, and X1 is oxygen, or a pharmaceutically acceptable salt or solvate thereof.

18. The compound of claim 1, wherein R1 is R1—III, R2a and R2b are hydrogen, and X1 is oxygen, or a pharmaceutically acceptable salt or solvate thereof.

19. The compound of claim 1, wherein R1 is R1—IV, R2a and R2b are hydrogen, and X1 is oxygen, or a pharmaceutically acceptable salt or solvate thereof.