WO2009081259A1 - Phenoxy-pyridyl derivatives - Google Patents

Abstract

Compounds and pharmaceutically acceptable salts of the compounds are disclosed, wherein the compounds have the structure of Formula (I), as defined in the specification. Corresponding pharmaceutical compositions, methods of treatment, methods of synthesis, and intermediates are also disclosed.

Description

PHENOXY-PYRIDYL DERIVATIVES

FIELD OF THE INVENTION

The present invention comprises a novel class of compounds having the structure of formula I (including tautomers and salts of those compounds) and pharmaceutical compositions comprising a compound of formula I. The present invention also comprises methods of treating a subject by administering a therapeutically effective amount of a compound of formula I to the subject. These compounds are useful for the conditions disclosed herein. The present invention further comprises methods for making the compounds of formula I and corresponding intermediates.

BACKGROUND OF THE INVENTION

Many types of mental, behavioral, and neurological disorders originate from disturbances in neuronal circuits that convey signals using certain monoamine neurotransmitters. Monoamine neurotransmitters include, for example, norepinephrine (noradrenaline), serotonin (5-HT), and dopamine. Lower-than-normal levels of these neurotransmitters are associated with a variety of symptoms including lack of energy, motivation, and interest in life. Thus, a normal level of monoaminergic neurotransmission is essential to maintaining drive and capacity for reward. These neurotransmitters travel from the terminal of a neuron across a small gap (i.e., the synaptic cleft) and bind to receptor molecules on the surface of a second neuron. This binding elicits intracellular changes that initiate or activate a response or change in the postsynaptic neuron. Inactivation occurs primarily by transport (i.e., reuptake) of the neurotransmitter back into the presynaptic neuron. Abnormality in noradrenergic transmission results in various types of depression, mental, behavioral, and neurological disorders attributed to a variety of symptoms including a lack of energy, motivation, and interest in life. See generally, R. J. Baldessarini, "Drugs and the Treatment of Psychiatric Disorders: Depression and Mania" in Goodman and Gilman's The Pharmacological Basis of Therapeutics, McGraw-Hill. N.Y., N.Y., pp. 432 439 (1996).

Drugs that impact monoamine neurotransmission either directly as a result of efficacy at postsynaptic receptors or indirectly through inhibition of reuptake into presynaptic terminals are widely used to treat disorders including attention deficit hyperactivity disorder (ADHD), depression, and anxiety. For example, in ADHD stimulant medications that increase norepinephrine and dopamine neurotransmission throughout the brain are commonly prescribed, but carry a burden of abuse liability. Alternatively, norepinephrine reuptake inhibitors (NRI) which more selectively increase norepinephrine neurotransmission with less impact on dopamine, are also used to treat ADHD albeit with less efficacy and a slower onset of action than stimulant medications. In addition, NRI agents are widely used to treat symptoms of depression and anxiety, although again taking many days before full efficacy is demonstrated. Finally compounds with serotoniniA (5-HT1A) receptor partial agonist properties are commonly used to treat symptoms of depression and anxiety, and evidence indicates that they could be used to treat symptoms of ADHD and other disorders associated with deficits in cognitive function like schizophrenia, bipolar disorders and Alzheimer's disease as well.

Studies indicate that adding 5-HT1A partial agonist properties to a norepinephrine reuptake inhibitor will produce efficacy comparable to stimulants with a fast onset of action in treating the primary symptoms of ADHD, but without the abuse liability associated with stimulant medications. Adding 5-HT1 A partial agonism to an NRI agent increases extracellular levels of both norepinephrine and dopamine within the prefrontal cortex, a region of the brain important for attention and executive function, to a degree similar to stimulant medications. In contrast and unlike stimulants, this combination of pharmacologies does not impact extracellular dopamine levels within the nucleus accumbens, a region of the brain associated with reward behavior and abuse liability, to a degree greater than seen with NRI agents alone. Moreover, preclinical behavioral studies measuring antidepressant efficacy and cognitive function demonstate that compounds possessing both NRI and 5-HT1A partial agonist properties are more effective than NRI agents alone. Thus, the present invention describes agents possessing NRI and 5-HT1A partial agonist properties that will be useful in treating symptoms of disorders wherein modulation of monoamine neurotransmission is required such as ADHD, depression, anxiety, bipolar disorders and Alzheimer's disease.

Accordingly, it would be desirable to have compounds acting as both NRI and 5-HT1A agonists to treat individuals suffering from a variety of conditions where inhibiting reuptake of norepinephrine, and having 5-HT1A agonist activity, provides a benefit while reducing or eliminating the adverse side effects associated with conventional norepinephrine reuptake inhibitors. There also is a need for the use of such compounds to treat disorders of the central nervous system that are associated with deficits or imbalances in catecholamine neurotransmission. Furthermore, there is a need for pharmaceutical compositions containing such compounds. Still further, there is a need for medicaments containing such compounds, and the use of such compositions in the manufacture of such compounds.

SUMMARY OF THE INVENTION

The invention is directed to a class of compounds, including the pharmaceutically acceptable salts of the compounds, having the structure of formula I:

I or a pharmaceutically acceptable salt thereof, wherein:

X ₁ is O or S(O)_P; is either a single bond or a double bond, wherein, when is a single bond, Y is N or CR₃, and when is a double bond, Y is C; each Ri is independently selected from the group consisting of hydrogen, halogen, alkoxy, -CN, and alkyl, wherein each Ri alkyl is optionally independently substituted by one to three halogens; each R₂ is independently selected from the group consisting of halogen, -NO₂, -CN, -N(R₄)₂, R₄, and -OR₄; or two R₂ substituents on adjacent carbons taken together with the adjacent carbons form a carbocyclic or heterocyclic ring optionally substituted with halogen, hydroxy, -CN, alkyl, or alkoxy; wherein each R₄ is independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, heterocycloalkyl and heteroaryl; or two R₄ groups on the same nitrogen atom may be taken together with the nitrogen atom to form a 5 to 8 membered heterocyclic ring which optionally has 1 to 3 additional ring heteroatoms selected from the group consisting of N, O, and S; and each R₄ alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl is optionally independently substituted by one to three substituents independently selected from the group consisting of halogen, hydroxy, -CN, -(CrCβ)alkyl, -(C_rC₆)alkoxy, -CF₃, -OCF₃, -N[(CH₂)_tR₄]₂, -NO₂, -(CH₂)_tN[(CH₂)_tR₄](C=O)[(CH₂),R4], -S(Ci-C₆)alkyl, -(S=O)(C_rC_β)alkyl, -S(=O)₂(C₁-C₆)alkyl, -(C=O)O(Ci -C₆)alkyl, -O(C=O)(C_rC₆)alkyl,

-(C=O)(Ci -C₆)alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl; each R₃ is independently selected from the group consisting of hydrogen, halogen, -(CH₂)_tOH, -(CH₂)_tCF₃, -(CH₂)_tC≡N, -NO₂, -(CH₂)_tN[(CH₂)_tR₄]_2l -(CH₂),-alkyl, -(CH₂)_tO[(CH₂)_tR₄], -(CH₂)»(C₃-Ci₂)cycloalkyl_> -(CH₂)t-aryl, -(CH₂)_t-heterocycloalkyl and -(CH₂)_theteroaryl; or two R₃ groups each attached to the same carbon atom of the ring containing Y, taken together with the carbon atom, form a three to seven membered carbocyclic ring; n is an integer selected from 0, 1 and 2; m is an integer selected from 0, 1 , 2, 3 and 4; n1 is an integer selected from 1 , 2, and 3; p is an integer selected from 0, 1 and 2; and each t is an integer independently selected from 0, 1 , 2, 3, 4, and 5.

In one embodiment of the invention n is 1. In another embodiment of the invention n is 2.

In another embodiment of the invention R₄ is hydrogen.

In another embodiment of the invention n1 is 1.

In another embodiment of the invention n1 is 2.

In another embodiment of the invention p is 0. In another embodiment of the invention p is 1. In another embodiment of the invention p is 2.

In one embodiment of the invention Xi is O.

In another embodiment of the invention Xi is S.

In another embodiment of the invention each Ri is hydrogen. In another embodiment of the invention each R₂ is hydrogen.

In another embodiment of the invention, each Ri is independently halogen or CrC₆ alkyl. In one example of this embodiment, n is 1 and Ri is fluorine, chlorine, alkyl such as methyl, or trifluoroalkyl. In another example of this embodiment, n is 2 and each Ri is fluorine. In another example of this embodiment, n is 2 and each Ri is alkyl such as methyl. In another example of this embodiment, n is 2 wherein one Ri is fluorine and the other R₁ is chlorine. In another example of this embodiment, n is 2 wherein one Ri is alkyl such as methyl and the other Ri is chlorine or fluorine.

In another embodiment of the invention Y is N and each R₂ is independently halogen or alkyl.

In one example of this embodiment, each R₂ is independently fluorine, chlorine, or methyl.

In another embodiment of the invention Y is CH and each R₂ is independently halogen or alkyl. In one example of this embodiment, each R₂ is independently fluorine, chlorine, or methyl.

In another embodiment of the invention, m is 1.

In another embodiment of the invention, m is 2.

In another embodiment of the invention, each R₂ is independently halogen, alkyl optionally substituted with one to three halogens, heteroaryl, or alkoxy optionally substituted with one to three halogens.

In one example of this embodiment, m is 1 and R₂ is fluorine, chlorine, alkyl optionally substituted with one to three halogens such as methyl or trifluoromethyl, or alkoxy optionally substituted with one to three halogens such as methoxy or trifluoromethoxy. In another example of this embodiment, m is 2 and each R₂ is fluorine. In another example of this embodiment, m is 2 and each R₂ is chlorine. In another example of this embodiment, m is 2 and each R₂ is alkyl such as methyl. In another example of this embodiment, m is 2 wherein one R₂ is fluorine and the other R₂ is chlorine. In another example of this embodiment, m is 2 wherein one R₂ is alkyl such as methyl and the other R₂ is chlorine or fluorine. In another example of this embodiment, m is 2 wherein one R₂ is alkoxy such as methoxy and the other R₂ is chlorine or fluorine.

In another embodiment of the invention, each R₃ is hydrogen.

In another embodiment of the invention, is a single bond and Y is N.

In another embodiment of the invention, is a single bond and Y is CR₃.

In another embodiment of the invention, is a double bond and

Y is C. Exemplary compounds according to the invention include the compounds disclosed in Table 1 herein or pharmaceutically acceptable salts thereof.

The compounds of formula I are useful for the treatment of a variety of neurological and psychiatric disorders, including but not limited to: acute neurological and psychiatric disorders such as cerebral deficits subsequent to cardiac bypass surgery and grafting, stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage, dementia (including AIDS-induced dementia), Alzheimer's disease, Huntington's Chorea, amyotrophic lateral sclerosis, ocular damage, retinopathy, cognitive disorders, including cognitive disorders associated with schizophrenia and bipolar disorders, idiopathic and drug- induced Parkinson's disease, muscular spasms and disorders associated with muscular spasticity including tremors, epilepsy, convulsions, migraine (including migraine headache), urinary incontinence, substance tolerance, substance withdrawal (including, substances such as opiates, nicotine, tobacco products, alcohol, benzodiazepines, cocaine, sedatives, hypnotics, etc.), psychosis, mild cognitive impairment, obesity, schizophrenia, anxiety (including generalized anxiety disorder, social anxiety disorder, panic disorder, post-traumatic stress disorder and obsessive compulsive disorder), mood disorders (including depression, mania, bipolar disorders), trigeminal neuralgia, hearing loss, tinnitus, macular degeneration of the eye, emesis, brain edema, pain (including acute and chronic pain states, severe pain, intractable pain, neuropathic pain, and post-traumatic pain), tardive dyskinesia, sleep disorders (including narcolepsy), attention deficit/hype ractivity disorder, autism, Asperger's disease, and conduct disorder. Accordingly, in one embodiment, the invention provides a method for treating a condition in a mammal, such as a human, selected from the conditions above, comprising administering a compound of formula I to the mammal. The mammal is preferably a mammal in need of such treatment. As examples, the invention provides a method for treating attention deficit/hyperactivity disorder, schizophrenia and Alzheimer's Disease.

In another embodiment the present invention provides methods of treating neurological and psychiatric disorders associated with norepinephrine reuptake inhibition, 5HT1a agonist activity, or both comprising: administering to a patient in need thereof an amount of a compound of formula I effective in treating such disorders. The compound of formula I is optionally used in combination with another active agent. Such an active agent may be, for example, an atypical antipsychotic or a cholinesterase inhibitor. Such atypical antipsychotics include, but are not limited to, ziprasidone, clozapine, olanzapine, risperidone, quetiapine, aripiprazole, paliperidone, and such cholinesterase inhibitors include but are not limited to donepezil and galantamine.

The invention is also directed to a pharmaceutical composition comprising a compound of formula I, and a pharmaceutically acceptable carrier. The composition may be, for example, a composition for treating a condition selected from the group consisting of acute neurological and psychiatric disorders such as cerebral deficits subsequent to cardiac bypass surgery and grafting, stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage, dementia (including AIDS-induced dementia), Alzheimer's disease, Huntington's Chorea, amyotrophic lateral sclerosis, ocular damage, retinopathy, cognitive disorders, including but not limited to cognitive disorders associated with schizophrenia and bipolar disorders, idiopathic and drug- induced Parkinson's disease, muscular spasms and disorders associated with muscular spasticity including tremors, epilepsy, convulsions, migraine (including migraine headache), urinary incontinence, substance tolerance, substance withdrawal (including, substances such as opiates, nicotine, tobacco products, alcohol, benzodiazepines, cocaine, sedatives, hypnotics, etc.), psychosis, mild cognitive impairment, obesity, schizophrenia, anxiety (including generalized anxiety disorder, social anxiety disorder, panic disorder, post-traumatic stress disorder and obsessive compulsive disorder), mood disorders (including depression, mania, bipolar disorders), trigeminal neuralgia, hearing loss, tinnitus, macular degeneration of the eye, emesis, brain edema, pain (including acute and chronic pain states, severe pain, intractable pain, neuropathic pain, and post-traumatic pain), tardive dyskinesia, sleep disorders (including narcolepsy), attention deficit/hyperactivity disorder, autism, Asperger's disease, and conduct disorder, wherein the composition contains an amount of the compound of formula I that is effective in the treatment of such conditions. DETAILED DESCRIPTION OF THE INVENTION

This detailed description of embodiments is intended only to acquaint others skilled in the art with Applicants' invention, its principles, and its practical application so that others skilled in the art may adapt and apply the invention in its numerous forms, as it may be best suited to the requirements of a particular use. This invention, therefore, is not limited to the embodiments described in this specification, and may be variously modified.

Abbreviations and Definitions TABLE A - Abbreviations

The term "alkyl" refers to a linear or branched-chain saturated hydrocarbyl substituent (i.e., a substituent obtained from a hydrocarbon by removal of a hydrogen) containing from one to twenty carbon atoms; in one embodiment from one to twelve carbon atoms; in another embodiment, from one to ten carbon atoms; in another embodiment, from one to six carbon atoms; and in another embodiment, from one to four carbon atoms. Examples of such substituents include methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl and tert-butyl), pentyl, iso-amyl, hexyl and the like.

The term "benzyl" refers to methyl radical substituted with phenyl, i.e.,

the following structure:

The term "cycloalkyl" refers to a saturated carbocyclic substituent having three to fourteen carbon atoms. In one embodiment, a cycloalkyl substituent has three to ten carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term "cycloalkyl" also includes substituents that are fused to a C₆-

Cio aromatic ring or to a 5-10-membered heteroaromatic ring, wherein a group having such a fused cycloalkyl group as a substituent is bound to a carbon atom of the cycloalkyl group. When such a fused cycloalkyl group is substituted with one or more substituents, the one or more substitutents, unless otherwise specified, are each bound to a carbon atom of the cycloalkyl group. The fused C₆-Ci₀ aromatic ring or to a 5-10-membered heteroaromatic ring may be optionally substituted with halogen, CrC₆ alkyl, C₃-Ci₀ cycloalkyl, or =O.

A cycloalkyl may be a single ring, which typically contains from 3 to 6 ring atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Alternatively, 2 or 3 rings may be fused together, such as bicyclodecanyl and decalinyl.

The term "aryl" refers to an aromatic substituent containing one ring or two or three fused rings. The aryl substituent may have six to eighteen carbon atoms. As an example, the aryl substituent may have six to fourteen carbon atoms. The term "aryl" may refer to substituents such as phenyl, naphthyl and anthracenyl. The term "aryl" also includes substituents such as phenyl, naphthyl and anthracenyl that are fused to a C₄-Ci₀ carbocyclic ring, such as a C₅ or a C₆ carbocyclic ring, or to a 4-10-membered heterocyclic ring, wherein a group having such a fused aryl group as a substituent is bound to an aromatic carbon of the aryl group. When such a fused aryl group is substituted with one more substituents, the one or more substitutents, unless otherwise specified, are each bound to an aromatic carbon of the fused aryl group. The fused C₄-Ci₀ carbocyclic or 4-10-membered heterocyclic ring may be optionally substituted with halogen, d-Cβ alkyl, C₃- C₁₀ cycloalkyl, or =0. Examples of aryl groups include accordingly phenyl, naphthalenyl, tetrahydronaphthalenyl (also known as "tetralinyl"), indenyl, isoindenyl, indanyl, anthracenyl, phenanthrenyl, benzonaphthenyl (also known as "phenalenyl"), and fluorenyl.

In some instances, the number of carbon atoms in a hydrocarbyl substituent (i.e., alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, etc.) is indicated by the prefix "C_x-Cy-," wherein x is the minimum and y is the maximum number of carbon atoms in the substituent. Thus, for example, "CrCβ-alky!" refers to an alkyl substituent containing from 1 to 6 carbon atoms. Illustrating further, C₃-C₆-cycloalkyl refers to saturated cycloalkyl containing from 3 to 6 carbon ring atoms.

In some instances, the number of atoms in a cyclic substituent containing one or more heteroatoms (i.e., heteroaryl or heterocycloalkyl) is indicated by the prefix "X-Y-membered", wherein wherein x is the minimum and y is the maximum number of atoms forming the cyclic moiety of the substituent. Thus, for example, 5-8-membered heterocycloalkyl refers to a heterocycloalkyl containing from 5 to 8 atoms, including one ore more heteroatoms, in the cyclic moiety of the heterocycloalkyl. The term "hydrogen" refers to hydrogen substituent, and may be depicted as -H.

The term "hydroxy" or "hydroxyl" refers to -OH. When used in combination with another term(s), the prefix "hydroxy" indicates that the substituent to which the prefix is attached is substituted with one or more hydroxy substituents. Compounds bearing a carbon to which one or more hydroxy substituents include, for example, alcohols, enols and phenol.

The term "hydroxyalkyl" refers to an alkyl that is substituted with at least one hydroxy substituent. Examples of hydroxyalkyl include hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxybutyl.

The term "cyano" (also referred to as "nitrile") means -CN, which also

may be depicted:

The term "carbonyl" means -C(O)-, which also may be depicted as:

The term "amino" refers to -NH₂.

The term "alkylamino" refers to an amino group, wherein at least one alkyl chain is bonded to the amino nitrogen in place of a hydrogen atom.

Examples of alkylamino substituents include monoalkylamino such as methylamino (exemplified by the formula -NH(CH₃)), which may also be

depicted:

and dialkylamino such as dimethylamino,

(exemplified by the formula

-N(CH₃J₂, which may also be depicted:

.

The term "halogen" refers to fluorine (which may be depicted as -F), chlorine (which may be depicted as -Cl), bromine (which may be depicted as -Br), or iodine (which may be depicted as -I). In one embodiment, the halogen is chlorine. In another embodiment, the halogen is a fluorine. The prefix "halo" indicates that the substituent to which the prefix is attached is substituted with one or more independently selected halogen substituents. For example, haloalkyl refers to an alkyl that is substituted with at least one halogen substituent. Where more than one hydrogen is replaced with halogens, the halogens may be the identical or different. Examples of haloalkyls include chloromethyl, dichloromethyl, difluorochloromethyl, dichlorofluoromethyl, trichloromethyl, 1 -bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, difluoroethyl, pentafluoroethyl, difluoropropyl, dichloropropyl, and heptafluoropropyl. Illustrating further, "haloalkoxy" refers to an alkoxy that is substituted with at least one halogen substituent. Examples of haloalkoxy substituents include chloromethoxy, 1 -bromoethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy (also known as "perfluoromethyloxy"), and 2,2,2-trifluoroethoxy. It should be recognized that if a substituent is substituted by more than one halogen substituent, those halogen substituents may be identical or different (unless otherwise stated). The term "oxo" refers to =0.

The term "oxy" refers to an ether substituent, and may be depicted as -O-. The term "alkoxy" refers to an alkyl linked to an oxygen, which may also be represented as

-O-R, wherein the R represents the alkyl group. Examples of alkoxy include methoxy, ethoxy, propoxy and butoxy.

The term "heterocycloalkyl" refers to a saturated or partially saturated ring structure containing a total of 3 to 14 ring atoms. At least one of the ring atoms is a heteroatom (i.e., oxygen, nitrogen, or sulfur), with the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur. A heterocycloalkyl alternatively may comprise 2 or 3 rings fused together, wherein at least one such ring contains a heteroatom as a ring atom (i.e., nitrogen, oxygen, or sulfur). In a group that has a heterocycloalkyl substituent, the ring atom of the heterocycloalkyl substituent that is bound to the group may be the at least one heteroatom, or it may be a ring carbon atom, where the ring carbon atom may be in the same ring as the at least one heteroatom or where the ring carbon atom may be in a different ring from the at least one heteroatom. Similarly, if the heterocycloalkyl substituent is in turn substituted with a group or substituent, the group or substituent may be bound to the at least one heteroatom, or it may be bound to a ring carbon atom, where the ring carbon atom may be in the same ring as the at least one heteroatom or where the ring carbon atom may be in a different ring from the at least one heteroatom.

The term "heterocycloalkyl" also includes substituents that are fused to a Cβ-Cio aromatic ring or to a 5-10-membered heteroaromatic ring, wherein a group having such a fused heterocycloalkyl group as a substituent is bound to a heteroatom of the heterocyclocalkyl group or to a carbon atom of the heterocycloalkyl group. When such a fused heterocycloalkyl group is substituted with one more substituents, the one or more substitutents, unless otherwise specified, are each bound to a heteroatom of the heterocyclocalkyl group or to a carbon atom of the heterocycloalkyl group. The fused C₆-Ci₀ aromatic ring or 5-10-membered heteroaromatic ring may be optionally substituted with halogen, d-C₆ alkyl, C₃-Ci₀ cycloalkyl, CrC₆ alkoxy, or =0.

The term "heteroaryl" refers to an aromatic ring structure containing from 5 to 14 ring atoms in which at least one of the ring atoms is a heteroatom (i.e., oxygen, nitrogen, or sulfur), with the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur. A heteroaryl may be a single ring or 2 or 3 fused rings. Examples of heteroaryl substituents include 6-membered ring substituents such as pyridyl, pyrazyl, pyrimidinyl, and pyridazinyl; 5-membered ring substituents such as triazolyl, imidazolyl, furanyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1 ,2,3-, 1 ,2,4-, 1 ,2,5-, or 1 ,3,4-oxadiazolyl and isothiazolyl; 6/5-membered fused ring substituents such as benzothiofuranyl, isobenzothiofuranyl, benzisoxazolyl, benzoxazolyl, purinyl, and anthranilyl; and 6/6-membered fused rings such as quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, and 1 ,4-benzoxazinyl. In a group that has a heteroaryl substituent, the ring atom of the heteroaryl substituent that is bound to the group may be the at least one heteroatom, or it may be a ring carbon atom, where the ring carbon atom may be in the same ring as the at least one heteroatom or where the ring carbon atom may be in a different ring from the at least one heteroatom. Similarly, if the heteroaryl substituent is in turn substituted with a group or substituent, the group or substituent may be bound to the at least one heteroatom, or it may be bound to a ring carbon atom, where the ring carbon atom may be in the same ring as the at least one heteroatom or where the ring carbon atom may be in a different ring from the at least one heteroatom. The term "heteroaryl" also includes pyridyl N-oxides and groups containing a pyridine N-oxide ring. Examples of single-ring heteroaryls include furanyl, dihydrofuranyl, tetradydrofuranyl, thiophenyl (also known as "thiofuranyl"), dihydrothiophenyl, tetrahydrothiophenyl, pyrrolyl, isopyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, isoimidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, dithiolyl, oxathiolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl, thiaθdiazolyl, oxathiazolyl, oxadiazolyl (including oxadiazolyl, 1 ,2,4-oxadiazolyl (also known as "azoximyl"), 1 ,2,5-oxadiazolyl (also known as "furazanyl"), or 1 ,3,4-oxadiazolyl), oxatriazolyl (including 1 ,2,3,4-oxatriazolyl or 1 ,2,3,5-oxatriazolyl), dioxazolyl (including 1 ,2,3-dioxazolyl, 1 ,2,4-dioxazolyl, 1 ,3,2-dioxazolyl, or 1 ,3,4-dioxazolyl), oxathiazolyl, oxathiolyl, oxathiolanyl, pyranyl (including 1 ,2-pyranyl or 1 ,4-pyranyl), dihydropyranyl, pyridinyl (also known as "azinyl"), piperidinyl, diazinyl (including pyridazinyl (also known as "1 ,2-diazinyl"), pyrimidinyl (also known as "1 ,3-diazinyl" or "pyrimidyl"), or pyrazinyl (also known as "1 ,4-diazinyl")), piperazinyl, triazinyl (including s-triazinyl (also known as "1 ,3,5-triazinyl"), as-triazinyl (also known 1 ,2,4-triazinyl), and v-triazinyl (also known as "1 ,2,3-triazinyl")), oxazinyl (including 1 ,2,3-oxazinyl, 1 ,3,2-oxazinyl, 1 ,3,6-oxazinyl (also known as "pentoxazolyl"), 1 ,2,6-oxazinyl, or 1 ,4-oxazinyl), isoxazinyl (including o-isoxazinyl or p-isoxazinyl), oxazolidinyl, isoxazolidinyl, oxathiazinyl (including 1 ,2,5-oxathiazinyl or 1 ,2,6-oxathiazinyl), oxadiazinyl (including 1 ,4,2-oxadiazinyl or 1 ,3,5,2-oxadiazinyl), morpholinyl, azepinyl, oxepinyl, thiepinyl, and diazepinyl.

Examples of 2-fused-ring heteroaryls include, indolizinyl, pyrindinyl, pyranopyrrolyl, 4H-quinolizinyl, purinyl, naphthyridinyl, pyridopyridinyl (including pyrido[3,4-b]-pyridinyl, pyrido[3,2-b]-pyridinyl, or pyrido[4,3-b]-pyridinyl), and pteridinyl, indolyl, isoindolyl, indoleninyl, isoindazolyl, benzazinyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl, benzopyranyl, benzothiopyranyl, benzoxazolyl, indoxazinyl, anthranilyl, benzodioxolyl, benzodioxanyl, benzoxadiazolyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, benzothiazolyl, benzothiadiazolyl, benzimidazolyl, benzotriazolyl, benzoxazinyl, benzisoxazinyl, and tetrahydroisoquinolinyl.

Examples of 3-fused-ring heteroaryls or heterocycloalkyls include 5,6-dihydro-4H-imidazo[4,5, 1 -ij]quinoline, 4,5-dihydroimidazo[4,5, 1 -hφndole, 4,5,6,7-tetrahydroimidazo[4,5,1-jk][1]benzazepine, and dibenzofuranyl.

Other examples of fused-ring heteroaryls include benzo-fused heteroaryls such as indolyl, isoindolyl (also known as "isobenzazolyl" or "pseudoisoindolyl"), indoleninyl (also known as "pseudoindolyl"), isoindazolyl (also known as "benzpyrazolyl"), benzazinyl (including quinolinyl (also known as "1 -benzazinyl") or isoquinolinyl (also known as "2-benzazinyl")), phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl (including cinnolinyl (also known as "1 ,2-benzodiazinyl") or quinazolinyl (also known as "1 ,3-benzodiazinyl")), benzopyranyl (including "chromanyl" or "isochromanyl"), benzothiopyranyl (also known as "thiochromanyl"), benzoxazolyl, indoxazinyl (also known as "benzisoxazolyl"), anthranilyl, benzodioxolyl, benzodioxanyl, benzoxadiazolyl, benzofuranyl (also known as "coumaronyl"), isobenzofuranyl, benzothienyl (also known as "benzothiophenyl," "thionaphthenyl," or "benzothiofuranyl"), isobenzothienyl (also known as "isobenzothiophenyl," "isothionaphthenyl," or "isobenzothiofuranyl"), benzothiazolyl, benzothiadiazolyl, benzimidazolyl, benzotriazolyl, benzoxazinyl (including 1 ,3,2-benzoxazinyl, 1 ,4,2-benzoxazinyl, 2,3,1 -benzoxazinyl, or 3,1 ,4-benzoxazinyl), benzisoxazinyl (including 1 ,2-benzisoxazinyl or 1 ,4-benzisoxazinyl), tetrahydroisoquinolinyl , carbazolyl, xanthenyl, and acridinyl. The term "heteroaryl" also includes substituents such as pyridyl and quinolinyl that are fused to a C₄-Ci₀ carbocyclic ring, such as a C₅ or a C₆ carbocyclic ring, or to a 4-10-membered heterocyclic ring, wherein a group having such a fused aryl group as a substituent is bound to an aromatic carbon of the heteroaryl group or to a heteroatom of the heteroaryl group. When such a fused heteroaryl group is substituted with one more substituents, the one or more substitutents, unless otherwise specified, are each bound to an aromatic carbon of the heteroaryl group or to a heteroatom of the heteroaryl group. The fused C₄-Ci₀ carbocyclic or 4-10-membered heterocyclic ring may be optionally substituted with halogen, d-Cβ alkyl, C₃- Ci₀ cycloalkyl, or =0.

A substituent is "substitutable" if it comprises at least one carbon, sulfur, oxygen or nitrogen atom that is bonded to one or more hydrogen atoms. Thus, for example, hydrogen, halogen, and cyano do not fall within this definition. If a substituent is described as being "substituted," a non-hydrogen substituent is in the place of a hydrogen substituent on a carbon, oxygen, sulfur or nitrogen of the substituent. Thus, for example, a substituted alkyl substituent is an alkyl substituent wherein at least one non-hydrogen substituent is in the place of a hydrogen substituent on the alkyl substituent. To illustrate, monofluoroalkyl is alkyl substituted with a fluoro substituent, and difluoroalkyl is alkyl substituted with two fluoro substituents. It should be recognized that if there is more than one substitution on a substituent, each non-hydrogen substituent may be identical or different (unless otherwise stated). If a substituent is described as being "optionally substituted," the substituent may be either (1 ) not substituted, or (2) substituted. If a carbon of a substituent is described as being optionally substituted with one or more of a list of substituents, one or more of the hydrogens on the carbon (to the extent there are any) may separately and/or together be replaced with an independently selected optional substituent. If a nitrogen of a substituent is described as being optionally substituted with one or more of a list of substituents, one or more of the hydrogens on the nitrogen (to the extent there are any) may each be replaced with an independently selected optional substituent. One exemplary substituent may be depicted as -N R' R," wherein R' and R" together with the nitrogen atom to which they are attached, may form a heterocyclic ring. The heterocyclic ring formed from R' and R" together with the nitrogen atom to which they are attached may be partially or fully saturated. In one embodiment, the heterocyclic ring consists of 3 to 7 atoms. In another embodiment, the heterocyclic ring is selected from the group consisting of pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, pyridyl and thiazolyl.

This specification uses the terms "substituent," "radical," and "group" interchangeably.

If a group of substituents are collectively described as being optionally substituted by one or more of a list of substituents, the group may include: (1) unsubstitutable substituents, (2) substitutable substituents that are not substituted by the optional substituents, and/or (3) substitutable substituents that are substituted by one or more of the optional substituents.

If a substituent is described as being optionally substituted with up to a particular number of non-hydrogen substituents, that substituent may be either (1 ) not substituted; or (2) substituted by up to that particular number of non-hydrogen substituents or by up to the maximum number of substitutable positions on the substituent, whichever is less. Thus, for example, if a substituent is described as a heteroaryl optionally substituted with up to 3 non-hydrogen substituents, then any heteroaryl with less than 3 substitutable positions would be optionally substituted by up to only as many non-hydrogen substituents as the heteroaryl has substitutable positions. To illustrate, tetrazolyl (which has only one substitutable position) would be optionally substituted with up to one non-hydrogen substituent. To illustrate further, if an amino nitrogen is described as being optionally substituted with up to 2 non- hydrogen substituents, then the nitrogen will be optionally substituted with up to 2 non-hydrogen substituents if the amino nitrogen is a primary nitrogen, whereas the amino nitrogen will be optionally substituted with up to only 1 non-hydrogen substituent if the amino nitrogen is a secondary nitrogen. A prefix attached to a multi-moiety substituent only applies to the first moiety. To illustrate, the term "alkylcycloalkyl" contains two moieties: alkyl and cycloalkyl. Thus, a d-C₆- prefix on CrC₆-alkylcycloalkyl means that the alkyl moiety of the alkylcycloalkyl contains from 1 to 6 carbon atoms; the CrC₆- prefix does not describe the cycloalkyl moiety. To illustrate further, the prefix "halo" on haloalkoxyalkyl indicates that only the alkoxy moiety of the alkoxyalkyl substituent is substituted with one or more halogen substituents. If the halogen substitution may only occur on the alkyl moiety, the substituent would be described as "alkoxyhaloalkyl." If the halogen substitution may occur on both the alkyl moiety and the alkoxy moeity, the substituent would be described as "haloalkoxyhaloalkyl."

When a substituent is comprised of multiple moieties, unless otherwise indicated, it is the intention for the final moiety to serve as the point of attachment to the remainder of the molecule. For example, in a substituent A- B-C, moiety C is attached to the remainder of the molecule. In a substituent A-B-C-D, moiety D is attached to the remainder of the molecule. Similarly, in a substituent aminocarbonylmethyl, the methyl moiety is attached to the remainder of the molecule, where the substituent may also be be depicted as

In a substituent trifluoromethylaminocarbonyl, the carbonyl moiety is attached to the remainder of the molecule, where the

substituent may also be depicted as

If substituents are described as being "independently selected" from a group, each substituent is selected independent of the other. Each substituent therefore may be identical to or different from the other substituent(s). Isomers

When an asymmetric center is present in a compound of formula I, hereinafter referred to as the compound of the invention, the compound may exist in the form of optical isomers (enantiomers). In one embodiment, the present invention comprises enantiomers and mixtures, including racemic mixtures of the compounds of formula I. In another embodiment, for compounds of formulae I that contain more than one asymmetric center, the present invention comprises diastereomeric forms (individual diastereomers and mixtures thereof) of compounds. When a compound of formula I contains an alkenyl group or moiety, geometric isomers may arise. Tautomeric Forms

The present invention comprises the tautomeric forms of compounds of formula I. Where structural isomers are interconvertible via a low energy barrier, tautomeric isomerism ('tautomerism') can occur. This can take the form of proton tautomerism in compounds of formula I containing, for example, an imino, keto, or oxime group, or so-called valence tautomerism in compounds which contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism. The various ratios of the tautomers in solid and liquid form is dependent on the various substituents on the molecule as well as the particular crystallization technique used to isolate a compound.

Salts

The compounds of this invention may be used in the form of salts derived from inorganic or organic acids. Depending on the particular compound, a salt of the compound may be advantageous due to one or more of the salt's physical properties, such as enhanced pharmaceutical stability in differing temperatures and humidities, or a desirable solubility in water or oil. In some instances, a salt of a compound also may be used as an aid in the isolation, purification, and/or resolution of the compound.

Where a salt is intended to be administered to a patient (as opposed to, for example, being used in an in vitro context), the salt preferably is pharmaceutically acceptable. The term "pharmaceutically acceptable salt" refers to a salt prepared by combining a compound of formula I with an acid whose anion, or a base whose cation, is generally considered suitable for human consumption. Pharmaceutically acceptable salts are particularly useful as products of the methods of the present invention because of their greater aqueous solubility relative to the parent compound. For use in medicine, the salts of the compounds of this invention are non-toxic "pharmaceutically acceptable salts." Salts encompassed within the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid.

Suitable pharmaceutically acceptable acid addition salts of the compounds of the present invention when possible include those derived from inorganic acids, such as hydrochloric, hydrobromic, hydrofluoric, boric, fluoroboric, phosphoric, metaphosphoric, nitric, carbonic, sulfonic, and sulfuric acids, and organic acids such as acetic, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isothionic, lactic, lactobionic, maleic, malic, methanesulfonic, trifluoromethanesulfonic, succinic, toluenesulfonic, tartaric, and trifluoroacetic acids. Suitable organic acids generally include, for example, aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids.

Specific examples of suitable organic acids include acetate, trifluoroacetate, formate, propionate, succinate, glycolate, gluconate, digluconate, lactate, malate, tartaric acid, citrate, ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate, glutamate, benzoate, anthranilic acid, mesylate, stearate, salicylate, p-hydroxybenzoate, phenylacetate, mandelate, embonate (pamoate), methanesulfonate, ethanesulfonate, benzenesulfonate, pantothenate, toluenesulfonate, 2-hydroxyethanesulfonate, sufanilate, cyclohexylaminosulfonate, algenic acid, β-hydroxybutyric acid, galactarate, galacturonate, adipate, alginate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, dodecylsulfate, glycoheptanoate, glycerophosphate, heptanoate, hexanoate, nicotinate, 2-naphthalesulfonate, oxalate, palmoate, pectinate, 3-phenylpropionate, picrate, pivalate, thiocyanate, tosylate, and undecanoate. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, i.e., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable organic ligands, e.g., quaternary ammonium salts. In another embodiment, base salts are formed from bases which form non-toxic salts, including aluminum, arginine, benzathine, choline, diethylamine, diolamine, glycine, lysine, meglumine, olamine, tromethamine and zinc salts.

Organic salts may be made from secondary, tertiary or quaternary amine salts, such as tromethamine, diethylamine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine. Basic nitrogen-containing groups may be quaternized with agents such as lower alkyl (CrC₆) halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (i.e., dimethyl, diethyl, dibuytl, and diamyl sulfates), long chain halides (i.e., decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides), arylalkyl halides (i.e., benzyl and phenethyl bromides), and others.

In one embodiment, hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts. The compounds of the invention and their salts may exist in both unsolvated and solvated forms.

Prodrugs

Also within the scope of the present invention are so-called "prodrugs" of the compound of the invention. Thus, certain derivatives of the compound of the invention which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into the compound of the invention having the desired activity, for example, by hydrolytic cleavage. Such derivatives are referred to as "prodrugs." Further information on the use of prodrugs may be found in "Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T Higuchi and W Stella) and "Bioreversible Carriers in Drug Design," Pergamon Press, 1987 (ed. E B Roche, American Pharmaceutical Association). Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of any of formula I with certain moieties known to those skilled in the art as "pro-moieties" as described, for example, in "Design of Prodrugs" by H Bundgaard (Elsevier, 1985).

Isotopes

The present invention also includes isotopically labelled compounds, which are identical to those recited in formula I, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹¹C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶CI, respectively. Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically labelled compounds of the present invention, for example those into which radioactive isotopes such as ³H and ¹⁴C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., ²H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half- life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labelled compounds of formula I of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples and Preparations below, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.

Administration and Dosing

Typically, a compound of the invention is administered in an amount effective to treat a condition as described herein. The compounds of the invention are administered by any suitable route in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. Therapeutically effective doses of the compounds required to treat the progress of the medical condition are readily ascertained by one of ordinary skill in the art using preclinical and clinical approaches familiar to the medicinal arts. The compounds of the invention may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth. In another embodiment, the compounds of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.

In another embodiment, the compounds of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally. In another embodiment, the compounds of the invention can also be administered intranasally or by inhalation. In another embodiment, the compounds of the invention may be administered rectally or vaginally. In another embodiment, the compounds of the invention may also be administered directly to the eye or ear.

The dosage regimen for the compounds and/or compositions containing the compounds is based on a variety of factors, including the type, age, weight, sex and medical condition of the patient; the severity of the condition; the route of administration; and the activity of the particular compound employed. Thus the dosage regimen may vary widely. Dosage levels of the order from about 0.01 mg to about 100 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions. In one embodiment, the total daily dose of a compound of the invention (administered in single or divided doses) is typically from about 0.01 to about 100 mg/kg. In another embodiment, total daily dose of the compound of the invention is from about 0.1 to about 50 mg/kg, and in another embodiment, from about 0.5 to about 30 mg/kg (i.e., mg compound of the invention per kg body weight). In one embodiment, dosing is from 0.01 to 10 mg/kg/day. In another embodiment, dosing is from 0.1 to 1.0 mg/kg/day. Dosage unit compositions may contain such amounts or submultiples thereof to make up the daily dose. In many instances, the administration of the compound will be repeated a plurality of times in a day (typically no greater than 4 times). Multiple doses per day typically may be used to increase the total daily dose, if desired.

For oral administration, the compositions may be provided in the form of tablets containing 0.01 , 0.05, 0.1 , 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 75.0, 100, 125, 150, 175, 200, 250 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient. A medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, or in another embodiment, from about 1mg to about 100 mg of active ingredient. Intravenously, doses may range from about 0.1 to about 10 mg/kg/minute during a constant rate infusion.

Suitable subjects according to the present invention include mammalian subjects. Mammals according to the present invention include, but are not limited to, canine, feline, bovine, caprine, equine, ovine, porcine, rodents, lagomorphs, primates, and the like, and encompass mammals in utero. In one embodiment, humans are suitable subjects. Human subjects may be of either gender and at any stage of development. Use in the Preparation of a Medicament

In another embodiment, the invention comprises the use of one or more compounds of the invention for the preparation of a medicament for the treatment of the conditions recited herein.

Pharmaceutical Compositions

For the treatment of the conditions referred to above, the compound of the invention can be administered as compound per se. Alternatively, pharmaceutically acceptable salts are suitable for medical applications because of their greater aqueous solubility relative to the parent compound. In another embodiment, the present invention comprises pharmaceutical compositions. Such pharmaceutical compositions comprise a compound of the invention presented with a pharmaceutically-acceptable carrier. The carrier can be a solid, a liquid, or both, and may be formulated with the compound as a unit-dose composition, for example, a tablet, which can contain from 0.05% to 95% by weight of the active compounds. A compound of the invention may be coupled with suitable polymers as targetable drug carriers. Other pharmacologically active substances can also be present. The compounds of the present invention may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. The active compounds and compositions, for example, may be administered orally, rectally, parenterally, or topically. Oral administration of a solid dose form may be, for example, presented in discrete units, such as hard or soft capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of at least one compound of the present invention. In another embodiment, the oral administration may be in a powder or granule form. In another embodiment, the oral dose form is sub-lingual, such as, for example, a lozenge. In such solid dosage forms, the compounds of formula I are ordinarily combined with one or more adjuvants. Such capsules or tablets may contain a controlled-release formulation. In the case of capsules, tablets, and pills, the dosage forms also may comprise buffering agentsor may be prepared with enteric coatings.

In another embodiment, oral administration may be in a liquid dose form. Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art (i.e., water). Such compositions also may comprise adjuvants, such as wetting, emulsifying, suspending, flavoring (e.g., sweetening), and/or perfuming agents.

In another embodiment, the present invention comprises a parenteral dose form. "Parenteral administration" includes, for example, subcutaneous injections, intravenous injections, intraperitoneally, intramuscular injections, intrasternal injections, and infusion. Injectable preparations (i.e., sterile injectable aqueous or oleaginous suspensions) may be formulated according to the known art using suitable dispersing, wetting agents, and/or suspending agents. In another embodiment, the present invention comprises a topical dose form. "Topical administration" includes, for example, transdermal administration, such as via transdermal patches or iontophoresis devices, intraocular administration, or intranasal or inhalation administration. Compositions for topical administration also include, for example, topical gels, sprays, ointments, and creams. A topical formulation may include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. When the compounds of this invention are administered by a transdermal device, administration will be accomplished using a patch either of the reservoir and porous membrane type or of a solid matrix variety. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated - see, for example, J Pharm Sci, 88 (10), 955-958, by Finnin and Morgan (October 1999).

Formulations suitable for topical administration to the eye include, for example, eye drops wherein the compound of this invention is dissolved or suspended in suitable carrier. A typical formulation suitable for ocular or aural administration may be in the form of drops of a micronised suspension or solution in isotonic, pH-adjusted, sterile saline. Other formulations suitable for ocular and aural administration include ointments, biodegradable (i.e., absorbable gel sponges, collagen) and non-biodegradable (i.e., silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes. A polymer such as crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride. Such formulations may also be delivered by iontophoresis.

For intranasal administration or administration by inhalation, the active compounds of the invention are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant. Formulations suitable for intranasal administration are typically administered in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurised container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable propellant, such as 1 ,1 ,1 ,2- tetrafluoroethane or 1 ,1 ,1 ,2,3,3,3-heptafluoropropane. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.

In another embodiment, the present invention comprises a rectal dose form. Such rectal dose form may be in the form of, for example, a suppository. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate. Other carrier materials and modes of administration known in the pharmaceutical art may also be used. Pharmaceutical compositions of the invention may be prepared by any of the well-known techniques of pharmacy, such as effective formulation and administration procedures. The above considerations in regard to effective formulations and administration procedures are well known in the art and are described in standard textbooks. Formulation of drugs is discussed in, for example, Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania, 1975; Liberman, et al., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Kibbe, et al., Eds., Handbook of Pharmaceutical Excipients (3^rd Ed.), American Pharmaceutical Association, Washington, 1999.

Co-administration The compounds of the present invention can be used, alone or in combination with other therapeutic agents, in the treatment of various conditions or disease states. The compound(s) of the present invention and other therapeutic agent(s) may be may be administered simultaneously (either in the same dosage form or in separate dosage forms) or sequentially. An exemplary therapeutic agent may be, for example, a metabotropic glutamate receptor agonist.

The administration of two or more compounds "in combination" means that the two compounds are administered closely enough in time that the presence of one alters the biological effects of the other. The two or more compounds may be administered simultaneously, concurrently or sequentially. Additionally, simultaneous administration may be carried out by mixing the compounds prior to administration or by administering the compounds at the same point in time but at different anatomic sites or using different routes of administration. The phrases "concurrent administration," "co-administration," "simultaneous administration," and "administered simultaneously" mean that the compounds are administered in combination.

Kits The present invention further comprises kits that are suitable for use in performing the methods of treatment described above. In one embodiment, the kit contains a first dosage form comprising one or more of the compounds of the present invention and a container for the dosage, in quantities sufficient to carry out the methods of the present invention. In another embodiment, the kit of the present invention comprises one or more compounds of the invention.

Intermediates

In another embodiment, the invention relates to the novel intermediates useful for preparing the compounds of the invention. General Synthetic Schemes

The compounds of the formula I may be prepared by the methods described below, together with synthetic methods known in the art of organic chemistry, or modifications and derivatisations that are familiar to those of ordinary skill in the art. The starting materials used herein are commercially available or may be prepared by routine methods known in the art (such as those methods disclosed in standard reference books such as the COMPENDIUM OF ORGANIC SYNTHETIC METHODS, Vol. I-VI (published by Wiley-lnterscience)). Preferred methods include, but are not limited to, those described below. During any of the following synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This can be achieved by means of conventional protecting groups, such as those described in T. W. Greene, Protective Groups in Organic Chemistry, John Wiley & Sons, 1981 ; T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons, 1991 , and T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons, 1999, which are hereby incorporated by reference.

Compounds of formula I, or their pharmaceutically acceptable salts, can be prepared according to the reaction Schemes discussed herein below.

Unless otherwise indicated, the substituents in the Schemes are defined as above. Isolation and purification of the products is accomplished by standard procedures, which are known to a chemist of ordinary skill.

It will be understood by one skilled in the art that the various symbols, superscripts and subscripts used in the schemes, methods and examples are used for convenience of representation and/or to reflect the order in which they are introduced in the schemes, and are not intended to necessarily correspond to the symbols, superscripts or subscripts in the appended claims.

The schemes are representative of methods useful in synthesizing the compounds of the present invention. They are not to constrain the scope of the invention in any way.

Working Examples

The following illustrate the synthesis of various compounds of the present invention. Additional compounds within the scope of this invention may be prepared using the methods illustrated in these Examples, either alone or in combination with techniques generally known in the art.

Scheme 1

Scheme 2

Pd-C/H₂/MeOH

Scheme 3.

Scheme 4

Pd₂dba3, Dave-Phos, f-BuOK/ toluene

60⁰C

Experi mentals

General Procedure A:

A mixture of 3-bromo-2-chloro pyridine, the appropriate phenol and potassium carbonate in Λ/,Λ/-dimethylformamide was heated at 150⁰C overnight. The reaction was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The crude product was purified by silica gel chromatography to afford the desired bromopyridine. General Procedure A':

A mixture of 3-bromo-2-chloropyridine, the appropriate phenol and cesium carbonate in dimethyl sulfoxide was heated at 120 ⁰C overnight. The reaction was cooled to room temperature and diluted with three volumes of water, causing the product to precipitate out of solution. This precipitate was filtered off and washed with water, then dissolved in ethyl acetate. This solution was dried over anhydrous magnesium sulfate and concentrated in vacuo to give the crude product with >95% purity. General Procedure B:

A mixture of appropriate bromopyridine, tert-butyl 4-(5,5-dimethyl-1 ,3,2- dioxaborinan-2-yl)-5,6-dihydropyridine-1 (2H)-carboxylate and cesium fluoride in Λ/,Λ/-dimethylformamide was degassed for 30 minutes, and [1 , 1'-Bis (diphenylphosphino)ferrocene] palladium (II) was added. The reaction mixture was heated at 100 ^°C overnight. The reaction mixture was cooled to room temperature, and the solvent was evaporated. To the residue was added ethyl acetate, and the suspension was filtered through a pad of Celite. The filtrate was washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by silica gel chromatography to afford the desired te/t-butyl carboxylate protected dihydropyridine. General Procedure C:

To a solution of appropriate te/t-butyl carboxylate protected dihydropyridine in methanol was added palladium on carbon and the suspension was hydrogenated at 30 psi until the reduction was complete. The mixture was filtered through a pad of Celite, and the filtrate was concentrated in vacuo. The crude product was used directly in the next step or was purified by silica gel chromatography to afford the desired te/t-butyl carboxylate protected piperidine. General Procedure D:

X = N; CH To dry methanol under N₂ at 0 ^°C was added acetyl chloride. The solution was stirred at room temperature for 30 minutes, and then transferred to a flask containing appropriate te/t-butyl carboxylate protected piperidine or te/t-butyl carboxylate protected piperazine. The mixture was stirred overnight at room temperature. The solvent was evaporated to afford target compound. General Procedure E:

A mixture of appropriate bromopyridine, te/ϊ-butyl piperazine-1- carboxylate and sodium tert-butoxide in toluene was flushed with N₂ for 10 min. To the reaction mixture, tris(dibenzylideneacetone)dipalladium and Dave-Phos was added and heated to 60 ^°C overnight. The reaction mixture was cooled to room temperature and diluted with ethyl acetate and water. The organic layer was extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified by silica gel chromatography to afford the desired tert-butyl carboxylate protected piperazine.

General Procedure F:

To dry methanol under N₂ at 0 ^°C was added appropriate tert-butyl carboxylate protected piperidine. To the solution, 2.4M solution of HCI in MeOH was added and the mixture was stirred overnight. The solvent was removed in vacuo to result in the desired product.

Example #1

7ert-Butyl-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,6- dihydropyridine-1 (2H)-carboxylate:

n-Butyllithium (924 ml_, 2.3 mol, 2.5 M in hexane) was added slowly to a solution of diisopropylamine (323.3 ml_, 3.2 mol) in THF (6 L) at -78 °C and stirred for 1 h. A solution of tert-butyl 4-oxopiperidine-i-carboxylate (400 g, 2.01 mol) in THF (2 L) was added and the mixture was stirred for 1 h at -78 ⁰C. A solution of Λ/-phenyltriflimide (753 g, 2.11 mol) in THF (2 L) was added at -78 ⁰C and the reaction mixture was allowed to warm to rt and stirred at rt overnight. The reaction mixture was diluted with ethyl acetate and washed with brine, and the separated organic phase was dried over Na₂SO₄, filtered, and concentrated. The crude residue was purified by silica gel column chromatography (hexanes/ethyl acetate, 5:1) to afford tert-butyl 4- (trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1 (2H)-carboxylate as a brown oil. To an oven dried flask containing tert-butyl 4-(trifluoromethylsulfonyloxy)- 5,6-dihydropyridine-1(2H)-carboxylate (12 g, 36.25 mmol), 2-(5,5-dimethyl- 1 ,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1 ,3,2-dioxaborinane (9.82 g, 43.5 mmol) and K₃PO₄ (24.62 g, 116 mmol) were added toluene (100 mL) and dioxane (40 mL). While stirring the reaction mixture at room temperature, the air in the flask was removed and refilled with N₂. This process was repeated three times, followed by the addition of [1 ,1'- Bis(diphenylphosphino)ferrocene]palladium(ll)chloride (4.89 g, 5.35 mmol) and the reaction mixture was stirred overnight at 110 ⁰C, cooled to room temperature and filtered through a pad of Celite, and the filtrate was evaporated in vacuo. The dark red oily material was chromatographed on silica column (ethyl acetate/hexanes 4:96 to 10:90) to yield compound tert- Butyl-4-(5,5-dimethyl-1 ,3₍2-dioxaborinan-2-yl)-5,6-dihydropyridine-1 [2H)- carboxylate (7.59 g, 71%) as an orange solid. ¹H NMR (400 MHz, CDCI₃) δ 6.41 (br. s, 1 H), 3.94 (s, 2H), 3.63 (s, 4H), 3.42 (s, 2H), 2.18 (s, 2H), 1.44 (s, 9H), 0.97 (s, 6H).

3-Bromo-2-phenoxypyridine:

A mixture of 3-bromo-2-chloropyridine (19.24 g, 0.1 mol), phenol (9.41 g, 0.1 mol) and potassium carbonate (20.73 g, 0.15 mol) in N, N- dimethylformamide (100 ml_) was heated with stirring at 150 ^°C overnight. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate (2 x 300 mL). The combined organic layers were dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (hexanes/ethyl acetate, 1 :0 - 30:1 ) to give 3-bromo-2- phenoxypyridine (12 g, 58 %). ¹H NMR (400 MHz, CDCI₃): δ 8.07 (dd, J = 1.6 & 5.2 Hz, 1 H), 7.93 (dd, J = 1.6 & 7.6 Hz, 1 H), 7.42 (t, 2H), 7.23 (t, 1 H), 7.16 (d, 2H), 6.89 (q, J = 5.2 & 7.6 Hz, 1 H). ES-MS (m/z) for C₁₁H₈BrO: 249.79 & 251.78 [M+1]⁺.

Terf-butyl 4-(2-phenoxypyridin-3-yl)-5,6-dihydropyridine-1 (2H) carboxylate:

A mixture of 3-bromo-2-phenoxypyridine (2.5 g, 0.01 mol), tert-butyl 4- (5,5-dimethyl-1 ,3,2-dioxaborinan-2-yl)-5,6-dihydropyridine-1 (2H)-carboxylate (2.95 g, 0.01 mol) and cesium fluoride (2.28 g, 0.015 mol) in N₁N- dimethylformamide (30 mL) was degassed for 30 minutes, and [1 , 1'-Bis (diphenylphosphino)ferrocene] palladium (II) (1.1 g, 0.0015 mol) was added. The reaction mixture was heated at 100 ^°C overnight, cooled to room temperature, and the solvent was evaporated. To the residue was added ethyl acetate, and the suspension was filtered through a pad of Celite. The filtrate was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (hexanes/ ethyl acetate, 15:1 - 8:1) to give the te/t-butyl 4-(2-phenoxypyridin-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (1.86 g, 53 %). ¹H NMR (400 MHz, CDCI₃): δ 8.07 (dd, 1 H), 7.58 (dd, 1 H), 7.39 (t, 2H), 7.19 (t, 1 H), 7.10 (d, 2H), 6.99 (m, 1 H), 5.98 (s, 1 H), 4.08 (br s, 2H), 3.61 (m, 2H), 2.59 (br s, 2H), 1.49 (s, 9H). ES-MS (m/z) for C₂IH₂₄N₂O₃: 352.99 [M+1]⁺.

Terf-butyl 4-(2-phenoxypyridin-3-yl)piperϊdine-1-carboxylate:

To a solution of fe/t-butyl 4-(2-phenoxypyridin-3-yl)-5,6-dihydropyridine- 1 (2H)-carboxylate (0.8 g, 2.3 mmol) in methanol (30 ml.) was added palladium (0.2 g, 10 wt % on activated carbon), and the suspension was hydrogenated at 25 psi until the reduction was complete. The mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (hexanes/ethyl acetate, 20:1 - 8:1 ) to give tert-butyl 4-(2-phenoxypyridin-3- yl)piperidine-1-carboxylate (0.63 g, 78 %). ¹H NMR (400 MHz, CDCI₃): δ 8.02 (dd, 1 H), 7.55 (dd, 1 H), 7.40 (t, 2H), 7.19 (t, 1 H), 7.10 (d, 2H), 6.98 (q, 1 H), 4.38 (s, 2H), 3.14 (m, 1 H), 2.85 (m, 2H), 1.95 (d, 2H), 1.64 (m, 2H), 1.48 (s, 9H). ES-MS (m/z) for C₂₁H₂₆N₂O₃: 355.01 [M+1]⁺.

2-Phenoxy-3-(piperidin-4-yl)pyridine hydrochloride:

To a cold solution of dry methanol (25 mL) under N₂ was added acetyl chloride (1 mL) at 0 ^°C. The solution was stirred for 30 minutes, and then transferred to a flask containing tert-butyl 4-(2-phenoxypyridin-3-yl)piperidine- 1 -carboxylate (0.22 g, 0.62 mmol). The mixture was stirred overnight at room temperature. The solvent was evaporated to afford target 2-phenoxy-3-

(piperidin-4-yl)pyridine (0.13 g, 72%). ¹H NMR (400 MHz, CDCI₃): δ 7.96 (dd,

1 H), 7.77 (m, 1 H), 7.41 (t, 2H), 7.21 (t, 1 H), 7.13 (m, 1 H), 7.07 (d, 2H), 3.52

(d, 2H), 3.31 (m, 1 H), 3.18 (t, 2H), 2.20 (d, 2H), 2.06 (m, 2H). ES-MS (m/z) for Ci₆H₁₈N₂O/1.35HCI: 254.95 [M+1]⁺. CHN calculated for Ci₆Hi₈N₂O/1.35HCI:

C 63.31 %; H 6.43 %; N 9.23 %; found: C 63.27 %; H 6.49 %; N 8.85 %.

Example #2 3-(Piperidin-4-yl)-2-(p-tolyloxy)pyridine trifluoroacetic acid salt:

Using General Procedure D, terf-butyl 4-(2-(p-tolyloxy)pyridin-3- yl)piperidine-1 -carboxylate (90 mg, 0.22 mmol) was reacted with acetyl chloride (17.5 mg, 0.223 mmol) in methanol (6 ml) then purified with HPLC with 0.025% trifluoroacetic acid to afford the desired product as an oil (46 mg, 49%). ¹H NMR (400 MHz, CD₃OD) δ 2.03 (qd, J=12.86, 4.15 Hz, 2 H), 2.14 - 2.24 (m, 2 H), 2.34 (s, 3 H), 3.18 (td, J=12.96, 2.70 Hz, 2 H), 3.26 - 3.37 (m, 1 H), 3.47 - 3.57 (m, 2 H), 6.91 - 6.99 (m, 2 H), 7.10 (dd, J=7.46, 4.98 Hz, 1 H), 7.21 (d, J=7.88 Hz, 2 H), 7.74 (dd, J=7A6, 1.66 Hz, 1 H), 7.94 (dd, J=AU, 1.87 Hz, 1 H). MS-APCI (m/z): 269 [M+1]⁺. Example # 3 3-Bromo-2-(4-(trifluoromethoxy)phenoxy)pyridine:

Using General Procedure A, 3-bromo-2-chloro pyridine (3.03 g, 15.7 mmol) was reacted with 4-(trifluoromethoxy)phenol (3.93 g, 22 mmol) and potassium carbonate (4.35 g, 31.5 mmol) in Λ/,Λ/-dimethylformamide (20 ml) to afford the desired product as oil (3.65 g, 69%). ¹H NMR (400 MHz, CDCI₃) δ

6.88 (dd, J=7.60, 4.87 Hz, 1 H), 7.14 - 7.19 (m, 2 H), 7.21 - 7.27 (m, 2 H),

7.90 (dd, J=7.80, 1.75 Hz, 1 H), 8.04 (dd, J=4.87, 1.75 Hz, 1 H). MS-APCI (m/z): 335 [M+1]⁺.

Terf-butyl 4-(2-(4-(trifluoromethoxy)phenoxy)pyridin-3-yl)-5,6- dihydropyridine-1(2H)-carboxylate:

Using General Procedure B, 3-bromo-2-(4- (trifluoromethoxy)phenoxy)pyridine (551.7 mg, 1.651 mmol) was reacted with fert-butyl 4-(5,5-dimethyl-1 ,3,2-dioxaborinan-2-yl)-5,6-dihydropyridine-1 (2H)- carboxylate (585 mg, 1.98 mmol), cesium fluoride (502 mg, 3.30 mmol) and [1 , 1'-Bis (diphenylphosphino)ferrocene] palladium (II) (67.4 mg, 0.0826 mmol) in Λ/,Λ/-dimethylformamide (5 ml) to afford the desired product as an oil (440mg, 61 %). ¹H NMR (400 MHz, CDCI₃) δ 1.46 (s, 9 H), 2.50 - 2.59 (m, 2 H), 3.59 (t, J=5.65 Hz, 2 H), 4.06 (d, J=2.73 Hz, 2 H), 5.89 - 5.99 (m, 1 H), 7.00 (dd, J=7.41 , 4.87 Hz, 1 H), 7.05 - 7.14 (m, 2 H), 7.18 - 7.24 (m, 2 H), 7.58 (dd, J=7.41 , 1.95 Hz, 1 H), 8.03 (dd, J=4.97, 1.85 Hz, 1 H). MS-APCI (m/z): 302 [M+1]⁺. Te/t-butyl 4-(2-(4-(trifluoromethoxy)phenoxy)pyridin-3- yl)piperidine-1 -carboxylate:

Using General Procedure C, te/t-butyl 4-(2-(4- (trifluoromethoxy)phenoxy)pyridin-3-yl)-5,6-dihydropyridine-1 (2H)-carboxylate (430 mg, 0.985 mmol) was reduced to the desired product as oil (410 mg, 95%). ¹H NMR (400 MHz, CD₃OD) δ 1.44 (s, 9 H), 1.66 (qd, J=12.82, 12.65, 4.39 Hz, 2 H), 1.84 - 1.95 (m, 2 H), 2.77 - 2.97 (m, 2 H), 3.14 (tt, J=11.89, 3.31 Hz, 1 H), 4.17 - 4.27 (m, 2 H), 7.07 - 7.16 (m, 3 H), 7.26 - 7.33 (m, 2 H), 7.73 (dd, J=7.21 , 1.56 Hz, 1 H), 7.92 (dd, J=4.87, 1.75 Hz, 2 H).

3-(Piperidin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)pyridine hydrochloride salt:

Using General Procedure D, tert-butyl 4-(2-(4- (trifluoromethoxy)phenoxy)pyridin-3-yl)piperidine-1 -carboxylate (400.6 mg, 0.914 mmol) was reacted with acetyl chloride (71.7 mg, 0.914 mmol) in methanol (6 ml) to afford the desired product as a solid (250 mg, 73%). ¹H NMR (400 MHz, CD₃OD) δ 2.06 (qd, J=12.86, 4.15 Hz, 2 H), 3.19 (td, J=12.96, 2.70 Hz, 2 H), 3.31 - 3.41 (m, 1 H), 3.49 - 3.58 (m, 2 H), 7.19 - 7.27 (m, 3 H), 7.36 (d,

1.66 Hz, 1 H), 8.02 (dd, J=4.98, 1.66 Hz, 1 H). MS-APCI (m/z): 339 [M+1]⁺.

Example #4

3-Bromo-2-(2-chloro-4-methylphenoxy)pyridine:

Using General Procedure A, 3-bromo-2-chloro pyridine (3.10 g, 16.1 mmol) was reacted with 2-chloro-4-cresol (3.22 g, 22.6 mmol) and potassium carbonate (5.57 g, 40.3 mmol) in Λ/,Λ/-dimethylformamide (20 ml) to afford the desired product was a solid (4.33 g, 90%). MS-APCI (m/z): 297 [M+1]⁺.

Terf-butyl 4-(2-(2-chloro-4-methylphenoxy)pyridin-3-yl)-5,6- dihydropyridine-1(2H)-carboxylate:

Using General Procedure B, 3-bromo-2-(2-chloro-4- methylphenoxy)pyridine (538.3 mg, 1.803 mmol) was reacted with te/t-butyl 4- (5,5-dimethyl-1 ,3,2-dioxaborinan-2-yl)-5,6-dihydropyridine-1 (2H)-carboxylate (639 mg, 2.16 mmol), cesium fluoride (548 mg, 3.61 mmol) and [1 , 1 '-Bis (diphenylphosphino)ferrocene] palladium (II) (74 mg, 0.09 mmol) in N, N- dimethylformamide (5 ml) to afford the desired product as oil (240 mg, 33%). ¹H NMR (400 MHz, CDCI₃) δ 1.47 (s, 9 H), 2.33 (s, 3 H), 2.59 - 2.68 (m, 2 H), 3.62 (t, .£=5.46 Hz, 2 H), 4.05 - 4.13 (m, 2 H), 5.97 - 6.04 (m, 1 H), 6.94 (dd, J=7.41 , 4.87 Hz, 1 H), 7.04 (d, J=8.19 Hz, 1 H), 7.07 - 7.1 1 (m, 1 H), 7.26 (d, J=1.36 Hz, 1 H), 7.55 (dd, J=7.41 , 1.95 Hz, 1 H), 7.98 (dd, J=Λ.87, 1.75 Hz, 1 H). MS-APCI (m/z): 401 [M+1]⁺. 2-(2-Chloro-4-methylphenoxy)-3-(piperidin-4-yl)pyrϊdine:

First, te/t-butyl 4-(2-(2-chloro-4-methylphenoxy)pyridin-3-yl)piperidine- 1 -carboxylate was synthesized as oil (355.3 mg, 88 %) using General Procedure C with tert-butyl 4-(2-(2-chloro-4-methylphenoxy)pyridin-3-yl)-5,6- dihydropyridine-1 (2H)-carboxylate (400 mg, 0.998 mmol). Then using General Procedure D te/t-butyl 4-(2-(2-chloro-4-methylphenoxy)pyridin-3- yl)piperidine-1-carboxylate (106 mg, 0.263 mmol) was reacted with acetyl chloride (15 mg, 0.191 mmol) in methanol (6 ml) to afford the desired product as a solid (78 mg, 98 %). 1H NMR (400 MHz, CD₃OD-Qf₄) δ ppm 2.09 (qd, J=13.27, 3.73 Hz,2 H), 2.20 - 2.30 (m, 2 H), 2.36 (s, 3 H), 3.20 (td, J=13.06, 2.90 Hz, 2 H), 3.35 (tt, J=12.44, 3.73 Hz, 1 H), 3.49 - 3.58 (m, 2 H), 7.04 - 7.13 (m, 2 H), 7.18 (dd, J=8.29, 2.07 Hz, 1 H), 7.28 - 7.35 (m, 1 H), 7.74 (dd, J=7.46, 1.66 Hz, 1 H), 7.89 (dd, J=4.98, 2.07 Hz, 1 H). MS-APCI (m/z+): 304 (M+H).

Example #5

3-Bromo-2-(2-(trifluoromethoxy)phenoxy)pyridine:

Using General Procedure A, 3-bromo-2-chloropyridine (3.9 g, 20.33 mmol) was reacted with 2-(trifluoromethoxy)phenol (3.8 g, 21.35 mmol)and potassium carbonate (5.6 g, 40.66 mmol) in Λ/,Λ/-dimethylformamide (15 ml) to afford the desired product (4.1 g, 60%).¹H NMR (400 MHz, CDCI₃): δ 8.07 (dd, 1 H), 7.96 (dd, 1 H), 7.41-7.24 (m, 4H), 6.92-6.85 (m, 1 H). ¹⁹F NMR (400 MHz, CDCI₃) δ -58 (s). ES-MS (m/z): 333.8 [M+1]⁺.

Tert-butyl 4-(2-(2-(tπfluoromethoxy)phenoxy)pyridin-3-yl)-5,6- dihydropyridine-1(2H)-carboxylate:

Using General Procedure B, 3-bromo-2-(2- (trifluoromethoxy)phenoxy)pyridine (2.8 g, 8.4 mmol) was reacted with tert- butyl 4-(5,5-dimethyl-1 ,3,2-dioxaborinan-2-yl)-5,6-dihydropyridine-1 (2H)- carboxylate (2.97 g, 10.1 mmol), cesium fluoride (1.9 g, 12.6 mmol) and [1 , 1'- Bis (diphenylphosphino)ferrocene] palladium (II) (0.92 g, 1.3 mmol) in N₁N- dimethylformamide (15 ml) to afford the desired product (2.3 g, 64%).¹H NMR (400 MHz, CDCI₃) δ 8.02 (dd, 1 H), 7.59 (dd, 1 H), 7.38-7.19 (m, 4H), 7.02-6.96 (m, 1 H), 5.99 (s, 1 H), 4.18-4.07 (br s, 2H), 3.73-3.58 (br s, 2H), 2.66-2.54 (br s, 2H), 1.44 (S, 9H). ¹⁹F NMR (400 MHz, CDCI₃) δ -58 (s). ES-MS (m/z): 437.09 [M+1]⁺.

Tert-butyl 4-(2-(2-(trifluoromethoxy)phenoxy)pyridin-3- yl)piperidine-1-carboxylate:

Using General Procedure C, tert-butyl 4-(2-(2- (trifluoromethoxy)phenoxy)pyridin-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (2.14 g, 4.9 mmol) was reduced to the desired product (1.42 g, 68%). ¹H NMR (400 MHz, CDCI₃) δ 7.99 (dd, 1 H), 7.58 (dd, 1 H), 7.39-7.18 (m, 4H), 7.02-6.96 (m, 1 H), 4.43-4.17 (br s, 2H), 3.19-3.07 (m, 1 H), 2.99-2.73 (br s, 2H), 1.98 (d, 2H), 1.77-1.54 (m, 2H), 1.44 (s, 9H). ¹⁹F NMR (400 MHz, CDCI₃) δ -58 (s).

3-(Piperidin-4-yl)-2-(2-(trifluoromethoxy)phenoxy)pyridine hydrochloride:

Using General Procedure D, te/t-butyl 4-(2-(2- (trifluoromethoxy)phenoxy)pyridin-3-yl)piperidine-1-carboxylate (1.4 g, 3.1 mmol) was reacted with acetyl chloride (4.4 ml_, 62.1 mmol) in methanol (40 ml) to afford the desired product (1.1 g, 91%). ¹H NMR (400 MHz, CD₃OD) δ 7.98 (dd, 1 H), 7.78 (dd, 1 H), 7.42-7.11 (m, 4H), 7.16-7.09 (m, 1 H), 3.56 (d, 2H), 3.42-3.28 (m, 1 H), 3.19 (t, 2H), 2.28-1.99 (m, 4H). ¹⁹F NMR (400 MHz, CD₃OD) δ -59 (s) ppm. ES-MS (m/z): 339.03 [M+1]⁺. CHN calculated for Ci₇Hi₇F₃N₂O₂-I HCI.0.33H2O: C 53.62 %; H 4.94 %; N 7.36 %, and found: C 53.49 %; H 4.98 %; N 7.51 %.

Example # 6

3-Bromo-2-(2-(trifluoromethyl)phenoxy)pyridine:

Using General Procedure A₁ 3-bromo-2-chloropyridine (2.37 g, 12.3 mmol) was reacted with 2-trifluoromethylphenol (2 g, 12 mmol) and potassium carbonate (4.02 g, 12.3 mol) in Λ/,Λ/-dimethylformamide (10 ml) to afford the desired product (0.3 g, 8 %). ¹H NMR (400 MHz, CDCI₃): δ 8.04 (dd, 1 H), 7.95 (dd, 1 H), 7.72 (d, 1 H), 7.60 (t, 1 H), 7.34 (d, 2H), 7.26 (d, 1 H), 6.92 (q, 1 H). ES-MS (m/z) for Ci₂H₇BrF₃NO: 317.86 & 319.81 [M+1]⁺.

Te/t-butyl 4-(2-(2-(trifluoromethyl)phenoxy)pyridin-3-yl)-5,6- dihydropyridine-1(2H)-carboxylate:

Using General Procedure B, 3-bromo-2-(2- trifluoromethylphenoxy)pyridine (0.3 g, 0.9 mmol) was reacted with te/t-butyl

4-(5,5-dimethyl-1 ,3,2-dioxaborinan-2-yl)-5,6-dihydropyridine-1 (2H)- carboxylate (0.362 g, 1.23 mmol), cesium fluoride (215 mg, 1.42 mmol) and

[1 , 1'-Bis (diphenylphosphino)ferrocene] palladium (II) (0.104 g, 0.1415 mol) in

Λ/,Λ/-dimethylformamide (5 ml) to afford the desired product (0.35 g, 85 %). ¹H NMR (400 MHz, CDCI₃): δ 8.03 (dd, 1 H), 7.70 (d, 1 H), 7.60 (dd, 1 H), 7.56 (t, 1 H), 7.38 (t, 1 H), 7.17 (d, 1 H), 7.02 (q, 1 H), 5.98 (s, 1 H), 4.08 (br s, 2H), 3.61 (t, 2H), 2.58 (m, 2H), 1.49 (s, 9H). rerf-butyl 4-(2-(2-(trifluorornethyl)phenoxy)pyridin-3-yl)piperidine- 1-carboxylate:

Using General Procedure C, tert-butyl 4-(2-(2- (trifluoromethyl)phenoxy)pyridin-3-yl)-5,6-dihydropyridine-1 (2H)-carboxylate (0.3 g, 3.1 mmol) was reduced to the desired product (0.3 g, 98 %). ¹H NMR (400 MHz, CDCI₃): δ 8.00 (dd, 1 H), 7.71 (dd, 1 H), 7.60-7.54 (m, 2H), 7.29 (d, 1 H), 7.25 (d, 2H), 7.01 (q, 2H), 4.28 (br s, 2H), 3.14 (m, 1 H), 2.84 (t, 2H), 1.95 (d, 2H), 1.62 (m, 2H), 1.48 (s, 9H). ES-MS (m/z) for C₂₂H₂₅F₃N₂O₃: 423.16 [M+1]⁺.

3-(Piperidin-4-yl)-2-(2-(trifluoromethyl)phenoxy)pyridine hydrochloride:

Using General Procedure D, tert-butyl 4-(2-(2- (trifluoromethyl)phenoxy)pyridin-3-yl)piperidine-1-carboxylate (0.3 g, 0.7 mmol) was reacted with acetyl chloride (1 mL) in methanol (25 ml) to afford the desired product (0.2 g, 80%). ¹H NMR (400 MHz, CD₃OD): δ 7.96 (d, 1 H), 7.80 (d, 1 H), 7.75 (d, 1 H), 7.66 (t, 1 H), 7.39 (t, 1 H), 7.25 (d, 1 H), 7.15 (q, 1 H), 3.56 (d, 2H), 3.34 (m, 1 H), 3.18 (t, 2H), 2.22 (d, 2H), 2.06 (m, 2H). ¹⁹F NMR (376 MHz, CD₃OD): δ -63.2. ES-MS (m/z) for C₁₇H₁₇F₃N₂OzM .25HCI: 323.09 [M+1]⁺. CHN calculated for C₁₇H₁₇F₃N₂O/^"! .25HCI: C 55.50 %; H 5.00 %; N 7.61 %, and found: C 55.56 %; H 5.43 %; N 7.42 %.

Example #7 3-Bromo-2-(2-methoxyphenoxy)pyridine:

Using General Procedure A, 3-bromo-2-chloropyridine (5 g, 26 mmol) was reacted with 2-methoxyphenol (3.2 g, 26 mmol) and potassium carbonate (5.39 g, 39 mmol) in Λ/,Λ/-dimethylformamide (25 ml) to afford the desired product (3.7 g, 51%). ¹H NMR (400 MHz, CDCI₃): δ 8.02 (dd, 1 H), 7.91 (dd, 1 H), 7.28-7.14 (m, 2H), 7.04-6.96 (m, 2H), 6.85 (q, 1 H), 3.75 (s, 3H). ES-MS (m/z) for C₁₂H₁₀BrNO₂: 279.86 & 281.81 [M+1]⁺.

Terf-butyl 4-(2-(2-methoxyphenoxy)pyridin-3-yl)-5,6- dihydropyridine-1(2H)-carboxylate:

Using General Procedure B, 3-bromo-2-(2-methoxyphenoxy)pyridine

(1.07 g, 3.82 mmol) was reacted with fert-butyl 4-(5,5-dimethyl-1 ,3,2- dioxaborinan-2-yl)-5,6-dihydropyridine-1 (2H)-carboxylate (1.35 g, 4.58 mmol), cesium fluoride (0.87 g, 5.7 mmol) and [1 , 1 '-Bis (diphenylphosphino)ferrocene] palladium (II) (0.42 g, 0.57 mmol) in N₁N- dimethylformamide (10 ml) to afford the desired product (1.20 g, 82 %). ¹H NMR (400 MHz, CDCI₃): δ 8.00 (dd, 1 H), 7.55 (dd, 1 H), 7.24-7.08 (m, 2H), 7.08-6.88 (m, 3H), 6.02 (s, 1 H), 4.09 (br s, 2H), 3.74 (s, 3H), 3.63 (br s, 2H), 2.65 (br s, 2H), 1.49 (s, 9H). ES-MS (m/z) for Chemical Formula: C₂₂H₂₆N₂O₄: 383.08 [M+1]⁺. Terf-butyl 4-(2-(2-methoxyphenoxy)pyridin-3-yl)piperidine-1- carboxylate:

Using General Procedure C, tert-butyl 4-(2-(2-methoxyphenoxy)pyridin- 3-yl)-5,6-dihydropyridine-1 (2H)-carboxylate (1.2 g, 3.1 mmol) was reduced to the desired product (0.9 g, 74 %). ¹H NMR (400 MHz, CDCI₃): δ 7.95 (dd, 1 H), 7.50 (dd, 1 H), 7.18 (t, 1 H), 7.11 (d, 1 H), 6.99 (m, 2H), 6.92 (q, 1 H), 4.26 (s, 2H)₁ 3.17 (m, 1 H), 2.86 (br s, 2H), 2.02 (d, 2H), 1.63 (m, 2H), 1.48 (s, 9H). ES-MS (m/z) for C₂₂H₂₈N₂O₄: 385.10 [M+1]⁺.

2-(2-Methoxyphenoxy)-3-(piperidin-4-yl)pyridine dihydrochloride:

Using General Procedure D, te/t-butyl 4-(2-(2-methoxyphenoxy)pyridin- 3-yl)piperidine-1 -carboxylate (0.84 g, 2.2 mmol) was reacted with acetyl chloride (2 ml_) in methanol (50 ml) to afford the desired product (0.72 g, quant.). ¹H NMR (400 MHz, CD₃OD): δ 8.17 (d, 1 H), 8.00 (d, 1 H), 7.42-7.28 (m, 3H), 7.21 (d, 1 H), 7.09 (t, 1 H), 3.73 (s, 3H), 3.56 (d, 2H), 3.46 (m, 1 H), 3.22 (t, 2H), 2.27 (d, 2H), 2.12 (m, 2H). ES-MS (m/z) for Ci₇H₂₀N₂O₂/2HCI: 285.09 [M+1]⁺. CHN calculated for C₁₇H₂oN₂θ₂/2HCI/2H₂O: C 51.91 %; H 6.66 %; N 7.12 %, and found: C 52.87 %; H 6.44 %; N 7.07 %.

Example #8

3-Bromo-2-(2-ethoxyphenoxy)pyridine:

Using General Procedure A, 3-bromo-2-chloro pyridine (1.0 g, 5.3 mmol) was reacted with 2-ethoxyphenol (732 mg, 5.3 mmol) and potassium carbonate (1.1 g, 8.0 mmol) in Λ/,Λ/-dimethylformamide (10 ml) to afford the desired product (0.58 g, 37 %). ¹H NMR (400 MHz, CDCI₃): δ 8.04 (dd, 1 H), 7.92 (dd, 1 H), 7.24-7.16 (m, 2H), 7.05-6.96 (m, 2H), 6.86 (m, 1 H), 3.97 (q, 2H), 1.14 (t, 3H). ES-MS (m/z) for C₁₃H₁₂BrNO₂: 293.85 & 295.84 [M+1]⁺.

Tert-butyl 4-(2-(2-ethoxyphenoxy)pyridin-3-yl)-5,6-dihydropyridine- 1(2H)-carboxylate:

Using General Procedure B, 3-bromo-2-(2-ethoxyphenoxy)pyridine (0.58 g, 1.97 mmol) was reacted with te/t-butyl 4-(5,5-dimethyl-1 ,3,2- dioxaborinan-2-yl)-5,6-dihydropyridine-1 (2H)-carboxylate (873 mg, 2.96 mmol), cesium fluoride (449 mg, 2.96 mmol) and [1 , 1'-Bis (diphenylphosphino)ferrocene] palladium (II) (216 mg, 2.96 mmol) in N, N- dimethylformamide (10 ml) to afford the desired product (0.57 g, 73 %). ¹H NMR (400 MHz, CDCI₃): δ 8.00 (dd, 1 H), 7.55 (dd, 1 H), 7.17 (t, 2H), 7.04-6.90 (m, 3H), 6.00 (s, 1 H), 4.11 (br s, 2H), 3.95 (q, 2H), 3.64 (br s, 2H), 2.67 (br s, 2H), 1.50 (s, 9H), 1.10 (t, 3H). ES-MS (m/z) for Chemical Formula: C₂₃H₂₈N₂O₄: 397.20 [M₊I]⁺.

Terf-butyl 4-(2-(2-ethoxyphenoxy)pyridin-3-yl)piperidine-1 - carboxylate:

Using General Procedure C, tø/t-butyl 4-(2-(2-ethoxyphenoxy)pyridin-3- yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.57 g, 2.3 mmol) was reduced to the desired product (0.63 g, 78 %). ¹H NMR (400 MHz, CDCI₃): δ 8.02 (dd, 1 H), 7.55 (dd, 1 H), 7.40 (t, 2H), 7.19 (t, 1 H), 7.10 (d, 2H), 6.98 (q, 1 H), 4.38 (s, 2H), 3.14 (m, 1 H), 2.85 (m, 2H), 1.95 (d, 2H), 1.64 (m, 2H), 1.48 (s, 9H). ES-MS (m/z) for C₂₃H₃₀N₂O₄: 399.03 [M+1]⁺.

2-(2-Ethoxyphenoxy)-3-(piperidin-4-yl)pyridine hydrochloride:

Using General Procedure D, tert-butyl 4-(2-(2-ethoxyphenoxy)pyridin-3- yl)piperidine-1-carboxylate (0.22 g, 0.62 mmol) was reacted with acetyl chloride (1 ml_) in methanol (25 ml) to afford the desired product (0.30 g, quant.). ¹H NMR (400 MHz, CDCI₃): δ 8.14 (br s, 1 H), 7.82 (br s, 1 H), 7.36- 6.96 (m, 5H), 3.95 (q, 2H), 3.67 (br s, 2H), 3.41 (br s, 1 H), 3.08 (br s, 2H), 2.28 (br s, 4H), 1.02 (t, 3H). ES-MS (m/z) for Ci₈H₂₂N₂O₂/2HCI: 299.02 [M+1]⁺. CHN calculated for

C 58.23 %; H 6.52 %; N 7.54 %, and found: C 58.61 %; H 6.73 %; N 7.55 %.

Example #9 Te/f-butyl 4-(2-hydroxypyridin-3-yl)piperidine-1 -carboxylate:

To a solution of te/t-butyl-4-(2-phenoxypyridin-3-yl)-5,6- dihydropyridine-1 (2H)-carboxylate (1.0 g, 2.3 mmol) in methanol (30 mL) was added palladium (0.2 g, 10 wt % on activated carbon), and the suspension was hydrogenated at 35 psi for 4 hours. The mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography using 10 % methanol in ethyl acetate to give tert-butyl 4-(2-hydroxypyridin-3-yl)piperidine-1- carboxylate (0.68 g, 86 %). ¹H NMR (400 MHz, CDCI₃): δ 11.77 (s, 1 H), 7.24 (d, J = 7.2 Hz, 2H), 6.25 (t, J = 7.2 & 6.8 Hz, 1 H), 4.23 (s, 2H), 3.02 (m, 1 H), 2.86 (m, 2H), 1.88 (d, 2H), 1.70-1.40 (m, 2H), 1.48 (s, 9H). ES-MS (m/z) for Ci₅H₂₂N₂O₃: 278.97 [M+1]⁺.

Terf-butyl 4-(2-(2-fluorophenoxy)pyridin-3-yl)piperidine-1- carboxylate:

A mixture of 4-(2-hydroxypyridin-3-yl)piperidine-1 -carboxylate (340 mg, 1.2 mmol), 2-fluoro-1-iodobenzene (272 mg, 1.22 mmol), cesium carbonate (797 mg, 2.45 mmol) and 2,2,6,6-tetramethylheptane-3,5-dione (56 mg, 0.31 mmol) in 1 -methyl-2-pyrrolidinone (10 mL) was degassed and filled with nitrogen. To this mixture was added copper (I) chloride (61 mg, 0.61 mmol), the mixture was degassed and filled with nitrogen three times. This mixture was then heated at 120 ^°C overnight, cooled down to room temperature, diluted with ethyl acetate, filtered through a pad of Celite. The filtrate was washed thoroughly with water. The separated organic phase was concentrated under reduced pressure and purified over silica gel (hexanes/ethyl acetate,10:1 - 4:1 ) to afford te/t-butyl 4-(2-(2- fluorophenoxy)pyridin-3-yl)piperidine-1-carboxylate (0.177 g, 39 %). ¹H NMR (400 MHz, CDCI₃): δ 7.96 (dd, J = 1.6 & 4.8 Hz, 1 H), 7.54 (d, J = 7.2 Hz, 1 H), 7.25-7.15 (m, 4H), 6.97 (dd, 1 H), 4.28 (br s, 2H), 3.17 (m, 1 H), 2.87 (t, 2H), 1.99 (d, 2H), 1.65 (m, 2H), 1.49 (s, 9H). ¹⁹F NMR (376 MHz, CDCI₃): δ - 128.888. 2-(2-Fluorophenoxy)-3-(piperidin-4-yl)pyridine hydrochloride:

To a 0 C solution of dry methanol (25 ml_) under nitrogen was added acetyl chloride (1 ml_) at 0 ^°C. The solution was stirred for 30 minutes, and then transferred to a flask containing te/t-butyl 4-(2-(2-fluorophenoxy)pyridin- 3-yl)piperidine-1-carboxylate (177 mg, 0.17 mmol). The mixture was stirred overnight at room temperature. The solvent was evaporated to afford target 2- (2-fluorophenoxy)-3-(piperidin-4-yl)pyridine hydrochloride (120 mg). ¹H NMR (400 MHz, CD₃OD): δ 8.14 (d, J = 7.6 Hz, 1 H), 8.06 (d, J = 5.2 Hz, 1 H), 7.44- 7.26 (m, 5H), 3.57 (d, 2H), 3.45 (m, 1 H), 3.23 (m, 2H), 2.26-1.90 (m, 4H). ES- MS (m/z) for C₁₆H₁₇FN₂OZHCI: 273.03 (M⁺+1). ¹⁹F NMR (376 MHz, CDCI₃): δ -131.586. CHN calculated for C₁₆H₁₇FN₂O/1.2HCI: C 60.80 %; H 5.80 %; N 8.86 %, and found: C 61.11 %; H 6.07 %; N 8.51 %.

Example #10

Terf-butyl 4-(2-(2-chlorophenoxy)pyridin-3-yl)piperidine-1- carboxylate:

A mixture of 4-(2-hydroxypyridin-3-yl)piperidine-1-carboxylate (0.34 g, 1.2 mmol), 2-chloro-1-iodobenzene (292 mg, 1.22 mmol), cesium carbonate (797 mg, 2.45 mmol) and 2,2₎6,6-tetramethylheptane-3,5-dione (56 mg, 0.31 mmol) in 1 -methyl-2-pyrrolidinone (10 ml_) was degassed and filled with nitrogen. To this mixture was added copper (I) chloride (61 mg, 0.61 mmol), the mixture was degassed and filled with nitrogen three times. This mixture was then heated at 120 C overnight. The mixture was cooled to room temperature, diluted with ethyl acetate, and filtered through a pad of Celite. The filtrate was washed thoroughly with water. The separated organic phase was concentrated under reduced pressure and purified over silica gel (hexanes/ethyl acetate, 10:1 - 4:1) to afford terf-butyl 4-(2-(2- chlorophenoxy)pyridin-3-yl)piperidine-1-carboxylate (66 mg, 14 %). ¹H NMR (400 MHz, CDCI₃): δ 7.96 (d, J= 3.6 Hz, 1 H), 7.55 (d, J= 7.2 Hz, 1 H), 7.48 (d, J = 7.2 Hz, 1 H), 7.32 (t, 1 H), 7.23-7.15 (m, 2H), 6.97 (t, 1 H), 4.28 (br s, 2H), 3.19 (m, 1 H), 2.87 (br s, 2H), 2.02 (d, 2H), 1.66 (m, 2H), 1.49 (s, 9H).

2-(2-Chlorophenoxy)-3-(piperidin-4-yl)pyridine hydrochloride salt:

To a cold solution of dry methanol (25 ml_) under nitrogen was added acetyl chloride (1 ml_) at 0 ⁰C. The solution was stirred for 30 minutes, and then transferred to a flask containing tert-butyl 4-(2-phenoxypyridin-3- yl)piperidine-1 -carboxylate (66 mg, 0.17 mmol). The mixture was stirred overnight at room temperature. The solvent was evaporated to afford target 2- (2-chlorophenoxy)-3-(piperidin-4-yl)pyridine hydrochloride (0.044 g, 80%). ¹H NMR (400 MHz, CD₃OD): δ 7.90 (del, 1 H), 7.78 (dd, 1 H)₁ 7.50 (dd, 1 H), 7.38 (m, 1 H), 7.28-7.21 (m, 2H), 7.11 (dd, 1 H), 3.55 (d, 2H), 3.38 (m, 1 H), 3.21 (t, 2H), 2.27 (d, 2H), 2.11 (m, 2H). ES-MS (m/z) for C₁₆H₁₇CIN₂OZHCI: 289.03 [M+1]⁺. ¹³C NMR (400 MHz, CD₃OD): δ 160.4, 149.8, 144.9, 137.2, 130.4, 128.2, 127.1 , 126.8, 126.4, 124.2, 119.4, 44.4, 34.3, 27.9..

Example #11 3-Bromo-2-(2-chloro-3-(trifluoromethyl)phenoxy)pyridine:

Using General Procedure A, 3-bromo-2-chloro pyridine (3.52 g, 18.3 mmol) was reacted with 2-chloro-3-(trifluoromethyl)phenol (4.32 g, 22 mmol) and potassium carbonate (4.29 g, 27.5 mmol) in Λ/,Λ/-dimethylformamide (15 ml) to afford the desired product as an oil (3.59 g, 56%). ¹H NMR (400 MHz, CDCI₃) δ 6.93 (dd, J=7.60, 4.87 Hz, 1 H), 7.41 - 7.46 (m, 2 H), 7.59 - 7.64 (m, 1 H), 7.96 (dd, ^=7.70, 1.66 Hz, 1 H), 8.00 (dd, J=4.78, 1.66 Hz, 1 H). MS- APCI (m/z): 351 (M+H).

Teit-butyl 4-(2-(2-chloro-3-(trifluoromethyl)phenoxy)pyridin-3-yl)- 5,6-dihydropyridine-1(2H)-carboxylate:

Using General Procedure B, 3-bromo-2-(2-chloro-3- (trifluoromethyl)phenoxy)pyridine (3.5 g, 9.93 mmol) was reacted with tert- butyl 4-(5,5-dimethyl-1 ,3,2-dioxaborinan-2-yl)-5,6-dihydropyridine-1 (2H)- carboxylate (3.68 g, 11.9 mmol), cesium fluoride (2.26 g, 14.9 mmol) and [1 , 1'-Bis (diphenylphosphino)ferrocene] palladium (II) (162 mg, 0.199 mmol) in Λ/,Λ/-dimethylformamide (20 ml) to afford the desired product as a solid (320 mg, 7%). ¹H NMR (400 MHz, CDCI₃) δ 1.47 (s, 9 H), 2.60 - 2.67 (m, 2 H), 3.62 (t, J=5.65 Hz, 2 H), 4.06 - 4.08 (m, 2 H), 6.00 - 6.05 (m, 1 H), 7.00 (dd, J=7.41 , 4.87 Hz, 1 H), 7.34 - 7.42 (m, 2 H), 7.56 (dd, J=7.31 , 2.05 Hz, 1 H), 7.59 (dd, Λ=7.41 , 1 .95 Hz, 1 H), 7.96 (dd, J=4.87, 1.75 Hz, 1 H). MS-APCI (m/z): 455 (M+H), 354 (M-100).

Te/f-butyl 4-(2-(2-chloro-3-(trifluoromethyl)phenoxy)pyridin-3- yl)piperidine-1 -carboxylate:

Using General Procedure C, tert-butyl 4-(2-(2-chloro-3- o (trif luoromethyl)phenoxy)-pyridin-3-yl)-5,6-dihydropyridine-1 (2H)-carboxylate (300 mg, 0.660 mmol) was reduced to the desired product as oil (220 mg, 73%). ¹H NMR (400 MHz, CDCI₃) δ 1 .17 - 1.33 (m, 2 H), 1.46 (s, 9 H), 1 .59 - 1.76 (m, 2 H), 1.97 - 2.03 (m, 2 H), 2.74 - 2.96 (m, 2 H), 3.16 (tt, dd, J=12.48, 3.31 Hz, 1 H), 7.00 (dd, dd, J=7.41 , 4.87 Hz, 1 H)₁ 7.39 - 7.43 (m, 2 H), 7.54 -5 7.59 (m, 2 H)₁ 7.92 (dd, J=4.87, 1.75 Hz, 1 H). MS-APCI (m/z): 457 (M+H), 357 (M+H-100).

2-(2-Chloro-3-(trifluoromethyl)phenoxy)-3-(piperidin-4-yl)pyridine hydrochloride salt:

0 Using General Procedure D, tert-butyl 4-(2-(2-chloro-3-

(trifluoromethyl)phenoxy)-pyridin-3-yl)piperidine-1 -carboxylate (220 mg, 0.521 mmol) was reacted with acetyl chloride (0.741 ml, 10.4 mmol) in methanol (5 ml) to afford the desired product as a solid (130 mg, 63%). ¹H NMR (400 MHz, CD₃OD) δ 2.15 (m, 2 H), 2.24 (d, J=1.75 Hz, 2 H), 3.20 (t, J=2.53 Hz, 1 H),5 3.29 (dt, .£=3.27, 1.58 Hz, 4 H), 3.54 (d, J=12.67 Hz, 1 H), 7.15 (m, 1 H), 7.55 (m, 2 H), 7.68 (d, J=1.68 Hz, 1 H), 7.77 (d, J=λ A Hz, 1.4 Hz, 1 H), 7.95 (m, 1 H). MS-APCI (m/z+): 357 (M+H).

Example #12 3-Bromo-2-(2-chloro-6-methoxyphenoxy)pyridine:

Using General Procedure A, 3-bromo-2-chloro pyridine (485.4 mg, 2.522 mmol) was reacted with 2-chloro-6-methoxylphenol (400 mg, 252 mmol) and potassium carbonate (591 mg, 3.78 mmol) in N, N- dimethylformamide (5 ml) to afford the desired product as a solid (280 mg, 35%). ¹H NMR (400 MHz, CDCI₃) δ 3.76 (s, 3 H), 6.90 (dd, J=8.19, 1.56 Hz, 1 H), 6.93 (dd, J=6.63, 2.92 Hz, 1 H), 7.06 (dd, J=6.63,1.56 Hz, 1 H), 7.14 (t, J=6.63 Hz, 1 H), 7.91 (dd, J=7.60, 1.56 Hz, 1 H), 7.98 (dd, J=4.78, 1.66 Hz, 1 H). MS-APCI (m/z): 315 (M+H).

Te/t-butyl 4-(2-(2-chloro-6-methoxyphenoxy)pyridin-3-yl)-5,6- dihydropyridine-1 (2H)-carboxylate:

Using General Procedure B, 3-bromo-2-(2-chloro-6- methoxyphenoxy)pyridine (280 mg, 0.89 mmol) was reacted with tert-butyl 4- (5,5-dimethyl-1 ,3,2-dioxaborinan-2-yl)-5,6-dihydropyridine-1 (2H)-carboxylate (330 mg, 1.07 mmol), cesium fluoride (203 mg, 1.34 mmol) and [1 , 1 '-Bis (diphenylphosphino)ferrocene] palladium (II) (14.5 mg, 0.018 mmol) in N, N- dimethylformamide (4 ml) to afford the desired product as a solid (180 mg, 49%). ¹H NMR (400 MHz, CDCI₃) δ 2.61 - 2.73 (m, 2 H), 3.57 - 3.67 (m, 2 H), 3.73 (s, 3 H), 4.04 - 4.13 (m, 2 H), 6.02 - 6.07 (m, 1 H), 6.89 (dd, J=8.19, 1.56 Hz, 1 H), 6.93 (dd, J=7.41 , 4.87 Hz, 1 H), 7.05 (dd, J=8.19, 1.56 Hz, 1 H), 7.12 (t, J=8.19 Hz, 1 H), 7.54 (dd, J=7.41 , 1.95 Hz, 1 H), 7.93 (dd, J=4.87, 1.95 Hz, 1 H). MS-APCI (m/z): 417 (M+H), 317 (M+H-100).

7erf-butyl 4-(2-(2-chloro-6-methoxyphenoxy)pyridin-3- yl)piperidine-1 -carboxylate:

Using General Procedure C, tert-butyl 4-(2-(2-chloro-6- methoxyphenoxy)pyridin-3-yl)-5,6-dihydropyridine-1 (2H)-carboxylate (180 mg, 0.432 mmol) was reduced to the desired product as glass (180 mg, quant). ¹H NMR (400 MHz, CDCI₃) δ 1.49 (s, 9 H) 1.57 - 1.72 (m, 4 H), 2.01 - 2.12 (m, 2 H), 2.80 - 2.95 (m, 2 H), 3.21 (tt, J=12.09, 3.31 Hz, 1 H), 6.87 - 6.97 (m, 2 H), 7.07 (dd, J=8.19, 1.56 Hz,1 H), 7.13 (t, J=8.19 Hz,1 H), 7.52 (dd, J=7.41 , 1.36 Hz, 1 H), 7.91 (dd, J=4.97, 1.85 Hz, 1 H). MS-APCI (m/z): 419 (M+H), 319 (M+H-100).

2-(2-Chloro-6-methoxyphenoxy)-3-(piperidin-4-yl)pyridine hydrochloride salt:

Using General Procedure D, terf-butyl 4-(2-(2-chloro-6- methoxyphenoxy)pyridin-3-yl)piperidine-1 -carboxylate (200 mg, 0.477 mmol) was reacted with acetyl chloride (0.679 ml, 9.55 mmol) in methanol (5 ml) to afford the desired product as a solid (100 mg, 59%). ¹H NMR (400 MHz, CD₃OD) δ 2.00-2.20 (m, 4 H), 3.29 (dt, J=3.27, 1.58 Hz, 2 H), 3.35 (m, 1 H), 3.51 (d, J=3.2 Hz, 2 H), 3.71 (s, 3 H), 7.00-7.10 (m, 3H), 7.21 (t, J=3.2 Hz, 1 H), 7.70 (t, 3.2 Hz, 1 H) 7.82 (m, 1 H). MS-APCI (m/z): 319 (M+H).

Example #13 3-Bromo-2-(2,3-dichlorophenoxy)pyridine:

Using General Procedure A, 3-bromo-2-chloro pyridine (1.5 g, 7.79 mmol) was reacted with 2,3-dichlorophenol (1.78 g, 10.9 mmol) and potassium carbonate (2.37 g, 17.1 mmol) in Λ/,Λ/-dimethylformamide (7.79 ml) to afford the desired product as a solid (1.2 g, 48%). MS-APCI (m/z): 319 (M+H).

7eιf-butyl 4-(2-(2,3-dichlorophenoxy)pyridin-3-yl)-5,6- dihydropyridine-1(2H)-carboxylate:

Using General Procedure B, 3-bromo-2-(2,3-dichlorophenoxy)pyridine (324 mg, 1.02 mmol) was reacted with tert-butyl 4-(5,5-dimethyl-1 ,3,2- dioxaborinan-2-yl)-5,6-dihydropyridine-1 (2H)-carboxylate (377 mg, 1.22 mmol), cesium fluoride (463 mg, 3.05 mmol) and [1 , 1 '-Bis (diphenylphosphino)ferrocene] palladium (II) (119 mg, 0.163 mmol) in N, N- dimethylformamide (2.5 ml) to afford the desired product as a solid (428 mg, 58%). ¹H NMR (400 MHz, CDCI₃) δ 1.47 (s, 9 H), 2.57 - 2.66 (m, 2 H), 3.56 - 3.66 (m, 2 H), 4.04 - 4.12 (m, 2 H), 5.98 - 6.04 (m, 1 H), 6.99 (dd,

, 4.97 Hz, 1 H), 7.09 (dd, Λ=8.09, 1.46 Hz, 1 H), 7.23 (t, J=8.19 Hz, 1 H), 7.33 (dd, J=8.19, 1.56 Hz, 1 H), 7.58 (dd, J=7.41 , 1.95 Hz, 1 H), 7.97 (dd, ^4.87, 1.75 Hz, 1 H). MS-APCI (m/z): 421 (M+H)

Terf-butyl 4-(2-(2,3-dichlorophenoxy)pyridin-3-yl)piperidine-1 - carboxylate:

Using General Procedure C, tert-butyl 4-(2-(2,3- dichlorophenoxy)pyridin-3-yl)-5,6-dihydropyridine-1 (2H)-carboxylate (246 mg, 0.584 mmol) was reduced to the desired product (244 mg, 99%). MS-APCI (m/z): 423 (M+H).

2-(2,3-Dichlorophenoxy)-3-(piperidin-4-yl)pyridine hydrochloride salt:

Using General Procedure D, tert-butyl 4-(2-(2,3- dichlorophenoxy)pyridin-3-yl)piperidine-1 -carboxylate (244 mg, 0.576 mmol) was reacted with acetyl chloride (0.41 ml, 5.76 mmol) in methanol (5 ml) then purified with ion exchange column followed by silica gel chromatography to afford the desired product as gum (111 mg, 60%). ¹H NMR (400 MHz, CDCI₃) δ 1.61 - 1.78 (m, 2 H), 1.95 - 2.02 (m, 2 H), 2.80 (dt, J=12.28, 2.53 Hz, 2H),

3.13 (tt, J=12.16, 3.46 Hz, 1 H), 3.22 (dt, J=11.82, 3.12 Hz, 2 H), 6.98 (dd, J=7.41 , 4.87 Hz, 1 H), 7.21 - 7.25 (m, 2 H), 7.32 (dd, J=7.99, 1.56 Hz, 1 H),

7.60 (dd, J=7.41 , 1.75 Hz, 1 H), 7.92 (dd, J=4.97, 1.85 Hz, 1 H). MS-APCI

(m/z): 323 (M+H).

Example #14 3-Bromo-2-(2,4-dichlorophenoxy)pyridine:

Using General Procedure A, 3-bromo-2-chloro pyridine (1.50 g, 7.79 mmol) was reacted with 2,4-dichlorophenol (1.78 g, 10.9 mmol) and potassium carbonate (2.37 g, 17.1 mmol) in Λ/,Λ/-dimethylformamide (7.79 ml) to afford the desired product as a solid (1.49 g, 60%). ¹H NMR (400 MHz, CDCI₃) δ 6.90 (dd, J=7.60, 4.87 Hz, 1 H), 7.17 (d, J=8.77 Hz, 1 H), 7.29 (dd, J=8.58, 2.53 Hz, 1 H), 7.47 (d, J=2.34 Hz, 1 H), 7.93 (dd, J=7.70, 1.66 Hz, 1 H), 8.00 (dd, J=4.87, 1.75 Hz, 1 H). MS-APCI (m/z): 319 (M+H).

Te/t-butyl 4-(2-(2,4-dichlorophenoxy)pyιϊdin-3-yl)-5,6- dihydropyridine-1(2H)-carboxylate:

Using General Procedure B, 3-bromo-2-(2,4-dichlorophenoxy)pyridine (300 mg, 0.940 mmol) was reacted with tert-butyl 4-(5,5-dimethyl-1 ,3,2- dioxaborinan-2-yl)-5,6-dihydropyridine-1 (2H)-carboxylate (349 mg, 1.13 mmol), cesium fluoride (429 mg, 2.82 mmol) and [1 , 1'-Bis (diphenylphosphino)ferrocene] palladium (II) (110 mg, 0.150 mmol) in N₁N- dimethylformamide (2.35 ml) to afford the desired product as a solid (221 mg, 56%). ¹H NMR (400 MHz, CDCI₃) δ 1.48 (s, 9 H), 2.57 - 2.66 (m, 2 H), 3.62 (t, J=5.65 Hz, 2 H), 4.08 (q, J=2.53 Hz, 2 H), 5.97 - 6.03 (m, 1 H), 6.99 (dd, ^7.41 , 4.87 Hz, 1 H), 7.11 (d, J=8.77 Hz, 1 H), 7.26 (dd, J=8.77, 2.53 Hz, 1 H), 7.45 (d, J=2.34 Hz, 1 H), 7.57 (dd, J=7.31 , 1.85 Hz, 1 H), 7.97 (dd, J=4.87, 1.95 Hz, 1 H). MS-APCI (m/z): 421 (M+H).

Terf-butyl 4-(2-(2,4-dichlorophenoxy)pyridin-3-yl)piperidine-1 - carboxylate:

Using General Procedure C, tert-butyl 4-(2-(2,4- dichlorophenoxy)pyridin-3-yl)-5,6-dihydropyridine-1 (2H)-carboxylate (171 mg, 0.406 mmol) was reduced to the desired product as glass (160 mg, 93%). MS-APCI (m/z): 423 (M+H). 2-(2,4-Dichlorophenoxy)-3-(piperidin-4-yl)pyridine hydrochloride salt:

Using General Procedure F, te/f-butyl 4-(2-(2,4- dichlorophenoxy)pyridin-3-yl)piperidine-1 -carboxylate (171 mg, 0.404 mmol) was reacted with HCI solution (8 ml) in methanol (3 ml) to afford the desired product as a solid (21 mg, 14%). ¹H NMR (400 MHz, DMSO-dfe) δ 1.91 - 2.03

(m, 2 H), 2.02 - 2.13 (m, 2 H), 3.01 - 3.15 (m, 2 H), 3.19 - 3.30 (m, 2 H), 3.33 -

3.38 (m, 1 H), 7.16 (dd, J=7.41 , 4.87 Hz, 1 H), 7.36 (d, J=8.77 Hz, 1 H), 7.50 (dd, J=8.77, 2.53 Hz, 1 H), 7.73 (dd, J=7.51 , 1.66 Hz, 1 H), 7.78 (d, J=2.53

Hz, 1 H), 7.95 (dd, J=4.87, 1.75 Hz, 1 H). MS-APCI (m/z): 323 (M+H).

Example #15 3-Bromo-2-(2-fluoro-4-methylphenoxy)pyridine:

Using General Procedure A, 3-bromo-2-chloropyridine (3.0 g, 15.6 mmol) was reacted with 2-fluoro-4-methylphenol (1.97 g, 15.6 mmol) and potassium carbonate (3.65 g, 23.4 mmol) in Λ/,/V-dimethylformamide (15 ml) to afford the desired product as glass (3.3 g, 75%). ¹H NMR (400 MHz, CDCI₃) δ 2.36 (s, 3 H), 6.87 (dd, J=7.70, 4.78 Hz, 1 H), 6.93 - 7.03 (m, 2 H), 7.11 (t, J=8.58 Hz, 1 H), 7.90 (dd, J=7.60, 1.75 Hz, 1 H), 8.02 (dd, J=4.87, 1.75 Hz, 1 H). MS-APCI (m/z): 283 (M+H).

Tert-butyl 4-(2-(2-fluoro-4-methylphenoxy)pyridin-3-yl)-5,6- dihydropyridine-1(2H)-carboxylate:

Using General Procedure B, 3-bromo-2-(2-fluoro-4- methylphenoxy)pyridine (3.3 g, 1.7 mmol) was reacted with tert-butyl 4-(5,5- dimethyl-1 ,3,2-dioxaborinan-2-yl)-5,6-dihydropyridine-1 (2H)-carboxylate (3.68 g, 11.9 mmol), cesium fluoride (2.26 g, 14.9 mmol) and [1 , 1'-Bis

(diphenylphosphino)ferrocene] palladium (II) (162 mg, 0.199 mmol) in N, N- dimethylformamide (20 ml) to afford the desired product as gum (2.6 g, 58%).

¹H NMR (400 MHz, CDCI₃) δ 1.46 (s, 9 H), 2.33 (s, 3 H), 2.55 - 2.64 (m, 2 H),

3.61 (t, J=5.65 Hz, 2 H), 4.03 - 4.12 (m, 2 H), 5.94 - 6.02 (m, 1 H), 6.92 - 7.01 (m, 3 H), 7.06 (t, J=8.58 Hz, 1 H), 7.54 (dd, J=7.31 , 1.85 Hz, 1 H), 7.99 (dd,

J=4.97, 1.85 Hz, 1 H). MS-APCI (m/z): 385 (M+H), 285 (M+1-100).

Terf-butyl 4-(2-(2-fluoro-4-methylphenoxy)pyridin-3-yl)piperidine- 1-carboxylate:

Using General Procedure C, te/t-butyl 4-(2-(2-fluoro-4- methylphenoxy)pyridin-3-yl)-5,6-dihydropyridine-1 (2H)-carboxylate (1.5 g, 3.9 mmol) was reduced to the desired product as gum (1.18 g, 78%). ¹H NMR (400 MHz, CDCI₃) δ 1.45 (s, 9 H), 1.53 - 1.72 (m, 2 H), 1.91 - 2.01 (m, 2 H), 2.34 (s, 3 H), 2.75 - 2.95 (m, 2 H), 3.14 (tt, J=12.28, 3.51 Hz, 1 H), 4.11 - 4.40 (m, 2 H), 6.90 - 7.01 (m, 3 H), 7.07 (t, J=7.99 Hz, 1 H), 7.51 (dd, J=7.21 , 1.56 Hz, 1 H), 7.94 (dd, J=4.87, 1.75 Hz 1 H). MS-APCI (m/z+): 387 (M+H), 287 (M+1-100).

2-(2-Fluoro-4-methylphenoxy)-3-(piperidin-4-yl)pyrϊdine hydrochloride salt:

Using General Procedure D, tert-butyl 4-(2-(2-fluoro-4- methylphenoxy)pyridin-3-yl)piperidine-1 -carboxylate (1.2 g, 2.9 mmol) was reacted with acetyl chloride (4.1 ml, 58 mmol) in methanol (50 ml) to afford the desired product as a solid (830 mg, 89%). ¹H NMR (400 MHz, CD₃OD) δ 2.07 (td, J=13.01 , 3.61 Hz, 2 H), 2.22 (d, J=1.75 Hz, 2 H), 2.35 (s, 3 H), 3.18 (td, J=13.06, 3.12 Hz, 2 H), 3.29 (dt, J=3.27, 1.58 Hz, 1 H), 3.52 (dd, J=10.62, 1.85 Hz, 2 H), 7.00 - 7.11 (m, 4 H), 7.73 (dd, J=7.51 , 1.85 Hz, 1 H), 7.89 (dd, J=4.97, 1.85 Hz, 1 H). MS-APCI (m/z+): 287 (M+H). Example #16

Terf-butyl 4-(2-(2-ethoxy-6-fluorophenoxy)pyridin-3-yl)-5,6- dihydropyridine-1(2H)-carboxylate:

Using General Procedure A, reaction of 3-bromo-2-chloropyridine (600 mg, 3.12 mmol), 2-ethoxy-6-fluorophenol (445 mg, 3.12 mmol) and potassium carbonate (862 mg, 6.24 mmol) in Λ/,Λ/-dimethylformamide (2.60 ml) afforded

3-bromo-2-(2-ethoxy-6-fluorophenoxy)pyridine as a solid (800 g, 86%). Then using General Procedure B, reaction of 3-bromo-2-(2-ethoxy-6- fluorophenoxy)pyridine (348 mg, 1.12 mmol) with te/f-butyl 4-(5,5-dimethyl- 1 ,3,2-dioxaborinan-2-yl)-5,6-dihydropyridine-1 (2H)-carboxylate (414 mg, 1.34 mmol), cesium fluoride (508 mg, 3.34 mmol) and [1 , 1'-Bis

(diphenylphosphino)ferrocene] palladium (II) (130 mg, 0.178 mmol) in N₁N- dimethylformamide (2.79 ml) afforded the desired product as an oil (208 mg, 45%). ¹H NMR (400 MHz, CDCI₃) δ 1.15 (t, J=7.02 Hz, 3 H), 1.47 (s, 9 H), 2.59 - 2.70 (m, 2 H), 3.61 (t, J=5.36 Hz, 2 H), 3.95 (q, J=7.02 Hz, 2 H), 4.02 - 4.10 (m, 2 H), 5.94 - 6.04 (m, 1 H), 6.68 - 6.82 (m, 2 H), 6.91 (dd, Λ=7.31 , 4.97 Hz, 1 H), 7.06 (ddd_f J=B.A3, 6.14 Hz, 1 H), 7.51 (dd, J=7.31 , 1.85 Hz, 1 H), 7.94 (dd, J=4.87, 1.95 Hz, 1 H). MS-APCI (m/z): 415 (M+H).

2-(2-Ethoxy-6-fluorophenoxy)-3-(piperidin-4-yl)pyridine trifluoroacetic acid salt:

Using General Procedure C, reaction of te/t-butyl 4-(2-(2-ethoxy-6- fluorophenoxy)-pyridin-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (244 mg,

0.589 mmol) afforded te/t-butyl 4-(2-(2-ethoxy-6-fluorophenoxy)pyridin-3- yl)piperidine-1-carboxylate as an oil (220 mg, 90%). Then using General

Procedure D, te/t-butyl 4-(2-(2-ethoxy-6-fluorophenoxy)pyridin-3-yl)piperidine-

1 -carboxylate (139 mg, 0.334 mmol) was reacted with acetyl chloride (26.2 mg, 0.334 mmol) in methanol (2 ml) then purified by HPLC with 0.025% trifluoroacetic acid to afford the desired product as a solid (73 mg, 46%). ¹H

NMR (400 MHz, CD₃OD) δ 1.10 (t, J=6.92 Hz, 3 H), 2.01 - 2.18 (m, 2 H), 2.23

- 2.27 (m, 2 H), 3.11 - 3.24 (m, 2 H), 3.25 - 3.43 (m, 2 H), 3.46 - 3.58 (m, 2

H), 3.95 (q, J=6.89 Hz, 2 H), 6.74 - 6.91 (m, 2 H), 7.05 (dd, J=7.31 , 4.97 Hz, 1 H), 7.04 - 7.18 (m, 1 H), 7.70 (d, J=7.41 Hz, 1 H), 7.84 (d, J=3.31 Hz, 1 H).

MS-APCI (m/z): 318 (M+H).

Example #17 te/t-butyl 4-(2-(4-fluoro-2-methoxyphenoxy)pyridin-3-yl)-5,6- dihydropyridine-1(2H)-carboxylate:

Using General Procedure A, reaction of 3-bromo-2-chloropyridine (600 mg, 3.12 mmol), 2-methoxy-4-fluorophenol (443 mg, 3.12 mmol) and potassium carbonate (862 mg, 6.24 mmol) in Λ/,Λ/-dimethylformamide (3 ml) afforded 3-bromo-2-(4-fluoro-2-methoxyphenoxy)pyridine as a solid (750 mg, 81 %). Then using General Procedure B, 3-bromo-2-(4-fluoro-2- methoxyphenoxy)pyridine (460 mg, 1.54 mmol) was reacted with te/t-butyl 4- (5,5-dimethyl-1 ₎3,2-dioxaborinan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (573 mg, 1.85 mmol), cesium fluoride (703 mg, 4.63 mmol) and [1 , 1 '-Bis (diphenylphosphino)ferrocene] palladium (II) (181 mg, 0.247 mmol) in N, N- dimethylformamide (3.86 ml) to afford the desired product (313 mg, 51 %). ¹H NMR (400 MHz, CDCI₃) δ 1.46 (s, 9 H), 2.54 - 2.64 (m, 2 H), 3.60 (t, J=5.36 Hz, 2 H), 3.66 (s, 3 H), 4.06 (d, J=2.53 Hz, 2 H), 5.94 - 6.01 (m, 1 H), 6.83 - 6.89 (m, 3 H), 6.93 (dd, J=7.31 , 4.97 Hz, 1 H), 7.53 (dd, J=7.31 , 1.85 Hz, 1 H), 7.96 (dd, J=4.87, 1.95 Hz, 1 H). MS-APCI (m/z): 401 (M+H), 301 (M+H- 100).

Tert-butyl 4-(2-(4-fluoro-2-methoxyphenoxy)pyridin-3- yl)piperidine-1-carboxylate:

Using General Procedure C, te/t-butyl 4-(2-(4-fluoro-2- methoxyphenoxy)pyridin-3-yl)-5,6-dihydropyridine-1 (2H)-carboxylate (189 mg, 0.472 mmol) was reduced to the desired product as oil (144 mg, 76%). ¹H NMR (400 MHz, CD₃OD) δ 2.03 - 2.32 (m, 4 H), 3.20 (d, J=5.07 Hz, 2 H), 3.41 - 3.52 (m, 1 H), 3.55 (d, J=11.89 Hz, 2 H), 3.72 (s, 3 H), 7.09 - 7.19 (m, 1 H), 7.17 - 7.30 (m, 2 H), 7.45 - 7.56 (m, 1 H), 8.08 (d, J=4.87 Hz, 1 H), 8.26 - 8.36 (m, 1 H).

2-(4-Fluoro-2-methoxyphenoxy)-3-(piperidin-4-yl)pyridine:

Using General Procedure D, te/f-butyl 4-(2-(4-fluoro-2- methoxyphenoxy)pyridin-3-yl)piperidine-1-carboxylate (76.9 mg, 0.191 mmol) was reacted with acetyl chloride (15 mg, 0.191 mmol) in methanol (2 ml) to afford the desired product as a solid (65 mg, quant). ¹H NMR (400 MHz, CD₃OD) δ 2.05 (dq, J=13.69, 4.15 Hz, 2 H), 2.19 - 2.29 (m, 2 H), 3.19 (td, J=12.96, 2.70 Hz, 2 H), 3.28 - 3.39 (m, 1 H), 3.48 - 3.57 (m, 2 H), 3.65 (s, 3 H), 6.93 - 7.01 (m, 2 H), 7.03 - 7.11 (m, 2 H), 7.72 (d, J=6.22 Hz, 1 H), 7.88 (dd, J=4.98, 2.07 Hz, 1 H). MS-APCI (m/z): 303 (M+H).

Tert-butyl 4-(2-(2-ethyl-4-fluorophenoxy)pyridin-3-yl)-5,6- dihydropyridine-1 (2H)-carboxylate:

Using General Procedure A, reaction of 3-bromo-2-chloro pyridine (600 mg, 3.12 mmol), 2-ethyl-4-fluorophenol (437 mg, 3.12 mmol) and potassium carbonate (826 mg, 6.24 mmol) in Λ/,Λ/-dimethylformamide (3 ml) afforded 3- bromo-2-(2-ethyl-4-fluorophenoxy)pyridine as an oil (778 mg, 84%). Then using General Procedure B, 3-bromo-2-(2-ethyl-4-fluorophenoxy)pyridine (250 mg, 0.844 mmol) was reacted with te/t-butyl 4-(5,5-dimethyl-1 ,3,2- dioxaborinan-2-yl)-5,6-dihydropyridine-1 (2H)-carboxylate (313 mg, 1.01 mmol), cesium fluoride (385 mg, 2.53 mmol) and [1 , 1 '-Bis (diphenylphosphino)ferrocene] palladium (II) (98.8 mg, 0.135 mmol) in N,N- dimethylformamide (2.11 ml) to afford the desired product as a solid (221 mg, 66%). ¹H NMR (400 MHz, CDCI₃) δ 1.13 (t, J=7.60 Hz, 3 H), 1.48 (s, 9 H), 2.50 (q, J=7.60 Hz, 2 H), 2.55 - 2.63 (m, 2 H), 3.61 (t, J=5.56 Hz, 2 H), 4.08 (d, J=2.14 Hz, 2 H), 5.93 - 5.99 (m, 1 H), 6.87 - 7.01 (m, 4 H), 7.54 (dd, J=7.41 , 1.95 Hz, 1 H), 7.98 (dd, J=4.87, 1.95 Hz, 1 H). MS-APCI (m/z+): 399 (M+H).

2-(2-Ethyl-4-fluorophenoxy)-3-(piperidin-4-yl)pyridine trifluoroacetic acid salt:

Using General Procedure C, reaction of te/t-butyl 4-(2-(2-ethyl-4- fluorophenoxy)pyridin-3-yl)-5,6-dihydropyridine-1 (2H)-carboxylate (224 mg, 0.562 mmol) afforded fe/t-butyl 4-(2-(2-ethyl-4-fluorophenoxy)pyridin-3- yl)piperidine-1-carboxylate as oil (186 mg, 83%). Then using General Procedure D, tert-butyl 4-(2-(2-ethyl-4-fluorophenoxy)pyridin-3-yl)piperidine-1- carboxylate (146 mg, 0.365 mmol) was reacted with acetyl chloride (28.6 mg, 0.365 mmol) in methanol (2 ml) then purified with HPLC with 0.025% trifluoroacetic acid to afford the desired product as oil (103 mg, 63%). ¹H NMR (400 MHz, CD₃OD) δ 1.15 (t, J=7.67 Hz, 3 H), 2.07 (qd, J=13.27, 3.32 Hz, 2 H), 2.17 - 2.28 (m, 2 H), 2.52 (q, J=7.46 Hz, 2 H), 3.20 (td, J=13.06, 2.90 Hz, 2 H), 3.36 (tt, J=12.18, 3.42, 3.32 Hz, 1 H), 3.51 - 3.58 (m, 2 H), 6.93 - 6.99 (m, 2 H), 7.04 - 7.12 (m, 2 H), 7.75 (dd, J=7.46, 1.66 Hz, 1 H), 7.90 (dd, J=4.98, 1.66 Hz, 1 H). MS-APCI (m/z): 301 (M+H). Example #19

2-Fluoro-6-methylphenol:

To a solution of 3-fluoro-2-hydroxybenzaldehyde (5.84 g, 41.7 mmol) in methanol (60 ml_) was added 10% palladium in charcoal (4.4 g, 4.2 mmol) and the mixture was hydrogenated at 60 psi for 3 h. The mixture was filtered through a pad of Celite and the filtrate was evaporated. The crude was purified by flash column chromatography using 5% ethyl acetate in hexanes to obtain the desired product (2.89 g, 55%). ¹H NMR (400 MHz, CDCI₃) δ 6.99- 6.73 (m, 3H), 5.12 (d, 1 H), 2.26 (s, 3H). ¹⁹F NMR (400 MHz, CDCI₃) δ -143

(S). 3-Bromo-2-(2-fluoro-6-methylphenoxy) pyridine:

Using General Procedure A', 3-bromo-2-chloropyridine (1.39 g, 7.21 mmol) was reacted with 2-fluoro-6-methylphenol (1.00 g, 7.93 mmol) and cesium carbonate (3.56 g, 10.8 mmol) in dimethyl sulfoxide (8 ml) to afford the desired product (1.93 g, 90%).¹H NMR (400 MHz, CDCI₃): δ 8.02 (dd, 1 H), 7.96 (dd, 1 H), 7.18-6.84 (m, 4H), 2.21 (s, 3H). ¹⁹F NMR (400 MHz, CDCI₃) δ - 129 (S). ES-MS m/z 281.94 [M+1]+. re/t-butyl 4-(2-(2-fluoro-6-methylphenoxy)pyridin-3-yl)-5,6- dihydropyridine-1(2H)-carboxylate:

Using General Procedure B, 3-bromo-2-(2-fluoro-6- methylphenoxy)pyridine (2.5 g, 8.9 mmol) was reacted with te/t-butyl 4-(5,5- dimethyl-1 ,3,2-dioxaborinan-2-yl)-5,6-dihydropyridine-1 (2H)-carboxylate (3.15 g, 10.67 mmol), cesium fluoride (2.03 g, 13.34 mmol) and [1 , 1 '-Bis (diphenylphosphino)ferrocene] palladium (II) (0.98 g, 1.33 mmol) in N,N- dimethylformamide (15 ml) to afford the desired product (2.09 g, 62%).¹H NMR (400 MHz, CDCI₃) δ 7.99 (dd, 1 H), 7.58 (dd, 1 H), 7.15-6.92 (m, 4H), 5.99 (s, 1 H), 4.18-4.07 (br s, 2H), 3.73-3.58 (br s, 2H), 2.66-2.54 (br s, 2H), 2.21 (s, 3H), 1.44 (s, 9H). ¹⁹F NMR (400 MHz, CDCI₃) δ -130 (s).

Terf-butyl 4-(2-(2-fluoro-6-methylphenoxy)pyridin-3-yl)piperidine- 1-carboxylate:

Using General Procedure C, tert-butyl 4-(2-(2-fluoro-6- methylphenoxy)pyridin-3-yl)-5,6-dihydropyridine-1 (2H)-carboxylate (2 g, 5.21 mmol) was reduced to the desired product (1.83 g, 92%). ¹H NMR (400 MHz, CDCI₃) δ 7.99 (dd, 1 H), 7.58 (dd, 1 H), 7.19-6.91 (m, 4H), 4.43-4.17 (br s, 2H), 3.22-3.11 (m, 1 H), 2.99-2.73 (br s, 2H), 2.21 (s, 3H), 1.98 (d, 2H), 1.81-1.58 (m, 2H), 1.44 (s, 9H). ¹⁹F NMR (400 MHz, CDCI₃) δ -130 (s).

2-(2-Fluoro-6-methylphenoxy)-3-(piperidin-4-yl)pyridine dihydrochloride:

Using General Procedure D, terf-butyl 4-(2-(2-fluoro-6- methylphenoxy)pyridin-3-yl)piperidine-1-carboxylate (1.8 g, 4.7 mmol) was reacted with acetyl chloride (6.7 ml_, 94 mmol) in methanol (50 ml) to afford the desired product (1.51 g, 95%). ¹H NMR (400 MHz, CD₃OD) δ 7.92 (dd,

1 H), 7.78 (dd, 1 H), 7.19-6.98 (m, 4H), 3.58 (d, 2H), 3.42-3.34 (m, 1 H), 3.19 (t, 2H)₁ 2.31-2.04 (m, 7H). ¹⁹F NMR (400 MHz, CD₃OD) δ -133 (s). ES-MS m/z 287.11 [M+1]⁺. CHN calculated for C₁₇H₁₉FN₂CI .5HCI.0.17H2O: C 59.35 %; H 6.10 %; N 8.14 %, and found: C 59.41 %; H 6.22 %; N 8.15 %.

Example #20 3-Bromo-2-(2-fluoro-4-methoxyphenoxy)pyridine:

Using General Procedure A, 3-bromo-2-chloropyridine (500 mg, 2.60 mmol) was reacted with 2-fluoro-4-methoxylphenol (443 mg, 3.12 mmol) and potassium carbonate (718 mg, 5.20 mmol) in Λ/,Λ/-dimethylformamide (5 ml) to afford the desired product as a solid (685 mg, 88%). 1 H NMR (400 MHz, CDCI₃) δ 3.80 (s, 3 H,) 6.66 - 6.77 (m, 2 H), 6.86 (dd, J=7.70, 4.78 Hz, 1 H), 7.14 (t, J=8.77 Hz, 1 H), 7.90 (dd, J=7.70, 1.66 Hz, 1 H)₁ 8.02 (dd, J=4.78, 1.66 Hz, 1 H). MS-APCI (m/z): 299 (M+H).

Teit-butyl 4-(2-(2-fluoro-4-methoxyphenoxy)pyridin-3-yl)-5,6- dihydropyridine-1 (2H)-carboxylate:

Using General Procedure B, 3-bromo-2-(2-fluoro-4- methoxyphenoxy)pyridine (580 mg, 1.95 mmol) was reacted with tert-butyl 4- (5,5-dimethyl-1 ,3,2-dioxaborinan-2-yl)-5,6-dihydropyridine-1 (2H)-carboxylate (686 mg, 2.33 mmol), cesium fluoride (887 mg, 5.84 mmol) and [1 , 1 '-Bis (diphenylphosphino)ferrocene] palladium (II) (285 mg, 0.389 mmol) in N₁N- dimethylformamide (10 ml) to afford the desired product as a solid (628 mg, 81 %). ¹H NMR (400 MHz, CDCI₃) δ 1.47 (s, 9 H), 2.56 - 2.64 (m, 2 H), 3.62 (t, J=5.46 Hz, 2 H), 3.79 (s, 3 H), 4.05 - 4.11 (m, 2 H)₁ 5.95 - 6.01 (m, 1 H), 6.66 - 6.76 (m, 2 H), 6.94 (dd, J=7.31 , 4.97 Hz, 1 H), 7.10 (t, J=8.77 Hz, 1 H), 7.54 (dd, J=7.31 , 1.85 Hz, 1 H), 7.99 (dd, J=4.97, 1.85 Hz, 1 H). rerf-butyl 4-(2-(2-fluoro-4-methoxyphenoxy)pyridin-3- yl)piperidine-1 -carboxylate:

Using General Procedure C, te/t-butyl 4-(2-(2-fluoro-4- methoxyphenoxy)pyridin-3-yl)-5,6-dihydropyridine-1 (2H)-carboxylate (610 mg,

1.52 mmol) was reduced to the desired product as a solid (190 mg, 31 %). ¹H

NMR (400 MHz, CDCI₃) δ 1.47 (s, 9 H), 1.56 - 1.70 (m, 2 H), 1.91 - 2.00 (m, 2

H), 2.78 - 2.92 (m, 2 H), 3.14 (tt, dd, J=12.09, 3.31 Hz, 1 H), 3.79 (s, 3 H),

4.16 - 4.40 (m, 2 H), 6.67 - 6.76 (m, 2 H), 6.93 (dd, J=7.41 , 4.87 Hz₁ 1 H), 7.10 (t, dd, J=8.77, 1 H), 7.50 (dd, J=7.41 , 1.17 Hz, 1 H), 7.94 (dd, J=4.97,

1.85 Hz, 1 H). MS-APCI (m/z): 403 (M+H).

2-(2-Fluoro-4-methoxyphenoxy)-3-(piperidin-4-yl)pyridine:

Using General Procedure D, te/f-butyl 4-(2-(2-fluoro-4- methoxyphenoxy)pyridin-3-yl)piperidine-1 -carboxylate (175 mg, 0.435 mmol) was reacted with acetyl chloride (341 mg, 4.35 mmol) in methanol (10 ml) then purified with ion exchange column to afford the desired product as a solid

(128 mg, 97%). ¹H NMR (400 MHz, CDCI₃) δ 1.62 - 1.74 (m, 2 H), 1.99 (dt,

J=13.26, 2.93 Hz, 2 H), 2.83 (dt, J=12.18, 2.53 Hz, 2 H), 3.15 (tt, J=12.09, 3.51 Hz, 1 H), 3.23 (dt, J= 11.70, 3.22 Hz, 2 H), 3.82 (s, 3 H), 6.69 - 6.80 (m, 2

H), 6.96 (dd, J=7.41 , 5.07 Hz, 1 H), 7.13 (t, J=8.58 Hz, 1 H), 7.57 (dd, J=7.41 ,

1.95 Hz, 1 H), 7.96 (dd, J=5.07, 1.95 Hz, 1 H). MS-APCI (m/z): 303 (M+H).

Example #21 3-Bromo-2-(2-chloro-6-fluorophenoxy)pyridine:

Using General Procedure A, 3-bromo-2-chloropyridine (3.0 g, 16 mmol) was reacted with 2-chloro-6-fluorophenol (2.28 g, 15.6 mmol) and potassium carbonate (3.23 g, 23.4 mol) in Λ/,Λ/-dimethylformamide (10 ml) to afford the desired product (1.5 g, 31%). ¹H NMR (400 MHz, CDCI₃): δ 8.01 (dd, 1 H), 7.96 (dd, 1 H), 7.30-7.10 (m, 3H), 6.93 (q, 1 H). ¹⁹F NMR (376 MHz, CDCI₃): δ - 125.25. ES-MS (m/z) for CnH₉BrCIFNO: 301.79, 303.81 [M+1]⁺.

Terf-butyl 4-(2-(2-chloro-6-fluorophenoxy)pyridin-3-yl)-5,6- dihydropyridine-1(2H)-carboxylate:

Using General Procedure B, 3-bromo-2-(2-chloro-6- fluorophenoxy)pyridine (1.45 g, 4.8 mmol) was reacted with te/f-butyl 4-(5,5- dimethyl-1 ,3,2-dioxaborinan-2-yl)-5,6-dihydropyridine-1 (2H)-carboxylate (1.7 g, 0.00575 mol), cesium fluoride (1.09 g, 7.2 mmol) and [1 , 1'-Bis (diphenylphosphino)ferrocene] palladium (II) (0.527 g, 0.72 mmol) in N₁N- dimethylformamide (10 ml) to afford the desired product (1.49 g, 82%). ¹H NMR (400 MHz, CDCI₃): δ 7.96 (dd, 1 H), 7.59 (dd, 1 H), 7.30-7.06 (m, 3H), 7.00 (q, 1 H), 6.05 (m, 1 H), 4.11 (br s, 2H), 3.65 (t, 2H), 2.66 (br s, 2H), 1.50 (s, 9H). ¹⁹F NMR (376 MHz, CDCI₃): δ -125.144. ES-MS (m/z) for C₂₁ H₂₂CIFN₂O₃: 404.95 [M+1 ]⁺.

Terf-butyl 4-(2-(2-chloro-6-fluorophenoxy)pyridin-3-yl)piperidine-1- carboxylate:

Using General Procedure C, te/f-butyl 4-(2-(2-chloro-6- fluorophenoxy)pyridin-3-yl)-5,6-dihydropyridine-1 (2H)-carboxylate (0.3 g, 0.7 mmol) was reduced to the desired product (0.29 g, 96 %). ¹H NMR (400 MHz, CDCI₃): δ 7.93 (dd, 1 H), 7.56 (dd, 1 H), 7.30-7.08 (m, 3H), 6.99 (q, 1 H), 4.30 (s, 2H), 3.79 (s, 3H), 3.20 (m, 1 H), 2.88 (br s, 2H), 2.04 (d, 2H), 1.67 (m, 2H), 1.49 (S, 9H). ¹⁹F NMR (376 MHz, CDCI₃): δ -125.452. ES-MS (m/z) for C_2IH₂₄CIFN₂O₃: 406.88 [M+1]⁺.

2-(2-Chloro-6-fluorophenoxy)-3-(piperidin-4-yl)pyridine hydrochloride:

Using General Procedure D, te/t-butyl 4-(2-(2-chloro-6- fluorophenoxy)pyridin-3-yl)piperidine-1-carboxylate (0.29 g, 0.713 mmol) was reacted with acetyl chloride (1 ml) in methanol (25 ml) to afford the desired product (0.20 g, 82%). ¹H NMR (400 MHz, CD₃OD): δ 7.90 (d, 1 H), 7.78 (d, 1 H), 7.37-7.18 (m, 3H), 7.13 (q, 1 H), 3.55 (d, 2H), 3.39 (m, 1 H), 3.25 (t, 2H), 2.27 (d, 2H), 2.13 (m, 2H). ¹⁹F NMR (376 MHz, CDCI₃): δ -127.996. ES-MS (m/z) for C₁₆H₁₆CIFN₂O: 306.96 [M+1]⁺. CHN calculated for C₁₆H₁₆CIFN₂O/1.4HCI: C 53.71 %; H 4.90 %; N 7.83 %, and found: C 53.87 %; H 5.14 %; N 7.69 %. Example #22

3-Bromo-2-(2,6-difluorophenoxy)pyridine:

Using General Procedure A, 3-bromo-2-chloropyridine (500 mg, 2.60 mmol) was reacted with 2,6-difluorophenol (406 mg, 3.12 mmol) and potassium carbonate (718 mg, 5.20 mmol) in Λ/,Λ/-dimethylformamide (5 ml) to afford the desired product as a solid (560 mg, 75%). ¹H NMR (400 MHz, CDCI₃) δ 6.91 (dd, J=7.60, 4.87 Hz, 1 H), 6.97 - 7.03 (m, 2 H), 7.15 - 7.20 (m, 1 H), 7.93 (dd, J=7.70, 1.66 Hz, 1 H), 8.00 (dd, J=4.78, 1.66 Hz, 1 H). MS- APCI (m/z+): 285 (M+H).

Tert-butyl 4-(2-(2,6-difluorophenoxy)pyridin-3-yl)-5,6- dihydropyridine-1 (2H)-carboxylate:

Using General Procedure B, 3-bromo-2-(2,6-difluorophenoxy)pyridine (480 mg, 1.47 mmol) was reacted with terf-butyl 4-(5,5-dimethyl-1 ,3,2- dioxaborinan-2-yl)-5,6-dihydropyridine-1 (2H)-carboxylate (520 mg, 1.76 mmol), cesium fluoride (669 mg, 4.40 mmol) and [1 , 1'-Bis (diphenylphosphino)ferrocene] palladium (II) (215 mg, 0.295 mmol) in N,N- dimethylformamide (10 ml) to afford the desired product as a solid (315 mg, 62%). ¹H NMR (400 MHz, CDCI₃) δ 1.48 (s, 9 H), 2.56 - 2.67 (m, 2 H), 3.63 (t, J=5.65 Hz, 2 H), 4.05 - 4.14 (m, 2 H), 5.98 - 6.05 (m, 1 H), 6.93 - 7.04 (m, 3 H), 7.09 - 7.19 (m, 1 H), 7.57 (dd, J=7.41 , 1.95 Hz, 1 H), 7.96 (dd, J=4.87, 1.75 Hz, 1 H).

Te/t-butyl 4-(2-(2,6-difluorophenoxy)pyridin-3-yl)piperidine-1- carboxylate:

Using General Procedure C, tert-butyl 4-(2-(2,6- difluorophenoxy)pyridin-3-yl)-5,6-dihydropyridine-1 (2H)-carboxylate (350 mg, 0.901 mmol) was reduced to the desired product as gum (99 mg, 28%). ¹H NMR (400 MHz, CDCI₃) δ 1.47 (s, 9 H), 1.57 - 1.71 (m, 2 H), 2.79 - 2.93 (m, 2 H), 3.17 (tl, J =12.28, 3.31 Hz, 1 H), 4.08 - 4.36 (m, 1 H), 6.95 - 7.04 (m, 3 H), 7.09 - 7.20 (m, 1 H), 7.53 (dd, J=7.12, 1.46 Hz, 1 H), 7.92 (dd, J=4.97, 1.85 Hz, 1 H). MS-APCI (m/z): 391 (M+H).

2-(2,6-Difluorophenoxy)-3-(piperidin-4-yl)pyridine:

Using General Procedure D, tert-butyl 4-(2-(2,6- difluorophenoxy)pyridin-3-yl)piperidine-1 -carboxylate (99 mg, 0.25 mmol) was reacted with acetyl chloride (0.180 ml, 2.54 mmol) in methanol (5 ml) then purified with ion exchange column to afford the desired product as a solid (67 mg, 91%). ¹H NMR (400 MHz, CDCI₃) δ 1.59 - 1.74 (m, 2 H), 1.98 - 2.01 (m, 2 H), 2.81 (dt, J=12.09, 2.34 Hz, 2 H), 3.14 (tt, ./=12.09, 3.51 Hz, 1 H), 3.20 - 3.23 (m, 2 H), 6.93 - 7.04 (m, 2 H), 7.08 - 7.18 (m, 1 H), 7.58 (dd, J=7.41 , 1.95 Hz, 1 H), 7.91 (dd, J=5.07, 1.95 Hz, 1 H). MS-APCI (m/z+): 291 (M+H).

Example #23

3-Bromo-2-(2,3-difluorophenoxy)pyridine:

Using General Procedure A, 3-bromo-2-chloro pyridine (5.91 g, 30.7 mmol) was reacted with 2,3-difluorophenol (4.2 g, 32 mmol) and potassium carbonate (8.5 g, 61 mmol) in Λ/,Λ/-dimethylformamide (20 ml) to afford the desired product (4.85 g, 56%).¹H NMR (400 MHz, CDCI₃): δ 8.05 (dd, 1 H), 7.96 (dd, 1 H), 7.18-6.09 (m, 4H). ¹⁹F NMR (400 MHz, CDCI₃) δ -136 (s), -152

(S).

Tert-butyl 4-(2-(2,3-difluorophenoxy)pyridin-3-yl)-5,6- dihydropyridine-1(2H)-carboxylate:

Using General Procedure B, 3-bromo-2-(2,3-difluorophenoxy)pyridine

(2.78 g, 9.72 mmol) was reacted with tert-butyl 4-(5,5-dimethyl-1 ,3,2- dioxaborinan-2-yl)-5,6-dihydropyridine-1 (2H)-carboxylate (3.4 g, 11.7 mmol), cesium fluoride (2.2 g, 14.6 mmol) and [1 , 1'-Bis (diphenylphosphino)ferrocene] palladium (II) (1.07 g, 1.45 mmol) in N,N- dimethylformamide (15 ml) to afford the desired product (2.72 g, 73%).¹H NMR (400 MHz, CDCI₃) δ 8.02 (dd, 1 H), 7.61 (dd, 1 H), 7.26-6.84 (m, 4H), 6.02 (s, 1 H), 4.21 -4.06 (br s, 2H), 3.73-3.57 (br s, 2H), 2.71 -2.54 (br s, 2H), 1.44 (s, 9H). ¹⁹F NMR (400 MHz, CDCI₃) δ -137 (s), -152 (s).

Te/f-butyl 4-(2-(2,3-dif luorophenoxy)pyridin-3-yl)piperϊdine-1 - carboxylate:

Using General Procedure C, tert-butyl 4-(2-(2,3- difluorophenoxy)pyridin-3-yl)-5,6-dihydropyridine-1 (2H)-carboxylate (2.69 g, 6.93 mmol) was reduced to the desired product (2.15 g, 80%). ¹H NMR (400 MHz, CDCI₃) δ 7.99 (dd, 1 H), 7.58 (dd, 1 H), 7.18-6.92 (m, 4H), 4.43-4.17 (br s, 2H), 3.19-3.07 (m, 1 H), 2.99-2.73 (br s, 2H), 1.98 (d, 2H)₁ 1.77-1.54 (m, 2H), 1.44 (s, 9H).

2-(2,3-Difluorophenoxy)-3-(piperidin-4-yl)pyridine dihydrochloride:

Using General Procedure D, te/t-butyl 4-(2-(2,3- difluorophenoxy)pyridin-3-yl)piperidine-1-carboxylate (2.0 g, 5.1 mmol) was reacted with acetyl chloride (7.3 ml_, 103 mmol) in methanol (50 ml) to afford the desired product (1.6 g, 89%). ¹H NMR (400 MHz, CD₃OD) δ 7.98 (dd, 1 H),

7.78 (dd, 1 H), 7.25-7.02 (m, 4H), 3.56 (d, 2H), 3.42-3.25 (m, 1 H), 3.19 (t, 2H),

2.28-1.99 (m, 4H). ¹⁹F NMR (400 MHz, CD₃OD) δ -140 (s), -156 (s). ES-MS (m/z) 291.01 [M+1]⁺. HPLC purity: 95.62%. CHN calculated for

Ci₆H₁₆F₂N₂O-1.7HCI: C 54.74 %; H 5.07 %; N 7.98 %, and found: C 54.93 %;

H 5.37 %; N 7.98 %.

Example #24 & 25

3-Bromo-2-(2-fluoro-6-methoxyphenoxy)pyridine:

Using General Procedure A, 3-bromo-2-chloropyridine (3 g, 0.0156 mol) was reacted with 2-fluoro-6-methoxyphenol (2.216 g, 0.0156 mol) and potassium carbonate (3.23 g, 0.0234 mol) in Λ/,Λ/-dimethylformamide (10 ml) to afford the desired product (1.0 g, 23 %). ¹H NMR (400 MHz, CDCI₃): δ 8.01 (del, 1 H), 7.92 (dd, 1 H), 7.17 (m, 1 H), 6.88 (q, 1 H)₁ 6.86-6.78 (m, 2H), 3.80 (s, 3H). ES-MS (m/z) for Ci₂H₉BrFNO₂: 297.82 & 299.77 [M+1]⁺.

7erf-butyl 4-(2-(2-fluoro-6-methoxyphenoxy)pyridin-3-yl)-5,6- dihydropyridine-1(2H)-carboxylate:

Using General Procedure B, 3-bromo-2-(2-fluoro-6- methoxyphenoxy)pyridine (1.0 g, 3.4 mmol) was reacted with tert-butyl 4-(5,5- dimethyl-1 ,3,2-dioxaborinan-2-yl)-5,6-dihydropyridine-1 (2H)-carboxylate (1.2 g, 4.0 mmol), cesium fluoride (0.763 g, 5.03 mmol) and [1 , 1 '-Bis (diphenylphosphino)ferrocene] palladium (II) (0.368 g, 0.503 mmol) in N₁N- dimethylformamide (10 ml) to afford the desired product (1.1 g, 82 %). ¹H NMR (400 MHz, CDCI₃): δ 7.98 (dd, 1 H), 7.56 (dd, 1 H), 7.15 (m, 1H), 6.95 (q, 1 H), 6.90-6.67 (m, 2H), 6.05 (s, 1 H), 4.10 (br s, 2H), 3.78 (s, 3H), 3.60 (br s, 2H), 2.65 (br s, 2H), 1.49 (s, 9H). ES-MS (m/z) for C₂₂H₂₅FN₂O₄: 401.11 [M+1]⁺.

Te/t-butyl 4-(2-(2-fluoro-6-methoxyphenoxy)pyridin-3- yl)piperidine-1 -carboxylate:

Using General Procedure C, fert-butyl 4-(2-(2-fluoro-6- methoxyphenoxy)pyridin-3-yl)-5,6-dihydropyridine-1 (2H)-carboxylate (1.1 g,

3.1 mol) was reduced to the desired product (1.1 g, 100 %). ¹H NMR (400

MHz, CDCI₃): δ 7.94 (dd, 1 H), 7.52 (dd, 1 H), 7.15 (m, 1 H), 6.95 (q, 1 H), 6.86- 6.78 (m, 2H), 4.27 (s, 2H), 3.79 (s, 3H), 3.20 (m, 1 H), 2.88 (br s, 2H), 2.04 (d, 2H), 1.64 (m, 2H), 1.48 (s, 9H). ES-MS (m/z) for C₂₂H₂₇FN₂O₄: 403.00 [M+1]⁺.

2-(2-Fluoro-6-methoxyphenoxy)-3-(piperidin-4-yl)pyridine dihydrochloride:

Using General Procedure D, tert-butyl 4-(2-(2-fluoro-6- methoxyphenoxy)pyridin-3-yl)piperidine-1 -carboxylate (1.1 g, 2.7 mmol) was reacted with acetyl chloride (4 ml_) in methanol (100 ml) to afford the desired product (0.70 g, 85%). ¹H NMR (400 MHz, CD₃OD): δ 7.88 (d, 1 H), 7.77 (d, 1 H), 7.23 (m, 1 H), 7.11 (q, 1 H), 6.94 (d, 1 H), 6.85 (t, 1 H), 3.75 (s, 3H), 3.55

(d, 2H), 3.37 (m, 1 H), 3.20 (t, 2H), 2.27 (d, 2H), 2.09 (m, 2H). ES-MS (m/z) for

Ci₇H₁₉FN₂O₂/2HCI: 302.99 [M+1]⁺. CHN calculated for Ci₇Hi₉FN₂O₂/2HCI: C

54.41 %; H 5.64 %; N 7.46 %, and found: C 54.80 %; H 5.60 %; N 7.66 %.

Alternatively, purification by HPLC with 0.025% trifluoroacetic acid afforded the desired product as the trifluoroacetate salt.

Example #26

3-Bromo-2-(2,5-difluorophenoxy)pyridine:

Using General Procedure A, 3-bromo-2-chloropyridine (4.7 g, 24.2 mmol) was reacted with 2,5-difluorophenol (3.47 g, 26.7 mmol) and potassium carbonate (6.7 g, 48.5 mmol) in /V,Λ/-dimethylformamide (20 ml) to afford the desired product (4.2 g, 62%).¹H NMR (400 MHz, CDCI₃): δ 8.05 (dd, 1 H), 7.96

(dd, 1 H), 7.18-6.09 (m, 4H). ES-MS m/z 287.74 [M+1]⁺. Te/t-butyl 4-(2-(2,5-difluorophenoxy)pyridin-3-yl)-5,6- dihydropyridine-1(2H)-carboxylate:

Using General Procedure B, 3-bromo-2-(2,5-difluorophenoxy)pyridine (2.0 g, 7.0 mmol) was reacted with te/t-butyl 4-(5,5-dimethyl-1 ,3,2- dioxaborinan-2-yl)-5,6-dihydropyridine-1 (2H)-carboxylate (2.5 g, 8.4 mmol), cesium fluoride (1.6 g, 10 mmol) and [1 , 1'-Bis (diphenylphosphino)ferrocene] palladium (II) (0.77 g, 1.1 mmol) in Λ/,Λ/-dimethylformamide (15 ml) to afford the desired product (2.1 g, 78%).¹H NMR (400 MHz, CDCI₃) δ 8.02 (dd, 1 H), 7.61 (dd, 1 H), 7.16-6.84 (m, 4H), 6.02 (s, 1 H), 4.18-4.03 (br s, 2H), 3.69-3.54

(br s, 2H), 2.64-2.56 (br s, 2H), 1.44 (s, 9H). ¹⁹F NMR (400 MHz, CDCI₃) δ -

118 (s), -134 (s).

Terf-butyl 4-(2-(2,5-dif luorophenoxy)pyridin-3-yl)piperidine-1 - carboxylate:

Using General Procedure C, te/t-butyl 4-(2-(2,5- difluorophenoxy)pyridin-3-yl)-5,6-dihydropyridine-1 (2H)-carboxylate (1.38 g, 3.53 mmol) was reduced to the desired product (1.34 g, 98%). ¹H NMR (400 MHz, CDCI₃) δ 7.99 (dd, 1 H), 7.58 (dd, 1 H), 7.18-6.83 (m, 3H), 4.24-4.11 (br s, 2H), 3.19-3.07 (m, 1 H), 2.99-2.76 (br s, 2H), 1.98 (d, 2H), 1.77-1.57 (m, 2H), 1.44 (s, 9H). ¹⁹F NMR (400 MHz, CDCI₃) δ -117 (s), -134 (s). 2-(2,5-Difluorophenoxy)-3-(piperidin-4-yl)pyridine dihydrochloride:

Using General Procedure D, tert-butyl 4-(2-(2,5- difluorophenoxy)pyridin-3-yl)piperidine-1-carboxylate (1.57 g, 4.02 mmol) was reacted with acetyl chloride (5.7 ml_, 80.5 mmol) in methanol (50 ml) to afford the desired product (1.21 g, 85%). ¹H NMR (400 MHz, CD₃OD) δ 7.98 (dd,

1 H)₁ 7.78 (dd, 1 H), 7.29-6.98 (m, 3H), 3.56 (d, 2H), 3.41 -3.25 (m, 1 H), 3.19 (t,

2H), 2.26-1.99 (m, 4H). ¹⁹F NMR (400 MHz, CD₃OD) δ -119 (s), -136 (s). ES-

MS (m/z) 290.95 [M+1]⁺. CHN calculated for C₁₆H₁₆F₂N₂O.2HCI: C 52.91 %; H 4.99 %; N 7.71 %, and found: C 52.60 %; H 5.07 %; N 7.50 %.

Example #27 3-Bromo-2-(2,4-difluorophenoxy)pyridine:

Using General Procedure A, 3-bromo-2-chloro pyridine (3.0 g, 16 mmol) was reacted with 2,4-difluorophenol (2.0 g, 16 mmol) and potassium carbonate (3.23 g, 23.4 mol) in Λ/,Λ/-dimethylformamide (10 ml) to afford the desired product (2.2 g, 48 %). ¹H NMR (400 MHz, CDCI₃): δ 8.05 (dd, 1 H), 7.96 (dd, 1 H), 7.26 (m, 1 H), 7.02-6.88 (m, 3H). ES-MS (m/z) for C₁₁H₆BrF₂NO: 285.78 & 287.80 [M+1]⁺. Te/t-butyl 4-(2-(2,4-difluorophenoxy)pyridin-3-yl)-5,6- dihydropyridine-1(2H)-carboxylate:

Using General Procedure B, 3-bromo-2-(2,4-difluorophenoxy)pyridine (1.91 g, 6.68 mmol) was reacted with tert-butyl 4-(5,5-dimethyl-1 ,3,2- dioxaborinan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (2.36 g, 8.01 mmol), cesium fluoride (1.52 g, 10.0 mmol) and [1 , 1'-Bis (diphenylphosphino)ferrocene] palladium (II) (0.73 g, 1.0 mmol) in N, N- dimethylformamide (15 ml) to afford the desired product (2.08 g, 80 %). ¹H NMR (400 MHz, CDCI₃): δ 8.01 (dd, 1 H), 7.59 (dd, 1 H), 7.18 (m, 1 H), 7.04- 6.86 (m, 3H), 6.00 (s, 1 H), 4.10 (br s, 2H), 3.64 (s, 3H), 2.61 (br s, 2H), 1.49 (s, 9H). ES-MS (m/z) for Chemical Formula: C₂IH₂₄F₂N₂O₃: 388.94 [M+1]⁺.

Te/f-butyl 4-(2-(2,4-dif luorophenoxy)pyridin-3-yl)piperidine-1 - carboxylate:

Using General Procedure C, te/t-butyl 4-(2-(2,4- difluorophenoxy)pyridin-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (2.0 g, 5.2 mmol) was reduced to the desired product (1.8 g, 90 %). ¹H NMR (400 MHz, CDCI₃): δ 7.95 (dd, 1 H), 7.54 (dd, 1 H), 7.19 (m, 1 H), 7.02-6.88 (m, 3H), 4.29 (s, 2H), 3.15 (m, 1 H), 2.87 (br s, 2H), 1.97 (d, 2H), 1.65 (m, 2H), 1.49 (s, 9H). ES-MS (m/z) for C₂i H₂₄F₂N₂O₃: 391.02 [M+1]⁺. 2-(2,4-Difluorophenoxy)-3-(piperidin-4-yl)pyridine hydrochloride:

Using General Procedure D, tert-butyl 4-(2-(2,4- difluorophenoxy)pyridin-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (1.8 g, 4.6 mmol) was reacted with acetyl chloride (4 ml_) in methanol (100 ml) to afford the desired product (1.5 g, quant). ¹H NMR (400 MHz, CD₃OD): δ 8.02-7.96

(m, 2H)₁ 7.38 (m, 1 H), 7.26 (q, 1 H)₁ 7.17 (m, 1 H), 7.06 (m, 1 H), 3.56 (d, 2H),

3.40 (m, 1 H), 3.22 (t, 2H), 2.22 (d, 2H), 2.12 (m, 2H). ¹⁹F NMR (376 MHz,

CD₃OD): δ-115.22 and -126.32. ES-MS (m/z) for Ci₆H₁₇ F₂N₂O/2HCI: 290.95

[M+1]⁺. CHN calculated for Ci₆H₁₇ F₂N₂O/2HCI/2.5H₂O: C 47.07 %; H 5.68 %; N 6.86 %, and found: C 46.98 %; H 5.25 %; N 6.76 %.

Example #28 3-Bromo-2-(naphthalen-1-yloxy)pyridine:

Using General Procedure A, 3-bromo-2-chloro pyridine (2.00 g, 10.4 mmol) was reacted with 1-naphthol (2.1 g, 15 mmol) and potassium carbonate

(3.16 g, 22.9 mmol) in Λ/,Λ/-dimethylformamide (10.4 ml) to afford the desired product as a solid (1.41 g, 45%). ¹H NMR (400 MHz, CDCI₃) δ 6.88 (dd,

J=7.41 , 5.07 Hz, 1 H), 7.29 (dd, J=7.60, 0.97 Hz, 1 H), 7.42 - 7.53 (m, 3 H),

7.73 - 7.77 (m, 1 H), 7.86 - 7.91 (m, 1 H), 7.92 - 7.95 (m, 1 H), 7.96 - 8.00 (m, 2 H). MS-APCI (m/z): 300 [M+1]⁺.

Terf-butyl 4-(2-(naphthalen-1 -yloxy)pyridin-3-yl)-5,6- dihydropyridine-1(2H)-carboxylate:

Using General Procedure B, 3-bromo-2-(naphthalen-1-yloxy)pyridine (320 mg, 1.06 mmol) was reacted with te/t-butyl 4-(5,5-dimethyl-1 ,3,2- dioxaborinan-2-yl)-5,6-dihydropyridine-1 (2H)-carboxylate (395 mg, 1.28 mmol), cesium fluoride (485 mg, 3.20 mmol) and [1 , 1'-Bis (diphenylphosphino)ferrocene] palladium (II) (125 mg, 0.17 mmol) in N₁N- dimethylformamide (2.66 ml) to afford the desired product as a gum (221 mg, 65%). ¹H NMR (400 MHz, CDCI₃) δ 1.45 (s, 9 H), 2.56 - 2.66 (m, 2 H), 3.52 (t, J=5.56 Hz, 2 H), 3.96 - 4.03 (m, 2 H), 6.02 - 6.08 (m, 1 H), 7.07 - 7.17 (m, 2 H), 7.41 - 7.54 (m, 3 H), 7.686 - 7.77 (m, 2 H), 7.89 (dd, J=7.8, 5.8 Hz, 2 H), 8.09 (d, J=4.24 Hz 1 H). MS-APCI (m/z): 403 [M+1]⁺.

Te/t-butyl 4-(2-(naphthalen-1 -yloxy)pyridin-3-yl)piperidine-1 - carboxylate:

Using General Procedure C, terf-butyl 4-(2-(naphthalen-1-yloxy)pyridin-

3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (277 mg, 0.688 mmol) was reduced to the desired product (300 mg, quant). ¹H NMR (400 MHz, CDCI₃) δ 1.42 - 1.50 (m, 2 H), 1.47 (s, 9 H), 1.68 - 1.78 (m, 2 H)₁ 2.01 - 2.09 (m, 2 H), 2.75 - 2.91 (m, 2 H), 3.27 (tt, J=12.32, 3.97 Hz, 1 H), 6.97 (dd, J=7.41 , 4.87 Hz, 1 H), 7.14 (dd, J=7.54, 1.12 Hz, 1 H), 7.40 - 7.51 (m, 3 H), 7.59 (dd, Λ=7.51 , 1.85 Hz, 1 H), 7.70 (d, J=8.19 Hz, 1 H), 7.86 - 7.91 (m, 2 H), 7.93 (dd, J=4.87, 1.95 Hz, 1 H). MS-APCI (m/z): 405 [M+1]⁺.

2-(Naphthalen-1-yloxy)-3-(piperϊdin-4-yl)pyridine hydro chloride:

Using General Procedure D, ferf-butyl 4-(2-(naphthalen-1-yloxy)pyridin- 3-yl)piperidine-1-carboxylate (300 mg, 0.742 mmol) was reacted with acetyl chloride (1.06 ml, 14.8 mmol) in methanol (5 ml) to afford the desired product as a solid (230 mg, 91%). ¹H NMR (400 MHz, CD₃OD) δ 1.15-2.40 (m, 4 H), 3.20 (m, 2 H), 3.40-3.60 (m, 3 H), 7.15 (m, 2 H), 7.4-7.6 (m, 3H), 7.85-8.00 (m 5H). MS-APCI (m/z): 305 [M+1]⁺.

Example #29

Terf-butyl 4-(2-(2,3-dichlorophenoxy)pyridin-3-yl)piperazine-1 - carboxylate:

Using General Procedure E, 3-bromo-2-(2,3-dichlorophenoxy)pyridine (200mg, 0.627 mmol), tert-butyl piperazine-1 -carboxylate (140 mg, 0.752 mmol) and sodium tert-butoxide (90.4 mg, 0.940 mmol) in toluene (2 ml) were combined, followed by the addition of tris(dibenzylideneacetone)dipalladium (28.7 mg, 0.0313 mmol) and Dave-Phos (37.0 mg, 0.0940 mmol) to afford the desired product as a solid (174 mg, 64%). ¹H NMR (400 MHz, CDCI₃) δ 3.13 - 3.20 (m, 4 H), 3.56 - 3.63 (m, 4 H), 6.97 (dd, J=7.80, 4.87 Hz, 1 H), 7.12 (dd, J=8.19, 1.56 Hz, 1 H), 7.20 - 7.26 (m, 2 H), 7.33 (dd, J=7.99, 1.56 Hz, 1 H), 7.71 (dd, J=4.87, 1.56 Hz, 1 H). MS-APCI (m/z+): 424 [M+1]⁺. 1-(2-(2,3-Dichlorophenoxy)pyridin-3-yl)piperazine:

Using General Procedure D, tert-butyl 4-(2-(2,3- dichlorophenoxy)pyridin-3-yl)piperazine-1-carboxylate (170 mg, 0.401 mmol) was reacted with acetyl chloride (0.285 ml, 4.01 mmol) in methanol (5 ml) then purified with ion exchange column to afford the desired product as a solid (89 mg, 68%). ¹H NMR (400 MHz, CDCI₃) δ 2.99 - 3.08 (m, 4 H), 3.14 - 3.21 (m, 4 H), 6.95 (dd, J=7.80, 4.87 Hz, 1 H), 7.10 (dd, J=8.19, 1.56 Hz, 2 H), 7.19 - 7.26 (m, 2 H), 7.30 (dd, J=7.99, 1.56 Hz, 1 H), 7.68 (dd, J=4.78, 1.66 Hz, 1 H). MS-APCI (m/z): 324 [M+1]⁺.

Example #30 Tert-butyl 4-(2-(3-fluoro-2-methoxyphenoxy)pyridin-3- yl)piperazine-1 -carboxylate:

Using General Procedure A, reaction of 3-bromo-2-chloro pyridine (600 mg, 3.12 mmol), 3-fluoro-2-methoxyphenol (593 mg, 3.74 mmol) and potassium carbonate (862 mg, 6.24 mmol) in Λ/,Λ/-dimethylformamide (3 ml) afforded 3-bromo-2-(3-fluoro-2-methoxyphenoxy)pyridine as a solid (655 mg, 71 %). Then using General Procedure E, 3-bromo-2-(3-fluoro-2- methoxyphenoxy)pyridine (350 mg, 1.17 mmol), te/f-butyl piperazine-1- carboxylate (262 mg, 1.41 mmol) and sodium tert-butoxide (169 mg, 1.76 mmol) in toluene (2 ml) were combined, followed by the addition of tris(dibenzylideneacetone)dipalladium (54 mg, 0.059 mmol) and Dave-Phos (69.3 mg, 0.176 mmol) to afford the desired product as a solid (284 mg, 67%). MS-APCI (m/z): 404 [M+1]⁺, 304 [M+1-100]⁺.

1-(2-(3-Fluoro-2-methoxyphenoxy)pyridin-3-yl)piperazine:

Using General Procedure D, tert-butyl 4-(2-(3-fluoro-2- methoxyphenoxy)pyridin-3-yl)piperazine-1-carboxylate (295 mg, 0.731 mmol) was reacted with acetyl chloride (114 mg, 1.46 mmol) in methanol (8 ml) then treated with 2M NH₃ in MeOH after the purification to afford the desired product as oil (99 mg, 50%). ¹H NMR (400 MHz, CD₃OD) δ 2.97 (d, J=5.1 Hz, 2 H), 3.14 (d, J=4.9 Hz, 2 H), 3.16 (br. 2, 1 H), 3.33 (s, 3 H), 3.71 (d, JM .4 Hz, 2 H), 6.88 (dt, J=7.8, 1.7 Hz, 1 H), 7.03 (m, 3 H), 7.38 (dd, J=7.8, 1.6 Hz, 1 H), 7.61 (dd, J=4.9, 1.8 Hz, 1 H) Example #31

1-(2-(2-Ethoxy-6-fluorophenoxy)pyridin-3-yl)piperazine:

Using General Procedure A, reaction of 3-bromo-2-chloro pyridine (600 mg, 3.12 mmol), 2-ethoxy-6-fluorophenol (445 mg, 3.12 mmol) and potassium carbonate (862 mg, 6.24 mmol) in Λ/,Λ/-dimethylformamide (2.60 ml) afforded 3-bromo-2-(2-ethoxy-6-fluorophenoxy)pyridine as a solid (800 mg, 86%). Then using General Procedure E, 3-bromo-2-(2-ethoxy-6- fluorophenoxy)pyridine (352 mg, 1.09 mmol) was reacted with tert-butyl piperazine-1-carboxylate (243 mg, 1.31 mmol), sodium terf-butoxide (157 mg, 1.63 mmol), tris(dibenzylideneacetone)dipalladium (49.4 mg, 0.054 mmol) and Dave-Phos (64.1 mg, 0.163 mmol) in toluene (2 ml) to result in tert-butyl 4-(2- (2-ethoxy-6-fluorophenoxy)pyridin-3-yl)piperazine-1-carboxylate as a solid (298 mg, 67%). Then using General Procedure D, terf-butyl 4-(2-(2-ethoxy-6- fluorophenoxy)pyridin-3-yl)piperazine-1-carboxylate (253 mg, 0.605 mmol) was reacted with acetyl chloride (2.1 ml, 28.8 mmol) in methanol (8 ml) then treated with 2M NH₃ in MeOH after the purification to afford the desired product as gum (33 mg, 17%). ¹H NMR (400 MHz, CD₃OD) δ 1.14 (t, J=6.92 Hz, 3 H), 2.98 - 3.03 (m, 4 H), 3.16 - 3.23 (m, 4 H), 3.97 (q, J=7.02 Hz, 2 H), 6.81 (dd, J=8.38, 1.36 Hz, 1 H), 6.86 (dt, J=8.48, 1.32 Hz, 1 H), 7.00 (dd, J=7.80, 4.87 Hz, 1 H), 7.15 (td, J=8.48, 6.04 Hz, 1 H), 7.37 (dd, J=7.80, 1.56 Hz, 1 H).

Example #32 rerf-butyl 4-(2-(4-fluoro-2-methoxyphenoxy)pyridin-3- yl)piperazine-1-carboxylate:

Using General Procedure A, reaction of 3-bromo-2-chloropyridine (500 mg, 2.60 mmol), 2-fluoro-6-methoxyphenol (443 mg, 3.12 mmol) and potassium carbonate (718 mg, 5.20 mmol) in Λ/,Λ/-dimethylformamide (5 ml) afforded 3-bromo-2-(4-fluoro-2-methoxyphenoxy)pyridine as a solid (1.49 g, 60%). Then using General Procedure E, 3-bromo-2-(4-fluoro-2- methoxyphenoxy)pyridine (313 mg, 1.05 mmol), te/t-butyl piperazine-1- carboxylate (235 mg, 1.26 mmol) and sodium tert-butoxide (151 mg, 1.58 mmol) in toluene (2 ml) was reacted together followed by the addition of tris(dibenzylideneacetone)dipalladium (48.5 mg, 0.053 mmol) and Dave-Phos (62.2 mg, 0.158 mmol) to afford the desired product as a solid (290 mg, 69%). MS-APCI (m/z): 404 [M+1]\ 304 [M+H-100]⁺.

1-(2-(4-Fluoro-2-methoxyphenoxy)pyridin-3-yl)piperazine:

Using General Procedure D, tert-butyl 4-(2-(4-fluoro-2- methoxyphenoxy)pyridin-3-yl)piperazine-1 -carboxylate (262 mg, 0.649 mmol) was reacted with acetyl chloride (101 mg, 1.29 mmol) in methanol (8 ml) then treated with 2M NH₃ in MeOH after the purification to afford the desired product a solid (116 mg, 59%). ¹H NMR (400 MHz, CD₃OD) δ 2.93 - 2.99 (m, 4 H), 3.11 - 3.18 (m, 4 H), 3.67 (s, 3 H), 6.87 (dd, J=8.97, 3.12 Hz, 1 H), 6.90 - 6.96 (m, 1 H), 7.01 (dd, J=7.80, 4.87 Hz, 1 H), 7.05 (dd, J=8.97, 5.07 Hz, 1 H), 7.37 (dd, J=7.70, 1.66 Hz, 1 H), 7.58 (dd, J=4.87, 1.56 Hz, 1 H). MS-APCI (m/z): 304 [M+1]⁺. Example #33

Tert-butyl 4-(2-(2-ethyl-4-fluorophenoxy)pyridin-3-yl)piperazine-1- carboxylate:

Using General Procedure A, reaction of 3-bromo-2-chloropyridine (600 mg, 3.12 mmol), 2-ethyl-4-fluorophenol (437 mg, 3.12 mmol) and potassium carbonate (862 mg, 6.24 mmol) in Λ/,Λ/-dimethylformamide (3 ml) afforded 1-

(2-bromophenoxy)-2-ethyl-4-fluorobenzene as an oil (778 g, 84%). Then using General Procedure E, 3-bromo-2-(2-ethyl-4-fluorophenoxy)pyridine (311 mg, 1.05 mmol), tert-butyl piperazine-1-carboxylate (235 mg, 1.26 mmol) and sodium te/t-butoxide (151 mg, 1.58 mmol) in toluene (2 ml) were combined, followed by the addition of tris(dibenzylideneacetone)dipalladium (48.5 mg,

0.053 mmol) and Dave-Phos (62.2 mg, 0.158 mmol), and the reaction afforded the desired product as a solid (306 mg, 73%). ¹H NMR (400 MHz,

CD₃OD) δ 1.13 (t, J=4.97 Hz, 3 H), 1.46 (s, 9 H), 2.51 (q, J=7.47 Hz, 2 H), 3.06 - 3.15 (m, 4 H), 3.50 - 3.62 (m, 4 H), 6.87 - 6.93 (m, 2 H), 6.97 - 7.05 (m,

2 H), 7.37 (dd, J=7.80, 1.56 Hz, 1 H), 7.60 (dd, J=4.97, 1.66 Hz, 1 H). MS-

APCI (m/z): 402 [M₊I]⁺, 302 [M+1-100]⁺. 1-(2-(2-Ethyl-4-fluorophenoxy)pyridin-3-yl)piperazine:

Using General Procedure D, te/t-butyl 4-(2-(2-ethyl-4- fluorophenoxy)pyridin-3-yl)piperazine-1 -carboxylate (260 mg, 0.648 mmol) was reacted with acetyl chloride (2.2 ml, 31 mmol) in methanol (13 ml) then treated with 2M NH₃ in MeOH after the purification to afford the desired product a gum (151 mg, 77%). ¹H NMR (400 MHz, CD₃OD) δ 1.14 (t, J=4.97 Hz, 3 H), 2.52 (q, J=7.54 Hz, 2 H), 2.94 - 3.00 (m, 4 H), 3.11 - 3.18 (m, 4 H), 6.89 - 6.94 (m, 2 H), 6.99 - 7.06 (m, 2 H), 7.39 (dd, J=7.80, 1.56 Hz, 1 H), 7.60 (dd, J=4.97, 1.66 Hz, 1 H). MS-APCI (m/z): 302 [M+1]⁺.

Example #34

Te/t-butyl 4-(2-(2-chloro-6-fluorophenoxy)pyridin-3-yl)piperazine- 1-carboxylate:

Using General Procedure E, 3-bromo-2-(2-chloro-6- fluorophenoxy)pyridine (310mg, 1.04 mmol), fe/t-butyl piperazine-1- carboxylate (232 mg, 1.25 mmol) and sodium fert-butoxide (175 mg, 1.56 mmol) in toluene (1 ml) were combined, followed by the addition of tris(dibenzylideneacetone)dipalladium (47.6 mg, 0.0520 mmol) and Dave- Phos (61.4 mg, 0.156 mmol), and the reaction afforded the desired product as a solid (130 mg, 31 %). ¹H NMR (400 MHz, CDCI₃) δ 1.47 (s, 9 H), 3.13 - 3.21 (m, 4 H), 3.58 - 3.65 (m, 4 H), 6.94 (dd, J=7.60, 4.87 Hz, 1 H), 7.07 - 7.18 (m, 2 H), 7.21 (dd, J=7.70, 1.66 Hz, 1 H), 7.26 (dt, J=7.80, 1.75 Hz, 1 H), 7.67 (dd, J=4.78, 1.66 Hz, 1 H). MS-APCI (m/z): 408 [M+1]⁺, 308 [M+H-100]⁺. 1-(2-(2-Chloro-6-fluorophenoxy)pyridin-3-yl)piperazine:

Using General Procedure D, te/t-butyl 4-(2-(2-chloro-6- fluorophenoxy)pyridin-3-yl)piperazine-1-carboxylate (130 mg, 0.319 mmol) was reacted with acetyl chloride (0.227 ml, 3.19 mmol) in methanol (5 ml) then purified with ion exchange column to afford the desired product as a solid

(59 mg, 60%). ¹H NMR (400 MHz, CDCI₃) δ 3.06 - 3.08 (m, 4 H), 3.17 - 3.24

(m, 4 H), 6.94 (dd, J=7.80, 4.68 Hz, 1 H), 7.06 - 7.17 (m, 1 H), 7.22 (dd,

J=7.80, 1.56 Hz, 1 H), 7.26 (dt, J=8.19, 1.95 Hz, 1 H), 7.64 (dd, J=4.68, 1.56 Hz, 1 H). MS-APCI (m/z): 308 [M+1]⁺.

Example #35

7eιt-butyl 4-(2-(2-fluoro-6-methoxyphenoxy)pyridin-3- yl)piperazine-1 -carboxylate:

Using General Procedure E, 3-bromo-2-(2-fluoro-6- methoxyphenoxy)pyridine (287mg, 0.963 mmol), te/t-butyl piperazine-1 - carboxylate (269 mg, 1.44 mmol) and sodium te/t-butoxide (162 mg, 144 mmol) in toluene (1 ml) were combined, followed by the addition of tris(dibenzylideneacetone)dipalladium (44.1 mg, 0.048 mmol) and Dave-Phos (56.8 mg, 0.144 mmol), and the reaction afforded the desired product as a solid (410 mg, quant). ¹H NMR (400 MHz, CDCI₃) δ 1.47 (s, 9 H), 3.12 - 3.20 (m, 4 H), 3.58 - 3.64 (m, 4 H), 3.76 (s, 3 H), 6.76 - 6.84 (m, 2 H), 6.90 (dd, J=7.80, 4.87 Hz, 1 H), 7.13 (td, J=8.43, 6.14 Hz, 1 H), 7.17 (dd, J=7.70, 1.66 Hz, 1 H), 7.68 (dd, J=4.87, 1.75 Hz, 1 H). MS-APCI (m/z): 404 [M+1]⁺, 304 [M+1 -100]⁺.

1-(2-(2-Fluoro-6-methoxyphenoxy)pyridin-3-yl)piperazine:

Using General Procedure D, te/t-butyl 4-(2-(2-fluoro-6- methoxyphenoxy)pyridin-3-yl)piperazine-1-carboxylate (410 mg, 1.02 mmol) was reacted with acetyl chloride (0.723 ml, 10.2 mmol) in methanol (10 ml) then purified with ion exchange column to afford the desired product as a solid (252 mg, 82%). ¹H NMR (400 MHz, CDCI₃) δ 3.07 - 3.13 (m, 4 H), 3.19 - 3.27 (m, 4 H), 3.76 (s, 3 H), 6.75 - 6.84 (m, 2 H), 6.90 (dd, J=7.60, 4.87 Hz, 1 H), 7.12 (td, J=8.43, 6.14 Hz, 1 H), 7.19 (dd, J=7.70, 1.66 Hz, 1 H), 7.66 (dd, J=4.87, 1.56 Hz, 1 H). MS-APCI (m/z): 304 [M+1]⁺.

Table 1 shows the structure of the compounds and relevant biological data that were measured in each case either on the compound as a free base or on the pharmaceutically acceptable salt of the compound disclosed in the Table. In the table, (S) refers to SPA Binding Assay; (F) refers to Filtration Binding Assay. Each assay is disclosed in greater detail hereinbelow.

TABLE 1

Example #5 94.2 (S) 23.2 17600 25.0

3-(Piperidin-4-yl)-2-(2- (F) 61.8 (trif luorom ethoxy)phenox) pyridine hydrochloride

Example # 6 98.4 (S) 80.4

3-(Piperidin-4-yl)-2-(2- (F) 89.6 (trifluoromethyl)phenoxy) pyridine hydrochloride

Example #7 93.5 (S) 54.0

2-(2-Methoxyphenoxy)-3- (F) 61.2

(piperidin-4-yl)pyridine dihydrochloride

Example #8 97.5 (S) 5.1

2-(2-Ethoxyphenoxy)-3-

(piperidin-4-yl)pyridine hydrochloride

Example #9 89.0 (S) 81.2 163 91

2-(2-Fluorophenoxy)-3- (F) 96.0

(piperidin-4-yl)pyridine hydrochloride

Example #10 98.4 (S) 81.2 372 39.9

2-(2-Chlorophenoxy)-3- (F) 96.0 (piperidin-4-yl)pyridine hydrochloride salt

Example #11 (F) 67.5

2-(2-Chloro-3- (trifluoromethyl)phenoxy)- 3-(piperidin-4-yl)pyridine hydrochloride salt

Example #12 95.1 (F) 79.1 2120 19.9

2-(2-Chloro-6- methoxyphenoxy)-3- (piperidin-4-yl)pyridine hydrochloride salt

Example #13 102 (F) 91.0 415 45.7

2-(2,3-Dichlorophenoxy)- 3-(piperidin-4-yl)pyridine hydrochloride salt

Example #14 92.7 (F) 90.4

2-(2,4-Dichlorophenoxy)- 3-(piperidin-4-yl)pyridine hydrochloride salt

Example #15 87.3 (F) 92.1

2-(2-Fluoro-4- methylphenoxy)-3- (piperidin-4-yl)pyridine hydrochloride salt

Example #16 93.1 (F) 48.2

2-(2-Ethoxy-6- fluorophenoxy)-3- (piperidin-4-yl)pyridine trifluoroacetic acid salt

Example #17 93.6

2-(4-Fluoro-2- methoxyphenoxy)-3-

(piperidin-4-yl)pyridine

Example #18 97.3 (F) 70.9

2-(2-Ethyl-4- fluorophenoxy)-3- (piperidin-4-yl)pyridine trifluoroacetic acid salt

Example #19 99.0 (S) 84.6 129 59.6

2-(2-Fluoro-6- (F) 97.4 methylphenoxy)-3- (piperidin-4-yl)pyridine dihydrochloride

Example #20 52.9 (S) 54.4 829 61.2

2-(2-Fluoro-4- (F) 94.1 methoxyphenoxy)-3-

(piperidin-4-yl)pyridine

Example #21 99.9 (S) 89.6 88.7 25.8

2-(2-Chloro-6- (F) 98.2 fluorophenoxy)-3- (piperidin-4-yl)pyridine hydrochloride

Example #22 96.2 (S) 80.9

2-(2,6-Difluorophenoxy)- 3-(piperidin-4-yl)pyridine

Example #23 76.9 (S) 68.2

2-(2,3-Difluorophenoxy)- 3-(piperidin-4-yl)pyridine dihydrochloride

Example #24 88.1

2-(2-Fluoro-6- methoxyphenoxy)-3- (piperidin-4-yl)pyridine trifluoroacetic acid salt

Example #25 97.1 (S) 90.4 176 68.8

2-(2-Fluoro-6- (F) 95.3 methoxyphenoxy)-3- (piperidin-4-yl)pyridine dihydrochloride

Example #26 97.5 (S) 64.9

2-(2,5-Difluorophenoxy)- 3-(piperidin-4-yl)pyridine dihydrochloride

Example #27 96.9 (S) 74.7 1010 62.3

2-(2,4-Difluorophenoxy)- (F) 94.4 3-(piperidin-4-yl)pyridine hydrochloride

Example #28 97.9 (F) 90.6

2-(Naphthalen-1 -yloxy)-3- (piperidin-4-yl)pyridine hydro chloride

Example #35 60.8 (S) 87.8 93.9 25.0

1-(2-(2-Fluoro-6- (F) 98.4 methoxyphenoxy)pyridin-

3-yl)piperazine

When introducing elements of the present invention or the exemplary embodiment(s) thereof, the articles "a," "an," "the" and "said" are intended to mean that there are one or more of the elements. The terms "comprising," "including" and "having" are intended to be inclusive and mean that there may be additional elements other than the listed elements. Although this invention has been described with respect to specific embodiments, the details of these embodiments are not to be construed as limitations to the invention, the scope of which is defined by the appended claims. Biological Protocols

NET Binding Assay

Cell pellets (7 to 15 g) were thawed on ice and resuspended in 3 ml of membrane prep buffer (20 mM HEPES, pH 7.4 @24°C, 1 complete protease inhibitor tablet ((Roche catalog #11697498001) /50 ml buffer) per ml of packed cell volume, using a vortex mixer to disperse the cell pellet. The cells were then allowed to swell on ice for 10 min. The suspension was homogenized for 4 x 10 second bursts at 25,000 rpm on a PT3100 polytron. The homogenate was spun at 3,000 rpm for 20 min in a SS34 rotor cooled to 4⁰C. The supernatant was decanted into new 50 ml centrifuge tubes and the pellets were rehomogenized in 10-15 ml of membrane prep buffer and spun as described above. The supernatants were then pooled and spun at 17,500 rpm in the SS34 rotor (35,000 x g) for 30 min at 4⁰C. The supernatants were discarded and the cell pellets were resuspended by vigorous pipetting in 1 ml membrane prep buffer per 1 ml of original packed cell volume. Protein concentrations were determined with the BCA Protein Assay Kit (Pierce, #23227) utilizing the microplate assay procedure. The membranes were stored in 1 ml aliquots at -8O⁰C until use.

SPA beads (Wheat germ agglutinin coated polyvinyltoluene;

Amersham #RPNQ0001 ) (500 mg) were added to 10 ml of 4⁰C assay buffer (30 mM HEPES, 180 mM NaCI, pH 7.4) and placed on ice. Membrane/bead slurry was prepared by addition of 6 ml of 50 mg/ml bead slurry with 2 ml of 3 mg/ml stock membrane preparation in the presence of 2 ml of cold assay buffer (0.6 mg membrane/ml in slurry), and was incubated for 2 hours at 4⁰C on a top-to-tail shaker. The slurry was spun at 1200 rpm for 5 min at 4⁰C, and the pellet was washed 2X in cold assay buffer and resuspended to the original slurry volume.

Compound concentration-response 11 -point curves were tested in Vz log scale, starting at 10 μM final concentration in the reaction mixture. Columns 1 and 24 in a Costar 3706 384-well white, clear bottom plate were left for vehicle controls and the non-specific binding component. Samples concentrations were added in single wells in duplicate plating. Wells contained:

0.5 μl 100% DMSO spots (total binding, compound, or standard) 30 μl [3H]Nisoxetine in assay buffer 20 μl bead/membrane slurry in assay buffer

After all additions were made, the plate was sealed and shaken for 1 hour at room temperature.

The plate was then dark adapted for 6 to 10 hours prior to counting in the Wallac Trilux Microbeta scintillation counter. 5HT1 A SPA Binding Assay

HEK-293 EBNA cell membrane (Catalog # RBHS1AM) stably expressing the 5HT1a receptor was purchased from Perkin Elmer. The cells were grown under standard cell culture techniques, harvested, and received frozen suspended in 5OmM TRIS-HCI, 0.5mM EDTA, 1OmM MgCI₂, 10% sucrose, pH to 7.4. The company provides both receptor concentration (Bmax), ligand affinity (Kd), and also calculates the protein concentration. Subsequently, these membrane preparations are stored at -8O⁰C until needed. Lyophilized wheat germ agglutinin SPA beads (WGA-SPA) are reconstituted in 10 ml_ of assay buffer (5OmM TRIS MgCI₂, pH 7.4). To initiate coupling of the beads to the membrane, the bead suspension is added to the cell membranes to maintain a bead concentration of 500 μg/well and a protein concentration of 10μg/ well (384-well plate format). This bead/membrane mixture is rocked gently for 30 minutes at 4⁰C. After 30 minutes the suspension is then centrifuged at 1000 rpm at 25⁰C. The supernatant is carefully discarded and the remaining pellet is diluted in assay buffer and aliquoted into assay plates to initiate incubation. Binding studies were carried out in 50μl_ assay volume using Costar 3705 (white, clear bottom) 384 well plates to which 0.5-1.0 ml_ of compound in 100% DMSO was prespotted, 20μL of [3H]-8-OH-DPAT (final concentration of 5nM and 30μL of bead/membrane slurry are added sequentially using Titertek Multidrops. Plates are sealed with clear adhesive and allowed to incubate overnight at 25⁰C. The nonspecific binding was defined by using 1μM Lisuride. The plates were counted in a Packard Trilux Microbeta Scintillation Counter using a normalized protocol for 3H-SPA counting The data was analyzed using an Excel macro which used the statistical average for the high control (Total Binding) values and the 1 μM lisuride values as the low control (Nonspecific binding) values. Z factors were determined for each plate using these values. Active compounds were further titrated to determine Ki values. Ki values were determined by analysis using a least squares nonlinear regression curve fit assuming a one site competition ligand binding model. 5HT1A Filtration Binding Assay

As an alternate binding affinity assay, HeLa cells transfected with the human 5HT1A receptor were incubated in a solution containing 50OuI of 50 mM Tris-HCI, 10 mM MgSO4, 0.5 mM EDTA, 0.1% Ascorbic acid at pH 7.4 (solution A) and the diluted test agent, plus 1.5 nM [3H]8-OH-DPAT in a 96- well format. In cases where non-specific binding was determined 1OuM of [3H]8-OH-DPAT was used. The solution was left to incubate at 4C for 1 hour. The assay is terminated by filtration of solution over GF/C filters that have been pre-soaked in 0.3% polyethylenimine with solution A. Next the filters are washed three times with 500 ul of an ice cold solution containing 50 mM Tris- HCI pH 7.4. Filters are then dried, placed into a vial containing scintillant fluid and radiation levels are determined using a scintillation counter. Affinity of the compounds for the human 5HT1A receptor is calculated using GraphPad and Ligand data analysis programs. GTPΎS-5HT1 A Binding Assay

CHO cells transfected with human 5 HT1 A receptor were maintained in Ultra CHO (Cambrex, 12-724Q) media supplemented with 10% dialyzed FBS (Gibco 26400 036), 1% Geneticin (Gibco 10131-027), and 0.5% Pen/Strep (Gibco 15140 122). Cells are grown in 15OmM cell culture dishes and harvested in ice-cold PBS by scraping the plates when the cells are approx. 80% confluent. Cells are collected in PBS and centrifuged at 4⁰C at low speed (2500 rpm) until pellet forms. The pellet is then homogenized in tissue buffer with a polytron, and centrifuged at 4⁰C at high speed (20,000 rpm) for 15 min. Repeat this washing at least 4 times. After final wash, the protein can be measured and the homogenate aliquoted appropriately. . Working stocks were prepared as followed:

• Compounds were diluted in assay buffer to a final concentration of 10 uM

• 100μM Guanosine 5'-diphsophate, sodium salt (GDP, Sigma, Catalog No. G7127) in assay buffer • 1 nM ³⁵S-GTPγS (NEN#NEG-030H, 1250 Ci/mmol) in assay buffer

• On the day of the assay, the cell homogenate was thawed and washed two additional times in assay buffer (20 mM Hepes, pH 7.4, 120 mM NaCI, 10 mM MgCI₂J mM EDTA). Membranes were suspended at a final concentration of 0.2mg/ml_ in assay buffer. To each well of a 96-well plate, the following was added: 33μl compound 20μl GDP 77μl assay buffer 20μl ³⁵S-GTPγS

50μl membranes (10μg)

All of the above components are added to the plate 96-well for a final volume of 200μl. The plates are incubated at 3O⁰C for 60 minutes. To terminate the assay, the plates are aspirated and filtered into (non PEI coated) plates with ice cold 5OmM Tris (pH-7) and washed 3X. The dried plates are counted on TopCount.

Claims

CLAIMS We claim:

1. A compound or Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

X ₁ is O or S(O)_P; is either a single bond or a double bond, wherein, when irmzz j_S a single bond, Y is N or CR₃, and when is a double bond, Y is C; each Ri is independently selected from the group consisting of hydrogen, halogen, alkoxy, -CN, and alkyl, wherein each Ri alkyl is optionally independently substituted by one to three halogens; each R₂ is independently selected from the group consisting of halogen, -NO₂, -CN, -N(R₄)₂, R₄, and -OR₄; or two R₂ substituents on adjacent carbons taken together with the adjacent carbons form a carbocyclic or heterocyclic ring optionally substituted with halogen, hydroxy, -CN, alkyl, or alkoxy; wherein each R4 is independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, heterocycloalkyl and heteroaryl; or two R₄ groups on the same nitrogen atom may be taken together with the nitrogen atom to form a 5 to 8 membered heterocyclic ring which optionally has 1 to 3 additional ring heteroatoms selected from the group consisting of N, O, and S; and each R₄ alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl is optionally independently substituted by one to three substituents independently selected from the group consisting of halogen, hydroxy, -CN, -(Ci-Cβ)alkyl, -(Ci-C₆)alkoxy, -CF₃, -OCF₃, -N[(CH₂),R₄]₂, -NO₂, -(CH₂),N[(CH₂),R₄](C=O)[(CH₂)_tR₄], -S(C_rCβ)alkyl, -(S=O)(Ci -C₆)alkyl, -S(=O)₂(Ci-Cβ)alkyl, -(C=O)O(Ci -C₆)alkyl, -O(C=O)(d-C₆)alkyl,

-(C=O)(Ci -C₆)alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl; each R₃ is independently selected from the group consisting of hydrogen, halogen, -(CH₂)_tOH, -(CH₂),CF₃, -(CH₂)_tC≡N, -NO₂, -(CH₂),N[(CH₂)_tR₄]₂₎ -(CH₂)_t-alkyl, -(CH₂),O[(CH₂),R₄], -(CH₂)_t(C₃-Ci₂)cycloalkyl, -(CH₂)_t-aryl,

and -(CH₂)_theteroaryl; or two R₃ groups each attached to the same carbon atom of the ring containing Y, taken together with the carbon atom, form a three to seven membered carbocyclic ring n is an integer selected from 0, 1 and 2; m is an integer selected from 0, 1 , 2, 3 and 4; n1 is an integer selected from 1 , 2, and 3; p is an integer selected from 0, 1 and 2; and each t is an integer independently selected from 0, 1 , 2, 3, 4, and 5.

2. A compound of claim 1 or pharmaceutically acceptable salt thereof wherein n is 1.

3. A compound of claim 1 or pharmaceutically acceptable salt thereof wherein n is 2.

4. A compound of claim 1 or pharmaceutically acceptable salt thereof wherein R₄ is hydrogen.

5. A compound of claim 1 or pharmaceutically acceptable salt thereof wherein n1 is 1.

6. A compound of claim 1 or pharmaceutically acceptable salt thereof wherein n1 is 2.

7. A compound of claim 1 or pharmaceutically acceptable salt thereof wherein X₁ is O.

8. A compound of claim 1 or pharmaceutically acceptable salt thereof wherein Xi is S.

9. A compound of claim 1 or pharmaceutically acceptable salt thereof wherein p is 0.

10. A compound of claim 1 or pharmaceutically acceptable salt thereof wherein p is 1.

11. A compound of claim 1 or pharmaceutically acceptable salt thereof wherein p is 2.

12. A compound of claim 1 or pharmaceutically acceptable salt thereof wherein each R₁ is hydrogen.

13. A compound of claim 1 or pharmaceutically acceptable salt thereof wherein each R₂ is hydrogen.

14. A compound of claim 1 or pharmaceutically acceptable salt thereof wherein each R₁ is independently halogen or C₁ -Ce alkyl.

15. A compound of Claim 14 or pharmaceutically acceptable salt thereof wherein n is 1 and R₁ is fluorine, chlorine, alkyl or trifluoroalkyl.

16. A compound of Claim 14 or pharmaceutically acceptable salt thereof wherein n is 2 and each R₁ is fluorine.

17. A compound of Claim 14 or pharmaceutically acceptable salt thereof wherein n is 2 and each R₁ is alkyl.

18. A compound of Claim 14 or pharmaceutically acceptable salt thereof wherein n is 2 and one R₁ is fluorine and the other R₁ is chlorine.

19. A compound of Claim 14 or pharmaceutically acceptable salt thereof wherein n is 2 and one R₁ is alkyl and the other R₁ is chlorine or fluorine.

20. A compound of claim 1 or pharmaceutically acceptable salt thereof wherein Y is N and each R₂ is independently halogen or alkyl.

21 . A compound of claim 20 or pharmaceutically acceptable salt thereof wherein each R₂ is independently fluorine, chlorine, or methyl.

22. A compound of claim 1 or pharmaceutically acceptable salt thereof wherein Y is CH and each R₂ is independently halogen or alkyl.

23.A compound of Claim 22 or pharmaceutically acceptable salt thereof wherein each R₂ is independently fluorine, chlorine, or methyl.

24. A compound of claim 1 or pharmaceutically acceptable salt thereof wherein m is 1.

25. A compound of claim 1 or pharmaceutically acceptable salt thereof wherein m is 2.

26. A compound of claim 1 or pharmaceutically acceptable salt thereof wherein each R₂ is independently halogen, alkyl optionally substituted with one to three halogens, heteroaryl, or alkoxy optionally substituted with one to three halogens.

27. A compound of Claim 26 or pharmaceutically acceptable salt thereof wherein m is 1 and R₂ is fluorine, chlorine, alkyl optionally substituted with one to three halogens, or alkoxy optionally substituted with one to three halogens.

28. A compound of Claim 26 or pharmaceutically acceptable salt thereof wherein m is 2 and each R₂ is fluorine.

29. A compound of Claim 26 or pharmaceutically acceptable salt thereof wherein m is 2 and each R₂ is chlorine.

30. A compound of Claim 26 or pharmaceutically acceptable salt thereof wherein m is 2 and each R₂ is alkyl.

31. A compound of Claim 26 or pharmaceutically acceptable salt thereof wherein m is 2 wherein one R₂ is fluorine and the other R₂ is chlorine.

32. A compound of Claim 26 or pharmaceutically acceptable salt thereof wherein m is 2 wherein one R₂ is alkyl and the other R₂ is chlorine or fluorine.

33. A compound of Claim 26 or pharmaceutically acceptable salt thereof wherein m is 2 and one R₂ is alkoxy and the other R₂ is chlorine or fluorine.

34.A compound of claim 1 or pharmaceutically acceptable salt thereof wherein each R₃ is hydrogen.

35. A compound of claim 1 or pharmaceutically acceptable salt thereof wherein z=z=z js a single bond and Y is N.

36. A compound of claim 1 or pharmaceutically acceptable salt thereof wherein is a single bond and Y is CR₃.

37. A compound of claim 1 or pharmaceutically acceptable salt thereof wherein is a double bond and Y is C.

38. A compound selected from the group consisting of the compounds disclosed in Table 1 herein, or a pharmaceutically acceptable salt thereof.

39. A method for the treatment of a condition selected from the group consisting of acute neurological and psychiatric disorders such as cerebral deficits subsequent to cardiac bypass surgery and grafting, stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage, dementia (including AIDS-induced dementia), Alzheimer's disease, Huntington's Chorea, amyotrophic lateral sclerosis, ocular damage, retinopathy, cognitive disorders, including cognitive disorders associated with schizophrenia and bipolar disorders, idiopathic and drug- induced Parkinson's disease, muscular spasms and disorders associated with muscular spasticity including tremors, epilepsy, convulsions, migraine (including migraine headache), urinary incontinence, substance tolerance, substance withdrawal (including, substances such as opiates, nicotine, tobacco products, alcohol, benzodiazepines, cocaine, sedatives, hypnotics, etc.), psychosis, mild cognitive impairment, obesity, schizophrenia, anxiety (including generalized anxiety disorder, social anxiety disorder, panic disorder, post-traumatic stress disorder and obsessive compulsive disorder), mood disorders (including depression, mania, bipolar disorders), trigeminal neuralgia, hearing loss, tinnitus, macular degeneration of the eye, emesis, brain edema, pain (including acute and chronic pain states, severe pain, intractable pain, neuropathic pain, and post-traumatic pain), tardive dyskinesia, sleep disorders (including narcolepsy), attention deficit/hyperactivity disorder, autism, Asperger's disease, and conduct disorder, comprising administering a compound of claim 1 or a pharmaceutically acceptable salt thereof to the mammal.

40. The method of claim 39, wherein the condition is cognitive disorders, including cognitive disorders associated with schizophrenia, bipolar disorders, Alzheimer's Disease, pain (including acute and chronic pain states, severe pain, intractable pain, neuropathic pain, and post-traumatic pain), attention deficit/hyperactivity disorder, autism, and Asperger's disease.

41. A method for treating neurological and psychiatric disorders associated with norepinephrine reuptake inhibition, 5HT1a agonist activity, or both, comprising administering to a patient in need thereof an amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof effective in treating such disorders.

42. The method of claim 41 , further comprising administering an atypical antipsychotic

43. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

44.A composition for treating a condition selected from the group consisting of of acute neurological and psychiatric disorders such as cerebral deficits subsequent to cardiac bypass surgery and grafting, stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage, dementia (including AIDS-induced dementia), Alzheimer's disease, Huntington's Chorea, amyotrophic lateral sclerosis, ocular damage, retinopathy, cognitive disorders, including cognitive disorders associated with schizophrenia and bipolar disorders, idiopathic and drug- induced Parkinson's disease, muscular spasms and disorders associated with muscular spasticity including tremors, epilepsy, convulsions, migraine (including migraine headache), urinary incontinence, substance tolerance, substance withdrawal (including, substances such as opiates, nicotine, tobacco products, alcohol, benzodiazepines, cocaine, sedatives, hypnotics, etc.), psychosis, mild cognitive impairment, obesity, schizophrenia, anxiety (including generalized anxiety disorder, social anxiety disorder, panic disorder, post-traumatic stress disorder and obsessive compulsive disorder), mood disorders (including depression, mania, bipolar disorders), trigeminal neuralgia, hearing loss, tinnitus, macular degeneration of the eye, emesis, brain edema, pain (including acute and chronic pain states, severe pain, intractable pain, neuropathic pain, and post-traumatic pain), tardive dyskinesia, sleep disorders (including narcolepsy), attention deficit/hyperactivity disorder, autism, Asperger's disease, and conduct disorder in a mammal, wherein the composition contains an amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof that is effective in the treatment of such conditions.

45. The composition of claim 44, further comprising an atypical antipsychotic.

46. The composition of claim 44, further comprising a cholinesterase inhibitor.