RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No. 60/962,823, filed Aug. 1, 2007, the entire teachings of which are incorporated herein by reference.

FIELD OF THE INVENTION

This invention relates to biologically active chemical compounds, namely vinyl-phenyl derivatives that may be used for immunosuppression or to treat or prevent inflammatory conditions, allergic disorders and immune disorders.

BACKGROUND OF THE INVENTION

Inflammation is a mechanism that protects mammals from invading pathogens. However, while transient inflammation is necessary to protect a mammal from infection, uncontrolled inflammation causes tissue damage and is the underlying cause of many illnesses. Inflammation is typically initiated by binding of an antigen to T-cell antigen receptor. Antigen binding by a T-cell initiates calcium influx into the cell via calcium ion channels, such as Ca²⁺-release-activated Ca²⁺ channels (CRAC). Calcium ion influx in turn initiates a signaling cascade that leads to activation of these cells and an inflammatory response characterized by cytokine production.

Interleukin 2 (IL-2) is a cytokine that is secreted by T cells in response to calcium ion influx into the cell. IL-2 modulates immunological effects on many cells of the immune system. For example, it is a potent T cell mitogen that is required for T cell proliferation, promoting their progression from G1 to S phase of the cell cycle; it stimulates the growth of NK cells; and it acts as a growth factor to B cells and stimulates antibody synthesis.

IL-2, although useful in the immune response, can cause a variety of problems. IL-2 damages the blood-brain barrier and the endothelium of brain vessels. These effects may be the underlying causes of neuropsychiatric side effects observed under IL-2 therapy, e.g. fatigue, disorientation and depression. It also alters the electrophysiological behavior of neurons.

Due to its effects on both T and B cells, IL-2 is a major central regulator of immune responses. It plays a role in inflammatory reactions, tumor surveillance, and hematopoiesis.

It also affects the production of other cytokines, inducing IL-1, TNF-Î± and TNF-Î² secretion, as well as stimulating the synthesis of IFN-Î³ in peripheral leukocytes.

T cells that are unable to produce IL-2 become inactive (anergic). This renders them potentially inert to any antigenic stimulation they might receive in the future. As a result, agents which inhibit IL-2 production can be used for immunosuppression or to treat or prevent inflammation and immune disorders. This approach has been clinically validated with immunosuppressive drugs such as cyclosporin, FK506, and RS61443. Despite this proof of concept, agents that inhibit IL-2 production remain far from ideal. Among other problems, efficacy limitations and unwanted side effects (including dose-dependant nephrotoxicity and hypertension) hinder their use.

Over production of proinflammatory cytokines other than IL-2 has also been implicated in many autoimmune diseases. For example, Interleukin 5 (IL-5), a cytokine that increases the production of eosinophils, is increased in asthma. Overproduction of IL-5 is associated with accumulation of eosinophils in the asthmatic bronchial mucosa, a hall mark of allergic inflammation. Thus, patients with asthma and other inflammatory disorders involving the accumulation of eosinophils would benefit from the development of new drugs that inhibit the production of IL-5.

Interleukin 4 (IL-4) and interleukin 13 (IL-13) have been identified as mediators of the hypercontractility of smooth muscle found in inflammatory bowel disease and asthma. Thus, patients with asthma and inflammatory bowel disease would benefit from the development of new drugs that inhibit IL-4 and IL-13 production.

Granulocyte macrophage-colony stimulating factor (GM-CSF) is a regulator of maturation of granulocyte and macrophage lineage population and has been implicated as a key factor in inflammatory and autoimmune diseases. Anti-GM-CSF antibody blockade has been shown to ameliorate autoimmune disease. Thus, development of new drugs that inhibit the production of GM-CSF would be beneficial to patients with an inflammatory or autoimmune disease.

There is a continuing need for new drugs which overcome one or more of the shortcomings of drugs currently used for immunosuppression or in the treatment or prevention of inflammatory disorders, allergic disorders and autoimmune disorders. Desirable properties of new drugs include efficacy against diseases or disorders that are currently untreatable or poorly treatable, new mechanism of action, oral bioavailability and/or reduced side effects.

SUMMARY OF THE INVENTION

This invention meets the above-mentioned needs by providing certain vinyl-phenyl derivatives that inhibit the activity of CRAC ion channels and inhibit the production of IL-2, IL-4, IL-5, IL-13, GM-CSF, TNF-Î±, and IFNÎ³. These compounds are particularly useful for immunosuppression and/or to treat or prevent inflammatory conditions, allergic disorders and immune disorders.

In one embodiment, the invention relates to compounds of structural formula (I):

[Image Omitted]

- or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein:
- X₁and X₂are, independently, CH or N;
- one of X₃or X₆is NR₂₉, and the other is CH₂, CHR₂, or C(R₂)₂;
- L is a linker selected from the group consisting of â€”NHCH₂â€”, â€”CH₂NHâ€”, â€”NR₅â€”C(O)â€”, â€”C(O)â€”NR₅â€”, â€”NR₅â€”C(S)â€”, â€”C(S)â€”NR₅â€”, â€”NR₅â€”C(NR₈)â€”, â€”C(NR₈)â€”NR₅â€”, â€”NR₅C(S)NR₅â€”, â€”NR₅C(NR₈)NR₅â€”, or â€”NR₅CR^aR^bNR₅â€”;
- Y is a substituted phenyl, provided that Y is not substituted with â€”NHC(O)R₃₀;
- R₁is H or a substituent;
- R₂, for each occurrence is, independently, a substituent, provided that R₂is not â• O or â• C(R₂₈)₂;
- R₄is a substituent;
- R^aand R^b, for each occurrence, are independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, cyano, nitro, halo, â€”OR₅, â€”SR₅, â€”NR₆R₇, â€”C(O)NR₆R₇, â€”NR₅C(O)R₅, â€”C(O)R₅, â€”C(O)OR₅, â€”OC(O)R₅, â€”C(O)SR₅, â€”SC(O)R₅, â€”C(S)NR₆R₇, â€”NR₅C(S)R₅, â€”C(S)R₅, â€”C(S)OR₅, â€”OC(S)R₅, â€”C(S)SR₅, â€”SC(S)R₅, â€”C(NR₈)NR₆R₇, â€”NR₅C(NR₈)R₅, â€”C(NR₈)R₅, â€”C(NR₈)OR₅, â€”OC(NR₈)R₅, â€”C(NR₈)SR₅, â€”SC(NR₈)R₅, â€”OC(O)OR₅, â€”OC(O)NR₆R₇, â€”NR₅C(O)OR₅, â€”NR₅C(O)NR₆R₇, â€”SC(O)OR₅, â€”SC(O)NR₆R₇, â€”SC(O)SR₅, â€”NR₅C(O)SR₅, â€”OC(O)SR₅, â€”OC(S)OR₅, â€”OC(S)NR₆R₇, â€”NR₅C(S)OR₅, â€”NR₅C(S)NR₆R₇, â€”SC(S)OR₅, â€”SC(S)NR₆R₇, â€”SC(S)SR₅, â€”NR₅C(S)SR₅, â€”OC(S)SR₅, â€”OC(NR₈)OR₅, â€”OC(NR₈)NR₆R₇, â€”NR₅C(NR₈)OR₅, â€”NR₅C(NR₈)NR₆R₇, â€”SC(NR₈)OR₅, â€”SC(NR₈)NR₆R₇, â€”SC(NR₈)SR₅, â€”NR₅C(NR₈)SR₅, or â€”OC(NR₈)SR₅;
- R₅, for each occurrence, is independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
- R₆and R₇, for each occurrence are, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R₆and R₇taken together with the nitrogen to which they are attached are an optionally substituted heterocyclyl or optionally substituted heteroaryl;
- R₈, for each occurrence, is independently â€”H, a halo, an alkyl, â€”OR₅, â€”NR₆R₇, â€”C(O)R₅, â€”C(O)OR₅, or â€”C(O)NR₆R₇;
- R₂₈, for each occurrence is, independently, H or a substituent;
- R₂₉is â€”C(O)R₃₀or a N-containing 6-membered aromatic ring;
- R₃₀is â€”H, â€”OR₅, â€”SR₅, â€”NR₆R₇, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
- m is 0, 1, or 2; and
- n is 0, 1 or 2.

In one aspect, the compound of formula (I) is not:

- 5-[4-(2,6-difluoro-benzoylamino)-phenyl]-4-methyl-2,4-dihydro-2H-pyridine-1-carboxylic acid ethyl ester;
- Ethyl 3-(4-(2,6-difluorobenzamido)phenyl)-4-methyl-5,6-dihydropyridine-1(2H)-carboxylate;
- Ethyl 4-(4-(2,6-difluorobenzamido)phenyl)-3-methyl-5,6-dihydropyridine-1(2H)-carboxylate;
- 2,6-Difluoro-N-[4-(1-methoxycarbonyl-4-thiazol-2-yl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide;
- 2,6-Difluoro-N-[4-(1-methoxycarbonyl-4-isopropyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide;
- 2,6-Difluoro-N-[4-(1-methoxycarbonyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide;
- 2,6-Difluoro-N-[4-(1-allyloxycarbonyl-3-methyl-1,2,5,6-tetrahydro-pyridin-4-yl)-phenyl]-benzamide;
- 2,6-Difluoro-N-[4-(1-phenyloxycarbonyl-3-methyl-1,2,5,6-tetrahydro-pyridin-4-yl)-phenyl]-benzamide;
- 2,6-Difluoro-N-[4-(1-acetyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide;
- 2,6-Difluoro-N-[4-(1-cyclopropylcarbonyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide;
- 2,6-Difluoro-N-{4-[1-(pyridine-3-carbonyl)-cyclopropanecarbonyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl]-phenyl}-benzamide; or
- 2,6-Difluoro-N-[4-(1-pyrimidin-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide.

A compound of the invention or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof is particularly useful inhibiting immune cell (e.g., mast cells, T-cells and/or B-cells) activation (e.g., cytokine production and/or proliferation in response to an antigen;

and or mast cell degranulation). In particular, a compound of the invention or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof can inhibit the production of certain cytokines that regulate immune cell activation. For example, a compound of the invention or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof can inhibit the production of IL-2, IL-4, IL-5, IL-13, GM-CSF, TNF-Î±, INF-Î³ or combinations thereof. Moreover, a compound of the invention or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof can modulate the activity of one or more ion channel involved in activation of immune cells, such as CRAC ion channels.

In one embodiment, compounds of the invention or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof are particularly useful for inhibiting mast cell degranulation. Mast cell degranulation has been implicated in allergic reactions.

A compound of the invention or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof is particularly useful for immunosuppression or for treating or preventing inflammatory conditions, allergic disorders, and immune disorders.

The invention also encompasses pharmaceutical compositions comprising a compound of the invention or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof; and a pharmaceutically acceptable carrier or vehicle. These compositions may further comprise additional agents. These compositions are useful for immunosuppression and treating or preventing inflammatory conditions, allergic disorders and immune disorders.

The invention further encompasses methods for treating or preventing inflammatory conditions, allergic disorders, and immune disorders, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, or a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof. These methods may also comprise administering to the subject an additional agent separately or in a combination composition with the compound of the invention or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof.

The invention further encompasses methods for suppressing the immune system of a subject, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, or a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof. These methods may also comprise administering to the subject an additional agent separately or in a combination composition with the compound of the invention or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof.

The invention further encompasses methods for inhibiting immune cell activation, including inhibiting proliferation of T cells and/or B cells, in vivo or in vitro comprising administering to the cell an effective amount of a compound of the invention or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof or a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof.

The invention further encompasses methods for inhibiting cytokine production in a cell (e.g., IL-2, IL-4, IL-5, IL-13, GM-CSF, TNF-Î±, and/or INF-Î³ production) in vivo or in vitro comprising administering to a cell an effective amount of a compound of the invention or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof or a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof.

The invention further encompasses methods for modulating ion channel activity (e.g., CRAC channel activity) in vivo or in vitro comprising administering an effective amount of a compound of the invention or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof or a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof.

All of the methods of this invention may be practice with a compound of the invention alone, or in combination with other agents, such as other immunosuppressive agents, anti-inflammatory agents, agents for the treatment of allergic disorders or agents for the treatment of immune disorders.

DETAILED DESCRIPTION OF THE INVENTIONDefinitions

Unless otherwise specified, the below terms used herein are defined as follows:

As used herein, the term an â€œaromatic ringâ€ or â€œarylâ€ means a monocyclic or polycyclic-aromatic ring or ring radical comprising carbon and hydrogen atoms. Examples of suitable aryl groups include, but are not limited to, phenyl, tolyl, anthacenyl, fluorenyl, indenyl, azulenyl, and naphthyl, as well as benzo-fused carbocyclic moieties such as 5,6,7,8-tetrahydronaphthyl. An aryl group can be unsubstituted or substituted with one or more substituents (including without limitation alkyl (preferably, lower alkyl or alkyl substituted with one or more halo), hydroxy, alkoxy (preferably, lower alkoxy), alkylsulfanyl, cyano, halo, amino, and nitro. In certain embodiments, the aryl group is a monocyclic ring, wherein the ring comprises 6 carbon atoms.

As used herein, the term â€œalkylâ€ means a saturated straight chain or branched non-cyclic hydrocarbon typically having from 1 to 10 carbon atoms. Representative saturated straight chain alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl and n-decyl; while saturated branched alkyls include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylpentyl, 2,2-dimethylhexyl, 3,3-dimtheylpentyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylpentyl, 3-ethylpentyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, 2-methyl-4-ethylpentyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-methyl-4-ethylhexyl, 2,2-diethylpentyl, 3,3-diethylhexyl, 2,2-diethylhexyl, 3,3-diethylhexyl and the like. Alkyl groups included in compounds of this invention may be optionally substituted with one or more substituents. Examples of substituents include, but are not limited to, amino, alkylamino, alkoxy, alkylsulfanyl, oxo, halo, acyl, nitro, hydroxyl, cyano, aryl, alkylaryl, aryloxy, arylsulfanyl, arylamino, carbocyclyl, carbocyclyloxy, carbocyclylthio, carbocyclylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclylthio, and the like. In addition, any carbon in the alkyl segment may be substituted with oxygen (â• O), sulfur (â• S), or nitrogen (â• NR²², wherein R²²is â€”H, an alkyl, acetyl, or aralkyl). Lower alkyls are typically preferred for the compounds of this invention.

The term alkylene refers to an alkyl group or a cycloalkyl group that has two points of attachment to two moieties (e.g., {â€”CH₂â€”}, â€”{CH₂CH₂â€”},

[Image Omitted]

wherein the brackets indicate the points of attachment). Alkylene groups may be substituted or unsubstituted with one or more substituents.

An aralkyl group refers to an aryl group that is attached to another moiety via an alkylene linker. Aralkyl groups can be substituted or unsubstituted with one or more substituents.

The term â€œalkoxy,â€ as used herein, refers to an alkyl group which is linked to another moiety though an oxygen atom. Alkoxy groups can be substituted or unsubstituted with one or more substituents.

The term â€œalkylsulfanyl,â€ as used herein, refers to an alkyl group which is linked to another moiety though a divalent sulfur atom. Alkylsulfanyl groups can be substituted or unsubstituted with one or more substituents.

The term â€œarylsulfanyl,â€ as used herein, refers to an aryl group which is linked to another moiety though a divalent sulfur atom. Arylsulfanyl groups can be substituted or unsubstituted with one or more substituents.

The term â€œalkyl esterâ€ as used herein, refers to a group represented by the formula â€”C(O)OR₃₂, wherein R₃₂is an alkyl group. A lower alkyl ester is a group represented by the formula â€”C(O)OR₃₂, wherein R₃₂is a lower alkyl group.

The term â€œheteroalkyl,â€ as used herein, refers to an alkyl group which has one or more carbons in the alkyl chain replaced with an â€”Oâ€”, â€”Sâ€” or â€”NR₂₇â€”, wherein R₂₇is H or a lower alkyl. Heteroalkyl groups can be substituted or unsubstituted with one or more substituents.

The term â€œalkylamino,â€ as used herein, refers to an amino group in which one hydrogen atom attached to the nitrogen has been replaced by an alkyl group. The term â€œdialkylamino,â€ as used herein, refers to an amino group in which two hydrogen atoms attached to the nitrogen have been replaced by alkyl groups, in which the alkyl groups can be the same or different. Alkylamino groups and dialkylamino groups can be substituted or unsubstituted with one or more substituents.

As used herein, the term â€œalkenylâ€ means a straight chain or branched, hydrocarbon radical typically having from 2 to 10 carbon atoms and having at least one carbon-carbon double bond. Representative straight chain and branched alkenyls include vinyl, allyl, 1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl, 1-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 2-decenyl, 3-decenyl and the like. Alkenyl groups can be substituted or unsubstituted with one or more substituents.

As used herein, the term â€œalkynylâ€ means a straight chain or branched, hydrocarbon radical typically having from 2 to 10 carbon atoms and having at lease one carbon-carbon triple bond. Representative straight chain and branched alkynyls include acetylenyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl, 4-pentynyl,-1-hexynyl, 2-hexynyl, 5-hexynyl, 1-heptynyl, 2-heptynyl, 6-heptynyl, 1-octynyl, 2-octynyl, 7-octynyl, 1-nonynyl, 2-nonynyl, 8-nonynyl, 1-decynyl, 2-decynyl, 9-decynyl and the like. Alkynyl groups can be substituted or unsubstituted with one or more substituents.

As used herein, the term â€œcycloalkylâ€ means a saturated, mono- or polycyclic alkyl radical typically having from 3 to 14 carbon atoms. Representative cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, adamantly, decahydronaphthyl, octahydropentalene, bicycle[ 1.1.1]pentanyl, and the like. Cycloalkyl groups can be substituted or unsubstituted with one or more substituents.

As used herein, the term â€œcycloalkenylâ€ means a cyclic non-aromatic alkenyl radical having at least one carbon-carbon double bond in the cyclic system and typically having from 5 to 14 carbon atoms. Representative cycloalkenyls include cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, cycloheptatrienyl, cyclooctenyl, cyclooctadienyl, cyclooctatrienyl, cyclooctatetraenyl, cyclononenyl, cyclononadienyl, cyclodecenyl, cyclodecadienyl and the like. Cycloalkenyl groups can be substituted or unsubstituted with one or more substituents.

As used herein, the term â€œheterocyclylâ€ means a monocyclic or polycyclic heterocyclic ring (typically having 3- to 14-members) which is either a saturated ring or an unsaturated non-aromatic ring. A 3-membered heterocyclyl can contain up to 3 heteroatoms, and a 4- to 14-membered heterocyclyl can contain from 1 to about 8 heteroatoms. Each heteroatom is independently selected from nitrogen, which can be quaternized; oxygen; and sulfur, including sulfoxide and sulfone. The heterocyclyl may be attached via any heteroatom or carbon atom. Representative heterocyclyls include morpholinyl, thiomorpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, 4H-pyranyl, tetrahydropyrindinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like. A heteroatom may be substituted with a protecting group known to those of ordinary skill in the art, for example, the hydrogen on a nitrogen may be substituted with a tert-butoxycarbonyl group. Furthermore, the heterocyclyl may be optionally substituted with one or more substituents (including without limitation a halo, an alkyl, a haloalkyl, or aryl). Only stable isomers of such substituted heterocyclic groups are contemplated in this definition.

As used herein, the term â€œheteroaromaticâ€ or â€œheteroarylâ€ means a monocyclic or polycyclic heteroaromatic ring (or radical thereof) comprising carbon atom ring members and one or more heteroatom ring members (such as, for example, oxygen, sulfur or nitrogen). Typically, the heteroaromatic ring has from 5 to about 14 ring members in which at least 1 ring member is a heteroatom selected from oxygen, sulfur and nitrogen. In another embodiment, the heteroaromatic ring is a 5 or 6 membered ring and may contain from 1 to about 4 heteroatoms. In another embodiment, the heteroaromatic ring system has a 7 to 14 ring members and may contain from 1 to about 7 heteroatoms. Representative heteroaryls include pyridyl, furyl, thienyl, pyrrolyl, oxazolyl, imidazolyl, indolizinyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, triazolyl, pyridinyl, thiadiazolyl, pyrazinyl, quinolyl, isoquniolyl, indazolyl, benzoxazolyl, benzofuryl, benzothiazolyl, indolizinyl, imidazopyridinyl, isothiazolyl, tetrazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, indolyl, tetrahydroindolyl, azaindolyl, imidazopyridyl, qunizaolinyl, purinyl, pyrrolo[2,3]pyrimidyl, pyrazolo[3,4]pyrimidyl or benzo(b)thienyl and the like. Heteroaryl groups may be optionally substituted with one or more substituents

A heteroaralkyl group refers to a heteroaryl group that is attached to another moiety via an alkylene linker. Heteroaralkyl groups can be substituted or unsubstituted with one or more substituents.

As used herein, the term â€œN-containing 6-membered aromatic ringâ€ means an optionally substituted 6-membered aromatic ring that contains one or more N atoms. In one embodiment, the ring contains one N atom. In another embodiment, the ring contains two N atoms.

As used herein, the term â€œhalogenâ€ or â€œhaloâ€ means â€”F, â€”Cl, â€”Br or â€”I.

As used herein, the term â€œhaloalkylâ€ means an alkyl group in which one or more â€”H is replaced with a halo group. Examples of haloalkyl groups include â€”CF₃, â€”CHF₂, â€”CCl₃, â€”CH₂CH₂Br, â€”CH₂CH(CH₂CH₂Br)CH₃, â€”CHICH₃, and the like.

As used herein, the term â€œhaloalkoxyâ€ means an alkoxy group in which one or more â€”H is replaced with a halo group. Examples of haloalkoxy groups include â€”OCF₃and â€”OCHF₂.

The terms â€œbioisostereâ€ and â€œbioisosteric replacementâ€ have the same meanings as those generally recognized in the art. Bioisosteres are atoms, ions, or molecules in which the peripheral layers of electrons can be considered substantially identical. The term bioisostere is usually used to mean a portion of an overall molecule, as opposed to the entire molecule itself. Bioisosteric replacement involves using one bioisostere to replace another with the expectation of maintaining or slightly modifying the biological activity of the first bioisostere. The bioisosteres in this case are thus atoms or groups of atoms having similar size, shape and electron density. Preferred bioisosteres of esters, amides or carboxylic acids are compounds containing two sites for hydrogen bond acceptance. In one embodiment, the ester, amide or carboxylic acid bioisostere is a 5-membered monocyclic heteroaryl ring, such as an optionally substituted 1H-imidazolyl, an optionally substituted oxazolyl, 1H-tetrazolyl, [1,2,4]triazolyl, or an optionally substituted [1,2,4]oxadiazolyl.

As used herein, the terms â€œsubjectâ€ , â€œpatientâ€ and â€œanimalâ€ , are used interchangeably and include, but are not limited to, a cow, monkey, horse, sheep, pig, mini pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit, guinea pig and human. The preferred subject, patient or animal is a human.

As used herein, the term â€œlowerâ€ refers to a group having up to four carbon atoms. For example, a â€œlower alkylâ€ refers to an alkyl radical having from 1 to 4 carbon atoms, and a â€œlower alkenylâ€ or â€œlower alkynylâ€ refers to an alkenyl or alkynyl radical having from 2 to 4 carbon atoms, respectively. A lower alkoxy or a lower alkylsulfanyl refers to an alkoxy or an alkylsulfanyl having from 1 to 4 carbon atoms. Lower substituents are typically preferred.

Where a particular substituent, such as an alkyl substituent, occurs multiple times in a given structure or moiety, the identity of the substituent is independent in each case and may be the same as or different from other occurrences of that substituent in the structure or moiety. Furthermore, individual substituents in the specific embodiments and exemplary compounds of this invention are preferred in combination with other such substituents in the compounds of this invention, even if such individual substituents are not expressly noted as being preferred or not expressly shown in combination with other substituents.

The compounds of the invention are defined herein by their chemical structures and/or chemical names. Where a compound is referred to by both a chemical structure and a chemical name, and the chemical structure and chemical name conflict, the chemical structure is determinative of the compound's identity.

Suitable substituents for an alkyl, alkoxy, alkylsulfanyl, alkylamino, dialkylamino, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, aralkyl, heteroaryl, and heteroaralkyl groups include any substituent which will form a stable compound of the invention. Examples of substituents for an alkyl, alkoxy, alkylsulfanyl, alkylamino, dialkylamino, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, aralkyl, heteroaryl, and heteroaralkyl include an alkyl, an alkoxy, an alkylsulfanyl, an alkylamino, a dialkylamino, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, a heterocyclyl, an aryl, a heteroaryl, an aralkyl, a heteraralkyl, a haloalkyl, â€”C(O)NR₂₃R₂₄, â€”NR₂₅C(O)R₂₆, halo, â€”OR₅, cyano, nitro, haloalkoxy, â€”C(O)R₂₅, â€”NR₂₃R₂₄, â€”SR₂₅, â€”C(O)OR₂₅, â€”OC(O)R₂₅, â€”NR₂₅C(O)NR₂₃R₂₄, â€”OC (O)NR₂₃R₂₄, â€”NR₂₅C(O)OR₂₆, â€”S(O)_pR₂₅, or â€”S(O)_pNR₂₃R₂₄, wherein R₂₃and R₂₄, for each occurrence are, independently, H, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, a heterocyclyl, an aryl, a heteroaryl, an aralkyl, or a heteraralkyl; or R₂₃and R₂₄taken together with the nitrogen to which they are attached is a heterocyclyl or a heteroaryl; and R₂₅and R₂₆for each occurrence are, independently, H, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, a heterocyclyl, an aryl, a heteroaryl, an aralkyl, or a heteraralkyl;

In addition, alkyl, cycloalkyl, alkylene, a heterocyclyl, and any saturated portion of a alkenyl, cycloalkenyl, alkynyl, aralkyl, and heteroaralkyl groups, may also be substituted with â• O, â• S, â• Nâ€”R₂₂.

When a heterocyclyl, heteroaryl, or heteroaralkyl group contains a nitrogen atom, it may be substituted or unsubstituted. When a nitrogen atom in the aromatic ring of a heteroaryl group has a substituent the nitrogen may be a quaternary nitrogen.

Choices and combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable compounds. The term â€œstableâ€ , as used herein, refers to compounds which possess stability sufficient to allow manufacture and which maintains the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject). Typically, such compounds are stable at a temperature of 40Â° C. or less, in the absence of excessive moisture, for at least one week. Such choices and combinations will be apparent to those of ordinary skill in the art and may be determined without undue experimentation.

Unless indicated otherwise, the compounds of the invention containing reactive functional groups (such as, without limitation, carboxy, hydroxy, and amino moieties) also include protected derivatives thereof. â€œProtected derivativesâ€ are those compounds in which a reactive site or sites are blocked with one ore more protecting groups. Suitable protecting groups for carboxy moieties include benzyl, tert-butyl, and the like. Suitable protecting groups for amino and amido groups include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and the like. Suitable protecting groups for hydroxy include benzyl, trimethyl silyl (TMS) and the like. Other suitable protecting groups are well known to those of ordinary skill in the art and include those found in T. W. Greene, Protecting Groups in Organic Synthesis, John Wiley & Sons, Inc. 1981, the entire teachings of which are incorporated herein by reference.

As used herein, the term â€œcompound(s) of this inventionâ€ and similar terms refers to a compound of any one of formulas (I), (IIA), (IIB), (IIIA), (IIIB), (IVA), (IVB), (VA), or (VB), or Table 1, or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof and also include protected derivatives thereof.

As used herein and unless otherwise indicated, the term â€œprodrugâ€ means a derivative of a compound that can hydrolyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide a compound of this invention. Prodrugs may only become active upon such reaction under biological conditions, but they may have activity in their unreacted forms. Examples of prodrugs contemplated in this invention include, but are not limited to, analogs or derivatives of compounds of any one of formulas (I), (IIA), (IIB), (IIIA), (IIIB), (IVA), (IVB), (VA), or (VB), or Table 1 that comprise biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues. Other examples of prodrugs include derivatives of compounds of any one of formulas (I), (IIA), (IIB), (IIIA), (IIIB), (IVA), (IVB), (VA), or (VB), or of Table 1 that comprise â€”NO, â€”NO₂, â€”ONO, or â€”ONO₂moieties. Prodrugs can typically be prepared using well-known methods, such as those described by 1 BURGER'S MEDICIIVAL CHEMISTRY AND DRUG DISCOVERY (1995) 172-178, 949-982 (Manfred E. Wolff ed., 5^thed), the entire teachings of which are incorporated herein by reference.

As used herein and unless otherwise indicated, the terms â€œbiohydrolyzable amideâ€ , â€œbiohydrolyzable esterâ€ , â€œbiohydrolyzable carbamateâ€ , â€œbiohydrolyzable carbonateâ€ , â€œbiohydrolyzable ureideâ€ and â€œbiohydrolyzable phosphate analogueâ€ mean an amide, ester, carbamate, carbonate, ureide, or phosphate analogue, respectively, that either: 1) does not destroy the biological activity of the compound and confers upon that compound advantageous properties in vivo, such as uptake, duration of action, or onset of action; or 2) is itself biologically inactive but is converted in vivo to a biologically active compound. Examples of biohydrolyzable amides include, but are not limited to, lower alkyl amides, Î±-amino acid amides, alkoxyacyl amides, and alkylaminoalkylcarbonyl amides. Examples of biohydrolyzable esters include, but are not limited to, lower alkyl esters, alkoxyacyloxy esters, alkyl acylamino alkyl esters, and choline esters. Examples of biohydrolyzable carbamates include, but are not limited to, lower alkylamines, substituted ethylenediamines, aminoacids, hydroxyalkylamines, heterocyclic and heteroaromatic amines, and polyether amines.

As used herein, the term â€œpharmaceutically acceptable salt,â€ is a salt formed from an acid and a basic group of one of the compounds of any one of formulas (I), (IIA), (IIB), (IIIA), (IIIB), (IVA), (IVB), (VA), or (VB), or of Table 1. Illustrative salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1â€²-methylene-bis-(2-hydroxy-3-naphthoate)) salts. The term â€œpharmaceutically acceptable saltâ€ also refers to a salt prepared from a compound of any one of formulas (I), (IIA), (IIB), (IIIA), (IIIB), (IVA), (IVB), (VA), or (VB), or Table 1 having an acidic functional group, such as a carboxylic acid functional group, and a pharmaceutically acceptable inorganic or organic base. Suitable bases include, but are not limited to, hydroxides of alkali metals such as sodium, potassium, and lithium; hydroxides of alkaline earth metal such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, and organic amines, such as unsubstituted or hydroxy-substituted mono-, di-, or trialkylamines; dicyclohexylamine; tributyl amine; pyridine; N-methyl,N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-hydroxy-lower alkyl amines), such as mono-, bis-, or tris-(2-hydroxyethyl)-amine, 2-hydroxy-tert-butylamine, or tris-(hydroxymethyl)methylamine, N,N,-di-lower alkyl-N-(hydroxy lower alkyl)-amines, such as N,N-dimethyl-N-(2-hydroxyethyl)-amine, or tri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; and amino acids such as arginine, lysine, and the like. The term â€œpharmaceutically acceptable saltâ€ also refers to a salt prepared from a compound of any one of formulas (I), (IIA), (IIB), (IIIA), (IIIB), (IVA), (IVB), (VA), or (VB), or Table 1 having a basic functional group, such as an amino functional group, and a pharmaceutically acceptable inorganic or organic acid. Suitable acids include, but are not limited to, hydrogen sulfate, citric acid, acetic acid, oxalic acid, hydrochloric acid, hydrogen bromide, hydrogen iodide, nitric acid, phosphoric acid, isonicotinic acid, lactic acid, salicylic acid, tartaric acid, ascorbic acid, succinic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucaronic acid, saccharic acid, formic acid, benzoic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.

When a disclosed compound is named or depicted by structure, it is to be understood that solvates (e.g., hydrates) of the compound or its pharmaceutically acceptable salts are also included. â€œSolvatesâ€ refer to crystalline forms wherein solvent molecules are incorporated into the crystal lattice during crystallization. Solvate may include water or nonaqueous solvents such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine, and EtOAc. Solvates, wherein water is the solvent molecule incorporated into the crystal lattice, are typically referred to as â€œhydratesâ€ . Hydrates include a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

When a disclosed compound is named or depicted by structure, it is to be understood that the compound, including solvates thereof, may exist in crystalline forms, non-crystalline forms or a mixture thereof. The compounds or solvates may also exhibit polymorphism (i.e. the capacity to occur in different crystalline forms). These different crystalline forms are typically known as â€œpolymorphs.â€ It is to be understood that when named or depicted by structure, the disclosed compounds and solvates (e.g., hydrates) also include all polymorphs thereof. As used herein, the term â€œpolymorphâ€ means solid crystalline forms of a compound of the present invention or complex thereof. Different polymorphs of the same compound can exhibit different physical, chemical and/or spectroscopic properties. Different physical properties include, but are not limited to stability (e.g., to heat or light), compressibility and density (important in formulation and product manufacturing), and dissolution rates (which can affect bioavailability). Differences in stability can result from changes in chemical reactivity (e.g., differential oxidation, such that a dosage form discolors more rapidly when comprised of one polymorph than when comprised of another polymorph) or mechanical characteristics (e.g., tablets crumble on storage as a kinetically favored polymorph converts to thermodynamically more stable polymorph) or both (e.g., tablets of one polymorph are more susceptible to breakdown at high humidity). Different physical properties of polymorphs can affect their processing. For example, one polymorph might be more likely to form solvates or might be more difficult to filter or wash free of impurities than another due to, for example, the shape or size distribution of particles of it. In addition, one polymorph may spontaneously convert to another polymorph under certain conditions.

When a disclosed compound is named or depicted by structure, it is to be understood that clathrates (â€œinclusion compoundsâ€ ) of the compound or its pharmaceutically acceptable salts, solvates or polymorphs are also included. As used herein, he term â€œclathrateâ€ means a compound of the present invention or a salt thereof in the form of a crystal lattice that contains spaces (e.g., channels) that have a guest molecule (e.g., a solvent or water) trapped within.

As used herein, the term â€œasthmaâ€ means a pulmonary disease, disorder or condition characterized by reversible airway obstruction, airway inflammation, and increased airway responsiveness to a variety of stimuli.

â€œImmunosuppressionâ€ refers to impairment of any component of the immune system resulting in decreased immune function. This impairment may be measured by any conventional means including whole blood assays of lymphocyte function, detection of lymphocyte proliferation and assessment of the expression of T cell surface antigens. The antisheep red blood cell (SRBC) primary (IgM) antibody response assay (usually referred to as the plaque assay) is one specific method. This and other methods are described in Luster, M. I., Portier, C., Pait, D. G., White, K. L., Jr., Gennings, C., Munson, A. E., and Rosenthal, G. J. (1992). â€œRisk Assessment in Immunotoxicology I: Sensitivity and Predictability of Immune Tests.â€ Fundam. Appl. Toxicol., 18, 200-210. Measuring the immune response to a T-cell dependent immunogen is another particularly useful assay (Dean, J. H., House, R. V., and Luster, M. I. (2001). â€œImmunotoxicology: Effects of, and Responses to, Drugs and Chemicals.â€ In Principles and Methods of Toxicology: Fourth Edition (A. W. Hayes, Ed.), pp. 1415-1450, Taylor & Francis, Philadelphia, Pa.).

The compounds of this invention can be used to treat subjects with immune disorders. As used herein, the term â€œimmune disorderâ€ and like terms means a disease, disorder or condition caused by the immune system of an animal, including autoimmune disorders. Immune disorders include those diseases, disorders or conditions that have an immune component and those that are substantially or entirely immune system-mediated. Autoimmune disorders are those wherein the animal's own immune system mistakenly attacks itself, thereby targeting the cells, tissues, and/or organs of the animal's own body. For example, the autoimmune reaction is directed against the nervous system in multiple sclerosis and the gut in Crohn's disease. In other autoimmune disorders such as systemic lupus erythematosus (lupus), affected tissues and organs may vary among individuals with the same disease. One person with lupus may have affected skin and joints whereas another may have affected skin, kidney, and lungs. Ultimately, damage to certain tissues by the immune system may be permanent, as with destruction of insulin-producing cells of the pancreas in Type 1 diabetes mellitus. Specific autoimmune disorders that may be ameliorated using the compounds and methods of this invention include without limitation, autoimmune disorders of the nervous system (e.g., multiple sclerosis, myasthenia gravis, autoimmune neuropathies such as Guillain-BarrÃ©, and autoimmune uveitis), autoimmune disorders of the blood (e.g., autoimmune hemolytic anemia, pernicious anemia, and autoimmune thrombocytopenia), autoimmune disorders of the blood vessels (e.g., temporal arteritis, anti-phospholipid syndrome, vasculitides such as Wegener's granulomatosis, and Behcet's disease), autoimmune disorders of the skin (e.g., psoriasis, dermatitis herpetiformis, pemphigus vulgaris, and vitiligo), autoimmune disorders of the gastrointestinal system (e.g., Crohn's disease, ulcerative colitis, primary biliary cirrhosis, and autoimmune hepatitis), autoimmune disorders of the endocrine glands (e.g., Type 1 or immune-mediated diabetes mellitus, Grave's disease. Hashimoto's thyroiditis, autoimmune oophoritis and orchitis, and autoimmune disorder of the adrenal gland); and autoimmune disorders of multiple organs (including connective tissue and musculoskeletal system diseases) (e.g., rheumatoid arthritis, systemic lupus erythematosus, scleroderma, polymyositis, dermatomyositis, spondyloarthropathies such as ankylosing spondylitis, and Sjogren's syndrome). In addition, other immune system mediated diseases, such as graft-versus-host disease and allergic disorders, are also included in the definition of immune disorders herein. Because a number of immune disorders are caused by inflammation, there is some overlap between disorders that are considered immune disorders and inflammatory disorders. For the purpose of this invention, in the case of such an overlapping disorder, it may be considered either an immune disorder or an inflammatory disorder. â€œTreatment of an immune disorderâ€ herein refers to administering a compound or a composition of the invention to a subject, who has an immune disorder, a symptom of such a disease or a predisposition towards such a disease, with the purpose to cure, relieve, alter, affect, or prevent the autoimmune disorder, the symptom of it, or the predisposition towards it.

As used herein, the term â€œallergic disorderâ€ means a disease, condition or disorder associated with an allergic response against normally innocuous substances. These substances may be found in the environment (such as indoor air pollutants and aeroallergens) or they may be non-environmental (such as those causing dermatological or food allergies). Allergens can enter the body through a number of routes, including by inhalation, ingestion, contact with the skin or injection (including by insect sting). Many allergic disorders are linked to atopy, a predisposition to generate the allergic antibody IgE. Because IgE is able to sensitize mast cells anywhere in the body, atopic individuals often express disease in more than one organ. For the purpose of this invention, allergic disorders include any hypersensitivity that occurs upon re-exposure to the sensitizing allergen, which in turn causes the release of inflammatory mediators. Allergic disorders include without limitation, allergic rhinitis (e.g., hay fever), sinusitis, rhinosinusitis, chronic or recurrent otitis media, drug reactions, insect sting reactions, latex reactions, conjunctivitis, urticaria, anaphylaxis and anaphylactoid reactions, atopic dermatitis, asthma and food allergies.

The compounds of this invention can be used to prevent or to treat subjects with inflammatory disorders. As used herein, an â€œinflammatory disorderâ€ means a disease, disorder or condition characterized by inflammation of body tissue or having an inflammatory component. These include local inflammatory responses and systemic inflammation. Examples of such inflammatory disorders include: transplant rejection, including skin graft rejection; chronic inflammatory disorders of the joints, including arthritis, rheumatoid arthritis, osteoarthritis and bone diseases associated with increased bone resorption; inflammatory bowel diseases such as ileitis, ulcerative colitis, Barrett's syndrome, and Crohn's disease; inflammatory lung disorders such as asthma, adult respiratory distress syndrome, and chronic obstructive airway disease; inflammatory disorders of the eye including corneal dystrophy, trachoma, onchocerciasis, uveitis, sympathetic ophthalmitis and endophthalmitis; chronic inflammatory disorders of the gums, including gingivitis and periodontitis; tuberculosis; leprosy; inflammatory diseases of the kidney including uremic complications, glomerulonephritis and nephrosis; inflammatory disorders of the skin including sclerodermatitis, psoriasis and eczema; inflammatory diseases of the central nervous system, including chronic demyelinating diseases of the nervous system, multiple sclerosis, AIDS-related neurodegeneration and Alzheimer's disease, infectious meningitis, encephalomyelitis, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and viral or autoimmune encephalitis; autoimmune disorders, immune-complex vasculitis, systemic lupus and erythematodes; systemic lupus erythematosus (SLE); and inflammatory diseases of the heart such as cardiomyopathy, ischemic heart disease hypercholesterolemia, atherosclerosis;

as well as various other diseases with significant inflammatory components, including preeclampsia; chronic liver failure, brain and spinal cord trauma, and cancer. There may also be a systemic inflammation of the body, exemplified by gram-positive or gram negative shock, hemorrhagic or anaphylactic shock, or shock induced by cancer chemotherapy in response to pro-inflammatory cytokines, e.g., shock associated with pro-inflammatory cytokines. Such shock can be induced, e.g., by a chemotherapeutic agent used in cancer chemotherapy. â€œTreatment of an inflammatory disorderâ€ herein refers to administering a compound or a composition of the invention to a subject, who has an inflammatory disorder, a symptom of such a disorder or a predisposition towards such a disorder, with the purpose to cure, relieve, alter, affect, or prevent the inflammatory disorder, the symptom of it, or the predisposition towards it.

An â€œeffective amountâ€ is the quantity of compound in which a beneficial outcome is achieved when the compound is administered to a subject or alternatively, the quantity of compound that possess a desired activity in-vivo or in-vitro. In the case of inflammatory disorders and autoimmune disorders, a beneficial clinical outcome includes reduction in the extent or severity of the symptoms associated with the disease or disorder and/or an increase in the longevity and/or quality of life of the subject compared with the absence of the treatment. The precise amount of compound administered to a subject will depend on the type and severity of the disease or condition and on the characteristics of the subject, such as general health, age, sex, body weight and tolerance to drugs. It will also depend on the degree, severity and type of inflammatory disorder, autoimmune disorder, allergic disorder, or the degree of immunosuppression sought. The skilled artisan will be able to determine appropriate dosages depending on these and other factors. Effective amounts of the disclosed compounds typically range between about 1 mg/m²per day and about 10 grams/m²per day, and preferably between 10 mg/m²per day and about 1 gram/m².

The compounds of the invention may contain one or more chiral centers and/or double bonds and, therefore, may exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers), enantiomers, or diastereomers. According to this invention, the chemical structures depicted herein, including the compounds of this invention, encompass all of the corresponding compoundsâ€™ enantiomers and stereoisomers, that is, both the stereomerically pure form (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) and enantiomeric, diastereomeric, and geometric isomeric mixtures. In some cases, one enantiomer, diastereomer, or geometric isomer will possess superior activity or an improved toxicity or kinetic profile compared to others. In those cases, such enantiomers, diastereomers, and geometric isomers of a compound of this invention are preferred.

The term â€œinhibit production of IL-2â€ and like terms means inhibiting IL-2 synthesis (e.g. by inhibiting transcription (mRIVA expression), or translation (protein expression)) and/or inhibiting IL-2 secretion in a cell that has the ability to produce and/or secrete IL-2 (e.g., T lymphocyte). Likewise, the term â€œinhibiting production of IL-4, IL-5, IL-13, GM-CSF, TNF-Î± or INF-Î³ means inhibiting the synthesis (e.g. by inhibiting transcription, or translation) and/or inhibiting the secretion in a cell that has the ability to produce and/or secrete these cytokines.

As used herein, a composition that â€œsubstantiallyâ€ comprises a compound means that the composition contains more than about 80% by weight, more preferably more than about 90% by weight, even more preferably more than about 95% by weight, and most preferably more than about 97% by weight of the compound.

As used herein, a composition that is â€œsubstantially freeâ€ of a compound means that the composition contains less than about 20% by weight, more preferably less than about 10% by weight, even more preferably less than about 5% by weight, and most preferably less than about 3% by weight of the compound.

As used herein, a reaction that is â€œsubstantially completeâ€ means that the reaction contains more than about 80% by weight of the desired product, more preferably more than about 90% by weight of the desired product, even more preferably more than about 95% by weight of the desired product, and most preferably more than about 97% by weight of the desired product.

As used herein, a racemic mixture means about 50% of one enantiomer and about 50% of is corresponding enantiomer relative to all chiral centers in the molecule. The invention encompasses all enantiomerically-pure, enantiomerically-enriched, diastereomerically pure, diastereomerically enriched, and racemic mixtures of the compounds of any one of formulas (I), (IIA), (IIB), (IIIA), (IIIB), (IVA), (IVB), (VA), or (VB), or Table 1.

Enantiomeric and diastereomeric mixtures can be resolved into their component enantiomers or stereoisomers by well known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent. Enantiomers and diastereomers can also be obtained from diastereomerically- or enantiomerically-pure intermediates, reagents, and catalysts by well known asymmetric synthetic methods.

When administered to a patient, e.g., to a non-human animal for veterinary use or for improvement of livestock, or to a human for clinical use, the compounds of the invention are typically administered in isolated form or as the isolated form in a pharmaceutical composition. As used herein, â€œisolatedâ€ means that the compounds of the invention are separated from other components of either (a) a natural source, such as a plant or cell, preferably bacterial culture, or (b) a synthetic organic chemical reaction mixture. Preferably, via conventional techniques, the compounds of the invention are purified. As used herein, â€œpurifiedâ€ means that when isolated, the isolate contains at least 95%, preferably at least 98%, of a single compound of the invention by weight of the isolate.

Only those choices and combinations of substituents that result in a stable structure are contemplated. Such choices and combinations will be apparent to those of ordinary skill in the art and may be determined without undue experimentation.

The invention can be understood more fully by reference to the following detailed description and illustrative examples, which are intended to exemplify non-limiting embodiments of the invention.

Specific Embodiments

The invention relates to compounds and pharmaceutical compositions that are particularly useful for immunosuppression or to treat or prevent inflammatory conditions, immune disorders, and allergic disorders.

In one embodiment, the invention relates to compounds of structural formula (I):

[Image Omitted]

- or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein:
- X₁and X₂are, independently, CH or N;
- one of X₃or X₆is NR₂₉, and the other is CH₂, CHR₂, or C(R₂)₂;
- L is a linker selected from the group consisting of â€”NHCH₂â€”, â€”CH₂NHâ€”, â€”NR₅â€”C(O)â€”, â€”C(O)â€”NR₅â€”, â€”NR₅â€”C(S)â€”, â€”C(S)â€”NR₅â€”, â€”NR₅â€”C(NR₈)â€”, â€”C(NR₈)â€”NR₅â€”, â€”NR₅C(S)NR₅â€”, â€”NR₅C(NR₈)NR₅â€”, or â€”NR₅CR^aR^bNR₅â€”;
- Y is a substituted phenyl, provided that Y is not substituted with â€”NHC(O)R₃₀;
- R₁is H or a substituent;
- R₂, for each occurrence is, independently, a substituent, provided that R₂is not â• O or â• C(R₂₈)₂;
- R₄is a substituent;
- R^aand R^b, for each occurrence, are independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, cyano, nitro, halo, â€”OR₅, â€”SR₅, â€”NR₆R₇, â€”C(O)NR₆R₇, â€”NR₅C(O)R₅, â€”C(O)R₅, â€”C(O)OR₅, â€”OC(O)R₅, â€”C(O)SR₅, â€”SC(O)R₅, â€”C(S)NR₆R₇, â€”NR₅C(S)R₅, â€”C(S)R₅, â€”C(S)OR₅, â€”OC(S)R₅, â€”C(S)SR₅, â€”SC(S)R₅, â€”C(NR₈)NR₆R₇, â€”NR₅C(NR₈)R₅, â€”C(NR₈)R₅, â€”C(NR₈)OR₅, â€”OC(NR₈)R₅, â€”C(NR₈)SR₅, â€”SC(NR₈)R₅, â€”OC(O)OR₅, â€”OC(O)NR₆R₇, â€”NR₅C(O)OR₅, â€”NR₅C(O)NR₆R₇, â€”SC(O)OR₅, â€”SC(O)NR₆R₇, â€”SC(O)SR₅, â€”NR₅C(O)SR₅, â€”OC(O)SR₅, â€”OC(S)OR₅, â€”OC(S)NR₆R₇, â€”NR₅C(S)OR₅, â€”NR₅C(S)NR₆R₇, â€”SC(S)OR₅, â€”SC(S)NR₆R₇, â€”SC(S)SR₅, â€”NR₅C(S)SR₅, â€”OC(S)SR₅, â€”OC(NR₈)OR₅, â€”OC(NR₈)NR₆R₇, â€”NR₅C(NR₈)OR₅, â€”NR₅C(NR₈)NR₆R₇, â€”SC(NR₈)OR₅, â€”SC(NR₈)NR₆R₇, â€”SC(NR₈)SR₅, â€”NR₅C(NR₈)SR₅, or â€”OC(NR₈)SR₅;
- R₅, for each occurrence, is independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
- R₆and R₇, for each occurrence are, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R₆and R₇taken together with the nitrogen to which they are attached are an optionally substituted heterocyclyl or optionally substituted heteroaryl;
- R₈, for each occurrence, is independently â€”H, a halo, an alkyl, â€”OR₅, â€”NR₆R₇, â€”C(O)R₅, â€”C(O)OR₅, or â€”C(O)NR₆R₇;
- R₂₈, for each occurrence is, independently, H or a substituent;
- R₂₉is â€”C(O)R₃₀or a N-containing 6-membered aromatic ring;
- R₃₀is â€”H, â€”OR₅, â€”SR₅, â€”NR₆R₇, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
- m is 0, 1, or 2; and
- n is 0, 1 or 2.

In one aspect, the compound of formula (I) is not:

- 5-[4-(2,6-difluoro-benzoylamino)-phenyl]-4-methyl-2,4-dihydro-2H-pyridine-1-carboxylic acid ethyl ester;
- Ethyl 3-(4-(2,6-difluorobenzamido)phenyl)-4-methyl-5,6-dihydropyridine-1(2H)-carboxylate;
- Ethyl 4-(4-(2,6-difluorobenzamido)phenyl)-3-methyl-5,6-dihydropyridine-1(2H)-carboxylate;
- 2,6-Difluoro-N-[4-(1-methoxycarbonyl-4-thiazol-2-yl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide;
- 2,6-Difluoro-N-[4-(1-methoxycarbonyl-4-isopropyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide;
- 2,6-Difluoro-N-[4-(1-methoxycarbonyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide;
- 2,6-Difluoro-N-[4-(1-allyloxycarbonyl-3-methyl-1,2,5,6-tetrahydro-pyridin-4-yl)-phenyl]-benzamide;
- 2,6-Difluoro-N-[4-(1-phenyloxycarbonyl-3-methyl-1,2,5,6-tetrahydro-pyridin-4-yl)-phenyl]-benzamide;
- 2,6-Difluoro-N-[4-(1-acetyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide;
- 2,6-Difluoro-N-[4-(1-cyclopropylcarbonyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide;
- 2,6-Difluoro-N-{4-[1-(pyridine-3-carbonyl)-cyclopropanecarbonyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl]-phenyl}-benzamide; or
- 2,6-Difluoro-N-[4-(1-pyrimidin-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide.

In another embodiment, the invention relates to compounds represented by formula (IIA) or (IIB):

[Image Omitted]

- or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein
- R₃₁is halo, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
- p is 1, 2, 3, 4 or 5; and
- R₁, R₃₀, L, X₁, and X₂are defined as for formula (I).

In another embodiment, the invention relates to compounds represented by formula (IIIA) or (IIIB):

[Image Omitted]

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein R₁, R₃₀, L, X₁, and X₂are defined as for formula (I) and R₃₁is defined as for formulas (IIA) and (IIB).

In another embodiment, the invention relates to compounds represented by formula (IVA) or (IVB):

[Image Omitted]

- or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein
- each of X₇, X₈, X₉, X₁₀, and X₁₁are independently CH, CR₂, or N, provided that at least one of X₇, X₈, X₉, X₁₀, or X₁₁is N;
- R₃₁is halo, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
- p is 1, 2, 3, 4 or 5; and

R₁, L, X₁, and X₂are defined as for formula (I)

In another embodiment, the invention relates to compounds represented by formula (VA) or (VB):

[Image Omitted]

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein R₁, L, X₁, and X₂are defined as for formula (I) and X₇, X₈, X₉, X₁₀, and X₁₁are defined as for formulas (IVA) and (IVB).

In some embodiments of the compounds represented by formula (I), (IIA), (IIB), (IIIA), (IIIB), (IVA), (IVB), (VA), or (VB), R₁is selected from the group consisting of a halo, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl. In one aspect, R₁is selected from the group consisting of halo or an optionally substituted lower alkyl. In one aspect, R₁is selected from the group consisting of â€”CH₂OAc, CH₃, or Cl.

In some embodiments of the compounds represented by formula (I), (IIA), (IIB), (IIIA), (IIIB), (IVA), (IVB), (VA), or (VB), L is â€”NHCH₂â€”, â€”CH₂NHâ€”, â€”NHâ€”C(O)â€”, or â€”C(O)â€”NHâ€”. In one aspect, L is â€”NHC(O)â€”.

In some embodiments of the compounds represented by formula (I), (IIA), (IIB), (IIIA), (IIIB), (IVA), (IVB), (VA), or (VB), X₁and X₂are both CH.

In some embodiments of the compounds represented by formula (I), (IIA), (IIB), (IIIA), (IIIB), (IVA), (IVB), (VA), or (VB), X₁and X₂are both N.

In some embodiments of the compounds represented by formula (I), (IIA), (IIB), (IIIA), (IIIB), (IVA), (IVB), (VA), or (VB), X₁is N and X₂is CH.

In some embodiments of the compounds represented by formula (I), (IIA), (IIB), (IIIA), (IIIB), (IVA), (IVB), (VA), or (VB), X₂is N and X₁is CH.

In some embodiments of the compounds represented by formula (I), Y is substituted with one to two substituents. In one aspect, the one to two substituents are each independently a lower alkyl or a halo. In another aspect, Y is a difluorophenyl. In a further aspect, Y is 2,6-difluorophenyl.

In some embodiments of the compounds represented by formula (I), X₃is CH₂and X₆is NR₂₉.

In some embodiments of the compounds represented by formula (I), X₆is CH₂and X₃is NR₂₉.

In some embodiments of the compounds represented by formula (I), m is 0.

In some embodiments of the compounds represented by formula (I), Y is a difluorophenyl;

L is â€”NHC(O)â€”; R₁is selected from the group consisting of halo or an optionally substituted lower alkyl; and m is 0.

In some embodiments of the compounds represented by formula (IIA), (IIB), (IIIA), (IIIB), (IVA), (IVB), (VA), or (VB), each R₃₁is independently a lower alkyl or a halo. In one aspect, R₃₁is halo. In one aspect, R₃₁is F.

In some embodiments of the compounds represented by formula (IIA), (IIB), (IVA), or (IVB), p is 1 or 2. In one aspect, each R₃₁is independently a lower alkyl or a halo. In one aspect, R₃₁is halo. In one aspect, R₃₁is F.

In some embodiments of the compounds represented by formula (IIIA), (IIIB), (VA), or (VB), each R₃₁is independently a lower alkyl or a halo. In one aspect, each R₃₁is halo. In another aspect, each R₃₁is F.

In some embodiments of the compounds represented by formula (IIA), (IIB), (IIIA), or (IIIB), R₃₀is selected from the group consisting of â€”OR₅, optionally substituted alkyl, optionally substituted aryl, and optionally substituted heteroaryl. In one aspect, R₃₀is selected from the group consisting of â€”OR₅and optionally substituted heteroaryl. In another aspect, R₃₀is â€”OR₅and R₅is a lower alkyl. In a further aspect, R₃₀is a pyridine ring.

In some embodiments of the compounds represented by formula (IVA), (IVB), (VA), or (VB), two of X₇, X₈, X₉, X₁₀, and X₁₁are N. In one aspect, X₇and X₁₁are both N.

In some embodiments of the compounds represented by formula (IVA), (IVB), (VA), or (VB), one of X₇, X₈, X₉, X₁₀, and X₁₁is N.

In some embodiments of the compounds represented by formula (IIIA) or (IIIB), each R₃₁is halo;

L is â€”NHC(O)â€”; R₁is selected from the group consisting of halo or an optionally substituted lower alkyl; and R₃₀is selected from the group consisting of â€”OR₅and optionally substituted heteroaryl. In one aspect, each R₃₁is F. In one aspect, X₁and X₂are both CH. In another aspect, X₁and X₂are both N. In a further aspect, X₁is N and X₂is CH.

In some embodiments of the compounds represented by formula (VA), or (VB), each R₃₁is halo;

L is â€”NHC(O)â€”; R₁is selected from the group consisting of halo or an optionally substituted lower alkyl; and two of X₇, X₈, X₉, X_X10, and X₁₁are N. In one aspect, each R₃₁is F. In one aspect, X₁and X₂are both CH. In another aspect, X₁and X₂are both N. In a further aspect, X₁is N and X₂is CH.

In one embodiment, the compounds of the invention are not compounds disclosed in U.S. patent application Ser. No. 11/699,002.

In another embodiment, the invention relates to compounds selected from the group consisting of:

ethyl 3-(6-(2,6-difluorobenzamido)pyridin-3-yl)-4-methyl-5,6-dihydropyridine-1(2H)-carboxylate;

allyl 3-(acetoxymethyl)-4-(4-(2,6-difluorobenzamido)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate;

2,6-difluoro-N-(5-(4-methyl-1-picolinoyl-1,2,5,6-tetrahydropyridin-3-yOpyridin-2-yl(benzamide hydrochloride;

ethyl 3-(acetoxymethyl)-4-(4-(2,6-difluorobenzamido)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate or

ethyl 4-chloro-3-(4-(2,6-difluorobenzamido)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate;

- or pharmaceutically acceptable salts, solvates, clathrates, or prodrugs thereof.

In another embodiment, the invention relates to 2,6-difluoro-N-(5-(4-methyl-1-(pyrimidin-2-yl)-1,2,5,6-tetrahydropyridin-3-yl)pyrazin-2-yl)benzamide hydrochloride or pharmaceutically acceptable salts, solvates, clathrates, or prodrugs thereof.

In another embodiment, the invention relates to

2,6-difluoro-N-(5-(4-methyl-1-(pyridin-2-yl)-1,2,5,6-tetrahydropyridin-3-yl)pyridin-2-yl(benzamide;

2,6-difluoro-N-(5-(4-methyl-1-(pyridin-2-yl)-1,2,5,6-tetrahydropyridin-3-yl)pyridin-2-yl(benzamide hydrochloride;

2,6-difluoro-N-(4-(4-methyl-1-(pyridin-2-yl)-1,2,5,6-tetrahydropyridin-3-yl)phenyl)benzamide;

2,4-difluoro-N-(4-(4-methyl-1-(pyridin-2-yl)-1,2,5,6-tetrahydropyridin-3-yl)phenyl)benzamide;

2,6-difluoro-N-(5-(4-methyl-1-(pyrazin-2-yl)-1,2,5,6-tetrahydropyridin-3-yl)pyrazin-2-yl)benzamide;

N-(5-(1-(3-chloropyrazin-2-yl)-4-methyl-1,2,5,6-tetrahydropyridin-3-yl)pyrazin-2-yl)-2,6-difluorobenzamide;

2,6-difluoro-N-(4-(4-methyl-1-(pyridin-2-yl)-1,2,5,6-tetrahydropyridin-3-yl)phenyl)benzamide hydrochloride;

2-chloro-6-fluoro-N-(4-(4-methyl-1-(pyridin-2-yl)-1,2,5,6-tetrahydropyridin-3-yl)phenyl)benzamide hydrochloride;

N-(5-(1-(3-chloropyridin-2-yl)-4-methyl-1,2,5,6-tetrahydropyridin-3-yl)pyrazin-2-yl)-2,6-difluorobenzamide hydrochloride;

N-(5-(1-(3-chloropyrazin-2-yl)-4-methyl-1,2,5,6-tetrahydropyridin-3-yl)pyrazin-2-yl)-2,4-difluorobenzamide;

2,6-difluoro-N-(5-(1-(3-fluoropyridin-2-yl)-4-methyl-1,2,5,6-tetrahydropyridin-3-yl)pyrazin-2-yl)benzamide hydrochloride;

2,4-difluoro-N-(5-(1-(3-fluoropyridin-2-yl)-4-methyl-1,2,5,6-tetrahydropyridin-3-yl)pyrazin-2-yl(benzamide hydrochloride;

N-(5-(1-(3-cyanopyridin-2-yl)-4-methyl-1,2,5,6-tetrahydropyridin-3-yl)pyrazin-2-yl)-2,6-difluorobenzamide;

N-(5-(1-(3,5-difluoropyridin-2-yl)-4-methyl-1,2,5,6-tetrahydropyridin-3-yl)pyrazin-2-yl)-2,6-difluorobenzamide;

N-(5-(1-(3,5-dichloropyridin-2-yl)-4-methyl-1,2,5,6-tetrahydropyridin-3-yl)pyrazin-2-yl)-2,6-difluorobenzamide;

N-(5-(1-(3-bromopyridin-2-yl)-4-methyl-1,2,5,6-tetrahydropyridin-3-yl)pyrazin-2-yl)-2,6-difluorobenzamide;

N-(4-(1-(3-aminopyrazin-2-yl)-4-methyl-1,2,5,6-tetrahydropyridin-3-yl)phenyl)-2,6-difluorobenzamide;

4-(1-(3-chloropyrazin-2-yl)-4-methyl-1,2,5,6-tetrahydropyridin-3-yl)â€”N-(2,6-difluorobenzyl)aniline;

N-(4-(1-(3-cyanopyrazin-2-yl)-4-methyl-1,2,5,6-tetrahydropyridin-3-yl)phenyl)-2,6-difluorobenzamide;

2,6-difluoro-N-(4-(1-(3-fluoropyrazin-2-yl)-4-methyl-1,2,5,6-tetrahydropyridin-3-yl)phenyl)benzamide;

N-(4-(1-(3-chloropyrazin-2-yl)-4-methyl-1,2,5,6-tetrahydropyridin-3-yl)phenyl)-2,6-difluorobenzamide; or

In another embodiment, the invention relates to

2,6-difluoro-N-(5-(4-methyl-1-(pyrimidin-2-yl)-1,2,5,6-tetrahydropyridin-3-yl)pyrazin-2-yl(benzamide hydrochloride

2,6-difluoro-N-(5-(4-methyl-1-(pyridin-2-yl)-1,2,5,6-tetrahydropyridin-3-yl)pyridin-2-yl)benzamide;