WO2016144792A1

WO2016144792A1 - Alpha 7 nicotinic acetylcholine receptor allosteric modulators, their derivatives and uses thereof

Info

Publication number: WO2016144792A1
Application number: PCT/US2016/020984
Authority: WO
Inventors: David G. Putman; Olivier Dasse; Derk Hogenkamp
Original assignee: Alpharmagen, Llc
Priority date: 2015-03-06
Filing date: 2016-03-04
Publication date: 2016-09-15
Also published as: WO2016144797A1

Abstract

The present application is related to compounds represented by Formula I, which are novel positive allosteric modulators of α7 nAChRs. The application also discloses the treatment of disorders that are responsive to enhancement of acetylcholine action on α7 nAChRs in a mammal by administering an effective amount of a compound of Formula I.

Description

Alpha 7 Nicotinic Acetylcholine Receptor Allosteric Modulators, Their Derivatives and Uses Thereof

Cross Reference and Related Application

[0001] This application claims priority to U.S. Provisional Application Serial No. 62/129,163, filed on March 6, 2015, which is incorporated by reference in its entirety.

Background

[0002] The disclosure of the present application is in the field of medicinal chemistry. In particular, this application discloses a class of novel compounds that allosterically modulate the a7 nicotinic acetylcholine receptor (a7 nAChR) and may be used to treat disorders amenable to modulation of the a7 nAChR.

[0003] a7 nAChRs belong to the ligand-gated ion channel superfamily of Cys-loop receptors. The Cys-loop superfamily includes muscle and neuronal nAChRs, 5-hydroxytryptamine type 3 (5HT3), γ-aminobutyric acidA (GABAA), GABAC and glycine receptors. oc7 nAChRs are ion channels that recognize acetylcholine and choline as endogenous orthosteric ligands and also bind nicotine at the orthosteric site. a7 nAChRs contain 5 orthosteric receptor sites per receptor. Agonist binding to the orthosteric site effects functional states of the receptor depending on the concentration and kinetics of agonist application. Four functional states have been described for a7 nAChRs: one open and three closed states (resting, fast-onset desensitized, slow-onset desensitized). Unlike agonists, allosteric modulators of oc7 nAChRs do not bind to the orthosteric site, and cannot affect the functional state of the ion channel by themselves. An allosteric modulator of a7 nAChRs requires the presence of an agonist to activate the channel, and in-turn potentiates the action of the agonist. In the brain, activation of neuronal a7 nAChRs mediates fast synaptic transmission and controls synaptic transmission by the major inhibitory and excitatory neurotransmitters, GABA and glutamate.

[0004] a7 nAChRs mediate the predominant nicotinic current in hippocampal neurons. The a7 nAChR was initially identified from a chick brain library as an oc-bungarotoxin binding protein that exhibits -40% sequence homology to other nAChRs. a7 nAChRs share similar features of other neuronal and muscle nAChRs such as a pentameric Cys- loop receptor structure and M2 segment of each subunit lining of the channel pore, however the a7 nAChRs exhibits a homopentameric structure when reconstituted in Xenopus oocytes, a characteristic shared only with the a8 and a9 nAChRs. Heterologously expressed homomeric a7 nAChRs in Xenopus oocytes are inactivated by oc-bungarotoxin with high affinity, whereas other nAChRs are not. a? nAChRs have also been pharmacologically identified by distinct types of whole cell currents elicited by nicotinic agonists in hippocampal neurons. When exposed to various nicotinic agonists, whole cell recordings from cultured hippocampal neurons show, in general, type IA currents that have a very brief open time, high conductance, very high Ca⁺⁺ permeability, decay rapidly, and are sensitive to blockade by methyllycaconitine (MLA) and oc- bungarotoxin. The properties of these nicotinic currents in hippocampal neurons correspond to the currents mediated by a? nAChRs expressed in oocytes.

Summary of the Invention

[0005] Briefly, this invention is generally directed to allosteric modulators of the a7 nAChR, as well as to methods for their preparation and use, and to pharmaceutical compositions containing the same. More specifically, the positive allosteric a? nAChR modulators of this invention are compounds represented by the general structure:

I

including pharmaceutically acceptable salts, solvates, and prodrugs thereof, wherein R¹,

R², R³, R⁴, and R⁵, and X¹, X², X³, X⁴, X⁵, and X⁶, and n are as defined below.

[0006] Further, the present invention is directed to ²H, ³H, ⁿC, ¹⁸F, ³⁵S, ³⁶C1, ¹⁴C and ¹²⁵I labeled compounds of Formula I and their use as pharmaceuticals and as stablely isotopically labeled analogs or as radioligands for their binding site on the a? nAChR complex.

[0007] Further, the present invention is directed to racemic mixtures, enantiomers, diasteriomers, and geometric isomers of the compounds of Formula I and their use as pharmaceuticals. [0008] This invention also is directed to methods of treating disorders responsive to enhancement of acetylcholine action on a7 nAChRs in a mammal by administering an effective amount of a compound of Formula I as described herein. Compounds of the present invention may be used in the treatment and/or prevention of a variety of disorders, including those of the central nervous system (CNS) and the peripheral nervous system (PNS). Disorders of the CNS and the PNS include neurodegenerative diseases, senile dementias, schizophrenia, Alzheimer's disease, learning, cognition and attention deficits, cognitive impairment due to Alzheimer's disease, mild cognitive impairment (MCI), cognitive impairment associated with schizophrenia (CIAS), cognitive impairment due to major depression, cognitive impairment due to bipolar disease, memory loss, Lewy Body dementia, attention-deficit disorder, attention deficit hyperactivity disorder, anxiety, mania, manic depression, Parkinson's disease, Huntington's disease, depression, amyotrophic lateral sclerosis, brain inflammation, cognitive deficit due to traumatic brain injury, Tourette' s syndrome, and autism spectrum disorder. Compounds of the invention are also useful in the treatment (therapeutic or prophylactic), prevention or delay of progression of dyskinesia associated with dopamine agonist therapy in Parkinson's disease. In addition, compounds of the present invention may be used to treat pain, inflammation, septic shock, ulcerative colitis, irritable bowel syndrome and Crohn's disease. In addition, compounds of the invention are useful in tobacco cessation treatment (Brunzell et al. Neuropsychopharm. 2011, 1-10), in the treatment of diabetes (Marrero et al. JPET, 2009, 332, 173) and in treating jetlag. Compounds are also useful in treating immune system disorders, Fragile X, autism spectrum disorder, Angelman's syndrome, Rett syndrome, Prader Willi syndrome and Down's syndrome.

[0009] The present invention also is directed to pharmaceutical formulations which include a compound of the present invention. Such formulations contain a therapeutically effective amount of a compound of Formula I, pharmaceutically acceptable salts, solvates, and prodrugs thereof and one or more pharmaceutically acceptable carriers or diluents.

[0010] Additional embodiments and advantages of the invention will be set forth in part in the description that follows, and in part will be apparent from the description, or may be learned by practice of the invention. The embodiments and advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. [0011] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.

Detailed Description Definitions

[0012] Unless specifically noted otherwise herein, the definitions of the terms used are standard definitions used in the art of organic synthesis and pharmaceutical sciences.

[0013] The term "halogen" or "halo" as used herein refers to a halogen radical selected from fluoro, chloro, bromo and iodo. Preferably, the halogen is fluoro.

[0014] The term "cyano" refers to -C≡N.

[0015] The term "nitro" refers to -N0₂.

[0016] The term "hydroxyl" refers to -OH.

[0017] The term "alkyl" refers to a saturated aliphatic hydrocarbon radical. "Alkyl" refers to both branched and unbranched alkyl groups. "Alkyl" includes but is not limited to straight chain alkyl groups containing from one to six carbon atoms and branched alkyl groups containing from three to ten carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, 1 -methylethyl (isopropyl), 1,1-dimethylethyl (i<?ri-butyl), and the like. It may be abbreviated "Alk". It should be understood that any combination term using an "alk" or "alkyl" prefix refers to analogs according to the above definition of "alkyl" including the number of carbon atoms. For example, terms such as "alkoxy", "alkylthio", "alkylamino" refer to alkyl groups linked to a second group via an oxygen, sulfur, or nitrogen atom, respectively.

[0018] The term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced with halogen atoms. This term includes but is not limited to groups such as perhaloalkyl, including trifluoromethyl, and mono- and di-halo alkyl, including mono fluoromethyl and difluoromethyl. In one embodiment the haloalkyl groups are alkyl groups substituted with one or more fluoro or chloro. In one embodiment, the alkyl group has 1-2 carbon atoms and can be specified as in (Cl-C2)-4- haloalkoxyphenyl. In one embodiment, the alkyl has 1-2 carbon atoms and the halo refers to one or more fluoro and is specified as in (Cl-C2)-4-fluoroalkoxyphenyl. The term "haloalkoxy" refers to haloalkyl groups linked to a second group via an oxygen atom. [0019] The term"perhaloalkyl" refers to an alkyl group in which all of the hydrogen atoms are replaced with halogen atoms. The term includes but is not limited to groups such as trifluoromethyl and pentafluoroethyl. The term "perhaloalkoxy" refers to perhaloalkyl groups linked to a second group via an oxygen atom. In one embodiment, the alkyl group has 1-2 carbon atoms and can be specified as in (Cl-C2)-4-perhaloalkoxyphenyl or (Cl- C2)-4-perfluoroalkoxyphenyl.

[0020] As used herein "solvate" refers to a complex of variable stoichiometry formed by a solute (e.g. a compound of Formula I or a salt, ester or prodrug thereof) and a solvent. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute. Examples of suitable solvents include water, methanol, ethanol and acetic acid. Generally the solvent used is a pharmaceutically acceptable solvent. Examples of suitable pharmaceutically acceptable solvents include water, ethanol and acetic acid. Generally the solvent used is water.

[0021] "Isomers" mean any compound with an identical molecular formula but having a difference in the nature or sequence of bonding or arrangement of the atoms in space. Examples of such isomers include, for example, E- and Z-isomers of double bonds, enantiomers, and diastereomers. Compounds of the present invention depicting a bond with a straight line or "squiggly line" representation that is attached to a double bond, unless specifically noted otherwise, is intended to encompass a single isomer and/or both isomers of the double bond as shown below mean any compound with an identical molecular formula but having a difference in the nature or sequence of bonding or arrangement of the atoms in space.

[0022] As used herein "allosteric modulator" of a? nAChRs refers to a compound that binds allosterically to the a? nAChR, thereby increasing (positive allosteric modulator) or decreasing (negative allosteric modulator) the agonist-evoked response in cells. The compounds of the present invention are positive allosteric modulators.

[0023] As used herein "disorders amenable to modulation of a? nAChRs" refers to neurodegenerative diseases, senile dementias, schizophrenia, Alzheimer's disease, learning, cognition and attention deficits, memory loss, Lewy Body dementia, attention- deficit disorder, attention deficit hyperactivity disorder, anxiety, mania, manic depression, Parkinson's disease, Huntington's disease, depression, cognitive impairment due to Alzheimer's disease, mild cognitive impairment (MCI), cognitive impairment associated with schizophrenia (CIAS), cognitive impairment due to major depression, cognitive impairment due to bipolar disease, amyotrophic lateral sclerosis, brain inflammation, cognitive deficit due to traumatic brain injury ("TBI"), Tourette's syndrome, and autism spectrum disorder. In addition, such disorders include immune system disorders such as, but not limited to, type I diabetes, multiple schlerosis, and rheumatoid arthritis.

"Disorders amenable to modulation of a7 nAChRs" also include pain, inflammation, septic shock, ulcerative colitis, Crohn's disease, irritable bowel syndrome, and jet lag. Also included are autism spectrum disorders, inflammation, and mild cognitive impairment. Also included are cognitive disorders related to learning or memory.

[0024] As used herein "a cognitive disorder related to learning or memory" refers to mild cognitive impairment, age related cognitive decline, senile dementia and Alzheimer's disease, particularly cognitive impairment associated with senile dementia and Alzheimer's disease.

[0025] As used herein "exhibiting at least 100% modulation of the nicotine EC₅ using 0.3 μΜ of the compound in Xenopus oocytes" refers to the assay performed in Xenopus oocytes expressing human a7 nAChRs as described below in "Oocyte

Electrophysiology." Other percentages reflect the modulation as found by the same assay.

[0026] As used herein "inhibit VEGF activity with an IC50 greater than 1 μΜ" refers to compounds of the invention that are weak inhibitors of VEGF as described below in "VEGF Inhibition Assay." Specifically, using the "VEGF Inhibition Assay", if 1 μΜ of compound inhibits VEGF phosphorylation at 50%, then the IC50 is approximately 1 μΜ. As used herein "near 100% or higher phosphorylation" means 85% or higher, preferably 90% or higher phosphorylation of VEGFR2 using ΙμΜ of test compounds in the "VEGF Inhibition Assay" provided below.

[0027] By "effective amount," in the context of treating a condition is meant the administration of that amount of active compound(s) to an individual in need of such treatment, either in a single dose or as part of a series, that is effective for alleviating or treating symptoms of that condition. The effective amount will vary depending on the health and physical condition of the individual to be treated, the formulation of the composition, the assessment of the medical situation, and other relevant factors. It is expected that the amount will be determined through clinical trials. [0028] The articles "a" and "an" are used herein to refer to one or to more than one (i.e. to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0029] As used herein, theterm "or" is generally employed in the sense as including "and/or" unless the context of the usage clearly indicates otherwise.

[0030] The term "compound" shall be understood to cover any and all isomers (e.g.

enantiomers, stereoisomers, diastereomers, rotomers, tautomers) or any misture of isomers, prodrugs, solvates, and pharmaceutically acceptable salts of said compound unless stated otherwise. Where the plural form is used for compounds, salts, and the like, this is taken to mean also a single compound, salt, or the like.

[0031] Chemical compound names were generated using ChemDraw Professional 15.0.

Compositions and Methods for the Treatment of Disorders Amendable to Modulation of 7 nAChRs

[0032] In one aspect, the pres compound of Formula I:

I

or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:

X¹ and X² are independently selected from the group consisting of is N and CH, wherein at least one of X¹ and X² are CH;

n is an integer 0 or 1 ;

R¹ is selected from the group consisting of

R² is selected from the group consisting of 4-halophenyl, (Cl -C2)-4-fluoroalkoxyphenyl, 2-hydroxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, and 2-isoxazol-3-yl;

R³ is selected from the group consisting of -H, halogen, -CF₃, -CN, -OCF₃, -S(0)2CF₃, - OH, and -OCH2cyclopropyl; R⁴ is selected from the group consisting of -H, halogen, -CF3, -CN, -CH2OH, and - CH₂N(CH₃)₂;

R⁵ is selected from the group consisting of -H, halogen, -OCH3, and -OCF3;

X³ and X⁴ are independently selected from the group consisting of N and CH;

X⁵ is selected from the group consisting of N and CR³; and

X⁶ is selected from the group consisting of N and CR⁵ wherein at least two of X³ , X⁴ , X⁵ and X⁶ have a carbon;

with the provisos that when X¹ and X² are CH, n is 1, and R² is 4-fluorophenyl, then R¹ is not 4-(trifluoromethyl)phenyl; and that when X¹ and X² are CH, n is 1, and R² is 4-halophenyl, then R¹ is not 3-(trifluoromethyl)phenyl.

[0033] In one embodiment, R² is selected from the group consisting of 4-halophenyl, (Cl-C2)-4-fluoroalkoxyphenyl, 2-hydroxyphenyl, 3-methoxyphenyl, and 4- methoxyphenyl. In another embodiment, R² is 4-halophenyl or (Cl-C2)-4- haloalkoxyphenyl. In one such embodiment, the (Cl-C2)-4-haloalkoxyphenyl is 4- fluoromethoxyphenyl, 4-difluoromethoxyphenyl, or 4-trifluoromethoxyphenyl.

[0034] In one embodiment, X² is CH.

[0035] In one embodiment, X² is CH, and X¹ is N.

[0036] In one embodiment, n is i.

[0037] , R¹ is

[0038] In one embodiment, R³ is selected from the group consisting of -CF3, -OCF3, and -

CN.

[0039] In one embodiment, R⁴ is selected from the group consisting of -H, -CF3, and-CN.

[0040] nt, R¹ is

R² is selected from the group consisting 4-halophenyl, (Cl-C2)-4- fluoroalkoxyphenyl, 2-hydroxyphenyl, 3-methoxyphenyl, and 4-methoxyphenyl; X³ is CH; X⁴ is N; X⁵ is CR³ and X⁶ is CR⁵ , provided that R¹ is not unsubstituted pyridyl. In one such embodiment, R³ is selected from the group consisting of - CF3, -OCF3, and -CN. In one such embodiment, R⁴ is selected from the group consisting of -H, -CF3, and -CN.

[0041] In one embodiment, R¹ is

R² is selected from the group consisting of 4-halophenyl, (Cl-C2)-4- fluoroalkoxyphenyl, 2-hydroxyphenyl, 3-methoxyphenyl, and 4-methoxyphenyl; X³ is CH; X⁴ is CH; X⁵ is CR³ and X⁶ is CR⁵ , provided that R¹ is not

unsubstituted phenyl. In one such embodiment, R³ is selected from the group consisting of -CF3, -OCF3, and -CN. In one such embodiment, R⁴ is selected from the group consisting of -H, -CF3, and -CN.

[0042] , X² is CH, n is 1 , and R¹ is

one such embodiment, R² is selected from the group consisting of 4-halophenyl, (Cl-C2)-4-fluoroaIkoxyphenyl, 2-hydroxyphenyl, 3- methoxyphenyl, and 4-methoxyphenyl, X³ is CH, X⁴ is N, X⁵ is CR³ and X⁶ is CR⁵, provided that R¹ is not unsubstituted pyridyl. In one such embodiment, R³ is selected from the group consisting of -CF3, -OCF3, and -CN. In one such embodiment, R⁴ is selected from the group consisting of -H, -CF3, and -CN.

[0043] X² is CH, n is 1 , and R¹ is

s selected from the group consisting of 4-halophenyl, and (Cl- C2)-4-fluoroalkoxyphenyl, X³ and X⁴ are CH, X⁵ is CR³ and X⁶ is CR⁵ , provided that R¹ is not unsubstituted phenyl. In one such embodiment, R³ is selected from the group consisting of -CF3, -OCF3, and -CN. In one such embodiment, R⁴ is selected from the group consisting of -H, -CF3, and -CN.

[0044] In one embodiment, X² is CH, X¹ is N, n is 1 , and R¹ is

. in one such embodiment, R² is selected from the group consisting of 4-halophenyl, and (Cl-C2)-4-fluoroalkoxyphenyl, X³ is CH, X⁴ is N, X⁵ is CR³ and X⁶ is CR⁵, provided that R¹ is not unsubstituted pyridyl. In one such embodiment, R³ is selected from the group consisting of -CF3, -OCF3, and -CN. In one such embodiment, R⁴ is selected from the group consisting of -H, -CF3, and - CN.

[0045] In one embodiment, X² is CH, X¹ is N, n is 1 , and R¹ is

, R² is selected from the group consisting of 4-halophenyl, and (Cl- C2)-4-fluoroalkoxyphenyl, X³ and X⁴ are CH, X⁵ is CR³ and X⁶ is CR⁵ , provided that R¹ is not unsubstituted phenyl. In one such embodiment, R³ is selected from the group consisting of -CF3, -OCF3, and -CN. In one such embodiment, R⁴ is selected from the group consisting of -H, -CF3, and -CN.

[0046] In one embodiment, the compounds of Formula I modulate the activity of an EC5 concentration of nicotine in Xenopus oocytes by at least 50% when using 0.3 μΜ of the compound. In such embodiment, the compounds also inhibit VEGF activity with an IC50 greater than ΙμΜ. In other such embodiments, the compounds also exhibit greater than 75% phosphorylation of VEGFR2 using 1 μΜ of test compound in the "VEGF Inhibition Assay". In other such embodiments, the compounds near 100% or higher

phosphorylation of VEGFR2 using 1 μΜ of test compound in the "VEGF Inhibition Assay".

[0047] In one embodiment, the compounds of Formula I modulate the activity of an EC5 concentration of nicotine in Xenopus oocytes by at least 100% when using 0.3 μΜ of the compound. In such embodiment, the compounds also inhibit VEGF activity with an IC50 greater than ΙμΜ. In other such embodiments, the compounds also exhibit greater than 75% phosphorylation of VEGFR2 using 1 μΜ of test compound in the "VEGF Inhibition Assay". In other such embodiments, the compounds also exhibit near 100% or higher phosphorylation of VEGFR2 using 1 μΜ of test compound in the "VEGF Inhibition Assay".

[0048] In one embodiment, the compounds of Formula I modulate the activity of an EC5 concentration of nicotine in Xenopus oocytes by at least 500% when using 0.3 μΜ of the compound. In such embodiment, the compounds also inhibit VEGF activity with an IC50 greater than ΙμΜ. In other such embodiments, the compounds also exhibit greater than 75% phosphorylation of VEGFR2 using 1 μΜ of test compound in the "VEGF Inhibition Assay".

[0049] In other such embodiments, the compounds also exhibit near 100% or higher phosphorylation of VEGFR2 using 1 μΜ of test compound in the "VEGF Inhibition Assay".

[0050] In one embodiment, the compounds of Formula I modulate the activity of an EC₅ concentration of nicotine in Xenopus oocytes by at least 1000% when using 0.3 μΜ of the compound. In such embodiment, the compounds also inhibit VEGF activity with an IC50 greater than ΙμΜ. In other such embodiments, the compounds also exhibit greater than 75% phosphorylation of VEGFR2 using 1 μΜ of test compound in the "VEGF Inhibition Assay". In other such embodiments, the compounds also exhibit near 100% or higher phosphorylation of VEGFR2 using 1 μΜ of test compound in the "VEGF Inhibition Assay".

[0051] In one embodiment, the compounds of Formula I modulate the activity of an EC5 concentration of nicotine in Xenopus oocytes by at least 2000% when using 0.3 μΜ of the compound. In such embodiment, the compounds also inhibit VEGF activity with an IC50 greater than ΙμΜ. In other such embodiments, the compounds also exhibit greater than 75% phosphorylation of VEGFR2 using 1 μΜ of test compound in the "VEGF Inhibition Assay". In other such embodiments, the compounds also exhibit near 100% or higher phosphorylation of VEGFR2 using 1 μΜ of test compound in the "VEGF Inhibition Assay".

[0052] In one aspect, the compounds of Formula I include N-(5-chloropyridin-2-yl)-2- ((4-fluorobenzyl)amino)nicotinamide (Compound 3);

3-((4-fluorobenzyl)amino)-N-(6-(trifluoromethyl)pyridin-3-yl)pyrazine-2- carboxamide (Compound 20);

3-((4-fluorobenzyl)amino)-N-(4-(trifluoromethyl)phenyl)pyrazine-2-carboxamide (Compound 23);

N-(3-fluoro-4-(trifluoromethyl)phenyl)-3-((4-fluorobenzyl)amino)pyrazine-2- carboxamide (Compound 26);

2-((4-fluorobenzyl)amino)-N-(6-(trifluoromethyl)pyridin-3-yl)nicotinamide (Compound 31);

N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-((4-fluorobenzyl)amino)pyrazine-2- carboxamide (Compound 38); 3-((4-fluorobenzyl)amino)-N-(5-(trifluoromethyl)pyridin-3-yl)pyrazine-2- carboxamide (Compound 41);

3-((4-fluorobenzyl)amino)-N-(4-(trifluoromethoxy)phenyl)pyrazine-2- carboxamide (Compound 43);

N-(3-cyano-4-(trifluoromethyl)phenyl)-3-((4-fluorobenzyl)amino)pyrazine-2- carboxamide (Compound 46);

N-(3-cyano-4-(trifluoromethyl)phenyl)-2-((4-fluorobenzyl)amino)nicotinamide (Compound 47);

N-(4-cyano-3-(trifluoromethyl)phenyl)-2-((4-fluorobenzyl)amino)nicotinamide (Compound 49);

3-((4-fluorobenzyl)amino)-N-(6-(trifluoromethyl)pyridin-3-yl)pyridazine-4- carboxamide (Compound 53);

3-((4-fluorobenzyl)amino)-N-(5-(trifluoromethyl)thiophen-2-yl)pyrazine-2- carboxamide (Compound 54);

2-((4-fluorobenzyl)amino)-N-(6-(trifluoromethoxy)pyridin-3-yl)nicotinamide (Compound 56);

2-((4-fluorobenzyl)amino)-N-(3-(hydroxymethyl)-4- (trifluoromethyl)phenyl)nicotinamide (Compound 75);

2-((4-fluorobenzyl)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

(Compound 80);

2- ((4-fluorophenyl)amino)-N-(6-(trifluoromethyl)pyridin-3-yl)nicotinamide (Compound 94);

N-(6-cyanopyridin-3-yl)-2-((4-fluorobenzyl)amino)nicotinamide (Compound 96); and

and pharmaceutically acceptible salts thereof.

[0053] In one aspect, the compounds of Formula I include N-(5-chloropyridin-2-yl)-2- ((4-fluorobenzyl)amino)nicotinamide (Compound 3);

3- ((4-fluorobenzyl)amino)-N-(6-(trifluoromethyl)pyridin-3-yl)pyrazine-2- carboxamide (Compound 20);

N-(3-fluoro-4-(trifluoromethyl)phenyl)-3-((4-fluorobenzyl)amino)pyrazine-2- carboxamide (Compound 26); 2- ((4-fluorobenzyl)amino)-N-(6-(trifluoromethyl)pyridin-3-yl)nicotinamide (Compound 31);

N-(4-fluoro-3-(trifluoromethyl)plienyl)-3-((4-fluorobenzyl)amino)pyrazine-2- carboxamide (Compound 38);

3- ((4-fluorobenzyl)amino)-N-(5-(trifluoromethyl)pyridin-3-yl)pyrazine-2- carboxamide (Compound 41);

2-((4-fluorobenzyl)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

(Compound 80);

2-((4-fluorophenyl)amino)-N-(6-(trifluoromethyl)pyridin-3-yl)nicotinamide (Compound 94);

N-(6-cyanopyridin-3-yl)-2-((4-fluorobenzyl)amino)nicotinamide (Compound 96); N-(2-fluoro-4-(trifluoromethyl)plienyl)-2-((4-fluorobenzyl)amino)nicotinamide (Compound 105);

2-((4-fluorobenzyl)amino)-N-(2-methoxy-4-(trifluoromethyl)phenyl)nicotinamide (Compound 106);

2-((4-methoxybenzyl)amino)-N-(4-(trifluoromethyl)plienyl)nicotinamide (Compound 111); 2-((3-methoxybenzyl)amino)-N-(4-(trifluoromethyl)phenyl)nicotinamide (Compound 112);

2-((4-fluorobenzyl)thio)-N-(4-(trifluoromethyl)phenyl)nicotinamide (Compound 114);

2- ((2-hydroxybenzyl)amino)-N-(4-(trifluoromethyl)plienyl)nicotinamide (Compound 115); and

pharmaceutically acceptable salts thereof.

In one aspect, the compounds of Formula I include

N-(4-chlorophenyl)-3-((4-fluorobenzyl)amino)pyrazine-2-carboxamide

(Compound 7);

N-(4-cyanophenyl)-3-((4-fluorobenzyl)amino)pyrazine-2-carboxamide

(Compound 39);

3- ((4-fluorobenzyl)amino)-N-(6-(trifluoromethoxy)pyridin-3-yl)pyrazine-2- carboxamide (Compound 57);

3-((4-fluorobenzyl)amino)-N-(3-(trifluoromethyl)phenyl)pyrazine-2-carboxamide (Compound 40);

N-(3,4-difluorophenyl)-3-((4-fluorobenzyl)amino)pyrazine-2-carboxamide (Compound 37);

3-((4-fluorobenzyl)amino)-N-(3-(hydroxymethyl)-4- (trifluoromethyl)phenyl)pyrazine-2-carboxamide (Compound 76);

3-((4-fluorophenyl)amino)-N-(4-(trifluoromethyl)phenyl)pyrazine-2-carboxamide (Compound 44);

3-((4-fluorobenzyl)amino)-N-(5-(trifluoromethyl)pyridin-3-yl)pyrazine-2- carboxamide (Compound 41);

3-((4-fluorobenzyl)amino)-N-(4-(trifluoromethyl)phenyl)pyrazine-2-carboxamide (Compound 23); N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-((4-fluorobenzyl)amino)pyrazine-2- carboxamide (Compound 38);

N-(3-cyano-4-(trifluoromethyl)phenyl)-3-((4-fluorobenzyl)amino)pyrazine-2- carboxamide (Compound 46); and

N-(4-cyano-3-(trifluoromethyl)phenyl)-3-((4-fluorobenzyl)amino)pyrazine-2- carboxamide (Compound 50), and pharmaceutically acceptable salts thereof.

[0055] The Compound numbers correspond to the Example numbers provided in Table 1 below. Althought the salt form may be depicted in Table 1, non-salt forms are included in the present invention.

[0056] Table 1.

Example

Example Name Example Structure Number

N-(4-cyanophenyl)-3-((4-

39

fluorobenzyl)amino)pyrazine-2-carboxamide

3-((4-fluorobenzyl)amino)-N-(3-

40 (trifluoromethyl)phenyl)pyrazine-2- carboxamide

3-((4-fluorobenzyl)amino)-N-(5-

41 (trifluoromethyl)pyridin-3-yl)pyrazine-2- carboxamide

0

N-(4-acetylphenyl)-3-((4-

42

fluorobenzyl)amino)pyrazine-2-carboxamide

3-((4-fluorobenzyl)amino)-N-(4-

43 (trifluoromethoxy)phenyl)pyrazine-2- carboxamide dp*

3-((4-fluorophenyl)amino)-N-(4-

44 (trifluoromethyl)phenyl)pyrazine-2- _p

carboxamide trifluoroacetic acid salt Example

Example Name Example Structure Number

4-((4-fluorobenzyl)amino)-N-(6-

45 (trifluoromethyl)pyridin-3-yl)pyrimidine-5- carboxamide

N-(3-cyano-4-(trifluoromethyl)phenyl)-3-((4-

46

fluorobenzyl)amino)pyrazine-2-carboxamide

N-(3-cyano-4-(trifluoromethyl)phenyl)-2-((4-

47

fluorobenzyl)amino)nicotinamide

2-((4-fluorobenzyl)amino)-N-(4-

48

((trifluoromethyl)sulfonyl)phenyl)nicotinamide

N-(4-cyano-3-(trifluoromethyl)phenyl)-2-((4-

49

fluorobenzyl)amino)nicotinamide

N-(4-cyano-3-(trifluoromethyl)phenyl)-3-((4-

50

fluorobenzyl)amino)pyrazine-2-carboxamide

Example

Example Name Example Structure Number

N-(6-cyanopyridin-3-yl)-2-((4-

96

fluorobenzyl)amino)nicotinamide

2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-

97

N- (6- (trifluoromethyl)pyridin- 3 - yl) nicotinamide

3-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-

98 N-(4-(trifluoromethyl)phenyl)pyrazine-2- carboxamide

2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-

99

N- (4- (trifluoromethyl)phenyl) nicotinamide

tert-butyl 4-(((3-((4-

100 (trifluoromethyl)phenyl)carbamoyl)pyridin-2- yl)amino)methyl)piperidine- 1 -carboxylate

2-((piperidin-4-ylmethyl)amino)-N-(4-

101 (trifluoromethyl)phenyl)nicotinamide

trifluoroacetic acid salt

[0057] In one aspect, the compounds of the invention are useful in treating disorders responsive to enhancement of acetylcholine action on a7 nAChRs in a mammal by administering an effective amount of a compound of Formula I as described herein. Compounds of the present invention may be used in the treatment and/or prevention of a variety of disorders, including those of the central nervous system (CNS) and the peripheral nervous system (PNS). In one embodiment, disorders of the CNS and the PNS include neurodegenerative diseases, senile dementias, schizophrenia, Alzheimer's disease, learning, cognition and attention deficits, cognitive impairment associated with schizophrenia (CIAS), cognitive impairment due to major depression, cognitive impairment due to bipolar disease, cognitive impairment due to Alsheimer's disease, memory loss, Lewy Body dementia, attention-deficit disorder, attention deficit hyperactivity disorder, anxiety, mania, manic depression, Parkinson' s disease,

Huntington's disease, depression, amyotrophic lateral sclerosis, brain inflammation, cognitive deficit due to traumatic brain injury, Tourette' s syndrome, and autism spectrum disorder. Compounds of the invention are also useful in the treatment (therapeutic or prophylactic), prevention or delay of progression of dyskinesia associated with dopamine agonist therapy in Parkinson's disease. In addition, compounds of the present invention may be used to treat pain, inflammation, septic shock, ulcerative colitis, irritable bowel syndrome and Crohn's disease. In addition, compounds of the invention are useful in tobacco cessation treatment (Brunzell et al. Neuropsychopharm. 2011, 1-10), in the treatment of diabetes (Marrero et al. JPET, 2009, 332, 173) and in treating jetlag.

Compounds are also useful in treating immune system disorders, Fragile X, autism spectrum disorder, Angelman's syndrome, Rett syndrome, Prader Willi syndrome and Down' s syndrome. In addition, the compounds of the present invention may be used to treat immune system disorders, such as, but not limited to, type I diabetes, multiple sclerosis, and rheumatoid arthritis. In addition, the compounds of the invention can be used in treating or preventing jet lag. In addition, the compounds of the invention can be used to treat a neurodegenerative disorder. In addition, the compounds of the invention can be used to treat senile dementia. In addition, the compounds of the invention can be used to treat cognitive impairment associated with Alzheimer's disease. In addition, the compounds of the invention can be used to treat schizophrenia. In addition, the compounds of the invention can be used to treat mild cognitive impairment. In addition, the compounds of the invention can be used to treat Parkinson's disease. In addition, the compounds of the invention can be used to treat Lewy body dementia. In addition, the compounds of the invention can be used to treat cognitive impairment due to major depression. In addition, the compounds of the invention can be used to treat

inflammation. In addition, the compounds of the invention can be used to treat brain inflammation. In addition, the compounds of the invention can be used to treat an immune system disorder. In addition, the compounds of the invention can be used to treat pain, inflammation, septic shock, ulcerative colitis, Crohn's disease, or irritable bowel syndrome. In addition, the compounds of the invention may be used to treat a cognitive disorder related to learning or memory including mild cognitive impairment, age related cognitive decline, senile dementia and Alzheimer' s disease. In addition, the compounds of the invention may be used to treat cognitive impairment associated with senile dementia and cognitive impairment associated with Alzheimer's disease. In addition, the compounds of the invention can be used to treat autism spectrum disorder. In addition, the compounds of the present invention can be used in treating cognitive impairment associated with schizophrenia (CIAS). In addition, the compounds of the present invention can be used in treating cognitive impairment due to major depression. In addition, the compounds of the present invention can be used in treating cognitive impairment due to bipolar disease.

[0058] In one aspect, the compounds of the present invention that have at least 50% modulation of the nicotine EC₅ using 0.3 μΜ of the compound in Xenopus oocytes are used in the methods of treatment. In another aspect, such compounds inhibit VEGF activity with an IC50 of greater than 1 μΜ. In other such embodiments, the compounds also exhibit greater than 75% phosphorylation of VEGFR2 using 1 μΜ of test compound in the "VEGF Inhibition Assay". In other such embodiments, the compounds also exhibit near 100% or higher phosphorylation of VEGFR2 using 1 μΜ of test compound in the "VEGF Inhibition Assay". [0059] In one aspect, the compounds of the present invention that have at least 100% modulation of the nicotine EC₅ using 0.3 μΜ of the compound in Xenopus oocytes are used in the methods of treatment. In another aspect, such compounds inhibit VEGF activity with an IC50 of greater than 1 μΜ. In other such embodiments, the compounds also exhibit greater than 75% phosphorylation of VEGFR2 using 1 μΜ of test compound in the "VEGF Inhibition Assay". In other such embodiments, the compounds also exhibit near 100% or higher phosphorylation of VEGFR2 using 1 μΜ of test compound in the "VEGF Inhibition Assay".

[0060] In one aspect, the compounds of the present invention that have at least 500% modulation of the nicotine EC5 using 0.3 μΜ of the compound in Xenopus oocytes are used in the methods of treatment. In another aspect, such compounds inhibit VEGF activity with an IC50 of greater than 1 μΜ. In other such embodiments, the compounds also exhibit greater than 75% phosphorylation of VEGFR2 using 1 μΜ of test compound in the "VEGF Inhibition Assay". In other such embodiments, the compounds also exhibit near 100% or higher phosphorylation of VEGFR2 using 1 μΜ of test compound in the "VEGF Inhibition Assay".

[0061] In one aspect, the compounds of the present invention that have at least 1000% modulation of the nicotine EC5 using 0.3 μΜ of the compound in Xenopus oocytes are used in the methods of treatment. In another aspect, such compounds inhibit VEGF activity with an IC50 of greater than 1 μΜ. In other such embodiments, the compounds also exhibit greater than 75% phosphorylation of VEGFR2 using 1 μΜ of test compound in the "VEGF Inhibition Assay". In other such embodiments, the compounds also exhibit near 100% or higher phosphorylation of VEGFR2 using 1 μΜ of test compound in the "VEGF Inhibition Assay".

[0062] In one aspect, the compounds of the present invention that have at least 2000% modulation of the nicotine EC5 using 0.3 μΜ of the compound in Xenopus oocytes are used in the methods of treatment. In another aspect, such compounds inhibit VEGF activity with an IC50 of greater than 1 μΜ. In other such embodiments, the compounds also exhibit greater than 75% phosphorylation of VEGFR2 using 1 μΜ of test compound in the "VEGF Inhibition Assay". In other such embodiments, the compounds also exhibit near 100% or higher phosphorylation of VEGFR2 using 1 μΜ of test compound in the "VEGF Inhibition Assay". [0063] In another aspect, there is provided pharmaceutical compositions comprising a compound of Formula I, and pharmaceutically acceptable salts, solvate, and prodrugs thereof, and a pharmaceutically acceptable excipient, carrier or diluent. In another aspect, there is provided pharmaceutical compositions comprising a compound of Formula I, and pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable excipient, carrier or diluent.

[0064] In yet another aspect there is provided the use of a compound of Formula I, pharmaceutically acceptable salts, solvates, and prodrugs thereof, as a medicament, and in one aspect a medicament for use in the various indications provided herein. In another aspect, the present invention is directed a compound of Formula I or a pharmaceutically acceptable salt, solvate, or prodrug thereof to treat disorders amenable to modulation of a7 nAChRs. In one embodiment, the disorder is a neurodegenerative disorder. In another embodiment, the disorder is a senile dementia. In another embodiment, the disorder is schizophrenia. In another embodiment, the disorder is a cognition deficit disorder. In another embodiment, the disorder is cognitive impairment due to Alzheimer' s disease. In another embodiment, the disorder includes cognition and attention deficits, memory loss, Lewy Body dementia, attention-deficit disorder, attention deficit hyperactivity disorder, anxiety, mania, manic depression, Parkinson's disease, Huntington's disease, depression, amyotrophic lateral sclerosis, brain inflammation, cognitive deficit due to traumatic brain injury, and Tourette's syndrome. In another embodiment, the disorder is, pain, inflammation, septic shock, ulcerative colitis, Crohn's disease, and irritable bowel syndrome. In another embodiment the disorder is inflammation. In another embodiment, the disorder is depression and the treatment comprising the administration of a compound of Formula I or a pharmaceutically acceptable salt or prodrug thereof and the administration of an SSRI drug, a drug that augments 5-HT release or blocks 5-HT reuptake. In yet another embodiment, the disorder is an immune system disorder. In yet another embodiment, the disorder is cognitive impairment associated with schizophrenia. In yet another embodiment, the disorder is cognitive impairment due to major depression. In yet another embodiment, the disorder is cognitive impairment due to bipolar disease.

[0065] In another aspect, there is provided a method for the treatment of disorders related to learning and memory such as mild cognitive impairment, age related cognitive decline, senile dementia, and Alzheimer's disease comprising administering to a patient in need of such treatment a compound of Formula I or a pharmaceutically acceptable salt, solvates or prodrug thereof. In one embodiment the treatment of such disorders is achieved via modulation of mono and divalent cation conductance through the site mediating the action of a compound of Formula I or a pharmaceutically acceptable salt, solvates, or prodrug thereof.

[0066] In another aspect, there is a provided a method for the treatment of Fragile X, autism spectrum disorder, Angelman's syndrome, Rett syndrome, Prader Willi syndrome and Down' s syndrome by administering a compounds of Formula I, a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0067] For use in medicine, the salts of the compounds of Formula I will be pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds according to the invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, hydobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, fumaric acid, maleic acid, succinic acid, formic acid, acetic acid, proprionic acid, glycolic acid, pyruvic acid, malonic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, cinnamic acid, mandelic acid, sulfonic acids, salicilic acid, or phosphoric acid. Furthermore, where the compound comprises an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic ligands, e.g. quaternary ammonium salts. Examples of other salts formed with acidic compounds include aluminum salts, procaine, dibenzylamine, N- ethylpiperine, Ν,Ν'-dibenzylethylenediamine, and triethylamine salts. Standard methods for the preparation of pharmaceutically acceptable salts and their formulations are well known in the art, and are disclosed in various references, including for example, "Remington: The Science and Practice of Pharmacy", A. Gennaro, ed., 20th edition, Lippincott, Williams & Wilkins, Philadelphia, PA.

[0068] The present invention includes prodrugs of the compounds of Formula I above. In general, such prodrugs will be functional derivatives of the compounds of Formula I that are readily convertible in vivo into the required compound of Formula I. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985. Such prodrugs include but are not limited to ester prodrugs from alcohols and acids, phosphate prodrugs of alcohols, and N-oxide derivatives of heteroaryl moieties. The prodrug can be a formulation to achieve a goal of improved chemical stability, improved patient acceptance and compliance, improved bioavailability, prolonged duration of action, improved organ selectivity, improved formulation (e.g., increased hydro solubility), and/or decreased side effects (e.g., toxicity).

[0069] Where the compounds of the present invention have at least one asymmetric center, they may accordingly exist as enantiomers. Where the compounds possess two or more asymmetric centers, they may additionally exist as diastereoisomers. It is to be understood that all such stereoisomers and mixtures thereof in any proportion are encompassed within the scope of the present invention. Where the compounds possess geometrical isomers, all such isomers and mixtures thereof in any proportion are encompassed within the scope of the present invention.

[0070] Tautomers of the compounds of the invention are encompassed by the present application. Thus, for example, a carbonyl includes its hydroxyl tautomer.

[0071] In the above methods of use, it is contemplated that a compound of Formula I would be used:

I

or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:

n is an integer 0 or 1 ;

1 is selected from the group consisting of

R² is selected from the group consisting of

4-halophenyl, (Cl-C2)-4-fluoroaIkoxyphenyl, 2-hydroxyphenyl, 3- methoxyphenyl, 4-methoxyphenyl, and 2-isoxazol-3-yl; R³ is selected from the group consisting of -H, halogen, -CF3, -CN, -OCF3, - S(0)₂CF₃, -OH, and -OCH₂cyclopropyl;

R⁴ is selected from the group consisting of -H, halogen, -CF3, -CN, -CH2OH, and -CH₂N(CH₃)₂;

R⁵ is selected from the group consisting of -H, halogen, -OCH3, and -OCF3;

X³ and X⁴ are independently selected from the group consisting of N and CH; X⁵ is selected from the group consisting of N and CR³; and

X⁶ is selected from the group consisting of N and CR⁵ wherein at least two of X³ , X⁴ , X⁵ and X⁶ have a carbon; with the provisos that when X¹ and X² are CH, n is 1 , and R² is 4-fluorophenyl, then R¹ is not 4-(trifluoromethyl)phenyl; and that when X¹ and X² are CH, n is 1, and R² is 4- halophenyl, then R¹ is not 3-(trifluoromethyl)phenyl.

[0072] In one embodiment in the above methods of use, R² is selected from the group consisting of 4-halophenyl, (Cl-C2)-4-fluoroaIkoxyphenyl, 2-hydroxyphenyl, 3- methoxyphenyl, and 4-methoxyphenyl. In another embodiment, R² is 4-halophenyl, or

(Cl-C2)-4-haloalkoxyphenyl. In one such embodiment, the (Cl-C2)-4-haloalkoxyphenyl is 4-fluoromethoxyphenyl or 4-trifluoromethoxyphenyl.

[0073] In one embodiment in the above methods of use, X² is CH.

[0074] In one embodiment in the above methods of use, X² is CH, and X¹ is N.

[0075] In one embodiment in the above methods of use, n is 1.

[0076] in the above methods of use, R¹ is

[0077] In one embodiment in the above methods of use, R³ is selected from the group consisting of -CF3, -OCF3, and -CN.

[0078] In one embodiment in the above methods of use, R⁴ is selected from the group consisting of -H, -CF3, and -CN.

[0079] nt in the above methods of use, R¹ is

[0080] nt in the above methods of use, R¹ is

[0081] in the above methods of use, X² is CH, n is 1 , and R¹ is

[0082] in the above methods of use, X² is CH, n is 1 , and R¹ is

is selected from the group consisting of 4-halophenyl, and (Cl-

C2)-4-fluoroalkoxyphenyl, X³ and X⁴ are CH, X⁵ is CR³ and X⁶ is CR⁵ , provided that R¹ is not unsubstituted phenyl. In one such embodiment, R³ is selected from the group consisting of -CF3, -OCF3, and -CN. In one such embodiment, R⁴ is selected from the group consisting of -H, -CF3, and -CN. [0083] In one embodiment in the above methods of use, X² is CH, X¹ is N, n is 1, and R¹ is

. In one such embodiment, R² is selected from the group consisting of 4-halophenyl, and (Cl-C2)-4-fluoroalkoxyphenyl, X³ is CH, X⁴ is N, X⁵ is CR³ and X⁶ is CR⁵, provided that R¹ is not unsubstituted pyridyl. In one such embodiment, R³ is selected from the group consisting of -CF3, -OCF3, and -CN. In one such embodiment, R⁴ is selected from the group consisting of -H, -CF3, and -

CN.

[0084] In one embodiment in the above methods of use, X² is CH, X¹ is N, n is 1, and R¹ is

, R² is selected from the group consisting of 4-halophenyl, and (Cl-

C2)-4-fluoroalkoxyphenyl, X³ and X⁴ are CH, X⁵ is CR³ and X⁶ is CR⁵ , provided that R¹ is not unsubstituted phenyl. In one such embodiment, R³ is selected from the group consisting of -CF3, -OCF3, and -CN. In one such embodiment, R⁴ is selected from the group consisting of -H, -CF3, and -CN.

[0085] In one embodiment in the above methods of use, the compounds of Formula I modulate the activity of an EC5 concentration of nicotine in Xenopus oocytes by at least 50% when using 0.3 μΜ of the compound. In such embodiment, the compounds also inhibit VEGF activity with an IC50 greater than Ι μΜ. In other such embodiments, the compounds also exhibit greater than 75% phosphorylation of VEGFR2 using 1 μΜ of test compound in the "VEGF Inhibition Assay". In other such embodiments, the compounds also exhibit near 100% or higher phosphorylation of VEGFR2 using 1 μΜ of test compound in the "VEGF Inhibition Assay".

[0086] In one embodiment in the above methods of use, the compounds of Formula I modulate the activity of an EC5 concentration of nicotine in Xenopus oocytes by at least 100% when using 0.3 μΜ of the compound. In such embodiment, the compounds also inhibit VEGF activity with an IC50 greater than Ι μΜ. In other such embodiments, the compounds also exhibit greater than 75% phosphorylation of VEGFR2 using 1 μΜ of test compound in the "VEGF Inhibition Assay". In other such embodiments, the compounds also exhibit near 100% or higher phosphorylation of VEGFR2 using 1 μΜ of test compound in the "VEGF Inhibition Assay"..

[0087] In one embodiment in the above methods of use, the compounds of Formula I modulate the activity of an ECs concentration of nicotine in Xenopus oocytes by at least 500% when using 0.3 μΜ of the compound. In such embodiment, the compounds also inhibit VEGF activity with an IC50 greater than Ι μΜ. In other such embodiments, the compounds also exhibit greater than 75% phosphorylation of VEGFR2 using 1 μΜ of test compound in the "VEGF Inhibition Assay". In other such embodiments, the compounds also exhibit near 100% or higher phosphorylation of VEGFR2 using 1 μΜ of test compound in the "VEGF Inhibition Assay"..

[0088] In one embodiment in the above methods of use, the compounds of Formula I modulate the activity of an EC5 concentration of nicotine in Xenopus oocytes by at least 1000% when using 0.3 μΜ of the compound. In such embodiment, the compounds also inhibit VEGF activity with an IC50 greater than Ι μΜ. In other such embodiments, the compounds also exhibit greater than 75% phosphorylation of VEGFR2 using 1 μΜ of test compound in the "VEGF Inhibition Assay". In other such embodiments, the compounds also exhibit near 100% or higher phosphorylation of VEGFR2 using 1 μΜ of test compound in the "VEGF Inhibition Assay"..

[0089] In one embodiment in the above methods of use, the compounds of Formula I modulate the activity of an EC5 concentration of nicotine in Xenopus oocytes by at least 2000% when using 0.3 μΜ of the compound. In such embodiment, the compounds also inhibit VEGF activity with an IC50 greater than Ι μΜ. In other such embodiments, the compounds also exhibit greater than 75% phosphorylation of VEGFR2 using 1 μΜ of test compound in the "VEGF Inhibition Assay". In other such embodiments, the compounds also exhibit near 100% or higher phosphorylation of VEGFR2 using 1 μΜ of test compound in the "VEGF Inhibition Assay"..

[0090] In one embodiment in the above methods of use, the compounds of Formula I include N-(5-cMoropyridin-2-yl)-2-((4-fluorobenzyl)amino)nicotinamide (Compound 3);

3-((4-fluorobenzyl)amino)-N-(4-(trifluoromethyl)phenyl)pyrazine-2-carboxamide (Compound 23); N-(3-fluoro-4-(trifluoromethyl)phenyl)-3-((4-fluorobenzyl)amino)pyrazine-2- carboxamide (Compound 26);

2- ((4-fluorobenzyl)amino)-N-(6-(trifluoromethyl)pyridin-3-yl)nicotinamide (Compound 31);

N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-((4-fluorobenzyl)amino)pyrazine-2- carboxamide (Compound 38);

2-((4-fluorobenzyl)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

(Compound 80);

and pharmaceutically acceptible salts thereof.

[0091] In one embodiment in the above methods of use, the compounds of Formula I include N-(5-cMoropyridin-2-yl)-2-((4-fluorobenzyl)amino)nicotinamide (Compound 3); 3-((4-fluorobenzyl)amino)-N-(6-(trifluoromethyl)pyridin-3-yl)pyrazine-2- carboxamide (Compound 20);

2-((4-fluorobenzyl)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

(Compound 80);

N-(6-cyanopyridin-3-yl)-2-((4-fluorobenzyl)amino)nicotinamide (Compound 96); N-(2-fluoro-4-(trifluoromethyl)phenyl)-2-((4-fluorobenzyl)amino)nicotinamide (Compound 105);

2-((4-methoxybenzyl)amino)-N-(4-(trifluoromethyl)phenyl)nicotinamide

(Compound 111);

2-((3-methoxybenzyl)amino)-N-(4-(trifluoromethyl)phenyl)nicotinamide

(Compound 112);

2- ((2-hydroxybenzyl)amino)-N-(4-(trifluoromethyl)phenyl)nicotinamide

(Compound 115); and

pharmaceutically acceptable salts thereof.

[0092] In one embodiment in the above methods of use, the compounds of Formula I include

N-(4-chlorophenyl)-3-((4-fluorobenzyl)amino)pyrazine-2-carboxamide

(Compound 7);

N-(4-cyanophenyl)-3-((4-fluorobenzyl)amino)pyrazine-2-carboxamide

(Compound 39);

3-((4-fluorobenzyl)amino)-N-(6-(trifluoromethyl)pyridin-3-yl)pyrazine-2- carboxamide (Compound 20); 3-((4-fluorobenzyl)amino)-N-(4-(trifluoromethoxy)phenyl)pyrazine-2- carboxamide (Compound 43);

Formulations

[0093] Compounds of the invention are administered orally in a total daily dose of about 0.001 mg/kg/dose to about 100 mg/kg/dose, alternately from about 0.01 mg/kg/dose to about 10 mg/kg/dose. The use of time-release preparations to control the rate of release of the active ingredient may be employed. The dose may be administered in as many divided doses as is convenient. When other methods are used (e.g. intravenous administration), compounds are administered to the affected tissue at a rate from 0.05 to 10 mg/kg/hour, alternately from 0.1 to 1 mg/kg/hour. Such rates are easily maintained when these compounds are intravenously administered as discussed below.

[0094] For the purposes of this invention, the compounds may be administered by a variety of means including orally, parenterally, by inhalation spray, topically, or rectally in formulations containing pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used here includes subcutaneous, intravenous, intramuscular, and intraarterial injections with a variety of infusion techniques. Intraarterial and intravenous injection as used herein includes administration through catheters. Oral administration is generally employed.

[0095] Pharmaceutical compositions containing the active ingredient may be in any form suitable for the intended method of administration. When used for oral use for example, tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable. These excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.

[0096] Formulations for oral use may be also presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.

[0097] Aqueous suspensions of the invention contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydro xypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxy-benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin. [0098] Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oral suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.

[0099] Dispersible powders and granules of the invention suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those disclosed above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.

[00100] The pharmaceutical compositions of the invention may also be in the form of oil-in- water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, a mineral oil, such as liquid paraffin, or a mixture of these. Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening and flavoring agents.

[00101] Syrups and elixirs may be formulated with sweetening agents, such as glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent.

[00102] The pharmaceutical compositions of the invention may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol or prepared as a lyophilized powder. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils may conventionally be employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may likewise be used in the preparation of injectables.

[00103] The amount of active ingredient that may be combined with the carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a time-release formulation intended for oral administration to humans may contain approximately 0.01 to 1000 mg of active material compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 99% of the total compositions. The pharmaceutical composition can be prepared to provide easily measurable amounts for administration. For example, an aqueous solution intended for intravenous infusion should contain from about 1 to 1000 μg of the active ingredient per milliliter of solution in order that infusion of a suitable volume at a rate of about 10 mL/hr can occur.

[00104] As noted above, formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be administered as a bolus, electuary or paste.

[00105] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free flowing form such as a powder or granules, optionally mixed with a binder (e.g., povidone, gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose) surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropyl methylcellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach. This is particularly advantageous with the compounds of Formula I when such compounds are susceptible to acid hydrolysis. [00106] Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

[00107] Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.

[00108] Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.

[00109] Formulations suitable for parenteral administration include aqueous and nonaqueous isotonic sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

[00110] Suitable unit dosage formulations are those containing a daily dose or unit, daily sub-dose, or an appropriate fraction thereof, of a compound of Formula I.

[00111] It will be understood, however, that the specific dose level for any particular patient will depend on a variety of factors including the activity of the specific compound employed; the age, body weight, general health, sex and diet of the individual being treated; the time and route of administration; the rate of excretion; other drugs which have previously been administered; and the severity of the particular disease undergoing therapy, as is well understood by those skilled in the art.

[00112] In order that the invention may be readily understood, particular embodiments will now be described by way of the following non-limiting examples.

Examples

[00113] General Methods [00114] Standard procedures and chemical transformation and related methods are well known to one skilled in the art, and such methods and procedures have been described, for example, in standard references such as Fiesers' Reagents for Organic Synthesis, John Wiley and Sons, New York, NY, 2002; Organic Reactions, vols. 1-83, John Wiley and Sons, New York, NY, 2006; March J. and Smith M.: Advanced Organic Chemistry, 6th ed., John Wiley and Sons, New York, NY; and Larock R.C.: Comprehensive Organic Transformations, Wiley- VCH Publishers, New York, 1999. All texts and references cited herein are incorporated by reference in their entirety.

[00115] Reactions using compounds having functional groups may be performed on compounds with functional groups that may be protected. A "protected" compound or derivatives means derivatives of a compound where one or more reactive site or sites or functional groups are blocked with protecting groups. Protected derivatives are useful in the preparation of the compounds of the present invention or in themselves; the protected derivatives may be the biologically active agent. An example of a comprehensive text listing suitable protecting groups may be found in T. W. Greene, Protecting Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, Inc. 1999.

[00116] Compounds of Formula I can be prepared according to scheme X. Reaction of 2-chloronicotinoyl chloride with a substituted aromatic amine yields the expected amide. Reaction of this amide with a primary amine in DMSO then affords compounds of Formula I.

[00117] Scheme X

Reagents/Solvents: a. Substituted Anilines/Aminopyridines/CH₂CI₂ b. R₂NH₂/DMSO/Heat

[00118] Compounds of Formula I can also be prepared according to Scheme Y. Reaction of 2-chloro nicotinoic acid (or 3-chloropyrazine-2-carboxylic acid) with a substituted aromatic amine in the presence of a coupling agent such as HATU (1- [Bis(dimethylamino)methylene]- 1H- 1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) yields the expected amide. Reaction of this amide with a primary amine then provides compounds of Formula I. [00119] Scheme Y

X=N, CH

Reagents/Solvents: a. Substituted Anilines/Aminopyridines/DMF/HATU b. R₂NH₂/DMSO/Heat

[00120] Most of chemicals were purchased from Sinopharm Chemical Reagent Co.(SCRC), Sigma- Aldrich, Alfa or other vendors.

[00121] ¾ NMR or ¹⁹F NMR spectra were recorded on Bruker AV lll 400 or Bruker AV III 500.

[00122] LCMS measurements were run on an Agilent 1200 HPLC/6100 SQ System using the follow conditions:

[00123] HPLC Method A: Mobile Phase: A: Water (0.01% TFA) B: ACN (0.01% TFA); Gradient Phase: 5% B increase to 95% B within 1.4 min, 95% B with 1.6 min (total runtime: 3 min); Flow Rate: 2.3 mL/min; Column: SunFire C18, 4.6*50mm, 3.5μιη ; Column Temperature: 50 °C. Detectors: ADC ELSD, DAD (214 nm and 254 nm), ES- API.

[00124] HPLC Method B: Mobile Phase: A: Water (10 mM NH4HCO3) B: Acetonitrile; Gradient Phase: 5% to 95% B within 1.5 min, 95% B for 1.5 min (total runtime:3 min); Flow Rate: 2.0 mL/min; Column: XBridge C18, 4.6*50 mm, 3.5 μιη ; Column Temperature: 40 °C. Detectors: ADC ELSD, DAD(214 nm and 254 nm), MSD (ES-API).

HPLC was taken on an Agilent LC 1200 instrument. Mobile phase: A: water (0.01% TFA) B: ACN (0.01% TFA), Gradient: 0 min 5% B, 3 min 5% B, 10 min 95% B, 15 min 95% B. Flow Rate: 1.2 mL/min, Column: Eclipse XDB-C18, 4.6*150 mm, 5 μτη, Column Temperature: 40 °C. Detectors: DAD (214 nm and 254 nm), MSD (ES-API).

[00125] General Synthetic Procedures

[00126] General Procedure A:

5 A2

[00127] To a solution of 5-chloro-lH-indole (5) (1.50 g, 9.93 mmols, 1.0 eq) in glacial acetic acid (10 niL) under nitrogen at 15 - 17 °C was added in one portion sodium cyanoborohydride (1.94 g, 30.8 mmols, 3.1 eq). After the addition, the mixture was stirred for 2 hours at 15 - 17 °C. Water (50 mL) was then added and the mixture was cooled in an ice-bath. Sodium hydroxide pellets were added slowly until a strong basic pH (10 ~ 12) was obtained. The mixture was extracted with diethyl ether. The organic layer was washed sequentially with water and brine. The organic extracts were dried over Na2S0₄, filtered and concentrated. The residue was purified by SGC (eluting with PE/EA, 10/1 to 8/1) to give A2 (700 mg, 4.57 mmols, 46.0%) as a light yellow oil.

[00128] LCMS: ESI-MS: m/z: 153.9 [M+H]⁺; RT = 1.37 min. (Method A).

[00129] The same General Procedure A can be used to produce other intermediates by substituting the starting indole with another appropriate indole.

[00130] General Procedure B:

9 Coupling Product B

[00131] A solution of 9 (119 mg, 0.657 mmols, 1.5 eq), Al (100 g, 0.438 mmols, 1.0 eq), HATU (333 mg, 0.876 mmols, 2.0 eq) and DIPEA (170 mg, 1.31 mmols, 3.0 eq) in DMF (10 mL) was stirred at 25 °C overnight under nitrogen. The mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over Na2S0₄, filtered and concentrated. The residue was purified by Preparative-TLC (Petroleum ether/ethyl acetate, 2/1) to give the desired product Coupling Product B (120 mg, 0.307 mmols, 69.8%) as a white solid.

[00132] LCMS: ESI-MS: m/z: 392.2 [M+H]⁺; RT = 2.04 min. (Method A)

[00133] HPLC: RT = 10.53 min. [00134] ^LH NMR (500 MHz, DMSO-d<5): δ 8.11 (dd, 1H, Ji = 5.0Hz, h = 1.0Hz), 7.82 (brs, 1H), 7.58 (dd, 1H, Ji = 7.0Hz, h = 1.5Hz), 7.38 (d, 1H, / = 2.5Hz), 7.30 - 7.25 (m, 5H), 7.19 (t, 1H, / = 6.5Hz), 7.08 (t, 1H, / = 6.0Hz), 6.62 (dd, 1H, Ji = 7.0Hz, J₂ = 5.0Hz), 4.57 (d, 2H, / = 5.5Hz), 3.74 (s, 2H), 1.26 (s, 6H) ppm.

[00135] The same General Procedure B can be used to couple other combinations of amines and carboxylic acids to form the corresponding amides.

[00136] General Procedure C:

[00137] Compound 13 was synthesized by the reaction of compound 8 and 5- chloroisoindoline using the General Procedure B. Yield: 61.6%

[00138] LCMS: ESI-MS : m/z: 293.1 [M+H]⁺; RT = 1.81 min. (Method A)

[00139] The mixture of 13 (180 mg, 0.616 mmols) and benzamine (2.0 mL) in DMSO

(5 mL) was stirred at 150 °C for 16 h after being degassed and protected with N₂. Added ethyl acetate (100 mL) and washed with aqueous HC1 (2 N, 30 mL x 3) then the organic layer was dried over Na2SC¼ and concentrated to be purified by chromatography column

(Petroleum ether/ethyl acetate , 5/1) to give the desired Coupling Product C (80.0 mg,

0.229 mmols, 37.2 %) as a white solid.

[00140] The same General Procedure C can be used to couple other combinations of amines and carboxylic acids to form the corresponding amides, followed by coupling of a second amine to form an appropriate substituted amine.

[00141] General Procedure D:

[00142] A mixture of 19 (1.50 g, 9.49 mmols, 1.0 eq), l-(4-fluorophenyl)ethanamine (2.64 g, 19.0 mmols, 2.0 eq) and K₂C0₃ (3.93 g, 28.5 mmols, 3.0 eq) in NMP (30 mL) was degassed, purged with nitrogen, and stirred at 140 °C for 16 hours. The mixture was diluted with ethyl acetate (100 mL) and washed with 2 N aqueous HCl (30 mL x 3). The organic layer was dried over Na2SC¼, filtered, and concentrated, the residue was purified by recrystallization (Petroleum ether/ethyl acetate) to give the desired product 20 (2.00 g, 7.66 mmols, 80.6%) as a white solid.

[00143] LCMS: ESI-MS: m/z: 262.2 [M+H]⁺; RT = 1.87 min. (Method A).

[00144] General Procedure D can be used to couple various haloheteroarylacids with various amines to form the desired substituted aminoarylacids.

[00145] G

Coupling Product E

[00146] To a mixture of 20 (400 mg, 1.53 mmols, 1.0 eq) in dichloromethane (15 mL) was added oxalyl chloride (0.175 mL, 1.84 mmols, 1.2 eq) and DMF (0.005 mL, a catalytic amount) at 0 °C dropwise. The mixture was stirred at room temperature overnight under nitrogen. The mixture was concentrated to give the desired product 21 (430 mg, crude) as a light yellow solid, which was used in the next step directly without further purification.

[00147] To a mixture of 5 (231 mg, 1.53 mmols, 1.0 eq) in anhydrous THF (6 mL) was added NaH (122 mg, 3.06 mmols, 2.0 eq, 60 % in oil) at 0 °C under nitrogen. After the addition was complete, the reaction mixture was stirred at room temperature for 30 minutes. A solution of 21 (430 mg, crude, 1.0 eq) in THF (5 mL) was added dropwise at 0 °C. The reaction mixture was stirred at room temperature overnight under nitrogen. The mixture was quenched with water (10 mL), and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic extracts were washed with brine, dried over Na2S0₄, filtered, and concentrated. The residue was purified by preparative-TLC (Petroleum ether/ethyl acetate, 2/1) to give the desired product Coupling Product E (120 mg, 0.304 mmols, 19.9% for two steps) as a yellow solid.

[00148] LCMS: ESI-MS: m/z: 395.1 [M+H]⁺; RT = 2.48 min. (Method A)

[00149] HPLC: RT = 12.72 min.

[00150] ¾ NMR (500 MHz, DMSO-d<5): δ 8.34 (d, / = 8.8 Hz, 1H), 8.29 (d, / = 2.3 Hz, 1H), 8.02 - 7.94 (m, 2H), 7.92 (d, J = 2.4 Hz, 1H), 7.75 (d, J = 2.1 Hz, 1H), 7.47 (dd, 7 = 8.6, 5.6 Hz, 2H), 7.40 (dd, J = 8.8, 2.1 Hz, 1H), 7.14 (t, J = 8.9 Hz, 2H), 6.73 (d, J = 3.8 Hz, 1H), 5.31 (t, J = 7.1 Hz, 1H), 1.52 (d, / = 6.9 Hz, 3H).

[00151] General Procedure E can be used to couple other combinations of amines and carboxylic acids, through the corresponding acid chloride, to form the corresponding amides.

[00152] Synthesis of common Intermediate 14:

[00153] Step l :

[00154] To an ice-cooled mixture of compound 8 (12.7 mmols, 2.0 g, 1.0 eq) in dichloromethane (25 mL) were added oxalyl chloride (1.80 mL, 19.1 mmols, 1.5 eq) and DMF (0.5 mL). The reaction mixture was stirred at 25 °C for 1 hours. Formation of the acid chloride was monitored by quenching an aliquot with methanol and analyzing by TLC to check the formation of methyl ester with respect to acid 8. At the end of the reaction, solvent was evaporated under reduced pressure and the residue was used directly for Step 2.

[00155] Step 2: [00156] Acid chloride obtained from Step 1, was taken up in dichloro methane (20 mL) and a solution of 2 (11.5 mmols, 1.9 g, 0.9 eq) and triethyl amine (38.2 mmols, 3.86 g, 3.0 eq) in dichloromethane (10 mL) was added drop wise at 0 °C. The reaction was stirred at 25 °C for 30 min. The reaction progress was monitored by TLC. It was then diluted with dichloromethane, and washed successively with saturation solution ammonium chloride, saturation solution sodium bicarbonate and brine. The crude product was purified by silica gel chromatography (Petroleum ether/ethyl acetate, 4/1) to give the desired product 14 (2.00 g, 6.53 mmols, 51.3%) as a white solid.

[00157] In general, the synthetic route for Common Intermediate 14 can be used to couple a variety of aryl acids, through their corresponding acid chlorides, with various amines.

[00158] Synthetic Procedures

[00159] Example 1

[00160] N-(5-chloropyridin-2-yl)-3-((4-fluorobenzyl)amino)pyrazine-2-carboxamide

[00161] Compound 30 was similarly prepared as the synthesis of Intermediate 14, while in Step 2, pyridine was used as the base and solvent. Yield: 44.2%

[00162] A mixture of 30 (200 mg, 0.746 mmols) and (4-fluorophenyl)methanamine (2 mL, excess) was sealed and heated to 100 °C for 16 hours. To the reaction mixture was added ethyl acetate (100 mL) and washed with 2 N aqueous HC1 (30 mL x 3). The organic layer was dried over Na2S0₄, filtered, and concentrated. The crude product was purified by Prep-HPLC to give the desired product Example 1 (138 mg, 0.386 mmols, 50.6%) as a yellow solid.

[00163] LCMS: ESI-MS: m/z: 357.9 [M+H]⁺; RT = 1.92 min. (Method A)

[00164] HPLC: RT = 12.14 min.

[00165] ¾ NMR (500 MHz, DMSO-d<5): δ 10.40 (s, 1H), 8.87 (t, / = 5.9 Hz, 1H), 8.44 (d, / = 2.4 Hz, 1H), 8.40 (d, / = 2.3 Hz, 1H), 8.20 (d, / = 8.9 Hz, 1H), 8.01 (dd, / = 8.9, 2.6 Hz, 1H), 7.93 (d, / = 2.3 Hz, 1H), 7.41 (dd, / = 8.6, 5.6 Hz, 2H), 4.70 (d, / = 5.9 Hz, 2H) ppm.

[00166] Example 2

[00167] N-(5-chloropyrimidin-2-yl)-3-((4-fluorobenzyl)amino)pyrazine-2- carboxamide

[00168] To a stirred solution of 31 (2.00 g, 11.6 mmols, 1.0 eq) in DMSO (20 mL) were added (4-fluorophenyl)methanamine (2.90 g, 23.2 mmols, 2.0 eq) and TEA (4.1 mL, 29.0 mmol, 2.5 eq). The mixture was heated to 80 °C for 4 hrs. After cooling down, it was diluted with ethyl acetate (150 mL), washed with brine (30 mL x 3), dried over MgSC , filtered and concentrated to give crude product. Purified by column chromatography on silica (Petroleum ether/ethyl acetate, 5/1 to 3/2) to give the desired product 32 (2.65 g, 10.2 mmols, 87.5%) as a pale yellow solid.

[00169] LCMS: ESI-MS: m/z: 262.1 [M+H]⁺; RT = 1.91 min. (Method A)

[00170] To a suspension of 5-chloropyrimidin-2-amine (149 mg, 1.16 mmols, 2.0 eq) in dry toluene (6 mL) was added dropwise 2M (AlMe3)2 in toluene (0.73 mL, 1.46 mmols, 2.6 eq) at room temperature under N₂. The reaction mixture was stirred at room temperature for 50 min under N₂. Then a solution of 32 (150 mg, 0.575 mmols, 1.0 eq) in dichloromethane (2 mL) was added dropwise to the reaction mixture. The reaction mixture was stirred at 70 °C for 4 hrs under N₂. The mixture was cooled to room temperature, quenched with ice-water (10 mL), then diluted with ethyl acetate (200 mL). The organic layer was washed with brine (80 mL x 3), dried over MgSC , filtered, and concentrated. The crude product was purified by Preparative-TLC (dichloromethanol/ethyl acetate, 6/1) to give Example 2 (130 mg, 0.362 mmols, 62.9%) as a yellow solid.

[00171] LCMS: ESI-MS: m/z: 358.9 [M+H]⁺; RT = 1.71 min. (Method A)

[00172] HPLC: RT = 10.76 min. [00173] ¾ NMR (500 MHz, DMSO-i/6): δ 10.68 (s, 1H), 8.90 (d, / = 5.7 Hz, 1H),

8.85 (s, 2H), 8.40 (d, J = 1.8 Hz, 1H), 7.93 (d, / = 1.8 Hz, 1H), 7.49 - 7.30 (m, 2H), 7.15

(t, / = 8.8 Hz, 2H), 4.69 (d, / = 5.6 Hz, 2H) ppm.

[00174] ¹⁹F NMR (500 MHz, DMSO- e): δ - 1 16.06 ppm.

[00175] Example 3

[00176] N-(5-chloropyridin-2-yl)-2-((4-fluorobenzyl)amino)nicotinamide

[00177] Example 3 was similarly prepared as the synthesis of compound Example 1.

[00178] LCMS: ESI-MS: m/z: 356.9 [M+H]⁺; RT = 1.64 min. (Method A)

[00179] HPLC: RT = 10.00 min.

[00180] ¾ NMR (500 MHz, DMSO- 6): δ 8.09 (dd, / = 4.9, 1.7 Hz, 1H), 7.71 - 7.59 (m, 1H), 7.40 (dd, J = 8.8, 2.5 Hz, 1H), 7.37 (s, 1H), 7.33 - 7.18 (m, 2H), 7.18 - 6.99 (m, 2H), 6.65 (dd, 7 = 7.4, 5.0 Hz, 1H), 4.57 (d, J = 5.7 Hz, 2H), 4.05 (t, / = 8.3 Hz, 2H), 3.11 (t, / = 8.3 Hz, 2H) ppm.

[00181] Example 4

[00182] N-(5-chloropyrimidin-2-yl)-2-((4-fluorobenzyl)amino)nicotinamide

[00183] Example 4 was similarly prepared as the synthesis of compound Example 2.

[00184] LCMS: ESI-MS: m/z: 358.1 [M+H]⁺; RT = 1.75 min. (Method A)

[00185] HPLC: RT = 8.87 min.

[00186] Ή NMR (500 MHz, DMSO-t/6) 5 11.18 (s, 1H), 8.83 (s, 2H), 8.50 (t, / = 5.8 Hz, 1H), 8.23 (dd, / = 4.7, 1.6 Hz, 1H), 8.14 (dd, / = 7.7, 1.7 Hz, 1H), 7.38 (dd, / = 8.4, 5.7 Hz, 2H), 7.13 (t, / = 8.9 Hz, 2H), 6.65 (dd, / = 7.7, 4.8 Hz, 1H), 4.64 (d, / = 5.7 Hz, 2H) ppm.

[00187] ¹⁹F NMR (500 MHz, DMSO-ifc): δ -116.37 ppm

[00188] Example 5

-(4-chlorophenyl)-3-((2-hydroxyethyl)amino)pyrazine-2-carboxamide

[00190] Compound 47 was synthesized by the reaction of compound 3 and 4- chlorobenzenamine using the General Procedure B. Yield: 63.5%

[00191] Compound Example 5 was similarly synthesized from compound 47 and 2- aminoethanol (5.0 eq) at 100 °C using the General Procedure C. Yield: 68.6%

Example 5

[00192] LCMS: ESI-MS: m/z: 293.0 [M+H]⁺; RT = 1.56 min. (Method A)

[00193] HPLC: RT = 9.67 min.

[00194] ¾ NMR (500 MHz, DMSO-d<5): δ 10.73 (s, 1H), 8.72 (t, / = 5.2 Hz, 1H), 8.34 (d, / = 2.3 Hz, 1H), 8.03 - 7.70 (m, 3H), 7.53 - 7.17 (m, 2H), 4.88 (t, / = 5.1 Hz, 1H), 3.60 (dd, 7 = 10.8, 5.4 Hz, 2H), 3.53 (q, 7 = 5.3 Hz, 2H) ppm.

[00195] Compounds Examples 6, 7, 8, 9, 10, 11, 12, 13 and 14 were similarly prepared as the synthesis of compound Example 5.

[00196] Example 6

[00197] N-(4-chlorophenyl)-3-((2-methoxyethyl)amino)pyrazine-2-carboxamide

Example 6

[00198] LCMS: ESI-MS: m/z: 307.1 [M+H]⁺; RT = 2.14 min. (Method A)

[00199] HPLC: RT = 11.07 min [00200] Ή NMR (500 MHz, DMSO-t/6): δ 10.74 (s, IH), 8.68 (s, IH), 8.36 (s, IH), 8.02 - 7.79 (m, 3H), 7.41 (d, / = 8.6 Hz, 2H), 3.75 - 3.59 (m, 2H), 3.54 (t, / = 5.2 Hz, 2H), 3.31 (s, 3H) ppm.

[00201] Example 7

[00202] N-(4-chlorophenyl)-3-((4-fluorobenzyl)amino)pyrazine-2-carboxamide

[00203] LCMS: ESI-MS: m/z: 356.9 [M+H]⁺; RT = 2.42 min. (Method B)

[00204] HPLC: RT = 11.95 min

[00205] Ή NMR (500 MHz, CDCb): δ 9.86 (s, IH), 8.99 (s, IH), 8.26 (d, / = 2.3 Hz,

IH), 7.78 (d, / = 2.3 Hz, IH), 7.63 (d, / = 8.8 Hz, 2H), 7.39 - 7.29 (m, 4H), 7.02 (t, / =

8.6 Hz, 2H), 4.72 (d, 7 = 5.7 Hz, 2H) ppm.

[00206] ¹⁹F NMR (376 MHz, DMSO-£¾): δ -115.52 (s) ppm.

[00207] Example 8

[00208] N-(4-chlorophenyl)- -(prop-2-yn-l -ylamino )pyrazine-2-carboxamide

Example 8

[00209] LCMS: ESI-MS: m/z: 287.1 [M+H]⁺; RT = 2.15 min. (Method A)

[00210] HPLC: RT = 11.02 min

[00211] Ή NMR (500 MHz, CDCb): δ 9.84 (s, IH), 8.80 (s, IH), 8.31 (d, / = 2.4 Hz, IH), 7.82 (d, / = 2.4 Hz, IH), 7.70 - 7.60 (m, 2H), 7.39 - 7.30 (m, 2H), 4.34 (dd, / = 5.5, 2.5 Hz, 2H), 2.23 (t, J = 2.5 Hz, IH) ppm.

[00212] Example 9

[00213] N-(4-chlorophenyl)-3-(methylamino)pyrazine-2-carboxamide

Example 9

[00214] LCMS: ESI-MS: m/z: 263.0 [M+H]⁺; RT = 1.75 min. (Method A)

[00215] HPLC: RT = 11.07 min

[00216] Ή NMR (500 MHz, CDCb): δ 9.84 (s, IH), 8.54 (s, IH), 8.27 (d, / = 2.4 Hz, IH), 7.72 (d, / = 2.3 Hz, IH), 7.67 - 7.59 (m, 2H), 7.38 - 7.29 (m, 2H), 3.08 (d, / = 4.9 Hz, 3H) ppm.

[00217] Example 10

[00218] N-(4-chlorophenyl)- -(cyclopropylamino)pyrazine-2-carboxamide

Example 10

[00219] LCMS: ESI-MS: m/z: 289.1 [M+H]⁺; RT = 2.22 min. (Method A)

[00220] HPLC : RT = 11.43 min

[00221] Ή NMR (500 MHz, DMSO-d6): δ 10.75 (s, IH), 8.57 (s, IH), 8.42 (d, / = 2.2 Hz, IH), 7.96 (d, / = 2.2 Hz, IH), 7.87 (d, / = 8.8 Hz, 2H), 7.41 (d, / = 8.8 Hz, 2H), 2.96 - 2.75 (m, IH), 0.79 (t, / = 5.9 Hz, 2H), 0.55 (d, / = 7.1 Hz, 2H) ppm.

[00222] Example 11

[00223] N-(4-chlorophenyl)- -((cyclopropylmethyl)amino)pyrazine-2-carboxamide

Example 11

[00224] LCMS: ESI-MS: m/z: 303.0 [M+H]⁺; RT = 2.42 min. (Method B)

[00225] HPLC: RT = 12.00 min

[00226] Ή NMR (500 MHz, DMSO-d6): δ 10.74 (s, IH), 8.67 (t, / = 5.3 Hz, IH), 8.34 (d, / = 2.2 Hz, IH), 7.91- 7.89 (m, 3H), 7.41 (d, / = 8.8 Hz, 2H), 3.34 - 3.28 (m, 2H), 1.13 (tt, / = 7.4, 3.9 Hz, IH), 0.55 - 0.44 (m, 2H), 0.27 (q, / = 4.8 Hz, 2H) ppm.

[00227] Example 12 [00228] 3-(tert-butylamino)- e-2-carboxamide

Example 12

[00229] LCMS: ESI-MS: m/z: 305.0 [M+H]⁺; RT = 2.01 min. (Method A)

[00230] HPLC: RT = 12.78 min

[00231] Ή NMR (500 MHz, CDCb): δ 9.91 (s, IH), 8.76 (s, IH), 8.21 (d, / = 2.3 Hz, IH), 7.67 (d, / = 2.3 Hz, IH), 7.65 - 7.58 (m, 2H), 7.38 - 7.29 (m, 2H), 1.51 (s, 9H) ppm.

[00232] Example 13

[00233] N-(4-chlorophenyl)- -(oxetan-3-ylamino)pyrazine-2-carboxamide

Example 13

[00234] LCMS: ESI-MS: m/z: 305.0 [M+H]⁺; RT = 1.65 min. (Method A)

[00235] HPLC: RT = 10.47 min.

[00236] ¾ NMR (500 MHz, OMSO-d6): δ 10.80 (s, IH), 8.93 (d, / = 5.3 Hz, IH), 8.35 (d, / = 2.3 Hz, IH), 7.98 (d, J = 2.4 Hz, IH), 7.91 (d, J = 8.9 Hz, 2H), 7.43 (d, / = 8.9 Hz, 2H), 5.76 (s, IH), 5.02 (m, IH), 4.85 (t, / = 6.8 Hz, 2H), 4.53 (t, / = 6.4 Hz, 2H) ppm.

[00237] Example 14

[00238] N-(4-chlorophenyl)-3-( ( tetrahydro-2H-pyran-4-yl)amino )pyrazine-2- carboxamide

Example 14

[00239] LCMS: ESI-MS: m/z: 333.0 [M+H]⁺; RT = 2.27 min. (Method B)

[00240] HPLC: RT = 11.28 min [00241] Ή NMR (500 MHz, DMSO-d6): δ 10.77 (s, 1H), 8.59 (d, / = 7.4 Hz, 1H), 8.36 (d, / = 2.4 Hz, 1H), 7.92 (d, / = 2.3 Hz, 1H), 7.91 - 7.85 (m, 2H), 7.48 - 7.34 (m, 2H), 4.23 - 4.08 (m, 1H), 3.87 (dd, / = 8.2, 3.4 Hz, 2H), 3.46 (td, / = 11.4, 2.0 Hz, 2H), 1.95 (d, / = 10.3 Hz, 2H), 1.53 (qd, / = 10.9, 4.2 Hz, 2H) ppm.

[00242] Example 15

[00 -(4-chlorophenyl)-3-(pyridin-2-ylamino)pyrazine-2-carboxamide

[00244] A mixture of 47 (400 mg, 1.50 mmols, 1.0 eq), pyridin-2-amine (141 mg, 1.50 mmols, 1.0 eq), Pd₂(dba)₃ (137 mg, 0.150 mmols, 0.1 eq), Xantphos (174 mg, 0.300 mmols, 0.2 eq) and i-BuONa (288 mg, 3.00 mmols, 2.0 eq) in dioxane (20 mL) was heated to reflux for 16 hours under nitrogen. After the reaction mixture was cooled to room temperature, the insoluble matter was removed by filtration and the filtrate was concentrated. The residue was dissolved in ethyl acetate and washed with water followed by brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by Prep-HPLC to give the desired product Example 15 (65.0 mg, 0.200 mmols, 13.3 %) as a yellow solid.

[00245] LCMS: ESI-MS: m/z: 326.1 [M+H]⁺; RT = 2.31 min. (Method B)

[00246] HPLC: RT = 9.10 min.

[00247] ¾ NMR (500 MHz, CDCb): δ 11.77 (s, 1H), 9.96 (s, 1H), 8.53 (s, 2H), 8.25 (d, / = 7.8 Hz, 1H), 8.09 (s, 1H), 7.79 (t, / = 7.6 Hz, 1H), 7.72 (d, / = 8.7 Hz, 2H), 7.36 (d, / = 8.7 Hz, 2H), 7.05 (t, / = 6.0 Hz, 1H) ppm.

[00248] Example 16

[002 -(4-chlorophenyl)-3-(pyridazin-3-ylamino)pyrazine-2-carboxamide

100 °C, 16 h xamp e [00250] A solution of 47 (200 mg, 0.749 mmols, 1.0 eq), pyridazin-3-amine (142 mg, 1.50 mmols, 2.0 eq), Pd(OAc)₂ (16.8 mg, 0.0749 mmols, 0.1 eq), BINAP (93.4 mg, 0.150 mmols, 0.2 eq) and CS2CO3 (492 mg, 1.50 mmols, 2.0 eq) in toluene (20 mL) was heated to reflux for 16 hours under nitrogen. After the reaction mixture was cooled to room temperature, the insoluble matter was removed by filtration and the filtrate was concentrated. The residue was dissolved in ethyl acetate, washed with water and brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by Prep-HPLC to give the desired product Example 16 (50.0 mg, 0.153 mmols, 20.5%) as a light yellow solid.

[00251] LCMS: ESI-MS: m/z: 327.1 [M+H]⁺; RT = 1.57 min. (Method A)

[00252] HPLC: RT = 9.80 min.

[00253] ^lH NMR (500 MHz, CDCb): δ 12.07 (s, 1H), 9.96 (s, 1H), 8.92 (d, / = 3.5 Hz, 1H), 8.75 (d, / = 9.1 Hz, 1H), 8.44 (d, / = 2.3 Hz, 1H), 8.14 (d, / = 2.3 Hz, 1H), 7.73 (d, / = 8.8 Hz, 2H), 7.51 (dd, 7 = 9.1, 4.6 Hz, 1H), 7.38 (d, / = 8.8 Hz, 2H) ppm.

[00254] Example 17

[00255] -(4-chlorophenyl)-3-((4-fluorophenyl)amino)pyrazine-2-carboxamide

[00256] A solution of 47 (120 mg, 0.449 mmols, 1.0 eq) and 4-fluorobenzenamine (2 mL, neat) was heated to 160 °C for 6 hours under nitrogen in a sealed tube. After the reaction mixture was cooled to room temperature, the reaction mixture was dissolved in ethyl acetate and washed with water followed by brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by Preparative-TLC (dichloromethanol / methanol, 20/1) and then re-crystallization (methanol / n-hexane) to give the desired product Example 17 (60.0 mg, 0.175 mmols, 39.0%) as a green solid.

[00257] LCMS: ESI-MS: m/z: 343.1 [M+H]⁺; RT = 1.92 min. (Method A)

[00258] HPLC: RT = 12.11 min. [00259] ¾ NMR (400 MHz, OMSO-d6): δ 10.96 (s, 1H), 10.86 (s, 1H), 8.46 d, J = 2.4 Hz, 1H), 8.14 (d, / = 2.4 Hz, 1H), 8.02 - 7.84 (m, 2H), 7.84 - 7.59 (m, 2H), 7.53 - 7.32 (m, 2H), 7.30 - 7.08 (m, 2H) ppm.

[00260] ¹⁹F NMR (376 MHz, DMSO-d<5): δ -119.79 (s) ppm.

[00261] Example 18 N-(4-chlorophenyl)-2-((2-hydroxyethyl)amino)nicotinamide And Example 19 N-(4-chlorophenyl)-2-((2-methoxyethyl)amino)nicotinamide

[00262] Compound 48 was synthesized by the reaction of compound 8 and 4- chloroaniline using the General Procedure B. Yield: 58.6%

[00263] Compounds Example 18 and Example 19 were synthesized by the reaction of compound 48 and appropriate amine monomer (5.0 eq) at 130 °C using the General Procedure C.

[00264] Example 18

[00265] N-(4-chlorophenyl -2-((2-hydroxyethyl)amino)nicotinamide

Example 18

[00266] LCMS: ESI-MS: m/z: 292.1 [M+H]⁺; RT = 1.46 min. (Method A)

[00267] HPLC: RT = 7.56 min.

[00268] ¾ NMR (500 MHz, DMSO-d<5): δ 10.30 (s, 1H), 8.21 (d, / = 3.6 Hz, 1H), 8.10 (t, J = 4.9 Hz, 1H), 8.05 (d, / = 7.4 Hz, 1H), 7.74 (d, / = 8.7 Hz, 2H), 7.41 (d, / = 8.7 Hz, 2H), 4.80 (t, / = 4.9 Hz, 1H), 3.56 (dd, / = 10.5, 5.2 Hz, 2H), 3.48 (dd, / = 10.6, 5.2 Hz, 2H) ppm.

[00269] Example 19

[00270] N-(4-chlorophenyl)-2-((2-methoxyethyl)amino)nicotinamide

Example 19

[00271] LCMS: ESI-MS: m/z: 306.0 [M+H]⁺; RT = 1.39 min. (Method C)

[00272] Method C: Mobile Phase: A: Water (0.01% TFA) B: ACN (0.01% TFA);

Gradient Phase: 5% B increase to 95% B within 1.2 min, 95% B with 1.8 min (total runtime: 3 min); Flow Rate: 2.2 mL/min; Column: Poroshell 120 EC- C18, 4.6*30mm, 2.7 ; Column Temperature: 50 °C. Detectors: ADC ELSD, DAD (214 nm and 254 nm), MSD (ES-API).

[00273] HPLC: RT = 8.38 min.

[00274] ¾ NMR (500 MHz, DMSO-i 6): δ 10.44 (s, 1H), 8.39 (brs, 1H), 8.22 - 8.18 (m, 2H), 7.84 - 7.64 (m, 2H), 7.50 - 7.31 (m, 2H), 6.88 - 6.65 (m, 1H), 3.60 (t, / = 5.2 Hz, 2H), 3.52 (t, / = 5.3 Hz, 2H), 3.29 (s, 3H) ppm.

[00275] Example 20

[00276] 3-((4-fluorobenzyl)amino)-N-(6-(trifluoromethyl)pyridin-3-yl)pyrazine-2- carboxamide

Example 20

[00277] Compound 50 was similarly prepared as the synthesis of Intermediate 14. Yield: 52.1%.

[00278] LCMS: ESI-MS: m/z: 303.1 [M+H]⁺; RT = 1.79 min. (Method A)

[00279] Example 20 was synthesized by the reaction of compound 50 and (4- fluorophenyl)methanamine (5.0 eq) at 100 °C using the General Procedure C. Yield:

72.6%.

[00280] LCMS: ESI-MS: m/z: 392.1 [M+H]⁺; RT = 2.32 min. (Method B)

[00281] HPLC: RT = 11.32 min.

[00282] ½ NMR (400 MHz, DMSO-i 6): δ 11.21 (s, 1H), 9.21 (d, / = 2.0Hz, 1H),

8.93 (t, / = 5.6Hz, 1H), 8.55 (dd, / = 8.8, 2.0Hz, 1H), 8.39 (d, / = 2.0Hz, 1H), 7.97 (d, / = 2.4Hz, 1H), 7.92 (d, / = 8.8Hz, 1H), 7.41 (m, 2H), 7.15 (t, / = 8.8Hz, 2H), 4.70 (d, / =

6.0Hz, 2H) ppm.

[00283] ¹⁹F NMR (376 MHz,

[00284] OMSO-d6): -65.73 (s), -116.11 (s) ppm.

[00285] Example 20-HCl

[00286] 3-((4-fluorobenzyl)amino)-N-(6-(trifluoromethyl)pyridin-3-yl)pyrazine-2- carboxa

Example 20 Example 20-HCl

[00287] To a solution of Example 20 (50 mg, 0.128 mmols, 1.0 eq) in dioxane (5 mL) was added HCl (4.0 M in dioxane, 0.32 mL, 1.28 mmols, 10.0 eq) at 0 °C, then the solution was stirred at room temperature for 2 hours. The solvent was removed in vacuo to afford the desired compound Example 20-HCl (42.0 mg, 0.098 mmols, 76.6%) as a yellow solid.

[00288] LCMS: ESI-MS: m/z: 392.1 [M-HC1+H]⁺; RT = 2.30 min. (Method B)

[00289] HPLC: RT = 11.31 min

[00290] Ή NMR (400 MHz, CDCb): δ 10.11 (s, 1H), 8.82 (s, 2H), 8.51 (d, / = 8.4 Hz, 1H), 8.32 (s, 1H), 7.82 (s, 1H), 7.70 (d, / = 8.5 Hz, 1H), 7.35 (t, / = 6.4 Hz, 2H), 7.03 (t, / = 8.4 Hz, 2H), 4.74 (d, / = 5.3 Hz, 2H) ppm.

[00291] ¹⁹F NMR (376 MHz, OMSO-d6): -67.32 (s), -115.34 (s) ppm.

[00292] Example 21

[00293] 3-((2-hydroxyethyl)amino)-N-(4-(trifluoromethyl)phenyl)pyrazine-2- carboxamide

[00294] Examples 21, 22, 23, 24, 25, 26, 27, 28, and 29 were similarly prepared as the synthesis of compound Example 19.

Example 21

Example 21

[00295] LCMS: ESI-MS: m/z: 327.0 [M+H]⁺; RT = 1.61 min. (Method A)

[00296] HPLC: RT = 9.96 min.

[00297] ¾ NMR (500 MHz, DMSO-d<5): δ 10.93 (s, IH), 8.70 (t, / = 5.2 Hz, IH), 8.37 (d, / = 2.3 Hz, IH), 8.10 (d, / = 8.6 Hz, 2H), 7.91 (d, / = 2.3 Hz, IH), 7.73 (d, / = 8.6 Hz, 2H), 4.90 (t, / = 5.1 Hz, IH), 3.63 - 3.60 (m, 2H), 3.56 - 3.53 (m, 2H) ppm.

[00298] ¹⁹F NMR (376 MHz, DMSO-d<5): δ -60.36 (s) ppm.

[00299] Example 22

[00300] 3-((2-methoxyethyl)amino )-N-(4-( trifluoromethyl)phenyl)pyrazine-2- carboxamide

[00301]

Example 22

[00302] LCMS: ESI-MS: m/z: 341.0 [M+H]⁺; RT = 1.78 min. (Method A)

[00303] HPLC: RT = 11.19 min.

[00304] ¾ NMR (500 MHz, DMSO-d<5): δ 10.93 (s, IH), 8.65 (t, / = 5.2 Hz, IH), 8.38 (d, / = 2.2 Hz, IH), 8.09 (d, / = 8.5 Hz, 2H), 7.93 (d, / = 2.3 Hz, IH), 7.73 (d, / = 8.6 Hz, 2H), 3.65 (dd, / = 10.8, 5.4 Hz, 2H), 3.55 (t, / = 5.4 Hz, 2H), 3.31 (s, 3H) ppm. [00305] ¹⁹F NMR (376 MHz, DMSO): δ -60.37 (s) ppm.

[00306] Example 23

[00307] 3-((4-fluorobenzyl)amino )-N-(4-( trifluoromethyl)phenyl)pyra

carboxamide

Example 23

[00308] LCMS: ESI-MS: m/z: 391.1 [M+H]⁺; RT = 1.93 min. (Method A)

[00309] HPLC: RT = 11.92 min.

[00310] ¾ NMR (500 MHz, OMSO-d6): δ 10.97 (s, 1H), 8.97 (t, / = 5.9 Hz, 1H), 8.37 (d, / = 2.3 Hz, 1H), 8.10 (d, J = 8.5 Hz, 2H), 7.95 (d, J = 2.3 Hz, 1H), 7.72 (d, J = 8.7 Hz, 2H), 7.41 (dd, J = 8.6, 5.7 Hz, 2H), 7.22 - 7.08 (m, 2H), 4.69 (d, / = 5.9 Hz, 2H) ppm.

[00311] ¹⁹F NMR (376 MHz, OMSO-d6): δ -60.37(s), 116.10 (s) ppm.

[00312] Example 24

[00313] 3-((4-fluorobenzyl)amino)-N-(2-(trifluoromethyl)pyridin-4-yl)pyrazine-2- carboxamide

Example 24

[00314] LCMS: ESI-MS: m/z: 392.1 [M+H]⁺; RT = 1.80 min. (Method A)

[00315] HPLC: RT = 11.28 min.

[00316] ¾ NMR (400 MHz, OMSO-d6): δ 11.34 (s, 1H), 8.93 (s, 1H), 8.67 (d, J = 5.6 Hz, 1H), 8.53 (d, / = 1.8 Hz, 1H), 8.40 (d, / = 2.3 Hz, 1H), 8.15 (dd, / = 5.5, 1.8 Hz, 1H), 7.97 (d, / = 2.3 Hz, 1H), 7.41 (dd, / = 8.5, 5.7 Hz, 2H), 7.14 (t, / = 8.9 Hz, 2H), 4.70 (d, J = 6.0 Hz, 2H) ppm. [00317] ¹⁹F NMR (376 MHz, DMSO-^6): δ -66.83 (s), -116.15 (s) ppm.

[00318] Example 25

[00319] N-(4-chloro-2-(trifluoromethoxy)phenyl)-3-((4-fluorobenzyl)amino

2-carboxamide

[00320] LCMS: ESI-MS: m/z: 441.0 [M+H]⁺; RT = 2.04 min. (Method A)

[00321] HPLC: RT = 12.93 min.

[00322] Ή NMR (400 MHz, DMSO-t/6): δ 10.45 (s, IH), 8.88 (s, IH), 8.39 (d, J = 2.3 Hz, IH), 8.14 (d, J = 8.8 Hz, IH), 7.94 (d, J = 2.3 Hz, IH), 7.67 (s, IH), 7.56 (dd, / = 8.8, 2.3 Hz, IH), 7.40 (dd, / = 8.5, 5.6 Hz, 2H), 7.14 (t, / = 8.9 Hz, 2H), 4.69 (d, / = 6.0 Hz, 2H) ppm.

[00323] ¹⁹F NMR (376 MHz, DMSO- 6): -56.97 (s), -116.08 (s) ppm.

[00324] Example 26

[00325] N-(3-fliioro-4-(trifluoromethyl)phenyl)-3-((4-fluorobenzyl)ammo)pyrazine-2- carboxamide

Example 26

[00326] LCMS: ESI-MS: m/z: 409.1 [M+H]⁺; RT = 2.34 min. (Method A)

[00327] HPLC : RT = 11.99 min

[00328] Ή NMR (500 MHz, DMSO-t/6): δ 11.14 (s, IH), 8.92 (t, J = 6.0 Hz, IH), 8.39 (d, / = 2.3 Hz, IH), 8.08 (d, / = 13.9 Hz, IH), 7.95 (dd, / = 12.5, 5.6 Hz, 2H), 7.77 (t, / = 8.6 Hz, IH), 7.42 (dd, / = 8.4, 5.7 Hz, 2H), 7.15 (t, / = 8.8 Hz, 2H), 4.70 (d, / = 6.0 Hz, 2H) ppm.

[00329] ¹⁹F NMR (376 MHz, DMSO- 6): -59.17 (d, / = 11.5 Hz), - 1 14.58 (q, / = 12.0 Hz), - 116.09 (s) ppm.

[00330] Example 27 [00331] 3-(( tetrahydro-2H-pyran-4-yl jamino )-N-(4-( trifluoromethyl)phenyl)pyrazine- 2-carboxamide

Example 27

[00332] LCMS: ESI-MS: m/z: 367.0 [M+H]⁺; RT = 2.28 min. (Method B)

[00333] HPLC: RT = 11.37 min.

[00334] Ή NMR (400 MHz, DMSO- 6): δ 10.94 (s, IH), 8.55 (d, J = 7.3 Hz, IH), 8.38 (d, / = 2.3 Hz, IH), 8.09 (d, / = 8.5 Hz, 2H), 7.94 (d, = 2.3 Hz, IH), 7.72 (d, / = 8.7 Hz, 2H), 4.30 - 4.11 (m, IH), 3.89 (t, J = 3.5 Hz, IH), 3.86 (t, J = 3.3 Hz, IH), 3.48 (dt, / = 11.1 , 5.7 Hz, 2H), 1.96 (d, / = 10.0 Hz, 2H), 1.65 - 1.45 (m, 2H) ppm.

[00335] ¹⁹F NMR (376 MHz, DMSO- 6): δ -60.37 (s) ppm

[00336] Example 28

[00337] 3-((4-hydroxycyclohexyl)amino)-N-(4-(trifluoromethyl)phenyI)pyrazine-2- carboxamide

Example 28

[00338] LCMS: ESI-MS: m/z: 381.2 [M+H]⁺; RT = 1.71 min. (Method A)

[00339] HPLC: RT = 10.64 min.

[00340] ^!H NMR (400 MHz, DMSO- 6): δ 10.91 (s, IH), 8.47 (d, J = 7.6 Hz, IH), 8.38 (d, J = 2.3 Hz, IH), 8.08 (d, / = 8.6 Hz, 2H), 7.90 (d, / = 2.3 Hz, IH), 7.71 (d, / = 8.7 Hz, 2H), 4.60 (d, / = 4.2 Hz, IH), 3.95 - 3.85 (m, IH), 3.54 - 3.47 (m, IH), 2.02 - 1.99 (m, 2H), 1.86 - 1.84 (m, 2H), 1.39 - 1.28 (m, 4H) ppm.

[00341] ¹⁹F NMR (376 MHz, DMSO- 6): δ -60.37 (s) ppm.

[00342] Example 29

[00343] 3-((4-fl orobenzyl)amino)-N-(3-(trifluoromethyl)isothiaz.ol-5-yl)pyrazine-2- carboxamide

Example 29

[00344] LCMS: ESI-MS: m/z: 382.2 [M+H]⁺; RT = 1.93 min. (Method A)

[00345] HPLC: RT = 9.88 min.

[00346] ^lH NMR (400 MHz, OMSO-d6): δ 8.39 (s, IH), 8.30 (dd, / = 4.7, 1.6 Hz,

IH), 7.71 (dd, / = 7.8, 1.7 Hz, IH), 7.27 (dd, / = 8.5, 5.5 Hz, 2H), 6.96 (dd, / = 12.1, 5.3

Hz, 2H), 6.65 (s, IH), 6.57 (dd, / = 7.8, 4.7 Hz, IH), 4.67 (d, J = 5.1 Hz, 2H) ppm.

[00347] ¹⁹F NMR (376 MHz, DMSO-d6): δ -62.88 (s), - 116.05 (s) ppm.

[00348] Compounds Examples 30, 31, 32, 33, 34, and 35 were similarly prepared using General Procedure C.

[00349] Example 30

[00350] N-(4-chloro-2-fluorophenyl)-2-(prop-2-yn-l-ylamino)nicotinamide

[00351]

Example 30

[00352] LCMS: ESI-MS: m/z: 304.1 [M+H]⁺; RT = 1.91 min. (Method A)

[00353] HPLC: RT = 9.61 min.

[00354] ¾ NMR (400 MHz, DMSO-d6): δ 10.26 (s, IH), 8.29 (dd, / = 4.8, 1.7 Hz, IH), 8.24 (brs, IH), 8.16 (dd, / = 7.8, 1.7 Hz, IH), 7.64 - 7.46 (m, 2H), 7.38 - 7.25 (m, IH), 6.76 (dd, / = 7.7, 4.9 Hz, IH), 4.21 (s, 2H), 3.06 (t, / = 2.4 Hz, IH) ppm.

[00355] ¹⁹F NMR (376 MHz, DMSO-d6): δ -74.32 (s) ppm.

[00356] Example 31

[00357] 2-((4-fluorobenzyl)amino)-N-(6-(trifluoromethyl)pyridin-3-yl)nicotinamide

Example 31

[00358] LCMS: ESI-MS: m/r 391.1 [M+H]⁺; RT = 1.64 min. (Method A)

[00359] HPLC: RT = 10.00 min.

[00360] ^lU NMR (400 MHz, DMSO-t/6): δ 10.75 (s, IH), 9.04 (d, / = 2.0 Hz, IH), 8.48 - 8.31 (m, 2H), 8.25 (dd, / = 4.7, 1.5 Hz, IH), 8.16 (dd, / = 7.7, 1.6 Hz, IH), 7.92 (d, / = 8.6 Hz, IH), 7.38 (dd, / = 8.4, 5.8 Hz, 2H), 7.14 (t, / = 8.9 Hz, 2H), 6.72 (dd, / = 7.7, 4.8 Hz, IH), 4.65 (d, / = 5.8 Hz, 2H) ppm.

[00361] ¹⁹F NMR (376 MHz, DMSO- d6): δ -65.69 (s), -116.42 (s) ppm.

[00362] Example 32

[00363] 2-((4-fluorobenzyl)amino)-N-(2-(trifluoromethyl)pyridin-4-yl)nicotinamide

Example 32

[00364] LCMS: ESI-MS: m/r 391.1 [M+H]⁺; RT = 1.65 min. (Method A)

[00365] HPLC: RT = 10.08 min.

[00366] ^lH NMR (400 MHz, DMSO- 6): δ 10.85 (s, IH), 8.66 (d, J = 5.5 Hz, IH), 8.36 (s, IH), 8.31 - 8.22 (m, IH), 8.15 (dd, J = 7.7, 1.6 Hz, IH), 8.01 - 7.86 (m, IH), 7.38 (dd, J = 8.4, 5.7 Hz, 2H), 7.13 (t, J = 8.9 Hz, 2H), 6.72 (dd, J = 7.7, 4.8 Hz, IH), 4.66 (d, 7 = 5.9 Hz, 2H) ppm.

[00367] Example 33

[00368] 2 -( ( 4-hydroxycyclohexyl )amino )-N-(4-( trifluoromethyl )phenyl Nicotinamide

Example 33

[00369] LCMS: ESI-MS: m/r. 380.1 [M+H]⁺; RT = 1.44 min. (Method A) [00370] HPLC: RT = 8.35 min.

[00371] ^lH NMR (400 MHz, DMSO- 6): δ 10.46 (s, IH), 8.24 (dd, / = 4.8, 1.7 Hz, IH), 8.11 (dd, J = 7.8, 1.8 Hz, IH), 7.91 (d, / = 8.6 Hz, 2H), 7.71 (d, J = 8.7 Hz, 2H), 6.64 (dd, / = 7.7, 4.8 Hz, IH), 4.56 (d, / = 4.2 Hz, IH), 3.94 - 3.92 (m, IH), 3.48 - 3.47 (m, IH), 2.00 -1.98 (m, 2H), 1.84 - 1.82 (m, 2H), 1.36 - 1.20 (m, 4H) ppm.

[00372] ¹⁹F NMR (376 MHz, DMSO-t/6): δ -60.33 (s) ppm.

[00373] Example 34

[00374] 2-((tetrahydro-2H-pyran-4-yl)amino)-N-(4- ( trifluoromethyl )phenyl Nico

Example 34

[00375] LCMS: ESI-MS: m/r. 366.2 [M+H]⁺; RT = 1.50 min. (Method A)

[00376] HPLC: RT = 8.99 min.

[00377] ^lH NMR (400 MHz, DMSO- 6): δ 10.49 (s, IH), 8.25 (dd, 7 = 4.8, 1.6 Hz, IH), 8.13 (dd, J = 7.7, 1.7 Hz, IH), 8.01 (d, J = 7.2 Hz, IH), 7.93 (d, J = 8.6 Hz, 2H), 7.72 (d, / = 8.7 Hz, 2H), 6.68 (dd, / = 7.7, 4.8 Hz, IH), 4.32 - 4.1 1 (m, IH), 3.88 - 3.84 (m, 2H), 3.57 - 3.38 (m, 2H), 1.94 (d, / = 10.4 Hz, 2H), 1.57 - 1.36 (m, 2H) ppm.

[00378] ¹⁹F NMR (376 MHz, DMSO- 6): δ -60.34 (s) ppm.

[00379] Example 35

[00380] 2-((4-fluorobenzyl)amino)-N-(3-(trifluoromethyl)isothiazo

Example 35

[00381] LCMS: ESI-MS: m/r. 381.0 [M+H]⁺; RT = 2.04 min. (Method B)

[00382] HPLC: RT = 8.44 min. [00383] ¾ NMR (400 MHz, CDCb): δ 8.39 (brs, IH), 8.30 (dd, / = 4.7, 1.6 Hz, IH), 7.71 (dd, / = 7.8, 1.7 Hz, IH), 7.27 (dd, / = 8.5, 5.5 Hz, 2H), 6.96 (dd, / = 12.1 , 5.3 Hz, 2H), 6.65 (s, IH), 6.57 (dd, / = 7.8, 4.7 Hz, IH), 4.67 (d, / = 5.1 Hz, 2H) ppm.

[00384] ¹⁹F NMR (376 MHz, CDCb): δ -63.96 (s), -115.63 (s) ppm.

[00385] Example 36

[00386] N-(4-chloro-2-fluorophenyl)-3-((4-fluorobenzyl)amino)pyrazine-2- carboxamide

20 (R₄=F, R₅=H) Example 36

[00387] Example 36 was synthesized by the reaction of compound 20 (R4 = F, R5 =

H) and 4-chloro-2-fluoroaniline using the General Procedure B.

[00388] LCMS: ESI-MS: m/z: 374.9 [M+H]⁺; RT = 1.97 min. (Method A)

[00389] HPLC: RT = 12.40 min.

[00390] Ή NMR (500 MHz, CDCb): δ 10.10 (s, IH), 8.88 (s, IH), 8.38 (t, / = 8.5 Hz,

IH), 8.27 (d, J = 2.3 Hz, IH), 7.81 (d, J = 2.3 Hz, IH), 7.35 (dd, J = 8.6, 5.4 Hz, 2H),

7.19-7.14 (m, 2H), 7.08 - 6.94 (m, 2H), 4.72 (d, / = 5.8 Hz, 2H) ppm.

[00391] ¹⁹F NMR (376 MHz, DMSO- 6): -115.53 (s), -127.51 (s) ppm.

[00392] Examples 37, 38, 39, 40, 41, 42, and 43 were similarly prepared as the synthesis of compound Example 36.

[00393] Example 37

[00394] N-(3,4-difluorophenyl)-3-((4-fluorobenzyl)amino)pyrazine-2-carboxamide

Example 37 [00395] LCMS: ESI-MS: m/z: 359.0 [M+H]⁺; RT = 1.87 min. (Method A)

[00396] HPLC: RT = 11.65 min.

[00397] ^lH NMR (500 MHz, DMSO- 6): δ 10.88 (s, IH), 8.97 (t, / = 5.9 Hz, IH), 8.35 (d, / = 2.3 Hz, IH), 8.01 (ddd, / = 13.3, 7.5, 2.5 Hz, IH), 7.93 (d, J = 2.3 Hz, IH), 7.75 - 7.63 (m, IH), 7.51 - 7.33 (m, 3H), 7.15 (t, J = 8.9 Hz, 2H), 4.68 (d, J = 5.9 Hz, 2H) ppm.

[00398] ¹⁹F NMR (376 MHz, DMSO-^6): δ -116.10(s), -137.44 (s), -137.51 (s), - 143.98 (s), -144.04 (s) ppm.

[00399] Example 38

[00400] N-(4-fluoro-3-( trifluoromethyl )phenyl )-3-{{4-fluorobenzyl )amino )pyrazine-2- carboxamide

Example 38

[00401] LCMS: ESI-MS: m/z: 409.1 [M+H]⁺; RT = 1.91 min. (Method A)

[00402] HPLC: RT = 11.88 min.

[00403] ^lH NMR (500 MHz, DMSO- 6): δ 11.03 (s, IH), 8.98 (t, / = 5.9 Hz, IH), 8.42 (dd, / = 6.6, 2.5 Hz, IH), 8.36 (d, = 2.3 Hz, IH), 8.20 - 8.07 (m, IH), 7.94 (d, / = 2.3 Hz, IH), 7.53 (t, J = 9.8 Hz, IH), 7.41 - 7.39 (m, 2H), 7.14 (t, / = 8.9 Hz, IH), 4.68 (d, J = 6.0 Hz, 2H) ppm.

[00404] ¹⁹F NMR (376 MHz, OMSO-d6): δ -60.16 (d, / = 12.4 Hz), -116.17 (s), - 121.80 (q, / = 12.4 Hz) ppm.

[00405] Example 39

[00406] N-(4-cyanophenyl)-3-((4-fluorobenzyl)amino )pyrazine-2-carboxamide

11

Example 39

[00407] LCMS: ESI-MS: m/z: 348.0 [M+H]⁺; RT = 2.45 min. (Method B)

[00408] HPLC: RT = 11.15 min.

[00409] Ή NMR (400 MHz, CDCb): δ 10.07 (s, IH), 8.86 (s, IH), 8.29 (d, / = 2.2

Hz, IH), 7.83 - 7.79 (m, 3H), 7.66 (d, / = 8.7 Hz, 2H), 7.35 (dd, / = 8.4, 5.5 Hz, 2H), 7.03

(t, / = 8.7 Hz, 2H), 4.72 (d, / = 5.7 Hz, 2H) ppm.

[00410] ¹⁹F NMR (376 MHz, DMSO-t/6): δ -115.38 (s) ppm.

[00411] Example 40

[00412] 3-((4-fluorobenzyl)amino)-N-(3-(trifluoromethyl)phenyl)pyrazine-2- carboxamide

Example 40

[00413] LCMS: ESI-MS: m/z: 391.0 [M+H]⁺; RT = 2.59 min. (Method B)

[00414] HPLC : RT = 11.92 min.

[00415] ¾ NMR (400 MHz, CDCb): δ 9.99 (s, IH), 8.94 (s, IH), 8.27 (d, / = 2.3 Hz, IH), 8.03 (s, IH), 7.83 (d, / = 8.2 Hz, IH), 7.78 (d, / = 2.3 Hz, IH), 7.49 (t, / = 8.0 Hz, IH), 7.40 (d, / = 7.8 Hz, IH), 7.35 (dd, / = 8.6, 5.4 Hz, 2H), 7.09 - 6.95 (m, 2H), 4.72 (d, 7 = 5.8 Hz, 2H) ppm.

[00416] ¹⁹F NMR (376 MHz, DMSO- 6) δ -62.72 (s), -115.55 (s) ppm.

[00417] Example 41

[00418] 3-((4-fluorobenzyl)amino)-N-(5-(trifluoromethyl)pyridin-3-yl)pyrazine-2- carboxamide

Example 41

[00419] LCMS: ESI-MS: m/z: 392.1 [M+H]⁺; RT = 1.80 min. (Method A)

[00420] HPLC: RT = 11.30 min.

[00421] Ή NMR (400 MHz, CDCb): δ 10.08 (s, 1H), 8.93 (s, 1H), 8.73 (s, 1H), 8.61

(s, 2H), 8.25 (d, / = 2.2 Hz, 1H), 7.75 (d, / = 2.2 Hz, 1H), 7.28 (dd, / = 8.5, 5.4 Hz, 2H),

6.96 (t, J = 8.7 Hz, 2H), 4.67 (d, J = 5.8 Hz, 2H) ppm.

[00422] ¹⁹F NMR (376 MHz, DMSO-d<5): δ -62.44 (s), -115.31 (s) ppm.

[00423] Example 42

[00424] N-(4-acetylphenyl)-3-((4-fluorobenzyI)amino)pyrazine-2-carboxamide

Example 42

[00425] LCMS: ESI-MS: m/z: 365.1 [M+H]⁺; RT = 1.76 min. (Method A)

[00426] HPLC: RT = 11.08 min.

[00427] ¾ NMR (400 MHz, OMSO-d6): δ 10.90 (s, 1H), 8.97 (s, 1H), 8.36 (d, / = 2.1 Hz, 1H), 8.10 - 7.82 (m, 3H), 7.54 - 7.31 (m, 1H), 7.15 (t, J = 8.8 Hz, 1H), 4.69 (d, 7 = 5.8 Hz, 2H), 2.55 (s, 3H) ppm.

[00428] ¹⁹F NMR (376 MHz, DMSO-d<5): δ -116.11 (s) ppm.

[00429] Example 43

[00430] 3-((4-fluorobenzyl)amino )-N-(4-( trifluoromethoxy)phenyl)pyrazine-2- carboxamide

Example 43

[00431] LCMS: ESI-MS: m/z: 407.1 [M+H]⁺; RT = 1.89 min. (Method A)

[00432] HPLC: RT = 11.96 min.

[00433] ¾ NMR (400 MHz, DMSO-d<5): 10.83 (s, 1H), 8.98 (t, / = 5.9 Hz, 1H), 8.35 (d, / = 2.4 Hz, 1H), 8.03 - 7.85 (m, 2H), 7.48 - 7.28 (m, 3H), 7.22 - 7.06 (m, 1H), 4.68 (d, 7 = 5.9 Hz, 2H) ppm.

[00434] ¹⁹F NMR (376 MHz, OMSO-d6): δ -56.99 (s), -116.11 (s) ppm.

[00435] Example 44

[00436] 3-((4-fluorophenyl)amino)-N-(4-( trifluoromethyl)phenyl)pyrazine-2- ca

[00437] A mixture of 51 (120 mg, 0.399 mmols, 1.0 eq), 4-fluoroaniline (44 mg, 0.399 mmols, 1.0 eq), Cul (76 mg, 0.399 mmols, 1.0 eq), DIPEA (103 mg, 0.798 mmols, 2.0 eq) and CS2CO3 (393 mg, 1.20 mmols, 3.0 eq) in dioxane (10 mL) was heated to 95 °C for 16 hours under nitrogen. After the reaction mixture was cooled to room temperature, the insoluble matter was removed by filtration and the filtrate was concentrated. The residue was dissolved in ethyl acetate and washed sequentially with water and brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by Prep-HPLC to give the desired product Example 44 as a TFA salt (20.0 mg, 0.053 mmols, 13.3 %) as a yellow solid.

[00438] LCMS: ESI-MS: m/z: 377.1 [M+H]⁺; RT = 1.92 min. (Method A)

[00439] HPLC: RT = 12.06 min. [00440] ¾ NMR (400 MHz, OMSO-d6): δ 11.14 (s, 1H), 10.78 (s, 1H), 8.48 d, J = 2.2 Hz, 1H), 8.17 (d, J = 2.3 Hz, 1H), 8.13 (d, / = 8.4 Hz, 2H), 7.83 - 7.66 (m, 4H), 7.21 (t, / = 8.8 Hz, 2H) ppm.

[00441] ¹⁹F NMR (376 MHz, DMSO-d6): δ -60.25 (d, / = 2.2 Hz), -119.66 ppm

[00442] Example 45

[00443] 4-((4-fluorobenzyl)amino)-N-(6-(trifluoromethyl)pyridin-3-yl)pyrimidine-5 ca

[00444] Compound 62 was similarly prepared as the synthesis of compound 12.

[00445] LCMS: ESI-MS: m/z: 248.2 [M+H]⁺; RT = 1.19 min. (Method A)

[00446] A mixture of 62 (380 mg, 1.54 mmol, 1.0 eq) and 6-(trifluoromethyl)pyridin- 3-amine (249 mg, 1.54 mmol, 1.0 eq) in Pyridine (5 mL) was cooled to -15 °C, and POCb (0.28 mL, 3.08 mmol, 2.0 eq) was added dropwise. The resulting mixture was stirred at room temperature for 3 hours. After 62 was consumed, the reaction was quenched with sat. aqueous NH4CI. The aqueous layer was extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine, dried over Na2S0₄, filtered, and concentrated under reduced pressure to give a brown oil which was purified by Prep-HPLC to give Example 45 (45.0 mg, 0.115 mmol, 9.09%) as a white solid.

[00447] LCMS: ESI-MS: m/z: 302.1 [M+H]⁺; RT = 1.55 min. (Method A)

[00448] HPLC: RT = 8.87 min. [00449] ¾ NMR (400 MHz, DMSO-d<5): δ 10.88 (s, 1H), 9.04 (d, / = 2.2 Hz, 1H), 8.83 (s, 1H), 8.78 (s, 1H), 8.60 (s, 1H), 8.39 (dd, / = 8.6, 2.2 Hz, 1H), 7.93 (d, / = 8.6 Hz, 1H), 7.48 - 7.33 (m, 2H), 7.23 - 7.04 (m, 2H), 4.69 (d, / = 6.0 Hz, 2H) ppm.

[00450] ¹⁹F NMR (376 MHz, OMSO-d6): δ -65.71 (s), -115.99 (s) ppm.

[00451] Example 46

[00452] N-(3-cyano-4-(trifluoromethyl)phenyl)-3-((4-fluorobenzyl)amino)pyrazine-2-

^ mixture of 63 (15.0 g, 79.4 mmol, 1.0 eq) in NH4OH (150 mL) and 1,4-dioxane (40 mL) was heated to 120 °C in a Parr bomb under 10 atm overnight. The reaction mixture was extracted with DCM (100 mL x 3). The combined organic extracts were washed with brine, dried over Na2S0₄, filtered, and concentrated. The residue was purified by SGC (eluting with Petroleum ether / ethyl acetate, 4 / 1) to give the desired product 64 (9.00 g,

48.4 mmols, 61.0%) as a white solid.

[00453] LCMS: ESI-MS: m/z: 187.1 [M+H]⁺; RT = 1.46 min. (Method A)

[00454] Compound 65 was similarly prepared as the synthesis of Intermediate 14. Yield: 41.9%

[00455] LCMS: ESI-MS: m/z: 327.0 [M+H]⁺; RT = 1.58 min. (Method A)

[00456] Example 46 was similarly synthesized from 65 and (4- fluorophenyl)methanamine using General Procedure C. Yield: 66.5%

[00457] LCMS: ESI-MS: m/z: 416.0 [M+H]⁺; RT = 1.85 min. (Method A)

[00458] HPLC: RT = 11.57 min.

[00459] ¾ NMR (400 MHz, DMSO-d<5): δ 11.29 (s, 1H), 8.93 (t, / = 6.0 Hz, 1H), 8.64 (s, 1H), 8.41 - 8.39 (m, 1H), 8.02 (d, / = 8.8 Hz, 1H), 7.97 (d, 7 = 2.1 Hz, 1H), 7.51 - 7.32 (m, 1H), 7.15 (t, / = 8.8 Hz, 1H), 4.70 (d, / = 5.9 Hz, 2H) ppm.

[00460] ¹⁹F NMR (376 MHz, DMSO-d<5): δ -59.87 (s), -116.10 (s) ppm. [00461] Example 47

[00462] N-(3-cyano-4-(trifluoromethyl)phenyl)-2-((4- fluorobenzyl jamino Nicotinamide

[00463] Example 47 was similarly prepared as the synthesis of compound Example 46. Yield: 67.4%

[00464] LCMS: ESI-MS: m/z: 415.1 [M+H]⁺; RT = 1.71 min. (Method A)

[00465] HPLC: RT = 10.46 min.

[00466] ¾ NMR (400 MHz, DMSO-d<5): 10.80 (s, IH), 8.46 (s, IH), 8.36 (t, / = 5.8 Hz, IH), 8.28 - 8.22 (m, IH), 8.22 - 8.09 (m, 2H), 8.01 (d, J = 8.9 Hz, IH), 7.38 (dd, / = 8.2, 5.9 Hz, IH), 7.13 (t, / = 8.9 Hz, IH), 6.72 (dd, / = 7.7, 4.8 Hz, IH), 4.65 (d, / = 5.8 Hz, 2H) ppm.

[00467] ¹⁹F NMR (376 MHz, DMSO-d6): δ -59.85 (s), -116.41 (s) ppm.

[00468] Example 48

[00469] 2-((4-fluorobenzyl)amino )-N-(4-

( ( trifluoromethyl)sulfonyl)phenyl)nicotinamide

[00

Example 48 was similarly prepared from 36 and 4-(trifluoromethylsulfonyl) aniline

General Procedure E.

[00471] LCMS: ESI-MS: m/z: 454.1 [M+H]⁺; RT = 1.72 min. (Method A)

[00472] HPLC: RT = 10.54 min.

[00473] Ή NMR (400 MHz, DMSCW6): δ 10.80 (s, IH), 8.31 (s, IH), 8.25 (dd, / = 4.7, 1.6 Hz, IH), 8.14 (m, 5H), 7.39 (dd, / = 8.5, 5.7 Hz, 2H), 7.14 (t, / = 8.9 Hz, 2H), 6.72 (dd, / = 7.7, 4.8 Hz, IH), 4.65 (d, / = 5.7 Hz, 2H) ppm. [00474] ¹⁹F NMR (376 MHz, DMSO- 6): -78.79 (s), -116.39 (s) ppm.

[00475] Examples 49 and 50 were similarly prepared as the synthesis of compound

Example 48.

[00476] Example 49

[00477] N-(4-cyano-3-(trifluoromethyl)phenyl)-2-((4- fluorobenzyl jamino Nicotinamide

Example 49

[00478] LCMS: ESI-MS: m/z: 415.0 [M+H]⁺; RT = 1.98 min. (Method A)

[00479] HPLC: RT = 10.43 min.

[00480] ^lU NMR (400 MHz, DMSO-t/6): 510.87 (s, IH), 8.43 (s, IH), 8.34 (s, IH), 8.26 - 8.13 (m, 4H), 7.40 - 7.36 (m, 2H), 7.13 (t, / = 8.8 Hz, 2H), 6.72 (dd, / = 7.5, 4.9 Hz, IH ), 4.66 (d, J = 6.0 Hz, 2H) ppm.

[00481] ¹⁹F NMR (376 MHz, DMSO- 6): δ -60.37 (s) ppm

[00482] Example 50

[00483] N-(4-cyano-3-(trifluoromethyl)phenyl)-3-((4-fl owbenzyl)amino)pyrazine-2- carboxamide

Example 50

[00484] LCMS: ESI-MS: m/z: 416.0 [M+H]⁺; RT = 2.15 min. (Method A)

[00485] HPLC: RT = 11.53 min.

[00486] ^lH NMR (400 MHz, DMSO- 6): δ 1 1.37 (s, IH), 8.93 (s, IH), 8.68 (s, IH), 8.39 (d, / = 2.0 Hz, IH), 8.35 (d, J = 8.8 Hz, IH), 8.15 (d, J = 8.4 Hz, IH), 7.96 (d, J = 1.6 Hz, 1H), 7.40 (dd, J = 8.4, 1.6 Hz, 2H), 7.14 (t, J = 8.8 Hz, 2H), 4.70 (d, / = 6.0 Hz, 2H) ppm.

[00487] ¹⁹F NMR (376 MHz, DMSO-d6): δ -61.09 (s), -116.16 (s) ppm.

[00488] Example 51

[00489] 2-((4-fluorobenzyl)amino )-N-(2-( trifluoromethyl)thiazol-5-yl)nicotinamide

[00490] A solution of 67 (280 mg, 1.04 mmols, 1.0 eq) and trifluoroacetic acid (4 mL) in dichloromethane (5 mL) was stirred at room temperature for 3 hours. The mixture was concentrated and the residue was redissolved in dichloromethane (20 mL). This solution was washed with aqueous sat. NaHCCb (10 mL x 3) and brine. The organic layer was dried over Na2S0₄, filtered, and concentrated to give 68 (160 mg, crude) as a light yellow solid, which was used in the next step directly without further purification.

[00491] LCMS: ESI-MS: m/z: 169.1 [M+H]⁺; RT = 1.44 min. (Method B)

[00492] Compound 69 was similarly prepared as the synthesis of Intermediate 14. Yield: 9.70% for two steps.

[00493] Example 51 was similarly synthesized from 69 and (4- fluorophenyl)methanamine using General Procedure C. Yieid: 38.8%

[00494] LCMS: ESI-MS: m/z: 397.0 [M+H]⁺; RT = 2.28 min. (Method B)

[00495] HPLC: RT = 10.16 min.

[00496] ^lH NMR (400 MHz, CDCb): δ 8.84 (s, 1H), 8.48 (s, 1H), 8.32 (d, / = 4.6 Hz, 1H), 7.98 (s, 1H), 7.77 (d, / = 7.7 Hz, 1H), 7.35 (dd, / = 7.7, 5.7 Hz, 2H), 7.01 (t, / = 8.5 Hz, 2H), 6.61 (dd, / = 7.6, 4.8 Hz, 1H), 4.73 (d, / = 5.4 Hz, 2H) ppm.

[00497] ¹⁹F NMR (376 MHz, CDCb): δ -61.54 (s), -115.95 (s) ppm. [00498] Example 52

[00499] 3-((4-fluorobenzyl)amino)-N-(2-(rrifluoromethyl)thiazol-5-yl)pyrazine-2- carboxamide

Example 52

[00500] Example 52 was similarly prepared as the synthesis of compound Example 51. Yield: 62.0%

[00501] LCMS: ESI-MS : m/z: 398.1 [M+H]⁺; RT = 2.01 min. (Method A)

[00502] HPLC: RT = 10.78 min.

[00503] ^lU NMR (400 MHz, CDCb): 10.65 (s, 1H), 8.80 (s, 1 H), 8.28 (d, 7 = 2.3 Hz, 1H), 7.98 (s, 1H), 7.80 (d, J = 2.3 Hz, 1H), 7.35 (dd, J = 8.6, 5.4 Hz, 1H), 7.09 - 6.97 (m, 1H), 4.73 (d, J = 5.8 Hz, 2H) ppm.

[00504] ¹⁹F NMR (376 MHz, CDCb): δ -61.51 (s), -115.47 (s) ppm.

[00505] Example 53

[00506] 3-((4-fl orobenzyl)amino)-N-(6-(trifl oromethyl)pyridin-3-yl)pyridazine-4- ca

[00507] To a solution of 70 (800 mg, 4.30 mmol, 1.0 eq) in THF ( 10 mL) was added 2M aqueous LiOH (4.3 mL, 8.60 mmol, 2.0 eq) at 0 °C. The solution was stirred at room temperature. After 1 hour, the reaction mixture was acidified with 2 N aq. HCl to pH = 3 - 4, and the solvent was removed under vacuum. The crude mixture was diluted with dichloromethane / methanol (10 / 1, 110 mL). The insoluble matter was removed by filtration and the filtrate was concentrated to give the desired product 71 (900 mg, crude) as a white solid, which was used in the next step directly without further purification.

[00508] Compound 72 was similarly prepared as the synthesis of Intermediate 14. Yield: 7.70% for two steps.

[00509] Example 53 was synthesized by the reaction of compound 72 and (4- fluorophenyl)methanamine (5.0 eq) at 100 °C using the General Procedure C. Yield: 69.4%.

[00510] LCMS: ESI-MS: m/z: 392.1 [M+H]⁺; RT = 2.04 min. (Method B)

[00511] HPLC: RT = 9.57 min

[00512] ¾ NMR (400 MHz, DMSO): δ 11.14 (s, 1H), 9.03 (d, / = 2.3 Hz, 1H), 8.74 (d, / = 4.8 Hz, 1H), 8.41 (dd, / = 8.6, 2.2 Hz, 1H), 7.95 (d, / = 8.6 Hz, 1H), 7.90 (t, / = 5.9 Hz, 1H), 7.76 (d, / = 4.9 Hz, 1H), 7.43 (dd, / = 8.6, 5.6 Hz, 2H), 7.24 - 7.02 (m, 2H), 4.74 (d, 7 = 5.9 Hz, 2H).

[00513] ¹⁹F NMR (376 MHz, DMSO-d<5): -65.78 (s), -116.35 (s) ppm.

[00514] Example 54

[00515] 3-((4-fluorobenzyl)amino)-N-(5-(trifluoromethyl)thiophen-2-yl)pyrazine-2- ca

[00516] To a mixture of 73 (400 mg, 2.04 mmols, 1.0 eq) in t-BuOH (10 mL) was added triethylamine (0.500 mL, 3.67 mmols, 1.8 eq) and diphenylphosphoryl azide (DPPA) (1.01 g, 3.67 mmols, 1.8 eq). The mixture was heated to 90 °C overnight under nitrogen. Thin layer chromatography (TLC) indicated that the reaction was complete. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (20 mL) and washed sequentially with aqueous sat. NaHCCb, citric acid (10% aqueous) and brine. The organic solution was dried over MgS0₄, filtered, and concentrated. The residue was purified by SGC (5 to 20% ethyl acetate / petroleum ether) to give the desired product 74 (320 mg, 1.20 mmols, 58.7%) as a white solid.

[00517] LCMS: ESI-MS: m/z: 212 [M-55]⁺; RT = 2.22 min. (Method B)

[00518] ¾ NMR (400 MHz, DMSO-d<5): δ 11.05 (brs, 1H), 7.37 (dd, / = 4.0, 1.2 Hz, 1H), 6.52 (d, / = 3.6 Hz, 1H), 1.48 (s, 9H) ppm.

[00519] Compound 75 was similarly prepared from 3 and 74 using General Procedure D and General Procedure E. Yield: 40.4%

[00520] LCMS: ESI-MS: m/z: 308 [M-100+l]⁺; RT = 1.90 min. (Method A)

[00521] To a mixture of 75 (160 mg, 0.393 mmols, 1.0 eq) in dichloromethane (6 mL) was added trifluoroacetic acid (3 mL) dropwise at 0 °C. The reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated. The residue was dissolved in ethyl acetate (20 mL) and washed sequentially with aqueous sat. NaHCCb

(10 mL x 3) and brine. The solution was dried over MgS0₄, filtered, and concentrated, the residue was purified by Preparative-TLC (petroleum ether / ethyl acetate, 3 / 1) to give the desired product 76 (80.0 mg, 0.261 mmols, 66.3%) as a white solid.

[00522] LCMS: ESI-MS: m/z: 308.1 [M+H]⁺; RT = 1.90 min. (Method A)

[00523] Example 54 was similarly synthesized from compound 7 and (4- fluorophenyl) methanamine (5.0 eq) at 130 °C using the General Procedure C. Yield:

54.4%

Example 54 [00524] LCMS: ESI-MS : m/z: 397.1 [M+H]⁺; RT = 2.38 min. (Method B)

[00525] HPLC: RT = 10.04 min.

[00526] ¾ NMR (500 MHz, DMSO-d<5): δ 12.46 (s, 1H), 8.84 (t, / = 6.0 Hz, 1H), 8.38 (d, / = 2.3 Hz, 1H), 7.96 (d, / = 2.3 Hz, 1H), 7.52 (d, / = 3.0 Hz, 1H), 7.41 (dd, / = 8.5 , 5.7 Hz, 2H), 7.19 (d, J = 3.5 Hz, 1H), 7.14 (d, J = 8.9 Hz, 2H), 4.70 (d, / = 6.0 Hz, 2H) ppm.

[00527] ¹⁹F NMR (376 MHz, DMSO-ifc): δ -52.80 (s), -116.12 (s) ppm.

[00528] Example 55

[00529] 2-((4-fluorophenyl)amino)-N-(6-(trifluoromethoxy)pyridin-3-yl)nicotinamide Example 56

[00530] 2-((4-fluorobenzyl)amino)-N-(6-(trifluoromethoxy)pyridin-3-yl)nicotinamide and Example 57

[00531] 3-((4-fluorobenzyl)amino)-N-(6-(trifluoromethoxy)pyridin-3-yl)pyrazine-2- carboxamide

Example 56

[00532] An LDA solution was prepared from n-BuLi (2.5M in hexane, 9.0 mL, 22.4 mmols, 1.3 eq) and diisopropylamine (2.60 g, 25.9 mmols, 1.5 eq) in THF (10 mL) at 0 °C. To the LDA solution was added a solution of 77 (3.40 g, 17.3 mmols, 1.0 eq) in THF (10 mL) dropwise at -78 °C. The solution was stirred at -78 °C for 2 hours. After TMSC1 (2.42 g, 22.4 mmols, 1.3 eq) was added dropwise, the reaction mixture was allowed to warm up to room temperature and stirred for 1 hour. Water (120 mL) was added. The aqueous layer was extracted with ethyl acetate (100 mL x 3), and the combined organic layers were dried over Na2S0₄ and concentrated. The crude was purified on silica gel using petroleum ether (100 percent) as an eluent to afford the desired compound 78 (3.90 g, 14.4 mmols, 83.2%) as a yellow oil.

[00533] A solution of sodium azide (1.77 g, 27.3 mmols, 1.5 eq) in H2O (5 mL) was added to a solution of benzenesulfonyl chloride (3.20 g, 18.2 mmols, 1.0 eq) in acetone (20 mL) at room temperature. After 3 hours, the reaction solution was concentrated. Ethyl acetate (80 mL) was added, then the organic layer was washed with brine (30 mL x 3), dried over Na2S0₄, filtered, and concentrated to give benzenesulfonyl azide (3.20 g, crude) as an oil, which was used in the next step directly without further purification.

[00534] n-BuLi (2.5M in hexane, 6.6 mL, 16.4 mmols, 1.3 eq) was added to a solution of 2,2,6,6- ϊ ei.ramelhylpiperidme (HTMP, 2.67 g, 18.9 mmols, 1.5 eq) in THF (7 mL) at 0 °C. After 0.5 h, a solution of 78 (3.40 g, 12.6 mmols) in THF (7 mL) was added at -78 °C. The solution was stirred at -78 °C for 3 hours. A solution of benzenesulfonyl azide (3.20 g, crude) in THF (6 mL) was added at -78 °C. After 1 hour, the reaction was quenched with saturated aqueous solution of ammonium chloride (100 mL), extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine, dried over Na2S0₄, filtered, and concentrated to afford the desired product 79 (4.50 g, crude) as an oil, which was used in the next step directly without further purification.

[00535] Compound 79 (4.50 g, crude) was dissolved in anhydrous THF (20 mL) and added dropwise to a suspension of LiAlfU (954 mg, 25.2 mmol) in THF (20 mL) at 0 °C. The reaction mixture was stirred at room temperature for 16 hours before being quenched with water (100 mL) at 0 °C, and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine, dried over Na2SC¼, filtered, and concentrated to get the desired product 80 (2.78 g, crude) as an oil, which was used in the next step directly without further purification.

[00536] Compound 80 (2.78 g, crude) was treated with tetrabutylammonium fluoride (1.0 M in THF, 12.7 mL, 12.7 mmol, 1.3 eq) for 16 hours at 25 °C. The mixture was neutralized by addition of sodium hydroxide (4% in water, 40 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were dried over Na2S0₄, filtered, and concentrated. The residue was purified by chromatography on silica gel (ethyl acetate / petroleum ether, 1 / 5) to afford the desired product 81 (2.00 g, 9.43 mmols, 74.5% for three steps) as a yellow solid.

[00537] A mixture of 81 (2.00 g, 9.43 mmols, 1.0 eq), Pd/C (10%, 1.0 g), HCOONH₄ (1.2 g, 18.9 mmols, 2.0 eq.) in MeOH (20 mL) was heated to 55 °C for 16 hours. The reaction mixture was cooled to room temperature, filtered through celite, and the filtrate was concentrated. The residue was partitioned between ethyl acetate (100 mL) and NaOH (4% in water, 30 mL). The organic layer were washed with brine, dried over Na2S0₄, filtered, and concentrated to afford the desired product 82 (1.50 g, 8.38 mmols, 89.4%) as a yellow oil.

[00538] Compound 83 was similarly prepared as the synthesis of Intermediate 14. Yield: 31.5%.

[00539] Example 55 was synthesized by the reaction of compound 83 and 4- fluoroaniline (5.0 eq) at 130 °C using the General Procedure C. Yield: 24.3%.

[00540] Compound Example 56 was synthesized by the reaction of compound 83 and (4-fluorophenyl)methanamine (5.0 eq) at 130 °C using the General Procedure C. Yield:

52.4%.

[00541] Example 57 was similarly prepared as the synthesis of compound Example 56.

[00542] Example 55

[00543] 2-((4-fluoroph ridin-3-yl)nicotinamide

Example 55

[00544] LCMS: ESI-MS: m/z: 393.1 [M+H]⁺; RT = 2.24 min. (Method B)

[00545] HPLC: RT = 9.72 min

[00546] ¾ NMR (400 MHz, DMSO-d<5): δ 10.77 (s, 1H), 10.14 (s, 1H), 8.67 (d, / = 2.6 Hz, 1H), 8.37 - 8.35 (m, 2H), 8.26 (dd, / = 7.7, 1.8 Hz, 1H), 7.74 - 7.65 (m, 2H), 7.37 (d, / = 8.8 Hz, 1H), 7.14 (t, / = 8.9 Hz, 2H), 6.96 (dd, / = 7.7, 4.8 Hz, 1H) ppm.

[00547] ¹⁹F NMR (376 MHz, OMSO-d6): -55.26 (s), -121.09 (s) ppm. [00548] Example 56

[00549] 2-((4-fluorobenzyl)amino)-N-(6-(trifluoromethoxy)pyridin-3-yl)nicotinamide

Example 56

[00550] LCMS: ESI-MS: m/z: 407.1 [M+H]⁺; RT = 2.14 min. (Method B)

[00551] HPLC: RT = 9.30 min

[00552] Ή NMR (400 MHz, CDCh): δ 8.41 - 8.28 (m, 3H), 8.24 (dd, J = 8.8, 2.8 Hz, 1H), 7.78 - 7.75 (m, 2H), 7.34 (dd, / = 8.5, 5.5 Hz, 2H), 7.07 (d, J = 8.8 Hz, 1H), 7.00 (t, / = 8.7 Hz, 2H), 6.62 (dd, / = 7.7, 4.8 Hz, 1H), 4.71 (d, / = 5.6 Hz, 2H) ppm.

[00553] ¹⁹F NMR (376 MHz, DMSO- 6): -55.26 (s), -116.42 (s) ppm.

[00554] Example 57

[00555] 3-((4-f iorobenzyl)amino)-N-(6-(rrifliwromethoxy)pyridin-3-yl)pyrazine-2- carboxamide

Example 57

[00556] Example 57 was synthesized using a similar method to that of Example 56. LCMS: ESI-MS: m/z: 408.2 [M+H]⁺; RT = 1.95 min. (Method A)

[00557] HPLC: RT = 10.20 min

[00558] ^lH NMR (400 MHz, DMSO- 6): δ 11.04 (s, 1H), 8.94 (t, J = 5.9 Hz, 1H), 8.80 (d, / = 2.6 Hz, 1H), 8.44 (dd, 7 = 8.9, 2.7 Hz, 1H), 8.37 (d, / = 2.3 Hz, 1H), 7.95 (d, J = 2.4 Hz, 1H), 7.40 (dd, J = 8.7, 5.6 Hz, 2H), 7.34 (d, J = 8.9 Hz, 1H), 7.14 (t, J = 8.9 Hz, 2H), 4.69 (d, J = 5.9 Hz, 2H) ppm.

[00559] ¹⁹F NMR (376 MHz, DMSO-t/6): -55.23 (s), -116.11 (s) ppm. [00560] Example 58

[00561] 3-((4-fluorophenyl)amino)-N-(6-(trifluoromethyl)pyridin-3-yl)pyrazine-2- carboxamide

[00562] Example 58 was similarly prepared as the synthesis of compound Example 20.

Example 58

[00563] LCMS: ESI-MS: m/z: 378.1 [M+H]⁺; RT = 2.33 min. (Method B)

[00564] HPLC: RT = 11.43 min

[00565] ¾ NMR (400 MHz, OMSO-d6): δ 11.27 (s, 1H), 9.23 (d, / = 2.2 Hz, 1H), 8.91 (t, J = 5.9 Hz, 1H), 8.50 (dd, J = 8.6, 2.5 Hz, 1H), 8.39 (d, 7 = 2.3 Hz, 1H), 8.04 (d, J = 8.7 Hz, 1H), 7.97 (d, J = 2.3 Hz, 1H), 7.41 (dd, J = 8.6, 5.6 Hz, 2H), 7.15 (t, J = 8.9 Hz, 2H) ppm.

[00566] ¹⁹F NMR (376 MHz, OMSO-d6): -65.77 (s), -119.53 (s) ppm.

[00567] Example 59

[00568] 3-((( tetrahydro-2H-pyran-4-yl jmethyl )amino)-N-(6-( trifluoromethyl)pyridin- 3 -yl)pyrazine-2-carboxamide

[00569] Example 59 was similarly prepared as the synthesis of compound Example 20.

Example 59

[00570] LCMS: ESI-MS: m/z: 382.1 [M+H]⁺; RT = 2.15 min. (Method B)

[00571] HPLC: RT = 10.63 min

[00572] ¾ NMR (400 MHz, DMSO-d<5): δ 11.19 (s, 1H), 9.19 (d, / = 2.3 Hz, 1H),

8.61 (t, / = 5.8 Hz, 1H), 8.56 (dd, / = 8.6, 2.2 Hz, 1H), 8.39 (d, / = 2.3 Hz, 1H), 7.93 - 7.91 (m, 2H), 3.86 (dd, J = 11.3, 3.1 Hz, 2H), 3.41 (t, / = 6.4 Hz, 2H), 3.31

2H), 1.92 - 1.82 (m, 1H), 1.63 - 1.59 (m, 2H), 1.31 - 1.21 (m, 2H) ppm.

[00573] ¹⁹F NMR (376 MHz, DMSO-d<5): -65.73 (s) ppm.

[00574] Example 60

[00575] 2-( ( ( tetrahydro-2H-pyran-3-yl)methyl)amino)-N-(4-

[00576] To a solution of 84 (400 mg, 3.51 mmols, 1.0 eq) in EtOH (20 mL) was added a solution of hydro ylamine hydrochloride (605 mg, 8.78 mmols, 2.5 eq) in H2O (5 mL) at room temperature. The resulting solution was heated to reflux for 16 hours. The reaction mixture was cooled to room temperature and concentrated. The crude mixture was partitioned between saturated sodium carbonate solution and ethyl acetate. The organic layer was washed with brine, dried over Na2S0₄, filtered, and concentrated to afford the desired product 85 (400 mg, crude) as an oil, which was used in the next step directly without further purification.

[00577] A mixture of 85 (400 mg, crude) and Pd/C (10%, 100 mg) in MeOH (10 mL) was stirred at room temperature for 16 hours under H2 (g) (1 atm). T he reaction mixture was filtered through a pad of celite. The filtrate was concentrated to obtain the desired product 86 (200 mg, crude) as an oil, which was used in the next step directly without further purification.

[00578] Compound 87 was similarly prepared as the synthesis of Intermediate 14. Yield: 67.1%

[00579] Example 60 was synthesized by the reaction of compound 87 and compound 86 (5.0 eq) at 130 °C using the General Procedure C. Yield: 34.9%.

[00580] Example 60

[00581] 2-( ( ( tetrahydro-2H-pyran-3-yl)methyl)amino)-N-(4- ( trifluoromethyl jphenyl Nicotinamide

Example 60

[00582] LCMS: ESI-MS: m/z: 380.1 [M+H]⁺; RT = 2.16 min. (Method B)

[00583] HPLC: RT = 9.46 min.

[00584] ¾ NMR (400 MHz, DMSO-d<5): δ 10.48 (s, 1H), 8.23 (dd, 7 = 4.8, 1.8 Hz,

1H), 8.10 (dd, 7 = 7.7, 1.8 Hz, 1H), 8.02 (t, 7 = 5.7 Hz, 1H), 7.93 (d, 7 = 8.5 Hz, 2H), 7.72

(d, 7 = 8.6 Hz, 2H), 6.66 (dd, 7 = 7.7, 4.8 Hz, 1H), 3.84 - 3.66 (m, 2H), 3.36 - 3.32 (m,

2H), 3.15 (dd, 7 = 11.1 , 9.2 Hz, 1H), 1.92 - 1.69 (m, 2H), 1.65 - 1.54 (m, 1H), 1.53 -

1.39 (m, 1H), 1.38 - 1.15 (m, 1H) ppm.

[00585] ¹⁹F NMR (376 MHz, DMSO-d<5): -60.33 (s) ppm.

[00586] Example 61

[00587] 2-((oxetan-3-ylmethyl)amino)-N-(4-(trifluoromethyl)phenyl)nicotinamide

[00588]

Example 61

[00589] Example 61 was synthesized by the reaction of compound 87 and oxetan-3-yl methanamine (2.0 eq) at 130 °C using the General Procedure C. Yield: 47.5%.

[00590] LCMS: ESI-MS: m/z: 352.0 [M+H]⁺; RT = 1.77 min. (Method B)

[00591] HPLC: RT = 7.19 min

[00592] ¾ NMR (400 MHz, DMSO-d<5): δ 15.00 (s, 1H), 8.05 (dd, 7 = 7.1, 1.8 Hz, 1H), 7.85 (d, 7 = 8.5 Hz, 2H), 7.67 (d, 7 = 8.6 Hz, 2H), 7.45 (dd, 7 = 6.6, 1.8 Hz, 1H), 6.02 (t, 7 = 6.8 Hz, 1H), 4.81 (t, 7 = 4.5 Hz, 1H), 4.13 - 4.01 (m, 1H), 3.77 (dd, 7 = 12.6, 9.0 Hz, 1H), 3.73 - 3.60 (m, 1H), 3.55 - 3.45 (m, 1H), 3.38 (dd, 7 = 10.0, 5.6 Hz, 1H), 3.29 (d, 7 = 8.4 Hz, 1H), 2.19 - 1.93 (m, 1H) ppm.

[00593] ¹⁹F NMR (376 MHz, DMSO-d<5): -60.22 (s) ppm. [00594] Examples 62, 63, 64, 65, 66, 67, 68, 69, and 70 were similarly prepared as the synthesis of Example 61.

[00595] Example 62

[00596] 2-((( tetrahydrofuran-3-yl)methyl)amino )-N-(4- (trifluoromethyljphenyljnicotinamide trifluoroacetic acid salt

Example 62

[00597] LCMS: ESI-MS: m/r. 366.1 [M+H]⁺; RT = 1.74 min. (Method A)

[00598] HPLC : RT = 8.85 min

[00599] ^lU NMR (400 MHz, DMSO-t/6): δ 10.63 (s, IH), 8.36 (s, IH), 8.22 (dd, 7 = 5.5, 4.1 Hz, 2H), 7.93 (d, / = 8.5 Hz, 2H), 7.74 (d, / = 8.6 Hz, 2H), 6.84 - 6.71 (m, IH), 3.82 - 3.56 (m, 3H), 3.49 - 3.42 (m, 3H), 2.59 - 2.55 (m, IH), 1.93 - 2.0 l(m, IH), 1.57 - 1.66(m, IH) ppm.

[00600] ¹⁹F NMR (376 MHz, DMSO- 6): -60.36 (s), -74.68 (s) ppm.

[00601] Example 63

[00602] 2-((2-(methylamino)-2-oxoethyl)amino)-N-(4- ( trifluoromethyl jphenyl Nicotinamide

Example 63

[00603] LCMS: ESI-MS: m/r. 353.1 [M+H]⁺; RT = 1.92 min. (Method B)

[00604] HPLC: RT = 7.68 min

[00605] ^lH NMR (400 MHz, DMSO- 6): δ 10.52 (s, IH), 8.22 (d, J = 4.8 Hz, 2H), 8.11 (d, / = 7.6 Hz, IH), 7.96 (d, / = 8.5 Hz, 2H), 7.88 (d, / = 4.6 Hz, IH), 7.73 (d, / = 8.5 Hz, 2H), 6.71 (dd, 7 = 7.6, 4.9 Hz, IH), 4.00 (d, J = 5.1 Hz, 2H), 2.60 (d, J = 4.6 Hz, 3H) ppm.

[00606] ¹⁹F NMR (376 MHz, DMSO-t/6): -60.31 (s) ppm. [00607] Example 64

[00608] 2-((2-amino-2-oxoethyl)amino)-N-(4-(trifluoromethyl)phenyl)nicotinam

Example 64

[00609] LCMS: ESI-MS: m/r. 339.2 [M+H]⁺; RT = 1.39 min. (Method A)

[00610] HPLC: RT = 7.42 min

[00611] ^lH NMR (400 MHz, DMSO- 6): δ 10.52 (s, IH), 8.22 (s, 2H), 8.10 (d, / =

7.5 Hz, IH), 7.96 (d, J = 8.2 Hz, 2H), 7.73 (d, J = 8.1 Hz, 2H), 7.46 (s, IH), 7.08 (s, IH),

6.80 - 6.61 (m, IH), 3.99 (d, 7 = 4.1 Hz, 2H) ppm.

[00612] ¹⁹F NMR (376 MHz, DMSO-t/6): -60.31 (s) ppm.

[00613] Example 65

[00614] 2-(oxetan-3-ylamin -N-(4-( trifluoromethyl)phenyl)nicotinamide

Example 65

[00615] LCMS: ESI-MS: m/r. 338.1 [M+H]⁺; RT = 1.38 min. (Method A)

[00616] HPLC: RT = 7.64 min.

[00617] ^lH NMR (400 MHz, CDCb): δ 12.62 (s, IH), 8.10 (dd, J = 7.1, 1.6 Hz, IH),

7.82 (d, J = 8.5 Hz, 2H), 7.58 (d, J = 8.5 Hz, 2H), 7.26 (dd, J = 6.5, 1.5 Hz, IH), 5.97 (t, J

= 6.8 Hz, IH), 4.49 - 4.43 (m, IH), 4.23 - 4.11 (m, 2H), 3.93 (dd, 7 = 11.3, 3.8 Hz, IH),

3.67 (dd, 7 = 11.3, 3.6 Hz, IH) ppm.

[00618] ¹⁹F NMR (376 MHz, CDCb): δ -61.96 (s) ppm.

[00619] Example 66

[00620] 2-((l-methylazetidin-3-yl)amino)-N-(4-(trifluoromethyl)phenyl)nicotm^

Example 66 [00621] LCMS: ESI-MS: m/z: 351.0 [M+H]⁺; RT = 1.93 min. (Method B)

[00622] HPLC: RT = 7.96 min

[00623] ¾ NMR (400 MHz, CDCb): δ 12.62 (s, IH), 8.01 (dd, / = 7.0, 1.5 Hz, IH), 7.76 (d, J = 8.4 Hz, 2H), 7.51 (d, / = 8.5 Hz, 2H), 7.17 (dd, / = 6.5, 1.6 Hz, IH), 5.87 (t, / = 6.8 Hz, IH), 4.46 - 4.34 (m, IH), 4.11 (t, / = 10.9 Hz, IH), 3.98 (dd, / = 10.9, 8.1 Hz, IH), 2.80 (dd, / = 11.6, 5.1 Hz, IH), 2.67 (dd, / = 11.6, 5.4 Hz, IH), 2.45 (s, 3H) ppm.

[00624] ¹⁹F NMR (376 MHz, DMSO-d<5): -61.96 (s) ppm.

[00625] Example 67

[00626] 2-((2-hydroxyprop yljphenyljnicotinamide

Example 67

[00627] LCMS: ESI-MS: m/z: 340.1 [M+H]⁺; RT = 1.83 min. (Method B)

[00628] HPLC: RT = 8.27 min

[00629] ¾ NMR (400 MHz, DMSO): δ 10.46 (s, IH), 8.23 (dd, / = 4.8, 1.7 Hz, IH), 8.10 (dd, / = 7.7, 1.7 Hz, IH), 8.03 (d, 7 = 7.4 Hz, IH), 7.93 (d, J = 8.5 Hz, 2H), 7.72 (d, / = 8.6 Hz, 2H), 6.65 (dd, / = 7.7, 4.8 Hz, IH), 4.83 (t, / = 5.3 Hz, IH), 4.25 - 4.13 (m, IH), 3.49 (dt, / = 9.7, 4.8 Hz, IH), 3.41 (dt, / = 10.6, 5.5 Hz, IH), 1.16 (d, / = 6.6 Hz, 3H) ppm.

[00630] ¹⁹F NMR (376 MHz, DMSO-d<5): -60.32 (s) ppm.

[00631] Example 68

[00632] 2-( ( ( l,3-dioxolan-2-yl)methyl)amino)-N-(4- ( trifluoromethyl jphenyl Nicotinamide

Example 68

[00633] LCMS: ESI-MS: m/z: 368.0 [M+H]⁺; RT = 2.09 min. (Method B)

[00634] HPLC: RT = 9.18 min. [00635] ¾ NMR (400 MHz, OMSO-d6): δ 10.51 (s, 2H), 8.24 (dd, 7 = 4.8, 1.7 Hz, 1H), 8.14 - 8.11 (m, 2H), 7.93 (d, / = 8.5 Hz, 2H), 7.73 (d, J = 8.6 Hz, 2H), 6.71 (dd, 7 = 7.7, 4.8 Hz, 2H), 5.02 (t, J = 4.1 Hz, 1H), 3.94 - 3.92 (m, 2H), 3.88 - 3.78 (m, 2H), 3.64 (dd, J = 5.5, 4.3 Hz, 2H) ppm.

[00636] ¹⁹F NMR (376 MHz, DMSO-de): δ -60.35 (s) ppm.

[00637] Example 69

[00638] 2-((isoxaz.ol-3-ylme methyl)phenyl)nicotinamide

Example 69

[00639] LCMS: ESI-MS: m/z: 363.1 [M+H]⁺; RT = 2.08 min. (Method B)

[00640] HPLC: RT = 8.41 min.

[00641] 1H NMR (400 MHz, DMSO): δ 10.55 (s, 1H), 8.80 (d, / = 1.4 Hz, 1H), 8.37

(t, / = 6.0 Hz, 1H), 8.25 (dd, / = 4.8, 1.5 Hz, 1H), 8.14 (dd, / = 7.6, 1.5 Hz, 1H), 7.95 (d,

/ = 8.6 Hz, 2H), 7.73 (d, / = 8.6 Hz, 2H), 6.75 (dd, / = 7.7, 4.9 Hz, 1H), 6.49 (d, / = 1.5

Hz, 1H), 4.74 (d, J = 5.5 Hz, 2H) ppm.

[00642] ¹⁹F NMR (376 MHz, DMSO-d6): -60.34 (s) ppm.

[00643] Example 70

[00644] 2-((4-fluorobenzyl )amino )-N-(4-( trifluoromethyl)phenyl)nicotinamide

Example 70

[00645] LCMS: ESI-MS: m/z: 390.2 [M+H]⁺; RT = 1.78 min. (Method A)

[00646] HPLC: RT = 9.35 min.

[00647] ^lH NMR (400 MHz, OMSO-d6): δ 10.53 (s, 1H), 8.33 (t, / = 6.0 Hz, 1H), 8.26 - 8.18 (m, 1H), 8.12 (d, / = 6.0 Hz, 1H), 7.93 (d, / = 8.7 Hz, 2H), 7.72 (d, / = 8.7 Hz, 2H), 7.38 (dd, J = 8.5, 5.8 Hz, 2H), 7.13 (t, J = 8.9 Hz, 2H), 6.70 (dd, / = 7.6, 4.8 Hz, 1H), 4.64 (d, / = 5.5 Hz, 2H) ppm.

[00648] ¹⁹F NMR (376 MHz, DMSO-ifc): δ -60.33 (s), -116.43 (s) ppm.

[00649] Example 71

[00650] 2-((2-oxopropyl)amino)-N-(4-(trifluoromethyl)phenyl)nicotinamide trifluoroacetic acid salt and Example 72 2-(((2-methyl-l,3-dioxolan-2-yl)methyl)amino)- N-

[00651] A mixture of chloroacetone 88 (3.20 g, 34.8 mmol, 1.0 eq) and potassium 1,3- dioxoisoindolin-2-ide (6.43 g, 34.8 mmol, 1.0 eq) in DMF (10 mL) was stirred at 20 °C overnight under nitrogen. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2S0₄, filtered, and concentrated. The residue was purified by SGC (petroleum ether / ethyl acetate, 6 / 1) to afford the desired product 89 (4.00 g, 19.7 mmols, 60.6%) as a white solid.

[00652] LCMS: ESI-MS: m/z: 204.2 [M+H]⁺; RT = 1.40 min. (Method A)

[00653] To a mixture of 89 (4.00 g, 19.7 mmol, 1.0 eq), 4-methylbenzenesulfonic acid (1.02 g, 5.91 mmol, 0.3 eq) and ethane- 1 ,2-diol (20 mL) in toluene (20 mL) was stirred at 110 °C overnight under nitrogen. The mixture was concentrated and the residue was purified by SGC (petroleum ether / ethyl acetate, 5 / 1) to afford the desired product 90 (2.90 g, 11.7 mmol, 59.5%) as a white solid.

[00654] LCMS: ESI-MS: m/z: 248.2 [M+H]⁺; RT = 1.49 min. (Method A)

[00655] To a mixture of 90 (2.90 g, 11.7 mmols, 1.0 eq) in ethanol (30 mL) was added hydrazine (85% in water, 10 mL) and the reaction mixture was heated to reflux for 2 hours. After the reaction mixture was cooled to room temperature, the insoluble matter was removed by filtration and the filtrate was concentrated. The residue was dissolved in tetrahydrofuran (200 mL) and washed sequentially with water and brine. The organic phase was dried over Na2S0₄, filtered, and concentrated to give the desired product 91 (420 mg, crude) as a light yellow oil, which was used in the next step directly without further purification.

[00656] LCMS: ESI-MS: m/z: 118.2 [M+H]⁺; RT = 1.09 min. (Method A)

[00657] Example 72 was similarly synthesized from compound 87 and 91 (10.0 eq) at

140 °C using the General Proc

Example 72

[00658] LCMS: ESI-MS: m/z: 382.1 [M+H]⁺; RT = 1.58 min. (Method A)

[00659] HPLC: RT = 8.46 min.

[00660] ¾ NMR: (400 MHz, MeOD-d4): 8.51 (dd, / = 7.6 Hz, 1.6 Hz, 1H), 8.11 (dd, J = 6.0, 1.6 Hz, 1H), 7.92 (d, J = 8.4 Hz, 2H), 7.70 (d, / = 8.4 Hz, 2H), 7.01 (dd, / = 7.6, 6.4 Hz, 1H), 4.03 - 4.01 (m, 4H), 3.75 (s, 2H), 1.44 (s, 3H) ppm.

[00661] ¹⁹F NMR: (376 MHz, MeOD-d4): -63.72 (s), -77.18 (s) ppm.

[00662] A solution of Example 72 (32 mg, 0.0646 mmols, 1.0 eq) and trifluoroacetic acid (5 mL) in dichloromethane (5 mL) was stirred at room temperature for 3 days. After the mixture was concentrated, the residue was redissoved in dichloromethane (20 mL) and washed sequentially with aqueous sat. NaHCC (10 mL x 3) and brine. The organic layer was dried over Na2SC¼, filtered, and concentrated, the residue was purified by Prep- HPLC to give Example 71 (27 as a white solid.

Example 71

[00663] LCMS: ESI-MS: m/z: 338.0 [M+H]⁺; RT = 21.5 min. (Method A)

[00664] HPLC: RT = 8.88 min. [00665] ¾ NMR (400 MHz, MeOO-d4): δ 8.65 (d, / = 8.0 Hz, 1H), 8.48 (d, / = 6.3 Hz, 1H), 7.95 (d, J = 8.5 Hz, 2H), 7.70 (d, / = 8.7 Hz, 2H), 7.15 (t, / = 7.0 Hz, 1H), 4.03 (dd, / = 33.2, 12.4 Hz, 2H), 1.95 (s, 3H) ppm.

[00666] ¹⁹F NMR (376 MHz, MeOD-d4): δ -63.71 (s), -77.16 (s) ppm.

[00667] Example 73

[0

[00669] To a mixture of 92 (2.00 g, 27.8 mmols, 1.0 eq) in dichloromethane (30 mL) was added 2-(triphenylphosphoranylidene)acetonitrile (8.34 g, 27.8 mmols, 1.0 eq) and stirred at room temperature. After 16 hours, the solvent was removed under reduced pressure and the residue was purified by chromatography on silica gel (petroleum ether / ethyl acetate, 3 / 1) to give the desired product 93 (1.10 g, 11.6 mmols, 41.7%) as a white solid.

[00670] ¾ NMR (400 MHz, CDCb): δ 5.43 - 5.34 (m, 2H), 5.31 - 5.29 (m, 2H), 5.28 - 5.22 (m, lH) ppm.

[00671] To a mixture of 93 (500 mg, 5.32 mmols, 1.0 eq) in methanol (10 mL) was added Raney-Ni (300 mg in water) and stirred at room temperature under hydrogen atmosphere (1 atm) for 12 hours. The mixture was then filtered through a pad of celite. The filtrate was concentrated to give 94 (600 mg, crude) as a light yellow oil, which was used in the next step directly without further purification.

[00672] Example 73 was similarly synthesized from compound 87 and 94 (5.0 eq) at 130 °C using the General Procedure C. Yield: 69.8%

[00673] LCMS: ESI-MS: m/z: 366.2 [M+H]⁺; RT = 1.93 min. (Method B)

[00674] HPLC: RT = 7.69 min.

[00675] ¾ NMR (400 MHz, DMSO-d<5): δ 10.74 (s, 1H), 8.20 (dd, / = 4.8, 1.6 Hz, 1H), 7.92 (d, / = 8.4 Hz, 2H), 7.72 (d, / = 8.8 Hz, 2H), 7.68 (dd, 7 = 7.2, 1.6 Hz, 1H), 6.68 (dd, / = 7.6, 4.8 Hz, 1H), 4.65 (t, / = 5.2 Hz, 1H), 3.47 - 3.36 (m, 4H), 3.31 - 3.29 (m, 1H), 3.23 - 3.18 (m, 1H), 2.34 - 2.29 (m, 1H), 1.95 - 1.90 (m, 1H), 1.67 - 1.62 (m, 1H) ppm.

[00676] ¹⁹F NMR (376 MHz, DMSO-ifc): δ -60.28 (s) ppm. [00677] Example 74

[00678] N-f 3-cyano-4-( trifluoromethyl)phenyl)-2-( ( oxetan-3- y

[00679] Compound 95 was similarly prepared as the synthesis of Intermediate 14. Yield: 54.3%

[00680] Example 74 was similarly synthesized from compound 95 and oxetan-3-yl methanamine (5.0 eq) at 130 °C using the General Procedure C. Yield: 32.4%

[00681] LCMS: ESI-MS : m/z: 377.2 [M+H]⁺; RT = 1.26 min. (Method A)

[00682] HPLC: RT = 7.29 min.

[00683] ^lH NMR (400 MHz, CDCb) : δ 14.86 (s, 1H), 8.18 - 8.07 (m, 2H), 8.06 - 7.97 (m, 1H), 7.62 (d, 7 = 8.7 Hz, 1H), 6.90 (dd, / = 6.7, 1.8 Hz, 1H), 5.91 (t, / = 6.9 Hz, 1H), 3.96 (ddd, J = 12.5, 4.0, 2.0 Hz, 1H), 3.86 - 3.74 (m, 2H), 3.69 (ddd, J = 15.6, 4.7, 2.0 Hz, 1H), 3.57 (dd, / = 10.6, 8.3 Hz, 1H), 3.45 - 3.29 (m, 1H), 2.35 - 2.08 (m, 1H) ppm.

[00684] ¹⁹F NMR (376 MHz, CDCb): δ -61.01 (s) ppm.

[00685] Example 75

[00686] 2-((4-fluorobenzyl)amino)-N-(3-(hydroxymethyl)-4- ( trifluoromethyl jphenyl Nicotinamide

Example 75

[00687] A mixture of 96 (1.00 g, 4.25 mmols, 1.0 eq) and Pd/C (10%, 400 mg) in ethyl acetate (40 mL) was stirred at room temperature for 16 hours under ¾ (1 atm). The reaction mixture was filtered through celite, and the filtrate was concentrated to get the desired product 97 (860 mg, 4.19 mmols, 98.6%) as a white solid.

[00688] To a solution of 97 (860 mg, 4.19 mmols, 1.0 eq) in THF (10 mL) was added BH₃ (1.0 M in THF, 16.8 mmols, 4.0 eq) at 0 °C. The resulting solution was heated to 50 °C for 16 hours. The reaction mixture was cooled to 0 °C, quenched with MeOH (20 mL) and concentrated. The residue was purified by chromatography on silica gel (ethyl acetate / petroleum ether, 1 / 2) to afford the desired product 98 (580 mg, 3.04 mmols, 72.5%) as a white solid.

[00689] To a solution of 98 (500 mg, 2.62 mmols, 1.0 eq) in DMF (6 mL) was added imidazole (1.42 g, 20.9 mmols, 8.0 eq) and TBSC1 (1.60 g, 10.5 mmols, 4.0 eq) at 0 °C. The resulting solution was stirred at room temperature for 16 hours. The reaction mixture was quenched with ice water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over Na2S0₄, filtered, and concentrated. The residue was purified by chromatography on silica gel (ethyl acetate / petroleum ether, 1 / 3) to afford the desired product 99 (700 mg, 2.29 mmols, 87.6%) as a yellow solid.

[00690] Compound 100 was similarly prepared as the synthesis of Intermediate 14. Yield: 61.5%. [00691] Compound 101 was synthesized by the reaction of compound 100 and (4- fluorophenyl) ethanamine (5.0 eq) at 115 °C using the General Procedure C. Yield:

27.8%.

[00692] To a solution of 101 (180 mg, 0.338 mmols, 1.0 eq) in THF (10 mL) was added TBAF (1.0 M in THF, 4.0 mL, excess) at 0 °C. The resulting solution was stirred at room temperature for 16 hours. The reaction mixture was quenched with saturated aqueous solution of ammonium chloride (50 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with brine, dried over Na2S0₄, filtered, and concentrated. The residue was purified by chromatography on silica gel (dichloromethane / methanol, 10 / 1) to get the desired product Example 75 (120 mg, 0.286 mmols, 84.5%) as a yellow solid.

[00693] LCMS: ESI-MS: m/z: 420.1 [M+H]⁺; RT = 2.10 min. (Method B)

[00694] HPLC: RT = 8.97 min

[00695] ¾ NMR (400 MHz, DMSO-d<5): δ 10.54 (s, 1H), 8.39 (t, 7 = 5.9 Hz, 1H),

8.22 (dd, 7 = 4.8, 1.6 Hz, 1H), 8.20 - 8.11 (m, 2H), 7.85 (d, 7 = 8.9 Hz, 1H), 7.65 (d, 7 =

8.7 Hz, 1H), 7.38 (dd, 7 = 8.5, 5.7 Hz, 2H), 7.13 (t, 7 = 8.9 Hz, 2H), 6.69 (dd, 7 = 7.7, 4.8

Hz, 1H), 5.54 (t, 7 = 5.5 Hz, 1H), 4.67 - 4.63 (m, 4H) ppm.

[00696] ¹⁹F NMR (376 MHz, DMSO-d<5): -58.44 (s), -116.45 (s) ppm

[00697] Example 76

[00698] 3-((4-fluorobenzyl)amino)-N-(3-(hydroxymethyl)-4- (trifluoromethyl)phenyl)pyrazine-2-carboxamide

[00699] Example 76 was similarly prepared as the synthesis of compound Example

75.

Example 76

[00700] LCMS: ESI-MS: m/z: 421.0 [M+H]⁺; RT = 2.19 min. (Method B)

[00701] HPLC: RT = 9.46 min [00702] ¾ NMR (400 MHz, DMSO-d<5): δ 10.95 (s, 1H), 9.03 (t, / = 5.8 Hz, 1H), 8.55 - 8.39 (m, 2H), 8.00 (d, / = 2.3 Hz, 1H), 7.94 (d, / = 8.3 Hz, 1H), 7.71 (d, / = 8.6 Hz, 1H), 7.48 (dd, J = 8.3, 5.7 Hz, 2H), 7.21 (t, / = 8.9 Hz, 2H), 5.57 (t, / = 5.5 Hz, 1H), 4.76 - 4.72 (m, 4H).

[00703] ¹⁹F NMR (376 MHz, DMSO-d<5): -59.57 (s), -115.53 (s) ppm.

[00704] Example 77

[00705] N-( 3-( ( dimethylamino )methyl)-4-( trifluoromethyl)phenyl)-2-((4- fluorobenzyljaminojnicotinamide hydrochloride salt

[00706] To a solution of Example 75 (95 mg, 0.227 mmols, 1.0 eq) in dichloromethane / THF (1 / 1, 20 mL) was added Dess-Martin Periodinane (289 mg, 0.681 mmols, 3.0 eq) portionwise at 0 °C. The reaction mixture was stirred at room temperature for 16 hours and concentrated. Ethyl acetate (50 mL) was added and the organic layer was washed sequentially with saturated sodium bicarbonate solution and brine. The organic solution was dried over Na2S0₄, filtered, and concentrated to get the desired product 102 (130 mg, crude) as a brown solid, which was used in the next step directly without further purification.

[00707] Dimethylamine (2.0 M in THF, 6.0 mL) and NaBH(OAc)₃ (1.44 g, 2.27 mmols, 30 eq) were added to a solution of 102 (130 mg, crude) in MeOH (10 mL), and stirred at room temperature for 16 hours. The reaction mixture was quenched with saturated sodium bicarbonate solution (60 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with brine, dried over Na2S0₄, filtered, and concentrated. The residue was purified by Prep-HPLC to obtain Example 77 free base (40 mg, 0.089 mmols, 39.2% for two steps).

[00708] Example 77 was similarly prepared as the synthesis of compound Example 20-HCl.

[00709] LCMS: ESI-MS: m/z: 447.1 [M-HC1+H]⁺; RT = 2.23 min. (Method B)

[00710] HPLC: RT = 9.67 min

[00711] Ή NMR (400 MHz, MeOD-i/4): δ 8.75 (d, / = 6.4 Hz, 1H), 8.30 (s, 1H), 8.15 (d, J = 5.1 Hz, 1H), 8.01 (d, J = 8.5 Hz, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.50 (dd, J = 8.5, 5.3 Hz, 2H), 7.24 - 7.11 (m, 3H), 4.75 (s, 2H), 4.56 (s, 2H), 2.98 (s, 6H) ppm.

[00712] ¹⁹F NMR (376 MHz, OMSO-d6): -56.98 (s), -116.47 (s) ppm.

[00713] Example 78

[00714] N-(3-(( dimethylamino )methyl)-4-( trifluoromethyl)phenyl)-3-( ( 4- fluorobenzyl )amino )pyrazine-2-carboxamide hydrochloride salt

Example 78

[00715] Example 78 was similarly prepared as the synthesis of compound Example 77.

[00716] LCMS: ESI-MS: m/z: 448.2 [M-HC1+H]⁺; RT = 2.37 min. (Method B)

[00717] HPLC: RT = 10.33 min

[00718] ¾ NMR (400 MHz, MeOO-d4): δ 8.40 - 8.31 (m, 2H), 8.02 (d, / = 9.6 Hz, 1H), 7.94 (d, 7 = 2.3 Hz, 1H), 7.89 (d, / = 8.8 Hz, 1H), 7.43 (dd, / = 8.3, 5.7 Hz, 2H), 7.08 (t, / = 8.8 Hz, 2H), 4.76 (s, 2H), 4.53 (s, 2H), 2.99 (s, 6H) ppm.

[00719] ¹⁹F NMR (376 MHz, OMSO-d6): -58.54 (s), -117.92 (s) ppm.

[00720] Example 79

[00721] N-(3-cyano-4-(trifluoromethyl)phenyl)-2-(prop-2-yn-l-ylamino)nicotinamide

[00722] A solution of 94 (100 mg, 0.308 mmols, 1.0 eq), prop-2-yn-l -amine (169 mg, 3.08 mmols, 10.0 eq), and N-ethyl-N-isopropylpropan-2-amine (DIPEA, 199 mg, 1.54 mmols, 5.0 eq) in dioxane (6 mL) was heated to 70 °C for 3 days under nitrogen in a sealed tube. After the reaction mixture was cooled to room temperature, the reaction mixture was dissolved in ethyl acetate and washed with water followed by brine. The organic phase was dried over Na2S0₄, filtered, and concentrated. The residue was purified by Preparative- TLC (petroleum ether / ethyl acetate, 2 / 1) to give the desired product Example 79 (33.0 mg, 0.0959 mmols, 31.1%) as a yellow solid.

[00723] LCMS: ESI-MS: m/z: 345.1 [M+H]⁺; RT = 2.09 min. (Method B)

[00724] HPLC: RT = 8.80 min.

[00725] ¾ NMR (400 MHz, DMSO-d<5): δ 10.39 (s, 1H), 8.33 (t, / = 5.7 Hz, 1H), 8.21 (d, / = 3.3 Hz, 1H), 8.09 (d, / = 6.1 Hz, 1H), 7.80 (d, / = 9.1 Hz, 2H), 7.37 (dd, / = 11.7, 6.6 Hz, 3H), 7.13 (t, / = 8.9 Hz, 2H), 6.69 (dd, / = 7.6, 4.8 Hz, 1H), 4.63 (d, / = 5.7 Hz, 2H) ppm.

[00726] ¹⁹F NMR (376 MHz, DMSO-de): δ -61.30 (s) ppm

[00727] Example 80

[00728] 2-((4-fluorobenzyl)amino )-N-(4-( trifluoromethoxyjphenyljnicotinamide

[00729] Compound 103 was similarly prepared as the synthesis of Intermediate 14. Yield: 49.8%

[00730] Example 80 was similarly synthesized from compound 103 and (4- fluorophenyl) methanamine (5.0 eq) at 130 °C using the General Procedure C. Yield: 24.4%

[00731] LCMS: ESI-MS: m/z: 406.2 [M+H]⁺; RT = 1.78 min. (Method A) [00732] HPLC: RT = 9.35 min.

[00733] ¾ NMR (400 MHz, DMSO-d<5): δ 10.39 (s, 1H), 8.33 (t, / = 5.7 Hz, 1H), 8.21 (d, / = 3.3 Hz, 1H), 8.09 (d, / = 6.1 Hz, 1H), 7.80 (d, / = 9.1 Hz, 2H), 7.37 (dd, / = 11.7, 6.6 Hz, 4H), 7.13 (t, / = 8.9 Hz, 2H), 6.69 (dd, / = 7.6, 4.8 Hz, 1H), 4.63 (d, / = 5.7 Hz, 2H) ppm.

[00734] ¹⁹F NMR (376 MHz, DMSO-ifc): δ -57.01 (s), -116.43 (s) ppm.

[00735] Example 81

[00736] 2-(( oxetan-3-ylmethyl)amino )-N-( 6-( trifluoromethyl)pyridin-3- yljnicotinamide

[00737] Compound 104 was similarly prepared as the synthesis of Intermediate 14. Yield: 83.4%

[00738] A mixture of 104 (150 mg, 0.498 mmols), oxetan-3-ylmethanamine (87.0 mg, 0.997 mmols, 2.0 eq) and triethylamine (0.208 mL, 1.49 mmols, 3.0 eq) in DMSO (3 mL) was stirred at 130 °C for 16 hours after being degassed and protected with N₂. The mixture was cooled to room temperature, diluted with ethyl acetate (100 mL) and washed with aqueous HC1 (2 N, 30 mL x 3). The organic layer was dried over Na2S0₄ and concentrated. The residue was purified by Preparative-TLC (dichloromethane / methanol / triethylamine, 10 / 1 / 0.2) to give the desired product (60 mg, 0.170 mmols, 34.2%) as a yellow solid.

[00739] LCMS: ESI-MS: m/z: 353.1 [M+H]⁺; RT = 1.32 min. (Method A)

[00740] HPLC: RT = 6.61 min

[00741] ¾ NMR (400 MHz, CDCb): δ 8.75 (s, 1H), 8.57 (dd, / = 8.8, 1.6 Hz, 1H), 8.24 (d, / = 6.8 Hz, 1H), 7.66 (d, / = 8.8 Hz, 1H), 6.98 (d, / = 6.0 Hz, 1H), 6.00 (t, / = 6.8 Hz, 1H), 4.06-4.03 (m, 1H), 3.90 - 3.85 (m, 2H), 3.77 (dd, / = 15.6, 2.8 Hz, 1H), 3.68 - 3.63 (m, 1H), 3.43 (q, / = 8.0 Hz, 1H), 2.32 - 2.29 (m, 2H) ppm.

[00742] ¹⁹F NMR (376 MHz, DMSO-d<5): -65.47 (s) ppm.

[00743] [00744] Example 82,83,84,85,86,87,88 and 89 were similarly prepared synthesis of compound Example 81.

[00745]

[00746] Example 82

[00747] N-(4-fluorophenyl)-2-((oxetan-3-ylmethyl)amino)nicotinamide

[00748]

Example 82

[00749] LCMS: ESI-MS: m/r. 302.3 [M+H]⁺; RT = 1.26 min. (Method A)

[00750] HPLC: RT = 5.96 min.

[00751] Ή NMR (400 MHz, CDCb): δ 14.14 (brs, IH), 8.21 (d, / = 5.9 Hz, IH), 7.67 (dd, / = 9.0, 5.0 Hz, 2H), 7.01 (t, / = 8.7 Hz, 2H), 6.89 (d, / = 5.8 Hz, IH), 5.93 (t, / = 6.7 Hz, IH), 4.00 (d, J = 1 1.1 Hz, IH), 3.84 - 3.80 (m, 2H), 3.73 (dd, 7 = 15.7, 2.5 Hz, IH), 3.67 - 3.54 (m, IH), 3.39 (dd, 7 = 15.6, 7.7 Hz, IH), 2.27 - 2.24 (m, IH) ppm.

[00752] ¹⁹F NMR (376 MHz, DMSO-t/6): -119.41 (s) ppm.

[00753] Example 83

[00754] N-(4-chlorophenyl -2-((oxetan-3-ylmethyl)amino)nicotinamide

Example 83

[00755] LCMS: ESI-MS: m/z: 318.1 [M+H]⁺; RT = 1.38 min. (Method A)

[00756] HPLC: RT = 6.78 min

[00757] Ή NMR (400 MHz, DMSO- 6): δ 14.72 (brs, IH), 8.03 (d, J = 8.0 Hz, IH), 7.68 (d, J = 8.8 Hz, 2H), 7.45 (brs, IH), 7.37 (d, / = 8.8 Hz, 2H), 6.03 - 6.00 (brs, IH), 4.82 (d, / = 4.5 Hz, IH), 4.06 (d, / = 13.0 Hz, IH), 3.80 - 3.75 (m, IH), 3.64 (dd, / = 15.6, 3.2 Hz, 1H), 3.54 - 3.43 (m, 1H), 3.40 - 3.35 (m, 1H), 3.29 - 3.26 (m, 1H), 2.08 - 2.03 (m, 1H) ppm.

[00758] Example 84

[00759] 2-(( oxetan-3-ylmeth l)amino )-N-( 3-( trifluoromethyljphenyljnicotinamide

Example 84

[00760] LCMS: ESI-MS: m/z: 352.1 [M+H]⁺; RT = 1.51 min. (Method B)

[00761] HPLC: RT = 7.03 min.

[00762] ¾ NMR (400 MHz, MeOO-d4): δ 8.07 (dd, / = 7.1, 1.4 Hz, 1H), 8.03 (s, 1H), 7.64 (d, / = 8.0 Hz, 1H), 7.41 (t, / = 8.0 Hz, 1H), 7.29 (t, / = 8.0 Hz, 2H), 6.08 (t, / = 6.7 Hz, 1H), 4.06 (d, / = 11.5 Hz, 1H), 3.81 (dd, / = 12.7, 8.9 Hz, 1H), 3.65 (ddd, / = 15.0, 4.6, 1.9 Hz, 1H), 3.58 (dd, / = 11.1, 5.7 Hz, 1H), 3.47 (dd, / = 11.1, 7.2 Hz, 1H), 3.32 (dd, / = 15.1, 8.3 Hz, 1H), 2.18 - 2.07 (m, 1H) ppm.

[00763] ¹⁹F NMR (376 MHz, DMSO-d6): δ -61.26 (s) ppm.

[00764] Example 85

[00765] 2-((oxetan-3-ylmeth l)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

Example 85

[00766] LCMS: ESI-MS: m/z: 368.1 [M+H]⁺; RT = 1.94 min. (Method B)

[00767] HPLC: RT = 7.87 min.

[00768] 1H NMR (400 MHz, CDC13): δ 8.21 (dd, J = 7.0, 1.5 Hz, 1H), 7.76 (dd, J = 7.2, 2.4 Hz, 2H), 7.16 (d, J = 8.6 Hz, 2H), 6.90 (d, J = 5.4 Hz, 1H), 5.94 (t, J = 6.8 Hz, 1H), 4.00 (dd, J = 12.5, 1.8 Hz, 1H), 3.88 - 3.78 (m, 2H), 3.73 (ddd, J = 15.6, 4.7, 2.0 Hz, 1H), 3.62 (dd, J = 10.6, 8.2 Hz, 1H), 3.39 (dd, J = 15.6, 7.9 Hz, 1H), 2.29 - 2.23 (m, 1H) ppm.

[00769] ¹⁹F NMR (376 MHz, CDCb): -58.09 (s) ppm.

[00770] Example 86

[00771] N-(4-cyanophenyl)- -((oxetan-3-ylmethyl)amino)nicotinamide

Example 86

[00772] LCMS: ESI-MS: m/z: 309.1 [M+H]⁺; RT = 1.27 min. (Method A)

[00773] HPLC: RT = 5.46 min.

[00774] ¾ NMR (400 MHz, CDCb): δ 14.69 (s, 1H), 8.20 (d, 7 = 5.9 Hz, 1H), 7.81 (d, 7 = 8.7 Hz, 2H), 7.59 (d, 7 = 8.7 Hz, 2H), 6.93 (d, 7 = 5.2 Hz, 1H), 5.95 (t, 7 = 6.8 Hz, 1H), 4.01 (d, 7 = 10.6 Hz, 1H), 3.84 (dd, 7 = 12.0, 8.0 Hz, 2H), 3.79 - 3.69 (m, 1H), 3.62 (t, 7 = 9.5 Hz, 1H), 3.40 (dd, 7 = 15.4, 8.0 Hz, 1H), 2.28 - 2.26 (m, 1H) ppm.

[00775] Example 87

[00776] N-f 3-chlorophenyl -2-( ( oxetan-3 -ylmethyl jamino Nicotinamide

Example 87

[00777] LCMS: ESI-MS: m/z: 318.0 [M+H]⁺; RT = 1.49 min. (Method A)

[00778] HPLC: RT = 6.71 min.

[00779] ¾ NMR (400 MHz, MeOO-d4): δ 8.14 (dd, 7 = 7.2, 1.6 Hz, 1H), 7.86 (t, 7 = 2.0 Hz, 1H), 7.43 (d, 7 = 9.2 Hz, 1H), 7.36 (d, 7 = 6.4 Hz, 1H), 7.31 (t, 7 = 8.0 Hz, 1H), 7.10 (d, 7 = 8.4 Hz, 1H), 6.12 (t, 7 = 6.8 Hz, 1H), 4.14 (d, 7 = 11.6 Hz, 1H), 3.89 (dd, 7 = 13.0, 9.0 Hz, 1H), 3.79 - 3.72 (m, 1H), 3.69 (dd, 7 = 11.1, 5.7 Hz, 1H), 3.57 (dd, 7 = 11.1, 7.3 Hz, 1H), 3.42 (dd, 7 = 15.3, 8.1 Hz, 1H), 2.24 - 2.20 (m, 1H) ppm. [00780] Example 88

[00781] N-(3,4-dichlorophenyl)-2-((oxetan-3-ylmethyl)amino)nicotinamide

Example 88

[00782] LCMS: ESI-MS: m/r. 352.0 [M+H]⁺; RT = 1.81 min. (Method B)

[00783] HPLC: RT = 7.65 min.

[00784] ^lH NMR (400 MHz, DMSO- 6): δ 15.00 (s, IH), 8.14 (d, J = 2.3 Hz, IH), 8.04 (d, 7 = 7.0 Hz, IH), 7.62 - 7.41 (m, 3H), 6.04 (t, J = 5.9 Hz, IH), 4.82 (t, J = 5.1 Hz, IH), 4.07 (d, J = 13.5 Hz, IH), 3.81 - 3.75 (m, IH), 3.68 - 3.63 (m, IH), 3.49 (dt, / = 10.7, 5.2 Hz, IH), 3.40 - 3.35 (m, IH), 3.31 - 3.24 (m, IH), 2.10 - 1.98 (m, IH) ppm.

[00785] Example 89

[00786] 2-(( (3-methyloxetan-3-yl)methyl)amino )-N-(4- ( trifluoromethyl )phenyl Nicotinamide

Example 89

[00787] LCMS: ESI-MS: m/z: 366.1 [M+H]⁺; RT = 1.73 min. (Method B)

[00788] HPLC : RT = 7.83 min.

[00789] Ή NMR (400 MHz, DMSO-t/6): δ 15.00 (s, IH), 8.06 (dd, J = 7.0, 1.7 Hz, IH), 7.85 (d, J = 8.4 Hz, 2H), 7.67 (d, / = 8.6 Hz, 2H), 7.44 (dd, / = 6.6, 1.6 Hz, IH), 6.03 (t, / = 6.8 Hz, IH), 4.88 (t, / = 5.2 Hz, IH), 3.83 (d, / = 12.8 Hz, IH), 3.65 (d, / = 12.6 Hz, IH), 3.42 (d, / = 14.8 Hz, IH), 3.25 (d, / = 15.7 Hz, 3H), 0.92 (s, 3H) ppm.

[00790] ¹⁹F NMR (376 MHz, DMSO- 6): δ -60.22 (s) ppm.

[00791] Example 90

[00792] N-(4-(cyclopropylmethoxy)phenyl)-2-((oxetan-3- ylmethyljamino Nicotinamide

[00793] A mixture of 105 (2.00 g, 14.1 mmols, 1.0 eq), (bromomethyl)cyclopropane (2.92 g, 21.6 mmols, 1.5 eq) and K₂C0₃ (5.96 g, 43.2 mmols, 3.0 eq) in DMF (15 mL) was stirred at room temperature for 16 hours. The mixture was diluted with ethyl acetate (120 mL) and washed with brine (50 mL x 3). The organic layer was dried over Na2S0₄, filtered and concentrated to give the desired product 106 (3.00 g, crude) as a white solid, which was used directly in the next reaction without further purification.

[00794] A mixture 106 (2.95 g, crude) and 10 percent Pd/C (600 mg) in ethyl acetate (100 mL) was stirred under 1 atm hydrogen gas for 16 hours at room temperature. The mixture was filtered through celite and the filtrate was concentrated to give the target compound 107 (2.50 g, crude) as a brown oil, which was used directly in the next reaction without further purification.

[00795] Compound 108 was similarly prepared as the synthesis of Intermediate 14. Yield: 58.6% for three steps.

[00796] Example 90 was similarly prepared as the syntheses of compounds Example 81.

[00797] Example 90

[00798] N-(4-(cyclopropylmethoxy)phenyl)-2-((oxetan-3- ylmethyljamino Nicotinamide

[00799] LCMS: ESI-MS: m/z: 354.1 [M+H]⁺; RT = 1.36 min. (Method B)

[00800] HPLC: RT = 7.52 min.

[00801] ¾ NMR (400 MHz, MeOO-d4): δ 8.16 (dd, 7 = 7.1, 1.3 Hz, 1H), 7.58 - 7.50 (m, 2H), 7.47 (d, / = 6.3 Hz, 1H), 6.95 - 6.85 (m, 2H), 6.27 (dd, / = 6.0, 5.2 Hz, 1H), 4.20 (d, J = 11.8 Hz, 1H), 3.95 (dd, / = 12.7, 8.9 Hz, 1H), 3.78 - 3.65 (m, 2H), 3.58 (dd, / = 11.1 , 7.1 Hz, 1H), 3.41 (dd, / = 14.9, 8.3 Hz, 1H), 2.24 (s, 1H), 1.30 - 1.26 (m, 1H), 0.68 - 0.57 (m, 2H), 0.35 (q, / = 4.6 Hz, 2H) ppm.

[00802] Example 91

[00803] 2-( ((2-oxopyrrolidin-l-yl)methyl)amino )-N-( 4- (trifluoromethyljphenyljnicotinamide trifluoroacetic acid salt

[00804] A mixture of 109 (3.00 g, 35.3 mmols, 1.0 eq) and paraformaldehyde (1.50 g) in chlorotrimethylsilane (40 mL) was heated to reflux for 48 hours. The mixture was cooled to room temperature and concentrated to give the desired product 110 (5.00 g, crude) as a yellow oil, which was used directly in the next reaction without further purification.

[00805] A mixture of 110 (4.95 g, crude) and potassium l,3-dioxoisoindolin-2-ide (10.3 g, 55.8 mmols, 1.6 eq) in DMF (25 mL) was stirred at room temperature for 16 hours. The mixture was poured into water (60 mL) and filtered. The solid was collected and dried to give the desired product 111 (3.00 g, 12.2 mmols, 34.7% for two steps) as a white solid.

[00806] To a solution of 111 (3.00 g, 12.2 mmols, 1.0 eq) in ethanol (20 mL) was added hydrazine hydrate (2.44 g, 48.8 mmols, 4.0 eq) at 0 °C. The solution was stirred at room temperature for 16 hours. The insoluble matter was removed through filtration and the filtrate was concentrated to give the desired product 112 (1.20 g, crude) as a colorless oil, which was used directly in the next reaction without further purification. [00807] Example 102 free base was synthesized by the reaction of compound 112 and compound 87 using the General Procedure C, the crude product was purified by Prep-

HPLC (TFA as modifier) to give Example 91. Yield: 14.5%.

[00808] LCMS: ESI-MS: m/z: 379.1 [M+H]⁺; RT = 1.37 min. (Method B)

[00809] HPLC: RT = 8.42 min.

[00810] ¾ NMR (400 MHz, MeOO-d4): δ 8.48 (dd, / = 7.6, 1.5 Hz, 1H), 8.29 (dd, / = 5.9, 1.6 Hz, 1H), 7.93 (d, / = 8.5 Hz, 2H), 7.69 (d, / = 8.6 Hz, 2H), 7.09 (dd, / = 7.6, 5.9 Hz, 1H), 5.03 (s, 2H), 3.66 (t, / = 7.2 Hz, 2H), 2.49 (t, / = 8.1 Hz, 2H), 2.16 - 2.06 (m, 2H) ppm.

[00811] ¹⁹F NMR (376 MHz, MeOO-d4): δ -63.68 (s), -77.32 (s) ppm.

[00812] Example 92

[00813] 2-(( oxetan-3-ylmethyljamino )-N-( 5-( trifluoromethyl)pyridin-2-

[00814] Compound 114 was similarly prepared as the synthesis of Intermediate 14. Yield: 14.1%.

[00815] A mixture of 114 (150 mg, 0.526 mmols, 1.0 eq), oxetan-3-ylmethanamine (114 mg, 1.32 mmols, 2.5 eq) and triethylamine (159 mg, 1.58 mmols, 3.0 eq) in DMF (5 mL) was sealed and heated to 70 °C for 16 hours and 130 °C for 2.5 hours. The mixture was cooled to room temperature, diluted with ethyl acetate (50 mL), and washed with brine (20 mL x 3). The organic layer was dried over Na2S0₄, filtered and concentrated. The residue was purified by Preparative-TLC (dichloromethane / methanol / N¾ (7.0 N in methanol), 8 / 1 / 0.2) and recrystallization with dichloromethane / petroleum ether to give the desired product Example 92 (28.0 mg, 0.080 mmols, 15.1%) as a yellow solid.

[00816] LCMS: ESI-MS: m/z: 353.0 [M+H]⁺; RT = 1.41 min. (Method B)

[00817] HPLC: RT = 6.67 min.

[00818] ¾ NMR (400 MHz, MeOD-d4): δ 8.57 (s, 1H), 8.35 - 8.31 (m, 2H), 8.01 (dd, / = 8.8, 2.3 Hz, 1H), 7.56 (d, / = 6.4 Hz, 1H), 6.40 (t, / = 6.9 Hz, 1H), 4.28 - 4.24 (m, 1H), 4.02 (dd, / = 12.9, 9.0 Hz, 1H), 3.81 - 3.76 (m, 1H), 3.70 (dd, / = 11.1 , 5.7 Hz, 1H), 3.59 (dd, / = 11.1 , 7.0 Hz, 1H), 3.44 (dd, / = 14.6, 8.4 Hz, 1H), 2.35 - 2.25 (m, 1H) ppm.

[00819] ¹⁹F NMR (376 MHz, MeOO-d4): δ -63.29 (s) ppm.

[00820] Example 93

[00821] N-( 3-(hydroxymethyl)-4-( trifluoromethyl)phenyl)-2-( ( oxetan-3-

[00822] Compound 115 was similarly prepared as the syntheses of compounds Example 81. Yield: 66.4%

[00823] Compound Example 93 free base was similarly prepared as the synthesis of compounds Example 75, the crude was purified by Prep-HPLC (TFA as modifier) to give Example 93. Yield: 15.0%

[00824] Example 93

[00825] N-( 3-(hydroxymethyl)-4-( trifluoromethyl)phenyl)-2-( ( oxetan-3- ylmethyljamino Nicotinamide

Example 93

[00826] LCMS: ESI-MS: m/z: 382.1 [M+H]⁺; RT = 1.34 min. (Method B)

[00827] HPLC: RT = 6.60 min.

[00828] ¾ NMR (400 MHz, MeOO-d4) δ 8.45 (dd, 7 = 7.5, 1.2 Hz, 1H), 8.13 (s, 1H), 8.11 - 8.02 (m, 1H), 7.86 (d, / = 9.4 Hz, 1H), 7.68 (d, / = 8.6 Hz, 1H), 7.05 - 6.89 (m, 1H), 4.82 (s, 2H), 4.52 (dd, / = 13.4, 2.2 Hz, 1H), 4.27 (dd, 7 = 13.4, 9.3 Hz, 1H), 3.81 - 3.71 (m, 2H), 3.67 (dd, / = 11.2, 6.3 Hz, 1H), 3.45 (dd, / = 13.5, 8.8 Hz, 1H), 2.59 - 2.36 (m, 1H) ppm.

[00829] ¹⁹F NMR (376 MHz, MeOO-d4): δ -61.30 (s), -77.02 (s) ppm.

[00830] Example 94 [00831] 2-((4-fluorophenyl)amino)-N-(6-(trifluoromethyl)pyridin-3-yl)nicotinamide

[00832] Example 94 was similarly prepared as the synthesis of compounds Example 55.

Example 94

[00833] LCMS: ESI-MS: m/z: 377.0 [M+H]⁺; RT = 1.72 min. (Method A)

[00834] HPLC: RT = 10.63 min.

[00835] ¾ NMR (400 MHz, DMSO-d<5) δ 10.96 (s, 1H), 10.06 (s, 1H), 9.06 (d, / = 1.9 Hz, 1H), 8.45 (d, J = 8.6 Hz, 1H), 8.40 - 8.32 (m, 1H), 8.28 (dd, / = 7.7, 1.6 Hz, 1H), 7.96 (d, / = 8.6 Hz, 1H), 7.70 (dd, / = 9.0, 5.0 Hz, 2H), 7.15 (t, / = 8.9 Hz, 2H), 6.97 (dd, 7 = 7.7, 4.8 Hz, lH) ppm.

[00836] ¹⁹F NMR (376 MHz, MeOD-d4): δ -67.41 (s), -119.66 (s) ppm.

[00837] Example 95

[00838] N-(6-cyanopyridin-3-yl)-3-((4-fluorobenzyl)amino)pyrazine-2-carboxamide and

[00839] Example 96

[00840] N-(6-cyanopyridin-3-yl)-2-((4-fluorobenzyl)amino)nicotinamide

[00841] Example 95 and Example 96 were similarly prepared as the synthesis of compound Example 1.

[00842] Example 95

[00843] N-(6-cyanopyridin-3-yl)-3-((4-fluorobenzyl)amino)pyrazine-2-carboxamide

Example 95

[00844] LCMS: ESI-MS: m/z: 349.1 [M+H]⁺; RT = 1.70 min. (Method A)

[00845] HPLC: RT = 10.67 min. [00846] ¾ NMR (400 MHz, OMSO-d6): δ 11.27 (s, IH), 9.23 (d, 7 = 2.1 Hz, IH), 8.91 (t, 7 = 5.9 Hz, IH), 8.50 (dd, 7 = 8.6, 2.5 Hz, IH), 8.39 (d, 7 = 2.3 Hz, IH), 8.04 (d, 7 = 8.6 Hz, IH), 7.97 (d, 7 = 2.3 Hz, IH), 7.41 (dd, 7 = 8.6, 5.6 Hz, 2H), 7.24 - 7.01 (m, 2H), 4.70 (d, 7 = 5.9 Hz, 2H) ppm.

[00847] ¹⁹F NMR (376 MHz, DMSO-d<5): -116.09 (s) ppm.

[00848] Example 96

[00849] N-(6-cyanopyridin-3-yl)-2-((4-fluorobenzyl)amino)nicotinamide

Example 96

[00850] LCMS: ESI-MS: m/z 348.2 [M+H]⁺; RT = 1.54 min. (Method A)

[00851] HPLC: RT = 9.43 min.

[00852] ¾ NMR (400 MHz, DMSO-i 6): δ 10.67 (brs, IH), 9.03 (s, IH), 8.58 - 7.84 (m, 5H), 7.38 (s, 2H), 7.14 (d, 7 = 8.1 Hz, 2H), 6.72 (s, IH), 4.66 (s, 2H) ppm.

[00853] ¹⁹F NMR (376 MHz, DMSO-d<5): -116.39 (s) ppm.

[00854] Example 97

[00855] 2-((( tetrahydro-2H-pyran-4-yl )methyl )amino )-N-(6-( trifluoromethyl)pyridin- -yl)nicotinamide

104 Example 97

[00856] Example 97 was similarly synthesized from compound 104 and (tetrahydro- 2H-pyran-4-yl)methanamine (5.0 eq) at 100 °C using the General Procedure C. Yield: 67.3%.

[00857] LCMS: ESI-MS : m/z: 381.1 [M+H]⁺; RT = 1.40 min. (Method A). [00858] HPLC: RT = 8.38 min.

[00859] ¾ NMR (400 MHz, DMSO-d<5): δ 10.70 (s, IH), 9.02 (s, IH), 8.42 (d, / = 8.6 Hz, IH), 8.26 (d, / = 3.3 Hz, IH), 8.13 (dd, / = 11.5, 6.5 Hz, 2H), 7.92 (d, / = 8.6 Hz, IH), 6.68 (dd, / = 7.6, 4.8 Hz, IH), 3.85 (dd, / = 11.0, 2.8 Hz, 2H), 3.43 - 3.35 (m, 2H), 3.27 (t, / = 11.1 Hz, 2H), 1.93 - 1.74 (m, IH), 1.60 (d, J = 11.7 Hz, 2H), 1.24 (qd, / = 12.4, 4.1 Hz, 2H) ppm.

[00860] ¹⁹F NMR (376 MHz, DMSO-d<5): -65.68 (s) ppm.

[00861] Example 98

[00862] 3-((( tetrahydro-2H-pyran-4-yl jmethyl jamino )-N-(4-

(trifluoromethyl)phenyl)pyrazine-2-carboxamide

[00863]

[00864] Example 98 was similarly synthesized from compounds 51, 87 and (tetrahydro-2H-pyran-4-yl)methanamine (5.0 eq) at 100 °C using the General Procedure C. Yield: 87.1% and 39.7%.

[00865] Example 98

[00866] 3-((( tetrahydro-2H-pyran-4-yl jmethyl jamino j-N-(4- (trifluoromethyljphenyljpyrazine-2-c rboxamide

Example 98

[00867] LCMS: ESI-MS: m/z: 381.2 [M+H]⁺; RT = 1.83 min. (Method A)

[00868] HPLC: RT = 11.53 min.

[00869] ¾ NMR (400 MHz, DMSO-d<5): δ 10.94 (s, IH), 8.67 (t, / = 5.7 Hz, IH), 8.37 (d, / = 2.2 Hz, IH), 8.09 (d, / = 8.5 Hz, 2H), 7.91 (d, / = 2.3 Hz, IH), 7.72 (d, / = 8.6 Hz, 2H), 3.86 (dd, / = 11.2, 3.1 Hz, 2H), 3.40 (t, / = 6.3 Hz, 2H), 3.28 (t, / = 11.0 Hz, 2H), 1.91 - 1.83 (m, IH), 1.61 (d, / = 12.1 Hz, 2H), 1.26 (qd, / = 12.3, 4.5 Hz, 2H) ppm.

[00870] ¹⁹F NMR (376 MHz, DMSO-d<5): -60.36 (s) ppm.

[00871] Example 99

[00872] 2-( ( ( tetrahydro-2H-pyran-4-yl jmethyl jaminoj-N-(4- ( trifluoromethyl jphenyl jnicotinamide [00873] Example 99 was similarly synthesized from compounds 51, 87 and (tetrahydro-2H-pyran-4-yl)methanamine (5.0 eq) at 100 °C using the General Procedure C. Yield: 87.1% and 39.7%.

Example 99

[00874] LCMS: ESI-MS: m/z: 380.1 [M+H]⁺; RT = 1.48 min. (Method A)

[00875] HPLC: RT = 8.89 min.

[00876] ¾ NMR (400 MHz, DMSO-d6): δ 10.50 (s, 1H), 8.24 (d, / = 3.4 Hz, 1H), 8.11 (d, / = 6.1 Hz, 2H), 7.93 (d, / = 8.5 Hz, 2H), 7.72 (d, / = 8.6 Hz, 2H), 6.66 (dd, / = 7.6, 4.8 Hz, 1H), 3.85 (dd, 7 = 11.1 , 3.1 Hz, 2H), 3.27 (t, J = 11.1 Hz, 4H), 1.83 (d, J = 3.9 Hz, 1H), 1.60 (d, / = 12.9 Hz, 2H), 1.22 (ddd, / = 16.1, 9.8, 5.9 Hz, 2H) ppm.

[00877] ¹⁹F NMR (376 MHz, DMSO-d6): -60.32 (s) ppm.

[00878] Example 100

[00879] tert-butyl 4-( ((3-((4-( trifluoromethyl)phenyl)carbamoyl)pyridin-2- yl)amino)methyl)piperidine-l-carboxylate

[00880] Example 100 was similarly synthesized from compound 87 and i<?ri-butyl 4- (aminomethyl)piperidine-l-carboxylate (5.0 eq) at 150 °C using the General Procedure C. Yield: 50.2%

Example 100

[00881] LCMS: ESI-MS: m/z: 479.1 [M+H]⁺; RT = 1.69 min. (Method A)

[00882] HPLC: RT = 10.43 min. [00883] ¾ NMR (400 MHz, DMSO-d<5): δ 10.49 (s, 1H), 8.23 (dd, 7 = 4.8, 1.7 Hz, 1H), 8.11 (dd, 7 = 7.7, 1.8 Hz, 2H), 7.93 (d, 7 = 8.5 Hz, 2H), 7.72 (d, 7 = 8.7 Hz, 2H), 6.66 (dd, 7 = 7.7, 4.8 Hz, 1H), 3.94 (d, 7 = 11.3 Hz, 2H), 3.37 - 3.34 (m, 2H), 2.67 (brs, 2H), 1.77 (brs, 1H), 1.66 (d, 7 = 11.9 Hz, 2H), 1.39 (s, 9H), 1.06 (ddd, 7 = 24.8, 12.4, 4.1 Hz, 2H) ppm.

[00884] ¹⁹F NMR (376 MHz, DMSO-d<5): -60.33 (s) ppm.

[00885] Example 101

[00886] 2-((piperidin-4-ylmethyl)amino)-N-(4-(trifluoromethyl)phenyl)nicotin trifluoroacetic acid salt

Example 100 _{Examp|e 101}

[00887] To a mixture of Example 100 (140 mg, 0.293 mmols, 1.0 eq) in dichloromethane (6 mL) was added trifluoroacetic acid (3 mL) dropwise at 0 °C. The reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated. The residue was dissolved in ethyl acetate (20 mL) and washed sequentially with aqueous sat. NaHCCb (10 mL x 3) and brine. The solution was dried over MgS0₄, filtered and concentrated. The residue was purified by Prep-HPLC (TFA as modifier) to give Example 101 (90 mg, 0.238 mmols, 81.3%) as a white solid.

[00888] LCMS: ESI-MS: m/z: 379.1 [M+H]⁺; RT = 1.33 min. (Method A)

[00889] HPLC: RT = 7.69 min.

[00890] ¾ NMR (400 MHz, DMSO-d<5): δ 10.61 (s, 1H), 8.63 (brs, 1H), 8.23 (d, 7 = 4.4 Hz, 1H), 8.19 - 8.08 (m, 2H), 7.96 (d, 7 = 8.5 Hz, 2H), 7.72 (d, 7 = 8.5 Hz, 2H), 6.66 (dd, 7 = 7.4, 5.0 Hz, 1H), 3.40 - 3.37 (m, 2H), 3.23 (d, 7 = 12.7 Hz, 2H), 2.79 (t, 7 = 12.2 Hz, 2H), 1.91 - 1.79 (m, 3H), 1.38 (dd, 7 = 23.0, 11.3 Hz, 2H) ppm.

[00891] ¹⁹F NMR (376 MHz, DMSO-d<5): -60.31 (s), -73.48 (s) ppm.

[00892] Example 102

[00893] 2-( ( (l-methylpiperidin-4-yl)methyl)amino)-N-(4- ( trifluoromethyl jphenyl Nicotinamide

[00894] To a mixture of Example 101 (60 mg, 0.159 mmols, 1.0 eq) in THF (5 mL) and methanol (5 mL) was added 37 % aq. Formaldehyde (1 mL), acetic acid (0.1 mL) and NaBfbCN (20 mg, 0.318 mmols, 2.0 eq) at room temperature. After stirred at room temperature for 1 hour, the reaction solution was partitioned with ethyl acetate and sat. aq. NaHC03. The organic layer was washed with brine, dried over Na2S0₄, filtered and concentrated. The residue was purified by Prep-HPLC (NH1HCO3 as modifier) to give Example 102 (30 mg, 0.076 mmols, 48.2%) as a white solid.

[00895] LCMS: ESI-MS: m/z: 393.2 [M+H]⁺; RT = 1.33 min. (Method A)

[00896] HPLC: RT = 7.77 min.

[00897] ¾ NMR (400 MHz, DMSO-d<5): δ 10.49 (s, 1H), 8.23 (d, / = 3.3 Hz, 1H), 8.11 (dd, J = 1.1 , 1.6 Hz, 2H), 7.92 (d, / = 8.4 Hz, 2H), 7.72 (d, / = 8.5 Hz, 2H), 6.65 (dd, / = 7.7, 4.8 Hz, 1H), 3.33 - 3.31 (s, 2H), 2.74 (d, / = 11.4 Hz, 2H), 2.12 (s, 3H), 1.79 (t, / = 10.7 Hz, 2H), 1.64 (d, / = 11.4 Hz, 2H), 1.54 - 1.51 (m, 1H), 1.26 - 1.20 (m, 2H) ppm.

[00898] ¹⁹F NMR (376 MHz, DMSO-d<5): -60.31 (s) ppm.

[00899] Example 103

[00900] 2-((4-(( dimethylamino )methyl)benzyl jamino )-N-(4- ( trifluoromethyl jphenyl Nicotinamide

[00901] The mixture of 117 (2.00 g, 10.3 mmols, 1.0 eq), dimethylammonium chloride (8.31 g, 102 mmols, 10.0 eq), K₂C0₃ (1.42 g, 10.3 mmols, 1.0 eq) and Et₃N (2.86 ml, 20.5 mmols, 2.0 eq) in THF (50 mL) was stirred at 60 °C for overnight under nitrogen. The mixture was diluted with water, extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over Na2S0₄, filtered and concentrated to give the desired product 118 (1.30 g, 8.12 mmols, 79.3%) as a light yellow oil, which was used in the next reaction directly without further purification.

[00902] To a mixture of 118 (1.30 g, 8.12 mmols, 1.0 eq) in THF (10 mL) was added a solution of 1 M borane tetrahydrofuran complex (24.4 mL, 24.4 mmols, 3.0 eq). The mixture was heated at reflux temperature for 16 hours under nitrogen. After cooled to room temperature, a 1 M solution of HCl in methanol (20 mL) was added, the reaction mixture was heated to reflux for 1 hour. After cooled to room temperature, the precipitation was collected by filtration. The solid was washed with diethyl ether, and dried in vacuo to give 119 (1.50 g, 7.50 mmols, 92.6%) as a white solid.

[00903] Example 103 was similarly synthesized from compound 119 and 87 at 130 °C using the General Procedure C. Yield: 6.22%.

[00904] LCMS: ESI-MS: m/z: 429.1 [M+H]⁺; RT = 2.22 min. (Method B)

[00905] HPLC: RT = 9.98 min.

[00906] ¾ NMR (400 MHz, DMSO-d<5): δ 10.52 (s, 1H), 8.33 (t, / = 5.7 Hz, 1H), 8.23 (dd, 7 = 4.8, 1.7 Hz, 1H), 8.13 (dd, J = 7.7, 1.8 Hz, 1H), 7.93 (d, J = 8.5 Hz, 2H), 7.71 (d, / = 8.6 Hz, 2H), 7.29 (d, / = 8.1 Hz, 2H), 7.22 (d, / = 8.1 Hz, 2H), 6.70 (dd, / = 7.7, 4.8 Hz, 1H), 4.64 (d, J = 5.7 Hz, 2H), 3.34 (s, 2H), 2.11 (s, 6H) ppm.

[00907] ¹⁹F NMR (376 MHz, DMSO-d<5): -60.34 (s) ppm.

[00908] Example 104

[00909] -(4-(hydroxymethyl)phenyl)-2-((oxetan-3-ylmethyl)amino)nicotinamide

[00910] Compound 120 was similarly prepared as the synthesis of Intermediate 14. Yield: 59.3%

[00911] Example 104 was similarly synthesized from compound 120 and oxetan-3- ylmethanamine (5.0 eq) at 130 °C using the General Procedure C. Yield: 29.0%

[00912] LCMS: ESI-MS: m/z: 314.1 [M+H]⁺; RT = 1.10 min. (Method A)

[00913] HPLC: RT = 4.66 min. [00914] ¾ NMR (500 MHz, MeOO-d4): δ 8.32 (d, / = 7.0 Hz, 1H), 7.82 (brs, 1H), 7.67 (d, / = 8.4 Hz, 2H), 7.38 (d, / = 8.4 Hz, 2H), 6.67 (s, 1H), 4.61 (s, 2H), 4.39 (d, / = 12.9 Hz, 1H), 4.26 - 4.03 (m, 1H), 3.80 - 3.69 (m, 2H), 3.64 (dd, / = 11.1, 6.6 Hz, 1H), 3.44 (dd, / = 14.0, 8.6 Hz, 1H), 2.40 - 2.36 (m, 1H) ppm.

[00915] Example 105

[00916] N-(2-fluoro-4-(trifluoromethyl)phenyl)-2-((4- fluorobenzyl jamino Nicotinamide

[00917] Step l :

[00918] To an ice-cooled mixture of compound 8 (200 mg, 1.27 mmols, 1.0 eq) in dichloromethane (20 mL) were added oxalyl chloride (0.145 mL, 1.52 mmols, 1.2 eq) and DMF (0.05 mL). The reaction mixture was stirred at 25 °C for 1 hour. Formation of the acid chloride was monitored by quenching an aliquot with methanol and analyzing by TLC to check the formation of the methyl ester with respect to acid 8. At the end of the reaction, solvent was evaporated under reduced pressure and the residue was used directly for Step 2.

[00919] Step 2:

[00920] Acid chloride obtained from Step 1, was taken up in dichloromethane (20 mL) and a solution of 2-fluoro-4-(trifluoromethyl)aniline (217 mg, 1.21 mmols, 0.950 eq) and triethylamine (0.530 mL, 3.81 mmols, 3.0 eq) in dichloromethane (3 mL) was added dropwise at 0 °C. The reaction was stirred at 25 °C overnight. The reaction was diluted with dichloromethane, washed successively with saturated aqueous solution of ammonium chloride, saturated aqueous solution of sodium bicarbonate and brine. The organic layer was dried over Na2S0₄, filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate, 4 / 1) to give the desired product 121 (210 mg, 0.660 mmols, 51.8%) as a white solid. [00921] LCMS: ESI-MS: m/z: 319.0 [M+H]+; RT = 1.96 min. (Method A)

[00922] A solution of 121 (210 mg, 0.660 mmols, 1.0 eq), l-(4- fluorophenyl)ethanamine (165 mg, 1.32 mmols, 2.0 eq) and DIPEA (0.345 mL, 1.98 mmols, 3.0 eq) in DMSO (3 mL) was heated to 130 °C overnight under nitrogen. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over Na2S0₄, filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate, 3 / 1) to give the desired product Example 105 (200 mg, 0.491 mmols, 74.3%) as a white solid.

[00923] LCMS: ESI-MS: m/z: 408.1 [M+H]+; RT = 2.37 min. (Method B)

[00924] HPLC: RT = 11.05 min.

[00925] ¾ NMR (500 MHz, DMSO- d6): δ 8.26 (d, J = 2.4 Hz, 1H), 8.12 (s, 1H), 7.90 (d, / = 2.2 Hz, 1H), 7.62 (s, 1H), 7.38 (s, 1H), 7.30 (s, 1H), 4.22 (t, / = 8.3 Hz, 2H), 4.14 (d, / = 3.4 Hz, 2H), 3.12 (t, / = 8.3 Hz, 2H), 3.04 (s, 1H) ppm.

[00926] ¹⁹F NMR (376 MHz, OMSO-d6): -61.49 (s), -109.46 (s), -116.48 (s) ppm.

[00927] Example 106 (a white solid) and Example 107 (a white solid) were similarly prepared as the synthesis of Example 105.

[00928] Example 106

[00929] 2-((4-fluorobenzyl)amino )-N-(2-methoxy-4- ( trifluoromethyl jphenyl Nicotinamide

[00930] LCMS: ESI-MS: m/z: 420.1 [M+H]+; RT = 2.05 min. (Method A)

[00931] HPLC: RT = 10.87 min.

[00932] ¾ NMR (500 MHz, DMSO- d6): δ 9.71 (s, 1H), 8.44 (t, / = 5.8 Hz, 1H), 8.23 (dd, 7 = 4.8, 1.6 Hz, 1H), 8.12 (dd, J = 7.7, 1.7 Hz, 1H), 7.94 (d, J = 8.2 Hz, 1H), 7.43 - 7.26 (m, 4H), 7.13 (t, / = 8.9 Hz, 2H), 6.68 (dd, / = 7.6, 4.8 Hz, 1H), 4.62 (d, / = 5.7 Hz, 2H), 3.92 (s, 3H) ppm.

[00933] ¹⁹F NMR (376 MHz, DMSO-d<5): -60.44 (s), -116.40 (s) ppm. [00934] Example 107

[00935] 2-((4-fluorobenzyl)amino)-4-methoxy-N-(4- ( trifluoromethyl jphenyl Nicotinamide

[00936] LCMS: ESI-MS: m/z: 420.1 [M+H]+; RT = 1.59 min. (Method A)

[00937] HPLC: RT = 9.91 min.

[00938] ^lH NMR (500 MHz, DMSO- d6): δ 10.51 (s, 1H), 8.02 (d, J = 5.9 Hz, 1H), 7.92 (d, J = 8.5 Hz, 1H), 7.70 (d, J = 8.7 Hz, 1H), 7.41 - 7.26 (m, 2H), 7.10 (t, J = 8.9 Hz, 1H), 6.48 (d, J = 6.0 Hz, 1H), 4.56 (d, J = 5.9 Hz, 1H), 3.84 (s, 2H) ppm.

[00939] 19 F NMR (376 MHz, DMSO-d<5): -60.27 (s), -116.82 (s) ppm.

[00940] Example 108

[00941] 2-((4-hydroxybenzyl)amino)-N-(4-(trifluoromethyl)phenyl)nicotinamide

[00942] LCMS: ESI-MS: m/z: 388.1 [M+H]+; RT = 2.09 min. (Method B)

[00943] HPLC: RT = 9.14 min.

[00944] Ή NMR (400 MHz, MeOD-cW): δ 8.20 (dd, / = 4.9, 1.8 Hz, 1H), 8.08 (dd, J = 1.1, 1.8 Hz, 1H), 7.86 (d, / = 8.5 Hz, 2H), 7.63 (d, / = 8.6 Hz, 2H), 7.20 (d, / = 8.5 Hz, 2H), 6.79 - 6.72 (m, 2H), 6.68 (dd, / = 7.7, 4.9 Hz, 1H), 4.55 (s, 2H) ppm.

[00945] ¹⁹F NMR (376 MHz, MtOO-d4): -63.58 (s) ppm.

[00946] Example 109

[00947] 2-((3-hydwxybenzyl)amino )-N-(4-( trifluoromethyl )phenyl Nicotinamide

[00948] LCMS: ESI-MS: m/z: 388.2 [M+H]+; RT = 1.86 min. (Method A)

[00949] HPLC: RT = 9.36 min.

[00950] ¾ NMR (400 MHz, DMSO-d<5): δ 10.53 (s, 1H), 9.32 (s, 1H), 8.32 (t, J = 5.8 Hz, 1H), 8.23 (dd, 7 = 4.8, 1.7 Hz, 1H), 8.13 (dd, / = 7.7, 1.7 Hz, 1H), 7.94 (d, 7 = 8.6 Hz, 2H), 7.72 (d, / = 8.7 Hz, 2H), 7.10 (t, / = 7.7 Hz, 1H), 6.76 - 6.73 (m, 2H), 6.70 (dd, / = 7.7, 4.8 Hz, 1H), 6.62 (dd, / = 8.0, 1.7 Hz, 1H), 4.58 (d, / = 5.7 Hz, 2H) ppm.

[00951] ¹⁹F NMR (376 MHz, DMSO-d<5): -60.34 (s) ppm.

[00952] Example 110

-(benzylamino)-N-(4-(trifluoromethyl)phenyl)nicotinamide

[00954] A solution of 3 (1.00 mg, 7.09 mmols, 1.0 eq), 20 (1.14 g, 7.09 mmols, 1.0 eq), HATU (5.39 g, 14.2 mmols, 2.0 eq) and DIPEA (2.74 g, 21.3 mmols, 3.0 eq) in DMF (25 mL) was stirred at 25 °C overnight under nitrogen. The mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over Na2S04, filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate, 2 / 1) to give the desired product 21 (800 mg, 2.82 mmols, 38.1%) as a white solid.

[00955] LCMS: ESI-MS: m/z: 285.1 [M+H]+; RT = 2.61 min. (Method A)

[00956] A solution of 21 (80.0 mg, 0.282 mmols, 1.0 eq), phenylmethanamine (121 mg, 1.13 mmols, 4.0 eq) and DIPEA (109 mg, 0.846 mmols, 3.0 eq) in DMSO (2 mL) was heated to 130 °C overnight under nitrogen. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over Na2S0₄, filtered, and concentrated. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate, 4 / 1) to give Example 110 (100 mg, 0.269 mmols, 95.0%) as a white solid.

[00957] LCMS: ESI-MS: m/z: 372.1 [M+H]+; RT = 2.32 min. (Method B)

[00958] HPLC: RT = 10.26 min.

[00959] ^!H NMR (500 MHz, DMSO- d6): δ 10.54 (s, 1H), 8.34 (t, J = 5.6 Hz, 1H),

8.23 (dd, J = 4.8, 1.6 Hz, 1H), 8.13 (dd, J = 7.7, 1.7 Hz, 1H), 7.93 (d, J = 8.6 Hz, 1H),

7.72 (d, / = 8.6 Hz, 1H), 7.33 (q, / = 8.0 Hz, 2H), 7.24 (d, / = 6.5 Hz, 1H), 6.70 (dd, / =

7.6, 4.8 Hz, 1H), 4.66 (d, / = 5.7 Hz, 2H) ppm.

[00960] ¹⁹F NMR (376 MHz, DMSO- 6): -60.34 (s) ppm.

[00961] Example 111

[00962] 2-((4-methoxybenzyl)a methyl)phenyl)nico

[00963] LCMS: ESI-MS: m/z: 402.1 [M+H]+; RT = 2.28 min. (Method B)

[00964] HPLC: RT = 10.06 min.

[00965] Ή NMR (400 MHz, CDCb): δ 8.32 (dd, 7 = 4.8, 1.7 Hz, 1H), 8.23 (t, / = 4.9 Hz, 1H), 7.80 (s, 1H), 7.74 (dd, 7 = 7.7, 1.7 Hz, 1H), 7.64 (q, 7 = 8.8 Hz, 4H), 7.31 (d, / = 8.6 Hz, 2H), 6.91 - 6.81 (m, 2H), 6.59 (dd, / = 7.7, 4.8 Hz, 1H), 4.66 (d, / = 5.4 Hz, 2H), 3.79 (s, 3H) ppm.

[00966] ¹⁹F NMR (376 MHz, CDCb): -62.18 (s) ppm.

[00967] Example 112

[00968] 2-((3-methoxybenzyl)ammo)-N-(4-(trifluoromethyl)phenyl)nicotinamide

[00969]

[00970] LCMS: ESI-MS: m/z: 402.1 [M+H]+; RT = 2.29 min. (Method B)

[00971] HPLC: RT = 10.26 min. [00972] Ή NMR (400 MHz, CDCb): δ 8.38 - 8.25 (m, 2H), 7.81 (s, 1H), 7.74 (dd, J = 7.7, 1.6 Hz, 1H), 7.67 (d, / = 8.7 Hz, 2H), 7.62 (d, / = 8.8 Hz, 2H), 7.23 (d, / = 7.9 Hz, 1H), 6.97 (d, / = 7.7 Hz, 1H), 6.93 (s, 1H), 6.79 (dd, / = 8.2, 2.4 Hz, 1H), 6.60 (dd, / = 7.7, 4.8 Hz, 1H), 4.72 (d, / = 5.6 Hz, 2H), 3.79 (s, 3H) ppm.

[00973] ¹⁹F NMR (376 MHz, CDCb): -62.18 (s) ppm.

[00974] Example 113

[00975] 2-((2-methoxybenzyl)amino)-N-(4-(trifluoromethyl)phenyl)nicotinamide

[00977] Example 113 (a white solid) was similarly prepared as the synthesis of Example 110. Yield: 74.8%.

[00978] LCMS: ESI-MS: m/z: 402.1 [M+H]+; RT = 1.91 min. (Method A)

[00979] HPLC: RT = 10.09 min.

[00980] Ή NMR (400 MHz, CDCb): δ 8.31 - 8.28 (m, 2H), 7.80 (s, 1H), 7.71 (dd, J = 7.7, 1.7 Hz, 1H), 7.67 (d, J = 8.7 Hz, 2H), 7.61 (d, J = 8.7 Hz, 2H), 7.34 (dd, J = 7.3, 1.3 Hz, 1H), 7.23 (dd, 7 = 7.8, 1.6 Hz, 1H), 6.95 - 6.83 (m, 2H), 6.55 (dd, 7 = 7.7, 4.8 Hz, 1H), 4.75 (d, / = 5.7 Hz, 2H), 3.87 (s, 3H) ppm.

[00981] ¹⁹F NMR (376 MHz, CDCb): -62.16 (s) ppm.

[00982] Example 114

[00983] 2-((4-fluorobenzyl)thio )-N-(4-( trifluoromethyl)phenyl jnicotinamide

[00984] A mixture of 21 (100 mg, 0.352 mmols, 1.0 eq), (4- fluorophenyl)methanethiol (125 mg, 0.880 mmols, 2.5 eq) and t-BuOK (59.1 mg, 0.528 mmols, 1.5 eq) in 1 ,4-dioxane (10 mL) was stirred at 85 °C for 16 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed sequentially with water and brine. The organic layer was dried over Na2S0₄, filtered and concentrated. The residue was purified by Preparative-TLC (petroleum ether/ethyl acetate, 2 / 1) to give Example 114 (126 mg, 0.310 mmols, 88.2%) as a white solid.

[00985] LCMS: ESI-MS: m/z: 407.1 [M+H]+; RT = 2.27 min. (Method B)

[00986] HPLC: RT = 11.25 min.

[00987] ¾ NMR (400 MHz, DMSO-d<5): δ 10.81 (s, 1H), 8.63 (dd, J = 4.9, 1.7 Hz, 1H), 7.99 (dd, 7 = 7.6, 1.7 Hz, 1H), 7.90 (d, J = 8.5 Hz, 2H), 7.73 (d, J = 8.6 Hz, 2H), 7.44 (dd, / = 8.6, 5.6 Hz, 2H), 7.31 (dd, / = 7.6, 4.9 Hz, 1H), 7.10 (t, / = 8.9 Hz, 2H), 4.42 (s, 2H) ppm.

[00988] ¹⁹F NMR (376 MHz, DMSO-d<5): -60.39 (s), -115.72 (s) ppm.

[00989] Example 115

[00990] -((2-hydroxybenzyl)amino)-N-(4-(trifluoromethyl)phenyl)nicotinamide

xamp e Example 115

[00991] To a stirred solution of Example 113 (115 mg, 0.287 mmols, 1.0 eq ) in DCM (15 mL) was added BBr₃ (1.43 mL, 1.43 mmols, 1.0 M in DCM, 5.0 eq) at -40 °C. After being stirred at room temperature for 3 hours, the reaction mixture was quenched with MeOH (20 mL) and concentrated. The residue was purified by recrystallization from ethyl acetate and n-hexanes to give the desired product Example 115 (92.0 mg, 0.238 mmols, 82.8%) as a white solid.

[00992] LCMS: ESI-MS: m/z: 388.2 [M+H]+; RT = 2.25 min. (Method B)

[00993] HPLC: RT = 10.05 min.

[00994] ^lH NMR (400 MHz, CDCb): δ 11.39 (s, 1H), 8.70 (t, / = 6.5 Hz, 1H), 8.21 (dd, J = 5.1 , 1.6 Hz, 1H), 7.94 (s, 1H), 7.77 - 7.67 (m, 3H), 7.64 (d, / = 8.7 Hz, 2H), 7.25 - 7.17 (m, 2H), 6.93 (d, / = 8.0 Hz, 1H), 6.87 (td, / = 7.4, 1.1 Hz, 1H), 6.55 (dd, / = 7.6, 5.1 Hz, 1H), 4.54 (d, / = 6.6 Hz, 2H) ppm.

[00995] ¹⁹F NMR (376 MHz, CDCb): -62.21 (s) ppm. [00996] Example 116

[00997] 3-(benzylamino)-N-(4-(trifluoromethyl)phenyl)pyrazine-2-carboxamide

[009

[00999] Example 116 (a white solid) was similarly prepared as the synthesis of Example 110. Yield: 64.6% for two steps.

[001000] LCMS: ESI-MS: m/z: 373.1 [M+H]+; RT = 2.43 min. (Method B)

[001001] HPLC: RT = 12.06 min.

[001002] ¾ NMR (400 MHz, DMSO-d<5): δ 10.96 (s, 1H), 8.96 (t, / = 5.8 Hz, 1H), 8.37 (d, / = 2.3 Hz, 1H), 8.09 (d, / = 8.5 Hz, 2H), 7.95 (d, / = 2.3 Hz, 1H), 7.72 (d, / = 8.6 Hz, 2H), 7.38 - 7.31 (m, 4H), 7.25 (t, J = 7.0 Hz, 1H), 4.71 (d, J = 5.9 Hz, 2H) ppm.

[001003] ¹⁹F NMR (376 MHz, DMSO-d<5): -60.38 (s) ppm.

Oocyte Electrophysiology

[001004] OOCYTE ELECTROPHYSIOLOGY: Individual compounds were tested for modulation of submaximal nicotine-evoked currents at a7 nAChRs using Xenopus oocytes expressing human receptors. For each oocyte, the maximal nicotine-evoked currents were determined typically in response to 1 mM nicotine. All other currents were scaled to this value. The concentration of nicotine was adjusted to evoke a fractional current of approximately 0.05 (5% of max, or "EC₅")_> and this concentration of nicotine was used to generate ECs control currents. Increasing concentrations of test compounds were applied using a micro capillary linear array to oocytes alone (pretreatment) and then in combination with the EC₅ concentration of nicotine (co-application). See, Ng et al.

PNAS 2007. This protocol allowed measurement of both direct effects of test compounds on a7 nAChRs, and modulatory effects of compounds on nicotine-evoked responses. mRNA was prepared and stored using conventional techniques with a cDNA clone encoding the human al nicotinic receptor subunit (NCBI Reference Sequence:

NM_000746.5 ; CCDS10027.1). Preparation, micro-injection and maintenance of oocytes were performed as reported in detail previously (Whittemore et al., Mol. Pharmacol. 50: 1364-1375, 1996). Individual oocytes were injected with 5 - 50 ng of the mRNA. Following injections, oocytes were maintained at 16-17 °C in Barth's medium. Two- electrode voltage clamp recordings were made 3-14 days following mRNA injections at a holding voltage of -70 mV unless specified. The nicotinic recordings were done in Ca⁺⁺- free Ringer solution (mM: NaCl, 115; KC1, 2; BaCb, 1.8; HEPES, 5; pH 7.4) to limit Ca⁺⁺- activated chloride and muscarinic currents. Drug and wash solutions were applied using a microcapillary "linear array" (Hawkinson et al, Mol. Pharmacol. 49: 897-906, 1996) in order to allow rapid application of agonists. Currents were recorded on a PC- based computer for subsequent analysis. Test compounds were made up in DMSO over a concentration range of 0.001 - 10 mM and diluted 1000-fold into the Ca⁺⁺-free Ringer solution just prior to testing (final [DMSO] < 0.1%). The concentration-dependence of modulation was analyzed using GraphPad "Prism" curve-fitting software.

[001005] Positive allosteric modulators can also be assayed by imaging of calcium flux through a7 nAChR transiently expressed in a cell line, including HEK-293 and cell cultered neurons, (see for example international published application WO 2006/071184)

[001006] The modulation of compounds of the invention was determined in oocytes expressing human a7 nAChRs as described above. In one embodiment, compounds of the invention exhibited at least 50% modulation of the nicotine EC₅ at 0.3 μΜ of the compound. In one embodiment, compounds of the invention exhibited at least 100% modulation of the nicotine EC₅ at 0.3 μΜ of the compound. In another embodiment, compounds of the invention exhibited at least 200% modulation of the nicotine EC₅ at 0.3 μΜ of the compound. In another embodiment, compounds of the invention exhibited at least 500% modulation of the nicotine ECs at 0.3 μΜ of the compound. In another embodiment, compounds of the invention exhibited at least 1000% modulation of the nicotine EC₅ at 0.3 μΜ of the compound. In another embodiment, compounds of the invention exhibited at least 2000% modulation of the nicotine EC₅ at 0.3 μΜ of the compound.

[001007] Table 2. Oocyte Electrophysiology Assay Data

[001008] Examples that exhibit an average modulation of the ECs of nicotine using 0.3 μΜ of compound of less than 50% are denoted as while examples that exhibit an average modulation of the EC₅ of nicotine using 0.3 μΜ of compound of greater than 50% are denoted as "+".

Metabolic Stability Assays

[001009] METABOLIC STABILITY ASSAYS: Studies were carried out in human and rat liver microsomes ("HLM" and "RLM," respectively). Human and rat liver microsomes were purchased from BD Gentest. DMSO stocks were prepared for the test compounds. Aliquots of the DMSO solutions were diluted to 0.5 mM by acetonitrile, then further diluted by liver microsomes/buffer to 1.5 μΜ. 30 of 1.5 μΜ solutions were mixed with 15 of 6 mM NADPH, which had been pre-warmed to 37 °C, at a final test compound concentration of 1 μΜ. The plates were kept in a 37 °C water bath for the duration of the experiment. At each time point (0, 5, 15, 30, 45 minutes), 135 μί of acetonitrile was added into corresponding wells. After the final time point was sampled, the plates were shaken at a vibrator (IKA, MTS 2/4) for 10 min (600 rpm min) and then centrifuged at 5594 g for 15 min (Thermo Multifuge x 3R). Aliquots of the supernatant were removed, diluted 1 :1 into distilled water, and analyzed by LC-MS/MS. The peak area response ratio to internal standard (PARR) of the compounds at 5, 15, 30, 45 minutes was compared to the PARR at time 0 to determine the percent of test compound remaining at each time point. Half-lives were calculated using Excel software, fitting to a single-phase exponential decay equation.

[001010] In one aspect of the present invention, preferred compounds exhibited human liver microsome clearance values less than 20 ml/min/kg. In another aspect of the present invention, preferred compounds exhibited human liver microsome clearance values less than 15 ml/min/kg. In another aspect of the present invention, preferred compounds exhibited human liver microsome clearance values less than 10 ml/min kg. In another aspect of the present invention, preferred compounds exhibited human liver microsome clearance values less than 5 ml/min/kg. In another aspect of the present invention, preferred compounds exhibited rat liver microsome clearance values less than 200 ml/min/kg. In another aspect of the present invention, preferred compounds exhibited rat liver microsome clearance values less than 100 ml/min/kg. In another aspect of the present invention, preferred compounds exhibited rat liver microsome clearance values less than 50 ml/min/kg. In another aspect of the present invention, preferred compounds exhibited rat liver microsome clearance values less than 25 ml/min/kg. In another aspect of the present invention, preferred compounds exhibited rat liver microsome clearance values less than 10 ml/min/kg.

Cytochrome P450 Inhibition Assay

[001011] CYTOCHROME P450 INHIBITION ASSAY: Studies were carried out in human liver microsomes. Human liver microsomes were purchased from BD Gentest. DMSO stocks were prepared for the test compounds. Aliquots of the DMSO solutions were diluted 1 :3 by acetonitrile:ACN mixture (v/v: 40:60) to "400x" intermediate solutions, then further diluted by liver microsomes/buffer to "2x" intermediate solutions. "2x" intermediate solutions were mixed with "2x" NADPH/substrate solutions, which had been pre-warmed to 37 °C (final test compound concentrations were 10 μΜ, 3.3 μΜ, 1.1 μΜ, 0.37 μΜ, 0.122 μΜ, 0.041 μΜ, 0.0136 μΜ, and 0 μΜ). The plates were kept in a 37 °C water bath for the duration of the experiment. At the end of incubation (5 minutes for 3A4; 45 minutes for 2C19; 10 minutes for 1A2, 2C9, 2D6), 120 μΐ. of acetonitrile was added into corresponding wells. After the final time point was sampled, the plates were shaken at a vibrator (IKA, MTS 2/4) for 10 min (600 rpm/min) and then centrifuged at 5594 g for 15 min (Thermo Multifuge x 3R). Aliquots of the supernatant were removed, diluted 1 :1 into distilled water, and analyzed by LC-MS/MS. The peak area response ratio to internal standard (PARR) of the compounds at 10 μΜ, 3.3 μΜ, 1.1 μΜ, 0.37 μΜ, 0.122 μΜ, 0.041 μΜ, and 0.0136 μΜ was compared to the PARR at 0 μΜ to determine the percent of metabolite generation from substrate at each test compound concentration. IC50 values were calculated using XLfit or Graphpad software, fitting to a sigmoidal dose-response (variable slope) equation.

[001012] In one aspect of the present invention, preferred compounds exhibited IC50 values greater than 5 μΜ in the cytochrome P450 inhibition assay. In another aspect of the present invention, preferred compounds exhibited IC50 values greater than 10 μΜ in the cytochrome P450 inhibition assay. hERG Inhibition Assay

[001013] HERG INHIBITION ASSAY: hERG study was conducted with automated patch clamp machine, Qpatch-48HT (Sophion Biosciences, Denmark). Cultured CHO cells stably expressing hERG channels (provided by Sophion Biosciences, Denmark) were harvested from culture flasks of 70-90% cell confluence rate and prepared as cell suspension with a cell density of 3-8 x 10⁶ cells/ml in serum-free media (CHO-S-SFM II, cat# 12052 Invitrogen; 25 mM HEPES). Cells in such condition were placed into Qpatch cell stir chamber and used within 4 hours.

[001014] For each run, cells were first spun down by the built-in Qpatch centrifuge and re-suspended in extracellular solution (in mM, 2 CaC12, 1 MgC12, 4 KC1, 145 NaCl, 10 Glucose, 10 HEPES, pH 7.4, osmolarity -305 mOsm). Qplate-48 that holds one cell in each of its 48 channels for the later voltage-clamped assay were primed with the extracellular solution and intracellular solution (in mM, 5.4 CaC12, 1.75 MaC12, 120 KC1, 10 HEPES, 5 EGTA, 4 NaATP, pH 7.25, Osmolarity -280-295 mOsm). Cells were dispatched by Qpatch robotic dispensing guns into each Qplate channel and went through the process of gigo-olm sealing and whole cell configuration. Whole-cell recordings were performed in voltage-clamp mode at a holding potential of -80 mV. The hERG current was activated by depolarizing at +20 mV for 5 sec, after which the current was taken back to -50 mV for 5 sec to remove the inactivation and observe the deactivating tail current. The maximum amount of tail current size was used to determine hERG current amplitude. The above voltage protocol was applied to the cells every 15 sec throughout the whole procedure. External solution containing 0.1 % DMSO (vehicle) was applied to the cells to establish the baseline. Compound solution was added and the cells were kept in the test solution until the compound's effect reached a steady state or for a maximum of 4 min. For dose response assay (0.1, 0.3, 1, 3, 10 and 30 μΜ), compound was applied to the cells accumulatively from low to high concentrations. Washout with extracellular solution was performed after compound testing. Positive control cisapride 0.1 μΜ was used on each cell after compound testing to ensure the normal response and the good quality of the cell. hERG current sizes of each cell at each compound concentration were compared to that at the vehicle stage and the % of inhibition at each dose was thus calculated. hERG IC50 curve was plotted with Graphpad Prism.

[001015] In one aspect of the present invention, preferred compounds exhibited IC50 values greater than 30 μΜ in the hERG inhibition assay. In another aspect of the present invention, preferred compounds exhibited IC50 values greater than 20 μΜ in the hERG inhibition assay. In one aspect of the present invention, preferred compounds exhibited IC50 values greater than 10 μΜ in the hERG inhibition assay.

Plasma Stability Assay

[001016] PLASMA STABILITY ASSAY: Studies are carried out in plasma. Plasma is prepared under approval of IRB and IACUC on sodium heparin. pH of Plasma is monitored and used within the range of pH 7.4 to pH 8. DMSO stocks are prepared for the test compounds. Aliquots of the DMSO solutions are diluted to 0.05 mM by 0.05 mM Sodium phosphate buffer with 0.5% BSA. Then 10 of 0.05 mM solutions are dosed into 90 μΐ, of plasma in duplicates (n=2), which have been pre- warmed to 37 °C, at a final test compound concentration of 5 μΜ. The plates are kept in a 37 °C water bath for the duration of the experiment. At each timepoint (0, 5, 15, 30, 45, 60, and 120 minutes), 400 μΐ_^ of acetonitrile is added into corresponding wells. After the final timepoint is sampled, the plates are shaken at the vibrator (IKA, MTS 2/4) for 10 min (600 rpm min) and then centrifuge at 5594 g for 15 min (Thermo Multifuge x 3R). Aliquots of the supernatant are removed, diluted 1 : 1 into distilled water, and analyzed by LC-MS/MS. The peak area response ratio to internal standard (PARR) of the compounds at 5, 15, 30, 45, 60, and 120 minutes is compared to the PARR at time 0 to determine the percent of test compound remaining at each timepoint. Half-lives are calculated using Excel software, fitting to a single-phase exponential decay equation.

Caco-2 Permeability Assay

[001017] CACO-2 PERMEABILITY ASSAY: Caco-2 cells are obtained from American Tissue Culture Collection (Rockville, MD). The cells are maintained in Modified Eagle's medium (MEM), containing 10% heat-inactivated fetal bovine serum (FCS), and 1 % non-essential amino acids, in CO2 at 37°C. Cells are seeded on polycarbonate filter inserts (Millipore, CAT#PSHT 010 R5).

[001018] The cells are cultivated for 21-28 days prior to the transport experiments. The transepithelial electric resistance (TEER) and Lucifer Yellow permeability are checked routinely before and after the assay. Compounds are dissolved at 10 mM in 100% dimethyl sulfoxide (DMSO) and diluted for studies in Hanks Balanced Salt Solution

(HBSS, Invitrogen, Cat# 14025-092) with 25 mM HEPES, pH 7.4. Compounds are tested at 10 μΜ, and in both the apical-to-basolateral (A-B) and basolateral-to-apical (B-A) directions, and are conducted at 37 °C for 90 min. At the end of incubation, donor samples are diluted 10-fold by assay buffer, then 60 of receiver and diluted-donor samples are mixed with 60 of acetonitrile, and analyzed by LC-MS/MS. The concentrations of the compounds are quantified by standard curve.

VEGF Inhibition Assay

[001019] VEGF INHIBITION ASSAY: The assay is a commercial assay and was performed by ProQinase GmbH, Freiburg, Germany. Test Samples: Test samples were dissolved in 100% DMSO. The stock solutions were diluted to cover the concentrations in the assay. Sunitinib was used as a positive control and was tested in the range of ΙΟΟηΜ to 0.030 nM.

[001020] Cell Culture: Kinase VEGF-R2: In the cellular VEGF-R2 phosphorylation assay the cell line HUE, a spontaneously immortalized human umbilical vein endothelial cell clone, is used, which expresses endogenously a high level of VEGF-R2. Stimulation of these cells with human vascular endothelial growth factor A (VEGF-A) results in receptor tyrosine autophosphorylation. HUE cells were plated in Endothelial Cell Growth Medium (ECGM) supplemented with 10% FCS in multiwell cell culture plates. After starvation in Endothelial Cell Basal Medium (ECBM) supplemented with 10% FCS overnight cells were incubated with compounds in serum-free ECBM.

[001021] Application of compounds and stimulation of cells: Prediluted test samples were added 1 :100 to the cell culture medium resulting in a final DMSO concentration of 1%. After 90min incubation at 37°C, cells were stimulated with 100 ng/ml of VEGF-A for a duration of 3 minutes. Cells treated with Staurosporine [10 uM] are defined as Low control (n=8). The median value of those wells represents the background and is set to 0%. Cells treated with solvent alone are defined as High control (n=8). The mean value of those wells is set to 100%. Test sample-treated cells as well as High and Low control are stimulated in identical manner.

[001022] Substrate specific ELISA: Quantification of substrate phosphorylation was assessed in 96-well plates via sandwich ELISA using a substrate specific capture antibody and an anti-phosphotyrosine detection antibody. Raw data were converted into percent substrate phosphorylation relative to High controls, which were set to 100%. The IC50 value for Sunitinib, 4.4x10 M, was determined using GraphPad Prism 5 software with constrain of bottom to 0 and top to 100 using a nonlinear regression curve fit with variable hill slope. The equation is a four-parameter logistic equation. In the assay results as presented, a value of 100% or higher corresponds to no inhibition of VEGFR2 phosphorylation, while a value of 0% corresponds to complete inhibition of VEGFR2 phosphorylation. If 1 μΜ of compound inhibits VEGF phosphorylation at 50%, than the IC50 is approximately 1 μΜ.

[001023] In one aspect of the present invention, preferred compounds exhibit a percentage of phosphorylated VEGFR2 using 1 μΜ of test compound near 100% or higher, corresponding to no inhibition of VEGFR2 phosphorylation. In another aspect of the present invention, preferred compounds exhibit a percentage of phosphorylated VEGFR2 using 1 μΜ of test compound greater than 75%. In another aspect of the present invention, preferred compounds exhibit a percentage of phosphorylated VEGFR2 using 1 μΜ of test compound greater than 50%.

[001024] VEGF Inhibition Assay results are presented in Table 6.

[001025] Table 6: VEGF Inhibition Assay Data

Novel Object Recognition Assay

[001026] NOVEL OBJECT RECOGNITION ASSAY: Novel Object Recognition (NOR). Adult CD1 mice (Charles River Laboratories, Wilmington, MA) are used in the NOR paradigm. The animals are allowed to explore the chamber in the absence of any objects for two 15 min sessions on day 1 to ensure habituation to the empty apparatus and testing room. On day 2, animals are subject to acquisition for one 10 min period with two identical objects. The familiar and novel objects are counterbalanced to ensure there is no object preference. A tall glass test tube (A) and a 15 mL plastic test tube (B) are used as familiar/novel objects. Immediately after acquisition, the mice are dosed with 0.7 mg/kg (2.1 μιηοΐ/kg) scopolamine hydrochloride subcutaneously (sc). Half the animals are then dosed with either compound 7z dissolved in 80% PEG/20% saline or an equivalent dose of a vehicle (80% PEG 400/20% saline solution). Then 30 min after injection, the animals are videorecorded exploring for one 5 min session with one familiar object from acquisition and one novel object. A single-blinded experimenter watching the recorded video, scores the animal's exploration of novel and familiar objects, and analyzes the mice for their retention of the familiar object. Object exploration is defined as an interaction with the object, which includes sniffing, licking, touching, or closely staring at the objects. The objects are chosen so that the animals can not sit or stand on them. The percent time spent with the novel object is defined as the time spent with novel divided by the total time spent with both novel and familiar objects. Results are analyzed as a mean + SEM. Analysis of the data is accomplished using a One- Way ANOVA followed by a post hoc Dunnet' s t test. The data can also be presented as a discrimination index. This index is defined as: (Time spent with novel object - Time spent with familiar object)/(Time spent with novel object + Time spent with familiar object).

[001027] The various features and embodiments of the present invention, referred to in individual sections above apply, as appropriate, to other sections, mutatis mutandis. Consequently features specified in one section may be combined with features specified in others sections, as appropriate.

[001028] The patents and publications listed herein describe the general skill in the art and are hereby incorporated by reference in their entireties for all purposes and to the same extent as if each was specifically and individually indicated to be incorporated by reference. In the case of any conflict between a cited reference and this specification, the specification shall control. In describing embodiments of the present application, specific terminology is employed for the sake of clarity. However, the invention is not intended to be limited to the specific terminology so selected. Nothing in this specification should be considered as limiting the scope of the present invention. All examples presented are representative and non-limiting. The above-described embodiments may be modified or varied, without departing from the invention, as appreciated by those skilled in the art in light of the above teachings. It is therefore to be understood that, within the scope of the claims and their equivalents, the invention may be practiced otherwise than as specifically described.

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula I:

I

or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:

n is an integer 0 or 1 ;

1 is selected from the group consisting of

R² is selected from the group consisting of 4-halophenyl, (Cl-C2)-4- fluoroalkoxyphenyl, 2-hydroxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, and 2- isoxazol-3-yl;

R³ is selected from the group consisting of -H, halogen, -CF₃, -CN, -OCF₃, - S(0)₂CF₃, -OH, and -OCH₂cyclopropyl;

R⁴ is selected from the group consisting of -H, halogen, -CF₃, -CN, -CH2OH, and -CH₂N(CH₃)₂;

R⁵ is selected from the group consisting of -H, halogen, -OCH₃, and -OCF₃;

X⁶ is selected from the group consisting of N and CR⁵ wherein at least two of X³ , X⁴ , X⁵ and X⁶ have a carbon; with the provisos that when X¹ and X² are CH, n is 1, and R² is 4-fluorophenyl, then R¹ is not 4-(trifluoromethyl)phenyl; and that when X¹ and X² are CH, n is 1, and R² is 4-halophenyl, then R¹ is not 3-(trifluoromethyl)phenyl. The compounds of claim 1 , wherein R² is selected from the group consisting of 4- halophenyl, (Cl-C2)-4-fluoroalkoxyphenyl, 2-hydroxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, and pharmaceutically acceptable salts, solvates, and prodrugs thereof.

The compounds of claim 1, wherein X² is CH, and pharmaceutically acceptable salts, solvates, and prodrugs thereof.

The compounds of claim 3, wherein X¹ is N, and pharmaceutically acceptable salts, solvates, and prodrugs thereof.

The compounds of claim 1, wherein n is 1, and pharmaceutically acceptable salts, solvates, and prodrugs thereof.

s of claim 1, wherein R¹ is

, and pharmaceutically acceptable salts, solvates, and prodrugs thereof.

The compounds of claim 6, wherein R² is selected from the group consisting of 4- halophenyl, (Cl-C2)-4-fluoroalkoxyphenyl, 2-hydroxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, X³ is CH, X⁴ is N, X⁵ is CR³ and X⁶ is CR⁵, provided R¹ is not unsubstituted pyridyl, and pharmaceutically acceptable salts, solvates, and prodrugs thereof.

The compounds of claim 7, wherein R³ is selected from the group consisting of - CF3, -OCF3, and -CN, and pharmaceutically acceptable salts, solvates, and prodrugs thereof.

The compounds of claim 6, wherein R² is selected from the group consisting of 4- halophenyl, (Cl-C2)-4-fluoroalkoxyphenyl, 2-hydroxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, X³ and X⁴ are CH, X⁵ is CR³, and X⁶ is CR⁵, provided R¹ is not unsubstituted phenyl, and pharmaceutically acceptable salts, solvates, and prodrugs thereof.

The compounds of claim 9, wherein R³ is selected from the group consisting of - CF3, -OCF3, and -CN; R⁴ is selected from the group consisting of -H, -CF3, and - CN, and pharmaceutically acceptable salts, solvates, and prodrugs thereof.

11. s of claim 1, wherein X² is CH, n is 1, R¹ is

, and pharmaceutically acceptable salts, solvates, and prodrugs thereof.

12. The compounds of claim 11, wherein X¹ is N, and pharmaceutically acceptable salts, solvates, and prodrugs thereof.

13. The compounds of claim 11, wherein R² is selected from the group consisting of 4-halophenyl, (Cl-C2)-4-fluoroalkoxyphenyl, 2-hydroxyphenyl, 3- methoxyphenyl, 4-methoxyphenyl, X³ is CH, X⁴ is N, X⁵ is CR³ and X⁶ is CR⁵, provided R¹ is not unsubstituted pyridyl, and pharmaceutically acceptable salts, solvates, and prodrugs thereof.

14. The compounds of claim 13, wherein R³ is selected from the group consisting of - CF3, -OCF3, and -CN, and pharmaceutically acceptable salts, solvates, and prodrugs thereof.

15. The compounds of claim 11, wherein R² is selected from the group consisting of 4-halophenyl, (Cl-C2)-4-fluoroalkoxyphenyl, X³ and X⁴ are CH, X⁵ is CR³, and X⁶ is CR⁵, provided R¹ is not unsubstituted phenyl, and pharmaceutically acceptable salts, solvates, and prodrugs thereof.

16. The compounds of claim 15, wherein R³ is selected from the group consisting of - CF3, -OCF3, and -CN; R⁴ is selected from the group consisting of -H, -CF3, and - CN, and pharmaceutically acceptable salts, solvates, and prodrugs thereof.

17. The compounds of claim 12, wherein R² is selected from the group consisting of 4-halophenyl, (Cl-C2)-4-fluoroalkoxyphenyl, X³ is CH, X⁴ is N, X⁵ is CR³ and X⁶ is CR⁵ , provided R¹ is not unsubstituted pyridyl, and pharmaceutically acceptable salts, solvates, and prodrugs thereof.

18. The compounds of claim 17, wherein R³ is selected from the group consisting of - CF3, -OCF3, and -CN, and pharmaceutically acceptable salts, solvates, and prodrugs thereof.

19. The compounds of claim 12, wherein R² is selected from the group consisting of 4-halophenyl, (Cl-C2)-4-fluoroalkoxyphenyl, X³ and X⁴ are CH, X⁵ is CR³, and X⁶ is CR⁵, provided R¹ is not unsubstituted phenyl, and pharmaceutically acceptable salts, solvates, and prodrugs thereof.

20. The compounds of claim 19, wherein R³ is selected from the group consisting of - CF3, -OCF3, and -CN; R⁴ is selected from the group consisting of -H, -CF3, and - CN, and pharmaceutically acceptable salts, solvates, and prodrugs thereof.

21. The compounds of any one of claims 1 to 20 that exhibit at least 50% modulation of the nicotine EC5 using 0.3 μΜ of said compound in Xenopus oocytes and pharmaceutically acceptable salts, solvates, and prodrugs thereof.

22. The compounds of any one of claims 1 to 20 that exhibit at least 100% modulation of the nicotine EC5 using 0.3 μΜ of said compound in Xenopus oocytes and pharmaceutically acceptable salts, solvates, and prodrugs thereof.

23. The compounds of claim 21 that inhibit VEGF activity with an IC50 greater than 1 μΜ and pharmaceutically acceptable salts, solvates, and prodrugs thereof.

24. The compounds of claim 21 that exhibit greater than 75% phosphorylation of VEGFR2 using 1 μΜ of test compound in the VEGF Inhibition Assay.

25. The compounds of claim 1 selected from the group consisting of:

N-(5-chloropyridin-2-yl)-2-((4-fluorobenzyl)amino)nicotinamide (Compound 3); 3-((4-fluorobenzyl)amino)-N-(6-(trifluoromethyl)pyridin-3-yl)pyrazine-2- carboxamide (Compound 20);

N-(3-cyano-4-(trifluoromethyl)phenyl)-2-((4-fluorobenzyl)amino)nicotinamide (Compound 47); N-(4-cyano-3-(trifluoromethyl)phenyl)-2-((4-fluorobenzyl)amino)nicotinamide (Compound 49);

2-((4-fluorobenzyl)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

(Compound 80);

2-((4-methoxybenzyl)amino)-N-(4-(trifluoromethyl)plienyl)nicotinamide (Compound 111);

2-((3-methoxybenzyl)amino)-N-(4-(trifluoromethyl)plienyl)nicotinamide (Compound 112);

2- ((2-hydroxybenzyl)amino)-N-(4-(trifluoromethyl)plienyl)nicotinamide

(Compound 115); and pharmaceutically acceptable salts, solvates, and prodrugs thereof.

26. The compounds of claim 1 selected from the group consisting of:

N-(4-chlorophenyl)-3-((4-fluorobenzyl)amino)pyrazine-2-carboxamide

(Compound 7);

N-(4-cyanophenyl)-3-((4-fluorobenzyl)amino)pyrazine-2-carboxamide

(Compound 39);

3- ((4-fluorobenzyl)amino)-N-(6-(trifluoromethoxy)pyridin-3-yl)pyrazine-2- carboxamide (Compound 57); 3-((4-fluorobenzyl)amino)-N-(3-(trifluoromethyl)phenyl)pyrazine-2-carboxamide (Compound 40);

N-(4-cyano-3-(trifluoromethyl)phenyl)-3-((4-fluorobenzyl)amino)pyrazine-2- carboxamide (Compound 50), and pharmaceutically acceptable salts, solvates, and prodrugs thereof.

27. A method for treating a disorder amenable to modulation of a7 nAChR comprising administering to a patient in need of such treatment an effective amount of a compound according to any one of Claims 1-26, a pharmaceutically acceptable salt, solvate, or prodrug thereof.

28. A method of treating a disorder selected from neurodegenerative diseases, senile dementias, schizophrenia, Alzheimer's disease, learning, cognition and attention deficits, memory loss, Lewy Body dementia, attention-deficit disorder, attention deficit hyperactivity disorder, anxiety, mania, manic depression, Parkinson's disease, Huntington's disease, depression, cognitive impairment due to Alzheimer's disease, mild cognitive impairment (MCI), cognitive impairment associated with schizophrenia (CIAS), cognitive impairment due to major depression, cognitive impairment due to bipolar disease, amyotrophic lateral sclerosis, brain inflammation, cognitive deficit due to traumatic brain injury, Tourette' s syndrome, and autism spectrum disorder comprising administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 26 or pharmaceutically acceptable salts, solvates, and prodrugs thereof.

29. A method for treating a cognitive disorder related to learning or memory comprising administering to a patient in need of such treatment an effective amount of a compound according to any one of claims 1 to 26 or pharmaceutically acceptable salts, solvates and prodrugs thereof.

30. The method of claim 27 further comprising administering to a patient in need of such treatment an effective amount of a compound of any one of Claims 1 to 26 or a pharmaceutically acceptable salt, solvate, or prodrug thereof, with activity for positive allosteric modulation of currents at oc7 nAChR receptors in which modulated currents retain the rapid native kinetics and native desensitization of the receptor observed in the absence of said compound or pharmaceutically acceptable salt, solvate, or prodrug thereof.

31. The method of Claim 28, wherein the disorder is a neurodegenerative disorder.

32. The method of Claim 28, wherein the disorder is a senile dementia.

33. The method of Claim 28, wherein the disorder is cognitive impairment due to Alzheimer' s disease.

34. The method of Claim 28, wherein the disorder is schizophrenia.

35. The method of Claim 28, wherein the disorder is mild cognitive impairment.

36. The method of Claim 28, wherein the disorder is Parkinson's disease.

37. The method of Claim 28, wherein the disorder is Lewy body dementia.

38. The method of Claim 28, wherein the disorder is cognitive impairment due to major depression.

39. The method of Claim 27, wherein the disorder is inflammation.

40. The method of Claim 27, wherein the disorder is an immune system disorder.

41. The method of Claim 27, wherein the composition is administered to treat pain, inflammation, septic shock, ulcerative colitis, Crohn's disease or irritable bowel syndrome.

42. The method of Claim 28 wherein the condition treated is autism spectrum disorder.

43. The method of Claim 28 wherein the condition is cognitive impairment associated with schizophrenia (CIAS).

44. The method of claim 28 wherein the condition is cognitive impairment due to bipolar disease.