# Patent

## Title
Quinoxaline derivatives as GPR6 modulators

## Abstract

The present invention provides compounds of Formula (I):




that are GPR6 modulators and are therefore useful for the treatment of diseases treatable by modulation of GPR6, in particular treating Parkinson disease, levodopa induced dyskinesias, Huntington's disease, other dyskinesias, akinesias, and motor disorders involving dysfunction of the striatum, schizophrenia and drug addiction. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds.

## Background
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a divisional of U.S. application Ser. No. 14/421,516, now U.S. Pat. No. 9,487,526, having a 371(c) date of Feb. 13, 2015, which is the U.S. National Stage entry under 35 U.S.C. §371 of International Application PCT/US2013/054715, filed Aug. 13, 2013, which claims the benefit of U.S. Provisional Application No. 61/682,704, filed Aug. 13, 2012, and of U.S. Provisional Application No. 61/696,748, filed Sep. 4, 2012, which are herein incorporated by reference.


FIELD OF INVENTION
The present invention provides compounds that are G-protein-coupled receptor 6 (hereinafter referred to as GPR6) modulators and are therefore useful for the treatment of diseases treatable by modulation of GPR6, in particular treating Parkinson disease, levodopa induced dyskinesias, Huntington's disease, other dyskinesias, akinesias, and motor disorders involving dysfunction of the striatum, schizophrenia and drug addiction. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds.
BACKGROUND
Parkinson disease (PD) is a degenerative disorder of the central nervous system. The motor symptoms of Parkinson's disease result from the death of dopamine-generating cells in the substantia nigra, a region of the midbrain. Degeneration of the nigrostriatal pathway causes reduction in the striatal concentration of dopamine. Dopamine is a neurotransmitter or chemical messenger in the body which affects brain processes controlling movement, balance, walking, emotional response, and ability to experience pleasure and pain. The major striatal targets of dopaminergic innervation reside in the medium spiny neurons (MSNs) of the striatopallidal (indirect) and striatonigral (direct) output pathways. The MSNs of the direct output pathway express D1 dopamine receptors whereas those in the indirect pathway express D2 receptors. Currently, there is no cure for Parkinson's disease, but drugs can relieve at least some of the symptoms. Modem treatments are effective at managing the early motor symptoms of the disease, mainly through the use of levodopa. About 75% of Parkinson's disease patients are treated with levodopa, a prodrug for dopamine discovered over 50 years ago (Dopamine Replacement Therapy).
Levodopa has common serious side effects including induced dyskinesia (LID), impulsive control disorders (ICD), psychotic symptoms and sleep disturbances. LID is progressive (90% of PD patients develop LID within 10 yrs). Accordingly there is a need for new treatments that are effective in treating PD. The present invention can fulfill this and related needs.
SUMMARY
Irreversible adaptations occur in D1 receptor signaling in MSNs in rodent models of LID including reduced desensitization leading of hypersensitivity in the direct pathway. Genetic inactivation of D1 but not D2 receptors abolishes LID in mice. However blockade of D1 receptor signaling does not affect the antiparkinsonian efficacy of L-DOPA. cAMP pathways modulated by D1/D2 dopamine receptors in MSN have been implicated in LID. Dopamine D2 receptors in MSN are Gi coupled, i.e., an agonist of D2 decreases the level of intracellular cAMP.
The GPR6 receptor exhibits high expression in the central nervous system (CNS) with minimal expression in peripheral tissues. GPR6 is highly selectively enriched in D2 receptor expressing MSNs in the striatum. The striatum plays a central role in modulating important behaviors including movement, reward, and motivational processes. GPR6 is GPCR that exhibits receptor signaling via the Gs pathway. Thus, GPR6 agonist activity results in an increase in intracellular cAMP levels whereas antagonists or inverse agonists cause a decrease in cAMP levels. GPR6 activity is therefore functionally opposed to D2 receptor signaling. Therefore, antagonism or inverse agonism of Gs coupled GPR6 should decrease cAMP in MSNs—a functional alternative to dopamine mediated activation of D2 receptors. As such, compounds that modulate the activity of GPR6 have utility in a variety of neurological and psychiatric disorders, for example movement disorders including Parkinson's disease, levodopa induced dyskinesias, and Huntington's disease either alone or in combination with other agents are approved for the treatment of Parkinson's disease including L-DOPA, dopaminergic agonists, MAO B inhibitors, DOPA decarboxylase inhibitors and COMT inhibitors. Other potential disease indications that could be treated by modulation of GPR6 include non-levodopa induced dyskinesias, akinesias, and motor disorders involving dysfunction of the striatumdrug addiction and eating disorders, cognitive disorders, schizophrenia, bipolar disorders, and depression.
Accordingly, in a first aspect, provided is a compound of Formula (I):




wherein:

R1 is a heterocycloamino ring substituted with Ra, Rb, and Rc wherein:

    
    
        Ra is —Z—Ar where Z is C1-6 alkylene, C1-6 haloalkylene, —O—, —C(O)—, —NH—, or —S(O)n- wherein n is 0, 1, or 2; and Ar is C3-10 cycloalkyl, C3-7 heterocycloalkyl, C3-7 heterocycloalkenyl, C6-10 aryl, or C1-9 heteroaryl wherein C3-10 cycloalkyl, C3-7 heterocycloalkenyl, C3-7 heterocycloalkyl, C6-10 aryl, and C1-9 heteroaryl are optionally substituted with 1 to 3 substituents independently selected from C1-6 alkyl, halo, hydroxy, oxo, C1-6 alkoxy, C1-6 thioalkoxy, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 haloalkoxy, C1-6 alkylcarbonyl, C1-6 alkylsulphonyl, cyano, C2-12 alkoxyalkyloxy, C1-9 amide, or C1-6 hydroxyalkyloxy; and
        Rb and Rc are independently hydrogen, C1-6 alkyl, hydroxy, or halo;
    
    


R2 is —ORe or —NRdRe wherein Rd is hydrogen or C1-6 alkyl and Re is C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C2-12 alkoxyalkyl, C1-12 aminoalkyl, C3-10 cycloalkyl, C4-16 cycloalkylalkyl, C6-10 aryl, C1-9 heteroaryl, C3-7 heterocyclyl, or C3-7 heterocycloalkenyl wherein C6-10 aryl, C1-9 heteroaryl, C3-7 heterocyclyl, and C3-7 heterocycloalkenyl are optionally substituted with 1 to 3 substituents independently selected from C1-6 alkyl, halo, hydroxy, oxo, C1-6 alkoxy, C1-6 haloalkyl or C1-6 haloalkoxy, or cyano;
all X1-X4 are carbon or one or two of X1-X4 are N and the rest of X1-X4 are carbon;
R3, R4, R5, and R6 are independently absent, hydrogen, C1-6 alkyl, halo, hydroxy, C1-6 alkoxy, C1-6 alkoxycarbonyl, C1-6 haloalkyl, C1-6 haloalkoxy, C1-9 amide, C3-7 heterocyclyl, C1-8 alkylamino, or cyano;
or a pharmaceutically acceptable salt thereof.
In a second aspect, provided is a pharmaceutical composition comprising a compound of Formula (I) (or embodiments thereof disclosed herein) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
In a third aspect, provided is a method of treating a disease treatable by administration of an antagonist and/or inverse agonist of GPR6 which method comprises administrating to the patient in need thereof a therapeutically effective amount of a compound of Formula (I) (or embodiments thereof disclosed herein) or a pharmaceutically acceptable salt thereof.
The method of third aspect wherein the disease is Parkinson disease, levodopa induced dyskinesia, non-levodopa induced dyskinesias, akinesias, motor disorders involving dysfunction of the striatum, drug addiction, eating disorders, cognitive disorders, schizophrenia, bipolar disorders, or depression. The method of third aspect wherein the compound of Formula (I) is administered in combination with an antipsychotic drug. The method of third aspect wherein the compound of Formula (I) is administered in combination with a dopamine agonist (e.g., Levodopa).
In a fourth aspect, provided is a compound of Formula (I) (or any embodiments thereof) or a pharmaceutically acceptable salt thereof for use as medicament. In one aspect of the fourth aspect, provided is the use of a compound of Formula (I) (or any embodiments thereof) or the pharmaceutical salts thereof for the treatment of a disease treatable by administration of an antagonist and/or inverse agonist of GPR6 such as Parkinson disease, levodopa induced dyskinesia, non-levodopa induced dyskinesias, akinesias, motor disorders involving dysfunction of the striatum, drug addiction, eating disorders, cognitive disorders, schizophrenia, bipolar disorders, or depression. Also, one aspect of the fourth aspect, provided is the use of a compound of Formula (I) (or any embodiments thereof) or the pharmaceutical salts thereof in combination with an antipsychotic drug. Also, one aspect of the fourth aspect, provided is the use of a compound of Formula (I) (or any embodiments thereof) or the pharmaceutical salts thereof in combination with a dopamine agonist (e.g., Levodopa).


DETAILED DESCRIPTION
Definitions
Unless otherwise stated, the following terms used in the specification and claims are defined for the purposes of this Application and have the following meaning:
“C1-6 alkyl” means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, butyl (including all isomeric forms), pentyl (including all isomeric forms), and the like.
“C1-4 alkyl” means a linear saturated monovalent hydrocarbon radical of one to four carbon atoms or a branched saturated monovalent hydrocarbon radical of three to four carbon atoms.
“C1-8 alkylamino” means a —NR′R′′ where R′ is hydrogen or C1-4 alkyl and R′′ is C1-4 alkyl.
“C1-6 alkylene” means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of two to six carbon atoms unless otherwise stated e.g., methylene, ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene, pentylene, and the like.
“C1-6 alkylsulfonyl” means a —SO2R radical where R is C1-6 alkyl as defined above, e.g., methylsulfonyl, ethylsulfonyl, and the like.
“C1-9 amide” refers to a —C(O)NRR′ group in which R is selected from the group consisting of hydrogen and C1-4 alkyl, and R′ is selected from the group consisting of hydrogen, C1-4 alkyl, or R and R′ together with the nitrogen to which they are attached form a 4 to 8 membered, saturated, ring optionally having an additional ring heteroatom selected from the group N, O, and S, in particular, an azetinyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-methylpiperazin-1-yl, or morpholinlyl ring.
“C1-12 aminoalkyl” means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with at least one, preferably one or two, —NRR′ where R is hydrogen, C1-6 alkyl, or —C(O)R′′ where R′′ is C1-6 alkyl, each as defined above, and R′ is selected from hydrogen, C1-6 alkyl, C1-6 hydroxyalkyl, or C2-12 alkoxyalkyl, each as defined herein, e.g., aminomethyl, methylaminoethyl, 2-ethylamino-2-methylethyl, 1,3-diaminopropyl, dimethylaminomethyl, diethylaminoethyl, acetylaminopropyl, and the like.
“C1-6 alkoxy” means a —OR radical where R is C1-6 alkyl as defined above, e.g., methoxy, ethoxy, propoxy, or 2-propoxy, n-, iso-, or tert-butoxy, and the like.
“C2-12 alkoxyalkyl” means C1-6 alkyl radical as defined above that is substituted with one or two C1-6 alkoxy group as defined above, e.g., methoxymethyl, ethoxymethyl, 2-methoxyethyl, and the like.
“C2-12 alkoxyalkyloxy” means —OR radical where R is C2-12 alkoxyalkyl as defined above, e.g., methoxymethyloxy, 2-methoxyethyloxy, ethoxymethyloxy, and the like.
“C1-6 alkylcarbonyl” means a —C(O)R radical where R is C1-6 alkyl as defined above, e.g., methylcarbonyl, ethylcarbonyl, and the like.
“C1-6 alkoxycarbonyl” means a —C(O)OR radical where R is C1-6 alkyl as defined above, e.g., methoxycarbonyl, ethoxycarbonyl, and the like.
“C6-10 aryl” means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 10 ring atoms e.g., phenyl or naphthyl.
“C3-10 cycloalkyl” means a cyclic saturated monovalent hydrocarbon radical of three to ten carbon atoms, e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and the like.
“C4-16 cycloalkylalkyl” means -(alkylene)-R where R is C3-10 cycloalkyl as defined above, e.g., cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, or cyclohexylmethyl, and the like.
“Carbonyl” means —C═(O) group.
“Halo” means fluoro, chloro, bromo, or iodo, preferably fluoro or chloro.
“C1-6 haloalkyl” means C1-6 alkyl radical as defined above, which is substituted with one or more halogen atoms, preferably one to five halogen atoms, preferably fluorine or chlorine, including those substituted with different halogens, e.g., —CH2Cl, —CF3, —CHF2, —CH2CF3,
—CF2CF3, and the like. When the C1-6 alkyl is substituted with only fluoro, it is referred to in this Application as C1-6 fluoroalkyl.
“C1-6 haloalkylene” means C1-6 alkylene as defined above wherein one to three hydrogen atoms have been replaced by halo, preferably fluoro. e.g., fluoromethylene, difluoromethylene, 1,2, or 3-fluoroethylene, —CH(CHF2)—, —CH(CF3)—, and the like.
“C1-6 haloalkoxy” means a —OR radical where R is C1-6 haloalkyl as defined above e.g., —OCF3, —OCHF2, and the like. When R is C1-6 haloalkyl where the C1-6 alkyl is substituted with only fluoro, it is referred to in this Application as fluoroalkoxy.
“C1-6 hydroxyalkyl” means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with one or two hydroxy groups, provided that if two hydroxy groups are present they are not both on the same carbon atom. Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2-(hydroxymethyl)-3-hydroxypropyl, preferably 2-hydroxyethyl, 2,3-dihydroxypropyl, and 1-(hydroxymethyl)-2-hydroxyethyl.
“C1-6 hydroxyalkoxy” or “C1-6 hydroxyalkyloxy” means a —OR radical where R is hydroxyalkyl as defined above.
“C3-7 heterocycloalkyl” or “C3-7 heterocyclyl” means a saturated monovalent monocyclic group of 4 to 8 ring atoms in which one or two ring atoms are heteroatom selected from N, O, or S(O)n, where n is an integer from 0 to 2, the remaining ring atoms being C, unless stated otherwise. More specifically the term C3-7 heterocyclyl includes, but is not limited to, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, piperazinyl, tetrahydropyranyl, thiomorpholinyl, and the like.
The term “heterocyclamino” means a saturated monocyclic group of 4 to 8 ring atoms in which one or two ring atoms are heteroatom selected from N, O, or S(O)n where n is an integer from 0 to 2, provided that at least one ring member is N. More specifically the term heterocycloamino includes, but is not limited to, azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, homopiperazinyl, and the like.
“C3-7 heterocycloalkenyl” or “C3-7 heterocyclylalkenyl” means a nonaromatic, unsaturated monovalent monocyclic group of 4 to 8 ring atoms in which one or two ring atoms are heteroatom selected from N, O, or S(O)n, where n is an integer from 0 to 2, the remaining ring atoms being C. Additionally, one or two ring carbon atoms in the heterocyclalkenyl ring can optionally be replaced by a —C(O)— group. More specifically the term heterocycloalkenyl includes, but is not limited to, dihydropiperidinyl, and the like.
“C1-9 heteroaryl” means a monovalent monocyclic or bicyclic fully unsaturated radical of 5 to 10 ring atoms where one or more, preferably one, two, or three, ring atoms are heteroatom selected from N, O, or S, the remaining ring atoms being carbon, unless stated otherwise. Representative examples include, but are not limited to, furyl, thienyl, pyrrolyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, azepinyl, diazepinyl, benzazepinyl, benzodiazepinyl, benzofuryl, benzothienyl, indolyl, isoindolyl, benzimidazolyl, benzisothiazolyl, benzisoxazolyl, benzoxadiazolyl, benzoxazolyl, benzopyrazinyl, benzopyrazolyl, imidazopyridyl, pyrazolopyridyl, pyrrolopyridyl, quinazolyl, thienopyridyl, imidazopyridyl, quinolyl, isoquinolyl benzothiazolyl, and the like.
“C1-6 thioalkoxy” means a —SR radical where R is C1-6 alkyl as defined above, e.g., thiomethoxy, thioethoxy, and the like.
“GPR6 modulators” as used herein means that the compounds of the invention are antagonists i.e, block the action of a GPR6 agonist by competitive binding to the GPR6 receptor or are inverse agonists of GPR6 i.e., bind to the GPR6 receptor and induces a pharmacological response opposite to its agonist thereby reducing its baseline intracellular activity. A GPR6 modulator may possess both antagonist and inverse agonist activity within the same compound.
The present invention also includes the prodrugs of compounds of Formula (I). The term prodrug is intended to represent covalently bonded carriers, which are capable of releasing the active ingredient of Formula (I) when the prodrug is administered to a mammalian subject. Release of the active ingredient occurs in vivo. Prodrugs can be prepared by techniques known to one skilled in the art. These techniques generally modify appropriate functional groups in a given compound. These modified functional groups however regenerate original functional groups in vivo or by routine manipulation. Prodrugs of compounds of Formula (I) include compounds wherein a hydroxy, amino, carboxylic, or a similar group is modified. Examples of prodrugs include, but are not limited to esters (e.g., acetate, formate, and benzoate derivatives), carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxy or amino functional groups in compounds of Formula (I)), amides (e.g., trifluoroacetylamino, acetylamino, and the like), and the like. Prodrugs of compounds of Formula (I) are also within the scope of this invention.
The present invention also includes protected derivatives of compounds of Formula (I). For example, when compounds of Formula (I) contain groups such as hydroxy, carboxy, thiol or any group containing a nitrogen atom(s), these groups can be protected with a suitable protecting groups. A comprehensive list of suitable protective groups can be found in T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc. (1999), the disclosure of which is incorporated herein by reference in its entirety. The protected derivatives of compounds of Formula (I) can be prepared by methods well known in the art.
A “pharmaceutically acceptable salt” of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts include: acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as formic acid, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, 4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. It is understood that the pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, which is incorporated herein by reference.
The compounds of the present invention may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of materials. All chiral, diastereomeric, meso, racemic forms are within the scope of this invention, unless the specific stereochemistry or isomeric form is specifically indicated.
Additionally, as used herein the term C1-6 alkyl and terms derived therefrom includes all the possible isomeric forms of said C1-6 alkyl group. Furthermore, the cyclic groups such as C6-10 aryl, C1-9 heteroaryl, C3-6 heterocycloalkyl include all the positional isomers. Furthermore, all polymorphic forms and hydrates of a compound of Formula (I) are within the scope of this invention.
The terms “compound” and “a compound of the invention” and “compound of the present invention” and the like, and their plural expressions include the embodiment of Formula (I) and the other more particular embodiments encompassed by Formula (I) described herein and exemplified compounds described herein and a pharmaceutically acceptable salt of each of these embodiments. All references to compounds, include all isotopes of the atoms contained therein, including isotopically-labeled compounds.
The compounds of the present invention may exist as tautomers. All tautomeric forms the compounds of the invention are contemplated to be within the scope of the present invention.
“Optional” or “optionally” means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, “C3-6 heterocycloalkyl group optionally substituted with an C1-6 alkyl group” means that the alkyl may but need not be present, and the description includes situations where the heterocycloalkyl group is substituted with an alkyl group and situations where the heterocycloalkyl group is not substituted with alkyl.
The terms “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” mean a carrier or an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic in the amounts used, and neither biologically nor otherwise undesirable, and includes a carrier or an excipient that is acceptable for veterinary use as well as human pharmaceutical use. “A pharmaceutically acceptable carrier/excipient” as used in the specification and claims includes both one and more than one such excipient. Pharmaceutically acceptable excipients are well known in the art, such as those in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985.
The terms “condition,” “disorder,” and “disease” relate to any unhealthy or abnormal state.
“Treat,” “treating,” or “treatment” of a disease includes:
(1) preventing the disease, i.e. causing the clinical symptoms of the disease not to develop in a mammal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease;
(2) inhibiting the disease, i.e., arresting, controlling, slowing, stopping, or reducing the development of the disease or its clinical symptoms; or
(3) relieving the disease, i.e., causing regression of the disease or its clinical symptoms or improvement of the disease or its clinical symptoms
The terms “treat,” “treating,” and “treatment,” do not necessarily indicate a total elimination of any or all symptoms or a cure of the disease.
As used herein the terms “patient” and “subject” includes humans and non-human animals, for example, mammals, such as mice, rats, guinea pigs, dogs, cats, rabbits, cows, horses, sheep, goats, and pigs. The term also includes birds, fish, reptiles, amphibians, and the like. It is understood that a more particular patient is a human. Also, more particular patients and subjects are non-human mammals, such as mice, rats, and dogs.
A “therapeutically effective amount” means the amount of a compound of Formula (I) that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease. The “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated. A “therapeutically effective amount” means the amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof that, when administered in single or multiple doses, to a mammal for treating a disease, is sufficient to effect such treatment for the disease. The “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated, the degree of or involvement or the severity of the condition, disorder, or disease, the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances.
The term “disease treatable by administration of an antagonist and/or inverse agonist of GPR6” includes Parkinson Disease, levodopa induced dyskinesia, non-levodopa induced dyskinesias, akinesias, motor disorders involving dysfunction of the striatum, drug addiction, eating disorders, cognitive disorders, schizophrenia, bipolar disorders, or depression.
Representative compounds of Formula (I) having the structure where Rb and Rc are hydrogen and R* represents R3, R4, R5, and R6 and when other than hydrogen are identified at the positions indicated in Table 1 below are:















COMPOUND TABLE 1





Cpd
X
Z
Ar
Re
R*
Salt
MSCalc
MSObs





















 















1
N
CH2
3-methylphenyl
cyclopropyl

TFA
373.494
374.3


4
N
C(O)
3-CF3phenyl
cyclopropyl

TFA
441.4489
442.3


5
N
CH2
3-chlorophenyl
cyclopropyl

TFA
393.9124
394.2


6
N
C(O)
4-
cyclopropyl

TFA
451.5413
452.2





methylsulfonylphenyl







7
N
C(O)
2,5-dichlorophenyl
cyclopropyl

TFA
442.341
442.2


8
N
C(O)
3,4-dichlorophenyl
cyclopropyl

TFA
442.341
442.2


9
N
C(O)
3-chloro-4-
cyclopropyl

TFA
437.922
438.2





methoxyphenyl







10
N
C(O)
3,5-dichlorophenyl
cyclopropyl

TFA
442.341
442.2


11
N
C(O)
3-chlorophenyl
cyclopropyl

TFA
407.896
408.2


12
N
C(O)
4-chlorophenyl
cyclopropyl

TFA
407.896
408.2


13
N
CH2
pyridin-3-yl
cyclopropyl

TFA
360.4555
361.3


14
N
C(O)
2,3-dichlorophenyl
cyclopropyl

TFA
442.341
442.2


15
N
C(O)
2-chlorophenyl
cyclopropyl

TFA
407.896
408.2


16
N
C(O)
3-methylphenyl
cyclopropyl

TFA
387.4775
388.3


17
N
CH2
pyridin-4-yl
cyclopropyl

TFA
360.4555
361.2


18
N
CH2
3-CF3phenyl
cyclopropyl

TFA
427.4654
428.3


19
N
CH2
4-chlorophenyl
cyclopropyl

TFA
393.9124
394.2


20
N
CH2
pyridin-2-yl
cyclopropyl

TFA
360.4555
361.2


21
N
CH2
3-chlorophenyl
4-

TFA
508.8406
509.2






bromophenyl






24
N
CH2
3-chlorophenyl
phenyl

TFA
429.9445
430.2


25
N
CH2
3-chlorophenyl
4-trifluoro-

TFA
513.942
514.3






methoxyphenyl






26
N
CH2
3-chlorophenyl
4-n-

TFA
472.0243
472.3






propylphenyl






27
N
C(O)
4-CF3phenyl
cyclopropyl

TFA
441.4489
442.3


28
N
CH2
2-chlorophenyl
cyclopropyl

TFA
393.9124
394.3


29
N
CH2
4-
cyclopropyl

TFA
437.5578
438.3





methylsulfonylphenyl







30
N
CH2
3-chlorophenyl
4-methyl-

TFA
443.9711
444.25






phenyl






31
N
CH2
3-chlorophenyl
4-methoxy-

TFA
459.9706
560.3






phenyl






32
N
CH2
3-chlorophenyl
2-methoxy-

TFA
459.9706
460.3






phenyl






33
N
CH2
2,5-dichlorophenyl
cyclopropyl

TFA
428.3575
428.2


34
N
CH2
4-CF3phenyl
cyclopropyl

TFA
427.4654
428.3


35
N
CH2
3-chlorophenyl
3-methoxy-

TFA
459.9706
460.3






phenyl






36
N
CH2
3-chlorophenyl
4-tert-butyl-

TFA
486.0509
486.3






phenyl






37
N
CH2
3-chlorophenyl
4-

TFA
488.0237
488.3






isopropoxy-










phenyl






38
N
CH2
3-chlorophenyl
4-

TFA
447.935
448.3






fluorophenyl






39
N
C(O)
2,5-dichlorophenyl
cyclopentyl

TFA
470.3942
470.3


40
N
CH2
2,5-dichlorophenyl
cyclopentyl

TFA
456.4107
456.2


41
N
C(O)
2,5-dichlorophenyl
phenyl

TFA
478.3731
478.2


42
N
CH2
2,5-dichlorophenyl
cyclopropyl-

TFA
442.3841
442.2






methyl






43
N
CH2
2,5-dichlorophenyl
phenyl

TFA
464.3896
464.2


45
N
CH2
2,5-dichlorophenyl
cyclopropyl
7-Br
TFA
507.2536
508.15


46
N
CH2
2,5-dichlorophenyl
cyclopropyl
6-Br
TFA
507.2536
508.1


47
N
CH2
2,5-dichlorophenyl
cyclopropyl
7-
TFA
458.3835
458.2







OCH3





48
N
CH2
2,3-dichlorophenyl
cyclopropyl

TFA
428.3575
428.2


49
N
CH2
2,4-dichlorophenyl
cyclopropyl

TFA
428.3575
428.2


50
N
CH2
2,6-dichlorophenyl
cyclopropyl

TFA
428.3575
428.2


51
N
CH2
3-chlorophenyl
3-

TFA
508.8406
509.9






bromophenyl






52
N
CH2
3-chlorophenyl
2-

TFA
508.8406
510






bromophenyl






53
N
CH2
3-chlorophenyl
pyridin-3-yl

TFA
430.9326
431


54
N
C(O)
2,5-dichlorothien-3-yl
cyclopropyl


448.3688
448.2


55
N
CH2
2,5-dichlorophenyl
cyclopropyl
7-F

446.348
446.2


56
N
CH2
2,5-dichlorophenyl
3-methoxy-


494.4156
494.2






phenyl






57
N
CH2
2,5-dichlorophenyl
4-methoxy-


494.4156
494.2






phenyl






58
N
CH2
2,5-dichlorophenyl
4-


489.3991
489.2






cyanophenyl






59
N
CH2
2,5-dichlorophenyl
cyclopropyl
6-CN

453.367
453.2


60
N
CH2
2,5-dichlorophenyl
2-methoxy-


494.4156
494.2






phenyl






61
N
CH2
2,5-dichlorophenyl
4-


482.3801
482.2






fluorophenyl






62
N
C(CCH3)
2,5-dichlorophenyl
cyclopropyl

TFA
442.3841
443.2


64
N
CH2
2,5-dichlorophenyl
4-


543.2857
544.15






bromophenyl






65
N
CH2
3-bromophenyl
cyclopropyl


438.3635
438.2/440.2


66
N
CH2
2,5-dichlorophenyl
3-


460.3994
461.2






methoxy-










propyl






67
N
C(O)
2-chloro-4-
cyclopropyl


485.9864
486.2





methylsulfonylphenyl







68
N
C(O)
3,6-dichloropyridin-
cyclopropyl


443.3291
443.2





2-yl







69
N
C(O)
benzofuran-3-yl
cyclopropyl

TFA
413.4717
414.30


70
N
CH2
3-chlorophenyl
pyridin-4-yl

TFA
430.9326
431.1


71
N
CH2
3-chlorophenyl
thia[1,3,4]

TFA
437.9484
438






diazol-2-yl






72
N
C(O)
3,4-dimethylphenyl
cyclopropyl

TFA
401.5041
402.1


73
N
CH2
3,4-dimethylphenyl
cyclopropyl

TFA
387.5206
388.1


74
N
C(O)
2,4-dichlorophenyl
cyclopropyl

TFA
442.341
442


75
N
C(O)
4-cyanophenyl
cyclopropyl

TFA
398.4604
399.1


76
N
CH2
4-cyanophenyl
cyclopropyl

TFA
384.4769
384.9


77
N
C(O)
4-ethylphenyl
cyclopropyl

TFA
401.5041
402.1


78
N
CH2
4-ethylphenyl
cyclopropyl

TFA
387.5206
388.1


79
N
CH2
3,4-dichlorophenyl
cyclopropyl

TFA
428.3575
427.9


80
N
C(O)
2,5-difluorophenyl
cyclopropyl

TFA
409.4319
410


81
N
CH2
2,5-difluorophenyl
cyclopropyl

TFA
395.4483
396


82
N
C(O)
naphth-2-yl
cyclopropyl

TFA
423.5096
424.1


83
N
CH2
naphth-2-yl
cyclopropyl

TFA
409.5261
410


84
N
C(O)
4-tert-butylphenyl
cyclopropyl

TFA
429.5573
430.3


85
N
C(O)
2-bromo-5-
cyclopropyl

TFA
482.373
482





methoxyphenyl







86
N
C(O)
3-bromo-4-
cyclopropyl

TFA
482.373
482





methoxyphenyl







87
N
C(O)
4-bromo-2-
cyclopropyl

TFA
486.7921
488





chlorophenyl







88
N
C(O)
5-fluoro-2-
cyclopropyl

TFA
405.468
406





methylphenyl







89
N
C(O)
3-bromo-4-
cyclopropyl

TFA
470.3374
472





fluorophenyl







90
N
C(O)
4-bromo-2-
cyclopropyl

TFA
470.3374
470





fluorophenyl







91
N
C(O)
5-bromo-2-
cyclopropyl

TFA
470.3374
470





fluorophenyl







92
N
C(O)
4-ethoxyphenyl
cyclopropyl

TFA
417.5035
418.1


93
N
C(O)
3-isopropylphenyl
cyclopropyl

TFA
415.5307
416.1


94
N
CH2
4-bromophenyl
cyclopropyl

TFA
438.3635
439.7


95
N
CH2
3-cyanophenyl
cyclopropyl

TFA
384.4769
385


96
N
CH2
4-fluorophenyl
cyclopropyl

TFA
377.4579
378


97
N
CH2
4-isopropylphenyl
cyclopropyl

TFA
401.5471
402.1


98
N
C(O)
5-methylisoxazol-3-
cyclopropyl


378.4277
379.3





yl







99
N
CH2
2,5-dichlorothien-3-yl
cyclopropyl

TFA
434.3853
434.1


100
N
CH2
benzofuran-3-yl
cyclopropyl


399.4882
400.30


101
N
CH2
3,6-dichloropyridin-
cyclopropyl

TFA
429.3456
429.3





2-yl







102
N
C(O)
cyclohexyl
cyclopropyl


379.4986
380.3


103
N
CH2
2,5-dichlorophenyl
cyclopropyl
5-CH3

456.4107
456.25







7-CH3





104
N
CH2
2,5-dichlorophenyl
cyclopropyl
6-CH3

456.4107
456.2







8-CH3





105
N
SO2
phenyl
cyclopropyl


409.5046
410.3


106
N
(CH2)2
phenyl
cyclopropyl


373.494
374.30


107
N
(CH2)2
4-chlorophenyl
cyclopropyl


407.939
408.30


108
N
(CH2)2
4-methoxyphenyl
cyclopropyl


403.52
404.35


109
N
CH2
cyclohexyl
cyclopropyl


365.515
366.4


110
N
CH2
2,5-dichlorophenyl
isobutyl

TFA
444.4
444


111
N
CH2
2,5-dichlorophenyl
isopropyl

TFA
430.3734
430.1


112
N
CH2
2,5-dichlorophenyl
2-ethylbutyl

TFA
472.4531
472.1


113
N
CH2
2,5-dichlorophenyl
4-

TFA
472.4531
472.2






methylpentan-










2-yl






114
N
CH2
2,5-dichlorophenyl
2,2-

TFA
458.4266
458.2






dimethylpropyl






115
N
CH2
2,5-dichlorophenyl
3-

TFA
458.4266
458.1






methylbutyl






116
N
CH2
2,5-dichlorophenyl
but-2-yl

TFA
444.4
444.1


117
N
CH2
2,5-dichlorophenyl
n-propyl

TFA
430.3734
430


118
N
CH2
2,5-dichlorophenyl
2-

TFA
446.3728
446






methoxyethyl






119
N
CH2
2,5-dichlorophenyl
cyclobutyl

TFA
442.3841
441.9


120
N
CH2
2,5-dichlorophenyl
cyclopropyl
5-Br

507.2536
508.1


121
N
C(O)
4-isopropylphenyl
cyclopropyl

TFA
415.5307
416.1


122
N
C(O)
4-bromo-2-
cyclopropyl

TFA
466.3736
468





methylphenyl







123
N
C(O)
2-chloro-3,6-
cyclopropyl

TFA
443.8769
444





difluorophenyl







124
N
SO2
4-OCF3phenyl
cyclopropyl


493.502
494.2


125
N
CH2
3-chlorophenyl
thiazol-2-yl

TFA
436.9603
437


126
N
CH2
3-chlorophenyl
pyrimidin-2-

TFA
431.9207
432






yl






127
N
CH2
3-chlorophenyl
pyrimidin-5-

TFA
431.9207
432






yl






128
N
SO2
cyclopentyl
cyclopropyl


401.5257
402.3


129
N
CH2
5-fluoro-2-
cyclopropyl

TFA
391.4844
391.9





methylphenyl







130
N
C(O)
2-chloro-5-
cyclopropyl

TFA
533.7925
533.94





iodophenyl







131
N
C(O)
5-bromo-2-
cyclopropyl

TFA
466.3736
468.2





methylphenyl







132
N
C(O)
4-OCF3phenyl
cyclopropyl

TFA
457.4483
458.04


134
N
CH2
2,5-dichlorophenyl
cyclopropyl
8-Br
TFA
507.2536
508.1


135
N
C(O)
indol-6-yl
cyclopropyl

TFA
412.487
413


136
N
C(O)
5-chloro-2-
cyclopropyl

TFA
421.9225
422.03





methylphenyl







137
N
C(O)
4-chloro-2-
cyclopropyl

TFA
421.9225
422.04





methylphenyl







138
N
C(O)
2,4-dimethylphenyl
cyclopropyl

TFA
401.5041
402.04


139
N
C(O)
2-chloro-5-
cyclopropyl

TFA
437.922
438





methoxyphenyl







140
N
C(O)
3-cyano-4-
cyclopropyl

TFA
456.5395
457.07





isopropoxyphenyl







141
N
C(O)
2-methoxy-5-
cyclopropyl

TFA
487.4743
488.04





trifluoromethoxy-










phenyl







142
N
C(O)
2,3,5-trichlorophenyl
cyclopropyl

TFA
476.7861
476.01


143
N
C(O)
2-chloro-6-
cyclopropyl

TFA
475.894
476





trifluoromethylphenyl







144
N
(CH2)2
2,5-dichlorophenyl
cyclopropyl


442.3841
443.25


145
N
CH2
2,5-dichlorophenyl
pyridin-3-yl


465.3777
466.25


146
N
C(O)
4-
cyclopropyl

TFA
421.9225
422





chloromethylphenyl







147
N
C(O)
indol-5-yl
cyclopropyl

TFA
412.487
413.1


148
N
C(O)
4-bromo-3-
cyclopropyl

TFA
466.3736
468





methylphenyl







149
N
CH2
2-chloro-4-
cyclopropyl

TFA
472.0028
472.2





methylsulfonylphenyl







151
N
CH2
2,5-dichlorophenyl
cyclopropyl
7-CN
TFA
453.367
453.2


152
N
C(O)
4-fluoro-3-
cyclopropyl

TFA
421.4674
422.1





methoxyphenyl







153
N
C(O)
3-bromo-4-
cyclopropyl

TFA
466.3736






methylphenyl







154
N
C(O)
4-chloro-3-
cyclopropyl

TFA
421.9225
422





methylphenyl







155
N
C(O)
4-fluoro-2-
cyclopropyl


405.468
406





methylphenyl







156
N
CH2
4-fluoro-2-
cyclopropyl

TFA
391.4844
392





methylphenyl







157
N
CH2
5-methylisoxazol-3-
cyclopropyl

TFA
364.4442
365.3





yl







158
N
CH2
2,5-dichlorophenyl
pyridin-3-yl
7-CN

490.3871
490.2


159
N
C(O)
4-chlorophenyl
cyclopropyl
6-CN

432.9054
433.25


160
N
C(O)
4-chlorophenyl
cyclopropyl
6-F

425.8864
426.20


161
N
SO2
phenyl
cyclopropyl
6-CN

434.5141
435.30


162
N
SO2
phenyl
pyridin-3-yl
H

446.5248
447.30


163
N
CH2
3-chlorophenyl
cyclopropyl
6-CN

418.9219
419.25


164
N
CH2
2,5-dichlorophenyl
tert-butyl

TFA
444.4
444


165
N
CH2
2,5-dichlorophenyl
3,3-

TFA
472.4531
472.1






dimethylbutyl






166
N
CH2
2,5-dichlorophenyl
2-ethoxyethyl

TFA
460.3994
460


167
N
CH2
2,5-dichlorophenyl
2-

TFA
474.426
474.1






isopropoxyethyl






168
N
CH2
2,5-dichlorophenyl
3-

TFA
474.426
474.1






ethoxypropyl






169
N
CH2
2,5-dichlorophenyl
cyclohexyl

TFA
470.4373
470.1


170
N
CH2
2,5-dichlorophenyl
tetrahydropyran-

TFA
472.4101
472






4-yl






171
N
CH2
2,5-dichlorophenyl
(R)-3-

TFA
446.3728
446






hydroxyprop-










2-yl






172
N
CH2
2,5-dichlorophenyl
pyrazin-2-yl

TFA
466.3658
466


173
N
CH2
2,5-dichlorophenyl
pyrimidin-4-

TFA
466.3658
466






yl






174
N
CH2
2,5-dichlorophenyl
pyridazin-3-

TFA
466.3658
466






yl






175
N
CH2
2,5-dichlorophenyl
pyridin-3-yl
6-F
TFA
483.3681
483.25


176
N
CH2
2,5-dichlorophenyl
1,2,4-triazin-

TFA
467.3538
467.1






3-yl






177
N
CH2
2,5-dichlorophenyl
5,6-dimethyl-

TFA
495.407
495.3






1,2,4-triazin-










3-yl






178
N
CH2
2,5-dichlorophenyl
3,4-

TFA
483.393
483






dimethylisoxazol-










5-yl






179
N
C(O)
3-bromo-2-
cyclopropyl

TFA
466.3736
468.1





methylphenyl







180
N
C(O)
3,5-difluorophenyl
cyclopropyl

TFA
409.4319
410.1


181
N
C(O)
4-bromophenyl
cyclopropyl

TFA
452.347
454


182
N
C(O)
3-cyanophenyl
cyclopropyl

TFA
398.4604
399.1


183
N
C(O)
3-bromophenyl
cyclopropyl

TFA
452.347
453.6


184
N
C(O)
2,6-dichlorophenyl
cyclopropyl

TFA
442.341
441.8


185
N
C(O)
2-bromo-4-methyl-
cyclopropyl

TFA
466.3736
468





phenyl







186
N
C(O)
4-cyano-2-fluoro-
cyclopropyl

TFA
416.4508
417.1





phenyl







187
N
C(O)
benzo[d][1,2,3]thiadiazol-
cyclopropyl

TFA
431.5134
432





5-yl







188
N
C(O)
2-chloro-5-fluoro-
cyclopropyl

TFA
425.8864
425.9





phenyl







189
N
C(O)
2,6-difluorophenyl-3-
cyclopropyl

TFA
423.4584
424.2





methylphenyl







190
N
C(O)
2-methoxy-5-
cyclopropyl

TFA
471.4749
471.9





trifluoromethylphenyl







191
N
C(O)
4-bromo-3-
cyclopropyl


520.345
521.8





trifluoromethylphenyl







192
N
CH2
3,5-difluorophenyl
cyclopropyl

TFA
395.4483
395.9


193
N
CH2
4-chloro-3-methyl-
cyclopropyl

TFA
407.939
407.9





phenyl







194
N
CH2
2,3-dimethylphenyl
cyclopropyl

TFA
387.5206
388.1


195
N
CH2
2-bromo-5-
cyclopropyl

TFA
468.3894
469.8





methoxyphenyl







196
N
CH2
3-bromo-4-
cyclopropyl

TFA
468.3894
469.7





methoxyphenyl







197
N
CH2
4-bromo-2-
cyclopropyl

TFA
472.8085
473.7





chlorophenyl







198
N
CH2
3-bromo-4-
cyclopropyl

TFA
456.3539
455.8





fluorophenyl







199
N
CH2
4-bromo-2-
cyclopropyl

TFA
456.3539
457.8





fluorophenyl







200
N
CH2
5-bromo-2-
cyclopropyl

TFA
456.3539
457.6





fluorophenyl







201
N
CH2
5-bromo-2-
cyclopropyl

TFA
452.39
453.7





methylphenyl







202
N
CH2
indol-6-yl
cyclopropyl

TFA
398.5034
398.9


203
N
CH2
5-chloro-2-methyl-
cyclopropyl

TFA
407.939
407.9





phenyl







204
N
CH2
4-chloro-2-methyl-
cyclopropyl

TFA
407.939
408.1





phenyl







205
N
CH2
2-chloro-3,6-
cyclopropyl

TFA
429.8934
429.9





difluorophenyl







206
N
CH2
2,4-dimethylphenyl
cyclopropyl

TFA
387.5206
388


207
N
CH2
2-chloro-5-
cyclopropyl

TFA
423.9384
423.9





methoxyphenyl







208
N
CH2
2-chloro-5-fluoro-
cyclopropyl

TFA
411.9029
411.9





phenyl







209
N
CH2
2-chloro-6-
cyclopropyl

TFA
461.9104
462.1





trifluoromethylphenyl







210
N
CH2
3-isopropylphenyl
cyclopropyl

TFA
401.5471
401.9


211
N
SO2
phenyl
cyclopropyl
6-F

427.4951
428.25


112
N
CH2
2,5-difluorophenyl
cyclopropyl
6-F

413.4388
414.30


213
N
CH2
2,5-dichlorophenyl
pyridin-4-yl

TFA
465.3777
465


214
N
CH2
2,5-difluorophenyl
cyclopropyl
6-F
TFA
431.4293
432







7-F





215
N
CH2
3-chloro-4-
cyclopropyl

TFA
423.9384
423.9





methoxyphenyl







216
N
CH2
4-bromo-3-
cyclopropyl

TFA
452.39
451.9





methylphenyl







217
N
CH2
4-bromo-2-
cyclopropyl

TFA
452.39
453.9





methylphenyl







218
N
CH2
2-chloro-5-
cyclopropyl

TFA
519.809
519.8





iodophenyl







219
N
CH2
2-methoxy-5-
cyclopropyl

TFA
473.4908
473.9





trifluoromethoxy-










phenyl







220
N
CH2
2,3,5-trichlorophenyl
cyclopropyl

TFA
462.8026
463.6


221
N
CH2
2-chloro-5-
cyclopropyl

TFA
412.891
413





fluoropyridin-3-yl







222
N
C(O)
4-chlorophenyl
pyridin-3-yl

TFA
444.9161
445.20


223
N
SO2
3-chlorophenyl
cyclopropyl
6-CN

468.9591
469.20


224
N
SO2
3-chlorophenyl
cyclopropyl
6-F

461.9402
462.20


225
N
SO2
2,5-dichlorophenyl
cyclopropyl
6-CN

503.4042
504.20


226
N
SO2
4-chlorophenyl
cyclopropyl
6-CN
TFA
468.9591
469.2


227
N
CH2
2,5-dichlorophenyl
pyridin-2-yl

TFA
465.3777
465


228
N
CH2
2,5-difluorophenyl
pyridin-3-yl

TFA
432.4685
433.1


229
N
C(O)
4-chloro-3-
pyridin-3-yl

TFA
458.9427
459.1





methylphenyl







230
N
CH2
2,5-dichlorophenyl
cyclopropyl
6-F
TFA
464.3384
464







7-F





231
N
C(O)
3-bromoo-4-
cyclopropyl
6-F
TFA
506.3184
507.8





fluorophenyl

7-F





232
N
CH2
2-bromo-5-
cyclopropyl

TFA
472.8085
473.8





chlorophenyl







233
N
CH2
5-chloro-2-
cyclopropyl

TFA
461.9104
462.1





trifluoromethylphenyl







234
N
CH2
2,6-difluoro-3-
cyclopropyl

TFA
409.4749
410.1





methylphenyl







235
N
CH2
2-methoxy-5-
cyclopropyl

TFA
457.4914
458.1





trifluoromethylphenyl







236
N
SO2
2-methylphenyl
cyclopropyl
6-CN

448.5406
449.30


237
N
SO2
3-fluorophenyl
cyclopropyl
6-CN
TFA
452.5045
453.1


238
N
SO2
3-methylphenyl
cyclopropyl
6-CN

448.5406
449.30


239
N
SO2
4-methylphenyl
cyclopropyl
6-CN

448.5406
449.30


240
N
SO2
2-fluorophenyl
cyclopropyl
6-CN
TFA
452.5045
453.2


241
N
CH2
2,5-dichlorophenyl
cyclopropyl
5-CN
TFA
453.367
453.25


242
N
C(O)
4-chlorophenyl
cyclopropyl
6-F

443.8769
444.2







7-F





243
N
SO2
2-chlorophenyl
cyclopropyl
6-CN
TFA
468.9591
469.2


244
N
SO2
4-fluorophenyl
cyclopropyl
6-CN
TFA
452.5045
453.3


245
N
CH2
3-chlorophenyl
cyclopropyl
6-F
TFA
429.8934
430.3







7-F





246
N
C(O)
4-bromo-3-
cyclopropyl
6-F

488.3279
489.25





fluorophenyl







247
N
CH2
2,5-dichlorophenyl
cyclopropyl
8-CN
TFA
453.367
453.2


248
N
SO2
2-bromophenyl
cyclopropyl
6-CN

513.4102
514.20


249
N
SO2
3-bromophenyl
cyclopropyl
6-CN

513.4102
514.10


250
N
SO2
4-bromophenyl
cyclopropyl
6-CN

513.4102
514.20


251
N
SO2
2-cyanophenyl
cyclopropyl
6-CN
TFA
459.5235
460.3


252
N
SO2
3-cyanophenyl
cyclopropyl
6-CN
TFA
459.5235
460.3


253
N
SO2
4-cyanophenyl
cyclopropyl
6-CN
TFA
459.5235
460.3


254
N
CH2
4-fluorophenyl
cyclopropyl
6-CN

402.4673
403.30


255
N
C(O)
3-bromo-4-
cyclopropyl
6-CN
TFA
495.3469
496.8





fluorophenyl







256
N
CH2
2,5-difluorophenyl
cyclopropyl
6-CN
TFA
420.4578
420.9


257
N
CH2
2,5-dichlorophenyl
isopropyl
6-CN
TFA
455.3829
455


258
N
CH2
2,5-difluorophenyl
isopropyl
6-CN
TFA
422.4737
423


259
N
C(O)
3-bromo-4-
isopropyl
6-CN
TFA
497.3628
498.8





fluorophenyl







260
N
CH2
2,5-difluorophenyl
cyclobutyl
6-CN
TFA
434.4844
435.1


261
N
C(O)
3-bromo-4-
cyclobutyl
6-CN
TFA
509.3735
508.8





fluorophenyl







264
N
C(O)
2,5-dichloropyridin-
cyclopropyl
6-CN

468.3386
468.2





4-yl







265
N
C(O)
4-chlorophenyl
cyclobutyl
6-CN

446.932
447.30


266
N
C(O)
4-chlorophenyl
isopropyl
6-CN

434.9213
435.30


268
N
CH2
2,5-dichlorophenyl
2,2,2-

TFA
470.3182
469.8






trifluoroethyl






269
N
SO2
3,5-dimethylisoxazol-
cyclopropyl
6-CN
TFA
453.5174
454





4-yl







270
N
SO2
2,5-dimethylphenyl
cyclopropyl
6-CN
TFA
462.5672
463.1


271
N
SO2
4-methoxyphenyl
cyclopropyl
6-CN
TFA
464.5401
465.1


272
N
SO2
2-methoxyphenyl
cyclopropyl
6-CN
TFA
464.5401
465.1


273
N
SO2
3-methoxyphenyl
cyclopropyl
6-CN
TFA
464.5401
465.1


274
N
SO2
5-chlorothien-2-yl
cyclopropyl
6-CN
TFA
474.9868
474.9


275
N
SO2
2,4,6-trimethylphenyl
cyclopropyl
6-CN
TFA
476.5938
477.1


276
N
SO2
2-methoxy-4-
cyclopropyl
6-CN
TFA
478.5667
479





methylphenyl







277
N
SO2
5-chloro-1,3-
cyclopropyl
6-CN
TFA
486.9777
487.1





dimethylpyrazol-4-yl







278
N
SO2
2,3,4-trifluorophenyl
cyclopropyl
6-CN
TFA
488.4855
489.1


279
N
SO2
4-tert-butylphenyl
cyclopropyl
6-CN
TFA
490.6204
491.1


280
N
SO2
4-chloro-2-5-
cyclopropyl
6-CN
TFA
497.0123
497.1





dimethylphenyl







281
N
SO2
3-chloro-5-fluoro-2-
cyclopropyl
6-CN
TFA
500.9762
501





methylphenyl







282
N
SO2
4-trifluoro-
cyclopropyl
6-CN
TFA
518.5115
519.3





methoxyphenyl







283
N
SO2
5-bromothien-2-yl
cyclopropyl
6-CN
TFA
519.4379
520.8


284
N
SO2
4-bromo-2-
cyclopropyl
6-CN
TFA
531.4006
532.7





fluorophenyl







285
N
SO2
2-chloro-5-trifluoro-
cyclopropyl
6-CN
TFA
536.9571
537





methylphenyl







286
N
SO2
4-bromo-2-
cyclopropyl
6-CN
TFA
547.8552
548.9





chlorophenyl







293
N
CH2
2,6-dichlorophenyl
cyclopropyl
6-CN
TFA
453.367
453.2


294
N
C(O)
4-chlorophenyl
cyclobutylmethyl
6-CN





295
N
C(O)
2,5-dichlorophenyl
cyclobutylmethyl
6-CN





296
N
C(O)
2,5-dichloropyridin-
cyclopropyl
6-CN
TFA
468.3386
468.2





3-yl







297
N
C(O)
4-chlorophenyl
oxetan-3-yl
6-CN

429.3456
429.2


299
N
CH2
2,5-dichlorophenyl
oxetan-3-yl
6-CN





302
N
C(O)
4-chlorophenyl
cyclopropyl
7-CN
TFA
432.9054
433.2


304
N
CH2
2,5-difluorophenyl
cyclopropyl
7-CN
TFA
420.4578
421.3


307
N
SO2
4-fluorophenyl
cyclopropyl
7-CN
TFA
452.5045
453.2


308
N
CH2
2,5-dichlorophenyl
pyridin-3-yl
6-CN
TFA
490.3871
490.2


310
N
CH2
2,5-difluorophenyl
pyridine-3-yl
6-CN

457.4779
458.3


 


312
N
CH2
2,5-difluorophenyl




6-CN





 


313
N
CH2
2,5-dichlorophenyl




6-CN





 


319
N
CH2
2,5-difluorophenyl




6-CN





 


320
N
SO2
4-ethylphenyl
cyclopropyl
6-CN
TFA
462.5672
462.9


 


321
N
CH2
2,5-difluorophenyl




6-CN





 


322
N
SO2
2-fluoro-5-methyl-
cyclopropyl
6-CN
TFA
466.5311
467.2





phenyl







 


323
N
C(O)
4-chlorophenyl




6-CN





 


324
N
CH2
2,5-difluorophenyl




6-CN





 


325
N
SO2
3,4-difluorophenyl
cyclopropyl
6-CN
TFA
470.495
470.9


 


326
N
C(O)
4-chlorophenyl




6-CN





 


327
N
C(O)
4-chlorophenyl
pyridin-3-yl
6-CN

469.9256
470.2


328
N
SO2
2,5-dimethoxyphenyl
cyclopropyl
6-CN
TFA
494.566
495.1


329
N
SO2
2-chloro-4-trifluoro-
cyclopropyl
6-CN
TFA
536.9571
537





methylphenyl







332
N
CH2
2,5-difluorophenyl
6-
6-CN
TFA
487.5039
488.30






methoxypyridin-










3-yl






333
N
CH2
2,5-dichlorophenyl
1-
6-CN
TFA
481.3771
481.2






oxocyclobut-










3-yl






334
N
CH2
2,5-difluorophenyl
1-
6-CN
TFA
448.4679
449.3






oxocyclobut-










3-yl






335
N
CH2
2,5-dichlorophenyl
cyclobutyl
6-CN
TFA
467.3936
467


336
N
C(O)
4-chlorophenyl
2-fluoroethyl
6-CN
TFA
438.8852
438.8


337
N
CH2
2,5-dichlorophenyl
2,2-
6-CN

477.3372
476.8






difluoroethyl






338
N
C(O)
4-chlorophenyl
2,2-
6-CN

456.8757
457.1






difluoroethyl






339
N
CH2
2,5-dichlorophenyl
isoxazol-3-yl
6-CN
TFA
480.3493
479.8


340
N
C(O)
4-chlorophenyl
isoxazol-3-yl
6-CN
TFA
459.8877
460


341
N
SO2
3-cyano-4-fluoro-
cyclopropyl
6-CN
TFA
477.514
478





phenyl







342
N
CH2
2,4-difluorophenyl
cyclopropyl
6-CN
TFA
420.4578
421.3


343
N
SO2
5-chloro-2-
cyclopropyl
6-CN
TFA
498.9851
499





methoxyphenyl







344
N
SO2
5-chloro-2,4-
cyclopropyl
6-CN
TFA
504.9401
505





difluorophenyl







345
N
SO2
5-bromo-6-
cyclopropyl
6-CN
TFA
548.8433
549.9





chloropyridin-3-yl







346
N
SO2
4-bromo-2,5-
cyclopropyl
6-CN
TFA
549.3911
550.8





difluorophenyl







347
N
CH2
2,5-dichlorophenyl
2-fluoroethyl
6-CN
TFA
459.3467
459


348
N
CH2
2,5-difluorophenyl
2-fluoroethyl
6-CN
TFA
426.4376
426.9


349
N
CH2
2,5-difluorophenyl
2,2-
6-CN
TFA
444.428
444.9






difluoroethyl






352
N
CH2
2,4,5-trifluorophenyl
cyclopropyl
6-CN
TFA
438.4482
439.2


357
N
SO2
2,4-dimethoxyphenyl
cyclopropyl
6-CN

494.566
494.9


367
N
CH2
5-chloro-2-fluoro-
cyclopropyl
6-CN
TFA
436.9124
437.2





phenyl







371
N
CH2
2,4-difluorophenyl
pyridin-3-yl
6-CN
TFA
457.4779
458.30


373
N
CH2
2,4-difluorophenyl
cyclopropyl
7-CN
TFA
420.4578
421.25


374
N
CH2
5-chloro-2-fluoro-
cyclopropyl
7-CN
TFA
436.9124
437.20





phenyl







375
N
CH2
2,4,5-trifluorophenyl
cyclopropyl
7-CN
TFA
438.4482
439.30


376
N
CH2
2,4,5-trifluorophenyl
pyridin-3-yl
6-CN
TFA
475.4684
476.30


377
N
C(O)
4-chloro-2-fluoro-
pyridin-3-yl
6-CN
TFA
487.9161
488.20





phenyl







378
N
CH2
2,5-difluorophenyl
isoxazol-3-yl
6-CN

447.4401
448


399
N
CH2
2,5-difluorophenyl
3,3,3-
6-CN
TFA
476.4451
477.3






trifluoropropyl






400
N
CH2
2,4-difluorophenyl
3,3,3-
6-CN
TFA
476.4451
477.2






trifluoropropyl






401
N
CH2
2,5-difluorophenyl
cyclopropyl
6-Br
TFA
474.3444
474.2/476.2


402
N
CH2
5-chloro-2-
cyclopropyl
6-Br
TFA
490.799
490.1/492.1





fluorophenyl







403
N
CH2
2,4-difluorophenyl
cyclopropyl
6-Br
TFA
474.3444
474.2/476.2


404
N
CH2
2,4-difluorophenyl
2,2-
6-CN

444.428
445.2






difluoroethyl






407
N
CH2
2,4-difluorophenyl
2-
6-CN
TFA
438.4731
439.3






methoxyethyl






408
CH
CH2
5-methyloxazol-2-yl
cyclopropyl

TFA
363.4561
364.3


409
CH
CH2
3-methyl-[1,2,4]-
cyclopropyl

TFA
364.4442
365.3





oxadiazol-5-yl







410
CH
CH2
phenyl
phenyl

TFA
394.5114
395.1


411
CH
O
phenyl
cyclopropyl


360.4521
361.30


412
CH
NH
4-chlorophenyl
cyclopropyl

TFA
393.9124
394.3


414
CH
CH2
2,4-difluorophenyl
pyridin-3-yl
6-CN
TFA
456.4899
457.30


415
CH
CH2
2,4-difluorophenyl
cyclopropyl
6-CN
TFA
419.4697
420.3


462
CH
CH2
2,4-difluorophenyl
isopropyl
6-CN

421.4856
422.3


463
CH
CH2
2,4-difluorophenyl
cyclobutyl
6-CN

433.4963
434.3


466
CH
O
4-chloro-2-
cyclopropyl
6-CN
TFA
437.8972
438.20





fluorophenyl







467
CH
O
4-chloro-2-
isopropyl
6-CN
TFA
439.913
440.20





fluorophenyl







469
CH
O
2,4-difluorophenyl
cyclopropyl
6-CN
TFA
421.4425
422.20


470
CH
C(O)
5-chloro-2-
cyclopropyl
6-CN
TFA
449.9078
450.20





fluorophenyl







471
CH
CHF
2,5-difluorophenyl
cyclopropyl
6-CN
TFA
437.4602
438.3


 


472
CH
CH2




cyclopropyl
6-CN
TFA
418.4667
419.2


 


473
CH
C(O)
2,5-difluorophenyl
cyclopropyl
6-CN
TFA
433.4532
434.2


475
CH
O
4-chloro-2-
cyclopropyl
7-CN
TFA
437.8972
438.20





fluorophenyl







479
CH
CH2
2,4-difluorophenyl
cyclopropyl
6-F
TFA
430.4412
431.25







7-F





480
CH
CH2
2,4-difluorophenyl
cyclopropyl
6-F
TFA
412.4507
413.30


481
CH
CHF
2,4-difluorophenyl
cyclopropyl
6-CN
TFA
437.4602
438.20


482
CH
CHF
2,4-difluorophenyl
isopropyl
6-CN
TFA
439.4761
440.30


483
CH
CHF
2,5-difluorophenyl
cyclobutyl
6-CN
TFA
451.4868
452.3


485
CH
CHF
2,5-difluorophenyl
cyclopropyl
7-CN
TFA
437.4602
438.3


486
CH
CHF
2,5-difluorophenyl
isopropyl
6-CN
TFA
439.4761
440.3


488
CH
CHF
2,4-difluorophenyl
cyclopropyl
7-CN
TFA
437.4602
438.30


492
CH
(R)—CHF
2,4-difluorophenyl
cyclopropyl
6-CN
TFA
437.4602
438.20


496
CH
CH2
2,4-difluorophenyl
cyclopropyl
6-Br
TFA
473.3563
473.3/475.2


497
CH
CH2
2,4-difluorophenyl
3,3,3-
6-CN
TFA
475.457
476.3






trifluoropropyl






499
CH
CHF
2,5-difluorophenyl
3,3,3-
6-CN
TFA
493.4474
494.3






trifluoropropyl






500
CH
O
2,4-difluorophenyl
3,3,3-
6-CN
TFA
477.4298
478.2






trifluoropropyl






501
CH
CHF
2,5-difluorophenyl
cyclopropyl
6-Br
TFA
491.3468
491.2/493.2


502
CH
O
2,4-difluorophenyl
cyclopropyl
6-Br
TFA
475.3291
475.2/477.2


504
CH
(S)—CHF
2,5-difluorophenyl
isopropyl
6-CN

439.4761
440.1


505
CH
(R)—CHF
2,5-difluorophenyl
isopropyl
6-CN

439.4761
440.1


506
CH
(S)—CHF
2,4-difluorophenyl
cyclopropyl
6-CN

437.4602
438.2


507
CH
(R)—CHF
2,4-difluorophenyl
cyclopropyl
6-CN

437.4602
438.1


508
CH
(S)—CHF
2,4-difluorophenyl
isopropyl
6-CN

439.4761
440.1


509
CH
(R)—CHF
2,4-difluorophenyl
isopropyl
6-CN

439.4761
440


510
CH
(S)—CHF
2,4-difluorophenyl
cyclopropyl
7-CN

437.4602
438.1


511
CH
(R)—CHF
2,4-difluorophenyl
cyclopropyl
7-CN

437.4602
438.1


512
CH
CHF
2,4-difluorophenyl
2,2-
6-CN

461.4304
462.2






difluoroethyl






513
CH
CH2
2,4-difluorophenyl
2,2-
6-CN

443.4399
444.2






difluoroethyl






514
CH
O
2,4-difluorophenyl
2,2-
6-CN

445.4128
446.2






difluoroethyl






515
CH
(S)—CHF
2,4-difluorophenyl
cyclopropyl
6-CN
TFA
437.4602
438.3


519
CH
CH2
2,4-difluorophenyl
2-
6-CN

437.485
438.3






methoxyethyl






522
CH
O
2,4-difluorophenyl
2-
6-CN

439.4578
440.25






methoxyethyl 






523
CH
CHF
2,4-difluorophenyl
2-
6-CN

455.4755
456.3






methoxyethyl






 


527
CH
CH2




cyclopropyl
6-CN

434.9213
435.2


 


530
CH
CH2




cyclopropyl
6-CN

418.4667
419.3


 


534
CH
CF2
5-chloro-2-
cyclopropyl
6-CN

471.9052
472.2





fluorophenyl







 


536
CH
CH2




cyclopropyl
6-CN

434.9213
435.3


 


546
CH
CF2
2,4-difluorophenyl
cyclopropyl
6-CN

455.4507
456.2


548
CH
CF2
2,5-difluorophenyl
cyclopropyl
6-CN

455.4507
456.3


627
CH
O
2-fluoro-4-
isopropyl

HCl
438.373
439.8





chlorophenyl







628
CH
C(O)
3-isopropylamino-5-
isopropyl
7-CN

491.027
491.0





chlorophenyl







 













 















3
N
CH2
3-methylphenyl
cyclopropyl


374.482
375.3


23
N
CH2
3-chlorophenyl
phenyl

TFA
430.9326
431.2


63
N
CH2
2,5-dichlorophenyl
cyclopropyl


429.3456
429.2


150
N
CH2
2,5-dichlorophenyl
pyridin-3-yl

TFA
466.3658
466.2


 













 















133
N
CH2
2,5-
cyclopropyl

TFA
429.3456
429.2





dichlorophenyl







262
N
C(O)
4-chlorophenyl
cyclopropyl


408.884
409.25


263
N
CH2
2,5-difluorophenyl
cyclopropyl

TFA
396.4364
397.3


267
N
C(O)
4-trifluoromethyl-
cyclopropyl

TFA
442.437
443.3





phenyl







287
N
SO2
4-fluorophenyl
cyclopropyl

TFA
428.4832
429.3


288
N
C(O)
4-difluoromethyl-
cyclopropyl

TFA
424.4465
425.3





phenyl







289
N
CH2
5-chloro-2-
cyclopropyl

TFA
460.9074
461.3





difluoro-










methoxyphenyl







290
N
CH2
4-fluorophenyl
cyclopropyl

TFA
378.4459
379.3


298
N
CH2
2,6-
cyclopropyl

TFA
429.3456
429.2





dichlorophenyl







300
N
CH2
5-chloro-2-
cyclopropyl

TFA
452.9796
453.3





propoxy-phenyl







301
N
SO2
4-trifluoromethyl-
cyclopropyl

TFA
478.4907
479.3





phenyl







305
N
CH2
2-methoxy-5-tert-
cyclopropyl

TFA
446.5878
447.4





butylphenyl







306
N
CH2
2,5-
cyclopropyl

TFA
388.5086
389.3





dimethylphenyl







311
N
CH2
2,6-difluorophenyl
cyclopropyl

TFA
396.4364
397.3


314
N
CH2
3-chloro-4-fluoro-
cyclopropyl

TFA
412.891
413.3





phenyl







315
N
CH2
2,4,5-
cyclopropyl

TFA
414.4268
415.3





trifluorophenyl







316
N
CH2
4-chloro-3-fluoro-
cyclopropyl

TFA
412.891
413.3





phenyl







317
N
CH2
3,4-difluorophenyl
cyclopropyl

TFA
396.4364
397.3


318
N
CH2
2,4-difluorophenyl
cyclopropyl

TFA
396.4364
397.3


330
N
CH2
5-chloro-2-fluoro-
cyclopropyl

TFA
412.891
413.3





phenyl







331
N
CH2
2-chloro-5-fluoro-
cyclopropyl

TFA
412.891
413.2





phenyl







350
N
CH2
5-chloro-2-fluoro-
cyclopropyl
8-Cl
TFA
447.336
448.20





phenyl







351
N
CH2
2,5-difluorophenyl
cyclopropyl
8-Cl
TFA
430.8814
431.20


353
N
CH2
2,4-difluorophenyl
cyclopropyl
8-Cl
TFA
430.8814
431.20


354
N
CH2
2,4,5-
cyclopropyl
8-Cl
TFA
448.8719
449.20





trifluorophenyl







358
N
C(O)
4-chloro-3-fluoro-
cyclopropyl

TFA
426.8745
427.2





phenyl







359
N
C(O)
3,4-difluorophenyl
cyclopropyl

TFA
410.4199
411.3


360
N
C(O)
3-chloro-4-fluoro-
cyclopropyl

TFA
426.8745
427.2





phenyl







361
N
C(O)
4-chloro-2-fluoro-
cyclopropyl

TFA
426.8745
427.2





phenyl







362
N
C(O)
2-chloro-4-fluoro-
cyclopropyl

TFA
426.8745
427.2





phenyl







365
N
CH2
2,4-difluorophenyl
2,2-

TFA
420.4066
421.20






difluoroethyl






366
N
CH2
5-chloro-2-fluoro-
2,2-

TFA
436.8612
437.20





phenyl
difluoroethyl






368
N
C(O)
4-chloro-2-fluoro-
2,2-

TFA
450.8447
451.20





phenyl
difluoroethyl






370
N
CH2
2,4,5-
2,2-

TFA
438.3971
439.20





trifluorophenyl
difluoroethyl






372
N
C(O)
4-chloro-2-
cyclopropyl

TFA
424.8835
425.2





hydroxy-phenyl







380
N
C(O)
4-chloro-2-
cyclopropyl

TFA
438.91
439.2





methoxy-phenyl







381
N
C(O)
2-fluoro-4-
cyclopropyl

TFA
460.4274
461.3





trifluoro-










methylphenyl







382
N
C(O)
3-fluoro-5-
cyclopropyl

TFA
427.8625
428.3





chloropyridin-2-yl







383
N
C(O)
2-fluoro-4-methyl-
cyclopropyl

TFA
406.456
407.3





phenyl







384
N
C(O)
2-fluoro-4-
cyclopropyl

TFA
422.4554
423.2





methoxy-phenyl







385
N
C(O)
4-chloro-2-
cyclopropyl

TFA
422.9106
423.3





methyl-phenyl







386
N
C(O)
4-cyano-2-fluoro-
cyclopropyl

TFA
417.4389
418.3





phenyl







387
N
C(O)
4-fluoro-2-
cyclopropyl

TFA
408.4288
409.3





hydoxy-phenyl







388
N
C(O)
4-chloro-2,6-
cyclopropyl

TFA
444.865
445.2





difluorophenyl







389
N
C(O)
3-fluoropyridin-2-
cyclopropyl

TFA
393.4175
394.3





yl







391
N
C(O)
4-chloro-2-
cyclopropyl

TFA
476.882
477.3





trifluoro-










methylphenyl







393
N
C(O)
2,4,6-
cyclopropyl

TFA
428.4104
429.3





trifluorophenyl







394
N
C(O)
2,4-difluoro-6-
cyclopropyl

TFA
426.4193
427.3





hydroxyphenyl







395
N
CH2
2,4-difluorophenyl
cyclopropyl
7-CH3
TFA
410.463
411.3


396
N
CH2
5-chloro-2-
cyclopropyl
7-CH3
TFA
426.9176
427.3





fluorophenyl







405
N
CH2
2,4-difluorophenyl
cyclopropyl
7-Br
TFA
475.3325
475.2/477.2


406
N
CH2
2,4-difluorophenyl
2-

TFA
414.4517
415.3






methoxyethyl






413
CH
CH2
2,4-difluorophenyl
cyclopropyl

TFA
395.4483
396.3


416
CH
O
2-chlorophenyl
cyclopropyl

TFA
395.8853
396.20


417
CH
O
2-fluorophenyl
cyclopropyl

TFA
379.4307
380.25


418
CH
O
3-fluorophenyl
cyclopropyl

TFA
379.4307
380.30


419
CH
C(O)
4-fluorophenyl
cyclopropyl

TFA
391.4414
392.30


420
CH
CH2
4-fluorophenyl
cyclopropyl

TFA
377.4579
378.30


421
CH
C(O)
3,4-difluorophenyl
cyclopropyl

TFA
409.4319
410.30


422
CH
SO2
4-fluorophenyl
cyclopropyl

TFA
427.4951
428.30


423
CH
CH2
4-chlorophenyl
cyclopropyl

TFA
393.9124
394.30


424
CH
O
4-chlorophenyl
cyclopropyl

TFA
395.8853
396.30


425
CH
O
3-chlorophenyl
cyclopropyl

TFA
395.8853
396.25


428
CH
CH2
2,4-difluorophenyl
cyclopropyl
7-CH3
TFA
409.47
410.3


429
CH
C(O)
4-chlorophenyl
cyclopropyl

TFA
407.896
408.30


430
CH
O
2,5-difluorophenyl
cyclopropyl

TFA
397.4211
398.30


431
CH
O
2,4,6-
cyclopropyl

TFA
415.4116
416.30





trifluorophenyl







432
CH
O
4-fluorophenyl
cyclopropyl

TFA
379.4307
380.30


433
CH
O
2,4-difluorophenyl
cyclopropyl

TFA
397.4211
398.20


434
CH
C(O)
2-fluorophenyl
cyclopropyl

TFA
391.4414
392.25


435
CH
C(O)
2,5-difluorophenyl
cyclopropyl

TFA
409.4319
410.25


436
CH
O
5-chloro-2-
cyclopropyl

TFA
413.8757
414.20





fluorophenyl







437
CH
O
phenyl
cyclopropyl

TFA
361.4402
362.25


438
CH
C(O)
2,4-difluorophenyl
cyclopropyl

TFA
409.4319
410.30


440
CH
C(O)
2,5-difluorophenyl
cyclopropyl
7-CH3
TFA
423.4584
424.3


441
CH
O
2,4-difluorophenyl
cyclopropyl
7-CH3
TFA
411.4477
412.3


442
CH
O
4-chloro-2-
cyclopropyl

TFA
413.8757
414.20





fluorophenyl







443
CH
C(O)
2,4,6-
cyclopropyl

TFA
427.4223
428.25





trifluorophenyl







444
CH
C(O)
4-chloro-2,6-
cyclopropyl

TFA
443.8769
444.20





difluorophenyl







445
CH
CH2
2,5-difluorophenyl
cyclopropyl

TFA
395.4483
396.3


446
CH
C(O)
4-chloro-2-
cyclopropyl

TFA
425.8864
426.20





fluorophenyl







447
CH
C(O)
5-chloro-2-
cyclopropyl

TFA
425.8864
426.20





fluorophenyl







448
CH
CHF
2,4-difluorophenyl
cyclopropyl


413.4388
414.30


449
CH
CHF
4-fluorophenyl
cyclopropyl


395.4483
396.30


450
CH
CF—
2,4-difluorophenyl
cyclopropyl

TFA






(CH3)








451
CH
C(O)
morphiolin-4-yl
cyclopropyl

TFA




452
CH
CH2
2,4-difluorophenyl
cyclopropyl

TFA
396.4364
397.2


453
CH
CHF
5-chloro-2-
cyclopropyl


429.8934
430.25





fluorophenyl







454
CH
CHF
2,5-difluorophenyl
cyclopropyl
7-CH3

427.4654
428.30


455
CH
C(O)
3-
cyclopropyl

TFA







methoxyazetidin-










1-yl







456
CH
C(O)
4-
cyclopropyl

TFA







methylpiperazin-










1-yl







457
CH
C(O)
pyrrolidin-1-yl
cyclopropyl

TFA




458
CH
C(O)
piperidin-1-yl
cyclopropyl

TFA




459
CH
NH
2,4-difluorophenyl
cyclopropyl

TFA
396.4364
397.3


460
CH
C(CH3)F
5-chloro-2-
cyclopropyl


443.92
444.20





fluorophenyl







461
CH
CHF
2,5-difluorophenyl
cyclopropyl


413.4388
414.20


464
CH
CH2
2,4-difluorophenyl
cyclopropyl
7-Br
TFA
474.3444
474.2/476.2


465
CH
(S)—CHF
2,5-difluorophenyl
cyclopropyl
7-CH3

427.4654
428.3


468
CH
O
4-chloro-2-
cyclopropyl
7-CH3
TFA
427.9023
428.20





fluorophenyl







 


474
CH
CH2




cyclopropyl
7-CH3
TFA
408.4719
409.3


 


476
CH
H2
2,4-difluorophenyl
cyclopropyl
7-CN

420.4578
421.25


477
CH
O
2,4-difluorophenyl
cyclopropyl
7-Cl
TFA
431.8662
432.2


478
CH
(R)—CHF
2,5-difluorophenyl
cyclopropyl
7-CH3
HCl
427.4654
427.9


484
CH
CH2
2,4-difluorophenyl
cyclopropyl
7-OCH3
TFA
425.4743
426.3


487
CH
CHF
2,5-difluorophenyl
cyclopropyl
8-Cl
TFA
447.8839
448.2


489
CH
CHF
2,4-difluorophenyl
cyclopropyl
7-CH3
TFA
427.4654
428.30


490
CH
CHF
2,4-difluorophenyl
cyclopropyl
7-Cl
TFA
447.8839
448.2


491
CH
CH2
2,4-difluorophenyl
cyclopropyl
7-OH
TFA
411.4477
412.3


493
CH
CHF
2,4-difluorophenyl
cyclopropyl
5-CH3
TFA
427.4654
428.30


494
CH
CH2
2,4-difluorophenyl
cyclopropyl
5-CH3
TFA
409.4749
410.30


495
CH
O
2,4-difluorophenyl
cyclopropyl
5-CH3
TFA
411.4477
412.30


498
CH
(R)—CHF
2,4-difluorophenyl
cyclopropyl
7-CH3
TFA
427.4654
428.30


503
CH
(S)—CHF
2,4-difluorophenyl
cyclopropyl
7-CH3
TFA
427.4654
428.30


516
CH
CHF
2,4-difluorophenyl
cyclopropyl
7-Br
TFA
492.3348
492.2/494.2


517
CH
(S)—CHF
2,4-difluorophenyl
cyclopropyl
5-CH3
TFA
427.4654
428.3


518
CH
(S)—CHF
2,4-difluorophenyl
cyclopropyl

TFA
413.4388
414.3


520
CH
CH2
2,4-difluorophenyl
2-

TFA
413.4636
414.3






methoxyethyl,






521
CH
CHF
2,4-difluorophenyl
2-

TFA
431.4541
432.2






methoxyethyl,






524
CH
(R)—CHF
2,4-difluorophenyl
cyclopropyl
7-Cl
TFA
447.8839
448.2


525
CH
(S)—CHF
2,4-difluorophenyl
cyclopropyl
7-Cl
TFA
447.8839
448.2


526
CH
O
2,4-difluorophenyl
2-

TFA
415.4364
416.3






methoxyethyl






 


528
CH
CH2




cyclopropyl
5-CH3

408.4719
409.3


 


529
CH
CH2




cyclopropyl
5-CH3

424.9265
425.2


 


531
CH
CH2




cyclopropyl


394.4453
395.3


 


532
CH
CH2




cyclopropyl
5-CH3

408.4719
409.3


 


533
CH
CH2




cyclopropyl


410.8999
411.2


 


535
CH
CF2
5-chloro-2-
cyclopropyl
7-CH3

461.9104
462.2





fluorophenyl







537
CH
CF2
5-chloro-2-
cyclopropyl
5-CH3

461.9104
462.2





fluorophenyl







 


538
CH
CH2




cyclopropyl
5-CH3

424.9265
425.2


 


539
CH
CH2




cyclopropyl
7-CH3

424.9265
425.3


 


540
CH
CF2
5-chloro-2-
cyclopropyl


447.8839
448.2





fluorophenyl







541
CH
CF2
2,5-difluorophenyl
cyclopropyl


431.4293
432.2


542
CH
CF2
2,5-difluorophenyl
cyclopropyl
7-CH3

445.4558
446.3


543
CH
(R)—CHF
2,4-difluorophenyl
cyclopropyl
7-CH3





544
CH
CF2
2,4-difluorophenyl
cyclopropyl
5-CH3

445.4558
446.2


545
CH
CF2
2,5-difluorophenyl
cyclopropyl
5-CH3

445.4558
446.3


547
CH
CF2
2,4-difluorophenyl
cyclopropyl


431.4293
432.2


549
CH
(S)—CHF
2,4-difluorophenyl
cyclopropyl
7-CN

438.178
439.3


550
CH
(R)—CHF
2,4-difluorophenyl
cyclopropyl
7-CN

438.178
439.2


553
CH
O
pyridin-3-yl
cyclopropyl


362.1855
363.2


554
CH
O
4-methoxyphenyl
cyclopropyl


391.2008
392.3


555
CH
O
pyridin-2-yl
cyclopropyl


362.1855
363.2


556
CH
O
pyridin-4-yl
cyclopropyl


362.1855
363.2


557
CH
C(O)
2-methoxyphenyl
cyclopropyl

TFA
403.2008
404.3


558
CH
O
4-cyanophenyl
cyclopropyl


386.1855
387.2


559
CH
C(O)
2-chlorophenyl
cyclopropyl

TFA
407.1513
408.2


560
CH
O
3-methoxyphenyl
cyclopropyl

TFA
391.2008
392.3


561
CH
O
2-methoxyphenyl
cyclopropyl

TFA
391.2008
392.3


562
CH
C(O)
phenyl
cyclopropyl


373.1903
374.2


563
CH
C(O)
2,3-difluorophenyl
cyclopropyl

TFA
409.1714
410.2


564
CH
C(O)
3-chlorophenyl
cyclopropyl


407.1513
408.2


565
CH
O
3-cyanophenyl
cyclopropyl


386.1855
387.3


566
CH
C(O)
3-methoxyphenyl
cyclopropyl


403.2008
404.3


567
CH
C(O)
2-mehylphenyl
cyclopropyl

TFA
387.2059
388.3


568
CH
C(O)
2,6-difluorophenyl
cyclopropyl

TFA
409.1714
410.3


569
CH
C(O)
2-chloro-5-
cyclopropyl

TFA
425.1419
426.2





fluorophenyl







570
CH
C(O)
3-fluorophenyl
cyclopropyl

TFA
391.1808
392.3


571
CH
C(O)
2,3-difluoro-6-
cyclopropyl

TFA
443.877
444.2





chlorophenyl







572
CH
C(O)
2-fluoro-4-
cyclopropyl

TFA
409.457
410.2





methoxyphenyl







573
CH
C(O)
3-fluoro-2-
cyclopropyl

HCl
425.886
426.2





chlorophenyl







574
CH
C(O)
5-chlorothien-3-yl
cyclopropyl

HCl
413.924
414.2


575
CH
C(O)
thien-2-yl
cyclopropyl

TFA
379.479
380.2


576
CH
O
2-cyanophenyl
cyclopropyl


386.449
387.2


577
CH
C(O)
2-fluoro-6-
cyclopropyl


425.886
426.2





chlorophenyl







578
CH
C(O)
3-cyanophenyl
cyclopropyl

TFA
398.460
399.3


579
CH
(S)—CHF
2,4-difluorophenyl
cyclopropyl
7-
TFA
484.540
485.3







C(O)N(CH3)2





580
CH
(R)—CHF
2,4-difluorophenyl
cyclopropyl
7-
TFA
484.540
485.3







C(O)N(CH3)2





581
CH
(S)—CHF
2,4-difluorophenyl
cyclopropyl
5-
TFA
526.5734
527.3







C(O)morpholin-










4-yl





582
CH
(R)—CHF
2,4-difluorophenyl
cyclopropyl
5-
TFA
526.5734
527.3







C(O)morpholin-










4-yl





583
CH
C(O)
2-
cyclopropyl

TFA
419.543
420.3





thiomethoxyphenyl







584
CH
O
4-(1-
cyclopropyl

TFA
403.497
404.2





oxoethyl)phenyl







585
CH
O
4-(1-
cyclopropyl

TFA
405.5128
406.3





hydroxyethyl)










phenyl







586
CH
C(O)
thien-3-yl
cyclopropyl

TFA
379.479
380.2


587
CH
C(O)
2-bromophenyl
cyclopropyl

TFA
451.367
452.1


588
CH
C(O)
2-bromopyrid-3-yl
cyclopropyl

TFA
453.355
453.2/455.2


589
CH
C(O)
2-fluoro-5-
cyclopropyl

TFA
416.451
417.3





cyanophenyl







590
CH
O
4-(N,N-
cyclopropyl

TFA
432.554
433.3





dimethylamide)










phenyl







591
CH
(R)—CHF
2,4-difluorophenyl
cyclopropyl
7-
TFA
496.527
497.3







C(O)azetidin-










1-yl





592
CH
(R)—CHF
2,4-difluorophenyl
cyclopropyl
7-C(O)(4-

514.5178
515.3







fluoroazetidin-










1-yl





593
CH
(S)—CHF
2,4-difluorophenyl
cyclopropyl
7-
TFA
496.527
497.3







C(O)azetidin-










1-yl





594
CH
CH2
2,4-difluorophenyl
cyclopropyl
7-Cl

429.893
430.3


595
CH
C(O)
6-fluoro-3-
cyclopropyl

TFA
437.553
438.3





thiomethyoxy










phenyl







597
CH
C(O)
6-chloro-3-
cyclopropyl
7-Cl

467.3505
467.2





cyanophenyl







598
CH
C(O)
2-(N,N-
cyclopropyl
7-

540.616
541.3





dimethylamide)-5-

C(O)N(CH3)2








cyanophenyl







599
CH
O
2,4-difluorophenyl
cyclopropyl
7-

468.499
469.3







C(O)N(CH3)2





602
CH
O
4-
cyclopropyl

TFA
407.552
408.3





thiomethyoxy










phenyl







603
CH
O
4-ethyoxyphenyl
cyclopropyl

TFA
405.513
406.3


604
CH
C(O)
6-fluoro-3-
cyclopropyl
7-C(O)(4-
TFA
495.346
495.2/497.2





cyanophenyl

methylpiperazin-










1-yl)





606
CH
O
2-fluoro-4-
cyclopropyl
5-

480.555
481.4





methoxyphenyl

C(O)N(CH3)2





607
CH
C(O)
2-fluoro-4-
cyclopropyl
5-CN
TFA
434.489
435.3





methoxyphenyl







608
CH
C(O)
2-fluoro-4-
cyclopropyl
5-
TFA
494.581
495.4





methoxyphenyl

(morpholin-










4-yl)





610
N
C(O)
3-fluoro-6-
cyclopropyl
7-

497.952
498.3





chlorophenyl

C(O)N(CH3)2





612
CH
O
2-fluoro-4-
cyclopropyl
5-
TFA
522.591
523.4





methoxyphenyl

(morpholin-










4-yl)





613
N
CH2
2-fluoro-4-
cyclopropyl
7-
TFA
509.570
510.4





methoxyphenyl

(morpholin-










4-yl)





614
N
CH2
2,4-difluorophenyl
cyclopropyl
5-CN
TFA
421.465
422.3


615
N
CH2
2-fluoro-4-
cyclopropyl
5-CN
TFA
433.501
434.4





methoxyphenyl







616
N
CH2
2-fluoro-4-
cyclopropyl
7-
TFA
479.569
480.4





methoxyphenyl

C(O)N(CH3)2





631
CH
O
2-fluoro-4-
isopropyl
7-
TFA
486.989
487.3





chlorophenyl

C(O)N(CH3)2





632
CH
C(O)
3,5-difluorophenyl
isopropyl
7-CN
TFA
436.478
437.3


635
N
CH2
2,4-difluorophenyl
isopropyl
7-
TFA
469.551
470.4







C(O)N(CH3)2





636
CH
C(O)
3,5-difluorophenyl
isopropyl
7-
TFA
482.545
483.4







C(O)N(CH3)2





637
CH
CH2
2-fluoro-4-
isopropyl
7-CN
TFA
434.529
435.4





methoxyphenyl







646
CH
O
2,4-difluorophenyl
tert-butyl
7-CN

438.473
439.4


647
CH
O
2-fluoro-4-
isopropyl

TFA
398.434
493.8





hydroxyphenyl







648
CH
O
2,4-difluorophenyl
2,2-
7-
TFA
492.469
493.8






difluoroethyl
C(O)N(CH3)2





653
CH
SO2
4-fluorophenyl
cyclopropyl
7-CH3
TFA
441.522
442.9


 













 















291
N
CH2
2,5-difluorophenyl
cyclopropyl

TFA
396.4364
397.3


292
N
CH2
2,5-dichlorophenyl
cyclopropyl

TFA
429.3456
429.2


303
N
C(O)
4-chlorophenyl
cyclopropyl

TFA
408.884
409.3


309
N
SO2
4-fluorophenyl
cyclopropyl

TFA
428.4832
429.2


355
N
CH2
2,4,5-
cyclopropyl

TFA
414.4268
415.3





trifluorophenyl







356
N
CH2
2,4-difluorophenyl
cyclopropyl

TFA
396.4364
397.3


363
N
CH2
2,4-difluorophenyl
2,2-

TFA
420.4066
421.2






difluoroethyl






364
N
CH2
2,4,5-
2,2-

TFA
438.3971
439.2





trifluorophenyl
difluoroethyl






369
N
CH2
2,4,5-
pyridin-3-yl

TFA
451.447
452.3





trifluorophenyl







390
N
CH2
2,5-difluorophenyl
pyridin-3-yl
6-CN
TFA
433.4565
434.25


397
N
CH2
2,4-difluorophenyl
cyclopropyl
6-Br
TFA
475.3325
475.2/477.2


398
N
CH2
2,4-difluorophenyl
cyclopropyl
6-CN
TFA
421.4458
422.25


426
CH
CH2
2,4-difluorophenyl
cyclopropyl

TFA
395.4483
396.3


427
CH
CH2
2,4-difluorophenyl
2,2-


419.4185
320.3






difluoroethyl






439
CH
CH2
2,4-difluorophenyl
cyclopropyl
6-CH3
TFA
409.4749
410.3


551
CH
(S)—CHF
2,4-difluorophenyl
cyclopropyl
6-CN

438.178
439.2


552
CH
(R)—CHF
2,4-difluorophenyl
cyclopropyl
6-CN

438.178
439.2


611
CH
O
2-fluoro-4-
cyclopropyl

TFA
409.477
410.3





methoxyphenyl







617
CH
O
2-fluoro-4-
cyclopropyl

TFA
395.450
396.3





hydroxyphenyl







618
CH
O
2-fluoro-4-
isopropyl

TFA
411.473
412.3





methoxyphenyl







621
CH
O
2,4-difluorophenyl
isopropyl

TFA
399.457
400.3


622
CH
CHF
2,4-difluorophenyl
isopropyl

TFA
415.474
416.3


623
CH
O
2-fluoro-4-
ethyl

TFA
397.466
398.3





methoxyphenyl







655
CH
O
2,4-difluorophenyl
isopropyl


399.437
400.0


656
CH
O
2,4-difluorophenyl
cyclobutyl


411.448
412.0


 













 















2
N
CH2
3-methylphenyl
cyclopropyl

TFA
374.482
375.3


22
N
CH2
3-chlorophenyl
phenyl

TFA
430.9326
431.25


44
N
CH2
2,5-dichlorophenyl
cyclopropyl

TFA
429.3456
429.2


 













 















392
N
CH2
2,4-difluorophenyl
cyclopropyl

TFA
397.4244
398.25


452
CH
CH2
2,4-difluorophenyl
cyclopropyl

TFA
396.4364
397.2


596
CH
(S)—CHF
2,4-difluorophenyl
cyclopropyl

TFA
414.455
415.3


600
CH
O
2-fluoro-4-
cyclopropyl

TFA
410.469
411.3





methoxyphenyl







601
CH
(R)—CHF
2,4-difluorophenyl
cyclopropyl

TFA
414.455
415.3


605
CH
O
2-fluoro-4-
cyclopropyl


535.633
536.4





methoxyphenyl







619
CH
O
2-fluoro-4-
cyclopropyl

TFA
426.530
427.3





thiomethoxy










phenyl







620
CH
O
2,4-difluorophenyl
cyclopropyl

TFA
398.429
399.3


624
CH
O
2-fluoro-4-
cyclopropyl

TFA
396.418
397.3





methoxyphenyl







625
CH
O
2-fluoro-4-
isopropyl

TFA
412.848
413.4





cyanophenyl







626
CH
O
2-fluoro-4-
cyclopropyl

TFA
404.460
405.3





cyanophenyl







633
CH
O
2,4-difluorophenyl
isopropyl

TFA
400.445
401.3


634
CH
CHF
2,4-difluorophenyl
isopropyl

TFA
416.462
417.3


638
CH
O
2-fluoro-4-
(S)-sec-

TFA
426.507
427.0





methoxyphenyl
butyl






639
CH
O
2-fluoro-4-
(R)-sec-

TFA
426.507
427.0





methoxyphenyl
butyl






640
CH
O
2-fluoro-4-
isopropyl

TFA
406.464
407.9





cyanophenyl







641
CH
(R)—CHF
2,4-difluorophenyl
isopropyl

TFA
415.463
416.9


642
CH
C(O)
2-fluoro-4-
isopropyl

TFA
424.491
425.0





methoxyphenyl







643
CH
CH2
2-fluoro-4-
isopropyl

TFA
410.508
411.0





methoxyphenyl







644
CH
O
2-fluoro-4-
isopropyl

TFA
415.899
416.9





chlorophenyl







645
CH
(R)—CHF
2,4-difluorophenyl
2-

TFA
428.473
429.0






methylcyclo-










propyl






647
CH
O
2-fluoro-4-
isopropyl

TFA
398.434
493.8





hydroxyphenyl







649
N
CH2
3-methoxyphenyl
isopropyl

TFA
399.440
400.0


650
CH
O
3-methoxyphenyl
isopropyl

TFA
397.470
395.0


651
CH
O
2,4-difluorophenyl
isopropyl
5-CH3
TFA
428.478
428.9







7-CH3





652
CH
O
2,4-difluorophenyl
isopropyl
7-CH3
TFA
414.452
415.0


654
CH
O
2-fluoro-4-
cyclopropyl

TFA
414.864
414.9





chlorophenyl







657
CH
O
2-fluoro-4-
isopropyl

TFA
430.451
430.9





fluoromethoxy-










phenyl














and are named as

    N-cyclopropyl-3-(4-(3-methylbenzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-2-(4-(3-methylbenzyl)piperazin-1-yl)pyrido[2,3-b]pyrazin-3-amine, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-3-(4-(3-methylbenzyl)piperazin-1-yl)pyrido[2,3-b]pyrazin-2-amine
    (4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)(3-(trifluoromethyl)phenyl)methanone, 2,2,2-trifluoroacetic acid salt
    3-(4-(3-chlorobenzyl)piperazin-1-yl)-N-cyclopropylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    (4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)(4-(methylsulfonyl)phenyl)methanone, 2,2,2-trifluoroacetic acid salt
    (4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)(2,5-dichlorophenyl)methanone, 2,2,2-trifluoroacetic acid salt
    (4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)(3,4-dichlorophenyl)methanone, 2,2,2-trifluoroacetic acid salt
    (3-chloro-4-methoxyphenyl)(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt
    (4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)(3,5-dichlorophenyl)methanone, 2,2,2-trifluoroacetic acid salt
    (3-chlorophenyl)(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt
    (4-chlorophenyl)(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-3-(4-(pyridin-3-ylmethyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    (4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)(2,3-dichlorophenyl)methanone, 2,2,2-trifluoroacetic acid salt
    (2-chlorophenyl)(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt
    (4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)(m-tolyl)methanone, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-3-(4-(pyridin-4-ylmethyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-3-(4-(3-(trifluoromethyl)benzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(4-chlorobenzyl)piperazin-1-yl)-N-cyclopropylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-3-(4-(pyridin-2-ylmethyl)piperazin-1-yl)quinoxalin-2-amine, 22,2,2-trifluoroacetic acid salt
    N-(4-bromophenyl)-3-(4-(3-chlorobenzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    2-(4-(3-chlorobenzyl)piperazin-1-yl)-N-phenylpyrido[2,3-b]pyrazin-3-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(3-chlorobenzyl)piperazin-1-yl)-N-phenylpyrido[2,3-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(3-chlorobenzyl)piperazin-1-yl)-N-phenylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(3-chlorobenzyl)piperazin-1-yl)-N-(4-(trifluoromethoxy)phenyl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(3-chlorobenzyl)piperazin-1-yl)-N-(4-propylphenyl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    (4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)(4-(trifluoromethyl)phenyl)methanone, 2,2,2-trifluoroacetic acid salt
    3-(4-(2-chlorobenzyl)piperazin-1-yl)-N-cyclopropylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-3-(4-(4-(methylsulfonyl)benzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(3-chlorobenzyl)piperazin-1-yl)-N-(p-tolyl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(3-chlorobenzyl)piperazin-1-yl)-N-(4-methoxyphenyl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(3-chlorobenzyl)piperazin-1-yl)-N-(2-methoxyphenyl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-3-(4-(4-(trifluoromethyl)benzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(3-chlorobenzyl)piperazin-1-yl)-N-(3-methoxyphenyl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    N-(4-(tert-butyl)phenyl)-3-(4-(3-chlorobenzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(3-chlorobenzyl)piperazin-1-yl)-N-(4-isopropoxyphenyl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(3-chlorobenzyl)piperazin-1-yl)-N-(4-fluorophenyl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    (4-(3-(cyclopentylamino)quinoxalin-2-yl)piperazin-1-yl)(2,5-dichlorophenyl)methanone, 2,2,2-trifluoroacetic acid salt
    N-cyclopentyl-3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    (2,5-dichlorophenyl)(4-(3-(phenylamino)quinoxalin-2-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt
    N-(cyclopropylmethyl)-3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-N-phenylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-2-(4-(2,5-dichlorobenzyl)piperazin-1-yl)pyrido[2,3-b]pyrazin-3-amine, 2,2,2-trifluoroacetic acid salt
    7-bromo-N-cyclopropyl-3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    6-bromo-N-cyclopropyl-3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt mixture of N-cyclopropyl-3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-7-methoxyquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt and
    N-cyclopropyl-3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-7-methoxyquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-3-(4-(2,3-dichlorobenzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-3-(4-(2,4-dichlorobenzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-3-(4-(2,6-dichlorobenzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    N-(3-bromophenyl)-3-(4-(3-chlorobenzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    N-(2-bromophenyl)-3-(4-(3-chlorobenzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(3-chlorobenzyl)piperazin-1-yl)-N-(pyridin-3-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    (4-(3-(cyclopropylamino) quinoxalin-2-yl)piperazin-1-yl)(2,5-dichlorothiophen-3-yl)methanone mixture of N-cyclopropyl-3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-7-fluoroquinoxalin-2-amine and
    N-cyclopropyl-3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-7-fluoroquinoxalin-2-amine
    3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-N-(3-methoxyphenyl) quinoxalin-2-amine
    3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-N-(4-methoxyphenyl) quinoxalin-2-amine
    4-((3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)quinoxalin-2-yl)amino)benzonitrile
    2-(cyclopropylamino)-3-(4-(2,5-dichlorobenzyl)piperazin-1-yl) quinoxaline-6-carbonitrile
    3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-N-(2-methoxyphenyl) quinoxalin-2-amine
    3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-N-(4-fluorophenyl)quinoxalin-2-amine
    N-cyclopropyl-3-(4-(1-(2,5-dichlorophenyl)ethyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)pyrido[2,3-b]pyrazin-2-amine
    N-(4-bromophenyl)-3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)quinoxalin-2-amine
    3-(4-(3-bromobenzyl)piperazin-1-yl)-N-cyclopropylquinoxalin-2-amine
    3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-N-(3-methoxypropyl)quinoxalin-2-amine
    (2-chloro-4-(methylsulfonyl)phenyl)(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)methanone
    (4-(3-(cyclopropylamino) quinoxalin-2-yl)piperazin-1-yl) (3,6-dichloropyridin-2-yl)methanone benzofuran-3-yl(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt
    3-(4-(3-chlorobenzyl)piperazin-1-yl)-N-(pyridin-4-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    N-(3-(4-(3-chlorobenzyl)piperazin-1-yl)quinoxalin-2-yl)-1,3,4-thiadiazol-2-amine, 2,2,2-trifluoroacetic acid salt
    (4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)(3,4-dimethylphenyl)methanone, 2,2,2-trifluoroacetic acid salt 2,2,2-trifluoroacetic acid, N-cyclopropyl-3-(4-(3,4-dimethylbenzyl)piperazin-1-yl)quinoxalin-2-amine salt
    (4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)(2,4-dichlorophenyl)methanone, 2,2,2-trifluoroacetic acid salt
    4-(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazine-1-carbonyl)benzonitrile, 2,2,2-trifluoroacetic acid salt
    4-((4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)methyl)benzonitrile, 2,2,2-trifluoroacetic acid salt
    (4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)(4-ethylphenyl)methanone, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-3-(4-(4-ethylbenzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-3-(4-(3,4-dichlorobenzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    (4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)(2,5-difluorophenyl)methanone, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-3-(4-(2,5-difluorobenzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    (4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)(naphthalen-2-yl)methanone, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-3-(4-(naphthalen-2-ylmethyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    (4-(tert-butyl)phenyl)(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt
    (2-bromo-5-methoxyphenyl)(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt
    (3-bromo-4-methoxyphenyl)(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt
    (4-bromo-2-chlorophenyl)(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt
    (4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)(5-fluoro-2-methylphenyl)methanone, 2,2,2-trifluoroacetic acid salt
    (3-bromo-4-fluorophenyl)(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt
    (4-bromo-2-fluorophenyl)(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt
    (5-bromo-2-fluorophenyl)(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt
    (4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)(4-ethoxyphenyl)methanone, 2,2,2-trifluoroacetic acid salt
    (4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)(3-isopropylphenyl)methanone, 2,2,2-trifluoroacetic acid salt
    3-(4-(4-bromobenzyl)piperazin-1-yl)-N-cyclopropylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-((4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)methyl)benzonitrile, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-3-(4-(4-fluorobenzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-3-(4-(4-isopropylbenzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    (4-(3-(cyclopropylamino) quinoxalin-2-yl)piperazin-1-yl)(5-methylisoxazol-3-yl)methanone
    N-cyclopropyl-3-(4-((2,5-dichlorothiophen-3-yl)methyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(benzofuran-3-ylmethyl)piperazin-1-yl)-N-cyclopropylquinoxalin-2-amine
    N-cyclopropyl-3-(4-((3,6-dichloropyridin-2-yl)methyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt cyclohexyl(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)methanone
    N-cyclopropyl-3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-5,7-dimethylquinoxalin-2-amine
    N-cyclopropyl-3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-6,8-dimethylquinoxalin-2-amine
    N-cyclopropyl-3-(4-(phenylsulfonyl)piperazin-1-yl)quinoxalin-2-amine
    N-cyclopropyl-3-(4-phenethylpiperazin-1-yl) quinoxalin-2-amine
    3-(4-(4-chlorophenethyl)piperazin-1-yl)-N-cyclopropylquinoxalin-2-amine
    N-cyclopropyl-3-(4-(4-methoxyphenethyl)piperazin-1-yl)quinoxalin-2-amine
    3-(4-(cyclohexylmethyl)piperazin-1-yl)-N-cyclopropylquinoxalin-2-amine
    3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-N-isobutylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-N-isopropylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-N-(2-ethylbutyl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-N-(4-methylpentan-2-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-N-neopentylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-N-isopentylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    N-(sec-butyl)-3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-N-propylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-N-(2-methoxyethyl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    N-cyclobutyl-3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    5-bromo-N-cyclopropyl-3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)quinoxalin-2-amine
    (4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)(4-isopropylphenyl)methanone, 2,2,2-trifluoroacetic acid salt
    (4-bromo-2-methylphenyl)(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt
    (2-chloro-3,6-difluorophenyl)(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-3-(4-((4-(trifluoromethoxy)phenyl)sulfonyl)piperazin-1-yl)quinoxalin-2-amine
    N-(3-(4-(3-chlorobenzyl)piperazin-1-yl)quinoxalin-2-yl)thiazol-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(3-chlorobenzyl)piperazin-1-yl)-N-(pyrimidin-2-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(3-chlorobenzyl)piperazin-1-yl)-N-(pyrimidin-5-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(cyclopentylsulfonyl)piperazin-1-yl)-N-cyclopropylquinoxalin-2-amine
    N-cyclopropyl-3-(4-(5-fluoro-2-methylbenzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    (2-chloro-5-iodophenyl)(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt
    (5-bromo-2-methylphenyl)(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt
    (4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)(4-(trifluoromethoxy)phenyl)methanone, 2,2,2-trifluoroacetic acid salt
    8-bromo-N-cyclopropyl-3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    8-bromo-N-cyclopropyl-3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    (4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)(1H-indol-6-yl)methanone, 2,2,2-trifluoroacetic acid salt
    (5-chloro-2-methylphenyl)(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt
    (4-chloro-2-methylphenyl)(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt
    (4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)(2,4-dimethylphenyl)methanone, 2,2,2-trifluoroacetic acid salt
    (2-chloro-5-methoxyphenyl)(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt
    5-(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazine-1-carbonyl)-2-isopropoxybenzonitrile, 2,2,2-trifluoroacetic acid salt
    (4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)(2-methoxy-5-(trifluoromethoxy)phenyl)methanone, 2,2,2-trifluoroacetic acid salt
    (4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)(2,3,5-trichlorophenyl)methanone, 2,2,2-trifluoroacetic acid salt
    (2-chloro-6-(trifluoromethyl)phenyl)(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-3-(4-(2,5-dichlorophenethyl)piperazin-1-yl)quinoxalin-2-amine
    3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-N-(pyridin-3-yl)quinoxalin-2-amine
    (4-(chloromethyl)phenyl)(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt
    (4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)(1H-indol-5-yl)methanone, 2,2,2-trifluoroacetic acid salt
    (4-bromo-3-methylphenyl)(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt
    3-(4-(2-chloro-4-(methylsulfonyl)benzyl)piperazin-1-yl)-N-cyclopropylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-N-(pyridin-3-yl)pyrido[2,3-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(cyclopropylamino)-2-(4-(2,5-dichlorobenzyl)piperazin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    (4-(3-(cyclopropylamino) quinoxalin-2-yl)piperazin-1-yl)(4-fluoro-3-methoxyphenyl)methanone, 2,2,2-trifluoroacetic acid salt
    (3-bromo-4-methylphenyl)(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt
    (4-chloro-3-methylphenyl)(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt
    (4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)(4-fluoro-2-methylphenyl)methanone
    N-cyclopropyl-3-(4-(4-fluoro-2-methylbenzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-3-(4-((5-methylisoxazol-3-yl)methyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    2-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-3-(pyridin-3-ylamino)quinoxaline-6-carbonitrile
    3-(4-(4-chlorobenzoyl)piperazin-1-yl)-2-(cyclopropylamino)quinoxaline-6-carbonitrile
    (4-chlorophenyl)(4-(3-(cyclopropylamino)-7-fluoroquinoxalin-2-yl)piperazin-1-yl)methanone
    2-(cyclopropylamino)-3-(4-(phenylsulfonyl)piperazin-1-yl)quinoxaline-6-carbonitrile
    3-(4-(phenylsulfonyl)piperazin-1-yl)-N-(pyridin-3-yl)quinoxalin-2-amine
    3-(4-(3-chlorobenzyl)piperazin-1-yl)-2-(cyclopropylamino)quinoxaline-6-carbonitrile
    N-(tert-butyl)-3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt 3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-N-(3,3-dimethylbutyl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-N-(2-ethoxyethyl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-N-(2-isopropoxyethyl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-N-(3-ethoxypropyl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    N-cyclohexyl-3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-N-(tetrahydro-2H-pyran-4-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    (R)-2-((3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)quinoxalin-2-yl)amino)propan-1-ol, 2,2,2-trifluoroacetic acid salt
    3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-N-(pyrazin-2-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-N-(pyrimidin-4-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-N-(pyridazin-3-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt mixture of 3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-6-fluoro-N-(pyridin-3-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt and
    3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-7-fluoro-N-(pyridin-3-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-N-(1,2,4-triazin-3-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-N-(5,6-dimethyl-1,2,4-triazin-3-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    N-(3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)quinoxalin-2-yl)-3,4-dimethylisoxazol-5-amine, 2,2,2-trifluoroacetic acid salt
    (3-bromo-2-methylphenyl)(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt
    (4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)(3,5-difluorophenyl)methanone, 2,2,2-trifluoroacetic acid salt
    (4-bromophenyl)(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt
    3-(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazine-1-carbonyl)benzonitrile, 2,2,2-trifluoroacetic acid salt
    (3-bromophenyl)(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt
    (4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)(2,6-dichlorophenyl)methanone, 2,2,2-trifluoroacetic acid salt
    (2-bromo-4-methylphenyl)(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt
    4-(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazine-1-carbonyl)-3-fluorobenzonitrile, 2,2,2-trifluoroacetic acid salt benzo[d][1,2,3]thiadiazol-5-yl(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt
    (2-chloro-5-fluorophenyl)(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt
    (4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)(2,6-difluoro-3-methylphenyl)methanone, 2,2,2-trifluoroacetic acid salt
    (4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)(2-methoxy-5-(trifluoromethyl)phenyl)methanone, 2,2,2-trifluoroacetic acid salt
    (4-bromo-3-(trifluoromethyl)phenyl)(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)methanone
    N-cyclopropyl-3-(4-(3,5-difluorobenzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(4-chloro-3-methylbenzyl)piperazin-1-yl)-N-cyclopropylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-3-(4-(2,3-dimethylbenzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(2-bromo-5-methoxybenzyl)piperazin-1-yl)-N-cyclopropylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(3-bromo-4-methoxybenzyl)piperazin-1-yl)-N-cyclopropylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(4-bromo-2-chlorobenzyl)piperazin-1-yl)-N-cyclopropylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(3-bromo-4-fluorobenzyl)piperazin-1-yl)-N-cyclopropylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(4-bromo-2-fluorobenzyl)piperazin-1-yl)-N-cyclopropylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(5-bromo-2-fluorobenzyl)piperazin-1-yl)-N-cyclopropylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(5-bromo-2-methylbenzyl)piperazin-1-yl)-N-cyclopropylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-((1H-indol-6-yl)methyl)piperazin-1-yl)-N-cyclopropylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(5-chloro-2-methylbenzyl)piperazin-1-yl)-N-cyclopropylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(4-chloro-2-methylbenzyl)piperazin-1-yl)-N-cyclopropylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(2-chloro-3,6-difluorobenzyl)piperazin-1-yl)-N-cyclopropylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-3-(4-(2,4-dimethylbenzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(2-chloro-5-methoxybenzyl)piperazin-1-yl)-N-cyclopropylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(2-chloro-5-fluorobenzyl)piperazin-1-yl)-N-cyclopropylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(2-chloro-6-(trifluoromethyl)benzyl)piperazin-1-yl)-N-cyclopropylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-3-(4-(3-isopropylbenzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-6-fluoro-3-(4-(phenylsulfonyl)piperazin-1-yl)quinoxalin-2-amine
    N-cyclopropyl-3-(4-(2,5-difluorobenzyl)piperazin-1-yl)-6-fluoroquinoxalin-2-amine
    3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-N-(pyridin-4-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-3-(4-(2,5-difluorobenzyl)piperazin-1-yl)-6,7-difluoroquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(3-chloro-4-methoxybenzyl)piperazin-1-yl)-N-cyclopropylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(4-bromo-3-methylbenzyl)piperazin-1-yl)-N-cyclopropylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(4-bromo-2-methylbenzyl)piperazin-1-yl)-N-cyclopropylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(2-chloro-5-iodobenzyl)piperazin-1-yl)-N-cyclopropylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-3-(4-(2-methoxy-5-(trifluoromethoxy)benzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-3-(4-(2,3,5-trichlorobenzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-((2-chloro-5-fluoropyridin-3-yl)methyl)piperazin-1-yl)-N-cyclopropylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    (4-chlorophenyl)(4-(3-(pyridin-3-ylamino)quinoxalin-2-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt
    3-(4-((3-chlorophenyl)sulfonyl)piperazin-1-yl)-2-(cyclopropylamino)quinoxaline-6-carbonitrile
    3-(4-((3-chlorophenyl)sulfonyl)piperazin-1-yl)-N-cyclopropyl-6-fluoroquinoxalin-2-amine
    2-(cyclopropylamino)-3-(4-((2,5-dichlorophenyl)sulfonyl)piperazin-1-yl)quinoxaline-6-carbonitrile
    3-(4-((4-chlorophenyl)sulfonyl)piperazin-1-yl)-2-(cyclopropylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-N-(pyridin-2-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(2,5-difluorobenzyl)piperazin-1-yl)-N-(pyridin-3-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    (4-chloro-3-methylphenyl)(4-(3-(pyridin-3-ylamino)quinoxalin-2-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-6,7-difluoroquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    (3-bromo-4-fluorophenyl)(4-(3-(cyclopropylamino)-6,7-difluoroquinoxalin-2-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt
    3-(4-(2-bromo-5-chlorobenzyl)piperazin-1-yl)-N-cyclopropylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(5-chloro-2-(trifluoromethyl)benzyl)piperazin-1-yl)-N-cyclopropylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-3-(4-(2,6-difluoro-3-methylbenzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-3-(4-(2-methoxy-5-(trifluoromethyl)benzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    2-(cyclopropylamino)-3-(4-(o-tolylsulfonyl)piperazin-1-yl)quinoxaline-6-carbonitrile
    2-(cyclopropylamino)-3-(4-((3-fluorophenyl)sulfonyl)piperazin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    2-(cyclopropylamino)-3-(4-(m-tolylsulfonyl)piperazin-1-yl)quinoxaline-6-carbonitrile
    2-(cyclopropylamino)-3-(4-tosylpiperazin-1-yl)quinoxaline-6-carbonitrile
    2-(cyclopropylamino)-3-(4-((2-fluorophenyl)sulfonyl)piperazin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    2-(cyclopropylamino)-3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)quinoxaline-5-carbonitrile, 2,2,2-trifluoroacetic acid salt
    (4-chlorophenyl)(4-(3-(cyclopropylamino)-6,7-difluoroquinoxalin-2-yl)piperazin-1-yl)methanone
    3-(4-((2-chlorophenyl)sulfonyl)piperazin-1-yl)-2-(cyclopropylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    2-(cyclopropylamino)-3-(4-((4-fluorophenyl)sulfonyl)piperazin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    3-(4-(3-chlorobenzyl)piperazin-1-yl)-N-cyclopropyl-6,7-difluoroquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    (4-bromo-3-fluorophenyl)(4-(3-(cyclopropylamino)-7-fluoroquinoxalin-2-yl)piperazin-1-yl)methanone
    3-(cyclopropylamino)-2-(4-(2,5-dichlorobenzyl)piperazin-1-yl)quinoxaline-5-carbonitrile, 2,2,2-trifluoroacetic acid salt
    3-(4-((2-bromophenyl)sulfonyl)piperazin-1-yl)-2-(cyclopropylamino)quinoxaline-6-carbonitrile
    3-(4-((3-bromophenyl)sulfonyl)piperazin-1-yl)-2-(cyclopropylamino)quinoxaline-6-carbonitrile
    3-(4-((4-bromophenyl)sulfonyl)piperazin-1-yl)-2-(cyclopropylamino)quinoxaline-6-carbonitrile
    3-(4-((2-cyanophenyl)sulfonyl)piperazin-1-yl)-2-(cyclopropylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    3-(4-((3-cyanophenyl)sulfonyl)piperazin-1-yl)-2-(cyclopropylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    3-(4-((4-cyanophenyl)sulfonyl)piperazin-1-yl)-2-(cyclopropylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    2-(cyclopropylamino)-3-(4-(4-fluorobenzyl)piperazin-1-yl)quinoxaline-6-carbonitrile
    3-(4-(3-bromo-4-fluorobenzoyl)piperazin-1-yl)-2-(cyclopropylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    2-(cyclopropylamino)-3-(4-(2,5-difluorobenzyl)piperazin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-2-(isopropylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    3-(4-(2,5-difluorobenzyl)piperazin-1-yl)-2-(isopropylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    3-(4-(3-bromo-4-fluorobenzoyl)piperazin-1-yl)-2-(isopropylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    2-(cyclobutylamino)-3-(4-(2,5-difluorobenzyl)piperazin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    3-(4-(3-bromo-4-fluorobenzoyl)piperazin-1-yl)-2-(cyclobutylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    (4-chlorophenyl)(4-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperazin-1-yl)methanone
    N-cyclopropyl-3-(4-(2,5-difluorobenzyl)piperazin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    2-(cyclopropylamino)-3-(4-(2,5-dichloroisonicotinoyl)piperazin-1-yl)quinoxaline-6-carbonitrile
    3-(4-(4-chlorobenzoyl)piperazin-1-yl)-2-(cyclobutylamino)quinoxaline-6-carbonitrile
    3-(4-(4-chlorobenzoyl)piperazin-1-yl)-2-(isopropylamino)quinoxaline-6-carbonitrile
    (4-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperazin-1-yl)(4-(trifluoromethyl)phenyl)methanone, 2,2,2-trifluoroacetic acid salt
    3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-N-(2,2,2-trifluoroethyl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    2-(cyclopropylamino)-3-(4-((3,5-dimethylisoxazol-4-yl)sulfonyl)piperazin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    2-(cyclopropylamino)-3-(4-((2,5-dimethylphenyl)sulfonyl)piperazin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    2-(cyclopropylamino)-3-(4-((4-methoxyphenyl)sulfonyl)piperazin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    2-(cyclopropylamino)-3-(4-((2-methoxyphenyl)sulfonyl)piperazin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    2-(cyclopropylamino)-3-(4-((3-methoxyphenyl)sulfonyl)piperazin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    3-(4-((5-chlorothiophen-2-yl)sulfonyl)piperazin-1-yl)-2-(cyclopropylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    2-(cyclopropylamino)-3-(4-(mesitylsulfonyl)piperazin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    2-(cyclopropylamino)-3-(4-((2-methoxy-4-methylphenyl)sulfonyl)piperazin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    3-(4-((5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperazin-1-yl)-2-(cyclopropylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    2-(cyclopropylamino)-3-(4-((2,3,4-trifluorophenyl)sulfonyl)piperazin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    3-(4-((4-(tert-butyl)phenyl)sulfonyl)piperazin-1-yl)-2-(cyclopropylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    3-(4-((4-chloro-2,5-dimethylphenyl)sulfonyl)piperazin-1-yl)-2-(cyclopropylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    3-(4-((3-chloro-5-fluoro-2-methylphenyl)sulfonyl)piperazin-1-yl)-2-(cyclopropylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    2-(cyclopropylamino)-3-(4-((4-(trifluoromethoxy)phenyl)sulfonyl)piperazin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    3-(4-((5-bromothiophen-2-yl)sulfonyl)piperazin-1-yl)-2-(cyclopropylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    3-(4-((4-bromo-2-fluorophenyl)sulfonyl)piperazin-1-yl)-2-(cyclopropylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    3-(4-((2-chloro-5-(trifluoromethyl)phenyl)sulfonyl)piperazin-1-yl)-2-(cyclopropylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    3-(4-((4-bromo-2-chlorophenyl)sulfonyl)piperazin-1-yl)-2-(cyclopropylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-3-(4-((4-fluorophenyl)sulfonyl)piperazin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    (4-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperazin-1-yl)(4-(difluoromethyl)phenyl)methanone, 2,2,2-trifluoroacetic acid salt
    3-(4-(5-chloro-2-(difluoromethoxy)benzyl)piperazin-1-yl)-N-cyclopropylpyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-3-(4-(4-fluorobenzyl)piperazin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-2-(4-(2,5-difluorobenzyl)piperazin-1-yl)pyrido[3,4-b]pyrazin-3-amine, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-2-(4-(2,5-dichlorobenzyl)piperazin-1-yl)pyrido[3,4-b]pyrazin-3-amine, 2,2,2-trifluoroacetic acid salt
    2-(cyclopropylamino)-3-(4-(2,6-dichlorobenzyl)piperazin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    3-(4-(3-chlorobenzoyl)piperazin-1-yl)-2-((cyclobutylmethyl)amino)quinoxaline-6-carbonitrile
    2-((cyclobutylmethyl)amino)-3-(4-(2,5-dichlorobenzoyl)piperazin-1-yl)quinoxaline-6-carbonitrile
    2-(cyclopropylamino)-3-(4-(2,5-dichloronicotinoyl)piperazin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    3-(4-(4-chlorobenzoyl)piperazin-1-yl)-2-(oxetan-3-ylamino)quinoxaline-6-carbonitrile
    N-cyclopropyl-3-(4-(2,6-dichlorobenzyl)piperazin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-2-(oxetan-3-ylamino)quinoxaline-6-carbonitrile
    3-(4-(5-chloro-2-propoxybenzyl)piperazin-1-yl)-N-cyclopropylpyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-3-(4-((4-(trifluoromethyl)phenyl)sulfonyl)piperazin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    2-(4-(4-chlorobenzoyl)piperazin-1-yl)-3-(cyclopropylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    (4-chlorophenyl)(4-(3-(cyclopropylamino)pyrido[3,4-b]pyrazin-2-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt
    3-(cyclopropylamino)-2-(4-(2,5-difluorobenzyl)piperazin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    3-(4-(5-(tert-butyl)-2-methoxybenzyl)piperazin-1-yl)-N-cyclopropylpyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-3-(4-(2,5-dimethylbenzyl)piperazin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(cyclopropylamino)-2-(4-((4-fluorophenyl) sulfonyl)piperazin-1-yl) quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-2-(pyridin-3-ylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-2-(4-((4-fluorophenyl)sulfonyl)piperazin-1-yl)pyrido[3,4-b]pyrazin-3-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(2,5-difluorobenzyl)piperazin-1-yl)-2-(pyridin-3-ylamino)quinoxaline-6-carbonitrile
    N-cyclopropyl-3-(4-(2,6-difluorobenzyl)piperazin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(2,5-difluorobenzyl)piperazin-1-yl)-2-((6-oxo-1,6-dihydropyridin-3-yl)amino)quinoxaline-6-carbonitrile
    3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-2-((6-oxo-1,6-dihydropyridin-3-yl)amino)quinoxaline-6-carbonitrile
    3-(4-(3-chloro-4-fluorobenzyl)piperazin-1-yl)-N-cyclopropylpyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-3-(4-(2,4,5-trifluorobenzyl)piperazin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(4-chloro-3-fluorobenzyl)piperazin-1-yl)-N-cyclopropylpyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-3-(4-(3,4-difluorobenzyl)piperazin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-3-(4-(2,4-difluorobenzyl)piperazin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(2,5-difluorobenzyl)piperazin-1-yl)-2-((6-oxo-1,6-dihydropyridin-4-yl)amino)quinoxaline-6-carbonitrile
    2-(cyclopropylamino)-3-(4-((4-ethylphenyl)sulfonyl)piperazin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    3-(4-(2,5-difluorobenzyl)piperazin-1-yl)-2-((6-oxo-1,6-dihydropyridin-2-yl)amino)quinoxaline-6-carbonitrile
    2-(cyclopropylamino)-3-(4-((2-fluoro-5-methylphenyl)sulfonyl)piperazin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    3-(4-(4-chlorobenzoyl)piperazin-1-yl)-2-((6-oxo-1,6-dihydropyridin-2-yl)amino)quinoxaline-6-carbonitrile
    3-(4-(2,5-difluorobenzyl)piperazin-1-yl)-2-((6-oxo-1,6-dihydropyridin-2-yl)amino)quinoxaline-6-carbonitrile
    2-(cyclopropylamino)-3-(4-((3,4-difluorophenyl)sulfonyl)piperazin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    3-(4-(4-chlorobenzoyl)piperazin-1-yl)-2-((2-oxo-1,2-dihydropyridin-3-yl)amino)quinoxaline-6-carbonitrile
    3-(4-(4-chlorobenzoyl)piperazin-1-yl)-2-(pyridin-3-ylamino)quinoxaline-6-carbonitrile
    2-(cyclopropylamino)-3-(4-((2,5-dimethoxyphenyl)sulfonyl)piperazin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    3-(4-((2-chloro-4-(trifluoromethyl)phenyl)sulfonyl)piperazin-1-yl)-2-(cyclopropylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    3-(4-(5-chloro-2-fluorobenzyl)piperazin-1-yl)-N-cyclopropylpyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(2-chloro-5-fluorobenzyl)piperazin-1-yl)-N-cyclopropylpyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(2,5-difluorobenzyl)piperazin-1-yl)-2-((6-methoxypyridin-3-yl)amino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-2-((3-oxocyclobutyl)amino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    3-(4-(2,5-difluorobenzyl)piperazin-1-yl)-2-((3-oxocyclobutyl)amino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    2-(cyclobutylamino)-3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    3-(4-(4-chlorobenzoyl)piperazin-1-yl)-2-((2-fluoroethyl)amino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-2-((2,2-difluoroethyl)amino)quinoxaline-6-carbonitrile
    3-(4-(4-chlorobenzoyl)piperazin-1-yl)-2-((2,2-difluoroethyl)amino)quinoxaline-6-carbonitrile
    3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-2-(isoxazol-3-ylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    3-(4-(4-chlorobenzoyl)piperazin-1-yl)-2-(isoxazol-3-ylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    3-(4-((3-cyano-4-fluorophenyl)sulfonyl)piperazin-1-yl)-2-(cyclopropylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    2-(cyclopropylamino)-3-(4-(2,4-difluorobenzyl)piperazin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    3-(4-((5-chloro-2-methoxyphenyl)sulfonyl)piperazin-1-yl)-2-(cyclopropylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    3-(4-((5-chloro-2,4-difluorophenyl)sulfonyl)piperazin-1-yl)-2-(cyclopropylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    3-(4-((5-bromo-6-chloropyridin-3-yl)sulfonyl)piperazin-1-yl)-2-(cyclopropylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    3-(4-((4-bromo-2,5-difluorophenyl)sulfonyl)piperazin-1-yl)-2-(cyclopropylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-2-((2-fluoroethyl)amino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    3-(4-(2,5-difluorobenzyl)piperazin-1-yl)-2-((2-fluoroethyl)amino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    3-(4-(2,5-difluorobenzyl)piperazin-1-yl)-2-((2,2-difluoroethyl)amino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    8-chloro-3-(4-(5-chloro-2-fluorobenzyl)piperazin-1-yl)-N-cyclopropylpyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    8-chloro-N-cyclopropyl-3-(4-(2,5-difluorobenzyl)piperazin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    2-(cyclopropylamino)-3-(4-(2,4,5-trifluorobenzyl)piperazin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    8-chloro-N-cyclopropyl-3-(4-(2,4-difluorobenzyl)piperazin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    8-chloro-N-cyclopropyl-3-(4-(2,4,5-trifluorobenzyl)piperazin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-2-(4-(2,4,5-trifluorobenzyl)piperazin-1-yl)pyrido[3,4-b]pyrazin-3-amine, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-2-(4-(2,4-difluorobenzyl)piperazin-1-yl)pyrido[3,4-b]pyrazin-3-amine, 2,2,2-trifluoroacetic acid salt
    2-(cyclopropylamino)-3-(4-((2,4-dimethoxyphenyl)sulfonyl)piperazin-1-yl)quinoxaline-6-carbonitrile
    (4-chloro-3-fluorophenyl)(4-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt
    (4-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperazin-1-yl)(3,4-difluorophenyl)methanone, 2,2,2-trifluoroacetic acid salt
    (3-chloro-4-fluorophenyl)(4-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt
    (4-chloro-2-fluorophenyl)(4-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt
    (2-chloro-4-fluorophenyl)(4-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt
    2-(4-(2,4-difluorobenzyl)piperazin-1-yl)-N-(2,2-difluoroethyl)pyrido[3,4-b]pyrazin-3-amine, 2,2,2-trifluoroacetic acid salt
    N-(2,2-difluoroethyl)-2-(4-(2,4,5-trifluorobenzyl)piperazin-1-yl)pyrido[3,4-b]pyrazin-3-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(2,4-difluorobenzyl)piperazin-1-yl)-N-(2,2-difluoroethyl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(5-chloro-2-fluorobenzyl)piperazin-1-yl)-N-(2,2-difluoroethyl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(5-chloro-2-fluorobenzyl)piperazin-1-yl)-2-(cyclopropylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    (4-chloro-2-fluorophenyl)(4-(2-((2,2-difluoroethyl)amino)pyrido[3,4-b]pyrazin-3-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt
    N-(pyridin-3-yl)-2-(4-(2,4,5-trifluorobenzyl)piperazin-1-yl)pyrido[3,4-b]pyrazin-3-amine, 2,2,2-trifluoroacetic acid salt
    N-(2,2-difluoroethyl)-3-(4-(2,4,5-trifluorobenzyl)piperazin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(2,4-difluorobenzyl)piperazin-1-yl)-2-(pyridin-3-ylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    (4-chloro-2-hydroxyphenyl)(4-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt
    3-(cyclopropylamino)-2-(4-(2,4-difluorobenzyl)piperazin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    2-(4-(5-chloro-2-fluorobenzyl)piperazin-1-yl)-3-(cyclopropylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    3-(cyclopropylamino)-2-(4-(2,4,5-trifluorobenzyl)piperazin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    2-(pyridin-3-ylamino)-3-(4-(2,4,5-trifluorobenzyl)piperazin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    3-(4-(4-chloro-2-fluorobenzoyl)piperazin-1-yl)-2-(pyridin-3-ylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    3-(4-(2,5-difluorobenzyl)piperazin-1-yl)-2-(isoxazol-3-ylamino)quinoxaline-6-carbonitrile
    2-(4-(2,4-difluorobenzyl)piperazin-1-yl)-N-(pyridin-3-yl)pyrido[3,4-b]pyrazin-3-amine
    (4-chloro-2-methoxyphenyl)(4-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt
    (4-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperazin-1-yl)(2-fluoro-4-(trifluoromethyl)phenyl)methanone, 2,2,2-trifluoroacetic acid salt
    (5-chloro-3-fluoropyridin-2-yl)(4-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt
    (4-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperazin-1-yl)(2-fluoro-4-methylphenyl)methanone, 2,2,2-trifluoroacetic acid salt
    (4-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperazin-1-yl)(2-fluoro-4-methoxyphenyl)methanone, 2,2,2-trifluoroacetic acid salt
    (4-chloro-2-methylphenyl)(4-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt
    4-(4-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperazine-1-carbonyl)-3-fluorobenzonitrile, 2,2,2-trifluoroacetic acid salt
    (4-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperazin-1-yl)(4-fluoro-2-hydroxyphenyl)methanone, 2,2,2-trifluoroacetic acid salt
    (4-chloro-2,6-difluorophenyl)(4-(2-(cyclopropylamino)pyrido[34-b]pyrazin-3-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt
    (4-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperazin-1-yl)(3-fluoropyridin-2-yl)methanone, 2,2,2-trifluoroacetic acid salt
    2-(4-(2,5-difluorobenzyl)piperazin-1-yl)-N-(pyridin-3-yl)pyrido[3,4-b]pyrazin-3-amine, 2,2,2-trifluoroacetic acid salt
    (4-chloro-2-(trifluoromethyl)phenyl)(4-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-3-(4-(2,4-difluorobenzyl)piperazin-1-yl)pyrazino[2,3-d]pyridazin-2-amine, 2,2,2-trifluoroacetic acid salt
    (4-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperazin-1-yl)(2,4,6-trifluorophenyl)methanone, 2,2,2-trifluoroacetic acid salt
    (4-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperazin-1-yl)(2,4-difluoro-6-hydroxyphenyl)methanone, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-3-(4-(2,4-difluorobenzyl)piperazin-1-yl)-7-methylpyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(5-chloro-2-fluorobenzyl)piperazin-1-yl)-N-cyclopropyl-7-methylpyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    7-bromo-3-(cyclopropylmethyl)-2-(4-(2,4-difluorobenzyl)piperazin-1-yl)pyrido[3,4-b]pyrazine 2,2,2-trifluoroacetate
    3-(cyclopropylamino)-2-(4-(2,4-difluorobenzyl)piperazin-1-yl)pyrido[3,4-b]pyrazine-7-carbonitrile, 2,2,2-trifluoroacetic acid salt
    3-(4-(2,5-difluorobenzyl)piperazin-1-yl)-2-((3,3,3-trifluoropropyl)amino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    3-(4-(2,4-difluorobenzyl)piperazin-1-yl)-2-((3,3,3-trifluoropropyl)amino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    6-bromo-N-cyclopropyl-3-(4-(2,5-difluorobenzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    6-bromo-3-(4-(5-chloro-2-fluorobenzyl)piperazin-1-yl)-N-cyclopropylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    6-bromo-N-cyclopropyl-3-(4-(2,4-difluorobenzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(2,4-difluorobenzyl)piperazin-1-yl)-2-((2,2-difluoroethyl)amino)quinoxaline-6-carbonitrile
    7-bromo-N-cyclopropyl-3-(4-(2,4-difluorobenzyl)piperazin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(2,4-difluorobenzyl)piperazin-1-yl)-N-(2-methoxyethyl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(2,4-difluorobenzyl)piperazin-1-yl)-2-((2-methoxyethyl)amino)quinoxaline-6-carbonitrile
    N-cyclopropyl-3-(4-((5-methyloxazol-2-yl)methyl)piperidin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-3-(4-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)piperidin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-benzylpiperidin-1-yl)-N-phenylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-3-(4-phenoxypiperidin-1-yl)quinoxalin-2-amine
    3-(4-((4-chlorophenyl)amino)piperidin-1-yl)-N-cyclopropylquinoxalin-2-amine, 22,2,2-trifluoroacetic acid salt
    N-cyclopropyl-3-(4-(2,4-difluorobenzyl)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(2,4-difluorobenzyl)piperidin-1-yl)-2-(pyridin-3-ylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    2-(cyclopropylamino)-3-(4-(2,4-difluorobenzyl)piperidin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    3-(4-(2-chlorophenoxy)piperidin-1-yl)-N-cyclopropylpyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-3-(4-(2-fluorophenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-3-(4-(3-fluorophenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    (1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)(4-fluorophenyl)methanone, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-3-(4-(4-fluorobenzyl)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    (1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)(3,4-difluorophenyl)methanone, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-3-(4-((4-fluorophenyl)sulfonyl)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(4-chlorobenzyl)piperidin-1-yl)-N-cyclopropylpyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(4-chlorophenoxy)piperidin-1-yl)-N-cyclopropylpyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(3-chlorophenoxy)piperidin-1-yl)-N-cyclopropylpyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-2-(4-(2,4-difluorobenzyl)piperidin-1-yl)pyrido[3,4-b]pyrazin-3-amine, 2,2,2-trifluoroacetic acid salt
    2-(4-(2,4-difluorobenzyl)piperidin-1-yl)-N-(2,2-difluoroethyl)pyrido[3,4-b]pyrazin-3-amine
    N-cyclopropyl-3-(4-(2,4-difluorobenzyl)piperidin-1-yl)-7-methylpyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    (4-chlorophenyl)(1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)methanone, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-3-(4-(2,5-difluorophenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-3-(4-(2,4,6-trifluorophenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-3-(4-(4-fluorophenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    (1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)(2-fluorophenyl)methanone, 2,2,2-trifluoroacetic acid salt
    (1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)(2,5-difluorophenyl)methanone, 2,2,2-trifluoroacetic acid salt
    3-(4-(5-chloro-2-fluorophenoxy)piperidin-1-yl)-N-cyclopropylpyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-3-(4-phenoxypiperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    (1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)(2,4-difluorophenyl)methanone, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-2-(4-(2,4-difluorobenzyl)piperidin-1-yl)-7-methylpyrido[3,4-b]pyrazin-3-amine, 2,2,2-trifluoroacetic acid salt
    (1-(2-(cyclopropylamino)-7-methylpyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)(2,5-difluorophenyl)methanone, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7-methylpyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(4-chloro-2-fluorophenoxy)piperidin-1-yl)-N-cyclopropylpyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    (1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)(2,4,6-trifluorophenyl)methanone, 2,2,2-trifluoroacetic acid salt
    (4-chloro-2,6-difluorophenyl)(1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)methanone, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-3-(4-(2,5-difluorobenzyl)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    (4-chloro-2-fluorophenyl)(1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)methanone, 2,2,2-trifluoroacetic acid salt
    (5-chloro-2-fluorophenyl)(1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)methanone, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine
    N-cyclopropyl-3-(4-(fluoro(4-fluorophenyl)methyl)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine
    N-cyclopropyl-3-(4-(2,4-difluorobenzyl)piperidin-1-yl)pyrazino[2,3-d]pyridazin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-((5-chloro-2-fluorophenyl)fluoromethyl)piperidin-1-yl)-N-cyclopropylpyrido[3,4-b]pyrazin-2-amine
    N-cyclopropyl-3-(4-((2,5-difluorophenyl)fluoromethyl)piperidin-1-yl)-7-methylpyrido[3,4-b]pyrazin-2-amine
    (1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)(3-methoxy azetidin-1-yl)methanone
    (1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)(4-methylpiperazin-1-yl)methanone
    (1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)(pyrrolidin-1-yl)methanone
    (1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)(piperidin-1-yl)methanone
    N-cyclopropyl-3-(4-((2,4-difluorophenyl)amino)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 22,2,2-trifluoroacetic acid salt
    3-(4-(1-(5-chloro-2-fluorophenyl)-1-fluoroethyl)piperidin-1-yl)-N-cyclopropylpyrido[3,4-b]pyrazin-2-amine
    N-cyclopropyl-3-(4-((2,5-difluorophenyl)fluoromethyl)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine
    3-(4-(2,4-difluorobenzyl)piperidin-1-yl)-2-(isopropylamino)quinoxaline-6-carbonitrile
    2-(cyclobutylamino)-3-(4-(2,4-difluorobenzyl)piperidin-1-yl)quinoxaline-6-carbonitrile
    7-bromo-N-cyclopropyl-3-(4-(2,4-difluorobenzyl)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    (S)—N-cyclopropyl-3-(4-((2,5-difluorophenyl)fluoromethyl)piperidin-1-yl)-7-methylpyrido[3,4-b]pyrazin-2-amine
    3-(4-(4-chloro-2-fluorophenoxy)piperidin-1-yl)-2-(cyclopropylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    3-(4-(4-chloro-2-fluorophenoxy)piperidin-1-yl)-2-(isopropylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    3-(4-(4-chloro-2-fluorophenoxy)piperidin-1-yl)-N-cyclopropyl-7-methylpyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    2-(cyclopropylamino)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    3-(4-(5-chloro-2-fluorobenzoyl)piperidin-1-yl)-2-(cyclopropylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    2-(cyclopropylamino)-3-(4-((2,5-difluorophenyl)fluoromethyl)piperidin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    2-(cyclopropylamino)-3-(4-((4-fluoro-2-oxopyridin-1 (2H)-yl)methyl)piperidin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    2-(cyclopropylamino)-3-(4-(2,5-difluorobenzoyl)piperidin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    1-((1-(2-(cyclopropylamino)-7-methylpyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)methyl)-4-fluoropyridin-2(1H)-one, 2,2,2-trifluoroacetic acid salt
    2-(4-(4-chloro-2-fluorophenoxy)piperidin-1-yl)-3-(cyclopropylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    2-(cyclopropylamino)-3-(4-(2,4-difluorobenzyl)piperidin-1-yl)pyrido[3,4-b]pyrazine-7-carbonitrile
    7-chloro-N-cyclopropyl-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    (R)—N-cyclopropyl-3-(4-((2,5-difluorophenyl)fluoromethyl)piperidin-1-yl)-7-methylpyrido[3,4-b]pyrazin-2-amine, hydrogen chloride salt
    N-cyclopropyl-3-(4-(2,4-difluorobenzyl)piperidin-1-yl)-6,7-difluoroquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-3-(4-(2,4-difluorobenzyl)piperidin-1-yl)-6-fluoroquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    2-(cyclopropylamino)-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-2-(isopropylamino)quinxaine-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    2-(cyclobutylamino)-3-(4-((2,5-difluorophenyl)fluoromethyl)piperidin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-3-(4-(2,4-difluorobenzyl)piperidin-1-yl)-7-methoxypyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(cyclopropylamino)-2-(4-((2,5-difluorophenyl)fluoromethyl)piperidin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    3-(4-((2,5-difluorophenyl)fluoromethyl)piperidin-1-yl)-2-(isopropylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    8-chloro-N-cyclopropyl-3-(4-((2,5-difluorophenyl)fluoromethyl)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(cyclopropylamino)-2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-7-methylpyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    7-chloro-N-cyclopropyl-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    2-(cyclopropylamino)-3-(4-(2,4-difluorobenzyl)piperidin-1-yl)pyrido[3,4-b]pyrazin-7-ol, 2,2,2-trifluoroacetic acid salt
    (R)-2-(cyclopropylamino)-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-5-methylpyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-3-(4-(2,4-difluorobenzyl)piperidin-1-yl)-5-methylpyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-methylpyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    6-bromo-N-cyclopropyl-3-(4-(2,4-difluorobenzyl)piperidin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(2,4-difluorobenzyl)piperidin-1-yl)-2-((3,3,3-trifluoropropyl)amino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    (R)—N-cyclopropyl-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-7-methylpyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-((2,5-difluorophenyl)fluoromethyl)piperidin-1-yl)-2-((3,3,3-trifluoropropyl)amino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-2-((3,3,3-trifluoropropyl)amino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    6-bromo-N-cyclopropyl-3-(4-((2,5-difluorophenyl)fluoromethyl)piperidin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    6-bromo-N-cyclopropyl-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
    (S)—N-cyclopropyl-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-7-methylpyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    (S)-3-(4-((2,5-difluorophenyl)fluoromethyl)piperidin-1-yl)-2-(isopropylamino)quinoxaline-6-carbonitrile
    (R)-3-(4-((2,5-difluorophenyl)fluoromethyl)piperidin-1-yl)-2-(isopropylamino)quinoxaline-6-carbonitrile
    (S)-2-(cyclopropylamino)-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)quinoxaline-6-carbonitrile
    (R)-2-(cyclopropylamino)-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)quinoxaline-6-carbonitrile
    (S)-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-2-(isopropylamino)quinoxaline-6-carbonitrile
    (R)-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-2-(isopropylamino)quinoxaline-6-carbonitrile
    (S)-3-(cyclopropylamino)-2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)quinoxaline-6-carbonitrile
    (R)-3-(cyclopropylamino)-2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)quinoxaline-6-carbonitrile
    2-((2,2-difluoroethyl)amino)-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)quinoxaline-6-carbonitrile
    3-(4-(2,4-difluorobenzyl)piperidin-1-yl)-2-((2,2-difluoroethyl)amino)quinoxaline-6-carbonitrile
    2-((2,2-difluoroethyl)amino)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)quinoxaline-6-carbonitrile
    (S)-2-(cyclopropylamino)-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt
    7-bromo-N-cyclopropyl-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    (S)—N-cyclopropyl-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-5-methylpyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    (S)—N-cyclopropyl-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(2,4-difluorobenzyl)piperidin-1-yl)-2-((2-methoxyethyl)amino)quinoxaline-6-carbonitrile
    3-(4-(2,4-difluorobenzyl)piperidin-1-yl)-N-(2-methoxyethyl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-N-(2-methoxyethyl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-2-((2-methoxy ethyl)amino) quinoxaline-6-carbonitrile
    3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-2-((2-methoxyethyl)amino)quinoxaline-6-carbonitrile
    (R)-7-chloro-N-cyclopropyl-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    (S)-7-chloro-N-cyclopropyl-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-(2-methoxyethyl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-((4-chloro-2-oxopyridin-1(2H)-yl)methyl)piperidin-1-yl)-2-(cyclopropylamino)quinoxaline-6-carbonitrile
    1-((1-(2-(cyclopropylamino)-5-methylpyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)methyl)-5-fluoropyridin-2(1H)-one
    4-chloro-1-((1-(2-(cyclopropylamino)-5-methylpyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)methyl)pyridin-2(1H)-one
    2-(cyclopropylamino)-3-(4-((5-fluoro-2-oxopyridin-1(2H)-yl)methyl)piperidin-1-yl)quinoxaline-6-carbonitrile
    1-((1-(2-(cyclopropylamino)pyrido[34-b]pyrazin-3-yl)piperidin-4-yl)methyl)-4-fluoropyridin-2(1H)-one
    1-((1-(2-(cyclopropylamino)-5-methylpyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)methyl)-4-fluoropyridin-2(1H)-one
    5-chloro-1-((1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)methyl)pyridin-2(1H)-one
    3-(4-((5-chloro-2-fluorophenyl)difluoromethyl)piperidin-1-yl)-2-(cyclopropylamino)quinoxaline-6-carbonitrile
    3-(4-((5-chloro-2-fluorophenyl)difluoromethyl)piperidin-1-yl)-N-cyclopropyl-7-methylpyrido[3,4-b]pyrazin-2-amine
    3-(4-((5-chloro-2-oxopyridin-1(2H)-yl)methyl)piperidin-1-yl)-2-(cyclopropylamino)quinoxaline-6-carbonitrile
    3-(4-((5-chloro-2-fluorophenyl)difluoromethyl)piperidin-1-yl)-N-cyclopropyl-5-methylpyrido[3,4-b]pyrazin-2-amine
    5-chloro-1-((1-(2-(cyclopropylamino)-5-methylpyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)methyl)pyridin-2(1H)-one
    5-chloro-1-((1-(2-(cyclopropylamino)-7-methylpyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)methyl)pyridin-2(1H)-one
    3-(4-((5-chloro-2-fluorophenyl)difluoromethyl)piperidin-1-yl)-N-cyclopropylpyrido[3,4-b]pyrazin-2-amine
    N-cyclopropyl-3-(4-((2,5-difluorophenyl)difluoromethyl)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine
    N-cyclopropyl-3-(4-((2,5-difluorophenyl)difluoromethyl)piperidin-1-yl)-7-methylpyrido[3,4-b]pyrazin-2-amine
    N-cyclopropyl-3-(4-((2,4-difluorophenyl)difluoromethyl)piperidin-1-yl)-5-methylpyrido[3,4-b]pyrazin-2-amine
    N-cyclopropyl-3-(4-((2,5-difluorophenyl)difluoromethyl)piperidin-1-yl)-5-methylpyrido[3,4-b]pyrazin-2-amine
    2-(cyclopropylamino)-3-(4-((2,4-difluorophenyl)difluoromethyl)piperidin-1-yl)quinoxaline-6-carbonitrile
    N-cyclopropyl-3-(4-((2,4-difluorophenyl)difluoromethyl)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine
    2-(cyclopropylamino)-3-(4-((2,5-difluorophenyl)difluoromethyl)piperidin-1-yl)quinoxaline-6-carbonitrile
    (S)-2-(cyclopropylamino)-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)pyrido[3,4-b]pyrazine-7-carbonitrile
    (R)-2-(cyclopropylamino)-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)pyrido[3,4-b]pyrazine-7-carbonitrile
    (R)-3-(cyclopropylamino)-2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)pyrido[3,4-b]pyrazine-7-carbonitrile
    (S)-3-(cyclopropylamino)-2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)pyrido[3,4-b]pyrazine-7-carbonitrile
    N-cyclopropyl-3-(4-(pyridin-3-yloxy)piperidin-1-yl)pyrido[3,4-b]pyridin-2-amine
    N-cyclopropyl-3-(4-(4-methoxyphenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine
    N-cyclopropyl-3-(4-(pyridin-2-yloxy)piperidin-1-yl)pyrido[3,4-b]pyridin-2-amine
    N-cyclopropyl-3-(4-(pyridin-4-yloxy)piperidin-1-yl)pyrido[3,4-b]pyridin-2-amine
    (1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)(2-methoxyphenyl)methanone, 2,2,2-trifluoroacetic acid salt
    4-((1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)oxy)benzonitrile
    (2-chlorophenyl)(1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)methanone, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-3-(4-(3-methoxyphenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-3-(4-(2-methoxyphenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    (1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)(phenyl)methanone
    (1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)(2,3-difluorophenyl)methanone, 2,2,2-trifluoroacetic acid salt
    (3-chlorophenyl)(1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)methanone
    3-((1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)oxy)benzonitrile
    (1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)(3-methoxyphenyl)methanone
    (1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)(o-tolyl)methanone, 2,2,2-trifluoroacetic acid salt
    (1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)(2,6-difluorophenyl)methanone, 2,2,2-trifluoroacetic acid salt
    (2-chloro-5-fluorophenyl)(1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)methanone, 2,2,2-trifluoroacetic acid salt
    (1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)(3-fluorophenyl)methanone, 2,2,2-trifluoroacetic acid salt
    (6-chloro-2,3-difluorophenyl)(1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)methanone, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    (2-chloro-3-fluorophenyl)(1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)methanone, hydrogen chloride salt
    (2-chlorothiophen-3-yl)(1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)methanone,
    hydrogen chloride salt
    (1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)(thiophen-2-yl)methanone, 2,2,2-trifluoroacetic acid salt
    2-((1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)oxy)benzonitrile
    (2-chloro-6-fluorophenyl)(1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)methanone
    (S)-2-(cyclopropylamino)-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-N,N-dimethylpyrido[3,4-b]pyrazine-7-carboxamide, 2,2,2-trifluoroacetic acid salt
    (S)-2-(cyclopropylamino)-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-N,N-dimethylpyrido[3,4-b]pyrazine-7-carboxamide, 2,2,2-trifluoroacetic acid salt
    (R)-2-(cyclopropylamino)-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-N,N-dimethylpyrido[3,4-b]pyrazine-7-carboxamide, 2,2,2-trifluoroacetic acid salt
    (S)-(2-(cyclopropylamino)-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)pyrido[3,4-b]pyrazin-7-yl)(morpholino)methanone, 2,2,2-trifluoroacetic acid salt
    (R)-(2-(cyclopropylamino)-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)pyrido[3,4-b]pyrazin-7-yl)(morpholino)methanone, 2,2,2-trifluoroacetic acid salt
    (1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)(2-(methylthio)phenyl)methanone, 2,2,2-trifluoroacetic acid salt
    1-(4-((1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)oxy)phenyl)ethanone, 2,2,2-trifluoroacetic acid salt
    2,2,2-trifluoroacetic acid, 1-(4-((1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)oxy)phenyl)ethanol salt
    (1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)(thiophen-3-yl)methanone, 2,2,2-trifluoroacetic acid salt
    (2-bromophenyl)(1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)methanone, 2,2,2-trifluoroacetic acid salt
    (2-bromopyridin-3-yl)(1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)methanone, 2,2,2-trifluoroacetic acid salt
    3-(1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidine-4-carbonyl)-4-fluorobenzonitrile, 2,2,2-trifluoroacetic acid salt
    4-((1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)oxy)-N,N-dimethylbenzamide, 2,2,2-trifluoroacetic acid salt
    (R)-azetidin-1-yl(2-(cyclopropylamino)-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)pyrido[3,4-b]pyrazin-7-yl)methanone
    (R)-(2-(cyclopropylamino)-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)pyrido[3,4-b]pyrazin-7-yl)(3-fluoroazetidin-1-yl)methanone
    (S)-azetidin-1-yl(2-(cyclopropylamino)-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)pyrido[3,4-b]pyrazin-7-yl)methanone
    7-chloro-N-cyclopropyl-3-(4-(2,4-difluorobenzyl)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine
    (1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)(2-fluoro-5-(methylthio)phenyl)methanone, 2,2,2-trifluoroacetic acid salt
    (S)—N-cyclopropyl-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)pyrazino[2,3-d]pyridazin-2-amine, 2,2,2-trifluoroacetic acid salt
    4-chloro-3-(1-(7-chloro-2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidine-4-carbonyl)benzonitrile
    3-(4-(5-cyano-2-(dimethylcarbamoyl)benzoyl)piperidin-1-yl)-2-(cyclopropylamino)-N,N-dimethylpyrido[3,4-b]pyrazine-7-carboxamide
    2-(cyclopropylamino)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N,N-dimethylpyrido[3,4-b]pyrazine-7-carboxamide
    N-cyclopropyl-3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)pyrazino[2,3-d]pyridazin-2-amine, 2,2,2-trifluoroacetic acid salt
    (R)—N-cyclopropyl-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)pyrazino[2,3-d]pyridazin-2-amine, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-3-(4-(4-(methylthio)phenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-3-(4-(4-ethoxyphenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(1-(7-bromo-2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidine-4-carbonyl)-4-fluorobenzonitrile
    (2-(cyclopropylamino)-3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazin-7-yl)(4-methylpiperazin-1-yl)methanone
    2-(cyclopropylamino)-3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-N,N-dimethylpyrido[3,4-b]pyrazine-5-carboxamide
    2-(cyclopropylamino)-3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazine-5-carbonitrile, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-5-morpholinopyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    N2-cyclopropyl-3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-N5,N5-dimethylpyrido[3,4-b]pyrazine-2,5-diamine, 2,2,2-trifluoroacetic acid salt
    3-(4-(2-chloro-5-fluorobenzoyl)piperazin-1-yl)-2-(cyclopropylamino)-N,N-dimethylpyrido[3,4-b]pyrazine-7-carboxamide
    N-cyclopropyl-2-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazin-3-amine, 2,2,2-trifluoroacetic acid salt
    azetidin-1-yl(2-(cyclopropylamino)-3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazin-5-yl)methanone, 2,2,2-trifluoroacetic acid salt
    (2-(cyclopropylamino)-3-(4-(2,4-difluorobenzyl)piperazin-1-yl)pyrido[3,4-b]pyrazin-7-yl)(morpholino)methanone, 2,2,2-trifluoroacetic acid salt
    2-(cyclopropylamino)-3-(4-(2,4-difluorobenzyl)piperazin-1-yl)pyrido[3,4-b]pyrazine-5-carbonitrile, 2,2,2-trifluoroacetic acid salt
    2-(cyclopropylamino)-3-(4-(2-fluoro-4-methoxybenzyl)piperazin-1-yl)pyrido[3,4-b]pyrazine-5-carbonitrile, 2,2,2-trifluoroacetic acid salt
    2-(cyclopropylamino)-3-(4-(2-fluoro-4-methoxybenzyl)piperazin-1-yl)-N,N-dimethylpyrido[3,4-b]pyrazine-7-carboxamide, 2,2,2-trifluoroacetic acid salt
    4-((1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)oxy)-3-fluorophenol, 2,2,2-trifluoroacetic acid salt
    3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-N-isopropylpyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-N-isopropylpyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-3-(4-(2-fluoro-4-(methylthio)phenoxy)piperidin-1-yl)pyrazino[2,3-d]pyridazin-2-amine, 2,2,2-trifluoroacetic acid salt
    N-cyclopropyl-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazino[2,3-d]pyridazin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropylpyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-N-isopropylpyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    N-ethyl-3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
    4-((1-(3-(cyclopropylamino)pyrazino[2,3-d]pyridazin-2-yl)piperidin-4-yl)oxy)-3-fluorophenol
    3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-N-isopropylpyrazino[2,3-d]pyridazin-2-amine, 2,2,2-trifluoroacetic acid salt
    4-((1-(2-(cyclopropylamino)pyrido[34-b]pyrazin-3-yl)piperidin-4-yl)oxy)-3-fluorobenzonitrile, 22,2,2-trifluoroacetic acid salt
    2-(4-(4-chloro-2-fluorophenoxy)piperidin-1-yl)-3-(isopropylamino)quinoxaline-6-carbonitrile, hydrogen chloride salt
    2-(4-(2-chloro-5-(isopropylamino)benzoyl)piperidin-1-yl)-3-(isopropylamino)quinoxaline-6-carbonitrile
    3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-2-(isopropylamino)pyrido[3,4-b]pyrazine-7-carbonitrile, 2,2,2-trifluoroacetic acid salt
    3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-2-(isopropylamino)-N,N-dimethylpyrido[3,4-b]pyrazine-7-carboxamide, 2,2,2-trifluoroacetic acid salt
    3-(4-(4-chloro-2-fluorophenoxy)piperidin-1-yl)-2-(isopropylamino)-N,N-dimethylpyrido[3,4-b]pyrazine-7-carboxamide, 2,2,2-trifluoroacetic acid salt
    3-(4-(2,5-difluorobenzoyl)piperidin-1-yl)-2-(isopropylamino)pyrido[3,4-b]pyrazine-7-carbonitrile, 2,2,2-trifluoroacetic acid salt
    3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropylpyrazino[2,3-d]pyridazin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropylpyrazino[2,3-d]pyridazin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(2,4-difluorobenzyl)piperazin-1-yl)-2-(isopropylamino)-N,N-dimethylpyrido[3,4-b]pyrazine-7-carboxamide, 2,2,2-trifluoroacetic acid salt
    3-(4-(2,5-difluorobenzoyl)piperidin-1-yl)-2-(isopropylamino)-N,N-dimethylpyrido[3,4-b]pyrazine-7-carboxamide, 2,2,2-trifluoroacetic acid salt
    3-(4-(2-fluoro-4-methoxybenzyl)piperidin-1-yl)-2-(isopropylamino)pyrido[3,4-b]pyrazine-7-carbonitrile, 2,2,2-trifluoroacetic acid salt
    (S)—N-(sec-butyl)-3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)pyrazino[2,3-d]pyridazin-2-amine, 2,2,2-trifluoroacetic acid salt
    (R)—N-(sec-butyl)-3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)pyrazino[2,3-d]pyridazin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-fluoro-4-((1-(3-(isopropylamino)pyrazino[2,3-d]pyridazin-2-yl)piperidin-4-yl)oxy)benzonitrile, 2,2,2-trifluoroacetic acid salt
    (R)-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-N-isopropylpyrazino[2,3-d]pyridazin-2-amine, 2,2,2-trifluoroacetic acid salt
    (2-fluoro-4-methoxyphenyl)(1-(3-(isopropylamino)pyrazino[2,3-d]pyridazin-2-yl)piperidin-4-yl)methanone, 2,2,2-trifluoroacetic acid salt
    3-(4-(2-fluoro-4-methoxybenzyl)piperidin-1-yl)-N-isopropylpyrazino[2,3-d]pyridazin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(4-chloro-2-fluorophenoxy)piperidin-1-yl)-N-isopropylpyrazino[2,3-d]pyridazin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-(4-chloro-2-fluorophenoxy)piperidin-1-yl)-N-isopropylpyrazino[2,3-d]pyridazin-2-amine, 2,2,2-trifluoroacetic acid salt
    3-(4-((R)-(2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-N-((1R,2R)-2-methylcyclopropyl)pyrazino[2,3-d]pyridazin-2-amine, 2,2,2-trifluoroacetic acid salt
    2-((2,2-difluoroethyl)amino)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazine-7-carbonitrile, 2,2,2-trifluoroacetic acid salt
    2-(tert-butylamino)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazine-7-carbonitrile
    3-fluoro-4-((1-(3-(isopropylamino)pyrazino[2,3-d]pyridazin-2-yl)piperidin-4-yl)oxy)phenol, 2,2,2-trifluoroacetic acid salt
    2-((2,2-difluoroethyl)amino)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N,N-dimethylpyrido[3,4-b]pyrazine-7-carboxamide, 2,2,2-trifluoroacetic acid salt
    3-(4-(2,4-difluorobenzyl)piperazin-1-yl)-N-isopropylpyrazino[2,3-d]pyridazin-2-amine 2,2,2-trifluoroacetate
    N-isopropyl-3-(4-(3-methoxyphenoxy)piperidin-1-yl)pyrazino[2,3-d]pyridazin-2-amine 2,2,2-trifluoroacetate
    3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-5,8-dimethylpyrazino[2,3-d]pyridazin-2-amine 2,2,2-trifluoroacetate
    3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-8-methylpyrazino[2,3-d]pyridazin-2-amine
    N-cyclopropyl-3-(4-((4-fluorophenyl)sulfonyl)piperidin-1-yl)-7-methylpyrido[3,4-b]pyrazin-2-amine 2,2,2-trifluoroacetate
    3-(4-(4-chloro-2-fluorophenoxy)piperidin-1-yl)-N-cyclopropylpyrazino[2,3-d]pyridazin-2-amine 2,2,2-trifluoroacetate
    2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropylpyrido[3,4-b]pyrazin-3-amine
    N-cyclobutyl-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazin-3-amine
    3-(4-(2-fluoro-4-(fluoromethoxy)phenoxy)piperidin-1-yl)-N-isopropylpyrazino[2,3-d]pyridazin-2-amine











COMPOUND TABLE 2







MS(obs)



(M+ + 1


















1.
N-cyclopropyl-3-(3-(thiazol-5-ylmethyl)piperidin-1-yl)quinoxalin-2-amine,




2,2,2-trifluoroacetic acid salt


2.
N-cyclopropyl-3-(3-(4-fluorobenzyl)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-



amine, 2,2,2-trifluoroacetic acid salt


3.
2-(cyclopropylamino)-3-(1-(2,5-dichlorobenzyl)piperidin-4-yl)quinoxaline-6-
452.2



carbonitrile, 2,2,2-trifluoroacetic acid salt


4.
2-(cyclopropylamino)-3-(1-(2,5-difluorobenzyl)piperidin-4-yl)quinoxaline-6-
420.3



carbonitrile, 2,2,2-trifluoroacetic acid salt


5.
3-(1-(4-chlorobenzoyl)piperidin-4-yl)-2-(cyclopropylamino)quinoxaline-6-
432.25



carbonitrile, 2,2,2-trifluoroacetic acid salt


6.
N-cyclopropyl-3-(1-(2,4-difluorobenzyl)piperidin-4-yl)-7-methylpyrido[3,4-
410.3



b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt


7.
N-cyclopropyl-3-(4-(2,5-dichlorobenzyl)-2-methylpiperazin-1-yl)quinoxalin-2-
442.2



amine


8.
(4-(3-(cyclopropylamino)quinoxalin-2-yl)-3-methylpiperazin-1-yl)(2,5-
456.2



dichlorophenyl)methanone, 2,2,2-trifluoroacetic acid salt


9.
N-cyclopropyl-3-(4-(2,5-dichlorobenzyl)-3-isopropylpiperazin-1-yl)quinoxalin-
470.3



2-amine


10.
N-cyclopropyl-3-(4-(2,5-dichlorobenzyl)-3-methylpiperazin-1-yl)quinoxalin-2-
442.25.



amine, 2,2,2-trifluoroacetic acid salt









It is understood that R3, R4, R5, and R6 are substituents on carbon such that each of X1-X4 that are carbon will have a substituent selected from R3, R4, R5, and R6 and that one or two of X1-X4 are N, then one or two of R3, R4, R5, and R6 are absent.
EMBODIMENTS
Embodiment (1)
A compound of Formula (I):




wherein:
R1 is a heterocycloamino ring substituted with Ra, Rb, and Rc wherein:

    
    
        Ra is —Z—Ar where Z is C1-6 alkylene, C1-6 haloalkylene, —O—, —C(O)—, —NH—, or —S(O)n- wherein n is 0, 1, or 2; and Ar is C3-10 cycloalkyl, C3-7 heterocycloalkyl, C3-7 heterocycloalkenyl, C6-10 aryl, or C1-9 heteroaryl wherein C3-10 cycloalkyl, C3-7 heterocycloalkenyl, C3-7 heterocycloalkyl, C6-10 aryl, and C1-9 heteroaryl are optionally substituted with 1 to 3 substituents independently selected from C1-6 alkyl, halo, hydroxy, oxo, C1-6 alkoxy, C1-6 thioalkoxy, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 haloalkoxy, C1-6 alkylcarbonyl, C1-6 alkylsulphonyl, cyano, C2-12 alkoxyalkyloxy, C1-9 amide, or C1-6 hydroxyalkyloxy; and
        Rb and Rc are independently hydrogen, C1-6 alkyl, hydroxy, or halo; R2 is —ORe or —NRdRe wherein Rd is hydrogen or C1-6 alkyl and Re is C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C2-12 alkoxyalkyl, C1-12 aminoalkyl, C3-10 cycloalkyl, C4-16 cycloalkylalkyl, C6-10 aryl, C1-9 heteroaryl, C3-7 heterocyclyl, or C3-7 heterocycloalkenyl wherein C6-10 aryl, C1-9 heteroaryl, C3-7 heterocyclyl, and C3-7 heterocycloalkenyl are optionally substituted with 1 to 3 substituents independently selected from C1-6 alkyl, halo, hydroxy, oxo, C1-6 alkoxy, C1-6 haloalkyl or C1-6 haloalkoxy, or cyano;
    
    


all X1-X4 are carbon or one or two of X1-X4 are N and the rest of X1-X4 are carbon;
R3, R4, R5, and R6 are independently absent, hydrogen, C1-6 alkyl, halo, hydroxy, C1-6 alkoxy, C1-6 alkoxycarbonyl, C1-6 haloalkyl, C1-6 haloalkoxy, C1-9 amide, C3-7 heterocyclyl, C1-s alkylamino, or cyano;
or a pharmaceutically acceptable salt thereof.
Embodiment 2
The compound or pharmaceutically acceptable salt of embodiment 1, wherein:
R1 is a heterocycloamino ring of formula:




where X is carbon or nitrogen, and
R2 is —ORe or —NRdRe wherein Rd is hydrogen or C1-6 alkyl; and Re is C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C2-12 alkoxyalkyl, C1-12 aminoalkyl, C3-10 cycloalkyl, C3-10 oxocycloalkyl, phenyl, monocylic C1-5 heteroaryl, or C3-7 heterocyclylalkenyl wherein phenyl, C1-9 heteroaryl, and C3-7 heterocyclylalkenyl are optionally substituted with 1 to 3 substituents independently selected from C1-6 alkyl, halo, hydroxy, oxo, C1-6 alkoxy, C1-6 haloalkyl or C1-6 haloalkoxy, or cyano.
Within the compounds in embodiment 2, in one group of compounds, R1 is a heterocycloamino ring of formula




Embodiment 3
The compound or pharmaceutically acceptable salt of embodiment 1 or 2 or any groups contained therein, wherein R2 is —NRdRe. Within the compounds in embodiment 3, in one group of compounds, Rd is hydrogen.
Embodiment 4
The compound or pharmaceutically acceptable salt of any of the previous embodiments 1-3 and groups contained therein, wherein R1 is a heterocycloamino ring of formula:




where X is carbon or nitrogen.
Within the compounds in embodiment 4, in one group of compounds, R1 is a heterocycloamino ring of formula:




Embodiment 5
The compound or pharmaceutically acceptable salt of any of the previous embodiments 1-4 and groups contained therein, wherein all X1-X4 are carbon.
Embodiment 6
The compound or pharmaceutically acceptable salt of any of the previous embodiments 1-5 and groups contained therein, wherein X1-X4 are carbon and each of R3, R4, R5, and R6 are hydrogen.
Embodiment 7
The compound or pharmaceutically acceptable salt of any of the previous embodiments 1-4 and groups contained therein, wherein X1, X3 and X4 are carbon and X2 is CR3 or X1, X2 and X4 are carbon and X3 is CR3.
(a) Within the groups in embodiment 7, in one group of compounds each and R4, R5, and R6 are hydrogen and X2 is CR3. Within groups of compounds in (a), in one group of compounds R3 is halo, C1-6 alkyl, C1-6 alkoxy or cyano. Within groups of compounds in (a), in one group of compounds R3 is cyano, methyl, methoxy, chloro or fluoro. Within groups of compounds in (a), in yet another group of compounds R3 is halo or cyano. Within groups of compounds in (a), in one group of compounds R3 is cyano or fluoro.
(b) Within the groups in embodiment 7, in another group of compounds each and R4, R5, and R6 are hydrogen and X3 is CR3. Within groups of compounds in (b), in one group of compounds R3 is halo, C1-6 alkyl, C1-6 alkoxy or cyano. Within groups of compounds in (b), in one group of compounds R3 is cyano, methyl, methoxy, chloro or fluoro. Within groups of compounds in (b), in one group of compounds R3 is cyano or fluoro.
Embodiment 8
The compound or pharmaceutically acceptable salt of any of the previous embodiments 1-4 and groups contained therein, wherein one or both of X2 and X3 are nitrogen and the remaining X1-X4 are carbon.
(a). Within groups in embodiment 8, in one group of compounds X2 is N. Within groups of compounds in (a), in one group of compounds X2 is N, X1 is CR3 where R3 is hydrogen, halo, C1-6 alkyl, C1-6 alkoxy, cyano or hydroxy and R4 is absent, and each of R5 and R6 are hydrogen. Within groups of compounds in (a), in another group of compounds X2 is N, X1 is CR3 where R3 is fluoro, chloro, methyl, ethyl, cyano, or methoxy and R4 is absent, and each of R5 and R6 are hydrogen. Within groups of compounds in (a), in another group of compounds X2 is N and R3 is absent, and each of R4, R5, and R6 are hydrogen.
(b). Within groups in embodiment 8, in another group of compounds X2 is N, X3 is CR3 where R3 is hydrogen, C1-6 alkyl, C1-6 alkoxy, halo, or cyano and X1 and X4 are carbon. Within groups of compounds in (b), in another group of compounds X2 is N, X3 is CR3 where R3 is cyano, fluoro, chloro, methyl, ethyl, or methoxy and R4 is absent, and each of R5 and R6 are hydrogen. Within groups of compounds in (b), in another group of compounds X2 is N, X3 is CR3 where R3 is cyano, fluoro, chloro, methyl, or methoxy and R4 is absent, and each of R5 and R6 are hydrogen.
(c). Within groups in embodiment 8, in another group of compounds X3 is N. Within groups of compounds in (c), in one group of compounds X3 is N, X2 is CR3 where R3 is hydrogen, halo, C1-6 alkyl, C1-6 alkoxy, or cyano and R4 is absent, and each of R5 and R6 are hydrogen. Within groups of compounds in (c), in another group of compounds X3 is N, X2 is CR3 where R3 is fluoro, chloro, methyl, ethyl, cyano, or methoxy and R4 is absent, and each of R5 and R6 are hydrogen. Within groups of compounds in (c), in another group of compounds X3 is N, X2 is CR3 where R3 is fluoro, chloro, methyl, cyano, or methoxy and X1 and X4 are CH. Within groups of compounds in (c), in another group of compounds X3 is N and each of R4, R5, and R6 are hydrogen.
(d). Within groups in embodiment 8, in yet another group of compounds X2 and X3 are nitrogen. Within groups of compounds in (d), in one group of compounds and R4 each of R5 and R6 are hydrogen.
Embodiment 9
The compound or pharmaceutically acceptable salt of any of the previous embodiments 1-8 and groups contained therein, wherein R2 is —NHRe.
Embodiment 10
The compound or pharmaceutically acceptable salt of any of the previous embodiments 1-8 and groups contained therein, wherein R2 is —NHRe wherein Re is C3-10 cycloalkyl. Within the groups in embodiment 10, in one group of compounds, Re is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Within the groups in embodiment 10, in another group of compounds, Re is cyclopropyl.
Embodiment 11
The compound or pharmaceutically acceptable salt of any of the previous embodiments 1-8 and groups contained therein, wherein R2 is —NHRe wherein Re is C4-16 cycloalkylalkyl. Within the groups in embodiment 11, in one group of compounds, Re is cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or cyclohexylmethyl. Within the groups in embodiment 10, in another group of compounds, Re is cyclopropylmethyl.
Embodiment 12
The compound or pharmaceutically acceptable salt of any of the previous embodiments 1-8 and groups contained therein, wherein R2 is —NHRe wherein Re is C1-6 alkyl. Within the groups in embodiment 12, in one group of compounds, Re is isobutyl, tert-butyl, n-propyl, isopropyl, 2-ethylbutyl, 4-methylpent-2-yl, 2,2-dimethylpropyl, 3,3-dimethylbutyl, 3-methylbutyl, but-2-yl. Within the groups in embodiment 12, in another group of compounds, Re is isopropyl.
Embodiment 13
The compound or pharmaceutically acceptable salt of any of the previous embodiments 1-8 and groups contained therein, wherein R2 is —NHRe wherein Re is hydroxyalkyl. Within the groups in embodiment 12, in one group of compounds, Re is 2-hydroxyethyl, 3-hydroxypropyl, or (R)-3-hydroxyprop-2-yl.
Embodiment 14
The compound or pharmaceutically acceptable salt of any of the previous embodiments 1-8 and groups contained therein, wherein R2 is —NHRe wherein Re is C2-12 alkoxyalkyl. Within the groups in embodiment 12, in one group of compounds, Re is 2-methoxyethyl, 3-methoxypropyl, 2-ethoxyethyl, 2-isopropoxyethyl, or 3-ethoxypropyl.
Embodiment 15
The compound or pharmaceutically acceptable salt of any of the previous embodiments 1-8 and groups contained therein, wherein R2 is —NHRe wherein Re is C1-12 aminoalkyl.
Embodiment 16
The compound or pharmaceutically acceptable salt of any of the previous embodiments 1-8 and groups contained therein, wherein R2 is —NHRe wherein Re is C1-6 haloalkyl. Within the groups in embodiment 12, in one group of compounds Re is 2,2,2-trifluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, or 3,3,3-trifluoropropyl.
Embodiment 17
The compound or pharmaceutically acceptable salt of any of the previous embodiments 1-8 and groups contained therein, wherein R2 is —NHRe wherein Re is C3-7 heterocyclyl or C3-7 heterocycloalkenyl optionally substituted with 1 to 3 substituents independently selected from C1-6 alkyl, halo, hydroxy, C1-6 alkoxy, C1-6 haloalkyl or C1-6 haloalkoxy, or cyano. Within the groups in embodiment 12, in one group of compounds, Re is tetrahydropyran-4-yl, oxetan-3-yl, or of the formula:




Embodiment 18
The compound or pharmaceutically acceptable salt of any of the previous embodiments 1-8 and groups contained therein, wherein R2 is —NHRe wherein Re is monocylic C1-9 heteroaryl optionally substituted with 1 to 3 substituents independently selected from C1-6 alkyl, halo, hydroxy, C1-6 alkoxy, haloalkyl or haloalkoxy, or cyano. Within the groups in embodiment 18, in one group of compounds, Re is pyridin-3-yl, pyridin-2-yl, pyridin-4-yl, thia[1,3,4]diazol-2-yl, thiazol-2-yl, pyrimidin-2-yl, pyrimidin-5-yl, pyrazin-2-yl, pyrimidin-6-yl, pyridazin-3-yl, 1,2,4-triazin-3-yl, 5,6-dimethyl-1,2,4-triazin-3-yl, 3,4-dimethylisoxazol-5-yl, 2-hydroxypyridin-5-yl (tautomeric form pyridin-2(1H)-one), 2-methoxypyridin-5-yl, or isoxazol-3-yl.
Embodiment 19
The compound or pharmaceutically acceptable salt of any of the previous embodiments 1-8 and groups contained therein, wherein R2 is —NHRe wherein Re is phenyl optionally substituted with 1 to 3 substituents independently selected from C1-6 alkyl, halo, hydroxy, C1-6 alkoxy, haloalkyl or haloalkoxy, or cyano. Within the groups in embodiment 19, in one group of compounds, Re is 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 4-fluorophenyl, phenyl, 4-trifluoromethoxyphenyl, 4-n-propylphenyl, 4-methylphenyl, 4-tert-butylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-isopropoxyphenyl, or 4-cyanophenyl.
Embodiment 20
The compound or pharmaceutically acceptable salt of any of the previous embodiments 1-19 and groups contained therein, wherein R1 is a heterocycloamino ring of formula:




Within this group of compounds in another embodiment are compounds, wherein R1 is a heterocycloamino ring of formula:





Embodiment 21
The compound or pharmaceutically acceptable salt of any of the previous embodiments 1-19 and groups contained therein, wherein R1 is a heterocycloamino ring of formula:




Within this group of compounds in another embodiment are compounds, wherein R1 is a heterocycloamino ring of formula:





Embodiment 22
The compound or pharmaceutically acceptable salt of any of the previous embodiments 1-21 wherein Z is C1-6 alkyene. Within the groups in embodiment 22, in one group of compounds Z is —CH2—, —CH(CH3)—, or —(CH2)2, more preferably —CH2—.
Embodiment 23
The compound or pharmaceutically acceptable salt of any of the previous embodiments 1-20 wherein Z is C1-6 haloalkylene. Within the groups in embodiment 23, in one group of compounds Z is —*CHF—; —*CF(CH3)—, or —CF2— where the stereochemistry at *C is (RS), (R) or (S). Within the groups in embodiment 23, in one group of compounds Z is —*CHF— where the stereochemistry at *C is (RS), (R) or (S).
Embodiment 24
The compound or pharmaceutically acceptable salt of any of the previous embodiments 1-20 wherein Z is —O— provided Z is attached to a carbon atom in R1.
Embodiment 25
The compound or pharmaceutically acceptable salt of any of the previous embodiments 1-21 wherein wherein Z is —C(O)—.
Embodiment 26
The compound or pharmaceutically acceptable salt of any of the previous embodiments 1-21 wherein wherein Z is SO2.
Embodiment 27
The compound or pharmaceutically acceptable salt of any of the previous embodiments 1-20 wherein Z is —NH— provided Z is attached to a carbon atom in R1.
Embodiment 28
The compound or pharmaceutically acceptable salt of any of the previous embodiments 1-27 wherein Ar is phenyl optionally substituted with 1 to 3 substituents independently selected from C1-6 alkyl, halo, hydroxy, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkylsulphonyl, C1-6 alkylcarbonyl, cyano, C2-12 alkoxyalkyloxy, or C1-6 hydroxyalkyloxy. Within the groups in embodiment 28, in one group of compounds in one group of compounds Ar is phenyl optionally substituted with 1 to 3 substituents independently selected from halo or cyano, preferably fluoro. Within the groups in embodiment 28, in another group of compounds Ar is phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4-ethylphenyl, 3-isopropylphenyl, 4-ethoxyphenyl, 3-CF3phenyl, 4-CF3phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-chloromethylphenyl, 4-difluoromethylphenyl, 2-bromophenyl, 4-bromophenyl, 2-cyanophenyl, 3-cyanophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 4-isopropylphenyl, 3-bromophenyl, 4-methylsulfonylphenyl, 4-cyanophenyl, 4-tert-butylphenyl, 3-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-OCF3phenyl,2,3-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl, 2-chloro-4-methylsulfonylphenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 3,4-dimethylphenyl, 4-fluoro-2-methylphenyl, 2-fluoro-5-methylphenyl, 5-fluoro-2-methylphenyl, 5-chloro-2-difluoromethoxyphenyl, 4-chloro-3-methylphenyl, 2,3-dimethylphenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl, 2-bromo-5-chlorophenyl, 3-bromo-4-methylphenyl, 2-bromo-4-methylphenyl, 3-bromo-2-methylphenyl, 4-fluoro-3-methoxyphenyl, 2-bromo-5-methoxyphenyl, 3-bromo-4-methoxyphenyl, 4-bromo-2-chlorophenyl, 3-bromo-4-fluorophenyl, 4-bromo-2-fluorophenyl, 4-bromo-3-methylphenyl, 4-bromo-2-methylphenyl, 4-bromo-3-fluorophenyl, 4-chloro-2-methoxyphenyl, 5-bromo-2-fluorophenyl, 5-bromo-2-methylphenyl, 5-chloro-2-methylphenyl, 5-chloro-2-trifluoromethylphenyl, 4-chloro-2-methylphenyl, 4-chloro-3-methylphenyl, 2-chloro-5-methoxyphenyl, 3-chloro-4-methoxyphenyl, 2-chloro-4-fluorophenyl, 2-chloro-5-fluorophenyl, 3-chloro-4-fluorophenyl, 2-chloro-6-trifluoromethylphenyl, 2-chloro-5-iodophenyl, 4-chloro-2-hydroxyphenyl, 2-methoxy-4-methylphenyl, 2-methoxy-5-trifluoromethoxyphenyl, 2-methoxy-5-trifluoromethylphenyl, 2-chloro-6-difluoromethoxyphenyl, 5-chloro-2-propoxyphenyl, 2-methoxy-5-tert-butylphenyl, 4-chloro-2-fluorophenyl, 5-chloro-2-fluorophenyl, 4-cyano-2-fluorophenyl, 4-bromo-3-trifluoromethylphenyl, 2-fluoro-4-trifluoromethylphenyl, 3-cyano-4-isopropoxyphenyl, 2-fluoro-4-methylphenyl, 2-fluoro-4-methoxyphenyl, 4-fluoro-2-hydroxyphenyl, 4-chloro-2-trifluoromethylphenyl, 4-chloro-3-fluorophenyl, 2-chloro-5-trifluoromethylphenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2-chloro-4-trifluoromethylphenyl, 3-cyano-4-fluorophenyl, 5-chloro-2-methoxyphenyl, 2-chloro-3,6-difluorophenyl, 2,3,5-trichlorophenyl, 2,6-difluoro-3-methylphenyl, 4-chloro-2,6-difluorophenyl, 2,4,6-trifluorophenyl, 2,4-difluoro-6-hydroxyphenyl, 2,4,5-trifluorophenyl, 2,4,6-trimethylphenyl, 2,3,4-trifluorophenyl, 4-chloro-2-5-dimethylphenyl, 3-chloro-5-fluoro-2-methylphenyl, 5-chloro-2,4-difluorophenyl, or 4-bromo-2,5-difluorophenyl. Within the groups in embodiment 28, in yet another group of compounds Ar is 5-chloro-2-fluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl.
Embodiment 29
The compound or pharmaceutically acceptable salt of any of the previous embodiments 1-27 wherein Ar is C1-9 heteroaryl optionally substituted with 1 to 3 substituents independently selected from C1-6 alkyl, halo, hydroxy, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkylsulphonyl, C1-6 alkylcarbonyl, cyano, C2-12 alkoxyalkyloxy, or C1-6 hydroxyalkyloxy. Within the groups in embodiment 29, in one group of compounds Ar is monocyclic C1-9 heteroaryl optionally substituted with 1 to 3 substituents independently selected from C1-6 alkyl, halo, hydroxy, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkylsulphonyl, C1-6 alkylcarbonyl, cyano, C2-12 alkoxyalkyloxy, or C1-6 hydroxyalkyloxy. Within the groups in embodiment 29, in another group of compounds Ar is Ar is pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, 2,5-dichlorothien-3-yl, benzofuran-3-yl, 2,5-difluoropyridin-3-yl, 2,5-dichloropyridin-4-yl, 5-chloro-2-fluoropyridin-2-yl, 3-fluoropyridin-2-yl, 3,6-dichloropyridin-2-yl, 5-methylisoxazol-3-yl, indol-5-yl, indol-6-yl, benzo[d][1,2,3]thiadiazol-5-yl, 3,5-dimethylisoxazol-4-yl, 5-chlorothien-2-yl, 5-bromothien-2-yl, 5-chloro-1,3-dimethylpyrazol-4-yl, 5-bromo-6-chloropyridin-3-yl, 3-methyl-[1,2,4]-oxadiazol-5-yl, thiazol-5-yl, 5-methyloxazol-2-yl, 3-fluoro-5-chloropyridin-2-yl, or 2-chloro-5-fluoropyridin-3-yl.
Embodiment 30
The compound or pharmaceutically acceptable salt of any of the previous embodiments 1-27 wherein Ar is Ar is C3-7 heterocycloalkenyl optionally substituted with 1 to 3 substituents independently selected from C1-6 alkyl, halo, hydroxy, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkylsulphonyl, C1-6 alkylcarbonyl, cyano, C2-12 alkoxyalkyloxy, or C1-6 hydroxyalkyloxy. Within the groups in embodiment 29, in one group of compounds Ar is of the formula:




Embodiment 31
The compound or pharmaceutically acceptable salt of any of the previous embodiments 1-30 wherein Rb and Rc are hydrogen.
General Synthetic Scheme
Compounds of this invention can be made by the methods depicted in the reaction schemes shown below.
The starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Bachem (Torrance, Calif.), or Sigma (St. Louis, Mo.) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition) and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989). These schemes are merely illustrative of some methods by which the compounds of this invention can be synthesized, and various modifications to these schemes can be made and will be suggested to one skilled in the art having referred to this disclosure. The starting materials and the intermediates, and the final products of the reaction may be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography and the like. Such materials may be characterized using conventional means, including physical constants and spectral data.
Unless specified to the contrary, the reactions described herein take place at atmospheric pressure over a temperature range from about −78° C. to about 150° C., more preferably from about 0° C. to about 125° C. and most preferably at about room (or ambient) temperature, e.g., about 20° C.
Compounds of Formula (I) where R1 is heterocycloamino attached to the core ring via nitrogen atom, R2 is NRdRe, Rb, Rc, R3, R4, R5, R6, X1, X2, X3, X4, Ar, and Z are as defined in the Summary of the Invention can be prepared as illustrated and described in Scheme A below.




Treatment of a compound of formula 1 where Rd and Re are defined in the Summary of the Invention with a compound of formula 2 where Hal is halo, R3, R4, R5, X1, X2, X3, and X4 are as defined in the Summary of the Invention, provides a compound of formula 3. Compounds of formula 1 are either commercially available or can be ready prepared by methods well known in the art. The reaction is carried out in a suitable organic solvent like dioxane, ethanol, tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide and the like (with or without a base such as sodium hydride, diisopropylethylamine or triethylamine) and takes upon heating at a suitable temperature between 20 to 150° C.
Compounds of formula 2 are either commercially available or can be readily prepared by methods well known in the art. For example, compounds of formula 2 where halo is chloro can be prepared by condensation of an aryl diamine with oxalic acid in a suitable aqueous acid, which upon treatment with a halogenating reagent such as thionyl chloride or phosphorous oxychloride and the like (with or without catalytic N,N-dimethylformamide) provides the compound of formula 2 were Hal is Cl. Compounds of formula 2 such as where X2 or X3 is nitrogen, as well as where R3 or R4 or R5 is C1-6 alkyl, cyano, and halo are commercially available.
Treatment of compound 3 with a heterocycloamino compound of formula 4 provides a compound of Formula (I). The reaction is carried out with or without base such as diisopropylethylamine and triethylamine, in a suitable organic solvent like dioxane, n-butanol, dimethyl sulfoxide and the like. Compounds of formula 4 are either commercially available or they can be readily prepared by methods well known in the art. For example, compounds of formula 4 where Z is oxygen can be prepared by Mitsunobu reaction between a piperidinol and an aryl alcohol. The reaction is usually carried out in the presence of a phosphine such as PPh3, PMe3, and the like and an activating reagent such as DEAD, DIAD and the like, in a suitable organic solvent such as tetrahydrofuran, toluene, dichloromethane, acetonitrile and the like. The reaction is usually carried out in the 0-80° C. temperature range.
Alternatively, a compound of formula 3 can be treated with piperazine which can be further modified by reductive amination, alkylation, arylation, amidation, sulfonylation and the like to provide a compound of Formula (I).
Compounds of Formula (I) can be converted to other compounds of Formula (I). For example, compounds of Formula (I) where Z is monosubstituted with fluorine can be prepared from the corresponding carbonyl by first reducing the carbonyl group to an alcohol group and then fluorination under conditions well known in the art. The reaction is typically carried out in the presence of a fluorinating agent such as DAST and the like, in a suitable solvent such as methanol and the like. The reaction is usually carried out in the −78 to 25° C. temperature range.
Alternatively, compounds of Formula (I) where Z is methylene can be prepared from the corresponding carbonyl compound by conditions well known in the art. The reaction is typically carried out in the presence of a reducing agent such as diisobutylaluminum hydride, borane-tetrahydrofuran, sodium borohydride and the like, in a suitable organic solvent such as dichloromethane, tetrahydrofuran, and the like.
Compounds of Formula (I) can also be prepared by reversing the order of addition of compounds of formula 1 and formula 4. Addition of compounds of formula 4 with compounds of formula 2 as defined in the Summary of the Invention, followed by addition of compounds of formula 1 as defined in the Summary of the Invention, provides a compound of Formula (I) with a different regiochemical outcome as that shown in Scheme A.
Detailed descriptions of some such transformations are provided in Working Examples below.
Alternatively, compounds of Formula (I) where R1 is heterocycloamino attached to the core ring via carbon atom, R2 is NRdRe, Rb, Rc, R3, R4, R5, R6, X1, X2, X3, X4, Ar, and Z are as defined in the Summary of the Invention, can be prepared as illustrated and described in Scheme B below.




Compounds of formula 6 can be prepared by reaction of a compound of formula 3 with a heterocycloaminoalkenyl of formula 5 where PG is a nitrogen protecting group. The reaction is carried out in the presence of a common palladium catalyst such as Pd(PPh3)2Cl2, Pd(PPh3)4, Pd2dba3 and the like and a base such as K2C(O)3 and the like in a suitable organic solvent such as acetonitrile, dioxane, N,N-dimethylformamide and the like. The reaction is usually heated up to 70-175° C. Compounds of formula 5 such as tetrahydropyridine are commercially available.
Compounds of formula 7 can be prepared by hydrogenation of a compound of formula 6. The reaction is usually carried out in the presence of a common palladium catalyst such as Pd on carbon and the like under a hydrogen atmosphere in a suitable organic solvent such as methanol, ethanol and the like. Acidic hydrolysis of the carbamate group provides the compound in formula 7.
Compounds of formula 7 can be converted to compounds of Formula (I). For example, compounds of formula 7 can be subjected to alkylation, arylation, sulfonylation, reductive amination and the like under conditions well known in the art.
Utility
The GPR6 receptor exhibits high expression in the central nervous system (CNS) with minimal expression in peripheral tissues. GPR6 is highly selectively enriched in D2 receptor expressing MSNs in the striatum. The striatum plays a central role in modulating important behaviors including movement, reward, and motivational processes. GPR6 is GPCR that exhibits receptor signaling via the Gs pathway. Thus, GPR6 agonist activity results in an increase in intracellular cAMP levels whereas antagonists or inverse agonists cause a decrease in cAMP levels. GPR6 activity is therefore functionally opposed to D2 receptor signaling which operates via the Gi pathway i.e., an agonist decreases the level of intracellular cAMP. As such, compounds that modulate the activity of GPR6 have utility in a variety of neurological and psychiatric disorders. For example, the pathological hallmark of Parkinson disease (PD) is neuronal cell loss within the substantia nigra. Degeneration of the nigrostriatal pathway causes reduction in the striatal concentration of dopamine which results in motor and nonmotor clinical manifestations. The major striatal targets of dopaminergic innervation reside in the medium spiny neurons (MSNs) of the striatopallidal (indirect) and striatonigral (direct) output pathways. The MSNs of the direct output pathway express D1 dopamine receptors whereas those in the indirect pathway express D2 receptors.
About 75% of Parkinson's disease patients are treated with levodopa, a prodrug for dopamine discovered over 50 years ago (Dopamine Replacement Therapy). Levodopa has common serious side effects including induced dyskinesia (LID), impulsive control disorders (ICD), psychotic symptoms and sleep disturbances. LID is progressive (90% of PD patients develop LID within 10 yrs). Irreversible adaptations occur in D1 receptor signaling in MSNs in rodent models of LID including reduced desensitization leading to hypersensitivity in the direct pathway. Genetic inactivation of D1 but not D2 receptors abolishes LID in mice. However blockade of D1 receptor signaling does not affect the antiparkinsonian efficacy of L-DOPA. cAMP pathways modulated by D1/D2 dopamine receptors in MSN have been implicated in LID in PD. Dopamine D2 receptors in MSN are Gi coupled, inhibiting cAMP generation. Antagonism or inverse agonism of Gs coupled GPR6 should decrease cAMP in MSNs—a functional alternative to dopamine mediated activation of D2 receptors. As such, compounds that modulate the activity of GPR6 have utility in a variety of neurological and psychiatric disorders. For example movement disorders including Parkinson's disease and Huntington's disease either alone or in combination with other agents are approved for the treatment of Parkinson's disease including L-DOPA, dopaminergic agonists, MAO B inhibitors, DOPA decarboxylase inhibitors and C(O)MT inhibitors. Other potential disease indications that could be treated by modulation of GPR6 include drug addiction and eating disorders, cognitive disorders, schizophrenia, bipolar disorders, and depression.
Testing
The GPR6 inhibitory activity of the compounds of the present invention can be tested using the in vitro assay and in vivo assay described in working Example I and II below.
Administration and Pharmaceutical Composition
In general, the compounds of this invention will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. Therapeutically effective amounts of compounds of Formula (I) may range from about 0.01 to about 100 mg per kg patient body weight per day, which can be administered in single or multiple doses. Preferably, the dosage level will be about 0.1 to about 50 mg/kg per day; more preferably about 0.5 to about 10 mg/kg per day. For oral administration, the compositions are preferably provided in the form of tablets containing about 1.0 to about 1000 milligrams of the active ingredient, particularly about 1.0, 5.0, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of the active ingredient. The actual amount of the compound of this invention, i.e., the active ingredient, will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound utilized, the route and form of administration, and other factors.
In general, compounds of this invention will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration. The preferred manner of administration is oral using a convenient daily dosage regimen, which can be adjusted according to the degree of affliction. Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions.
The choice of formulation depends on various factors such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills or capsules are preferred) and the bioavailability of the drug substance. Recently, pharmaceutical formulations have been developed especially for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area i.e., decreasing particle size. For example, U.S. Pat. No. 4,107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1,000 nm in which the active material is supported on a crosslinked matrix of macromolecules. U.S. Pat. No. 5,145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical formulation that exhibits remarkably high bioavailability.
The compositions are comprised of in general, a compound of formula (I) in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the compound of formula (I). Such excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.
Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like. Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc. Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols.
Compressed gases may be used to disperse a compound of this invention in aerosol form. Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.
Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 18th ed., 1990).
The level of the compound in a formulation can vary within the full range employed by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt %) basis, from about 0.01-99.99 wt % of a compound of formula (I) based on the total formulation, with the balance being one or more suitable pharmaceutical excipients. Preferably, the compound is present at a level of about 1-80 wt %.
The compounds of the present invention may be used in combination with one or more other drugs in the treatment of diseases or conditions for which compounds of the present invention or the other drugs may have utility, where the combination of the drugs together are safer or more effective than either drug alone. Such other drug(s) may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of the present invention. When a compound of the present invention is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the compound of the present invention can be used. However, the combination therapy may also include therapies in which the compound of the present invention and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients may be used in lower doses than when each is used singly.
Accordingly, the pharmaceutical compositions of the present invention also include those that contain one or more other active ingredients, in addition to a compound of the present invention.
The above combinations include combinations of a compound of the present invention not only with one other active compound, but also with two or more other active compounds. Likewise, compounds of the present invention may be used in combination with other drugs that are used in the prevention, treatment, control, amelioration, or reduction of risk of the diseases or conditions for which compounds of the present invention are useful. Such other drugs may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of the present invention. When a compound of the present invention is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of the present invention is preferred. Accordingly, the pharmaceutical compositions of the present invention also include those that also contain one or more other active ingredients, in addition to a compound of the present invention. The weight ratio of the compound of the present invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used.
In one embodiment, the compound of the present invention may be administered in combination with anti-Alzheimer's agents, beta-secretase inhibitors, gamma-secretase inhibitors, HMG-CoA reductase inhibitors, NSAID's including ibuprofen, vitamin E, and anti-amyloid antibodies. In another embodiment, the compound of the present invention may be administered in combination with sedatives, hypnotics, anxiolytics, antipsychotics, antianxiety agents, cyclopyrrolones, imidazopyridines, pyrazolopyrimidines, minor tranquilizers, melatonin agonists and antagonists, melatonergic agents, benzodiazepines, barbiturates, 5HT-2 antagonists, PDE10 antagonists, and the like, such as: adinazolam, allobarbital, alonimid, alprazolam, amisulpride, amitriptyline, amobarbital, amoxapine, aripiprazole, bentazepam, benzoctamine, brotizolam, bupropion, busprione, butabarbital, butalbital, capuride, carbocloral, chloral betaine, chloral hydrate, clomipramine, clonazepam, cloperidone, clorazepate, chlordiazepoxide, clorethate, chlorpromazine, clozapine, cyprazepam, desipramine, dexclamol, diazepam, dichloralphenazone, divalproex, diphenhydramine, doxepin, estazolam, ethchlorvynol, etomidate, fenobam, flunitrazepam, flupentixol, fluphenazine, flurazepam, fluvoxamine, fluoxetine, fosazepam, glutethimide, halazepam, haloperidol, hydroxyzine, imipramine, lithium, lorazopam, lormetazepam, maprotiline, mecloqualone, melatonin, mephobarbital, meprobamate, methaqualone, midaflur, midazolam, nefazodone, nisobamate, nitrazopam, nortriptyline, olanzapine, oxazepam, paraldehyde, paroxetine, pentobarbital, perlapine, perphenazine, phenelzine, phenobarbital, prazepam, promethazine, propofol, protriptyline, quazepam, quetiapine, reclazepam, risperidone, roletamide, secobarbital, sertraline, suproclone, temazopam, thioridazine, thiothixene, tracazolate, kanylcypromaine, trazodone, triazolam, trepipam, tricetamide, triclofos, trifluoperazine, trimetozine, trimipramine, uldazepam, venlafaxine, zaleplon, ziprasidone, zolazepam, zolpidem, and salts thereof, and combinations thereof.
In another embodiment, the compound of the present invention may be administered in combination with levodopa (with or without a selective extracerebral decarboxylase inhibitor such as carbidopa or benserazide), anticholinergics such as biperiden (optionally as its hydrochloride or lactate salt) and trihexyphenidyl (benzhexol) hydrochloride, C(O)MT inhibitors such as entacapone, MOA-B inhibitors, antioxidants, A2a adenosine receptor antagonists, cholinergic agonists, NMDA receptor antagonists, serotonin receptor antagonists and dopamine receptor agonists such as alentemol, bromocriptine, fenoldopam, lisuride, naxagolide, pergolide and praripexole. It will be appreciated that the dopamine agonist may be in the form of a pharmaceutically acceptable salt, for example, alentemol hydrobromide, bromocriptine mesylate, fenoldopam mesylate, naxagolide hydrochloride and pergolide mesylate. Lisuride and pramipexol are commonly used in a non-salt form.
In another embodiment, the compound of the present invention may be administered in combination with a compound from the phenothiazine, thioxanthene, heterocyclic dibenzazepine, butyrophenone, diphenylbutylpiperidine and indolone classes of neuroleptic agent. Suitable examples of phenothiazines include chlorpromazine, mesoridazine, thioridazine, acetophenazine, fluphenazine, perphenazine and trifluoperazine. Suitable examples of thioxanthenes include chlorprothixene and thiothixene. An example of a dibenzazepine is clozapine. An example of a butyrophenone is haloperidol. An example of a diphenylbutylpiperidine is pimozide. An example of an indolone is molindolone. Other neuroleptic agents include loxapine, sulpiride and risperidone. It will be appreciated that the neuroleptic agents when used in combination with the subject compound may be in the form of a pharmaceutically acceptable salt, for example, chlorpromazine hydrochloride, mesoridazine besylate, thioridazine hydrochloride, acetophenazine maleate, fluphenazine hydrochloride, flurphenazine enathate, fluphenazine decanoate, trifluoperazine hydrochloride, thiothixene hydrochloride, haloperidol decanoate, loxapine succinate and molindone hydrochloride. Perphenazine, chlorprothixene, clozapine, haloperidol, pimozide and risperidone are commonly used in a non-salt form. Thus, the compound of the present invention may be administered in combination with acetophenazine, alentemol, aripiprazole, amisulpride, benzhexol, bromocriptine, biperiden, chlorpromazine, chlorprothixene, clozapine, diazepam, fenoldopam, fluphenazine, haloperidol, levodopa, levodopa with benserazide, levodopa with carbidopa, lisuride, loxapine, mesoridazine, molindolone, naxagolide, olanzapine, pergolide, perphenazine, pimozide, pramipexole, quetiapine, risperidone, sulpiride, tetrabenazine, trihexyphenidyl, thioridazine, thiothixene, trifluoperazine or ziprasidone.
In another embodiment, the compound of the present invention may be administered in combination with an anti-depressant or anti-anxiety agent, including norepinephrine reuptake inhibitors (including tertiary amine tricyclics and secondary amine tricyclics), selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamine oxidase (RIMAs), serotonin and noradrenaline reuptake inhibitors (SNRIs), corticotropin releasing factor (CRF) antagonists, adrenoreceptor antagonists, neurokinin-1 receptor antagonists, atypical anti-depressants, benzodiazopines, 5-HTA agonists or antagonists, especially 5-HTA partial agonists, and corticotropin releasing factor (CRF) antagonists. Specific agents include: amitriptyline, clomipramine, doxepin, imipramine and trimipramine; amoxapine, desipramine, maprotiline, nortriptyline and protriptyline; fluoxetine, fluvoxamine, paroxetine and sertraline; isocarboxazid, phenelzine, tranylcypromine and selegiline; moclobemide, venlafaxine; duloxetine; aprepitant; bupropion, lithium, nefazodone, trazodone and viloxazine; alprazolam, chlordiazepoxide, clonazopam, chlorazepate, diazopam, halazepam, lorazepam, oxazopam and prazepam; buspirone, flesinoxan, gepirone and ipsapirone, and pharmaceutically acceptable salts thereof.
EXAMPLES
The following preparations of the intermediate (References) and compounds of Formula (I) (Examples) are given to enable those skilled in the art to more clearly understand and to practice the present invention. They should not be considered as limiting the scope of the invention, but merely as being illustrative and representative thereof.
Synthetic Examples
Reference A
Synthesis of 3-chloro-N-cyclopropylquinoxalin-2-amine




A solution of 2,3-dichloroquinoxaline (400 mg, 2.010 mmol), cyclopropanamine (149 mg, 2.61 mmol) and N-ethyl-N-isopropylpropan-2-amine (526 μl, 3.01 mmol) in dioxane (2871 μl) was heated at 80° C. for 2 days. ISCO purification (10-40% EtOAc/hexanes) afforded the title compound as a light yellow solid.
Utilizing similar reaction conditions described above, following compounds were synthesized using commercially available amines and quinoxalines:
3-chloro-2-(cyclopropylamino)quinoxaline-6-carbonitrile; 3-chloro-N-cyclopropyl-6-fluoroquinoxalin-2-amine; 3-chloro-N-cyclopropyl-6,7-difluoroquinoxalin-2-amine; 3-chloro-2-(isopropylamino)quinoxaline-6-carbonitrile; 3-chloro-N-(2,2-difluoroethyl)pyrido-[3,4-b]pyrazin-2-amine; 3-chloro-N-cyclopropylpyrido[3,4-b]pyrazin-2-amine; 3,8-dichloro-N-cyclopropylpyrido[3,4-b]pyrazin-2-amine; 3-chloro-N-cyclopropyl-7-methylpyrido[3,4-b]pyrazin-2-amine; 3-chloro-N-cyclopropyl-5-methylpyrido[3,4-b]pyrazin-2-amine; 3-chloro-2-(cyclobutylamino)quinoxaline-6-carbonitrile; 3-chloro-2-((2-fluoroethyl)amino)-quinoxaline-6-carbonitrile; 3-chloro-N-(3-methoxypropyl)quinoxalin-2-amine; 3-chloro-2-((3,3,3-trifluoropropyl)amino)quinoxaline-6-carbonitrile; 6-bromo-3-chloro-N-cyclopropylquinoxalin-2-amine; 7-bromo-3-chloro-N-cyclopropylpyrido[3,4-b]pyrazin-2-amine, and 3,7-dichloro-N-cyclopropylpyrido[3,4-b]pyrazin-2-amine.
Reference B
Synthesis of 5-bromo-3-chloro-N-cyclopropylquinoxalin-2-amine and 8-bromo-3-chloro-N-cyclopropylquinoxalin-2-amine




A solution of 5-bromo-2,3-dichloroquinoxaline (250 mg, 0.899 mmol), cyclopropanamine (71.7 μl, 1.034 mmol) and N-ethyl-N-isopropylpropan-2-amine (157 μl, 0.899 mmol) in dioxane (1285 μl) was heated at 80° C. overnight. ISCO purification (20-80% EtOAc/Hexanes) yielded both pure title compounds as yellow solids.
Reference C
Synthesis of N-cyclopropyl-3-(piperazin-1-yl)quinoxalin-2-amine dihydrochloride




Step 1: tert-butyl 4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazine-1-carboxylate
A solution of 3-chloro-N-cyclopropylquinoxalin-2-amine (503 mg, 2.290 mmol), tert-butyl piperazine-1-carboxylate (640 mg, 3.43 mmol) and DIPEA (1200 μl, 6.87 mmol) in dioxane (4580 μl) was stirred at 140° C. overnight. ISCO purification (10-70% EtOAc/hexanes) afforded the title compound as an ivory solid.
Step 2: N-cyclopropyl-3-(piperazin-1-yl)quinoxalin-2-amine dihydrochloride
A solution of tert-butyl 4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazine-1-carboxylate (127 mg, 0.344 mmol) in dioxane (859 μl) was treated with HCl (859 μl, 3.44 mmol, 4 M in dioxane) at RT and the reaction stirred for 4 h. The solvent was removed under reduced pressure to afford the title compound as a tan solid.
Following the procedure described above, following compounds were synthesized using commercially available starting materials.
2-(cyclopropylamino)-3-(piperazin-1-yl)quinoxaline-6-carbonitrile; N-cyclopropyl-6-fluoro-3-(piperazin-1-yl)quinoxalin-2-amine; 3-(piperazin-1-yl)-N-(pyridin-3-yl)quinoxalin-2-amine; 2-(isopropylamino)-3-(piperazin-1-yl)quinoxaline-6-carbonitrile; 2-(cyclobutylamino)-3-(piperazin-1-yl)quinoxaline-6-carbonitrile; and N-cyclopropyl-6,7-difluoro-3-(piperazin-1-yl)quinoxalin-2-amine.
Reference D
Synthesis of 2-chloro-3-(piperazin-1-yl)quinoxaline, hydrogen chloride salt




Step 1: tert-butyl 4-(3-chloroquinoxalin-2-yl)piperazine-1-carboxylate
A solution of 2,3-dichloroquinoxaline (2 g, 10.05 mmol), tert-butyl piperazine-1-carboxylate (2.059 g, 11.05 mmol) and N-ethyl-N-isopropylpropan-2-amine (2.63 ml, 15.07 mmol) in dioxane (10.05 ml) was heated at 80° C. for 18 h. ISCO purification (5-10% EtOAc in hexanes) afforded the title compound as a yellow oil.
Step 2: 2-chloro-3-(piperazin-1-yl)quinoxaline, hydrogen chloride salt
A solution of tert-butyl 4-(3-chloroquinoxalin-2-yl)piperazine-1-carboxylate (243 mg, 0.697 mmol) in dioxane (1742 μl) was treated with HCl (1393 μl, 5.57 mmol, 4 M in dioxane) dropwise at RT and the resulting reaction mixture was stirred overnight. The solvent was removed under reduced pressure and the title compound was obtained as a yellow solid.
Reference E
Synthesis of 3-chloro-N-(pyridin-3-yl)quinoxalin-2-amine




To a solution of 2,3-dichloroquinoxaline (10 g, 50.2 mmol) in ethanol (50 mL) was added pyridin-3-amine (4.73 g, 50.2 mmol). The reaction mixture was stirred at 20° C. for 2 h. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was dried and concentrated under reduced pressure to yield the title compound as an orange-brown solid.
Reference F
Synthesis of 3-chloro-2-((6-methoxypyridin-3-yl)amino)quinoxaline-6-carbonitrile




To a suspension of NaH (10.71 mg, 0.268 mmol, 60% in mineral oil) in THF (1116 μl) was added 6-methoxypyridin-3-amine (26.8 μl, 0.245 mmol). The mixture was stirred at RT for 30 min before 2,3-dichloroquinoxaline-6-carbonitrile (50 mg, 0.223 mmol) was added. The reaction mixture was stirred for 12 h at 70° C., then for 48 h at RT. ISCO purification (0-60% EtOAc/hexanes) afforded the title compound as a yellow solid.
Following the procedure described above, 3-chloro-2-(pyridin-3-ylamino)-quinoxaline-6-carbonitrile was synthesized.
Reference G
Synthesis of 3-chloro-N-(pyrazin-2-yl)quinoxalin-2-amine




A suspension of 2,3-dichloroquinoxaline (200 mg, 1.005 mmol) and pyrazin-2-amine (191 mg, 2.010 mmol) in DMF (3 ml) was treated with NaH (80 mg, 2.010 mmol, 60% in mineral oil). Stirring was continued for 2 h at 15° C., then the reaction mixture was poured into water, extracted with EtOAc, dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound. The crude material was used without further purification.
Following the procedure described above, following compounds were synthesized using commercially available starting materials.
3-chloro-N-(pyrimidin-4-yl)quinoxalin-2-amine; 3-chloro-N-(pyridazin-3-yl)quinoxalin-2-amine; 3-chloro-N-(1,2,4-triazin-3-yl)quinoxalin-2-amine; 3-chloro-N-(5,6-dimethyl-1,2,4-triazin-3-yl)quinoxalin-2-amine; 3-chloro-N-(pyridin-4-yl)quinoxalin-2-amine; 3-chloro-N-(pyridin-2-yl)quinoxalin-2-amine; N-(3-chloroquinoxalin-2-yl)-3,4-dimethylisoxazol-5-amine; and N-(3-chloroquinoxalin-2-yl)isoxazol-3-amine.
Reference H
Synthesis of 3-chloro-N-(2,2,2-trifluoroethyl)quinoxalin-2-amine




A suspension of Et3N (0.420 ml, 3.01 mmol), 2,3-dichloroquinoxaline (200 mg, 1.005 mmol), and 2,2,2-trifluoroethanamine (199 mg, 2.010 mmol) in DMSO (5 ml) was heated at 120° C. under microwave irradiation for 1 h. The reaction mixture was concentrated under reduced pressure to give the title compound, which was used without further purification.
Following the procedure described above, 3-chloro-2-((2,2-difluoroethyl)amino)quinoxaline-6-carbonitrile was synthesized.
Reference I
Synthesis of 8-chloro-N-cyclopropyl-3-(piperazin-1-yl)pyrido[3,4-b]pyrazin-2-amine




A mixture of 3,8-dichloro-N-cyclopropylpyrido[3,4-b]pyrazin-2-amine (100 mg, 0.392 mmol) and piperazine (338 mg, 3.92 mmol) in EtOH (10 ml) was heated at 40° C. for 3 h. The reaction was concentrated to dryness and partitioned between EtOAc and water. The insoluble material was collected by filtration then dried under vacuum to give the title compound as a tan solid.
Reference J
Synthesis of piperazin-1-yl(3-(trifluoromethyl)phenyl)methanone, hydrogen chloride salt




Step 1: tert-butyl 4-(3-(trifluoromethyl)benzoyl)piperazine-1-carboxylate
A solution of 3-(trifluoromethyl)benzoic acid (1.22 g, 6.44 mmol) and HATU (2.45 g, 6.44 mmol) in DMF (16.1 mL) and iPr2NEt (16.1 mmol, 2.81 mL) was stirred at RT for 30 min, followed by the addition of tert-butyl piperazine-1-carboxylate (1.2 g, 6.44 mmol). The resulting reaction mixture was stirred at RT overnight. Purification by column chromatography (25% EtOAc/hexanes) afforded the title compound as a yellow solid.
Step 2: piperazin-1-yl(3-(trifluoromethyl)phenyl)methanone, hydrogen chloride salt
A solution of tert-butyl 4-(3-(trifluoromethyl)benzoyl)piperazine-1-carboxylate (600 mg, 1.674 mmol) in dioxane (5.58 mL) was treated with HCl (3.35 mL, 13.39 mmol, 4 M in dioxane) at RT. After stirring for 12 h, the reaction mixture was diluted with hexanes and filtered. The solid was dissolved in MeOH and the solvent was removed under reduced pressure to afford the title compound as a white solid.
Following the procedure described above, following compounds were synthesized using commercially available carboxylic acids.
(4-(methylsulfonyl)phenyl)(piperazin-1-yl)methanone, hydrogen chloride salt; (2,5-dichlorophenyl)(piperazin-1-yl)methanone, hydrogen chloride salt; (2,5-dichlorophenyl)-(piperazin-1-yl)methanone, hydrogen chloride salt; (3-chloro-4-methoxyphenyl)(piperazin-1-yl)methanone, hydrogen chloride salt; (3,5-dichlorophenyl)(piperazin-1-yl)methanone, hydrogen chloride salt; (3-chlorophenyl)(piperazin-1-yl)methanone, hydrogen chloride salt; (2,3-dichlorophenyl)(piperazin-1-yl)methanone, hydrogen chloride salt; (5-methylisoxazol-3-yl)(piperazin-1-yl)methanone, hydrogen chloride salt; (4-chlorophenyl)(piperazin-1-yl)methanone, hydrogen chloride salt; and (4-chloro-2-fluorophenyl)(piperazin-1-yl)methanone hydrogen chloride salt.
Reference K
Synthesis of piperazin-1-yl(4-(trifluoromethyl)phenyl)methanone 2,2,2-trifluoroacetate




Step 1: tert-butyl 4-(4-(trifluoromethyl)benzoyl)piperazine-1-carboxylate
4-(Trifluoromethyl)benzoic acid (1.531 g, 8.05 mmol) and HATU (3.06 g, 8.05 mmol) were dissolved in DMF (20.1 mL) at RT, then iPr2NEt (3.33 mL, 20.13 mmol) was added and the solution stirred for 30 min. tert-Butyl piperazine-1-carboxylate (1.5 g, 8.05 mmol) was then added and stirring continued for 16 h.
ISCO purification yielded the title compound as a yellow oil.
Step 2: piperazin-1-yl(4-(trifluoromethyl)phenyl)methanone 2,2,2-trifluoroacetate
A solution of tert-butyl 4-(4-(trifluoromethyl)benzoyl)piperazine-1-carboxylate (1.78 g, 4.97 mmol) in DCM (9.9 mL) was treated with TFA (64.6 mmol, 5 mL) dropwise via syringe at RT. The resulting reaction mixture was stirred until complete by LCMS, then quenched with sat. NaHCO3 and extracted with DCM. The organic layers were combined and dried over MgSO4. Purification by column chromatography (15% MeOH/DCM) afforded the title compound as a yellow solid.
Reference L
Synthesis of 1-(pyridin-3-ylmethyl)piperazine dihydrochloride salt




Step 1: tert-butyl 4-(pyridin-3-ylmethyl)piperazine-1-carboxylate
A solution of tert-butyl piperazine-1-carboxylate (306 mg, 1.643 mmol) and nicotinaldehyde (157 μl, 1.643 mmol) in DCE (5476 μl) was treated with sodium triacetoxyborohydride (487 mg, 2.300 mmol) at RT. The resulting reaction mixture was stirred at RT for 2 h. Purification by column chromatography (50% EtOAc/hexanes, then 10% MeOH/DCM) gave the title compound as a clear oil.
Step 2: 1-(pyridin-3-ylmethyl)piperazine dihydrochloride salt
A solution of tert-butyl 4-(pyridin-3-ylmethyl)piperazine-1-carboxylate (359 mg, 1.29 mmol) in dioxane (4.31 mL) was treated with HCl (2.58 mL, 10.35 mmol, 4 M in dioxane) dropwise at RT and the resulting reaction mixture was stirred for 18 h. After dilution with hexanes, the reaction mixture was filtered and the solid obtained was dissolved in MeOH. The solvent was removed under reduced pressure to afford the title compound as an ivory solid.
Following the procedure described above, following compounds were synthesized using commercially available aldehydes:
1-(pyridin-4-ylmethyl)piperazine, dihydrogen chloride salt; 1-(pyridin-2-ylmethyl)piperazine, dihydrogen chloride salt; 1-(3-bromobenzyl)piperazine, hydrogen chloride salt; 1-(5-chloro-2-(difluoromethoxy)benzyl)piperazine, hydrogen chloride salt; 1-(4-fluorobenzyl)piperazine, hydrogen chloride salt; 1-(2,5-dimethylbenzyl)piperazine, hydrogen chloride salt; 1-(2,4-difluorobenzyl)piperazine, hydrogen chloride salt; 1-(2,4,5-trifluorobenzyl)piperazine, hydrogen chloride salt; 1-(2,5-difluorobenzyl)piperazine, hydrogen chloride salt; 1-(5-chloro-2-fluorobenzyl)piperazine, hydrogen chloride salt; 1-(2,5-dichlorobenzyl)piperazine, hydrogen chloride salt; and 1-(2,6-dichlorobenzyl)piperazine, hydrogen chloride salt.
Reference M
Synthesis of (2-chloro-4-(methylsulfonyl)phenyl)(piperazin-1-yl)methanone, hydrogen chloride salt




Step 1: tert-butyl 4-(2-chloro-4-(methylsulfonyl)benzoyl)piperazine-1-carboxylate
A solution of 2-chloro-4-(methylsulfonyl)benzoic acid (550 mg, 2.344 mmol) in DCM (7813 μl) and DMF (2 drops) was treated with oxalyl chloride (411 μl, 4.69 mmol) at RT and the reaction mixture was stirred for 2 h. A solution of tert-butyl piperazine-1-carboxylate (960 mg, 5.16 mmol) and Et3N (719 μl, 5.16 mmol) in DCM (4.6 mL) was cooled to 0° C. and the crude acid chloride solution was added dropwise. The reaction mixture was allowed to warm up to RT and stirred for 3 h. ISCO purification (75% EtOAc/hexanes) afforded the title compound as a white solid.
Step 2: (2-chloro-4-(methylsulfonyl)phenyl)(piperazin-1-yl)methanone, hydrogen chloride salt
A solution of tert-butyl 4-(2-chloro-4-(methylsulfonyl)benzoyl)piperazine-1-carboxylate (581 mg, 1.442 mmol) in dioxane (4.81 mL) was treated with HCl (3605 μl, 14.42 mmol, 4 M in dioxane) and the resulting reaction mixture stirred at RT overnight. The solvent was removed to afford the title compound as a white solid.
Following the procedure described above, (3,6-dichloropyridin-2-yl)(piperazin-1-yl)methanone, dihydrogen chloride salt was synthesized using commercially available carboxylic acid.
Reference N
Synthesis of 4-(2,5-difluorophenoxy)piperidine hydrochloride




Step 1: tert-butyl 4-(2,5-difluorophenoxy)piperidine-1-carboxylate
To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (150 mg, 0.745 mmol) in THF (2484 μl) was added 2,5-difluorophenol (107 mg, 0.820 mmol) and triphenylphosphine (235 mg, 0.894 mmol). The mixture was cooled to 0° C. and DEAD (487 μl, 1.230 mmol, 40% wt in PhMe) was added dropwise. The mixture was then heated at 65° C. for 7 h then at RT for 18 h. ISCO purification (0-100% EtOAc/hexanes) yielded the title compound as a colorless oil.
Step 2: 4-(2,5-difluorophenoxy)piperidine hydrochloride
To a solution of tert-butyl 4-(2,5-difluorophenoxy)piperidine-1-carboxylate (71 mg, 0.227 mmol) in dioxane (755 μl) was added HCl (283 μl, 1.133 mmol, 4 M in dioxane). The mixture was stirred at RT for 16 h then concentrated under reduced pressure to afford the title compound as a white solid.
Following the procedure described above, following compounds were synthesized using commercially available aryl alcohols:
4-(2,4,6-trifluorophenoxy)piperidine hydrochloride; 4-(5-chloro-2-fluorophenoxy)-piperidine hydrochloride; and 4-(4-chloro-2-fluorophenoxy)piperidine hydrochloride.
Reference O
Synthesis of (2-fluorophenyl)(piperidin-4-yl)methanone hydrochloride




Step 1: tert-butyl 4-(2-fluorobenzoyl)piperidine-1-carboxylate
To a −78° C. solution of 1-bromo-2-fluorobenzene (88 μl, 0.808 mmol) in THF (4080 μl) was added n-BuLi (1154 μl, 1.616 mmol, 1.4 M in PhMe) dropwise. After stirring at −78° C. for 15 min, a solution of tert-butyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (200 mg, 0.734 mmol) in THF (1 mL) was added dropwise. The ice bath was removed and the reaction mixture was warmed to RT then stirred for 2 h. The solution was cooled to −30° C. and sat. aq. NH4Cl (10 mL) was added. Upon reaching RT, the solution was diluted with EtOAc and the organic layer was washed with H2O. The solvents were removed under reduced pressure and then ISCO purification (0-100% EtOAc/hexanes) yielded the title compound as a yellow oil.
Step 2: (2-fluorophenyl)(piperidin-4-yl)methanone hydrochloride
To a solution of tert-butyl 4-(2-fluorobenzoyl)piperidine-1-carboxylate (125 mg, 0.407 mmol) in dioxane (1356 μl) was added HCl (508 μl, 2.033 mmol, 4 M in dioxane). The mixture was stirred at 45° C. for 2 h then the solvents were removed under reduced pressure to afford the title compound as a light yellow solid.
Following the procedure described above, following compounds were synthesized using commercially available aryl bromides:
(2-fluorophenyl)(piperidin-4-yl)methanone hydrochloride; (2,5-difluorophenyl)-(piperidin-4-yl)methanone hydrochloride; piperidin-4-yl(2,4,6-trifluorophenyl)methanone hydrochloride; (4-chloro-2,6-difluorophenyl)(piperidin-4-yl)methanone hydrochloride; (4-chloro-2-fluorophenyl)(piperidin-4-yl)methanone hydrochloride; (5-chloro-2-fluorophenyl)(piperidin-4-yl)methanone hydrochloride; and (2,4-difluorophenyl)(piperidin-4-yl)methanone hydrochloride; (2-methoxyphenyl)(piperidin-4-yl)methanone hydrochloride; (2-chlorophenyl)(piperidin-4-yl)methanone hydrochloride; phenyl(piperidin-4-yl)methanone hydrochloride; (2,3-difluorophenyl)(piperidin-4-yl)methanone hydrochloride; (3-chlorophenyl)(piperidin-4-yl)methanone hydrochloride; piperidin-4-yl(o-tolyl)methanone hydrochloride; (2,6-difluorophenyl)(piperidin-4-yl)methanone hydrochloride; (2-chloro-5-fluorophenyl)(piperidin-4-yl)methanone hydrochloride; (3-fluorophenyl)(piperidin-4-yl)methanone hydrochloride; piperidin-4-yl(thiophen-2-yl)methanone, hydrogen chloride salt; (2-chlorothiophen-3-yl)(piperidin-4-yl)methanone hydrochloride; piperidin-4-yl(thiophen-3-yl)methanone hydrochloride; 3-(piperidine-4-carbonyl)benzonitrile hydrochloride; (2-(methylthio)phenyl)(piperidin-4-yl)methanone hydrochloride; 4-fluoro-3-(piperidine-4-carbonyl)benzonitrile hydrochloride; (6-chloro-2,3-difluorophenyl)(piperidin-4-yl)methanone hydrochloride; (2-chloro-3-fluorophenyl)(piperidin-4-yl)methanone hydrochloride.
Reference P
Synthesis of (R/S)-4-((2,4-difluorophenyl)fluoromethyl)piperidine hydrochloride




Step 1: tert-butyl 4-((2,4-difluorophenyl)(hydroxy)methyl)piperidine-1-carboxylate
To a 0° C. solution of tert-butyl 4-(2,4-difluorobenzoyl)piperidine-1-carboxylate (1.28 g, 3.93 mmol) in MeOH (15.74 ml) was added NaBH4 (0.372 g, 9.84 mmol). The ice bath was removed and the reaction mixture stirred for 2 h at RT then was quenched with sat. aq. NH4Cl. The organic layer was extracted with EtOAc, washed with H2O and dried over MgSO4. The solvent was removed under reduced pressure to yield the title compound as a white hygroscopic solid.
Step 2: tert-butyl 4-((2,4-difluorophenyl)fluoromethyl)piperidine-1-carboxylate
To a −78° C. solution of tert-butyl 4-((2,4-difluorophenyl)(hydroxy)methyl)piperidine-1-carboxylate (200 mg, 0.611 mmol) in CH2Cl2 (3055 μl) was added DAST (242 μl, 1.833 mmol). The mixture was stirred at −78° C. for 30 min., then quenched with MeOH. ISCO purification (0-100% EtOAc/hexanes) afforded the title compound as a colorless oil.
Step 3: (R/S)-4-((2,4-difluorophenyl)fluoromethyl)piperidine hydrochloride
To a solution of tert-butyl 4-((2,4-difluorophenyl)fluoromethyl)piperidine-1-carboxylate (148 mg, 0.449 mmol) in dioxane (1498 μl) was added HCl (337 μl, 1.348 mmol, 4 M in dioxane). The mixture was heated at 45° C. for 16 h then concentrated under reduced pressure to yield the title compound as a white solid.
Note: Optically pure compounds were obtained by chiral SFC separation of racemic compound.
Following the procedure described above, (R/S)-4-((2,5-difluorophenyl)-fluoromethyl)-piperidine hydrochloride was synthesized.
Reference Q
Synthesis of 4-((2,4-difluorophenyl)difluoromethyl)piperidine hydrochloride




Step 1: tert-butyl 4-((2,4-difluorophenyl)difluoromethyl)piperidine-1-carboxylate
To a solution of tert-butyl 4-(2,4-difluorobenzoyl)piperidine-1-carboxylate (7.7 g, 23.67 mmol) in DCM (100 ml) was added DAST (46.9 ml, 355 mmol). The reaction mixture was stirred at reflux for 2 days. Purification by column chromatography afforded the title compound.
Step 2: 4-((2,4-difluorophenyl)difluoromethyl)piperidine hydrochloride
To a solution of tert-butyl 4-((2,4-difluorophenyl)difluoromethyl)piperidine-1-carboxylate (2.6 g, 7.49 mmol) in DCM (10 mL) was added HCl (2.28 mL, 74.9 mmol). The mixture was stirred at −78° C. for 16 h then concentrated under reduced pressure to yield the title compound as a white solid.
Following the procedure described above, following compounds were synthesized using commercially available starting materials.
4-((2,5-difluorophenyl)difluoromethyl)piperidine hydrochloride; and 4-((5-chloro-2-fluorophenyl)difluoromethyl)piperidine hydrochloride.
Reference R
Synthesis of 4-fluoro-1-(piperidin-4-ylmethyl)pyridin-2(1H)-one, hydrogen chloride salt




Step 1: tert-butyl 4-((4-fluoro-2-oxopyridin-1 (2H)-yl)methyl)piperidine-1-carboxylate
A solution of 4-fluoropyridin-2(1H)-one (112 mg, 0.990 mmol), tert-butyl 4-(bromomethyl)piperidine-1-carboxylate (276 mg, 0.990 mmol) and potassium carbonate (274 mg, 1.981 mmol) in dioxane (1981 μl) was stirred at 80° C. until complete by LCMS analysis. HPLC purification afforded the title compound as a white solid.
Step 2: 4-fluoro-1-(piperidin-4-ylmethyl)pyridin-2(1H)-one, hydrogen chloride salt
A solution of tert-butyl 4-((4-fluoro-2-oxopyridin-1 (2H)-yl)methyl)piperidine-1-carboxylate (100 mg, 0.322 mmol) in dioxane (644 μl) was treated with HCl (806 μl, 3.22 mmol, 4 M in dioxane) dropwise via syringe at RT and the resulting reaction mixture stirred for 3 h. The solvent was removed under reduced pressure to yield the title compound as a white solid.
Following the procedure described above, following compounds were synthesized using commercially available pyridinones:
4-chloro-1-(piperidin-4-ylmethyl)pyridin-2(1H)-one hydrochloride; 5-fluoro-1-(piperidin-4-ylmethyl)pyridin-2(1H)-one hydrochloride; and 5-chloro-1-(piperidin-4-ylmethyl)pyridin-2(1H)-one hydrochloride.
Reference S
Synthesis of 1-(1-(2,5-dichlorophenyl)ethyl)piperazine hydrochloride




Step 1: tert-butyl 4-(1-(2,5-dichlorophenyl)ethyl)piperazine-1-carboxylate
A 10-mL screwtop vial containing tert-butyl piperazine-1-carboxylate (200 mg, 1.074 mmol), 1-(2,5-dichlorophenyl)ethanone (203 mg, 1.074 mmol), sodium triacetoxyborohydride (341 mg, 1.611 mmol), and acetic acid (92 μl, 1.611 mmol) in DCE (3579 μl) was stirred at RT overnight. 1 M KOH was added with rapid stirring for 30 min, then the reaction mixture was extracted with ether. The combined organic layer was washed with brine and the organic extracts were combined, filtered through MgSO4, and concentrated to afford the title compound.
Step 2: 1-(1-(2,5-dichlorophenyl)ethyl)piperazine hydrochloride
A 10-mL screwtop vial containing tert-butyl 4-(1-(2,5-dichlorophenyl)ethyl)-piperazine-1-carboxylate (270 mg, 0.751 mmol) and HCl (1879 μl, 7.51 mmol, 4 M in dioxane) in DCM (2505 μl) was stirred overnight and concentrated under reduced pressure to give the title compound.
Reference T
Synthesis of N-(4-chlorophenyl)piperidin-4-amine dihydrochloride




Step 1: tert-butyl 4-((4-chlorophenyl)amino)piperidine-1-carboxylate
A 20-mL screwtop vial containing tert-butyl 4-oxopiperidine-1-carboxylate (500 mg, 2.509 mmol), acetic acid (287 μl, 5.02 mmol), and 4-chloroaniline (320 mg, 2.509 mmol) in DCE (6274 μl) was stirred for 10 min then sodium triacetoxyborohydride (745 mg, 3.51 mmol) was added and the reaction mixture was stirred overnight. ISCO purification (0-15% EtOAc/hexanes) afforded the title compound.
Step 2: N-(4-chlorophenyl)piperidin-4-amine dihydrochloride
A 5-mL screwtop vial containing tert-butyl 4-((4-chlorophenyl)amino)piperidine-1-carboxylate (150 mg, 0.483 mmol) was stirred in HCl (965 μl, 3.86 mmol, 4 M in dioxane) overnight. Concentration under reduced pressure gave the title compound.
Reference U
Synthesis of N-(2,4-difluorophenyl)piperidin-4-amine bis(2,2,2-trifluoroacetate)




Step 1: tert-butyl 4-((2,4-difluorophenyl)amino)piperidine-1-carboxylate
A 10-mL screwtop vial containing 2,4-difluoroaniline (130 mg, 1.004 mmol), acetic acid (115 μl, 2.008 mmol), and tert-butyl 4-oxopiperidine-1-carboxylate (200 mg, 1.004 mmol) in DCE (2509 μl) was stirred for 10 min and then sodium triacetoxyborohydride (319 mg, 1.506 mmol) was added. After 2 h, the mixture was added to 1 M KOH, then the reaction mixture was extracted with ether. The combined organic layers were washed with brine, filtered through MgSO4, and concentrated to afford the title compound.
Step 2. N-(2,4-difluorophenyl)piperidin-4-amine bis(2,2,2-trifluoroacetate)
A 50-mL round-bottomed flask containing tert-butyl 4-((2,4-difluorophenyl)amino)piperidine-1-carboxylate (314 mg, 1.005 mmol) in TFA (3 mL) was stirred at RT for 2 h. Concentration under reduced pressure yielded the title compound.
Reference V
Synthesis of 7-bromo-2,3-dichloropyrido[3,4-b]pyrazine




Step 1: 7-bromopyrido[3,4-b]pyrazine-2,3(1H,4H)-dione hydrochloride
To a solution of 6-bromopyridine-3,4-diamine (467 mg, 2.484 mmol) in HCl (3726 μl, 14.90 mmol, 4 M aq) was added oxalic acid (257 mg, 2.86 mmol). The mixture was heated at 120° C. for 14 h then filtered, washed with cold water and dried under vacuum to yield the title compound as a tan solid.
Step 2: 7-bromo-2,3-dichloropyrido[3,4-b]pyrazine
To 7-bromopyrido[3,4-b]pyrazine-2,3(1H,4H)-dione hydrochloride (626 mg, 2.248 mmol) was added thionyl chloride (6070 μl, 83 mmol) and N,N-dimethylformamide (174 μl, 2.248 mmol). The reaction mixture was heated at 80° C. overnight then poured into ice water and filtered. The solid was dried under vacuum for 2 h to give the title compound as a pale solid that was used without further purification.
Reference W
Synthesis of 2,3,7-trichloropyrido[3,4-b]pyrazine




Step 1: 7-bromopyrido[3,4-b]pyrazine-2,3(1H,4H)-dione hydrochloride
To a solution of 6-bromopyridine-3,4-diamine (467 mg, 2.484 mmol) in HCl (3726 μl, 14.90 mmol, 4 M aq) was added oxalic acid (257 mg, 2.86 mmol). The mixture was heated at 120° C. for 14 h then filtered, washed with cold water and dried under vacuum to yield the title compound as a tan solid.
Step 2: 2,3,7-trichloropyrido[3,4-b]pyrazine
To 7-bromopyrido[3,4-b]pyrazine-2,3(1H,4H)-dione hydrochloride (130 mg, 0.467 mmol) was added POCl3 (1305 μl, 14.00 mmol) and N,N-dimethylformamide (36.1 μl, 0.467 mmol). The mixture was heated at 120° C. for 16 h then poured into ice water. The mixture was extracted with EtOAc, washed with water, dried over Na2SO4 and concentrated under reduced pressure. The crude material was dried under vacuum then used directly without further purification.
Reference X
Synthesis of 2-(cyclopropylamino)-3-(piperidin-4-yl)quinoxaline-6-carbonitrile




Step 1: tert-butyl 4-(7-cyano-3-(cyclopropylamino)quinoxalin-2-yl)-5,6-dihydropyridine-1 (2H)-carboxylate
A 10 mL microwave vial containing 3-chloro-2-(cyclopropylamino)quinoxaline-6-carbonitrile (200 mg, 0.817 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (455 mg, 1.471 mmol), bis(triphenylphosphine)palladium(II) chloride (115 mg, 0.163 mmol), and potassium carbonate (339 mg, 2.452 mmol) in MeCN (4087 μl) was degassed with nitrogen for 10 min then heated to 150° C. for 1 h. Concentration under reduced pressure and ISCO purification (35% EtOAc/hexanes) gave the title compound.
Step 2: 2-(cyclopropylamino)-3-(1,2,3,6-tetrahydropyridin-4-yl)quinoxaline-6-carbonitrile dihydrochloride
A 5 mL screwtop-vial containing tert-butyl 4-(7-cyano-3-(cyclopropylamino)quinoxalin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (220 mg, 0.562 mmol) and HCl (2810 μl, 11.24 mmol, 4 M in dioxane) in CH2Cl2 (Volume: 562 μl) was stirred overnight and concentrated to yield the title compound.
Step 3: 2-(cyclopropylamino)-3-(piperidin-4-yl)quinoxaline-6-carbonitrile
To a 5 mL screw-top vial containing 2-(cyclopropylamino)-3-(1,2,3,6-tetrahydropyridin-4-yl)quinoxaline-6-carbonitrile dihydrochloride (18 mg, 0.049 mmol) and 10% palladium on carbon (5.26 mg, 0.049 mmol) in methanol (247 μl) was bubbled hydrogen under balloon pressure for 30 min. Filtration, concentration, and HPLC purification gave the title compound.
Reference Y
Synthesis of N-cyclopropyl-7-methyl-3-(piperidin-4-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt




Step 1: tert-butyl 4-(2-(cyclopropylamino)-7-methylpyrido[3,4-b]pyrazin-3-yl)-5,6-dihydropyridine-1 (2H)-carboxylate
A vial charged with 3-chloro-N-cyclopropyl-7-methylpyrido[3,4-b]pyrazin-2-amine (50 mg, 0.213 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (119 mg, 0.383 mmol), potassium carbonate (88 mg, 0.639 mmol) and Pd(PPh3)2Cl2 (29.9 mg, 0.043 mmol), was evacuated/refilled with nitrogen (3×). MeCN (1065 μl) was added to the reaction mixture and the vial was evacuated and refilled with nitrogen (3×). The resulting mixture was heated at 80° C. overnight. ISCO purification (0-5% MeOH/DCM) gave the title compound as an off-white solid.
Step 2: tert-butyl 4-(2-(cyclopropylamino)-7-methylpyrido[3,4-b]pyrazin-3-yl)piperidine-1-carboxylate, 2,2,2-trifluoroacetic acid salt
A mixture of tert-butyl 4-(2-(cyclopropylamino)-7-methylpyrido[3,4-b]pyrazin-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (30 mg, 0.079 mmol) and 10% palladium on carbon (3 mg, 2.82 mol) in MeOH (393 μl) was stirred under a hydrogen balloon at RT overnight. HPLC purification gave the title compound as an off-white solid.
Step 3: N-cyclopropyl-7-methyl-3-(piperidin-4-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
To a solution of tert-butyl 4-(2-(cyclopropylamino)-7-methylpyrido[3,4-b]pyrazin-3-yl)piperidine-1-carboxylate 2,2,2-trifluoroacetate (18 mg, 0.036 mmol) in DCM (0.3 ml) at 0° C. was added TFA (0.15 ml). The resulting solution was stirred at 0° C. for 2 h and then concentrated under reduced pressure to yield the title compound as a colorless oil.
Reference Z
Synthesis of N-cyclopropyl-3-(3-methylpiperazin-1-yl)quinoxalin-2-amine dihydrochloride




Step 1: tert-butyl 4-(3-(cyclopropylamino)quinoxalin-2-yl)-2-methylpiperazine-1-carboxylate
To a solution of 3-chloro-N-cyclopropylquinoxalin-2-amine (100 mg, 0.455 mmol) in dioxane (455 μl) was added tert-butyl 2-methylpiperazine-1-carboxylate (137 mg, 0.683 mmol) and iPr2EtN (119 μl, 0.683 mmol). The mixture was heated at 130° C. for 60 h. Purification by ISCO (0-60% EtOAc/Hexanes) yielded the title compound as a yellow oil.
Step 2: N-cyclopropyl-3-(3-methylpiperazin-1-yl)quinoxalin-2-amine dihydrochloride
To a solution of tert-butyl 4-(3-(cyclopropylamino)quinoxalin-2-yl)-2-methylpiperazine-1-carboxylate (177 mg, 0.462 mmol) in dioxane (1539 μl) was added HCl (346 μl, 1.385 mmol, 4 M in dioxane). The mixture was heated at 75° C. for 20 h. The solvent was removed under reduced pressure to yield the title compound as a tan solid.
Synthesized by a similar procedure, using commercially available Boc-piperazines:
methyl 4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazine-2-carboxylate dihydrochloride; N-cyclopropyl-3-(3-(methoxymethyl)piperazin-1-yl)quinoxalin-2-amine dihydrochloride; N-cyclopropyl-3-(3-isopropylpiperazin-1-yl)quinoxalin-2-amine dihydrochloride; N-cyclopropyl-3-(2-methylpiperazin-1-yl)quinoxalin-2-amine dihydrochloride; 3-(3-benzylpiperazin-1-yl)-N-cyclopropylquinoxalin-2-amine dihydrochloride
Reference AA
Synthesis of 1-(4-(piperidin-4-yloxy)phenyl)ethanone, hydrogen chloride salt




Step 1: tert-butyl 4-(4-acetylphenoxy)piperidine-1-carboxylate
To a 20 mL screwtop vial containing tert-butyl 4-hydroxypiperidine-1-carboxylate (500 mg, 2.484 mmol), 1-(4-hydroxyphenyl)ethanone (372 mg, 2.73 mmol), and triphenylphosphine (782 mg, 2.98 mmol) in THF (8281 μl) was added DEAD (1475 μl, 3.73 mmol) dropwise and heated to 50° C. for 4 h. ISCO purification (0-100% hexanes/ethyl acetate) gave the title compound.
Step 2: 1-(4-(piperidin-4-yloxy)phenyl)ethanone, hydrogen chloride salt
To a 10 mL screwtop vial containing tert-butyl 4-(4-acetylphenoxy)piperidine-1-carboxylate (580 mg, 1.816 mmol) and HCl (2270 μl, 9.08 mmol, 4 M in dioxane) in dioxane (3632 μl) was stirred for 2 h and concentrated to yield the title compound as a white solid.
Synthesized by a similar procedure, using commercially available phenols: N,N-dimethyl-4-(piperidin-4-yloxy)benzamide, hydrogen chloride salt; 4-(4-(methylthio)phenoxy)piperidine, hydrogen chloride salt; 4-(4-ethoxyphenoxy)piperidine, hydrogen chloride salt
Reference AB
Synthesis of (2-fluoro-5-(methylthio)phenyl)(piperidin-4-yl)methanone, hydrogen chloride salt




Step 1: tert-butyl 4-(2-fluoro-5-(methylthio)benzoyl)piperidine-1-carboxylate
To a 50 mL round-bottomed flask containing (3-bromo-4-fluorophenyl)(methyl)sulfane (250 mg, 1.131 mmol) in THF (5654 μl) at −78° C. was added tert-butyllithium (1397 μl, 2.375 mmol) dropwise by syring-pump. After 10 min, tert-butyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (339 mg, 1.244 mmol) was added and the reaction mixture was warmed to RT then quenched with AcOH. ISCO purification (20% ethyl acetate in hexanes) gave the title compound.
Step 2: (2-fluoro-5-(methylthio)phenyl)(piperidin-4-yl)methanone, hydrogen chloride salt
A 5 mL screwtop vial containing tert-butyl 4-(2-fluoro-5-(methylthio)benzoyl)piperidine-1-carboxylate (200 mg, 0.566 mmol) and HCl (2.122 mL, 8.49 mmol, 4 M in dioxane) in dioxane (1.132 mL) was stirred overnight. Concentration in vacuo yielded the title compound as a white solid. Synthesized by a similar procedure, using commercially available aryl bromides: 3-fluoro-4-(piperidin-4-yloxy)phenol, hydrogen chloride salt
Reference AC
Synthesis of 4-(2-fluoro-4-(2-fluoroethoxy)phenoxy)piperidine, hydrogen chloride salt




Step 1: tert-butyl 4-(2-fluoro-4-(2-fluoroethoxy)phenoxy)piperidine-1-carboxylate
A 5 mL screwtop vial containing tert-butyl 4-(2-fluoro-4-hydroxyphenoxy)piperidine-1-carboxylate (42 mg, 0.135 mmol) and sodium hydride (4.86 mg, 0.202 mmol, 60% dispersion in mineral oil) in DMF (674 μl) was stirred for 10 min then added 1-bromo-2-fluoroethane (30.2 μl, 0.405 mmol). After 2 h the reaction mixture was poured into water, extracted with ether (2×) and filtered through MgSO4, Concentration in vacuo yielded the title compound.
Step 2: 4-(2-fluoro-4-(2-fluoroethoxy)phenoxy)piperidine, hydrogen chloride salt
A 5 mL screwtop vial containing tert-butyl 4-(2-fluoro-4-(2-fluoroethoxy)phenoxy)piperidine-1-carboxylate (45 mg, 0.126 mmol) and HCl (472 Cl, 1.889 mmol, 4 M in dioxane) in dioxane (252 Cl) was stirred overnight then concentrated to give the title compound.
Reference AD
Synthesis of 5-chloro-N-cyclopropyl-3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine




Step 1: 5-bromopyrido[3,4-b]pyrazine-2,3(1H,4H)-dione
A solution of 1,2-di(1H-imidazol-1-yl)ethane-1,2-dione (1.456 g, 7.66 mmol) and 2-bromopyridine-3,4-diamine (1.2 g, 6.38 mmol) in DMF (21.27 ml) was stirred at RT overnight. The precipitate was filtered and washed with anhydrous THF to give the title compound as a grey solid.
Step 2: 2,3,5-trichloropyrido[3,4-b]pyrazine
To a flask containing 5-bromopyrido[3,4-b]pyrazine-2,3(1H,4H)-dione (1.5 g, 6.20 mmol) was added sulfurous dichloride (16.74 ml, 229 mmol) and N,N-dimethylformamide (0.480 ml, 6.20 mmol). The mixture was heated at 78° C. overnight then water was added to quench the reaction. Filtration afforded the title compound as a light yellow solid.
Step 3: 3,5-dichloro-N-cyclopropylpyrido[3,4-b]pyrazin-2-amine
To a solution of 2,3,5-trichloropyrido[3,4-b]pyrazine (600 mg, 2.56 mmol) in DCM (12.8 mL) at 0° C. was slowly added N-ethyl-N-isopropylpropan-2-amine (1341 μl, 7.68 mmol) and cyclopropanamine (248 μl, 3.58 mmol). The reaction was stirred at 0° C. for 3 h. ISCO purification (0-100% EtOAc in hexanes) yielded the title compound as a white solid.
Step 4: 5-chloro-N-cyclopropyl-3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine
A solution of 3,5-dichloro-N-cyclopropylpyrido[3,4-b]pyrazin-2-amine (57 mg, 0.223 mmol), 4-(2-fluoro-4-methoxyphenoxy)piperidine, HCl (76 mg, 0.290 mmol, 4 M in dioxane) and N-ethyl-N-isopropylpropan-2-amine (156 μl, 0.894 mmol) in dioxane (745 μl) was heated at 60° C. for 2 h. ISCO purification (10-60% ethyl acetate in hexanes) gave the title compound as a white solid.
Synthesized by a similar procedure, using reference compound piperizines: 5-chloro-N-cyclopropyl-3-(4-(2,4-difluorophenoxy)piperazin-1-yl)pyrido[3,4-b]pyrazin-2-amine; 5-chloro-N-cyclopropyl-3-(4-(2-fluoro-4-methoxyphenoxy)piperazin-1-yl)pyrido[3,4-b]pyrazin-2-amine.
Reference AF
Synthesis of (5-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6-(isopropylamino)pyrazine-2,3-diyl)dimethanol




Step 1: 5,6-dichloropyrazine-2,3-dicarboxylic acid dihydrochloride
A suspension of 2,3-dichloroquinoxaline (10 g, 50.2 mmol) in H2O (500 mL) was heated to 95° C. with stirring and KMnO4 (39.7 g, 251 mmol) in hot H2O (600 mL) was added dropwise over 2 h. The reaction continued stirring for another 2 h, and then the solid MnO2 was removed by filtration from the hot suspension and washed twice with hot H2O. The combined filtrate was concentrated to 100 mL, cooled to 0° C., and acidified with cold conc. HCl (pH<0). Filtration afforded the title compound as a colorless solid.
Step 2: dimethyl 5,6-dichloropyrazine-2,3-dicarboxylate
To a suspension of 5,6-dichloropyrazine-2,3-dicarboxylic acid dihydrochloride (310 mg, 1.000 mmol) in MeOH (3 ml) was added SOCl2 (0.584 ml, 8.00 mmol), dropwise, at 0° C. The reaction mixture was allowed to stir at 60° C. for 3 h and was then concentrated to dryness. EtOAc was added and the suspension was filtered. The filtrate was concentrated in vacuo and purified by column chromatograph (petroleum ether in ethyl acetate=20:1, then 15:1) to give the title compound as a solid.
Step 3: dimethyl 5-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6-(isopropylamino)pyrazine-2,3-dicarboxylate
A solution of dimethyl 5,6-dichloropyrazine-2,3-dicarboxylate (2 g, 7.55 mmol) in dioxane (7.55 ml) and DMF (7.55 ml) was treated with propan-2-amine (0.643 ml, 7.55 mmol) and DIPEA (3.29 ml, 18.86 mmol) and then stirred at RT overnight. Then, 4-(2,4-difluorophenoxy)piperidine hydrochloride (1.884 g, 7.55 mmol), and DIPEA (3.29 ml, 18.86 mmol) were added and the resulting reaction mixture stirred at 90° C. for 8 h. ISCO purification gave dimethyl the title compound as a white solid.
Step 4: (5-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6-(isopropylamino)pyrazine-2,3-diyl)dimethanol
To a solution of dimethyl 5-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6-(isopropylamino)pyrazine-2,3-dicarboxylate (2 g, 4.31 mmol) in THF (43.1 ml) at 0° C. was added Super-hydride (21.53 ml, 21.53 mmol) and the reaction was stirred at RT for 2 h. Then, the reaction was quenched with 1 N HCl (pH=2-4). Saturated NaHCO3 was added to adjust the pH to 8 and then the reaction mixture was extracted with ethyl acetate (30 mL×2). ISCO purification (10-80% ethyl acetate in hexanes) gave the title compound as a colorless oil.
Example 1
Synthesis of N-cyclopropyl-3-(4-(3-methylbenzyl)piperazin-1-yl)naphthalen-2-amine




A solution of 3-chloro-N-cyclopropylquinoxalin-2-amine (30 mg, 0.137 mmol), 1-(3-methylbenzyl)piperazine (39.0 mg, 0.205 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.072 ml, 0.410 mmol) in dioxane (0.25 ml) was heated at 150° C. overnight. HPLC purification afforded the title compound as a white solid. MS (ESI, pos. ion) m/z: 374.3 (M+1)
Using similar reaction conditions as described above, and utilizing intermediates prepared as described above or commercially available piperazines and piperidines, following compounds were synthesized which were purified by either HPLC or ISCO:
N-cyclopropyl-3-(4-(3-methylbenzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-3-(3-(thiazol-5-ylmethyl)piperidin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; 5-bromo-N-cyclopropyl-3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)quinoxalin-2-amine; 8-bromo-N-cyclopropyl-3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-2-(4-(3-methylbenzyl)piperazin-1-yl)pyrido[2,3-b]pyrazin-3-amine, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-2-(4-(2,5-dichlorobenzyl)piperazin-1-yl)pyrido[2,3-b]pyrazin-3-amine, 2,2,2-trifluoroacetic acid salt; 7-bromo-N-cyclopropyl-3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; 6-bromo-N-cyclopropyl-3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; mixture of N-cyclopropyl-3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-7-methoxyquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt and N-cyclopropyl-3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-7-methoxyquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; mixture of N-cyclopropyl-3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-7-fluoroquinoxalin-2-amine and N-cyclopropyl-3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-7-fluoroquinoxalin-2-amine; 2-(cyclopropylamino)-3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)quinoxaline-6-carbonitrile; 3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-N-(2-methoxyphenyl)quinoxalin-2-amine; 3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-N-(4-fluorophenyl)quinoxalin-2-amine; N-(4-bromophenyl)-3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)quinoxalin-2-amine; N-cyclopropyl-3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-5,7-dimethylquinoxalin-2-amine; N-cyclopropyl-3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-6,8-dimethylquinoxalin-2-amine; 8-bromo-N-cyclopropyl-3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt; (4-chlorophenyl)(4-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperazin-1-yl)methanone; N-cyclopropyl-3-(4-(2,5-difluorobenzyl)piperazin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt; 2-(cyclopropylamino)-3-(4-(2,6-dichlorobenzyl)piperazin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-2-(pyridin-3-ylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 3-(4-(2,5-difluorobenzyl)piperazin-1-yl)-2-(pyridin-3-ylamino)quinoxaline-6-carbonitrile; 3-(4-(4-chlorobenzoyl)piperazin-1-yl)-2-(pyridin-3-ylamino)quinoxaline-6-carbonitrile; N-cyclopropyl-3-(4-(2,4-difluorobenzyl)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt; 2-(cyclopropylamino)-3-(4-(2,4-difluorobenzyl)piperidin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 7-bromo-N-cyclopropyl-3-(4-(2,4-difluorobenzyl)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt; 7-chloro-N-cyclopropyl-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt; 7-chloro-N-cyclopropyl-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-(2,4-difluorobenzyl)piperazin-1-yl)-2-((2,2-difluoroethyl)amino)quinoxaline-6-carbonitrile; 2-((2,2-difluoroethyl)amino)-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)quinoxaline-6-carbonitrile; 3-(4-(2,4-difluorobenzyl)piperidin-1-yl)-2-((2,2-difluoroethyl)amino)quinoxaline-6-carbonitrile; 2-((2,2-difluoroethyl)amino)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)quinoxaline-6-carbonitrile; 3-(4-(2,4-difluorobenzyl)piperidin-1-yl)-2-((2-methoxyethyl)amino)quinoxaline-6-carbonitrile; 3-(4-(2,4-difluorobenzyl)piperidin-1-yl)-N-(2-methoxyethyl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-(2,4-difluorobenzyl)piperazin-1-yl)-N-(2-methoxyethyl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-N-(2-methoxyethyl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-(2,4-difluorobenzyl)piperazin-1-yl)-2-((2-methoxyethyl)amino)quinoxaline-6-carbonitrile; 3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-2-((2-methoxyethyl)amino)quinoxaline-6-carbonitrile; 3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-2-((2-methoxyethyl)amino)quinoxaline-6-carbonitrile; 3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-(2-methoxyethyl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-3-(4-((2,4-difluorophenyl)difluoromethyl)piperidin-1-yl)-5-methylpyrido[3,4-b]pyrazin-2-amine; 2-(cyclopropylamino)-3-(4-((2,4-difluorophenyl)difluoromethyl)piperidin-1-yl)quinoxaline-6-carbonitrile; N-cyclopropyl-3-(4-((2,4-difluorophenyl)difluoromethyl)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine; N-cyclopropyl-3-(4-phenoxypiperidin-1-yl)quinoxalin-2-amine; 3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-N-(pyridin-3-yl)quinoxalin-2-amine; 3-(4-(2,5-difluorobenzyl)piperazin-1-yl)-2-((6-methoxypyridin-3-yl)amino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 3-(4-(2,4-difluorobenzyl)piperazin-1-yl)-N-(2,2-difluoroethyl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-(5-chloro-2-fluorobenzyl)piperazin-1-yl)-N-(2,2-difluoroethyl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt; (4-chloro-2-fluorophenyl)(4-(2-((2,2-difluoroethyl)amino)pyrido[3,4-b]pyrazin-3-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt; N-(2,2-difluoroethyl)-3-(4-(2,4,5-trifluorobenzyl)piperazin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-(2,4-difluorobenzyl)piperazin-1-yl)-2-(pyridin-3-ylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 2-(pyridin-3-ylamino)-3-(4-(2,4,5-trifluorobenzyl)piperazin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 3-(4-(4-chloro-2-fluorobenzoyl)piperazin-1-yl)-2-(pyridin-3-ylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 3-(4-(2,4-difluorobenzyl)piperidin-1-yl)-2-(pyridin-3-ylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 3-(4-(2-chlorophenoxy)piperidin-1-yl)-N-cyclopropylpyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-3-(4-(2-fluorophenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-3-(4-(3-fluorophenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt; (1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)(4-fluorophenyl)methanone, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-3-(4-(4-fluorobenzyl)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt; (1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)(3,4-difluorophenyl)methanone, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-3-(4-((4-fluorophenyl)sulfonyl)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-(4-chlorobenzyl)piperidin-1-yl)-N-cyclopropylpyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-(4-chlorophenoxy)piperidin-1-yl)-N-cyclopropylpyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-(3-chlorophenoxy)piperidin-1-yl)-N-cyclopropylpyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt; (4-chlorophenyl)(1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)methanone, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-3-(3-(4-fluorobenzyl)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-3-(4-(2,5-difluorophenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-3-(4-(2,4,6-trifluorophenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-3-(4-(4-fluorophenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt; (1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)(2-fluorophenyl)methanone, 2,2,2-trifluoroacetic acid salt; (1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)(2,5-difluorophenyl)methanone, 2,2,2-trifluoroacetic acid salt; 3-(4-(5-chloro-2-fluorophenoxy)piperidin-1-yl)-N-cyclopropylpyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-3-(4-phenoxypiperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt; (1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)(2,4-difluorophenyl)methanone, 2,2,2-trifluoroacetic acid salt; 3-(4-(4-chloro-2-fluorophenoxy)piperidin-1-yl)-N-cyclopropylpyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt; (1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)(2,4,6-trifluorophenyl)methanone, 2,2,2-trifluoroacetic acid salt; (4-chloro-2,6-difluorophenyl)(1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)methanone, 2,2,2-trifluoroacetic acid salt; (4-chloro-2-fluorophenyl)(1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)methanone, 2,2,2-trifluoroacetic acid salt; (5-chloro-2-fluorophenyl)(1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)methanone, 2,2,2-trifluoroacetic acid salt; 3-(4-(4-chloro-2-fluorophenoxy)piperidin-1-yl)-2-(cyclopropylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 3-(4-(4-chloro-2-fluorophenoxy)piperidin-1-yl)-2-(isopropylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 3-(4-(4-chloro-2-fluorophenoxy)piperidin-1-yl)-N-cyclopropyl-7-methylpyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt; 2-(cyclopropylamino)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 3-(4-(5-chloro-2-fluorobenzoyl)piperidin-1-yl)-2-(cyclopropylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-3-(4-(2,4-difluorobenzyl)piperidin-1-yl)-6,7-difluoroquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-3-(4-(2,4-difluorobenzyl)piperidin-1-yl)-6-fluoroquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; 2-(cyclopropylamino)-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-2-(isopropylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 3-(cyclopropylamino)-2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-3-(4-((2,4-difluorophenyl)-fluoromethyl)piperidin-1-yl)-7-methylpyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-5-methylpyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-3-(4-(2,4-difluorobenzyl)piperidin-1-yl)-5-methylpyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-methylpyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-3-(4-(2,4-difluoro-phenoxy)piperidin-1-yl)-5-methylpyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-(4-chlorobenzoyl)piperazin-1-yl)-2-(cyclobutylamino)quinoxaline-6-carbonitrile; 3-(4-(4-chlorobenzoyl)piperazin-1-yl)-2-(isopropylamino)quinoxaline-6-carbonitrile; N-cyclopropyl-3-(4-(1-(2,5-dichlorophenyl)ethyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-((4-chlorophenyl)amino)piperidin-1-yl)-N-cyclopropylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-3-(4-((2,4-difluoro-phenyl)amino)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt; (4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)(3-(trifluoromethyl)phenyl)methanone, 2,2,2-trifluoroacetic acid salt; 3-(4-(3-chlorobenzyl)piperazin-1-yl)-N-cyclopropylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; (4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)(4-(methylsulfonyl)phenyl)methanone, 22,2,2-trifluoroacetic acid salt; (4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)(2,5-dichlorophenyl)methanone, 2,2,2-trifluoroacetic acid salt; (4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)(3,4-dichlorophenyl)methanone, 2,2,2-trifluoroacetic acid salt; (3-chloro-4-methoxyphenyl)(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt; (4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)(3,5-dichlorophenyl)methanone, 2,2,2-trifluoroacetic acid salt; (3-chlorophenyl)(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-3-(4-(pyridin-3-ylmethyl)piperazin-1-yl)quinoxalin-2-amine, 22,2,2-trifluoroacetic acid salt; (4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)(2,3-dichlorophenyl)methanone, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-3-(4-((5-methyloxazol-2-yl)methyl)piperidin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-3-(4-(pyridin-4-ylmethyl)piperazin-1-yl)quinoxalin-2-amine, 22,2,2-trifluoroacetic acid salt; N-cyclopropyl-3-(4-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)piperidin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-3-(4-(pyridin-2-ylmethyl)piperazin-1-yl)quinoxalin-2-amine, 22,2,2-trifluoroacetic acid salt; (4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)(4-(trifluoromethyl)phenyl)methanone, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-3-(4-(2,4-dichlorobenzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-3-(4-(2,6-dichlorobenzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-(3-bromobenzyl)piperazin-1-yl)-N-cyclopropylquinoxalin-2-amine; 3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-N-(3-methoxypropyl)quinoxalin-2-amine; (2-chloro-4-(methylsulfonyl)phenyl)(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)methanone; (4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)(3,6-dichloropyridin-2-yl)methanone; (4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)(5-methylisoxazol-3-yl)methanone; (4-chlorophenyl)(4-(3-(cyclopropylamino)-6,7-difluoroquinoxalin-2-yl)piperazin-1-yl)methanone; (4-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperazin-1-yl)(4-(trifluoromethyl)phenyl)methanone, 2,2,2-trifluoroacetic acid salt; 3-(4-(5-chloro-2-(difluoromethoxy)benzyl)piperazin-1-yl)-N-cyclopropylpyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-3-(4-(4-fluorobenzyl)piperazin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-3-(4-(2,6-dichlorobenzyl)piperazin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-3-(4-(2,5-dimethylbenzyl)piperazin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt; 2-(cyclopropylamino)-3-(4-(2,4-difluorobenzyl)piperazin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 2-(cyclopropylamino)-3-(4-(2,4,5-trifluorobenzyl)piperazin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 3-(4-(5-chloro-2-fluorobenzyl)piperazin-1-yl)-2-(cyclopropylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; (1-(2-(cyclopropylamino)-7-methylpyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)(2,5-difluorophenyl)methanone, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7-methylpyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-(2,4-difluorobenzyl)piperidin-1-yl)-2-(isopropylamino)quinoxaline-6-carbonitrile; 2-(cyclobutylamino)-3-(4-(2,4-difluorobenzyl)piperidin-1-yl)quinoxaline-6-carbonitrile; 2-(cyclopropylamino)-3-(4-((2,5-difluorophenyl)fluoromethyl)piperidin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 2-(cyclopropylamino)-3-(4-((4-fluoro-2-oxopyridin-1(2H)-yl)methyl)piperidin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 2-(cyclopropylamino)-3-(4-(2,5-difluorobenzoyl)piperidin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 1-((1-(2-(cyclopropylamino)-7-methylpyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)methyl)-4-fluoropyridin-2(1H)-one, 2,2,2-trifluoroacetic acid salt; 2-(cyclobutylamino)-3-(4-((2,5-difluorophenyl)fluoromethyl)piperidin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 3-(cyclopropylamino)-2-(4-((2,5-difluorophenyl)fluoromethyl)piperidin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 3-(4-((2,5-difluorophenyl)fluoromethyl)piperidin-1-yl)-2-(isopropylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 8-chloro-N-cyclopropyl-3-(4-((2,5-difluorophenyl)-fluoromethyl)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt; 6-bromo-N-cyclopropyl-3-(4-(2,4-difluorobenzyl)piperidin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-(2,4-difluorobenzyl)piperidin-1-yl)-2-((3,3,3-trifluoropropyl)-amino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 3-(4-((2,5-difluorophenyl)-fluoromethyl)piperidin-1-yl)-2-((3,3,3-trifluoropropyl)amino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-2-((3,3,3-trifluoropropyl)amino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 3-(4-(2,5-difluorobenzyl)piperazin-1-yl)-2-((3,3,3-trifluoropropyl)amino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 3-(4-(2,4-difluorobenzyl)piperazin-1-yl)-2-((3,3,3-trifluoropropyl)amino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 6-bromo-N-cyclopropyl-3-(4-(2,5-difluorobenzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; 6-bromo-3-(4-(5-chloro-2-fluorobenzyl)piperazin-1-yl)-N-cyclopropylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; 6-bromo-N-cyclopropyl-3-(4-(2,4-difluorobenzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; 6-bromo-N-cyclopropyl-3-(4-((2,5-difluorophenyl)fluoromethyl)piperidin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; 6-bromo-N-cyclopropyl-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; 7-bromo-N-cyclopropyl-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt; 7-bromo-N-cyclopropyl-3-(4-(2,4-difluorobenzyl)-piperazin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-((4-chloro-2-oxopyridin-1 (2H)-yl)methyl)piperidin-1-yl)-2-(cyclopropylamino)-quinoxaline-6-carbonitrile; 1-((1-(2-(cyclopropylamino)-5-methylpyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)methyl)-5-fluoropyridin-2(1H)-one; 4-chloro-1-((1-(2-(cyclopropylamino)-5-methylpyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)methyl)pyridin-2(1H)-one; 2-(cyclopropylamino)-3-(4-((5-fluoro-2-oxopyridin-1(2H)-yl)methyl)piperidin-1-yl)quinoxaline-6-carbonitrile; 1-((1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)methyl)-4-fluoropyridin-2(1H)-one; 1-((1-(2-(cyclopropylamino)-5-methylpyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)methyl)-4-fluoropyridin-2(1H)-one; 5-chloro-1-((1-(2-(cyclopropylamino)-pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)methyl)pyridin-2(1H)-one; 3-(4-((5-chloro-2-fluorophenyl)difluoromethyl)piperidin-1-yl)-2-(cyclopropylamino)quinoxaline-6-carbonitrile; 3-(4-((5-chloro-2-fluorophenyl)difluoromethyl)piperidin-1-yl)-N-cyclopropyl-7-methylpyrido[3,4-b]pyrazin-2-amine; 3-(4-((5-chloro-2-oxopyridin-1 (2H)-yl)methyl)piperidin-1-yl)-2-(cyclopropylamino)quinoxaline-6-carbonitrile; 3-(4-((5-chloro-2-fluorophenyl)difluoro-methyl)piperidin-1-yl)-N-cyclopropyl-5-methylpyrido[3,4-b]pyrazin-2-amine; 5-chloro-1-((1-(2-(cyclopropylamino)-5-methylpyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)methyl)pyridin-2(1H)-one; 5-chloro-1-((1-(2-(cyclopropylamino)-7-methylpyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)methyl)pyridin-2(1H)-one; 3-(4-((5-chloro-2-fluorophenyl)difluoromethyl)-piperidin-1-yl)-N-cyclopropylpyrido[3,4-b]pyrazin-2-amine; N-cyclopropyl-3-(4-((2,5-difluorophenyl)difluoromethyl)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine; N-cyclopropyl-3-(4-((2,5-difluorophenyl)difluoromethyl)piperidin-1-yl)-7-methylpyrido[3,4-b]pyrazin-2-amine; N-cyclopropyl-3-(4-((2,5-difluorophenyl)-difluoromethyl)piperidin-1-yl)-5-methylpyrido[3,4-b]pyrazin-2-amine; 2-(cyclopropylamino)-3-(4-((2,5-difluorophenyl)difluoromethyl)piperidin-1-yl)quinoxaline-6-carbonitrile, and 7-chloro-N-cyclopropyl-3-(4-(2,4-difluorobenzyl)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine; N-cyclopropyl-3-(4-(pyridin-3-yloxy)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine; N-cyclopropyl-3-(4-(4-methoxyphenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine; N-cyclopropyl-3-(4-(pyridin-2-yloxy)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine; N-cyclopropyl-3-(4-(pyridin-4-yloxy)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine; (1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)(2-methoxyphenyl)methanone, 2,2,2-trifluoroacetic acid salt; 4-((1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)oxy)benzonitrile; (2-chlorophenyl)(1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)methanone, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-3-(4-(3-methoxyphenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-3-(4-(2-methoxyphenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt; (1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)(phenyl)methanone; (1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)(2,3-difluorophenyl)methanone, 2,2,2-trifluoroacetic acid salt; (3-chlorophenyl)(1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)methanone; 3-((1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)oxy)benzonitrile; (1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)(3-methoxyphenyl)methanone; (1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)(o-tolyl)methanone, 2,2,2-trifluoroacetic acid salt; (1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)(2,6-difluorophenyl)methanone, 2,2,2-trifluoroacetic acid salt; (2-chloro-5-fluorophenyl)(1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)methanone, 2,2,2-trifluoroacetic acid salt; (1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)(3-fluorophenyl)methanone, 2,2,2-trifluoroacetic acid salt; 1-(4-((1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)oxy)phenyl)ethanone, 2,2,2-trifluoroacetic acid salt; 4-((1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)oxy)-N,N-dimethylbenzamide, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-3-(4-(4-(methylthio)phenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt; (1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)(2-fluoro-5-(methylthio)phenyl)methanone, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-3-(4-(4-ethoxyphenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-3-(4-(2-fluoro-4-(2-fluoroethoxy)phenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt; 4-((1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)oxy)-3-fluorophenol, 2,2,2-trifluoroacetic acid salt; (6-chloro-2,3-difluorophenyl)(1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)methanone, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt; (2-chloro-3-fluorophenyl)(1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)methanone, hydrogen chloride salt; (2-chlorothiophen-3-yl)(1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)methanone, hydrogen chloride salt; (1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)(thiophen-2-yl)methanone, 2,2,2-trifluoroacetic acid salt; 3-(1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidine-4-carbonyl)benzonitrile, hydrogen chloride salt; (1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)(2-(methylthio)phenyl)methanone, 2,2,2-trifluoroacetic acid salt; (1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)(thiophen-3-yl)methanone, 2,2,2-trifluoroacetic acid salt; 3-(1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidine-4-carbonyl)-4-fluorobenzonitrile, 2,2,2-trifluoroacetic acid salt; 3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-N-isopropylpyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropylpyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-N-isopropylpyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt; N-ethyl-3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt; 2-((1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)oxy)benzonitrile; (2-chloro-6-fluorophenyl)(1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)methanone; (2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-3-(4-((4-fluorophenyl)sulfonyl)piperidin-1-yl)-7-methylpyrido[3,4-b]pyrazin-2-amine 2,2,2-trifluoroacetate
Example 2
Synthesis of 3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-N-(pyrazin-2-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt




3-Chloro-N-(pyrazin-2-yl)quinoxalin-2-amine (210 mg, 0.815 mmol) and 1-(2,5-dichlorobenzyl)piperazine (220 mg, 0.896 mmol) were added to n-BuOH (0.8 ml). After stirring for 2 h at 90° C., the reaction mixture was purified by HPLC to yield the title compound as a yellow solid. MS (ESI, pos. ion) m/z: 466.0 (M+1)
Utilizing similar reaction conditions as described above, following compounds were synthesized:
3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-N-(pyrimidin-4-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-N-(pyridazin-3-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-N-(1,2,4-triazin-3-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-N-(5,6-dimethyl-1,2,4-triazin-3-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; N-(3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)quinoxalin-2-yl)-3,4-dimethylisoxazol-5-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-N-(pyridin-4-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-N-(pyridin-2-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-N-(2,2,2-trifluoroethyl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; and 2-(cyclobutylamino)-3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt.
Example 3
Synthesis of 3-(4-(4-chlorobenzoyl)piperazin-1-yl)-2-((2-fluoroethyl)amino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt




A suspension of 3-chloro-2-((2,2-difluoroethyl)amino)quinoxaline-6-carbonitrile (50 mg, 0.186 mmol), (4-chlorophenyl)(piperazin-1-yl)methanone hydrochloride (72.9 mg, 0.279 mmol) and DIPEA (0.098 ml, 0.558 mmol) in DMSO (1 ml) was stirred at RT for 16 h. After HPLC purification, most of MeCN was removed under reduced pressure. The resulting suspension was neutralized with solid Na2CO3 and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated to afford the title compound as a yellow solid. MS (ESI, pos. ion) m/z: 438.8 (M+1)
Utilizing similar reaction conditions described above, following compounds were synthesized:
3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-2-((2,2-difluoroethyl)amino)quinoxaline-6-carbonitrile; 3-(4-(4-chlorobenzoyl)piperazin-1-yl)-2-((2,2-difluoroethyl)amino)quinoxaline-6-carbonitrile; 3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-2-(isoxazol-3-ylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 3-(4-(4-chlorobenzoyl)piperazin-1-yl)-2-(isoxazol-3-ylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-2-((2-fluoroethyl)amino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 3-(4-(2,5-difluorobenzyl)piperazin-1-yl)-2-((2-fluoroethyl)amino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 3-(4-(2,5-difluorobenzyl)piperazin-1-yl)-2-((2,2-difluoroethyl)amino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 3-(4-(2,5-difluorobenzyl)piperazin-1-yl)-2-(isoxazol-3-ylamino)quinoxaline-6-carbonitrile.
Example 4
Synthesis of benzofuran-3-yl(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)methanone




To a 1-dram vial was added benzofuran-3-carboxylic acid (11.84 mg, 0.073 mmol), HATU (27.8 mg, 0.073 mmol), and iPr2EtN (44.7 μl, 0.256 mmol) in DMF (365 μl). After stirring at RT for 30 min, N-cyclopropyl-3-(piperazin-1-yl)quinoxalin-2-amine, 2HCl (25 mg, 0.073 mmol) was added. The reaction mixture was stirred for 3 h and then HPLC purification yielded the title compound as a colorless oil. MS (ESI, pos. ion) m/z: 414.3 (M+1)
Utilizing similar reaction conditions described above, following compounds were synthesized:
(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)(3,4-dimethylphenyl-1-yl)methanone, 2,2,2-trifluoroacetic acid salt; (4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)(2,4-dichlorophenyl)methanone, 2,2,2-trifluoroacetic acid salt; 4-(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazine-1-carbonyl)benzonitrile, 2,2,2-trifluoroacetic acid salt; (4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)(4-ethylphenyl)methanone, 2,2,2-trifluoroacetic acid salt; (4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)(2,5-difluorophenyl)methanone, 2,2,2-trifluoroacetic acid salt; (4-(3-(cyclopropylamino)-quinoxalin-2-yl)piperazin-1-yl)(naphthalen-2-yl)methanone, 2,2,2-trifluoroacetic acid salt; (2-bromo-5-methoxyphenyl)(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt; (3-bromo-4-methoxyphenyl)(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt; (4-bromo-2-chlorophenyl)(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt; (4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)(5-fluoro-2-methylphenyl)methanone, 2,2,2-trifluoroacetic acid salt; (3-bromo-4-fluorophenyl)(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt; (4-bromo-2-fluorophenyl)(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt; (5-bromo-2-fluorophenyl)(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt; (4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)(4-ethoxyphenyl)methanone, 2,2,2-trifluoroacetic acid salt; (4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)(3-isopropylphenyl)methanone, 2,2,2-trifluoroacetic acid salt; (4-(3-(cyclopropylamino)-quinoxalin-2-yl)piperazin-1-yl)(4-isopropylphenyl)methanone, 2,2,2-trifluoroacetic acid salt; (4-bromo-2-methylphenyl)(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt; (2-chloro-3,6-difluorophenyl)(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt; (2-chloro-5-iodophenyl)(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt; (5-bromo-2-methylphenyl)(4-(3-(cyclopropylamino)-quinoxalin-2-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt; (4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)(4-(trifluoromethoxy)phenyl)methanone, 2,2,2-trifluoroacetic acid salt; (4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)(1H-indol-6-yl)methanone, 2,2,2-trifluoroacetic acid salt; (5-chloro-2-methylphenyl)(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt; (4-chloro-2-methylphenyl)(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt; (4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)(2,4-dimethylphenyl)methanone, 2,2,2-trifluoroacetic acid salt; (2-chloro-5-methoxyphenyl)(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt; 5-(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazine-1-carbonyl)-2-isopropoxybenzonitrile, 2,2,2-trifluoroacetic acid salt; (4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)(2-methoxy-5-(trifluoromethoxy)phenyl)methanone, 2,2,2-trifluoroacetic acid salt; (4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)(2,3,5-trichlorophenyl)-methanone, 2,2,2-trifluoroacetic acid salt; (2-chloro-6-(trifluoromethyl)phenyl)(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt; (4-(chloromethyl)phenyl)(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt; (4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)(1H-indol-5-yl)methanone, 2,2,2-trifluoroacetic acid salt; (4-bromo-3-methylphenyl)(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt; (4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)(4-fluoro-3-methoxyphenyl)methanone, 2,2,2-trifluoroacetic acid salt; (3-bromo-4-methylphenyl)(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt; (4-chloro-3-methylphenyl)(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt; (4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)(4-fluoro-2-methylphenyl)methanone; (3-bromo-2-methylphenyl)(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt; (4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)(3,5-difluorophenyl)methanone, 2,2,2-trifluoroacetic acid salt; (4-bromophenyl)(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt; 3-(4-(3-(cyclopropylamino)-quinoxalin-2-yl)piperazine-1-carbonyl)benzonitrile, 2,2,2-trifluoroacetic acid salt; (3-bromophenyl)(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt; (4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)(2,6-dichlorophenyl)methanone, 2,2,2-trifluoroacetic acid salt; (2-bromo-4-methylphenyl)(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt; 4-(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazine-1-carbonyl)-3-fluorobenzonitrile, 2,2,2-trifluoroacetic acid salt; benzo[d][1,2,3]thiadiazol-5-yl(4-(3-(cyclopropylamino)-quinoxalin-2-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt; (2-chloro-5-fluorophenyl)(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt; (4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)(2-methoxy-5-(trifluoromethyl)phenyl)methanone, 2,2,2-trifluoroacetic acid salt; (4-bromo-3-(trifluoromethyl)phenyl)(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)methanone; (4-chloro-3-methylphenyl)(4-(3-(pyridin-3-ylamino)quinoxalin-2-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt; (3-bromo-4-fluorophenyl)(4-(3-(cyclopropylamino)-6,7-difluoroquinoxalin-2-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt; 3-(4-(3-bromo-4-fluorobenzoyl)piperazin-1-yl)-2-(cyclopropylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 3-(4-(3-bromo-4-fluorobenzoyl)piperazin-1-yl)-2-(isopropylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 3-(4-(3-bromo-4-fluorobenzoyl)piperazin-1-yl)-2-(cyclobutylamino)-quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; (4-chlorophenyl)(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt; (2-chlorophenyl)(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt; (4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)(m-tolyl)methanone, 2,2,2-trifluoroacetic acid salt; (4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)(2,5-dichlorothiophen-3-yl)methanone; (4-(2-(cyclopropylamino)pyrido-[3,4-b]pyrazin-3-yl)piperazin-1-yl)(4-(difluoromethyl)phenyl)methanone, 2,2,2-trifluoroacetic acid salt; (4-chloro-3-fluorophenyl)(4-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt; (4-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperazin-1-yl)(3,4-difluorophenyl)methanone, 2,2,2-trifluoroacetic acid salt; (3-chloro-4-fluorophenyl)(4-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt; (4-chloro-2-fluorophenyl)(4-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt; (2-chloro-4-fluorophenyl)(4-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt; (4-chloro-2-hydroxyphenyl)(4-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt; (4-chloro-2-methoxyphenyl)(4-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt; 3-(1-(4-chlorobenzoyl)piperidin-4-yl)-2-(cyclopropylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; (4-(3-(cyclopropylamino)quinoxalin-2-yl)-3-methylpiperazin-1-yl)(2,5-dichlorophenyl)methanone, 2,2,2-trifluoroacetic acid salt.
Example 5
Synthesis of cyclohexyl(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)methanone




A solution of N-cyclopropyl-3-(piperazin-1-yl)quinoxalin-2-amine dihydrochloride (50 mg, 0.146 mmol) and Et3N (30.5 μl, 0.219 mmol) in DCM (365 μl) was treated with cyclohexanecarbonyl chloride (23.93 μl, 0.175 mmol) dropwise via syringe at RT. The resulting reaction mixture was stirred for 2 h. ISCO purification (40% EtOAc/Hexanes) afforded the title compound as a light-yellow solid. MS (ESI, pos. ion) m/z: 380.3 (M+1)
Example 6
Synthesis of 3-(4-(4-chlorobenzoyl)piperazin-1-yl)-2-(cyclopropylamino)quinoxaline-6-carbonitrile




To a solution of 4-chlorobenzoic acid (6.39 mg, 0.041 mmol) in CH2Cl2 (136 μl) was added 3 drops DMF and oxalyl chloride (5.36 μl, 0.061 mmol). The reaction mixture was allowed to stir at RT for 60 min then added to a solution of 2-(cyclopropylamino)-3-(piperazin-1-yl)quinoxaline-6-carbonitrile, 2HCl (15 mg, 0.041 mmol) and triethylamine (19.92 μl, 0.143 mmol) in CH2Cl2 (200 μl). The reaction mixture was allowed to stir at RT for 2 h. ISCO purification (0-100% EtOAc/Hexanes) yielded the title compound as a yellow oil. MS (ESI, pos. ion) m/z: 433.3 (M+1)
Utilizing similar reaction conditions described above, following compounds were synthesized:
(4-chlorophenyl)(4-(3-(cyclopropylamino)-7-fluoroquinoxalin-2-yl)piperazin-1-yl)methanone; (4-chlorophenyl)(4-(3-(pyridin-3-ylamino)quinoxalin-2-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt; (4-bromo-3-fluorophenyl)(4-(3-(cyclopropylamino)-7-fluoroquinoxalin-2-yl)piperazin-1-yl)methanone; 2-(cyclopropylamino)-3-(4-(2,5-dichloroisonicotinoyl)piperazin-1-yl)quinoxaline-6-carbonitrile; 2-(cyclopropylamino)-3-(4-(2,5-dichloronicotinoyl)piperazin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; (4-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperazin-1-yl)(2-fluoro-4-(trifluoromethyl)phenyl)methanone, 2,2,2-trifluoroacetic acid salt; (5-chloro-3-fluoropyridin-2-yl)(4-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt; (4-(2-(cyclopropylamino)-pyrido[3,4-b]pyrazin-3-yl)piperazin-1-yl)(2-fluoro-4-methylphenyl)methanone, 2,2,2-trifluoroacetic acid salt; (4-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperazin-1-yl)(2-fluoro-4-methoxyphenyl)methanone, 2,2,2-trifluoroacetic acid salt; (4-chloro-2-methylphenyl)(4-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt; 4-(4-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperazine-1-carbonyl)-3-fluorobenzonitrile, 2,2,2-trifluoroacetic acid salt; (4-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperazin-1-yl)(4-fluoro-2-hydroxyphenyl)-methanone, 2,2,2-trifluoroacetic acid salt; (4-chloro-2,6-difluorophenyl)(4-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt; (4-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperazin-1-yl)(3-fluoropyridin-2-yl)methanone, 2,2,2-trifluoroacetic acid salt; (4-chloro-2-(trifluoromethyl)phenyl)(4-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt; (4-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperazin-1-yl)(2,4,6-trifluorophenyl)methanone, 2,2,2-trifluoroacetic acid salt; and (4-(2-(cyclopropylamino)-pyrido [3,4-b]pyrazin-3-yl)piperazin-1-yl)(2,4-difluoro-6-hydroxyphenyl)methanone, 2,2,2-trifluoroacetic acid salt.
Example 7
Synthesis of 3-(4-(benzofuran-3-ylmethyl)piperazin-1-yl)-N-cyclopropylquinoxalin-2-amine




To a solution of benzofuran-3-yl(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)methanone, TFA (8 mg, 0.015 mmol) in THF (152 μl) was added triethylamine (2.114 μl, 0.015 mmol). The mixture was cooled to 0° C. and BH3-THF (76 μl, 0.076 mmol, 1 M in THF) was added. The reaction mixture was stirred at RT for 18 h. ISCO purification (0-60% EtOAc/Hexanes) yielded the title compound as a yellow oil. MS (ESI, pos. ion) m/z: 400.3 (M+1)
Utilizing similar reaction conditions described above, following compounds were synthesized:
N-cyclopropyl-3-(4-((2,5-dichlorothiophen-3-yl)methyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-3-(4-((3,6-dichloropyridin-2-yl)methyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-(cyclohexylmethyl)piperazin-1-yl)-N-cyclopropylquinoxalin-2-amine; 3-(4-(2-chloro-4-(methylsulfonyl)benzyl)piperazin-1-yl)-N-cyclopropylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-3-(4-((5-methylisoxazol-3-yl)methyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; and 3-(4-(3-chlorobenzyl)piperazin-1-yl)-N-cyclopropyl-6,7-difluoroquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt.
Example 8
Synthesis of N-cyclopropyl-3-(4-(5-fluoro-2-methylbenzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt




To a solution of (4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)(5-fluoro-2-methylphenyl)methanone 2,2,2-trifluoroacetate (65 mg, 0.125 mmol) in THF (1 ml) was added diisobutylaluminum hydride (142 mg, 1.001 mmol, 1 M in hexanes) at RT. The reaction mixture was stirred at RT for 16 h. HPLC purification afforded the title compound as a white solid. MS (ESI, pos. ion) m/z: 391.9 (M+1)
Utilizing similar reaction conditions described above, following compounds were synthesized:
N-cyclopropyl-3-(4-(4-fluoro-2-methylbenzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-(4-chloro-3-methylbenzyl)piperazin-1-yl)-N-cyclopropylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-(2-bromo-5-methoxybenzyl)piperazin-1-yl)-N-cyclopropylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-(3-bromo-4-methoxybenzyl)piperazin-1-yl)-N-cyclopropylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-(4-bromo-2-chlorobenzyl)piperazin-1-yl)-N-cyclopropylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-(3-bromo-4-fluorobenzyl)piperazin-1-yl)-N-cyclopropylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-(4-bromo-2-fluorobenzyl)piperazin-1-yl)-N-cyclopropylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-(5-bromo-2-fluorobenzyl)piperazin-1-yl)-N-cyclopropylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-(5-bromo-2-methylbenzyl)piperazin-1-yl)-N-cyclopropylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-((1H-indol-6-yl)methyl)piperazin-1-yl)-N-cyclopropylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-(5-chloro-2-methylbenzyl)piperazin-1-yl)-N-cyclopropylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-(4-chloro-2-methylbenzyl)piperazin-1-yl)-N-cyclopropylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-(2-chloro-3,6-difluorobenzyl)-piperazin-1-yl)-N-cyclopropylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-(2-chloro-5-methoxybenzyl)piperazin-1-yl)-N-cyclopropylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-(2-chloro-6-(trifluoromethyl)benzyl)piperazin-1-yl)-N-cyclopropylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-3-(4-(3-isopropylbenzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-(3-chloro-4-methoxybenzyl)piperazin-1-yl)-N-cyclopropylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-(4-bromo-3-methylbenzyl)piperazin-1-yl)-N-cyclopropylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-(4-bromo-2-methylbenzyl)piperazin-1-yl)-N-cyclopropylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-(2-chloro-5-iodobenzyl)piperazin-1-yl)-N-cyclopropylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-3-(4-(2-methoxy-5-(trifluoromethoxy)benzyl)-piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-3-(4-(2,3,5-trichlorobenzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-((2-chloro-5-fluoropyridin-3-yl)methyl)piperazin-1-yl)-N-cyclopropylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-(2-bromo-5-chlorobenzyl)piperazin-1-yl)-N-cyclopropylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-(5-chloro-2-(trifluoromethyl)-benzyl)piperazin-1-yl)-N-cyclopropylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-3-(4-(2,6-difluoro-3-methylbenzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; and N-cyclopropyl-3-(4-(2-methoxy-5-(trifluoromethyl)benzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt.
Example 9
Synthesis of N-cyclopentyl-3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)quinoxalin-2-amine




A solution of (4-(3-(cyclopentylamino)quinoxalin-2-yl)piperazin-1-yl)(2,5-dichlorophenyl)methanone (16 mg, 0.034 mmol) in THF (0.35 mL) and DCM (0.35 mL) was added trifluoromethanesulfonic acid anhydride (0.017 mL, 0.102 mmol) at RT and the resulting reaction mixture stirred for 1 h. NaBH4 (3.86 mg, 0.102 mmol) was then added in one portion and stirring continued at RT for 1 h. HPLC purification afforded the title compound as a white solid. MS (ESI, pos. ion) m/z: 456.2 (M+1)
Utilizing similar reaction conditions described above, following compounds were synthesized:
3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-N-phenylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-3-(4-(3-(trifluoromethyl)benzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-(4-chlorobenzyl)piperazin-1-yl)-N-cyclopropylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-(2-chlorobenzyl)-piperazin-1-yl)-N-cyclopropylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-3-(4-(4-(methylsulfonyl)benzyl)piperazin-1-yl)quinoxalin-2-amine, 22,2,2-trifluoroacetic acid salt; N-cyclopropyl-3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-3-(4-(4-(trifluoromethyl)-benzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-3-(4-(2,3-dichlorobenzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
Example 10
Synthesis of 3-(4-(3-chlorobenzyl)piperazin-1-yl)-2-(cyclopropylamino)quinoxaline-6-carbonitrile




To a solution of 2-(cyclopropylamino)-3-(piperazin-1-yl)quinoxaline-6-carbonitrile, 2HCl (15 mg, 0.041 mmol) and triethylamine (11.38 μl, 0.082 mmol) in DCE (204 μl) was added 3-chlorobenzaldehyde (4.63 μl, 0.041 mmol) then sodium triacetoxyborohydride (12.12 mg, 0.057 mmol). The reaction mixture was stirred at RT for 2 h. ISCO purification (0-100% EtOAc/Hexanes) afforded the title compound as a colorless oil. MS (ESI, pos. ion) m/z: 419.3 (M+1)
Utilizing similar reaction conditions described above, following compounds were synthesized and purified by either HPLC or ISCO):
N-cyclopropyl-3-(4-(2,5-difluorobenzyl)piperazin-1-yl)-6-fluoroquinoxalin-2-amine; 2-(cyclopropylamino)-3-(4-(4-fluorobenzyl)piperazin-1-yl)quinoxaline-6-carbonitrile; 8-chloro-3-(4-(5-chloro-2-fluorobenzyl)piperazin-1-yl)-N-cyclopropylpyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt; 8-chloro-N-cyclopropyl-3-(4-(2,5-difluorobenzyl)-piperazin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt; 8-chloro-N-cyclopropyl-3-(4-(2,4-difluorobenzyl)piperazin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt; 8-chloro-N-cyclopropyl-3-(4-(2,4,5-trifluorobenzyl)piperazin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt; 2-(4-(2,5-difluorobenzyl)piperazin-1-yl)-N-(pyridin-3-yl)pyrido[3,4-b]pyrazin-3-amine, 2,2,2-trifluoroacetic acid salt; 7-bromo-N-cyclopropyl-2-(piperazin-1-yl)pyrido[3,4-b]pyrazin-3-amine 2,2,2-trifluoroacetate; 3-(4-(5-chloro-2-propoxybenzyl)piperazin-1-yl)-N-cyclopropylpyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-(5-(tert-butyl)-2-methoxybenzyl)piperazin-1-yl)-N-cyclopropylpyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-3-(4-(2,6-difluorobenzyl)piperazin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-(3-chloro-4-fluorobenzyl)piperazin-1-yl)-N-cyclopropylpyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-3-(4-(2,4,5-trifluorobenzyl)piperazin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-(4-chloro-3-fluorobenzyl)piperazin-1-yl)-N-cyclopropylpyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-3-(4-(3,4-difluorobenzyl)piperazin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-3-(4-(2,4-difluorobenzyl)piperazin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-(5-chloro-2-fluorobenzyl)piperazin-1-yl)-N-cyclopropylpyrido[3,4-b]pyrazin-2-amine, and 2,2,2-trifluoroacetic acid salt; 3-(4-(2-chloro-5-fluorobenzyl)piperazin-1-yl)-N-cyclopropylpyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt; 2-(cyclopropylamino)-3-(1-(2,5-dichlorobenzyl)piperidin-4-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 2-(cyclopropylamino)-3-(1-(2,5-difluorobenzyl)piperidin-4-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-3-(1-(2,4-difluorobenzyl)piperidin-4-yl)-7-methylpyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-3-(4-(2,5-dichlorobenzyl)-2-methylpiperazin-1-yl)quinoxalin-2-amine; methyl 4-(3-(cyclopropylamino)quinoxalin-2-yl)-1-(2,5-dichlorobenzyl)piperazine-2-carboxylate; N-cyclopropyl-3-(4-(2,5-dichlorobenzyl)-3-isopropylpiperazin-1-yl)quinoxalin-2-amine; N-cyclopropyl-3-(4-(2,5-dichlorobenzyl)-3-methylpiperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-3-(4-(2,5-dichlorobenzyl)-3-(methoxymethyl)piperazin-1-yl)quinoxalin-2-amine; 3-(3-benzyl-4-(2,5-dichlorobenzyl)piperazin-1-yl)-N-cyclopropylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt.
Example 11
Synthesis of 2,2,2-trifluoroacetic acid, N-cyclopropyl-3-(4-(3,4-dimethylbenzyl)piperazin-1-yl)quinoxalin-2-amine salt




A mixture of N-cyclopropyl-3-(piperazin-1-yl)quinoxalin-2-amine hydrochloride (100 mg, 0.327 mmol), 4-(chloromethyl)-1,2-dimethylbenzene (152 mg, 0.981 mmol) and Et3N (0.137 ml, 0.981 mmol) was stirred in DMF (3 ml) at 50° C. for 16 h. HPLC purification yielded the title compound as a yellow oil. MS (ESI, pos. ion) m/z: 388.1 (M+1)
Utilizing similar reaction conditions described above, following compounds were synthesized:
4-((4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)methyl)benzonitrile, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-3-(4-(4-ethylbenzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-3-(4-(3,4-dichlorobenzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-3-(4-(2,5-difluorobenzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-3-(4-(naphthalen-2-ylmethyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-(4-bromobenzyl)piperazin-1-yl)-N-cyclopropylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-((4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)methyl)benzonitrile, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-3-(4-(4-fluorobenzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-3-(4-(4-isopropylbenzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-3-(4-(3,5-difluorobenzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-3-(4-(2,3-dimethylbenzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-3-(4-(2,4-dimethylbenzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-(2-chloro-5-fluorobenzyl)-piperazin-1-yl)-N-cyclopropylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-3-(4-(2,5-difluorobenzyl)piperazin-1-yl)-6,7-difluoroquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-(2,5-difluorobenzyl)piperazin-1-yl)-N-(pyridin-3-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; 2-(cyclopropylamino)-3-(4-(2,5-difluorobenzyl)-piperazin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-2-(isopropylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 3-(4-(2,5-difluorobenzyl)piperazin-1-yl)-2-(isopropylamino)-quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 2-(cyclobutylamino)-3-(4-(2,5-difluorobenzyl)piperazin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt.
Example 12
Synthesis of N-cyclopropyl-3-(4-(3-methylbenzyl)piperazin-1-yl)pyrido[2,3-b]pyrazin-2-amine




Step 1: 2-chloro-3-(4-(3-methylbenzyl)piperazin-1-yl)pyrido[2,3-b]pyrazine
To a solution of 2,3-dichloropyrido[2,3-b]pyrazine (100 mg, 0.50 mmol) in dioxane (0.5 mL) was added dropwise a solution of 1-(3-methylbenzyl)piperazine (100 mg, 0.525 mmol) in dioxane (1.0 mL), followed by N-ethyl-N-isopropylpropan-2-amine (0.096 mL, 0.550 mmol). The resulting solution was stirred at RT overnight. Column chromatography purification yielded the title compound as a brown oil.
Step 2: N-cyclopropyl-3-(4-(3-methylbenzyl)piperazin-1-yl)pyrido[2,3-b]pyrazin-2-amine
A solution of 2-chloro-3-(4-(3-methylbenzyl)piperazin-1-yl)pyrido[2,3-b]pyrazine (34.5 mg, 0.097 mmol), cyclopropanamine (7.79 mg, 0.136 mmol) and DIPEA (0.026 mL, 0.146 mmol) in dioxane (0.3 mL) was heated at 100° C. for 8 h. Column chromatography purification gave the title compound as a colorless oil. MS (ESI, pos. ion) m/z: 375.3 (M+1)
Utilizing similar reaction conditions described above, following compounds were synthesized and purified by either HPLC or ISCO:
3-(4-(3-chlorobenzyl)piperazin-1-yl)-N-(4-fluorophenyl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; (4-(3-(cyclopentylamino)quinoxalin-2-yl)piperazin-1-yl)(2,5-dichlorophenyl)methanone, 2,2,2-trifluoroacetic acid salt; (2,5-dichlorophenyl)(4-(3-(phenylamino)quinoxalin-2-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt; N-(cyclopropylmethyl)-3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-N-(3-methoxyphenyl)-quinoxalin-2-amine; 3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-N-(4-methoxyphenyl)-quinoxalin-2-amine; 4-((3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)quinoxalin-2-yl)amino)benzonitrile; N-cyclopropyl-3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)pyrido[2,3-b]pyrazin-2-amine; 3-(cyclopropylamino)-2-(4-(2,5-dichlorobenzyl)piperazin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-2-(4-(2,5-difluorobenzyl)piperazin-1-yl)pyrido[3,4-b]pyrazin-3-amine, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-2-(4-(2,5-dichlorobenzyl)piperazin-1-yl)pyrido[3,4-b]pyrazin-3-amine, 2,2,2-trifluoroacetic acid salt; 2-(4-(4-chlorobenzoyl)piperazin-1-yl)-3-(cyclopropylamino)-quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; (4-chlorophenyl)(4-(3-(cyclopropylamino)pyrido[3,4-b]pyrazin-2-yl)piperazin-1-yl)methanone, 2,2,2-trifluoroacetic acid salt; 3-(cyclopropylamino)-2-(4-(2,5-difluorobenzyl)piperazin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 3-(cyclopropylamino)-2-(4-((4-fluorophenyl)-sulfonyl)piperazin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 3-(cyclopropylamino)-2-(4-((4-fluorophenyl)sulfonyl)piperazin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-2-(4-(2,4,5-trifluorobenzyl)-piperazin-1-yl)pyrido[3,4-b]pyrazin-3-amine, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-2-(4-(2,4-difluorobenzyl)piperazin-1-yl)pyrido[3,4-b]pyrazin-3-amine, 2,2,2-trifluoroacetic acid salt; 2-(4-(2,4-difluorobenzyl)piperazin-1-yl)-N-(2,2-difluoroethyl)pyrido[3,4-b]pyrazin-3-amine, 2,2,2-trifluoroacetic acid salt; N-(2,2-difluoroethyl)-2-(4-(2,4,5-trifluorobenzyl)-piperazin-1-yl)pyrido[3,4-b]pyrazin-3-amine, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-2-(4-(2,4-difluorobenzyl)piperidin-1-yl)pyrido[3,4-b]pyrazin-3-amine, 2,2,2-trifluoroacetic acid salt; 2-(4-(2,4-difluorobenzyl)piperidin-1-yl)-N-(2,2-difluoroethyl)pyrido[3,4-b]pyrazin-3-amine; N-cyclopropyl-2-(4-(2,4-difluorobenzyl)piperidin-1-yl)-7-methylpyrido[3,4-b]-pyrazin-3-amine, 2,2,2-trifluoroacetic acid salt; 3-(cyclopropylamino)-2-(4-(2,4-difluorobenzyl)piperazin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 2-(4-(5-chloro-2-fluorobenzyl)piperazin-1-yl)-3-(cyclopropylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 3-(cyclopropylamino)-2-(4-(2,4,5-trifluorobenzyl)piperazin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; and 2-(4-(4-chloro-2-fluorophenoxy)piperidin-1-yl)-3-(cyclopropylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt.
Example 13
Synthesis of N-(4-bromophenyl)-3-(4-(3-chlorobenzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt




A solution of DIPEA (0.026 ml, 0.151 mmol), 1-(3-chlorobenzyl)piperazine (19.06 mg, 0.090 mmol) and 2,3-dichloroquinoxaline (20 mg, 0.100 mmol) in dioxane (0.2 mL) was heated at 60° C. for 6 h. Then DIPEA (0.026 ml, 0.151 mmol) and 4-bromoaniline (25.9 mg, 0.151 mmol) were added. The resulting solution was stirred at 180° C. overnight. HPLC purification gave the title compound as a yellow solid. MS (ESI, pos. ion) m/z: 509.2 (M+1)
Utilizing similar reaction conditions described above, 2-(4-(3-chlorobenzyl)piperazin-1-yl)-N-phenylpyrido[2,3-b]pyrazin-3-amine, 2,2,2-trifluoroacetic acid salt was synthesized.
Example 14
Synthesis of 3-(4-(3-chlorobenzyl)piperazin-1-yl)-N-phenylpyrido[2,3-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt




To a solution of 2,3-dichloropyrido[2,3-b]pyrazine (20 mg, 0.100 mmol) in dioxane (0.3 mL) was added aniline (9.78 mg, 0.105 mmol) and N-ethyl-N-isopropylpropan-2-amine (38.8 mg, 0.30 mmol). The reaction mixture was heated at 150° C. overnight, then 1-(3-chlorobenzyl)piperazine (31.6 mg, 0.150 mmol) was added. The resulting solution was heated at 150° C. overnight. HPLC purification afforded the title compound as a yellow solid. MS (ESI, pos. ion) m/z: 431.2 (M+1)
Utilizing similar reaction conditions described above, following compounds were synthesized:
3-(4-(3-chlorobenzyl)piperazin-1-yl)-N-phenylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-(3-chlorobenzyl)piperazin-1-yl)-N-(4-(trifluoromethoxy)-phenyl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-(3-chlorobenzyl)piperazin-1-yl)-N-(4-propylphenyl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-(3-chlorobenzyl)piperazin-1-yl)-N-(p-tolyl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-(3-chlorobenzyl)piperazin-1-yl)-N-(4-methoxyphenyl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-(3-chlorobenzyl)piperazin-1-yl)-N-(2-methoxyphenyl)-quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-(3-chlorobenzyl)piperazin-1-yl)-N-(3-methoxyphenyl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; N-(4-(tert-butyl)phenyl)-3-(4-(3-chlorobenzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; and 3-(4-(3-chlorobenzyl)piperazin-1-yl)-N-(4-isopropoxyphenyl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt.
Example 15
Synthesis of 3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-N-(pyridin-3-yl)pyrido[2,3-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt




Step 1: 2-chloro-3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)pyrido[2,3-b]pyrazine
To a solution of 2,3-dichloropyrido[2,3-b]pyrazine (21 mg, 0.105 mmol) and 1-(2,5-dichlorobenzyl)piperazine, HCl (31.0 mg, 0.110 mmol) in dioxane (350 μl) was added N-ethyl-N-isopropylpropan-2-amine (56.8 μl, 0.325 mmol) dropwise at RT. The resulting mixture was stirred at RT overnight and HPLC purification yielded the title compound as a yellow solid.
Step 2: 3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-N-(pyridin-3-yl)pyrido[2,3-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
A mixture of 2-chloro-3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)pyrido[2,3-b]pyrazine (25 mg, 0.061 mmol), pyridin-3-amine (7.48 mg, 0.080 mmol) and NaH (9.79 mg, 0.245 mmol, 60% in mineral oil) in THF (266 μL) was stirred at RT for 3 h. After quenching with methanol (0.5 mL), HPLC purification afforded the title compound as a yellow solid. MS (ESI, pos. ion) m/z: 466.2 (M+1)
Utilizing similar reaction conditions described above, following compounds were synthesized:
2-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-3-(pyridin-3-ylamino)quinoxaline-6-carbonitrile; mixture of 3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-6-fluoro-N-(pyridin-3-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt and 3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-7-fluoro-N-(pyridin-3-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; N-(pyridin-3-yl)-2-(4-(2,4,5-trifluorobenzyl)piperazin-1-yl)pyrido[3,4-b]pyrazin-3-amine, 2,2,2-trifluoroacetic acid salt; and 2-(4-(2,4-difluorobenzyl)piperazin-1-yl)-N-(pyridin-3-yl)pyrido[3,4-b]pyrazin-3-amine.
Example 16
Synthesis of 2-(cyclopropylamino)-3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)quinoxaline-5-carbonitrile, 2,2,2-trifluoroacetic acid salt




A vial containing 5-bromo-N-cyclopropyl-3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)quinoxalin-2-amine (20 mg, 0.039 mmol), dicyanozinc (2.78 mg, 0.024 mmol), Pd2(dba)3 (1.805 mg, 1.971 mol) and dppf (2.186 mg, 3.94 mol) in anhydrous NMP (0.3 mL) was evacuated and purged with N2 (3×). The resulting mixture was heated at 120° C. for 2 h. HPLC purification gave the title compound as a grey solid. MS (ESI, pos. ion) m/z: 453.3 (M+1)
Utilizing similar reaction conditions described above, following compounds were synthesized:
3-(cyclopropylamino)-2-(4-(2,5-dichlorobenzyl)piperazin-1-yl)quinoxaline-5-carbonitrile, 2,2,2-trifluoroacetic acid salt; 2-(cyclopropylamino)-3-(4-(2,4-difluoro-benzyl)piperidin-1-yl)pyrido[3,4-b]pyrazine-7-carbonitrile; and 3-(cyclopropylamino)-2-(4-(2,4-difluorobenzyl)piperazin-1-yl)pyrido[3,4-b]pyrazine-7-carbonitrile, 2,2,2-trifluoroacetic acid salt.
Example 17
Synthesis of N-cyclopropyl-3-(4-(2,4-difluorobenzyl)piperazin-1-yl)pyrazino[2,3-d]pyridazin-2-amine, 2,2,2-trifluoroacetic acid salt




Step 1: pyrazino[2,3-d]pyridazine-2,3(1H,4H)-dione
A solution of pyridazine-4,5-diamine (200 mg, 1.816 mmol), oxalic acid (196 mg, 2.179 mmol) and aq hydrogen chloride (2.7 mL, 10.90 mmol, 4.0 N) was heated at reflux for 20 h. The reaction mixture was cooled to RT and the resulting precipitate was filtered, washed with water and dried under vacuum to afford the title compound as a white solid.
Step 2: 2,3-dichloropyrazino[2,3-d]pyridazine
A solution of pyrazino[2,3-d]pyridazine-2,3(1H,4H)-dione hydrochloride (300 mg, 1.496 mmol) in phosphoryl trichloride (1812 μl, 19.44 mmol) was heated at 120° C. overnight. Removal of the excess POCl3 under reduced pressure gave the title compound as a black sticky oil, which was used directly in the next step without further purification.
Step 3: N-cyclopropyl-3-(4-(2,4-difluorobenzyl)piperazin-1-yl)pyrazino[2,3-d]pyridazin-2-amine, 2,2,2-trifluoroacetic acid salt
To a solution of 2,3-dichloropyrazino[2,3-d]pyridazine hydrochloride (48 mg, 0.202 mmol) in DCM (1.0 mL) at 0° C. was added N-ethyl-N-isopropylpropan-2-amine (177 μl, 1.011 mmol) dropwise, followed by slow addition of cyclopropanamine (11.19 μl, 0.162 mmol). The reaction mixture was stirred at 0° C. for 20 min and then 1-(2,4-difluorobenzyl)piperazine hydrochloride (75 mg, 0.303 mmol) and DIPEA (0.2 mL) were added and stirring continued at 0° C. for 30 min. HPLC purification afforded the title compound as a light yellow solid. MS (ESI, pos. ion) m/z: 398.3 (M+1)
Utilizing similar reaction conditions described above, N-cyclopropyl-3-(4-(2,4-difluorobenzyl)piperidin-1-yl)pyrazino[2,3-d]pyridazin-2-amine, 2,2,2-trifluoroacetic acid salt was synthesized.
Example 18
Synthesis of N-cyclopropyl-3-(4-(2,5-difluorobenzyl)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt




Step 1: tert-butyl 4-(2,5-difluorobenzylidene)piperidine-1-carboxylate
To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (64.1 mg, 0.322 mmol) in THF (1.6 mL) at −78° C. was added LiHMDS (386 μl, 0.386 mmol, 1.0 N in MeOt-Bu). After the reaction mixture was stirred at −78° C. for 30 min, a solution of tert-butyl 4-oxopiperidine-1-carboxylate (64.1 mg, 0.322 mmol) in THF (0.3 mL) was added. The reaction mixture was allowed to warm to RT and stirred for 48 h. Column chromatography purification gave the title compound as a white solid.
Step 2: 4-(2,5-difluorobenzylidene)piperidine
To a solution of tert-butyl 4-(2,5-difluorobenzylidene)piperidine-1-carboxylate (20 mg, 0.065 mmol) in DCM (0.6 ml) at 0° C. was added TFA (0.3 mL, 3.89 mmol) and stirring continued at 0° C. for 2 h. Removal of the solvent yielded the title compound as a colorless oil, which was used directly in the next step without further purification.
Step 3: N-cyclopropyl-3-(4-(2,5-difluorobenzylidene)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine
A solution of 3-chloro-N-cyclopropylpyrido[3,4-b]pyrazin-2-amine (127 mg, 0.574 mmol), 4-(2,5-difluorobenzylidene)piperidine (100 mg, 0.478 mmol) and DIPEA (167 μl, 0.956 mmol) in dioxane (0.8 mL) was heated at 80° C. for 8 h. HPLC purification afforded the title compound.
Step 4: N-cyclopropyl-3-(4-(2,5-difluorobenzyl)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt
To a solution of N-cyclopropyl-3-(4-(2,5-difluorobenzylidene)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine 2,2,2-trifluoroacetate (21.2 mg, 0.042 mmol) in MeOH (209 μl) was added 10% Pd/C (4 mg, 3.76 mol). The reaction mixture was stirred under a H2 atmosphere overnight. HPLC purification yielded the title compound as a light yellow solid. MS (ESI, pos. ion) m/z: 396.3 (M+1)
Example 19
Synthesis of N-cyclopropyl-3-(4-(2,4-difluorobenzyl)piperidin-1-yl)-7-methoxypyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt




A vial charged with 7-chloro-N-cyclopropyl-3-(4-(2,4-difluorobenzyl)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine (15 mg, 0.035 mmol), Pd2(dba)3 (2.56 mg, 2.79 mol), and Cs2CO3 (11.37 mg, 0.035 mmol) was evacuated and purged with N2 (3×). After MeOH (0.3 ml) was added, the mixture was again evacuated and purged with N2 (2×) and then heated at 100° C. overnight. HPLC purification gave the title compound as a grey solid. MS (ESI, pos. ion) m/z: 426.3 (M+1)
Example 20
Synthesis of 2-(cyclopropylamino)-3-(4-(2,4-difluorobenzyl)piperidin-1-yl)pyrido[3,4-b]pyrazin-7-ol, 2,2,2-trifluoroacetic acid salt




A vial charged with 7-chloro-N-cyclopropyl-3-(4-(2,4-difluorobenzyl)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine (25 mg, 0.058 mmol), Pd2(dba)3 (4.26 mg, 4.65 mol), potassium trimethylsilanolate (22.38 mg, 0.174 mmol) and cesium carbonate (18.95 mg, 0.058 mmol) was evacuated and purged with N2 (3×). After DMF (0.29 mL) was added, the mixture was again evacuated and purged with N2 (2×) and then heated at 110° C. overnight. HPLC purification yielded the title compound as a yellow solid. MS (ESI, pos. ion) m/z: 412.3 (M+1)
Example 21
Synthesis of 2-(cyclopropylamino)-3-(4-(phenylsulfonyl)piperazin-1-yl)quinoxaline-6-carbonitrile




To a solution of 2-(cyclopropylamino)-3-(piperazin-1-yl)quinoxaline-6-carbonitrile, 2HCl (15 mg, 0.041 mmol) in CH2Cl2 (204 μl) was added triethylamine (17.08 μl, 0.123 mmol). After stirring for 10 min, benzenesulfonyl chloride (6.27 μl, 0.049 mmol) was added and the reaction mixture was stirred at RT for 2 h. ISCO purification (0-60% EtOAc/Hexanes) afforded the title compound as a white solid. MS (ESI, pos. ion) m/z: 435.3 (M+1)
Utilizing similar reaction conditions described above, following compounds were synthesized and purified by either ISCO or HPLC:
3-(4-(phenylsulfonyl)piperazin-1-yl)-N-(pyridin-3-yl)quinoxalin-2-amine; N-cyclopropyl-6-fluoro-3-(4-(phenylsulfonyl)piperazin-1-yl)quinoxalin-2-amine; 3-(4-((3-chlorophenyl)sulfonyl)piperazin-1-yl)-2-(cyclopropylamino)quinoxaline-6-carbonitrile; 3-(4-((3-chlorophenyl)sulfonyl)piperazin-1-yl)-N-cyclopropyl-6-fluoroquinoxalin-2-amine; 2-(cyclopropylamino)-3-(4-((2,5-dichlorophenyl)sulfonyl)piperazin-1-yl)quinoxaline-6-carbonitrile; 2-(cyclopropylamino)-3-(4-(o-tolylsulfonyl)piperazin-1-yl)quinoxaline-6-carbonitrile; 2-(cyclopropylamino)-3-(4-(m-tolylsulfonyl)piperazin-1-yl)quinoxaline-6-carbonitrile; 2-(cyclopropylamino)-3-(4-tosylpiperazin-1-yl)quinoxaline-6-carbonitrile; 3-(4-((2-bromophenyl)sulfonyl)piperazin-1-yl)-2-(cyclopropylamino)quinoxaline-6-carbonitrile; 3-(4-((3-bromophenyl)sulfonyl)piperazin-1-yl)-2-(cyclopropylamino)quinoxaline-6-carbonitrile; 3-(4-((4-bromophenyl)sulfonyl)piperazin-1-yl)-2-(cyclopropylamino)-quinoxaline-6-carbonitrile; N-cyclopropyl-3-(4-((4-fluorophenyl)sulfonyl)piperazin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-2-(4-((4-fluorophenyl)sulfonyl)piperazin-1-yl)pyrido[3,4-b]pyrazin-3-amine, 2,2,2-trifluoroacetic acid salt; 2-(cyclopropylamino)-3-(4-((3,5-dimethylisoxazol-4-yl)sulfonyl)piperazin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 2-(cyclopropylamino)-3-(4-((2,5-dimethylphenyl)sulfonyl)piperazin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 2-(cyclopropylamino)-3-(4-((4-methoxyphenyl)sulfonyl)piperazin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 2-(cyclopropylamino)-3-(4-((2-methoxyphenyl)sulfonyl)piperazin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 2-(cyclopropylamino)-3-(4-((3-methoxyphenyl)sulfonyl)piperazin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 3-(4-((5-chlorothiophen-2-yl)sulfonyl)piperazin-1-yl)-2-(cyclopropylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 2-(cyclopropylamino)-3-(4-(mesitylsulfonyl)piperazin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 2-(cyclopropylamino)-3-(4-((2-methoxy-4-methylphenyl)sulfonyl)-piperazin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 3-(4-((5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperazin-1-yl)-2-(cyclopropylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 2-(cyclopropylamino)-3-(4-((2,3,4-trifluorophenyl)sulfonyl)piperazin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 3-(4-((4-(tert-butyl)phenyl)sulfonyl)piperazin-1-yl)-2-(cyclopropylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 3-(4-((4-chloro-2,5-dimethylphenyl)-sulfonyl)piperazin-1-yl)-2-(cyclopropylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 3-(4-((3-chloro-5-fluoro-2-methylphenyl)sulfonyl)piperazin-1-yl)-2-(cyclopropylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 2-(cyclopropylamino)-3-(4-((4-(trifluoromethoxy)phenyl)sulfonyl)piperazin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 3-(4-((5-bromothiophen-2-yl)sulfonyl)piperazin-1-yl)-2-(cyclopropylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 3-(4-((4-bromo-2-fluorophenyl)sulfonyl)piperazin-1-yl)-2-(cyclopropylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 3-(4-((2-chloro-5-(trifluoromethyl)phenyl)-sulfonyl)piperazin-1-yl)-2-(cyclopropylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 3-(4-((4-bromo-2-chlorophenyl)sulfonyl)piperazin-1-yl)-2-(cyclopropylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 2-(cyclopropylamino)-3-(4-((4-ethylphenyl)sulfonyl)piperazin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 2-(cyclopropylamino)-3-(4-((2-fluoro-5-methylphenyl)sulfonyl)piperazin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 2-(cyclopropylamino)-3-(4-((3,4-difluorophenyl)sulfonyl)piperazin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 2-(cyclopropylamino)-3-(4-((2,5-dimethoxyphenyl)sulfonyl)piperazin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 3-(4-((2-chloro-4-(trifluoromethyl)phenyl)sulfonyl)piperazin-1-yl)-2-(cyclopropylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 3-(4-((3-cyano-4-fluorophenyl)sulfonyl)piperazin-1-yl)-2-(cyclopropylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 3-(4-((5-chloro-2-methoxyphenyl)sulfonyl)piperazin-1-yl)-2-(cyclopropylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 3-(4-((5-chloro-2,4-difluorophenyl)sulfonyl)piperazin-1-yl)-2-(cyclopropylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 3-(4-((5-bromo-6-chloropyridin-3-yl)sulfonyl)piperazin-1-yl)-2-(cyclopropylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 3-(4-((4-bromo-2,5-difluorophenyl)sulfonyl)piperazin-1-yl)-2-(cyclopropylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 2-(cyclopropylamino)-3-(4-((2,4-dimethoxyphenyl)sulfonyl)piperazin-1-yl)quinoxaline-6-carbonitrile; N-cyclopropyl-3-(4-(phenylsulfonyl)piperazin-1-yl)quinoxalin-2-amine; N-cyclopropyl-3-(4-((4-(trifluoromethoxy)phenyl)sulfonyl)piperazin-1-yl)quinoxalin-2-amine; 3-(4-(cyclopentylsulfonyl)piperazin-1-yl)-N-cyclopropylquinoxalin-2-amine; 3-(4-((4-chlorophenyl)sulfonyl)piperazin-1-yl)-2-(cyclopropylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 2-(cyclopropylamino)-3-(4-((3-fluorophenyl)sulfonyl)-piperazin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 2-(cyclopropylamino)-3-(4-((2-fluorophenyl)sulfonyl)piperazin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 3-(4-((2-chlorophenyl)sulfonyl)piperazin-1-yl)-2-(cyclopropylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 2-(cyclopropylamino)-3-(4-((4-fluorophenyl)sulfonyl)piperazin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 3-(4-((2-cyanophenyl)sulfonyl)piperazin-1-yl)-2-(cyclopropylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 3-(4-((3-cyanophenyl)sulfonyl)piperazin-1-yl)-2-(cyclopropylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; 3-(4-((4-cyanophenyl)sulfonyl)piperazin-1-yl)-2-(cyclopropylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; and N-cyclopropyl-3-(4-((4-(trifluoromethyl)phenyl)sulfonyl)piperazin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt.
Example 22
Synthesis of N-cyclopropyl-3-(4-phenethylpiperazin-1-yl)quinoxalin-2-amine




Step 1: 1-(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)-2-phenylethanone
To a solution of 2-phenylacetic acid (11.93 mg, 0.088 mmol) in CH2Cl2 (438 μl) was added DMF (3 drops) and oxalyl chloride (11.51 μl, 0.131 mmol), then the mixture was allowed to stir for 60 min. The acid chloride was added to a solution of N-cyclopropyl-3-(piperazin-1-yl)quinoxalin-2-amine, 2HCl (30 mg, 0.088 mmol) and triethylamine (36.7 μl, 0.263 mmol) in CH2Cl2 (400 μl). The reaction mixture was allowed to stir at RT for 2 h. ISCO purification (0-100% EtOAc/Hexanes yielded the title compound as a yellow oil.
Step 2: N-cyclopropyl-3-(4-phenethylpiperazin-1-yl)quinoxalin-2-amine
To a solution of 1-(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)-2-phenylethanone (5 mg, 0.013 mmol) in THF (43.0 μl) was added BH3-THF (64.5 μl, 0.065 mmol, 1 M in THF). The mixture was stirred at RT for 16 h. ISCO purification (0-80% EtOAc/Hexanes) afforded the title compound as a yellow oil. MS (ESI, pos. ion) m/z: 374.3 (M+1)
Utilizing similar reaction conditions described above, following compounds were synthesized and purified by either HPLC or ISCO:
3-(4-(4-chlorophenethyl)piperazin-1-yl)-N-cyclopropylquinoxalin-2-amine; N-cyclopropyl-3-(4-(4-methoxyphenethyl)piperazin-1-yl)quinoxalin-2-amine; N-cyclopropyl-3-(4-(2,5-dichlorophenethyl)piperazin-1-yl)quinoxalin-2-amine.
Example 23
Synthesis of 3-(4-benzylpiperidin-1-yl)-N-phenylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt




Step 1: 2-(4-benzylpiperidin-1-yl)-3-chloroquinoxaline
A solution of 2,3-dichloroquinoxaline (1 g, 5.02 mmol) and EtOH (25 ml) was treated with 4-benzylpiperidine (1.233 g, 7.03 mmol). The reaction mixture was stirred at 15° C. for 15 h. The solvent was removed under reduced pressure to give the title compound, which was used for the next step without further purification.
Step 2: 3-(4-benzylpiperidin-1-yl)-N-phenylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
2-(4-Benzylpiperidin-1-yl)-3-chloroquinoxaline (200 mg, 0.592 mmol) and aniline (55.1 mg, 0.592 mmol) was stirred in n-BuOH (0.6 ml) at 90° C. for 16 h. The solvent was removed under reduced pressure and HPLC purification afforded the title compound as a yellow solid.
Utilizing similar reaction conditions described above, following compounds were synthesized:
N-(3-bromophenyl)-3-(4-(3-chlorobenzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; N-(2-bromophenyl)-3-(4-(3-chlorobenzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-(3-chlorobenzyl)piperazin-1-yl)-N-(pyridin-3-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-(3-chlorobenzyl)piperazin-1-yl)-N-(pyridin-4-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; N-(3-(4-(3-chlorobenzyl)piperazin-1-yl)quinoxalin-2-yl)-1,3,4-thiadiazol-2-amine, 2,2,2-trifluoroacetic acid salt; N-(3-(4-(3-chlorobenzyl)piperazin-1-yl)quinoxalin-2-yl)thiazol-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-(3-chlorobenzyl)piperazin-1-yl)-N-(pyrimidin-2-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; and 3-(4-(3-chlorobenzyl)piperazin-1-yl)-N-(pyrimidin-5-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt.
Example 24
Synthesis of 3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-N-isobutylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt




Step 1: 2-chloro-3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)quinoxaline
A suspension of 2-chloro-3-(piperazin-1-yl)quinoxaline (2.5 g, 10.05 mmol), 1,4-dichloro-2-(chloromethyl)benzene (2.358 g, 12.06 mmol) and Et3N (4.20 ml, 30.2 mmol) in DMF (20 ml) was stirred at RT for 16 h. The reaction mixture was poured into water and extracted with EtOAc. The organic phase was dried, concentrated, and chromatographed on silica gel to give the title compound.
Step 2: 3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-N-isobutylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt
A suspension of 2-chloro-3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)quinoxaline (50 mg, 0.123 mmol) and 2-methylpropan-1-amine (90 mg, 1.226 mmol) was heated in n-BuOH (1 ml) at 130° C. under microwave irradiation for 1 h. HPLC purification afforded the title compound as a white solid. MS (ESI, pos. ion) m/z: 444.0 (M+1)
Utilizing similar reaction conditions described above, following compounds were synthesized using commercially available amines:
3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-N-isopropylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-N-(2-ethylbutyl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-N-(4-methylpentan-2-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-N-neopentylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-N-isopentylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; N-(sec-butyl)-3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-N-propylquinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-N-(2-methoxyethyl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; N-cyclobutyl-3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; N-(tert-butyl)-3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-N-(3,3-dimethylbutyl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-N-(2-ethoxyethyl)-quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-N-(2-isopropoxyethyl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-N-(3-ethoxypropyl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; N-cyclohexyl-3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-(2,5-dichlorobenzyl)piperazin-1-yl)-N-(tetrahydro-2H-pyran-4-yl)quinoxalin-2-amine, 2,2,2-trifluoroacetic acid salt; and (R)-2-((3-(4-(2,5-dichlorobenzyl)-piperazin-1-yl)quinoxalin-2-yl)amino)propan-1-ol, 2,2,2-trifluoroacetic acid salt
Example 25
Synthesis of (R/S)—N-cyclopropyl-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine




Step 1: (1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)(2,4-difluorophenyl)methanol
To a solution of (1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)(2,4-difluorophenyl)methanone, TFA (50 mg, 0.096 mmol) in MeOH (478 μl) was added NaBH4 (10.84 mg, 0.287 mmol). The mixture was stirred at RT for 2 h then purified by ISCO (0-100% EtOAc/hexanes) to yield the title compound as a colorless oil.
Step 2: (R/S)—N-cyclopropyl-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine
To a −78° C. solution of (1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)(2,4-difluorophenyl)methanol (7 mg, 0.017 mmol) in CH2Cl2 (85 μl) was added DAST (6.74 μl, 0.051 mmol). The reaction mixture was stirred for 30 min then quenched with a few drops of MeOH. ISCO purification (0-100% EtOAc/hexanes) yielded the title compound as a colorless oil. MS (ESI, pos. ion) m/z: 414.3 (M+1)
Note: Optically pure final compounds were obtained by chiral SFC separation of racemic compound.
Utilizing similar reaction conditions described above, following compounds were synthesized:
(R/S)—N-cyclopropyl-3-(4-(fluoro(4-fluorophenyl)methyl)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine; (R/S)-3-(4-((5-chloro-2-fluorophenyl)fluoromethyl)piperidin-1-yl)-N-cyclopropylpyrido[3,4-b]pyrazin-2-amine; (R/S)—N-cyclopropyl-3-(4-((2,5-difluorophenyl)-fluoromethyl)piperidin-1-yl)-7-methylpyrido[3,4-b]pyrazin-2-amine; and (R/S)—N-cyclopropyl-3-(4-((2,5-difluorophenyl)fluoromethyl)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine
Example 26
Synthesis of (S)—N-cyclopropyl-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-7-methylpyrido[3,4-b]pyrazin-2-amine 2,2,2-trifluoroacetate




To a solution of 3-chloro-N-cyclopropyl-7-methylpyrido[3,4-b]pyrazin-2-amine (10 mg, 0.043 mmol) in dioxane (85 μl) was added (S)-4-((2,4-difluorophenyl)fluoromethyl)piperidine, HCl (14.72 mg, 0.055 mmol) and iPr2EtN (29.8 μl, 0.170 mmol). The mixture was heated at 80° C. for 2 h. HPLC purification afforded the title compound as a yellow oil. MS (ESI, pos. ion) m/z: 428.3 (M+1)
Utilizing similar reaction conditions described above, following compounds were synthesized
using chiral intermediate compounds: (R)—N-cyclopropyl-3-(4-((2,4-difluorophenyl)-fluoromethyl)piperidin-1-yl)-7-methylpyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt; (S)-2-(cyclopropylamino)-3-(4-((2,4-difluorophenyl)fluoromethyl)-piperidin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; (S)—N-cyclopropyl-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-5-methylpyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt; (S)—N-cyclopropyl-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt; (R)-2-(cyclopropylamino)-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt; (R)-7-chloro-N-cyclopropyl-3-(4-((2,4-difluorophenyl)-fluoromethyl)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt; and (S)-7-chloro-N-cyclopropyl-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt.
Example 27
Synthesis of (R/S)-3-(4-(1-(5-chloro-2-fluorophenyl)-1-fluoroethyl)piperidin-1-yl)-N-cyclopropylpyrido[3,4-b]pyrazin-2-amine




Step 1: 1-(5-chloro-2-fluorophenyl)-1-(1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)ethanol
To a −78° C. solution of (5-chloro-2-fluorophenyl)(1-(2-(cyclopropylamino)-pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)methanone, TFA (18 mg, 0.033 mmol) in THF (167 μl) was added methyl magnesium bromide (33.3 μl, 0.100 mmol, 3 M in Et2O). The mixture was stirred at −78° C. for 1 h then RT for 1 h. A few drops of H2O were added to quench the reaction, which was then filtered through a syringe filter and the solvents were removed under reduced pressure to yield the title compound as a tan solid.
Step 2: (R/S)-3-(4-(1-(5-chloro-2-fluorophenyl)-1-fluoroethyl)piperidin-1-yl)-N-cyclopropylpyrido[3,4-b]pyrazin-2-amine
To a −78° C. solution of 1-(5-chloro-2-fluorophenyl)-1-(2-(cyclopropylamino)-pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)ethanol (13 mg, 0.029 mmol) in CH2Cl2 (147 μl) was added DAST (11.66 μl, 0.088 mmol). The mixture was stirred at −78° C. for 30 min then warmed to 10° C. and added another 3 eq DAST (11.66 μl, 0.088 mmol). The reaction mixture was quenched with a few drops of H2O and ISCO purification (30-100% EtOAc/hexanes) afforded the title compound as a colorless oil. MS (ESI, pos. ion) m/z: 444.2 (M+1)
Example 28
Synthesis of (R/S)-3-(4-((2,5-difluorophenyl)fluoromethyl)piperidin-1-yl)-2-(isopropylamino)quinoxaline-6-carbonitrile, 2,2,2-trifluoroacetic acid salt




A solution of (R/S)-4-((2,5-difluorophenyl)fluoromethyl)piperidine hydrochloride (28 mg, 0.105 mmol) and 3-chloro-2-(isopropylamino)quinoxaline-6-carbonitrile (20 mg, 0.081 mmol) in dioxane (162 μl) and DIPEA (42.5 μl, 0.243 mmol) was stirred at 75° C. for 3 h. HPLC purification afforded the title compound as an ivory solid. MS (ESI, pos. ion) m/z: 440.3 (M+1)
Note: Optically pure final compounds were obtained by chiral SFC separation of racemic compound.
Utilizing similar reaction conditions described above, following compounds were synthesized:
(R/S)-2-(cyclopropylamino)-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)quinoxaline-6-carbonitrile; (R/S)-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-2-(isopropylamino)quinoxaline-6-carbonitrile; and (R/S)-3-(cyclopropylamino)-2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)quinoxaline-6-carbonitrile.
Example 29
Synthesis of (S)-2-(cyclopropylamino)-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)pyrido[3,4-b]pyrazine-7-carbonitrile




Step 1: 7-bromo-3-chloro-N-cyclopropylpyrido[3,4-b]pyrazin-2-amine
To solution of 7-bromo-2,3-dichloropyrido[3,4-b]pyrazine (90 mg, 0.323 mmol) in DCM (1613 μl) at 0° C. was added a solution of cyclopropanamine (26.8 μl, 0.387 mmol) in DCM (0.2 mL), followed by the addition of DIPEA (169 μl, 0.968 mmol). The resulting solution was stirred at 0° C. for 2 h. ISCO purification (0-50% EtOAc/Hexanes) gave the title compound as an off-white solid.
Step 2: (S)-7-bromo-N-cyclopropyl-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine
A mixture of 7-bromo-3-chloro-N-cyclopropylpyrido[3,4-b]pyrazin-2-amine (30 mg, 0.100 mmol), (S)-4-((2,4-difluorophenyl)fluoromethyl)piperidine, HCl (31.9 mg, 0.120 mmol) and DIPEA (0.052 ml, 0.300 mmol) in dioxane (0.3 ml) was heated at 80° C. for 8 h. Silica gel column chromatography purification gave the title compound as a white solid.
Step 3: (S)-2-(cyclopropylamino)-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)pyrido[3,4-b]pyrazine-7-carbonitrile
To a vial was added (S)-7-bromo-N-cyclopropyl-3-(4-((2,4-difluorophenyl)-fluoromethyl)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine (25 mg, 0.051 mmol), Pd2(dba)3 (2.325 mg, 2.54 mol), dicyanozinc (3.58 mg, 0.030 mmol) and dppf (2.82 mg, 5.08 mol) in NMP (508 μl). The vial was evacuated and filled with N2 (3×) then heated at 120° C. for 2 h. HPLC and ISCO purification afforded the title compound as a white solid. MS (ESI, pos. ion) m/z: 439.2 (M+1)
Utilizing similar reaction conditions described above, using reference compounds, the following compounds were synthesized: (R)-2-(cyclopropylamino)-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)pyrido[3,4-b]pyrazine-7-carbonitrile; 3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-2-(isopropylamino)pyrido[3,4-b]pyrazine-7-carbonitrile, 2,2,2-trifluoroacetic acid salt; 3-(4-(2,5-difluorobenzoyl)piperidin-1-yl)-2-(isopropylamino)pyrido[3,4-b]pyrazine-7-carbonitrile, 2,2,2-trifluoroacetic acid salt; 3-(4-(2-fluoro-4-methoxybenzyl)piperidin-1-yl)-2-(isopropylamino)pyrido[3,4-b]pyrazine-7-carbonitrile, 2,2,2-trifluoroacetic acid salt; 2-((2,2-difluoroethyl)amino)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazine-7-carbonitrile, 2,2,2-trifluoroacetic acid salt; 2-(tert-butylamino)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazine-7-carbonitrile
Example 30
Synthesis of (S)-3-(cyclopropylamino)-2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)pyrido[3,4-b]pyrazine-7-carbonitrile




Step 1: (S)-7-bromo-3-chloro-2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)pyrido[3,4-b]pyrazine
To a mixture of 7-bromo-2,3-dichloropyrido[3,4-b]pyrazine (30 mg, 0.108 mmol) in DCM (1 ml) at 0° C. was added (S)-4-((2,4-difluorophenyl)fluoromethyl)piperidine, HCl (31.4 mg, 0.118 mmol), followed by addition of N-ethyl-N-isopropylpropan-2-amine (0.056 ml, 0.323 mmol). The resulting mixture was stirred at 0° C. for 2 h. ISCO purification gave the title compound as a yellow solid.
Step 2: (S)-7-bromo-N-cyclopropyl-2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)pyrido[3,4-b]pyrazin-3-amine
A solution of (S)-7-bromo-3-chloro-2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)pyrido[3,4-b]pyrazine (40 g, 85 mmol), cyclopropanamine (38.7 g, 678 mmol) and DIPEA (22.22 ml, 127 mmol) in dioxane (0.3 ml) was heated at 80° C. for 24 h. Silica gel column chromatography purification gave the title compound as a white solid.
Step 3: (S)-3-(cyclopropylamino)-2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)pyrido[3,4-b]pyrazine-7-carbonitrile
To a vial was added (S)-7-bromo-N-cyclopropyl-2-(4-((2,4-difluorophenyl)-fluoromethyl)piperidin-1-yl)pyrido[3,4-b]pyrazin-3-amine (17 mg, 0.035 mmol), Pd2(dba)3 (1.581 mg, 1.726 mol), dicyanozinc (2.433 mg, 0.021 mmol) and dppf (1.914 mg, 3.45 mol) in NMP (345 μl). The vial was evacuated and filled with N2 (3×) then heated at 120° C. for 2 h. HPLC and ISCO purification afforded the title compound as a white solid. MS (ESI, pos. ion) m/z: 439.2 (M+1).
Utilizing similar reaction conditions described above, (R)-3-(cyclopropylamino)-2-(4-((2,4-difluorophenyl)-fluoromethyl)piperidin-1-yl)pyrido[3,4-b]pyrazine-7-carbonitrile was synthesized.
Example 31
Synthesis of 2,2,2-trifluoroacetic acid, 1-(4-((1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)oxy)phenyl)ethanol salt




A 5 mL screwtop vial containing 1-(4-((1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)oxy)phenyl)ethanone 2,2,2-trifluoroacetate (130 mg, 0.251 mmol) and sodium tetrahydroborate (28.5 mg, 0.754 mmol) in MeOH (1256 μl) was stirred for 30 min. HPLC purification afforded the title compound as a clear oil. MS (ESI, pos. ion) m/z: 406.3 (M+1).
Example 32
Synthesis of 2-(4-(4-chloro-2-fluorophenoxy)piperidin-1-yl)-3-(isopropylamino)quinoxaline-6-carbonitrile




Step 1: 3-chloro-2-(4-(4-chloro-2-fluorophenoxy)piperidin-1-yl)quinoxaline-6-carbonitrile
To a solution of 2,3-dichloroquinoxaline-6-carbonitrile (400 mg, 1.785 mmol) and 4-(4-chloro-2-fluorophenoxy)piperidine (615 mg, 2.68 mmol) in dichloromethane (40 ml) was added triethylamine (0.025 ml, 0.179 mmol), which was stirred at 20° C. for 6 h. Water was added and the reaction was extracted with dichloromethane (2×) and the combined organic layers were concentrated. Purification by column chromatography (PE:EtOAc=50:1) afforded the title compound as a yellow solid.
Step 2: 2-(4-(4-chloro-2-fluorophenoxy)piperidin-1-yl)-3-(isopropylamino)quinoxaline-6-carbonitrile
To a solution of 3-chloro-2-(4-(4-chloro-2-fluorophenoxy)piperidin-1-yl)quinoxaline-6-carbonitrile (100 mg, 0.240 mmol) in DMSO (10 ml) was added triethylamine (0.033 ml, 0.240 mmol) and propan-2-amine (142 mg, 2.397 mmol), which was stirred at 120° C. for 16 h. HPLC purification afforded the title compound as a yellow solid. MS (ESI, pos. ion) m/z: 439.8 (M+1).
Utilizing similar reaction conditions described above, 2-(4-(2-chloro-5-(isopropylamino)benzoyl)piperidin-1-yl)-3-(isopropylamino)quinoxaline-6-carbonitrile was synthesized.
Example 33
Synthesis of 3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-2-(isopropylamino)-N,N-dimethylpyrido[3,4-b]pyrazine-7-carboxamide, 2,2,2-trifluoroacetic acid salt




Step 1: 7-bromo-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropylpyrido[3,4-b]pyrazin-2-amine
A solution of 4-(2,4-difluorophenoxy)piperidine hydrochloride (150 mg, 0.599 mmol) and 7-bromo-3-chloro-N-isopropylpyrido[3,4-b]pyrazin-2-amine (139 mg, 0.461 mmol) in dioxane (922 μl) and DIPEA (242 μl, 1.383 mmol) was stirred at 90° C. for 4 h. ISCO purification (40% EtOAc in hexanes) afforded the title compound as an orange solid.
Step 2: 3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-2-(isopropylamino)-N,N-dimethylpyrido[3,4-b]pyrazine-7-carboxamide, 2,2,2-trifluoroacetic acid salt
A solution of 7-bromo-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropylpyrido[3,4-b]pyrazin-2-amine (30 mg, 0.063 mmol), phenyl formate (13.68 μl, 0.125 mmol), diacetoxypalladium (2.82 mg, 0.013 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (14.52 mg, 0.025 mmol) and triethylamine (17.48 μl, 0.125 mmol) in MeCN (314 μl) was stirred at 80° C. overnight. Dimethylamine (157 μl, 0.314 mmol) was then added and stirring continued at 80° C. for 1 h. HPLC purification afforded the title compound as a yellow solid. MS (ESI, pos. ion) m/z: 471.3 (M+1).
Utilizing similar reaction conditions described above, the following compounds were synthesized: 3-(4-(4-chloro-2-fluorophenoxy)piperidin-1-yl)-2-(isopropylamino)-N,N-dimethylpyrido[3,4-b]pyrazine-7-carboxamide, 2,2,2-trifluoroacetic acid salt; 3-(4-(2,4-difluorobenzyl)piperazin-1-yl)-2-(isopropylamino)-N,N-dimethylpyrido[3,4-b]pyrazine-7-carboxamide, 2,2,2-trifluoroacetic acid salt; 3-(4-(2,5-difluorobenzoyl)piperidin-1-yl)-2-(isopropylamino)-N,N-dimethylpyrido[3,4-b]pyrazine-7-carboxamide, 2,2,2-trifluoroacetic acid salt; (S)-2-(cyclopropylamino)-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-N,N-dimethylpyrido[3,4-b]pyrazine-7-carboxamide, 2,2,2-trifluoroacetic acid salt; (R)-2-(cyclopropylamino)-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-N,N-dimethylpyrido[3,4-b]pyrazine-7-carboxamide, 2,2,2-trifluoroacetic acid salt; (S)-(2-(cyclopropylamino)-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)pyrido[3,4-b]pyrazin-7-yl)(morpholino)methanone, 2,2,2-trifluoroacetic acid salt; (R)-(2-(cyclopropylamino)-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)pyrido[3,4-b]pyrazin-7-yl)(morpholino)methanone, 2,2,2-trifluoroacetic acid salt; (2-(cyclopropylamino)-3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazin-7-yl)(4-methylpiperazin-1-yl)methanone; 2,2,2-trifluoroacetic acid salt; (2-(cyclopropylamino)-3-(4-(2,4-difluorobenzyl)piperazin-1-yl)pyrido[3,4-b]pyrazin-7-yl)(morpholino)methanone, 2,2,2-trifluoroacetic acid salt; 2-(cyclopropylamino)-3-(4-(2-fluoro-4-methoxybenzyl)piperazin-1-yl)-N,N-dimethylpyrido[3,4-b]pyrazine-7-carboxamide, 2,2,2-trifluoroacetic acid salt; 2-((2,2-difluoroethyl)amino)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N,N-dimethylpyrido[3,4-b]pyrazine-7-carboxamide, 2,2,2-trifluoroacetic acid salt; 2-(cyclopropylamino)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N,N-dimethylpyrido[3,4-b]pyrazine-7-carboxamide;
Example 34
Synthesis of 3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-N-isopropylpyrazino[2,3-d]pyridazin-2-amine, 2,2,2-trifluoroacetic acid salt




Step 1: pyrazino[2,3-d]pyridazine-2,3(1H,4H)-dione
A mixture of pyridazine-4,5-diamine (4 g, 36.3 mmol) and di(1H-imidazol-1-yl)methanone (7.07 g, 43.6 mmol) in DMF (145 ml) was heated at 75° C. for 16 h. Then 60 mL THF was added and the reaction mixture was stirred at RT for 1 h. Filtration, followed by wash with THF, gave the title compound as a grey powder. The material was used directly in the next step without further purification.
Step 2: 2,3-dichloropyrazino[2,3-d]pyridazine
A mixture of pyrazino[2,3-d]pyridazine-2,3(1H,4H)-dione (1 g, 6.09 mmol) in phosphoryl trichloride (22.72 ml, 244 mmol) was heated at 133° C. for 24 h. After removal of POCl3 in vacuo, ice was added to the reaction flask. Then, 120 mL cold ethyl acetate was added and the mixture was made basic with sat. NaHCO3 while at 0° C. After filtration, the organic layer was quickly separated and dried with Na2SO4. After the drying agent was filtered off, the filtrate was used immediately in the next step without further purification.
Step 3: 3-chloro-N-isopropylpyrazino[2,3-d]pyridazin-2-amine
Half of the above ethyl acetate solution was transferred to a reaction flask at 0° C., then propan-2-amine (0.052 ml, 0.607 mmol) and DIPEA (0.530 ml, 3.03 mmol) was added. The reaction mixture was stirred at 0° C. for 15 min and then used in the next step without purification.
Step 4: 3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-N-isopropylpyrazino[2,3-d]pyridazin-2-amine, 2,2,2-trifluoroacetic acid salt
Half of the reaction solution was transferred to a reaction flask at 0° C., and then 4-(2-fluoro-4-methoxyphenoxy)piperidine, HCl (0.199 g, 0.760 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.265 ml, 1.520 mmol) were added. The reaction mixture was stirred at 0° C. for 1 h and at RT for 2 h. HPLC purification afforded the title compound as a brown solid. MS (ESI, pos. ion) m/z: 413.4 (M+1).
Utilizing similar reaction conditions described above, the following compounds were synthesized: (S)—N-cyclopropyl-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)pyrazino[2,3-d]pyridazin-2-amine, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)pyrazino[2,3-d]pyridazin-2-amine, 2,2,2-trifluoroacetic acid salt; (R)—N-cyclopropyl-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)pyrazino[2,3-d]pyridazin-2-amine, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-3-(4-(2-fluoro-4-(methylthio)phenoxy)piperidin-1-yl)pyrazino[2,3-d]pyridazin-2-amine, 2,2,2-trifluoroacetic acid salt; N-cyclopropyl-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazino[2,3-d]pyridazin-2-amine, 2,2,2-trifluoroacetic acid salt; 4-((1-(3-(cyclopropylamino)pyrazino[2,3-d]pyridazin-2-yl)piperidin-4-yl)oxy)-3-fluorophenol; 3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropylpyrazino[2,3-d]pyridazin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-N-isopropylpyrazino[2,3-d]pyridazin-2-amine, 2,2,2-trifluoroacetic acid salt; (S)—N-(sec-butyl)-3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)pyrazino[2,3-d]pyridazin-2-amine, 2,2,2-trifluoroacetic acid salt; (R)—N-(sec-butyl)-3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)pyrazino[2,3-d]pyridazin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-fluoro-4-((1-(3-(isopropylamino)pyrazino[2,3-d]pyridazin-2-yl)piperidin-4-yl)oxy)benzonitrile, 2,2,2-trifluoroacetic acid salt; (R)-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-N-isopropylpyrazino[2,3-d]pyridazin-2-amine, 2,2,2-trifluoroacetic acid salt; (2-fluoro-4-methoxyphenyl)(1-(3-(isopropylamino)pyrazino[2,3-d]pyridazin-2-yl)piperidin-4-yl)methanone, 2,2,2-trifluoroacetic acid salt; 3-(4-(2-fluoro-4-methoxybenzyl)piperidin-1-yl)-N-isopropylpyrazino[2,3-d]pyridazin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-(4-chloro-2-fluorophenoxy)piperidin-1-yl)-N-isopropylpyrazino[2,3-d]pyridazin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-((R)-(2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-N-((1R,2R)-2-methylcyclopropyl)pyrazino[2,3-d]pyridazin-2-amine, 2,2,2-trifluoroacetic acid salt; 3-(4-(2,4-difluorobenzyl)piperazin-1-yl)-N-isopropylpyrazino[2,3-d]pyridazin-2-amine 2,2,2-trifluoroacetate; N-isopropyl-3-(4-(3-methoxyphenoxy)piperidin-1-yl)pyrazino[2,3-d]pyridazin-2-amine 2,2,2-trifluoroacetate; 3-(4-(4-chloro-2-fluorophenoxy)piperidin-1-yl)-N-cyclopropylpyrazino[2,3-d]pyridazin-2-amine 2,2,2-trifluoroacetate; 3-(4-(2-fluoro-4-(fluoromethoxy)phenoxy)piperidin-1-yl)-N-isopropylpyrazino[2,3-d]pyridazin-2-amine.
Example 35
Synthesis of 2-(cyclopropylamino)-3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-N,N-dimethylpyrido[3,4-b]pyrazine-5-carboxamide




A vial was charged with 5-chloro-N-cyclopropyl-3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine (40 mg, 0.090 mmol), diacetoxypalladium (4.05 mg, 0.018 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (20.86 mg, 0.036 mmol), phenyl formate (22.01 mg, 0.180 mmol) and triethylamine (24.91 μl, 0.180 mmol). The vial was purged with nitrogen and MeCN (410 μl) was added. The mixture was heated at 100° C. for 14 h. Then, dimethylamine (225 μl, 0.451 mmol) in THF was added and the mixture was stirred at RT for 2 h. HPLC purification afforded the title compound as a yellow solid. MS (ESI, pos. ion) m/z: 481.4 (M+1).
Utilizing similar reaction conditions described above, and using commercially available amines, the following compounds were synthesized: (2-(cyclopropylamino)-3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazin-5-yl)(morpholino)methanone, 2,2,2-trifluoroacetic acid salt; azetidin-1-yl(2-(cyclopropylamino)-3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazin-5-yl)methanone, 2,2,2-trifluoroacetic acid salt.
Example 36
Synthesis of 2-(cyclopropylamino)-3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazine-5-carbonitrile, 2,2,2-trifluoroacetic acid salt




To a vial was added 5-chloro-N-cyclopropyl-3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine (22 mg, 0.050 mmol), dicyanozinc (5.82 mg, 0.050 mmol), zinc (2.59 mg, 0.040 mmol), bis(2,2,2-trifluoroacetyl)palladium (4.47 mg, 0.015 mmol) and [1,1′-binaphthalen]-2-yldi-tert-butylphosphine (11.85 mg, 0.030 mmol). After purging with nitrogen for 2 min, NMP (248 μl) was added. The resulting reaction mixture was heated at 100° C. overnight. HPLC purification yielded the title compound as a light yellow film. MS (ESI, pos. ion) m/z: 435.3 (M+1).
Utilizing similar reaction conditions described above, and using reference compounds, the following compounds were synthesized: 2-(cyclopropylamino)-3-(4-(2,4-difluorobenzyl)piperazin-1-yl)pyrido[3,4-b]pyrazine-5-carbonitrile, 2,2,2-trifluoroacetic acid salt; 2-(cyclopropylamino)-3-(4-(2-fluoro-4-methoxybenzyl)piperazin-1-yl)pyrido[3,4-b]pyrazine-5-carbonitrile, 2,2,2-trifluoroacetic acid salt.
Example 37
Synthesis of N-cyclopropyl-3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-5-morpholinopyrido[3,4-b]pyrazin-2-amine, 2,2,2-trifluoroacetic acid salt




A solution of 5-chloro-N-cyclopropyl-3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazin-2-amine (13 mg, 0.029 mmol), morpholine (3.83 μl, 0.044 mmol) and DIPEA (0.015 ml, 0.088 mmol) in dioxane (0.25 ml) was heated at 150° C. overnight. HPLC purification gave the title compound as white solid. MS (ESI, pos. ion) m/z: 495.4 (M+1).
Utilizing similar reaction conditions described above, and using commercially available amines, the following compounds were synthesized: N2-cyclopropyl-3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-N5,N5-dimethylpyrido[3,4-b]pyrazine-2,5-diamine, 2,2,2-trifluoroacetic acid salt.
Example 38
Synthesis of 2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropylpyrido[3,4-b]pyrazin-3-amine




Step 1: 3-chloro-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazine
A 500 mL round bottom flask equipped with a stir bar, septum, and N2 inlet was charged with 2,3-dichloropyrido[3,4-b]pyrazine (9.0 g, 36.0 mmol), 4-(2,4-difluorophenoxy)piperidine hydrochloride (9.44 g, 37.8 mmol), and DCM (90 ml) to furnish an orange suspension. Next, N-ethyl-N-isopropylpropan-2-amine (18.81 ml, 108 mmol) was added to the flask over 2 min at 0° C. The reaction mixture was stirred at 0° C. for 3 h under nitrogen to furnish an orange suspension. The reaction mixture was partitioned between saturated aqueous NH4Cl (100 mL), EtOAc (500 mL), MeOH (50 mL) and H2O (25 mL) to furnish two layers. The layers were separated and the aqueous phase was washed with EtOAc (2×100 mL). MeOH (10 mL) was added during each phase separation. The organic extracts were combined, washed with saturated NaHCO3 (100 mL), brine (100 mL), dried over Na2SO4, filtered, rinsed with EtOAc, and dried in vacuo. Purification by silica gel column (10-50% EtOAc in hexanes) provided the title compound as a yellow-orange solid.
Step 2: 2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-fluoropyrido[3,4-b]pyrazine
To a vial charged with 3-chloro-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazine (1.0 g, 2.65 mmol) and potassium fluoride (0.200 g, 3.45 mmol) was added DMSO (5.0 mL) in one portion at 23° C. The mixture was stirred at 23° C. for 2 h to furnish an orange suspension. The crude reaction mixture was used in the next step without further workup or purification.
Step 3: 2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropylpyrido[3,4-b]pyrazin-3-amine
To the crude reaction mixture of 2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-fluoropyrido[3,4-b]pyrazine was added N-ethyl-N-isopropylpropan-2-amine (0.924 mL, 5.31 mmol) and propan-2-amine (0.684 mL, 7.96 mmol) at 23° C. to furnish a red solution. The reaction mixture was stirred at 23° C. for 20 h. The reaction mixture was diluted with H2O (20 mL) and stirred for 15 min at 23° C. to furnish an orange suspension. The resulting solid was filtered, rinsed with H2O and dried in vacuo. Purification on silica gel (0-100% ethyl acetate in heptanes) provided the title compound as a light yellow solid. MS (ESI, pos. ion) m/z: 400.0 (M+1).
Utilizing similar reaction conditions described above, and using commercially available amines, the following compound was synthesized: N-cyclobutyl-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazin-3-amine.
Example 39
Synthesis of 3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-5,8-dimethylpyrazino[2,3-d]pyridazin-2-amine 2,2,2-trifluoroacetate




Step 1: 5-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6-(isopropylamino)pyrazine-2,3-dicarbaldehyde
A solution of (5-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6-(isopropylamino)pyrazine-2,3-diyl)dimethanol (100 mg, 0.245 mmol) and Dess-Martin Periodinane (260 mg, 0.612 mmol) in DCM (2448 μl) was stirred at RT for 3 h. The reaction mixture was quenched with 2 mL sat. Na2S2O4 and sat. NaHCO3 and stirred at RT for 15 min. ISCO purification gave the title compound as a yellow solid.
Step 2: 1,1′-(5-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6-(isopropylamino)pyrazine-2,3-diyl)diethanol
To a solution of 5-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6-(isopropylamino)pyrazine-2,3-dicarbaldehyde (32 mg, 0.079 mmol) in degassed THF (1 mL) at −78° C. was added methylmagnesium bromide (0.198 mL, 0.277 mmol, 1.4 M in toluene). The reaction was stirred at −78° C. for 2 h then ethyl acetate (3 mL) was added, followed by sat. NaHCO3 (3 mL). The mixture was allowed to warm to RT then the aqueous layer was extracted with ethyl acetate (5 mL×2). ISCO purification (0-100% ethyl acetate in heptanes) gave the title compound as a yellow oil.
Step 3: 3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-5,8-dimethylpyrazino[2,3-d]pyridazin-2-amine 2,2,2-trifluoroacetate
A solution of 1,1′-(5-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6-(isopropylamino)pyrazine-2,3-diyl)diethanol (13 mg, 0.030 mmol) and Dess-Martin Periodinane (29.1 mg, 0.069 mmol) in DCM (298 μl) was stirred at RT for 5 h. Then, 3 drops of NH2NH2—H2O were added to the reaction mixture and stirring continued for 1 h. HPLC purification gave the title compound as a brown solid. MS (ESI, pos. ion) m/z: 428.9 (M+1).
Example 40
Synthesis of 3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-8-methylpyrazino[2,3-d]pyridazin-2-amine




Step 1: (3-(((tert-butyldimethylsilyl)oxy)methyl)-5-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6-(isopropylamino)pyrazin-2-yl)methanol and (3-(((tert-butyldimethylsilyl)oxy)methyl)-6-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-(isopropylamino)pyrazin-2-yl)methanol
To a solution of (5-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6-(isopropylamino)pyrazine-2,3-diyl)dimethanol (800 mg, 1.959 mmol) in DCM (9793 μl) at 0° C. was added DIPEA (513 μl, 2.94 mmol), followed a solution of TBS-Cl (310 mg, 2.057 mmol) in DCM (3 mL), and one crystal of DMAP. The reaction was stirred at 0° C. for 3 h and then RT overnight. ISCO purification (0-50% ethyl acetate in heptane) gave a mixture of the title compounds as a colorless oil.
Step 2: 3-(((tert-butyldimethylsilyl)oxy)methyl)-5-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6-(isopropylamino)pyrazine-2-carbaldehyde and 3-(((tert-butyldimethylsilyl)oxy)methyl)-6-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-(isopropylamino)pyrazine-2-carbaldehyde
A solution of (3-(((tert-butyldimethylsilyl)oxy)methyl)-5-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6-(isopropylamino)pyrazin-2-yl)methanol (598 mg, 1.144 mmol, as a mixture of regioisomers) and Dess-Martin Periodinane (728 mg, 1.716 mmol) in DCM (11.4 mL) was stirred at RT for 3 h. Then, sat. NaHCO3 (10 mL) and sat. Na2S2O3 (10 mL) were added and the resulting mixture was stirred vigorously for 15 min. The organic phase was extracted with ethyl acetate (10 mL×2). ISCO purification (0-100% ethyl acetate in heptane) gave a mixture of the title compounds as a light yellow oil.
Step 3. 1-(3-(((tert-butyldimethylsilyl)oxy)methyl)-5-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6-(isopropylamino)pyrazin-2-yl)ethanol and 1-(3-(((tert-butyldimethylsilyl)oxy)methyl)-6-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-(isopropylamino)pyrazin-2-yl)ethanol
To a solution of 3-(((tert-butyldimethylsilyl)oxy)methyl)-6-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-(isopropylamino)pyrazine-2-carbaldehyde (241 mg, 0.463 mmol, as a mixture of regioisomers) in THF (4628 μl) at −78° C. was added methylmagnesium bromide (827 μl, 1.157 mmol, 1.4 M in toluene). The resulting solution was stirred at −78° C. for 1 h and warmed up to 0° C. for 30 min. 1 N HCl was added to quench the reaction and the mixture was extracted with ethyl acetate (15 mL×2). ISCO purification (0-60% ethyl acetate in heptane) gave a mixture of the title compounds as a light yellow oil.
Step 4: 1-(5-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-(hydroxymethyl)-6-(isopropylamino)pyrazin-2-yl)ethanol and 1-(6-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-(hydroxymethyl)-5-(isopropylamino)pyrazin-2-yl)ethanol
To a solution of 1-(3-(((tert-butyldimethylsilyl)oxy)methyl)-5-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6-(isopropylamino)pyrazin-2-yl)ethanol (137 mg, 0.255 mmol, as a mixture of regioisomers) in THF (2552 μl) was added TBAF (306 μl, 0.306 mmol) at RT. The reaction was stirred for 1 h then quenched with sat. NaHCO3 (3 mL) and water (3 mL). The mixture was extracted with ethyl acetate (10 mL×2).
ISCO purification gave a mixture of the title compounds as a yellow oil.
Step 5: 3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-5-methylpyrazino[2,3-d]pyridazin-2-amine and 3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-8-methylpyrazino[2,3-d]pyridazin-2-amine
A solution of 1-(5-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-(hydroxymethyl)-6-(isopropylamino)pyrazin-2-yl)ethanol (31 mg, 0.073 mmol, as a mixture of regioisomers) and Dess-Martin Periodinane (78 mg, 0.183 mmol) in DCM (734 μl) was stirred at RT for 4 h. Then, 5-6 drops of NH2NH2—H2O was added at 0° C. and the reaction mixture was stirred at RT for 1 h. HPLC purification gave the isolated title compounds. MS (ESI, pos. ion) m/z: 415.0 (M+1).
Biological Examples
Example I
Inhibition of cAMP Activity of GPR6 In Vitro Assay
This cell based assay measures the ability of compounds to inhibit the constitutive cAMP activity of GPR6 receptor expressed in CHO-K1 cells. CHO cells were stably expressed with GPR6 receptor, whose expression is controlled by a tetracycline inducable element. The cells were cultured in medium containing F12K, 10% FBS, 1% Penn/Strep, 200 ug/mL Hygromycin. GPR6 receptor expression was induced for 20 hrs with 1 μg/ml doxycycline (sigma D9891) in growth media. After addition of doxycycline cells were plated at a density of 250-500 cells per well in half-volume black clear bottom plates (Costar) and place in an incubator (37°, 5% C(O)2) for 20 hours prior to cAMP assays.
Culture media was removed from cells and they were washed with 50 μL of Ringer's Buffer (MgCl2 0.047 mg/mL, NaH2PO4 0.18 mg/mL, Na2HPO4 0.1 mg/mL, KCl 0.34 mg/mL, NaHC(O)3 1.26 mg/mL, D-glucose 1.8 mg/mL, NaCl 7 mg/mL; pH=7.4). Compounds suspended in DMSO were diluted in Ringer's Buffer containing 0.5% fatty acid free BSA and incubated on cells for 45 min at 370 and 5% C(O)2. After incubation cells were incubated for 10 min at room temp with Eu-cAMP tracer solution from a Perkin Elmer Lance HTRF UltracAMP assay kit (TRF0264). Then ULightTM-anti-cAMP solution from the Lance HTRF kit was added and incubated on a shaker at room temp for 1 hour prior to HTRF detection in a BMG PolarStar Omega.
IC50 curves were generated with a four-parameter logistic equation using GraphPad Prism 5.03. The specific compounds of this invention had an IC50 value of less than about 100 micromolar.
In approximate IC50 value of a representative number of compounds of Formula (I) in this assay is provided in the table below.










Compound Table 1















IC50

IC50

IC50

IC50


Cpd no.
(um)
Cpd no.
(um)
Cpd no.
(um)
Cpd no.
(um)

















1
17.687
53
1.20
126
46.99
230
0.80


2
45.394
58
5.53
133
0.032
239
4.74


3
24.575
59
0.25
134
1.64
240
4.59


5
40.644
63
1.13
154
0.72
241
0.65


9
10.07
66
1.94
157
105.44
247
1.49


17
25.90
67
1.03
158
0.44
248
1.85


20
69.18
75
21.78
162
4.63
251
4.34


21
3.03
81
4.58
167
3.33
252
2.54


22
7.67
85
7.55
170
4.07
256
0.38


30
26.24
89
4.78
171
1.57
257
0.31


31
6.14
95
22.16
172
2.34
263
0.12


33
2.16
98
3.21
174
1.67
265
0.30


38
5.73
99
6.03
177
17.82
280
0.45


39
6.15
100
3.96
194
3.64
281
0.96


42
3.16
103
5.31
211
9.44
282
4.29


45
2.34
105
5.66
214
1.47
283
0.42


46
4.82
110
6.03
221
20.42
285
1.36


47
3.36
111
3.31
223
5.62
288
2.65


292
0.056
115
3.98
226
0.57
289
0.27


302
0.34
122
10.30
227
3.29
291
0.14


306
0.38
426
0.027
415
0.064
484
0.029


315
0.05
427
0.078
416
1.51
486
0.098


329
1.30
428
0.02
421
8.39
488
0.029


330
0.029
430
1.10
424
0.31
489
0.007


333
0.097
431
0.17
493
0.009
520
0.030


336
0.96
444
0.20
494
0.002
523
0.34


340
15.43
447
0.035
495
0.018
524
0.015


351
0.062
452
0.021
498
0.006
525
0.029


363
0.23
461
0.020
500
0.16
526
0.67


369
0.40
465
0.011
502
1.43
532
0.38


392
0.26
469
0.09
504
0.082
536
0.93


400
0.39
471
0.075
509
0.049
539
0.77


413
0.019
476
0.015
513
0.071
540
0.046


414
0.39
479
0.14
516
0.029
545
0.045


550
0.017
480
0.072
518
0.024
547
0.016


551
0.045
481
0.024
519
0.25
549
0.011


552
0.024
554
0.19
557
1.92
558
1.94


559
0.067
564
11
565
15.37
567
5.78


569
0.062
568
2.18
571
3.90
572
0.021


573
2.8
574
4.81
575
6.75
576
2.883


577
4.9
578
7.21
579
0.01
580
0.008


581
0.006
582
0.007
584
1.74
585
6.04


586
2.29
587
0.078
588
2.74
589
0.069


591
0.022
592
0.026
593
0.023
594
0.031


595
0.478
596
0.026
597
0.089
599
0.005


600
0.02
601
0.022
602
0.146
603
1.023


604
0.054
605
0.036
606
0.054
607
0.043


608
0.717
609
0.051
610
1.572
611
0.044


612
0.114
613
0.092
614
0.066
615
0.088


616
0.939
617
0.054
618
0.012
619
0.014


620
0.018
621
0.021
622
0.029
623
0.039


625
0.006
626
0.09
627
0.051
628
0.276


629
0.008
630
0.007
631
0.006
632
0.028


633
0.004
634
0.006
635
0.04
636
0.016


637
0.026
638
0.021
639
0.03
640
0.072


641
0.014
642
0.054
643
0.015
644
0.007


645
0.145
646
0.538
648
0.065
649
0.044


650
1.00
651
0.06
652
0.031
653
0.093


654
0.03
655
0.02
656
0.014
657
0.008



















Compound Table 2















IC50

IC50

IC50

IC50


Cpd no.
(um)
Cpd no.
(um)
Cpd no.
(um)
Cpd no.
(um)





3
0.84
8
79.62
9
17.7




6
0.53
7
6.64









Example II
Haloperidol-Induced Catalepsy—In Vivo Rodent Parkinson's Disease Model
The motor symptoms of Parkinson's disease include akinesia, bradykinesia, rigidity, tremor and postural abnormalities and are associated with the loss of nigral dopaminergic cells and a decline in striatal dopamine levels. Administration of haloperidol to rodents leads to a transient parkinsonian-like state that is reversed by the administration of L-Dopa (Duty, S.; Jenner, P. Br. J. Pharmacol. (2011), 164, 1357-1391) and other drugs that have been clinically validated for the treatment of Parkinson's disease. Haloperidol antagonizes dopamine D2 and, to a lesser extent, D1 receptors in medium spiny neurons that comprise the indirect and direct pathways of the motor circuit respectively. The resultant block of striatal dopamine transmission results in abnormal downstream firing within the basal ganglia circuits that is manifest as symptoms of muscle rigidity and catalepsy. Catalepsy has been postulated to reflect the clinical features of Parkinson's disease, whereby patients experience an inability of to initiate movements.
Male Sprague-Dawley rats (Charles River, Calco, Italy) weighing 175-200 g are used. Alternatively, male C57Bl6 mice weighing 25-35 g were used. The cataleptic state was induced by the subcutaneous administration of the dopamine receptor antagonist haloperidol (0.3 mg/kg, sc), 90 min before testing the animals on the vertical grid test. For this test, the rats or mice were placed on the wire mesh cover of a 25 cm×43 cm plexiglass cage placed at an angle of about 70 degrees with the bench table. The subject was placed on the grid with all four legs abducted and extended (“frog posture”). The use of such an unnatural posture is essential for the specificity of this test for catalepsy. The time span from placement of the paws until the first complete removal of one paw (descent latency) was measured maximally for 120 sec for rats. For mice, the front paws of a mouse was placed on a horizontal metal bar raised 2′′ above a Plexiglas platform and time was recorded for up to 30 seconds per trial. The test ended when the animal's front paws returned to the platform or after 30 seconds. The test was repeated three times and the average of the three trials was reported as the intensity index of catalepsy.
Catalepsy was measured 30 min, 120 min, and/or 240 min after dosing the subjects a 0.3 mg/kg i.p. dose of haloperidol along with the GPR6 modulator test compound. Test compound plasma and brain levels were determined by collected tissue samples at the end of the experiment, which was either at the 120 or 240 min time point. A representative number of compounds of the invention were administered in a dose range from 0.1 to 100 mg/kg i.p, sc or po in conjunction with haloperidol. The A2a antagonist KW6002 (istradefylline) was dosed at 0.6 mg/kg i.p. as a positive control. The compounds of the invention produced reversal of haloperidol-induced catalepsy. The results of a representative no. of compounds of this invention in this assay are disclosed in the table below.
















Dose

% reversal













Cpd No.
Species
(mpk)
Route
30 min
120 min















33
mouse
30
ip
48.1
41.4


53
′′
30
ip
13.6
15.4


59
′′
10
ip
42
18.8


59
′′
30
ip
27.4
15.7


50
′′
30
ip
40.4
29.6


415
rat
10
sc
36.9
25.1









Formulation Examples
The following are representative pharmaceutical formulations containing a compound of Formula (I).
Tablet Formulation
The following ingredients are mixed intimately and pressed into single scored tablets.















Quantity per tablet



Ingredient
mg



















compound of this invention
400



cornstarch
50



croscarmellose sodium
25



lactose
120



magnesium stearate
5










Capsule Formulation
The following ingredients are mixed intimately and loaded into a hard-shell gelatin capsule.















Quantity per capsule



Ingredient
mg



















compound of this invention
200



lactose spray dried
148



magnesium stearate
2










Injectable Formulation
Compound of the invention (e.g., compound 1) in 2% HPMC, 1% Tween 80 in DI water, pH 2.2 with MSA, q.s. to at least 20 mg/mL.

## Claims

1. A method of treating a disease, disorder or condition in a subject, the method comprising administering to the subject a compound of formula (I):




or a pharmaceutically acceptable salt thereof, wherein:
R1 is a heterocycloamino ring substituted with Ra, Rb, and Re wherein:
Ra is —Z—Ar where Z is C1-6 alkylene, C1-6 haloalkylene, —O—, —C(O)—, —NH—, or —S(O)n- wherein n is 0, 1, or 2; and Ar is C3-10 cycloalkyl, C3-7 heterocycloalkyl, C3-7 heterocycloalkenyl, C6-10 aryl, or C1-9 heteroaryl wherein C3-10 cycloalkyl, C3-7 heterocycloalkenyl, C3-7 heterocycloalkyl, C6-10 aryl, and C1-9 heteroaryl are optionally substituted with 1 to 3 substituents independently selected from C1-6 alkyl, halo, hydroxy, oxo, C1-6 alkoxy, C1-6 thioalkoxy, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 haloalkoxy, C1-6 alkylcarbonyl, C1-6 alkylsulphonyl, cyano, C2-12 alkoxyalkyloxy, C1-9 amide, or C1-6 hydroxyalkyloxy; and
Rb and Re are independently hydrogen, C1-6 alkyl, hydroxy, or halo;

R2 is —ORe or —NRdRe wherein Rd is hydrogen or C1-6 alkyl and Re is C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C2-12 alkoxyalkyl, C1-12 aminoalkyl, C3-10 cycloalkyl, C4-16 cycloalkylalkyl, C6-10 aryl, C1-9 heteroaryl, C3-7 heterocyclyl, or C3-7 heterocycloalkenyl wherein C6-10 aryl, C1-9 heteroaryl, C3-7 heterocyclyl, and C3-7 heterocycloalkenyl are optionally substituted with 1 to 3 substituents independently selected from C1-6 alkyl, halo, hydroxy, oxo, C1-6 alkoxy, C1-6 haloalkyl or C1-6 haloalkoxy, or cyano;
all X1-X4 are carbon or one or two of X1-X4 are N and the rest of X1-X4 are carbon;
R3, R4, R5, and R6 are independently absent, hydrogen, C1-6 alkyl, halo, hydroxy, C1-6 alkoxy, C1-6 alkoxycarbonyl, C1-6 haloalkyl, C1-6 haloalkoxy, C1-9 amide, C3-7 heterocyclyl, C1-8 alkylamino, or cyano;
wherein the disease, disorder or condition is selected from Parkinson disease and levodopa induced dyskinesia.

2. The method according to claim 1 wherein R1 is piperidinyl.

3. The method according to claim 1 wherein R1 is piperazinyl.

4. The method according to claim 3 wherein Z is C1-6 alkylene.

5. The method according to claim 3 wherein Z is —C(O)—.

6. The method according to claim 4 wherein Ar is C6-10 aryl optionally substituted with 1 to 3 substituents independently selected from C1-6 alkyl, halo, hydroxy, oxo, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkylcarbonyl, C1-6 alkylsulphonyl, cyano, C2-12 alkoxyalkyloxy, C1-9 amide, or C1-6 hydroxyalkyloxy.

7. The method according to claim 4 wherein Ar is C1-9 heteroaryl optionally substituted with 1 to 3 substituents independently selected from C1-6 alkyl, halo, hydroxy, oxo, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkylcarbonyl, C1-6 alkylsulphonyl, cyano, C2-12 alkoxyalkyloxy, C1-9 amide, or C1-6 hydroxyalkyloxy.

8. The method according to claim 1 wherein R2 is —NRdRe wherein Rd is hydrogen and Re is C1-6 alkyl or C3-10 cycloalkyl.

9. The method according to claim 1 wherein all X1-X4 are carbon.

10. The method according to claim 6 wherein all X1-X4 are carbon.

11. The method according to claim 1 wherein all X1, X3, X4 are carbon, R6 is absent, and X2 is N.

12. The method according to claim 1 wherein all X1, X2, X4 are carbon, R6 is absent, and X3 is N.

13. The method according to claim 1 wherein all X1 and X4 are carbon, R5 and R6 are absent, and X2 and X3 are N.

14. The method according to claim 1, wherein the compound of formula (I) is selected from the group consisting of:
N-cyclopropyl-3-(4-(3-methylbenzyl)piperazin-1-yl)quinoxalin-2-amine;
(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)(2,5-dichlorophenyl)methanone
2-(4-(3-chlorobenzyl)piperazin-1-yl)-N-phenylpyrido[2,3-b]pyrazin-3-amine;
3-(4-(4-bromobenzyl)piperazin-1-yl)-N-cyclopropylquinoxalin-2-amine;
(4-(3-(cyclopropylamino)quinoxalin-2-yl)piperazin-1-yl)(3-isopropylphenyl)methanone;
N-cyclopropyl-3-(4-(2,5-dichlorophenethyl)piperazin-1-yl)quinoxalin-2-amine;
3-(4-((2-chloro-5-(trifluoromethyl)phenyl)sulfonyl)piperazin-1-yl)-2-(cyclopropylamino)quinoxaline-6-carbonitrile;
(4-chloro-2,6-difluorophenyl)(1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)methanone;
(S)-2-(cyclopropylamino)-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)quinoxaline-6-carbonitrile;
(1-(2-(cyclopropylamino)pyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)(pyrrolidin-1-yl)methanone;
N-cyclobutyl-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazin-3-amine; and
a pharmaceutically acceptable salt of any one of the above-mentioned compounds.

15. The method according to claim 1, wherein the compound of formula (I) is N-cyclopropyl-3-(4-(2,4-difluorobenzyl)piperidin-1-yl)-5-methylpyrido[3,4-b]pyrazin-2-amine or a pharmaceutically acceptable salt thereof.

16. The method according to claim 1, wherein the compound of formula (I) is (R)—N-cyclopropyl-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-7-methylpyrido[3,4-b]pyrazin-2-amine or a pharmaceutically acceptable salt thereof.

17. The method according to claim 1, wherein the compound of formula (I) is 2-(cyclopropylamino)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N,N-dimethylpyrido[3,4-b]pyrazine-7-carboxamide or a pharmaceutically acceptable salt thereof.

18. The method according to claim 1, wherein the compound of formula (I) is 3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-N-isopropylpyrazino[2,3-d]pyridazin-2-amine or a pharmaceutically acceptable salt thereof.

19. The method according to claim 1, wherein the compound of formula (I) is 3-(4-(4-chloro-2-fluorophenoxy)piperidin-1-yl)-2-(isopropylamino)-N,N-dimethylpyrido[3,4-b]pyrazine-7-carboxamide or a pharmaceutically acceptable salt thereof.

20. The method according to claim 1, wherein the compound of formula (I) is 3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropylpyrazino[2,3-d]pyridazin-2-amine or a pharmaceutically acceptable salt thereof.

21. The method according to claim 1, wherein the compound of Formula (I) is administered in combination with a dopamine agonist.

22. The method according to claim 21, wherein the dopamine agonist is Levodopa.