Pyridinylacetamide derivatives as sodium channel activators.

Abstract

The present disclosure provides a compound of formula (I): The compound of TIFF2024534572000889.tif43164, In the formula, R 1 , R 2 , R 3 , R 3a , R 4 , Y, and X are as described herein, or as a stereoisomer, enantiomer, or tautomer, or mixtures thereof, or a pharma- ceutically acceptable salt, solvate, or prodrug thereof, as well as pharmaceutical compositions comprising compounds of formula (I) as described herein, which are useful as voltage-gated sodium channel modulators and thus useful for treating seizure disorders such as epilepsy.

Description

[Technical Field]

[0001] The present disclosure is directed to pyridinylacetamide derivatives, as their stereoisomers, enantiomers, or tautomers, or mixtures thereof, or pharmaceutically acceptable salts, solvates, or prodrugs, and pharmaceutical compositions comprising said pyridinylacetamide derivatives, which are useful as voltage-gated sodium channel activators and therefore useful for treating seizure disorders such as epilepsy. [Background technology]

[0002] 2. Description of Related Art 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). Epilepsy is characterized by abnormal electrical activity in the brain that leads to seizures. For epidemiological purposes, the definition requires two or more unprovoked seizures of any type.

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

[0004] Although the pathophysiology of most types of epilepsy remains poorly understood, it is known that epileptic seizures result from excessively synchronous and sustained firing of a group of neurons. Persistent elevation of neuronal excitability is common to all epilepsy syndromes. Therapeutic strategies for treating epilepsy involve reducing neuronal excitability through various mechanistic pathways. Over the past two decades, several novel AEDs have been developed and marketed to broaden the therapeutic spectrum and improve the risk / benefit profile by targeting different mechanisms of action. Currently available AEDs are thought to act by inhibiting synaptic vesicle glycoproteins, enhancing inhibitory GABAergic neurotransmission, reducing glutamate-mediated excitatory neurotransmission, or inhibiting voltage-gated sodium or calcium channels. Despite this, up to 30% of patients continue to have uncontrolled seizures, with conventional treatments remaining ineffective (see Brown, DA et al., Nature (1980), 283:673-676, and Elger, CE et al., Epilepsy Behav. (2008), 12:501-539). Refractory patients have a poor quality of life, are unable to drive, and have difficulty working or living independently. In addition, many patients exhibit behavioral, neurological, and / or intellectual disabilities as sequelae of their seizure disorder. Despite the fact that sodium-gated channels play a key role in regulating neuronal excitability, current drugs have little or no effect on these channels in neurons. Therefore, drugs with novel mechanisms of action or improvements over currently available AEDs are needed to address the significant unmet clinical need for seizure control in patients with treatment-resistant epilepsy.

[0005] Na V 1.1 is a voltage-gated sodium channel (Na ) containing one pore-forming α-subunit encoded by SCN1A and two related β-subunits encoded by SCN1B to SCN4B. V ) Na V1.1 and its subfamily (Na V 1.2, Na V 1.3, and Na V 1.6) is primarily expressed 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 mostly 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 CNS disorders (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, W. A., 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 Genetic association between 1.1 channels and brain penetrant Na VIt has been suggested that 1.1 activators may have significant therapeutic potential for treating Dravet syndrome (Jensen, HSet et al., Trends Pharmacol Sci (2014), Vol. 35, pp. 113-118, and Richards, KLet et al., Proc Natl Acad Sci USA (2018), Vol. 115, pp. E8077-E8085). However, potent and selective Na V 1.1 No activators have been reported so far. In recent years, the following few 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, N. et al., Neurosci Lett (2018), Vol. 662, pp. 29-35). A very recently developed activator, Lu AE98134, is a Na V In HEK cells expressing 1.1, the total area under the curve for the duration of the depolarizing pulse from 1 μM to 1 μM increased, but Na V Low selectivity for 1.5 and Na V Moderate selectivity issues 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 mainly 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 desirable for a drug candidate. On the other hand, electrophysiological data for Lu AE98134 suggest that Na α is a potent inhibitor of FSIN excitability. V Recently, the previously reported Na 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 has been published (Miyazaki, T. et al., Bioorg Med Chem Lett (2019), Vol. 29, No. 6, pp. 815-820). Although great progress has been made in this field, there remains a great need for compounds that are voltage-gated sodium channel activators and therefore useful for 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] Brown, D.A. et al., Nature (1980), 283:673-676 [Non-patent document 3] Elger, CE et al., Epilepsy Behav. (2008), 12:501-539 [Non-patent document 4] Han,S.et al.,Nature(2012),Vol.489,pp.385-390 [Non-Patent Document 5] Oakley,JCet al.Epilepsia(2011),Vol.52(Suppl.2),pp.59-61 [Non-patent document 6] Verret,L.et al.,Cell(2012),Vol.149,pp.708-721 [Non-Patent Document 7] Catterall,WA,Ann Rev Pharmacol Toxicol(2014),Vol.54,pp.317-338 [Non-patent document 8] Mantegazza,M.et al.,Proc Natl Acad Sci USA(2005),Vol.102,pp.18177-18182 [Non-Patent Document 9] Jensen,HSet al.,Trends Pharmacol Sci(2014),Vol.35,pp.113-118 Summary of the Invention [Means for solving the problem]

[0007] The present disclosure provides voltage-gated sodium channel activators, particularly Na V 1.1 Pyridinylacetamide derivatives, as stereoisomers, enantiomers, or tautomers thereof, or mixtures thereof, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, which are useful as activators and therefore useful for treating seizure disorders such as epilepsy and Dravet syndrome, and pharmaceutical compositions comprising said pyridinylacetamide derivatives.

[0008] Thus, in some embodiments, the present disclosure provides a compound of formula (I): [ka] A compound of the formula During the ceremony, [ka] represents a double or single bond to fill all valences, Y is N or NR 4a and X is C(R 7) or N, R 1 teeth, [ka] is selected from where: [ka] each occurrence independently represents a double bond or a single bond so as to satisfy all valences; n is 0, 1, 2, 3, 4, or 5; R 1a is hydrogen or alkyl, Each R 1b are independently halo, alkyl, haloalkyl, cyano, heterocyclylalkyl, -R 8 -N(R 9 )2, -R 8 -C(=O)N(R 9 )2, or -R 8 -OR 9 Or or two Rs attached to adjacent carbons 1b’ together with the carbon to which they are attached form an optionally substituted N-heteroaryl, an optionally substituted N-heterocyclyl, an optionally substituted O-heterocyclyl, or an optionally substituted aryl; R 1c is N or -Si(CH3)3, R 2 teeth, [ka] is selected from where: m is 0, 1, 2, 3, or 4; Each R 5 are independently halo, alkyl, haloalkyl, or -R 10 -CN or or two R 5 together with the carbon to which they are both attached form an optionally substituted O-heterocyclyl, or or two R 5 together with the carbon to which they are both attached form an optionally substituted N-heterocyclyl, or or two R 5 together with the carbon to which they are both attached form an optionally substituted cycloalkyl, or or two R 5 are linked to form an optionally substituted alkylene chain, R 3 is alkyl, -R 8 -N(R 9 )2, -R 8 -OR 9 or R 3 teeth, [ka] is selected from where: p is 0, 1, 2, 3, 4, or 5; R 6a is hydrogen, alkyl, cycloalkyl, haloalkyl, -C(=O)R 9 , optionally substituted arylalkyl, or optionally substituted heteroaryl; Each R 6b are independently alkyl, halo, haloalkyl, -R 8 -OR 9 , -R 8 -N(R 9 )2, -R 8 -C(=O)OR 9 , -R 8 -C(=O)N(R 9 )2, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; or two R 6b together with the carbon to which they are both attached form an optionally substituted N-heterocyclyl, or or two R 6btogether with the carbon to which they are both attached form an optionally substituted O-heterocyclyl, or or two R's 6b together with the carbon to which they are both attached form an optionally substituted cycloalkyl, or or two R's 6b are linked to form an optionally substituted alkylene chain, or or R 6b The emergence of and R 1b are linked to form an optionally substituted alkylene chain, R 3a is hydrogen or alkyl, R 4 is hydrogen, alkyl, -R 8 -OR 9 , halo, haloalkyl, or cyano; or R 4 is R 4 together with the carbon to which it is attached, R 4a Combined with R 4a together with the nitrogen to which it is attached form an optionally substituted 5-membered N-heteroaryl; R 7 is hydrogen, alkyl, halo, or -R 8 -OR 9 and Each R 8 are independently a direct bond or an optionally substituted alkylene chain; Each R 9 are independently hydrogen, alkyl, haloalkyl, carboxyalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, or optionally substituted aryl; or two R's 9 together with the nitrogen to which they are both attached form an optionally substituted heterocyclyl; However, if X is N, then R 3 teeth, [ka] Selected from: The compounds are intended to be any stereoisomer, enantiomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0009] In some embodiments, the present disclosure provides a compound of formula (II): [ka] A compound of the formula: During the ceremony, X is C(R 7 ) or N, R 1 teeth, [ka] is selected from where: [ka] represents a double or single bond, n is 0, 1, 2, 3, 4, or 5; R 1a is hydrogen or alkyl, Each R 1b are independently halo, alkyl, haloalkyl, cyano, heterocyclylalkyl, -R 8 -N(R 9 )2, -R 8 -C(=O)N(R 9 )2, or -R 8 -OR 9 Or or two Rs attached to adjacent carbons 1b’ together with the carbon to which they are attached form an optionally substituted N-heteroaryl; R 2 teeth, [ka] is selected from where: m is 0, 1, 2, 3, or 4; Each R5 are independently halo, alkyl, haloalkyl, or -R 10 -CN or or two R 5 together with the carbon to which they are both attached form an optionally substituted O-heterocyclyl, or or two R 5 together with the carbon to which they are both attached form an optionally substituted cycloalkyl, or or two R 5 together with the carbons to which they are attached form an optionally substituted alkylene chain, R 3 is alkyl, -R 8 -N(R 9 )2, -R 8 -OR 9 or R 3 teeth, [ka] is selected from where: p is 0, 1, 2, 3, 4, or 5; R 6a is hydrogen, alkyl, cycloalkyl, haloalkyl, -C(=O)R 9 , optionally substituted arylalkyl, or optionally substituted heteroaryl; Each R 6b are independently alkyl, halo, -R 8 -OR 9 , -R 8 -N(R 9 )2, -R 8 -C(=O)OR 9 , -R 8 -C(=O)N(R 9 )2, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; or two R 6b together with the carbon to which they are both attached form an optionally substituted N-heterocyclyl, or or two R's 6b together with the carbon to which they are both attached form an optionally substituted O-heterocyclyl, or or two R's 6b together with the carbon to which they are both attached form an optionally substituted cycloalkyl, or or two R's 6b together with the carbons to which they are attached form an optionally substituted alkylene chain, R 3a is hydrogen or alkyl, R 4 is hydrogen, alkyl, -R 8 -OR 9 , halo, haloalkyl, or cyano; R 7 is hydrogen, alkyl, halo, or -R 8 -OR 9 and Each R 8 are independently a direct bond or an optionally substituted alkylene chain; Each R 9 are independently hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, or optionally substituted aryl; or two R's 9 together with the nitrogen to which they are both attached form an optionally substituted heterocyclyl; however, If X is N, then R 3 teeth, [ka] Selected from: The compounds are intended to be any stereoisomer, enantiomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0010] In other embodiments, the present disclosure is directed to a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (I) or (II) as described above, as a stereoisomer, enantiomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically 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 a voltage-gated sodium channel, comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of Formula (I) or (II) as above, as a stereoisomer, enantiomer, or tautomer, or a mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0012] In another embodiment, the present disclosure is directed to a method for the treatment of epilepsy and / or an epileptic seizure disorder in a mammal, preferably a human, comprising administering to the mammal in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) or (II) as described above as a stereoisomer, enantiomer, or tautomer, or a mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or a therapeutically effective amount of a compound of Formula (I) or (II) as described above as a stereoisomer, enantiomer, or tautomer, or a mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a pharmaceutically acceptable excipient.

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

[0014] In other embodiments, the present disclosure is directed to one or more other compounds of Formula (I) or (II), or to pharmaceutical therapies in combination with one or more other approved therapies, or any combination thereof, to enhance the efficacy of existing or future drug therapies or to reduce adverse events associated with approved therapies. In one embodiment, the present disclosure is directed to pharmaceutical compositions of compounds of Formula (I) or (II) in combination with established or future therapies for the indications listed herein. DETAILED DESCRIPTION OF THE INVENTION

[0015] definition Certain chemical groups named herein may be preceded by an abbreviation indicating the total number of carbon atoms found in the indicated chemical group. For example, C7-C 12 Alkyl refers to an alkyl group having a total of 7 to 12 carbon atoms, as defined below, and includes C4 to C 12 Cycloalkylalkyl represents a cycloalkylalkyl group, as defined below, having a total of 4 to 12 carbon atoms. The total number of carbons in the shorthand notation does not include carbons that may exist in substituents of the described group.

[0016] In addition to the foregoing, as used in this specification and the appended claims, the following terms have the meanings indicated unless expressly stated to the contrary.

[0017] A "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, as a stereoisomer, enantiomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0018] "Amino" refers to the -NH2 radical.

[0019] "Cyano" refers to the -CN radical.

[0020] "Hydroxy" refers to the -OH radical.

[0021] "Imino" refers to the =NH substituent.

[0022] "Nitro" refers to the -NO2 radical.

[0023] "Oxo" refers to the =O substituent.

[0024] "Thioxo" refers to the =S substituent.

[0025] "Trifluoromethyl" refers to the -CF3 radical.

[0026] "Alkyl" refers to a straight or branched hydrocarbon chain radical, consisting solely of carbon and hydrogen atoms, without unsaturation, having from 1 to 12 carbon atoms, preferably from 1 to 8 carbon atoms or from 1 to 6 carbon atoms, attached to the remainder of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, etc. Unless otherwise stated 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)-R20 , -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 (where t is 1 to 2), -S(O) t OR 22 (where t is 1 to 2), -S(O) p R 22 (wherein p is 0 to 2), and -S(O) t N(R 20 ) 2 (where t is 1 to 2) (where each R 20 are independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, and each R 22 is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl).

[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, such as ethenyl, prop-1-enyl, but-1-enyl, pent-1-enyl, and penta-1,4-dienyl. Unless otherwise stated 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, etc. 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 (where t is 1 to 2), -S(O) t OR 22 (where t is 1 to 2), -S(O) p R 22 (wherein p is 0 to 2), and -S(O) t N(R 20 ) 2 (where t is 1 to 2) (where each R 20 are independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, and each R 22 is 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 otherwise stated 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(R20 )2, -N(R 20 )C(O)OR 22 , -N(R 20 )C(O)R 22 , -N(R 20 )S(O) t R 22 (where t is 1 to 2), -S(O) t OR 22 (where t is 1 to 2), -S(O) p R 22 (where p is 0 to 2), or -S(O) t N(R 20 ) 2 (where t is 1 to 2) (where each R 20 are independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, and each R 22 is 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, without unsaturation, having 1 to 12 carbon atoms, e.g., methylene, ethylene, propylene, n-butylene, etc., that connects 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 stated otherwise in the specification, 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 (where t is 1 to 2), -S(O) t OR 22 (where t is 1 to 2), -S(O) p R 22 (wherein p is 0 to 2), and -S(O) t N(R 20 ) 2 (where t is 1 to 2) (where each R 20 are independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, and each R 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 connects 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 stated otherwise in the specification, an alkenylene chain 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)-R20 , -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 (where t is 1 to 2), -S(O) t OR 22 (where t is 1 to 2), -S(O) p R 22 (wherein p is 0 to 2), and -S(O) t N(R 20 ) 2 (where t is 1 to 2) (where each R 20 are independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, and each R 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, aryl radicals can be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, including 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, phenanthrene, pleiadene, pyrene, and triphenylene. Unless otherwise specified herein, aryl groups include 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 (where t is 1 to 2), -R 21 -N=C(OR 20 )R 20 , -R 21 -S(O) t OR 22 (where t is 1 to 2), -R 21 -S(O) p R 22(where p is 0 to 2), and -R 21 -S(O) t N(R 20 ) 2 (wherein t is 1 to 2), wherein each R 20 are independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, and each R 21 are independently a direct bond or a straight or branched alkylene or alkenylene chain, and each R 22 is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

[0032] "Aralkyl" means an alkyl group of the formula: -R b -R c where R b is an alkylene chain as defined above, and R c is one or more aryl radicals as defined above, e.g., benzyl, diphenylmethyl, etc. 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. "Aralkenyl" refers to a group of the formula: -R d -R c where R d is an alkenylene chain as defined above, and R c is one or more aryl radicals as defined above. The aryl part of the aralkenyl radical may be optionally substituted as defined above for an aryl group. The alkenylene chain part of the aralkenyl radical may be optionally substituted as defined above for an alkenylene group.

[0033] "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, saturated or unsaturated, and 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 specified in the 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)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 (where t is 1 to 2), -R 21 -N=C(OR 20 )R 20 , -R 21 -S(O) t OR 22 (where t is 1 to 2), -R 21 -S(O) p R 22 (where p is 0 to 2), and -R21 -S(O) t N(R 20 ) 2 (wherein t is 1 to 2), wherein each R 20 are independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, and each R 21 are independently a direct bond or a straight or branched alkylene or alkenylene chain, and each R 22 is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

[0034] "Cycloalkylalkyl" refers to a group of the formula: -R b R g where R b is an alkylene chain as defined above, and R g is a cycloalkyl radical as defined above. The alkylene chain and the cycloalkyl radical may be optionally substituted as defined above.

[0035] "Fused" refers to any ring system described herein that is fused to an existing ring structure in the compounds of the present disclosure. When the fused ring system is a heterocyclyl or heteroaryl, any carbon in the existing ring structure that becomes part of the fused ring system may be replaced with a nitrogen.

[0036] "Halo" refers to bromo, chloro, fluoro, or iodo.

[0037] "Haloalkyl" refers to an alkyl radical, as defined above, that is substituted with 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 may be optionally substituted as defined above for an alkyl group.

[0038] "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 haloalkenyl radical may be optionally substituted as defined above for an alkenyl group.

[0039] "Carboxyalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more carboxy radicals. The alkyl portion of the carboxyalkyl radical may be optionally substituted as defined above for an alkyl group.

[0040] "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 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 within the heterocyclyl radical can be optionally oxidized, the nitrogen atom can be optionally quaternized, and the heterocyclyl radical can be partially saturated 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 any 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)OR22 , -R 21 -N(R 20 )C(O)R 22 , -R 21 -N(R 20 )S(O) t R 22 (where t is 1 to 2), -R 21 -N=C(OR 20 )R 20 , -R 21 -S(O) t OR 22 (where t is 1 to 2), -R 21 -S(O) p R 22 (where p is 0 to 2), and -R 21 -S(O) t N(R 20 ) 2 (wherein t is 1 to 2), wherein each R 20 are independently hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, and each R 21 are independently a direct bond or a straight or branched alkylene or alkenylene chain, and each R 22 is alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

[0041] "O-heterocyclyl" refers to a heterocyclyl radical, as defined above, containing at least one oxygen atom and no nitrogen atoms. The O-heterocyclyl radical may be optionally substituted as described above for heterocyclyl radicals.

[0042] "N-heterocyclyl" refers to a heterocyclyl radical, as defined above, containing at least one nitrogen. The N-heterocyclyl radical may be optionally substituted as described above for heterocyclyl radicals.

[0043] "Heterocyclylalkyl" refers to a group of the formula: -R b R h where R b is an alkylene chain as defined above, and R h is a 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 the 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 defined above for a heterocyclyl group.

[0044] "Heteroaryl" refers to a 5- to 14-membered ring system radical containing a hydrogen atom, 1 to 13 carbon atoms, 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and at least one aromatic ring. For purposes of this disclosure, the heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems, and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized, and the nitrogen atom may be optionally quaternized.Examples include, but are not limited to, 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 benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, benzoxazolinonyl, benzimidazolethionyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indo Rizinyl, isoxazolyl, naphthyridinyl, 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, pyri

[0023] Unless otherwise specified herein, heteroaryl groups include alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, oxo, thioxo, nitro, thioxo, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -R. 21 -OR20 , -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 (where t is 1 to 2), -R 21 -N=C(OR 20 )R 20 , -R 21 -S(O) t OR 22 (where t is 1 to 2), -R 21 -S(O) p R 22 (where p is 0 to 2), and -R 21 -S(O) t N(R 20 ) 2 (wherein t is 1 to 2), wherein each R 20 are independently hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, and each R 21 are independently a direct bond or a straight or branched alkylene or alkenylene chain, and each R 22 is alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

[0045] "N-heteroaryl" refers to a heteroaryl radical, as defined above, containing at least one nitrogen. The N-heteroaryl radical may be optionally substituted as defined above for a heteroaryl radical.

[0046] "Heteroarylalkyl" refers to a group of the formula: -R b R i where R b is an alkylene chain as defined above, and 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.

[0047] "Prodrug" is intended to refer to a compound that can be converted into a biologically active compound of the present disclosure under physiological conditions or by solvolysis. Thus, the term "prodrug" refers to a metabolic precursor of a pharmaceutically acceptable compound of the present disclosure. A prodrug may be inactive when administered to a subject in need thereof, but is converted in vivo to an active compound of the present disclosure. Prodrugs are usually rapidly converted in vivo, for example, by hydrolysis in blood, to yield the parent compound of the present disclosure. 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)). Discussions regarding prodrugs are presented in Higuchi, T., et al., "Pro-drugs as Novel Delivery Systems," ACS Symposium Series, Vol. 14, and Bioreversible Carriers in Drug Design, Ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference in their entireties.

[0048] The term "prodrug" is intended to encompass any covalently bonded carrier that releases an 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 such that the modifications are cleaved, either by routine manipulation or in vivo, to yield the parent compound 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 is cleaved to form a free hydroxy, amino, or 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 functional groups or amide derivatives of amine functional groups in the compounds of the present disclosure.

[0049] "Stable compound" and "stable structure" are intended to refer to 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.

[0050] As used herein, a "dangling bond," or a bond that is not shown as being directly attached to a particular atom of a molecule, may be attached at any alternative position on the dangling radical or molecule. Exemplary dangling bonds are shown in the following radicals: [ka]

[0051] In the above structure, R may be attached to any of the alternative positions of the radical. For example, R may be covalently attached to any of positions a to g as shown below: [ka]

[0052] "Mammal" includes both humans and domestic animals, e.g., laboratory animals and domestic pets (e.g., cats, dogs, pigs, cows, sheep, goats, horses, rabbits), and non-domesticated animals, e.g., wildlife.

[0053] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description encompasses instances in which the event or circumstance occurs and instances in which the event or circumstance does not occur. For example, "optionally substituted aryl" means that the aryl radical may or may not be substituted, and that the description encompasses both substituted aryl radicals and aryl radicals that have no substitution ("unsubstituted"). If a functional group is described as "optionally substituted," and similarly, a substituent on that functional group is described as "optionally substituted," then for the purposes of this disclosure, such repetitions are limited to five, and preferably, such repetitions are limited to two.

[0054] A "pharmaceutically acceptable carrier, diluent, or excipient" includes, but is not limited to, any adjuvant, carrier, excipient, flow agent, sweetener, diluent, preservative, dye / colorant, flavoring, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier recognized by the U.S. Food and Drug Administration as acceptable for use in humans or domestic animals.

[0055] "Pharmaceutically acceptable salt" includes both acid and base addition salts.

[0056] "Pharmaceutically acceptable acid addition salts" are those which retain the biological effectiveness and properties of the free base, which are not biologically or otherwise undesirable, and include those formed from inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentian acid, thiazolinone ... These include salts formed with cinnamic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxoglutaric 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, and undecylenic acid.

[0057] "Pharmaceutically acceptable base addition salts" refer to salts that retain the biological effectiveness and properties of the free acid and are not biologically or otherwise undesirable. These salts are prepared by 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 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, substituted 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.

[0058] In many cases, crystallization produces a solvate of the compound of the present disclosure. As used herein, the term "solvate" refers to an aggregate or solid form containing one or more molecules of the compound of the present disclosure together with one or more molecules of a 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 compound of the present disclosure can exist as a hydrate, including a monohydrate, a dihydrate, a hemihydrate, a sesquihydrate, a trihydrate, a tetrahydrate, etc., and corresponding solvate forms. The compound of the present disclosure can be a true solvate, but in other cases, the compound of the present disclosure may simply retain extraneous water or may be a mixture of water and some extraneous solvent.

[0059] A "pharmaceutical composition" refers to a formulation of a compound of the present disclosure and a vehicle generally accepted in the art for the delivery of a biologically active compound to a mammal, e.g., a human, including any pharmaceutically acceptable carrier, diluent, or excipient therefor.

[0060] "Seizure disorders" refers to seizures and disorders associated with seizures, such as focal 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, and 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, early infantile epileptic encephalopathy, early-onset epileptic encephalopathy, generalized epilepsy febrile seizures plus, Rett syndrome, multiple sclerosis, Alzheimer's disease, autism, ataxia, hypotonia, and paroxysmal dyskinesia. Preferably, the term "seizure disorder" refers to partial epileptic seizures (focal epilepsy).

[0061] A "therapeutically effective amount" refers to the range of amounts of a compound of the present disclosure that, when administered to a human, treats, ameliorates, or prevents a seizure disorder, preferably epilepsy, in the human, or exhibits a detectable therapeutic or prophylactic effect in a human with a seizure disorder. Effect is detected, for example, by a reduction in seizures (frequency) or the severity (quality) of seizures. The precise therapeutically effective amount for a given human will depend on that human's size and health, the nature and extent of the seizure disorder, the presence of any concomitant medications, and other variables known to those of skill in the art. The therapeutically effective amount for a given situation is determined by routine experimentation and is within the judgment of the clinician.

[0062] "Treatment" refers to therapeutic applications to slow or halt the progression of a seizure disorder, prophylactic applications to prevent the onset of a seizure disorder, and / or amelioration of a seizure disorder. Amelioration of a seizure disorder differs from therapeutic applications that slow or halt a seizure disorder in that amelioration methods not only completely halt the progression of the seizure disorder, but also result in some shift in cellular behavior toward the normal state that would be observed in the absence of the seizure disorder.

[0063] As used herein, "treating" or "treatment" includes treatment of a disease or condition of interest in a mammal, preferably a human, having the disease or condition of interest, and includes: (a) preventing a disease or condition from occurring in a mammal, particularly where such mammal is susceptible to the condition but has not yet been diagnosed as exhibiting it; (b) inhibiting the disease or condition, i.e., suppressing its onset; (c) alleviating (or ameliorating) the disease or condition, i.e., causing regression of the disease or condition; or (d) Relieving (or ameliorating) the symptoms caused by a disease or condition, i.e., alleviating a seizure disorder without addressing the underlying disease or condition.

[0064] 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 (so that the etiology is not yet understood) and therefore is not yet recognized as a disease, but merely as an undesirable state or syndrome (a particular set of symptoms more or less recognized by clinicians).

[0065] The compounds of the present disclosure may have at least one asymmetric carbon atom and therefore may exist as racemates, enantiomers, and / or diastereomers. In this disclosure, the terms diastereomer and diastereoisomer, as well as related terms, are synonymous and interchangeable. Unless otherwise specified, the present disclosure encompasses all enantiomeric and diastereomeric forms of the compounds of Formula (I) or (II). Pure stereoisomers, mixtures of enantiomers and / or diastereoisomers, and mixtures of different compounds of the present disclosure are encompassed herein. Thus, unless a specific stereoisomer, enantiomer, or diastereoisomer is identified, the compounds of Formula (I) or (II) may exist as racemates, racemic mixtures, or diastereomeric mixtures, as well as individual diastereoisomers or enantiomers, and all isomeric forms are encompassed in the present disclosure. In this disclosure, a racemate or racemic mixture does not refer exclusively to a 50:50 stereoisomeric mixture. Mixtures of various ratios of stereoisomers enriched in the other enantiomer or diastereoisomer are also contemplated.

[0066] "Enantiomer" refers to an asymmetric molecule that can exist in two different isomeric forms with different configurations in space. Other terms used to represent or refer to enantiomers include "stereoisomers" (because they differ in configuration or spatial arrangement around a chiral center; all enantiomers are stereoisomers, but not all stereoisomers are enantiomers) or "enantiomers" (because pure enantiomers are optically active (optical activity is the ability of different pure enantiomers to rotate plane-polarized light in different directions)). Because they lack a plane of symmetry, enantiomers do not correspond to their mirror images. Molecules that exist in two enantiomeric forms are chiral, meaning that they can be considered to occur 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 called chiral or asymmetric centers.

[0067] Enantiomers have the same empirical formula and are generally chemically identical in terms of reactivity, physical properties, and spectroscopic properties. However, enantiomers exhibit different chemical reactivities toward other asymmetric compounds and respond differently to physical perturbations of asymmetry. The most common perturbation of asymmetry is polarized light.

[0068] Enantiomers can rotate plane-polarized light; therefore, they are optically active. Two different enantiomers of the same compound rotate plane-polarized light in opposite directions. Thus, light can be rotated left or counterclockwise relative to a hypothetical observer (this is levorotatory or "l," or minus or "-"), or right or clockwise (this is dextrorotatory or "d," or plus or "+"). The optical rotation symbol (+) or (-) is not related to the R,S designation. An equal mixture of two chiral enantiomers is called a racemic mixture or racemate and is represented 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 because equal amounts of the (+) and (-) forms are present. Generally, the presence of a single enantiomer rotates polarized light in only one direction, and therefore a single enantiomer is said to be optically pure.

[0069] The "R" and "S" designations are used to denote the three-dimensional arrangement (or configuration) of atoms at a chiral center. This designation may appear as a prefix or a suffix. They may or may not be separated from the name of the enantiomer by a hyphen. They may or may not be connected by a hyphen. They may or may not be enclosed in parentheses. The method for determining the designation is to look at the priority arrangement of the groups at the chiral center when the lowest priority group is positioned away from a hypothetical observer. If the arrangement of the remaining three groups from highest to lowest priority is clockwise, then the chiral center has the "R" configuration; if the arrangement is counterclockwise, then the chiral center has the "S" configuration.

[0070] When used in reference to a racemate or racemic mixture, "resolution" or "resolving" refers to the separation of a racemate into its two enantiomeric forms (i.e., (+) and (-); (R) and (S) forms).

[0071] "Enantiomeric excess" or "ee" refers to a product in which one enantiomer is present in excess of the other and is defined as the absolute difference in mole fraction of each enantiomer. Enantiomeric excess is usually expressed as the percentage of one enantiomer relative to the other present in a mixture. In accordance with the principles of this disclosure, an (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%.

[0072] A particular compound may be labeled as "P1," "P2" (and beyond), or "D1," "D2" (and beyond). This distinction indicates that the compound is the first eluting peak (i.e., P1) from the chiral separation technique, and does not necessarily exhibit a particular stereochemistry.

[0073] "Tautomer" refers to a proton migration from one atom of a molecule to another atom of the same molecule. The present disclosure includes tautomers of any compounds of Formula (I) or (II) described herein.

[0074] Parentheses and brackets in substituents may be used herein to conserve space. Thus, the use of parentheses in a substituent indicates that the group enclosed in the parentheses is directly bonded to the atom preceding the parentheses. The use of brackets in a substituent also indicates that the group enclosed in the brackets is directly bonded to the atom preceding the brackets.

[0075] For example, a compound of formula (I) or (II) having the following structure: [ka] is referred to herein as (S)-6-chloro-N-(4-(2,5-difluorophenyl)-2-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)nicotinamide.

[0076] compound One embodiment of the present disclosure is a compound of Formula (I) or (II) as described above in the Summary of the Invention, as an individual stereoisomer, enantiomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. That is, one embodiment is a compound of Formula (I): [ka] A compound of the formula: During the ceremony, [ka] represents a double or single bond to fill all valences, Y is N or NR 4a and X is C(R 7 ) or N, R 1 teeth, [ka] is selected from where: [ka] each occurrence independently represents a double bond or a single bond so as to satisfy all valences; n is 0, 1, 2, 3, 4, or 5; R 1a is hydrogen or alkyl, Each R 1b are independently halo, alkyl, haloalkyl, cyano, heterocyclylalkyl, -R 8 -N(R 9 )2, -R 8 -C(=O)N(R 9 )2, or -R 8 -OR 9 Or or two Rs attached to adjacent carbons 1btogether with the carbon to which they are attached form an optionally substituted N-heteroaryl, an optionally substituted N-heterocyclyl, an optionally substituted O-heterocyclyl, or an optionally substituted aryl; R 1c is N or -Si(CH3)3, R 2 teeth, [ka] is selected from where: m is 0, 1, 2, 3, or 4; Each R 5 are independently halo, alkyl, haloalkyl, or -R 10 -CN or or two R's 5 together with the carbon to which they are both attached form an optionally substituted O-heterocyclyl, or or two R's 5 together with the carbon to which they are both attached form an optionally substituted N-heterocyclyl, or or two R's 5 together with the carbon to which they are both attached form an optionally substituted cycloalkyl, or or two R's 5 are linked to form an optionally substituted alkylene chain, R 3 is alkyl, -R 8 -N(R 9 )2, -R 8 -OR 9 or R 3 teeth, [ka] is selected from where: p is 0, 1, 2, 3, 4, or 5; R 6a is hydrogen, alkyl, cycloalkyl, haloalkyl, -C(=O)R9 , optionally substituted arylalkyl, or optionally substituted heteroaryl; Each R 6b are independently alkyl, halo, haloalkyl, -R 8 -OR 9 , -R 8 -N(R 9 )2, -R 8 -C(=O)OR 9 , -R 8 -C(=O)N(R 9 )2, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; or two R 6b together with the carbon to which they are both attached form an optionally substituted N-heterocyclyl, or or two R 6b together with the carbon to which they are both attached form an optionally substituted O-heterocyclyl, or or two R 6b together with the carbon to which they are both attached form an optionally substituted cycloalkyl, or or two R 6b are linked to form an optionally substituted alkylene chain, or or R 6b The emergence of and R 1b are linked to form an optionally substituted alkylene chain, R 3a is hydrogen or alkyl, R 4 is hydrogen, alkyl, -R 8 -OR 9 , halo, haloalkyl, or cyano; or R 4 is R 4 together with the carbon to which it is attached, R 4a Combined with R 4a together with the nitrogen to which it is attached form an optionally substituted 5-membered N-heteroaryl; R 7is hydrogen, alkyl, halo, or -R 8 -OR 9 and Each R 8 are independently a direct bond or an optionally substituted alkylene chain; Each R 9 are independently hydrogen, alkyl, haloalkyl, carboxyalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, or optionally substituted aryl; or two R's 9 together with the nitrogen to which they are both attached form an optionally substituted heterocyclyl; However, if X is N, then R 3 teeth, [ka] Selected from: The compounds are provided as their stereoisomers, enantiomers, or tautomers, or mixtures thereof, or as pharmaceutically acceptable salts, solvates, or prodrugs thereof.

[0077] Particular embodiments are of formula (II): [ka] A compound of the formula During the ceremony, X is C(R 7 ) or N, R 1 teeth, [ka] is selected from where: [ka] represents a double or single bond, n is 0, 1, 2, 3, 4, or 5; R 1a is hydrogen or alkyl, Each R1b are independently halo, alkyl, haloalkyl, cyano, heterocyclylalkyl, -R 8 -N(R 9 )2, -R 8 -C(=O)N(R 9 )2, or -R 8 -OR 9 Or or two Rs attached to adjacent carbons 1b together with the carbon to which they are attached form an optionally substituted N-heteroaryl; R 2 teeth, [ka] is selected from where: m is 0, 1, 2, 3, or 4; Each R 5 are independently halo, alkyl, haloalkyl, or -R 10 -CN or or two R 5 together with the carbon to which they are both attached form an optionally substituted O-heterocyclyl, or or two R 5 together with the carbon to which they are both attached form an optionally substituted cycloalkyl, or or two R 5 together with the carbons to which they are attached form an optionally substituted alkylene chain, R 3 is alkyl, -R 8 -N(R 9 )2, -R 8 -OR 9 or R 3 teeth, [ka] is selected from where: p is 0, 1, 2, 3, 4, or 5; R6a is hydrogen, alkyl, cycloalkyl, haloalkyl, -C(=O)R 9 , optionally substituted arylalkyl, or optionally substituted heteroaryl; Each R 6b are independently alkyl, halo, -R 8 -OR 9 , -R 8 -N(R 9 )2, -R 8 -C(=O)OR 9 , -R 8 -C(=O)N(R 9 )2, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; or two R's 6b together with the carbon to which they are both attached form an optionally substituted N-heterocyclyl, or or two R's 6b together with the carbon to which they are both attached form an optionally substituted O-heterocyclyl, or or two R's 6b together with the carbon to which they are both attached form an optionally substituted cycloalkyl, or or two R's 6b together with the carbons to which they are attached form an optionally substituted alkylene chain, R 3a is hydrogen or alkyl, R 4 is hydrogen, alkyl, -R 8 -OR 9 , halo, haloalkyl, or cyano; R 7 is hydrogen, alkyl, halo, or -R 8 -OR 9 and Each R 8 are independently a direct bond or an optionally substituted alkylene chain; Each R 9are independently hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, or optionally substituted aryl; or two R's 9 together with the nitrogen to which they are both attached form an optionally substituted heterocyclyl; However, if X is N, then R 3 teeth, [ka] Selected from: The compounds are provided as their stereoisomers, enantiomers, or tautomers, or mixtures thereof, or as pharmaceutically acceptable salts, solvates, or prodrugs thereof.

[0078] In some embodiments, X is C(R 7 In certain embodiments, X is C(R 7 ) and R 7 is hydrogen. In certain embodiments, X is C(R 7 ) and R 7 is halo. In some more specific embodiments, X is C(R 7 ) and R 7 is fluoro. In some particular embodiments, X is N.

[0079] In some embodiments, the compound, as a stereoisomer, enantiomer, or tautomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, has the following formula (Ia): [ka] and X, R 1 , R 2 , R 3 , R 3a , and R 4 are each as defined above in the Brief Description.

[0080] In certain embodiments, the compound, as a stereoisomer, enantiomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, has the following formula (Ib): [ka] and X, R 1 , R 2 , R 3 , R 3a , and R 4 are each as defined above in the Brief Description.

[0081] In some embodiments, R 1 teeth, [ka] is selected from where: Each R 1b are independently halo, alkyl, haloalkyl, cyano, heterocyclylalkyl, -R 8 -N(R 9 )2, -R 8 -C(=O)N(R 9 )2, or -R 8 -OR 9 and R 1c is N or -Si(CH3)3.

[0082] In certain embodiments, R 1 teeth, [ka] is selected from where: [ka] each occurrence independently represents a double bond or a single bond so as to satisfy all valences; n is 0, 1, 2, 3, 4, or 5; R1a is hydrogen or alkyl, Each R 1b are independently halo, alkyl, haloalkyl, cyano, heterocyclylalkyl, -R 8 -N(R 9 )2, -R 8 -C(=O)N(R 9 )2, or -R 8 -OR 9 Or or two Rs attached to adjacent carbons 1b together with the carbon to which they are attached form an optionally substituted N-heteroaryl, an optionally substituted N-heterocyclyl, an optionally substituted O-heterocyclyl, or an optionally substituted aryl.

[0083] In certain embodiments, R 1 teeth, [ka] is selected from where: [ka] each occurrence independently represents a double bond or a single bond so as to satisfy all valences; n is 0, 1, 2, 3, 4, or 5; R 1a is hydrogen or alkyl, Each R 1b are independently halo, alkyl, haloalkyl, cyano, heterocyclylalkyl, -R 8 -N(R 9 )2, -R 8 -C(=O)N(R 9 )2, or -R 8 -OR 9 Or or two Rs attached to adjacent carbons 1btogether with the carbon to which they are attached form an optionally substituted N-heteroaryl, an optionally substituted N-heterocyclyl, an optionally substituted O-heterocyclyl, or an optionally substituted aryl.

[0084] In certain embodiments, R 1 teeth, [ka] is selected from where: [ka] each occurrence independently represents a double bond or a single bond so as to satisfy all valences; n is 0, 1, 2, 3, 4, or 5; R 1a is hydrogen or alkyl, Each R 1b are independently halo, alkyl, haloalkyl, cyano, heterocyclylalkyl, -R 8 -N(R 9 )2, -R 8 -C(=O)N(R 9 )2, or -R 8 -OR 9 Or or two Rs attached to adjacent carbons 1b together with the carbon to which they are attached form an optionally substituted N-heteroaryl, an optionally substituted N-heterocyclyl, an optionally substituted O-heterocyclyl, or an optionally substituted aryl.

[0085] In certain embodiments, R 1 teeth, [ka] is selected from where: [ka] each occurrence independently represents a double bond or a single bond so as to satisfy all valences; n is 0, 1, 2, 3, 4, or 5; R 1a is hydrogen or alkyl, Each R 1b are independently halo, alkyl, haloalkyl, cyano, heterocyclylalkyl, -R 8 -N(R 9 )2, -R 8 -C(=O)N(R 9 )2, or -R 8 -OR 9 Or or two Rs attached to adjacent carbons 1b together with the carbon to which they are attached form an optionally substituted N-heteroaryl, an optionally substituted N-heterocyclyl, an optionally substituted O-heterocyclyl, or an optionally substituted aryl.

[0086] In some embodiments, R 1 teeth, [ka] is selected from where: [ka] each occurrence independently represents a double bond or a single bond so as to satisfy all valences; n is 0, 1, 2, 3, 4, or 5; R 1a is hydrogen or alkyl, Each R 1b are independently halo, alkyl, haloalkyl, cyano, heterocyclylalkyl, -R 8 -N(R 9 )2, -R 8 -C(=O)N(R 9 )2, or -R 8 -OR 9 Or or two Rs attached to adjacent carbons1b together with the carbon to which they are attached form an optionally substituted N-heteroaryl, an optionally substituted N-heterocyclyl, an optionally substituted O-heterocyclyl, or an optionally substituted aryl.

[0087] In certain embodiments, R 1 teeth, [ka] and where: n is 0, 1, 2, 3, 4, or 5; R 1a is hydrogen or alkyl, Each R 1b are independently halo, alkyl, haloalkyl, cyano, heterocyclylalkyl, -R 8 -N(R 9 )2, -R 8 -C(=O)N(R 9 )2, or -R 8 -OR 9 Or or two Rs attached to adjacent carbons 1b together with the carbon to which they are attached form an optionally substituted N-heteroaryl.

[0088] In some embodiments, R 1 has the following structure: [ka] It has one of the following.

[0089] In some embodiments, R 1 has the following structure: [ka] It has.

[0090] In certain embodiments, R 1 has the following structure: [ka] It has one of the following.

[0091] In some embodiments, R 1 has the following structure: [ka] It has one of the following.

[0092] In some embodiments, R 1 has the following structure: [ka] It has one of the following.

[0093] In certain embodiments, R 1 has the following structure: [ka] It has one of the following.

[0094] In certain embodiments, R 1 has the following structure: [ka] It has one of the following.

[0095] In some embodiments, R 1 teeth, [ka] is selected from where: n is 0, 1, 2, 3, 4, or 5; R 1a is hydrogen or alkyl, Each R 1bare independently halo, alkyl, haloalkyl, cyano, heterocyclylalkyl, -R 8 -N(R 9 )2, -R 8 -C(=O)N(R 9 )2, or -R 8 -OR 9 Or or two Rs attached to adjacent carbons 1b together with the carbon to which they are attached form an optionally substituted N-heteroaryl.

[0096] In some more specific embodiments, R 1 teeth, [ka] is selected from where: n is 0, 1, 2, 3, 4, or 5; R 1a is hydrogen or alkyl, Each R 1b are independently halo, alkyl, haloalkyl, cyano, heterocyclylalkyl, -R 8 -N(R 9 )2, -R 8 -C(=O)N(R 9 )2, or -R 8 -OR 9 Or or two Rs attached to adjacent carbons 1b together with the carbon to which they are attached form an optionally substituted N-heteroaryl.

[0097] In certain embodiments, R 1 teeth, [ka] is selected from where: n is 0, 1, 2, 3, 4, or 5; R 1a is hydrogen or alkyl, Each R 1b are independently halo, alkyl, haloalkyl, cyano, heterocyclylalkyl, -R 8 -N(R 9 )2, -R 8 -C(=O)N(R 9 )2, or -R 8 -OR 9 Or or two Rs attached to adjacent carbons 1b together with the carbon to which they are attached form an optionally substituted N-heteroaryl.

[0098] In some more specific embodiments, R 1 teeth, [ka] is selected from where: n is 0, 1, 2, 3, 4, or 5; R 1a is hydrogen or alkyl, Each R 1b are independently halo, alkyl, haloalkyl, cyano, heterocyclylalkyl, -R 8 -N(R 9 )2, -R 8 -C(=O)N(R 9 )2, or -R 8 -OR 9 Or or two Rs attached to adjacent carbons 1b together with the carbon to which they are attached form an optionally substituted N-heteroaryl.

[0099] In certain more specific embodiments, R 1 teeth, [ka] is selected from where: n is 0, 1, 2, 3, 4, or 5; R 1ais hydrogen or alkyl, Each R 1b are independently halo, alkyl, haloalkyl, cyano, heterocyclylalkyl, -R 8 -N(R 9 )2, -R 8 -C(=O)N(R 9 )2, or -R 8 -OR 9 Or or two Rs attached to adjacent carbons 1b together with the carbon to which they are attached form an optionally substituted N-heteroaryl.

[0100] In some embodiments, R 1 teeth, [ka] is selected from where: n is 0, 1, 2, 3, 4, or 5; R 1a is hydrogen or alkyl, Each R 1b are independently halo, alkyl, haloalkyl, cyano, heterocyclylalkyl, -R 8 -N(R 9 )2, -R 8 -C(=O)N(R 9 )2, or -R 8 -OR 9 Or or two Rs attached to adjacent carbons 1b together with the carbon to which they are attached form an optionally substituted N-heteroaryl.

[0101] In certain embodiments, R 1 teeth, [ka] and where: n is 0, 1, 2, 3, 4, or 5; R1a is hydrogen or alkyl, Each R 1b are independently halo, alkyl, haloalkyl, cyano, heterocyclylalkyl, -R 8 -N(R 9 )2, -R 8 -C(=O)N(R 9 )2, or -R 8 -OR 9 Or or two Rs attached to adjacent carbons 1b together with the carbon to which they are attached form an optionally substituted N-heteroaryl.

[0102] In certain embodiments, R 1 teeth, [ka] and where: Each R 1b are independently halo, alkyl, haloalkyl, cyano, heterocyclylalkyl, -R 8 -N(R 9 )2, -R 8 -C(=O)N(R 9 )2, or -R 8 -OR 9 is.

[0103] In some more specific embodiments, R 1 teeth, [ka] and where: Each R 1b is independently alkyl.

[0104] In more specific embodiments, R 1 has the following structure: [ka] It has one of the following.

[0105] In some specific embodiments, R 1 has the following structure: [ka] It has. In certain specific embodiments, R 1 has the following structure: [ka] It has one of the following.

[0106] In some embodiments, R 1 has the following structure: [ka] It has one of the following.

[0107] In certain embodiments, R 1 has the following structure: [ka] It has one of the following.

[0108] In some specific embodiments, R 1 has the following structure: [ka] It has one of the following.

[0109] In certain specific embodiments, R 1 has the following structure: [ka] It has one of the following.

[0110] In some embodiments, R 2 teeth, [ka] is selected from where: m is 0, 1, 2, 3, or 4; Each R 5 are independently halo, alkyl, haloalkyl, or -R 10 -CN or or two R's 5 together with the carbon to which they are both attached form an optionally substituted O-heterocyclyl, or or two R's 5 together with the carbon to which they are both attached form an optionally substituted N-heterocyclyl, or or two R's 5 together with the carbon to which they are both attached form an optionally substituted cycloalkyl, or or two R's 5 are linked to form an optionally substituted alkylene chain.

[0111] In some embodiments, R 2 teeth, [ka] is selected from where: m is 0, 1, 2, 3, or 4; Each R 5 are independently halo, alkyl, haloalkyl, or -R 10 -CN or or two R's 5 together with the carbon to which they are both attached form an optionally substituted O-heterocyclyl, or or two R's 5 together with the carbon to which they are both attached form an optionally substituted N-heterocyclyl, or or two R's 5 together with the carbon to which they are both attached form an optionally substituted cycloalkyl, or or two R's 5are linked to form an optionally substituted alkylene chain.

[0112] In some embodiments, R 2 teeth, [ka] and where: m is 0, 1, 2, 3, or 4; Each R 5 are independently halo, alkyl, haloalkyl, or -R 10 -CN or or two R's 5 together with the carbon to which they are both attached form an optionally substituted O-heterocyclyl, or or two R's 5 together with the carbon to which they are both attached form an optionally substituted N-heterocyclyl, or or two R's 5 together with the carbon to which they are both attached form an optionally substituted cycloalkyl, or or two R's 5 are linked to form an optionally substituted alkylene chain.

[0113] In some embodiments, R 2 teeth, [ka] is selected from where: m is 0, 1, 2, 3, or 4; Each R 5 are independently halo, alkyl, haloalkyl, or -R 10 -CN or or two R's 5 together with the carbon to which they are both attached form an optionally substituted O-heterocyclyl, or or two R's 5together with the carbon to which they are both attached form an optionally substituted cycloalkyl, or or two R's 5 together with the carbon to which they are attached form an optionally substituted alkylene chain.

[0114] In certain embodiments, R 2 teeth, [ka] and where: m is 0, 1, 2, 3, or 4; Each R 5 are independently halo, alkyl, haloalkyl, or -R 10 -CN or or two R's 5 together with the carbon to which they are both attached form an optionally substituted O-heterocyclyl, or or two R's 5 together with the carbon to which they are both attached form an optionally substituted cycloalkyl, or or two R's 5 together with the carbon to which they are attached form an optionally substituted alkylene chain.

[0115] In more specific embodiments, R 2 has the following structure: [ka] It has one of the following.

[0116] In some embodiments, R 2 has the following structure: [ka] It has one of the following.

[0117] In certain embodiments, R 2 has the following structure: [ka] It has one of the following.

[0118] In some embodiments, R 2 has the following structure: [ka] It has one of the following.

[0119] In some embodiments, R 2 has the following structure: [ka] It has one of the following.

[0120] In some embodiments, R 2 has the following structure: [ka] It has one of the following.

[0121] In certain embodiments, R 2 has the following structure: [ka] It has one of the following.

[0122] In some embodiments, R 2 has the following structure: [ka] It has one of the following.

[0123] In some embodiments, R 2 has the following structure: [ka] It has one of the following.

[0124] In certain embodiments, R 3 teeth, [ka] is selected from where: p is 0, 1, 2, 3, 4, or 5; R 6a is hydrogen, alkyl, cycloalkyl, haloalkyl, -C(=O)R 9 , optionally substituted arylalkyl, or optionally substituted heteroaryl; Each R 6b are independently alkyl, halo, haloalkyl, -R 8 -OR 9 , -R 8 -N(R 9 )2, -R 8 -C(=O)OR 9 , -R 8 -C(=O)N(R 9 )2, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; or two R 6b together with the carbon to which they are both attached form an optionally substituted N-heterocyclyl, or or two R 6b together with the carbon to which they are both attached form an optionally substituted O-heterocyclyl, or or two R 6b together with the carbon to which they are both attached form an optionally substituted cycloalkyl, or or two R 6b are linked to form an optionally substituted alkylene chain, or or R 6b The emergence of and R 1b are linked to form an optionally substituted alkylene chain.

[0125] In some embodiments, R 3 is alkyl, -R 8 -N(R 9 )2, or -R 8 -OR 9 In certain embodiments, R 3 teeth, [ka] is selected from where: p is 0, 1, 2, 3, 4, or 5; Each R 6b are independently alkyl, halo, haloalkyl, -R 8 -OR 9 , -R 8 -N(R 9 )2, -R 8 -C(=O)OR 9 , -R 8 -C(=O)N(R 9 )2, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; or two R's 6b together with the carbon to which they are both attached form an optionally substituted N-heterocyclyl, or or two R's 6b together with the carbon to which they are both attached form an optionally substituted O-heterocyclyl, or or two R's 6b together with the carbon to which they are both attached form an optionally substituted cycloalkyl, or or two R's 6b are linked to form an optionally substituted alkylene chain, or or R 6b The emergence of and R 1b are linked to form an optionally substituted alkylene chain.

[0126] In some embodiments, R 3 teeth, [ka] is selected from where: p is 0, 1, 2, 3, 4, or 5; Each R 6b are independently alkyl, halo, haloalkyl, -R 8 -OR 9 , -R 8 -N(R 9 )2, -R 8 -C(=O)OR 9 , -R 8 -C(=O)N(R 9 )2, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; or two R's 6b together with the carbon to which they are both attached form an optionally substituted N-heterocyclyl, or or two R's 6b together with the carbon to which they are both attached form an optionally substituted O-heterocyclyl, or or two R's 6b together with the carbon to which they are both attached form an optionally substituted cycloalkyl, or or two R's 6b are linked to form an optionally substituted alkylene chain, or or R 6b The emergence of and R 1b are linked to form an optionally substituted alkylene chain.

[0127] In certain embodiments, R 3 teeth, [ka] is selected from where: p is 0, 1, 2, 3, 4, or 5; R 6ais hydrogen, alkyl, cycloalkyl, haloalkyl, -C(=O)R 9 , optionally substituted arylalkyl, or optionally substituted heteroaryl; Each R 6b are independently alkyl, halo, haloalkyl, -R 8 -OR 9 , -R 8 -N(R 9 )2, -R 8 -C(=O)OR 9 , -R 8 -C(=O)N(R 9 )2, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; or two R 6b together with the carbon to which they are both attached form an optionally substituted N-heterocyclyl, or or two R 6b together with the carbon to which they are both attached form an optionally substituted O-heterocyclyl, or or two R 6b together with the carbon to which they are both attached form an optionally substituted cycloalkyl, or or two R 6b are linked to form an optionally substituted alkylene chain, or or R 6b The emergence of and R 1b are linked to form an optionally substituted alkylene chain.

[0128] In some embodiments, R 3 teeth, [ka] is selected from where: p is 0, 1, 2, 3, 4, or 5; R 6a is hydrogen, alkyl, cycloalkyl, haloalkyl, -C(=O)R 9, optionally substituted arylalkyl, or optionally substituted heteroaryl; Each R 6b are independently alkyl, halo, haloalkyl, -R 8 -OR 9 , -R 8 -N(R 9 )2, -R 8 -C(=O)OR 9 , -R 8 -C(=O)N(R 9 )2, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; or two R 6b together with the carbon to which they are both attached form an optionally substituted N-heterocyclyl, or or two R 6b together with the carbon to which they are both attached form an optionally substituted O-heterocyclyl, or or two R 6b together with the carbon to which they are both attached form an optionally substituted cycloalkyl, or or two R 6b are linked to form an optionally substituted alkylene chain, or or R 6b The emergence of and R 1b are linked to form an optionally substituted alkylene chain.

[0129] In certain embodiments, R 3 teeth, [ka] is selected from where: p is 0, 1, 2, 3, 4, or 5; R 6a is hydrogen, alkyl, cycloalkyl, haloalkyl, -C(=O)R 9 , optionally substituted arylalkyl, or optionally substituted heteroaryl; Each R 6b are independently alkyl, halo, haloalkyl, -R 8 -OR 9 , -R 8 -N(R 9 )2, -R 8 -C(=O)OR 9 , -R 8 -C(=O)N(R 9 )2, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; or two R's 6b together with the carbon to which they are both attached form an optionally substituted N-heterocyclyl, or or two R's 6b together with the carbon to which they are both attached form an optionally substituted O-heterocyclyl, or or two R's 6b together with the carbon to which they are both attached form an optionally substituted cycloalkyl, or or two R's 6b are linked to form an optionally substituted alkylene chain, or or R 6b The emergence of and R 1b are linked to form an optionally substituted alkylene chain.

[0130] In some embodiments, R 3 has the following structure: [ka] [ka] [ka] [ka] It has one of the following.

[0131] In some embodiments, R 3 has the following structure: [ka] It has one of the following.

[0132] In some embodiments, R 3 has the following structure: [ka] It has one of the following.

[0133] In certain embodiments, R 3 has the following structure: [ka] It has one of the following.

[0134] In some embodiments, R 3 has the following structure: [ka] It has one of the following.

[0135] In certain embodiments, R 3 has the following structure: [ka] It has one of the following.

[0136] In some embodiments, R 3 has the following structure: [ka] It has one of the following.

[0137] In some embodiments, R 3 has the following structure: [ka] It has.

[0138] In certain embodiments, R 3 has the following structure: [ka] It has one of the following.

[0139] In certain embodiments, R 3 has the following structure: [ka] It has one of the following.

[0140] In some embodiments, R 3 has the following structure: [ka] It has one of the following.

[0141] In some embodiments, R 3 has the following structure: [ka] It has one of the following.

[0142] In some embodiments, R 3 has the following structure: [ka] It has.

[0143] In certain embodiments, R 3 has the following structure: [ka] It has.

[0144] In some embodiments, R 3has the following structure: [ka] It has one of the following.

[0145] In some embodiments, R 3 has the following structure: [ka] It has one of the following.

[0146] In certain embodiments, R 3 has the following structure: [ka] It has one of the following.

[0147] In certain embodiments, R 3 has the following structure: [ka] It has.

[0148] In some embodiments, R 3 and R 1 Together they form the following structure: [ka] It has one of the following.

[0149] In certain embodiments, R 3 is alkyl, -R 8 -N(R 9 )2, -R 8 -OR 9 or R 3 teeth, [ka] is selected from where: p is 0, 1, 2, 3, 4, or 5; R 6a is hydrogen, alkyl, cycloalkyl, haloalkyl, -C(=O)R 9 , optionally substituted arylalkyl, or optionally substituted heteroaryl; Each R 6b are independently alkyl, halo, -R 8 -OR 9 , -R 8 -N(R 9 )2, -R 8 -C(=O)OR 9 , optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; or two R's 6b together with the carbon to which they are both attached form an optionally substituted N-heterocyclyl, or or two R's 6b together with the carbon to which they are both attached form an optionally substituted O-heterocyclyl, or or two R's 6b together with the carbon to which they are both attached form an optionally substituted cycloalkyl, or or two R's 6b together with the carbon to which they are attached form an optionally substituted alkylene chain.

[0150] In certain specific embodiments, R 3 is alkyl, -R 8 -N(R 9 )2, -R 8 -OR 9 or R 3 teeth, [ka] is selected from where: p is 0, 1, 2, 3, 4, or 5; R 6a is hydrogen, alkyl, cycloalkyl, haloalkyl, -C(=O)R 9, optionally substituted arylalkyl, or optionally substituted heteroaryl; Each R 6b are independently alkyl, halo, -R 8 -OR 9 , -R 8 -N(R 9 )2, -R 8 -C(=O)OR 9 , optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; or two R's 6b together with the carbon to which they are both attached form an optionally substituted N-heterocyclyl, or or two R's 6b together with the carbon to which they are both attached form an optionally substituted O-heterocyclyl, or or two R's 6b together with the carbon to which they are both attached form an optionally substituted cycloalkyl, or or two R's 6b together with the carbon to which they are attached form an optionally substituted alkylene chain.

[0151] In more specific embodiments, R 3 is alkyl, -R 8 -N(R 9 )2, -R 8 -OR 9 or R 3 teeth, [ka] is selected from where: p is 0, 1, 2, 3, 4, or 5; R 6a is hydrogen, alkyl, cycloalkyl, haloalkyl, -C(=O)R 9 , optionally substituted arylalkyl, or optionally substituted heteroaryl; Each R 6b are independently alkyl, halo, -R8 -OR 9 , -R 8 -N(R 9 )2, -R 8 -C(=O)OR 9 , optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; or two R 6b together with the carbon to which they are both attached form an optionally substituted N-heterocyclyl, or or two R 6b together with the carbon to which they are both attached form an optionally substituted O-heterocyclyl, or or two R 6b together with the carbon to which they are both attached form an optionally substituted cycloalkyl, or or two R 6b together with the carbon to which they are attached form an optionally substituted alkylene chain.

[0152] In some embodiments, R 3 is alkyl, -R 8 -N(R 9 )2, -R 8 -OR 9 or R 3 teeth, [ka] is selected from where: p is 0, 1, 2, 3, 4, or 5; R 6a is hydrogen, alkyl, cycloalkyl, haloalkyl, -C(=O)R 9 , optionally substituted arylalkyl, or optionally substituted heteroaryl; Each R 6b are independently alkyl, halo, -R 8 -OR 9 , -R 8 -N(R 9 )2, -R 8 -C(=O)OR9 , optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; or two R's 6b together with the carbon to which they are both attached form an optionally substituted N-heterocyclyl, or or two R's 6b together with the carbon to which they are both attached form an optionally substituted O-heterocyclyl, or or two R's 6b together with the carbon to which they are both attached form an optionally substituted cycloalkyl, or or two R's 6b together with the carbon to which they are attached form an optionally substituted alkylene chain.

[0153] In some embodiments, R 3 is alkyl, -R 8 -N(R 9 )2, -R 8 -OR 9 or R 3 teeth, [ka] is selected from where: p is 0, 1, 2, 3, 4, or 5; R 6a is hydrogen, alkyl, cycloalkyl, haloalkyl, -C(=O)R 9 , optionally substituted arylalkyl, or optionally substituted heteroaryl; Each R 6b are independently alkyl, halo, -R 8 -OR 9 , -R 8 -N(R 9 )2, -R 8 -C(=O)OR 9 , optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; or two R's6b together with the carbon to which they are both attached form an optionally substituted N-heterocyclyl, or or two R's 6b together with the carbon to which they are both attached form an optionally substituted O-heterocyclyl, or or two R's 6b together with the carbon to which they are both attached form an optionally substituted cycloalkyl, or or two R's 6b together with the carbon to which they are attached form an optionally substituted alkylene chain.

[0154] In some embodiments, R 3 is alkyl, -R 8 -N(R 9 )2, -R 8 -OR 9 or R 3 teeth, [ka] is selected from where: p is 0, 1, 2, 3, 4, or 5; R 6a is hydrogen, alkyl, cycloalkyl, haloalkyl, -C(=O)R 9 , optionally substituted arylalkyl, or optionally substituted heteroaryl; Each R 6b are independently alkyl, halo, -R 8 -OR 9 , -R 8 -N(R 9 )2, -R 8 -C(=O)OR 9 , optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; or two R's 6b together with the carbon to which they are both attached form an optionally substituted N-heterocyclyl, or or two R's 6btogether with the carbon to which they are both attached form an optionally substituted O-heterocyclyl, or or two R's 6b together with the carbon to which they are both attached form an optionally substituted cycloalkyl, or or two R's 6b together with the carbon to which they are attached form an optionally substituted alkylene chain.

[0155] In certain embodiments, R 3 is alkyl, -R 8 -N(R 9 )2, -R 8 -OR 9 or R 3 teeth, [ka] is selected from where: p is 0, 1, 2, 3, 4, or 5; R 6a is hydrogen, alkyl, cycloalkyl, haloalkyl, -C(=O)R 9 , optionally substituted arylalkyl, or optionally substituted heteroaryl; Each R 6b are independently alkyl, halo, -R 8 -OR 9 , -R 8 -N(R 9 )2, -R 8 -C(=O)OR 9 , optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; or two R's 6b together with the carbon to which they are both attached form an optionally substituted N-heterocyclyl, or or two R's 6b together with the carbon to which they are both attached form an optionally substituted O-heterocyclyl, or or two R's 6btogether with the carbon to which they are both attached form an optionally substituted cycloalkyl, or or two R's 6b together with the carbon to which they are attached form an optionally substituted alkylene chain.

[0156] In certain specific embodiments, R 3 is alkyl, -R 8 -N(R 9 )2, -R 8 -OR 9 or R 3 teeth, [ka] is selected from where: p is 0, 1, 2, 3, 4, or 5; R 6a is hydrogen, alkyl, cycloalkyl, haloalkyl, -C(=O)R 9 , optionally substituted arylalkyl, or optionally substituted heteroaryl; Each R 6b are independently alkyl, halo, -R 8 -OR 9 , -R 8 -N(R 9 )2, -R 8 -C(=O)OR 9 , optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; or two R's 6b together with the carbon to which they are both attached form an optionally substituted N-heterocyclyl, or or two R's 6b together with the carbon to which they are both attached form an optionally substituted O-heterocyclyl, or or two R's 6b together with the carbon to which they are both attached form an optionally substituted cycloalkyl, or or two R's6b together with the carbon to which they are attached form an optionally substituted alkylene chain.

[0157] In certain specific embodiments, R 3 is alkyl, -R 8 -N(R 9 )2, -R 8 -OR 9 or R 3 teeth, [ka] is selected from where: p is 0, 1, 2, 3, 4, or 5; R 6a is hydrogen, alkyl, cycloalkyl, haloalkyl, -C(=O)R 9 , optionally substituted arylalkyl, or optionally substituted heteroaryl; Each R 6b are independently alkyl, halo, -R 8 -OR 9 , -R 8 -N(R 9 )2, -R 8 -C(=O)OR 9 , optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; or two R 6b together with the carbon to which they are both attached form an optionally substituted N-heterocyclyl, or or two R 6b together with the carbon to which they are both attached form an optionally substituted O-heterocyclyl, or or two R 6b together with the carbon to which they are both attached form an optionally substituted cycloalkyl, or or two R 6b together with the carbon to which they are attached form an optionally substituted alkylene chain.

[0158] In some more specific embodiments, R 3 is alkyl, -R 8 -N(R 9 )2, -R 8 -OR 9 or R 3 teeth, [ka] is selected from where: p is 0, 1, 2, 3, 4, or 5; R 6a is hydrogen, alkyl, cycloalkyl, haloalkyl, -C(=O)R 9 , optionally substituted arylalkyl, or optionally substituted heteroaryl; Each R 6b are independently alkyl, halo, -R 8 -OR 9 , -R 8 -N(R 9 )2, -R 8 -C(=O)OR 9 , optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; or two R's 6b together with the carbon to which they are both attached form an optionally substituted N-heterocyclyl, or or two R's 6b together with the carbon to which they are both attached form an optionally substituted O-heterocyclyl, or or two R's 6b together with the carbon to which they are both attached form an optionally substituted cycloalkyl, or or two R's 6b together with the carbon to which they are attached form an optionally substituted alkylene chain.

[0159] In certain more specific embodiments, R 3 is alkyl, -R8 -N(R 9 )2, -R 8 -OR 9 or R 3 teeth, [ka] is selected from where: p is 0, 1, 2, 3, 4, or 5; R 6a is hydrogen, alkyl, cycloalkyl, haloalkyl, -C(=O)R 9 , optionally substituted arylalkyl, or optionally substituted heteroaryl; Each R 6b are independently alkyl, halo, -R 8 -OR 9 , -R 8 -N(R 9 )2, -R 8 -C(=O)OR 9 , optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; or two R 6b together with the carbon to which they are both attached form an optionally substituted N-heterocyclyl, or or two R 6b together with the carbon to which they are both attached form an optionally substituted O-heterocyclyl, or or two R 6b together with the carbon to which they are both attached form an optionally substituted cycloalkyl, or or two R 6b together with the carbon to which they are attached form an optionally substituted alkylene chain.

[0160] In some other specific embodiments, R 3 is alkyl, -R 8 -N(R 9 )2, -R 8 -OR 9 or R 3teeth, [ka] is selected from where: p is 0, 1, 2, 3, 4, or 5; R 6a is hydrogen, alkyl, cycloalkyl, haloalkyl, -C(=O)R 9 , optionally substituted arylalkyl, or optionally substituted heteroaryl; Each R 6b are independently alkyl, halo, -R 8 -OR 9 , -R 8 -N(R 9 )2, -R 8 -C(=O)OR 9 , optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; or two R 6b together with the carbon to which they are both attached form an optionally substituted N-heterocyclyl, or or two R 6b together with the carbon to which they are both attached form an optionally substituted O-heterocyclyl, or or two R 6b together with the carbon to which they are both attached form an optionally substituted cycloalkyl, or or two R 6b together with the carbon to which they are attached form an optionally substituted alkylene chain.

[0161] In some embodiments, R 3 is alkyl, -R 8 -N(R 9 )2, -R 8 -OR 9 or R 3 teeth, [ka] is selected from where: p is 0, 1, 2, 3, 4, or 5; R 6a is hydrogen, alkyl, cycloalkyl, haloalkyl, -C(=O)R 9 , optionally substituted arylalkyl, or optionally substituted heteroaryl; Each R 6b are independently alkyl, halo, -R 8 -OR 9 , -R 8 -N(R 9 )2, -R 8 -C(=O)OR 9 , optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; or two R's 6b together with the carbon to which they are both attached form an optionally substituted N-heterocyclyl, or or two R's 6b together with the carbon to which they are both attached form an optionally substituted O-heterocyclyl, or or two R's 6b together with the carbon to which they are both attached form an optionally substituted cycloalkyl, or or two R's 6b together with the carbon to which they are attached form an optionally substituted alkylene chain.

[0162] In some embodiments, R 3 is alkyl, -R 8 -N(R 9 )2, -R 8 -OR 9 or R 3 teeth, [ka] is selected from where: p is 0, 1, 2, 3, 4, or 5; Each R 6b are independently alkyl, halo, -R8 -OR 9 , -R 8 -N(R 9 )2, -R 8 -C(=O)OR 9 , optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; or two R's 6b together with the carbon to which they are both attached form an optionally substituted N-heterocyclyl, or or two R's 6b together with the carbon to which they are both attached form an optionally substituted O-heterocyclyl, or or two R's 6b together with the carbon to which they are both attached form an optionally substituted cycloalkyl, or or two R's 6b together with the carbon to which they are attached form an optionally substituted alkylene chain.

[0163] In some embodiments, R 3 is alkyl, -R 8 -N(R 9 )2, -R 8 -OR 9 or R 3 teeth, [ka] is selected from where: p is 0, 1, 2, 3, 4, or 5; Each R 6b are independently alkyl, halo, -R 8 -OR 9 , -R 8 -N(R 9 )2, -R 8 -C(=O)OR 9 , optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; or two R's 6btogether with the carbon to which they are both attached form an optionally substituted N-heterocyclyl, or or two R's 6b together with the carbon to which they are both attached form an optionally substituted O-heterocyclyl, or or two R's 6b together with the carbon to which they are both attached form an optionally substituted cycloalkyl, or or two R's 6b together with the carbon to which they are attached form an optionally substituted alkylene chain.

[0164] In certain embodiments, R 3 is alkyl, -R 8 -N(R 9 )2, -R 8 -OR 9 or R 3 teeth, [ka] is selected from where: p is 0, 1, 2, 3, 4, or 5; Each R 6b are independently alkyl, halo, -R 8 -OR 9 , -R 8 -N(R 9 )2, -R 8 -C(=O)OR 9 , optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; or two R's 6b together with the carbon to which they are both attached form an optionally substituted N-heterocyclyl, or or two R's 6b together with the carbon to which they are both attached form an optionally substituted O-heterocyclyl, or or two R's 6btogether with the carbon to which they are both attached form an optionally substituted cycloalkyl, or or two R 6b together with the carbon to which they are attached form an optionally substituted alkylene chain.

[0165] In some specific embodiments, R 3 is alkyl, -R 8 -N(R 9 )2, -R 8 -OR 9 or R 3 teeth, [ka] and where: p is 0, 1, 2, 3, 4, or 5; Each R 6b are independently alkyl, halo, -R 8 -OR 9 , -R 8 -N(R 9 )2, -R 8 -C(=O)OR 9 , optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; or two R 6b together with the carbon to which they are both attached form an optionally substituted N-heterocyclyl, or or two R 6b together with the carbon to which they are both attached form an optionally substituted O-heterocyclyl, or or two R 6b together with the carbon to which they are both attached form an optionally substituted cycloalkyl, or or two R 6b together with the carbon to which they are attached form an optionally substituted alkylene chain.

[0166] In some embodiments, R 3 is alkyl, -R 8-N(R 9 )2, or -R 8 -OR 9 In certain embodiments, R 3 is alkyl or -R 8 -N(R 9 )2. In some specific embodiments, R 3 is alkyl. In some more specific embodiments, R 3 has the following structure: [ka] [ka] [ka] It has one of the following.

[0167] In some embodiments, R 3 has the following structure: [ka] It has one of the following.

[0168] In some embodiments, R 3 has the following structure: [ka] It has one of the following.

[0169] In certain embodiments, R 3 has the following structure: [ka] It has one of the following.

[0170] In some specific embodiments, R 3 has the following structure: [ka] It has one of the following.

[0171] In some embodiments, R 3 has the following structure: [ka] It has one of the following.

[0172] In certain specific embodiments, R 3 has the following structure: [ka] It has one of the following.

[0173] In more specific embodiments, R 3 has the following structure: [ka] It has one of the following.

[0174] In certain embodiments, R 3 has the following structure: [ka] It has one of the following.

[0175] In certain embodiments, R 3 has the following structure: [ka] It has one of the following.

[0176] In some specific embodiments, R 3 has the following structure: [ka] It has.

[0177] In certain specific embodiments, R 3 has the following structure: [ka] It has.

[0178] In some more specific embodiments, R 3 has the following structure: [ka] It has one of the following.

[0179] In certain specific embodiments, R 3 has the following structure: [ka] It has.

[0180] In some embodiments, R 3 has the following structure: [ka] It has.

[0181] In certain embodiments, R 3 has the following structure: [ka] It has.

[0182] In some specific embodiments, R 3 has the following structure: [ka] It has.

[0183] In certain specific embodiments, R 3 has the following structure: [ka] It has.

[0184] In some embodiments, R 3 has the following structure: [ka] It has.

[0185] In certain embodiments, R 3 has the following structure: [ka] It has.

[0186] In some embodiments, R 3 has the following structure: [ka] It has one of the following.

[0187] In certain embodiments, R 3a is hydrogen. In some specific embodiments, R 3a is alkyl. In some more specific embodiments, R 3a is methyl.

[0188] In some embodiments, R 4 is hydrogen. In certain embodiments, R 4 is alkyl. In certain specific embodiments, R 4 is -CH3. In certain specific embodiments, R 4 is halo. In certain more specific embodiments, R 4 is fluoro. In certain specific embodiments, R 4 is halo. In some more specific embodiments, R 4 is chloro. In certain specific embodiments, R 4 is halo. In some more specific embodiments, R 4 is fluoro or chloro. In some embodiments, R 4 -R8 -OR 9 In more specific embodiments, R 4 is —OH or —OCH. In more specific embodiments, R 4 is —OH. In more specific embodiments, R 4 is —OCH. In some embodiments, R 4 is haloalkyl. In more specific embodiments, R 4 is —CF. In certain embodiments, R 4 is cyano.

[0189] In some specific embodiments, R 7 is alkyl. In certain embodiments, R 7 is -CH3.

[0190] In some embodiments, the compound is a compound as shown in Table 1 below, as a stereoisomer, enantiomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. [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

[0191] Another embodiment of the present disclosure is a pharmaceutical composition comprising one or more pharmaceutically 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, as a stereoisomer, enantiomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0192] Another embodiment of the present disclosure is a method of treating a disease or condition in a mammal modulated by a voltage-gated sodium channel, comprising administering to a mammal in need of treatment a therapeutically effective amount of a compound of Formula (I) or (II) as described above in the Summary of the Disclosure, as a stereoisomer, enantiomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0193] 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 to determine the effectiveness of a test compound in modulating voltage-gated sodium channels.

[0194] Specific embodiments of the compounds of the present disclosure are described in more detail in the Compound Preparation section below.

[0195] Utility 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 pharmaceutically acceptable salts, solvates, or prodrugs thereof, that are useful for treating seizure disorders, e.g., epilepsy and / or epileptic seizure disorders, in mammals, preferably humans.

[0196] In another embodiment, the compounds of Formula (I) or (II) as their stereoisomers, enantiomers, or tautomers, or mixtures thereof, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, disclosed herein are useful in treating epilepsy, seizure disorders, partial seizures (e.g., simple, complex, secondarily generalized, and focal onset), generalized seizures (e.g., absence seizures, myoclonic seizures, atonic seizures, tonic seizures, and tonic-clonic seizures), as well as photosensitive epilepsy, self-induced syncope, and the like. 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 syndromes, tuberous sclerosis complex, early infantile epileptic encephalopathy, early-onset epileptic encephalopathy, generalized epilepsy and febrile seizures plus (GE) FS+), Rett syndrome, multiple sclerosis, schizophrenia, autism, ataxia, hypotonia, and paroxysmal dyskinesia, Alzheimer's disease and tauopathies including, but not limited to, Alzheimer's disease, Pick's disease, progressive supranuclear palsy, 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 tauastrogliopathy, Richardson's syndrome, Down's syndrome, Parkinsonism, pure akinesia with freezing of gait, motor neuron symptoms or cerebellar ataxia, post-traumatic stress disorder (PTSD), or any combination thereof.

[0197] The present disclosure readily provides a number of different means for the identification of sodium channel modulating agents that are useful as therapeutic agents. Identification of sodium channel modulators can be assessed using a variety of in vitro and in vivo assays, such as measuring currents, measuring membrane potential, measuring ion flux (e.g., sodium), measuring sodium concentrations, measuring second messenger and transcript levels, measuring neurotransmitter levels, and using voltage-sensitive dyes, radioactive tracers, multi-electrode arrays, and patch clamp electrophysiology.

[0198] Such protocols involve screening compounds for their ability to modulate the activity of sodium channels, thereby identifying them as modulators.

[0199] Typical 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, N. et al., Neurosci Lett (2018), Vol. 662, pp. 29-35) use automated planar patch clamp techniques to study the effects of compounds on sodium channel gating. Sodium channel isoforms of interest are stably expressed in human embryonic kidney cells, and the current flowing through these channels in response to depolarizing voltage clamp steps from -120 mV to 0 mV is measured in the presence of increasing concentrations of compound. The area under the sodium current waveform, which correlates with the magnitude of sodium influx across the cell membrane, is used to quantify the effect on channel gating. Other parameters measured in the assay include peak current, the time constant of open-state inactivation, and the voltage dependence of steady-state inactivation characteristics. Concentration responses are used to determine the potency of each compound's effect on modulating the gating of sodium channel isoforms. Such techniques are known to those skilled in the art, and current technology can be deployed into low- or medium-throughput assays to evaluate compounds for their ability to modulate sodium channel behavior.

[0200] 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 channels. Certain substituents on the core structure of the compounds of the present disclosure tend to result in more potent inhibitory or potentiating compounds. SAR analysis is one of the means that those skilled in the art can currently use to identify preferred embodiments of the compounds of the present disclosure for use as therapeutic agents.

[0201] 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 discover other compounds that are similarly useful in treating or preventing the various diseases disclosed herein.

[0202] In another embodiment, a compound of Formula (I) or (II), as described above in the Summary of the Invention, as an individual stereoisomer, enantiomer, or tautomer, or mixtures thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, as a stereoisomer, enantiomer, tautomer, or mixtures thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and / or a pharmaceutical composition described herein comprising one or more compounds of the present disclosure, as described above in the Summary of the Invention, as a pharmaceutically acceptable excipient and a stereoisomer, enantiomer, or tautomer, or mixtures thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, can be used in the preparation of a medicament for the treatment of a disease or condition mediated by sodium channels in a mammal.

[0203] Pharmaceutical Compositions and Administration The present disclosure is also directed to pharmaceutical compositions containing a compound of Formula (I) or (II), as defined above in the Summary of the Invention, as a stereoisomer, enantiomer, or tautomer, or a mixture thereof, or a pharmaceutically 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 defined above in the Summary of the Invention, as a stereoisomer, enantiomer, or tautomer, or a mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, in a pharmaceutically acceptable carrier, excipient, or diluent, in an amount effective to modulate, preferably inhibit, voltage-gated sodium channels when administered to an animal, preferably a mammal, and most preferably a human patient, to treat a particular disease or condition, such as epilepsy.

[0204] Administration of a compound of Formula (I) or (II) as described above in the Summary of the Invention, in its pure form or in a suitable pharmaceutical composition, as its stereoisomer, enantiomer, or tautomer, or mixture thereof, or as a pharmaceutically acceptable salt, solvate, or prodrug, can be carried out by any of the recognized modes of drug administration that serve the same degree of practicality. Pharmaceutical compositions of the present disclosure can be prepared by combining a compound of the present disclosure with a suitable pharmaceutically acceptable carrier, diluent, or excipient, and can be formulated into solid, semi-solid, liquid, or gaseous preparations, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres, and aerosols. Typical routes of administration of such pharmaceutical compositions include, but are not limited to, oral, topical, transdermal, inhalation, parenteral, sublingual, rectal, intravaginal, and intranasal. As used herein, the term "parenteral" includes subcutaneous injection, intravenous, intramuscular, intrathecal, intrasternal injection, or infusion techniques. The pharmaceutical compositions of the present disclosure are formulated so that the active ingredients contained therein are bioavailable when the composition is administered to a patient. The composition administered to a subject or patient takes the form of one or more dosage units, where, for example, a tablet may be a single dosage unit, or a container of the compound of the present disclosure in aerosol form may contain multiple dosage units. Actual methods for preparing such dosage forms are known or 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). In any case, the composition administered contains a therapeutically effective amount of the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for treating the disease or condition of interest according to the teachings of the present disclosure.

[0205] Pharmaceutical compositions useful herein also contain a pharmaceutically acceptable carrier, including any suitable diluent or excipient, including any pharmaceutical agent that does not itself induce the production of antibodies harmful to the individual receiving the composition and 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 thorough discussion of pharmaceutically acceptable carriers, diluents, and other excipients is provided in REMINGTON'S PHARMACEUTICAL SCIENCES (Mack Pub. Co., NJ latest edition).

[0206] The pharmaceutical composition of the present disclosure can be in solid or liquid form.In one aspect, carrier(s) are particulate, so that composition is in the form of, for example, tablet or powder.When composition is, for example, oral syrup, injectable liquid or aerosol that is useful for, for example, inhalation administration, carrier(s) can be liquid.

[0207] 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 within the scope of forms considered herein to be either solid or liquid.

[0208] As a solid composition for oral administration, the pharmaceutical composition can be formulated into the form of powder, granules, compressed tablets, pills, capsules, chewing gum, wafers, etc. Such solid compositions usually contain one or more inert diluents or edible carriers. In addition, one or more of the following may be present: binders such as carboxymethylcellulose, ethylcellulose, microcrystalline cellulose, tragacanth gum, or gelatin; excipients such as starch, lactose, or dextrin; disintegrants such as alginic acid, sodium alginate, Primogel, corn starch, etc.; lubricants such as magnesium stearate or Sterotex; flow agents such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; flavorings such as peppermint, methyl salicylate, or orange flavoring; and coloring agents.

[0209] When the pharmaceutical composition is in the form of a capsule, eg, a gelatin capsule, it may contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol or oil.

[0210] The pharmaceutical composition may be in a liquid form, such as an elixir, syrup, solution, emulsion, or suspension. As two examples, the liquid may be for oral administration or for delivery by injection. For oral administration, a preferred composition contains, in addition to the compound of the present invention, one or more of a sweetener, a preservative, a dye / colorant, and a flavoring agent. For injection, a composition may contain one or more of a surfactant, a preservative, a wetting agent, a dispersing agent, a suspending agent, a buffer, a stabilizer, and an isotonic agent.

[0211] Liquid pharmaceutical compositions of the present disclosure, whether in solution, suspension, or other similar form, may contain one or more of the following auxiliary substances: sterile diluents, such as water for injection, saline, preferably physiological saline, Ringer's solution, or isotonic saline; fixed oils, such as synthetic monoglycerides or diglycerides, polyethylene glycol, glycerin, propylene glycol, or other solvents that can serve 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 placed in glass or plastic ampoules, disposable syringes, or multiple-dose vials. A preferred auxiliary substance is physiological saline. Pharmaceutical compositions for injection are preferably sterile.

[0212] Liquid pharmaceutical compositions of the present disclosure intended for either parenteral or oral administration should contain an amount of a compound of the present disclosure such that an appropriate dosage is achieved. Typically, this amount is at least 0.01% of a compound of the present disclosure in the composition. For oral administration, this amount may vary from 0.1% to about 70% by weight of the composition. Preferred oral pharmaceutical compositions contain from about 4% to about 50% of a compound of the present disclosure. Preferred pharmaceutical compositions and preparations according to the present disclosure are prepared so that a parenteral dosage unit contains from 0.01 to 10% by weight of the compound of the present disclosure, prior to dilution.

[0213] The pharmaceutical compositions of the present disclosure may be intended for topical administration, in which case the carrier may suitably comprise a solution base, emulsion base, ointment base, 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. Thickeners may be present in pharmaceutical compositions for topical administration. For transdermal administration, the compositions may include transdermal patches or iontophoresis devices. Topical formulations may contain a compound of the present disclosure in a concentration of about 0.1 to about 10% w / v (weight per unit volume).

[0214] The pharmaceutical composition of the present disclosure may be intended for rectal administration, for example, in the form of a suppository that dissolves in the rectum and releases the drug.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.

[0215] The pharmaceutical compositions of the present disclosure may contain various materials that modify the physical form of a solid or liquid dosage unit. For example, the compositions may contain materials that form a coating shell around the active ingredient. The materials that form the coating shell are usually inert and may be selected from, for example, sugar, shellac, and other enteric coating agents. Alternatively, the active ingredient may be encapsulated in a gelatin capsule.

[0216] Pharmaceutical compositions of the present disclosure, in solid or liquid form, may include an agent that binds to the compounds of the present disclosure and thereby aids in delivery of the compounds. Suitable agents that may act in this capacity include monoclonal or polyclonal antibodies, proteins, or liposomes.

[0217] The pharmaceutical compositions of the present disclosure may be comprised of dosage units that can be administered as an aerosol. The term aerosol is used to refer to a variety of systems, ranging from those of colloidal nature to systems consisting of pressurized containers. Delivery can be by liquefied or compressed gas or by a suitable pump system that dispenses the active ingredient. Aerosols of the compounds of the present disclosure can be delivered in single-phase, two-phase, or three-phase systems to deliver the active ingredient(s). Aerosol delivery includes the necessary containers, activators, valves, subcontainers, etc., which may together constitute a kit. One of ordinary skill in the art can determine a preferred aerosol without undue experimentation.

[0218] The pharmaceutical composition of the present disclosure can be prepared by methods well known in the pharmaceutical field.For example, the pharmaceutical composition intended for administration 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 promote the formation of a uniform solution or suspension.Surfactant is a compound that interacts with the compound of the present disclosure by non-covalent bonding, so as to promote the dissolution or uniform suspension of the compound in aqueous delivery system.

[0219] The compounds of the present disclosure, or pharmaceutically 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 duration of action of the compound; the patient's age, weight, health, sex, and diet; the mode and time of administration; the rate of excretion; the drug combination; the severity of the particular disorder or condition; and the subject being treated. Generally, 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).

[0220] The effective dose ranges set forth herein are not intended to be limiting, but rather represent preferred dose ranges. However, as understood and determined by those skilled in the relevant art, the most preferred dose will be tailored to the individual subject (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); Katzung, Basic and Clinical Pharmacology, Appleton and Lange, Norwalk, CT (1992).

[0221] The total dose required per treatment may be administered in multiple doses throughout the day or in a single dose, as needed. Generally, treatment is initiated with a lower dose that is less than the optimal dose of the compound. Thereafter, the dosage is gradually increased until the optimal effect under the circumstances is reached. The diagnostic pharmaceutical compound or pharmaceutical composition may be administered alone or in combination with other diagnostic and / or pharmaceutical agents that target the pathology or other symptoms of the pathology. The recipient of the administration of the compounds and / or compositions of the present disclosure may be any vertebrate, for example, a mammal. Among mammals, preferred recipients are mammals of the orders Primates (including humans, apes, and monkeys), Arteriodactyla (including horses, goats, cows, sheep, and 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 recipient is a human.

[0222] For topical application, an effective amount of a pharmaceutical composition according to the present disclosure is preferably administered to a target area adjacent to the peripheral nerve cells to be treated, such as the skin surface, mucosa, etc. Generally, this amount ranges 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 case about 0.001 mg to about 50 mg of active ingredient is used per cc of ointment base. Pharmaceutical compositions can be formulated as transdermal compositions or transdermal delivery devices ("patches"). Such compositions include, for example, a support, an active compound reservoir, a control membrane, a liner, and a contact adhesive. Such transdermal patches can be used to provide sustained, pulsatile, or on-demand delivery of a compound of the present disclosure, as needed.

[0223] The compositions of the present disclosure can be formulated to provide immediate, sustained, or delayed release of the 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 containing 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.

[0224] The compositions of the present disclosure may also be delivered by intranasal drug delivery systems for local, systemic, and nose-to-brain drug 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.

[0225] The present disclosure also relates to a shell or core type intravaginal drug delivery device suitable for administration to a woman or female animal. The device may be comprised of an active pharmaceutical ingredient within a polymer matrix surrounded by a shell, and may be capable of releasing the compound daily in a substantially zero-order pattern, similar to the devices used to administer testosterone as described in PCT Published Patent Application No. WO 98 / 50016.

[0226] Current methods for ocular delivery include topical administration (eye drops), subconjunctival injection, periocular injection, intravitreal injection, surgical implantation, and iontophoresis (using a weak electric current to transport ionized drugs to and through body tissues). One skilled in the art would combine the optimal excipients with the compound for safe and effective intraocular administration.

[0227] The most suitable route will depend on the nature and severity of the condition being treated. Those skilled in the art are also familiar with determining the mode of administration (e.g., oral, intravenous, inhalation, subcutaneous, rectal, etc.), dosage form, suitable pharmaceutical excipients, and other considerations related to delivery of the compound to the subject in need of treatment.

[0228] 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 any combination thereof, in the treatment of diseases and conditions mediated by sodium channels. For example, but not limited to, the compounds of the present disclosure may be used in combination with one or more other compounds of the present disclosure or one or more other therapeutic agents, or any combination thereof.

[0229] Acetazolamide (Diamox), brivaracetam (Brivion), cannabidiol (Epidiolex), carbamazepine (Tegretol), cenobamate (Excopri), clobazam (Flysium), clonazepam (Klonopin), eslicarbazepine acetate (Aptiom, Zebinix), ethosuximide (Zarontin), felbamate (Felbatol), fenfluramine (Fintepra), gabapentin (Neurontin), lacosamide (Vimpat), lamotrigine (Lamictal), levetiracetam (Kep It may be administered simultaneously, sequentially, or separately in combination with other therapeutic agents, including fluticasone (fluticasone), oxcarbazepine (Trileptal), perampanel (Ficompa), phenobarbital (Luminal), phenytoin (Dilantin), pregabalin (Lyrica), primidone, retigabine (Ezogabine), rufinamide (Banzel), stiripentol (Diacomit), sulthiame, tiagabine (Gabitril), topiramate (Topamax), valproate (Depakote), vigabatrin (Sabril), and zonisamide (Zonegran).

[0230] As used herein, "combination" refers to any mixture or permutation 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 otherwise clear from the context, "combination" can include simultaneous or sequential delivery of a compound of the present disclosure with one or more therapeutic agents. Unless otherwise clear from the context, "combination" can include dosage forms of a compound of the present disclosure with another therapeutic agent. Unless otherwise clear from the context, "combination" can include routes of administration of a compound of the present disclosure with another therapeutic agent. Unless otherwise clear from the context, "combination" can include formulations 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.

[0231] 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 using the pharmaceutical composition to regulate sodium channel activity, for treating seizure disorders such as epilepsy, and for other uses disclosed herein. Preferably, a commercial package contains one or more unit doses of the pharmaceutical composition. For example, such a unit dose may be sufficient for preparing an intravenous injection. It will be apparent to those skilled in the art that light- and / or air-sensitive compounds may require special packaging and / or formulation. For example, light-tight and / or airtight packaging may be used, and / or the compound may be formulated with appropriate coatings or excipients.

[0232] compound preparation The following reaction schemes illustrate methods of making compounds of the present disclosure, i.e., compounds of Formula (I) or (II) as described above in the Summary of the Invention, as stereoisomers, enantiomers, or tautomers thereof, or mixtures thereof, or pharmaceutically acceptable salts, solvates, or prodrugs thereof.

[0233] It will also be understood that those skilled in the art can prepare the compounds of the present disclosure by similar methods or methods known to those skilled in the art. It will also be understood that those skilled in the art can prepare other compounds of the present disclosure not specifically shown below by using appropriate starting components and modifying the synthetic parameters as necessary in a manner similar to that described below. In general, the starting components can be obtained from sources such as, for example, 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 can be prepared as described herein.

[0234] It is also understood that in the following description, combinations of substituents and / or variables of the depicted formula are permissible only if such combinations result in stable compounds.

[0235] It will also be understood 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.

[0236] Protecting groups can be added or removed by standard techniques known to those skilled in the art and as described herein.

[0237] The use of protecting groups is discussed in Greene, T.W. and P.G.M.Wuts, Greene's Protective Groups in Organic Synthesis (2006), 4 th Ed., Wiley. The protecting group may be a polymer resin, such as a Wang resin or a 2-chlorotrityl-chloride resin.

[0238] It will also be understood by those skilled in the art that such protected derivatives of the compounds of the present disclosure may not themselves have pharmacological activity, but may be administered to a mammal and subsequently metabolized in the body to form a pharmacologically active compound of the present disclosure. Such derivatives may therefore be described as "prodrugs." All prodrugs of compounds of formula (I) or (II) are included within the scope of the present disclosure.

[0239] The compounds of formula (I) or (II) may contain at least one asymmetric carbon atom and therefore may exist as racemates, enantiomers, and / or diastereomers. Specific enantiomers or diastereomers can be prepared by utilizing appropriate chiral starting materials or by using suitable asymmetric synthesis methods. Alternatively, diastereomeric or racemic mixtures of compounds of formula (I) or (II) can be resolved into their individual enantiomers or diastereomers. Methods for resolving 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., E.L. Eliel and S.H. Wilen, Stereochemistry of Organic Compounds; John Wiley & Sons: New York, 1994; Chapter 7, and references cited therein). Suitable methods such as crystallization (e.g., preferential crystallization, preferential crystallization in the presence of additives), asymmetric transformation of racemates, chemical separation methods (e.g., formation and separation of diastereomers such as diastereomeric salt mixtures or the use of other resolving agents; separation by complexes and clathrates), kinetic resolution (e.g., using titanium tartrate catalysts), enzymatic resolution (e.g., mediated by lipases), and chromatographic separation (e.g., HPLC using chiral stationary phases and / or simulated moving bed techniques, or supercritical fluid chromatography and related techniques) are some of the examples that may be applied (see, for example, T. J. Ward, Analytical Chemistry, 2002, 2863-2872).

[0240] Generally, compounds of formula (I) or (II) as described above in the Summary of the Invention can be synthesized according to the general procedures set forth in Reaction Schemes 1-2 below, where X, R 1 , R 2 , R 3 , R 4 , and R 7 is as defined herein, and Z 1 is Z 3is a suitable coupling partner of, for example, halo, such as iodo or chloro, and Z 2 is R 2a -NH-R 2b is a suitable coupling partner of, for example, halo, such as chloro, and Z 3 is Z 1 In addition, the reagent R 2a -NH-R 2b is the desired R 2 Similarly, R 3’ -NH2 is the desired R 3 In some embodiments, R 3’ -NH2 is the desired R 3 To obtain R 3’ -NH (e.g., R 3 is 4-methoxypiperidinyl, 4-methoxypiperidine, or R 3 In some embodiments, X is 7-methoxy-2-azaspiro[3.5]nonanyl, and X is 7-methoxy-2-azaspiro[3.5]nonane. 1 is, in each occurrence, a substituent that facilitates the reaction of interest (e.g., —OCl; i.e., in some embodiments, X 1 -C(=O)-X 1 is triphosgene). [ka] [ka]

[0241] All compounds prepared below that may exist in free base or free acid form can be converted to a pharmaceutically acceptable salt by treatment with an appropriate inorganic or organic base or acid. Salts of the compounds prepared below can be converted to their free base or free acid form by standard techniques. Furthermore, all compounds of the present disclosure that contain an acid or ester group can be converted to the corresponding ester or acid, respectively, by methods known to those skilled in the art or described herein.

[0242] The present disclosure also relates to the novel intermediate compounds 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 encompasses all polymorphs of the aforementioned species and their crystal forms.

[0243] The embodiments disclosed herein are intended to encompass all compounds that are isotopically labeled by replacing one or more atoms with atoms having a different atomic mass or mass number. Examples of isotopes that may be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as: 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 I can be mentioned.

[0244] Isotopically labeled compounds may generally be prepared by conventional techniques known to those skilled in the art, or by processes analogous to those described below and in the Examples below, using appropriate isotopically labeled reagents in place of conventionally used unlabeled reagents.

[0245] 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 present disclosure and are not intended to limit the scope of the disclosure.

[0246] In the following preparations and examples, all temperatures are set forth in degrees Celsius unless otherwise specified. 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 specified. The reactions described below were generally carried out in anhydrous solvents under a positive pressure of nitrogen or argon, or using a drying tube (unless otherwise specified), and reaction flasks were typically fitted with rubber septa for the introduction of substrates and reagents via syringe. Glassware was oven-dried and / or heat-dried. Yields were not optimized. Melting points were determined uncorrected using a Büchi hot-stage apparatus. 1 H NMR, 19 F and 13 C NMR data were acquired in deuterated CDCI, DMSO-d, CD, CDCN, or acetone-d solvent solutions, and chemical shifts (δ) were reported in parts per million (ppm) relative to peaks of trimethylsilane (TMS) or residual non-deuterated solvent as the reference standard. Where applicable, data are reported as follows: chemical shift, multiplicity, coupling constant in 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 (double doublet), and dt (triple doublet). Coupling constants, when indicated, are reported in Hz (Hertz). [Example]

[0247] Example 1: Synthesis of 1-(4-(2-fluorophenyl)-2-(pyrrolidin-1-yl)pyridin-3-yl)-3-(4-isopropylphenyl)urea [ka] Step 1: Preparation of 4-(2-fluorophenyl)-3-nitro-2-(pyrrolidin-1-yl)pyridine [ka] To a solution of 2-chloro-4-(2-fluorophenyl)-3-nitropyridine (1.66 g, 6.59 mmol) in anhydrous acetonitrile (15 mL) were added triethylamine (2.75 mL, 19.8 mmol) and pyrrolidine (0.55 mL, 6.60 mmol) at 0° C. The reaction mixture was stirred at ambient temperature for 2 hours and 40 minutes. The reaction mixture was then filtered, and the filtrate was diluted with DCM (50 mL) and washed with 1 M aqueous hydrogen chloride solution (50 mL), water (50 mL), and brine (50 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the title compound as a yellow solid (2.03 g, >99% yield). 1 H-NMR(300 MHz;CDCl3) δ 8.28 (d, J = 4.9 Hz, 1H), 7.44-7.36 (m, 1H), 7.28-7.11(m, 3H), 6.54 (d, J = 4.9 Hz, 1H), 3.48-3.44 (m, 4H), 1.99-1.95 (m, 4H). MS (ES+)m / z 288.4 (M+1).

[0248] Step 2: Preparation of 4-(2-fluorophenyl)-2-(pyrrolidin-1-yl)pyridin-3-amine [ka] To a solution of 4-(2-fluorophenyl)-3-nitro-2-(pyrrolidin-1-yl)pyridine (2.038 g, 7.09 mmol) in glacial acetic acid (35 mL) was added iron powder (2.38 g, 42.6 mmol). The reaction mixture was heated to 60° C. for 2 hours. The reaction mixture was then poured into ice and neutralized with saturated sodium bicarbonate and sodium carbonate solution until the pH reached 6.5. The mixture was extracted with ethyl acetate (3×100 mL). The combined organic phase was washed with saturated aqueous sodium bicarbonate solution (150 mL) and brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the title compound in quantitative yield. 1 H-NMR(300 MHz;CDCl3) δ 7.84 (d, J = 5.4 Hz, 1H), 7.49-7.37 (m, 2H), 7.32-7.20(m, 2H), 6.77 (d, J = 5.3 Hz, 1H), 3.86 (s, 2H), 3.64-3.61 (m, 4H), 2.05-1.97 (m,4H). MS (ES+) m / z 258.4 (M+1).

[0249] Step 3: Preparation of 1-(4-(2-fluorophenyl)-2-(pyrrolidin-1-yl)pyridin-3-yl)-3-(4-isopropylphenyl)urea [ka] To a solution of 4-(2-fluorophenyl)-3-nitro-2-(pyrrolidin-1-yl)pyridine (0.065 g, 0.253 mmol) in anhydrous 1,4-dioxane (1.0 mL) was added 1-isocyanato-4-isopropylbenzene (0.048 mL, 0.30 mmol). The reaction mixture was stirred at ambient temperature for 16 hours and then concentrated under reduced pressure to give a residue. The residue was purified by column chromatography eluting with a gradient of 5% to 100% ethyl acetate in heptane to give the title compound as a colorless solid (0.065 g, 62% yield). 1H-NMR(300 MHz;DMSO-d6) δ 8.41 (br s, 1H), 8.05 (d, J = 4.9 Hz, 1H), 7.43-7.31(m, 3H), 7.28-7.17 (m, 2H), 7.14-7.10 (m, 2H), 7.04-7.01 (m, 2H), 6.56 (dd, J =4.9, 0.7 Hz, 1H), 3.56-3.52 (m, 4H), 2.81-2.71 (m, 1H), 1.86-1.81 (m, 4H), 1.13(d, J = 6.9 Hz, 6H). MS (ES+) m / z 419.4 (M+1).

[0250] Example 2: Synthesis of 1-butyl-3-(4-(2-fluorophenyl)-2-(pyrrolidin-1-yl)pyridin-3-yl)urea [ka] To a solution of 4-(2-fluorophenyl)-3-nitro-2-(pyrrolidin-1-yl)pyridine (0.095 g, 0.37 mmol) in anhydrous 1,4-dioxane (1.0 mL) was added 1-isocyanatobutane (0.050 mL, 0.44 mmol). The reaction mixture was stirred at ambient temperature for 24 hours and then concentrated under reduced pressure to give a residue. The residue was purified by column chromatography eluting with a gradient of 10% to 100% ethyl acetate in heptane to give the title compound as a colorless solid (0.064 g, 48% yield). 1 H-NMR(300 MHz;DMSO-d6): δ 8.00 (d, J = 4.9 Hz, 1H), 7.42-7.35 (m, 1H), 7.32-7.25(m, 1H), 7.23-7.16 (m, 2H), 6.51 (dd, J = 4.9, 0.9 Hz, 1H), 5.82-5.76 (m, 1H), 3.51(t, J = 6.4 Hz, 4H), 2.86-2.80 (m, 2H), 1.85-1.81 (m, 4H), 1.18-1.01 (m, 4H), 0.78(q, J = 4.7 Hz, 3H). MS (ES+) m / z 357.4 (M+1).

[0251] Example 3: (S)-2-chloro-N-(4-(2,5-difluorophenyl)-2-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)pyrimidine-5-carboxamide formate [ka] Step 1: Preparation of 2-chloro-4-(2,5-difluorophenyl)-3-nitropyridine [ka] To a mixture of 2,4-dichloro-3-nitropyridine (8.00 g, 41.5 mmol) in dioxane (162 mL) and water (54 mL) was added (2,5-difluorophenyl)boronic acid (6.55 g, 41.5 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane (1.52 g, 1.86 mmol), and potassium carbonate (17.19 g, 124.4 mmol). The reaction mixture was stirred at 60 °C for 45 minutes. After cooling to ambient temperature, the mixture was diluted with water (500 mL) and extracted with ethyl acetate (3 × 500 mL). The combined organic solution was washed with brine (1000 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography using acetonitrile in water containing 0.1% formic acid as the eluent to give the title compound as a colorless solid (7.00 g, 62% yield). MS(ES+) m / z 271.3 (M + 1).

[0252] Step 2: Preparation of (S)-4-(2,5-difluorophenyl)-2-(3-fluoropyrrolidin-1-yl)-3-nitropyridine [ka] To a mixture of 2-chloro-4-(2,5-difluorophenyl)-3-nitropyridine (3.60 g, 12.3 mmol) in acetonitrile (35 mL) was added potassium carbonate (5.52 g, 39.9 mmol) and (S)-3-fluoropyrrolidine hydrochloride (1.84 g, 14.6 mmol). The reaction mixture was stirred at ambient temperature for 16 h. The mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of 5-6% ethyl acetate in petroleum ether to give the title compound as a yellow oil (3.00 g, 75% yield). MS (ES+) m / z 324.3 (M + 1).

[0253] Step 3: Preparation of (S)-4-(2,5-difluorophenyl)-2-(3-fluoropyrrolidin-1-yl)pyridin-3-amine [ka] To a mixture of (S)-4-(2,5-difluorophenyl)-2-(3-fluoropyrrolidin-1-yl)-3-nitropyridine (3.00 g, 9.28 mmol) in nitrogen-degassed methanol (20 mL) was added 10 wt% palladium on carbon (0.350 g). The reaction mixture was degassed under reduced pressure, purged with hydrogen several times, and stirred under a hydrogen atmosphere at ambient temperature for 1 hour. The mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of 2–10% ethyl acetate in petroleum ether to give the title compound as a colorless solid (1.70 g, 62% yield). MS (ES+) m / z 294.3 (M + 1).

[0254] Step 4: Preparation of (S)-2-chloro-N-(4-(2,5-difluorophenyl)-2-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)pyrimidine-5-carboxamide formate [ka] To a mixture of (S)-4-(2,5-difluorophenyl)-2-(3-fluoropyrrolidin-1-yl)pyridin-3-amine (0.100 g, 0.341 mmol) in tetrahydrofuran (4.0 mL) was added 2-chloropyrimidine-5-carboxylic acid (0.350 g, 0.33 mmol), 50 wt% 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (0.325 g, 0.511 mmol) in ethyl acetate, and N,N-diisopropylamine (0.088 g, 0.682 mmol). The reaction mixture was stirred at 70 °C for 12 hours. After cooling to ambient temperature, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic solution was washed with brine (3 × 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography using acetonitrile in water containing 0.1% formic acid as the eluent to give a residue that was further purified by preparative TLC using 50% ethyl acetate in petroleum ether as the eluent, followed by preparative reverse-phase HPLC using 27–57% acetonitrile in water containing 0.2% formic acid as the eluent to give the title compound as a yellow solid (0.017 g, 10% yield). 1 HNMR (400 MHz, CD3OD) δ 8.89-8.86 (m, 2H), 8.46 (br s, 0.3H), 8.19 (d,J = 5.0 Hz, 1H), 7.21-7.07 (m, 3H), 6.74 (d, J = 5.0 Hz, 1H), 5.36-5.21 (m, 1H), 3.90-3.67 (m, 4H), 2.26-2.01 (m, 2H). MS (ES+) m / z 434.2 (M + 1).

[0255] Examples 4 to 15 The following compounds were prepared in a similar manner as described in Example 3, utilizing appropriately substituted starting materials and intermediates. [Table 20-1] [Table 20-2] [Table 20-3] [Table 20-4] [Table 20-5] [Table 20-6] [Table 20-7] [Table 20-8] [Table 20-9]

[0256] Example 16: Synthesis of (S)—N-(4-(2,5-difluorophenyl)-2-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)-1-methylpiperidine-4-carboxamide [ka] Step 1: Preparation of (S)-tert-butyl 4-((4-(2,5-difluorophenyl)-2-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)carbamoyl)piperidine-1-carboxylate [ka] To a solution of (S)-4-(2,5-difluorophenyl)-2-(3-fluoropyrrolidin-1-yl)pyridin-3-amine (0.200 g, 0.682 mmol) and 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (0.188 g, 0.818 mmol) in tetrahydrofuran (4 mL) was added 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (0.651 g, 1.020 mmol, 50% purity in ethyl acetate) and diisopropylethylamine (0.176 g, 1.36 mmol). The mixture was stirred at 70 °C for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography eluting with aqueous formic acid (0.1%) in acetonitrile to give the title compound as a colorless solid (0.120 g, 35% yield). 1 HNMR (400 MHz, methanol-d4) δ 8.12 (d, J = 5.2 Hz, 1H), 7.23-7.18 (m, 2H),7.06-7.02 (m, 1H), 6.69 (d, J = 4.8 Hz, 1H), 5.41-5.27 (m, 1H), 3.99-3.89 (m, 4H),3.80-3.73 (m, 2H), 2.91-2.85 (m, 1H), 2.74 (s, 2H), 2.43-2.36 (m, 1H), 2.32-2.01(m, 2H), 1.91-1.87 (m, 1H), 1.55-1.51 (m, 2H), 1.46 (s, 9H).

[0257] Step 2: Preparation of (S)—N-(4-(2,5-difluorophenyl)-2-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)piperidine-4-carboxamide trifluoroacetate [ka] To a solution of (S)-tert-butyl 4-((4-(2,5-difluorophenyl)-2-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)carbamoyl)piperidine-1-carboxylate (0.100 g, 0.198 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (3.85 g, 33.7 mmol). The mixture was stirred at 20° C. for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography eluting with aqueous formic acid (0.1%) in acetonitrile to give the title compound (0.130 g, crude) as a colorless solid. 1 HNMR (400 MHz, methanol-d4) δ 8.52 (s, 1H), 8.13 (d, J = 4.8 Hz, 1H), 7.24-7.15(m, 2H), 7.04 (s, 1H), 6.67 (d, J = 5.2 Hz, 1H), 5.39-5.25 (m, 1H), 3.91-3.65 (m,4H), 3.27-3.25 (m, 2H), 2.93 (s, 2H), 2.59-2.53 (m, 1H), 2.32-2.02 (m, 2H), 1.71-1.55(m, 4H).

[0258] Step 3: Preparation of (S)—N-(4-(2,5-difluorophenyl)-2-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)-1-methylpiperidine-4-carboxamide [ka] To a solution of (S)—N-(4-(2,5-difluorophenyl)-2-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)piperidine-4-carboxamide trifluoroacetate (0.110 g, 0.212 mmol) in formic acid (4 mL) was added formaldehyde (1.09 g, 13.4 mmol, 37% purity in water). The mixture was stirred at 90° C. for 5 hours. The reaction mixture was cooled to 20° C. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC eluting with 27-57% aqueous ammonium hydroxide (0.05%) in acetonitrile to give the title compound as a colorless solid (0.0127 g, 13% yield). 1 HNMR (400 MHz, methanol-d4) δ 8.10 (d, J = 5.2 Hz, 1H), 7.22-7.12 (m, 2H),7.04-6.99 (m, 1H), 6.65 (d, J = 4.8 Hz, 1H), 5.38-5.24 (m, 1H), 3.90-3.66 (m, 4H), 2.82-2.79 (m, 2H), 2.31-2.26 (m, 1H), 2.23 (s, 3H), 2.19-1.95 (m, 4H), 1.51 (s,4H). MS (ES+) m / z 419.3 (M + 1).

[0259] Example 17: Synthesis of N-(4-(2,5-difluorophenyl)-2-((S)-3-fluoropyrrolidin-1-yl)pyridin-3-yl)-1-methylpiperidine-3-carboxamide [ka] Step 1: Preparation of tert-butyl 3-((4-(2,5-difluorophenyl)-2-((S)-3-fluoropyrrolidin-1-yl)pyridin-3-yl)carbamoyl)piperidine-1-carboxylate [ka] Following the procedure reported in Step 1 of Example 16, substituting 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid for 1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid, the title compound was isolated as a colorless solid (0.120 g, 35% yield). 1 HNMR (400 MHz, methanol-d4) δ 8.11 (d, J = 4.8 Hz, 1H), 7.26-7.15 (m, 2H),7.04-7.00 (m, 1H), 6.66 (d, J = 5.2 Hz, 1H), 5.39-5.25 (m, 1H), 3.90-3.72 (m, 4H),3.68 (s, 1H), 2.63 (s, 2H), 2.35-2.24 (m, 2H), 2.22-1.99 (m, 2H), 1.74-1.66 (m,1H), 1.61-1.59 (m, 1H), 1.45 (s, 9H), 1.39-1.29 (m, 2H).

[0260] Step 2: Preparation of N-(4-(2,5-difluorophenyl)-2-((S)-3-fluoropyrrolidin-1-yl)pyridin-3-yl)piperidine-3-carboxamide trifluoroacetate [ka] Following the procedure reported in step 2 of example 16, replacing (S)-tert-butyl 4-((4-(2,5-difluorophenyl)-2-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)carbamoyl)piperidine-1-carboxylate with tert-butyl 3-((4-(2,5-difluorophenyl)-2-((S)-3-fluoropyrrolidin-1-yl)pyridin-3-yl)carbamoyl)piperidine-1-carboxylate, the title compound was isolated as a colorless solid (0.050 g crude product). 1HNMR (400 MHz, methanol-d4) δ 8.45 (s, 1H), 8.15 (d, J = 5.0 Hz, 1H), 7.29-7.16(m, 2H), 7.08 (d, J = 2.4 Hz, 1H), 6.70 (d, J = 4.8 Hz, 1H), 5.45-5.23 (m, 1H),3.98-3.60 (m, 4H), 3.18-2.95 (m, 4H), 2.80 (s, 1H), 2.36-2.00 (m, 2H), 1.79 (d,J = 3.6 Hz, 1H), 1.68-1.34 (m, 3H).

[0261] Step 3: Preparation of N-(4-(2,5-difluorophenyl)-2-((S)-3-fluoropyrrolidin-1-yl)pyridin-3-yl)-1-methylpiperidine-3-carboxamide [ka] Following the procedure reported in Step 3 of Example 16, substituting (S)—N-(4-(2,5-difluorophenyl)-2-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)piperidine-4-carboxamide trifluoroacetate for N-(4-(2,5-difluorophenyl)-2-((S)-3-fluoropyrrolidin-1-yl)pyridin-3-yl)piperidine-3-carboxamide trifluoroacetate, the title compound was isolated as a colorless solid (0.0156 g, 30% yield). 1HNMR (400 MHz, methanol-d4) δ 8.10 (d, J = 5.2 Hz, 1H), 7.24-7.15 (m, 2H),7.04-6.99 (m, 1H), 6.65 (d, J = 5.2 Hz, 1H), 5.41-5.23 (m, 1H), 3.90-3.61 (m, 4H),2.71 (d, J = 11.2 Hz, 1H), 2.59-2.38 (m, 2H), 2.32-2.23 (m, 1H), 2.21 (s, 3H), 2.18-1.97(m, 1H), 1.92-1.87 (m, 2H), 1.62-1.44 (m, 3H), 1.20-1.1 (m, 1H). MS (ES+) m / z 419.3(M + 1).

[0262] Example 18: (1r,4S)—N-(4-(2,5-difluorophenyl)-6-((S)-3-fluoropyrrolidin-1-yl)pyrimidin-5-yl)-4-methoxycyclohexane-1-carboxamide [ka] Step 1: (S)-4-chloro-6-(3-fluoropyrrolidin-1-yl)pyrimidin-5-amine [ka] To a mixture of 4,6-dichloropyrimidin-5-amine (1.00 g, 6.10 mmol) in ethanol (10.0 mL) were added triethylamine (1.23 g, 12.2 mmol) and (S)-fluoropyrrolidine hydrochloride (0.766 g, 6.10 mmol). The reaction mixture was stirred at 80° C. for 12 hours. After cooling to ambient temperature, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography using 20% ​​ethyl acetate in petroleum ether as the eluent to give the title compound as a yellow oil (1.00 g, 76% yield): 1HNMR (400 MHz, CD3OD) δ 7.84 (s, 1H), 5.41-5.26 (m, 1H), 4.05-3.84 (m,4H), 2.34-2.23 (m, 1H), 2.20-2.03 (m, 1H).

[0263] Step 2: Preparation of (1r,4r)-4-methoxycyclohexane-1-carbonyl chloride [ka] To a mixture of (1r,4r)-4-methoxycyclohexanecarboxylic acid (0.100 g, 0.632 mmol) in thionyl chloride (3.28 g, 27.6 mmol) was added N,N-dimethylformamide (0.005 g, 0.06 mmol). The reaction mixture was stirred at 80° C. for 1 hour. After cooling to ambient temperature, the mixture was concentrated under reduced pressure to give a colorless solid, which was used in the next step without further purification.

[0264] Step 3: Preparation of (1r,4S)-N-(4-chloro-6-((S)-3-fluoropyrrolidin-1-yl)pyrimidin-5-yl)-4-methoxycyclohexane-1-carboxamide [ka] To a mixture of (S)-4-chloro-6-(3-fluoropyrrolidin-1-yl)pyrimidin-5-amine (0.110 g, 0.508 mmol) in dichloromethane (4.00 mL) was added pyridine (0.490 g, 6.19 mmol) and (1r,4r)-4-methoxycyclohexane-1-carbonyl chloride (0.110 g, 0.623 mmol). The reaction mixture was stirred at ambient temperature for 12 hours. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography using 50% ethyl acetate in petroleum ether as the eluent to give the title compound as a yellow solid (0.080 g, 43% yield): 1HNMR (400 MHz, CD3OD) δ 8.21 (s, 1H), 5.40-5.22 (m, 1H), 4.04-3.64 (m,4H), 3.37 (s, 3H), 2.47-2.38 (m, 1H), 2.34-2.24 (m, 1H), 2.21-2.09 (m, 4H), 2.06-1.96(m, 2H), 1.67-1.52 (m, 2H), 1.32-1.20 (m, 2H).

[0265] Step 4: Preparation of (S)-2-chloro-N-(4-(2,5-difluorophenyl)-2-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)pyrimidine-5-carboxamide formate [ka] To a mixture of (1r,4S)—N-(4-chloro-6-((S)-3-fluoropyrrolidin-1-yl)pyrimidin-5-yl)-4-methoxycyclohexane-1-carboxamide (0.600 g, 0.168 mmol) in dioxane (4.00 mL) and water (0.800 mL), (2,5-difluorophenyl)boronic acid (0.053 g, 0.336 mmol), dichloro 1,1′-bis(diphenylphosphino)ferrocene palladium(II) dichloromethane (0.012 g, 0.017 mmol), and potassium carbonate (0.070 g, 0.500 mmol) were added, and the mixture was purged with nitrogen for 10 minutes. The reaction mixture was stirred at 80° C. for 2 hours. After cooling to ambient temperature, the mixture was filtered through a bed of diatomaceous earth (i.e., Celite®) and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography using a gradient of 16-46% acetonitrile in water containing 0.05% ammonium hydroxide as eluent to give the title compound as a colorless solid (0.008 g, 11% yield). 1HNMR (400 MHz, CD3OD) δ 8.47 (s, 1H), 7.25-7.22 (m, 2H), 7.11-7.07 (m,1H), 5.42-5.28 (m, 1H), 4.13-3.65 (m, 4H), 3.31 (s, 3H), 3.12-3.04 (m, 1H), 2.37-2.27(m, 1H), 2.23-1.99 (m, 4H), 1.82-1.66 (m, 1H), 1.42-1.29 (m, 2H), 1.11-1.08 (m,3H). MS (ES+) m / z 435.0 (M + 1).

[0266] Example 19: (S)—N-(4-(2,5-difluorophenyl)-6-(3-fluoropyrrolidin-1-yl)pyrimidin-5-yl)-1-isopropyl-1H-pyrazole-4-carboxamide [ka] Step 1: Preparation of 1-isopropyl-1H-pyrazole-4-carbonyl chloride hydrochloride [ka] To a solution of thionyl chloride (7.38 g, 62.0 mmol) was added 1-isopropyl-1H-pyrazole-4-carboxylic acid (0.450 g, 2.92 mmol). The reaction mixture was stirred at 80° C. for 3 hours. After cooling to ambient temperature, the mixture was concentrated under reduced pressure to give a yellow oil, which was used in the next step without further purification.

[0267] Step 2: Preparation of (S)—N-(4-chloro-6-(3-fluoropyrrolidin-1-yl)pyrimidin-5-yl)-1-isopropyl-1H-pyrazole-4-carboxamide [ka] To a mixture of (S)-4-chloro-6-(3-fluoropyrrolidin-1-yl)pyrimidin-5-amine (0.400 g, 1.85 mmol) in dichloromethane (8.00 mL) was added sodium tert-butoxide (0.889 g, 9.25 mmol) and 1-isopropyl-1H-pyrazole-4-carbonyl chloride hydrochloride (0.479 g, 2.77 mmol). The reaction mixture was stirred at ambient temperature for 12 hours. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography using 50% ethyl acetate in petroleum ether as the eluent to give the title compound as a yellow solid (0.300 g, 46% yield). 1 HNMR (400 MHz, DMSO-d6) δ 9.73 (d, J = 6.0 Hz, 1H), 8.36 (d, J = 5.6Hz, 1H), 8.30 (d, J = 2.8 Hz, 1H), 8.02 (s, 1H), 5.43-5.30 (m, 1H), 4.56 (m, 1H), 3.95-3.88 (m, 1H), 3.81-3.69 (m, 2H), 3.62-3.49 (m, 1H), 2.24-2.01 (m, 2H), 1.45(d, J = 6.4 Hz, 6H).

[0268] Step 3: Preparation of (S)—N-(4-(2,5-difluorophenyl)-6-(3-fluoropyrrolidin-1-yl)pyrimidin-5-yl)-1-isopropyl-1H-pyrazole-4-carboxamide [ka] To a mixture of (S)—N-(4-chloro-6-(3-fluoropyrrolidin-1-yl)pyrimidin-5-yl)-1-isopropyl-1H-pyrazole-4-carboxamide (0.050 g, 0.142 mmol) in dioxane (5.00 mL) and water (0.100 mL), (2,5-difluorophenyl)boronic acid (0.034 g, 0.213 mmol), dichloro1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloromethane (0.010 g, 0.014 mmol), and potassium carbonate (0.039 g, 0.28 mmol) were added, and the mixture was purged with nitrogen for 10 minutes. The reaction mixture was stirred at 80° C. for 2 hours. After cooling to ambient temperature, the mixture was concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography using a gradient of 18 to 48% acetonitrile in water containing 0.23% formic acid as the eluent, followed by 15 to 45% acetonitrile in water containing 0.05% ammonium hydroxide as the eluent to give the title compound as a colorless solid (0.013 g, 21% yield). 1 HNMR (400 MHz, CD3OD) δ 8.50 (s, 1H), 8.07 (s, 1H), 7.82 (s, 1H), 7.17-7.14(m, 3H), 5.37-5.24 (m, 1H), 4.56-4.49 (m, 1H), 4.06-3.73 (m, 4H), 2.33-1.99 (m,2H), 1.48 (d, J = 6.8 Hz, 6H). MS (ES+) m / z 431.0 (M + 1).

[0269] Example 20: Synthesis of 1-cyclobutyl-N-(4-(2,5-difluorophenyl)-6-(3,3-difluoropyrrolidin-1-yl)pyrimidin-5-yl)-1H-pyrazole-4-carboxamide [ka] Step 1: Preparation of 1-cyclobutyl-N-(4,6-dichloropyrimidin-5-yl)-1H-pyrazole-4-carboxamide [ka] To a solution of 1-cyclobutylpyrazole-4-carboxylic acid (0.300 g, 1.81 mmol) in dichloromethane (2 mL) was added oxalic acid dichloride (0.252 g, 1.99 mmol) and dimethylformamide (0.0132 g, 0.181 mmol) dropwise at 0° C. The solution was stirred at 20° C. for 2 hours. The solution was evaporated under reduced pressure to give 1-cyclobutylpyrazole-4-carbonyl chloride (0.300 g, 1.62 mmol) as a pale yellow oil. To a solution of 4,6-dichloropyrimidin-5-amine (0.200 g, 1.22 mmol) in tetrahydrofuran (2 mL) was added sodium hydride (0.244 g, 6.10 mmol, 60% purity) in small portions at 0° C. The mixture was stirred at 0° C. for 1 hour, and then a solution of 1-cyclobutylpyrazole-4-carbonyl chloride (0.248 mg, 1.34 mmol) in tetrahydrofuran (1 mL) was added dropwise at 0° C. The mixture was stirred at 20° C. for 1 hour. The mixture was poured into water (20 mL). The mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by column chromatography eluting with 40% ethyl acetate in petroleum ether to give 1-cyclobutyl-N-(4,6-dichloropyrimidin-5-yl)-pyrazole-4-carboxamide as a white solid (0.230 g, 57% yield). 1 HNMR (400 MHz, CDCl3) δ 8.72 (s, 1H), 8.08 (s, 1H), 7.96 (s, 1H), 7.37(s, 1H), 4.89-4.76 (m, 1H), 2.65-2.47 (m, 4H), 2.01-1.85 (m, 2H).

[0270] Step 2: Preparation of N-(4-chloro-6-(3,3-difluoropyrrolidin-1-yl)-pyrimidin-5-yl)-1-cyclobutyl-1H-pyrazole-4-carboxamide [ka] To a mixture of 1-cyclobutyl-N-(4,6-dichloropyrimidin-5-yl)pyrazole-4-carboxamide (0.100 g, 0.320 mmol) and 3,3-difluoropyrrolidine hydrochloride (0.0920 g, 0.641 mmol) in ethanol (2 mL) was added N,N-diisopropylethylamine (0.207 g, 1.60 mmol) dropwise at 20° C. The solution was stirred at 70° C. for 2 hours. The mixture was cooled to 20° C. and poured into water (20 mL). The mixture was extracted with ethyl acetate (3×20 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 reverse-phase preparative HPLC eluting with 27-57% aqueous ammonium formate (10 mM) in acetonitrile to give the title compound as a colorless white solid (0.0900 g, 73% yield). 1 HNMR (400 MHz, CDCl3) δ 8.34 (s, 1H), 8.06 (s, 1H), 7.92 (s, 1H), 7.06-6.91(m, 1H), 4.89-4.76 (m, 1H), 4.10-3.83 (m, 4H), 2.67-2.48 (m, 4H), 2.45-2.30 (m,2H), 2.03-1.84 (m, 2H).

[0271] Step 3: Preparation of 1-cyclobutyl-N-(4-(2,5-difluorophenyl)-6-(3,3-difluoropyrrolidin-1-yl)pyrimidin-5-yl)-1H-pyrazole-4-carboxamide [ka] To a solution of N-(4-chloro-6-(3,3-difluoropyrrolidin-1-yl)pyrimidin-5-yl)-1-cyclobutyl-1H-pyrazole-4-carboxamide (0.0400 g, 0.105 mmol) and (2,5-difluorophenyl)boronic acid (0.0330 g, 0.209 mmol) in dioxane (1.5 mL) and water (0.15 mL) was added potassium carbonate (0.0433 g, 0.313 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.00853 g, 0.0105 mmol) in one portion at 20 °C. The mixture was stirred at 95 °C under a nitrogen atmosphere for 2 h. The mixture was cooled to 20 °C and poured into water (10 mL). The mixture was 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 preparative HPLC eluting with 24–54% aqueous ammonium formate (10 mM) in acetonitrile to give the title compound as a colorless off-white solid (0.0341 g, 98% purity). 1 HNMR (400 MHz, DMSO-d6) δ 9.55 (s, 1H), 8.58 (s, 1H), 8.21 (s, 1H), 7.86(s, 1H), 7.33-7.20 (m, 2H), 7.19-7.11 (m, 1H), 4.90-4.75 (m, 1H), 4.26-3.61 (m,4H), 2.49-2.30 (m, 6H), 1.85-1.68 (m, 2H). MS (ES+) m / z = 461.1 (M + 1).

[0272] Example 21: Synthesis of 1-cyclobutyl-N-(4-(3,3-difluoropyrrolidin-1-yl)-6-phenylpyrimidin-5-yl)-1H-pyrazole-4-carboxamide [ka] Following the procedure reported in Step 3 of Example 1, substituting 2,4-difluorophenylboronic acid for phenylboronic acid, the title compound was isolated as a colorless solid (0.0278 g, 49% yield). 1 HNMR (400 MHz, DMSO-d6) δ 9.59 (s, 1H), 8.57 (d, J = 0.8 Hz, 1H), 8.23(s, 1H), 7.90 (s, 1H), 7.68-7.52 (m, 2H), 7.44-7.29 (m, 3H), 4.94-4.75 (m, 1H), 4.17-4.02 (m, 1H), 4.01-3.80 (m, 2H), 3.79-3.67 (m, 1H), 2.49-2.30 (m, 6H), 1.84-1.70(m, 2H). MS (ES+) m / z = 425.2 (M + 1).

[0273] Example 22: Synthesis of (R)-1-cyclobutyl-N-(4-phenyl-6-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)-1H-pyrazole-4-carboxamide [ka] Step 1: Preparation of (R)-N-(4-chloro-6-(2-(trifluoromethyl)-pyrrolidin-1-yl)pyrimidin-5-yl)-1-cyclobutyl-1H-pyrazole-4-carboxamide [ka] To a solution of 1-cyclobutyl-N-(4,6-dichloropyrimidin-5-yl)pyrazole-4-carboxamide (0.200 g, 0.640 mmol) and diisopropylethylamine (0.414 g, 3.20 mmol) in butan-1-ol (1 mL) was added (R)-2-(trifluoromethyl)pyrrolidine (0.225 g, 1.28 mmol) in one portion at 20° C. The solution was stirred at 90° C. for 12 hours. The mixture was cooled to 20° C. and poured into water (10 mL). The mixture was extracted with ethyl acetate (3×20 mL). The combined organic fractions were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to give the title compound as a colorless solid (0.250 g, 94% yield). 1 HNMR (400 MHz, CDCl3) δ 8.37 (s, 1H), 8.08 (s, 1H), 7.95 (s, 1H), 7.25(s, 1H), 5.58-5.34 (m, 1H), 4.96-4.69 (m, 1H), 2.62-2.49 (m, 4H), 2.23-1.82 (m,8H).

[0274] Step 2: Preparation of (R)-1-cyclobutyl-N-(4-phenyl-6-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)-1H-pyrazole-4-carboxamide [ka] To a solution of (R)-N-(4-chloro-6-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)-1-cyclobutyl-1H-pyrazole-4-carboxamide (0.250 g, 0.603 mmol) and phenylboronic acid (0.147 g, 1.21 mmol) in dioxane (10 mL) and water (0.1 mL) was added potassium carbonate (0.250 g, 1.81 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.0492 g, 0.0603 mmol) in one portion at 20 °C. The mixture was stirred at 95 °C under a nitrogen atmosphere for 2 h. The mixture was cooled to 20 °C and poured into water (20 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 evaporated under reduced pressure. Purification by reverse-phase preparative HPLC eluting with 37-67% aqueous ammonium formate (10 mM) in acetonitrile afforded the title compound as an off-white solid (0.142 g, 50% yield). 1 HNMR (400 MHz, DMSO-d6) δ 9.81-9.47 (m, 1H), 8.61 (s, 1H), 8.23 ​​(d, J= 16.8 Hz, 1H), 7.91 (s, 1H), 7.62 (d, J = 5.2 Hz, 2H), 7.50-7.24 (m, 3H), 5.80-5.50(m, 1H), 4.83 (t, J = 7.6 Hz, 1H), 4.02-3.42 (m, 2H), 2.49-2.29 (m, 4H), 2.18-1.91(m, 4H), 1.86-1.67 (m, 2H). MS (ES+) m / z 457.1 (M + 1).

[0275] Example 23: Synthesis of N-(4-(3,3-difluoropyrrolidin-1-yl)-6-phenylpyrimidin-5-yl)-6-isopropylnicotinamide [ka] Step 1: Preparation of 4-chloro-6-(3,3-difluoropyrrolidin-1-yl)-pyrimidin-5-amine [ka] A mixture of 4,6-dichloropyrimidin-5-amine (4.00 g, 24.4 mmol), 3,3-difluoropyrrolidine hydrochloride (10.5 g, 73.2 mmol), and triethylamine (14.8 g, 146.4 mmol) in ethanol (80 mL) 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 reverse-phase chromatography eluting with 0.1% aqueous ammonium hydroxide to give the title compound (5.30 g, 93% yield) as a pale yellow solid. 1 HNMR (400 MHz, DMSO-d6) δ 7.90 (s, 1H), 4.92 (s, 2H), 3.98 (t, J = 13.6Hz, 2H), 3.79 (t, J = 7.2 Hz, 2H), 2.44 (td, J = 7.2, 13.6 Hz, 2H).

[0276] Step 2: Preparation of N-(4-chloro-6-(3,3-difluoropyrrolidin-1-yl)-pyrimidin-5-yl)-6-isopropylnicotinamide [ka] To a mixture of 6-isopropylnicotinic acid (0.300 g, 1.82 mmol) in tetrahydrofuran (7.5 mL) was added N,N-diisopropylethylamine (1.17 g, 9.08 mmol) and 2-chloro-1-methyl-pyridin-1-ium iodide (0.557 g, 2.18 mmol). The mixture was then stirred at 25 °C for 2 hours. To this mixture was added 4-chloro-6-(3,3-difluoropyrrolidin-1-yl)pyrimidin-5-amine (0.852 g, 3.63 mmol). The resulting mixture was stirred at 60 °C for 12 hours under a nitrogen atmosphere. The mixture was concentrated under reduced pressure. Purification by reverse-phase preparative HPLC eluting with 30-52% aqueous formic acid (0.225%) in acetonitrile afforded the title compound as a colorless solid (0.110 g, 16% yield). 1 HNMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 9.06 (d, J = 1.6 Hz, 1H), 8.38(s, 1H), 8.24 (dd, J = 2.4, 8.4 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 4.10 (q, J =12.4 Hz, 1H), 4.03-3.83 (m, 2H), 3.72 (td, J = 7.6, 11.2 Hz, 1H), 3.12 (td, J =6.8, 13.8 Hz, 1H), 2.46 (d, J = 6.4 Hz, 2H), 1.27 (d, J = 7.2 Hz, 6H).

[0277] Step 3: Preparation of N-(4-(3,3-difluoropyrrolidin-1-yl)-6-phenylpyrimidin-5-yl)-6-isopropylnicotinamide [ka] A mixture of N-(4-chloro-6-(3,3-difluoropyrrolidin-1-yl)pyrimidin-5-yl)-6-isopropylnicotinamide (0.0500 g, 0.131 mmol), phenylboronic acid (0.0240 g, 0.196 mmol), potassium carbonate (0.0543 g, 0.393 mmol), and [1,1-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (0.0958 g, 0.0131 mmol) in 1,4-dioxane (1 mL) and water (0.12 mL) was stirred at 80° C. for 12 hours under a nitrogen atmosphere. The mixture was diluted with ethyl acetate (5 mL) and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC eluting with 25-45% aqueous formic acid (0.225%) in acetonitrile to give the title compound as a colorless solid (0.0299 g, 53% yield). 1 HNMR (400 MHz, MeOD) δ 8.69 (dd, J = 0.4, 2.4 Hz, 1H), 8.55 (s, 1H), 8.00 (dd, J= 2.4, 8.0 Hz, 1H), 7.54-7.48 (m, 2H), 7.45-7.37 (m, 4H), 4.17-3.84 (m, 4H), 3.11(td, J = 6.8, 13.8 Hz, 1H), 2.53-2.38 (m, 2H), 1.30 (d, J = 7.2 Hz, 6H). MS (ES+) m / z 424.0 (M + 1).

[0278] Example 24: Synthesis of N-(4-(3,3-difluoropyrrolidin-1-yl)-6-(2-fluorophenyl)pyrimidin-5-yl)-6-isopropylnicotinamide [ka] Following the procedure reported in Step 3 of Example 23, substituting 2-F-phenylboronic acid for phenylboronic acid, the title compound was isolated as a colorless solid (0.0306 g, 57% yield). 1HNMR (400 MHz, MeOD) δ 8.66 (s, 1H), 8.57 (s, 1H), 7.99-7.98 (m, 1H), 7.45-7.39(m, 3H), 7.24-7.20 (m, 2H), 4.19-3.89 (m, 4H), 3.14-3.07 (m, 1H), 2.49-2.42 (m,2H), 1.29 (d, J = 7.2, 6H). MS (ES+) m / z 441.2 (M + 1).

[0279] Example 25: Synthesis of N-(4-(2,5-difluorophenyl)-6-(3,3-difluoropyrrolidin-1-yl)pyrimidin-5-yl)-6-isopropylnicotinamide [ka] Following the procedure reported in Step 3 of Example 23, substituting 2,5-di-F-phenylboronic acid for phenylboronic acid, the title compound was isolated as a colorless solid (0.0279 g, 52% yield). 1 HNMR (400 MHz, MeOD) δ 8.72 (s, 1H), 8.59 (s, 1H), 8.04-8.00 (m, 1H), 7.42 (d, J= 8.4 Hz, 1H), 7.20-7.15 (m, 3H), 4.08-3.94 (m, 4H), 3.15-3.10 (m, 1H), 2.49-2.42(m, 2H), 1.30 (d, J = 7.2, 6H). MS (ES+) m / z 459.2 (M + 1).

[0280] Example 26: Synthesis of N-(4-(3,3-difluoropyrrolidin-1-yl)-6-phenylpyrimidin-5-yl)-2-isopropylpyrimidine-5-carboxamide [ka] Step 1: Preparation of N-(4-chloro-6-(3,3-difluoropyrrolidin-1-yl)pyrimidin-5-yl)-6-isopropylnicotinamide [ka] To a mixture of 2-isopropylpyrimidine-5-carboxylic acid (0.0390 g, 0.234 mmol) in tetrahydrofuran (1 mL) was added pyridine (0.169 g, 2.13 mmol), 2-chloro-1-methyl-pyridin-1-ium iodide (0.163 g, 0.639 mmol), and 4-chloro-6-(3,3-difluoropyrrolidin-1-yl)pyrimidin-5-amine (0.0500 g, 0.213 mmol). The mixture was stirred at 60° C. for 12 hours. The mixture was quenched with saturated ammonium chloride (1 mL). The mixture was extracted with ethyl acetate (3×5 mL) and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC eluting with 30-50% aqueous formic acid (0.225%) in acetonitrile to give the title compound as a yellow solid (0.0180 g, 20% yield). 1 HNMR (400 MHz, MeOD-d4) δ 9.23 (s, 2H), 8.33 (s, 1H), 4.14-3.79 (m, 4H),3.36-3.33 (m, 1H), 2.52-2.36 (m, 2H), 1.39 (d, J = 6.8 Hz, 6H).

[0281] Step 2: Preparation of N-(4-(3,3-difluoropyrrolidin-1-yl)-6-phenylpyrimidin-5-yl)-2-isopropylpyrimidine-5-carboxamide formate [ka] A mixture of N-(4-chloro-6-(3,3-difluoropyrrolidin-1-yl)pyrimidin-5-yl)-6-isopropylnicotinamide (0.0170 g, 0.0444 mmol), phenylboronic acid (0.00812 g, 0.0666 mmol), potassium carbonate (0.0184 g, 0.133 mmol), and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.00325 g, 0.00444 mmol) in 1,4-dioxane (0.4 mL) and water (0.06 mL) was stirred at 80 °C for 12 hours under a nitrogen atmosphere. The mixture was quenched by the addition of water (5 mL) and extracted with ethyl acetate (3 × 10 mL). The organic phases were combined, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC eluting with 22-42% aqueous formic acid (0.225%) in acetonitrile to give the title compound as a colorless solid (0.0299 g, 53% yield). 1 HNMR (400 MHz, MeOD-d4) δ 8.88 (s, 2H), 8.55 (s, 1H), 8.48 (s, 0.37H),7.53-7.47 (m, 2H), 7.45-7.38 (m, 3H), 4.15-3.97 (m, 3H), 3.95-3.84 (m, 1H), 3.23(td, J = 7.2, 13.6 Hz, 1H), 2.55-2.37 (m, 2H), 1.33 (d, J = 6.8 Hz, 6H). MS (ES+) m / z 425.1 (M + 1).

[0282] Example 27: Synthesis of N-(4-(2,5-difluorophenyl)-6-(3,3-difluoropyrrolidin-1-yl)pyrimidin-5-yl)-2-isopropylpyrimidine-5-carboxamide [ka] Step 1: Preparation of 4-(2,5-difluorophenyl)-6-(3,3-difluoro-pyrrolidin-1-yl)pyrimidin-5-amine [ka] A mixture of 4-chloro-6-(3,3-difluoropyrrolidin-1-yl)pyrimidin-5-amine (0.500 g, 2.13 mmol), (2,5-difluorophenyl)boronic acid (0.505 g, 3.20 mmol), potassium carbonate (0.884 g, 6.39 mmol), and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.156 g, 0.213 mmol) in 1,4-dioxane (5 mL) and water (0.6 mL) was stirred at 80 °C for 12 hours under a nitrogen atmosphere. The mixture was quenched by the addition of water (5 mL) and extracted with ethyl acetate (3 × 10 mL). The organic phase was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography eluting with 10:1 ethyl acetate in petroleum ether to give the title compound as a yellow solid (0.350 g, 53% yield). 1 HNMR (400 MHz, CDCl3) δ 8.39 (s, 1H), 7.27-7.24 (m, 1H), 7.21-7.11 (m,2H), 3.98 (t, J = 13.2 Hz, 2H), 3.89 (t, J = 7.2 Hz, 2H), 3.41 (br s, 2H), 2.52-2.39(m, 2H).

[0283] Step 2: Preparation of N-(4-(2,5-difluorophenyl)-6-(3,3-difluoropyrrolidin-1-yl)pyrimidin-5-yl)-2-isopropylpyrimidine-5-carboxamide [ka] To a mixture of 2-isopropylpyrimidine-5-carboxylic acid (0.0681 g, 0.410 mmol) in tetrahydrofuran (1 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.331 g, 2.56 mmol), 2-chloro-1-methyl-pyridin-1-ium iodide (0.262 g, 1.02 mmol), and 4-(2,5-difluorophenyl)-6-(3,3-difluoropyrrolidin-1-yl)pyrimidin-5-amine (0.800 g, 0.256 mmol). The mixture was stirred at 60 °C for 12 hours. After cooling to ambient temperature, the mixture was diluted with water (0.5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC eluting with 36-56% aqueous formic acid (0.225%) in acetonitrile to give the title compound as a yellow solid (0.0552 g, 46% yield). 1 HNMR (400 MHz, MeOD-d4) δ 8.92 (s, 2H), 8.50 (s, 1H), 7.26-7.14 (m, 3H),4.22-3.80 (m, 4H), 3.24 (td, J = 6.8, 13.6 Hz, 1H), 2.55-2.38 (m, 2H), 1.34 (d,J = 6.8 Hz, 6H). MS (ES+) m / z 461.2(M + 1).

[0284] Example 28: Synthesis of N-(4-(3,3-difluoropyrrolidin-1-yl)-6-(2-fluorophenyl)pyrimidin-5-yl)-2-isopropylpyrimidine-5-carboxamide [ka] Step 1: Preparation of 4-(2-fluorophenyl)-6-(3,3-difluoro-pyrrolidin-1-yl)pyrimidin-5-amine [ka] The title compound was used directly in Step 2 according to the procedure reported in Step 1 of Example 26, substituting 4-(2,5-difluorophenyl)-6-(3,3-difluoropyrrolidin-1-yl)pyrimidin-5-amine for 4-(2-fluorophenyl)-6-(3,3-difluoropyrrolidin-1-yl)pyrimidin-5-amine.

[0285] Step 2: Synthesis of N-(4-(3,3-difluoropyrrolidin-1-yl)-6-(2-fluorophenyl)pyrimidin-5-yl)-2-isopropylpyrimidine-5-carboxamide [ka] Following the procedure reported in Step 2 of Example 26, substituting 2,5-difluorophenylboronic acid for 2-F-phenylboronic acid, the title compound was isolated as a yellow solid (0.0596 g, 49% yield). 1 HNMR (400 MHz, MeOD-d4) δ 8.86 (s, 2H), 8.58 (s, 1H), 7.47-7.40 (m, 2H),7.26-7.20 (m, 2H), 4.07-3.90 (m, 4H), 3.23 (td, J = 6.8, 13.5 Hz, 1H), 2.52-2.41(m, 2H), 1.32 (d, J = 6.8 Hz, 6H). MS (ES+) m / z 443.1 (M + 1).

[0286] Example 29: Synthesis of (S)—N-(4-(2,5-difluorophenyl)-6-(3-fluoropyrrolidin-1-yl)pyrimidin-5-yl)-1-methyl-1H-imidazole-4-carboxamide [ka] Step 1: Preparation of 1-methyl-1H-imidazole-4-carbonyl chloride [ka] A slurry of 1-methyl-1H-imidazole-4-carboxylic acid (0.500 g, 3.96 mmol) in dry dichloromethane (10 mL) at 20° C. was treated dropwise with oxalyl chloride (0.870 g, 6.85 mmol) and N,N-dimethylformamide (0.0290 g, 0.396 mmol). The reaction was immediately bubbled, and the slurry was stirred at 20° C. for 1 h. The reaction mixture was concentrated under reduced pressure to give 1-methyl-1H-imidazole-4-carbonyl chloride as a colorless solid (0.800 g, crude product, hydrochloride salt).

[0287] Step 2: Preparation of (S)—N-(4-chloro-6-(3-fluoropyrrolidin-1-yl)pyrimidin-5-yl)-1-methyl-1H-imidazole-4-carboxamide [ka] To a solution of (S)-4-chloro-6-(3-fluoropyrrolidin-1-yl)pyrimidin-5-amine (0.400 g, 1.85 mmol) in dichloromethane (10 mL) was added sodium tert-butoxide (0.887 g, 9.23 mmol) and 1-methyl-1H-imidazole-4-carbonyl chloride (0.501 g, 2.77 mmol, hydrochloride). The mixture was stirred at 20 °C for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with ethyl acetate (50%) in petroleum ether to give the title compound as a red oil (0.220 g, 37% yield). 1 HNMR (400 MHz, DMSO-d6) δ 9.69 (s, 1H), 8.26 (s, 1H), 7.78 (s, 1H), 7.75(s, 1H), 5.40-5.27 (m, 1H), 3.98-3.84 (m, 2H), 3.72 (s, 3H), 3.57-3.44 (m, 2H),2.20-2.07 (m, 2H).

[0288] Step 3: Preparation of (S)—N-(4-(2,5-difluorophenyl)-6-(3-fluoropyrrolidin-1-yl)pyrimidin-5-yl)-1-methyl-1H-imidazole-4-carboxamide [ka] A mixture of (S)—N-(4-chloro-6-(3-fluoropyrrolidin-1-yl)pyrimidin-5-yl)-1-methyl-1H-imidazole-4-carboxamide (0.0500 g, 0.154 mmol), (2,5-difluorophenyl)boronic acid (0.0486 g, 0.309 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.0113 g, 0.0154 mmol), and potassium carbonate (0.0638 g, 0.462 mmol) in dioxane (1.5 mL) and water (0.3 mL) was degassed and purged with nitrogen three times. The mixture was stirred at 100° C. under a nitrogen atmosphere for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC eluting with 4-34% aqueous formic acid (0.225%) in acetonitrile to give the title compound as a yellow solid (0.00330 g, 5% yield). 1 HNMR (400 MHz, methanol-d4) δ 8.49 (s, 1H), 7.59 (d, J = 2.4 Hz, 2H), 7.21-7.17(m, 1H), 7.13-7.09 (m, 2H), 5.35-5.21 (m, 1H), 4.04-3.99 (m, 2H), 3.91-3.76 (m,2H), 3.73 (s, 3H), 2.30-1.98 (m, 2H). MS (ES+) m / z 403.1 (M + 1).

[0289] Example 30: Synthesis of (S)—N-(4-(2,5-difluorophenyl)-2-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)-2-(4-isopropylphenyl)acetamide [ka] To a solution of (S)-4-(2,5-difluorophenyl)-2-(3-fluoropyrrolidin-1-yl)pyridin-3-amine (0.100 g, 0.341 mmol) and 2-(4-isopropylphenyl)acetic acid (0.0912 g, 0.511 mmol) in tetrahydrofuran (5 mL) was added 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (0.434 g, 0.682 mmol, 50% purity in ethyl acetate) and N,N-diisopropylethylamine (0.132 g, 1.02 mmol). The mixture was stirred at 70° C. for 12 hours. The reaction mixture was cooled to ambient temperature, poured into water (20 mL), and then extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (3 × 30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC eluting with 42–81% aqueous formic acid (0.225%) in acetonitrile to give the title compound (0.0608 g, 39% yield) as a colorless solid. 1 HNMR (400 MHz, methanol-d4) δ 8.07 (d, J = 4.8 Hz, 1H), 7.10-7.08 (m, 2H),7.06-7.03 (m, 2H), 6.98-6.96 (m, 2H), 6.95-6.91 (m, 1H), 6.61 (d, J = 5.2 Hz, 1H),5.28-5.13 (m, 1H), 3.78-3.54 (m, 4H), 3.38 (d, J = 2.0 Hz, 2H), 2.91-2.84 (m, 1H),2.22-1.93 (m, 2H), 1.24 (d, J = 6.8 Hz, 6H). MS (ES+) m / z 454.1 (M + 1).

[0290] Example 31: Synthesis of (R)—N-(4-(2,5-difluorophenyl)-6-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)-2-isopropylpyrimidine-5-carboxamide [ka] Step 1: Preparation of (R)-4-chloro-5-nitro-6-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidine [ka] To a solution of 4,6-dichloro-5-nitropyrimidine (0.500 g, 2.58 mmol) in acetonitrile (10 mL) was added potassium carbonate (1.78 g, 12.9 mmol) and (R)-2-(trifluoromethyl)pyrrolidine hydrochloride (0.460 g, 2.62 mmol). The mixture was stirred at 20° C. for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with a 10:1 mixture of petroleum ether and ethyl acetate to give (R)-4-chloro-5-nitro-6-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidine as a yellow oil (0.400 g, 52% yield). 1 HNMR (400 MHz, CDCl3) δ 8.46 (s, 1H), 5.58-5.51 (m, 1H), 3.63-3.58 (m,1H), 3.34-3.28 (m, 1H), 2.30-2.19 (m, 2H), 2.18-2.06 (m, 2H).

[0291] Step 2: Preparation of (R)-4-chloro-6-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-amine [ka] To a solution of (R)-4-chloro-5-nitro-6-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidine (0.400 g, 1.35 mmol) in methanol (20 mL) and water (2 mL) was added zinc (0.440 g, 6.73 mmol) and ammonium chloride (0.720 g, 13.6 mmol). The mixture was stirred at 60° C. for 12 hours. The reaction mixture was cooled to ambient temperature. The mixture was filtered and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL), washed with brine (3×100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with a 1:1 mixture of petroleum ether and ethyl acetate to give (R)-4-chloro-6-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-amine as a yellow oil (0.200 g, 56% yield). MS(ES+) m / z = 267.1 (M + 1).

[0292] Step 3: Preparation of (R)-4-(2,5-difluorophenyl)-6-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-amine [ka] To a solution of (R)-4-chloro-6-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-amine (0.150 g, 0.563 mmol) and (2,5-difluorophenyl)boronic acid (0.107 g, 0.678 mmol) in dioxane (6 mL) and water (0.6 mL) was added potassium carbonate (0.156 g, 1.13 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.046 g, 0.0563 mmol) in water (0.6 mL). The mixture was stirred at 90 °C for 1.5 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with a 10:1 mixture of petroleum ether and ethyl acetate to give (R)-4-(2,5-difluorophenyl)-6-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-amine as a yellow oil (0.140 g, 72% yield). 1 HNMR (400 MHz, CDCl3) δ 8.39 (s, 1H), 7.32-7.28 (m, 1H), 7.21-7.12 (m,2H), 5.64-5.55 (m, 1H), 3.41-3.35 (m, 1H), 2.35-2.24 (m, 1H), 2.19-2.07 (m, 2H),1.97-1.89 (m, 2H).

[0293] Step 4: Preparation of (R)—N-(4-(2,5-difluorophenyl)-6-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)-2-isopropylpyrimidine-5-carboxamide [ka] To a solution of (R)-4-(2,5-difluorophenyl)-6-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-amine (0.050 g, 0.145 mmol) and 2-isopropylpyrimidine-5-carboxylic acid (0.039 g, 0.235 mmol) in tetrahydrofuran (1 mL) was added 2-chloro-1-methylpyridinium iodide (0.149 g, 0.583 mmol) and diisopropylethylamine (0.188 g, 1.45 mmol). The mixture was stirred at 65 °C for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC eluting with 42-72% aqueous formic acid (0.225%) in acetonitrile to give the title compound. To a solution of the excess acylated by-product in methanol (2 mL) was added lithium hydroxide (0.5 M, 0.5 mL), and the mixture was stirred at 20 °C for 12 h. The mixture was concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC eluting with 42-72% aqueous formic acid (0.225%) in acetonitrile to give the title compound as a colorless solid (0.0087 g, 2% yield). 1 HNMR (400 MHz,CDCl3) δ 8.94 (s, 2H), 8.72 (s, 1H), 7.72 (d, J = 3.6 Hz,1H), 7.35-7.27 (m, 1H), 7.12-7.07 (m, 2H), 5.62-5.55 (m, 1H), 3.85-3.80 (m, 1H),3.65-3.59 (m, 1H), 3.32-3.25 (m, 1H), 2.20-2.09 (m, 3H), 2.06-2.01 (m, 1H), 1.37(d, J = 6.8 Hz, 6H). MS (ES+) m / z = 493.1 (M + 1).

[0294] Example 32: Synthesis of N-[2-(3,3-difluoropyrrolidin-1-yl)-4-(2-pyridyl)-3-pyridyl]-2-isopropyl-pyrimidine-5-carboxamide [ka] Step 1: Preparation of potassium 2-(3,3-difluoropyrrolidin-1-yl)-4-iodo-pyridine-3-carboxylate [ka] To a mixture of 2-fluoro-4-iodo-pyridine-3-carboxylic acid (12.5 g, 46.8 mmol) and potassium carbonate (12.9 g, 93.6 mmol) in N,N-dimethylformamide (500 mL) was added 3,3-difluoropyrrolidin-1-ium chloride (6.72 g, 46.8 mmol), and the mixture was stirred at 85 ° C. for 20 hours. After cooling to ambient temperature, the mixture was diluted with ethyl acetate (2500 mL), filtered through diatomaceous earth (i.e., Celite®), washed with ethyl acetate (500 mL), and the filtrate was concentrated under reduced pressure. The residue was stirred in a mixture of ethyl acetate (20 mL) and diethyl ether (250 mL) for 30 minutes, and the solid was filtered and washed with diethyl ether (50 mL). The residue was dried under reduced pressure to give the title compound as a brown solid (9.57 g, 47% yield). 1 HNMR (400 MHz, DMSO-d6) δ 7.45 (d, J = 5.2 Hz, 1H), 6.94 (d, J = 5.2 Hz,1H), 3.95 (t, J = 13.9 Hz, 2H), 3.73 (t, J = 7.3 Hz, 2H), 2.38 (tt, J = 14.4, 7.3Hz, 2H). MS (ES+) m / z 355.2 (M + 1).

[0295] Step 2: Preparation of [2-(3,3-difluoropyrrolidin-1-yl)-4-iodo-3-pyridyl]ammonium chloride [ka] To a mixture of potassium 2-(3,3-difluoropyrrolidin-1-yl)-4-iodo-pyridine-3-carboxylate (7.50 g, 19.1 mmol) and triethylamine (6.66 mL, 47.8 mmol) in N-methylpyrrolidone (190 mL), diphenylphosphoryl azide (6.17 mL, 28.7 mmol) was added, and the mixture was stirred at 95 °C for 3 h. After cooling to ambient temperature, the mixture was diluted with saturated aqueous sodium bicarbonate (1000 mL), and the aqueous phase was extracted with ethyl acetate (3 × 1000 mL). The organic phase was washed with brine (1000 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of 0–40% ethyl acetate in hexane. The residue was diluted with diethyl ether (50 mL), and hydrochloric acid (2 M solution in diethyl ether, 11.5 mL, 22.9 mmol) was added. Filtration, washing with diethyl ether (5 x 100 mL) and drying the residue under reduced pressure gave the title compound as a pale pink solid (4.80 g, 66%). 1 HNMR (400 MHz, DMSO-d6) δ 7.44-7.33 (m, 1H), 7.25 (d, J = 5.6 Hz, 1H),6.09 (s, 3H), 3.85 (t, J = 13.5 Hz, 2H), 3.59 (dd, J = 14.5, 7.4 Hz, 2H), 2.59-2.41(m, 2H). MS (ES+) m / z 326.3 (M + 1).

[0296] Step 3: Preparation of N-[2-(3,3-difluoropyrrolidin-1-yl)-4-iodo-3-pyridyl]-2-isopropylpyrimidine 5-carboxamide [ka] To a solution of 2-(3,3-difluoropyrrolidin-1-yl)-4-iodo-pyridin-3-amine hydrochloride (2.00 g, 5.53 mmol), 2-isopropylpyrimidine-5-carboxylic acid (1.37 g, 8.30 mmol), and 2-chloro-1-methyl-pyridin-1-ium iodide (5.65 g, 22.1 mmol) in tetrahydrofuran (50.0 mL), N,N-diisopropylethylamine (3.79 mL, 22.1 mmol) was added, 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 solution (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was diluted with methanol (100 mL), filtered, washed with methanol (50 mL), and the solid was concentrated under reduced pressure to give the title compound as a colorless solid (1.73 g, 66% yield). 1 HNMR (400 MHz, CDCl3) δ 9.20 (s, 2H), 7.78 (d, J = 4.8 Hz, 1H), 7.37 (s,1H), 7.28 (d, J = 5.1 Hz, 1H), 3.92-3.73 (m, 4H), 3.37-3.26 (m, 1H), 2.42-2.30 (m,2H), 1.41 (d, J = 6.9 Hz, 6H). MS (ES+) m / z 474.4 (M + 1).

[0297] Step 4: Preparation of N-[2-(3,3-difluoropyrrolidin-1-yl)-4-(2-pyridyl)-3-pyridyl]-2-isopropyl-pyrimidine-5-carboxamide [ka] To a solution of N-[2-(3,3-difluoropyrrolidin-1-yl)-4-iodo-3-pyridyl]-2-isopropyl-pyrimidine-5-carboxamide (0.100 g, 0.211 mmol), 2-(1,1,1-tributylstannyl)pyridine (0.0820 mL, 0.254 mmol), and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.0550 mg, 0.127 mmol) in degassed 1,4-dioxane (2.00 mL), palladium acetate (0.014 mg, 0.063 mmol) was added, and the mixture was stirred at 100 °C for 16 hours. After cooling to ambient temperature, the mixture was diluted with ethyl acetate (10 mL). The mixture was passed through a bed of diatomaceous earth (i.e., Celite®). The solid was washed with ethyl acetate (20 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of 0-10% methanol in dichloromethane, followed by reverse-phase preparative HPLC eluting with a gradient of 38-48% acetonitrile in water containing 10 mM ammonium formate to give the title compound as a solid (0.0100 g, 11% yield). 1 HNMR (400 MHz;DMSO-d6) δ 10.33 (s, 1H), 9.00 (s, 2H), 8.65-8.55 (m, 1H),8.12 (s, 1H), 7.84-7.59 (m, 2H), 7.34-7.21 (m, 1H), 6.97 (d, J = 5.0 Hz, 1H), 3.91(t, J = 13.6 Hz, 2H), 3.75 (t, J = 7.1 Hz, 2H), 3.17 (dt, J = 13.8, 6.9 Hz, 1H),2.40 (tt, J = 14.2, 7.1 Hz, 2H), 1.28 (d, J = 6.9 Hz, 6H). MS (ES+) m / z 425.3 (M+ 1).

[0298] Example 33: Synthesis of N-[2-(3,3-difluoropyrrolidin-1-yl)-4-(2-methylpyrazol-3-yl)-3-pyridyl]-2-isopropyl-pyrimidine-5-carboxamide [ka] To a solution of N-[2-(3,3-difluoropyrrolidin-1-yl)-4-iodo-3-pyridyl]-2-isopropyl-pyrimidine-5-carboxamide (0.0500 mg, 0.106 mmol), (1-methyl-1H-pyrazol-5-yl)boronic acid (0.0200 mg, 0.158 mmol), and potassium carbonate (0.0360 mg, 0.264 mmol) in degassed 1,4-dioxane (1.00 mL) and water (0.300 mL), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.0250 g, 0.0310 mmol) was added, and the mixture was stirred at 100° C. for 16 hours. After cooling to ambient temperature, the mixture was diluted with ethyl acetate (10 mL). The mixture was passed through a bed of diatomaceous earth (i.e., Celite®). The solid was washed with ethyl acetate (20 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of 0-10% methanol in dichloromethane, followed by reverse-phase preparative HPLC eluting with a gradient of 30-40% acetonitrile in water containing 10 mM ammonium formate to afford the title compound as a solid (0.0200 g, 44% yield). 1 HNMR (400 MHz;DMSO-d6) δ 10.19 (s, 1H), 8.96 (s, 2H), 8.12 (s, 1H), 7.30(s, 1H), 6.74 (s, 1H), 6.21 (s, 1H), 4.03-3.83 (m, 2H), 3.74 (dd, J = 15.6, 6.2Hz, 2H), 3.68 (s, 3H), 3.14 (ddd, J = 15.5, 9.5, 5.7 Hz, 1H), 2.44-2.24 (m, 2H),1.28 (d, J = 6.9 Hz, 6H). MS (ES+) m / z 428.3 (M + 1).

[0299] Example 34: Synthesis of N-[2-(3,3-difluoropyrrolidin-1-yl)-4-(1H-indazol-5-yl)-3-pyridyl]-2-isopropyl-pyrimidine-5-carboxamide [ka] To a solution of N-[2-(3,3-difluoropyrrolidin-1-yl)-4-iodo-3-pyridyl]-2-isopropyl-pyrimidine-5-carboxamide (0.0500 g, 0.100 mmol), 1H-indazol-5-ylboronic acid (0.0340 g, 0.200 mmol), and potassium carbonate (0.0350 g, 0.253 mmol) in 1,4-dioxane (1.00 mL) and water (0.300 mL), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.0250 g, 0.0306 mmol) was added, and the mixture was stirred at 100 °C for 2 hours. After cooling to ambient temperature, the mixture was diluted with ethyl acetate (10 mL). The mixture was filtered through a bed of diatomaceous earth (i.e., Celite®). The solid was washed with ethyl acetate (50 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of 0-10% methanol in dichloromethane, followed by reverse-phase preparative HPLC eluting with a gradient of 31-41% acetonitrile in water containing 10 mM ammonium formate to give the title compound as a colorless solid (0.0220 g, 47% yield). 1HNMR (400 MHz;DMSO-d6) δ 13.04 (s, 1H), 10.12 (s, 1H), 8.86 (s, 2H), 8.14(d, J = 5.0 Hz, 1H), 8.03 (s, 1H), 7.73 (s, 1H), 7.48 (d, J = 8.7 Hz, 1H), 7.34(dd, J = 8.6, 1.6 Hz, 1H), 6.80 (d, J = 5.0 Hz, 1H), 3.97-3.57 (m, 4H), 3.15-3.01(m, 1H), 2.43-2.31 (m, 2H), 1.19 (d, J = 6.9 Hz, 6H). MS (ES+) m / z 464.3 (M + 1).

[0300] Example 35: Synthesis of N-(2-(3,3-difluoropyrrolidin-1-yl)-4-((dimethyl(oxo)-λ6-sulfanylidene)amino)pyridin-3-yl)-2-isopropylpyrimidine-5-carboxamide [ka] To a solution of 2-[2-(3,3-difluoropyrrolidin-1-yl)-4-iodo-3-pyridyl]-1,4,6,7-tetrahydropyrano[3,4-d]imidazole (0.0600 g, 0.127 mmol), imino-dimethyl-oxo-λ-sulfane (0.0120 mL, 0.152 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.0120 g, 0.0130 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.0150 g, 0.0260 mmol) in 1,4-dioxane (1.20 mL) was added sodium tert-butoxide (0.0240 g, 0.0250 mmol), and the mixture was stirred at 100° C. for 1 hour. After cooling to ambient temperature, the mixture was diluted with ethyl acetate (50 mL). The mixture was filtered through a bed of diatomaceous earth (i.e., Celite®). The solid was washed with ethyl acetate (50 mL) and methanol (30 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of 0-20% methanol in dichloromethane, followed by reverse-phase preparative HPLC eluting with a gradient of 18-28% acetonitrile in water containing 10 mM ammonium formate to afford the title compound as a colorless solid (0.0300 g, 47% yield). 1 HNMR (400 MHz, DMSO-d6)δ 9.65 (s, 1H), 9.19 (s, 2H), 7.84 (d, J = 5.5Hz, 1H), 6.64 (d, J = 5.4 Hz, 1H), 3.91-3.61 (m, 4H), 3.26-3.19 (m, 1H), 3.17 (s,6H), 2.38 (ddd, J = 21.4, 14.2, 7.1 Hz, 2H), 1.31 (d, J = 6.9 Hz, 6H). MS (ES+) m / z439.3 (M + 1).

[0301] Example 36: Synthesis of N-[4-(1H-benzimidazol-5-yl)-2-(3,3-difluoropyrrolidin-1-yl)-3-pyridyl]-2-isopropyl-pyrimidine-5-carboxamide [ka] To a solution of N-[2-(3,3-difluoropyrrolidin-1-yl)-4-iodo-3-pyridyl]-2-isopropyl-pyrimidine-5-carboxamide (0.0500 g, 0.100 mmol), 1H-benzimidazol-5-ylboronic acid (0.0340 g, 0.200 mmol), and potassium carbonate (0.0350 g, 0.253 mmol) in 1,4-dioxane (1.00 mL) and water (0.300 mL), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.0250 g, 0.0306 mmol) was added, and the mixture was stirred at 100° C. for 2 hours. After cooling to ambient temperature, the mixture was diluted with ethyl acetate (10 mL). The mixture was filtered through a bed of diatomaceous earth (i.e., Celite®). The solid was washed with ethyl acetate (30 mL) and methanol (20 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of 0-10% methanol in dichloromethane, followed by reverse-phase preparative HPLC eluting with a gradient of 29-39% acetonitrile in water containing 10 mM ammonium formate to afford the title compound as a colorless solid (0.0180 g, 41% yield). 1 HNMR (400 MHz;DMSO-d6)δ 12.50 (d, J = 19.7 Hz, 1H), 10.16 (s, 1H), 8.91(d, J = 4.0 Hz, 2H), 8.21 (s, 1H), 8.19 (d, J = 2.8 Hz, 1H), 7.74-7.61 (m, 1H),7.52 (d, J = 8.7 Hz, 1H), 7.30-7.18 (m, 1H), 6.86 (d, J = 5.0 Hz, 1H), 4.12-3.59(m, 4H), 3.20-3.08 (m, 1H), 2.42 (ddd, J = 16.5, 12.0, 4.9 Hz, 2H), 1.25 (d, J =6.9 Hz, 6H). MS (ES+) m / z 464.3 (M + 1).

[0302] Example 37: Synthesis of N-[4-(6-amino-3-pyridyl)-2-(3,3-difluoropyrrolidin-1-yl)-3-pyridyl]-2-isopropyl-pyrimidine-5-carboxamide [ka] To a solution of N-[2-(3,3-difluoropyrrolidin-1-yl)-4-iodo-3-pyridyl]-2-isopropyl-pyrimidine-5-carboxamide (0.0500 g, 0.100 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (0.0470 g, 0.203 mmol), and potassium carbonate (0.0350 g, 0.253 mmol) in 1,4-dioxane (1.00 mL) and water (0.300 mL), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.025 g, 0.0306 mmol) was added, and the mixture was stirred at 90 ° C. for 1 hour. After cooling to ambient temperature, the mixture was diluted with ethyl acetate (10 mL). The mixture was filtered through a bed of diatomaceous earth (i.e., Celite®). The solid was washed with ethyl acetate (20 mL) and methanol (20 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of 0-10% methanol in dichloromethane, followed by reverse-phase preparative HPLC eluting with a gradient of 28-38% acetonitrile in water containing 10 mM ammonium formate to afford the title compound as a colorless solid (0.0350 g, 78% yield). 1HNMR (400 MHz;DMSO-d6) δ 10.11 (s, 1H), 8.98 (s, 2H), 8.09 (d, J = 5.0Hz, 1H), 7.93 (d, J = 1.8 Hz, 1H), 7.39 (dd, J = 8.6, 2.5 Hz, 1H), 6.73 (d, J =5.0 Hz, 1H), 6.49-6.21 (m, 1H), 6.03 (s, 2H), 4.01-3.47 (m, 4H), 3.20-3.10 (m, 1H),2.37 (dq, J = 21.7, 7.1 Hz, 2H), 1.24 (d, J = 6.9 Hz, 6H). MS (ES+) m / z 440.3 (M+ 1).

[0303] Example 38: Synthesis of N-[2-(3,3-difluoropyrrolidin-1-yl)-4-(3-fluorophenyl)-3-pyridyl]-2-isopropyl-pyrimidine-5-carboxamide [ka] To a solution of N-[2-(3,3-difluoropyrrolidin-1-yl)-4-iodo-3-pyridyl]-2-isopropyl-pyrimidine-5-carboxamide (0.0500 g, 0.100 mmol), (3-fluorophenyl)boronic acid (0.0300 g, 0.204 mmol), and potassium carbonate (0.0350 g, 0.253 mmol) in 1,4-dioxane (1.200 mL) and water (0.400 mL), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.0250 g, 0.0306 mmol) was added, and the mixture was stirred at 100 °C for 1 hour. After cooling to ambient temperature, the mixture was diluted with ethyl acetate (10 mL). The mixture was filtered through a bed of diatomaceous earth (i.e., Celite®). The solid was washed with ethyl acetate (30 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of 0-10% methanol in dichloromethane, followed by reverse-phase preparative HPLC eluting with a gradient of 49-59% acetonitrile in water containing 10 mM ammonium formate to give the title compound as a colorless solid (0.0360 g, 81% yield). 1 HNMR (400 MHz;DMSO-d6) δ 10.19 (s, 1H), 8.94 (s, 2H), 8.21 (d, J = 5.0Hz, 1H), 7.43 (td, J = 8.0, 6.1 Hz, 1H), 7.32-7.09 (m, 3H), 6.83 (d, J = 5.0 Hz,1H), 3.83 (d, J = 58.1 Hz, 4H), 3.24-3.12 (m, 1H), 2.49-2.36 (m, 2H), 1.27 (d, J= 6.9 Hz, 6H). MS (ES+) m / z 442.3 (M + 1).

[0304] Example 39: Synthesis of N-[4-(2,3-difluorophenyl)-2-(3,3-difluoropyrrolidin-1-yl)-3-pyridyl]-2-isopropyl-pyrimidine-5-carboxamide [ka] To a solution of N-[2-(3,3-difluoropyrrolidin-1-yl)-4-iodo-3-pyridyl]-2-isopropyl-pyrimidine-5-carboxamide (0.0500 g, 0.100 mmol), (2,3-difluorophenyl)boronic acid (0.033 g, 0.199 mmol), and potassium carbonate (0.0350 g, 0.253 mmol) in 1,4-dioxane (1.200 mL) and water (0.400 mL), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.0250 g, 0.0306 mmol) was added, and the mixture was stirred at 70 ° C. for 20 minutes. After cooling to ambient temperature, the mixture was diluted with ethyl acetate (10 mL). The mixture was filtered through a bed of diatomaceous earth (i.e., Celite®). The solid was washed with ethyl acetate (30 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of 0-10% methanol in dichloromethane, followed by reverse-phase preparative HPLC eluting with a gradient of 50-60% acetonitrile in water containing 10 mM ammonium formate to give the title compound as a colorless solid (0.0380 g, 82% yield). 1 HNMR (400 MHz;DMSO-d6) δ 10.18 (s, 1H), 8.85 (s, 2H), 8.18 (d, J = 4.9Hz, 1H), 7.35 (dd, J = 17.3, 9.0 Hz, 1H), 7.15 (dd, J = 12.6, 8.7 Hz, 1H), 7.06(t, J = 6.1 Hz, 1H), 6.81 (d, J = 4.9 Hz, 1H), 3.99-3.53 (m, 4H), 3.19-3.05 (m,1H), 2.43-2.33 (m, 2H), 1.22 (d, J = 6.9 Hz, 6H). MS (ES+) m / z 460.2 (M + 1).

[0305] Example 40: Synthesis of N-[2-(3,3-difluoropyrrolidin-1-yl)-4-(6-fluoro-1H-indazol-5-yl)-3-pyridyl]-2-isopropyl-pyrimidine-5-carboxamide [ka] Step 1: Preparation of 6-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole [ka] To a solution of 5-bromo-6-fluoro-1H-indazole (0.500 g, 2.33 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.29 g, 5.12 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.380 g, 0.460 mmol) in 1,4-dioxane (6.00 mL) was added potassium acetate (685 g, 6.98 mmol), and the mixture was stirred at 100 °C for 20 hours. After cooling to ambient temperature, the mixture was diluted with ethyl acetate (25 mL) and passed through a bed of diatomaceous earth (i.e., Celite®). The solid was washed with ethyl acetate (50 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of 0-100% methanol in dichloromethane to give the title compound as a brown oil (50% purity, 0.776 g, 63% yield). 1 HNMR (300 MHz;DMSO-d6) δ 13.12 (s, 1H), 8.10 (s, 1H), 7.80 (dd, J = 8.8,5.3 Hz, 1H), 7.00 (td, J = 9.2, 2.2 Hz, 1H), 1.16 (s, 12H). MS (ES+) m / z 263.1 (M+ 1).

[0306] Step 2: Preparation of N-[2-(3,3-difluoropyrrolidin-1-yl)-4-(6-fluoro-1H-indazol-5-yl)-3-pyridyl]-2-isopropyl-pyrimidine-5-carboxamide [ka] To a solution of N-[2-(3,3-difluoropyrrolidin-1-yl)-4-iodo-3-pyridyl]-2-isopropyl-pyrimidine-5-carboxamide (0.0750 g, 0.158 mmol), 6-fluoro-4-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl]-1H-indazole (50% pure, 0.175 g, 0.317 mmol), and potassium carbonate (0.0540 g, 0.396 mmol) in degassed 1,4-dioxane (1.50 mL) and water (0.450 mL), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.0380 g, 0.0470 mmol) was added, and the mixture was stirred at 100° C. for 48 hours. After cooling to ambient temperature, the mixture was diluted with ethyl acetate (10 mL). The mixture was passed through a bed of diatomaceous earth (i.e., Celite®). The solid was washed with ethyl acetate (20 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of 0-10% methanol in dichloromethane, followed by reverse-phase preparative HPLC eluting with a gradient of 35-45% acetonitrile in water containing 10 mM ammonium formate to afford the title compound as a solid (0.0190 g, 25% yield). 1 HNMR (500 MHz;DMSO-d6) δ 13.15 (s, 1H), 10.18 (s, 1H), 8.84 (s, 2H), 8.22(d, J = 5.0 Hz, 1H), 8.09 (s, 1H), 7.70 (d, J = 7.0 Hz, 1H), 7.40 (d, J = 10.4 Hz,1H), 6.85 (d, J = 4.9 Hz, 1H), 3.90 (bs, 2H), 3.76 (bs, 2H), 3.13 (dt, J = 13.8,6.9 Hz, 1H), 2.49-2.38 (m, 2H), 1.24 (d, J = 6.9 Hz, 6H). MS (ES+) m / z 482.2 (M +1).

[0307] Example 41: Synthesis of N-[2-(3,3-difluoropyrrolidin-1-yl)-4-(4-fluoro-1H-indazol-5-yl)-3-pyridyl]-2-isopropyl-pyrimidine-5-carboxamide [ka] Step 1: Preparation of 4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole [ka] To a solution of 5-bromo-4-fluoro-1H-indazole (0.750 g, 3.49 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.94 g, 7.67 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.570 g, 0.698 mmol) in 1,4-dioxane (6.00 mL) was added potassium acetate (1.02 g, 10.5 mmol), and the mixture was stirred at 100 °C for 20 hours. After cooling to ambient temperature, the mixture was diluted with ethyl acetate (50 mL) and passed through a bed of diatomaceous earth (i.e., Celite®). The solid was washed with ethyl acetate (50 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of 0-100% methanol in dichloromethane to give the title compound as a brown oil (50% purity, 960 mg, 52% yield). 1 HNMR (300 MHz;DMSO-d6) δ 13.39 (s, 1H), 7.93 (s, 1H), 7.53 (dd, J = 8.3,5.3 Hz, 1H), 6.88 (dd, J = 10.6, 7.5 Hz, 1H), 1.07 (s, 12H). MS (ES+) m / z 263.1 (M+ 1).

[0308] Step 2: Preparation of N-[2-(3,3-difluoropyrrolidin-1-yl)-4-(4-fluoro-1H-indazol-5-yl)-3-pyridyl]-2-isopropyl-pyrimidine-5-carboxamide [ka] To a solution of N-[2-(3,3-difluoropyrrolidin-1-yl)-4-iodo-3-pyridyl]-2-isopropyl-pyrimidine-5-carboxamide (0.0750 g, 0.158 mmol), 4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (50% pure, 0.166 g, 0.317 mmol), and potassium carbonate (0.0540 g, 0.396 mmol) in degassed 1,4-dioxane (1.50 mL) and water (0.450 mL), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.0380 g, 0.0470 mmol) was added, and the mixture was stirred at 100° C. for 48 hours. After cooling to ambient temperature, the mixture was diluted with ethyl acetate (10 mL). The mixture was passed through a bed of diatomaceous earth (i.e., Celite®). The solid was washed with ethyl acetate (20 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of 0-10% methanol in dichloromethane, followed by reverse-phase preparative HPLC eluting with a gradient of 36-46% acetonitrile in water containing 10 mM ammonium formate to afford the title compound as a solid (0.0270 g, 35% yield). 1HNMR (500 MHz;DMSO-d6) δ 13.42 (s, 1H), 10.18 (s, 1H), 8.86 (s, 2H), 8.29-8.14(m, 2H), 7.46-7.31 (m, 1H), 7.25 (d, J = 7.1 Hz, 1H), 6.87 (d, J = 4.9 Hz, 1H),3.91 (s, 2H), 3.76 (s, 2H), 3.14 (dt, J = 13.8, 6.9 Hz, 1H), 2.44 (dt, J = 21.2,7.0 Hz, 2H), 1.24 (d, J = 6.9 Hz, 6H). MS (ES+) m / z 482.3 (M + 1).

[0309] Example 42: Synthesis of N-[2-(3,3-difluoropyrrolidin-1-yl)-4-(1H-pyrazol-5-yl)-3-pyridyl]-2-isopropyl-pyrimidine-5-carboxamide [ka] To a solution of N-[2-(3,3-difluoropyrrolidin-1-yl)-4-iodo-3-pyridyl]-2-isopropyl-pyrimidine-5-carboxamide (0.0500 g, 0.100 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.0410 g, 0.201 mmol), and potassium carbonate (0.0350 g, 0.253 mmol) in 1,4-dioxane (1.20 mL) and water (0.400 mL), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.025 g, 0.0306 mmol) was added, and the mixture was stirred at 100° C. for 2 hours. After cooling to ambient temperature, the mixture was diluted with ethyl acetate (10 mL). The mixture was filtered through a bed of diatomaceous earth (i.e., Celite®). The solids were washed with ethyl acetate (50 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of 0-15% methanol in dichloromethane, followed by reverse-phase preparative HPLC eluting with a gradient of 50-60% acetonitrile in water containing 10 mM ammonium formate to afford the title compound as a colorless solid (0.0230 g, 55% yield). 1 H NMR (400 MHz;DMSO-d6)δ13.09 (bs, 1H), 10.23 (s, 1H), 9.17 (s, 2H), 8.09 (d, J = 5.4 Hz,1H), 7.91-7.51 (m, 1H), 7.14 (d, J = 3.3 Hz, 1H), 6.81-6.43 (m, 1H), 4.12-3.50 (m,4H), 3.23-3.13 (m, 1H), 2.36 (septet, J = 7.9 Hz, 2H), 1.27 (d, J = 6.9 Hz, 6H). MS(ES+) m / z 414.3 (M + 1).

[0310] Example 43: Synthesis of N-[4-(cyclopenten-1-yl)-2-(3,3-difluoropyrrolidin-1-yl)-3-pyridyl]-2-isopropyl-pyrimidine-5-carboxamide [ka] To a solution of N-[2-(3,3-difluoropyrrolidin-1-yl)-4-iodo-3-pyridyl]-2-isopropyl-pyrimidine-5-carboxamide (0.150 g, 0.301 mmol), 2-(cyclopenten-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.123 g, 0.602 mmol), and potassium carbonate (0.104 g, 0.753 mmol) in 1,4-dioxane (3.00 mL) and water (0.900 mL), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.074 g, 0.0903 mmol) was added, and the mixture was stirred at 80° C. for 2 hours. After cooling to ambient temperature, the mixture was diluted with ethyl acetate (10 mL). The mixture was filtered through a bed of diatomaceous earth (i.e., Celite®). The solid was washed with ethyl acetate (40 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of 0-5% methanol in dichloromethane to give the title compound as a brown solid (0.129 g, 93% yield). The residue (0.0300 g) was purified by reverse-phase preparative HPLC eluting with a gradient of 49-59% acetonitrile in water containing 10 mM ammonium formate to give the title compound as a colorless solid (0.0200 g). 1 HNMR (400 MHz;DMSO-d6)δ 10.13 (s, 1H), 9.19 (s, 2H), 8.06 (d, J = 5.0Hz, 1H), 6.78 (d, J = 5.1 Hz, 1H), 6.08-5.96 (m, 1H), 3.92-3.63 (m, 4H), 3.23 (septet, J = 6.9 Hz, 1H), 2.62-2.51 (m, 2H), 2.50-2.28 (m, 4H), 1.81 (p, J = 7.5 Hz, 2H),1.32 (d, J = 6.9 Hz, 6H). MS (ES+) m / z 414.3 (M + 1).

[0311] Example 44: Synthesis of N-[2-(3,3-difluoropyrrolidin-1-yl)-4-(5-fluoro-2-methoxy-phenyl)-3-pyridyl]-2-isopropyl-pyrimidine-5-carboxamide [ka] To a solution of N-[2-(3,3-difluoropyrrolidin-1-yl)-4-iodo-3-pyridyl]-2-isopropyl-pyrimidine-5-carboxamide (0.0500 g, 0.100 mmol), (5-fluoro-2-methoxy-phenyl)boronic acid (0.0360 g, 0.201 mmol), and potassium carbonate (0.0350 g, 0.253 mmol) in 1,4-dioxane (1.200 mL) and water (0.400 mL), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.0250 g, 0.0306 mmol) was added, and the mixture was stirred at 90° C. for 1 hour. After cooling to ambient temperature, the mixture was diluted with ethyl acetate (10 mL). The mixture was filtered through a bed of diatomaceous earth (i.e., Celite®). The solids were washed with ethyl acetate (50 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of 0-10% methanol in dichloromethane, followed by reverse-phase preparative HPLC eluting with a gradient of 45-55% acetonitrile in water containing 10 mM ammonium formate to afford the title compound as a colorless solid (0.032 g, 62% yield). 1HNMR (400 MHz;DMSO-d6) δ 9.94 (s, 1H), 8.84 (s, 2H), 8.16 (d, J = 4.9Hz, 1H), 7.18-7.08 (m, 1H), 7.04 (dd, J = 9.2, 4.6 Hz, 1H), 7.00-6.87 (m, 1H), 6.73(d, J = 4.9 Hz, 1H), 4.01-3.71 (m, 4H), 3.69 (s, 3H), 3.22-3.12 (m, 1H), 2.42 (dt,J = 21.8, 7.1 Hz, 2H), 1.27 (d, J = 6.9 Hz, 6H). MS (ES+) m / z 472.3 (M + 1).

[0312] Example 45: Synthesis of N-[2-(3,3-difluoropyrrolidin-1-yl)-4-(5-fluoro-2-methyl-phenyl)-3-pyridyl]-2-isopropyl-pyrimidine-5-carboxamide [ka] To a solution of N-[2-(3,3-difluoropyrrolidin-1-yl)-4-iodo-3-pyridyl]-2-isopropyl-pyrimidine-5-carboxamide (0.0500 g, 0.100 mmol), (5-fluoro-2-methyl-phenyl)boronic acid (0.0330 g, 0.201 mmol), and potassium carbonate (0.0350 g, 0.253 mmol) in 1,4-dioxane (1.20 mL) and water (0.400 mL), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.0250 g, 0.0301 mmol) was added, and the mixture was stirred at 90 ° C. for 1 hour. After cooling to ambient temperature, the mixture was diluted with ethyl acetate (10 mL). The mixture was filtered through a bed of diatomaceous earth (i.e., Celite®). The solid was washed with ethyl acetate (50 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of 0-10% methanol in dichloromethane, followed by reverse-phase preparative HPLC eluting with a gradient of 45-55% acetonitrile in water containing 10 mM ammonium formate to give the title compound as a colorless solid (0.0320 g, 62% yield). 1 HNMR (400 MHz;DMSO-d6)δ 10.01 (s, 1H), 8.77 (s, 2H), 8.19 (d, J = 5.0Hz, 1H), 7.33-7.14 (m, 1H), 7.03 (dd, J = 8.6, 5.8 Hz, 1H), 6.98-6.80 (m, 1H), 6.72(d, J = 5.2 Hz, 1H), 4.03-3.62 (m, 4H), 3.16 (dt, J = 13.8, 6.8 Hz, 1H), 2.49-2.37(m, 2H), 2.08 (s, 3H), 1.25 (d, J = 6.9 Hz, 6H). MS (ES+) m / z 456.3 (M + 1).

[0313] Example 46: Synthesis of N-[4-cyclopentyl-2-(3,3-difluoropyrrolidin-1-yl)-3-pyridyl]-2-isopropyl-pyrimidine-5-carboxamide [ka] To a solution of palladium (10% in a carbon matrix, 0.0610 g, 0.0570 mmol) in methanol (1.00 mL) was added a solution of N-[4-(cyclopenten-1-yl)-2-(3,3-difluoropyrrolidin-1-yl)-3-pyridyl]-2-isopropyl-pyrimidine-5-carboxamide (0.0500 g, 0.120 mmol) in methanol (1.00 mL). The mixture was stirred under hydrogen at 22° C. for 1 hour. The mixture was diluted with dichloromethane (10 mL) and filtered through a bed of diatomaceous earth (i.e., Celite®). The solid was washed with dichloromethane (50 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC eluting with a gradient of 49-59% acetonitrile in water containing 10 mM ammonium formate to give the title compound as a solid (0.0250 g, 52% yield). 1 HNMR (400 MHz;DMSO-d6) δ 10.14 (s, 1H), 9.25 (s, 2H), 8.06 (d, J = 5.1Hz, 1H), 6.81 (d, J = 5.3 Hz, 1H), 3.95-3.57 (m, 4H), 3.23 (dq, J = 13.8, 6.9 Hz,1H), 3.10-3.02 (m, 1H), 2.39 (tt, J = 14.0, 7.1 Hz, 2H), 1.96-1.83 (m, 2H), 1.78-1.62(m, 2H), 1.60-1.43 (m, 4H), 1.32 (d, J = 6.9 Hz, 6H). MS (ES+) m / z 416.3 (M + 1).

[0314] Example 47: Synthesis of N-[2-(3,3-difluoropyrrolidin-1-yl)-4-(1-methylpyrazol-3-yl)-3-pyridyl]-2-isopropyl-pyrimidine-5-carboxamide [ka] To a solution of N-[2-(3,3-difluoropyrrolidin-1-yl)-4-iodo-3-pyridyl]-2-isopropyl-pyrimidine-5-carboxamide (0.0500 g, 0.100 mmol), (1-methylpyrazol-3-yl)boronic acid (0.0266 g, 0.201 mmol), and potassium carbonate (0.0347 g, 0.251 mmol) in 1,4-dioxane (1.20 mL) and water (0.400 mL), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.0246 g, 0.0306 mmol) was added, and the mixture was stirred at 90 ° C. for 1 hour. After cooling to ambient temperature, the mixture was diluted with ethyl acetate (10 mL). The mixture was filtered through a bed of diatomaceous earth (i.e., Celite®). The solid was washed with ethyl acetate (30 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of 0-10% methanol in dichloromethane, followed by reverse-phase preparative HPLC eluting with a gradient of 33-43% acetonitrile in water containing 10 mM ammonium formate to give the title compound as a colorless solid (0.0336 g, 78% yield). 1 HNMR (400 MHz;DMSO-d6) δ 10.24 (s, 1H), 9.22 (s, 2H), 8.13 (d, J = 5.1Hz, 1H), 7.70 (d, J = 2.2 Hz, 1H), 7.16 (d, J = 5.2 Hz, 1H), 6.60 (d, J = 2.3 Hz,1H), 3.96-3.66 (m, 4H), 3.78 (s, 3H), 3.28-3.18 (m, 1H), 2.47-2.35 (m, 2H), 1.32(d, J = 6.9 Hz, 6H). MS (ES+) m / z 428.3 (M + 1).

[0315] Example 48: Synthesis of N-[2-(3,3-difluoropyrrolidin-1-yl)-4-(4-fluoro-2-methyl-pyrazol-3-yl)-3-pyridyl]-2-isopropyl-pyrimidine-5-carboxamide [ka] Step 1: Preparation of 4-fluoro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole [ka] To a solution of 5-bromo-4-fluoro-1-methyl-pyrazole (0.330 g, 1.84 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.03 g, 4.06 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.301 g, 0.369 mmol) in 1,4-dioxane (4.76 mL), potassium acetate (0.543 g, 5.53 mmol) was added, and the mixture was stirred at 100 ° C. for 20 hours. After cooling to ambient temperature, the mixture was diluted with EtOAc (20 mL). The mixture was filtered through a bed of diatomaceous earth (i.e., Celite®). The solid was washed with EtOAc (20 mL) and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of 0-10% methanol in dichloromethane to give the title compound as a colorless solid (60% purity, 261 mg, 34%). 1 HNMR (300 MHz;CDCl3) δ 7.28 (d, J = 4.4 Hz, 1H), 3.98 (s, 3H), 1.35 (s,12H); 19 F NMR (376 MHz; CDCl3) δ -166.15 (d, J = 4.4 Hz).

[0316] Step 2: Preparation of N-[2-(3,3-difluoropyrrolidin-1-yl)-4-(4-fluoro-2-methyl-pyrazol-3-yl)-3-pyridyl]-2-isopropyl-pyrimidine-5-carboxamide [ka] To a solution of N-[2-(3,3-difluoropyrrolidin-1-yl)-4-iodo-3-pyridyl]-2-isopropyl-pyrimidine-5-carboxamide (0.0500 g, 0.100 mmol), 4-fluoro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (60% purity, 0.0756 g, 0.201 mmol), and potassium carbonate (0.0347 g, 0.251 mmol) in 1,4-dioxane (1.20 mL) and water (0.400 mL), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.0246 g, 0.0306 mmol) was added, and the mixture was stirred at 90 °C for 3 hours. 4-Fluoro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (60% purity, 0.184 g, 0.489 mmol), potassium carbonate (0.0694 g, 0.502 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.0246 g, 0.0306 mmol) were added, and the mixture was stirred at 100 °C for 72 hours. After cooling to ambient temperature, the mixture was diluted with ethyl acetate (10 mL). The mixture was filtered through a bed of diatomaceous earth (i.e., Celite®). The solid was washed with ethyl acetate (30 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of 0-10% methanol in dichloromethane followed by reverse-phase preparative HPLC eluting with a gradient of 37-47% acetonitrile in water containing 10 mM ammonium formate to give the title compound as a white solid (0.007 g, 16% yield). 1HNMR (400 MHz;DMSO-d6) δ 10.36 (s, 1H), 8.99 (s, 2H), 8.28 (d, J = 4.9Hz, 1H), 7.44 (d, J = 4.3 Hz, 1H), 6.95 (d, J = 4.9 Hz, 1H), 3.98-3.69 (m, 4H),3.65 (s, 3H), 3.19 (dt, J = 13.9, 6.9 Hz, 1H), 2.43 (td, J = 13.9, 6.8 Hz, 2H),1.29 (d, J = 6.9 Hz, 6H). MS (ES+) m / z 446.3 (M + 1).

[0317] Example 49: Synthesis of N-[4-(5-cyano-2-fluoro-phenyl)-2-(3,3-difluoropyrrolidin-1-yl)-3-pyridyl]-2-isopropyl-pyrimidine-5-carboxamide [ka] To a solution of N-[2-(3,3-difluoropyrrolidin-1-yl)-4-iodo-3-pyridyl]-2-isopropyl-pyrimidine-5-carboxamide (0.0500 g, 0.106 mmol), (5-cyano-2-fluoro-phenyl)boronic acid (0.0261 g, 0.158 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.0173 g, 0.0211 mmol) in 1,4-dioxane (1.00 mL) and water (0.250 mL), potassium carbonate (0.0365 g, 0.264 mmol) was added, and the mixture was stirred at 100 ° C. for 1 hour. After cooling to ambient temperature, the mixture was diluted with ethyl acetate (25 mL) and passed through a bed of diatomaceous earth (i.e., Celite®). The solid was washed with ethyl acetate (50 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography eluting with a gradient of 15 to 100% acetonitrile in water containing 10 mM ammonium bicarbonate, followed by reverse-phase preparative HPLC eluting with a gradient of 45 to 55% acetonitrile in water containing 10 mM ammonium formate to give the title compound as a colorless solid (0.0240 g, 48% yield). 1 HNMR (400 MHz;DMSO-d6) δ 10.25 (s, 1H), 8.90 (s, 2H), 8.25 (d, J = 5.0Hz, 1H), 7.96-7.87 (m, 1H), 7.83 (d, J = 4.7 Hz, 1H), 7.58-7.48 (m, 1H), 6.87 (d,J = 4.9 Hz, 1H), 4.00-3.83 (m, 2H), 3.76 (tt, J = 14.0, 7.1 Hz, 2H), 3.18 (dt, J= 13.8, 6.9 Hz, 1H), 2.44 (dd, J = 14.2, 7.0 Hz, 2H), 1.27 (d, J = 6.9Hz, 6H). MS(ES+) m / z 467.3 (M + 1).

[0318] Example 50: Synthesis of N-[2-(3,3-difluoropyrrolidin-1-yl)-4-(2-fluoro-5-methoxy-phenyl)-3-pyridyl]-2-isopropyl-pyrimidine-5-carboxamide [ka] To a solution of N-[2-(3,3-difluoropyrrolidin-1-yl)-4-iodo-3-pyridyl]-2-isopropyl-pyrimidine-5-carboxamide (0.0500 g, 0.106 mmol), (2-fluoro-5-methoxy-phenyl)boronic acid (0.0269 g, 0.158 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.0173 g, 0.0211 mmol) in 1,4-dioxane (1.00 mL) and water (0.250 mL), potassium carbonate (0.0365 g, 0.264 mmol) was added, and the mixture was stirred at 100 ° C. for 1 hour. After cooling to ambient temperature, the mixture was diluted with ethyl acetate (25 mL) and passed through a bed of diatomaceous earth (i.e., Celite®). The solid was washed with ethyl acetate (50 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography eluting with a gradient of 15 to 100% acetonitrile in water containing 10 mM ammonium bicarbonate, followed by reverse-phase preparative HPLC eluting with a gradient of 43 to 53% acetonitrile in water containing 10 mM ammonium formate to give the title compound as a colorless solid (0.0260 g, 52% yield). 1HNMR (400 MHz;DMSO-d6) δ 10.16 (s, 1H), 8.90 (s, 2H), 8.21 (d, J = 5.0Hz, 1H), 7.17 (t, J = 9.2 Hz, 1H), 6.90 (dt, J = 9.0, 3.8 Hz, 1H), 6.87-6.75 (m,2H), 4.00-3.82 (m, 2H), 3.77 (ddd, J = 23.6, 16.6, 7.1 Hz, 2H), 3.65 (s, 3H), 3.25-3.11(m, 1H), 2.43 (dt, J = 21.3, 7.2 Hz, 2H), 1.27 (d, J = 6.9Hz, 6H). MS (ES+) m / z472.2 (M + 1).

[0319] Example 51: Synthesis of N-[4-(5-chloro-2-fluoro-phenyl)-2-(3,3-difluoropyrrolidin-1-yl)-3-pyridyl]-2-isopropyl-pyrimidine-5-carboxamide [ka] To a solution of N-[2-(3,3-difluoropyrrolidin-1-yl)-4-iodo-3-pyridyl]-2-isopropyl-pyrimidine-5-carboxamide (0.0500 g, 0.106 mmol), (5-chloro-2-fluoro-phenyl)boronic acid (0.0184 g, 0.106 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.0173 g, 0.0211 mmol) in 1,4-dioxane (1.00 mL) and water (0.250 mL), potassium carbonate (0.0365 g, 0.264 mmol) was added, and the mixture was stirred at 100 ° C. for 2 hours. After cooling to ambient temperature, the mixture was diluted with ethyl acetate (25 mL) and passed through a bed of diatomaceous earth (i.e., Celite®). The solid was washed with ethyl acetate (50 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography eluting with a gradient of 15 to 100% acetonitrile in water containing 10 mM ammonium bicarbonate, followed by reverse-phase preparative HPLC eluting with a gradient of 28 to 38% acetonitrile in water containing 10 mM ammonium formate to give the title compound as a colorless solid (0.00800 g, 16% yield). 1 HNMR (400 MHz;DMSO-d6) δ 10.24 (s, 1H), 8.92 (s, 2H), 8.23 ​​(d, J = 5.0Hz, 1H), 7.39 (ddd, J = 28.1, 13.6, 7.6 Hz, 3H), 6.86 (d, J = 4.9 Hz, 1H), 4.01-3.84(m, 2H), 3.84-3.63 (m, 2H), 3.19 (dt, J = 13.8,6.8 Hz, 1H), 2.44 (dd, J = 14.1,6.9 Hz, 2H), 1.28 (d, J = 6.9 Hz, 6H). MS (ES+) m / z 476.2 (M + 1).

[0320] Example 52: Synthesis of N-[2-(3,3-difluoropyrrolidin-1-yl)-4-[2-fluoro-5-(methylcarbamoyl)phenyl]-3-pyridyl]-2-isopropyl-pyrimidine-5-carboxamide [ka] To a solution of N-[2-(3,3-difluoropyrrolidin-1-yl)-4-iodo-3-pyridyl]-2-isopropyl-pyrimidine-5-carboxamide (0.0500 g, 0.100 mmol), [2-fluoro-5-(methylcarbamoyl)phenyl]boronic acid (0.0416 g, 0.201 mmol), and potassium carbonate (0.0347 g, 0.251 mmol) in 1,4-dioxane (1.20 mL) and water (0.40 mL), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.0246 g, 0.0301 mmol) was added, and the mixture was stirred at 100° C. for 1 hour. After cooling to ambient temperature, the mixture was diluted with ethyl acetate (10 mL). The mixture was filtered through a bed of diatomaceous earth (i.e., Celite®). The solids were washed with ethyl acetate (30 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of 0-15% methanol in dichloromethane, followed by reverse-phase preparative HPLC eluting with a gradient of 36-46% acetonitrile in water containing 10 mM ammonium formate to afford the title compound as a colorless solid (0.024 g, 48% yield). 1 HNMR (400 MHz;DMSO-d6) δ 10.24 (s, 1H), 8.86 (s, 2H), 8.44 (d, J = 4.1Hz, 1H), 8.23 ​​(d, J = 4.9 Hz, 1H), 7.87-7.74 (m, 2H), 7.34 (t, J = 9.2 Hz, 1H),6.85 (d, J = 4.9 Hz, 1H), 4.01-3.61 (m, 4H), 3.15 (septet, J = 6.9 Hz, 1H), 2.74 (d,J = 4.5 Hz, 3H), 2.48-2.38 (m, 2H), 1.26 (d, J = 6.9 Hz, 6H). MS (ES+) m / z 499.3(M + 1).

[0321] Example 53: Synthesis of N-[2-(3,3-difluoropyrrolidin-1-yl)-4-[5-(dimethylcarbamoyl)-2-fluoro-phenyl]-3-pyridyl]-2-isopropyl-pyrimidine-5-carboxamide [ka] To a solution of N-[2-(3,3-difluoropyrrolidin-1-yl)-4-iodo-3-pyridyl]-2-isopropyl-pyrimidine-5-carboxamide (0.0500 g, 0.100 mmol), [5-(dimethylcarbamoyl)-2-fluoro-phenyl]boronic acid (0.0446 g, 0.201 mmol), and potassium carbonate (0.0347 g, 0.251 mmol) in 1,4-dioxane (1.20 mL) and water (0.400 mL), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.0246 g, 0.0301 mmol) was added, and the mixture was stirred at 100° C. for 1 hour. After cooling to ambient temperature, the mixture was diluted with ethyl acetate (10 mL). The mixture was filtered through a bed of diatomaceous earth (i.e., Celite®). The solid was washed with ethyl acetate (30 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of 0-10% methanol in dichloromethane, followed by reverse-phase preparative HPLC eluting with a gradient of 34-44% acetonitrile in water containing 10 mM ammonium formate to afford the title compound as a white solid (0.042 g, 81% yield). 1HNMR (400 MHz;DMSO-d6) δ 10.22 (s, 1H), 8.90 (s, 2H), 8.22 (d, J = 5.0Hz, 1H), 7.43-7.35 (m, 1H), 7.31 (dd, J = 11.9, 6.0 Hz, 2H), 6.85 (d, J = 5.1 Hz,1H), 4.03-3.70 (m, 4H), 3.24-3.11 (m, 1H), 2.91 (bs, 3H), 2.64 (bs, 3H), 2.49-2.34(m, 2H), 1.26 (d, J = 6.9 Hz, 6H). MS (ES+) m / z 513.3 (M + 1).

[0322] Example 54: Synthesis of N-[2-(3,3-difluoropyrrolidin-1-yl)-4-[2-fluoro-5-(hydroxymethyl)phenyl]-3-pyridyl]-2-isopropyl-pyrimidine-5-carboxamide [ka] To a solution of N-[2-(3,3-difluoropyrrolidin-1-yl)-4-iodo-3-pyridyl]-2-isopropyl-pyrimidine-5-carboxamide (0.0500 g, 0.100 mmol), [2-fluoro-5-(hydroxymethyl)phenyl]boronic acid (0.035.9 g, 0.201 mmol), and potassium carbonate (0.0347 g, 0.251 mmol) in 1,4-dioxane (1.20 mL) and water (0.400 mL), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.0246 g, 0.0306 mmol) was added, and the mixture was stirred at 100° C. for 1 hour. After cooling to ambient temperature, the mixture was diluted with ethyl acetate (10 mL). The mixture was filtered through a bed of diatomaceous earth (i.e., Celite®). The solids were washed with ethyl acetate (30 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of 0-10% methanol in dichloromethane, followed by reverse-phase preparative HPLC eluting with a gradient of 32-42% acetonitrile in water containing 10 mM ammonium formate to afford the title compound as a colorless solid (0.0368 g, 78% yield). 1 HNMR (400 MHz;DMSO-d6) δ 10.16 (s, 1H), 8.88 (s, 2H), 8.20 (d, J = 5.0Hz, 1H), 7.32-7.23 (m, 2H), 7.23-7.14 (m, 1H), 6.79 (d, J = 4.8 Hz, 1H), 5.23 (t,J = 5.5 Hz, 1H), 4.40 (d, J = 5.5 Hz, 2H), 4.07-3.56 (m, 4H), 3.23-3.09 (m, 1H),2.48-2.33 (m, 2H), 1.27 (d, J = 6.9Hz, 6H). MS (ES+) m / z 472.3 (M + 1).

[0323] Example 55: Synthesis of N-[2-(3,3-difluoropyrrolidin-1-yl)-4-[2-fluoro-5-(morpholinomethyl)phenyl]-3-pyridyl]-2-isopropyl-pyrimidine-5-carboxamide [ka] To a solution of N-[2-(3,3-difluoropyrrolidin-1-yl)-4-iodo-3-pyridyl]-2-isopropyl-pyrimidine-5-carboxamide (0.0500 g, 0.100 mmol), 4-[[4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]morpholine (0.0679 g, 0.201 mmol), and potassium carbonate (0.0347 g, 0.251 mmol) in 1,4-dioxane (1.20 mL) and water (0.400 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.0246 g, 0.0306 mmol), and the mixture was stirred at 100°C for 1 hour. After cooling to ambient temperature, the mixture was diluted with ethyl acetate (10 mL). The mixture was filtered through a bed of diatomaceous earth (i.e., Celite®). The solids were washed with ethyl acetate (30 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of 0-10% methanol in dichloromethane, followed by reverse-phase preparative HPLC eluting with a gradient of 43-53% acetonitrile in water containing 10 mM ammonium bicarbonate, reverse-phase chromatography eluting with a gradient of 5-100% acetonitrile in water containing 10 mM ammonium formate, and finally purified again by reverse-phase preparative HPLC eluting with a gradient of 43-53% acetonitrile in water containing 10 mM ammonium bicarbonate to give the title compound as a colorless solid (0.012 g, 23% yield). 1HNMR (400 MHz;DMSO-d6) δ 10.19 (s, 1H), 8.91 (s, 2H), 8.20 (d, J = 5.0Hz, 1H), 7.45-7.06 (m, 3H), 6.80 (dd, J = 5.0, 0.9 Hz, 1H), 4.11-3.51 (m, 4H), 3.44-3.34(m, 4H), 3.32 (s, 2H), 3.23-3.07 (m, 1H), 2.48-2.37 (m, 2H), 2.19-2.07 (m, 4H),1.26 (d, J = 6.9 Hz, 6H). MS (ES+) m / z 541.3 (M + 1).

[0324] Example 56: Synthesis of N-[2-(3,3-difluoropyrrolidin-1-yl)-4-(2-fluoro-5-methoxy-phenyl)-3-pyridyl]-6-isopropyl-pyridine-3-carboxamide [ka] Step 1: Preparation of 2-(3,3-difluoropyrrolidin-1-yl)-4-(2-fluoro-5-methoxy-phenyl)pyridin-3-amine [ka] To a solution of 2-(3,3-difluoropyrrolidin-1-yl)-4-iodo-pyridin-3-amine hydrochloride (0.800 g, 2.10 mmol), (2-fluoro-5-methoxy-phenyl)boronic acid (0.752 g, 4.20 mmol), and potassium carbonate (1.02 g, 7.36 mmol) in dioxane (25.1 mL) and water (8.38 mL), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.515 g, 0.631 mmol) was added, and the mixture was stirred at 100 °C for 2 hours. After cooling to ambient temperature, the mixture was diluted with saturated aqueous sodium bicarbonate (150 mL). The aqueous phase was extracted with ethyl acetate (3 × 100 mL). The organic phase was washed with brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of 0-40% ethyl acetate in hexane to give the title compound as a red oil (0.622 g, 82% yield). 1 HNMR (400 MHz;CDCl3) δ 7.82 (d, J = 5.0 Hz, 1H), 7.12 (t, J = 9.1 Hz,1H), 6.92 (ddd, J = 9.0, 3.9, 3.2 Hz, 1H), 6.86 (dd, J = 5.7, 3.2 Hz, 1H), 6.83(dd, J = 5.0, 0.7 Hz, 1H), 3.81 (s, 3H), 3.78 (s, 2H), 3.70 (t, J = 13.1 Hz, 2H),3.55 (t, J = 7.1 Hz, 2H), 2.44 (septet, J = 7.1 Hz, 2H). MS (ES+) m / z 324.5 (M + 1).

[0325] Step 2: Preparation of N-[2-(3,3-difluoropyrrolidin-1-yl)-4-(2-fluoro-5-methoxy-phenyl)-3-pyridyl]-6-isopropyl-pyridine-3-carboxamide [ka] To a solution of 2-(3,3-difluoropyrrolidin-1-yl)-4-(2-fluoro-5-methoxy-phenyl)pyridin-3-amine (0.0400 g, 0.111 mmol), 6-isopropylpyridine-3-carboxylic acid hydrochloride (0.0337 g, 0.167 mmol), and N,N-diisopropylethylamine (0.0762 mL, 0.445 mmol) in tetrahydrofuran (1.00 mL), 2-chloro-1-methyl-pyridin-1-ium iodide (0.114 g, 0.445 mmol) was added, and the mixture was stirred at 65 ° C. for 20 hours. After cooling to ambient temperature, the mixture was diluted with saturated aqueous sodium bicarbonate (15 mL), and the aqueous phase was extracted with ethyl acetate (3 × 15 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of 0-15% methanol in dichloromethane, followed by reverse-phase chromatography eluting with a gradient of 5-100% acetonitrile in water containing 10 mM ammonium bicarbonate to give the title compound as a colorless solid (0.045 g, 86% yield). 1 HNMR (400 MHz;DMSO-d6) δ 9.91 (s, 1H), 8.69 (d, J = 1.7 Hz, 1H), 8.14(d, J = 5.0 Hz, 1H), 7.90 (dd, J = 8.2, 2.4 Hz, 1H), 7.32 (d, J = 7.8 Hz, 1H), 7.11(t, J = 9.2 Hz, 1H), 6.89-6.81 (m, 1H), 6.78 (dd, J = 5.9, 3.2 Hz, 1H), 6.75 (d,J = 5.0 Hz, 1H), 4.03-3.62 (m, 4H), 3.59 (s, 3H), 3.00 (septet, J = 7.0 Hz, 1H), 2.38(dt, J = 21.3, 7.2 Hz, 2H), 1.18 (d, J = 6.9 Hz, 6H). MS (ES+) m / z 471.3 (M + 1).

[0326] Example 57: Synthesis of N-[2-(3,3-difluoropyrrolidin-1-yl)-4-(3-methoxyphenyl)-3-pyridyl]-2-isopropyl-pyrimidine-5-carboxamide [ka] To a solution of N-[2-(3,3-difluoropyrrolidin-1-yl)-4-iodo-3-pyridyl]-2-isopropyl-pyrimidine-5-carboxamide (0.0750 g, 0.158 mmol), (3-methoxyphenyl)boronic acid (0.0482 g, 0.317 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.0259 g, 0.0317 mmol) in 1,4-dioxane (1.50 mL) and water (0.350 mL), potassium carbonate (0.0548 g, 0.396 mmol) was added, and the mixture was stirred at 100° C. for 1 hour. After cooling to ambient temperature, the mixture was diluted with ethyl acetate (25 mL) and passed through a bed of diatomaceous earth (i.e., Celite®). The solid was washed with ethyl acetate (50 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography eluting with a gradient of 15 to 100% acetonitrile in water containing 10 mM ammonium bicarbonate, followed by reverse-phase preparative HPLC eluting with a gradient of 48 to 58% acetonitrile in water containing 10 mM ammonium formate to give the title compound as a colorless solid (0.0395 g, 50% yield). 1 HNMR (500 MHz;DMSO-d6) δ 10.14 (s, 1H), 8.94 (s, 2H), 8.20 (d, J = 5.0Hz, 1H), 7.30 (t, J = 7.9 Hz, 1H), 7.01-6.85 (m, 3H), 6.81 (d, J = 5.0 Hz, 1H),4.00-3.74 (m, 4H), 3.70 (s, 3H), 3.19 (dt, J = 13.8, 6.9 Hz, 1H), 2.48-2.36 (m,2H), 1.28 (d, J = 6.9 Hz, 6H). MS (ES+) m / z 454.3 (M + 1).

[0327] Example 58: Synthesis of N-[2-(3,3-difluoropyrrolidin-1-yl)-4-(5-ethoxy-2-fluoro-phenyl)-3-pyridyl]-2-isopropyl-pyrimidine-5-carboxamide [ka] To a solution of N-[2-(3,3-difluoropyrrolidin-1-yl)-4-iodo-3-pyridyl]-2-isopropyl-pyrimidine-5-carboxamide (0.0750 g, 0.158 mmol), (5-ethoxy-2-fluoro-phenyl)boronic acid (0.0583 g, 0.317 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.0259 g, 0.0317 mmol) in 1,4-dioxane (1.50 mL) and water (0.350 mL), potassium carbonate (0.0548 g, 0.396 mmol) was added, and the mixture was stirred at 100 ° C. for 1 hour. After cooling to ambient temperature, the mixture was diluted with ethyl acetate (25 mL) and passed through a bed of diatomaceous earth (i.e., Celite®). The solid was washed with ethyl acetate (50 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography eluting with a gradient of 15 to 100% acetonitrile in water containing 10 mM ammonium bicarbonate, followed by reverse-phase preparative HPLC eluting with a gradient of 47 to 57% acetonitrile in water containing 10 mM ammonium formate to give the title compound as a colorless solid (0.0105 g, 13% yield). 1HNMR (400 MHz;DMSO-d6) δ 10.19 (s, 1H), 8.90 (s, 2H), 8.19 (d, J = 4.9Hz, 1H), 7.15 (t, J = 9.2 Hz, 1H), 6.88 (dt, J = 9.0, 3.6 Hz, 1H), 6.81 (d, J =4.7 Hz, 2H), 3.98-3.80 (m, 4H), 3.76 (s, 2H), 3.17 (dt, J = 13.8, 6.9 Hz, 1H), 2.42(dt, J = 21.4, 7.1 Hz, 2H), 1.26 (d, J = 6.9 Hz, 6H), 1.20 (t, J = 7.0Hz, 3H). MS(ES+) m / z 486.3 (M + 1).

[0328] Example 59: Synthesis of N-[2-(3,3-difluoropyrrolidin-1-yl)-4-(2-fluoro-4-methoxy-phenyl)-3-pyridyl]-2-isopropyl-pyrimidine-5-carboxamide [ka] To a solution of N-[2-(3,3-difluoropyrrolidin-1-yl)-4-iodo-3-pyridyl]-2-isopropyl-pyrimidine-5-carboxamide (0.0750 g, 0.158 mmol), (2-fluoro-4-methoxy-phenyl)boronic acid (0.0539 g, 0.317 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.0259 g, 0.0317 mmol) in 1,4-dioxane (1.50 mL) and water (0.350 mL), potassium carbonate (0.0548 g, 0.396 mmol) was added, and the mixture was stirred at 100 ° C. for 1 hour. After cooling to ambient temperature, the mixture was diluted with ethyl acetate (25 mL) and passed through a bed of diatomaceous earth (i.e., Celite®). The solid was washed with ethyl acetate (50 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography eluting with a gradient of 15 to 100% acetonitrile in water containing 10 mM ammonium bicarbonate, followed by reverse-phase preparative HPLC eluting with a gradient of 42 to 52% acetonitrile in water containing 10 mM ammonium formate to give the title compound as a colorless solid (0.0351 g, 47% yield). 1 HNMR (400 MHz;DMSO-d6) δ 10.16 (s, 1H), 8.93 (s, 2H), 8.16 (d, J = 4.2Hz, 1H), 7.23 (t, J = 8.7 Hz, 1H), 6.87 (dd, J = 12.2, 2.3 Hz, 1H), 6.77 (dd, J= 6.9, 3.7 Hz, 2H), 3.88 (bs, 2H), 3.72 (bs, 5H), 3.17 (dt, J = 13.8, 6.9 Hz, 1H),2.48-2.35 (m, 2H), 1.27 (d, J = 6.9 Hz, 6H). MS (ES+) m / z 472.2 (M + 1).

[0329] Example 60: Synthesis of N-[2-(3,3-difluoropyrrolidin-1-yl)-4-(2-fluoro-5-methoxy-phenyl)-3-pyridyl]-6-methoxy-pyridine-3-carboxamide [ka] To a solution of 2-(3,3-difluoropyrrolidin-1-yl)-4-(2-fluoro-5-methoxy-phenyl)pyridin-3-amine (0.0450 g, 0.125 mmol), 6-methoxypyridine-3-carboxylic acid (0.0288 g, 0.188 mmol), and 2-chloro-1-methyl-pyridin-1-ium iodide (0.128 g, 0.501 mmol) in tetrahydrofuran (1.63 mL) was added N,N-diisopropylethylamine (0.0858 mL, 0.501 mmol), and the mixture was stirred at 65 ° C. for 20 hours. After cooling to ambient temperature, the mixture was diluted with saturated aqueous sodium bicarbonate (15 mL), and the aqueous phase was extracted with ethyl acetate (3 × 15 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of 0-15% methanol in dichloromethane followed by preparative HPLC eluting with a gradient of 50-60% acetonitrile in water containing 10 mM ammonium bicarbonate to give the title compound as a colorless solid (0.0100 g, 17% yield). 1HNMR (500 MHz;DMSO-d6) δ 9.85 (s, 1H), 8.53 (d, J = 2.1 Hz, 1H), 8.19(d, J = 5.0 Hz, 1H), 7.98 (dd, J = 8.7, 2.5 Hz, 1H), 7.15 (t, J = 9.2 Hz, 1H), 6.89(t, J = 7.0 Hz, 2H), 6.84 (d, J = 5.7 Hz, 1H), 6.80 (d, J = 5.5 Hz, 1H), 3.90 (s,3H), 3.99-3.65 (m, 4H), 3.33 (s, 3H), 2.43 (ddd, J = 20.9, 13.9, 7.0Hz, 2H). MS(ES+) m / z 459.2 (M + 1).

[0330] Example 61: Synthesis of N-(2-(3,3-difluoropyrrolidin-1-yl)-4-(3-methyl-1H-pyrazol-5-yl)pyridin-3-yl)-2-isopropylpyrimidine-5-carboxamide [ka] To a solution of N-[2-(3,3-difluoropyrrolidin-1-yl)-4-iodo-3-pyridyl]-2-isopropyl-pyrimidine-5-carboxamide (0.080 g, 0.17 mmol), (3-methyl-1H-pyrazol-5-yl)boronic acid (0.032 g, 0.25 mmol), and potassium carbonate (0.070 g, 0.51 mmol) in degassed 1,4-dioxane (1.0 mL) and water (0.11 mL), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (1:1) (0.014 g, 0.017 mmol) was added, and the mixture was stirred at 90° C. for 16 hours. After cooling to ambient temperature, the mixture was diluted with ethyl acetate (10 mL). The mixture was passed through a bed of diatomaceous earth (i.e., Celite®). The solid was washed with ethyl acetate (20 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC eluting with a gradient of 10 to 40% acetonitrile in water containing 0.5% formic acid to afford the title compound as an off-white solid (0.025 g, 34% yield). 1 H-NMR(300 MHz;DMSO-d6): δ 12.86 (s, 1H), 10.27 (s, 1H), 9.22 (s, 2H), 8.12(d, J = 5.1 Hz, 1H), 7.12 (d, J = 5.1 Hz, 1H), 6.39 (s, 1H), 3.94-3.65 (m, 4H),3.24 (dt, J = 13.8, 6.9 Hz, 2H), 2.46-2.34 (m, 1H), 2.19 (s, 3H), 1.33 (d, J = 6.9Hz, 6H). MS (ESI+) m / z 428.2 (M+1).

[0331] Example 62: Synthesis of N-(2-(3,3-difluoropyrrolidin-1-yl)-4-(oxazol-5-yl)pyridin-3-yl)-2-isopropylpyrimidine-5-carboxamide [ka] To a solution of N-[2-(3,3-difluoropyrrolidin-1-yl)-4-iodo-3-pyridyl]-2-isopropyl-pyrimidine-5-carboxamide (0.080 g, 0.17 mmol), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-oxazole (0.049 g, 0.25 mmol), and potassium carbonate (0.070 g, 0.51 mmol) in degassed 1,4-dioxane (1.00 mL) and water (0.11 mL), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (1:1) (0.014 g, 0.017 mmol) was added, and the mixture was stirred at 90° C. for 16 hours. After cooling to ambient temperature, the mixture was diluted with ethyl acetate (10 mL). The mixture was passed through a bed of diatomaceous earth (i.e., Celite®). The solid was washed with ethyl acetate (20 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC eluting with a gradient of 5 to 65% acetonitrile in water containing 0.5% formic acid to afford the title compound as a colorless solid (0.025 g, 36% yield). 1 H-NMR(300 MHz;DMSO-d6): δ 10.53-10.49 (m, 1H), 9.27 (s, 2H), 8.55 (s, 1H),8.24 (d, J = 5.2 Hz, 1H), 7.57 (s, 1H), 7.17 (d, J = 5.2 Hz, 1H), 3.93-3.71 (m,4H), 3.25 (dt, J = 13.9, 7.0 Hz, 1H), 2.46-2.37 (m, 2H), 1.34 (d, J = 6.9 Hz, 6H). MS(ESI+) m / z 415.2 (M+1).

[0332] Example 63: Synthesis of 6-isopropyl-N-(2-morpholino-4-phenylpyridin-3-yl)nicotinamide [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 were 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 mixture 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 x 100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of 5-45% ethyl acetate in heptane to give the title compound as a colorless solid (2.95 g, 81% yield). MS (ES+) m / z 235.0 (M + 1).

[0333] Step 2: Preparation of 4-(3-nitro-4-phenylpyridin-2-yl)morpholine [ka] To a mixture of 2-chloro-3-nitro-4-phenylpyridine (0.500 g, 2.13 mmol) in anhydrous N,N-dimethylformamide (7.10 mL) was added potassium carbonate (0.884 g, 6.39 mmol) and morpholine (0.23 mL, 2.6 mmol). The reaction mixture was stirred at 50 °C for 30 min. After cooling to ambient temperature, the mixture was diluted with ethyl acetate (150 mL) and washed with saturated ammonium chloride (50 mL), water (4 × 50 mL), and brine (50 mL). The organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of 5–45% ethyl acetate in heptane to give the title compound as a yellow oil (0.328 g, 54% yield). MS (ES+) m / z 286.2 (M + 1).

[0334] Step 3: Preparation of 2-morpholino-4-phenylpyridin-3-amine [ka] A mixture of 2,4-dichloro-3-nitropyridine (0.328 g, 1.15 mmol) in methanol (1.9 mL) and ethyl acetate (1.9 mL) was degassed with nitrogen for 10 minutes. To the reaction mixture was added 10% palladium on carbon (0.075 g). The reaction mixture was degassed with hydrogen and stirred at ambient temperature for 16 hours. After cooling to ambient temperature, the mixture was filtered through a bed of diatomaceous earth (i.e., Celite®). The filter pad was washed with ethyl acetate (2 × 50 mL), and the combined filtrate was concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of 5–60% ethyl acetate in heptane to afford the title compound as a colorless solid (0.247 g, 84% yield). MS (ES+) m / z 256.2 (M + 1).

[0335] Step 4: Preparation of 6-isopropyl-N-(2-morpholino-4-phenylpyridin-3-yl)nicotinamide [ka] To a mixture of 2-morpholino-4-phenylpyridin-3-amine (0.050 g, 0.20 mmol) in anhydrous tetrahydrofuran (1.3 mL) was added N,N-diisopropylethylamine (0.34 mL, 2.0 mmol), 2-chloro-1-methylpyridinium iodide (0.200 g, 0.783 mmol), and isopropyl nicotinate hydrochloride (0.063 g, 0.31 mmol). The reaction mixture was stirred at 65 °C for 20 hours. After cooling to ambient temperature, the mixture was diluted with saturated ammonium chloride (50 mL) and extracted with ethyl acetate (3 × 100 mL). The combined extracts were washed with saturated ammonium chloride (3 × 50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of 15 to 100% ethyl acetate in heptane to give the title compound as a colorless oil. The residue was further purified by reverse phase column chromatography using a gradient of 10-65% acetonitrile in water containing 0.5% formic acid as eluent to give the title compound as a colorless solid (0.045 g, 56% yield). 1 HNMR (500 MHz, DMSO-d6) δ 9.94 (s, 1H), 8.78-8.78 (m, 1H), 8.28 (d, J= 5.0 Hz, 1H), 7.97 (dd, J = 8.1, 1.8 Hz, 1H), 7.43 (d, J = 7.3 Hz, 2H), 7.37 (t,J = 6.7 Hz, 3H), 7.32 (t, J = 7.2 Hz, 1H), 7.02 (d, J = 5.0 Hz, 1H), 3.62 (t, J= 4.5 Hz, 4H), 3.22-3.21 (m, 4H), 3.05 (Septet, J = 6.8 Hz, 1H), 1.23 (d, J = 6.9 Hz,6H). MS (ES+) m / z 403.2 (M + 1).

[0336] Examples 64 to 66 The following compounds were prepared in a similar manner as described in Example 63, utilizing appropriately substituted starting materials and intermediates. [Table 3-1] [Table 3-2] [Table 3-3]

[0337] Example 67: Synthesis of N-(2-(3,3-difluoroazetidin-1-yl)-4-phenylpyridin-3-yl)-2-isopropylpyrimidine-5-carboxamide [ka] Step 1: Preparation of 2-(3,3-difluoroazetidin-1-yl)-3-nitro-4-phenylpyridine [ka] To a mixture of 2-chloro-3-nitro-4-phenylpyridine (0.500 g, 2.13 mmol) in anhydrous N,N-dimethylformamide (7.10 mL) was added potassium carbonate (0.884 g, 6.39 mmol) and 3,3-difluoroazetidine hydrochloride (0.663 g, 5.11 mmol). The reaction mixture was stirred at 50 °C for 3 h. After cooling to ambient temperature, the mixture was diluted with ethyl acetate (150 mL), and the organic phase was washed with saturated ammonium chloride (50 mL), water (4 × 50 mL), brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of 5–45% ethyl acetate in heptane to give the title compound as a yellow oil (0.426 g, 69% yield). MS (ES+) m / z 292.0 (M + 1).

[0338] Step 2: Preparation of 2-(3,3-difluoroazetidin-1-yl)-4-phenylpyridin-3-amine [ka] A mixture of 2-(3,3-difluoroazetidin-1-yl)-3-nitro-4-phenylpyridine (0.453 g, 1.55 mmol) in methanol (2.6 mL) and ethyl acetate (2.6 mL) was degassed with nitrogen for 10 minutes. 10% palladium on carbon (0.075 g) was added to the reaction mixture. The reaction mixture was degassed with hydrogen and stirred at ambient temperature for 16 hours. The mixture was filtered through a bed of diatomaceous earth (i.e., Celite®), the filter pad was washed with ethyl acetate (2 × 50 mL), and the combined filtrate was concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of 5–35% ethyl acetate in heptane to give the title compound as a yellow solid (0.341 g, 84% yield). MS (ES+) m / z 262.0 (M + 1).

[0339] Step 3: Preparation of N-(2-(3,3-difluoroazetidin-1-yl)-4-phenylpyridin-3-yl)-2-isopropylpyrimidine-5-carboxamide [ka] To a mixture of 2-(3,3-difluoroazetidin-1-yl)-4-phenylpyridin-3-amine (0.050 g, 0.20 mmol) in anhydrous tetrahydrofuran (1.3 mL) was added N,N-diisopropylethylamine (0.42 mL, 2.4 mmol), 2-chloro-1-methylpyridinium iodide (0.245 g, 0.960 mmol), and 2-isopropylpyrimidine-5-carboxylic acid (0.064 g, 0.38 mmol). The reaction mixture was stirred at 65 °C for 3 days. After cooling to ambient temperature, the mixture was diluted with ethyl acetate (100 mL), washed with saturated ammonium chloride (35 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of 5 to 100% ethyl acetate in heptane to give the title compound as a colorless solid (0.024 g, 32% yield). 1H NMR (500 MHz, DMSO-d6) δ 10.14 (s, 1H),8.97 (s, 2H), 8.22 (d, J = 5.1 Hz, 1H), 7.42-7.37 (m, 4H), 7.34 (m, J = 7.4, 4.9,2.5 Hz, 1H), 6.90 (d, J = 5.1 Hz, 1H), 4.51-4.46 (m, 2H), 4.38-4.32 (m, 2H), 3.18 (septet, J = 6.9 Hz, 1H), 1.27 (d, J = 6.9 Hz, 6H). MS (ES+) m / z 410.2 (M + 1).

[0340] Example 68: The following compounds were prepared in a similar manner as described in Example 67, utilizing appropriately substituted starting materials and intermediates. [Table 4]

[0341] Example 69: Synthesis of 2-isopropyl-N-(4-phenyl-2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridin-3-yl)pyrimidine-5-carboxamide formate [ka] Step 1: Preparation of 6-(3-nitro-4-phenylpyridin-2-yl)-2-oxa-6-azaspiro[3.3]heptane [ka] To a mixture of 2-chloro-3-nitro-4-phenylpyridine (0.500 g, 2.13 mmol) in anhydrous N,N-dimethylformamide (7.10 mL) was added potassium carbonate (0.884 g, 6.39 mmol) and 2-oxa-6-azaspiro[3.3]heptane oxalic acid (0.967 g, 5.11 mmol). The reaction mixture was stirred at 50 °C for 3 h. After cooling to ambient temperature, the mixture was diluted with ethyl acetate (150 mL), washed with saturated ammonium chloride (50 mL), water (4 × 50 mL), brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of 5–30% ethyl acetate in heptane to give the title compound as a yellow oil (0.453 g, 71% yield). MS (ES+) m / z 298.0 (M + 1).

[0342] Step 2: Preparation of 4-phenyl-2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridin-3-amine [ka] A mixture of 6-(3-nitro-4-phenylpyridin-2-yl)-2-oxa-6-azaspiro[3.3]heptane (0.453 g, 1.55 mmol) in methanol (2.6 mL) and ethyl acetate (2.6 mL) was degassed with nitrogen for 10 minutes. 10% palladium on carbon (0.075 g) was added to the reaction mixture. The reaction mixture was degassed with hydrogen and stirred at ambient temperature for 16 hours. After cooling to ambient temperature, the mixture was filtered through a bed of diatomaceous earth (i.e., Celite®). The filter pad was washed with ethyl acetate (2 × 50 mL), and the combined filtrate was concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of 5–70% ethyl acetate in heptane to afford the title compound as a yellow solid (0.259 g, 62% yield). MS (ES+) m / z 268.2 (M + 1).

[0343] Step 3: 2-Isopropyl-N-(4-phenyl-2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridin-3-yl)pyrimidine-5-carboxamide formate [ka] To a mixture of 4-phenyl-2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridin-3-amine (0.050 g, 0.20 mmol) in anhydrous tetrahydrofuran (1.3 mL) was added N,N-diisopropylethylamine (0.42 mL, 2.4 mmol), 2-chloro-1-methylpyridinium iodide (0.245 g, 0.960 mmol), and 2-isopropylpyrimidine-5-carboxylic acid (0.064 g, 0.38 mmol). The reaction mixture was stirred at 65 °C for 3 days. After cooling to ambient temperature, the mixture was diluted with ethyl acetate (100 mL), and the organic phase was washed with saturated ammonium chloride (35 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of 5 to 100% ethyl acetate in heptane to give the title compound as a colorless oil. The residue was further purified by reverse phase column chromatography using a gradient of 10-55% acetonitrile in water containing 0.5% formic acid as eluent to give the title compound as a colorless solid (0.021 g, 27% yield). 1 HNMR (500 MHz, DMSO-d6) δ 10.10 (s, 1H), 8.99 (s, 2H), 8.45 (s, 0.35H),8.13 (d, J = 5.0 Hz, 1H), 7.40-7.35 (m, 4H), 7.34-7.31 (m, 1H), 6.72 (d, J = 5.0Hz, 1H), 4.67 (s, 4H), 4.27-4.24 (m, 2H), 4.14-4.11 (m, 2H), 3.19 (septet, J = 6.9Hz, 1H), 1.29 (d, J = 6.9 Hz, 6H). MS (ES+) 416.2 m / z (M + 1).

[0344] Examples 70 to 72 The following compounds were prepared in a similar manner as described in Example 69, utilizing appropriately substituted starting materials and intermediates. [Table 5-1] [Table 5-2] [Table 5-3]

[0345] Example 73: Synthesis of (R)-2-isopropyl-N-(4-phenyl-2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyridin-3-yl)pyrimidine-5-carboxamide [ka] Step 1: (R)-3-nitro-4-phenyl-2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyridine [ka] To a mixture of 2-chloro-3-nitro-4-phenylpyridine (0.505 g, 2.15 mmol) in anhydrous dimethyl sulfoxide (3.55 mL) was added N,N-diisopropylethylamine (1.55 mL, 8.61 mmol) and 2-(R)-2-trifluoromethylpyrrolidine (0.599 g, 2.15 mmol). The reaction mixture was stirred at 125 °C for 16 h. After cooling to ambient temperature, the mixture was diluted with saturated ammonium chloride (50 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with saturated ammonium chloride (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of 5–30% ethyl acetate in heptane to give the title compound as a yellow oil (0.444 g, 61% yield). MS (ES+) m / z 338.2 (M + 1).

[0346] Step 2: Preparation of (R)-4-phenyl-2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyridin-3-amine [ka] A mixture of (R)-3-nitro-4-phenyl-2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyridine (0.444 g, 1.32 mmol) in methanol (2.6 mL) and ethyl acetate (2.6 mL) was degassed with nitrogen for 10 minutes. To the reaction mixture was added 10% palladium on carbon (0.090 g). The reaction mixture was degassed with hydrogen and stirred at ambient temperature for 16 hours. The mixture was filtered through a bed of diatomaceous earth (i.e., Celite®), the filter pad was washed with ethyl acetate (2 × 50 mL), and the combined filtrates were concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of 5 to 35% ethyl acetate in heptane to afford the title compound as a yellow oil (0.329 g, 81% yield). MS (ES+) m / z 308.2 (M + 1).

[0347] Step 3: (R)-2-Isopropyl-N-(4-phenyl-2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyridin-3-yl)pyrimidine-5-carboxamide [ka] To a mixture of (R)-4-phenyl-2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyridin-3-amine (0.050 g, 0.16 mmol) in anhydrous tetrahydrofuran (1.3 mL) was added N,N-diisopropylethylamine (0.36 mL, 2.1 mmol), 2-chloro-1-methylpyridinium iodide (0.214 g, 0.836 mmol), and 2-isopropylpyrimidine-5-carboxylic acid (0.056 g, 0.33 mmol). The reaction mixture was stirred at 65 °C for 2 hours. After cooling to ambient temperature, the mixture was diluted with ethyl acetate (100 mL), and the organic phase was washed with saturated ammonium chloride (35 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of 10 to 100% ethyl acetate in heptane to give the title compound as a colorless oil. The residue was further purified by reverse phase column chromatography using a gradient of 10-90% acetonitrile in water containing 0.5% formic acid as eluent to give the title compound as a colorless solid (0.030 g, 32% yield). 1 HNMR (500 MHz, DMSO-d6) δ 10.16 (s, 1H), 8.94 (s, 2H), 8.21 (d, J = 5.0Hz, 1H), 7.43-7.35 (m, 4H), 7.34-7.29 (m, 1H), 6.91 (d, J = 4.9 Hz, 1H), 5.69-5.64(m, 1H), 3.66 (s, 1H), 3.42-3.24 (m, 1H), 3.17 (Septet, J = 7.1 Hz, 1H), 2.16-2.08(m, 1H), 1.98-1.91 (m, 2H), 1.89-1.82 (m, 1H), 1.27 (d, J = 6.9 Hz, 6H). MS (ESI)456.2 m / z (M + 1).

[0348] Example 74: Synthesis of 2-isopropyl-N-(4-phenyl-2-(pyrrolidin-1-yl)pyridin-3-yl)pyrimidine-5-carboxamide [ka] Step 1: Preparation of 3-nitro-4-phenyl-2-(pyrrolidin-1-yl)pyridine [ka] To a mixture of 2-chloro-3-nitro-4-phenylpyridine (0.629 g, 2.68 mmol) in anhydrous dimethyl sulfoxide (9.0 mL) was added potassium carbonate (1.11 g, 8.05 mmol) and pyrrolidine (0.45 mL, 5.4 mmol). The reaction mixture was stirred at ambient temperature for 16 h. The mixture was diluted with saturated ammonium chloride (50 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of 5–30% ethyl acetate in heptane to give the title compound as a yellow oil (0.716 g, 99% yield). MS (ES+) m / z 270.0 (M + 1).

[0349] Step 2: Preparation of 4-(phenyl)-2-(pyrrolidin-1-yl)pyridin-3-amine [ka] A mixture of 3-nitro-4-phenyl-2-(pyrrolidin-1-yl)pyridine (0.716 g, 2.66 mmol) in methanol (2.6 mL) and ethyl acetate (2.6 mL) was degassed with nitrogen for 10 minutes. To the reaction mixture was added 10% palladium on carbon (0.095 g). The reaction mixture was degassed with hydrogen and stirred at ambient temperature for 16 hours. The mixture was filtered through a bed of diatomaceous earth (i.e., Celite®), the filter pad was washed with ethyl acetate (2 × 50 mL), and the combined filtrate was concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of 5–35% ethyl acetate in heptane to afford the title compound as a yellow oil (0.521 g, 82% yield). MS (ES+) m / z 240.2 (M + 1).

[0350] Step 3: 2-Isopropyl-N-(4-phenyl-2-(pyrrolidin-1-yl)pyridin-3-yl)pyrimidine-5-carboxamide [ka] To a mixture of 4-phenyl-2-(pyrrolidin-1-yl)pyridin-3-amine (0.050 g, 0.16 mmol) in anhydrous tetrahydrofuran (1.3 mL) was added N,N-diisopropylethylamine (0.36 mL, 2.1 mmol), 2-chloro-1-methylpyridinium iodide (0.214 g, 0.836 mmol), and 2-isopropylpyrimidine-5-carboxylic acid (0.056 g, 0.33 mmol). The reaction mixture was stirred at 65° C. for 2 hours. After cooling to ambient temperature, the mixture was diluted with ethyl acetate (100 mL), and the organic phase was washed with saturated ammonium chloride (35 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography using a gradient of 10-55% acetonitrile in water containing 0.5% formic acid as eluent to give the title compound as a colorless solid (0.036 g, 45% yield). 1 H NMR (500 MHz,DMSO-d6) δ 10.09 (s, 1H), 8.91 (s, 2H), 8.11 (d, J = 4.9Hz, 1H), 7.36 (m, 4H), 7.32-7.30 (m, 1H), 6.63 (d, J = 4.9 Hz, 1H), 3.60-3.38 (m,4H), 3.16 (septet, J = 6.9 Hz, 1H), 1.85-1.77 (m, 4H), 1.26 (d, J = 6.9 Hz, 6H). MS (ES+) m / z 388.2 (M+1).

[0351] Example 75: Synthesis of N-(2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-4-phenylpyridin-3-yl)-2-isopropylpyrimidine-5-carboxamide [ka] Step 1: 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 mixture was stirred at 80° C. for 1.5 hours. After cooling to ambient temperature, the mixture was diluted with 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 anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure 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).

[0352] Step 2: 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), 2-chloro-1-methylpyridinium iodide (9.36 g, 36.6 mmol) and 2-isopropylpyrimidine-5-carboxylic acid (2.23 g, 13.4 mmol) were added. The reaction mixture 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 anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of 0 to 75% ethyl acetate in heptane to give the title compound as a yellow solid (2.85 g, 66% yield). 1H NMR (300 MHz, CDCl3) δ8.96 (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 (septet, J = 6.8 Hz, 1H), 1.35 (d, J = 6.9 Hz,6H). MS (ES+) m / z 353.0 (M + 1), 355.0 (M + 1).

[0353] Step 3: N-(2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-4-phenylpyridin-3-yl)-2-isopropylpyrimidine-5-carboxamide [ka] To a mixture of N-(2-chloro-4-phenylpyridin-3-yl)-2-isopropylpyrimidine-5-carboxamide (0.066 g, 0.19 mmol) in anhydrous 1,4-dioxane (1.9 mL), potassium tert-butoxide (0.104 g, 0.930 mmol), [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride (0.040 g, 0.056 mmol), and 6,6-difluoro-3-azabicyclo[3.1.0]hexane hydrochloride (0.058 g, 0.37 mmol) were added. The reaction mixture was degassed with nitrogen for 10 minutes and then stirred at 100° C. for 24 hours. The reaction mixture was cooled to ambient temperature, and [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride (0.040 g, 0.056 mmol) was added to the reaction mixture. The reaction mixture was stirred at 100 °C for 3 days under a nitrogen atmosphere. The reaction mixture was cooled to ambient temperature, and potassium tert-butoxide (0.104 g, 0.930 mmol) and 6,6-difluoro-3-azabicyclo[3.1.0]hexane hydrochloride (0.058 g, 0.37 mmol) were added to the reaction mixture. The reaction mixture was stirred at 100 °C for 18 hours. After cooling to ambient temperature, the mixture was diluted with saturated ammonium chloride (50 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of 20-100% ethyl acetate in heptane to give a colorless solid. The residue was further purified by reverse-phase column chromatography eluting with a gradient of 10-75% acetonitrile in water containing 0.5% formic acid as eluent to give the title compound as a colorless solid (0.015 g, 18% yield). 1H NMR (300 MHz, DMSO-d6) δ10.20-10.09 (m, 1H), 8.92 (s, 2H), 8.15 (d, J = 5.0 Hz, 1H), 7.41-7.28(m, 5H), 6.69 (d, J = 5.0 Hz, 1H), 5.43-5.24 (m, 1H), 3.91-3.52 (m, 4H), 3.17 (septet, J = 6.9 Hz, 1H), 2.24-1.88 (m, 2H), 1.26 (d, J = 6.9 Hz, 6H). MS (ES+) m / z436.2 (M+1).

[0354] Example 76: Synthesis of (R)—N-(2-(3-fluoropyrrolidin-1-yl)-4-phenylpyridin-3-yl)-2-isopropylpyrimidine-5-carboxamide [ka] To a mixture of N-(2-chloro-4-phenylpyridin-3-yl)-2-isopropylpyrimidine-5-carboxamide (0.075 g, 0.21 mmol) in anhydrous 1,4-dioxane (2.1 mL), potassium tert-butoxide (0.143 g, 0.1.27 mmol), [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride (0.058 g, 0.085 mmol), (R)-3-fluoropyrrolidine hydrochloride (0.107 g, 0.850 mmol) were added. The reaction mixture was degassed with nitrogen for 10 minutes and then stirred at 110° C. for 18 hours. After cooling to ambient temperature, the mixture was diluted with ethyl acetate (150 mL) and filtered through a pad of diatomaceous earth (i.e., Celite®). The filtrate was washed with saturated ammonium chloride (2 x 50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of 25 to 100% ethyl acetate in heptane to give the title compound (0.027 g, 31% yield) as a colorless solid. 1H NMR (300 MHz, DMSO-d6) δ10.18-10.11 (m, 1H), 8.92 (s, 2H), 8.15 (d, J = 5.0 Hz, 1H), 7.41-7.28(m, 5H), 6.69 (d, J = 5.0 Hz, 1H), 5.43-5.24 (m, 1H), 3.91-3.52 (m, 4H), 3.17 (septet, J = 6.9 Hz, 1H), 2.27-1.87 (m, 2H), 1.26 (d, J = 6.9 Hz, 6H). MS (ES+) m / z406.2 (M+1).

[0355] Example 77: The following compounds were prepared in a similar manner as described in Example 76, utilizing appropriately substituted starting materials and intermediates. [Table 6]

[0356] Example 78: Synthesis of 1-cyclobutyl-N-(4-(2-fluorophenyl)-2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridin-3-yl)-1H-pyrazole-4-carboxamide [ka] Step 1: Preparation of 2-chloro-4-(2-fluorophenyl)-3-nitropyridine [ka] A mixture of 2,4-dichloro-3-nitropyridine (10.00 g, 51.82 mmol) in dioxane (100 mL) and water (35 mL) was degassed with nitrogen for 10 minutes. 2-Fluorophenylboronic acid (7.98 g, 57.0 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (3.29 g, 3.89 mmol), and potassium carbonate (10.74 g, 77.7 mmol) were added to the reaction mixture. The reaction mixture was stirred at 60°C for 8 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 (2 x 100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of 0-30% ethyl acetate in heptane to give the title compound as a white solid (9.95 g, 76% yield). 1 HNMR (300 MHz, CDCl3) δ 8.60 (d, J = 5.0 Hz, 1H), 7.55-7.47 (m, 1H), 7.43(dd, J = 5.0, 1.3 Hz, 1H), 7.35-7.19 (m, 3H). MS (ES+) m / z 253.0 (M + 1).

[0357] Step 2: Preparation of 6-(4-(2-fluorophenyl)-3-nitropyridin-2-yl)-2-oxa-6-azaspiro[3.3]heptane [ka] To a mixture of 2-chloro-4-(2-fluorophenyl)-3-nitropyridine (4.00 g, 15.8 mmol) in N-methyl-2-pyrrolidone (53 mL) was added N,N-diisopropylethylamine (14 mL, 79 mmol) and 2-oxa-6-azaspiro[3.3]heptane oxalic acid (3.59 g, 19.0 mmol). The reaction mixture was stirred at 50 °C for 4 h. After cooling to ambient temperature, the mixture was diluted with saturated ammonium chloride (200 mL) and extracted with ethyl acetate (3 × 200 mL). The combined organic phases were washed with saturated ammonium chloride (2 × 200 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of 5 to 100% ethyl acetate in heptane to give the title compound as a colorless solid (1.458 g, 29% yield). MS(ES+) m / z 316.2 (M + 1).

[0358] Step 3: Preparation of 4-(2-fluorophenyl)-2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridin-3-amine [ka] A mixture of 6-(4-(2-fluorophenyl)-3-nitropyridin-2-yl)-2-oxa-6-azaspiro[3.3]heptane (1.458 g, 4.623 mmol) in methanol (7.7 mL) and ethyl acetate (7.7 mL) was degassed with nitrogen for 10 minutes. To the reaction mixture was added 10% palladium on carbon (0.245 g). The reaction mixture was degassed with hydrogen and stirred at ambient temperature for 16 hours. After cooling to ambient temperature, the mixture was filtered through a bed of diatomaceous earth (i.e., Celite®). The filter pad was washed with ethyl acetate (2 × 100 mL), and the combined filtrates were concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of 10 to 100% ethyl acetate in heptane to afford the title compound as a brown solid (0.741 g, 56% yield). MS (ES+) m / z 286.2 (M + 1).

[0359] Step 4: Preparation of 1-cyclobutyl-N-(4-(2-fluorophenyl)-2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridin-3-yl)-1H-pyrazole-4-carboxamide [ka] To a mixture of 4-(2-fluorophenyl)-2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridin-3-amine (0.050 g, 0.20 mmol) in anhydrous tetrahydrofuran (1.75 mL) was added N,N-diisopropylethylamine (0.31 mL, 1.75 mmol), 2-chloro-1-methylpyridinium iodide (0.224 g, 0.876 mmol), and 1-cyclobutyl-1H-pyrazole-4-carboxylic acid (0.087 g, 0.53 mmol). The reaction mixture was stirred at 65 °C for 18 hours. After cooling to ambient temperature, the mixture was diluted with ethyl acetate (100 mL), washed with saturated ammonium chloride (2 × 35 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography eluting with a gradient of preparative reverse-phase HPLC to afford the title compound as a colorless oil. The residue was further purified by reverse phase column chromatography using a gradient of 10-35% acetonitrile in water containing 0.5% formic acid as eluent to give the title compound as a colorless solid (0.023 g, 30% yield). 1 HNMR (300 MHz, DMSO-d6) δ 9.31 (s, 1H), 8.19 (d, J = 0.4 Hz, 1H), 8.09(d, J = 5.0 Hz, 1H), 7.88 (s, 1H), 7.37-7.10 (m, 4H), 6.68 (dd, J = 5.1, 1.2 Hz,1H), 4.82 (quintet, J = 8.2 Hz, 1H), 4.65-4.63 (m, 4H), 4.16-4.13 (m, 4H), 2.44-2.34(m, 4H), 1.80-1.71 (m, 2H). MS (ES+) 434.2 m / z (M+1).

[0360] Examples 79 to 84 The following compounds were prepared in a similar manner as described in Example 78, utilizing appropriately substituted starting materials and intermediates. [Table 7-1] [Table 7-2] [Table 7-3] [Table 7-4]

[0361] Example 85: Synthesis of N-(2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-(2-fluorophenyl)pyridin-3-yl)-2-methoxypyrimidine-5-carboxamide [ka] Step 1: Preparation of 8-(4-(2-fluorophenyl)-3-nitropyridin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane [ka] To a mixture of 2-chloro-4-(2-fluorophenyl)-3-nitropyridine (1.50 g, 5.94 mmol) in N-methyl-2-pyrrolidone (30 mL) was added N,N-diisopropylethylamine (5.3 mL, 30 mmol) and 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (1.78 g, 11.9 mmol). The reaction mixture was stirred at 50 °C for 3 days. After cooling to ambient temperature, the mixture was diluted with saturated ammonium chloride (150 mL) and extracted with ethyl acetate (3 × 150 mL). The combined organic phases were washed with saturated ammonium chloride (3 × 100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of 0–30% ethyl acetate in heptane to give the title compound as a colorless solid (1.95 g, 100% yield). MS(ES+) m / z 330.2 (M + 1).

[0362] Step 2: Preparation of 2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-(2-fluorophenyl)pyridin-3-amine [ka] To a mixture of 8-(4-(2-fluorophenyl)-3-nitropyridin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane (1.95 g, 5.92 mmol) in methanol (10 mL) and ethyl acetate (10 mL) was added ammonium formate (14.94 g, 236 mmol) and 10% palladium on carbon (0.400 g). The reaction mixture was stirred at 65°C for 0.5 h. After cooling to ambient temperature, the mixture was diluted with ethyl acetate (300 mL), washed with saturated sodium bicarbonate (2 x 100 mL), water (100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of 0 to 70% ethyl acetate in heptane to give the title compound as a pale pink solid (0.466 g, 26% yield). MS(ES+) m / z 300.2 (M + 1).

[0363] Step 3: Preparation of N-(2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-(2-fluorophenyl)pyridin-3-yl)-2-methoxypyrimidine-5-carboxamide [ka] To a mixture of 2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-(2-fluorophenyl)pyridin-3-amine (0.050 g, 0.17 mmol) in anhydrous tetrahydrofuran (1.7 mL) was added N,N-diisopropylethylamine (0.29 mL, 1.7 mmol), 2-chloro-1-methylpyridinium iodide (0.128 g, 0.50 mmol), and 2-methoxypyrimidine-5-carboxylic acid (0.028 g, 0.18 mmol). The reaction mixture was stirred at 65 °C for 4 hours. After cooling to ambient temperature, the mixture was diluted with ethyl acetate (100 mL), washed with saturated ammonium chloride (2 × 35 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of 30-100% ethyl acetate in heptane to give the title compound as a colorless solid (0.025 g, 34% yield). 1 HNMR (300 MHz, DMSO-d6) δ 10.06 (s, 1H), 8.83 (s, 2H), 8.21 (d, J = 5.0Hz, 1H), 7.39-7.31 (m, 2H), 7.27-7.15 (m, 2H), 6.90 (dd, J = 5.0, 0.9 Hz, 1H), 4.30(s, 2H), 3.96 (s, 3H), 3.66 (d, J = 10.4 Hz, 2H), 3.49 (d, J = 10.6 Hz, 2H), 1.90-1.82(m, 4H). MS (ES+) m / z 436.2 (M+1).

[0364] Example 86: Synthesis of N-(4-(2,5-difluorophenyl)-2-morpholinopyridin-3-yl)-4-isopropylbenzamide [ka] Step 1: Preparation of 4-(4-(2,5-difluorophenyl)-3-nitropyridin-2-yl)morpholine [ka] To a mixture of 2-chloro-4-(2,5-difluorophenyl)-3-nitro-pyridine (3.00 g, 11.1 mmol) in N-methyl-2-pyrrolidone (55 mL) was added N,N-diisopropylethylamine (9.9 mL, 55 mmol) and morpholine (1.45 mL, 16.6 mmol) at 0 °C. The reaction mixture was stirred at ambient temperature for 18 h. The mixture was diluted with saturated ammonium chloride (200 mL) and extracted with ethyl acetate (3 × 200 mL). The combined organic phases were washed with saturated water (4 × 200 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of 5–45% ethyl acetate in heptane to give the title compound as an orange oil (2.08 g, 58% yield). 1 HNMR (300 MHz, DMSO-d6) δ 8.33 (d, J = 4.9 Hz, 1H), 7.12-7.07 (m, 2H),6.97-6.91 (m, 1H), 6.73 (dd, J = 4.9, 0.5 Hz, 1H), 3.79-3.75 (m, 4H), 3.42-3.39(m, 4H). MS (ES+) m / z 322.2 (M+1).

[0365] Step 2: Preparation of 4-(4-(2,5-difluorophenyl)-3-nitropyridin-2-yl)morpholine [ka] To a mixture of 4-(4-(2,5-difluorophenyl)-3-nitropyridin-2-yl)morpholine (2.08 g, 6.47 mmol) in methanol (11 mL) and ethyl acetate (11 mL) was added ammonium formate (8.17 g, 130 mmol) and 10% palladium on carbon (0.207 g). The reaction mixture was stirred at 65°C for 4 hours. After cooling to ambient temperature, the mixture was diluted with ethyl acetate (300 mL) and filtered through a bed of diatomaceous earth (i.e., Celite®). The filtrate was washed with water (3 x 100 mL), brine (100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of 0 to 60% ethyl acetate in heptane to afford the title compound as a red oil (1.0871 g, 58% yield). MS(ES+) m / z 292.2 (M + 1).

[0366] Step 3: Preparation of N-(4-(2,5-difluorophenyl)-2-morpholinopyridin-3-yl)-4-isopropylbenzamide [ka] To a mixture of 4-(4-(2,5-difluorophenyl)-3-nitropyridin-2-yl)morpholine (0.050 g, 0.17 mmol) in anhydrous tetrahydrofuran (1.7 mL) was added N,N-diisopropylethylamine (0.30 mL, 1.7 mmol), 2-chloro-1-methylpyridinium iodide (0.218 g, 0.857 mmol), and 4-isopropylbenzoic acid (0.031 g, 0.189 mmol). The reaction mixture was stirred at 65° C. for 4 hours. After cooling to ambient temperature, N,N-diisopropylethylamine (0.15 mL, 0.85 mmol), 2-chloro-1-methylpyridinium iodide (0.145 g, 0.571 mmol), and 4-isopropylbenzoic acid (0.031 g, 0.189 mmol) were added to the reaction mixture, and the reaction mixture was heated to 65° C. for 24 hours. After cooling to ambient temperature, N,N-diisopropylethylamine (0.15 mL, 0.85 mmol), 2-chloro-1-methylpyridinium iodide (0.145 g, 0.571 mmol), and 4-isopropylbenzoic acid (0.031 g, 0.189 mmol) were added to the reaction mixture, and the reaction mixture was heated to 65° C. for 24 hours. The reaction mixture was cooled to ambient temperature, diluted with saturated ammonium chloride (50 mL), and extracted with ethyl acetate (3×75 mL). The combined organic phase was washed with saturated ammonium chloride (2 x 50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of 0 to 100% ethyl acetate in heptane to give the title compound (0.048 g, 64% yield) as a colorless solid. 1 H NMR (300 MHz, DMSO-d6) δ9.76 (s, 1H), 8.28 (d, J = 5.0 Hz, 1H), 7.63 (d, J = 8.2 Hz, 2H),7.32-7.15 (m, 5H), 7.02 (dd, J = 5.0, 1.1 Hz, 1H), 3.64 (t, J = 4.6 Hz, 4H), 3.22(t, J = 4.5 Hz, 4H), 2.92 (septet, J = 6.9 Hz, 1H), 1.20 (d, J = 6.9 Hz, 6H). MS (ES+)m / z 438.1 (M+1).

[0367] Examples 87 to 90 The following compounds were prepared in a similar manner as described in Example 86, utilizing appropriately substituted starting materials and intermediates. [Table 8-1] [Table 8-2]

[0368] Example 91: Synthesis of N-(2-(3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)-4-phenylpyridin-3-yl)-2-isopropylpyrimidine-5-carboxamide [ka] Step 1: Preparation of 6-(3-nitro-4-phenylpyridin-2-yl)-3-oxa-6-azabicyclo[3.1.1]heptane [ka] To a mixture of 2-chloro-3-nitro-4-phenylpyridine (0.610 g, 2.60 mmol) in N-methyl-2-pyrrolidone (8.7 mL) was added N,N-diisopropylethylamine (1.51 g, 8.66 mmol) and 4-methylbenzene-1-sulfonic acid 3-oxa-6-azabicyclo[3.1.1]heptane (0.235 g, 2.6 mmol). The reaction mixture was stirred at 60 °C for 24 h. After cooling to ambient temperature, the mixture was diluted with ethyl acetate (150 mL), washed with saturated ammonium chloride (5 × 50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of 0–50% ethyl acetate in heptane to give the title compound as a yellow oil (0.193 g, 75% yield). MS (ES+) m / z 298.2 (M + 1).

[0369] Step 2: Preparation of 2-(3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)-4-phenylpyridin-3-amine [ka] To a mixture of 6-(3-nitro-4-phenylpyridin-2-yl)-3-oxa-6-azabicyclo[3.1.1]heptane (0.193 g, 0.650 mmol) in methanol (2.2 mL) and ethyl acetate (2.2 mL) was added ammonium formate (1.016 g, 16.11 mmol) and 10% palladium on carbon (0.050 g). The reaction mixture was stirred at 65°C for 0.5 h. After cooling to ambient temperature, the mixture was diluted with ethyl acetate (200 mL), filtered through a bed of diatomaceous earth (i.e., Celite®), and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of 0 to 70% ethyl acetate in heptane to afford the title compound as a red oil (0.167 g, 96% yield). MS (ES+) m / z 268.2 (M + 1).

[0370] Step 3: N-(2-(3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)-4-phenylpyridin-3-yl)-2-isopropylpyrimidine-5-carboxamide [ka] To a mixture of 2-(3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)-4-phenylpyridin-3-amine (0.055 g, 0.20 mmol) in anhydrous tetrahydrofuran (2.0 mL) was added N,N-diisopropylethylamine (0.36 mL, 2.0 mmol), 2-chloro-1-methylpyridinium iodide (0.157 g, 0.614 mmol), and 2-isopropylpyrimidine-5-carboxylic acid (0.037 g, 0.23 mmol). The reaction mixture was stirred at 65 °C for 2.5 hours. After cooling to ambient temperature, the mixture was diluted with ethyl acetate (100 mL), washed with saturated ammonium chloride (2 × 30 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of 30-80% ethyl acetate in heptane to give the title compound as a colorless solid (0.063 g, 74% yield). 1 HNMR (300 MHz, DMSO-d6) δ 10.07 (s, 1H), 8.92 (s, 2H), 8.18 (d, J = 5.0Hz, 1H), 7.43-7.29 (m, 5H), 6.77 (d, J = 5.0 Hz, 1H), 4.37-4.18 (m, 4H), 3.63 (m,2H), 3.16 (septet, J = 6.9 Hz, 1H), 2.62 (dd, J = 6.7 Hz, 1H), 1.73 (d, J = 8.0 Hz,1H), 1.26 (d, J = 6.9 Hz, 6H). MS (ES+) m / z 416.2 (M + 1).

[0371] Example 92: Synthesis of N-(2-(3,3-difluoropyrrolidin-1-yl)-4-(2-fluorophenyl)pyridin-3-yl)-4-methoxypiperidine-1-carboxamide [ka] Step 1: Preparation of 2-chloro-4-(2-fluorophenyl)-3-nitropyridine [ka] A mixture of 2,4-dichloro-3-nitropyridine (5.0 g, 26 mmol), 1,4-dioxane (50 mL), and water (17 mL) was sparged with nitrogen for 10 minutes. 2-Fluorophenylboronic acid (3.6 g, 26 mmol), potassium carbonate (5.4 g, 39 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (2.2 g, 2.6 mmol) were added to the mixture, which was then sparged with nitrogen for 2 minutes. The reaction mixture was stirred at 60 °C for 4 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). The organic solution was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography eluting with 0-30% ethyl acetate in heptane to give the title compound as a colorless solid (4.0 g, 61% yield).

[0372] Step 2: Preparation of 4-(2-fluorophenyl)-2-(3,3-difluoropyrrolidin-1-yl)-3-nitropyridine [ka] To a mixture of 2-chloro-4-(2-fluorophenyl)-3-nitropyridine (2.0 g, 7.9 mmol), anhydrous potassium carbonate (3.3 g, 24 mmol), and 3,3-difluoropyrrolidine hydrochloride (1.5 g, 10 mmol) was added N,N-dimethylformamide (26 mL). The reaction mixture was stirred at ambient temperature for 24 hours. The reaction mixture was diluted with ethyl acetate (200 mL). The organic layer was washed with saturated ammonium chloride (2 × 50 mL). The organic solution was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography eluting with 5–35% ethyl acetate in heptane to give the title compound as a yellow oil (2.5 g, 98% yield). MS (ES+) m / z 324.2 (M + 1).

[0373] Step 3: Preparation of 2-(3,3-difluoropyrrolidin-1-yl)-4-(2-fluorophenyl)pyridin-3-amine [ka] To 4-(2-fluorophenyl)-2-(3,3-difluoropyrrolidin-1-yl)-3-nitropyridine (2.5 g, 7.8 mmol) was added anhydrous methanol (13 mL), ethyl acetate (13 mL), and 10% palladium on carbon (0.83 g). The reaction vessel was sealed, and the reaction mixture was sparged with hydrogen gas for 5 minutes. The reaction mixture was stirred under a hydrogen atmosphere for 24 hours. The reaction mixture was filtered through diatomaceous earth (i.e., Celite®), washed with ethyl acetate (5 × 20 mL), and concentrated under reduced pressure. The residue was purified by column chromatography eluting with 5–35% ethyl acetate in heptane to afford the title compound as a clear, colorless oil (1.6 g, 72% yield). MS (ES+) m / z 294.2 (M+1).

[0374] Step 4: Preparation of N-(2-(3,3-difluoropyrrolidin-1-yl)-4-(2-fluorophenyl)pyridin-3-yl)-4-methoxypiperidine-1-carboxamide [ka] To 2-(3,3-difluoropyrrolidin-1-yl)-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. To the mixture was added triphosgene (0.067 g, 0.23 mmol). The solution was stirred at 0° C. for 2.5 hours, after which 4-methoxypiperidine (0.24 g, 2.0 mmol), anhydrous tetrahydrofuran (1.1 mL), and N-ethyl-N-isopropylpropan-2-amine (0.44 g, 3.4 mmol) were added. The reaction mixture was warmed to ambient temperature and stirred for 2 hours. 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 under reduced pressure. The residue was purified by column chromatography eluting with a gradient of 10 to 100% ethyl acetate in heptane to give the title compound as a colorless solid (0.050 g, 32% yield). 1 H-NMR(500 MHz;DMSO-d6) δ 8.09 (d, J = 4.9 Hz, 1H), 7.90 (s, 1H), 7.42-7.38(m, 1H), 7.29-7.18 (m, 3H), 6.69-6.68 (m, 1H), 3.97-3.83 (m, 2H), 3.81-3.71 (m,2H), 3.53-3.48 (m, 2H), 3.24-3.18 (m, 4H), 2.91-2.83 (m, 2H), 2.48-2.40 (m, 2H),1.54-1.50 (m, 2H), 1.03-0.96 (m, 2H). MS (ES+) m / z 435.2 (M + 1).

[0375] Example 93: Synthesis of N-[2-(3,3-difluoropyrrolidin-1-yl)-4-(2-fluorophenyl)-3-pyridyl]-7-methoxy-2-azaspiro[3.5]nonane-2-carboxamide [ka] Step 1: Preparation of N-[2-(3,3-difluoropyrrolidin-1-yl)-4-(2-fluorophenyl)-3-pyridyl]-7-methoxy-2-azaspiro[3.5]nonane-2-carboxamide [ka] To 2-(3,3-difluoropyrrolidin-1-yl)-4-(2-fluorophenyl)pyridin-3-amine (0.11 g, 0.38 mmol) was added anhydrous tetrahydrofuran (3.8 mL), and the mixture was cooled in an ice-water bath. To the mixture was added triphosgene (0.057 g, 0.19 mmol). The solution was stirred at 0° C. for 2.5 hours, after which 7-methoxy-2-azaspiro[3.5]nonane (0.12 g, 0.76 mmol), anhydrous tetrahydrofuran (1.0 mL), and N-ethyl-N-isopropylpropan-2-amine (0.49 g, 3.8 mmol) were added. The reaction was allowed to warm to ambient temperature and stirred for 2 hours. 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 under reduced pressure. Purification by preparative HPLC eluting with a gradient of 10-80% acetonitrile in water containing 0.5% formic acid gave the title compound as a colorless solid (0.053 g, 28% yield). 1 H-NMR(300 MHz;DMSO-d6) δ 8.09 (d, J = 4.9 Hz, 1H), 7.79 (s, 1H), 7.47-7.40(m, 1H), 7.32-7.25 (m, 3H), 6.69 (dd, J = 5.0, 0.8 Hz, 1H), 3.96-3.87 (m, 2H), 3.75(t, J = 7.3 Hz, 2H), 3.24-3.21 (m, 4H), 3.21-3.19 (m, 3H), 3.09-3.07 (m, 1H), 2.49-2.39(m, 2H), 1.68-1.61 (m, 2H), 1.56-1.49 (m, 2H), 1.32-1.23 (m, 2H), 1.21-1.13 (m,2H). MS (ES+) m / z 475.2 (M + 1).

[0376] Example 94: Synthesis of N-[2-(3,3-difluoropyrrolidin-1-yl)-4-(2-fluorophenyl)-3-pyridyl]-6-methoxy-2-azaspiro[3.3]heptane-2-carboxamide [ka] Step 1: Preparation of N-[2-(3,3-difluoropyrrolidin-1-yl)-4-(2-fluorophenyl)-3-pyridyl]-6-methoxy-2-azaspiro[3.3]heptane-2-carboxamide [ka] To 2-(3,3-difluoropyrrolidin-1-yl)-4-(2-fluorophenyl)pyridin-3-amine (0.11 g, 0.38 mmol) was added anhydrous tetrahydrofuran (3.6 mL) and cooled in an ice-water bath. To the mixture was added triphosgene (0.11 g, 0.36 mmol). The solution was stirred at 0° C. for 18 hours, after which 6-methoxy-2-azaspiro[3.3]heptane hydrochloride (0.12 g, 0.73 mmol), anhydrous tetrahydrofuran (3.0 mL), and N-ethyl-N-isopropylpropan-2-amine (0.47 g, 3.6 mmol) were added. The reaction was allowed to warm to ambient temperature and stirred for 2 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 under reduced pressure. Purification by preparative HPLC eluting with a gradient of 10-80% acetonitrile in water containing 0.5% formic acid gave the title compound as a colorless solid (0.083 g, 50% yield). 1H-NMR(300 MHz;DMSO-d6) δ 8.09 (d, J = 4.9 Hz, 1H), 7.80 (s, 1H), 7.47-7.41(m, 1H), 7.32-7.24 (m, 3H), 6.70 (dd, J = 5.0, 0.8 Hz, 1H), 3.90 (t, J = 13.6 Hz,2H), 3.74 (t, J = 7.2 Hz, 2H), 3.64 (t, J = 6.8 Hz, 1H), 3.52 (s, 2H), 3.46 (s,2H), 3.07 (s, 3H), 2.43 (dt, J = 14.2, 7.1 Hz, 2H), 2.25 (ddd, J = 9.8, 6.8, 2.9Hz, 2H), 1.88-1.81 (m, 2H). MS (ES+) m / z 447.2 (M + 1).

[0377] Example 95: Synthesis of N-[2-(3,3-difluoropyrrolidin-1-yl)-4-(2-fluorophenyl)-3-pyridyl]-7-oxa-2-azaspiro[3.5]nonane-2-carboxamide [ka] Anhydrous tetrahydrofuran (3.9 mL) was added to 2-(3,3-difluoropyrrolidin-1-yl)-4-(2-fluorophenyl)pyridin-3-amine (0.12 g, 0.39 mmol) and cooled in an ice-water bath. To the mixture was added triphosgene (0.092 g, 0.31 mmol). The solution was stirred at 0° C. for 2.5 hours, after which 7-oxa-2-azaspiro[3.5]nonane hydrochloride (0.13 g, 0.78 mmol), anhydrous tetrahydrofuran (1.0 mL), anhydrous N,N-dimethylformamide (0.5 mL), and N-ethyl-N-isopropylpropan-2-amine (0.51 g, 3.9 mmol) were added. The reaction was allowed to warm to ambient temperature and stirred for 18 hours. The reaction mixture was diluted with ethyl acetate (150 mL), washed with saturated ammonium chloride (2 x 50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography eluting with 35 to 100% ethyl acetate in heptane afforded the title compound as a colorless solid (0.083 g, 50% yield). 1 H-NMR(300 MHz;DMSO-d6) δ 8.10-8.09 (m, 1H), 7.86-7.82 (m, 1H), 7.47-7.39(m, 1H), 7.31-7.23 (m, 3H), 6.70 (dd, J = 5.0, 0.8 Hz, 1H), 3.96-3.83 (m, 2H), 3.76(quintet, J = 6.8 Hz, 2H), 3.43-3.39 (m, 4H), 3.34-3.28 (m, 4H), 2.49-2.37 (m, 2H),1.45 (t, J = 5.0 Hz, 4H). MS (ES+) m / z 447.2 (M + 1).

[0378] Example 96: Synthesis of tert-butyl 2-[[2-(3,3-difluoropyrrolidin-1-yl)-4-(2-fluorophenyl)-3-pyridyl]carbamoyl]-2,7-diazaspiro[3.5]nonane-7-carboxylate [ka] Anhydrous tetrahydrofuran (4.1 mL) was added to 2-(3,3-difluoropyrrolidin-1-yl)-4-(2-fluorophenyl)pyridin-3-amine (0.12 g, 0.39 mmol) and cooled in an ice-water bath. To the mixture was added triphosgene (0.096 g, 0.32 mmol). The solution was stirred at 0° C. for 2.5 hours, after which tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate hydrochloride (0.22 g, 0.82 mmol), anhydrous tetrahydrofuran (1.0 mL), anhydrous N,N-dimethylformamide (0.5 mL), and N-ethyl-N-isopropylpropan-2-amine (0.53 g, 4.1 mmol) were added. The reaction was warmed to ambient temperature and stirred for 30 minutes. The reaction mixture was diluted with ethyl acetate (150 mL), washed with saturated ammonium chloride (2 x 50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography eluting with 20-100% ethyl acetate in heptane afforded the title compound (0.13 g, 52% yield) as a colorless solid. 1 H-NMR(300 MHz;DMSO-d6) δ 8.10-8.09 (m, 1H), 7.84 (s, 1H), 7.45 (ddd, J =8.4, 5.4, 3.3 Hz, 1H), 7.30-7.26 (m, 3H), 6.70 (dd, J = 5.0, 0.8 Hz, 1H), 3.96-3.86(m, 2H), 3.78-3.73 (m, 2H), 3.29 (s, 4H), 3.18-3.16 (m, 4H), 2.43 (dd, J = 14.2,7.1 Hz, 2H), 1.39 (d, J = 4.0Hz, 13H). MS (ES+) m / z 546.2 (M + 1).

[0379] Example 97: Synthesis of 7-acetyl-N-[2-(3,3-difluoropyrrolidin-1-yl)-4-(2-fluorophenyl)-3-pyridyl]-2,7-diazaspiro[3.5]nonane-2-carboxamide [ka] Step 1: Preparation of N-[2-(3,3-difluoropyrrolidin-1-yl)-4-(2-fluorophenyl)-3-pyridyl]-2,7-diazaspiro[3.5]nonane-2-carboxamide [ka] To tert-butyl 2-[[2-(3,3-difluoropyrrolidin-1-yl)-4-(2-fluorophenyl)-3-pyridyl]carbamoyl]-2,7-diazaspiro[3.5]nonane-7-carboxylate (0.11 g, 0.20 mmol) was added anhydrous dichloromethane (2.0 mL) and trifluoroacetic acid (2.0 mL) at ambient temperature. The solution was stirred at ambient temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (200 mL), washed with saturated sodium bicarbonate (3 × 50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was used in the next step without further purification (0.090 g, 100% yield). MS (ES+) m / z 446.2 (M + 1).

[0380] Step 2: Preparation of 7-acetyl-N-[2-(3,3-difluoropyrrolidin-1-yl)-4-(2-fluorophenyl)-3-pyridyl]-2,7-diazaspiro[3.5]nonane-2-carboxamide [ka] N-[2-(3,3-difluoropyrrolidin-1-yl)-4-(2-fluorophenyl)-3-pyridyl]-2,7-diazaspiro[3.5]nonane-2-carboxamide (0.090 g, 0.20 mmol) was added to anhydrous dichloromethane (2.0 mL) and cooled to 0 °C in an ice-water bath. To the mixture was added N-ethyl-N-isopropylpropan-2-amine (0.052 g, 0.40 mmol) and acetyl chloride (0.024 g, 0.30 mmol). The reaction mixture was allowed to warm to ambient temperature and stirred for 30 minutes. The reaction mixture was diluted with ethyl acetate (200 mL), washed with saturated ammonium chloride (2 × 50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography eluting with 20-100% ethyl acetate in heptane, then 0-50% methanol in ethyl acetate gave the title compound as a colorless solid (0.13 g, 52% yield). 1 H-NMR(300 MHz;DMSO-d6) δ 8.10 (d, J = 4.9 Hz, 1H), 7.84 (s, 1H), 7.50-7.42(m, 1H), 7.33-7.26 (m, 3H), 6.71-6.69 (m, 1H), 3.96-3.86 (m, 2H), 3.78-3.72 (m,2H), 3.34-3.22 (m, 8H), 2.47-2.37 (m, 2H), 1.99 (s, 3H), 1.48-1.44 (m, 2H), 1.40-1.33(m, 2H). MS (ES+) m / z 488.2 (M + 1).

[0381] Example 98: Synthesis of N-[2-(3,3-difluoropyrrolidin-1-yl)-4-(2-fluorophenyl)-3-pyridyl]-2-methoxy-7-azaspiro[3.5]nonane-7-carboxamide [ka] To 2-(3,3-difluoropyrrolidin-1-yl)-4-(2-fluorophenyl)pyridin-3-amine (0.070 g, 0.24 mmol), anhydrous tetrahydrofuran (2.4 mL) was added and cooled to 0 °C in an ice-water bath. To the mixture was added triphosgene (0.035 g, 0.12 mmol). The solution was stirred at 0 °C for 2.5 hours, after which 2-methoxy-7-azaspiro[3.5]nonane hydrochloride (0.092 g, 0.48 mmol), anhydrous tetrahydrofuran (1.5 mL), and N-ethyl-N-isopropylpropan-2-amine (0.31 g, 2.4 mmol) were added. The reaction mixture was warmed to...

Claims

1. Formula (I): 【Chemical 638】 or a pharmaceutically acceptable salt or solvate thereof, During the ceremony, 【Chemical Formula 639】 represents a double or single bond to fill all valences, Y is N or NR ４ａ and X is C(R ７ ) or N, R １ teeth, 【Hua721】 is selected from 【Hua 641】 each occurrence independently represents a double bond or a single bond so as to satisfy all valences; n is 0, 1, 2, 3, 4, or 5; R １ａ is hydrogen or alkyl, Each R １ｂ are independently halo, alkyl, haloalkyl, cyano, heterocyclylalkyl, -R ８ -N(R ９ ) ２ , -R ８ -C(=O)N(R ９ ) ２ , or -R ８ -OR ９ Or or two R bonded to adjacent carbons １ｂ together with the carbon to which they are attached form an optionally substituted N-heteroaryl, an optionally substituted N-heterocyclyl, an optionally substituted O-heterocyclyl, or an optionally substituted aryl; R １ｃ is N or -Si(CH ３ ) ３ and R ２ teeth, 【Chemical Formula 642】 is selected from m is 0, 1, 2, 3, or 4; Each R ５ are independently halo, alkyl, haloalkyl, or —R １０ -CN or or two R ５ together with the carbon to which they are both attached form an optionally substituted O-heterocyclyl, an optionally substituted N-heterocyclyl, an optionally substituted cycloalkyl, or or two R ５ are linked to form an optionally substituted alkylene chain, R ３ is alkyl, -R ８ -N(R ９ ) ２ , -R ８ -OR ９ , 【Chemical 722】 【Chemical 723】 is selected from p is 0, 1, 2, 3, 4, or 5; R ６ａ is hydrogen, alkyl, cycloalkyl, haloalkyl, —C(═O)R ９ , optionally substituted arylalkyl, or optionally substituted heteroaryl; Each R ６ｂ are independently alkyl, halo, haloalkyl, -R ８ -OR ９ , -R ８ -N(R ９ ) ２ , -R ８ -C(=O)OR ９ , -R ８ -C(=O)N(R ９ ) ２ , optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; or two R ６ｂ together with the carbon to which they are both attached form an optionally substituted N-heterocyclyl, an optionally substituted O-heterocyclyl, an optionally substituted cycloalkyl, or or two R ６ｂ are linked to form an optionally substituted alkylene chain, or or R ６ｂ The appearance of and R １ｂ are linked to form an optionally substituted alkylene chain, R ３ａ is hydrogen or alkyl, R ４ is hydrogen, alkyl, -R ８ -OR ９ , halo, haloalkyl, and cyano; or R ４ is R ４ together with the carbon to which R is attached. ４ａ Connected with R ４ａ together with the nitrogen to which it is attached form an optionally substituted 5-membered N-heteroaryl; R ７ is hydrogen, alkyl, halo, and —R ８ -OR ９ is selected from Each R ８ are independently a direct bond or an optionally substituted alkylene chain; Each R ９ are independently hydrogen, alkyl, haloalkyl, carboxyalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, or optionally substituted aryl; Two R's ９ together with the nitrogen to which they are both attached form an optionally substituted heterocyclyl; However, when X is N, R ３ teeth, 【Chemical Formula 644】 Selected from: The compound or a pharmaceutically acceptable salt or solvate thereof.

2. The compound is 【Chemical 724】 having a formula selected from X, R １ , R ２ , R ３ , R ３ａ , and R ４ are each as defined in claim 1; 2. The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof.

3. R １ but, 【Chemical Formula 647】 is selected from where: Each R １ｂ are independently halo, alkyl, haloalkyl, cyano, heterocyclylalkyl, -R ８ -N(R ９ ) ２ , -R ８ -C(=O)N(R ９ ) ２ , or -R ８ -OR ９ and R １ｃ is N or -Si(CH ３ ) ３ That is, 2. The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof.

4. R １ but, 【Chemical 725】 is selected from where: 【Chemical Formula 649】 each occurrence independently represents a double bond or a single bond so as to satisfy all valences; n is 0, 1, 2, 3, 4, or 5; R １ａ is hydrogen or alkyl, Each R １ｂ are independently halo, alkyl, haloalkyl, cyano, heterocyclylalkyl, -R ８ -N(R ９ ) ２ , -R ８ -C(=O)N(R ９ ) ２ , or -R ８ -OR ９ Or or two R bonded to adjacent carbons １ｂ together with the carbon to which they are attached form an optionally substituted N-heteroaryl, an optionally substituted N-heterocyclyl, an optionally substituted O-heterocyclyl, or an optionally substituted aryl; 2. The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof.

5. R １ but, 【Chemical 726】 is selected from 【Chemistry 651】 each occurrence independently represents a double bond or a single bond so as to satisfy all valences; n is 0, 1, 2, 3, 4, or 5; R １ａ is hydrogen or alkyl, Each R １ｂ are independently halo, alkyl, haloalkyl, cyano, heterocyclylalkyl, -R ８ -N(R ９ ) ２ , -R ８ -C(=O)N(R ９ ) ２ , or -R ８ -OR ９ Or or two R bonded to adjacent carbons １ｂ together with the carbon to which they are attached form an optionally substituted N-heteroaryl, an optionally substituted N-heterocyclyl, an optionally substituted O-heterocyclyl, or an optionally substituted aryl; 2. The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof.

6. R １ but, 【Chemical 654】 is selected from 【Chemistry 655】 each occurrence independently represents a double bond or a single bond so as to satisfy all valences; n is 0, 1, 2, 3, 4, or 5; R １ａ is hydrogen or alkyl, Each R １ｂ are independently halo, alkyl, haloalkyl, cyano, heterocyclylalkyl, -R ８ -N(R ９ ) ２ , -R ８ -C(=O)N(R ９ ) ２ , or -R ８ -OR ９ Or or two R bonded to adjacent carbons １ｂ together with the carbon to which they are attached form an optionally substituted N-heteroaryl, an optionally substituted N-heterocyclyl, an optionally substituted O-heterocyclyl, or an optionally substituted aryl; 2. The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof.

7. R １ but has the following structure: 【Hua 659-1】 【Hua 659-2】 having one of:

2. The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof.

8. R ２ but has the following structure: 【Chemistry 670】 having one of:

2. The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof.

9. R ２ but has the following structure: 【671】 having one of:

2. The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof.

10. R ３ but has the following structure: 【Hua 681-1】 【Hua 681-2】 【Hua 681-3】 【Hua 681-4】 having one of:

2. The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof.

11. R ３ and R １ which together form the following structure: 【Chemical 699】 having one of:

2. The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof.

12. R ３ａ is hydrogen or methyl; 2. The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof.

13. R ４ is hydrogen, methyl, fluoro, chloro, —OH, —OCH 3 , —CF 3 , or cyano; 2. The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof.

14. R ７ is methyl, 2. The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof.

15. The compound of claim 1, wherein the compound has the following structure: 【Hua727】 【Chemical 728】 【Chemical 729】 【Chemistry 730】 【Hua731】 【Chemical 732】 【Chemical 733】 【Chemical 734】 【Chemical 735】 【Chemical Formula 736】 【Hua737】 【Chemical 738】 【Chemical 739】 【Chemical 740】 【Chemical 741】 【Chemical 742】 【Chemical 743】 【Chemical 744】 【Chemical 745】 【Chemical 746】 【Hua747】 【Chemical 748】 【Chemical 749】 having one of:

2. The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof.

16. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt or solvate thereof.

17. 17. The pharmaceutical composition of claim 16 for use in the treatment of a mammalian disease or condition modulated by a voltage-gated sodium channel.

18. The pharmaceutical composition of claim 16 for use in treating a disease or condition in a mammal, comprising: The disease or condition is selected from the group consisting of 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 syndromes, tuberous sclerosis complex, and 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, hypotension, and 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, Parkinson's syndrome, 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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