Pyridinyl derivatives as sodium channel activators

Abstract

The present disclosure relates to a compound of formula (I): TIFF2024534573001268.tif37165 wherein X, Y, Z, R1, R2a, R2b, R3, and L are as described herein, or a stereoisomer, enantiomer, or tautomer thereof or mixtures thereof; or a pharma- ceutically acceptable salt, solvate, or prodrug thereof; and pharmaceutical compositions comprising compounds of formula (I) as described herein, which are useful as voltage-gated sodium channel modulators and thus are useful in the treatment of seizure disorders, e.g., epilepsy.

Description

[Technical field]

[0001] The present disclosure is directed to pyridinyl derivatives, as stereoisomers, enantiomers, or tautomers or mixtures thereof; or pharma- ceutically acceptable salts, solvates, or prodrugs thereof, that are useful as voltage-gated sodium channel activators and thus are useful in treating seizure disorders, e.g., epilepsy, and pharmaceutical compositions comprising the pyridinyl derivatives. [Background technology]

[0002] Epilepsy is a common seizure disorder with an estimated worldwide prevalence of 0.7% of the population (50 million people) (see Hirtz, D. et al., Neurology. (2007), 68:326-337). It is characterized by abnormal electrical discharge activity in the brain that leads to seizures. For epidemiological purposes, the definition requires multiple unprovoked seizures of any type.

[0003] Patients with epilepsy have an increased risk of death compared to the general population, primarily due to the etiology of the disease. However, in patients with uncontrolled epilepsy, the highest seizure-related risk of mortality is due to sudden unexpected death in epilepsy (SUDEP) (see Hitiris, N. et al., Epilepsy and Behavior (2007), 10:363-376). Patients who participate in clinical trials of investigational antiepileptic drugs (AEDs) have typically had epilepsy for more than 10 years and have failed multiple AED therapies.

[0004] Although the pathophysiology of most forms of epilepsy remains poorly understood, epileptic seizures are known to result from excessive simultaneous and sustained firing of groups of neurons. A persistent increase in neuronal excitability is common to all epileptic syndromes. Therapeutic strategies in treating epilepsy involve reducing neuronal excitability through various mechanistic pathways. Over the past two decades, several new AEDs have been developed and marketed to broaden the therapeutic spectrum by targeting different mechanisms of action and to improve the risk / benefit profile. Currently available AEDs are believed to act by inhibiting synaptic vesicle glycoproteins, potentiating inhibitory GABAergic neurotransmission, reducing glutamate-mediated excitatory neurotransmission, or inhibiting voltage-gated sodium or calcium channels. Despite this, up to 30% of patients remain refractory to conventional treatments and continue to have uncontrolled seizures (see Brown, DA et al., Nature (1980), 283:673-676, and Elger, CE et al., Epilepsy Behav. (2008), 12:501-539. Quality of life in refractory patients is poor; they cannot drive, they have difficulty working or living independently, and many patients also have behavioral, neurological, and / or intellectual disabilities as sequelae of their seizure disorder. Current drugs have minimal to no effect on neuronal sodium-gated channels, despite the fact that these channels have a major role in controlling neuronal excitability. Therefore, drugs with novel mechanisms of action or that improve on already marketed AEDs are needed to address a significant unmet clinical need for seizure control in patients with treatment-resistant epilepsy.

[0005] Na V 1.1 is a voltage-gated sodium channel (NaV ) is. V 1.1 and its subfamily (Na V 1.2, Na V 1.3 and Na V 1.6) is expressed primarily in the central nervous system (CNS) (Catterall, WA, J Physiol (2012), Vol. 590, pp. 2577-2589, and Catterall, WA, Neurochem Res (2017), Vol. 42, pp. 2495-2504). V 1.1 is mainly expressed in parvalbumin-positive fast-spiking interneurons (FSINs) and is involved in membrane depolarization and action potential (AP) firing (Ogiwara, I. et al., J Neurosci (2007), Vol. 27, pp. 5903-5914). V Loss of function of the 1.1 channel can result in disinhibition of excitatory pyramidal neurons causing various diseases of the CNS (Han, S. et al., Nature (2012), Vol. 489, pp. 385-390, Oakley, JC et al. Epilepsia (2011), Vol. 52 (Suppl. 2), pp. 59-61, and Verret, L. et al., Cell (2012), Vol. 149, pp. 708-721). Dravet syndrome is a rare inherited epileptic encephalopathy in which more than 70% of patients have a novel heterozygous mutation in the SCN1A gene (Catterall, WA, Ann Rev Pharmacol Toxicol (2014), Vol. 54, pp. 317-338). In these mutations, Na V Loss of function of the 1.1 channel has been reported (Mantegazza, M. et al., Proc Natl Acad Sci USA (2005), Vol. 102, pp. 18177-18182). V 1.1 Genetic association between brain penetrant Na VIt has been suggested that 1.1 activators may hold significant therapeutic potential for treating Dravet syndrome (Jensen, HSet al., Trends Pharmacol Sci (2014), Vol. 35, pp. 113-118, and Richards, KLet al., Proc Natl Acad Sci USA (2018), Vol. 115, pp. E8077-E8085). However, potent and selective Na V 1.1 Activators have not been reported to date. Recently, several Na V 1.1 Activators have been reported by Lundbeck: 2-methylbenzamide derivatives (Crestey, F. et al., ACS Chem Neurosci (2015), Vol. 6, pp. 1302-1308), AA43279 (Frederiksen, K. et al., Eur J Neurosci (2017), Vol. 46, pp. 1887-1896) and Lu AE98134 (von Schoubyea, NLet al., Neurosci Lett (2018), Vol. 662, pp. 29-35). The most recently developed activator, Lu AE98134, is a Na V 1.1-expressing HEK cells increased the total area under the curve for the duration of the depolarizing pulse from 1 μM, but not Na V Low selectivity for 1.5 and Na V Moderate selectivity problems for 1.2 were observed. Biologically, Na V 1.5 is the major cardiac sodium channel (Vincent, GM, Annu Rev Med (1998), Vol. 49, pp. 263-274), and Na V 1.2 is predominantly expressed in excitatory neurons (Gong, B. et al., J Comp Neurol (1999), Vol. 412, pp. 342-352, and Hu, W. et al., Nat Neurosci (2009), Vol. 12, pp. 996-1002). V 1.5 and Na VHigh selectivity for 1.2 is favorable for a drug candidate. Meanwhile, electrophysiological data on Lu AE98134 suggest that Na α-receptor antagonists are more effective in increasing FSIN excitability. V 1.1 has shown promising efficacy as an activator. V 1.1 Na compared to activators V 1.2 and Na V Highly potent Na with improved selectivity for 1.5 V 1.1 The discovery of 4-phenyl-2-(pyrrolidinyl)nicotinamide derivatives as activators was recently published (Miyazaki, T. et al., Bioorg Med Chem Lett (2019), Vo. 29, No. 6, pp. 815-820). Although significant progress has been made in this field, there remains a substantial need for compounds that are voltage-gated sodium channel activators and are thereby useful in treating seizure disorders, preferably epilepsy, in mammals, preferably humans. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Hirtz, D. et al., Neurology. (2007), 68:326-337 [Non-Patent Document 2] Hitiris, N. et al., Epilepsy and Behavior (2007), 10:363-376 [Non-Patent Document 3] Brown, D.A. et al., Nature (1980), 283:673-676 [Non-Patent Document 4] Elger, CE et al., Epilepsy Behav. (2008), 12:501-539 [Non-Patent Document 5] Catterall,WA,J Physiol(2012),Vol.590,pp.2577-2589 [Non-Patent Document 6] Catterall,WA,Neurochem Res(2017),Vol.42,pp.2495-2504 [Non-Patent Document 7] Ogiwara,I.et al.,J Neurosci(2007),Vol.27,pp.5903-5914 [Non-Patent Document 8] Han,S.et al.,Nature(2012),Vol.489,pp.385-390,Oakley,JCet al.Epilepsia(2011),Vol.52(Suppl.2),pp.59-61 [Non-Patent Document 9] Catterall,WA,Ann Rev Pharmacol Toxicol(2014),Vol.54,pp.317-338 Summary of the Invention [Means for solving the problem]

[0007] The present disclosure relates to voltage-gated sodium channel activators, particularly Na V 1.1 The present invention is directed to pyridinyl derivatives, as stereoisomers, enantiomers, or tautomers or mixtures thereof, that are useful as activators and therefore useful in treating seizure disorders, such as epilepsy and Dravet Syndrome; or to pharmaceutical compositions comprising the pyridinyl derivatives, as pharmaceutical acceptable salts, solvates, or prodrugs thereof.

[0008] Thus, some embodiments of the present disclosure include a compound of formula (I): [ka] (In the formula, X, Y, and Z are each independently N or CR 1b with the proviso that at least one, and not more than two, of X, Y, and Z is N; L is a direct bond, -NR 4 C(=O)- or -C(=O)NR4 - and; R 1 is methoxy, -R 5 N(R 6 ) 2 , alkenyl, or the structure: [ka] and each [ka] are independently single or double bonds such that all valences are satisfied; Each R 1a are independently alkyl, halo, haloalkyl, -R 5 OR 6 , -R 5 N(R 6 ) 2 , -R 5 OC(=O)R 6 , optionally substituted cycloalkyl, or -R 5 C(=O)OR 6 and; A is O, N, or C; Each R 1b is independently hydrogen, halo, alkyl, or haloalkyl; R 2a and R 2b together with the carbon to which they are attached form an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heterocyclyl, or an optionally substituted heteroaryl; or R 2a is hydrogen or alkyl; R 2b is optionally substituted heterocyclyl or optionally substituted cycloalkyl; or R 2a and R 2b are both alkyl; or R 2a is alkyl, R 2b is haloalkoxy; R 3 is alkyl, cyanoalkyl, -R 5 OR 6 , -R 5 N(R 6 ) 2 , optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclylalkyl; R 4 is hydrogen or alkyl; Each R 5 is independently a direct bond or an optionally substituted alkylene chain; Each R 6 is independently hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, or optionally substituted arylalkyl; or two R's 6 together with the nitrogen to which they are both attached form an optionally substituted heterocyclyl; n is 0, 1, 2, 3, 4, or 5) or a pharma- ceutically acceptable salt, solvate, isotopologue, or prodrug thereof.

[0009] In some embodiments, the present disclosure provides a compound of formula (II): [ka] (In the formula, each [ka] is independently a single bond or a double bond; A is O, N, or C; L is a direct bond, -NR 4 C(=O)- or -C(=O)NR 4 - and; Each R 1are independently alkyl, halo, haloalkyl, -R 5 OR 6 , -R 5 N(R 6 ) 2 , -R 5 OC(=O)R 6 , or -R 5 C(=O)OR 6 and; R 2a and R 2b together with the carbon to which they are attached form an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heterocyclyl, or an optionally substituted heteroaryl; R 3 is an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heterocyclyl, or an optionally substituted heteroaryl; R 4 is hydrogen or alkyl; Each R 5 is independently a direct bond or an optionally substituted alkylene chain; Each R 6 is independently hydrogen, alkyl, haloalkyl, or optionally substituted cycloalkyl; or two R's 6 together with the nitrogen to which they are both attached form an optionally substituted heterocyclyl; n is 0, 1, 2, 3, 4, or 5) or a pharma- ceutically acceptable salt, solvate, or prodrug thereof.

[0010] In other embodiments, the present disclosure is directed to a pharmaceutical composition comprising a pharma- ceutically acceptable excipient and a compound of formula (I) or (II) as described above, either as a stereoisomer, enantiomer, or tautomer, or mixtures thereof; or as a pharma- ceutically acceptable salt, solvate, or prodrug thereof.

[0011] In other embodiments, the present disclosure is directed to a method of treating a disease or condition in a mammal modulated by voltage-gated sodium channels, the method comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of formula (I) or (II) as described above, either as a stereoisomer, enantiomer, or tautomer, or mixtures thereof; or as a pharma- ceutically acceptable salt, solvate, or prodrug thereof.

[0012] In other embodiments, the present disclosure is directed to a method for the treatment of epilepsy and / or epileptic seizure disorders in a mammal, preferably a human, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of formula (I) or (II) as set forth above in its stereoisomer, enantiomer, or tautomer or mixtures thereof; or as a pharmaceutically acceptable salt, solvate, or prodrug thereof, of a compound of formula (I) or (II) or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or (II) as set forth above in its stereoisomer, enantiomer, or tautomer or mixtures thereof, or as a pharmaceutically acceptable salt, solvate, or prodrug thereof, of a compound of formula (I) or (II), and a pharmaceutically acceptable excipient.

[0013] In other embodiments, the present disclosure is directed to a method for preparing a compound of formula (I) or (II) as shown above in its stereoisomer, enantiomer, or tautomer or mixtures thereof; or a pharma- ceutically acceptable salt, solvate, or prodrug thereof; or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or (II) as shown above in its stereoisomer, enantiomer, or tautomer or mixtures thereof, or a pharma- ceutically acceptable salt, solvate, or prodrug thereof, and a pharma- ceutically acceptable excipient.

[0014] In other embodiments, the disclosure is directed to pharmaceutical therapies in combination with one or more other compounds of formula (I) or (II) or one or more other accepted therapies or in any combination thereof to increase the efficacy of existing or future drug therapies or to reduce adverse events associated with accepted therapies. In one embodiment, the disclosure is directed to pharmaceutical compositions combining a compound of formula (I) or (II) with established or future therapies for the indications listed herein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] definition Certain chemical groups named herein may be preceded by a shorthand notation indicating the total number of carbon atoms found in the indicated chemical group. For example, 7 -C 12 Alkyl represents an alkyl group, as defined below, having a total of 7 to 12 carbon atoms; 4 -C 12 Cycloalkylalkyl represents a cycloalkylalkyl group, as defined below, having a total of four to twelve carbon atoms. The total number of carbons in the shortened notation does not include carbons that may exist in substituents of the group being described.

[0016] In addition to the foregoing, as used in the specification and the appended claims, unless specified to the contrary, the following terms have the meanings indicated: "Compound of the disclosure" or "compounds of the disclosure" refers to a compound of Formula (I) or (II) as defined above in the Summary of the Invention, including any stereoisomer, enantiomer, or tautomer, or mixtures thereof; or a pharma- ceutically acceptable salt, solvate, or prodrug thereof.

[0017] "Amino" is -NH 2 Refers to radicals.

[0018] "Cyano" refers to the -CN radical.

[0019] "Hydroxy" refers to the -OH radical.

[0020] "Imino" refers to the =NH substituent.

[0021] "Nitro" is -NO 2 Refers to radicals.

[0022] "Oxo" refers to the =O substituent.

[0023] "Thioxo" refers to the =S substituent.

[0024] "Trifluoromethyl" is -CF 3 Refers to radicals.

[0025] "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms or 1 to 6 carbon atoms, attached to the remainder of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, etc. Unless stated otherwise specifically in the specification, an alkyl group may be optionally substituted with one of the following groups: alkyl, alkenyl, halo, haloalkenyl, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, trimethylsilanyl, -OR 20 , -OC(O)-R 20 , -N(R 20 ) 2 , -C(O)R 20 , -C(O)OR 20 , -C(O)N(R 20 ) 2 , -N(R 20 )C(O)OR 22 , -N(R 20 )C(O)R 22 , -N(R 20 )S(O) t R 22 (t is 1 to 2), -S(O) t OR 22 (t is 1 to 2), -S(O) p R 22 (p is 0 to 2), and -S(O) t N(R 20 ) 2 (t is 1 to 2) (wherein each R 20 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; 22 is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl).

[0026] "Alkoxy" refers to a group of the formula: -OR a (In the formula, R a refers to a radical having an alkyl radical, which is as defined above.

[0027] "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond, having 2 to 12 carbon atoms, preferably 2 to 8 carbon atoms, and attached to the remainder of the molecule by a single bond, e.g., ethenyl, prop-1-enyl, but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group may be optionally substituted with one of the following groups: alkyl, alkenyl, halo, haloalkenyl, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, trimethylsilanyl, -OR 20 , -OC(O)-R 20 , -N(R 20 ) 2 , -C(O)R 20 , -C(O)OR 20 , -C(O)N(R 20 ) 2 , -N(R 20 )C(O)OR 22 , -N(R 20 )C(O)R 22 , -N(R 20 )S(O) t R 22 (t is 1 to 2), -S(O) t OR 22 (t is 1 to 2), -S(O) p R 22 (p is 0 to 2), and -S(O) t N(R 20 ) 2 (t is 1 to 2) (wherein each R 20 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; 22is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl).

[0028] "Alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one triple bond, having 2 to 12 carbon atoms, preferably 1 to 8 carbon atoms, and attached to the remainder of the molecule by a single bond, e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. Unless stated otherwise specifically in the specification, alkynyl groups are optionally substituted with one or more of the following groups: alkyl, alkenyl, halo, haloalkenyl, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, trimethylsilanyl, -OR 20 , -OC(O)-R 20 , -N(R 20 ) 2 , -C(O)R 20 , -C(O)OR 20 , -C(O)N(R 20 ) 2 , -N(R 20 )C(O)OR 22 , -N(R 20 )C(O)R 22 , -N(R 20 )S(O) t R 22 (t is 1 to 2), -S(O) t OR 22 (t is 1 to 2), -S(O) p R 22 (p is 0 to 2), or -S(O) t N(R 20 ) 2 (t is 1 to 2) (wherein each R 20 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; 22is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl).

[0029] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain, consisting solely of carbon and hydrogen, containing no unsaturation, having from 1 to 12 carbon atoms, e.g., methylene, ethylene, propylene, n-butylene, etc., that links the rest of the molecule to a radical group. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless otherwise specifically stated herein, an alkylene chain can be optionally substituted with one of the following groups: alkyl, alkenyl, halo, haloalkenyl, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, trimethylsilanyl, -OR 20 , -OC(O)-R 20 , -N(R 20 ) 2 , -C(O)R 20 , -C(O)OR 20 , -C(O)N(R 20 ) 2 , -N(R 20 )C(O)OR 22 , -N(R 20 )C(O)R 22 , -N(R 20 )S(O) t R 22 (t is 1 to 2), -S(O) t OR 22 (t is 1 to 2), -S(O) p R 22 (p is 0 to 2), and -S(O) t N(R 20 ) 2 (t is 1 to 2) (wherein each R 20is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; 22 is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl).

[0030] "Alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbon chain, consisting solely of carbon and hydrogen, containing at least one double bond, having 2 to 12 carbon atoms, e.g., ethenylene, propenylene, n-butenylene, and the like, that links the rest of the molecule to a radical group. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a double bond or a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless otherwise specifically stated herein, an alkenylene chain can be optionally substituted with one of the following groups: alkyl, alkenyl, halo, haloalkenyl, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, trimethylsilanyl, -OR 20 , -OC(O)-R 20 , -N(R 20 ) 2 , -C(O)R 20 , -C(O)OR 20 , -C(O)N(R 20 ) 2 , -N(R 20 )C(O)OR 22 , -N(R 20 )C(O)R 22 , -N(R 20 )S(O) t R 22 (t is 1 to 2), -S(O) t OR 22 (t is 1 to 2), -S(O) p R 22 (p is 0 to 2), and -S(O) tN(R 20 ) 2 (t is 1 to 2) (wherein each R 20 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; 22 is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl).

[0031] "Aryl" refers to a hydrocarbon ring system radical containing hydrogen, 6 to 18 carbon atoms, and at least one aromatic ring. For purposes of this disclosure, the aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems. Aryl radicals include, but are not limited to, aryl radicals derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, heterocyclyl, pleiadene, pyrene, and triphenylene. Unless otherwise stated in the specification, an aryl group may be any of the following: alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -R 21 -OR 20 , -R 21 -OC(O)-R 20 , -R 21 -N(R 20 ) 2 , -R 21 -C(O)R 20 , -R 21 -C(O)OR 20 , -R 21 -C(O)N(R 20 ) 2 , -R 21 -N(R 20)C(O)OR 22 , -R 21 -N(R 20 )C(O)R 22 , -R 21 -N(R 20 )S(O) t R 22 (t is 1 to 2), -R 21 -N=C (or 20 )R 20 , -R 21 -S(O) t OR 22 (t is 1 to 2), -R 21 -S(O) p R 22 (p is 0 to 2), and -R 21 -S(O) t N(R 20 ) 2 (t is 1 to 2) (wherein each R 20 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; 21 is independently a direct bond or a straight or branched alkylene or alkenylene chain; each R 22 may be optionally substituted by one or more substituents independently selected from the group consisting of alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

[0032] An "aralkyl" or "arylalkyl" is a group of the formula -R b -R c A radical of formula (wherein R b is an alkylene chain as defined above, R cis one or more aryl radicals, as defined above, e.g., benzyl, diphenylmethyl, and the like. The alkylene chain part of the aralkyl radical can be optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical can be optionally substituted as described above for an aryl group.

[0033] "Aralkenyl" is a group of the formula -R d -R c A radical of formula (wherein R b is an alkenylene chain as defined above, R d is one or more aryl radicals, as defined above. The aryl part of the aralkenyl radical can be optionally substituted as described above for an aryl group. The alkenylene chain part of the aralkenyl radical can be optionally substituted as described above for an alkenylene group.

[0034] "Cycloalkyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which may include fused or bridged ring systems having 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, may be saturated or unsaturated, and is attached to the remainder of the molecule by a single bond. Monocyclic radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic radicals include, for example, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated in this specification, cycloalkyl groups include alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, nitro, oxo, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -R 21 -OR 20 , -R 21 -OC(O)-R 20 , -R 21 -N(R 20 ) 2 , -R 21 -C(O)R20 , -R 21 -C(O)OR 20 , -R 21 -C(O)N(R 20 ) 2 , -R 21 -N(R 20 )C(O)OR 22 , -R 21 -N(R 20 )C(O)R 22 , -R 21 -N(R 20 )S(O) t R 22 (t is 1 to 2), -R 21 -N=C (or 20 )R 20 , -R 21 -S(O) t OR 22 (t is 1 to 2), -R 21 -S(O) p R 22 (p is 0 to 2), and -R 21 -S(O) t N(R 20 ) 2 (t is 1 to 2) (wherein each R 20 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; 21 is independently a direct bond or a straight or branched alkylene or alkenylene chain; each R 22 may be optionally substituted by one or more substituents independently selected from the group consisting of alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

[0035] "Cycloalkylalkyl" refers to a group of the formula -R b R g A radical of formula (wherein R b is an alkylene chain as defined above, R gis a cycloalkyl radical as defined above. The alkylene chain and the cycloalkyl radical can be optionally substituted as defined above.

[0036] "Fused" refers to any ring system described herein that is fused to an existing ring structure in the compounds of the present disclosure. If the fused ring system is a heterocyclyl or heteroaryl, any carbon in the existing ring structure that becomes part of the fused ring system can be replaced with a nitrogen.

[0037] "Halo" refers to bromo, chloro, fluoro or iodo.

[0038] "Haloalkyl" refers to an alkyl radical, as defined above, substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl, 1-bromomethyl-2-bromoethyl, etc. The alkyl portion of the haloalkyl radical can be optionally substituted as described above for alkyl groups.

[0039] "Haloalkoxy" refers to a group having the formula: a (In the formula, R a refers to a radical having a haloalkyl radical, as defined above.

[0040] "Haloalkenyl" refers to an alkenyl radical, as defined above, that is substituted by one or more halo radicals, as defined above. The alkenyl portion of the haloalkyl radical can be optionally substituted as described above for an alkenyl group.

[0041] "Cyanoalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more cyano radicals (i.e., -CN). The alkyl portion of the cyanoalkyl radical can be optionally substituted as described above for alkyl groups.

[0042] "Hydroxyalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more hydroxy radicals (i.e., --OH). The alkyl portion of the hydroxyalkyl radical can be optionally substituted as described above for an alkyl group.

[0043] "Alkoxyalkylalkyl" refers to an alkyl radical as defined above that is substituted by one or more alkoxy radicals. The alkyl portion of the hydroxyalkyl radical can be optionally substituted as described above for an alkyl group.

[0044] "Haloalkoxyalkyl" refers to an alkyl radical as defined above that is substituted by one or more haloalkoxy radicals. The alkyl portion of the hydroxyalkyl radical can be optionally substituted as described above for alkyl groups.

[0045] "Heterocyclyl" refers to a stable 3- to 18-membered non-aromatic ring radical, which consists of 2 to 12 carbon atoms and 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system which can include fused or bridged ring systems; the nitrogen, carbon, or sulfur atoms in the heterocyclyl radical can be optionally oxidized; the nitrogen atom can be optionally quaternized; and the heterocyclyl radical can be partially or fully saturated. Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, dioxinyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trioxanyl, trithianyl, triazinanyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless otherwise stated in the specification, a heterocyclyl group can be selected from the group consisting of alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, oxo, thioxo, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -R 21 -OR 20 , -R 21 -OC(O)-R 20 , -R 21 -N(R 20 ) 2 , -R 21 -C(O)R 20 , -R 21 -C(O)OR 20 , -R 21 -C(O)N(R 20 ) 2 , -R 21 -N(R 20)C(O)OR 22 , -R 21 -N(R 20 )C(O)R 22 , -R 21 -N(R 20 )S(O) t R 22 (t is 1 to 2), -R 21 -N=C (or 20 )R 20 , -R 21 -S(O) t OR 22 (t is 1 to 2), -R 21 -S(O) p R 22 (p is 0 to 2), and -R 21 -S(O) t N(R 20 ) 2 (t is 1 to 2) (wherein each R 20 is independently hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; 21 is independently a direct bond or a straight or branched alkylene or alkenylene chain; each R 22 may be optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

[0046] "O-heterocyclyl" refers to a heterocyclyl radical as defined above that contains at least one oxygen atom and no nitrogen atoms. The O-heterocyclyl radical can be optionally substituted as described above for heterocyclyl radicals.

[0047] "Heterocyclylalkyl" refers to a group of the formula -R b R h (In the formula, R b is an alkylene chain as defined above, Rh refers to a radical of the formula: (heterocyclyl radical as defined above, provided that if the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl may be attached to the alkyl radical at a nitrogen atom). The alkylene chain of the heterocyclylalkyl radical may be optionally substituted as defined above for an alkylene chain. The heterocyclyl part of the heterocyclylalkyl radical may be optionally substituted as described above for a heterocyclyl group.

[0048] "Heteroaryl" refers to a 5-14 membered ring system radical containing a hydrogen atom, 1-13 carbon atoms, 1-6 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and at least one aromatic ring. For purposes of this disclosure, a heteroaryl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused or bridged ring systems; the nitrogen, carbon, or sulfur atoms in the heteroaryl radical can be optionally oxidized; and the nitrogen atom can be optionally quaternized.Examples include azepinyl, acridinyl, benzimidazolyl, benzthiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzo Thienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, benzoxazolinonyl, benzimidazolthionyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, na Phthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, pteridinonyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyridinonyl, pyrazinyl, pyrimidinyl, pririmidinonyl , pyridazinyl, pyrrolyl, pyrido[2,3-d]pyrimidinonyl, quinazolinyl, quinazolinonyl, quinoxalinyl, quinoxalinonyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, thieno[3,2-d]pyrimidin-4-onyl, thieno[2,3-d]pyrimidin-4-onyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl).Unless otherwise stated in the specification, heteroaryl groups include alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, oxo, thioxo, nitro, thioxo, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -R. 21 -OR 20 , -R21 -OC(O)-R 20 , -R 21 -N(R 20 ) 2 , -R 21 -C(O)R 20 , -R 21 -C(O)OR 20 , -R 21 -C(O)N(R 20 ) 2 , -R 21 -N(R 20 )C(O)OR 22 , -R 21 -N(R 20 )C(O)R 22 , -R 21 -N(R 20 )S(O) t R 22 (t is 1 to 2), -R 21 -N=C (or 20 )R 20 , -R 21 -S(O) t OR 22 (t is 1 to 2), -R 21 -S(O) p R 22 (p is 0 to 2), and -R 21 -S(O) t N(R 20 ) 2 (t is 1 to 2) (wherein each R 20 is independently hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; 21 is independently a direct bond or a straight or branched alkylene or alkenylene chain; each R 22 may be optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

[0049] "N-heteroaryl" refers to a heteroaryl radical as defined above containing at least one nitrogen. The N-heteroaryl radical can be optionally substituted as described above for heteroaryl radicals.

[0050] "Heteroarylalkyl" refers to a group of the formula -R b R i A radical of formula (wherein R b is an alkylene chain as defined above, R i is a heteroaryl radical as defined above. The heteroaryl part of the heteroarylalkyl radical may be optionally substituted as defined above for a heteroaryl group. The alkylene chain part of the heteroarylalkyl radical may be optionally substituted as defined above for an alkylene chain.

[0051] "Prodrug is meant to indicate a compound that can be converted under physiological conditions or by solvolysis to a biologically active compound of the disclosure. Thus, the term "prodrug" refers to a metabolic precursor of a compound of the disclosure that is pharma- ceutically acceptable. A prodrug may be inactive when administered to a subject in need thereof, but is converted in vivo to an active compound of the disclosure. Prodrugs are typically rapidly converted in vivo to produce the parent compound of the disclosure, for example, by hydrolysis in blood. Prodrug compounds often offer advantages of solubility, tissue compatibility, or delayed release in mammalian organisms (see Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam)). A discussion of prodrugs is provided in Higuchi, T., et al., "Pro-drugs as Novel Delivery Systems," ACS Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, Ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are fully incorporated by reference herein.

[0052] The term "prodrug" is also meant to include any covalently bonded carrier that releases the active compound of the present disclosure in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the compounds of the present disclosure can be prepared by modifying functional groups present in the compounds of the present disclosure in such a way that the modifications are cleaved either in routine manipulation or in vivo to the parent compounds of the present disclosure. Prodrugs include compounds of the present disclosure in which a hydroxy, amino or mercapto group is bonded to any group that cleaves to form a free hydroxy, free amino or free mercapto group, respectively, when a prodrug of the compound of the present disclosure is administered to a mammalian subject. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol or amide derivatives of amine functional groups in the compounds of the present disclosure, and the like.

[0053] "Stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

[0054] "Mammals" includes both humans and domesticated animals, such as laboratory animals and household pets (e.g., cats, dogs, pigs, cows, sheep, goats, horses, rabbits), and non-domestic animals, such as wildlife.

[0055] "Optional" or "optionally" means that the subsequently described circumstance event may or may not occur, and the description includes examples where said event or circumstance occurs and does not occur. For example, "optionally substituted aryl" means that the aryl radical may or may not be substituted, and the description includes both substituted and unsubstituted aryl radicals. When a functional group is described as "optionally substituted", and thus a substituent on the functional group is also described as "optionally substituted", etc., for purposes of this disclosure, such repetitions are limited to 5, and preferably such repetitions are limited to 2.

[0056] A "pharmaceutically acceptable carrier, diluent, or excipient" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier approved by the U.S. Food and Drug Administration as acceptable for use in humans or domesticated animals.

[0057] "Pharmaceutically acceptable salt" includes both acid and base addition salts.

[0058] "Pharmaceutically acceptable acid addition salts" refer to those acids which retain the biological effectiveness and properties of the free base, which are not biologically or otherwise undesirable, and which are not intended to be biologically or otherwise undesirable, and which are not intended to be biologically or otherwise undesirable, and which are not intended to be biologically or otherwise undesirable, and which are not intended to be biologically or otherwise undesirable, and which are not intended to be biologically or otherwise undesirable, and which are not intended to be biologically or otherwise undesirable, and which are not intended to be biologically or otherwise undesirable, and which are not intended to be biologically or otherwise undesirable, and which are not intended to be biologically or otherwise undesirable, and which are not intended to be biologically or otherwise undesirable, and It refers to those salts formed with coheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, and the like.

[0059] "Pharmaceutically acceptable base addition salts" refer to those salts which retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from the addition of an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.

[0060] Often, crystallization produces a solvate of the disclosed compound. As used herein, the term "solvate" refers to an aggregate or solid form that contains one or more molecules of the disclosed compound with one or more molecules of solvent. The solvent can be water, in which case the solvate can be a hydrate. Alternatively, the solvent can be an organic solvent. Thus, the disclosed compound can exist as a hydrate, including monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate, etc., as well as the corresponding solvate forms. The disclosed compound can be a true solvate, and in other cases, the disclosed compound may only retain incidental water, or may be a mixture of water and some incidental solvent.

[0061] "Pharmaceutical composition" refers to a formulation of a compound of the present disclosure and a vehicle generally acceptable for the delivery of the biologically active compound to a mammal, e.g., a human. Such a vehicle includes any pharma- ceutically acceptable carrier, diluent, or excipient therefor.

[0062] "Seizure disorders" include partial-onset (focal) seizures, photosensitive epilepsy, self-induced fainting, refractory epilepsy, Angelman syndrome, benign rolandic epilepsy, CDKL5 disorder, childhood and juvenile absence epilepsy, Dravet syndrome, frontal lobe epilepsy, Glut1 deficiency syndrome, hypothalamic hamartoma, infantile spasms / West syndrome, juvenile myoclonic epilepsy, Landau-Kleffner syndrome, Lennox-Gastaut syndrome (LGS), epilepsy with myoclonic absences, Ohtahara syndrome, Panayiovenous encephalopathy, and rheumatoid arthritis. It refers to seizures and seizure-related disorders such as Topolos syndrome, PCDH19 epilepsy, progressive myoclonic epilepsy, Rasmussen syndrome, ring chromosome 20 syndrome, reflex epilepsy, temporal lobe epilepsy, Lafora progressive myoclonic epilepsy, neurocutaneous syndromes, tuberous sclerosis, early infantile epileptic encephalopathy, early onset epileptic encephalopathy, generalized epilepsy with febrile seizures+, Rett syndrome, multiple sclerosis, Alzheimer's disease, autism, ataxia, hypotonia and paroxysmal dyskinesia. Preferably, the term "seizure disorder" refers to partial onset (focal) epilepsy.

[0063] "Therapeutically effective amount" refers to the range of amounts of the compounds of the present disclosure that, upon administration to a human, treat, ameliorate or prevent a seizure disorder, preferably epilepsy, in the human, or exhibit a detectable therapeutic or prophylactic effect in a human having a seizure disorder. The effect is detected, for example, by a reduction in seizures (frequency) or by the severity (quality) of the seizures. The exact therapeutically effective amount for a given human will depend on the size and health of the human, the nature and extent of the seizure disorder, the presence of any concomitant medications, and other variables known to those skilled in the art. The therapeutically effective amount for a given situation is determined by routine experimentation and is within the judgment of the clinician.

[0064] "Treatment" refers to therapeutic applications to slow or stop the progression of a seizure disorder, prophylactic applications to prevent the progression of a seizure disorder, and / or reversal of a seizure disorder. Reversal of a seizure disorder differs from therapeutic applications that slow or stop the seizure disorder in that in a reversal approach, not only is the progression of the seizure disorder halted completely, but cellular behavior shifts to some degree toward the normal state that would be observed in the absence of the seizure disorder.

[0065] "Treating" or "treatment", as used herein, includes treatment of a disease or condition of interest in a mammal, preferably a human, having the disease or condition of interest, including: (a) preventing a disease or condition from occurring in a mammal, particularly where such mammal is susceptible to, but has not yet been diagnosed as having, the condition; (b) inhibiting the disease or condition, i.e., halting its progression; (c) alleviating (ameliorating) the disease or condition, i.e., causing regression of the disease or condition; or (d) Relieving (ameliorating) symptoms caused by a disease or condition, i.e., alleviating a seizure disorder without addressing the underlying disease or condition. Includes:

[0066] As used herein, the terms "disease" and "condition" may be used interchangeably or may differ in that a particular ailment or condition may not have a known causative agent (whereby the etiology has not yet been elucidated) and therefore is not yet recognized as a disease, but is recognized as an undesirable condition or syndrome in which a more or less specific set of symptoms has been identified by a physician.

[0067] The compounds of the present disclosure may contain at least one asymmetric carbon atom and therefore may exist as racemates, enantiomers, and / or diastereoisomers. For the purposes of this disclosure, the terms diastereomer and diastereoisomer and related terms are equivalent and interchangeable. Unless otherwise indicated, this disclosure includes all enantiomers and diastereoisomers of the compounds of formula (I). Pure stereoisomers, mixtures of enantiomers and / or diastereoisomers, and mixtures of different compounds of this disclosure are included herein. Thus, the compounds of formula (I) or (II) may exist as racemates, racemic or diastereoisomeric mixtures and as individual diastereoisomers, or enantiomers, and all isomeric forms are included in this disclosure, unless a specific stereoisomer enantiomer or diastereoisomer is specified. For the purposes of this disclosure, racemates or racemic mixtures refer to a 50:50 mixture of stereoisomers only. Other enantiomerically- or diastereomerically-enriched mixtures of various ratios of stereoisomers are also contemplated.

[0068] "Enantiomer" refers to an asymmetric molecule that can exist in two different isomeric forms that have different configurations in space. Other terms used to designate or refer to enantiomers include "stereoisomers" (due to different arrangements or stereochemistry around a chiral center; all enantiomers are stereoisomers, but not all stereoisomers are enantiomers) or "optical isomers" (due to the optical activity of the pure enantiomers, which is the ability of different pure enantiomers to rotate plane-polarized light in different directions). Because they do not have a plane of symmetry, enantiomers are not identical to their mirror images; molecules that exist in two enantiomeric forms are chiral, which means that they can be viewed as occurring in "left" and "right" handed forms. The most common source of chirality in organic molecules is the presence of a tetrahedral carbon bonded to four different substituents or groups. Such carbons are referred to as chiral centers, or stereocenters.

[0069] Enantiomers have the same empirical chemical formula and are usually chemically identical in their reactions, their physical properties, and their spectroscopic properties. However, enantiomers exhibit different chemical reactivities towards other asymmetric compounds and respond differently to asymmetric physical perturbations. The most common asymmetric perturbation is polarized light.

[0070] Enantiomers can rotate plane polarized light; thus, enantiomers are optically active. Two different enantiomers of the same compound rotate plane polarized light in opposite directions; thus, light can be rotated to the left or counterclockwise (which is levorotatory or "l", or minus or "-") to a hypothetical observer, or it can be rotated to the right or clockwise (which is dextrorotatory or "d" or plus or "+"). The sign of optical rotation (+) or (-) is not related to the R,S designation. A mixture of equal amounts of two chiral enantiomers is called a racemic mixture, or racemate, and is designated by either the symbol (+ / -) or the prefix "d,l" to indicate a mixture of dextrorotatory and levorotatory forms. A racemate or racemic mixture exhibits zero optical rotation since equal amounts of (+) and (-) forms are present. Usually, a single enantiomer present rotates polarized light in only one direction; thus, a single enantiomer is said to be optically pure.

[0071] The designations "R" and "S" are used to indicate the three-dimensional configuration of the atoms (or configuration) of a stereocenter. The designations may appear as prefixes or as suffixes; they may or may not be separated from the enantiomer name by a hyphen; they may or may not be hyphenated; and they may or may not be surrounded by parentheses. The method for determining the designation should refer to the arrangement of the priority of the groups at the stereocenter when the least priority group is arranged away from a virtual observer: if the arrangement of the remaining three groups from most to least priority is clockwise, then the stereocenter is in the "R" configuration, and if the arrangement is counterclockwise, then the stereocenter is in the "S" configuration.

[0072] "Resolution" or "resolving", when used in reference to a racemate or mixture, refers to the separation of a racemate into its two enantiomeric forms (i.e., (+) and (-); (R) and (S) forms).

[0073] "Enantiomeric excess" or "ee" refers to a product in which one enantiomer is present over the other and is defined as the absolute difference in the mole fraction of each enantiomer. Enantiomeric excess is typically expressed as the percentage of the enantiomer present in the mixture relative to the other enantiomer. For purposes of this disclosure, the (S)-enantiomer of a compound prepared by the methods disclosed herein is considered to be "substantially free" of the corresponding (R)-enantiomer when the (S)-enantiomer is present in an enantiomeric excess of greater than 80%, preferably greater than 90%, more preferably greater than 95%, and most preferably greater than 99%.

[0074] A given compound is designated as "P1", "P2" (see below) or "D1", "D2" (see below). This designation indicates that the compound is the first eluting peak (i.e., P1) from the chiral separation technique and does not necessarily indicate a particular stereochemistry.

[0075] "Tautomer" refers to a proton shift of one atom of a molecule to another atom of the same molecule. The present disclosure includes tautomers of any compound of Formula (I) or (II) described herein.

[0076] "Isotopologue" refers to a collection of molecules with the same chemical structure, except that isotopic variations may exist between the constituent atoms of the molecule. Thus, it will be apparent to one skilled in the art that a compound represented by a particular chemical structure containing a deuterium atom as shown will also contain a smaller amount of isotopologues having hydrogen atoms at one or more of the designated deuterium positions in the structure. The relative amount of such isotopologues in a compound will depend on a number of factors, including the isotopic purity of the deuteration reagent used to make the compound and the efficiency of deuterium incorporation in the various synthetic steps used to prepare the compound. The relative amount of such isotopologues in total will be less than 49.9% of the compound. In other embodiments, the relative amount of such isotopologues in total will be less than 47.5%, less than 40%, less than 32.5%, less than 25%, less than 17.5%, less than 10%, less than 5%, less than 3%, less than 1%, or less than 0.5% of the compound.

[0077] The use of parentheses and brackets in substituents may be used herein to conserve space. Thus, the use of parentheses in a substituent indicates that the group contained within the parentheses is directly bonded to the atom preceding the parentheses. The use of brackets in a substituent indicates that the group contained within the parentheses is also directly bonded to the atom preceding the parentheses.

[0078] For example, if the compound has the structure: [ka] The compound of formula (I) or (II) having the formula: is named herein as (S)-6-chloro-N-(4-(2,5-difluorophenyl)-2-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)nicotinamide.

[0079] compound One embodiment of the present disclosure is a compound of Formula (I) or (II) as set forth above in the Summary of the Invention, either as an individual stereoisomer, enantiomer, or tautomer, or mixtures thereof; or as a pharma-ceutically acceptable salt, solvate, or prodrug thereof.

[0080] One embodiment is a compound of formula (I): [ka] (In the formula, X, Y, and Z are each independently N or CR 1b with the proviso that at least one, and not more than two, of X, Y, and Z is N; L is a direct bond, -NR 4 C(=O)- or -C(=O)NR 4 - and; R 1 is methoxy, -R 5 N(R 6 ) 2 , alkenyl, or the structure: [ka] and each [ka] are independently single or double bonds such that all valences are satisfied; Each R 1a are independently alkyl, halo, haloalkyl, -R 5 OR 6 , -R 5 N(R 6 ) 2 , -R 5 OC(=O)R 6 , optionally substituted cycloalkyl, or -R 5 C(=O)OR 6 and; A is O, N, or C; Each R1b is independently hydrogen, halo, alkyl, or haloalkyl; R 2a and R 2b together with the carbon to which they are attached form an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heterocyclyl, or an optionally substituted heteroaryl; or R 2a is hydrogen or alkyl; R 2b is optionally substituted heterocyclyl or optionally substituted cycloalkyl; or R 2a and R 2b are both alkyl; or R 2a is alkyl, R 2b is haloalkoxy; R 3 is alkyl, cyanoalkyl, -R 5 OR 6 , -R 5 N(R 6 ) 2 , optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclylalkyl; R 4 is hydrogen or alkyl; Each R 5 is independently a direct bond or an optionally substituted alkylene chain; Each R 6 is independently hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, or optionally substituted arylalkyl; or two R's 6 together with the nitrogen to which they are both attached form an optionally substituted heterocyclyl; n is 0, 1, 2, 3, 4, or 5) or a pharma- ceutically acceptable salt, solvate, isotopologue, or prodrug thereof.

[0081] In some embodiments, the compound has the following formula (Ia): [ka] (R 1 , R 1b , R 2a , R 2b , L and R 3 is as defined in the brief description) as its stereoisomer, enantiomer, or tautomer or mixture thereof; or as a pharma- ceutically acceptable salt, solvate, isotopologue, or prodrug thereof.

[0082] In certain embodiments, the compound has the following formula (Ia1): [ka] (R 1 , R 1b , R 2a , R 2b , L and R 3 is as defined in the brief description) as its stereoisomer, enantiomer, or tautomer or mixture thereof; or as a pharma- ceutically acceptable salt, solvate, isotopologue, or prodrug thereof.

[0083] In some embodiments, the compound has the following formula (Ib): [ka] (R 1 , R 1b , R 2a , R 2b , L and R 3 is as defined in the brief description) as its stereoisomer, enantiomer, or tautomer or mixture thereof; or as a pharma- ceutically acceptable salt, solvate, isotopologue, or prodrug thereof.

[0084] In certain embodiments, the compound has the following formula (Ib1): [ka] (R 1 , R 1b , R 2a , R 2b , L and R 3 is as defined in the brief description) as its stereoisomer, enantiomer, or tautomer or mixture thereof; or as a pharma- ceutically acceptable salt, solvate, isotopologue, or prodrug thereof.

[0085] In some embodiments, the compound has the following formula (Ic): [ka] (R 1 , R 1b , R 2a , R 2b , L and R 3 is as defined in the brief description) as its stereoisomer, enantiomer, or tautomer or mixture thereof; or as a pharma- ceutically acceptable salt, solvate, isotopologue, or prodrug thereof.

[0086] In certain embodiments, the compound has the following formula (Ic1): [ka] (R 1 , R 1b , R 2a , R 2b , L and R 3 is as defined in the brief description) as its stereoisomer, enantiomer, or tautomer or mixture thereof; or as a pharma- ceutically acceptable salt, solvate, isotopologue, or prodrug thereof.

[0087] In some embodiments, the compound has the following formula (Id): [ka] (R 1 , R 1b , R 2a , R 2b , L and R 3 is as defined in the brief description) as its stereoisomer, enantiomer, or tautomer or mixture thereof; or as a pharma- ceutically acceptable salt, solvate, isotopologue, or prodrug thereof.

[0088] In certain embodiments, the compound has the following formula (Ie): [ka] (R 1 , R 1b , R 2a , R 2b , L and R 3 is as defined in the brief description) as its stereoisomer, enantiomer, or tautomer or mixture thereof; or as a pharma- ceutically acceptable salt, solvate, isotopologue, or prodrug thereof.

[0089] One embodiment is a compound of formula (II): [ka] (In the formula, each [ka] is independently a single bond or a double bond; A is O, N, or C; L is a direct bond, -NR 4 C(=O)- or -C(=O)NR 4 - and; Each R 1 are independently alkyl, halo, haloalkyl, -R 5 OR 6 , -R 5 N(R 6 ) 2 , -R 5 OC(=O)R 6 , or -R 5 C(=O)OR 6 and; R 2a and R 2b together with the carbon to which they are attached form an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heterocyclyl, or an optionally substituted heteroaryl; R 3 is an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heterocyclyl, or an optionally substituted heteroaryl; R 4 is hydrogen or alkyl; Each R 5 is independently a direct bond or an optionally substituted alkylene chain; Each R 6 is independently hydrogen, alkyl, haloalkyl, or optionally substituted cycloalkyl; or two R's 6 together with the nitrogen to which they are both attached form an optionally substituted heterocyclyl; n is 0, 1, 2, 3, 4, or 5) or a pharma- ceutically acceptable salt, solvate, or prodrug thereof.

[0090] Another embodiment is a compound of formula (IIa): [ka] (In the formula, L is -NR 4 C(=O)- or -C(=O)NR 4 - and; Each R 1 are independently alkyl, halo, haloalkyl, -R 5 OR 6 , -R 5 N(R 6 ) 2 , -R 5 OC(=O)R 6 , or -R 5 C(=O)OR 6 and; R 2a and R 2b together with the carbon to which they are attached form an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heterocyclyl, or an optionally substituted heteroaryl; R 3 is an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heterocyclyl, or an optionally substituted heteroaryl; R 4 is hydrogen or alkyl; Each R 5 is independently a direct bond or an optionally substituted alkylene chain; Each R 6 is independently hydrogen, alkyl, haloalkyl, or optionally substituted cycloalkyl; or two R's 6 together with the nitrogen to which they are both attached form an optionally substituted heterocyclyl; n is 0, 1, 2, 3, 4, or 5) or a pharma- ceutically acceptable salt, solvate, or prodrug thereof; or a compound of formula (IIa):

[0091] In some embodiments, [ka] One occurrence of is a single bond. In certain other embodiments, [ka] One occurrence of is a double bond. In some other embodiments, [ka] One occurrence of is a single bond, [ka] The other occurrence of is a double bond. In some other particular embodiments, [ka] Both occurrences of are single bonds. In some particular embodiments, [ka] Both occurrences are double bonds.

[0092] In some embodiments, A is N, or C. In some embodiments, A is O. In some embodiments, A is C. In certain particular embodiments, A is N.

[0093] In some particular embodiments, [ka] The presence of both is a double bond, A is C.

[0094] In some embodiments, L is a direct bond. In certain embodiments, L is -C(=O)NR 4 In some particular embodiments, L is -NR 4In some more particular embodiments, L is -C(=O)NR 4 -OR-NR 4 C(=O)-.

[0095] In some embodiments, each R 1 are independently alkyl, halo, haloalkyl, -R 5 OR 6 , -R 5 N(R 6 ) 2 , or -R 5 OC(=O)R 6 In certain embodiments, each R 1 are independently alkyl, halo, haloalkyl, -R 5 OR 6 , or -R 5 N(R 6 ) 2 In some particular embodiments, each R 1 is independently alkyl, halo, haloalkyl, or -R 5 OR 6 In certain particular embodiments, each R 1 is independently alkyl, halo, or haloalkyl. In some more particular embodiments, each R 1 is independently alkyl or halo. In certain more particular embodiments, each R 1 is independently halo. In some embodiments, each R 1 is independently fluoro and n is 1 or 2. In some embodiments, R 1 is fluoro and n is 1. In some embodiments, R 1 has the following structure: [ka] has one of the following:

[0096] In certain embodiments, R 1 has the following structure: [ka] (In the formula, n is 1, 2, 3, 4, or 5) has one of the following:

[0097] In some embodiments, each R 1a is independently methyl, methoxy, trifluoromethyl, fluoro, chloro, or has the structure: [ka] has.

[0098] In some embodiments, R 1 has the following structure: [ka] has one of the following:

[0099] In some embodiments, R 1 has the following structure: [ka] has one of the following:

[0100] In certain embodiments, R 1 has the following structure: [ka] has one of the following:

[0101] In some embodiments, R 1 has the following structure: [ka] has one of the following:

[0102] In certain embodiments, R 1 has the following structure: [ka] has one of the following:

[0103] In some embodiments, R 1 has the following structure: [ka] has one of the following:

[0104] In certain embodiments, R 1 has the following structure: [ka] has one of the following:

[0105] In some embodiments, R 2a and R 2b together with the carbon to which they are attached form an optionally substituted cycloalkyl. In certain embodiments, R 2a and R 2b together with the carbon to which they are attached form an optionally substituted monocyclic, fused, or spirocyclic cycloalkyl. In a more particular embodiment, R 2a and R 2b together with the carbon to which they are attached form an optionally substituted cycloalkenyl. In some particular embodiments, R 2a and R 2b together with the carbon to which they are attached form an optionally substituted aryl. In certain embodiments, R 2a and R 2b together with the carbon to which they are attached form an optionally substituted heterocyclyl. In some embodiments, R 2a and R 2b together with the carbon to which they are attached form an optionally substituted N-heterocyclyl. In some particular embodiments, R 2a and R 2b together with the carbon to which they are attached form an optionally substituted monocyclic N-heterocyclyl. In some particular embodiments, R 2aand R 2b together with the carbon to which they are attached form an optionally substituted O-heterocyclyl. In a more particular embodiment, R 2a and R 2b together with the carbon to which they are attached form an optionally substituted monocyclic or fused O-heterocyclyl. In some more particular embodiments, R 2a and R 2b together with the carbon to which they are attached form an optionally substituted heteroaryl. In some particular embodiments, R 2a and R 2b together with the carbon to which they are attached form the following structure: [ka] as its stereoisomers, enantiomers, or tautomers or mixtures thereof; or as a pharma- ceutically acceptable salt, solvate, or prodrug thereof.

[0106] In some embodiments, R 3 is an optionally substituted cycloalkyl. In certain embodiments, R 3 is optionally substituted aryl. In some particular embodiments, R 3 is optionally substituted heterocyclyl. In certain particular embodiments, R 3 is an optionally substituted N-heterocyclyl. In some more particular embodiments, R 3 is optionally substituted heteroaryl. In certain more particular embodiments, R 3 is an optionally substituted N-heteroaryl. In some embodiments, R 3 is an optionally substituted 5- or 6-membered heteroaryl. In certain embodiments, R 3 is an optionally substituted fused bicyclic heteroaryl. In some embodiments, R 2a is hydrogen or alkyl; R 2bis an optionally substituted heterocyclyl or an optionally substituted cycloalkyl. In certain embodiments, R 2a and R 2b are both alkyl. In some embodiments, R 2a is alkyl, R 2b is haloalkoxy.

[0107] In certain embodiments, R 2a and R 2b together with the carbon to which they are attached form the following structure: [ka] Form one of the R 7a is hydrogen, alkyl, haloalkyl, -R 7c C(=O)R 7d , -R 7c C(=O)OR 7d or heterocyclyl; Each R 7b are independently alkyl, halo, haloalkyl, cyano, -R 7c OR 7d , or -R 7c OC(=O)R 7d and or two R's 7b join with the carbon to which they are both bonded to form -C(=O)-; Each R 7c is independently a direct bond or an optionally substituted alkylene chain; Each R 7d is independently hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, or optionally substituted arylalkyl; or two R's 7d together with the nitrogen to which they are both attached form an optionally substituted heterocyclyl; m is 0, 1, 2, 3, 4, or 5.

[0108] In some embodiments, R 2aand R 2b together with the carbon to which they are attached form the following structure: [ka] [ka] [ka] form one of the

[0109] In some embodiments, R 2a and R 2b together with the carbon to which they are attached form the following structure: [ka] form one of the

[0110] In some embodiments, R 2a and R 2b together with the carbon to which they are attached form the following structure: [ka] [ka] form one of the

[0111] In some embodiments, R 2a and R 2b together with the carbon to which they are attached form the following structure: [ka] form one of the

[0112] In some embodiments, R 2a and R 2b together with the carbon to which they are attached form the following structure: [ka] form one of the

[0113] In some embodiments, R 2a and R 2b together with the carbon to which they are attached form the following structure: [ka] form one of the

[0114] In certain embodiments, R 2a and R 2b together with the carbon to which they are attached form the following structure: [ka] form one of the

[0115] In some embodiments, R 2a and R 2b together with the carbon to which they are attached form the following structure: [ka] form one of the

[0116] In certain embodiments, R 2a and R 2b together with the carbon to which they are attached form the following structure: [ka] form one of the

[0117] In some particular embodiments, R 3 has the following structure: [ka] as its stereoisomer, enantiomer, or tautomer or mixture thereof; or a pharma- ceutically acceptable salt, solvate, or prodrug thereof.

[0118] In some embodiments, R 3 is alkyl. In certain embodiments, R 3 is cyanoalkyl. In some embodiments, R 3 -R 5 OR 6 In certain embodiments, R 3 -R 5 N(R 6 ) 2 In some embodiments, R 3 is an optionally substituted cycloalkyl. In some embodiments, R 3 is optionally substituted aryl. In certain other embodiments, R 3 is optionally substituted heterocyclyl. In a more particular embodiment, R 3 is an optionally substituted N-heterocyclyl. In some embodiments, R 3 is an optionally substituted heteroaryl. In some embodiments, R 3 is an optionally substituted N-heteroaryl. In certain embodiments, R 3 is an optionally substituted 5- or 6-membered heteroaryl. In some embodiments, R 3 is an optionally substituted fused bicyclic heteroaryl. In some embodiments, R 3 is optionally substituted cycloalkylalkyl. In certain embodiments, R 3 is an optionally substituted heterocyclylalkyl.

[0119] In some embodiments, R 3 has the following structure: [ka] [ka] (In the formula, R 8a is hydrogen, alkyl, haloalkyl, -C(=O)OR 8d , optionally substituted aryl, optionally substituted heterocyclylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted cycloalkyl; Each R 8b is independently alkyl, optionally substituted cycloalkyl, cyano, halo, -R 8c OR 8d , -OR 8c N(R 8d ) 2 , -C(=O)N(R 8d ) 2 , -R 8c N(R 8d ) 2 or optionally substituted heterocyclyl; Each R 8c is independently a direct bond or an optionally substituted alkylene chain; Each R 8d is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted cycloalkyl, or optionally substituted cycloalkylalkyl; or two R's 8d together with the nitrogen to which they are both attached form an optionally substituted heterocyclyl; p is 0, 1, 2, 3, 4, or 5) has one of the following:

[0120] In certain embodiments, R 3 has the following structure: [ka] [ka] [ka] [ka] [ka] [ka] [ka] has one of the following:

[0121] In some embodiments, R 3 has the following structure: [ka] has one of the following:

[0122] In certain embodiments, R 3 has the following structure: [ka] has one of the following:

[0123] In some embodiments, R 3 has the following structure: [ka] has one of the following:

[0124] In certain embodiments, R 3 has the following structure: [ka] has one of the following:

[0125] In some embodiments, R 3 has the following structure: [ka] [ka] has one of the following:

[0126] In some embodiments, R 3 has the following structure: [ka] [ka] [ka] [ka] has one of the following:

[0127] In certain embodiments, R 3 has the following structure: [ka] has one of the following:

[0128] In certain embodiments, L is a direct bond. In some embodiments, L is -C(=O)NR 4 - (i.e., L is -C(=O)NR 4 -* (wherein * is R 3 In some embodiments, L is -NR 4 C(=O)- (i.e., L is -NR 4 C(═O)-* (wherein * is R 3 ) which shows the connection to

[0129] In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is methyl. In some embodiments, R 4is ethyl, propyl, iso-propyl, butyl, isobutyl, or sec-butyl.

[0130] In certain embodiments, [ka] has the following structure: [ka] has one of the following:

[0131] In a more particular embodiment, [ka] has the following structure: [ka] has.

[0132] In some particular embodiments, [ka] has the following structure: [ka] has.

[0133] In certain embodiments, [ka] has the following structure: [ka] has.

[0134] In some more particular embodiments, [ka] has the following structure: [ka] has.

[0135] In certain embodiments, [ka] has the following structure: [ka] has.

[0136] In certain more particular embodiments, [ka] has the following structure: [ka] has one of the following:

[0137] In some embodiments, [ka] has the following structure: [ka] has one of the following:

[0138] In some embodiments, [ka] has the following structure: [ka] has one of the following:

[0139] In certain embodiments, [ka] has the following structure: [ka] has one of the following:

[0140] In certain embodiments, [ka] has the following structure: [ka] has one of the following:

[0141] In some embodiments, [ka] has the following structure: [ka] has.

[0142] In some particular embodiments, [ka] has the following structure: [ka] has one of the following:

[0143] In some embodiments, [ka] has the following structure: [ka] has one of the following:

[0144] In a more particular embodiment, -LR 3 has the following structure: [ka] has one of the following:

[0145] In some embodiments, -LR 3 has the following structure: [ka] has.

[0146] In a more particular embodiment, -LR 3 has the following structure: [ka] has one of the following:

[0147] In certain embodiments, -LR 3 has the following structure: [ka] has.

[0148] In some particular embodiments, -LR 3 has the following structure: [ka] has one of the following:

[0149] In some embodiments, -LR 3 has the following structure: [ka] has one of the following:

[0150] In certain more particular embodiments, -LR 3 has the following structure: [ka] has.

[0151] In some embodiments, the compound is a compound shown in Table 1 below, as a stereoisomer, enantiomer, or tautomer, or mixture thereof; or as a pharma- ceutically acceptable salt, solvate, or prodrug thereof.

[0152] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14]

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

Table 1-26

Table 1-27

Table 1-28

Table 1-29

Table 1-30

Table 1-31

Table 1-32

Table 1-33

Table 1-34

Table 1-35

Table 1-36

Table 1-37

Table 1-38

Table 1-39

Table 1-40

Table 1-41

Table 1-42

Table 1-43

Table 1-44

Table 1-45

Table 1-46

Table 1-47

Table 1-48

Table 1-49

Table 1-50

Table 1-51

Table 1-52

Table 1-53

Table 1-54

Table 1-55

Table 1-56

Table 1-57

Table 1-58

Table 1-59

Table 1-60

Table 1-61

Table 1-62

Table 1-63

Table 1-64

Table 1-65

Table 1-66

Table 1-67

Table 1-68

Table 1-69

Table 1-70

Table 1-71

Table 1-72

Table 1-73

Table 1-74

Table 1-75

Table 1-76

Table 1-77

Table 1-78

Table 1-79

Table 1-80

Table 1-81

Table 1-82

Table 1-83

Table 1-84

Table 1-85

Table 1-86

Table 1-87

Table 1-88

Table 1-89

Table 1-90

Table 1-91

Table 1-92

Table 1-93

Table 1-94

Table 1-95

Table 1-96

Table 1-97

Table 1-98

Table 1-99

Table 1-100

Table 1-101

Table 1-102

Table 1-103

Table 1-104

Table 1-105

Table 1-106

Table 1-107

Table 1-108

Table 1-109

Table 1-110

Table 1-111

Table 1-112

Table 1-113

Table 1-114

Table 1-115

Table 1-116

Table 1-117

Table 1-118

Table 1-119

Table 1-120

Table 1-121

Table 1-122

Table 1-123

Table 1-124

Table 1-125

Table 1-126

Table 1-127

Table 1-128

Table 1-129

Table 1-130

Table 1-131

Table 1-132

Table 1-133

Table 1-134

Table 1-135

Table 1-136

Table 1-137

Table 1-138

Table 1-139

Table 1-140

Table 1-141

Table 1-142

Table 1-143

Table 1-144

Table 1-145

Table 1-146

Table 1-147

Table 1-148

Table 1-149

Table 1-150

Table 1-151

Table 1-152

Table 1-153

Table 1-154

Table 1-155

Table 1-156

Table 1-157

Table 1-158

Table 1-159

Table 1-160

Table 1-161

Table 1-162

Table 1-163

Table 1-164

Table 1-165

Table 1-166

Table 1-167

Table 1-168

Table 1-169

Table 1-170

Table 1-171

Table 1-172

Table 1-173

Table 1-174

Table 1-175

Table 1-176

Table 1-177

Table 1-178

Table 1-179

Table 1-180

Table 1-181

Table 1-182

[0153] Another embodiment of the present disclosure is a pharmaceutical composition comprising one or more pharma- ceutically acceptable excipient(s) and a therapeutically effective amount of a compound of formula (I) or (II), as described above in the Summary of the Invention, including a stereoisomer, enantiomer, or tautomer thereof, or a mixture thereof; or a pharma- ceutically acceptable salt, solvate, or prodrug thereof.

[0154] Another embodiment of the present disclosure is a method of treating a disease or condition in a mammal modulated by voltage-gated sodium channels, the method comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of Formula (I) or (II) as described above in the Summary of the Invention, in its stereoisomer, enantiomer, or tautomer or mixtures thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0155] Another embodiment of the present disclosure is a method of using a compound of Formula (I) or (II) as a standard or control in an in vitro or in vivo assay in determining the effectiveness of a test compound in modulating voltage-gated sodium channels.

[0156] Certain embodiments of the compounds of the present disclosure are described in more detail below in the Compound Preparation section.

[0157] Uses and Testing of the Compounds of the Disclosure In one embodiment, the present disclosure is directed to compounds of formula (I) or (II), as individual stereoisomers, enantiomers, or tautomers thereof or mixtures thereof; or as pharma- ceutically acceptable salts, solvates, or prodrugs thereof, that are useful in the treatment of seizure disorders, e.g., epilepsy and / or epileptic seizure disorders, in a mammal, preferably a human.

[0158] In another embodiment, the compounds of formula (I) or (II) disclosed herein, individual stereoisomers, enantiomers, or tautomers thereof or mixtures thereof; or pharma- ceutically acceptable salts, solvates, or prodrugs thereof, are useful in the treatment of epilepsy, seizure disorders, partial seizures (e.g., simple, complex, secondary generalized, and focal occurrence), generalized seizures (e.g., absence, myoclonic, atonic, tonic, and tonic-clonic), as well as photosensitive epilepsy, self-induced fainting, refractory seizures, and the like. epilepsy, Angelman syndrome, benign rolandic epilepsy, CDKL5 disorders, childhood and juvenile absence epilepsy, Dravet syndrome, frontal lobe epilepsy, Glut1 deficiency syndrome, hypothalamic hamartoma, infantile spasms / West syndrome, juvenile myoclonic epilepsy, Landau-Kleffner syndrome, Lennox-Gastaut syndrome (LGS), epilepsy with myoclonic absences, Ohtahara syndrome, Panayiotopoulos syndrome, PCDH19 epilepsy, progressive myoclonic epilepsy, Rasmussen syndrome Syndrome, Ring 20 Syndrome, Reflex Epilepsy, Temporal Lobe Epilepsy, Lafora Progressive Myoclonic Epilepsy, Neurocutaneous Syndromes, Tuberous Sclerosis, Early Infantile Epileptic Encephalopathy, Early Onset Epileptic Encephalopathy, Generalized Epilepsy with Febrile Seizures+ (GEFS+), Rett Syndrome, Multiple Sclerosis, Schizophrenia, Autism, Ataxia, Hypotonia, Paroxysmal Dyskinesia, Tauopathies including but not limited to Alzheimer's Disease and Alzheimer's Disease, Pick's Disease, Progressive Supranuclear Palsy, Cerebral Useful in treating disorders including corticobasal syndrome, frontotemporal dementia, argyrophilic grain disease, frontotemporal lobar degeneration, globular glial tauopathy, MAPT mutations, primary age-related tauopathy, neurofibrillary tangle dementia, chronic traumatic encephalopathy (CTE), age-related tau astrogliopathy, Richardson syndrome, Down syndrome, Parkinson's disease, pure akinesia with freezing of gait, motor neuron symptoms or cerebellar ataxia, post-traumatic stress disorder (PTSD), or any combination thereof.

[0159] The present disclosure readily provides many different means for the identification of sodium channel modulators that are useful as therapeutic agents. Identification of sodium channel modulators can be assessed using a variety of in vitro and in vivo assays, for example, measuring currents, measuring membrane potentials, measuring ion fluxes (e.g., sodium), measuring sodium concentrations, measuring second messenger and transcript levels, measuring neurotransmitter levels, and using voltage-sensitive dyes, radioactive tracers, multiple electrode arrays, and patch-clamp electrophysiology.

[0160] One such protocol involves screening chemical agents for their ability to modulate the activity of sodium channels, thereby identifying them as modulators.

[0161] Exemplary assays described in (Crestey, F. et al., ACS Chem Neurosci (2015), Vol. 6, pp. 1302-1308), AA43279 (Frederiksen, K. et al., Eur J Neurosci (2017), Vol. 46, pp. 1887-1896) and Lu AE98134 (von Schoubyea, NLet al., Neurosci Lett (2018), Vol. 662, pp. 29-35) employ the use of automated planar patch clamp techniques to study the effects of chemical agents on sodium channel gating. Sodium channel isoforms of interest are stably expressed in human embryonic kidney cells and the current flowing through those channels in response to depolarized voltage clamp steps from -120 mV to 0 mV is measured in the presence of increasing concentrations of the chemical agent. The area under the sodium current trace, which correlates with the magnitude of sodium flux through the cell membrane, is used to quantify the effect on channel gating. Other parameters measured in the assay include peak current, time constant of open-state inactivation and voltage-dependence of steady-state inactivation characteristics. Concentration response is used to determine the potency of the effect of each chemical agent on the modulation of sodium channel isoform gating. Such techniques are known to those skilled in the art, and using current techniques, they can be developed into low- or medium-throughput assays to evaluate compounds for their ability to modulate sodium channel behavior.

[0162] The results of these assays provide the basis for the analysis of the structure-activity relationship (SAR) between the compounds of the present disclosure and sodium channel. Certain substituents on the core structure of the compounds of the present disclosure tend to provide more potent inhibitory or enhancing compounds. SAR analysis is one of the tools that those skilled in the art can currently use to identify the preferred embodiment of the compounds of the present disclosure for use as therapeutic agents.

[0163] In an alternative use of the present disclosure, the compounds of the present disclosure may be used in in vitro or in vivo studies as exemplary agents for comparative purposes to find other compounds that are also useful in treating, or protecting against, the various diseases disclosed herein.

[0164] In another embodiment, the pharmaceutical compositions described herein comprising a compound of Formula (I) or (II), as set forth above in the Summary of the Invention, in its individual stereoisomer, enantiomer, or tautomer, or mixtures thereof; or as a pharma- ceutically acceptable salt, solvate, or prodrug thereof, of a stereoisomer, enantiomer, tautomer, or mixture thereof, or as a pharma- ceutically acceptable salt, solvate, or prodrug thereof, and / or one or more compounds of the present disclosure, as set forth above in the Summary of the Invention, in its stereoisomer, enantiomer, or tautomer, or mixtures thereof, or as a pharma- ceutically acceptable salt, solvate, or prodrug thereof, may be used in the preparation of a medicament for the treatment of a sodium channel mediated disease or condition in a mammal.

[0165] Pharmaceutical Compositions and Administration The present disclosure is also directed to pharmaceutical compositions containing a compound of formula (I) or (II) as described above in the Summary of the Invention, in its stereoisomer, enantiomer, or tautomer or mixture thereof; or a pharma- ceutically acceptable salt, solvate, or prodrug thereof. In one embodiment, the present disclosure relates to a pharmaceutical composition comprising a compound of formula (I) or (II) as described above in the Summary of the Invention, in its stereoisomer, enantiomer, or tautomer or mixture thereof; or a pharma- ceutically acceptable salt, solvate, or prodrug thereof, in a pharma- ceutically acceptable carrier, excipient, or diluent, in an amount effective to modulate, preferably inhibit, voltage-gated sodium channels to treat a given disease or condition, e.g., epilepsy, when administered to an animal, preferably a mammal, most preferably a human patient.

[0166] The administration of the compounds of formula (I) or (II) as described above in the Summary of the Invention, in their pure form or in suitable pharmaceutical compositions, as stereoisomers, enantiomers, or tautomers or mixtures thereof; or as pharma-ceutically acceptable salts, solvates, or prodrugs thereof, may be carried out via any of the accepted modes of administration of drugs to achieve similar utility. The pharmaceutical compositions of the present disclosure may be prepared by combining the compounds of the present disclosure with suitable pharma-ceutically acceptable carriers, diluents, or excipients, and may be formulated into solid, semi-solid, liquid, or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres, and aerosol preparations. Typical routes of administration of such pharmaceutical compositions include, but are not limited to, oral, topical, transdermal, inhalation, parenteral, sublingual, rectal, vaginal, and intranasal. The term "parenteral" as used herein includes subcutaneous injection, intravenous, intramuscular, intrathecal, intrasternal injection or infusion techniques. The pharmaceutical compositions of the present disclosure are formulated so that the active ingredient contained therein is bioavailable upon administration of the composition to a patient. The composition administered to a subject or patient takes the form of one or more dosage units, for example, a tablet may be a single dosage unit, and a container of the compound of the present disclosure in aerosol form may hold multiple dosage units. The actual methods of preparing such dosage forms are known or will be apparent to those skilled in the art; see, for example, The Science and Practice of Pharmacy, 20th Edition (Philadelphia College of Pharmacy and Science, 2000). The composition administered will, in any event, contain a therapeutically effective amount of the compound of the present disclosure, or a pharma- ceutically acceptable salt thereof, for treating the disease or condition of interest according to the teachings of the present disclosure.

[0167] The pharmaceutical compositions useful herein also contain a pharma- ceutical carrier, including any pharmaceutical agent that does not itself induce the production of antibodies harmful to the individual receiving the composition, and any suitable diluent or excipient that may be administered without undue toxicity. Pharmaceutically acceptable carriers include, but are not limited to, liquids such as water, saline, glycerol, and ethanol. A detailed discussion of pharma-ceutical carriers, diluents, and other excipients is provided in REMINGTON'S PHARMACEUTICAL SCIENCES (Mack Pub. Co., NJ current edition).

[0168] The pharmaceutical composition of the present disclosure can be in solid or liquid form.In one embodiment, the carrier(s) is particulate, so that the composition is, for example, in tablet or powder form.The carrier(s) can be liquid, so that the composition is, for example, oral syrup, injectable liquid, or aerosol, for example, useful in inhalation administration.

[0169] When intended for oral administration, the pharmaceutical composition is preferably in either solid or liquid form, with semi-solid, semi-liquid, suspension and gel forms being included in the forms considered herein as either solid or liquid.

[0170] As a solid composition for oral administration, pharmaceutical composition can be formulated into powder, granule, compressed tablet, pill, capsule, chewing gum, wafer or similar form. Such solid composition typically contains one or more inert diluents or edible carriers. Also, one or more of the following can be present: binder, such as carboxymethylcellulose, ethylcellulose, microcrystalline cellulose, tragacanth or gelatin; excipient, such as starch, lactose or dextrin; disintegrant, such as alginic acid, sodium alginate, Primogel, corn starch, etc.; lubricant, such as magnesium stearate or Sterotex; glidant, such as colloidal silicon dioxide; sweetener, such as sucrose or saccharin; flavoring, such as peppermint, methyl salicylate or orange flavoring; and coloring.

[0171] When the pharmaceutical composition is in the form of a capsule, such as a gelatin capsule, it may contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol or oil.

[0172] The pharmaceutical composition can be in the form of liquid, for example, elixir, syrup, solution, emulsion or suspension. The liquid can be for oral administration or delivery by injection, as two examples. When intended for oral administration, the preferred composition contains, in addition to the compound, one or more of sweeteners, preservatives, dyes / colorants and flavor enhancers. In the composition intended for administration by injection, one or more of surfactants, preservatives, wetting agents, dispersing agents, suspending agents, buffers, stabilizers and isotonic agents can be included.

[0173] The liquid pharmaceutical compositions of the present disclosure, whether they are in solution, suspension or other similar form, may contain one or more of the following adjuvants: sterile diluents, such as water for injection, saline solution, preferably physiological saline, Ringer's solution, isotonic sodium chloride, fixed oils, such as synthetic mono- or diglycerides, polyethylene glycols, glycerin, propylene glycol or other solvents that can act as solvents or suspending media; antibacterial agents, such as benzyl alcohol or methylparabens; antioxidants, such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid; buffers, such as acetates, citrates or phosphates, and agents for adjusting tonicity, such as sodium chloride or dextrose. Parenteral preparations may be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. Saline is the preferred adjuvant. Injectable pharmaceutical compositions are preferably sterile.

[0174] Liquid pharmaceutical compositions of the present disclosure intended for either parenteral or oral administration should contain an amount of the compound of the present disclosure such that a suitable dosage will be obtained. Typically, this amount is at least 0.01% of the compound of the present disclosure in the composition. When intended for oral administration, this amount may vary to be 0.1 to about 70% by weight of the composition. A preferred oral pharmaceutical composition contains about 4% to about 50% of the compound of the present disclosure. Preferred pharmaceutical compositions and preparations according to the present disclosure are prepared such that a parenteral dosage unit contains 0.01 to 10% by weight of the undiluted compound of the present disclosure.

[0175] The pharmaceutical composition of the present disclosure may be intended for topical administration, in which case the carrier may suitably comprise a solution, emulsion, ointment or gel base. The base may comprise, for example, one or more of the following: petrolatum, lanolin, polyethylene glycol, beeswax, mineral oil, diluents such as water and alcohol, and emulsifiers and stabilizers. A thickening agent may be present in a pharmaceutical composition for topical administration. If intended for transdermal administration, the composition may comprise a transdermal patch or iontophoresis device. The topical formulation may contain a concentration of the compound of the present disclosure of about 0.1 to about 10% w / v (weight per unit volume).

[0176] The pharmaceutical composition of the present disclosure may be intended for rectal administration in the form of dissolving in the rectum and releasing the drug, for example, in a suppository.The composition for rectal administration may contain an oily base as a suitable non-irritating excipient.Such bases include, but are not limited to, lanolin, cocoa butter and polyethylene glycol.

[0177] The pharmaceutical composition of the present disclosure may contain various substances that modify the physical form of solid or liquid dosage units.For example, the composition may contain substances that form a coating shell around active ingredient.The substances that form the coating shell are typically inert and may be selected from, for example, sugar, shellac, and other enteric coating agents.Alternatively, active ingredient may be encapsulated in gelatin capsules.

[0178] The pharmaceutical compositions of the present disclosure, in solid or liquid form, may include an agent that binds to the compounds of the present disclosure, thereby aiding in the delivery of the compounds. Suitable agents that may act in this capacity include monoclonal or polyclonal antibodies, proteins, or liposomes.

[0179] The pharmaceutical compositions of the present disclosure may consist of dosage units that can be administered as an aerosol. The term aerosol is used to indicate a variety of systems, from those of colloidal nature to systems consisting of pressurized packages. Delivery may be by liquefied or compressed gas or by a suitable pump system to dispense the active ingredient. The aerosol compounds of the present disclosure may be delivered in single-phase, two-phase, or three-phase systems to deliver the active ingredient(s). Delivery of the aerosol includes the necessary containers, activators, valves, subcontainers, etc., which may together form a kit. Those skilled in the art may determine the preferred aerosol without undue experimentation.

[0180] The pharmaceutical composition of the present disclosure can be prepared by methodology well known in the pharmaceutical field.For example, the pharmaceutical composition intended to be administered by injection can be prepared by combining the compound of the present disclosure with sterile distilled water to form a solution.Surfactant can be added to facilitate the formation of a homogeneous solution or suspension.Surfactant is a compound that non-covalently interacts with the compound of the present disclosure to facilitate the dissolution or homogeneous suspension of the compound in aqueous delivery system.

[0181] The compounds of the present disclosure, or pharma- ceutically acceptable salts thereof, are administered in therapeutically effective amounts, which vary depending on a variety of factors, including the activity of the particular compound employed; the metabolic stability and length of action of the compound; the age, weight, general health, sex, and diet of the patient; the mode and time of administration; the rate of excretion; the drug combination; the severity of the particular disorder or condition; and the subject undergoing therapy. Typically, a therapeutically effective daily dose is from about 0.001 mg / Kg (i.e., 0.07 mg) to about 100 mg / Kg (i.e., 7.0 g) (for a 70 Kg mammal); preferably, a therapeutically effective dose is from about 0.01 mg / Kg (i.e., 0.7 mg) to about 50 mg / Kg (i.e., 3.5 g) (for a 70 Kg mammal); more preferably, a therapeutically effective dose is from about 1 mg / kg (i.e., 70 mg) to about 25 mg / Kg (i.e., 1.75 g) (for a 70 Kg mammal).

[0182] The effective dose ranges provided herein are not intended to be limiting and represent preferred dose ranges. However, the most preferred dosage will be tailored to the individual subject, as understood and determinable by one of ordinary skill in the art (see, e.g., Berkowet et al., eds., The Merck Manual, 16 th edition, Merck and Co., Rahway, NJ, 1992; Goodmanetna., eds., Goodman and Cilman's The Pharmacological Basis of Therapeutics, 10 th edition,Pergamon Press,Inc.,Elmsford,NY,(2001);Avery's Drug Treatment:Principles and Practice of Clinical Pharmacology and Therapeutics,3rd edition,ADIS Press,LTD.,Williams and Wilkins,Baltimore,MD.(1987),Ebadi,Pharmacology,Little,Brown and Co.,Boston,(1985);Osolci al., eds., Remington's Pharmaceutical Sciences, 18 th edition, Mack Publishing Co., Easton, PA (1990); see Katzung, Basic and Clinical Pharmacology, Appleton and Lange, Norwalk, CT (1992).

[0183] The total dose required for each treatment may be administered by multiple doses or a single dose over the course of the day, if desired. Usually, treatment is started with a smaller dosage that is less than the optimal dose of the compound. The dosage is then increased by small increments until the optimal effect is achieved under the circumstances. The diagnostic pharmaceutical compounds or compositions may be administered alone or in conjunction with other diagnostic and / or pharmaceutical agents directed to the pathology or other symptoms of the pathology. The recipient of administration of the compounds and / or compositions of the present disclosure may be any vertebrate animal, for example, a mammal. Among mammals, preferred recipients are mammals of the orders Primates (including humans, apes and monkeys), Artiodactyla (including horses, goats, cows, sheep, pigs), Rodentia (including mice, rats, rabbits, and hamsters), and Carnivora (including cats and dogs). Among birds, preferred recipients are turkeys, chickens, and other members of the same order. The most preferred recipients are humans.

[0184] For topical use, it is preferred to administer an effective amount of a pharmaceutical composition according to the present disclosure to a target area adjacent to the peripheral neurons to be treated, such as a skin surface, mucosa, etc. This amount will typically range from about 0.0001 mg to about 1 g of a compound of the present disclosure per application, depending on the area to be treated, whether the use is diagnostic, prophylactic or therapeutic, the severity of the condition, and the nature of the topical vehicle used. A preferred topical preparation is an ointment, in which about 0.001 to about 50 mg of active ingredient is used per cc of ointment base. The pharmaceutical composition may be formulated as a transdermal composition or transdermal delivery device ("patch"). Such compositions include, for example, a backing, an active compound reservoir, a control membrane, a backing, and a contact adhesive. Such transdermal patches may be used to provide continuous, pulsatile, or on-demand delivery of the compounds of the present disclosure as desired.

[0185] The compositions of the present disclosure can be formulated to provide rapid, sustained or delayed release of active ingredient after administration to a patient by using procedures known in the art.Controlled release drug delivery systems include osmotic pump systems and dissolution systems that contain polymer-coated reservoirs or drug-polymer matrix formulations.Examples of controlled release systems are provided in U.S. Patent Nos. 3,845,770 and 4,326,525 and PJ Kuzma et al., Regional Anesthesia 22(6):543-551(1997), all of which are incorporated herein by reference.

[0186] The compositions of the present disclosure may also be delivered via intranasal drug delivery systems for local, systemic, and nose-to-brain medical therapy. Controlled Particle Dispersion (CPD)™ technology, traditional nasal spray bottles, inhalers, or nebulizers are known to those skilled in the art to provide effective local and systemic delivery of drugs by targeting the olfactory region and paranasal sinuses.

[0187] The present disclosure also relates to an intravaginal shell or core drug delivery device suitable for administration to a human female or animal female, which contains an active pharmaceutical ingredient in a polymer matrix and is surrounded by a sheath, and may be capable of releasing the compound in a substantially zero order pattern on a daily basis similar to the devices used to apply testosterone as described in PCT Published Patent Application No. WO 98 / 50016.

[0188] Current methods for ocular delivery include topical administration (eye drops), subconjunctival injection, periocular injection, intravitreal injection, surgical implants, and iontophoresis (the use of a small electrical current to transport ionized drugs into or through body tissues). One of skill in the art will combine the most suitable excipients with the compounds for safe and effective intraocular administration.

[0189] The most suitable route will depend on the nature and severity of the condition being treated. Those skilled in the art will also be familiar with determining the method of administration (e.g., oral, intravenous, inhalation, subcutaneous, rectal, etc.), dosage form, suitable pharmaceutical excipients and other considerations relevant to delivery of the compound to a subject in need thereof.

[0190] Combination therapy The compounds of the present disclosure may be usefully combined with one or more other compounds of the present disclosure or one or more other therapeutic agents, or in any combination thereof, in the treatment of sodium channel-mediated diseases and conditions. For example, the compounds of the present disclosure may be usefully combined with one or more other compounds of the present disclosure or one or more other therapeutic agents, or in any combination thereof, in the treatment of sodium channel-mediated diseases and conditions. For example, the compounds of the present disclosure may be usefully combined with acetazolamide (Diamox), brivaracetam (Briviact), cannabidiol (Epidiolex), carbamazepine (Tegretol), cenobamate (Xcopri), clobazam (Frisium), clonazepam (Klonopin), eslicarbazepine acetate (Aptiom, Zebinix), ethosuximide (Zarontin), felbamate (Felbatol), fenfluramine (Fintepla), gabapentin (Neurontin), lacosamide (Vimpat), lamotrigine (Lamictal), levetiracetam (Keppra), It may be administered simultaneously, sequentially, or separately in combination with other therapeutic agents, including, but not limited to, oxcarbazepine (Trileptal), perampanel (Fycompa), phenobarbital (Luminal), phenytoin (Dilantin), pregabalin (Lyrica), primidone, retigabine (Ezogabine), rufinamide (Banzel), stilipentol (Diacomit), sulthiame, tiagabine (Gabitril), topiramate (Topamax), valproate (Depakote), vigabatrin (Sabril), zonisamide (Zonegran).

[0191] As used herein, "combination" refers to any mixture or exchange of one or more compounds of the present disclosure and one or more other compounds of the present disclosure or one or more additional therapeutic agents. Unless the context clearly indicates otherwise, "combination" may include simultaneous or sequential delivery of a compound of the present disclosure with one or more therapeutic agents. Unless the context clearly indicates otherwise, "combination" may include a dosage form of a compound of the present disclosure with another therapeutic agent. Unless the context clearly indicates otherwise, "combination" may include a route of administration of a compound of the present disclosure with another therapeutic agent. Unless the context clearly indicates otherwise, "combination" may include a formulation of a compound of the present disclosure with another therapeutic agent. Dosage forms, routes of administration, and pharmaceutical compositions include, but are not limited to, those described herein.

[0192] Kit of Parts The present disclosure also provides a kit containing a pharmaceutical composition comprising one or more compounds of the present disclosure. The kit also includes instructions for the use of the pharmaceutical composition to regulate the activity of sodium channels, for the treatment of seizure disorders, such as epilepsy, as well as other utilities disclosed herein. Preferably, the commercial package contains one or more unit doses of the pharmaceutical composition. For example, such a unit dose may be sufficient for the preparation of an intravenous injection. It will be clear to those skilled in the art that compounds that are sensitive to light and / or air may require special packaging and / or formulation. For example, packaging that is opaque to light and / or sealed from contact with ambient air and / or formulated with suitable coatings or excipients may be used.

[0193] compound preparation The following reaction schemes show methods for making the compounds of the present disclosure, i.e., compounds of formula (I) or (II) as described above in the Summary of the Invention, including stereoisomers, enantiomers, or tautomers or mixtures thereof; or a pharma-ceutically acceptable salt, solvate, or prodrug thereof.

[0194] It is also understood that those skilled in the art will be able to make the compounds of the present disclosure by similar methods or methods known to those skilled in the art. Those skilled in the art will be able to make other compounds of the present disclosure that are not specifically exemplified below by using appropriate starting components and modifying the parameters of synthesis as necessary in a manner similar to that described below. Typically, starting components can be obtained from sources such as Sigma Aldrich, Alfa Aesar, Combi-Blocks, Oakwood Chemicals, Matrix Scientific, and TCI, or can be synthesized according to sources known to those skilled in the art (see, for example, M.B. Smith and J. March, Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6th edition (Wiley, 2007)) or prepared as described herein.

[0195] It is also understood that in the description that follows, combinations of substituents and / or variables of the depicted formula TCI are permissible only if such contributions result in stable compounds.

[0196] It will also be appreciated by those skilled in the art that in the processes described below, functional groups of intermediate compounds may need to be protected by suitable protecting groups. Such functional groups include hydroxy, amino, mercapto and carboxylic acid. Suitable protecting groups for hydroxy include trialkylsilyl or diarylalkylsilyl (e.g., t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, and the like. Suitable protecting groups for amino include t-butoxycarbonyl, benzyloxycarbonyl, p-methoxybenzyl, trityl, and the like.

[0197] Protecting groups can be added or removed according to standard techniques known to those skilled in the art and described herein.

[0198] The use of protecting groups is described in Greene, T. W. and P. G. Muts, Greene's Protective Groups in Organic Synthesis (2006), 4 th Ed., Wiley. The protecting group can also be a polymer resin, such as a Wang resin or a 2-chlorotrityl-chloride resin.

[0199] It is also understood by those skilled in the art that such protected derivatives of the compounds of the present disclosure may not possess pharmacological activity as such, but they may be administered to a mammal and then metabolized in the body to form the pharmacologically active compounds of the present disclosure. Therefore, such derivatives may be described as "prodrugs". All prodrugs of the compounds of formula (I) or (II) are included within the scope of the present disclosure.

[0200] The compounds of formula (I) or (II) may contain at least one asymmetric carbon atom and therefore may exist as racemates, enantiomers, and / or diastereoisomers. A particular enantiomer or diastereoisomer may be prepared by utilizing suitable chiral starting materials or through the use of suitable asymmetric synthesis methods. Alternatively, diastereomeric or racemic mixtures of compounds of formula (I) or (II) may be resolved into their respective enantiomers or diastereoisomers. Methods for the resolution of diastereomeric or racemic mixtures of compounds of formula (I) or (II) described herein or intermediates prepared herein are well known in the art (e.g., EL Eliel and SH Wilen, in Stereochemistry of Organic Compounds; John Wiley & Sons: New York, 1994; Chapter 7, and references cited therein). Suitable processes such as crystallization (e.g. preferential crystallization, preferential crystallization in the presence of additives), asymmetric inversion of racemates, chemical separation (e.g. formation and separation of diastereomers, e.g. formation of diastereomeric salt mixtures or use of other resolving agents; separation via complexes and inclusion compounds), kinetic separation (e.g. using titanium tartrate catalysts), enzymatic separation (e.g. lipase mediated) and chromatographic separation (e.g. HPLC using chiral stationary phases and / or using simulated moving bed techniques, or supercritical fluid chromatography and related techniques) are some of the examples that may be applied (see, e.g., TJ Ward, Analytical Chemistry, 2002, 2863-2872).

[0201] In general, compounds of formula (I) or (II) as described above in the Summary of the Invention may be synthesized according to the general procedures set out below in Reaction Schemes 1-13, where appropriate starting materials, reagents, substituents, coupling partners, protecting groups, etc. are selected to carry out the reactions shown to arrive at the desired compounds of formula (I) or (II).

[0202] For example, in some embodiments of Reaction Schemes 1-13, R 1 teeth, [ka] R 2 teeth, [ka] where PG is a protecting group (e.g., an amine protecting group, e.g., Boc or Fmoc), and Z 1 is a halogen (e.g., F, Cl, Br, or I), and Z 2 is a halogen (e.g., F, Cl, Br, or I), and Z 3 is Z 1 and Z is a suitable coupling partner (e.g., a boronic acid or ester) for 4 is Z 2 and Z is a suitable coupling partner (e.g., a carboxylic acid, a boronic acid or an ester) for 5 is a halogen (e.g., F, Cl, Br, or I), and Z 6 is Z 5 and Z is a suitable coupling partner (e.g., a dialkylamine) for 7 is a halogen (e.g., F, Cl, Br, or I) and X is oxygen or carbon. X 1 is a suitable coupling group forming a linker (i.e., Z 5 In some embodiments, -X 1 -R 8b ' is R 8b Other variables (e.g., R 3 ) are as defined throughout this disclosure.

[0203] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0204] All compounds described below that can be prepared in free base or acid form can be converted to pharmaceutically acceptable salts by treating with appropriate inorganic or organic base or acid. The salts of the compounds prepared below can be converted to their free base or acid form by standard techniques. Furthermore, all compounds of the present disclosure that contain acid or ester groups can be converted to the corresponding ester or acid, respectively, by methods known to those skilled in the art or by methods described herein.

[0205] The present disclosure also relates to novel intermediate compounds as defined above, all salts, solvates, and complexes thereof, and all solvates and complexes of the salts thereof as defined above for the compounds of formula (I) or (II). The present disclosure includes all polymorphs of the aforementioned species and their crystalline habits.

[0206] The embodiments disclosed herein also encompass all compounds that are isotopically labeled by replacing one or more atoms with an atom having a different atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, e.g., 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 Each isotope of I is included.

[0207] Isotopically labeled compounds may generally be prepared by conventional techniques known to those of skill in the art, or by processes similar to those described below and in the Examples below, using appropriate isotopically labeled reagents in place of the non-labeled reagents previously used.

[0208] The following examples directed to the synthesis of compounds of the present disclosure; and the following biological examples are provided as a guide to aid in the practice of the disclosure and are not intended as limitations on the scope of the disclosure.

[0209] In the following preparations and examples, all temperatures are given in degrees Celsius unless otherwise indicated. Commercially available reagents were purchased from suppliers such as Sigma Aldrich, Alfa Aesar, Combi-Blocks, Oakwood Chemicals, Matrix Scientific, and TCI, and were used without further purification unless otherwise indicated. Reactions shown below were typically carried out in anhydrous solvents (unless otherwise noted) under a positive pressure of nitrogen or argon or using dry tubes, and reaction flasks were typically equipped with rubber septa for introduction of substrates and reagents via syringe. Glassware was oven-dried and / or heat-dried. Yields were not optimized. Melting points were determined on a Buchi hot stage apparatus and are uncorrected. 1 H NMR, 19 F and 13 C NMR data was analyzed using deuterated CDCI with chemical shifts (δ) reported in parts per million (ppm) relative to trimethylsilane (TMS) or residual non-deuterated solvent peaks as the reference standard. 3 , DMSO-d 6 , CD 3 OD, CD 3 CN, or acetone-d 6 Obtained in solvent solutions. Data are reported as follows, where applicable: chemical shift, multiplicity, coupling constant (Hz), and number of protons, fluorines, or carbon atoms. When peak multiplicities are reported, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad), dd (doublet of doublets), dt (doublet of triplets). Coupling constants, when given, are reported in H (Hertz). EXAMPLES

[0210] Example 1 Synthesis of 1-cyclobutyl-N-[2-(4,4-difluorocyclohexyl)-4-(2-fluorophenyl)-3-pyridyl]pyrazole-4-carboxamide [ka] Step 1. Preparation of 2-chloro-4-(2-fluorophenyl)nicotinaldehyde [ka] A mixture of 2-chloro-4-iodonicotinaldehyde (6.95 g, 26.0 mmol), 1,4-dioxane (86 ml), and water (10 ml) was sparged with nitrogen for 10 minutes. A flask was charged with 2-fluorophenylboronic acid (4.0 g, 29 mmol), potassium carbonate (9.0 g, 65 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (2.22 g, 2.60 mmol) and sparged for 2 minutes. The reaction mixture was stirred at 80° C. for 2 hours. After cooling to ambient temperature, the reaction mixture was diluted with ethyl acetate (300 ml). The organic layer was washed with saturated ammonium chloride (2×100 ml) and brine (150 ml). The organic solution was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Purification of the residue by column chromatography eluting with 0-30% ethyl acetate in heptane provided the title compound as a colorless oil that solidified on standing (5.82 g, 95% yield): MS (ESI+) m / z 235.0 (M+1), 237.0 (M+1).

[0211] Step 2. Preparation of 2-chloro-4-(2-fluorophenyl)nicotinic acid [ka] A mixture of 2-chloro-4-(2-fluorophenyl)nicotinaldehyde (5.0 g, 21 mmol), 1,4-dioxane (185 ml), and water (36 ml) was cooled in an ice / water bath. To this solution was added potassium permanganate (5.02 g, 31.8 mmol). The solution was warmed to ambient temperature and stirred for 4 hours. The pH of the solution was adjusted to >12 with 5 M sodium hydroxide solution (5 ml) and filtered. The pH of the filtrate was adjusted to <5 using concentrated hydrochloric acid (8 ml). The aqueous mixture was diluted with ethyl acetate (300 ml) and separated. The organic layer was washed with brine (2 x 100 ml). The organic solution was dried over magnesium sulfate, filtered, and concentrated in vacuo. The colorless oil was used without further purification (4.8 g, 90% yield): MS (ESI+) m / z 252.0 (M+1), 254.0 (M+1).

[0212] Step 3. Preparation of tert-butyl N-[2-chloro-4-(2-fluorophenyl)-3-pyridyl]carbamate [ka] To a solution of 2-chloro-4-(2-fluorophenyl)nicotinic acid (1.20 g, 4.77 mmol) in tert-butanol (22.6 ml) and N,N-dimethylformamide (22.6 ml) was added diphenylphosphon azide and triethylamine (1.21 g, 11.9 mmol). The solution was heated at 95° C. for 2 h. The reaction mixture was cooled to ambient temperature and diluted with ethyl acetate (500 ml). The reaction mixture was washed with saturated sodium bicarbonate solution (3×100 ml), water (50 ml), and brine (50 ml). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Purification of the residue by column chromatography eluting with 0-25% ethyl acetate in heptane provided the title compound as a colorless oil (1.27 g, 83% yield): MS (ES+) m / z 323.2 (M+1), 325.2 (M+1).

[0213] Step 4. Preparation of tert-butyl N-[2-(4,4-difluorocyclohexyl)-4-(2-fluorophenyl)-3-pyridyl]carbamate [ka] A vial containing tert-butyl N-[2-chloro-4-(2-fluorophenyl)-3-pyridyl]carbamate (1.07 g, 3.32 mmol), 4,4-difluorocyclohexanecarboxylic acid (0.93 g, 5.7 mmol), (4,4''-di-t-butyl-2,2''-bipyridine)bis[3,5-difluoro-2-[5-trifluoromethyl-2-pyridinyl-kN)phenyl-kC] Iridium(iii) hexafluorophosphate (0.037 g, 0.033 mmol), dichloro(dimethoxyethane)nickel (0.073 g, 0.33 mmol), 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (0.13 g, 0.50 mmol), cesium carbonate (1.95 g, 5.98 mmol), and N,N-dimethylformamide (55 ml) were added. The vial was sealed and the reaction mixture was stirred in front of a Kessil PR160L light (440 nm) for 24 hours. The reaction mixture was diluted with ethyl acetate (250 ml) and washed with saturated ammonium chloride solution (2×50 ml), water (50 ml), and brine (50 ml). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Purification of the residue by column chromatography eluting with 0-20% ethyl acetate in heptane afforded the title compound as a colorless solid (0.82 g, 61% yield): MS (ES+) m / z 407.2 (M+1).

[0214] Step 5. Preparation of 2-(4,4-difluorocyclohexyl)-4-(2-fluorophenyl)pyridin-3-amine [ka] To a mixture of tert-butyl N-[2-(4,4-difluorocyclohexyl)-4-(2-fluorophenyl)-3-pyridyl]carbamate (0.82 g, 2.5 mmol) in 1,4-dioxane (4.0 ml) was added 4M hydrochloric acid in 1,4-dioxane (7.5 ml, 30 mmol). The reaction mixture was stirred for 18 hours. The reaction mixture was diluted with ethyl acetate (90 ml) and washed with saturated ammonium hydroxide solution (2×20 ml), and brine (20 ml). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Purification of the residue by column chromatography eluting with 0-40% ethyl acetate in heptane provided the title compound as a yellow solid (0.61 g, 98% yield): 1 H-NMR (400 MHz; CDCl 3 ) δ 8.10 (d, J = 4.9 Hz, 1H), 7.26-7.07 (m, 4H), 6.93 (d, J = 4.9 Hz, 1H), 3.71-3.65 (s, 2H), 2.82-2.77 (m, 1H), 2.35-2.27 (m, MS(ES+)m / z307.2(M+1).

[0215] Step 6. Preparation of 1-cyclobutyl-N-[2-(4,4-difluorocyclohexyl)-4-(2-fluorophenyl)-3-pyridyl]pyrazole-4-carboxamide [ka] To a mixture of 2-(4,4-difluorocyclohexyl)-4-(2-fluorophenyl)pyridin-3-amine (0.050 g, 0.16 mmol), 1-cyclobutyl-1H-pyrazole-4-carboxylic acid (0.041 g, 0.24 mmol) and 2-chloro-1-methylpyridinium iodide (0.10 g, 0.41 mmol) was added anhydrous tetrahydrofuran (3.3 ml). The solution was heated at 55° C. for 1 minute and then N-ethyl-N-isopropylpropan-2-amine (0.21 g, 1.6 mmol) was added. The reaction mixture was stirred at 55° C. for 18 hours. The reaction mixture was cooled to ambient temperature and diluted with ethyl acetate (100 ml). The reaction mixture was washed with saturated ammonium chloride solution (2×50 ml). The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Purification of the residue by column chromatography eluting with 10-80% ethyl acetate in heptane provided the title compound as a colorless solid (0.021 g, 28% yield): 1 H-NMR (400 MHz; DMSO-d 6 ) δ 9.56 (s, 1H), 8.56 (d, J = 4.9 Hz, 1H), 8.21 (d, J = 0.4 Hz, 1H), 7.87 (s, 1H), 7.41-7.23 (m, 4H), 7.18 (td, J = 7.5, 1.1 Hz, 1H), 4.83 (Quintet, J = 8.4 Hz, 1H), 3.15-3.10 (m, 1H), 2.47-2.32 (m, 4H), 2.12-2.06 (m, 2H), 1.93-1.73 (m, 8H);MS(ES+)m / z455.2(M+1).

[0216] Example 2 Synthesis of N-[2-(4,4-difluorocyclohexyl)-4-(2-fluorophenyl)-3-pyridyl]-2-(dimethylamino)pyrimidine-5-carboxamide [ka] Step 1. Preparation of 2-chloro-N-[2-(4,4-difluorocyclohexyl)-4-(2-fluorophenyl)-3-pyridyl]pyrimidine-5-carboxamide [ka] To a mixture of 2-(4,4-difluorocyclohexyl)-4-(2-fluorophenyl)pyridin-3-amine (0.20 g, 0.65 mmol), 2-chloropyrimidine-5-carboxylic acid (0.16 g, 0.98 mmol) and 2-chloro-1-methylpyridinium iodide (0.42 g, 1.6 mmol) was added anhydrous tetrahydrofuran (13 ml). The solution was heated at 55° C. for 1 minute and then N-ethyl-N-isopropylpropan-2-amine (0.84 g, 6.5 mmol) was added. The reaction mixture was stirred at 55° C. for 45 hours. The reaction mixture was cooled to ambient temperature and diluted with ethyl acetate (100 ml). The reaction mixture was washed with saturated ammonium chloride solution (2×50 ml). The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Purification of the residue by column chromatography eluting with 5-50% ethyl acetate in heptane gave the title compound as a colorless solid (0.23 g, 80% yield): MS (ES+) m / z 447.2 (M+1), 447.2 (M+1).

[0217] Step 2. Preparation of N-[2-(4,4-difluorocyclohexyl)-4-(2-fluorophenyl)-3-pyridyl]-2-(dimethylamino)pyrimidine-5-carboxamide [ka] To a mixture of 2-chloro-N-[2-(4,4-difluorocyclohexyl)-4-(2-fluorophenyl)-3-pyridyl]pyrimidine-5-carboxamide (0.080 g, 0.18 mmol) in anhydrous 1-methyl-2-pyrrolidinone (0.4 ml) was added dimethylamine hydrochloride (0.15 g, 1.8 mmol) and 60% sodium hydride dispersion in mineral oil (0.014 g, 0.36 mmol). The solution was stirred at ambient temperature for 1 h. The reaction mixture was diluted with ethyl acetate (100 ml) and washed with saturated ammonium chloride solution (2×50 ml). The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Purification of the residue by column chromatography eluting with 10-100% ethyl acetate in heptane afforded the title compound as a colorless solid (0.024 g, 29% yield): 1 H-NMR (400 MHz; DMSO-d 6 ) δ 9.82 (s, 1H), 8.63 (s, 2H), 8.58 (d, J = 4.9 Hz, 1H), 7.41-7.31 (m, 3H), 7.29-7.24 (m, 1H), 7.20 (td, J = 7.5, 1.1 Hz, 1H), 3.16 (d, J = 6.3 Hz, 7H), 2.11-2.07 (m, 2H), 1.94-1.86 (m, 6H); MS(ES+)m / z456.2(M+1).

[0218] Example 3 Synthesis of N-[2-(4,4-difluorocyclohexyl)-4-(2-fluorophenyl)-3-pyridyl]-2-ethoxy-pyrimidine-5-carboxamide [ka] To 2-chloro-N-[2-(4,4-difluorocyclohexyl)-4-(2-fluorophenyl)-3-pyridyl]pyrimidine-5-carboxamide (0.080 g, 0.18 mmol) was added absolute ethanol (0.6 ml) and 60% sodium hydride dispersion in mineral oil (0.014 g, 0.36 mmol). The solution was stirred at ambient temperature for 1 h. The reaction mixture was diluted with ethyl acetate (100 ml) and washed with saturated ammonium chloride solution (2×50 ml). The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Purification of the residue by column chromatography eluting with 10-100% ethyl acetate in heptane afforded the title compound as a colorless solid (0.018 g, 21% yield): 1 H-NMR (400 MHz; DMSO-d 6 ) δ 10.17 (s, 1H), 8.85-8.83 (m, 2H), 8.60 (d, J = 4.9 Hz, 1H), 7.44-7.34 (m, 3H), 7.30-7.26 (m, 1H), 7.22 (td, J = 7.5, 1.1 Hz, 1H), 4.42 (q, J = 7.1 Hz, 2H), 3.20-3.15 (m, 1H), 2.13-2.06 (m, 2H), 1.98-1.83 (m, 6H), 1.35 (t, J = 7.1 Hz, 3H);MS(ES+)m / z457.0(M+1).

[0219] Example 4 Synthesis of N-[2-(4,4-difluorocyclohexyl)-4-(2-fluorophenyl)-3-pyridyl]-2-isopropoxy-pyrimidine-5-carboxamide [ka] To 2-chloro-N-[2-(4,4-difluorocyclohexyl)-4-(2-fluorophenyl)-3-pyridyl]pyrimidine-5-carboxamide (0.080 g, 0.18 mmol) was added anhydrous isopropanol (0.6 ml), anhydrous 1-methyl-2-pyrrolidinone (0.40 ml), and 60% sodium hydride dispersion in mineral oil (0.014 g, 0.36 mmol). The solution was stirred at 50° C. for 1 h. The reaction mixture was diluted with ethyl acetate (100 ml) and washed with saturated ammonium chloride solution (2×50 ml). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Purification of the residue by column chromatography eluting with 10-100% ethyl acetate in heptane provided the title compound as a colorless solid (0.020 g, 21% yield): 1 H-NMR (400 MHz; DMSO-d 6 ) δ 10.15 (d, J = 6.7 Hz, 1H), 8.83 (d, J = 3.7 Hz, 2H), 8.60 (d, J = 4.9 Hz, 1H), 7.44-7.33 (m, 3H), 7.31-7.26 (m, 1H), 7.22 (td, J = 7.5, 1.1 Hz, 1H), 5.26 (quintet, J = 6.2 Hz, 1H), 3.19-3.15 (m, 1H), 2.12-2.06 (m, 2H), 2.02-1.85 (m, 6H), 1.34 (t, J = 4.1 Hz, 6H);MS(ES+)m / z471.4(M+1).

[0220] Example 5 Synthesis of N-[2-(4,4-difluorocyclohexyl)-4-(2-fluorophenyl)-3-pyridyl]-4-methoxy-piperidine-1-carboxamide [ka] To 2-(4,4-difluorocyclohexyl)-4-(2-fluorophenyl)pyridin-3-amine (0.10 g, 0.34 mmol) was added anhydrous tetrahydrofuran (1.1 ml) and the mixture was cooled in an ice-water bath. Solid triphosgene (0.058 g, 0.20 mmol) was added. The solution was stirred at 0° C. for 2 hours and then warmed to ambient temperature for 1 hour. To the solution was added 4-methoxypiperidine (0.1 g, 1.0 mmol), anhydrous tetrahydrofuran (1.1 ml), and N-ethyl-N-isopropylpropan-2-amine (0.42 g, 3.3 mmol). The reaction was stirred at ambient temperature for 12 hours. The reaction mixture was diluted with ethyl acetate (100 ml), washed with saturated ammonium chloride (2×50 ml), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Purification of the residue by column chromatography eluting with a gradient of 10 to 100% ethyl acetate in heptane, followed by trituration with diethyl ether (5 ml) and filtration afforded the title compound as a colorless solid (0.036 g, 23% yield): 1 H-NMR (400 MHz; DMSO-d 6 ) δ 8.46 (d, J = 4.9 Hz, 1H), 8.05 (s, 1H), 7.43 (dddd, J = 8.5, 7.1, 5.4, 1.6 Hz, 1H), 7.34-7.20 (m, 4H), 3.61-3.58 (m, 2H), 3.33 (s, 3H), 3.23 (s, 3H), 3.13-3.10 (m, 1H), 2.95-2.89 (m, 2H), 2.15-2.09 (m, 2H), 1.90-1.78 (m, 6H), 1.65-1.61 (m, 2H), 1.16-1.07 (m, 2H); MS(ES+) m / z 448.2(M+1).

[0221] Example 6 Synthesis of N-[2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)-3-pyridyl]-2-isopropyl-pyrimidine-5-carboxamide [ka] Step 1. Preparation of 2-chloro-4-(2,5-difluorophenyl)pyridine-3-carbaldehyde [ka] To 2-chloro-4-iodonicotinaldehyde (10.0 g, 37.4 mmol) was added 1,4-dioxane (135 ml) and water (15.0 ml) and the mixture was sparged with nitrogen for 10 minutes. To the mixture was added 2.5-difluorophenylboronic acid (6.49 g, 41.1 mmol), potassium carbonate (15.5 g, 112 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (3.17 g, 3.74 mmol) and the solution was sparged with nitrogen for 2 minutes. The flask was sealed under a nitrogen atmosphere and heated to 85° C. for 5 hours. The reaction mixture was cooled to ambient temperature and diluted with ethyl acetate (300 ml). The organic layer was washed with saturated ammonium chloride (2×50 ml), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Purification of the residue by column chromatography eluting with 0-25% ethyl acetate in heptane provided the title compound as a brown solid (9.4 g, 99% yield): MS (ES+) m / z 254.0 (M+1), 256.0 (M+1).

[0222] Step 2. Preparation of 2-chloro-4-(2,5-difluorophenyl)pyridine-3-carboxylic acid [ka] To 2-chloro-4-(2,5-difluorophenyl)pyridine-3-carbaldehyde (9.4 g, 37 mmol) was added tert-butanol (468 ml), dichloromethane (128 ml), and 2-methyl-2-butene (119 ml). The reaction was cooled to 0° C. and then a mixture of sodium dihydrogen phosphate (15.7 g, 131 mmol) and sodium chlorite (10.6 g, 93.6 mmol) in water (205 ml) was added dropwise. The reaction was allowed to warm to ambient temperature and stirred for 18 hours. The reaction mixture was diluted with ethyl acetate (200 ml) and washed with 1 M hydrochloric acid until the pH of the aqueous solution was <2. The aqueous layer was washed with ethyl acetate (3×500 ml) and the combined organic phases were washed with 1 M hydrochloric acid (2×100 ml) and brine (2×100 ml). The organic solution was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The colorless oil was used without further purification (10.1 g, 100% yield): MS (ES+) m / z: 270.0 (M+1), 272.0 (M+1).

[0223] Step 3. Preparation of tert-butyl N-[2-chloro-4-(2,5-difluorophenyl)-3-pyridyl]carbamate [ka] To 2-chloro-4-(2,5-difluorophenyl)pyridine-3-carboxylic acid (10.1 g, 37.5 mmol) was added tert-butanol (150 ml) and N,N-dimethylformamide (150 ml), diphenylphosphon azide (15.5 g, 56.2 mmol), and triethylamine (9.48 g, 93.6 mmol). The solution was heated at 95° C. for 2 hours. The reaction mixture was cooled to ambient temperature and diluted with ethyl acetate (600 ml). The reaction mixture was washed with saturated ammonium chloride (150 ml), saturated sodium bicarbonate (2×150 ml), water (150 ml), and brine (50 ml). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Purification of the residue by column chromatography eluting with 0-50% ethyl acetate in heptane provided the title compound as a colorless solid (8.5 g, 67% yield): 1H-NMR (400 MHz; DMSO-d 6 ) δ 8.34 (d, J = 5.0 Hz, 1H), 7.43-7.38 (m, 1H), 7.30-7.25 (m, 1H), 7.17-7.07 (m, 2H), 6.32-6.30 (s, 1H), 1.31 (s, 9H);MS(ES+)m / z341.2(M+1), 343.2(M+1).

[0224] Step 4. Preparation of tert-butyl N-[2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)-3-pyridyl]carbamate [ka] tert-Butyl N-[2-chloro-4-(2,5-difluorophenyl)-3-pyridyl]carbamate (1.5 g, 4.6 mmol) in 4,4-difluorocyclohexanecarboxylic acid (1.3 g, 7.9 mmol), (4,4''-di-t-butyl-2,2''-bipyridine)bis[3,5-difluoro-2-[5-trifluoromethyl-2-pyridinyl-kN)phenyl-kC]iridide To the reaction mixture was added ammonium(iii) hexafluorophosphate (0.052 g, 0.046 mmol), dichloro(dimethoxyethane)nickel (0.10 g, 0.46 mmol), 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (0.19 g, 0.70 mmol), cesium carbonate (2.7 g, 8.4 mmol), and N,N-dimethylformamide (77 ml). The vial was sealed and the reaction mixture was stirred in front of a Kessil PR160L light (440 nm) for 24 hours. The reaction mixture was diluted with ethyl acetate (250 ml) and washed with saturated ammonium chloride solution (2×50 ml), water (50 ml), and brine (50 ml). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Purification of the residue by column chromatography eluting with 0-40% ethyl acetate in heptane provided the title compound as a yellow solid (0.98 g, 52% yield): MS (ES+) m / z 425.4 (M+1).

[0225] Step 5. Preparation of 2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)pyridin-3-amine [ka] To tert-butyl N-[2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)-3-pyridyl]carbamate (0.98 g, 2.4 mmol) was added a 4 M solution of hydrochloric acid in 1,4-dioxane (10 ml). The reaction mixture was stirred for 18 hours. The reaction mixture was diluted with ethyl acetate (100 ml), washed with saturated sodium bicarbonate (2×50 ml), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The resulting solid was used without further purification (0.84 g, 100% yield): 1 H-NMR (400 MHz; CDCl 3 ) δ 8.10 (d, J = 4.9 Hz, 1H), 7.23-7.18 (m, 1H), 7.16-7.07 (m, 2H), 6.93 (d, J = 4.9 Hz, 1H), 3.70-3.66 (m, 2H), 2.83-2.76 (m, MS(ES+)m / z325.2(M+1).

[0226] Step 6. Preparation of N-[2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)-3-pyridyl]-2-isopropyl-pyrimidine-5-carboxamide [ka] To a mixture of 2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)pyridin-3-amine (0.100 g, 0.31 mmol), 2-isopropylpyrimidine-5-carboxylic acid (0.077 g, 0.46 mmol) and 2-chloro-1-methylpyridinium iodide (0.20 g, 0.77 mmol) was added anhydrous tetrahydrofuran (6.2 ml). The solution was heated at 65° C. for 1 minute and then N-ethyl-N-isopropylpropan-2-amine (0.40 g, 3.1 mmol) was added. The reaction mixture was stirred at 65° C. for 3 hours. The reaction mixture was cooled to ambient temperature and diluted with methanol (5 ml) and 10 M sodium hydroxide (2 ml). The mixture was stirred at ambient temperature for 30 minutes and then it was diluted with ethyl acetate (150 ml). The organic layer was washed with saturated ammonium chloride solution (2×50 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Purification of the residue by reverse phase column chromatography eluting with 5-95% acetonitrile in water with 0.5% formic acid, followed by suspension in diethyl ether (10 ml) and filtration afforded the title compound as a colorless solid (0.019 g, 13% yield): 1 H-NMR (400 MHz; DMSO-d 6 ) δ 10.36 (s, 1H), 8.97 (s, 2H), 8.63 (d, J = 4.9 Hz, 1H), 7.39-7.34 (m, 2H), 7.30-7.23 (m, 2H), 3.24-3.17 (m, 2H), 2.10-1.82 (m, 8H), 1.29 (d, J = 6.9 Hz, 6H); MS(ES+)m / z473.2(M+1).

[0227] Example 7 Synthesis of N-[2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)-3-pyridyl]-2-isopropoxy-pyrimidine-5-carboxamide [ka] To a mixture of 2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)pyridin-3-amine (0.27 g, 0.31 mmol), 2-chloropyrimidine-5-carboxylic acid (0.20 g, 1.2 mmol) and 2-chloro-1-methylpyridinium iodide (0.53 g, 2.1 mmol) was added anhydrous tetrahydrofuran (17 ml). The solution was heated at 65° C. for 1 min and then N-ethyl-N-isopropylpropan-2-amine (1.1 g, 8.3 mmol) was added. The reaction mixture was stirred at 65° C. for 3 h. The reaction mixture was cooled to ambient temperature and then diluted with ethyl acetate (100 ml). The organic layer was washed with saturated ammonium chloride solution (2×50 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with 0-25% methanol in ethyl acetate. The solid was dissolved in isopropanol (15 ml) and N,N-dimethylformamide. To the solution was added a 60% suspension of sodium hydride in mineral oil (0.32 g, 8.3 mmol). The reaction mixture was heated to 50° C. for 2 h. After cooling to ambient temperature, the reaction mixture was diluted with ethyl acetate (150 ml), washed with saturated ammonium chloride (2×50 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Purification of the residue by preparative HPLC eluting with a gradient of 5-95% acetonitrile in water containing 0.5% formic acid provided the title compound as a colorless solid, which was triturated with diethyl ether (10 ml) and filtered (0.055 g, 13% yield): 1 H-NMR (400 MHz; DMSO-d 6) δ 10.20 (s, 1H), 8.87 (d, J = 2.6 Hz, 2H), 8.62 (d, J = 4.9 Hz, 1H), 7.38-7.37 (m, 1H), 7.33 (dd, J = 9.2, 4.6 Hz, 1H), 7.30-7.21 (m, 2H), 5.27 (quintet, J = 6.2 Hz, 1H), 3.21-3.17 (m, 1H), 2.12-2.06 (m, 2H), 1.99-1.83 (m, 6H), 1.34 (d, J = 6.2 Hz, 6H);MS(ES+)m / z489.2(M+1).

[0228] Example 8 Synthesis of N-[2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)-3-pyridyl]-6-methoxy-pyridine-3-carboxamide [ka] Step 1. Preparation of 6-chloro-N-[2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)-3-pyridyl]pyridine-3-carboxamide [ka] To a mixture of 2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)pyridin-3-amine (0.25 g, 0.77 mmol), 6-chloronicotinic acid (0.18 g, 1.2 mmol) and 2-chloro-1-methylpyridinium iodide (0.49 g, 1.9 mmol) was added anhydrous tetrahydrofuran (15 ml). The solution was heated at 55° C. for 1 minute and then N-ethyl-N-isopropylpropan-2-amine (1.0 g, 7.7 mmol) was added. The reaction mixture was stirred at 55° C. for 3 hours. The reaction mixture was cooled to ambient temperature and diluted with methanol (5 ml) and 10 M sodium hydroxide (2 ml). The mixture was stirred for 18 hours. The reaction was diluted with ethyl acetate (100 ml), washed with saturated ammonium chloride (2×20 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Purification of the residue by column chromatography eluting with a gradient of 10 to 90% ethyl acetate in heptane afforded the title compound as a colorless solid (0.18 g, 50% yield): 1 H-NMR (400 MHz; DMSO-d 6 ) δ 8.72-8.70 (m, 1H), 8.68-8.66 (m, 1H), 8.06-8.02 (m, 1H), 7.55-7.53 (m, 1H), 7.48-7.45 (m, 1H), 7.24-7.22 (m, 1H), 7.17-7.07 (m, 3H), 3.04-2.97 (m, 1H), 2.30-2.12 (m, 4H), 1.99-1.93 (m, 2H), 1.88-1.71 (m, 2H);MS(ES+)m / z464.4(M+1), 466.2(M+1).

[0229] Step 2. Preparation of N-[2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)-3-pyridyl]-6-methoxy-pyridine-3-carboxamide [ka] To a mixture of 6-chloro-N-[2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)-3-pyridyl]pyridine-3-carboxamide (0.090 g, 0.19 mmol) in anhydrous methanol (4.0 ml) was added a 60% dispersion of sodium hydride in mineral oil (0.021 g, 0.57 mmol). The solution was heated at 100° C. for 24 hours. The reaction mixture was cooled to ambient temperature and diluted with ethyl acetate (100 ml). The organic layer was washed with saturated ammonium chloride (2×50 ml), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Purification of the residue by column chromatography eluting with 10-90% ethyl acetate in heptane followed by preparative HPLC eluting with a gradient of 10-90% acetonitrile in water containing 0.5% formic acid provided the title compound as a colorless solid, which was purified from a 10:1 mixture of water and acetonitrile (0.009 g, 10% yield): 1 H-NMR (400 MHz; DMSO-d 6 ) δ 10.06 (s, 1H), 8.61 (d, J = 4.9 Hz, 1H), 8.57 (d, J = 2.2 Hz, 1H), 8.00 (dd, J = 8.7, 2.5 Hz, 1H), 7.36 (d, J = 4.8 Hz, 1H), 7.33 (td, J = 9.1, 4.6 Hz, 1H), 7.24 (tdd, J = 11.1, 7.6, 3.4 Hz, 2H), 6.90 (d, J = 8.7 Hz, 1H), 3.91 (s, 3H), 3.20-3.15 (m, 1H), 2.11-2.08 (m, 2H), 1.97-1.86 (m, 6H); MS(ES+) m / z 460.2(M+1).

[0230] Example 9 Synthesis of N-[4-(2,5-difluorophenyl)-2-(5,5-difluorotetrahydropyran-2-yl)-3-pyridyl]-2-isopropyl-pyrimidine-5-carboxamide [ka] Step 1. Preparation of tert-butyl N-[4-(2,5-difluorophenyl)-2-(5,5-difluorotetrahydropyran-2-yl)-3-pyridyl]carbamate [ka] tert-Butyl N-[2-chloro-4-(2,5-difluorophenyl)-3-pyridyl]carbamate (0.69 g, 2.0 mmol) in 4,4-difluorocyclohexanecarboxylic acid (0.33 g, 2.0 mmol), (4,4''-di-t-butyl-2,2''-bipyridine)bis[3,5-difluoro-2-[5-trifluoromethyl-2-pyridinyl-kN)phenyl-kC]iridide To the reaction mixture was added ammonium(iii) hexafluorophosphate (0.017 g, 0.015 mmol), dichloro(dimethoxyethane)nickel (0.034 g, 0.15 mmol), 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (0.062 g, 0.23 mmol), cesium carbonate (0.71 g, 2.2 mmol), and N,N-dimethylformamide (26 ml). The headspace of the vial was replaced with nitrogen, the vial was sealed, and the reaction mixture was stirred in front of a Kessil PR160L light (440 nm) for 24 hours. The reaction mixture was diluted with ethyl acetate (250 ml), washed with saturated ammonium chloride solution (2×50 ml), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Purification of the residue by column chromatography eluting with 0-50% ethyl acetate in heptane provided the title compound as a yellow oil (0.43 g, 65% yield): MS (ES+) m / z 427.2 (M+1).

[0231] Step 2. Preparation of 4-(2,5-difluorophenyl)-2-(5,5-difluorotetrahydropyran-2-yl)pyridin-3-amine [ka] To tert-butyl N-[4-(2,5-difluorophenyl)-2-(5,5-difluorotetrahydropyran-2-yl)-3-pyridyl]carbamate (0.43 g, 1.0 mmol) was added a 4 M solution of hydrochloric acid in 1,4-dioxane (10 ml). The reaction mixture was stirred for 3 hours. The reaction mixture was diluted with ethyl acetate (100 ml), washed with saturated sodium bicarbonate (2×50 ml), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The resulting brown oil was used without further purification (0.36 g, 100% yield): 1 H-NMR (400 MHz; CDCl 3 ) δ 7.85 (d, J = 4.8 Hz, 1H), 7.43-7.31 (m, 2H), 7.25 (ddd, J = 8.8, 5.6, 3.1 Hz, 1H), 7.01 (d, J = 4.8 Hz, 1H), 4.97 (s, 2H), 4.81 (dd, J = 10.6, 1.9 Hz, 1H), 4.00-3.90 (m, 2H), 2.41-2.13 (m, 3H), 2.02-1.97 (m, 1H); MS(ES+)m / z327.2(M+1).

[0232] Step 3. Preparation of N-[4-(2,5-difluorophenyl)-2-(5,5-difluorotetrahydropyran-2-yl)-3-pyridyl]-2-isopropyl-pyrimidine-5-carboxamide [ka] To a mixture of 4-(2,5-difluorophenyl)-2-(5,5-difluorotetrahydropyran-2-yl)pyridin-3-amine (0.065 g, 0.20 mmol), 2-isopropylpyrimidine-5-carboxylic acid (0.043 g, 0.26 mmol) and 2-chloro-1-methylpyridinium iodide (0.13 g, 0.51 mmol) was added anhydrous tetrahydrofuran (3.3 ml). The solution was heated at 60° C. for 1 minute and then N-ethyl-N-isopropylpropan-2-amine (0.26 g, 2.0 mmol) was added. The reaction mixture was stirred at 60° C. for 3 hours. The reaction mixture was cooled to ambient temperature and diluted with methanol (3 ml) and 10 M sodium hydroxide (2 ml). The mixture was stirred at ambient temperature for 20 minutes and then it was diluted with ethyl acetate (100 ml). The organic layer was washed with saturated ammonium chloride solution (2×50 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Purification of the residue by column chromatography eluting with 10-100% ethyl acetate in heptane afforded the title compound as a colorless solid (0.042 g, 44% yield): 1 H-NMR (400 MHz; DMSO-d 6 ) δ 10.39 (s, 1H), 8.98 (s, 2H), 8.68 (d, J = 4.9 Hz, 1H), 7.54-7.53 (m, 1H), 7.40-7.34 (m, 1H), 7.32-7.26 (m, 2H), 4.95-4.92 (m, 1H), 3.94-3.89 (m, 1H), 3.86-3.74 (m, 1H), 3.20 (dt, J = 13.8, 6.9 Hz, 1H), 2.33-2.21 (m, 3H), 1.98-1.95 (m, 1H), 1.29 (d, J = 6.9 Hz, 6H); MS(ES+) m / z 475.2(M+1).

[0233] Example 10 Synthesis of 2-isopropyl-N-(4-phenyl-2-(tetrahydro-2H-pyran-4-yl)pyridin-3-yl)pyrimidine-5-carboxamide [ka] Step 1. Preparation of 2-chloro-3-nitro-4-phenylpyridine [ka] A mixture of 2,4-dichloro-3-nitropyridine (3.00 g, 15.5 mmol) in dioxane (100 ml) and water (10 ml) was degassed with nitrogen for 10 minutes. To the reaction mixture was added phenylboronic acid (1.90 g, 15.5 mmol), dichloro 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloromethane (1.32 g, 1.55 mmol), and potassium carbonate (3.22 g, 23.3 mmol). The reaction was stirred at 60° C. for 4 hours. After cooling to ambient temperature, the mixture was filtered through a bed of diatomaceous earth (i.e., Celite®) and diluted with ethyl acetate (150 ml). The combined filtrate was washed with saturated ammonium chloride (3×100 ml), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography eluting with a gradient of 5-45% ethyl acetate in heptane to provide the title compound as a colorless solid (2.95 g, 81% yield): MS (ES+) m / z 235.0 (M+1).

[0234] Step 2. Preparation of 2-chloro-4-phenylpyridin-3-amine [ka] To a mixture of 2-chloro-3-nitro-4-phenylpyridine (6.00 g, 25.6 mmol) in ethanol (51 ml) and water (51 ml) was added ammonium chloride (13.7 g, 256 mmol) and iron (7.14 g, 128 mmol). The reaction was stirred at 80° C. for 1.5 hours. After cooling to ambient temperature, the mixture was diluted in ethyl acetate (600 ml) and filtered through a bed of diatomaceous earth (i.e., Celite®). The filtrate was washed with saturated sodium bicarbonate (2×200 ml), brine (200 ml), dried over magnesium sulfate, filtered, and concentrated in vacuo to provide the title compound as a colorless solid (5.30 g, 101% yield): MS (ES+) m / z 206.0 (M+1), 208.0 (M+1).

[0235] Step 3. Preparation of N-(2-chloro-4-phenylpyridin-3-yl)-2-isopropylpyrimidine-5-carboxamide [ka] To a mixture of 2-chloro-4-phenylpyridin-3-amine (2.50 g, 12.2 mmol) in anhydrous tetrahydrofuran (61 ml) and pyridine (9.80 ml, 122 mmol) was added 2-chloro-1-methylpyridinium iodide (9.36 g, 36.6 mmol) and 2-isopropylpyrimidine-5-carboxylic acid (2.23 g, 13.4 mmol). The reaction was stirred at 65° C. for 2 days. After cooling to ambient temperature, the mixture was diluted with saturated ammonium chloride (100 ml) and extracted with ethyl acetate (2×200 ml). The combined organic phases were washed with saturated ammonium chloride (100 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with a gradient of 0-75% ethyl acetate in heptane to provide the title compound as a yellow solid (2.85 g, 66% yield): 1 H NMR (300 MHz, CDCl 3) δ 8.96 (s, 2H), 8.41 (d, J = 5.0 Hz, 1H), 7.58 (s, 1H), 7.41 (s, 5H), 7.32 (d, J = 5.0 Hz, 1H), 3.27 (sept, J = 6.8 Hz, 1H), 1.35 (d, J = 6.9 Hz, 6H); MS(ES+)m / z353.0(M+1), 355.0(M+1).

[0236] Step 4. N-(2-(3,6-dihydro-2H-pyran-4-yl)-4-phenylpyridin-3-yl)-2-isopropylpyrimidine-5-carboxamide [ka] A mixture of N-(2-chloro-4-phenylpyridin-3-yl)-2-isopropylpyrimidine-5-carboxamide (0.300 g, 0.850 mmol) in dioxane (8.5 ml) and water (2.1 ml) was degassed with nitrogen for 10 minutes. To the reaction mixture was added tripotassium phosphate (1.26 g, 5.95 mmol), 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (0.536 g, 2.55 mmol), palladium(II) acetate (0.057 g, 0.26 mmol), and tricyclohexylphosphine tetrafluoroborate (0.188 g, 0.510 mmol). The reaction was stirred at 110° C. for 20 hours. After cooling to ambient temperature, the mixture was filtered through a bed of diatomaceous earth (i.e., Celite®) and the filter pad was washed with ethyl acetate (2×100 ml). The combined filtrates were washed with saturated ammonium chloride (2×75 ml) and concentrated in vacuo. The residue was purified by column chromatography eluting with a gradient of 40-100% ethyl acetate in heptane to provide the title compound as a colorless solid (0.325 g, 95% yield): 1 H NMR (300 MHz, CDCl 3) δ 10.30 (s, 1H), 8.94 (s, 2H), 8.60 (d, J = 4.9 Hz, 1H), 7.48-7.36 (m, 6H), 6.08 (dt, J = 2.8, 1.3 Hz, 1H), 4.08-4.07 (m, 2H), 3.76 (t, J = 5.4 Hz, 2H), 3.18 (sept, J = 6.9 Hz, 1H), 2.49-2.45 (m, 2H), 1.28 (d, J = 6.9 Hz, 6H);MS(ES+)m / z401.2(M+1).

[0237] Step 5. 2-Isopropyl-N-(4-phenyl-2-(tetrahydro-2H-pyran-4-yl)pyridin-3-yl)pyrimidine-5-carboxamide [ka] To a mixture of N-(2-(3,6-dihydro-2H-pyran-4-yl)-4-phenylpyridin-3-yl)-2-isopropylpyrimidine-5-carboxamide (0.078 g, 0.19 mmol) in methanol (1.0 ml) and ethyl acetate (1.0 ml) was added ammonium formate (0.123 g, 1.95 mmol) and 10% palladium on carbon (0.021 g). The reaction was stirred at 65° C. for 30 minutes. After cooling to ambient temperature, the mixture was diluted with ethyl acetate (50 ml), filtered through a bed of diatomaceous earth (i.e., Celite®), and the filtrate was concentrated in vacuo. The residue was purified by column chromatography eluting with a gradient of 50-100% ethyl acetate in heptane to provide the title compound as a colorless solid (0.037 g, 47% yield): 1 H NMR (300 MHz, DMSO-d 6) δ 10.31 (s, 1H), 8.99 (s, 2H), 8.61 (d, J = 4.9 Hz, 1H), 7.48-7.35 (m, 5H), 7.32 (d, J = 4.9 Hz, 1H), 3.92 (dd, J = 11.1, 3.9 Hz, 2H), 3.39 (t, J = 11.6 Hz, 2H), 3.27-3.15 (m, 2H), 1.90 (qd, J = 12.3, 4.1 Hz, 2H), 1.62 (d, J = 12.5 Hz, 2H), 1.28 (d, J = 6.9 Hz, 6H);MS(ES+)m / z403.2(M+1).

[0238] Example 11 Synthesis of (±)-2-isopropyl-N-(4-phenyl-2-(tetrahydrofuran-2-yl)pyridin-3-yl)pyrimidine-5-carboxamide [ka] Step 1. Preparation of 2-(furan-2-yl)-3-nitro-4-phenylpyridine [ka] A mixture of 2-chloro-3-nitro-4-phenylpyridine (0.500 g, 2.13 mmol) in dioxane (11 ml) and water (3.6 ml) was degassed with nitrogen for 10 minutes. To the reaction mixture was added potassium carbonate (0.442 g, 3.20 mmol), 2-furan boronic acid (0.715 g, 2.55 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloromethane (0.183 g, 0.213 mmol). The reaction was stirred at 100°C for 18 hours. After cooling to ambient temperature, the mixture was filtered through a bed of diatomaceous earth (i.e., Celite®) and the filter pad was washed with ethyl acetate (2 x 100 ml). The combined filtrate was washed with saturated ammonium chloride (2 x 75 ml), dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography eluting with a gradient of 0-30% ethyl acetate in heptane to provide the title compound as a yellow solid (0.540 g, 95% yield): MS (ES+) m / z 267.0 (M+1).

[0239] Step 2. Preparation of 2-(furan-2-yl)-4-phenylpyridin-3-amine [ka] To a mixture of 2-(furan-2-yl)-3-nitro-4-phenylpyridine (0.540 g, 2.03 mmol) in methanol (10.0 ml) and ethyl acetate (10.0 ml) was added ammonium formate (2.56 g, 40.6 mmol) and 10% palladium on carbon (0.108 g). The reaction was stirred at 65° C. for 1.5 hours. After cooling to ambient temperature, the mixture was diluted in ethyl acetate (300 ml) and filtered through a bed of diatomaceous earth (i.e., Celite®). The filtrate was washed with saturated sodium bicarbonate (2×100 ml), dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography eluting with a gradient of 5-100% ethyl acetate in heptane to provide the title compound as a red oil (0.392 g, 82% yield): MS (ES+) m / z 237.2 (M+1).

[0240] Step 3. Preparation of (±)-4-phenyl-2-(tetrahydrofuran-2-yl)pyridin-3-amine [ka] To a mixture of 2-(furan-2-yl)-4-phenylpyridin-3-amine (0.392 g, 1.66 mmol) in methanol (15.0 ml) was added 10% palladium on carbon (0.160 g) and formic acid (0.60 ml, 20 mmol). The reaction mixture was stirred under 50 psi of hydrogen for 3.5 hours. The mixture was diluted with ethyl acetate (150 ml) and filtered through a bed of diatomaceous earth (i.e., Celite®). The filtrate was washed with saturated sodium bicarbonate (2×50 ml), dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography eluting with a gradient of 5-60% ethyl acetate in heptane to provide the title compound as a yellow oil (0.218 g, 55% yield): MS (ES+) m / z 241.0 (M+1).

[0241] Step 4. Preparation of (±)-2-isopropyl-N-(4-phenyl-2-(tetrahydrofuran-2-yl)pyridin-3-yl)pyrimidine-5-carboxamide [ka] To a mixture of 4-phenyl-2-(tetrahydrofuran-2-yl)pyridin-3-amine (0.063 g, 0.26 mmol) in tetrahydrofuran (2.6 ml) was added N,N-diisopropylethylamine (0.46 ml, 2.6 mmol), 2-chloro-1-methylpyridinium iodide (0.201 g, 0.787 mmol), 2-isopropylpyrimidine-5-carboxylic acid (0.052 g, 0.31 mmol). The reaction was stirred at 65° C. for 18 hours. After cooling to ambient temperature, the mixture was diluted in ethyl acetate (100 ml), washed with saturated ammonium chloride (3×25 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with a gradient of 5-100% ethyl acetate in heptane to provide the title compound as a colorless solid (0.056 g, 55% yield): 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.37 (s, 1H), 9.01 (s, 2H), 8.61 (d, J = 4.9 Hz, 1H), 7.49-7.33 (m, 6H), 5.17 (t, J = 6.8 Hz, 1H), 3.94 (q, J = 7.3 Hz, 1H), 3.78 (td, J = 7.6, 5.5 Hz, 1H), 3.19 (sept, J = 6.9 Hz, 1H), 2.24-1.97 (m, 3H), 1.94-1.82 (m, 1H), 1.27 (d, J = 6.9 Hz, 6H);MS(ES+)m / z389.2(M+1).

[0242] Example 12 Synthesis of (±)-N-(2-(3-oxabicyclo[4.1.0]heptan-6-yl)-4-phenylpyridin-3-yl)-2-isopropylpyrimidine-5-carboxamide [ka] Step 1. Preparation of (±)-2-(3-oxabicyclo[4.1.0]heptan-6-yl)-3-nitro-4-phenylpyridine [ka] A mixture of 2-chloro-3-nitro-4-phenylpyridine (0.200 g, 0.852 mmol), cesium carbonate (0.555 g, 1.70 mmol), and (3-oxabicyclo[4.1.0]heptan-6-yl)trifluoroborate potassium salt (0.209 g, 1.02 mmol) in toluene (2.1 ml) and water (0.21 ml) was degassed with nitrogen for 10 min (Note: BF according to the literature procedure described in J. Med. Chem. 2019, 62, 6972). 3 K salt was synthesized). To the reaction mixture was added 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloromethane (0.073 g, 0.085 mmol) and the reaction was stirred at 110 °C for 18 h. After cooling to ambient temperature, the mixture was filtered through a bed of diatomaceous earth (i.e., Celite®) and the filter pad was washed with ethyl acetate (2 x 75 ml). The combined filtrates were washed with saturated ammonium chloride (2 x 50 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with a gradient of 0-30% ethyl acetate in heptane to provide the title compound as a yellow oil (0.062 g, 25% yield): MS (ES+) m / z 297.0 (M+1).

[0243] Step 2. Preparation of (±)-2-(3-oxabicyclo[4.1.0]heptan-6-yl)-4-phenylpyridin-3-amine [ka] A mixture of 2-(3-oxabicyclo[4.1.0]heptan-6-yl)-3-nitro-4-phenylpyridine (0.062 g, 0.21 mmol) in methanol (2.1 ml) and ethyl acetate (2.1 ml) was flushed with hydrogen for 10 minutes. To the reaction mixture was added 10% palladium on carbon (0.050 g). The reaction was stirred at ambient temperature for 30 minutes. The mixture was diluted with ethyl acetate (50 ml), filtered through a bed of diatomaceous earth (i.e., Celite®), and concentrated in vacuo to provide a colorless oil, which was used in the next step without further purification: MS (ES+) m / z 267.2 (M+1).

[0244] Step 3. Preparation of (±)-N-(2-(3-oxabicyclo[4.1.0]heptan-6-yl)-4-phenylpyridin-3-yl)-2-isopropylpyrimidine-5-carboxamide [ka] To a mixture of 2-(3-oxabicyclo[4.1.0]heptan-6-yl)-4-phenylpyridin-3-amine in anhydrous tetrahydrofuran (4.2 ml) was added N,N-diisopropylethylamine (0.37 ml, 2.1 mmol), 2-chloro-1-methylpyridinium iodide (0.161 g, 0.629 mmol), 2-isopropylpyrimidine-5-carboxylic acid (0.042 g, 0.25 mmol). The reaction was stirred at 65° C. for 1 h. After cooling to ambient temperature, the mixture was diluted in ethyl acetate (100 ml), washed with saturated ammonium chloride (2×25 ml), dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography eluting with a gradient of 20–100% ethyl acetate in heptane to provide a colorless solid. Further purification of the residue by reverse-phase column chromatography using a gradient of 10 to 75% acetonitrile in water containing 0.5% formic acid as eluent afforded the title compound as a colorless solid (0.019 g, 22% yield (over two steps)): 1 H NMR (300 MHz, DMSO-d 6) δ 10.28 (s, 1H), 9.03 (s, 2H), 8.51 (d, J = 4.9 Hz, 1H), 7.50-7.35 (m, 6H), 3.85-3.58 (m, 2H), 3.51-3.44 (m, 1H), 3.25-3.01 (m, 2H), 2.02-1.89 (m, 2H), 1.29 (d, J = 6.9 Hz, 6H), 0.87-0.72 (m, 2H); MS(ES+)m / z415.2(M+1).

[0245] Example 13 Synthesis of (±)-tert-butyl 2-(3-(2-isopropylpyrimidine-5-carboxamido)-4-phenylpyridin-2-yl)pyrrolidine-1-carboxylate [ka] N-(2-chloro-4-phenylpyridin-3-yl)-2-isopropylpyrimidine-5-carboxamide (0.142 g, 0.402 mmol), cesium carbonate (0.196 g, 1.70 mmol), nickel(II) chloride dimethoxyethane adduct (0.009 g, 0.04 mmol), 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (0.017 g, 0. To a mixture of (4,4''-di-tert-butyl-2,2''-bipyridine)bis[3,5-difluoro-2-[5-trifluoromethyl-2-pyridinyl-kN)phenyl-kC]iridium(iii) hexafluorophosphate (0.005 g, 0.004 mmol) and (4,4''-di-tert-butyl-2,2''-bipyridine)bis[3,5-difluoro-2-[5-trifluoromethyl-2-pyridinyl-kN)phenyl-kC]iridium(iii) hexafluorophosphate (0.005 g, 0.004 mmol) was added N,N-dimethylformamide (10 ml) and the headspace was flushed with nitrogen for 10 seconds. The vial was sealed and left in front of four Kessil PR160L lights (440 nm) for 18 hours. The reaction mixture was diluted with ethyl acetate (100 ml) and the organic phase was washed with saturated sodium bicarbonate (30 ml), water (3 x 30 ml), and brine (30 ml). The organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification of the residue by reverse-phase column chromatography using a gradient of 0 to 100% acetonitrile in water containing 0.5% formic acid as eluent afforded the title compound as a colorless solid (0.176 g, 90% yield): 1 H NMR (400 MHz, DMSO-d 6, rotamers exist) δ 10.52 (s, 0.4H), 10.20 (s, 0.5H), 9.02 (d, J = 1.3 Hz, 1H), 8.94 (d, J = 1.1 Hz, 1H), 8.55-8.53 (m, 1H), 7.49-7.33 (m, 6H), 5.18 (d, J = 7.5 Hz, 0.5H), 5.08 (d, J = 5.4 Hz, 0.5H), 3.59-3.52 (m, 1H), 3.45-3.37 (m, 1H), 3.19 (sept, J = 6.9 Hz, 1H), 2.33-2.14 (m, 1H), 1.98-1.75 (m, 3H), 1.37 (s, 4.5H), 1.28 (d, J = 6.9 Hz, 6H), 1.10 (s, 4.5H);MS(ES+)m / z488.2(M+1).

[0246] Example 14 Synthesis of N-(4-(2-fluorophenyl)-2-(tetrahydro-2H-pyran-4-yl)pyridin-3-yl)-2-isopropylpyrimidine-5-carboxamide [ka] Step 1. Preparation of 2-chloro-4-(2-fluorophenyl)pyridin-3-amine [ka] To a mixture of 2-chloro-4-(2-fluorophenyl)-3-nitro-pyridine (3.29 g, 13.0 mmol) in ethanol (26 ml) and water (26 ml) was added ammonium chloride (6.97 g, 130 mmol) and iron (5.46 g, 97.7 mmol). The reaction was stirred at 80° C. for 3 hours. After cooling to ambient temperature, the mixture was diluted in ethyl acetate (500 ml) and filtered through a bed of diatomaceous earth (i.e., Celite®). The filtrate was washed with saturated sodium bicarbonate (150 ml), water (150 ml), brine (150 ml), dried over magnesium sulfate, filtered, and concentrated in vacuo to provide the title compound as a colorless solid (1.97 g, 68% yield): MS (ES+) m / z 223.0 (M+1), 225.0 (M+1).

[0247] Step 2. Preparation of N-(2-chloro-4-(2-fluorophenyl)pyridin-3-yl)-2-isopropylpyrimidine-5-carboxamide [ka] To a mixture of 2-chloro-4-(2-fluorophenyl)pyridin-3-amine (1.00 g, 4.49 mmol) in anhydrous tetrahydrofuran (30 ml) and pyridine (3.6 ml, 45 mmol) was added 2-chloro-1-methylpyridinium iodide (3.44 g, 13.5 mmol) and 2-isopropylpyrimidine-5-carboxylic acid (0.821 g, 4.94 mmol). The reaction was stirred at 65° C. for 2 days. After cooling to ambient temperature, the mixture was diluted with saturated ammonium chloride (100 ml) and extracted with ethyl acetate (2×200 ml). The combined organic phases were washed with saturated ammonium chloride (100 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with a gradient of 10-75% ethyl acetate in heptane to provide the title compound as a yellow solid (1.700 g, 102% yield): 1 H NMR (400 MHz, CDCl 3) δ 8.94 (s, 2H), 8.45 (d, J = 5.0 Hz, 1H), 7.75 (s, 1H), 7.42-7.33 (m, 3H), 7.25-7.21 (m, 1H), 7.15 (dd, J = 10.3, 8.5 Hz, 1H), 3.27 (sept, J = 6.9 Hz, 1H), 1.35 (d, J = 6.9 Hz, 6H); 19 F NMR (400 MHz, CDCl 3 ) δ -114.9;MS(ES+)m / z371.0(M+1), 373.2(M+1).

[0248] Step 3. Preparation of N-(4-(2-fluorophenyl)-2-(tetrahydro-2H-pyran-4-yl)pyridin-3-yl)-2-isopropylpyrimidine-5-carboxamide [ka] N-(2-chloro-4-(2-fluorophenyl)pyridin-3-yl)-2-isopropylpyrimidine-5-carboxamide (0.100 g, 0.270 mmol), cesium carbonate (0.132 g, 0.405 mmol), nickel(II) chloride dimethoxyethane adduct (0.006 g, 0.03 mmol), 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (0 A mixture of (4,4''-di-tert-butyl-2,2''-bipyridine)bis[3,5-difluoro-2-[5-trifluoromethyl-2-pyridinyl-kN)phenyl-kC]iridium(iii) hexafluorophosphate (0.003 g, 0.003 mmol) was dissolved in N,N-dimethylformamide (6.7 ml) and flushed with nitrogen for 10 seconds. The vial was sealed and left in front of four Kessil PR160L lights (440 nm) for 4 hours. The reaction mixture was diluted with ethyl acetate (100 ml) and the organic phase was washed with saturated sodium bicarbonate (30 ml), water (3 x 30 ml), and brine (30 ml). The organic extract was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse phase column chromatography using a gradient of 0-100% acetonitrile in water containing 0.5% formic acid as eluent to afford a colorless solid. The residue was further purified by column chromatography using a gradient of 50-100% ethyl acetate in heptane as eluent to afford the title compound as a colorless solid (0.024 g, 21% yield): 1 H NMR (400 MHz, DMSO-d 6, rotamers exist) δ 10.32 (s, 1H), 8.92 (s, 2H), 8.63 (d, J = 4.9 Hz, 1H), 7.44-7.34 (m, 3H), 7.31-7.26 (m, 1H), 7.23 (td, J = 7.5, 0.9 Hz, 1H), 3.94-3.91 (m, 2H), 3.39 (t, J = 11.6 Hz, 2H), 3.30-3.15 (m, 2H), 1.97-1.86 (m, 2H), 1.63 (d, J = 12.1 Hz, 2H), 1.28 (d, J = 6.9 Hz, 6H); MS(ES+) m / z 421.2(M+1).

[0249] Examples 15 to 39 Example Error! Reference source not found. The following compounds were prepared in a similar manner to that described in step 3, utilizing appropriately substituted starting materials and intermediates: [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8] [Table 3-9] [Table 3-10] [Table 3-11] [Table 3-12] [Table 3-13] [Table 3-14] [Table 3-15] [Table 3-16]

[0250] Example 40 Preparation of 2-isopropyl-N-(4-phenyl-2-(pyrrolidin-2-yl)pyridin-3-yl)pyrimidine-5-carboxamide [ka] To a mixture of (±)-tert-butyl 2-(3-(2-isopropylpyrimidine-5-carboxamido)-4-phenylpyridin-2-yl)pyrrolidine-1-carboxylate (0.054 g, 0.11 mmol) in dichloromethane (0.4 ml) was added trifluoroacetic acid (0.20 ml, 2.6 mmol). The reaction mixture was stirred at ambient temperature for 1 h and the volatiles were removed in vacuo. The residue was purified by reverse phase column chromatography using a gradient of 0-100% acetonitrile in water containing 0.5% formic acid as eluent to provide the title compound as a colorless solid (0.027 g, 43% yield): 1 H NMR (400 MHz, DMSO-d 6) δ 9.04 (s, 2H), 8.63-8.62 (m, 1H), 8.32 (s, 1H), 7.50-7.35 (m, 6H), 4.68-4.64 (m, 1H), 3.27-3.13 (m, 2H), 3.01-2.95 (m, 1H), 1.88-1.73 (m, 4H), 1.28 (d, J = 6.7 Hz, 6H); MS(ES+)m / z388.2(M+1).

[0251] Example 41 Synthesis of (±)-N-[2-(4,4-difluoro-2-piperidyl)-4-(2-fluorophenyl)-3-pyridyl]-2-isopropyl-pyrimidine-5-carboxamide hydrochloride [ka] To a mixture of (±)-tert-butyl 4,4-difluoro-2-(4-(2-fluorophenyl)-3-(2-isopropylpyrimidine-5-carboxamido)pyridin-2-yl)piperidine-1-carboxylate (0.174 g, 0.312 mmol) in methanol (3.1 ml) was added hydrochloric acid (3.1 ml, 12 mmol, 4M in 1,4-dioxane). The reaction mixture was stirred at ambient temperature for 3 hours and concentrated in vacuo to provide the title compound as a colorless solid (0.142 g, 100% yield). Further purification of the title compound (0.020 g) by reverse phase column chromatography using a gradient of 5-100% acetonitrile in water containing 0.5% formic acid as eluent provided a colorless solid. The residue was redissolved in anhydrous 1,4-dioxane (0.3 ml) and hydrochloric acid (0.10 ml, 0.38 mmol, 4 M in dioxane) was added at ambient temperature. The mixture was stirred at ambient temperature for 5 minutes, diluted with diethyl ether (2 ml) and the mixture was filtered to give the title compound as a colorless solid (0.003 g): 1 H NMR (400 MHz, DMSO-d 6) δ 10.76 (s, 1H), 9.89-9.86 (m, 1H), 9.44 (q, J = 10.0 Hz, 1H), 9.07-8.99 (m, 2H), 8.81 (d, J = 5.0 Hz, 1H), 7.70 (dd, J = 5.0, 1.0 Hz, 1H), 7.51-7.41 (m, 2H), 7.37-7.27 (m, 2H), 4.90 (t, J = 10.4 Hz, 1H), 3.55-3.46 (m, 1H), 3.34-3.27 (m, 1H), 3.21 (sept, J = 6.9 Hz, 1H), 2.89-2.72 (m, 1H), 2.43-2.22 (m, 3H), 1.29 (d, J = 6.9 Hz, 6H); MS(ES+)m / z456.2(M+1).

[0252] Example 42 Synthesis of (±)-N-(4-(2-fluorophenyl)-2-(1-methylpyrrolidin-2-yl)pyridin-3-yl)-2-isopropylpyrimidine-5-carboxamide [ka] To a mixture of (±)-tert-butyl 2-(3-(2-isopropylpyrimidine-5-carboxamido)-4-phenylpyridin-2-yl)pyrrolidine-1-carboxylate (0.415 g, 0.938 mmol) in N,N-dimethylformamide (9.4 ml) at 0° C., triethylamine (0.82 ml, 4.7 mmol), iodomethane (0.49 ml, 1.126 mmol) were added and the reaction mixture was stirred at ambient temperature for 2 days. The mixture was diluted with ethyl acetate (150 ml), washed with saturated ammonium chloride (50 ml), water (3×50 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with a gradient of 30–100% ethyl acetate in heptane, followed by 0–25% methanol in ethyl acetate to provide a colourless solid (0.077 g, 19% yield): 1 H NMR (400 MHz, DMSO-d 6) δ 10.91 (s, 1H), 8.94 (s, 2H), 8.57 (d, J = 4.9 Hz, 1H), 7.44-7.35 (m, 3H), 7.29-7.18 (m, 2H), 3.71-3.67 (m, 1H), 3.24-3.09 (m, 2H), 2.31 (quintet, J = 8.3 Hz, 1H), 2.16-2.10 (m, 4H), 1.92-1.83 (m, 1H), 1.80-1.66 (m, 2H), 1.28 (d, J = 6.9 Hz, 6H);MS(ES+)m / z420.2(M+1).

[0253] Example 43 The following compounds were prepared in a manner similar to that described in Example 42, utilizing appropriately substituted starting materials and intermediates: [Table 4]

[0254] Example 44 Synthesis of 2-(2-(3,6-dihydro-2H-pyran-4-yl)-4-phenylpyridin-3-yl)-3,4,6,7-tetrahydropyrano[3,4-d]imidazole [ka] Step 1. Preparation of 2-chloro-4-phenylnicotinaldehyde [ka] To a mixture of 2-chloro-4-iodonicotinaldehyde (5.0 g, 18.7 mmol) in anhydrous dioxane (63 ml) and water (7 ml) was added phenylboronic acid (2.5 g, 21 mmol) and potassium carbonate (6.5 g, 47 mmol). The mixture was purged with nitrogen for 10 minutes. Dichloro[1,1'-bis(diphenyl-phosphino)ferrocene]palladium(II) dichloromethane adduct (1.5 g, 1.9 mmol) was then added to the mixture, and the reaction mixture was heated to 90°C for 3 hours. After cooling to ambient temperature, the reaction mixture was filtered through a bed of diatomaceous earth (i.e., Celite®) and the filtrate was concentrated under reduced pressure. Purification of the residue by column chromatography eluting with a gradient of 0-30% ethyl acetate in heptane provided the title compound as an off-white solid (4.0 g, 99% yield): 1 H-NMR (300 MHz; DMSO-d 6 ) δ 10.11 (s, 1H), 8.62 (d, J = 5.1 Hz, 1H), 7.57 (d, J = 5.1 Hz, 1H), 7.53-7.50 (m, 3H), 7.46-7.43 (m, 2H).

[0255] Step 2. Preparation of 2-(2-chloro-4-phenylpyridin-3-yl)-3,4,6,7-tetrahydropyrano[3,4-d]imidazole [ka] To a solution of 2-chloro-4-phenylnicotinaldehyde (0.60 g, 2.8 mmol), 3-bromooxan-4-one (0.74 g, 4.1 mmol) and concentrated ammonium hydroxide (0.65 ml, 4.1 mmol) in anhydrous N,N-dimethylformamide (5.6 ml) was added ammonium acetate (0.96 g, 12 mmol) portionwise. The reaction mixture was stirred at ambient temperature for 45 minutes and oxone (0.16 g, 2.7 mmol) was added to it. The reaction mixture was stirred at 65° C. for another 24 hours. After cooling to ambient temperature, the reaction mixture was diluted with ethyl acetate (30 ml) and extracted with water (30 ml×3). The combined organic layers were washed with brine (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by column chromatography eluting with a gradient of 20-100% ethyl acetate in heptane, followed by 0-10% methanol in dichloromethane afforded the title compound as a yellow solid (0.27 g, 31% yield): 1 H-NMR (300 MHz;MeOD): δ 8.46 (d, J = 5.2 Hz, 1H), 7.49 (d, J = 5.2 Hz, 1H), 7.31-7.28 (m, 3H), 7.19 (d, J = 1.8 Hz, 2H), 4.54 (t, J = 1.5 MS(ESI+)m / z=312.2(M+1);314.0(M+1).

[0256] Step 3. Preparation of 2-(2-(3,6-dihydro-2H-pyran-4-yl)-4-phenylpyridin-3-yl)-3,4,6,7-tetrahydropyrano[3,4-d]imidazole [ka] A mixture of 2-(2-chloro-4-phenylpyridin-3-yl)-3,4,6,7-tetrahydropyrano[3,4-d]imidazole (0.10 g, 0.32 mmol), 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (0.20 g, 0.96 mmol) and palladium(II) acetate (0.021 g, 0.096 mmol), tricyclohexylphosphine tetrafluoroborate (0.071 g, 0.19 mmol) and tripotassium phosphate (0.48 g, 2.2 mmol) in 1,4-dioxane (3.2 ml) was stirred for 15 minutes under nitrogen atmosphere. Water (0.80 ml) was added to the mixture, which was stirred at 110° C. for 12 hours. The mixture was filtered through diatomaceous earth (i.e., Celite®) and the filtrate was concentrated in vacuo. Purification by reverse phase preparative HPLC using 15-95% acetonitrile in water containing 0.5% formic acid as eluent provided the title compound (0.012 g, 12% yield): 1 H-NMR (300 MHz; DMSO-d 6 ): δ 8.65 (d, J = 5.0 Hz, 1H), 8.16 (s, 1H), 7.37 (d, J = 5.0 Hz, 1H), 7.31 (m, 3H), 7.19 (m, 2H), 5.61 (s, 1H), 4.44 (s, 2H), 4.01 (m, 2H), 3.82-3.78 (m, 2H), 3.66 (t, J = 5.3 Hz, 2H), 2.54 (m, 2H), 2.18 (m, 2H); MS(ESI+)m / z360.2(M+1).

[0257] Example 45 Synthesis of 2-(4-phenyl-2-(tetrahydro-2H-pyran-4-yl)pyridin-3-yl)-3,4,6,7-tetrahydropyrano[3,4-d]imidazole [ka] To a stirred solution of 2-(2-(3,6-dihydro-2H-pyran-4-yl)-4-phenylpyridin-3-yl)-3,4,6,7-tetrahydropyrano[3,4-d]imidazole (0.10 g, 0.28 mmol) in methanol (1.4 ml) and ethyl acetate (1.4 ml) under nitrogen atmosphere was added palladium on carbon (10%, wet support) (0.044 g, 0.42 mmol) and ammonium formate (0.63 g, 10 mmol). The reaction mixture was heated to 65° C. for 1 hour. To the mixture was added palladium on carbon (10%, wet support) (0.022 g, 0.21 mmol) and ammonium formate (0.32 g, 5 mmol). The mixture was stirred at 65° C. for 20 hours. After cooling to ambient temperature, the mixture was diluted with ethyl acetate (20 ml) and washed with water (2×25 ml). The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Purification of the residue by preparative reverse-phase HPLC using 15-95% acetonitrile in water containing 0.5% formic acid as eluent afforded the title compound as a colorless solid (0.0055 g, 5.4% yield). 1 H-NMR (300 MHz; DMSO-d 6 ): δ 11.66 (s,1H), 8.66 (d, J = 5.1 Hz, 1H), 7.33 (d, J = 5.1 Hz, 1H), 7.32-7.29 (m, 3H), 7.20-7.15 (m, 2H), 4.50 (s, 2H), 3.91-3.85 (m, 2H), 3.83-3.80 (m, 2H), 2.96-2.75 (m, 2H), 2.03-1.83 (m, 3H), 1.62-1.56 (m, 2H), 1.29-1.17 (m, 2H);MS(ESI+)m / z362.2(M+1).

[0258] Example 46 Synthesis of 2-(2-(4,4-difluorocyclohexyl)-4-phenylpyridin-3-yl)-3,4,6,7-tetrahydropyrano[3,4-d]imidazole [ka] (4,4''-di-t-butyl-2,2''-bipyridine)bis[3,5-difluoro-2-[5-trifluoromethyl-2-pyridinyl-N)phenyl-C]iridium(iii) hexafluorophosphate (2.9 mg, 0.0026 mmol), NiCl 2 To a mixture of glyme (5.6 mg, 0.026 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (10.3 mg, 0.039 mmol), 2-(2-chloro-4-phenylpyridin-3-yl)-3,4,6,7-tetrahydropyrano[3,4-d]imidazole (0.080 g, 0.26 mmol), cesium carbonate (0.13 g, 0.39 mmol) and 4,4-difluorocyclohexanecarboxylic acid (0.064 g, 0.39 mmol, 1.5 equiv.) was added N,N-dimethylformamide (5.8 ml). The mixture was purged with nitrogen for 10 seconds and sealed. The reaction mixture was then stirred in front of a Kessil PR160L light (440 nm) for 20 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (10 ml) and extracted with ethyl acetate (3×10 ml). The combined organic extracts were washed with water (3×25 ml) and brine (50 ml), dried over anhydrous sodium sulfate, and concentrated in vacuo. Purification of the residue by preparative reverse-phase HPLC using 5-50% acetonitrile in water containing 0.5% formic acid as eluent afforded the title compound as a colorless solid (0.012 g, 12% yield). 1 H-NMR (400 MHz; DMSO-d 6 ) δ 11.60 (s, 1H), 8.65 (d, J = 5.0 Hz, 1H), 7.35 (d, J = 5.0 Hz, 1H), 7.31 (m, 3H), 7.18-7.16 (m, 2H), 4.52-4.45 (m, 2H), 3.82 (s, 2H), 2.78-2.70 (m, 1H), 2.11-1.63 (m, 9H). MS(ESI+)m / z396.2(M+1).

[0259] Example 47 Synthesis of 2-(2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)pyridin-3-yl)-3,4,6,7-tetrahydropyrano[3,4-d]imidazole [ka] Step 1: Preparation of 2-chloro-4-(2,5-difluorophenyl)nicotinaldehyde [ka] To a solution of 2,5-difluorophenylboronic acid (3.3 g, 21 mmol), 2-chloro-4-iodonicotinaldehyde (5.0 g, 19 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (1.6 g, 1.9 mmol) in 1,4-dioxane (67 ml) was added potassium carbonate (7.8 g, 56 mmol) and purged with nitrogen for 5 minutes. To this was added water (7.5 ml) and the mixture was stirred at 90° C. for 3 hours. After cooling to ambient temperature, the reaction mixture was filtered through a bed of diatomaceous earth (i.e., Celite®) and the filtrate was concentrated under reduced pressure. Purification of the residue by column chromatography eluting with a gradient of 0-40% ethyl acetate in heptane afforded the title compound as an off-white solid (4.2 g, 87% yield): MS (ESI+) m / z 254.0 (M+1) 256.0 (M+1).

[0260] Step 2. Preparation of 2-(2-chloro-4-(2,5-difluorophenyl)pyridin-3-yl)-3,4,6,7-tetrahydropyrano[3,4-d]imidazole [ka] To a solution of 2-chloro-4-(2,5-difluorophenyl)nicotinaldehyde (0.30 g, 1.2 mmol), 3-bromooxan-4-one (0.42 g, 2.4 mmol) and concentrated ammonium hydroxide (0.64 ml, 16 mmol) in anhydrous N,N-dimethylformamide (2.4 ml) was added ammonium acetate (0.41 g, 5.3 mmol). The reaction mixture was stirred at ambient temperature for 45 minutes and then oxone (0.36 g, 0.59 mmol) was added to it. The reaction mixture was stirred at 65° C. for another 12 hours. After cooling to ambient temperature, the reaction mixture was diluted with ethyl acetate (20 ml) and washed with water (20 ml×3). The combined organic layers were washed with brine (40 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by column chromatography eluting with a gradient of 55 to 100% ethyl acetate in heptane afforded the title compound as a yellow solid (0.20 g, 49% yield): MS (ESI+) m / z = 348.0 (M+1), 350.2 (M+1).

[0261] Step 3. Preparation of 2-(2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)pyridin-3-yl)-3,4,6,7-tetrahydropyrano[3,4-d]imidazole [ka] (4,4''-di-t-butyl-2,2''-bipyridine)bis[3,5-difluoro-2-[5-trifluoromethyl-2-pyridinyl-N)phenyl-C]iridium(iii) hexafluorophosphate (2.9 mg, 0.0026 mmol), NiCl 2To a mixture of glyme (5.6 mg, 0.026 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (10.3 mg, 0.039 mmol), 2-(2-chloro-4-phenylpyridin-3-yl)-3,4,6,7-tetrahydropyrano[3,4-d]imidazole (0.080 g, 0.26 mmol), cesium carbonate (0.13 g, 0.39 mmol), and 4,4-difluorocyclohexanecarboxylic acid (0.056 g, 0.35 mmol) was added N,N-dimethylformamide (5.8 ml). The reaction mixture was purged with nitrogen for 10 seconds and sealed with a cap. The reaction mixture was stirred in front of a Kessil PR160L light (440 nm) for 20 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (10 ml) and extracted with ethyl acetate (3 x 10 ml). The combined organic extracts were washed with water (3×25 ml) and brine (50 ml), dried over anhydrous sodium sulfate, and concentrated in vacuo. Purification of the residue by preparative reverse-phase HPLC using 5-50% acetonitrile in water containing 0.5% formic acid as eluent provided the title compound as a colorless solid (0.0023 g, 2.2% yield); 1 H-NMR (400 MHz;MeOD) δ 8.69 (d, J = 4.6 Hz, 1H), 8.39 (s, 1H), 7.37 (d, J = 4.2 Hz, 1H), 7.12-7.10 (m, 2H), 6.93-6.90 (m, 1H), 4.59 (s, 2H), 3.94-3.93 (m, 2H), 2.66 (dd, J = 3.8, 0.7 Hz, 2H), 2.14-2.02 (m, 4H), 1.90-1.85 (m, 2H), 1.81-1.65 (m, 3H);MS(ESI+)m / z432.2(M+1).

[0262] Example 48 Synthesis of 2-(2-(3,3-difluorocyclopentyl)-4-(2,5-difluorophenyl)pyridin-3-yl)-3,4,6,7-tetrahydropyrano[3,4-d]imidazole [ka] In a 20 mL vial, add (4,4''-di-tert-butyl-2,2''-bipyridine)bis[3,5-difluoro-2-[5-trifluoromethyl-2-pyridinyl-N)phenyl-C]iridium(iii) hexafluorophosphate (2.9 mg, 0.0026 mmol), nickel(II) chloride ethylene glycol dimethyl ether complex (5.6 mg, 0.026 mmol), 4,4'-di-tert-butyl- 2,2'-bipyridine (10.3 mg, 0.039 mmol), 2-(2-chloro-4-phenylpyridin-3-yl)-3,4,6,7-tetrahydropyrano[3,4-d]imidazole (0.080 g, 0.26 mmol), cesium carbonate (0.13 g, 0.39 mmol), 3,3-difluorocyclopentane carboxylic acid (0.052 g, 0.35 mmol), a magnetic stir bar, and DMF (5.8 ml) were added. The reaction mixture was purged with nitrogen for 10 seconds and sealed with a cap. The reaction mixture was then stirred in front of a Kessil PR160L light (440 nm) for 20 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (10 ml) and extracted with ethyl acetate (3 x 10 ml). The combined organic extracts were washed with water (3×25 ml) and brine (50 ml), dried over anhydrous sodium sulfate, and concentrated in vacuo. Purification of the residue by preparative reverse-phase HPLC using 5-50% acetonitrile in water containing 0.5% formic acid as eluent afforded the title compound as an off-white solid (0.0025 g, 2.6% yield): 1 H-NMR (400 MHz;MeOD) δ 8.74 (d, J = 5.0 Hz, 1H), 8.27 (s, 1H), 7.38 (dd, J = 5.0, 0.9 Hz, 1H), 7.16-7.07 (m, 2H), 6.92 (ddd, J = 9.0, 5.2, 2.4 Hz, 1H), 4.59 (s, 2H), 3.95 (t, J = 5.5 Hz, 2H), 3.46-3.36 (m, 1H), 2.68-2.66 (m, 2H), 2.63-2.50 (m, 1H), 2.38-2.27 (m, 2H), 2.15-1.99 (m, 3H); MS(ESI+) m / z 418.2(M+1).

[0263] Example 49 Synthesis of N-(6-chloropyridin-3-yl)-2-cyclopentyl-4-(2-fluorophenyl)nicotinamide [ka] Step 1. Preparation of 2-chloro-4-iodonicotinic acid [ka] To a mixture of 2-chloro-4-iodopyridine (38.00 g, 158.7 mmol) in tetrahydrofuran (190 ml) was added 2M lithium diisopropylamide (87.0 ml, 175 mmol) at -70°C under an atmosphere of nitrogen and stirred for 1 h. Solid carbon dioxide (209.5 g, 4760 mmol) was added and the reaction mixture was stirred at -70°C for 2 h. After warming to ambient temperature, the mixture was diluted with 12 M hydrochloric acid until a pH of 2 was obtained. The mixture was extracted with 50% ethyl acetate in tetrahydrofuran (3 x 400 ml). The combined organic solutions were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by trituration with 9% ethyl acetate in petroleum ether (110 ml) and filtration afforded the title compound as a yellow solid (31 g, 69% yield): 1 H NMR (400 MHz, DMSO-d 6 ) δ 14.3 (br s, 1H), 8.12 (d, J = 4.8, 1H), 7.98 (d, J = 5.2, 1H).

[0264] Step 2. Preparation of tert-butyl 2-chloro-4-iodonicotinate [ka] To a mixture of 2-chloro-4-iodonicotinic acid (10.00 g, 35.28 mmol) in tert-butanol (100 ml) was added 4-(dimethylamino)pyridine (0.431 g, 3.53 mmol), triethylamine (3.57 g, 35.3 mmol), and di-tert-butyl dicarbonate (15.40 g, 70.56 mmol) and purged with nitrogen. The reaction mixture was stirred at 50° C. for 12 hours. After cooling to ambient temperature, the mixture was concentrated in vacuo. Purification of the residue by column chromatography using 17% ethyl acetate in petroleum ether as eluent provided the title compound as a yellow solid (31 g, 69% yield): MS (ES+) m / z 339.9 (M+1) and 441.9 (M+1).

[0265] Step 3. Preparation of tert-butyl 2-chloro-4-(2-fluorophenyl)nicotinate [ka] To a mixture of tert-butyl 2-chloro-4-iodonicotinate (8.50 g, 25.0 mmol) in dioxane (44 ml) and water (11 ml) was added (2-fluorophenyl)boronic acid (4.20 g, 30.0 mmol), potassium carbonate (6.92 g, 35.3 mmol), and bis(diphenylphosphino)ferrocene palladium(II) dichloromethane (1.83 g, 2.50 mmol) and purged with nitrogen. The reaction mixture was stirred at 80° C. for 12 hours. After cooling to ambient temperature, the mixture was diluted with water (250 ml) and extracted with ethyl acetate (3×200 ml). The combined organic solution was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification of the residue by column chromatography using 5% ethyl acetate in petroleum ether as eluent afforded the title compound as a colorless solid (7.00 g, 91% yield): MS (ES+) m / z 308.0 (M+1) and 310.0 (M+1).

[0266] Step 4: Preparation of tert-butyl 2-(cyclopent-1-en-1-yl)-4-(2-fluorophenyl)nicotinate [ka] To a mixture of tert-butyl 2-chloro-4-(2-fluorophenyl)nicotinate (1.00 g, 3.25 mmol), 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.946 g, 4.87 mmol) and sodium carbonate (1.55 g, 14.6 mmol) in 1,4-dioxane (8 ml) and water (0.8 ml) was added [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (0.238 g, 0.325 mmol) in a glove box. The mixture was stirred at 120° C. for 2 hours under microwave irradiation. After the mixture was cooled to ambient temperature, thiourea resin (0.100 g) was added. The mixture was stirred for 4 hours. The mixture was filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with a 10:1 mixture of petroleum ether in ethyl acetate to give the title compound as a yellow solid (0.700 g, 63% yield): 1 H NMR (400MHz, CDCl 3 ) δ 8.62 (d, J = 4.8 Hz, 1H), 7.43-7.36 (m, 1H), 7.32-7.27 (m, 1H), 7.22-7.13 (m, 2H), 7.12 (d, J = 4.8 Hz, 1H), 6.17 (quin, J = 2.0 Hz, 1H), 2.93-2.86 (m, 2H), 2.55 (qt, J = 7.2, 2.4 Hz, 2H), 2.09-1.99 (m, 2H), 1.25 (s, 9H).

[0267] Step 5. Preparation of 4-tert-butyl 2-cyclopentyl-4-(2-fluorophenyl)-nicotinate [ka] Palladium on carbon (0.300 g, 10% purity) was added to a solution of tert-butyl 2-(cyclopent-1-en-1-yl)-4-(2-fluorophenyl)-nicotinate (0.500 g, 1.47 mmol) in methanol (10 ml) under nitrogen atmosphere. The suspension was degassed in vacuum and purged with hydrogen several times. The mixture was stirred under hydrogen (15 psi) at 25° C. for 12 h. The mixture was filtered. The filtrate was concentrated in vacuum. The residue was used directly in the next step without further purification (0.500 g, crude): 1 H NMR (400MHz, CDCl 3 ) δ 8.62 (d, J = 4.8 Hz, 1H), 7.43-7.36 (m, 1H), 7.33-7.28 (m, 1H), 7.22-7.13 (m, 2H), 7.09 (d, J = 4.8 Hz, 1H), 3.39 (quin, J = 8.0 Hz, 1H), 2.10-1.95 (m, 4H), 1.93-1.85 (m, 2H), 1.72-1.66 (m, 2H), 1.28 (s, 9H).

[0268] Step 6. Preparation of 2-cyclopentyl-4-(2-fluorophenyl)nicotinic acid [ka] To a solution of tert-butyl 2-cyclopentyl-4-(2-fluorophenyl)nicotinate (0.500 g, 1.46 mmol) in dichloromethane (5 ml) was added trifluoroacetic acid (3.85 g, 33.8 mmol) at 0° C. The mixture was stirred at 25° C. for 12 h. The mixture was concentrated in vacuo. The mixture was purified by preparative HPLC eluting with a gradient of 17-47% acetonitrile in 0.225% formic acid in water to provide the title compound as a colorless solid (0.240 g, 57% yield): 1 H NMR (400MHz, CDCl 3) δ 8.68 (d, J = 5.2 Hz, 1H), 7.44-7.33 (m, 2H), 7.23-7.12 (m, 3H), 3.49-3.38(m, 1H), 2.13-2.02 (m, 2H), 1.99-1.83 (m, 4H), 1.75-1.62 (m, 2H);MS(ES+)m / z286.1(M+1).

[0269] Step 7. Preparation of N-(6-chloropyridin-3-yl)-2-cyclopentyl-4-(2-fluorophenyl)nicotinamide [ka] To a mixture of 2-cyclopentyl-4-(2-fluorophenyl)nicotinic acid (0.240 g, 0.841 mmol) and 6-chloropyridin-3-amine (0.216 g, 1.68 mmol) in tetrahydrofuran (0.8 ml) was added N-ethyl-N-isopropylpropan-2-amine (0.326 g, 2.52 mmol) and 2-chloro-1-methylpyridin-1-ium iodide (0.322 g, 1.26 mmol) under nitrogen atmosphere. The mixture was stirred at 70° C. for 12 h. After cooling to ambient temperature, the mixture was quenched with water (0.1 ml) and concentrated in vacuo. The mixture was purified by preparative HPLC eluting with a gradient of 50-72% acetonitrile in 0.225% formic acid in water to provide the title compound as a colorless solid (0.0129 g, 4% yield): 1 H NMR (400MHz, CDCl 3 ) δ 8.72 (d, J = 5.2 Hz, 1H), 8.08 (d, J = 2.8 Hz, 1H), 7.96 (dd, J = 8.8, 2.8 Hz, 1H), 7.41-7.33 (m, 2H), 7.26-7.20 (m, 2H), 7.20-7.11 (m, 3H), 3.40 (m, J = 8.4 Hz, 1H), 2.12-1.97 (m, 4H), 1.95-1.86 (m, 2H), 1.75-1.64 (m, 2H);MS(ES+)m / z396.0(M+1), 398.0(M+1).

[0270] Example 50 Synthesis of N-(6-chloropyridin-3-yl)-2-(cyclopent-1-en-1-yl)-4-(2-fluorophenyl)nicotinamide [ka] Step 1: Preparation of 2-(cyclopent-1-en-1-yl)-4-(2-fluorophenyl)-nicotinic acid [ka] To a solution of tert-butyl 2-cyclopentyl-4-(2-fluorophenyl)nicotinate (0.200 g, 0.589 mmol) in dichloromethane (3 ml) was added trifluoroacetic acid (2.31 g, 20.3 mmol) at 0° C. The mixture was stirred at 25° C. for 12 h. The mixture was concentrated in vacuo. The mixture was purified by preparative HPLC eluting with a gradient of 8-38% acetonitrile in 0.225% formic acid in water to provide the title compound as a colorless solid (0.100 g, 59% yield): 1 H NMR (400MHz, CDCl 3 ) δ 8.63 (d, J = 5.2 Hz, 1H), 7.46-7.39 (m, 1H), 7.35 (dt, J = 7.6, 1.8 Hz, 1H), 7.24-7.13 (m, 3H), 6.25 (t, J = 2.0 Hz, 1H), 2.92-2.78 (m, 2H), 2.54 (dt, J = 7.2, 2.4 Hz, 2H), 2.03 (quin, J = 7.6 Hz, 2H); MS(ES+)m / z284.0(M+1).

[0271] Step 2. Preparation of N-(6-chloropyridin-3-yl)-2-(cyclopent-1-en-1-yl)-4-(2-fluorophenyl)nicotinamide [ka] To a mixture of 2-(cyclopent-1-en-1-yl)-4-(2-fluorophenyl)nicotinic acid (0.0400 g, 0.141 mmol) and 6-chloropyridin-3-amine (0.0547 g, 0.0424 mmol) in tetrahydrofuran (0.4 ml) was added N-ethyl-N-isopropylpropan-2-amine (0.0547 g, 0.424 mmol), 2-chloro-1-methylpyridin-1-ium iodide (0.0541 g, 0.212 mmol) under nitrogen atmosphere. The mixture was stirred at 70° C. for 12 hours. After cooling to ambient temperature, the mixture was quenched with water (0.1 ml) and concentrated in vacuo. The mixture was purified by preparative HPLC eluting with a gradient of 45-67% acetonitrile in 0.225% formic acid in water to provide the title compound as a colorless solid (0.0253 g, 45% yield): 1 H NMR (400MHz, CDCl 3 ) δ 8.71 (d, J = 4.8 Hz, 1H), 8.13 (d, J = 2.4 Hz, 1H), 7.92 (dd, J = 2.4, 8.8 Hz, 1H), 7.44-7.32 (m, 3H), 7.26 (s, 1H), 7.25-7.17 (m, 2H), 7.13 (t, J = 8.8 Hz, 1H), 6.41 (s, 1H), 2.89 (t, J = 6.4 Hz, 2H), 2.58-2.48 (m, 2H), 2.00 (quin, J = 7.6 Hz, 2H);MS(ES+)m / z394.0(M+1), 396.0(M+1).

[0272] Example 51 Synthesis of 4-(2-fluorophenyl)-N-(6-isopropylpyridin-3-yl)-2-(tetrahydro-2H-pyran-4-yl)nicotinamide [ka] Step 1. Preparation of tert-butyl 2-(3,6-dihydro-2H-pyran-4-yl)-4-(2-fluorophenyl)nicotinate [ka] To a solution of tert-butyl 2-chloro-4-(2-fluorophenyl)nicotinate (0.400 g, 1.30 mmol) and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.273 g, 1.30 mmol) in dioxane (8 ml) and water (2 ml) was added sodium carbonate (0.276 g, 2.60 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.0951 g, 0.130 mmol) under nitrogen atmosphere. The mixture was stirred in a microwave at 120° C. for 2 hours. After cooling to ambient temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC eluting with a gradient of 27-47% acetonitrile in 0.225% formic acid in water to provide the title compound as a yellow oil (0.368 g, 61% yield): 1 H NMR (400 MHz, CDCl 3 ) δ 8.89 (d, J = 5.6 Hz, 1H), 7.64 (d, J = 5.6 Hz, 1H), 7.57-7.49 (m, 1H), 7.38-7.29 (m, 2H), 7.26-7.20 (m, 1H), 6.15 (s, 1H), 4.32 (d, J = 2.4 Hz, 2H), 3.98 (t, J = 5.2 Hz, 2H), 1.33 (s, 9H).

[0273] Step 2. Preparation of 2-(3,6-dihydro-2H-pyran-4-yl)-4-(2-fluorophenyl)nicotinic acid [ka] A mixture of tert-butyl 2-(3,6-dihydro-2H-pyran-4-yl)-4-(2-fluorophenyl)nicotinate (0.250 g, 0.703 mmol) in dichloromethane (1.5 ml) and trifluoroacetic acid (1.5 ml) was stirred at 25° C. for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC eluting with a gradient of 10-40% acetonitrile in 0.225% formic acid in water to provide the title compound as a colorless solid (0.100 g, 47% yield): 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.66-12.81 (m, 1H), 8.66 (d, J = 4.8 Hz, 1H), 7.57-7.45 (m, 1H), 7.43-7.24 (m, 4H), 6.03 (s, 1H), 4.16 (q, J = 2.4 Hz, 2H), 3.82 (t, J = 5.2 Hz, 2H), 2.61-2.53 (m, 2H); MS(ES+)m / z300.0(M+1).

[0274] Step 3. Preparation of 4-(2-fluorophenyl)-N-(6-isopropylpyridin-3-yl)-2-(tetrahydro-2H-pyran-4-yl)nicotinamide [ka] To a solution of 2-(3,6-dihydro-2H-pyran-4-yl)-4-(2-fluorophenyl)nicotinic acid (0.0700 g, 0.234 mmol) in tetrahydrofuran (2 ml) was added 2-chloro-1-methylpyridin-1-ium iodide (0.0720 mg, 0.281 mmol), N,N-diisopropylethylamine (0.151 g, 1.17 mmol) and 6-chloropyridin-3-amine (0.0360 g, 0.281 mmol). The mixture was stirred at 70° C. for 36 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC eluting with a gradient of 39-59% acetonitrile in 0.225% formic acid in water to provide the title compound as a colorless solid (0.00500 g, 50% yield): 1H NMR (400 MHz, DMSO-d 6 ) δ 10.81 (s, 1H), 8.73 (d, J = 4.8 Hz, 1H), 8.45-8.37 (m, 1H), 7.90-7.84 (m, 1H), 7.48-7.37 (m, 4H), 7.33-7.20 (m, 2H), 6.09 (s, 1H), 4.03 (d, J = 2.4 Hz, 2H), 3.76 (t, J = 5.2 Hz, 2H), 2.62 (d, J = 1.6 Hz, 2H); MS(ES+)m / z410.0, 412.0(M+1).

[0275] Example 52 Synthesis of 4-(2-fluorophenyl)-N-(6-isopropylpyridin-3-yl)-2-(tetrahydro-2H-pyran-4-yl)nicotinamide [ka] To a solution of 2-(3,6-dihydro-2H-pyran-4-yl)-4-(2-fluorophenyl)nicotinic acid (0.0800 g, 0.267 mmol) in tetrahydrofuran (2 ml) was added 2-chloro-1-methylpyridin-1-ium iodide (0.0820 g, 0.321 mmol), N-ethyl-N-isopropylpropan-2-amine (0.104 g, 0.802 mmol) and 6-isopropylpyridin-3-amine (0.146 g, 1.07 mmol). The mixture was stirred at 70° C. for 12 hours. After cooling to ambient temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC eluting with a gradient of 23-43% acetonitrile in 0.225% formic acid in water to provide the title compound as a colorless solid (0.00560 g, 0.0112 mmol, 4% yield, 93% purity, formate) as a yellow solid: 1 H NMR (400 MHz, DMSO-d 6) δ 10.56-10.50 (m, 1H), 8.71 (d, J = 4.8 Hz, 1H), 8.38 (d, J = 2.4 Hz, 1H), 7.69 (dd, J = 2.8, 8.4 Hz, 1H), 7.48-7.35 (m, 3H), 7.33-7.15 (m, 3H), 6.15-6.09 (m, 1H), 4.06 (d, J = 2.4 Hz, 2H), 3.77 (J = 5.2 Hz, 2H), 2.94 (td, J = 6.8, 13.6 Hz, 1H), 2.69 (s, 2H), 1.18 (d, J = 7.2 Hz, 6H); MS(ES+) m / z 418.1(M+1).

[0276] Example 53 Synthesis of 4-(2-fluorophenyl)-N-(6-isopropylpyridin-3-yl)-2-(tetrahydro-2H-pyran-4-yl)nicotinamide [ka] Step 1. Preparation of tert-butyl 4-(2-fluorophenyl)-2-(tetrahydro-2H-pyran-4-yl)nicotinate [ka] Palladium on activated carbon (0.550 g, 0.571 mmol, 10% purity) was added to a solution of tert-butyl 2-(3,6-dihydro-2H-pyran-4-yl)-4-(2-fluorophenyl)nicotinate (0.450 g, 1.27 mmol) in methanol (5 ml) under nitrogen atmosphere. The mixture was stirred at 25° C. for 12 hours under hydrogen (15 psi). The reaction mixture was filtered and the filtrate was evaporated under reduced pressure to provide the title compound as a colorless solid (0.450 g, 97% yield): 1 H NMR (400 MHz, CDCl 3) δ 8.65 (d, J = 5.2 Hz, 1H), 7.45-7.36 (m, 1H), 7.33-7.29 (m, 1H), 7.24-7.11 (m, 3H), 4.12 (dd, J = 3.6, 11.2 Hz, 2H), 3.57-3.47 (m, 2H), 3.21 (tt, J = 3.6, 11.6 Hz, 1H), 2.16 (dq, J = 4.4, 12.6 Hz, 2H), 1.80 (dd, J = 1.6, 11.6 Hz, 2H), 1.29 (s, 9H).

[0277] Step 2. Preparation of 4-(2-fluorophenyl)-N-(6-isopropylpyridin-3-yl)-2-(tetrahydro-2H-pyran-4-yl)nicotinamide [ka] To a solution of 4-(2-fluorophenyl)-2-(tetrahydro-2H-pyran-4-yl)nicotinic acid (0.0500 g, 0.166 mmol) in tetrahydrofuran (2 ml) was added 2-chloro-1-methylpyridin-1-ium iodide (0.0510 g, 0.200 mmol), N,N-diisopropylethylamine (0.0640 g, 0.498 mmol) and 6-isopropylpyridin-3-amine (0.0450 g, 0.332 mmol). The mixture was stirred at 70° C. for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC eluting with a gradient of 27-47% acetonitrile in 0.225% formic acid in water to provide the title compound as a colorless solid (0.00600 g, 7% yield): MS (ES+) m / z 420.0 (M+1).

[0278] Example 54 Synthesis of N-(2-(4,4-difluorocyclohexyl)-4-(3,4-dihydro-2H-pyran-6-yl)pyridin-3-yl)-2-isopropylpyrimidine-5-carboxamide [ka] Step 1. Preparation of tert-butyl (2-chloro-4-iodopyridin-3-yl)carbamate [ka] To a solution of 2-chloro-4-iodonicotinic acid (5.0 g, 18 mmol) in tert-butanol (84 ml) and N,N-dimethylformamide (71 ml) were added diphenylphosphon azide (5.7 ml, 26 mmol), and triethylamine (6.1, 44 mmol). The solution was heated at 90° C. for 4 h. The reaction mixture was cooled to ambient temperature and diluted with ethyl acetate (500 ml). The reaction mixture was washed with saturated sodium bicarbonate solution (3×250 ml), water (250 ml), and brine (250 ml). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Purification of the residue by column chromatography eluting with 5-40% ethyl acetate in heptane provided the title compound as an off-white solid (3.4 g, 54% yield): MS (ES+) m / z 355.0 (M+1), 357.0 (M+1).

[0279] Step 2. Preparation of 2-chloro-4-iodopyridin-3-amine trifluoroacetate [ka] To a mixture of tert-butyl (2-chloro-4-iodopyridin-3-yl)carbamate (0.82 g, 2.5 mmol) in dichloromethane (25 ml) was added trifluoroacetic acid (15 ml). The reaction mixture was stirred at ambient temperature for 1 h and the volatiles were removed in vacuo. The pale yellow solid was used without further purification (3.4 g, 96% yield): MS (ES+) m / z 254.8 (M+1), 256.8 (M+1).

[0280] Step 3. Preparation of N-(2-chloro-4-iodopyridin-3-yl)-2-isopropylpyrimidine-5-carboxamide [ka] To a solution of 2-chloro-4-iodopyridin-3-amine trifluoroacetate (0.83 g, 3.3 mmol), 2-isopropylpyrimidine-5-carboxylic acid (0.81 g, 4.9 mmol), and 2-chloro-1-methyl-pyridin-1-ium iodide (2.5 g, 9.8 mmol) in tetrahydrofuran (16 ml) was added N,N-diisopropylethylamine (5.7 ml, 33 mmol) and the mixture was stirred at 65° C. for 20 hours. After cooling to ambient temperature, the mixture was diluted with ethyl acetate (50 ml) and the organic phase was washed with saturated aqueous sodium bicarbonate (50 ml). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. A solution of the crude residue was dissolved in methanol / THF (1:1) (18 ml) and then sodium hydroxide (16 ml) was added to the mixture. After stirring for 15 minutes at ambient temperature, the reaction was quenched with saturated ammonium chloride solution (2×30 ml), diluted with ethyl acetate (20 ml), and washed with saturated sodium bicarbonate solution (3×30 ml), water (50 ml), and brine (50 ml). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Purification of the residue by column chromatography eluting with 5-100% ethyl acetate in heptane provided the title compound as an off-white solid (0.72 g, 54% yield).

[0281] Step 4. Preparation of N-(2-chloro-4-(3,4-dihydro-2H-pyran-6-yl)pyridin-3-yl)-2-isopropylpyrimidine-5-carboxamide [ka] A mixture of N-(2-chloro-4-iodopyridin-3-yl)-2-isopropylpyrimidine-5-carboxamide (0.090 g, 0.22 mmol) in dioxane (1.2 ml) and water (0.11 ml) was degassed with nitrogen for 10 min. The reaction mixture was added potassium carbonate (0.092 g, 0.67 mmol), 2-(3,4-dihydro-2H-pyran-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.070 g, 0.34 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and CH 2 Cl 2 Complex with (1:1) (0.019 g, 0.022 mmol) was added and the reaction mixture was stirred at 90° C. for 3 h. After cooling to ambient temperature, the mixture was filtered through a bed of diatomaceous earth (i.e., Celite®) and the filter pad was washed with ethyl acetate (2×100 ml). The combined filtrates were washed with saturated ammonium chloride (2×75 ml) and concentrated in vacuo. The residue was purified by column chromatography eluting with a gradient of 10-100% ethyl acetate in heptane to provide the title compound as an off-white solid (0.065 g, 80% yield): MS (ES+) m / z 359.0 (M+1), 361.0 (M+1).

[0282] Step 5. Preparation of N-(2-(4,4-difluorocyclohexyl)-4-(3,4-dihydro-2H-pyran-6-yl)pyridin-3-yl)-2-isopropylpyrimidine-5-carboxamide [ka] (4,4''-di-t-butyl-2,2''-bipyridine)bis[3,5-difluoro-2-[5-trifluoromethyl-2-pyridinyl-N)phenyl-C]iridium(iii) hexafluorophosphate (0.0019 g, 0.0017 mmol), NiCl 2To a mixture of glyme (0.0038 g, 0.017 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (0.0070 g, 0.026 mmol), N-(2-chloro-4-(3,4-dihydro-2H-pyran-6-yl)pyridin-3-yl)-2-isopropylpyrimidine-5-carboxamide (0.062 g, 0.17 mmol), cesium carbonate (0.11 g, 0.35 mmol) and 4,4-difluorocyclohexanecarboxylic acid (0.056 g, 0.34 mmol) was added N,N-dimethylformamide (4.3 ml). The mixture was purged with nitrogen for 10 seconds and sealed. The reaction mixture was then stirred in front of a Kessil PR160L light (440 nm) for 20 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (10 ml) and extracted with ethyl acetate (3×10 ml). The combined organic extracts were washed with water (3×25 ml) and brine (50 ml), dried over anhydrous sodium sulfate, and concentrated in vacuo. Purification of the residue by preparative reverse-phase HPLC using 5-85% acetonitrile in water containing 0.5% formic acid as eluent afforded the title compound as a colorless solid (0.010 g, 13% yield): 1 H-NMR (400 MHz; DMSO-d 6 ) δ 10.21 (s, 1H), 9.21 (s, 2H), 8.49 (d, J = 4.9 Hz, 1H), 7.28 (d, J = 5.0 Hz, 1H), 5.19 (t, J = 3.9 Hz, 1H), 3.96-3.94 (m, 1H), 3.28-3.20 (m, 2H), 3.16-3.08 (m, 1H), 2.10-2.03 (m, 3H), 2.00-1.72 (m, 9H), 1.33 (d, J = 6.9 Hz, 6H); MS(ES+)m / z443.2(M+1).

[0283] Example 55 Synthesis of N-(2'-(4,4-difluorocyclohexyl)-[2,4'-bipyridine]-3'-yl)-2-isopropylpyrimidine-5-carboxamide [ka] Step 1. Preparation of N-(2'-chloro-[2,4'-bipyridine]-3'-yl)-2-isopropylpyrimidine-5-carboxamide [ka] To a solution of N-(2-chloro-4-iodo-3-pyridyl)-2-isopropyl-pyrimidine-5-carboxamide (0.15 g, 0.36 mmol) in THF (2.0 ml) was added tetrakis(triphenylphosphine)palladium(0) (0.042 g, 0.036 mmol) and 2-pyridylzinc bromide (1.4 ml, 0.72 mmol). The mixture was stirred at 70° C. under nitrogen for 16 hours, after which a second portion of tetrakis(triphenylphosphine)palladium(0) (0.042 g, 0.036 mmol) and 2-pyridylzinc bromide (1.4 ml, 0.72 mmol) was added and stirred at 70° C. for a further 8 hours. After cooling to ambient temperature, the mixture was diluted with ethyl acetate (15 ml), washed with 1M HCl solution (2×20 ml), brine (20 ml) and concentrated in vacuo. The residue was purified by column chromatography eluting with a gradient of 10-100% ethyl acetate in heptane to provide the title compound as a pale yellow solid (0.10 g, 80% yield): MS (ES+) m / z 354.0 (M+1), 356.0 (M+1).

[0284] Step 2. Preparation of N-(2'-(4,4-difluorocyclohexyl)-[2,4'-bipyridine]-3'-yl)-2-isopropylpyrimidine-5-carboxamide [ka] (4,4''-di-t-butyl-2,2''-bipyridine)bis[3,5-difluoro-2-[5-trifluoromethyl-2-pyridinyl-N)phenyl-C]iridium(iii) hexafluorophosphate (0.0024 g, 0.0021 mmol), NiCl 2To a mixture of glyme (0.0047 g, 0.021 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (0.0086 g, 0.032 mmol), N-(2-chloro-4-(3,4-dihydro-2H-pyran-6-yl)pyridin-3-yl)-2-isopropylpyrimidine-5-carboxamide (0.073 g, 0.21 mmol), cesium carbonate (0.14 g, 0.43 mmol) and 4,4-difluorocyclohexanecarboxylic acid (0.070 g, 0.43 mmol) was added N,N-dimethylformamide (5.4 ml). The mixture was purged with nitrogen for 10 seconds and sealed. The reaction mixture was then stirred in front of a Kessil PR160L light (440 nm) for 20 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (10 ml) and extracted with ethyl acetate (3×10 ml). The combined organic extracts were washed with water (3×25 ml) and brine (50 ml), dried over anhydrous sodium sulfate, and concentrated in vacuo. Purification of the residue by preparative reverse-phase HPLC using 10-85% acetonitrile in water containing 0.5% formic acid as eluent afforded the title compound as a colorless solid (0.031 g, 33% yield): 1 H-NMR (400 MHz; DMSO-d 6 ): δ 10.46 (s, 1H), 9.06 (s, 2H), 8.65 (d, J = 5.0 Hz, 2H), 7.87 (td, J = 7.7, 1.8 Hz, 1H), 7.65 (s, 1H), 7.52 (d, J = 4.9 Hz, 1H), 7.41-7.39 (m, 1H), 3.21 (d quintet, J = 13.8, 6.9 Hz, 2H), 2.12-1.99 (m, 3H), 1.92-1.85 (m, 5H), 1.30 (d, J = 6.9 Hz, 6H);MS(ES+)m / z438.2(M+1).

[0285] Example 56 Synthesis of N-(2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)pyridin-3-yl)-6-(2-(dimethylamino)ethoxy)-5-fluoronicotinamide [ka] Step 1. Preparation of N-(2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)pyridin-3-yl)-5,6-difluoronicotinamide [ka] To a mixture of 2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)pyridin-3-amine (1.00 g, 3.08 mmol), 5,6-difluoropyridine-3-carboxylic acid (0.539 g, 3.39 mmol), 2-chloro-1-methyl-pyridin-1-ium iodide (1.02 g, 4.01 mmol) in tetrahydrofuran (10 ml) was added N,N-diisopropylethylamine (1.20 g, 9.25 mmol). The mixture was stirred at 70° C. for 12 h. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography eluting with a gradient of 0-25% ethyl acetate in petroleum ether to provide the title compound as a colorless solid (1.00 g, 2.15 mmol, 78% yield): 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.38 (s, 1H), 8.64 (d, J = 4.8 Hz, 1H), 8.39 (t, J = 1.8 Hz, 1H), 8.28 (dt, J = 2.0, 9.6 Hz, 1H), 7.39 (d, J = 5.4 Hz, 1H), 7.37-7.20 (m, 3H), 3.24-3.11 (m, 1H), 2.17-2.04 (m, 2H), 1.98-1.74 (m, 6H).

[0286] Step 2. Preparation of N-(2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)pyridin-3-yl)-6-(2-(dimethylamino)ethoxy)-5-fluoronicotinamide [ka] To a solution of N-(2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)pyridin-3-yl)-5,6-difluoronicotinamide (0.0500 g, 0.107 mmol) and 2-(dimethylamino)ethanol (0.0192 g, 0.215 mmol) in tetrahydrofuran (1 ml) was added potassium tert-butoxide (1 M in tetrahydrofuran, 0.200 ml) at 0° C. and the mixture was stirred at 25° C. for 12 hours. Water (10 ml) was added to the mixture and then the mixture was extracted with ethyl acetate (3×10 ml). The combined organic layers were washed with brine (30 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC eluting with a gradient of 15-35% acetonitrile in water containing 0.225% formic acid to provide the title compound as a colorless solid (0.0335 g, 52% yield): 1 H NMR (400 MHz, MeOD-d 4 ) δ 8.60 (d, J = 4.8 Hz, 1H), 8.53 (s, 1H), 8.36 (d, J = 2.0 Hz, 1H), 7.81 (dd, J = 2.0, 10.6 Hz, 1H), 7.35 (d, J = 4.8 Hz, 1H), 7.27-7.06 (m, 3H), 4.64-4.61 (m, 2H), 3.19-3.11 (m, 1H), 2.91 (t, J = 5.6 Hz, 2H), 2.42 (s, 6H), 2.19-2.00 (m, 4H), 1.94-1.77 (m, 4H);MS(ES+)m / z535.3(M+1).

[0287] Examples 57 to 60 The following compounds were prepared in a similar manner to that described in Example 56, utilizing appropriately substituted starting materials and intermediates: [Table 5-1] [Table 5-2] [Table 5-3]

[0288] Example 63 Synthesis of (S)-2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)-N-(2-(2-methylazetidin-1-yl)pyrimidin-5-yl)nicotinamide [ka] Step 1. Preparation of tert-butyl 2-chloro-4-(2,5-difluorophenyl)nicotinate [ka] To a solution of 2-chloro-4-(2,5-difluorophenyl)nicotinic acid (1.00 g, 3.71 mmol) in tert-butanol (10 ml) was added di-tert-butyl dicarbonate (1.62 g, 7.42 mmol), triethylamine (1.13 g, 11.1 mmol) and 4-dimethylaminopyridine (0.0453 g, 0.371 mmol). The mixture was stirred at 50° C. for 12 h. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography eluting with a gradient of 0-4% ethyl acetate in petroleum ether to provide the title compound as a colorless solid (0.800 g, 2.46 mmol, 66% yield): 1 H NMR (400 MHz, CDCl 3 ) δ 8.49 (d, J = 5.0 Hz, 1H), 7.32-7.25 (m, 1H), 7.22-7.05 (m, 3H), 1.41 (s, 9H).

[0289] Step 2. Preparation of tert-butyl 2-(4,4-difluorocyclohex-1-en-1-yl)-4-(2,5-difluorophenyl)nicotinate [ka] To a mixture of tert-butyl 2-chloro-4-(2,5-difluorophenyl)nicotinate (0.700 g, 2.15 mmol), 2-(4,4-difluorocyclohexen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.305 g, 1.25 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.157 g, 0.215 mmol) and potassium carbonate (0.891 g, 6.45 mmol) was added dioxane (10 ml) / water (2 ml). The mixture was degassed and purged with nitrogen three times, then the mixture was stirred at 100° C. for 12 hours under a nitrogen atmosphere. The reaction mixture was cooled to ambient temperature. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography eluting with a gradient of 0 to 10% ethyl acetate in petroleum ether to provide the title compound as a colorless solid (0.540 g, 62% yield): 1 H NMR (400 MHz, CDCl 3 ) δ 8.66 (d, J = 4.8 Hz, 1H), 7.20 (d, J = 4.8 Hz, 1H), 7.16-7.09 (m, 2H), 7.08-7.01 (m, 1H), 5.74 (s, 1H), 2.88 (t, J = 5.6 Hz, 2H), 2.68 (t, J = 13.2 Hz, 2H), 2.24 (tt, J = 13.6, 6.8 Hz, 2H), 1.35 (s, 9H).

[0290] Step 3. Preparation of tert-butyl 2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)nicotinate [ka] Palladium on carbon (0.450 g, 0.423 mmol, 10 wt%) was added to a solution of tert-butyl 2-(4,4-difluorocyclohex-1-en-1-yl)-4-(2,5-difluorophenyl)nicotinate (0.540 g, 1.33 mmol) in methanol (10 ml) under nitrogen atmosphere. The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred under hydrogen (15 psi) at 25° C. for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give the title compound as a colorless solid (0.450 g, crude): 1 H NMR (400 MHz, CDCl 3 ) δ 8.64 (d, J = 5.0 Hz, 1H), 7.18-7.07 (m, 3H), 7.03 (ddd, J = 8.0, 5.6, 2.8 Hz, 1H), 3.03 (t, J = 11.6 Hz, 1H), 2.31-2.22 (m, 2H), 2.19-2.08 (m, 2H), 2.03-1.95 (m, 2H), 1.90-1.74 (m, 2H), 1.34 (s, 9H).

[0291] Step 4. Preparation of 2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)nicotinic acid [ka] To a solution of tert-butyl 2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)nicotinate (0.450 g, 1.10 mmol) in dichloromethane (10 ml) was added trifluoroacetic acid (7.70 g, 67.5 mmol). The mixture was stirred at 25° C. for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase column chromatography eluting with 0.1% formic acid in water. To the product solution was added 1 ml of concentrated hydrochloric acid. The resulting solution was lyophilized to give the title compound as a colorless solid (0.310 g, 72% yield): 1 H NMR (400 MHz, DMSO-d 6) δ 8.69 (d, J = 4.8 Hz, 1H), 8.14 (s, 1H), 7.44-7.33 (m, 3H), 7.26 (ddd, J = 8.4, 5.2, 2.8 Hz, 1H), 3.16-3.00 (m, 1H), 2.13 (d, J = 6.8 Hz, 2H), 2.04-1.84 (m, 6H).

[0292] Step 5. Preparation of (S)-2-(2-methylazetidin-1-yl)-5-nitropyrimidine [ka] To a solution of (S)-2-methylazetidine hydrochloride (0.148 g, 1.38 mmol) and cesium carbonate (1.23 g, 3.76 mmol) in dimethylformamide (2 ml) was added 2-chloro-5-nitropyrimidine (0.200 g, 1.25 mmol) at 25° C. The mixture was then stirred at 25° C. for 12 hours. The residue was diluted with ethyl acetate (20 ml), washed with water (3×20 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound as a colorless solid (0.210 g, 82% yield): 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.07 (s, 2H), 4.69-4.57 (m, 1H), 4.23-4.05 (m, 2H), 2.60-2.53 (m, 1H), 2.04-1.94 (m, 1H), 1.50 (d, J = 6.4 Hz, 3H).

[0293] Step 6. Preparation of (S)-2-(2-methylazetidin-1-yl)pyrimidin-5-amine [ka] To a solution of (S)-2-(2-methylazetidin-1-yl)-5-nitropyrimidine (0.210 g, 1.08 mmol) in ethyl acetate (10 ml) was added palladium on carbon (0.0300 g, 10 wt%) at 25° C. under nitrogen atmosphere. The suspension was degassed and purged with hydrogen three times. The mixture was stirred under hydrogen (15 psi, balloon) at 25° C. for 1 h. The resulting mixture was filtered through Celite. The filter cake was washed with ethyl acetate (10 ml). The filtrate was concentrated under reduced pressure to give the title compound as a yellow solid (0.120 g, 64% yield): 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.85 (s, 2H), 4.57 (s, 2H), 4.22-4.10 (m, 1H), 3.76 (dt, J = 8.4, 4.0 Hz, 1H), 3.67 (q, J = 8.0 Hz, 1H), 2.26 (dtd, J = 10.4, 8.4, 4.0 Hz, 1H), 1.96-1.84 (m, 1H), 1.37 (d, J = 6.0 Hz, 3H).

[0294] Step 7. Preparation of (S)-2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)-N-(2-(2-methylazetidin-1-yl)pyrimidin-5-yl)nicotinamide [ka] To a solution of (S)-2-(2-methylazetidin-1-yl)pyrimidin-5-amine (0.0400 g, 0.244 mmol), 2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)nicotinic acid (0.0880 g, 0.249 mmol) and N,N-diisopropylethylamine (0.0960 g, 0.743 mmol) in tetrahydrofuran (2 ml) was added 2-chloro-1-methylpyridinium iodide (0.0750 g, 0.294 mmol) at 25° C. The mixture was stirred at 70° C. for 12 hours. After cooling to ambient temperature, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC eluting with a gradient of 46-76% acetonitrile in water containing 0.225% formic acid to provide the title compound as a colorless solid (0.0420 g, 34% yield): 1 H NMR (400 MHz, MeOD-d 4 ) δ 8.67 (d, J = 4.8 Hz, 1H), 8.23 ​​(s, 2H), 7.37 (dd, J = 4.8, 1.2 Hz, 1H), 7.30-7.14 (m, 3H), 4.52-4.40 (m, 1H), 4.10-3.99 (m, 1H), 3.98-3.85 (m, 1H), 3.12-3.00 (m, 1H), 2.47 (dtd, J = 10.8, 8.8, 5.2 Hz, 1H), 2.22-2.07 (m, 4H), 2.06-1.91 (m, 4H), 1.90-1.79 (m, 1H), 1.48 (d, J = 6.0 Hz, 3H);MS(ES+)m / z500.2(M+1).

[0295] Examples 64 to 74 The following compounds were prepared in a manner similar to that described in Example 63, utilizing appropriately substituted starting materials and intermediates: [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4] [Table 6-5] [Table 6-6]

[0296] Example 75 Synthesis of 2-(4,4-difluorocyclohexyl)-4-(2-fluorophenyl)-N-(2-((tetrahydrofuran-3-yl)oxy)pyrimidin-5-yl)nicotinamide [ka] Step 1. Preparation of 5-nitro-2-((tetrahydrofuran-3-yl)oxy)pyrimidine [ka] To a solution of 2-chloro-5-nitro-pyrimidine (0.100 g, 0.627 mmol) and tetrahydrofuran-3-ol (0.110 g, 1.25 mmol) in tetrahydrofuran (2 ml) was added potassium 2-methylpropan-2-olate (1 M in tetrahydrofuran, 0.94 ml) dropwise at 0° C. The mixture was stirred at 20° C. under nitrogen atmosphere for 12 hours. The mixture was poured into saturated aqueous sodium bicarbonate (10 ml) and extracted with ethyl acetate (3×20 ml). The combined organic layers were washed with brine (10 ml), dried over anhydrous sodium sulfate, filtered and the filtrate was evaporated under reduced pressure to provide the title compound as a pale yellow oil (0.150 g, crude): 1 H NMR (400 MHz, CDCl 3 ) δ 9.31 (s, 2H), 5.71-5.62 (m, 1H), 4.14-4.09 (m, 1H), 4.07-4.02 (m, 1H), 3.99-3.96 (m, 2H), 2.32-2.20 (m, 2H).

[0297] Step 2. Preparation of 2-((tetrahydrofuran-3-yl)oxy)pyrimidin-5-amine [ka] To a mixture of 5-nitro-2-tetrahydrofuran-3-yloxy-pyrimidine (0.150 g, crude) and ammonium chloride (0.760 g, 1.42 mmol) in ethanol (10 ml) and water (5 ml) was added iron powder (0.198 g, 3.55 mmol) in one portion at 20° C. The mixture was stirred at 90° C. for 12 h. The mixture was cooled to 20° C. and filtered. The filtrate was evaporated under reduced pressure. The residue was purified by flash silica gel chromatography eluting with ethyl acetate to provide the title compound as a colorless solid (0.0600 g, 46% yield): 1 H NMR (400 MHz, CDCl 3 ) δ 8.14 (s, 2H), 5.43 (s, 1H), 4.09 (m, 1H), 4.04-3.98 (m, 1H), 3.96-3.88 (m, 2H), 2.26-2.17 (m, 2H).

[0298] Step 3. Preparation of 2-(4,4-difluorocyclohexyl)-4-(2-fluorophenyl)-N-(2-((tetrahydrofuran-3-yl)oxy)pyrimidin-5-yl)nicotinamide [ka] Using an analogous procedure to that described in Example 63() utilizing appropriately substituted starting materials and intermediates, the title compound was provided as a yellow solid (0.069 g, 24% yield): 1 H NMR (400 MHz, CDCl 3) δ 8.72 (d, J = 5.2 Hz, 1H), 8.36 (s, 2H), 7.46-7.36 (m, 2H), 7.31 (br s, 1H), 7.27-7.16 (m, 3H), 5.50-5.42 (m, 1H), 4.12-4.05 (m, 1H), 4.03-3.96 (m, 1H), 3.95-3.88 (m, 2H), 3.15-3.00 (m, 1H), 2.31-2.14 (m, 6H), 2.02 (d, J = 13.6 Hz, 2H), 1.94-1.81 (m, 2H);MS(ES+)m / z499.1(M+1).

[0299] Example 76 Synthesis of 2-(4,4-difluorocyclohexyl)-4-(2-fluorophenyl)-N-(2-isopropoxypyrimidin-5-yl)nicotinamide [ka] Step 1. Preparation of 5-bromo-2-isopropoxypyrimidine [ka] To a mixture of propan-2-ol (40 ml) was added sodium hydride (2.58 g, 64.6 mmol, 60 wt%) with stirring at 0° C. The mixture was stirred at 60° C. for 30 min. To the mixture was added a solution of 5-bromo-2-chloropyrimidine (5.00 g, 25.9 mmol) in propan-2-ol (20 ml) at 0° C. and the resulting mixture was stirred at 90° C. for 12 h under nitrogen atmosphere. The reaction mixture was quenched with water (50 ml) with stirring at 0° C. The resulting mixture was extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (10 ml), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo to give the title compound as a pale yellow oil (3.00 g, crude): 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.73 (s, 2H), 5.25-5.06 (m, 1H), 1.31 (d, J = 6.4 Hz, 6H).

[0300] Step 2. Preparation of tert-butyl (2-isopropoxypyrimidin-5-yl)-carbamate [ka] To a mixture of 5-bromo-2-isopropoxy-pyrimidine (1.00 g, 4.61 mmol), tert-butyl carbamate (0.648 g, 5.53 mmol) and cesium carbonate (4.50 g, 13.8 mmol) in dioxane (20 ml) was added [2-(2-aminophenyl)-phenyl]-methylsulfonyloxy-palladium di-tert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (0.366 g, 0.461 mmol) in one portion at 20° C. The mixture was stirred at 70° C. under nitrogen atmosphere for 12 hours. The mixture was cooled to 20° C. and poured into water (10 ml). The mixture was extracted with ethyl acetate (3×30 ml). The combined organic layers were washed with brine (20 ml), dried over anhydrous sodium sulfate, filtered and the filtrate was evaporated under reduced pressure. The residue was purified by flash silica gel chromatography eluting with a gradient of 30% ethyl acetate in petroleum ether to provide the title compound as a yellow solid (0.600 g, 51% yield): 1 H NMR (400 MHz, CDCl 3 ) δ 8.55 (s, 2H), 6.75-6.44 (m, 1H), 5.24-5.14 (m, 1H), 1.52 (s, 9H), 1.38 (d, J = 6.4 Hz, 6H).

[0301] Step 3. Preparation of 2-isopropoxypyrimidin-5-amine [ka] To a solution of tert-butyl N-(2-isopropoxypyrimidin-5-yl)carbamate (0.400 g, 1.58 mmol) in dichloromethane (10 ml) was added hydrochloric acid / dioxane (4 M, 10 ml) dropwise at 20° C. The mixture was stirred at 20° C. for 1 h. The mixture was evaporated under reduced pressure. The residue was purified by preparative HPLC eluting with a gradient of water containing 0.1% ammonium hydroxide to provide the title compound as a yellow solid (0.0550 g, 22% yield): 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.93 (s, 2H), 5.03-4.95 (m, 1H), 4.91 (s, 2H), 1.24 (d, J = 6.4 Hz, 6H).

[0302] Step 4. Preparation of 2-(4,4-difluorocyclohexyl)-4-(2-fluorophenyl)-N-(2-isopropoxypyrimidin-5-yl)nicotinamide [ka] Using an analogous procedure to that described in Example 63(), utilizing appropriately substituted starting materials and intermediates, the title compound was provided as a yellow solid (0.0059 g, 7% yield): 1 H NMR (400 MHz, CDCl 3 ) δ 8.71 (d, J = 5.2 Hz, 1H), 8.31 (s, 2H), 7.45-7.35 (m, 2H), 7.26-7.17 (m, 3H), 7.15 (s, 1H), 5.26-5.15 (m, 1H), 3.15-3.01 (m, 1H), 2.29-2.14 (m, 4H), 2.05-1.96 (m, 2H), 1.92-1.81 (m, 2H), 1.37 (d, J = 6.4 Hz, 6H); MS(ES+)m / z471.1(M+1).

[0303] Example 77 Synthesis of 2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)-N-((1r,4r)-4-methoxycyclohexyl)nicotinamide [ka] To a solution of 2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)pyridine-3-carboxylic acid (0.0500 g, 0.142 mmol) in dichloromethane (1 ml) was added N,N-diisopropylethylamine (0.0549 g, 0.425 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.0646 g, 0.170 mmol). The mixture was stirred at 50° C. for 12 h. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was purified by preparative HPLC eluting with a gradient of 35-65% acetonitrile in water containing 0.225% formic acid to provide the title compound as a colorless solid (0.0388 g, 58% yield): 1 H NMR (400 MHz, CDCl 3 ) δ 8.64 (d, J = 4.8 Hz, 1H), 7.17-7.06 (m, 4H), 5.36 (d, J = 8.0 Hz, 1H), 3.79 (dtd, J = 14.8, 7.2, 3.6 Hz, 1H), 3.32 (s, 3H), 3.12-2.95 (m, 2H), 2.28-2.19 (m, 2H), 2.18-2.08 (m, 2H), 2.00-1.92 (m, 4H), 1.86-1.70 (m, 4H), 1.35-1.25 (m, 2H), 1.01-0.89 (m, 2H); MS(ES+) m / z 465.2(M+1).

[0304] Example 78 Synthesis of N-(2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)pyridin-3-yl)-2-(2-methylprop-1-en-1-yl)pyrimidine-5-carboxamide [ka] Step 1. Preparation of N-(2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)pyridin-3-yl)-2-(2-methylprop-1-en-1-yl)pyrimidine-5-carboxamide [ka] To a solution of 2-chloro-N-(2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)pyridin-3-yl)pyrimidine-5-carboxamide (0.100 g, 0.215 mmol) and 4,4,5,5-tetramethyl-2-(2-methylprop-1-en-1-yl)-1,3,2-dioxaborolane (0.0588 g, 0.323 mmol) in dioxane (5 ml) and water (1 ml) was added potassium carbonate (0.0892 g, 0.645 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.0315 g, 0.0430 mmol). The mixture was stirred at 100° C. for 12 hours under a nitrogen atmosphere. After cooling to ambient temperature, the mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate (20 ml) and water (20 ml). The layers were separated and the aqueous phase was extracted with ethyl acetate (3 x 20 ml). The combined organic extracts were washed with brine (20 ml), then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 25% ethyl acetate in petroleum ether to provide the title compound as a colorless solid (0.0600 g, 54% yield): 1 H NMR (400 MHz, DMSO-d 6) δ 10.32 (s, 1H), 8.97 (s, 2H), 8.62 (d, J = 4.8 Hz, 1H), 7.38 (d, J = 5.2 Hz, 1H), 7.34 (dd, J = 9.2, 4.8 Hz, 1H), 7.30-7.20 (m, MS(ES+)m / z485.3(M+1).

[0305] Step 2. Preparation of N-(2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)pyridin-3-yl)-2-(2-methylprop-1-en-1-yl)pyrimidine-5-carboxamide [ka] To a solution of N-(2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)pyridin-3-yl)-2-(2-methylprop-1-en-1-yl)pyrimidine-5-carboxamide (0.0600 g, 0.124 mmol) in methanol (5 ml) was added palladium on activated carbon (0.00600 g, 10 wt%) under nitrogen atmosphere. The mixture was degassed and purged with hydrogen three times. The mixture was stirred at 25° C. for 3 h under hydrogen atmosphere (15 psi). The resulting mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC eluting with a gradient of 48-78% acetonitrile in water containing 0.225% formic acid to provide the title compound as an off-white solid (0.0215 g, 0.0438 mmol, 35% yield): 1 H NMR (400 MHz, DMSO-d 6) δ 10.39 (s, 1H), 8.94 (s, 2H), 8.62 (d, J = 4.8 Hz, 1H), 8.46 (s, 1H), 7.37 (d, J = 4.8 Hz, 1H), 7.33 (dd, J = 9.2, 4.4 Hz, 1H), 7.30-7.20 (m, 2H), 3.23-3.17 (m, 1H), 2.80 (d, J = 7.2 Hz, 2H), 2.22 (tt, J = 13.6, 6.8 Hz, 1H), 2.08 (d, J = 4.4 Hz, 2H), 2.03-1.81 (m, 6H), 0.91 (d, J = 6.8 Hz, 6H); MS(ES+) m / z 487.3(M+1).

[0306] Examples 79 to 125 The following compounds were prepared in a manner similar to that described in the Examples disclosed herein (e.g., Example 56, Step 6) utilizing appropriately substituted starting materials and intermediates: [Table 7-1] [Table 7-2] [Table 7-3] [Table 7-4] [Table 7-5] [Table 7-6] [Table 7-7] [Table 7-8] [Table 7-9] [Table 7-10] [Table 7-11] [Table 7-12] [Table 7-13] [Table 7-14] [Table 7-15] [Table 7-16] [Table 7-17] [Table 7-18] [Table 7-19]

[0307] Example 126 and Example 127 Synthesis of N-(2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)pyridin-3-yl)-3-(trifluoromethyl)cyclobutane-1-carboxamide P1 and P2 [ka] N-(2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)pyridin-3-yl)-3-(trifluoromethyl)cyclobutane-1-carboxamide (0.0500 g, 0.0980 mmol) was purified by chiral SFC (column: DAICEL CHIRALPAK IG (250 mm×30 mm, 5 μm) eluting with 20% isopropanol containing 0.1% ammonium hydroxide in supercritical carbon dioxide to provide peak 1 (retention time=4.05 min) as a colorless solid (0.0128 g, 25% yield, 96% ee): 1 H NMR (400 MHz, MeOD) δ 8.55 (d, J = 4.8 Hz, 1H), 7.29 (d, J = 5.2 Hz, 1H), 7.27-7.14 (m, 2H), 7.14-7.00 (m, 1H), 3.27-3.16 (m, 1H), 3.14-2.99 (m, 1H), 2.96-2.77 (m, 1H), 2.53-2.09 (m, 5H), 2.09-1.93 (m, 3H), 1.92-1.69 (m, 4H);MS(ES+)m / z475.1(M+1).

[0308] Peak 2 (retention time = 4.96 min) was isolated as a colorless solid (0.0286 g, 55% yield, 96% ee): 1 H NMR (400 MHz, MeOD) δ 8.54 (d, J = 4.8 Hz, 1H), 7.28 (d, J = 4.8 Hz, 1H), 7.25-7.15 (m, 2H), 7.12-7.01 (m, 1H), 3.20-2.90 (m, 3H), 2.31-2.09 (m, 5H), 2.09-1.96 (m, 3H), 1.93-1.77 (m, 4H); MS(ES+)m / z 475.1(M+1).

[0309] Example 128 Synthesis of N-(2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)pyridin-3-yl)-2-(2-methylprop-1-en-1-yl)pyrimidine-5-carboxamide [ka] To a solution of 2-chloro-N-(2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)pyridin-3-yl)pyrimidine-5-carboxamide (0.0500 g, 0.108 mmol) in cyclobutanol (1 ml) was added cesium carbonate (0.105 g, 0.323 mmol). The mixture was stirred at 70° C. for 12 h. The mixture was cooled to ambient temperature and water (10 ml) was added. The mixture was extracted with ethyl acetate (3×20 ml). The combined organic layers were washed with brine (3×10 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC eluting with a gradient of 40-70% acetonitrile in water containing 0.225% formic acid to provide the title compound as a colorless solid (0.0267 g, 48% yield): 1 H NMR (400 MHz, CDCl 3 ) δ 8.82 (s, 2H), 8.69 (d, J = 4.8 Hz, 1H), 7.48 (s, 1H), 7.21 (d, J = 4.8 Hz, 1H), 7.18-7.01 (m, 3H), 5.25 (q, J = 7.2 Hz, 1H), 2.99 (t, J = 11.6 Hz, 1H), 2.56-2.41 (m, 2H), 2.29-2.08 (m, 6H), 2.00-1.82 (m, 4H), 1.75-1.68 (m, 2H); MS(ES+)m / z 501.3(M+1).

[0310] Example 129 Synthesis of (S)-N-(2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)pyridin-3-yl)-2-((1-methoxypropan-2-yl)oxy)pyrimidine-5-carboxamide [ka] To a solution of 2-chloro-N-(2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)pyridin-3-yl)pyrimidine-5-carboxamide (0.0500 g, 0.108 mmol) in dimethylformamide (0.5 ml) and tetrahydrofuran (0.5 ml) was added cesium carbonate (0.105 g, 0.323 mmol), 1,4-diazabicyclo[2.2.2]octane (0.00241 g, 0.0215 mmol) and (S)-1-methoxypropan-2-ol (0.0485 g, 0.538 mmol). The mixture was stirred at 50° C. for 12 hours. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was purified by preparative HPLC eluting with a gradient of 35-65% acetonitrile in water containing 0.225% formic acid to provide the title compound as a colorless solid (0.0151 g, 27% yield): 1 H NMR (400 MHz, CDCl 3 ) δ 8.83 (s, 2H), 8.69 (d, J = 4.8 Hz, 1H), 7.42 (s, 1H), 7.21 (d, J = 4.8 Hz, 1H), 7.17-7.05 (m, 3H), 5.54-5.43 (m, 1H), 3.69-3.63 (m, 1H), 3.59-3.52 (m, 1H), 3.40 (s, 3H), 3.07-2.93 (m, 1H), 2.28-2.20 (m, 2H), 2.19-2.08 (m, 2H), 1.95 (d, J = 13.2 Hz, 2H), 1.87-1.71 (m, 2H), 1.40 (d, J = 6.4 Hz, 3H); MS(ES+)m / z519.3(M+1).

[0311] Examples 130 to 154 The following compounds were prepared in a similar manner to that described in Example 129, utilizing appropriately substituted starting materials and intermediates: [Table 8-1] [Table 8-2] [Table 8-3] [Table 8-4] [Table 8-5] [Table 8-6] [Table 8-7] [Table 8-8] [Table 8-9] [Table 8-10] [Table 8-11] [Table 8-12] [Table 8-13]

[0312] Example 155 Synthesis of N-(2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)pyridin-3-yl)-2-(2-(difluoromethoxy)ethoxy)pyrimidine-5-carboxamide [ka] To a solution of N-[2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)-3-pyridyl]-2-(2-hydroxyethoxy)pyrimidine-5-carboxamide (0.0300 g, 0.061 mmol), cuprous iodide (0.00600 g, 0.0320 mmol) in acetonitrile (2 ml) at 70° C. was added 2,2-difluoro-2-fluorosulfonyl-acetic acid (0.0330 g, 0.183 mmol) in methyl cyanide (1 ml) dropwise over 30 min. The reaction mixture was stirred at this temperature for 1 h, then 2,2-difluoro-2-fluorosulfonyl-acetic acid (0.0330 g, 0.183 mmol) was added again dropwise over 30 min. The reaction mixture was diluted with ethyl acetate (30 ml) and washed with brine (2×10 ml). The organic layer was dried over sodium sulfate, and then the organic layer was concentrated under reduced pressure. The residue was purified by preparative HPLC eluting with a gradient of 40-70% acetonitrile in water containing 0.225% formic acid to provide the title compound as a colorless solid (0.00800 g, 23% yield): 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.26 (s, 1H), 8.90 (s, 2H), 8.63 (d, J = 4.8 Hz, 1H), 7.32 (s, 2H), 7.31-7.16 (m, 2H), 7.01-6.50 (t, J = 75.6 Hz, 1H), 4.60-4.55 (m, 2H), 4.33-4.09 (m, 2H), 3.23-3.13 (m, 1H), 2.10 (d, J = 3.2 Hz, 2H), 2.01-1.76 (m, 6H);MS(ES+)m / z541.3(M+1).

[0313] Example 156 Synthesis of N-(2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)pyridin-3-yl)-2-(2-(difluoromethoxy)ethoxy)pyrimidine-5-carboxamide [ka] Step 1. Preparation of methyl 5-((3-methylbut-3-en-1-yl)oxy)nicotinate [ka] To a mixture of methyl 5-hydroxynicotinate (4.00 g, 26.1 mmol) and 3-methylbut-3-en-1-ol (2.47 g, 28.7 mmol) in tetrahydrofuran (110 ml) was added triphenylphosphine (8.22 g, 31.3 mmol). The mixture was stirred at 25° C. under nitrogen atmosphere for 1 hour. Diethyl (E)-diazene-1,2-dicarboxylate (5.46 g, 31.3 mmol) was then added at 0° C. The mixture was stirred at 25° C. for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was poured into water (50 ml) and extracted with ethyl acetate (3×50 ml). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash silica gel chromatography eluting with 33% ethyl acetate in petroleum ether to provide the title compound as a colorless oil (4.00 g, 69% yield); 1 H NMR (400 MHz, CDCl 3 ) δ 8.81 (d, J = 1.6 Hz, 1H), 8.46 (d, J = 2.8 Hz, 1H), 7.76 (dd, J = 2.0, 2.8 Hz, 1H), 4.87 (s, 1H), 4.81 (s, 1H), 4.16 (t, J = 6.8 Hz, 2H), 3.94 (s, 3H), 2.53 (t, J = 6.8 Hz, 2H), 1.81 (s, 3H).

[0314] Step 2. Preparation of methyl 4,4-dimethyl-3,4-dihydro-2H-pyrano[3,2-b]pyridine-7-carboxylate [ka] To a mixture of methyl 5-((3-methylbut-3-en-1-yl)oxy)nicotinate (1.00 g, 4.52 mmol) in ethanol (20 ml) was added trifluoroacetic acid (1.03 g, 9.04 mmol). The mixture was stirred at 25° C. for 0.5 h. To the mixture were added tris[(Z)-1-methyl-3-oxo-but-1-enoxy]iron (0.79 g, 2.26 mmol), phenylsilane (1.22 g, 11.3 mmol) and 2-tert-butylperoxy-2-methyl-propane (1.98 g, 13.6 mmol) under nitrogen atmosphere. The mixture was stirred at 60° C. for 4 h. After cooling to ambient temperature, the reaction mixture was concentrated under reduced pressure. The residue was poured into water (20 ml) and extracted with ethyl acetate (3×15 ml). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography eluting with a gradient of 9% ethyl acetate in petroleum ether to provide the title compound as a colorless oil (0.500 g, 2.26 mmol, 50% yield): 1 H NMR (400 MHz, CDCl 3 ) δ 8.74 (d, J = 2.0 Hz, 1H), 7.65 (d, J = 2.0 Hz, 1H), 4.29-4.19 (m, 2H), 3.91 (s, 3H), 1.99-1.91 (m, 2H), 1.40 (s, 6H).

[0315] Step 3. Preparation of 4,4-dimethyl-3,4-dihydro-2H-pyrano[3,2-b]pyridine-7-carboxylic acid [ka] To a mixture of methyl 4,4-dimethyl-3,4-dihydro-2H-pyrano[3,2-b]pyridine-7-carboxylate (0.450 g, 2.03 mmol) in methanol (0.75 ml) and water (0.75 ml) was added sodium hydroxide (4 M, 9 ml). The mixture was stirred at 25° C. for 1 h. The reaction mixture was adjusted to pH=2 with hydrochloric acid (2 M). After filtration, the filter was concentrated in vacuo to provide the title compound as a colorless solid (0.180 g, 0.868 mmol, 43% yield): 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.50-12.95 (m, 1H), 8.61 (d, J = 2.0 Hz, 1H), 7.51 (d, J = 2.0 Hz, 1H), 4.30-4.16 (m, 2H), 2.02-1.82 (m, 2H), 1.33 (s, 6H).

[0316] Step 4. Preparation of N-(2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)pyridin-3-yl)-2-(2-(difluoromethoxy)ethoxy)pyrimidine-5-carboxamide [ka] To a mixture of 4,4-dimethyl-3,4-dihydro-2H-pyrano[3,2-b]pyridine-7-carboxylic acid (0.0500 g, 0.241 mmol), 2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)pyridin-3-amine (0.0782 g, 0.241 mmol), 2-chloro-1-methylpyridinium iodide (0.0739 g, 0.289 mmol) in tetrahydrofuran (1.5 ml) was added N,N-diisopropylethylamine (0.0935 g, 0.723 mmol). The mixture was stirred at 65° C. for 12 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was poured into water (20 ml) and extracted with ethyl acetate (3×15 ml). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the residue was purified by preparative HPLC eluting with a gradient of 50-80% acetonitrile in water containing 0.1% formic acid to provide the title compound as a colorless solid (0.0475 g, 35% yield): 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.16 (s, 1H), 8.60 (d, J = 4.8 Hz, 1H), 8.41-8.37 (m, 1H), 7.39-7.31 (m, 3H), 7.30-7.18 (m, 2H), 4.26- 4.18 (m, 2H), 3.21-3.10 (m, 1H), 2.15-2.02 (m, 2H), 2.00-1.76 (m, 8H), 1.31 (s, 6H); MS(ES+)m / z 514.4(M+1).

[0317] Example 157 Synthesis of N-(2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)pyridin-3-yl)-2-(3-methoxyazetidin-1-yl)pyrimidine-5-carboxamide [ka] To a solution of 2-chloro-N-(2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)pyridin-3-yl)pyrimidine-5-carboxamide (0.0500 g, 0.108 mmol) and 3-methoxyazetidine (0.0665 g, 0.538 mmol, hydrochloride salt) in dimethylsulfoxide (3 ml) was added N-ethyl-N-isopropylpropan-2-amine (0.209 g, 1.61 mmol). The mixture was stirred at 120° C. for 12 hours. After cooling to ambient temperature, ethyl acetate (10 ml) and water (10 ml) were added. The layers were separated and the aqueous phase was extracted with ethyl acetate (3×10 ml). The combined organic extracts were washed with brine (10 ml) and then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by preparative HPLC eluting with a gradient of 39-69% acetonitrile in water containing 0.225% formic acid to provide the title compound as a colorless solid (0.0306 g, 55% yield): 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.91 (s, 1H), 8.64 (s, 2H), 8.59 (d, J = 5.2 Hz, 1H), 7.37-7.28 (m, 2H), 7.28-7.16 (m, 2H), 4.41-4.20 (m, 3H), 3.95-3.87 (m, 2H), 3.26 (s, 3H), 3.22-3.07 (m, 1H), 2.08 (m, 2H), 2.00-1.74 (m, 6H); MS(ES+)m / z516.4(M+1).

[0318] Examples 158 to 182 The following compounds were prepared in a similar manner to that described in Example 157, utilizing appropriately substituted starting materials and intermediates: [Table 9-1] [Table 9-2] [Table 9-3] [Table 9-4] [Table 9-5] [Table 9-6] [Table 9-7] [Table 9-8] [Table 9-9] [Table 9-10] [Table 9-11] [Table 9-12] [Table 9-13]

[0319] Example 183 Synthesis of N-(2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)pyridin-3-yl)-2-(morpholine-4-carbonyl)pyrimidine-5-carboxamide [ka] Step 1. Preparation of (5-bromopyrimidin-2-yl)(morpholino)methanone [ka] To a mixture of 5-bromopyrimidine-2-carboxylic acid (1.00 g, 4.93 mmol), diisopropylethylamine (1.91 g, 14.8 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (2.25 g, 5.91 mmol) in dimethylformamide (10 ml) was added morpholine (0.644 g, 7.39 mmol) in one portion at 20° C. The mixture was stirred at 20° C. for 12 hours. The mixture was poured into water (10 ml) and extracted with ethyl acetate (3×10 ml). The combined organic layers were washed with brine (10 ml), dried over anhydrous sodium sulfate, filtered and the filtrate was evaporated under reduced pressure. The residue was purified by reverse phase chromatography eluting with 0.1% ammonium hydroxide in water to provide the title compound as a yellow solid (1.00 g, 74% yield): 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.10 (s, 2H), 3.71-3.60 (m, 4H), 3.54-3.48 (m, 2H), 3.24-3.19 (m, 2H).

[0320] Step 2. Preparation of methyl 2-(morpholine-4-carbonyl)pyrimidine-5-carboxylate [ka] To a mixture of (5-bromopyrimidin-2-yl)-morpholino-methanone (0.900 g, 3.31 mmol) and triethylamine (1.00 g, 9.92 mmol) in methanol (90 ml) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloro-palladium(II) (0.242 g, 0.331 mmol) in one portion at 20° C. The mixture was stirred at 80° C. under an atmosphere of carbon monoxide (50 psi) for 16 h. The mixture was cooled to 20° C. and evaporated under reduced pressure. The residue was purified by flash silica gel chromatography eluting with a gradient of 95-100% ethyl acetate in petroleum ether to provide the title compound as a brown solid (0.700 g, 84% yield): 1H NMR (400 MHz, DMSO-d 6 ) δ 9.31 (s, 2H), 3.93 (s, 3H), 3.67 (s, 4H), 3.56-3.48 (m, 2H), 3.22-3.15 (m, 2H).

[0321] Step 3. Preparation of 2-(morpholine-4-carbonyl)pyrimidine-5-carboxylic acid [ka] To a solution of methyl 2-(morpholine-4-carbonyl)pyrimidine-5-carboxylate (0.200 g, 0.796 mmol) in tetrahydrofuran (5 ml) and water (5 ml) was added potassium carbonate (0.165 g, 1.19 mmol) in one portion at 20° C. The mixture was stirred at 20° C. for 12 h. The mixture was adjusted to pH=3-4 with 10 wt% aqueous hydrochloric acid. The mixture was extracted with ethyl acetate (20 ml×5). The combined organic layers were washed with brine (10 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to provide the title compound as a brown solid (0.0500 g, 26% yield): 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.28 (s, 2H), 3.67 (s, 4H), 3.52-3.50 (m, 2H), 3.20-3.17 (m, 2H).

[0322] Step 4. Preparation of N-(2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)pyridin-3-yl)-2-(morpholine-4-carbonyl)pyrimidine-5-carboxamide [ka] To a mixture of 2-(morpholine-4-carbonyl)pyrimidine-5-carboxylic acid (0.0400 g, 0.169 mmol) and diisopropylethylamine (0.0872 g, 0.675 mmol) in tetrahydrofuran (1.5 ml) was added 2-chloro-1-methyl-pyridin-1-ium iodide (0.0517 g, 0.202 mmol) in one portion at 20° C. The mixture was stirred at 20° C. for 0.5 h, and then 2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)pyridin-3-amine (0.0820 g, 0.253 mmol) was added. The mixture was stirred at 70° C. for 12 h. The mixture was cooled to 20° C. and poured into water (10 ml). The mixture was extracted with ethyl acetate (10 ml×3). The combined organic layers were washed with brine (10 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure. The residue was purified by flash silica gel chromatography eluting with ethyl acetate followed by preparative HPLC eluting with a gradient of 1-30% ethanol in hexane to provide the title compound as a colorless solid (0.0180 g, 60% yield): 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.52 (s, 1H), 9.11 (s, 2H), 8.65 (d, J = 4.8 Hz, 1H), 7.43-7.33 (m, 2H), 7.33-7.23 (m, 2H), 3.68 (s, 4H), 3.53 (t, J = 4.4 Hz, 2H), 3.28-3.17 (m, 3H), 2.14-2.04(m, 2H), 2.04-1.77 (m, 6H);MS(ES+)m / z544.1(M+1).

[0323] Examples 184 to 185 The following compounds were prepared in a similar manner to that described in Example 183, utilizing appropriately substituted starting materials and intermediates: [Table 10]

[0324] Example 186 Synthesis of N-(2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)pyridin-3-yl)-2-(dimethylamino)acetamide [ka] Step 1. Preparation of 2-chloro-N-(2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)pyridin-3-yl)acetamide [ka] To a solution of 2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)pyridin-3-amine (0.100 g, 0.308 mmol), triethylamine (0.0945 g, 0.934 mmol) and N,N-dimethylpyridin-4-amine (0.00400 g, 0.0327 mmol) in dichloromethane (4 ml) was added 2-chloroacetyl chloride (0.0420 g, 0.372 mmol). The mixture was stirred at 25° C. for 12 hours. Triethylamine (0.156 g, 1.54 mmol) and 2-chloroacetyl chloride (0.175 g, 1.55 mmol) were then added. The resulting mixture was stirred at 25° C. for 2 hours. The reaction was quenched with water (5 ml). The organic solvent was removed under reduced pressure. The aqueous phase was extracted with ethyl acetate (2×10 ml). The combined extracts were washed with brine (10 ml), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC eluting with a gradient of 37-67% acetonitrile in water containing 0.225% formic acid to provide the title compound as a yellow solid (0.0650 g, 53% yield): 1 H NMR (400 MHz, CDCl 3) δ 8.66 (d, J = 4.8 Hz, 1H), 8.00 (s, 1H), 7.22-7.09 (m, 3H), 7.06-6.99 (m, 1H), 4.01 (s, 2H), 2.99-2.86 (m, 1H), 2.32-2.19 (m, 2H), 2.19-2.05 (m, 2H), 1.97-1.73 (m, 5H); MS(ES+)m / z401.1, 403.1(M+1).

[0325] Step 2. Preparation of N-(2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)pyridin-3-yl)-2-(dimethylamino)acetamide [ka] A mixture of 2-chloro-N-(2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)pyridin-3-yl)acetamide (0.0650 g, 0.162 mmol), dimethylamine (0.0270 g, 0.331 mmol, hydrochloride salt) and potassium carbonate (0.113 g, 0.818 mmol) in acetonitrile (5 ml) was stirred at 50° C. for 2 hours. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. Ethyl acetate (10 ml) and water (10 ml) were added and the layers were separated. The aqueous phase was extracted with ethyl acetate (2×10 ml). The combined extracts were washed with brine (10 ml), dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC eluting with a gradient of 9 to 39% acetonitrile in water containing 0.225% formic acid to provide the title compound as a colorless solid (0.0296 g, 44% yield): 1 H NMR (400 MHz, MeOD-d 4) δ 8.55 (d, J = 4.8 Hz, 1H), 7.29 (d, J = 4.8 Hz, 1H), 7.28-7.16 (m, 2H), 7.13 (ddd, J = 8.4, 5.6, 3.2 Hz, 1H), 3.14-2.99 (m, 3H), 2.28-2.11 (m, 8H), 2.10-1.97 (m, 2H), 1.97-1.78 (m, 4H); MS(ES+)m / z410.2, 412.2(M+1).

[0326] Example 187 Synthesis of N-(2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)pyridin-3-yl)-2-morpholinoacetamide [ka] Utilizing appropriately substituted starting materials and intermediates in a manner similar to those described in the examples disclosed herein, the title compound was provided as a colorless solid (0.119 g, 13% yield): 1 H NMR (400 MHz, MeOD-d 4 ) δ 8.57 (d, J = 5.2 Hz, 1H), 7.31 (d, J = 5.2 Hz, 1H), 7.29-7.19 (m, 2H), 7.14 (ddd, J = 8.4, 5.6, 2.8 Hz, 1H), 3.72-3.61 (m, 4H), 3.13-3.01 (m, 3H), 2.41-2.31 (m, 4H), 2.26-2.12 (m, 2H), 2.05 (d, J = 14.0 Hz, 2H), 1.90 (d, J = 14.4 Hz, 4H);MS(ES+)m / z452.1(M+1).

[0327] Example 188 Synthesis of 1-(tert-butyl)-3-(2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)pyridin-3-yl)urea [ka] Step 1. Preparation of 1-(tert-butyl)-3-(2-chloro-4-(2,5-difluorophenyl)pyridin-3-yl)urea [ka] A solution of tert-butyl (2-chloro-4-(2,5-difluorophenyl)pyridin-3-yl)carbamate (0.100 g, 0.293 mmol), 2-methylpropan-2-amine (0.0220 g, 0.300 mmol), 4-dimethylaminopyridine (0.0400 g, 0.327 mmol) and 4 Å molecular sieves (0.1 g) in N,N-dimethylformamide (5 ml) was stirred at 25° C. for 1 h under nitrogen atmosphere. The reaction mixture was warmed to 110° C. and stirred at 110° C. for 12 h. The mixture was cooled to 25° C. The reaction mixture was diluted with water (10 ml) and extracted with ethyl acetate (2×10 ml). The combined organic layers were washed with brine (10 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography eluting with a gradient of 50 to 65% ethyl acetate in petroleum ether to provide the title compound as a yellow oil (0.0800 g, 73% yield): 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.28 (d, J = 4.8 Hz, 1H), 7.76 (s, 1H), 7.41 (dd, J = 4.8, 1.2 Hz, 1H), 7.35 (dt, J = 9.2, 4.4 Hz, 1H), 7.30-7.19 (m, 2H), 6.18 (s, 1H), 1.06 (s, 9H); MS(ES+)m / z340.1, 342.1(M+1).

[0328] Step 2. Preparation of 1-(tert-butyl)-3-(2-(4,4-difluorocyclohex-1-en-1-yl)-4-(2,5-difluorophenyl)pyridin-3-yl)urea [ka] To a solution of 1-(tert-butyl)-3-(2-chloro-4-(2,5-difluorophenyl)pyridin-3-yl)urea (0.0800 g, 0.235 mmol) and 2-(4,4-difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.0630 g, 0.258 mmol) in dioxane (4 ml) and water (1 ml) under nitrogen atmosphere was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.0170 g, 0.0230 mmol) and potassium carbonate (0.0970 g, 0.701 mmol). The mixture was stirred at 100° C. for 2 hours. The reaction mixture was cooled to 25° C. The reaction mixture was diluted with water (10 ml) and extracted with ethyl acetate (2×10 ml). The combined organic layers were washed with brine (10 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography eluting with a gradient of 60-75% ethyl acetate in petroleum ether to provide the title compound as a yellow oil (0.0330 g, 29% yield): 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.41 (d, J = 4.8 Hz, 1H), 7.35 (dd, J = 9.2, 4.4 Hz, 1H), 7.32-7.27 (m, 2H), 7.27-7.21 (m, 2H), 6.00 (s, 1H), 5.77 (s, 1H), 2.70-2.64 (m, 4H), 2.20-2.06 (m, 2H), 1.11 (s, 9H).

[0329] Step 3. Preparation of 1-(tert-butyl)-3-(2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)pyridin-3-yl)urea [ka] Palladium on carbon (0.0300 g, 10 wt% purity) was added to a solution of 1-(tert-butyl)-3-(2-(4,4-difluorocyclohex-1-en-1-yl)-4-(2,5-difluorophenyl)pyridin-3-yl)urea (0.0300 g, 0.0710 mmol) in methanol (3 ml) under nitrogen atmosphere. The suspension was degassed and purged with hydrogen three times. The mixture was stirred under hydrogen (15 psi, balloon) at 25° C. for 12 h. The resulting mixture was filtered through Celite. The filter cake was washed with methanol (30 ml). The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC eluting with a gradient of 40-70% acetonitrile in water containing 0.225% formic acid to provide the title compound as a yellow solid (0.00530 g, 17% yield): 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.44 (d, J = 4.8 Hz, 1H), 7.50-7.41 (m, 1H), 7.34 (td, J = 9.2, 4.4 Hz, 1H), 7.31-7.24 (m, 1H), 7.24-7.15 (m, 2H), 6.04-5.95 (m, 1H), 3.10 (d, J = 5.2 Hz, 1H), 2.22-2.08 (m, 2H), 1.97-1.74 (m, 6H), 1.12 (s, 9H); MS(ES+)m / z424.2(M+1).

[0330] Examples 189 to 192 The following compounds were prepared in a manner similar to that described in the examples disclosed herein, utilizing appropriately substituted starting materials and intermediates: [Table 11-1] [Table 11-2]

[0331] Example 193 Synthesis of N-(2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)pyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxamide [ka] To a mixture of tert-butyl 6-((2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)pyridin-3-yl)carbamoyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (0.0500 g, 0.0911 mmol) in dichloromethane (1 ml) was added trifluoroacetic acid (0.154 g, 1.35 mmol). The mixture was stirred at 25 °C for 1 h, then saturated sodium bicarbonate (10 ml) was added. The mixture was extracted with ethyl acetate (3 x 15 ml). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC eluting with a gradient of 37-67% acetonitrile in water containing ammonium hydroxide to provide the title compound as a colorless solid (0.00800 g, 18% yield): 1 H NMR (400 MHz, CDCl 3 ) δ 8.58 (d, J = 4.8 Hz, 1H), 7.21-7.10 (m, 3H), 7.09-7.02 (m, 1H), 5.61 (s, 1H), 3.90 (s, 4H), 3.71 (s, 4H), 3.09 (t, J = 11.2 MS(ES+)m / z449.3(M+1).

[0332] Example 194 Synthesis of N-(2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)pyridin-3-yl)-6-methyl-2,6-diazaspiro[3.3]heptane-2-carboxamide [ka] To a mixture of N-(2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)pyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxamide (0.0600 g, 0.133 mmol) in methanol (2 ml) was added paraformaldehyde (0.0336 g, 0.535 mmol). The mixture was stirred at 25° C. for 0.5 h and then sodium cyanoborohydride (0.0160 g) was added. The mixture was stirred at 25° C. for 12 h. The residue was poured into water (20 ml) and extracted with ethyl acetate (3×15 ml). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC eluting with a gradient of 27-57% acetonitrile in water containing 0.05% ammonium hydroxide to provide the title compound as a colorless solid (0.0192 g, 30% yield): 1 H NMR (400 MHz, CDCl 3 ) δ 8.58 (d, J = 4.8 Hz, 1H), 7.21-7.09 (m, 3H), 7.06 (ddd, J = 8.4, 5.6, 2.8 Hz, 1H), 5.59 (s, 1H), 3.85 (s, 4H), 3.26 (s, 4H), 3.16-3.03 (m, 1H), 2.31-2.27 (m, 3H), 2.26-2.19 (m, 2H), 2.16-2.02 (m, 2H), 1.97-1.75 (m, 4H);MS(ES+)m / z 463.3(M+1).

[0333] Example 195 Synthesis of N-(2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)pyridin-3-yl)-2-(2-hydroxypropan-2-yl)pyrimidine-5-carboxamide [ka] Step 1. Preparation of 2-(5-bromopyrimidin-2-yl)propan-2-ol [ka] To a solution of methyl 5-bromopyrimidine-2-carboxylate (2.00 g, 9.22 mmol) in dichloromethane (40 ml) was added methylmagnesium bromide (3.00 M in tetrahydrofuran, 12.3 ml) dropwise at 0° C. The reaction mixture was stirred at 0° C. for 30 minutes. The reaction mixture was gradually warmed to 20° C. and stirred at 20° C. for 12 hours. The reaction was quenched with saturated ammonium chloride solution (20 ml) at 0° C. The mixture was diluted with ethyl acetate (30 ml) and water (30 ml). The layers were separated and the aqueous phase was extracted with ethyl acetate (2×30 ml). The organic layer was washed with brine (30 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography eluting with a gradient of 0-30% ethyl acetate in petroleum ether to provide the title compound as a yellow solid (1.10 g, 53% yield); 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.98 (s, 2H), 5.14 (s, 1H), 1.49 (s, 6H).

[0334] Step 2. Preparation of methyl 2-(2-hydroxypropan-2-yl)pyrimidine-5-carboxylate [ka] To a solution of 2-(5-bromopyrimidin-2-yl)propan-2-ol (1.40 g, 6.45 mmol) in methanol (40 ml) was added triethylamine (2.00 g, 19.8 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.476 g, 0.651 mmol) in one portion. The solution was stirred at 80° C. under an atmosphere of carbon monoxide (50 psi) for 16 h. The resulting mixture was cooled to 20° C. and filtered through a pad of Celite. The filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography eluting with a gradient of 0-40% ethyl acetate in petroleum ether to provide the title compound as a white solid (1.00 g, 78% yield);1 H NMR (400 MHz, DMSO-d 6 ) δ 9.23 (s, 2H), 5.26 (s, 1H), 3.91 (s, 3H), 1.51 (s, 6H).

[0335] Step 3. Preparation of 2-(2-hydroxypropan-2-yl)pyrimidine-5-carboxylic acid [ka] To a solution of methyl 2-(2-hydroxypropan-2-yl)pyrimidine-5-carboxylate (0.400 g, 2.04 mmol) in tetrahydrofuran (10 ml) was added a solution of lithium hydroxide hydrate (0.428 g, 10.2 mmol) in water (10 ml) at 0° C. The reaction mixture was stirred at 15° C. for 1 h. The residue was diluted with ethyl acetate (30 ml) and water (30 ml). The layers were separated and the aqueous phase was acidified to pH=4 with 1 M hydrochloric acid. The aqueous phase was extracted with ethyl acetate (3×30 ml). The organic layer was washed with brine (30 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to provide 2-(2-hydroxypropan-2-yl)pyrimidine-5-carboxylic acid as a colorless solid (0.0500 g, 13% yield): 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.19 (s, 2H), 5.24 (br s, 1H), 1.50 (s, 6H).

[0336] Step 4. Preparation of N-(2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)pyridin-3-yl)-2-(2-hydroxypropan-2-yl)pyrimidine-5-carboxamide [ka] Utilizing appropriately substituted starting materials and intermediates in a manner similar to those described in the examples disclosed herein, the title compound was provided as a colorless solid (0.0440 g, 54% yield): 1 H NMR (400 MHz, DMSO-d6 ) δ 10.40 (s, 1H), 9.01 (s, 2H), 8.63 (d, J = 4.8 Hz, 1H), 7.42-7.32 (m, 2H), 7.26 (dd, J = 8.0, 2.8 Hz, 2H), 5.20 (s, 1H), 3.27-3.14 (m, 1H), 2.20-2.04 (m, 2H), 2.03-1.73 (m, 6H), 1.50 (s, 6H); MS(ES+)m / z 489.2(M+1).

[0337] Example 196 Synthesis of N-(2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)pyridin-3-yl)-2-(2-methoxypropan-2-yl)pyrimidine-5-carboxamide [ka] Step 1. Preparation of methyl 2-(2-methoxypropan-2-yl)-pyrimidine-5-carboxylate [ka] To a solution of sodium hydride (0.245 g, 6.13 mmol, 60% purity) in dimethylformamide (8 ml) was added methyl 2-(2-hydroxypropan-2-yl)pyrimidine-5-carboxylate (0.400 g, 2.04 mmol) in dimethylformamide (3 ml) at 15° C. under nitrogen atmosphere. The reaction mixture was stirred at 50° C. for 0.5 h. To the mixture was added iodomethane (0.868 g, 6.12 mmol) dropwise and the reaction mixture was stirred at 50° C. for 2 h. The reaction mixture was added dropwise to 1M aqueous formic acid solution (10 ml) at 0° C. and then diluted with ethyl acetate (20 ml). The organic layer was washed with brine (25 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography eluting with a gradient of 0 to 40% ethyl acetate in petroleum ether to provide the title compound as a colorless solid (0.240 g, 56% yield): 1 H NMR (400 MHz, DMSO-d6 ) δ 9.25 (s, 2H), 3.91 (s, 3H), 3.01 (s, 3H), 1.55 (s, 6H).

[0338] Step 2. Preparation of 2-(2-methoxypropan-2-yl)pyrimidine-5-carboxylic acid [ka] To a solution of methyl 2-(2-methoxypropan-2-yl)pyrimidine-5-carboxylate (0.200 g, 0.951 mmol) in tetrahydrofuran (3 ml) was added lithium hydroxide monohydrate (0.0800 g, 1.91 mmol) in water (3 ml) at 0° C. and the reaction mixture was stirred at 15° C. for 1 h. The mixture was diluted with ethyl acetate (15 ml) and water (15 ml). The layers were separated and the aqueous phase was acidified to pH=3 with 1 M hydrochloric acid. The aqueous phase was extracted with ethyl acetate (2×20 ml). The organic layer was washed with brine (25 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to provide the title compound as a colorless solid (0.120 g, 64% yield): 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.77 (br s, 1H), 9.22 (s, 2H), 3.01 (s, 3H), 1.55 (s, 6H).

[0339] Step 3. Preparation of N-(2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)pyridin-3-yl)-2-(2-methoxypropan-2-yl)pyrimidine-5-carboxamide [ka] Utilizing appropriately substituted starting materials and intermediates in a manner similar to those described in the examples disclosed herein, the title compound was provided as a colorless solid (0.209 g, 79% yield): 1 H NMR (400 MHz, DMSO-d 6) δ 10.44(s, 1H), 9.02 (s, 2H), 8.63 (d, J = 4.8 Hz, 1H), 7.43-7.33 (m, 2H), 7.33-7.21 (m, 2H), 3.28-3.14 (m, 1H), 3.02 (s, 3H), 2.16-2.04 (m, 2H), 2.03-1.76 (m, 6H), 1.54 (s, 6H); MS(ES+)m / z 503.2(M+1).

[0340] Example 197 Synthesis of N-(2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)pyridin-3-yl)-2-(2-fluoropropan-2-yl)pyrimidine-5-carboxamide [ka] Step 1. Preparation of methyl 2-(2-fluoropropan-2-yl)pyrimidine-5-carboxylate [ka] A solution of methyl 2-(1-hydroxy-1-methyl-ethyl)pyrimidine-5-carboxylate (0.250 g, 1.27 mmol) in dichloromethane (10 ml) was added to the reaction mixture. 4 -sulfanamine (0.616 g, 3.82 mmol) was added dropwise at -65 °C under nitrogen atmosphere. The reaction mixture was stirred at 15 °C for 16 h. Saturated sodium bicarbonate solution (20 ml) was added to the mixture at 0 °C. The solution was extracted with dichloromethane (3 x 10 ml). The combined organic extracts were washed with brine (2 x 20 ml), then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography eluting with a gradient of 0-40% ethyl acetate in petroleum ether to provide the title compound as a colorless solid (0.210 g, 82% yield): 1 H NMR (400 MHz, DMSO-d 6) δ 9.28 (s, 2H), 3.92 (s, 3H), 1.77 (s, 3H), 1.71 (s, 3H).

[0341] Step 2. Preparation of 2-(2-methoxypropan-2-yl)pyrimidine-5-carboxylic acid [ka] Using an analogous procedure to those described in the Examples disclosed herein, utilizing appropriately substituted starting materials and intermediates, the title compound was afforded as a colorless solid (0.130 g, 69% yield) as a white solid: 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.26 (s, 2H), 1.77 (s, 3H), 1.72 (s, 3H).

[0342] Step 3. Preparation of N-(2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)pyridin-3-yl)-2-(2-fluoropropan-2-yl)pyrimidine-5-carboxamide [ka] Using an analogous procedure to those described in the examples disclosed herein, utilizing appropriately substituted starting materials and intermediates, the title compound was provided as a colorless solid (0.125 g, 0.242 mmol): 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.47 (s, 1H), 9.06 (s, 2H), 8.64 (d, J = 4.8 Hz, 1H), 7.42-7.33 (m, 2H), 7.32-7.21 (m, 2H), 3.27-3.12 (m, 1H), 2.15-2.05 (m, 2H), 2.04-1.79 (m, 6H), 1.76 (s, 3H), 1.71 (s, 3H); MS(ES+)m / z 491.3(M+1).

[0343] Example 198 Synthesis of N-(2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)pyridin-3-yl)-2-(2-fluoropropan-2-yl)pyrimidine-5-carboxamide [ka] Step 1. Preparation of methyl 5-((2-methylallyl)oxy)nicotinate [ka] To a mixture of methyl 5-hydroxynicotinate (4.00 g, 26.1 mmol) and 2-methylprop-2-en-1-ol (2.07 g, 28.7 mmol) in tetrahydrofuran (100 ml) was added triphenylphosphine (8.22 g, 31.3 mmol) under nitrogen atmosphere. The mixture was stirred at 25° C. for 1 h, and then diethyl (E)-diazene-1,2-dicarboxylate (5.46 g, 31.3 mmol) was added at 0° C. The mixture was stirred at 25° C. for 12 h. The residue was poured into water (30 ml) and extracted with ethyl acetate (3×30 ml). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash silica gel chromatography eluting with a gradient of 33% ethyl acetate in petroleum ether to provide the title compound as a yellow oil (2.0 g, 37% yield): 1 H NMR (400 MHz, CDCl 3 ) δ 8.82 (s, 1H), 8.50 (d, J = 2.8 Hz, 1H), 7.79-7.75 (m, 1H), 5.12 (s, 1H), 5.05 (s, 1H), 4.53 (s, 2H), 3.96 (s, 3H), 1.84 (s, 3H).

[0344] Step 2. Preparation of methyl 3,3-dimethyl-2,3-dihydrofuro[3,2-b]pyridine-6-carboxylate [ka] To a mixture of methyl 5-((2-methylallyl)oxy)nicotinate (1.00 g, 4.83 mmol) in ethanol (10 ml) was added trifluoroacetic acid (1.10 g, 9.65 mmol). The mixture was stirred at 25° C. for 1 h, then tris[(Z)-1-methyl-3-oxo-but-1-enoxy]iron (0.852 g, 2.41 mmol), phenylsilane (1.31 g, 12.1 mmol) and 2-tert-butylperoxy-2-methyl-propane (2.12 g, 14.5 mmol) were added under nitrogen atmosphere. The mixture was stirred at 110° C. in a sealed tube for 24 h. After cooling to ambient temperature, the reaction mixture was concentrated under reduced pressure. The residue was poured into water (20 ml) and extracted with ethyl acetate (3×15 ml). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. The residue was purified by flash silica gel chromatography eluting with a gradient of 33% ethyl acetate in petroleum ether to provide the title compound as a yellow oil (0.300 g, 12% yield): 1 H NMR (400 MHz, CDCl 3 ) δ 8.66 (s, 1H), 8.27 (s, 1H), 4.28 (s, 2H), 3.94 (s, 3H), 1.51 (s, 6H).

[0345] Step 3. Preparation of 3,3-dimethyl-2,3-dihydrofuro[3,2-b]pyridine-6-carboxylic acid [ka] To a mixture of methyl 3,3-dimethyl-2,3-dihydrofuro[3,2-b]pyridine-6-carboxylate (0.250 g, 1.21 mmol) in methanol (1.2 ml) was added a solution of sodium hydroxide (0.0965 g, 2.41 mmol) in water (1.2 ml). The mixture was stirred at 25° C. for 4 h. The reaction mixture was poured into water (10 ml) and adjusted to pH=2 with hydrochloric acid (2 M). The mixture was lyophilized to give 3,3-dimethyl-2,3-dihydrofuro[3,2-b]pyridine-6-carboxylic acid as a black-brown solid (0.310 g, crude): 1H NMR (400 MHz, DMSO-d 6 ) δ 8.57 (s, 1H), 8.44 (s, 1H), 4.35 (s, 2), 1.46 (s, 6H).

[0346] Step 4. Preparation of N-(2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)pyridin-3-yl)-2-(2-fluoropropan-2-yl)pyrimidine-5-carboxamide [ka] Using an analogous procedure to those described in the examples disclosed herein, utilizing appropriately substituted starting materials and intermediates, the title compound was provided as a colorless solid (0.125 g, 0.242 mmol): 1 H NMR (400 MHz, CDCl 3 ) δ 8.70 (d, J = 4.8 Hz, 1H), 8.26 (s, 1H), 8.11 (s, 1H), 7.47 (s, 1H), 7.23-7.21 (m, 1H), 7.20-7.14 (m, 1H), 7.14-7.07 (m, MS(ES+)m / z 500.4(M+1).

[0347] Example 199 Synthesis of N-(2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)pyridin-3-yl)-2-(1-(hydroxymethyl)cyclopropyl)acetamide [ka] Step 1. Synthesis of 2-(1-((benzyloxy)methyl)cyclopropyl)acetonitrile [ka] To a solution of 2-(1-(hydroxymethyl)cyclopropyl)acetonitrile (0.500 g, 4.50 mmol) in tetrahydrofuran (5 ml) was added sodium hydride (0.270 g, 6.75 mmol, 60% purity) at 0° C. under an atmosphere of nitrogen. The mixture was stirred at 25° C. for 0.5 h, then (bromomethyl)benzene (1.54 g, 9.00 mmol) was added at 25° C. The mixture was stirred at 25° C. for 12 h. The mixture was diluted with ethyl acetate (50 ml), washed with saturated sodium bicarbonate (3×50 ml), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography eluting with a gradient of 0–3% ethyl acetate in petroleum ether to provide the title compound as a colorless solid (0.660 g, 69% yield): 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.40-7.32 (m, 4H), 7.32-7.24 (m, 1H), 4.50 (s, 2H), 3.34 (s, 2H), 2.64 (s, 2H), 0.61-0.46 (m, 4H).

[0348] Step 2. Synthesis of 2-(1-((benzyloxy)methyl)cyclopropyl)acetic acid [ka] To a solution of 2-(1-((benzyloxy)methyl)cyclopropyl)acetonitrile (0.560 g, 2.78 mmol) in ethanol (6 ml) was added potassium hydroxide (1.56 g, 27.9 mmol) in water (6 ml) at 25° C. The mixture was stirred at 80° C. for 12 h. The mixture was poured into aqueous 1 M hydrochloric acid (50 ml). The mixture was extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried over sodium sulfate and filtered. The filtrate was evaporated under reduced pressure to give the title compound as a colourless oil (0.490 g, 68% yield): 1 H NMR (400 MHz, CDCl 3) δ 7.44-7.28 (m, 5H), 4.58 (s, 2H), 3.40 (s, 2H), 2.51 (s, 2H), 0.62-0.55 (m, 4H).

[0349] Step 3. Preparation of 2-(1-((benzyloxy)methyl)cyclopropyl)-N-(2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)pyridin-3-yl)acetamide [ka] Using an analogous procedure to those described in the examples disclosed herein, utilizing appropriately substituted starting materials and intermediates, the title compound was provided as a colorless solid (0.240 g, 48% yield): 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.44 (s, 1H), 8.53 (d, J = 4.8 Hz, 1H), 7.36-7.24 (m, 8H), 7.15 (ddd, J = 8.8, 5.6, 3.2 Hz, 1H), 4.46-4.37 (m, 2H), 3.37-3.28 (m, 4H), 3.10-3.05 (m, 1H), 2.23 (s, 1H), 2.17-2.06 (m, 2H), 1.92-1.70 (m, 5H), 0.45 (d, J = 4.4 Hz, 2H), 0.37 (d, J = 12.0 Hz, 2H);MS(ES+)m / z 527.3(M+1).

[0350] Step 4. Preparation of N-(2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)pyridin-3-yl)-2-(1-(hydroxymethyl)cyclopropyl)acetamide [ka] To a solution of 2-(1-((benzyloxy)methyl)cyclopropyl)-N-(2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)pyridin-3-yl)acetamide (0.0400 g, 0.0760 mmol) in methanol (4 ml) was added palladium on carbon (0.0200 g, 10 wt%) at 25° C. under nitrogen atmosphere. The suspension was degassed and purged with hydrogen three times. The mixture was stirred under hydrogen (15 psi, balloon) at 25° C. for 12 h. After completion of the reaction, the resulting mixture was filtered through Celite. The filter cake was washed with methanol (30 ml). The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC eluting with a gradient of 39-59% acetonitrile in water containing 0.225% formic acid to provide the title compound as a colorless solid (0.0152 mg, 45% yield): 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.48 (s, 1H), 8.53 (d, J = 4.4 Hz, 1H), 7.41-7.21 (m, 3H), 7.14 (s, 1H), 4.53 (s, 1H), 3.13 (s, 3H), 2.25-2.07 (m, 4H), 1.98-1.71 (m, 6H), 0.31 (d, J = 16.0 Hz, 4H); MS(ES+)m / z 437.2(M+1).

[0351] Example 200 Synthesis of N-(4-(4,4-difluorocyclohexyl)-6-(2,5-difluorophenyl)-2-methylpyrimidin-5-yl)-5-fluoro-6-methoxynicotinamide [ka] Step 1. Preparation of 4-chloro-6-(2,5-difluorophenyl)-2-methylpyrimidin-5-amine [ka] To a solution of 4,6-dichloro-2-methylpyrimidin-5-amine (0.200 g, 1.12 mmol), (2,5-difluorophenyl)boronic acid (0.159 g, 1.01 mmol) and potassium carbonate (0.310 g, 2.24 mmol) in dimethylformamide (5 ml) and water (1 ml) under nitrogen atmosphere was added tetrakis(triphenylphosphine)palladium(0) (0.130 g, 0.112 mmol). The mixture was stirred at 80° C. The mixture was cooled to 25° C. and concentrated under reduced pressure. The residue was purified by preparative HPLC eluting with a gradient of 25-55% acetonitrile in water containing 0.225% formic acid to provide the title compound as a colorless solid (0.0370 g, 12% yield): 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.41-7.37 (m, 2H), 7.36-7.31 (m, 1H), 5.43 (s, 2H), 2.45 (s, 3H); MS(ES+)m / z 256.0, 258.0(M+1).

[0352] Step 2. Preparation of 4-(4,4-difluorocyclohex-1-en-1-yl)-6-(2,5-difluorophenyl)-2-methylpyrimidin-5-amine [ka] To a solution of 4-chloro-6-(2,5-difluorophenyl)-2-methylpyrimidin-5-amine (0.0370 g, 0.144 mmol), 2-(4,4-difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.0390 g, 0.159 mmol) and potassium carbonate (0.0600 g, 0.434 mmol) in dioxane (4 ml) and water (1 ml) under nitrogen atmosphere was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.0110 g, 0.0150 mmol). The mixture was stirred at 100° C. for 2 hours. The mixture was cooled to 25° C. The mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography eluting with a gradient of 30 to 50% ethyl acetate in petroleum ether to provide the title compound as a yellow oil (0.0170 g, 31% yield): 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.41-7.35 (m, 2H), 7.34-7.29 (m, 1H), 6.03 (s, 1H), 4.92-4.70 (m, 2H), 2.78-2.72 (m, 2H), 2.61 (s, 2H), 2.44 (s, 3H), 2.19 (td, J = 7.2, 14.0 Hz, 2H); MS(ES+)m / z 338.1(M+1).

[0353] Step 3. Preparation of 4-(4,4-difluorocyclohexyl)-6-(2,5-difluorophenyl)-2-methylpyrimidin-5-amine [ka] Palladium on carbon (0.0170 g, 10 wt%) was added to a solution of 4-(4,4-difluorocyclohex-1-en-1-yl)-6-(2,5-difluorophenyl)-2-methylpyrimidin-5-amine (0.0170 g, 0.0500 mmol) in methanol (3 ml) under nitrogen atmosphere. The suspension was degassed and purged with hydrogen three times. The mixture was stirred at 25° C. under hydrogen (15 psi, balloon) for 1 h. After completion of the reaction, the resulting mixture was filtered through Celite. The filter cake was washed with methanol (15 ml). The filtrate was concentrated under reduced pressure to provide the title compound as a yellow oil (0.0120 g, 63% yield): MS (ES+) m / z 340.1 (M+1).

[0354] Step 4. Preparation of N-(4-(4,4-difluorocyclohexyl)-6-(2,5-difluorophenyl)-2-methylpyrimidin-5-yl)-5-fluoro-6-methoxynicotinamide [ka] Using an analogous procedure to those described in the examples disclosed herein, utilizing appropriately substituted starting materials and intermediates, the title compound was provided as a colorless solid (0.00770 g, 43% yield): 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.23 (s, 1H), 8.40 (d, J = 2.0 Hz, 1H), 7.95 (dd, J = 10.8, 2.0 Hz, 1H), 7.35-7.25 (m, 3H), 4.00 (s, 3H), 3.18-3.11 (m, 1H), 2.69 (s, 3H), 2.09-2.07 (m, 2H), 2.00-1.89 (m, 2H), 1.88-1.80 (m, 4H); MS(ES+)m / z493.1(M+1).

[0355] Example 201 Synthesis of N-(2-(4,4-difluorocyclohexyl)-4-(tetrahydro-2H-pyran-2-yl)pyridin-3-yl)-2-isopropylpyrimidine-5-carboxamide [ka] Step 1. Preparation of tert-butyl (2-chloro-4-(3,4-dihydro-2H-pyran-6-yl)pyridin-3-yl)carbamate [ka] A mixture of tert-butyl N-(2-chloro-4-iodo-3-pyridyl)carbamate (0.500 g, 1.41 mmol), 2-(3,4-dihydro-2H-pyran-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.355 g, 1.69 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.103 g, 0.141 mmol) and potassium carbonate (0.584 g, 4.23 mmol) in dioxane (5 ml) / water (1 ml) was stirred under nitrogen atmosphere at 70° C. for 12 hours. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography eluting with a gradient of 0 to 30% ethyl acetate in petroleum ether to provide the title compound as a colorless solid (0.400 g, 90% yield): 1 H NMR (400 MHz, CDCl 3 ) δ 8.19 (d, J = 5.2 Hz, 1H) 7.27 (d, J = 5.2 Hz, 1H), 6.63-6.37 (m, 1H), 5.32 (t, J = 4.0 Hz, 1H), 4.22-4.15 (m, 2H), 2.24 (dt, J = 4.4, 6.4 Hz, 2H), 2.01-1.87 (m, 2H), 1.51 (s, 9H).

[0356] Step 2. Preparation of tert-butyl (2-(4,4-difluorocyclohex-1-en-1-yl)-4-(3,4-dihydro-2H-pyran-6-yl)pyridin-3-yl)carbamate [ka] A mixture of 2-(4,4-difluorocyclohexen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.188 g, 0.772 mmol), tert-butyl (2-chloro-4-(3,4-dihydro-2H-pyran-6-yl)pyridin-3-yl)carbamate (0.200 g, 0.643 mmol), potassium carbonate (0.267 g, 1.93 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.0471 g, 0.0644 umol) in dioxane (2 ml) / water (0.4 ml) was stirred at 100° C. for 12 hours under nitrogen atmosphere. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography eluting with a gradient of 0 to 32% ethyl acetate in petroleum ether to provide the title compound as a colorless solid (0.200 g, 79% yield): 1 H NMR (400 MHz, CDCl 3 ) δ 8.36 (d, J = 4.8 Hz, 1H), 7.14 (d, J = 4.8 Hz, 1H), 6.94 (s, 1H), 5.82 (s, 1H), 5.22 (t, J = 4.0 Hz, 1H), 4.24-4.17 (m, 2H), 2.84 (s, 2H), 2.67 (t, J = 14.4 Hz, 2H), 2.29-2.10 (m, 4H), 2.03-1.91 (m, 2H), 1.47 (s, 9H).

[0357] Step 3. Preparation of tert-butyl (2-(4,4-difluorocyclohexyl)-4-(tetrahydro-2H-pyran-2-yl)pyridin-3-yl)carbamate [ka] To a solution of tert-butyl (2-(4,4-difluorocyclohex-1-en-1-yl)-4-(3,4-dihydro-2H-pyran-6-yl)pyridin-3-yl)carbamate (0.200 g, 0.509 mmol) in methanol (10 ml) was added palladium on carbon (0.200 g, 10 wt%) under nitrogen atmosphere. The suspension was degassed under vacuum and purged with hydrogen three times. The mixture was stirred under hydrogen (15 psi, balloon) at 25° C. for 12 h. The reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure to give the title compound as a colorless solid (0.180 g, crude): 1 H NMR (400 MHz, CDCl 3 ) δ 8.47 (d, J = 4.8 Hz, 1H), 7.18-7.17 (m, 1H), 6.94-6.73 (m, 1H), 4.42 (d, J = 7.2 Hz, 1H), 4.16 (d, J = 10.8 Hz, 1H), 3.69-3.56 (m, 1H), 3.13-2.91 (m, 1H), 2.31-2.17(m, 2H), 2.08-1.65 (m, 12H), 1.54 (s, 9H).

[0358] Step 4. Preparation of 2-(4,4-difluorocyclohexyl)-4-(tetrahydro-2H-pyran-2-yl)pyridin-3-amine [ka] A mixture of tert-butyl (2-(4,4-difluorocyclohexyl)-4-(tetrahydro-2H-pyran-2-yl)pyridin-3-yl)carbamate (0.180 g, 0.454 mmol) in hydrochloric acid / dioxane (4 M, 5 ml) was stirred at 10° C. for 12 h. The reaction mixture was concentrated under reduced pressure to provide the title compound as a colorless solid (0.150 g, crude): 1 H NMR (400 MHz, DMSO-d 6) δ 15.15-14.37 (m, 1H), 7.93 (d, J = 5.6 Hz, 1H), 7.58 (d, J = 5.2 Hz, 1H), 6.57-6.02 (m, 2H), 4.66 (d, J = 10.4 Hz, 1H), 4.09 (d, J = 11.2 Hz, 1H), 3.65-3.57 (m, 2H), 2.27-2.01 (m, 3H), 2.00-1.72 (m, 8H), 1.66-1.56 (s, 2H).

[0359] Step 5. Preparation of N-(2-(4,4-difluorocyclohexyl)-4-(tetrahydro-2H-pyran-2-yl)pyridin-3-yl)-2-isopropylpyrimidine-5-carboxamide [ka] Using an analogous procedure to those described in the examples disclosed herein, utilizing appropriately substituted starting materials and intermediates, the title compound was provided as a colorless solid (0.0327 g, 47% yield): 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.50-10.10 (m, 1H), 9.25 (s, 2H), 8.51 (d, J = 5.2 Hz, 1H), 7.36 (d, J = 5.2 Hz, 1H), 4.70-4.34 (m, 1H), 4.01 (d, J = 12.0 Hz, 1H), 3.59-3.42 (m, 1H), 3.28-3.19 (m, 1H), 3.09-2.98 (m, 1H), 2.12-1.66 (m, 10 H), 1.59-1.45 (m, 3H), 1.34 (d, J = 7.2 Hz, 6H), 1.30-1.21 (m, 1H); MS(ES+) m / z 445.2(M+1).

[0360] The following compounds were prepared in a manner similar to that described in the examples disclosed herein, utilizing appropriately substituted starting materials and intermediates: [Table 12]

[0361] Example 203 Synthesis of N-(2-(4,4-difluorocyclohexyl)-4-(tetrahydro-2H-pyran-2-yl)pyridin-3-yl)-2-isopropylpyrimidine-5-carboxamide [ka] Step 1. Preparation of N-(4-(4,4-difluorocyclohex-1-en-1-yl)-2-(3,4-dihydro-2H-pyran-6-yl)pyridin-3-yl)-2-isopropylpyrimidine-5-carboxamide [ka] To a mixture of 2-(3,4-dihydro-2H-pyran-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.0641 g, 0.305 mmol) and N-(2-chloro-4-(4,4-difluorocyclohex-1-en-1-yl)pyridin-3-yl)-2-isopropylpyrimidine-5-carboxamide (0.100 g, 0.255 mmol) in dioxane (3 ml) and water (0.6 ml) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.0186 g, 0.0255 mmol) and potassium carbonate (0.106 g, 0.764 mmol). The mixture was degassed and purged with nitrogen three times. The reaction mixture was stirred at 100° C. for 12 hours under nitrogen atmosphere. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography eluting with a gradient of 0 to 100% ethyl acetate in petroleum ether to provide the title compound as a yellow solid (0.0300 g, 25% yield: 1 H NMR (400 MHz, DMSO-d 6) δ 10.13 (s, 1H), 9.11 (s, 2H), 8.46 (d, J = 4.8 Hz, 1H), 7.29 (d, J = 4.8 Hz, 1H), 5.60 (s, 1H), 5.39-5.35 (m, 1H), 3.98-3.94 (m, 2H), 3.26-3.21 (m, 1H), 2.36-2.29 (m, 4H), 2.18-2.01 (m, 4H), 1.82-1.74 (m, 2H), 1.33 (d, J = 6.8 Hz, 6H).

[0362] Step 2. Preparation of N-(2-(4,4-difluorocyclohexyl)-4-(tetrahydro-2H-pyran-2-yl)pyridin-3-yl)-2-isopropylpyrimidine-5-carboxamide [ka] To a solution of N-(4-(4,4-difluorocyclohex-1-en-1-yl)-2-(3,4-dihydro-2H-pyran-6-yl)pyridin-3-yl)-2-isopropylpyrimidine-5-carboxamide (0.0200 g, 0.0454 mmol) in methanol (3 ml) was added palladium on activated carbon (0.0200 g, 0.0187 mmol, 10 wt%) under nitrogen atmosphere. The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred under hydrogen (15 psi, balloon) at 10° C. for 12 h. The reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC eluting with a gradient of 32-67% acetonitrile in water containing 0.225% formic acid to provide the title compound as a colorless solid (0.00920 g, 45% yield): 1 H NMR (400 MHz, CDCl 3) δ 9.56 (s, 1H), 9.26 (s, 2H), 8.41 (d, J = 5.2 Hz, 1H), 7.25 (d, J = 5.2 Hz, 1H), 4.65 (dd, J = 11.2, 2.0 Hz, 1H), 4.29-4.17 (m, 1H), 3.73-3.59 (m, 1H), 3.37 (Septet, J = 6.8 Hz, 1H), 2.82-2.62 (m, 1H), 2.29-2.09 (m, 3H), 2.02-1.87 (m, 3H), 1.85-1.56 (m, 8H), 1.43 (d, J = 6.8 Hz, 6H); MS(ES+) m / z 445.3(M+1).

[0363] Example 204 Synthesis of N-(4-(4,4-difluorocyclohexyl)-2-(2,5-difluorophenyl)pyridin-3-yl)-2-isopropoxypyrimidine-5-carboxamide [ka] Step 1. Preparation of 4-(4,4-difluorocyclohex-1-en-1-yl)-2-(2,5-difluorophenyl)-3-nitropyridine [ka] To a solution of 4-chloro-2-(2,5-difluorophenyl)-3-nitropyridine (1.00 g, 3.70 mmol), 2-(4,4-difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.10 g, 4.51 mmol) and potassium carbonate (1.53 g, 11.0 mmol) in dioxane (12 ml) / water (3 ml) under nitrogen atmosphere was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.270 g, 0.369 mmol). The mixture was stirred at 80° C. for 12 hours. The mixture was cooled to 25° C. and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography eluting with a gradient of 35 to 50% ethyl acetate in petroleum ether to provide the title compound as a yellow oil (1.20 g, 82% yield): 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.90 (d, J = 5.2 Hz, 1H), 7.72 (d, J = 5.2 Hz, 1H), 7.52-7.37 (m, 3H), 5.70 (s, 1H), 2.75-2.64 (m, 2H), 2.61-2.54 (m, 2H), 2.17 (tt, J = 13.9, 6.8 Hz, 2H); MS(ES+)m / z 353.1(M+1).

[0364] Step 2. Preparation of 4-(4,4-difluorocyclohexyl)-2-(2,5-difluorophenyl)pyridin-3-amine [ka] To a solution of 4-(4,4-difluorocyclohex-1-en-1-yl)-2-(2,5-difluorophenyl)-3-nitropyridine (1.20 g, 3.41 mmol) in methanol (15 ml) was added palladium on carbon (1.20 g, 10 wt%) under nitrogen atmosphere. The suspension was degassed and purged with hydrogen three times. The mixture was stirred under hydrogen (15 psi, balloon) at 25° C. for 12 h. The resulting mixture was filtered through Celite. The filter cake was washed with methanol (30 ml). The filtrate was concentrated under reduced pressure to provide the title compound as a colorless solid (0.900 g, 73% yield): 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.84 (d, J = 4.8 Hz, 1H), 7.38-7.27 (m, 2H), 7.23 (ddd, J = 8.8, 5.6, 3.2 Hz, 1H), 7.06 (d, J = 4.8 Hz, 1H), 4.89 (s, 2H), 2.89 (t, J = 11.2 Hz, 1H), 2.20-1.85 (m, 6H), 1.66-1.52 (m, 2H); MS(ES+)m / z325.1(M+1).

[0365] Step 3. Preparation of 2-chloro-N-(4-(4,4-difluorocyclohexyl)-2-(2,5-difluorophenyl)pyridin-3-yl)pyrimidine-5-carboxamide [ka] Using an analogous procedure to those described in the examples disclosed herein, utilizing appropriately substituted starting materials and intermediates, the title compound was provided as a yellow solid (0.240 g, 37% yield): 1 H NMR (400 MHz, DMSO-d 6) δ 10.49 (s, 1H), 8.98 (s, 2H), 8.61 (d, J = 5.2 Hz, 1H), 7.57 (d, J = 5.2 Hz, 1H), 7.34-7.26 (m, 2H), 7.25-7.19 (m, 1H), 3.09-2.96 (m, 1H), 2.21-2.01 (m, 3H), 1.93-1.80 (m, 3H), 1.78-1.65 (m, 2H); MS(ES+)m / z465.1, 467.1(M+1).

[0366] Step 4. Preparation of N-(4-(4,4-difluorocyclohexyl)-2-(2,5-difluorophenyl)pyridin-3-yl)-2-isopropoxypyrimidine-5-carboxamide [ka] A solution of 2-chloro-N-(4-(4,4-difluorocyclohexyl)-2-(2,5-difluorophenyl)pyridin-3-yl)pyrimidine-5-carboxamide (0.0500 g, 0.107 mmol) and cesium carbonate (0.105 g, 0.322 mmol) in isopropanol (1 ml) was stirred at 80° C. for 12 h. The mixture was cooled to 25° C. and concentrated under reduced pressure. The residue was purified by preparative HPLC eluting with a gradient of 40-70% acetonitrile in water containing 0.225% formic acid to provide the title compound as a colorless solid (0.0108 g, 20% yield): 1 H NMR (400 MHz, MeOD) δ 8.85 (s, 2H), 8.62 (d, J = 5.2 Hz, 1H), 7.63 (d, J = 5.2 Hz, 1H), 7.28-7.02 (m, 3H), 5.40-5.35 (m, 1H), 3.11-2.96 (m, 1H), 2.24-2.11 (m, 2H), 2.00-1.80 (m, 6H), 1.40 (d, J = 6.0 Hz, 6H); MS(ES+)m / z489.2(M+1).

[0367] Example 205 Synthesis of 6-(1-cyclopropylethoxy)-N-(4-(4,4-difluorocyclohexyl)-2-(2,5-difluorophenyl)pyridin-3-yl)-5-fluoronicotinamide [ka] Step 1. Preparation of N-(4-(4,4-difluorocyclohexyl)-2-(2,5-difluorophenyl)pyridin-3-yl)-5,6-difluoronicotinamide [ka] Using an analogous procedure to those described in the examples disclosed herein, utilizing appropriately substituted starting materials and intermediates, the title compound was provided as a yellow solid (0.180 g, 56% yield): 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.36 (s, 1H), 8.61 (d, J = 5.2 Hz, 1H), 8.36 (s, 1H), 8.26 (td, J = 9.6, 1.6 Hz, 1H), 7.56 (d, J = 5.2 Hz, 1H), 7.36-7.29 (m, 1H), 7.29-7.25 (m, 1H), 7.23-7.19 (m, 1H), 3.00 (t, J = 12.0 Hz, 1H), 2.16-2.04 (m, 2H), 1.94-1.59 (m, 6H);MS(ES+)m / z466.1(M+1).

[0368] Step 2. Preparation of 6-(1-cyclopropylethoxy)-N-(4-(4,4-difluorocyclohexyl)-2-(2,5-difluorophenyl)pyridin-3-yl)-5-fluoronicotinamide [ka] To a solution of N-(4-(4,4-difluorocyclohexyl)-2-(2,5-difluorophenyl)pyridin-3-yl)-5,6-difluoronicotinamide (0.0500 g, 0.107 mmol) and 1-cyclopropylethan-1-ol (0.0180 g, 0.208 mmol) in tetrahydrofuran (2 ml) at 0° C. was added potassium tert-butoxide (0.2 ml, 1M in tetrahydrofuran). The mixture was stirred at 25° C. for 12 hours. The reaction mixture was diluted with water (5 ml) and extracted with ethyl acetate (2×7 ml). The combined organic layers were washed with brine (8 ml), dried over sodium, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC eluting with a gradient of 54-82% acetonitrile in water containing 0.225% formic acid to provide the title compound as a colorless solid (0.0354 g, 61% yield): 1 H NMR (400 MHz, DMSO-d 6 ) δ10.09 (s, 1H), 8.58 (d, J = 5.2 Hz, 1H), 8.31 (d, J = 2.0 Hz, 1H), 7.89 (dd, J = 2.0, 11.2 Hz, 1H), 7.54 (d, J = 5.2 Hz, 1H), 7.33-7.13 (m, 3H), 4.83-4.73 (m, 1H), 2.99 (t, J = 12.0 Hz, 1H), 2.17-2.04 (m, 2H), 1.85 (d, J = 11.2 Hz, 4H), 1.79-1.60 (m, 2H), 1.37 (d, J = 6.0 Hz, 3H), 1.22-1.14 (m, 1H), 0.52 (t, J = 9.2 Hz, 2H), 0.37 (d, J = 4.8 Hz, 2H); MS(ES+)m / z532.2(M+1).

[0369] Example 206 Synthesis of N-(4-(4,4-difluorocyclohexyl)-2-phenylpyridin-3-yl)-2-isopropylpyrimidine-5-carboxamide [ka] Using an analogous procedure to those described in the examples disclosed herein, utilizing appropriately substituted starting materials and intermediates, the title compound was provided as a colorless solid (0.0300 g, 23% yield): 1 H NMR (400 MHz, CDCl 3 ) δ 8.69 (d, J = 5.2 Hz, 1H), 8.07 (d, J = 4.4 Hz, 1H), 7.40 (d, J = 5.2 Hz, 1H), 7.32-7.27 (m, 1H), 7.15-7.05 (m, 2H), 6.59 (s, 1H), 6.13 (tt, J = 54, 4.0 Hz, 1H), 4.50 (td, J = 13.2, 4.4 Hz, 2H), 2.86-2.75 (m, 1H), 2.31-2.17 (m, 2H), 2.01 (d, J = 7.2 Hz, 2H), 1.88-1.74 (m, 4H);MS(ES+)m / z 500.4(M+1).

[0370] Example 207 Synthesis of N-(4-(4,4-difluorocyclohexyl)-2-phenylpyridin-3-yl)-2-isopropylpyrimidine-5-carboxamide [ka] Step 1. Preparation of tert-butyl (2-chloro-4-(4,4-difluorocyclohex-1-en-1-yl)pyridin-3-yl)carbamate [ka] To a mixture of tert-butyl (2-chloro-4-iodopyridin-3-yl)carbamate (1.00 g, 2.82 mmol), 2-(4,4-difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.771 g, 3.16 mmol) and potassium carbonate (1.17 g, 8.46 mmol) in 1,4-dioxane (10 ml) and water (2 ml) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.206 g, 0.282 mmol) under nitrogen atmosphere. The mixture was stirred at 90° C. for 12 hours. After cooling to ambient temperature, the reaction mixture was concentrated under reduced pressure. The residue was poured into water (20 ml) and extracted with ethyl acetate (3×20 ml). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash silica gel chromatography eluting with 50% ethyl acetate in petroleum ether to provide the title compound as a yellow solid (0.800 g, 82% yield): 1 H NMR (400 MHz, CDCl 3 ) δ 8.19 (d, J = 5.2 Hz, 1H), 7.07 (d, J = 5.2 Hz, 1H), 6.25 (s, 1H), 5.67 (s, 1H), 2.74-2.56 (m, 4H), 2.15 (tt, J = 6.6, 13.6 Hz, 2H), 1.47 (s, 9H).

[0371] Step 2. Preparation of 2-chloro-4-(4,4-difluorocyclohex-1-en-1-yl)pyridin-3-amine [ka] A mixture of tert-butyl (2-chloro-4-(4,4-difluorocyclohex-1-en-1-yl)pyridin-3-yl)carbamate (0.800 g, 2.32 mmol) in hydrochloric acid in methanol (3 ml, 4 M) was stirred at 25° C. for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was poured into water (10 ml) and adjusted to pH=8 with aqueous sodium hydroxide (5 ml, 2 M). The mixture was extracted with ethyl acetate (3×20 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to provide the title compound as a yellow oil (0.550 g, 97% yield): 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.57 (d, J = 4.4 Hz, 1H), 6.92 (d, J = 4.4 Hz, 1H), 5.66 (s, 1H), 5.21 (s, 2H), 2.77-2.61 (m, 2H), 2.46-2.39 (m, 2H), 2.29-2.13 (m, 2H).

[0372] Step 3. Preparation of N-(2-chloro-4-(4,4-difluorocyclohex-1-en-1-yl)pyridin-3-yl)-2-isopropylpyrimidine-5-carboxamide [ka] To a mixture of 2-chloro-4-(4,4-difluorocyclohex-1-en-1-yl)pyridin-3-amine (0.100 g, 0.355 mmol), 2-isopropylpyrimidine-5-carboxylic acid (0.0679 g, 0.408 mmol) and 2-chloro-1-methyl-pyridin-1-ium iodide (0.136 g, 0.533 mmol) in tetrahydrofuran (2 ml) was added N,N-diisopropylethylamine (0.183 g, 1.42 mmol). The mixture was stirred at 70° C. for 12 hours and then aqueous sodium hydroxide (2 ml, 2M) was added. The mixture was stirred at 25° C. for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was poured into water (20 ml) and extracted with ethyl acetate (3×15 ml). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. The residue was purified by flash silica gel chromatography eluting with a gradient of 50% ethyl acetate in petroleum ether to provide the title compound as a yellow solid (0.100 g, 72% yield): 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.54 (s, 1H), 9.16 (s, 2H), 8.37 (d, J = 4.4 Hz, 1H), 7.43 (d, J = 4.4 Hz, 1H), 5.69 (s, 1H), 3.31-3.18 (m, 1H), 2.62 (t, J = 14.6 Hz, 2H), 2.56-2.51 (m, 2H), 2.18-2.02 (m, 2H), 1.32 (d, J = 6.8 Hz, 6H).

[0373] Step 4. Preparation of N-(4-(4,4-difluorocyclohex-1-en-1-yl)-2-phenylpyridin-3-yl)-2-isopropylpyrimidine-5-carboxamide [ka] To a mixture of N-(2-chloro-4-(4,4-difluorocyclohex-1-en-1-yl)pyridin-3-yl)-2-isopropylpyrimidine-5-carboxamide (0.100 g, 0.254 mmol), phenylboronic acid (0.0465 g, 0.381 mmol) and potassium carbonate (0.105 g, 0.763 mmol) in dioxane (1.5 ml) and water (0.3 ml) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.0186 g, 0.0254 mmol) under nitrogen atmosphere. The mixture was stirred at 90° C. for 12 hours. After cooling to ambient temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography eluting with a gradient of 20% ethyl acetate in petroleum ether to provide the title compound as a colorless solid (0.0800 g, 72% yield); 1 H NMR (400 MHz, CDCl 3 ) δ 8.84 (s, 2H), 8.57 (d, J = 4.8 Hz, 1H), 7.51 (s, 2H), 7.46-7.37 (m, 4H), 7.19 (d, J = 4.8 Hz, 1H), 5.61 (s, 1H), 3.27 (td, J = 6.8, 13.6 Hz, 1H), 2.78-2.48 (m, 4H), 2.14 (tt, J = 6.4, 13.6 Hz, 2H), 1.36 (d, J = 6.8 Hz, 6H).

[0374] Step 5. Preparation of N-(4-(4,4-difluorocyclohexyl)-2-phenylpyridin-3-yl)-2-isopropylpyrimidine-5-carboxamide [ka] To a mixture of N-(4-(4,4-difluorocyclohex-1-en-1-yl)-2-phenylpyridin-3-yl)-2-isopropylpyrimidine-5-carboxamide (0.0800 g, 0.184 mmol) in methanol (3 ml) was added palladium on carbon (0.0800 g, 10 wt%) under nitrogen atmosphere. The mixture was stirred at 25° C. under hydrogen (15 Psi) atmosphere for 12 h. The reaction mixture was filtered through Celite. The residue was purified by preparative HPLC eluting with a gradient of 34-64% acetonitrile in water containing 0.225% formic acid to provide the title compound as a colorless solid (0.00620 g, 8% yield): 1 H NMR (400 MHz, CDCl 3 ) δ 8.92 (s, 2H), 8.61 (d, J = 4.4 Hz, 1H), 7.50 (d, J = 4.0 Hz, 2H), 7.42 (d, J = 3.2 Hz, 3H), 7.34 (d, J = 4.8 Hz, 1H), 3.30 (dt, J = 13.8, 6.8 Hz, 1H), 2.88-2.73 (m, 1H), 2.33-2.18 (m, 2H), 2.14-1.97 (m, 2H), 1.89-1.73 (m, 4H), 1.38 (d, J = 6.8 Hz, 6H);MS(ES+)m / z 437.3(M+1).

[0375] Example 208 The following compounds were prepared in a similar manner to that described in Example 207, utilizing appropriately substituted starting materials and intermediates: [Table 13]

[0376] Example 210 Synthesis of N-(2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)pyridin-3-yl)-6-isopropoxypyridazine-4-carboxamide [ka] Step 1. Preparation of 6-chloro-N-(2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)pyridin-3-yl)pyridazine-4-carboxamide [ka] Using an analogous procedure to those described in the examples disclosed herein, utilizing appropriately substituted starting materials and intermediates, the title compound was provided as a colorless solid (0.0700 g, 32%): 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.65 (s, 1H), 9.36 (d, J = 1.6 Hz, 1H), 8.65 (d, J = 4.8 Hz, 1H), 8.08 (d, J = 1.6 Hz, 1H), 7.40-7.20 (m, 4H), 3.22-3.16 (m, 1H), 2.15-2.01 (m, 3H), 1.96-1.75 (m, 5H).

[0377] Step 2. Preparation of N-(2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)pyridin-3-yl)-6-isopropoxypyridazine-4-carboxamide [ka] To a mixture of 6-chloro-N-(2-(4,4-difluorocyclohexyl)-4-(2,5-difluorophenyl)pyridin-3-yl)pyridazine-4-carboxamide (0.0600 g, 0.129 mmol) in isopropanol (1 ml) was added cesium carbonate (0.126 g, 0.387 mmol). The resulting mixture was stirred at 90° C. for 36 h under nitrogen atmosphere. The mixture was diluted with N,N-dimethylformamide (1 ml) and ethyl acetate (10 ml). The residue was purified by preparative HPLC eluting with a gradient of 50-75% acetonitrile in water containing 0.225% formic acid to provide the title compound as a colorless solid (0.0228 g, 35% yield): 1H NMR (400 MHz, CDCl 3 ) δ 8.98 (s, 1H), 8.71 (d, J = 4.8 Hz, 1H), 7.63 (d, J = 1.6 Hz, 1H), 7.23 (d, J = 4.8 Hz, 1H), 7.19-7.04 (m, 4H), 5.63 (td, J = 6.4, 12.4 Hz, 1H), 3.02-2.90 (m, 1H), 2.33-2.10 (m, 4H), 1.99-1.90 (m, 2H), 1.87-1.71 (m, 2H), 1.44 (d, J = 6.4 Hz, 6H);MS(ES+)m / z489.2(M+1).

[0378] Example 211 Synthesis of N-(2-((3,3-difluoroazetidin-1-yl)methyl)-4-(2,5-difluorophenyl)pyridin-3-yl)-2-isopropylpyrimidine-5-carboxamide [ka] Step 1. Preparation of 3-amino-4-(2,5-difluorophenyl)picolinaldehyde [ka] To a solution of 2-chloro-4-(2,5-difluorophenyl)-3-nitropyridine (1.00 g, 3.70 mmol) in dimethylformamide (15 ml) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.270 g, 0.369 mmol), triethylsilane (1.30 g, 11.1 mmol), and triethylamine (1.10 g, 10.8 mmol) at 25° C. under an argon atmosphere. The suspension was degassed and purged with carbon monoxide three times. The mixture was stirred at 80° C. for 12 hours under carbon monoxide (50 psi). The reaction mixture was cooled to ambient temperature, diluted with water (30 ml), and extracted with ethyl acetate (2×30 ml). The combined organic layers were washed with brine (30 ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography eluting with a gradient of 35 to 50% ethyl acetate in petroleum ether to provide the title compound as a yellow solid (0.220 g, 17% yield): 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.98 (s, 1H), 8.10 (d, J = 4.4 Hz, 1H), 7.41-7.30 (m, 4H), 6.95 (s, 2H); MS(ES+)m / z235.1(M+1).

[0379] Step 2. Preparation of 2-((3,3-difluoroazetidin-1-yl)methyl)-4-(2,5-difluorophenyl)pyridin-3-amine [ka] A solution of 3-amino-4-(2,5-difluorophenyl)picolinaldehyde (0.150 g, 0.429 mmol, 67% purity), 3,3-difluoroazetidine hydrochloride (0.0830 g, 0.640 mmol) and N,N-diisopropylethylamine (0.111 g, 0.858 mmol) in 1,2-dichloroethane (5 ml) was stirred at 25° C. for 1 h. Sodium triacetoxyborohydride (0.455 g, 2.15 mmol) was added. The final mixture was stirred at 25° C. for 12 h. The reaction mixture was diluted with water (20 ml) and extracted with ethyl acetate (2×20 ml). The combined organic layers were washed with brine (15 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC eluting with a gradient of 10-40% acetonitrile in water containing 0.225% formic acid to provide the title compound as a yellow oil (0.100 g, 69% yield): 1 H NMR (400 MHz, MeOD) δ 7.84 (d, J = 5.2 Hz, 1H), 7.32-7.12 (m, 3H), 7.07 (d, J = 5.2 Hz, 1H), 3.95 (s, 2H), 3.67 (t, J = 12.0 Hz, 4H);MS(ES+)m / z312.1(M+1).

[0380] Step 3. Preparation of N-(2-((3,3-difluoroazetidin-1-yl)methyl)-4-(2,5-difluorophenyl)pyridin-3-yl)-2-isopropylpyrimidine-5-carboxamide [ka] Using an analogous procedure to those described in the examples disclosed herein, utilizing appropriately substituted starting materials and intermediates, the title compound was provided as a grey solid (0.00270 g, 6% yield): 1 H NMR (400 MHz, DMSO-d 6) δ 10.47-10.36 (m, 1H), 8.97 (s, 2H), 8.61 (d, J = 4.8 Hz, 1H), 7.46 (d, J = 4.8 Hz, 1H), 7.39-7.33 (m, 1H), 7.31-7.21 (m, 2H), 3.95 (s, 2H), 3.70 (t, J = 12.4 Hz, 4H), 3.20 (td, J = 6.8, 13.6 Hz, 1H), 1.29 (d, J = 6.8 Hz, 6H);MS(ES+)m / z460.3(M+1).

[0381] Example 212 and Example 213 Synthesis of N-(2-(1-(3,3-difluoroazetidin-1-yl)ethyl)-4-(2,5-difluorophenyl)pyridin-3-yl)-2-isopropylpyrimidine-5-carboxamide formate salts P1 and P2 [ka] Step 1. Preparation of 4-(2,5-difluorophenyl)-2-(1-ethoxyvinyl)-3-nitropyridine [ka] To a solution of 2-chloro-4-(2,5-difluorophenyl)-3-nitropyridine (2.00 g, 7.39 mmol) in dimethylformamide (100 ml) was added tributyl(1-ethoxyvinyl)stannane (5.13 g, 14.2 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.08 g, 1.48 mmol) under nitrogen atmosphere. The mixture was stirred at 100° C. for 1 hour under nitrogen atmosphere. The reaction mixture was cooled to ambient temperature. Saturated potassium fluoride (20 ml) was added to the reaction mixture. The mixture was then extracted with ethyl acetate (3×20 ml). The combined organic layers were washed with brine (3×20 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the title compound as a black solid (3.10 g, crude): 1 H NMR (400 MHz, CDCl 3) δ 8.73 (d, J = 4.8 Hz, 1H), 7.33 (d, J = 4.8 Hz, 1H), 7.15 (t, J = 6.0 Hz, 2H), 7.01 (t, J = 6.8 Hz, 1H), 5.23 (d, J = 2.4 Hz, 1H), 4.58 (d, J = 2.4 Hz, 1H), 3.90 (q, J = 7.2 Hz, 2H), 1.30 (t, J = 7.2 Hz, 3H).

[0382] Step 2. Preparation of 1-(4-(2,5-difluorophenyl)-3-nitropyridin-2-yl)ethan-1-one [ka] To a solution of 4-(2,5-difluorophenyl)-2-(1-ethoxyvinyl)-3-nitropyridine (3.10 g, 10.1 mmol) in tetrahydrofuran (100 ml) was added hydrochloric acid (12 M, 10 ml). The mixture was stirred at 25° C. for 12 h. The pH was adjusted to 7 with saturated sodium bicarbonate. Water (10 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate (3×20 ml). The combined organic layers were washed with brine (3×10 ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography eluting with a gradient of 0-20% ethyl acetate in petroleum ether to provide the title compound as a yellow solid (1.10 g, 39% yield): 1 H NMR (400 MHz, CDCl 3 ) δ 8.83 (d, J = 4.8 Hz, 1H), 7.58 (dd, J = 4.8, 0.8 Hz, 1H), 7.21-7.14 (m, 2H), 7.02 (tdd, J = 7.6, 5.6, 1.6 Hz, 1H), 2.79 (s, 3H).

[0383] Step 3. Preparation of 1-(3-amino-4-(2,5-difluorophenyl)pyridin-2-yl)ethan-1-one [ka] To a solution of 1-(4-(2,5-difluorophenyl)-3-nitropyridin-2-yl)ethan-1-one (1.10 g, 3.95 mmol) in ethanol (100 ml) and water (10 ml) were added iron powder (5.96 g, 107 mmol) and acetic acid (14.3 g, 237 mmol). The mixture was stirred at 80° C. for 12 h. After cooling to ambient temperature, the resulting mixture was filtered through Celite. The residue was purified by flash silica gel chromatography eluting with a gradient of 0-25% ethyl acetate in petroleum ether to provide the title compound as a yellow solid (0.700 g, 57% yield): 1 H NMR (400 MHz, CDCl 3 ) δ 8.07 (d, J = 4.4 Hz, 1H), 7.24-7.17 (m, 1H), 7.17-7.11 (m, 2H), 7.07 (ddd, J = 3.2, 5.2, 8.4 Hz, 1H), 6.32 (s, 2H), 2.76 (s, 3H).

[0384] Step 4. Preparation of 2-(1-(3,3-difluoroazetidin-1-yl)ethyl)-4-(2,5-difluorophenyl)pyridin-3-amine [ka] To a solution of 1-(3-amino-4-(2,5-difluorophenyl)pyridin-2-yl)ethan-1-one (0.600 g, 2.42 mmol) in 1,2-dichloroethane (10 ml) was added N,N-diisopropylethylamine (0.625 g, 4.83 mmol) and 3,3-difluoroazetidine hydrochloride (0.470 g, 3.63 mmol) and the mixture was stirred at 50° C. for 1 h. Sodium triacetoxyborohydride (2.56 g, 12.1 mmol) was added and the mixture was stirred at 50° C. for 12 h. The reaction mixture was cooled to ambient temperature. Water (10 ml) was added to the mixture, which was then extracted with ethyl acetate (3×20 ml). The combined organic layers were washed with brine (3×10 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography eluting with a gradient of 0 to 40% ethyl acetate in petroleum ether to provide the title compound as a yellow solid (0.320 g, 41% yield): 1 H NMR (400 MHz, CDCl 3 ) δ 7.94 (d, J = 4.8 Hz, 1H), 7.23-7.05 (m, 3H), 6.95 (d, J = 4.8 Hz, 1H), 5.64-4.83 (m, 2H), 3.90 (quartet, J = 6.8 Hz, 1H), 3.74-3.61 (m, 2H), 3.61-3.48 (m, 2H), 1.41 (d, J = 6.8 Hz, 3H).

[0385] Step 5. Preparation of N-(2-(1-(3,3-difluoroazetidin-1-yl)ethyl)-4-(2,5-difluorophenyl)pyridin-3-yl)-2-isopropylpyrimidine-5-carboxamide [ka] Using an analogous procedure to those described in the examples disclosed herein, utilizing appropriately substituted starting mate...

Claims

1. Compounds of formula (I): 【Chemical 735】 or a pharmaceutically acceptable salt or solvate thereof (In the formula, X, Y, and Z are each independently N or CR １ｂ with the proviso that at least one and not more than two of X, Y, and Z is N; L is a direct bond, —NR ４ C(=O)- and -C(=O)NR ４ - selected from; R １ is methoxy, -R ５ N (R ６ ) ２ , alkenyl, 【Chemical 781】 is selected from each 【Hua737】 are independently a single bond or a double bond such that all valences are satisfied; Each R １ａ are independently alkyl, halo, haloalkyl, -R ５ OR ６ , -R ５ N (R ６ ) ２ , -R ５ OC(=O)R ６ , optionally substituted cycloalkyl, or —R ５ C(=O)OR ６ and A is O, N, or C; Each R １ｂ are independently hydrogen, halo, alkyl, or haloalkyl; R ２ａ and R ２ｂ together with the carbon to which they are attached form an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heterocyclyl, or an optionally substituted heteroaryl; or R ２ａ is hydrogen or alkyl, and R ２ｂ is an optionally substituted heterocyclyl or an optionally substituted cycloalkyl; or R ２ａ and R ２ｂ are both alkyl; or R ２ａ is alkyl, and R ２ｂ is haloalkoxy; R ３ is alkyl, cyanoalkyl, -R ５ OR ６ , -R ５ N (R ６ ) ２ , optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted cycloalkylalkyl, and optionally substituted heterocyclylalkyl; R ４ is hydrogen or alkyl; Each R ５ is independently a direct bond or an optionally substituted alkylene chain; Each R ６ is independently hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, or optionally substituted arylalkyl; or two R's ６ together with the nitrogen to which they are both attached form an optionally substituted heterocyclyl; and n is 0, 1, 2, 3, 4, or 5.

2. The compound is 【Chemical 782】 (R １ , R １ｂ , R ２ａ , R ２ｂ , L and R ３ 2. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, having a formula selected from:

3. R １ has the following structure: 【Hua747】 (In the formula, n is 1, 2, 3, 4, or 5. or a pharmaceutically acceptable salt or solvate thereof.

4. R １ has the following structure: 【Chemical 783】 【Chemical 784】 or a pharmaceutically acceptable salt or solvate thereof.

5. R ２ａ and R ２ｂ together with the carbon to which they are attached form an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl, or an optionally substituted heteroaryl; 2. The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof.

6. R ２ａ and R ２ｂ together with the carbon to which they are attached form an optionally substituted heterocyclyl; 2. The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof.

7. R ２ａ is hydrogen or alkyl, and R ２ｂ is an optionally substituted heterocyclyl or an optionally substituted cycloalkyl; or R 2a and R 2b are both alkyl; or R 2a is alkyl and R 2b is haloalkoxy; 2. The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof.

8. R ２ａ and R ２ｂ together with the carbon to which they are attached form one of the following structures: 【Chemical 756】 R ７ａ is hydrogen, alkyl, haloalkyl, -R ７ｃ C(=O)R ７ｄ , -R ７ｃ C(=O)OR ７ｄ or heterocyclyl; Each R ７ｂ are independently alkyl, halo, haloalkyl, cyano, -R ７ｃ OR ７ｄ , or -R ７ｃ OC(=O)R ７ｄ and or two R's ７ｂ are connected together with the carbon to which they are both bonded to form -C(=O)-; Each R ７ｃ is independently a direct bond or an optionally substituted alkylene chain; Each R ７ｄ is independently hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, or optionally substituted arylalkyl; or two R's ７ｄ together with the nitrogen to which they are both attached form an optionally substituted heterocyclyl; m is 0, 1, 2, 3, 4, or 5; 2. The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof.

9. R ３ is selected from alkyl, cyanoalkyl, —R 5 OR 6 , and —R 5 N(R 6 ) 2 ; 2. The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof.

10. R ３ is selected from optionally substituted cycloalkyl and optionally substituted aryl; 2. The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof.

11. R ３ is optionally substituted heterocyclyl; 2. The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof.

12. R ３ is optionally substituted heteroaryl; 2. The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof.

13. R ３ is selected from optionally substituted cycloalkylalkyl and optionally substituted heterocyclylalkyl; 2. The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof.

14. R ３ has the following structure: 【Chemical 785】 【Chemical 786】 (In the formula, R ８ａ is hydrogen, alkyl, haloalkyl, —C(═O)OR ８ｄ , optionally substituted aryl, optionally substituted heterocyclylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted cycloalkyl; Each R ８ｂ are independently alkyl, optionally substituted cycloalkyl, cyano, halo, -R ８ｃ OR ８ｄ , -OR ８ｃ N (R ８ｄ ) ２ , -C(=O)N(R ８ｄ ) ２ , -R ８ｃ N (R ８ｄ ) ２ or optionally substituted heterocyclyl; Each R ８ｃ is independently a direct bond or an optionally substituted alkylene chain; Each R ８ｄ is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted cycloalkyl, or optionally substituted cycloalkylalkyl; or two R's ８ｄ together with the nitrogen to which they are both attached form an optionally substituted heterocyclyl; p is 0, 1, 2, 3, 4, or 5. or a pharmaceutically acceptable salt or solvate thereof.

15. L is selected from a direct bond, —C(═O)NR 4 —, —NR 4 C(═O)—, and —NR 4 C(═O)—; 2. The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof.

16. R ４ is selected from hydrogen and methyl; 2. The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof. 【Request 17】 【787】 【Hua788】 【Chemical 789】 【Chemical 790】 【Chemical 791】 【Chemical Formula 792】 【Chemical Formula 793】 【Chemical 794】 【Chemical 795】 【Chemical 796】 【Chemical 797】 【Chemical 798】 【Chemical 799】 【Hua800】 【Chemistry 801】 【Chemical 802】 【Chemistry 803】 【Chemistry 804】 【Chemistry 805】 【Chemistry 806】 【Chemical 807】 【Chemical 808】 【Chemistry 809】 【Chemical 810】 【Hua 811】 【Hua 812】 【Hua 813】 【Hua 814】 【Chemical 815】 【Hua 816】 【Hua 817】 【Hua 818】 【Hua 819】 【Hua 820】 【Hua 821】 【Hua 822】 【Hua 823】 【Hua 824】 【Hua 825】 【Hua 826】 【Hua 827】 【Hua 828】 【Hua 829】 【Chemical 830】 【Chemistry 831】 【Hua 832】 【Hua 833】 【Chemical 834】 【Chemistry 835】 【Hua 836】 【Hua 837】 【Hua 838】 【Chemical 839】 【Chemistry 840】 【Hua 841】 or a pharmaceutically acceptable salt, or solvate, or a stereoisomer, enantiomer, tautomer, or mixture thereof; or a pharmaceutically acceptable salt, or solvate, or a stereoisomer, enantiomer, tautomer, or mixture thereof.

18. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt or solvate thereof.

19. 20. The pharmaceutical composition of claim 18 for use in treating a disease or condition in a mammal that is modulated by a voltage-gated sodium channel.

20. The pharmaceutical composition of claim 18 for use in treating a disease or condition in a mammal, comprising: The disease or condition is epilepsy, seizure disorders, partial seizures, generalized seizures, photosensitive epilepsy, self-induced syncope, intractable epilepsy, Angelman syndrome, benign rolandic epilepsy, CDKL5 disorders, childhood and juvenile absence epilepsy, Dravet syndrome, frontal lobe epilepsy, Glut1 deficiency syndrome, hypothalamic hamartoma, infantile spasms / West syndrome, juvenile myoclonic epilepsy, Landau-Klöffner syndrome, Lennox-Gastaut syndrome (LGS), epilepsy with myoclonic absences, Ohtahara syndrome, Panayiotopoulos syndrome, PCDH19 epilepsy, progressive myoclonic epilepsy, Rasmussen syndrome, ring chromosome 20 syndrome, reflex epilepsy, temporal lobe epilepsy, Lafora-type progressive myoclonic epilepsy, neurocutaneous syndrome, tuberous sclerosis complex, early infantile seizures The pharmaceutical composition is selected from epileptic encephalopathy, early-onset epileptic encephalopathy, generalized epileptic febrile seizures plus (GEFS+), Rett syndrome, multiple sclerosis, schizophrenia, autism, ataxia and hypotonia, paroxysmal dyskinesia, Alzheimer's disease, tauopathy, Pick's disease, progressive supranuclear palsy, corticobasal syndrome, frontotemporal dementia, argyrophilic grain disease, frontotemporal lobar degeneration, globular glial tauopathy, MAPT mutation, primary age-related tauopathy, neurofibrillary tangle dementia, chronic traumatic encephalopathy (CTE), age-related tauastrogliopathy, Richardson syndrome, Down syndrome, Parkinsonism, pure akinesia with freezing of gait, motor neuron symptoms or cerebellar ataxia, post-traumatic stress disorder (PTSD), and any combination thereof.

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