COMPOUNDS WITH ACTIVITY AT CANNABINOID CB2 RECEPTORS

RELATED APPLICATIONS

[001] This application claims priority to the U.S. Provisional Application Serial No. 60/917,318, filed on May 10, 2007, by Ethan Burstein et al., and entitled "COMPOUNDS WITH ACTIVITY AT CANNABINOID CB2 RECEPTORS", and the U.S. Provisional Application Serial No. 60/942,746, filed on June 8, 2007, by Ethan Burstein et al., and entitled "COMPOUNDS WITH ACTIVITY AT CANNABINOID CB2 RECEPTORS", and the U.S. Provisional Application Serial No. 60/973,410, filed on September 18, 2007, by Ethan Burstein et al., and entitled "COMPOUNDS WITH ACTIVITY AT CANNABINOID CB2 RECEPTORS", all of which are incorporated by reference herein in their entirety, including any drawings.

FIELD OF THE INVENTION

[002] The present invention is in the field of pharmaceuticals, and in particular in the field of compounds that bind to cannabinoid CB2 receptors and diagnosis and treatment of diseases with these compounds.

BACKGROUND

[003] The cannabinoids, which are bioactive lipids found in the cannabis sativa (marijuana) plant, have been used recreationally and therapeutically for at least 5000 years. In addition to their well-documented effects on mood, cannabinoids (often in the form of marijuana) have been prescribed to treat nausea, pain, migraine, epilepsy, glaucoma, hypertension, cachexia and pain associated with childbirth. Two cannabinoid receptors, CBl and CB2, have been identified (reviewed in Howlett et al., 2004). Both are members of the G protein-coupled receptor superfamily, and are negatively coupled through Gi protein. The CB2 receptor has 44% sequence similarity to the CB 1 receptor.

[004] CB2 cannabinoid receptors were first cloned from differentiated human HL-60 myeloid cells, and are most highly expressed in spleen (Monro et al, 1993), and cells of the immune system such as B cells, T cells, natural killer cells, macrophages, monocytes, and neutrophils (Galiegue et al, 1995; Carlisle et al, 2002; Lee et al, 2001; Ueda et al, 2005). Lower levels of CB2 receptors are also found in epidermis including keratinocytes, hair follicles, sebocytes, and sweat glands (Stander

et al, 2005; Ibrahim et al, 2005; Walczak et al, 2005), as well as osteoblasts, osteoclasts, and osteocytes (Ofec et al, 2006), and stomach, lung, heart and testis (Onaivi et al, 2006). CB2 receptor expression has been reported in dorsal root ganglion (DRG) neurons (Ross et al, 2001; Beltramo et al, 2006; Walczak et al, 2005; Wotherspoon et al, 2005), and evidence for CB2 receptor expression in other peripheral neurons such as C- and Adelta-fibers has been reported (Martin et al, 2000; Patel et al, 2003; Yoshihara et al; 2004; Elmes et al, 2004). Recently CB2 receptor expression within the CNS has been described, at both the spinal and supraspinal levels. Specifically, CB2 receptors are found in lumbar (L3-L4) spinal cord (Beltramo et al, 2006; Walczak et al, 2005), and in cerebellar granule neurons (Skaper et al, 1996), cerebrovascular epithelium (Golech et al, 2004), microglia (Klegeris et al, 2003) and neurons of the brainstem (striatum, thalamic nuclei, hippocampus, amygdala, substantia nigra, periaqueductal gray, spinal trigeminal nucleus etc.), cortex and cerebellum (Ashton et al, 2006; Gong et al, 2006; Van Sickle et al; 2005).

[005] CB2 receptors have been implicated in a number of physiological processes including inflammation and perception of pain (Whiteside et al, 2007), immune system regulation (Sipe et al, 2005), neurogenesis (Palazuelos et al, 2006), and bone physiology (Karsak et al, 2005). Upregulation of CB2 receptors is associated with certain pathophysiological states. Increased CB2 receptor expression has been detected in dorsal horn of the spinal cord as well as primary afferent, C-fiber neurons in chronic constriction injury (CCI), spinal nerve ligation (SNL), complete sciatic nerve section, and saphenous nerve partial ligation models of neuropathic pain (Zhang et al, 2003; Walczak et al, 2005; Wotherspoon et al, 2005). CB2 receptors are upregulated in microglia and astrocytes from neuritic plaques found in Alzheimer's diseased brains (Benito et al, 2003), or by interferon gamma (Carlisle et al, 2002) or lipopolysaccharide (Cabral et al, 2005), and in T-lymphocytes from simian immunodeficiency virus-infected macaques (Benito et al, 2005). CB2 receptors are found in T-lymphocytes, astrocytes and perivascular and reactive microglia in multiple sclerosis plaques (Benito et al, 2007).

SUMMARY OF THE INVENTION [006] Disclosed herein is a compound of Formula I or Formula II

rmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein a) Ai, A ₂ , A ₃ , and A ₄ is each independently carbon or nitrogen; b) Di, D ₂ , D ₃ , D ₄ , and D ₅ is each independently carbon or nitrogen; c) Ri is selected from the group consisting of optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclic ring, and optionally substituted heterocyclic ring; d) R ₂ , R ₃ , R ₄ , and R5 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroalicyclyl, halogen, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, perhaloalkyl, CN, C(=Z)R', C(=Z)OR', C(=Z)NR'R", -C(R')=NR', -NR'R", -N=CR'R", N(R')C(=Z)R', N(R')C(=Z)NR'R", -S(O)NR ⁵ R", -S(O) ₂ NR ⁵ R", N(R')S(=0)R\ N(R')S(=0) ₂ R', -OR', -SR', and OC(=Z)R', wherein R' and R" are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heteroalicyclyl, and Z is oxygen or sulfur, provided that

R ₂ does not exist when Ai is nitrogen, R ₃ does not exist when A ₂ is nitrogen, R ₄ does not exist when A ₃ is nitrogen, and R ₅ does not exist when A ₄ is nitrogen; e) Re, R7, Rs, R9, and Rio is each independently selected from the group consisting of hydrogen, alkyl, halo, perhaloalkyl, hydroxy, and alkoxy, or R ₆ and R ₇ taken together along with the carbon atoms to which they

are attached, or R ₇ and Rs taken together along with the carbon atoms to which they are attached, or R ₈ and Rg taken together along with the carbon atoms to which they are attached, or Rg and Rio taken together along with the carbon atoms to which they are attached form a five- or six-membered ring selected from the group consisting of optionally substituted carbocyclic ring or optionally substituted heterocyclic ring, optionally substituted aryl, and optionally substituted heteroaryl, provided that

Re does not exist when Di is nitrogen, R ₇ does not exist when D ₂ is nitrogen, Rs does not exist when D ₃ is nitrogen, R ₉ does not exist when D ₄ is nitrogen; and Rio does not exist when D ₅ is nitrogen; and R25 is alkyl, optionally substituted with optionally substituted aryl, CC=Z)NR ₂₆ R ₂₇ , CN, C(=Z)R ₂₆ , C(=Z)OR ₂₆ , -C(R ₂₆ )=NR ₂₆ , -NR ₂₆ R ₂₇ , - N=CR ₂₆ R ₂₇ , N(R ₂₆ )C(=Z)R ₂₆ , N(R ₂₆ )C(=Z)NR ₂₆ R ₂₇ , -S(O)NR ₂₆ R ₂₇ , - S(O) ₂ NR ₂₆ R ₂₇ , N(R ₂₆ )S(=O)R ₂₆ , N(R ₂₆ )S(=O) ₂ R ₂₆ , -OR ₂₆ , -SR ₂₆ , and OC(=Z)R ₂₆ , wherein R ₂₆ and R ₂₇ are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heteroalicyclyl, and Z is oxygen or sulfur, or wherein R ₂₆ and R ₂₇ taken together along with the carbon atom, or nitrogen atom, to which they are attached form a five- or six- membered ring selected from the group consisting of optionally

substituted carbocyclic ring or optionally substituted heterocyclic ring, optionally substituted aryl, and optionally substituted heteroaryl.

[007] Disclosed are also methods of modulating the activity of a cannabinoid CB2 receptor comprising contacting a compound of Formula I or Formula II with the cannabinoid CB2 receptor.

[008] Also disclosed are methods of treating a disease or disorder associated with the CB2 receptor comprising identifying a subject in need thereof and administering to the subject a therapeutically effective amount of a compound of Formula I or Formula II.

DETAILED DESCRIPTION OF THE INVENTION

[009] CB2 receptor modulators (i.e., agonists, partial agonists, antagonists, or inverse agonists) have therapeutic utility for analgesia, acute and chronic pain, inflammatory pain, post-operative pain, neuropathic pain, muscle relaxation, immunosuppression, as anti-inflammatory agents, for allergies, glaucoma, bronchodilation, neuroprotection, osteoporosis and disorders of the skeletal system, cancer, neurodegenerative disorders including but not limited to Alzheimer's disease, Parkinson's disease (PD), and Huntington's disease, multiple sclerosis (MS), muscle spasticity, tremor, fibromyalgia, lupus, rheumatoid arthritis, myasthenia gravis, other autoimmune disorders, irritable bowel syndrome, interstitial cystitis, migraine, pruritis, excema, sebhorea, psoriasis, shingles, cerebral ischemia, cerebral apoplexy, craniocerebral trauma, stroke, spinal cord injury, liver cirrhosis, liver fibrosis, atherosclerosis, as an anti-tussive, asthma, nausea, emesis, gastric ulcers, and diarrhea.

[0010] Thus, in one aspect, disclosed herein is a compound of Formula I

rmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein a) A ₁ , A ₂ , A ₃ , and A ₄ is each independently carbon or nitrogen; b) D ₁ , D ₂ , D ₃ , D ₄ , and D ₅ is each independently carbon or nitrogen; c) Ri is selected from the group consisting of optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclic ring, and optionally substituted heterocyclic ring; d) R ₂ , R ₃ , R ₄ , and R ₅ is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroalicyclyl, halogen, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, perhaloalkyl, CN, C(=Z)R', C(=Z)OR', C(=Z)NR'R", -C(R')=NR', -NR'R", -N=CR ⁵ R", N(R')C(=Z)R\ N(R')C(=Z)NR'R", -S(O)NR ⁵ R", -S(O) ₂ NR ⁵ R", N(R')S(=0)R\ N(R')S(=0) ₂ R', -OR', -SR', and OC(=Z)R', wherein R' and R" are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heteroalicyclyl, and Z is oxygen or sulfur, provided that

R ₂ does not exist when Ai is nitrogen, R ₃ does not exist when A ₂ is nitrogen, R ₄ does not exist when A ₃ is nitrogen, and R ₅ does not exist when A ₄ is nitrogen; and e) Re, R7, Rs, R9, and Rio is each independently selected from the group consisting of hydrogen, alkyl, halo, perhaloalkyl, hydroxy, and alkoxy, or R ₆ and R ₇ taken together along with the carbon atoms to which they are attached, or R ₇ and Rs taken together along with the carbon atoms to which they are attached, or Rs and R9 taken together along with the carbon atoms to which they are attached, or R ₉ and Rio taken together along with the carbon atoms to which they are attached form a five- or six-membered ring selected from the group consisting of optionally substituted carbocyclic ring or optionally substituted heterocyclic ring, optionally substituted aryl, and optionally substituted heteroaryl,

provided that

Re does not exist when Di is nitrogen, R ₇ does not exist when D ₂ is nitrogen, Rs does not exist when D ₃ is nitrogen, R ₉ does not exist when D ₄ is nitrogen; and Rio does not exist when D ₅ is nitrogen.

[0011] In another aspect, disclosed herein is a compound of Formula II

or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein a) Ai, A ₂ , A ₃ , and A ₄ is each independently carbon or nitrogen; b) Ri is selected from the group consisting of optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclic ring, and optionally substituted heterocyclic ring; c) R ₂ , R ₃ , R ₄ , and R5 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroalicyclyl, halogen, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, perhaloalkyl, CN, C(=Z)R', C(=Z)OR', C(=Z)NR'R", -C(R')=NR', -NR'R", -N=CR'R", N(R')C(=Z)R', N(R')C(=Z)NR'R", -S(O)NR ⁵ R", -S(O) ₂ NR ⁵ R", N(R')S(=O)R\ N(R')S(=O) ₂ R', -OR', -SR', and OC(=Z)R', wherein R' and R" are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, optionally

substituted aryl, optionally substituted heteroaryl, and optionally substituted heteroalicyclyl, and Z is oxygen or sulfur, provided that

R ₂ does not exist when Ai is nitrogen, R ₃ does not exist when A ₂ is nitrogen, R ₄ does not exist when A ₃ is nitrogen, and R ₅ does not exist when A ₄ is nitrogen; and d) R ₂ 5 is alkyl, optionally substituted with optionally substituted aryl, CC=Z)NR ₂₆ R ₂₇ , CN, C(=Z)R ₂₆ , C(=Z)OR ₂₆ , -C(R ₂₆ )=NR ₂₆ , -NR ₂₆ R ₂₇ , - N=CR ₂₆ R ₂₇ , N(R ₂₆ )C(=Z)R ₂₆ , N(R ₂₆ )C(=Z)NR ₂₆ R ₂₇ , -S(O)NR ₂₆ R ₂₇ , - S(O) ₂ NR ₂₆ R ₂₇ , N(R ₂₆ )S(=O)R ₂₆ , N(R ₂₆ )S(=O) ₂ R ₂₆ , -OR ₂₆ , -SR ₂₆ , and OC(=Z)R ₂₆ , wherein R ₂₆ and R ₂₇ are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heteroalicyclyl, and Z is oxygen or sulfur, or wherein R ₂₆ and R ₂₇ taken together along with the carbon atom, or nitrogen atom, to which they are attached form a five- or six- membered ring selected from the group consisting of optionally substituted carbocyclic ring or optionally substituted heterocyclic ring, optionally substituted aryl, and optionally substituted heteroaryl.

[0012] The term "pharmaceutically acceptable salt" refers to a formulation of a compound that does not abrogate the biological activity and properties of the compound. Pharmaceutical salts can be obtained by reacting a compound of the invention with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid, salicylic acid and the like. Pharmaceutical salts can also be obtained by reacting a compound of the invention with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as

dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like.

[0013] The term "ester" refers to a chemical moiety with formula -(R) _n -COOR', where R and R' are independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring atom) and heteroalicyclic (bonded through a ring atom), and where n is 0 or 1.

[0014] An "amide" is a chemical moiety with formula -(R) _n -C(O)NHR' or -(R) _n -NHC(O)R', where R and R' are independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring atom) and heteroalicyclic (bonded through a ring atom), and where n is 0 or 1. An amide may be an amino acid or a peptide molecule attached to a molecule of the present invention, thereby forming a prodrug.

[0015] Any amine, hydroxy, or carboxyl side chain on the compounds of the present invention can be esterified or amidified. The procedures and specific groups used to achieve this end are known to those of skill in the art and can readily be found in reference sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3 ^rd Ed., John Wiley & Sons, New York, N.Y., 1999, which is incorporated herein in its entirety.

[0016] A "prodrug" refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. An example, without limitation, of a prodrug would be a compound of the present invention which is administered as an ester (the "prodrug") to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water-solubility is beneficial. A further example of a prodrug might be a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active moiety.

[0017] Whenever a group of this invention is described as being "optionally substituted" that group may be unsubstituted or substituted with one or more of the substituents described for that group. Likewise, when a group is described as being "unsubstituted or substituted," if substituted, the substituent may

be selected from the same group of substituents. Unless otherwise indicated, when a substituent is deemed to be "optionally subsituted," or "substituted" it is meant that the subsitutent is a group that may be substituted with one or more group(s) individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (hetereoalicyclyl)alkyl, hydroxy, protected hydroxyl, alkoxy, aryloxy, acyl, ester, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, and amino, including mono- and di-substituted amino groups, and the protected derivatives thereof. The protecting groups that may form the protective derivatives of the above substituents are known to those of skill in the art and may be found in references Greene and Wuts, Protective Groups in Organic Synthesis, 3 ^rd Ed., John Wiley & Sons, New York, NY, 1999, which is hereby incorporated by reference in its entirety.

[0018] As used herein, "C _m to C _n " or "C _m -C _n " in which "m" and "n" are integers refers to the number of carbon atoms in an alkyl, alkenyl, alkynyl and the rings of cycloalkyl and cycloalkenyl group. That is, the alkyl, alkenyl or alkynyl can contain from "m" to "n", inclusive, carbon atoms. If no "m" and "n" are designated with regard to an alkyl, alkenyl or alkynyl group herein, the broadest range described in these definitions is to be assumed. Thus "alkyl" alone means C ₁ -C ₂₀ alkyl. A "Ci to C ₄ alkyl" group refers to all alkyl groups having from 1 to 4 carbons, that is, CH ₃ -, CH ₃ CH ₂ -, CH ₃ CH ₂ CH ₂ -, CH ₃ CH(CH ₃ )-, CH ₃ CH ₂ CH ₂ CH ₂ -, CH ₃ CH ₂ CH(CH ₃ )- and (CH ₃ ) ₃ CH-, etc. With regard to cyclic compounds, "m" and "n" provide the number of possible carbon atoms in the ring.

[0019] As used herein, "alkyl" refers to a straight or branched chain fully saturated (no double or triple bonds) hydrocarbon (all carbon) group. An alkyl group of this invention may comprise from 1 - 20 carbon atoms, that is, "m" = 1 and "n" = 20, designated as a "Ci to C ₂ o alkyl." In some embodiments, "m" = 1 and "n":= 12 (Ci to Ci ₂ alkyl). In other embodiments, that "m" = 1 and "n" = 6 (Ci to C ₆ alkyl). Examples of alkyl groups include, without limitation, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec -butyl, tert-butyl, amyl, tert-amyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl.

[0020] An alkyl group of this invention may be substituted or unsubstituted. When substituted, the substituent group(s) is(are) one or more group(s) independently selected from cycloalkyl, aryl, heteroaryl, heteroalicyclyl, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, oxo, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, -NR ^a R ^b , protected hydroxyl, protected amino, protected carboxy and protected amido groups.

[0021] Examples of substituted alkyl groups include, without limitation, 2- oxo-prop-1-yl, 3-oxo-but-l-yl, cyanomethyl, nitromethyl, chloromethyl, hydroxymethyl, tetrahydropyranyloxymethyl, m-trityloxymethyl, propionyloxymethyl, aminomethyl, carboxymethyl, allyloxycarbonylmethyl, allyloxycarbonylaminomethyl, methoxymethyl, ethoxymethyl, t-butoxymethyl, acetoxymethyl, chloromethyl, bromomethyl, iodomethyl, trifluoromethyl, 6- hydroxyhexyl, 2,4-dichlorobutyl, 2-aminopropyl, 1 -chloroethyl, 2-chloroethyl, 1- bromoethyl, 2-chloroethyl, 1 -fluoroethyl, 2-fluoroethyl, 1-iodoethyl, 2-iodoethyl, 1- chloropropyl, 2-chloropropyl, 3-chloropropyl, 1-bromopropyl, 2-bromopropyl, 3- bromopropyl, 1-fluoropropyl, 2-fluoropropyl, 3-fluoropropyl, 1 -iodopropyl, 2- iodopropyl, 3-iodopropyl, 2-aminoethyl, 1 -aminoethyl, N-benzoyl-2-aminoethyl, N- acetyl-2-aminoethyl, N-benzoyl-1 -aminoethyl and N-acetyl-1 -aminoethyl.

[0022] As used herein, "alkenyl" refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more double bonds. Examples of alkenyl groups include, without limitation, vinyl (CH ₂ =CH-), allyl (CH ₃ CH=CH ₂ -), 1- propenyl, 2-propenyl, 1-butenyl, 2-butenyl; 1-pentenyl, 2-pentenyl, 3-pentenyl, 4- pentenyl, 3 -methyl- 1-butenyl, and the various isomers of hexenyl, heptenyl, octenyl, nonenyl, decenyl undecenyl and dodecenyl.

[0023] An alkenyl group of this invention may be unsubstituted or substituted. When substituted, the substituent(s) may be selected from the same groups disclosed above with regard to alkyl group substitution. Examples of substituted alkenyl groups include, without limitation, styrenyl, 3-chloro-propen-l-yl, 3-chloro-buten-l-yl, 3-methoxy-propen-2-yl, 3-phenyl-buten-2-yl and 1-cyano-buten- 3-yl.

[0024] As used herein, "alkynyl" refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more triple bonds.

[0025] An alkynyl group of this invention may be unsubstituted or substituted. When substituted, the substituent(s) may be selected from the same groups disclosed above with regard to alkyl group substitution.

[0026] As used herein, "cycloalkyl" refers to a completely saturated (no double bonds) hydrocarbon ring. Cycloalkyl groups of this invention may range from C3 to Cio, preferably at present from C3 to C ₇ . Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

[0027] As used herein, "cycloalkenyl" refers to a cycloalkyl group that contains one or more double bonds in the ring although, if there is more than one, they cannot form a fully delocalized pi-electron system in the ring (otherwise the group would be "aryl," as defined herein). A cycloalkenyl of this invention may have from 5 to 10 carbon atoms in the ring, i.e., it may be C ₅ to C ₁₀ , preferably at present C ₅ to C ₇ . An cycloalkenyl group of this invention may unsubstituted or substituted. When substituted, the substituent(s) may be selected from the same groups disclosed above with regard to alkyl group substitution.

[0028] As used herein, "acyl" refers to an "RC(=O)O-" Examples of acyl groups include, without limitation, formyl, acetyl, propionyl, butyryl, pentanoyl, pivaloyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl and benzoyl. Presently preferred acyl groups are acetyl and benzoyl.

[0029] An acyl group of this invention may be unsubstituted or substituted. When substituted, the substituent(s) may be selected from the same groups disclosed above with regard to alkyl group substitution. Example of substituted acyl groups include, without limitation, 4-phenylbutyroyl, 3- phenylbutyroyl, 3-phenylpropanoyl, 2-cyclohexanylacetyl, cyclohexanecarbonyl, 2- furanoyl and 3-dimethylaminobenzoyl.

[0030] The term "aromatic" refers to an aromatic group which has at least one ring having a conjugated pi electron system and includes both carbocyclic aryl (e.g., phenyl) and heterocyclic aryl groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups. The term "carbocyclic" refers to a compound which contains one or more covalently closed ring structures, wherein the atoms forming the backbone of the ring are all carbon atoms. The term "heteroaromatic" or "heteroaryl" refers to an

aromatic group, which contains at least one heterocyclic ring, which may be optionally substituted.

[0031] As used herein, "aryl" refers to a carbocyclic (all carbon) ring or two or more fused rings (rings that share two adjacent carbon atoms) that have a fully delocalized pi-electron system. Examples of aryl groups include, but are not limited to, benzene, and substituted benzene, such as toluene, aniline, xylene, and the like, naphthalene and substituted naphthalene, and azulene.

[0032] As used herein, "heteroaryl" refers to a ring or two or more fused rings that contain(s) one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and that have a fully delocalized pi-electron system. Examples of heteroaryl groups include, but are not limited to, furan, thiophene, pyrrole, pyrroline, pyrrolidine, oxazole, thiazole, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, isoxazole, isothiazole, triazole, thiadiazole, pyran, pyridine, piperidine, morpholine, thiomorpholine, pyridazine, pyrimidine, pyrazine, piperazine, triazine.

[0033] As used herein, "heteroalicyclic," "heteroalicyclyl," or "heterocyclic" refers to a ring or one or more fused rings having in the ring system one or more heteroatoms independently selected from nitrogen, oxygen and sulfur. The rings may also contain one or more double bonds provided that they do not create a fully delocalized pi-electron system in the rings. Heteroalicyclyl groups of this invention may be unsubstituted or substituted. When substituted, the substituent(s) may be one or more groups independently selected from the group consisting of, without limitation, halogen, hydroxy, protected hydroxy, cyano, nitro, alkyl, alkoxy, acyl, acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino, (monosubstituted)amino, protected (monosubstituted)amino, (disubstituted)amino, carboxamide, protected carboxamide, N-alkylcarboxamide, protected N- alkylcarboxamide, N,N-dialkylcarboxamide, trifluoromethyl, N-alkylsulfonylamino and N-(phenylsulfonyl)amino. Presently preferred heteroalicyclyl groups include, without limitation, morpholino, piperidinyl, piperazinyl, 2-amino-imidazoyl, tetrahydrofurano, pyrrolo, tetrahydrothiophenyl, hexylmethyleneimino and heptylmethyleneimino.

[0034] As used herein, "arylalkyl" or "aralkyl," which are used synonymously and interchangeably, refer to an aryl group covalently bonded to an

alkyl group, as defined herein. A "phenylalkyl" is a species of an aralkyl group, and refers to a phenyl ring covalently bonded to an alkyl group as defined herein. Examples, without limitation, of phenylalkyl groups include, without limitation, benzyl, 2-phenylethyl, 1-phenylpropyl, 4-phenylhexyl, 3-phenylamyl and 3-phenyl-2- methylpropyl. Presently preferred phenylalkyl groups are those wherein the phenyl group is covalently bonded to one of the presently preferred alkyl groups. A phenyl alkyl group of this invention may be unsubstituted or substituted. Examples of substituted phenylalkyl groups include, without limitation, 2-phenyl-l-chloroethyl, 2- (4-methoxyphenyl)ethyl, 4-(2,6-dihydroxy phenyl)hexyl, 2-(5-cyano-3- methoxyphenyl)pentyl, 3-(2,6-dimethylphenyl)propyl, 4-chloro-3-aminobenzyl, 6-(A- methoxyphenyl)-3-carboxy(n-hexyl), 5-(4-aminomethylphenyl)-3-

(aminomethyl)pentyl and 5-phenyl-3-oxo-pent-l-yl.

[0035] As used herein, "heteroarylalkyl" or "heteroaralkyl," which are used synonymously and interchangeably, and "heteroalicyclylalkyl" refer to a heteroaryl or a heteroalicyclyl group, respectively, covalently bonded to an alkyl group, as defined herein. Examples of such groups include, without limitation, 2- pyridylethyl, 3-pyridylpropyl, 4-furylhexyl, 3-piperazylamyl and 3-morpholinylbutyl. Presently preferred heteroarylalkyl and heteroalicyclylalkyl groups are those in which a presently preferred heteroaryl or heteroalicyclyl group is covalently bonded to a presently preferred alkyl group as disclosed herein.

[0036] As used herein, "phenyl" refers to a 6-member aryl group. A phenyl group may be unsubstituted or substituted. When substituted the substituent(s) is/are one or more, preferably one or two, group(s) independently selected from the group consisting of halogen, hydroxy, protected hydroxy, cyano, nitro, alkyl, alkoxy, acyl, acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, -NR ^a R ^b wherein R ^a and R ^b are as defined above but in addition R ^a may be an amino protecting group as defined herein, carboxamide, protected carboxamide, N-alkylcarboxamide, protected N- alkylcarboxamide, N,N-dialkylcarboxamide, trifluoromethyl, N-alkylsulfonylamino, N-(phenylsulfonyl)amino and phenyl (resulting in the formation of a biphenyl group).

[0037] Examples of substituted phenyl groups include, without limitation, 2, 3 or 4-chlorophenyl, 2,6-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 2, 3 or 4-bromophenyl, 3,4-dibromophenyl, 3-chloro-4-fluorophenyl, 2, 3 and A- fluorophenyl, 2, 3 or 4-hydroxyphenyl, 2,4-dihydroxyphenyl, the protected-hydroxy

derivatives thereof, 2, 3 or 4-nitrophenyl; 2, 3 or 4-cyanophenyl; 2, 3 or A- methylphenyl, 2,4-dimethylphenyl, 2, 3 or 4-(iso-propyl)phenyl, 2, 3 or A- ethylphenyl, 2, 3 or 4-(n-propyl)phenyl, 2,6-dimethoxyphenyl, 2, 3 or A- methoxyphenyl, 2, 3 or 4-ethoxyphenyl, 2, 3 or 4-(isopropoxy)phenyl, 2, 3 or 4-(t- butoxy)phenyl, 3-ethoxy-4-methoxyphenyl; 2, 3 or 4-trifluoromethylphenyl; 2, 3 or A- carboxyphenyl or 2,4-di(protected carboxy)phenyl; 2, 3, or 4-(protected hydroxymethyl)phenyl or 3,4-di(hydroxymethyl)phenyl; 2, 3 or A- (aminomethyl)phenyl or 2,4-(protected aminomethyl)phenyl; and 2, 3 or 4-(N- (methylsulfonylamino))phenyl.

[0038] As used herein, "phenylalkoxy" refers to a "phenylalkyl-O-" group with "phenyl" and "alkyl" as defined herein. A phenylalkoxy group of this invention may be substituted or unsubstituted on the phenyl ring, in the alkyl group or both. Examples of phenylalkoxy groups include, without limitation, 2-(4- hydroxyphenyl)ethoxy, 4-(4-methoxyphenyl)butoxy, (2R)-3-phenyl-2-amino- propoxy, (2S)-3-phenyl-2-amino-propoxy, 2-indanoxy, 6-phenyl-l-hexanoxy, cinnamyloxy, 2-phenyl-l-propoxy and 2,2-dimethyl-3 -phenyl- 1-propoxy.

[0039] As used herein, "halo" and "halogen" refer to the fluoro, chloro, bromo or iodo atoms. Presently preferred halogens are chloro and fluoro.

[0040] As used herein, "amino protecting group" refers to a group commonly employed to keep (i.e., to "block" or "protect") an amino group from reacting with a reagent while it reacts with an intended target functional group of a molecule.

[0041] As used herein, a "protected carboxamide" refers to a carboxamide in which the nitrogen is substituted with an amino protecting group.

[0042] Examples of amino protecting groups include, without limitation, formyl ("For"), trityl, phthalimido, trichloroacetyl, chloroacetyl, bromoacetyl, iodoacetyl groups, t-butoxycarbonyl ("Boc"), 2-(4-biphenylyl)propyl-2-oxycarbonyl ("Bpoc"), 2-phenylpropyl-2-oxycarbonyl ("Poc"), 2-(4-xenyl)isopropoxycarbonyl, 1 , 1 -diphenylethyl- 1 -oxycarbonyl, 1 , 1 -diphenylpropyl- 1 -oxycarbonyl, 2-(3 ,5 - dimethoxyphenyl)propyl-2-oxycarbonyl ("Ddz"), 2-(p-toluyl)propyl-2-oxycarbonyl, cyclopentanyloxycarbonyl, 1 -methylcyclopentanyloxycarbonyl, cyclohexanyloxy- carbonyl, 1-methylcyclohexanyloxycarbonyl, 2-methylcyclohexanyloxycarbonyl, 2- (4-toluylsulfonyl)-ethoxycarbonyl, 2-(methylsulfonyl)ethoxycarbonyl, 2-

(triphenylphosphino)-ethoxycarbonyl, 9-fluorenylmethoxycarbonyl ("Fmoc"), 2-

(trimethylsilyl)ethoxycarbonyl, allyloxycarbonyl, 1 -(trimethylsilylmethyl)prop- 1 - enyloxycarbonyl, 5-benzisoxalylmethoxycarbonyl, 4-acetoxybenzyl-oxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl, cyclopropyl- methoxycarbonyl, isobornyloxycarbonyl, 1 -piperidyloxycarbonyl, benzyloxycarbonyl ("Cbz"), 4-phenylbenzyloxycarbonyl, 2-methylbenzyloxy-carbonyl, -2,4,5,- tetramethylbenzyloxycarbonyl ("Tmz"), 4-methoxybenzyloxy- carbonyl, A- fluorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, 2- chlorobenzyloxycarbonyl, 2,4-dichlorobenzyl-oxycarbonyl, A- bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl, 4-nitrobenzyloxy -carbonyl, A- cyanobenzyloxycarbonyl, 4-(decyloxy) benzyloxycarbonyl, benzoylmethylsulfonyl, dithiasuccinoyl ("Dts"),2-(nitro)phenylsulfenyl ("Nps"), and diphenyl-phosphine oxide. The species of amino-protecting group employed is not critical so long as the derivatized amino group is stable to the conditions of the subsequent reaction(s) and can be removed at the appropriate point without disrupting the remainder of the molecule. Presently preferred amino-protecting groups are Boc, Cbz and Fmoc. Descriptions of these and other amino-protecting groups may be found in T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis," 2nd ed., John Wiley and Sons, New York, N.Y., 1991, Chapter 7, M. Bodanzsky, "Principles of Peptide Synthesis," 1st and 2nd revised ed., Springer-Verlag, New York, N.Y., 1984 and 1993, and Stewart and Young, "Solid Phase Peptide Synthesis," 2nd ed., Pierce Chemical Co., Rockford, III, 1984.

[0043] As used herein, the term "carboxy protecting group" refers to a labile ester commonly used to block or protect a carboxylic acid while reactions are carried out on other functional groups on the compound. Examples of carboxy protecting groups include, without limitation, t-butyl, 4-nitrobenzyl, A- methoxybenzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, 2,4,6-trimethylbenzyl, pentamethylbenzyl, 3,4-methylenedioxybenzyl, benzhydryl, 4,4'-dimethoxytrityl, 4,4',4"-trimethoxytrityl, 2-phenylpropyl, trimethylsilyl, t- butyldimethylsilyl, phenacyl, 2,2,2-trichloroethyl, -(trimethylsilyl)ethyl, -(di(n- butyl)methylsilyl)ethyl, p-toluenesulfonylethyl, 4-nitrobenzylsulfonylethyl, allyl, cinnamyl, and l-(trimethylsilylmethyl)-propenyl. The ester employed is not critical so long as it is stable to the conditions of subsequent reaction(s) and can be removed at the appropriate point without disrupting the remainder of the molecule. Further examples of carboxy -protecting groups are found in E. Haslam, "Protective Groups in

Organic Chemistry," J. G. W. McOmie, Ed., Plenum Press, New York, N.Y., 1973, Chapter 5, and T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis," 2nd ed., John Wiley and Sons, New York, N. Y., 1991, Chapter 5.

[0044] As used herein, a "hydroxyl protecting group" refers to a readily cleavable group that replaces the hydrogen of the hydroxyl group, such as, without limitation, tetrahydropyranyl, 2-methoxypropyl, 1-ethoxy ethyl, methoxymethyl, 2- methoxyethoxymethyl, methylthiomethyl, t-butyl, t-amyl, trityl, 4-methoxytrityl, 4,4'- dimethoxytrityl, 4,4',4"-trimethoxytrityl, benzyl, allyl, trimethylsilyl, (t- butyl)dimethylsilyl, and 2,2,2-trichloroethoxycarbonyl. The species of hydroxyl protecting groups is not critical so long as the derivatized hydroxyl group is stable to the conditions of subsequent reaction(s) and can be removed at the appropriate point without disrupting the remainder of the molecule. Further examples of hydroxy- protecting groups are described by C. B. Reese and E. Haslam, "Protective Groups in Organic Chemistry," J. G. W. McOmie, Ed., Plenum Press, New York, N.Y., 1973, Chapters 3 and 4, respectively, and T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis," 2nd ed., John Wiley and Sons, New York, N.Y., 1991, Chapters 2 and 3.

[0045] As used herein, "alkylthio" refers to an "alkyl-S-" group, with alkyl as defined above. Examples of alkylthio group include, without limitation, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio and t-butylthio.

[0046] As used herein, "alkylsulfinyl" refers to an "alkyl-SO-" group, with alkyl as defined above. Examples of alkylsulfinyl groups include, without limitation, methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl, n-butylsulfinyl and sec-butylsulfinyl.

[0047] As used herein, "alkylsulfonyl" refers to an "alkyl-SO ₂ -" group. Examples of alkylsulfonyl groups include, without limitation, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, and t- butylsulfonyl.

[0048] As used herein, "phenylthio," "phenylsulfinyl," and "phenylsulfonyl" refer to a "phenyl-S-," "phenyl-SO-," and "phenyl-SO ₂ -" group, phenyl as defined herein.

[0049] As used herein, "alkylaminocarbonyl" refers to an "alkylNHC(=O)-" group, with alkyl as defined herein. Examples of alkylaminocarbonyl groups include, without limitation, methylaminocarbonyl,

ethylaminocarbonyl, propylaminocarbonyl and butylaminocarbonyl. Examples of substituted alkylaminocarbonyl include,without limitation, methoxymethyl- aminocarbonyl, 2-chloroethylaminocarbonyl, 2-oxopropylaminocarbonyl and A- phenylbutylaminocarbonyl.

[0050] As used herein, "alkoxycarbonyl" refers to an "alkyl-OC(=O)-" group, with alkyl as defined above.

[0051] As used herein, "phenylaminocarbonyl" refers to a "phenyl-NHC(=O)-" group, with phenyl as defined above. Examples of substituted phenylaminocarbonyl groups include, without limitation, 2- chlorophenyl-aminocarbonyl, 3-chlorophenylaminocarbonyl, 2- nitorphenylaminocarbonyl, 4-biphenylaminocarbonyl, and A- methoxyphenylaminocarbonyl.

[0052] As used herein, "alkylaminothiocarbonyl" refers to an "alkyl- NHC(=O)-" group, with alkyl as defined above. Examples of alkylaminothiocarbonyl groups include, without limitation, methylaminothiocarbonyl, ethylaminothiocarbonyl, propylaminothiocarbonyl and butylaminothiocarbonyl.

[0053] Examples of alkyl-substituted alkylaminothiocarbonyl groups include, without limitation, methoxymethylaminothiocarbonyl, 2- chloroethylaminothiocarbonyl, 2-oxopropylaminothiocarbonyl and A- phenylbutylaminothiocarbonyl.

[0054] As used herein, "phenylaminothiocarbonyl" refers to a "phenyl- NHC(=S)-" group, with phenyl as defined above. Examples of phenylaminothiocarbonyl groups include, without limitation, 2- chlorophenylaminothiocarbonyl, 3-chlorophenyl-aminothiocarbonyl, 2- nitrophenylaminothiocarbonyl, 4-biphenylaminothiocarbonyl and A- methoxyphenylaminothiocarbonyl.

[0055] As used herein, "carbamoyl" refers to an "-NCO-" group.

[0056] As used herein, "hydroxyl" refers to an "-OH" group.

[0057] As used herein, "cyano" refers to a "-C≡N" group.

[0058] As used herein, "nitro" refers to an "-NO ₂ " group.

[0059] An "O-carboxy" group refers to a "RC(=O)O-" group with R as defined above.

[0060] A "C-carboxy" group refers to a "-C(O)OR" group with R as defined above.

[0061] An "acetyl" group refers to a CH ₃ C(=O)- group.

[0062] A "trihalomethanesulfonyl" group refers to an "X ₃ CSO ₂ -" group wherein X is a halogen.

[0063] An "isocyanato" group refers to an "-NCO" group.

[0064] A "thiocyanato" group refers to a "-CNS" group.

[0065] An "isothiocyanato" group refers to an " -NCS" group.

[0066] A "sulfinyl" group refers to an "-S(=O)-R" group with R as defined above.

[0067] An "S-sulfonamido" group refers to a "-SO ₂ NR" group with R as defined above.

[0068] An "N-sulfonamido" group refers to a "RSO ₂ NH-" group with R as defined above.

[0069] A "trihalomethanesulfonamido" group refers to an "X ₃ CSO ₂ NR-" group with X as halogen and R as defined above.

[0070] An "O-carbamyl" group refers to a "-OC(=O)-NR" group with R as defined above.

[0071] An "N-carbamyl" group refers to an "ROC(=O)NH-" group with R as defined above.

[0072] An "O-thiocarbamyl" group refers to a "-OC(=S)-NR" group with R as defined above.

[0073] "N-thiocarbamyl" group refers to an "ROC(=S)NH-" group with R as defined above.

[0074] A "C-amido" group refers to a "-C(=O)-NR ^a R ^b group with R ^a and R as defined above.

[0075] An "N-amido" group refers to a RC(=O)NH- group with R as defined above.

[0076] The term "haloalkyl" refers to an alkyl group where one or more of the hydrogen atoms are replaced by halogen. Such groups include but are not limited to , chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl and l-chloro-2- fluoromethyl, 2-fluoroisobutyl.

[0077] The term "perhaloalkyl" refers to an alkyl group in which all the hydrogen atoms are replaced by halogen atoms.

[0078] As used herein, an "ester" refers to a "-C(O)OR ^a " group with R ^a as defined herein.

[0079] As used herein, an "amide" refers to a "-C(0)NR ^a R ^b " group with R ^a and R ^b as defined herein.

[0080] Where the numbers of substituents are not specified (e.g. haloalkyl) there may be one or more substituents presents. For example "haloalkyl" may include one or more of the same or differents halogens. As another example "C ₁ -C ₃ alkoxy phenyl" may include one or more of the same of different alkoxygroups containing one, two or three atoms.

[0081] Any unsubstituted or monosubstituted amine group on a compound herein can be converted to an amide, any hydroxyl group can be converted to an ester and any carboxyl group can be converted to either an amide or ester using techniques well-known to those skilled in the art (see, for example, Greene and Wuts, Protective Groups in Organic Synthesis, 3 ^rd Ed., John Wiley & Sons, New York, NY, 1999). Compounds containing any such converted hydroxyl, amino and/or carboxylic acid groups are within the scope of this invention.

[0082] As used herein, an "ether" refers to a "-C-O-C-" group wherein either or both carbons may independently be part of an alkyl, alkenyl, alkynyl, aryl, heteroaryl or heteroalicyclyl group.

[0083] As used herein, a "halogenated ether" refers to an ether in which the groups to either side of the oxygen are both alkyl substituted with halogen.

[0084] As used herein, "amino acid" refers to any one of the twenty naturally-occurring L-amino acids, to their non-natural D-enantiomers, to non- naturally occurring amino acids such as, without limitation, norleucine ("NIe"), norvaline ("Nva"), L- or D-naphthalanine, ornithine ("Orn"), homoarginine (homoArg) and to other amino acids well-known in the peptide art such as those described in M. Bodanzsky, "Principles of Peptide Synthesis," 1st and 2nd revised ed., Springer-Verlag, New York, N.Y., 1984 and 1993, and Stewart and Young, "Solid Phase Peptide Synthesis," 2nd ed., Pierce Chemical Co., Rockford, 111.

[0085] When two substituents taken together along with the carbon atoms to which they are attached form a five- or six-membered optionally substituted carbocyclic ring or optionally substituted heterocyclic ring, or form a six-membered optionally substituted aryl, optionally substituted heteroaryl, it is meant that the following structure:

can be representative of, for example, the following structures:

where X is a heteroatom.

[0086] Throughout the present disclosure, when a particular compound comprises a chiral center, the scope of the present disclosure also includes compositions comprising the racemic mixture of the two enantiomers, as well as compositions comprising each enantiomer individually substantially free of the other enantiomer. Thus, for example, contemplated herein is a composition comprising the S enantiomer substantially free of the R enantiomer, or a composition comprising the R enantiomer substantially free of the S enantiomer. By "substantially free" it is meant that the composition comprises less than 10%, or less than 8%, or less than 5%, or less than 3%, or less than 1% of the minor enantiomer. If the particular compound comprises more than one chiral center, the scope of the present disclosure also includes compositions comprising a mixture of the various diastereomers, as well as compositions comprising each diastereomer substantially free of the other diastereomers. The recitation of a compound, without reference to any of its particular diastereomers, includes compositions comprising all four diastereomers, compositions comprising the racemic mixture of R,R and S, S isomers, compositions comprising the racemic mixture of R,S and S,R isomers, compositions comprising the R,R enantiomer substantially free of the other diastereomers, compositions comprising the S, S enantiomer substantially free of the other diastereomers, compositions comprising the R, S enantiomer substantially free of the other diastereomers, and compositions comprising the S,R enantiomer substantially free of the other diastereomers.

[0087] In some embodiments of the compound of Formula I or Formula II, Ri is an optionally substituted heteroaryl. The heteroaryl may be selected from the

group consisting of furan, thiophene, phthalazinone, pyrrole, oxazole, thiazole, imidazole, pyrazole, isoxazole, isothiazole, triazole, thiadiazole, pyran, pyridine, pyridazine, pyrimidine, pyrazine and triazine.. In some embodiments, the heteroaryl is pyridyl or thiophenyl.

[0088] In some embodiments of the compound of Formula I or Formula II, Ri is an optionally substituted aryl, which can be phenyl. In some of these embodiments, Ri is

where

R ₁₁ , Ri2, Ri3, R ₁₄ , and R15 is each independently selected from the group consisting of hydrogen, alkyl, halo, perhaloalkyl, hydroxy, alkoxy, and mercaptoalkyl, or Rn and R ₁₂ taken together along with the carbon atoms to which they are attached, or Ri ₂ and Ri 3 taken together along with the carbon atoms to which they are attached, or Ri ₃ and R ₁₄ taken together along with the carbon atoms to which they are attached, or R ₁₄ and Ri 5 taken together along with the carbon atoms to which they are attached form a five- or six-membered optionally substituted carbocyclic ring or optionally substituted heterocyclic ring, or form a six-membered optionally substituted aryl, optionally substituted heteroaryl.

[0089] In some embodiments, the alkyl is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec -butyl, tert-butyl, and methylencyclopropyl. In further embodiments, the alkoxy is selected from the group consisting of methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, and tert-butoxy. In additional embodiments, the halo is selected from the group consisting of fluoro, chloro, bromo, and iodo.

[0090] In some embodiments, Ri is

where a) B ₁ , B ₂ , B ₃ , B ₄ , B ₅ , and B ₆ is each independently selected from the group consisting of carbon, sulfur, oxygen, and nitrogen; b) B ₇ , B ₈ , B ₉ , Bio, and Bn is each independently selected from the group consisting of carbon, sulfur, oxygen, and nitrogen; c) Ri6, Ri7, Ri8, R-19, and R20 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroalicyclyl, halogen, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, perhaloalkyl, CN, C(=Z)R', C(=Z)OR', C(=Z)NR'R", -C(R')=NR', -NR'R", -N=CR ⁵ R", N(R')C(=Z)R\ N(R')C(=Z)NR'R", -S(O)NR ⁵ R", -S(O) ₂ NR ⁵ R", N(R')S(=O)R\ N(R')S(=O) ₂ R', -OR', -SR', and OC(=Z)R', wherein R' and R" are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heteroalicyclyl, and Z is oxygen or sulfur, or Ri6 and Rn taken together along with the carbon atoms to which they are attached, or Ri ₇ and Ris taken together along with the carbon atoms to which they are attached, or Ris and R19 taken together along with the carbon atoms to which they are attached, or R ₁ 9 and R ₂ o taken together along with the carbon atoms to which they are attached form a five- or six-membered optionally substituted carbocyclic ring or optionally substituted heterocyclic ring, or form a six-membered optionally substituted aryl, optionally substituted heteroaryl; provided that,

Ri6 does not exist when B ₂ is not carbon, Rn does not exist when B ₃ is not carbon, Ri 8 does not exist when B ₄ is not carbon, Ri ₉ does not exist when B ₅ is not carbon, and R ₂ o does not exist when B ₆ is not carbon; and d) R ₂ i, R ₂₂ , R ₂ 3, and R ₂₄ is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,

cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroalicyclyl, halogen, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, perhaloalkyl, CN, C(=Z)R', C(=Z)OR', C(=Z)NR'R", -C(R')=NR', -NR'R", -N=CR ⁵ R", N(R')C(=Z)R', N(R')C(=Z)NR'R", -S(O)NR ⁵ R", -S(O) ₂ NR ⁵ R", N(R')S(=0)R\ N(R')S(=0) ₂ R', -OR', -SR', and OC(=Z)R', wherein R' and R" are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heteroalicyclyl, and Z is oxygen or sulfur, or R _2I and R ₂₂ taken together along with the carbon atoms to which they are attached, or R ₂₂ and R ₂₃ taken together along with the carbon atoms to which they are attached, or R ₂₃ and R ₂₄ taken together along with the carbon atoms to which they are attached form a five- or six-membered optionally substituted carbocyclic ring or optionally substituted heterocyclic ring, or form a six-membered optionally substituted aryl, optionally substituted heteroaryl; provided that,

R _2I does not exist when B ₈ is not carbon, R ₂₂ does not exist when Bg is not carbon, R ₂ 3 does not exist when Bio is not carbon, and R ₂₄ does not exist when Bn is not carbon.

[0091] In some embodiments, at least three of B ₁ , B ₂ , B ₃ , B ₄ , B ₅ , and B ₆ are carbon. In other embodiments, at least two of B ₁ , B ₂ , B ₃ , B ₄ , B ₅ , and B ₆ are carbon. In further embodiments, at least one of Bi, B ₂ , B ₃ , B ₄ , B ₅ , and B ₆ is carbon. In some embodiments, at least three Of B ₇ , B ₈ , B ₉ , Bi ₀ , and Bn are carbon. In other embodiments, at least two of B ₇ , B ₈ , B ₉ , Bi ₀ , and Bn are carbon. In additional embodiments, at least one Of B ₇ , B ₈ , B ₉ , Bi ₀ , and Bn is carbon.

[0092] In some of the above embodiments, Ri is selected from the group consisting of:

[0093] In some embodiments of the compound of Formula I or Formula II, at least three of Ai, A ₂ , A3, and A ₄ are carbon. In other embodiments, at least two of A ₁ , A ₂ , A ₃ , and A ₄ are carbon. In further embodiments, at least one of Ai, A ₂ , A ₃ , and A ₄ is carbon. In certain embodiments, all of Ai, A ₂ , A ₃ , and A ₄ are carbon.

[0094] In some embodiments of the compound of Formula I or Formula II, Ai is nitrogen and A ₂ , A ₃ , and A ₄ are carbon. In other embodiments, A ₂ is nitrogen and A ₁ , A3, and A ₄ are carbon.

[0095] In some embodiments, R ₂ , R3, R ₄ , and R5 is each independently alkyl and the alkyl is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec -butyl, tert-butyl, and methylencyclopropyl. In other embodiments, R ₂ , R3, R ₄ , and R5 is each independently halo and the halo is selected from the group consisting of fluoro, chloro, bromo, and iodo.

[0096] In some embodiments of the compound of Formula I or Formula II, the

moiety is selected from the group consisting of

[0097] In some embodiments of the compound of Formula I, at least four of Di, D ₂ , D ₃ , D ₄ , and D ₅ are carbon. In some embodiments, at least three of Di, D ₂ , D ₃ , D ₄ , and D ₅ are carbon. In other embodiments, at least two of Di, D ₂ , D ₃ , D ₄ , and D ₅ are carbon. In further embodiments, at least one of D ₁ , D ₂ , D ₃ , D ₄ , and D ₅ is carbon. In certain embodiments, all of Di, D ₂ , D ₃ , D ₄ , and D ₅ are carbon.

[0098] In some embodiments of the compound of Formula I, R ₆ , R7, Rs, Rg, and Rio is each independently alkyl and the alkyl is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec -butyl, tert-butyl, and methylencyclopropyl. In other embodiments, R ₆ , R7, Rs, R9, and Rio is each independently alkoxy and the alkoxy is selected from the group consisting of methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, and tert-butoxy. In further embodiments, R ₆ , R7, Rs, R9, and Rio is each independently halo and the halo is selected from the group consisting of fluoro, chloro, bromo, and iodo.

[0099] In some embodiments of the compound of Formula I, the

moiety is selected from the group consisting of

[00100] In some embodiments of the compounds of Formula II, R ₂ 5 is C ₁ - C5 alkyl. In some embodiments, the alkyl is selected from the group consisting of methyl, ethyl, propyl, n-butyl, sec -butyl, and tert-butyl.

[00101] In some embodiments, the alkyl is substituted with an aryl. The substituent can be in the ortho, meta, or para position. In some of these embodiments, the aryl is a phenyl. In some embodiments, the aryl is substituted with one or more substituent selected from the group consisting of hydroxy, alkoxy, aryloxy, acyl, ester, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, and amino. In some embodiments, the aryl is substituted with one or more halogen. In some of these embodiments, the halogen is chloro. In some embodiments, R ₂ 5 is 4-chlorobenzyl.

[00102] In some embodiments, the alkyl is substituted with one or more heterocyclic group. In some of these embodiments, the heterocyclic group is optionally substituted, and is selected from the group consisting of morpholino, piperidinyl, piperazinyl, imidazoyl, tetrahydrofurano, and pyrrolo. In some embodiments, the heterocyclic group is a morpholino. In some embodiments, R ₂ 5 is 2-(N-morpholino)-ethyl.

[00103] In some embodiments, the alkyl is substituted with - C(=O)NR26R27. In some embodiments, R26 and R27 are each independently selected

from the group consisting of hydrogen, methyl, ethyl, propyl, n-butyl, sec -butyl, and tert-butyl.

[00104] In some embodiments, when the alkyl is substituted with - R26 and R27 taken together along with the nitrogen atom to which they are attached form a five- or six-membered optionally substituted heterocyclic ring. In some of these embodiments, the heterocyclic group is optionally substituted, and is selected from the group consisting of morpholino, piperidinyl, piperazinyl, imidazoyl, tetrahydrofurano, and pyrrolo. In some embodiments, the heterocyclic group is a

morpholino. In some embodiments, R ₂ 5 is

[00105] In another aspect, disclosed herein is a compound selected from the group consisting of:

CR-IO CR-I l CR-12

CR- 13 CR- 14 CR- 15

CR- 16 CR- 17 CR- 18

CR- 19 CR-20 CR-21

CR-22 CR-23 CR-24

CR-25 CR-26 CR-27

CR-118 CR-119 CR-120

[00106] The compounds disclosed herein can be synthesized using well- known synthetic organic chemistry techniques. For example, imidazo[l,2-α]pyridines disclosed herein can be synthesized using the general reaction scheme set forth in Scheme 1:

SCHEME 1 where bmim is l-butyl3-methylimidazolium bromide, and R ₁ , R ₂ and R3 can be chosen to mach the desired compound disclosed herein. Full experimental detail is found in Shaabani, A.; Soleimani, E.; Maleki, A. "Ionic liquid promoted one-pot synthesis of 3-amino imidazo[l,2-α]pyridines," Tetrahedron Lett. 2006, 47, 3031- 3034. Alternative synthetic methodology is disclosed in Sharma, A.; Behera, G.B. "Condensation of 2-Substituted N-Phenacylium Bromide with p- Dimethylaminobenzaldehyde & p-Nitrosodimethylaniline," Indian J. Chem. 1976, 745, 551-552.

[00107] Imidazo[l,2-α]pyrimidines disclosed herein can be synthesized using the general reaction scheme set forth in Scheme 2:

SCHEME 2

[00108] Full experimental detail is found in Bienayme, H; Bouzid, K. "A New Heterocyclic Multicomponent Reaction for the Combinatorial Synthesis of Fuesed 3-Aminoimidazoles," ^«gew. Chem. Int. Ed. 1998, 37(16), 2234-2237.

[00109] In another aspect, disclosed herein is a method of modulating the activity of a cannabinoid CB2 receptor comprising contacting a compound of Formula I or Formula II with the cannabinoid CB2 receptor.

[00110] In the context of the present disclosure, a "modulator" is defined as a compound that is an agonist, a partial agonist, an inverse agonist or an antagonist of a cannabinoid CB2 receptor. A modulator may increase the activity of the cannabinoid CB2 receptor, or may decrease the activity of the cannabinoid CB2 receptor. In the context of the present disclosure, an "agonist" is defined as a compound that increases the basal activity of a receptor (i.e. signal transduction mediated by the receptor). An "antagonist" is defined as a compound, which blocks the action of an agonist on a receptor. A "partial agonist" is defined as an agonist that displays limited, or less than complete, activity such that it fails to activate a receptor in vitro, functioning as an antagonist in vivo. An "inverse agonist" is defined as a compound that decreases the basal activity of a receptor.

[00111] In some embodiments, the compound of Formula I or Formula II preferentially binds to cannabinoid CB2 receptor as compared to cannabinoid CBl receptor. Therefore, in these embodiments, the compound of Formula I or Formula II is selective for CB2.

[00112] In some embodiments, the cannabinoid CB2 receptor activity is modulated in vitro, whereas in other embodiments, the cannabinoid CB2 receptor activity is modulated in vivo.

[00113] In another aspect, disclosed herein is a method of treating a disorder in a in a subject, the method comprising identifying a subject in need thereof, and administering to the subject a pharmaceutical composition comprising a compound of Formula I or Formula II.

[00114] In some embodiments, the disease or disorder is selected from the group consisting of acute and chronic pain, inflammatory pain, post-operative pain, neuropathic pain, muscle relaxation, a disease or disorder requiring immunosuppression, inflammation, allergies, glaucoma, bronchodilation, neuroprotection, osteoporosis and disorders of the skeletal system, cancer, neurodegenerative disorders, Alzheimer's disease, Parkinson's disease (PD), Huntington's disease, multiple sclerosis (MS), muscle spasticity, tremor, fibromyalgia, lupus, rheumatoid arthritis, myasthenia gravis, autoimmune disorders, irritable bowel syndrome, interstitial cystitis, migraine, pruritis, excema, sebhorea,

psoriasis, shingles, cerebral ischemia, cerebral apoplexy, craniocerebral trauma, stroke, spinal cord injury, liver cirrhosis, liver fibrosis, atherosclerosis, as an antitussive, asthma, nausea, emesis, gastric ulcers, and diarrhea.

[00115] In some embodiments, the disease or disorder is selected from the group consisting of multiple sclerosis, rheumatoid arthritis, arthritis, systemic lupus erythematosus (SLE), myasthenia gravis, diabetes mellitus type I, hepatitis, psoriasis, stroke, migraine, cluster headaches, chronic degenerative diseases, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's chorea, prison-associate neurodegeneration, peripheral pain, visceral pain, neuropathic pain, inflammatory pain, referred pain, arrhythmia, hypertension, myocardial ischemia, muscle spasm, tremor, malignant brain tumors, skin tumors, lung adenocarcinoma, glioma, and thyroid epithelioma.

[00116] In some embodiments, the disorder is an immune related disorder selected from the group consisting of tissue rejection in organ transplants, malabsorption syndromes, celiac, pulmonary diseases, asthma, Sjogren's syndrome, inflammatory bowel disease, and rheumatic diseases.

[00117] Pharmaceutical compositions comprising a compound of Formula I or Formula II are useful for treating indications having an inflammatory or autoimmune mechanism involved in their etiology or pathogenesis exemplified by arthritis, including rheumatoid arthritis, arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), myasthenia gravis, diabetes mellitus type I, hepatitis and psoriasis, immune related disorders including but not limited to tissue rejection in organ transplants, malabsorption syndromes such as celiac, pulmonary diseases such as asthma and Sjogren's syndrome, inflammatory bowel disease, and rheumatic diseases.

[00118] While the compounds of Formula I or Formula II are CB2 ligands, they also have neuroprotective properties. Thus, pharmaceutical compositions comprising a compound of Formula I or Formula II are useful in treating neurological disorders including but not limited to stroke, migraine, cluster headaches. The compositions disclosed herein are also effective in treating certain chronic degenerative diseases that are characterized by gradual selective neuronal loss. In this connection, the present compositions are effective in the treatment of Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's chorea, prison-associate neurodegeneration. Neuroprotection conferred by CB2 agonists

could also be effective in protection and/or treatment of neurotoxic agents, such as nerve gas, as well as other insults to brain or nervous tissue by way of chemical or biological agents.

[00119] By virtue of their analgesic properties it will be recognized that the compositions according to the present invention will be useful in treating pain including peripheral, visceral, neuropathic, inflammatory and referred pain. The present compositions are also effective in cardioprotection from arrhythmia, hypertension, and myocardial ischemia. The compositions disclosed herein are also effective in the treatment of muscle spasm and tremor.

[00120] The compositions comprising a compound of Formula I or Formula II are also effective in the treatment or prevention of certain cancers, including malignant brain tumors, skin tumors, lung adenocarcinoma, glioma, and thyroid epithelioma.

[00121] The term "subject" refers to an animal, preferably a mammal, and most preferably a human, who is the object of treatment, observation or experiment. The mammal may be selected from the group consisting of mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, primates, such as monkeys, chimpanzees, and apes, and humans.

[00122] The term "therapeutically effective amount" is used to indicate an amount of an active compound, or pharmaceutical agent, that elicits the biological or medicinal response indicated. This response may occur in a tissue, system, animal or human and includes alleviation of the symptoms of the disease being treated.

[00123] In one aspect, the present invention relates to a pharmaceutical composition comprising a compound of Formula I or Formula II, and a physiologically acceptable component such as a carrier, a diluent, a salt or an excipient, or a combination thereof.

[00124] The term "pharmaceutical composition" refers to a mixture of a compound disclosed herein with other chemical components, such as diluents or carriers. The pharmaceutical composition facilitates administration of the compound to a subject. Multiple techniques of administering a compound exist in the art including, but not limited to, oral, injection, aerosol, parenteral, and topical administration. Pharmaceutical compositions can also be obtained by reacting compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic

acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.

[00125] The term "carrier" defines a chemical compound that facilitates the incorporation of a compound into cells or tissues. For example dimethyl sulfoxide (DMSO) is a commonly utilized carrier as it facilitates the uptake of many organic compounds into the cells or tissues of a subject.

[00126] The term "diluent" defines chemical compounds diluted in water that will dissolve the compound of interest as well as stabilize the biologically active form of the compound. Salts dissolved in buffered solutions are utilized as diluents in the art. One commonly used buffered solution is phosphate buffered saline because it mimics the salt conditions of human blood. Since buffer salts can control the pH of a solution at low concentrations, a buffered diluent rarely modifies the biological activity of a compound.

[00127] The term "physiologically acceptable" defines a carrier or diluent that does not abrogate the biological activity and properties of the compound.

[00128] The pharmaceutical compositions described herein can be administered to a subject per se, or in pharmaceutical compositions where they are mixed with other active ingredients, as in combination therapy, or suitable carriers or excipient(s). Techniques for formulation and administration of the compounds of the instant application may be found in "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, PA, 18th edition, 1990.

[00129] Suitable routes of administration may, for example, include oral, rectal, transmucosal, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intranasal, or intraocular injections.

[00130] Alternatively, one may administer the compound in a local rather than systemic manner, for example, via injection of the compound directly into the area of pain, often in a depot or sustained release formulation. Furthermore, one may administer the drug in a targeted drug delivery system, for example, in a liposome coated with a tissue-specific antibody. The liposomes will be targeted to and taken up selectively by the organ.

[00131] The pharmaceutical compositions disclosed herein may be manufactured in a manner that is itself known, e.g., by means of conventional mixing,

dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tabletting processes.

[00132] Pharmaceutical compositions for use in accordance with the present disclosure thus may be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active compounds into preparations, which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any of the well-known techniques, carriers, and excipients may be used as suitable and as understood in the art; e.g., in Remington's Pharmaceutical Sciences, above.

[00133] For injection, the agents disclosed herein may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.

[00134] For oral administration, the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds disclosed herein to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated. Pharmaceutical preparations for oral use can be obtained by mixing one or more solid excipient with pharmaceutical combination disclosed herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

[00135] Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.

Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

[00136] Pharmaceutical preparations, which can be used orally, include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.

[00137] For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

[00138] For administration by inhalation, the compounds for use according to the present disclosure are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

[00139] The compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.

[00140] Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances, which increase the viscosity

of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents, which increase the solubility of the compounds to allow for the preparation of highly, concentrated solutions.

[00141] Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[00142] The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.

[00143] In addition to the formulations described previously, the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

[00144] A pharmaceutical carrier for the hydrophobic compounds disclosed herein is a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase. A common cosolvent system used is the VPD co-solvent system, which is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate 80™, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol. Naturally, the proportions of a co-solvent system may be varied considerably without destroying its solubility and toxicity characteristics. Furthermore, the identity of the co-solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of POLYSORBATE 80™; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g., polyvinyl pyrrolidone; and other sugars or polysaccharides may be used.

[00145] Alternatively, other delivery systems for hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are well known examples of delivery vehicles or carriers for hydrophobic drugs. Certain organic solvents such as dimethylsulfoxide also may be employed, although usually at the cost of greater toxicity. Additionally, the compounds may be delivered using a

sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials have been established and are well known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for stabilization may be employed.

[00146] Many of the compounds used in the pharmaceutical combinations disclosed herein may be provided as salts with pharmaceutically compatible counterions. Pharmaceutically compatible salts may be formed with many acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free acids or base forms.

[00147] Pharmaceutical compositions suitable for use in the methods disclosed herein include compositions where the active ingredients are contained in an amount effective to achieve its intended purpose. More specifically, a therapeutically effective amount means an amount of compound effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.

[00148] The exact formulation, route of administration and dosage for the pharmaceutical compositions disclosed herein can be chosen by the individual physician in view of the patient's condition. (See e.g., Fingl et al. 1975, in "The Pharmacological Basis of Therapeutics", Ch. 1 p. 1). Typically, the dose about the composition administered to the patient can be from about 0.5 to 1000 mg/kg of the patient's body weight, or 1 to 500 mg/kg, or 10 to 500 mg/kg, or 50 to 100 mg/kg of the patient's body weight. The dosage may be a single one or a series of two or more given in the course of one or more days, as is needed by the patient. Note that for almost all of the specific compounds mentioned in the present disclosure, human dosages for treatment of at least some condition have been established. Thus, in most instances, the methods disclosed herein will use those same dosages, or dosages that are between about 0.1% and 500%, or between about 25% and 250%, or between 50% and 100% of the established human dosage. Where no human dosage is established, as will be the case for newly discovered pharmaceutical compounds, a

suitable human dosage can be inferred from ED50 or ID50 values, or other appropriate values derived from in vitro or in vivo studies, as qualified by toxicity studies and efficacy studies in animals.

[00149] Although the exact dosage will be determined on a drug-by-drug basis, in most cases, some generalizations regarding the dosage can be made. The daily dosage regimen for an adult human patient may be, for example, an oral dose of between 0.1 mg and 500 mg of each ingredient, preferably between 1 mg and 250 mg, e.g. 5 to 200 mg or an intravenous, subcutaneous, or intramuscular dose of each ingredient between 0.01 mg and 100 mg, preferably between 0.1 mg and 60 mg, e.g. 1 to 40 mg of each ingredient of the pharmaceutical compositions disclosed herein or a pharmaceutically acceptable salt thereof calculated as the free base, the composition being administered 1 to 4 times per day. Alternatively the compositions disclosed herein may be administered by continuous intravenous infusion, preferably at a dose of each ingredient up to 400 mg per day. Thus, the total daily dosage by oral administration of each ingredient will typically be in the range 1 to 2000 mg and the total daily dosage by parenteral administration will typically be in the range 0.1 to 400 mg. Suitably the compounds will be administered for a period of continuous therapy, for example for a week or more, or for months or years.

[00150] Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety, which are sufficient to maintain the modulating effects, or minimal effective concentration (MEC). The MEC will vary for each compound but can be estimated from in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations.

[00151] Dosage intervals can also be determined using MEC value. Compositions should be administered using a regimen, which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%.

[00152] In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.

[00153] The amount of composition administered will, of course, be dependent on the subject being treated, on the subject's weight, the severity of the affliction, the manner of administration and the judgment of the prescribing physician.

[00154] The compositions may, if desired, be presented in a pack or dispenser device, which may contain one or more unit dosage forms containing the active ingredient. The pack may for example comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. Compositions comprising a compound disclosed herein formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

[00155] It will be understood by those of skill in the art that numerous and various modifications can be made without departing from the spirit of the present disclosure. Therefore, it should be clearly understood that the forms disclosed herein are illustrative only and are not intended to limit the scope of the present disclosure.

EXAMPLES

[00156] The following examples are provided as an illustration of the present invention, but should in no way be considered as limiting the scope of invention.

Example 1 : Synthesis of the Compounds

Analytical methods

Analytical HPLC/MS, Ammonium Acetate (AP)

[00157] System: Waters/Micromass ZQ2000 LC/MS system consisting of a ZQ single quadropole mass spectrometer equipped with an electrospray ionization interface, and a Waters Alliance HT with a 2795 Separation Module and 996 Photodiode Array Detector.

[00158] Column: Reversed phase column (Waters Xterra® MS Ci ₈ 3.5μm, 30x4.6mm ID) with a guard column cartridge system.

[00159] Mobile Phase: A: 1OmM aqueous Ammonium Acetate; B: 1OmM aqueous Ammonium Acetate Acetonitrile/Water (95:5).

[00160] Program: 10 min. gradient program starting at 30%B (initial hold for 0.5 min.), over 5 min. to 100%B, hold for 1.5 min., over 0.5 min. to 30%B, hold for 2.5 min. The flow rate was 1 mL/min.

Preparative HPLC/MS, Ammonium Acetate (PP)

[00161] System: Waters/Micromass LC/ZMD Autopurification system consisting of a ZMD single quadropole mass spectrometer equipped with an electrospray ionization interface, and a Waters 600E Gradient Pump with in-line degassing, 2700 Sample Manager and 996 Photodiode Array Detector.

[00162] Column: Reversed phase column (Waters Xterra® Prep MS C ₁₈ 5μm, 19xl00mm).

[00163] Mobile Phase: A: 1OmM aqueous Ammonium Acetate; B: 1OmM aqueous Ammonium Acetate Acetonitrile/Water (95:5).

[00164] Program: 12 min. gradient program starting at 30%B (initial hold for 2.5 min.), over 8.5 min. to 100%B, over 0.5 min. to 30%B, hold for 0.5 min. The flow rate was 17 mL/min.

Building block synthesis

ALDEHYDES

General procedure GPl

4-(2-fluoroethoxy)-2.6-dimethylbenzaldehvde

[00165] To a solution of 2-fluoroethanol (0.55 mL, 9.4 mmol) and N,N- diisopropylethylamine (3.2 mL, 18.7 mmol) in CH ₂ Cl ₂ (35 mL) at -78°C was added Tf ₂ O (1.44 mL, 8.7 mmol) dropwise. The mixture was stirred for 1.5h. A solution of 4-hydroxy-2,6-dimethylbenzaldehyde (1.02 g, 6.8 mmol) in CH ₂ Cl ₂ (4 mL) + DMF (2 mL) was added dropwise. After stirring for Ih the cooling bath was removed and the mixture stirred at room temperature overnight. The mixture was then diluted with diethyl ether (200 mL) and this mixture was washed with H ₂ O (2x 4OmL), 1 M HCl (40 mL), 1 M NaOH (40 mL) and brine and then dried over Na ₂ SO ₄ . After evaporation to dryness the title compound was obtained as a yellow oil that solidified on standing (l.Olg, 76%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.48 (s, IH), 6.62 (s, 2H),

4.82-4.80 (m, IH), 4.70-4.68 (m, IH), 4.30-4.28 (m, IH), 4.23-4.21 (m, IH), 2.60. ¹³ C NMR (IOO MHZ, CDCl ₃ ) δ 191.5, 161.4, 144.4, 126.4, 115.3, (82.4 + 80.7, d, J = 170 Hz), (67.0+66.8, d, J= 20 Hz), 21.0.

2,6-difluoro-3-(2-fluoroethoxy)benzaldehyde

[00166] Prepared according to GPl by using 2-fluoroethanol (0.34 mL, 5.8 mmol), 2,6-difluoro-3-hydroxybenzaldehyde (700 mg, 4.43 mmol), N,N- diisopropylethylamine (1.89 mL, 11.1 mmol) and Tf ₂ O (0.92 mL, 5.5 mmol) in CH ₂ Cl ₂ (30 mL) yielding the title compound as a yellow oil (647 mg, 72%). ¹ H νMR (400 MHz, CDCl ₃ ) δ 10.35 (m, IH), 7.27-7.21 (m, IH), 6.94-6.89 (m, IH), 4.82-4.80 (m, IH), 4.70-4.68 (m, IH), 4.34-4.32 (m, IH), 4.28-4.26 (m, IH).

2-chloro-4-fluoro-l-(2-fluoroethoxy)benzene

[00167] Prepared according to GPl by using 2-fluoroethanol (0.85 mL, 14.5 mmol), 2-chloro-4-fluorophenol (1.67 g, 11.4 mmol), N,N-diisopropylethylamine (5.00 mL, 29.2 mmol) and Tf ₂ O (2.40 mL, 14.5 mmol) in CH ₂ Cl ₂ (60 mL) with the exception that the phenol was added in neat CH ₂ Cl ₂ (3 mL). This yielded the title compound as a orange oil (2.22 g, 100%). ¹ H νMR (400 MHz, CDCl ₃ ) δ 7.16-7.12 (m, IH), 6.94-6.91 (m, 2H), 4.84-4.81 (m, IH), 4.72-4.70 (m, IH), 4.29-4.27 (m, IH), 4.23-4.20 (m, IH).

4-(2-fluoroethoxy)-3-methoxybenzaldehyde

[00168] Prepared according to GPl by using 2-fluoroethanol (628.0 mg, 9.28 mmol), N,N-diisopropylethylamine (3.56 mL, 2.1 mmol), Tf ₂ O (1.51 mL, 9.1 mmol) in CH ₂ Cl ₂ (35 mL) and vanillin (1.06 g, 7.0 mmol) in CH ₂ C1 ₂ :DMF 2: 1 (6 mL)

to give the title compound (1.41 g, 100%). LCMS m/z 199 [M+H] ⁺ , purity (UV/MS) 99/84.

2,6-difluoro-4-( ^' 2-fluoroethoxy)benzaldehvde

[00169] Prepared according to GPl by using 2-fluoroethanol (628.0 mg, 9.28 mmol), N,N-diisopropylethylamine (3.56 mL, 2.1 mmol), Tf ₂ O (1.51 mL, 9.1 mmol) and 2,6-difluoro-4-hydroxybenzaldehyde (1.10 g, 7.0 mmol) in CH2CI2 (35 mL) to give the title compound (1.2 g, 84%). ¹ H νMR (CDCl ₃ , 400 MHz) δ 10.20 (s, IH, CHO), 6.54-6.51 (m, 2H, ArH), 4.83-4.81 (m, IH, CH ₂ ), 4.72-4.70 (m, IH, CH ₂ ), 4.31-4.30 (m, IH, CH ₂ ), 4.24-4.22 (m, IH, CH ₂ ). LCMS m/z 205 [M+H] ⁺ , purity (UV/MS) 99/45.

4-(2-fluoroethoxy)-3-hvdroxybenzaldehyde

[00170] Prepared according to GPl by using 2-fluoroethanol (628.0 mg, 9.28 mmol), N,N-diisopropylethylamine (3.56 mL, 2.1 mmol), Tf ₂ O (1.51 mL, 9.1 mmol) in CH ₂ Cl ₂ (35 mL) and 3,4-dihydroxybenzaldehyde (967.0 mg, 7.0 mmol) in CH ₂ C1 ₂ :DMF 2: 1 (6 mL). The workup followed the original procedure but the extraction with NaOH (IM) was acidified with HCl(aq) and extracted with EtOH to afford the title compound (1.1 g, 86%). ¹ H νMR (CDCl ₃ , 400 MHz) δ 9.76 (s, IH, CHO), 7.42-7.39 (m, IH, ArH), 7.33-7.32 (m, IH, ArH), 7.11-7.09 (m, IH, ArH), 4.85-4.84 (m, IH, CH ₂ ), 4.74-4.72 (m, IH, CH ₂ ), 4.53 (br s, IH, OH), 4.41-4.39 (m, IH, CH ₂ ), 4.34-4.32 (m, IH, CH ₂ ). LCMS m/z 185 [M+H] ⁺ , purity (UV/MS) 56/53.

4-(2-hvdroxyethoxy)-2,6-dimethylbenzaldehvde

[00171] A dry flask was charged with 4-hydroxy-2,6- dimethylbenzaldehyde (2.04 g, 13.6 mmol), ethylenecarbonate (1.58 g, 17.9 mmol) and K ₂ CO ₃ (2.81 g, 20.3 mmol) in DMF (30 mL) and heated to 80 ⁰ C overnight. The mixture was poured into diethyl ether (400 mL) and the organic layer was washed with H ₂ O (2x 100 mL), 2M HCl (50 mL) and 2M NaOH (50 mL). The organic layer was then washed with brine followed by drying over Na ₂ SO ₄ to give the title compound as a yellow oil that solidified on standing (1.58g, 60%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.48 (s, IH), 6.61 (s, 2H), 4.14-4.12 (m, 2H), 3.98-3.96 (m, 2H), 2.60 (s, 6H).

General procedure GP2 2-chloro-4-fluoro-l-(fluoromethoxy)benzene

[00172] A MW reaction vessel was charged with 2-chloro-4-fluorophenol (1.03 g, 7.05 mmol), K ₂ CO ₃ (1.31g, 9.48 mmol) and CH ₃ CN (4 mL). The mixture was cooled to 0 ⁰ C before addition of bromofluoromethane (0.50 mL, 7.80 mmol). The vessel was capped and heated to 120 ⁰ C for 30 min. After cooling to room temperature the mixture was diluted with diethyl ether (200 mL). The organic layer was washed with H ₂ O, 2M NaOH, brine and then dried over Na ₂ SO ₄ and evaporated to dryness to give the pure title compound as a colorless liquid that solidified on standing. Yield 1.12 g (89%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.20-7.15 (m, 2H), 6.99-6.94 (m, IH), 5.74 (s, IH), 5.61 (s, IH).

4-chloro-2-fluoro-l-(fluoromethoxy)benzene

[00173] Prepared according to GP2 by using 4-chloro-2-fluorophenol (1.71 g, 11.7 mmol), K ₂ CO ₃ (1.93 g, 14.0 mmol) and bromofluoromethane (1.00 mL, 15.6 mmol) yielding the title compound (1.94g, 93%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.17-7.07 (m, 3H), 5.74 (s, IH), 5.61 (s, IH).

General procedure GP3 2-chloro-6-fluoro-3-(fluoromethoxy)benzaldehyde

[00174] A dry flask was charged with 2-chloro-4-fluoro-l-

(fluoromethoxy)benzene (1.12 g, 6.27 mmol) in THF (20 mL) and cooled to -65 ⁰ C (int). A solution of M-BuLi (2.0 M, 3.50 mL, 7.00 mmol) was added dropwise keeping the internal temperature below -50 ⁰ C. The mixture was stirred between -50 ⁰ C and - 65 ⁰ C for 30 min and then cooled to -78 ⁰ C. DMF (1.00 mL, 12.9 mmol) was added in one portion and the mixture was stirred at -78 ⁰ C for 15 min before being allowed to reach room temperature. The mixture was poured into ice-water which was slightly acidified with 2M HCl. The aquous layer was extracted with diethyl ether (3x 50 mL). The combined organic layers were washed with 2M HCl, H ₂ O, brine and dried over Na ₂ SO ₄ . Evaporation gave the title compound as yellow crystals (1.28 g, 99%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.45 (s, IH), 7.44-7.40 (m, IH), 7.12-7.08 (m, IH), 5.78 (m, sH), 5.64 (s, IH).

2-chloro-6-fluoro-3-(2-fluoroethoxy)benzaldehyde

[00175] Prepared according to GP3 by using 2-chloro-4-fluoro-l-(2- fluoroethoxy)benzene (2.22 g, 11.5 mmol), w-BuLi (2.0 M, 6.34 mL, 12.7 mmol) and DMF (1.79 mL, 23.1 mmol) in THF (35 mL) yielding the title compound (2.49 g, 98%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.45 (s, IH), 7.19-7.15 (m, IH), 7.08-7.03 (m, IH), 4.86-4.84 (m, IH), 4.74-4.72 (m, IH), 4.33-4.31 (m, IH), 4.26-4.24 (m, IH).

6-chloro-2-fluoro-3-(fluoromethoxy)benzaldehyde

[00176] Prepared according to GP3 by using 4-chloro-2-fluoro- 1 - (fluoromethoxy)benzene (1.94 g, 10.8 mmol), M-BuLi (2.2 M, 5.50 mL, 12.1 mmol) and DMF (2.00 mL, 25.8 mmol) in THF (30 mL) yielding the title compound (2.21 g, 99%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.43 (s, IH), 7.39-7.35 (m, IH), 7.26-7.22 (m, IH), 5.77 (s, IH), 5.63 (s, IH).

AMINES

5-methoxypyrimidin-2-amine

[00177] A MW reaction vessel was charged with 2-chloro-5- methoxypyrimidine (0.817 g, 5.65 mmol) and 25% NH ₃ (aq). The vessel was capped and heated to 150 ⁰ C for 3h. The mixture was evaporated to dryness. The resulting material was dissolved in CH ₂ Cl ₂ MeOH (1 : 1) and adsorbed onto silica. Purification by flash CC (eluent: 50-100 % EtOAc in heptane) gave the title compound as colorless crystals (386 mg, 55%). ¹ H NMR (400 MHz, dmso- _d6 ) δ 8.02 (s, IH), 6.06 (br s, IH), 3.71 (s, 3H).

ISOCYANIDES

OTHER Bulding Blocks

2-(2-chloro-6-fluorophenyl)-5-methoxyimidazorL2-a1pyridin -3-amine

[00178] In a MW vial equipped with a magnetic stirring bar 6- methoxypyridin-2 -amine (1.0 mmol, 124 mg), 2-fluoro-6-methoxybenzaldehyde (1.2 mmol, 190 mg) and polymer-bound scandium(III) bis(trifluoromethanesulfonate) (0.05 mmol, 14 mg) was dissolved in methanol (5 mL). Trimethylsilylcyanide (3 mmol, 297 mg) was added, the vial was capped and heated in a MW reactor at 140 ⁰ C for 20 min. The vial was decapped and sulfuric acid (cone, 5 drops) was added, the reaction mixture was left stirring at room temperature for 5 min, and then passed through a SCX cartridge. The crude product was purified by flash CC (eluent: 0-50 % EtOAc in heptane) yielding the title compound (106 mg, 36%). LCMS m/z 292 [M+H] ⁺ , purity (UV/MS) 93/78.

Final compound examples, by MCR

General Procedure GP6

[00179] The amino-pyridine (0.53mmol), isonitrile (0.53mmol), aldehyde (0.53mmol) and ZnCl ₂ (10%) were mixed in a MW reaction vessel and dissolved / suspended in 1,4-dioxane (4 mL). The vessel was capped and heated to 140 ⁰ C for 20 min. The solvent was evaporated and the crude product was purified by flash CC (2- 5% MeOH in CH ₂ C^). In some cases subsequent purification by pTLC (2-5% MeOH in CH2CI2) was required.

2-(2-(2-chloro-6-fluorophenyl)-5-methylimidazori.2-a1pyri din-3-ylamino)-l- morpholinoethanone

[00180] Prepared according to GP6 by using 2-amino-6-methylpyridine (58.0 mg, 0.53 mmol), N-morpholino-2-isocyano-acetamide (82.0 mg, 0.53 mmol), 2- chloro-6-fluorobenzaldehyde (84.0 mg, 0.53 mmol), zinc chloride (7.0 mg, 0.05 mmol) in 1,4-dioxane (8.0 mL) to give the title compound (23.1mg, 11%). ¹ H νMR (CH ₃ OD, 400 MHz) δ 7.47-7.44 (m, IH, ArH), 7.40-7.38 (m, IH, ArH), 7.34-7.30

(m, IH, ArH), 7.23-7.15 (m, 2H, ArH), 6.65-6.64 (m, IH, ArH), 3.72 (s, 2H, CH ₂ ), 3.54-3.50 (m, 4H, CH ₂ ), 3.39-3.37 (m, 2H, CH ₂ ), 3.24-3.21 (m, 2H, CH ₂ ), 2.99 (s, 3H, CH ₃ ). LCMS m/z 403 [M+H] ⁺ , purity (UV/MS) 97/74.

2-(2-(2,6-difluorophenyl)-5-methylimidazori,2-a1pyridin-3 -ylamino)-l- morpholinoethanone

[00181] Prepared according to GP6 by using 2-amino-6-methylpyridine (58.0 mg, 0.53 mmol), N-morpholino-2-isocyano-acetamide (82.0 mg, 0.53 mmol), 2,6-difluorobenzaldehyde (75.0 mg, 0.53 mmol), zinc chloride (7.0 mg, 0.05 mmol) in 1,4-dioxane (8.0 mL) to give the title compound (19.3mg, 10%). ¹ H νMR (CH ₃ OD, 400 MHz) δ 7.52-7.45 (m, IH, ArH), 7.34-7.31 (m, IH, ArH), 7.19-7.15 (m, IH, ArH), 7.12-7.07 (m, 2H, ArH), 6.65-6.63 (m, IH, ArH), 3.72 (s, 2H, CH ₂ ), 3.56-3.49 (m, 4H, CH ₂ ), 3.41-3.39 (m, 2H, CH ₂ ), 3.24-3.22 (m, 2H, CH ₂ ), 2.99 (s, 3H, CH ₃ ). LCMS m/z 387 [M+H] ⁺ , purity (UV/MS) 96/70.

2-(2-(4-(2-fluoroethoxy)-3-methoxyphenyl)-5-methylimidazo rL2-a1pyridin-3- ylamino)- 1 -morpholinoethanone

[00182] Prepared according to GP6 by using 2-amino-6-methylpyridine (58.0 mg, 0.53 mmol), N-morpholino-2-isocyano-acetamide (82.0 mg, 0.53 mmol), A- (2-fluoroethoxy)-3-methoxy benzaldehyde (98.0 mg, 0.53 mmol), zinc chloride (7.0 mg, 0.05 mmol) in 1,4-dioxane (8.0 mL) to give the title compound (16.3mg, 7%). ¹ H νMR (CH ₃ OD, 400 MHz) δ 7.52-7.45 (m, IH, ArH), 7.34-7.31 (m, IH, ArH), 7.19-

7.15 (m, IH, ArH), 7.12-7.07 (m, 2H, ArH), 6.65-6.63 (m, IH, ArH), 3.72 (s, 2H, CH ₂ ), 3.56-3.49 (m, 4H, CH ₂ ), 3.41-3.39 (m, 2H, CH ₂ ), 3.24-3.22 (m, 2H, CH ₂ ), 2.99 (s, 3H, CH ₃ ). LCMS m/z 443 [M+H] ⁺ , purity (UV/MS) 96/70.

General Procedure GP7

[00183] The amine (0.53mmol), isonitrile (0.53mmol), aldehyde (0.53mmol) and InCl ₃ (10%) were suspended in dry toluene. The reaction mixture was shaken at 110 ⁰ C for 72 h. The solvent was evaporated and the crude product was purified by flash CC (2-5% MeOH in CH ₂ Cl ₂ ). In some cases subsequent purification by pTLC (2-5% MeOH in CH ₂ Cl ₂ ) was required.

2-(2-chloro-6-fluorophenyl)-N-(2-morpholinoethyl)imidazor i,2-a1pyrimidin-3 -amine

[00184] Prepared according to GP7 by using 2-aminopyrimidine (20.0 mg, 0.21 mmol), 2-morpholinoethyl isocyanide (30.0 mg, 0.21 mmol), 2-chloro-6- fluorobenzaldehyde (33.4 mg, 0.21 mmol), indium chloride (4.4 mg, 0.02 mmol) in toluene (4.0 mL) to give the title compound (0.5 mg, 0.6%). LCMS m/z 376 [M+H] ⁺ , purity (UV/MS) 95/80.

2-(2-(3-fluoropyridin-2-yl)imidazori,2-a1pyrazin-3-ylamin o)-l-morpholinoethanone

[00185] Prepared according to GP7 by using aminopyrazine (50.0 mg, 0.53 mmol), N-morpholino-2-isocyano-acetamide (82.0 mg, 0.53 mmol), 3-fluoro-2- formylpyridine (66.0 mg, 0.53 mmol), indium chloride (11.0 mg, 0.05 mmol) in

toluene (8.0 mL) to give the title compound (8.8mg, 5%). LCMS m/z 357 [M+H] ⁺ , purity (UV/MS) 94/60.

2-(2-(6-fluoropyridin-2-yl)imidazorL2-a1pyrazin-3-ylamino )-l-morpholinoethanone

[00186] Prepared according to GP7 by using aminopyrazine (50.0 mg, 0.53 mmol), N-morpholino-2-isocyano-acetamide (82.0 mg, 0.53 mmol), 2-Fluoro-6- formylpyridine (66.0 mg, 0.53 mmol), indium chloride (11.0 mg, 0.05 mmol) in toluene (8.0 mL) to give the title compound (3.5 mg, 2%). LCMS m/z 357 [M+H] ⁺ , purity (UV/MS) 68/80.

General procedure GP8

2-(2-chloro-6-fluorophenyl)-ν-(2,3-dihydrobenzorbiri,41d ioxin-6-yl)-5- methylimidazori,2-a1pyridin-3 -amine

[00187] A 4 mL disposable glass reaction vessel equipped with a magnestic stirring bar was charged with 2-chloro-6-fluorobenzaldehyde (206 mg, 1.30 mmol), 6- isocyano-2,3-dihydrobenzo[b][l,4]dioxine (180 mg, 1.12 mmol), 6-methylpyridin-2- amine (111 mg, 1.03 mmol) and l-butyl-3-methylimidazolium bromide (340 mg, 1.55 mmol). The mixture was stirred at 60 ⁰ C overnight and then at 100 ⁰ C for 3h. The mixture was dissolved in a mixture of H ₂ O (2 mL) and EtOAc (5 mL) by vigerous shaking. The organic layer was adsorbed onto silica, and after purification by flash CC (eluent: 10-30 % EtOAc in heptane) the title compound was obtained as purple

crystals (286 mg, 67%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.51 (d, J = 9.1 Hz, IH), 7.25-7.22 (m, 2H), 7.13-7.09 (m, IH), 7.04-6.99 (m, IH), 6.61 (d, J = 8.5 Hz, IH), 6.50 (d, J = 6.8 Hz, IH), 6.00-5.95 (m, 2H), 5.11 (s, IH), 4.16-4.12 (m, 4H), 2.72 (s, 3H). ¹³ C NMR (100 MHz, CDCl ₃ ) (meaningful signals) δ 162.4+159.9 (d, J = 250 Hz), 144.1, 142.1, 136.8, 136.3, 135.5+135.4 (d, J = 4 Hz), 130.2+130.1 (d, J = 10 Hz), 125.3+125.2 (d, J = 4 Hz), 122.7, 117.7, 116.2, 114.3+114.0 (d, J = 23 Hz), 113.6, 106.7, 102.5, 64.6, 64.0, 19.0. LCMS m/z 410 [M+H] ⁺ , purity (UV/MS) 100/85.

2-(2-chloro-6-fluorophenyl)-5-methyl-N-(4-phenoxyphenyl)i midazori.2-a1pyridin-3- amine

[00188] Prepared according to GP8 by using 2-chloro-6- fluorobenzaldehyde (191 mg, 1.20 mmol), l-isocyano-4-phenoxybenzene (228 mg, 1.17 mmol), 6-methylpyridin-2 -amine (99 mg, 0.92 mmol) and l-butyl-3- methylimidazolium bromide (320 mg, 1.46 mmol) yielding the title compound after flash CC (eluent: 0-50 % EtOAc in heptane) (19 mg, 5 %). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.54-7.52 (m, IH), 7.27-7.23 (m, 4H), 7.15-7.11 (m, IH), 7.04-6.98 (m, 2H), 6.86-6.84 (m, 2H), 6.81-6.79 (m, 2H), 6.54-6.52 (m, IH), 6.47-6.43 (m, 2H), 5.31 (s, IH), 2.76 (s, 3H). LCMS m/z 444 [M+H] ⁺ , purity (UV/MS) 97/84.

Library synthesis, 96 well plates General Procedure GP 12

[00189] The isonitrile (0.08 mmol), aldehyde (0.11 mmol) and the amine (0.07 mmol) were dissolved in MeOH and HOAc (200%) was added. The 96 well plate was shaken overnight at room temperature, and then at 40 ⁰ C for 12 h. After

evaporation of the solvents and purification by preparative LCMS the products were obtained.

General Procedure GP 13

[00190] The isonitrile (0.05 mmol), aldehyde (0.05 mmol) and the amine (0.05 mmol) were dissolved in 1,4-dioxane and ZnCl ₂ (10%) was added to each well. The 96 well plate was shaken at 90 ⁰ C for 24 h. The product was worked up by passing the crude material through a SCX cartridge, that was subsequently eluded with NH ₃ (MeOH). After evaporation of the solvents and purification by preparative LCMS the products were obtained.

[00191] The following compounds were prepared as described in GP13:

[00192] 2-(2-chloro-6-fluorophenyl)-N-(3.4-difluorophenyl)-7- methylimidazo[1.2-a]pyridin-3 -amine: Amount made: 1.6 mg. LCMS m/z 388 [M+H] ⁺ , purity (UV/MS) 97/90.

[00193] 2-(2-chloro-6-fluorophenyl)-N-(4-chlorophenyl)-7- methylimidazori,2-a1pyridin-3 -amine: Amount made: 3.0 mg. LCMS m/z 386 [M+H] ⁺ , purity (UV/MS) 87/80.

[00194] 3-(2-(3-fluoro-4-hvdroxy-5-methoxyphenyl)-7-methylimidazori, 2- a1pyridin-3-ylamino)benzonitrile: Amount made: 0.1 mg. LCMS m/z 389 [M+H] ⁺ , purity (UV/MS) 92/90.

[00195] 4-(3-(4-chlorophenylamino)-7-methylimidazo[1.2-alpyridin-2-y l)- 2-fluoro-6-methoxyphenol: Amount made: 2.8 mg. LCMS m/z 398 [M+H] ⁺ , purity (UV/MS) 93/80.

[00196] 4-(3 -(benzo rdi [1.31 dioxol-5 -ylamino)-7-methylimidazo [1.2- a1pyridin-2-yl)-2-fluoro-6-methoxyphenol: Amount made: 1.9 mg. LCMS m/z 408 [M+H] ⁺ , purity (UV/MS) 91/85.

[00197] 3-(2-(2-chloro-6-fluorophenyl)imidazori.2-a1pyridin-3- ylamino)benzonitrile: Amount made: 3.2 mg. LCMS m/z 363 [M+H] ⁺ , purity (UV/MS) 94/92.

[00198] 2-(2-chloro-6-fluorophenyl)-N-(3.4-difluorophenyl)imidazoπ. 2- aipyridin-3 -amine: Amount made: 1.2 mg. LCMS m/z 374 [M+H] ⁺ , purity (UV/MS) 90/74.

[00199] 2-(2-chloro-6-fluorophenyl)-N-( ^' 3,4-dimethoxyphenyl)imidazorL2- alpyridin-3 -amine: Amount made: 2.1 mg. LCMS m/z 398 [M+H] ⁺ , purity (UV/MS) 91/87.

[00200] 2-(2-chloro-6-fluorophenyl)-N-( ^' 4-chlorophenyl)imidazor 1 ,2- aipyridin-3 -amine: Amount made: 3.3 mg. LCMS m/z i ^' ll [M+H] ⁺ , purity (UV/MS) 85/81.

[00201] 4-(3-(3.4-difluorophenylamino)imidazori.2-a1pyridin-2-yl)-2- fluoro-6-methoxyphenol: Amount made: 4.8 mg. LCMS m/z 386 [M+H] ⁺ , purity (UV/MS) 82/78.

[00202] 4-(3-(3,4-dimethoxyphenylamino)imidazorL2-a1pyridin-2-yl)-2- fluoro-6-methoxyphenol: Amount made: 3.6 mg. LCMS m/z 410 [M+H] ⁺ , purity (UV/MS) 88/58.

[00203] 4-(3-(4-chlorophenylamino)imidazo[1.2-alpyridin-2-yl)-2-fluo ro- 6-methoxyphenol: Amount made: 5.8 mg. LCMS m/z 384 [M+H] ⁺ , purity (UV/MS) 91/90.

[00204] 2-fluoro-6-methoxy-4-(3-(3-methoxyphenylamino)imidazor 12- aipyridin-2 -vDphenol : Amount made: 3.3 mg. LCMS m/z 380 [M+H] ⁺ , purity (UV/MS) 88/87.

[00205] 4-(3-(benzordiri.31dioxol-5-ylamino)imidazori.2-a1pyridin-2- yl)- 2-fluoro-6-methoxyphenol: Amount made: 3.2 mg. LCMS m/z 394 [M+H] ⁺ , purity (UV/MS) 95/64.

[00206] 3-(2-(2-chloro-6-fluorophenyl)-5-methylimidazori.2-a1pyridin -3- ylamino)benzonitrile: Amount made: 3.4 mg. LCMS m/z 311 [M+H] ⁺ , purity (UV/MS) 94/74.

[00207] 2-(2-chloro-6-fluorophenyl)-N-(3.4-dimethoxyphenyl)-5- methylimidazori,2-a1pyridin-3 -amine: Amount made: 0.3 mg. LCMS m/z 412 [M+H] ⁺ , purity (UV/MS) 80/90.

[00208] 2-f2-chloro-6-fluorophenyl>N-f4-chlorophenyl>5- methylimidazori.2-a1pyridin-3 -amine: Amount made: 4.6 mg. LCMS m/z 386 [M+H] ⁺ , purity (UV/MS) 87/92.

[00209] 2-(2-chloro-6-fluorophenyl)-N-(3-methoxyphenyl)-5- methylimidazori,2-a1pyridin-3 -amine: Amount made: 5.0 mg. LCMS m/z 382 [M+H] ⁺ , purity (UV/MS) 90/68.

[00210] N-fbenzordiri.31dioxol-5-vn-2-(2-cMoro-6-fluorophenvn-5- methylimidazo[l,2-a1pyridin-3 -amine: Amount made: 6.7 mg. LCMS m/z 396 [M+H] ⁺ , purity (UV/MS) 100/95.

[00211] 4-(3-(3.4-dimethoxyphenylamino)-5-methylimidazo[l,2-a1pyridi n- 2-yl)-2-fluoro-6-methoxyphenol: Amount made: 4.6 mg. LCMS m/z 424 [M+H] ⁺ , purity (UV/MS) 85/80.

[00212] 4-(3-(4-chlorophenylamino)-5-methylimidazori.2-a1pyridin-2-y l)- 2-fluoro-6-methoxyphenol: Amount made: 4.9 mg. LCMS m/z 398 [M+H] ⁺ , purity (UV/MS) 87/80.

[00213] 4-(3 -(benzo rdi [1.31 dioxol-5 -ylamino)-5 -methylimidazo [1.2- a1pyridin-2-yl)-2-fluoro-6-methoxyphenol: Amount made: 3.0 mg. LCMS m/z 408 [M+H] ⁺ , purity (UV/MS) 100/70.

[00214] 3-(2-(2-chloro-6-fluorophenyl)-6-methylimidazo[1.2-alpyridin -3- ylamino)benzonitrile: Amount made: 3.5 mg. LCMS m/z 311 [M+H] ⁺ , purity (UV/MS) 94/78.

[00215] 2-(2-chloro-6-fluorophenyl)-N-(3.4-difluorophenyl)-6- methylimidazo[1.2-a1pyridin-3 -amine: Amount made: 3.1 mg. LCMS m/z 388 [M+H] ⁺ , purity (UV/MS) 95/86.

[00216] 2-(2-chloro-6-fluorophenyl)-N-(3.4-dimethoxyphenyl)-6- methylimidazo[1.2-a1pyridin-3 -amine: Amount made: 6.1 mg. LCMS m/z 412 [M+H] ⁺ , purity (UV/MS) 95/72.

[00217] 4-(3-(3.4-difluorophenylamino)-6-methylimidazo[1.2-a1pyridin -2- yl)-2-fluoro-6-methoxyphenol: Amount made: 3.9 mg. LCMS m/z 400 [M+H] ⁺ , purity (UV/MS) 100/99.

[00218] 4-(3-(4-chlorophenylamino)-6-methylimidazo[1.2-a1pyridin-2-y l)- 2-fluoro-6-methoxyphenol: Amount made: 2.9 mg. LCMS m/z 398 [M+H] ⁺ , purity (UV/MS) 100/99.

[00219] 2-fluoro-6-methoxy-4-(3 -(3 -methoxyphenylamino)-6- methylimidazo[ 1.2-a1pyridin-2-yl)phenol: Amount made: 5.1 mg. LCMS m/z 394 [M+H] ⁺ , purity (UV/MS) 93/80.

[00220] 4-(3 -(benzo [di [1.31 dioxol-5 -ylamino)-6-methylimidazo [1.2- a1pyridin-2-yl)-2-fluoro-6-methoxyphenol: Amount made: 1.3 mg. LCMS m/z 408 [M+H] ⁺ , purity (UV/MS) 90/80.

[00221] N-fbenzordiri.31dioxol-5-vn-2-(2-cMoro-6-fluorophenvn-8- methylimidazori,2-a1pyridin-3 -amine: Amount made: 1.6 mg. LCMS m/z 396 [M+H] ⁺ , purity (UV/MS) 95/64.

[00222] 3-(2-(3-fluoro-4-hvdroxy-5-methoxyphenyl)-8-methylimidazorL2 - a1pyridin-3-ylamino)benzonitrile: Amount made: 0.3 mg. LCMS m/z 389 [M+H] ⁺ , purity (UV/MS) 85/48.

[00223] 4-(3-(3.4-difluorophenylamino)-8-methylimidazori.2-a1pyridin -2- yl)-2-fluoro-6-methoxyphenol: Amount made: 0.8 mg. LCMS m/z 400 [M+H] ⁺ , purity (UV/MS) 95/50.

[00224] 2-(2-chloro-6-fluorophenyl)-7-methyl-N-(4- moφholinophenyl)imidazori,2-a1pyridin-3-amine: Amount made: 0.6 mg. LCMS m/z 437 [M+H] ⁺ , purity (UV/MS) 100/70.

[00225] 2-f2-chloro-6-fluorophenyl>N-f4-chlorobenzyl>7- methylimidazori.2-a1pyridin-3 -amine: Amount made: 0.1 mg. LCMS m/z 400 [M+H] ⁺ , purity (UV/MS) 84/70.

[00226] 2-fluoro-6-methoxy-4-(7-methyl-3-(4-morpholinophenylamino)- imidazori,2-a1pyridin-2-yl)prienol: Amount made: 1.1 mg. LCMS m/z 449 [M+H] ⁺ , purity (UV/MS) 100/60.

[00227] 4-(3-(4-chlorobenzylamino)-7-methylimidazorL2-a1pyridin-2-yl )- 2-fluoro-6-methoxyphenol: Amount made: 0.2 mg. LCMS m/z 412 [M+H] ⁺ , purity (UV/MS) 94/80.

[00228] 4-(3-(3-chlorophenylamino)-7-methylimidazori.2-a1pyridin-2-y l)- 2-fluoro-6-methoxyphenol: Amount made: 1.2 mg. LCMS m/z 398 [M+H] ⁺ , purity (UV/MS) 66/40.

[00229] 4-(3-(3,4-dichlorophenylamino)-7-methylimidazorL2-a1pyridin- 2- yl)-2-fluoro-6-methoxyphenol: Amount made: 0.1 mg. LCMS m/z 432 [M+H] ⁺ , purity (UV/MS) 83/90.

[00230] 2-(2-chloro-6-fluorophenyl)-N-(4-morpholinophenyl)imidazo[1. 2- aipyridin-3 -amine: Amount made: 0.3 mg. LCMS m/z 423 [M+H] ⁺ , purity (UV/MS) 85/70.

[00231] 2-(2-chloro-6-fluorophenyl)-N-(3-chlorophenyl)imidazori,2- aipyridin-3 -amine: Amount made: 0.1 mg. LCMS m/z 372 [M+H] ⁺ , purity (UV/MS) 66/50.

[00232] 2-fluoro-6-methoxy-4-(3-(4-moφholinophenylamino)imidazori,2 - aipyridin-2 -vDphenol : Amount made: 1.2 mg. LCMS m/z 435 [M+H] ⁺ , purity (UV/MS) 100/40.

[00233] 4-(3-(3-chlorophenylamino)imidazorL2-a1pyridin-2-yl)-2-fluor o- 6-methoxyphenol: Amount made: 0.3 mg. LCMS m/z 384 [M+H] ⁺ , purity (UV/MS) 96/90.

[00234] 2-(2-chloro-6-fluorophenyl)-5-methyl-N-(4-morpholinoprienyl) - imidazori,2-a1pyridin-3-amine: Amount made: 1.2 mg. LCMS m/z 437 [M+H] ⁺ , purity (UV/MS) 95/90.

[00235] 2-(2-chloro-6-fluorophenyl)-N-(4-chlorobenzyl)-5- methylimidazori,2-a1pyridin-3 -amine: Amount made: 0.1 mg. LCMS m/z 400 [M+H] ⁺ , purity (UV/MS) 60/60.

[00236] 2-(2-chloro-6-fluorophenyl)-N-(3.4-dichlorophenyl)-5- methylimidazo-ri.2-a1pyridin-3-amine: Amount made: 0.1 mg. LCMS m/z 420 [M+H] ⁺ , purity (UV/MS) 54/40.

[00237] 2-fluoro-6-methoxy-4-(5-methyl-3-(4-morpholinophenylamino)- imidazori,2-a1pyridin-2-yl)prienol: Amount made: 2.3 mg. LCMS m/z 449 [M+H] ⁺ , purity (UV/MS) 100/90.

[00238] 4-(3-(4-chlorobenzylamino)-5-methylimidazorL2-a1pyridin-2-yl )- 2-fluoro-6-methoxyphenol: Amount made: 0.3 mg. LCMS m/z 412 [M+H] ⁺ , purity (UV/MS) 95/50.

[00239] 4-(3-(3-chlorophenylamino)-5-methylimidazori.2-a1pyridin-2-y l)- 2-fluoro-6-methoxyphenol: Amount made: 0.1 mg. LCMS m/z 398 [M+H] ⁺ , purity (UV/MS) 61/70.

[00240] 4-(3-(3,4-dichlorophenylamino)-5-methylimidazorL2-a1pyridin- 2- yl)-2-fluoro-6-methoxyphenol: Amount made: 0.1 mg. LCMS m/z 432 [M+H] ⁺ , purity (UV/MS) 65/30.

[00241] 2-(2-chloro-6-fluorophenyl)-6-methyl-N-(4-morpholinophenyl)- imidazori.2-a1pyridin-3-amine: Amount made: 0.8 mg. LCMS m/z 437 [M+H] ⁺ , purity (UV/MS) 99/80.

[00242] 2-(2-chloro-6-fluorophenyl)-N-(4-chlorobenzyl)-6- methylimidazori,2-a1pyridin-3 -amine: Amount made: 0.2 mg. LCMS m/z 400 [M+H] ⁺ , purity (UV/MS) 53/50.

[00243] 2-fluoro-6-methoxy-4-(6-methyl-3-(4-moφholinophenylamino)- imidazori,2-a1pyridin-2-yl)phenol: Amount made: 0.5 mg. LCMS m/z 449 [M+H] ⁺ , purity (UV/MS) 50/40.

[00244] 4-(3-(4-chlorobenzylamino)-6-methylimidazori,2-a1pyridin-2-y l)- 2-fluoro-6-methoxyphenol: Amount made: 0.1 mg. LCMS m/z 412 [M+H] ⁺ , purity (UV/MS) 83/70.

[00245] 4-(3-(3-chlorophenylamino)-6-methylimidazori.2-a1pyridin-2-y l)- 2-fluoro-6-methoxyphenol: Amount made: 0.3 mg. LCMS m/z 398 [M+H] ⁺ , purity (UV/MS) 90/70.

[00246] 2-fluoro-6-methoxy-4-(8-methyl-3-(4-morpholinophenylamino)- imidazori,2-a1pyridin-2-yl)phenol: Amount made: 0.3 mg. LCMS m/z 449 [M+H] ⁺ , purity (UV/MS) 100/60.

[00247] 2-(2-chloro-6-fluorophenyl)-N-(4-morpholinophenyl)imidazo[1. 2- aipyrazin-3 -amine : Amount made: 0.1 mg. LCMS m/z 424 [M+H] ⁺ , purity (UV/MS) 68/30.

[00248] 2-(2-chloro-6-fluorophenyl)-N-(4-chlorobenzyl)imidazor 1 ,2- aipyrazin-3 -amine: Amount made: 0.1 mg. LCMS m/z 387 [M+H] ⁺ , purity (UV/MS) 88/80.

[00249] 2-fluoro-6-methoxy-4-(3-(4-morpholinophenylamino)imidazorL2- aipyrazin-2 -vDphenol : Amount made: 1.3 mg. LCMS m/z 436 [M+H] ⁺ , purity (UV/MS) 100/50.

[00250] 4-(3-(4-chlorobenzylamino)imidazori.2-a1pyrazin-2-yl)-2-fluo ro- 6-methoxyphenol: Amount made: 0.1 mg. LCMS m/z 399 [M+H] ⁺ , purity (UV/MS) 91/80.

[00251] 2-(2-chloro-6-fluorophenyl)-N-(4-morpholinophenyl)imidazori, 2- aipyrimidin-3 -amine: Amount made: 1.4 mg. LCMS m/z 424 [M+H] ⁺ , purity (UV/MS) 100/70.

[00252] 2-fluoro-6-methoxy-4-(3-(4-morpholinophenylamino)imidazo[1.2 - a1pyrimidin-2-yl)phenol: Amount made: 0.1 mg. LCMS m/z 436 [M+H] ⁺ , purity (UV/MS) 100/40.

[00253] 2-(3-fluoropyridin-2-yl)-7-methyl-N-(2- moφholinoethyl)imidazori,2-a1pyridin-3-amine: Amount made: 0.2 mg. LCMS m/z 356 [M+H] ⁺ , purity (UV/MS) 92/70.

[00254] 2-(6-fluoropyridin-2-yl)-7-methyl-N-(2- morpholinoethyl)imidazori,2-a1pyridin-3-amine: Amount made: 0.9 mg. LCMS m/z 356 [M+H] ⁺ , purity (UV/MS) 55/50.

[00255] 2-(3-fluoropyridin-2-ylV7-methyl-N-(4-moφholinophenviy imidazori.2-a1pyridin-3-amine: Amount made: 1.6 mg. LCMS m/z 404 [M+H] ⁺ , purity (UV/MS) 60/30.

[00256] 2-(6-fluoropyridin-3-yl)-7-methyl-N-(4-morpriolinoprienyl)- imidazori,2-a1pyridin-3-amine: Amount made: 0.6 mg. LCMS m/z 404 [M+H] ⁺ , purity (UV/MS) 94/80.

[00257] 2-(6-fluoropyridin-2-yl)-7-methyl-N-(4- morpholinophenyl)imidazo-ri,2-a1pyridin-3-amine: Amount made: 0.2 mg. LCMS m/z 404 [M+H] ⁺ , purity (UV/MS) 63/80.

[00258] 2-(2-fluoropyridin-4-yl)-7-methyl-N-(4- morpholinophenyl)imidazo-ri.2-a1pyridin-3-amine: Amount made: 0.2 mg. LCMS m/z 404 [M+H] ⁺ , purity (UV/MS) 75/70.

[00259] l-(4-(2-(3-fluoro-4-hvdroxy-5-methoxyphenyl)-7- methylimidazor 1.2-a1pyridin-3 -ylamino)phenyl)ethanone: Amount made: 0.1 mg. LCMS m/z 406 [M+H] ⁺ , purity (UV/MS) 53/70.

[00260] l-(4-(2-(3-fluoropyridin-2-yl)-7-methylimidazorL2-a1pyridin- 3- ylamino)phenyl)ethanone: Amount made: 0.3 mg. LCMS m/z 361 [M+H] ⁺ , purity (UV/MS) 100/100.

[00261] l-(4-(2-(6-fluoropyridin-2-yl)-7-methylimidazori.2-a1pyridin -3- ylamino)phenyl)ethanone: Amount made: 0.7 mg. LCMS m/z 361 [M+H] ⁺ , purity (UV/MS) 100/100.

[00262] N-(2.3 -dihydrobenzo [bl \ 1.41 dioxin-6-yl)-2-(3 -fluoropyridin-2-yl)- 7-methylimidazori.2-a1pyridin-3-amine: Amount made: 1.0 mg. LCMS m/z 311 [M+H] ⁺ , purity (UV/MS) 100/90.

[00263] N-(2.3 -dihvdrobenzo M \ 1.41 dioxin-6-yl)-2-(6-fluoropyridin-3 -yl)- 7-methylimidazori.2-a1pyridin-3-amine: Amount made: 1.9 mg. LCMS m/z ?>11 [M+H] ⁺ , purity (UV/MS) 63/50.

[00264] N-(2.3 -dihvdrobenzo [bl \ 1.41 dioxin-6-yl)-2-(6-fluoropyridin-2-yl)- 7-methylimidazori.2-a1pyridin-3-amine: Amount made: 0.1 mg. LCMS m/z 311 [M+H] ⁺ , purity (UV/MS) 86/70.

[00265] 2-(3-fluoropyridin-2-yl)-N-(2-morpholinoethyl)imidazor 1 ,2- aipyridin-3 -amine: Amount made: 0.7 mg. LCMS m/z 342 [M+H] ⁺ , purity (UV/MS) 100/100.

[00266] 2-(6-fluoropyridin-2-yl)-N-( ^' 2-morpholinoethyl)imidazor 1 ,2- aipyridin-3 -amine: Amount made: 1.0 mg. LCMS m/z 342 [M+H] ⁺ , purity (UV/MS) 72/70.

[00267] 2-(6-fluoropyridin-3-yl)-N-(4-moφholinophenyl)imidazori.2- aipyridin-3 -amine: Amount made: 0.4 mg. LCMS m/z 390 [M+H] ⁺ , purity (UV/MS) 92/70.

[00268] 2-(6-fluoropyridin-2-yl)-N-(4-morpholinophenyl)imidazor 1 ,2-a ^" |- Pyridin-3-amine: Amount made: 0.6 mg. LCMS m/z 390 [M+H] ⁺ , purity (UV/MS) 95/60.

[00269] 1 -(4-(2-(3-fluoro-4-hydroxy-5-methoxyphenyl)imidazo[ 1.2- a1pyridin-3-ylamino)phenyl)ethanone: Amount made: 0.2 mg. LCMS m/z 392 [M+H] ⁺ , purity (UV/MS) 100/100.

[00270] 1 -(4-(2-(3 -fluoropyridin-2-yl)imidazo [ 1 ,2-alpyridin-3 -ylamino)- phenvDethanone: Amount made: 0.1 mg. LCMS m/z 347 [M+H] ⁺ , purity (UV/MS) 81/40.

[00271] 1 -(4-(2-(6-fluoropyridin-2-yl)imidazo [ 1 ,2-a1pyridin-3 -ylamino)- phenvDethanone: Amount made: 0.9 mg. LCMS m/z 347 [M+H] ⁺ , purity (UV/MS) 93/90.

[00272] 2-(3-fluoropyridin-2-ylV5-methyl-N-(2- morpholinoethyl)imidazori,2-a1pyridin-3-amine: Amount made: 1.1 mg. LCMS m/z 356 [M+H] ⁺ , purity (UV/MS) 100/90.

[00273] 2-(6-fluoropyridin-2-yl)-5-methyl-N-(2- morpholinoethyl)imidazori,2-a1pyridin-3-amine: Amount made: 0.1 mg. LCMS m/z 356 [M+H] ⁺ , purity (UV/MS) 92/70.

[00274] 2-(3-fluoropyridin-2-yl)-5-methyl-N-(4- morpholinophenyl)imidazo-ri.2-a1pyridin-3-amine: Amount made: 2.0 mg. LCMS m/z 404 [M+H] ⁺ , purity (UV/MS) 100/90.

[00275] 2-(6-fluoropyridin-3-yl)-5-methyl-N-(4- morpholinophenyl)imidazo-ri,2-a1pyridin-3-amine: Amount made: 0.3 mg. LCMS m/z 404 [M+H] ⁺ , purity (UV/MS) 95/80.

[00276] 2-(6-fluoropyridin-2-yl)-5-methyl-N-(4- morpholinophenyl)imidazo-ri,2-a1pyridin-3-amine: Amount made: 1.6 mg. LCMS m/z 404 [M+H] ⁺ , purity (UV/MS) 96/70.

[00277] 2-(2-fluoropyridin-4-yl)-5-methyl-N-(4- morpholinophenyl)imidazo-ri,2-a1pyridin-3-amine: Amount made: 1.7 mg. LCMS m/z 404 [M+H] ⁺ , purity (UV/MS) 55/40.

[00278] l-C4-( ^' 2-( ^' 3-fluoropyridin-2-ylV5-metliylimidazori.2-alpyridin-3- ylamino)phenyl)ethanone: Amount made: 0.7 mg. LCMS m/z 361 [M+H] ⁺ , purity (UV/MS) 100/90.

[00279] l-(4-(2-(6-fluoropyridin-2-yl)-5-methylimidazorL2-a1pyridin- 3- ylamino)phenyl)ethanone: Amount made: 0.3 mg. LCMS m/z 361 [M+H] ⁺ , purity (UV/MS) 95/80.

[00280] 2-(3-fluoropyridin-2-yl)-6-methyl-N-(2- morpholinoethyl)imidazori.2-a1pyridin-3-amine: Amount made: 0.7 mg. LCMS m/z 356 [M+H] ⁺ , purity (UV/MS) 100/90.

[00281] 2-(3-fluoropyridin-2-yl)-6-methyl-N-(4- morpholinophenyl)imidazo-ri,2-a1pyridin-3-amine: Amount made: 6.0 mg. LCMS m/z 404 [M+H] ⁺ , purity (UV/MS) 100/90.

[00282] 2-(6-fluoropyridin-3-yl)-6-methyl-N-(4- morpholinophenyl)imidazo-ri,2-a1pyridin-3-amine: Amount made: 0.3 mg. LCMS m/z 404 [M+H] ⁺ , purity (UV/MS) 85/60.

[00283] 2-(6-fluoropyridin-2-ylV6-methyl-N-(4- morpholinophenyl)imidazo-ri,2-a1pyridin-3-amine: Amount made: 0.1 mg. LCMS m/z 404 [M+H] ⁺ , purity (UV/MS) 59/50.

[00284] l-(4-(2-(3-fluoro-4-hvdroxy-5-methoxyphenyl)-6- methylimidazor 1 ,2-a1pyridin-3 -ylamino)phenyl)ethanone: Amount made: 0.1 mg. LCMS m/z 406 [M+H] ⁺ , purity (UV/MS) 76/80.

[00285] l-r4-r2-r3-fluoropyridin-2-ylV6-methylimidazori.2-alpyridin- 3- ylamino)phenyl)ethanone: Amount made: 0.9 mg. LCMS m/z 361 [M+H] ⁺ , purity (UV/MS) 100/90.

[00286] 1 -(4-(2-(6-fluoropyridin-2-yl)-6-methylimidazor 1 ,2-alpyridin-3- ylamino)phenyl)ethanone: Amount made: 0.1 mg. LCMS m/z 361 [M+H] ⁺ , purity (UV/MS) 100/90.

Example 2: CB2 Receptor Binding Assays

[00287] To show that CB2 compounds can block binding of a CB2 ligand to CB2 receptors the ability of compounds of Formula I or Formula II to block binding of CB2 ligand CP 55,940 (2-[(lS,2R,5S)-5-hydroxy-2-(3-hydroxypropyl) cyclohexyl]-5-(2-methyloctan-2-yl)phenol; CAS No. 83002-04-4) was examined in HEK-293T cells as follows.

[00288] Membrane preparation - HEK-293T cells were cultured according to ATCC (Manassas, VA) guidelines and transfected with human CB2 cDNA (SEQ ID NO: 1) (Genbank X74328), operably linked to the SV40 promoter, using Polyfect (Qiagen, Valencia, CA) or Fugene (Roche, Nutley, NJ.) according to manufacturer's instructions. 48 h after transfection cells were harvested in ice cold membrane buffer (20 mM HEPES, 6 mM MgCl ₂ , 1 mM EDTA, pH 7.2) using a cell scraper. Cells were transferred to a nitrogen cavitation chamber and a pressure of 900 bar was applied for 30 min. The pressure was released and the cell debris was collected and centrifuged at 1000 g at 4 ⁰ C for 10 min. The supernatant was collected and the spin was repeated until the supernatant was free of precipitate. Membranes were then pelleted by centrifugation at 12.000 g at 4 ⁰ C for 20 min. Membranes were resuspended in an appropriate amount of membrane buffer. The membrane concentration was determined using a BioRad (Hercules, CA) protein assay dye reagent according to manufacturer's instructions. Membranes were diluted to 1 mg/ml and aliquots snap- frozen in liquid nitrogen and store at -80 ⁰ C.

[00289] Binding assay - 0.5- 10 μg of membranes were incubated in binding buffer (50 mM Tris, 0.5 mM EDTA, 0.1% BSA, pH 7.4) in the presence of 1.5 nM radioligand ([ H]-CP 55,940 Perkin Elmer) and varying concentrations of ligands (total volume 100 μL in a 96 well plate). Membranes were filtered onto a 96 well GF/B filterplate (Packard Bioscience, Shelton, CT) and washed with 500 mL wash buffer (25mM HEPES, 1 mM CaCl ₂ , 5 mM MgCl ₂ , 0.25M NaCl) using a Filtermate 196 Harvester (Packard Instruments, Downers Grove, IL). The filter plates were dried under a heat lamp before addition of 50 μL of scintillation fluid to each well (Microscint 20, Packard, Shelton, CT). Plates were counted on a Topcount NXT (Packard, Shelton, CT).

[00290] Data Analysis - Graphs were plotted and K _D values were determined by nonlinear regression analysis using Prism software (GraphPad version 4.0, San Diego, CA, USA).

Table 1. Binding of CB 2 compounds to native CB2 receptors [00291] These results demonstrate that the compounds described herein bind with high affinity to native CB2 receptors.

Table 1

[00292] It will be appreciated that the CB2 receptor binding assay of the foregoing example may be used to identify compounds which are agonists, inverse agonists or antagonists of a CB2 receptor. The cannabinoid CB2 receptor used in the assay may consist essentially of SEQ ID NO:2. In further embodiments, the cannabinoid CB2 receptor used in the assay may have at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or greater than at least 99% amino acid identity with a full-length CB2 receptor.

REFERENCES

[00293] The following references are referenced in the text and are incorporated by reference herein in their entirety.

[00294] Ashton JC, Rahman RM, Nair SM, Sutherland BA, Glass M, Appleton I. Cerebral hypoxia-ischemia and middle cerebral artery occlusion induce expression of the cannabinoid CB2 receptor in the brain. Neurosci Lett. 2007 Jan 29;412(2): 114-7.

[00295] Beltramo M, Bernardini N, Bertorelli R, Campanella M, Nicolussi E, Fredduzzi S, Reggiani A. CB2 receptor-mediated antihyperalgesia: possible direct involvement of neural mechanisms. Eur J Neurosci. 2006 Mar;23(6): 1530-8.

[00296] Benito C, Nunez E, Tolon RM, Carrier EJ, Rabano A, Hillard CJ, Romero J. Cannabinoid CB2 receptors and fatty acid amide hydrolase are selectively overexpressed in neuritic plaque-associated glia in Alzheimer's disease brains. J Neurosci. 2003 Dec 3;23(35): 11136-41.

[00297] Benito C, Kim WK, Chavarria I, Hillard CJ, Mackie K, Tolon RM, Williams K, Romero J. A glial endogenous cannabinoid system is upregulated in the brains of macaques with simian immunodeficiency virus-induced encephalitis. J Neurosci. 2005 Mar 9;25(10):2530-6.

[00298] Benito C, Romero J, Tolon, R, Clemente D, Docagne F, Hillard, C, Guaza, C, Romero, J. Cannabinoid CBi and CB ₂ Recptors and fatty acid amide hydrolase are specific markers of plaque cell subtypes in human multiple sclerosis. J Neurosci. 2007 Feb. 28, 27(9):2396-2402.

[00299] Cabral GA, Marciano-Cabral F. Cannabinoid receptors in microglia of the central nervous system: immune functional relevance. J Leukoc Biol. 2005 Dec;78(6): 1192-7.

[00300] Carlisle SJ, Marciano-Cabral F, Staab A, Ludwick C, Cabral GA. Differential expression of the CB2 cannabinoid receptor by rodent macrophages and macrophage-like cells in relation to cell activation. Int Immunopharmacol. 2002 Jan;2(l):69-82.

[00301] Elmes SJ, Jhaveri MD, Smart D, Kendall DA, Chapman V. Cannabinoid CB2 receptor activation inhibits mechanically evoked responses of wide dynamic range dorsal horn neurons in naive rats and in rat models of inflammatory and neuropathic pain. Eur J Neurosci. 2004 Nov;20(9):2311-20.

[00302] Galiegue S, Mary S, Marchand J, Dussossoy D, Carriere D, Carayon P, Bouaboula M, Shire D, Le Fur G, Casellas P. Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations. Eur J Biochem. 1995 Aug 15;232(1):54-61.

[00303] Golech SA, McCarron RM, Chen Y, Bembry J, Lenz F, Mechoulam R, Shohami E, Spatz M. Human brain endothelium: coexpression and function of vanilloid and endocannabinoid receptors. Brain Res MoI Brain Res. 2004 Dec 6;132(l):87-92.

[00304] Gong JP, Onaivi ES, Ishiguro H, Liu QR, Tagliaferro PA, Brusco A, UhI GR. Cannabinoid CB2 receptors: immunohistochemical localization in rat brain. Brain Res. 2006 Feb 3; 1071(1): 10-23

[00305] Howlett AC, Breivogel CS, Childers SR, Deadwyler SA, Hampson RE, Porrino LJ. Cannabinoid physiology and pharmacology: 30 years of progress. Neuropharmacology. 2004;47 Suppl 1:345-58

[00306] Ibrahim MM, Porreca F, Lai J, Albrecht PJ, Rice FL, Khodorova A, Davar G, Makriyannis A, Vanderah TW, Mata HP, Malan TP Jr. CB2 cannabinoid receptor activation produces antinociception by stimulating peripheral release of endogenous opioids. Proc Natl Acad Sci U S A. 2005 Feb 22;102(8):3093-8.

[00307] Karsak M, Cohen-Solal M, Freudenberg J, Ostertag A, Morieux C, Kornak U, Essig J, Erxlebe E, Bab I, Kubisch C, de Vernejoul MC, Zimmer A. Cannabinoid receptor type 2 gene is associated with human osteoporosis. Hum MoI Genet. 2005 Nov 15;14(22):3389-96.

[00308] Klegeris A, Bissonnette CJ, McGeer PL. Reduction of human monocytic cell neurotoxicity and cytokine secretion by ligands of the cannabinoid- type CB2 receptor. Br J Pharmacol. 2003 Jun;139(4):775-86.

[00309] Lee SF, Newton C, Widen R, Friedman H, Klein TW. Downregulation of cannabinoid receptor 2 (CB2) messenger RNA expression during in vitro stimulation of murine splenocytes with lipopolysaccharide. Adv Exp Med Biol. 2001;493:223-8.

[00310] Martin RS, Luong LA, Welsh NJ, Eglen RM, Martin GR, MacLennan SJ. Effects of cannabinoid receptor agonists on neuronally-evoked contractions of urinary bladder tissues isolated from rat, mouse, pig, dog, monkey and human. Br J Pharmacol. 2000 Apr;129(8): 1707-15.

[00311] Munro S, Thomas KL, Abu-Shaar M. Molecular characterization of a peripheral receptor for cannabinoids. Nature. 1993 Sep 2;365(6441):61-5.

[00312] Ofek O, Karsak M, Leclerc N, Fogel M, Frenkel B, Wright K, Tarn J, Attar-Namdar M, Kram V, Shohami E, Mechoulam R, Zimmer A, Bab I. Peripheral

cannabinoid receptor, CB2, regulates bone mass. Proc Natl Acad Sci U S A. 2006 Jan 17;103(3):696-701.

[00313] Onaivi ES, Ishiguro H, Gong JP, Patel S, Perchuk A, Meozzi PA, Myers L, Mora Z, Tagliaferro P, Gardner E, Brusco A, Akinshola BE, Liu QR, Hope B, Iwasaki S, Arinami T, Teasenfitz L, UhI GR. Discovery of the presence and functional expression of cannabinoid CB2 receptors in brain. Ann N Y Acad Sci. 2006 Aug; 1074:514-36.

[00314] Palazuelos J, Aguado T, Egia A, Mechoulam R, Guzman M, Galve-Roperh I. Non-psychoactive CB2 cannabinoid agonists stimulate neural progenitor proliferation. FASEB J. 2006 Nov;20(13):2405-7.

[00315] Patel HJ, Birrell MA, Crispino N, HeIe DJ, Venkatesan P, Barnes PJ, Yacoub MH, Belvisi MG. Inhibition of guinea-pig and human sensory nerve activity and the cough reflex in guinea-pigs by cannabinoid (CB2) receptor activation. Br J Pharmacol. 2003 Sep;140(2):261-8.

[00316] Ross RA, Coutts AA, McFarlane SM, Anavi-Goffer S, Irving AJ, Pertwee RG, MacEwan DJ, Scott RH. Actions of cannabinoid receptor ligands on rat cultured sensory neurones: implications for antinociception. Neuropharmacology. 2001;40(2):221-32.

[00317] Skaper SD, Buriani A, Dal Toso R, Petrelli L, Romanello S, Facci L, Leon A.

[00318] The ALIAmide palmitoylethanolamide and cannabinoids, but not anandamide, are protective in a delayed postglutamate paradigm of excitotoxic death in cerebellar granule neurons. Proc Natl Acad Sci U S A. 1996 Apr 30;93(9):3984-9.

[00319] Sipe JC, Arbour N, Gerber A, Beutler E. Reduced endocannabinoid immune modulation by a common cannabinoid 2 (CB2) receptor gene polymorphism: possible risk for autoimmune disorders. J Leukoc Biol. 2005 Jul;78(l):231-8.

[00320] Stander S, Schmelz M, Metze D, Luger T, Rukwied R. Distribution of cannabinoid receptor 1 (CBl) and 2 (CB2) on sensory nerve fibers and adnexal structures in human skin. J Dermatol Sci. 2005 Jun;38(3): 177-88.

[00321] Ueda Y, Miyagawa N, Matsui T, Kaya T, Iwamura H. Involvement of cannabinoid CB(2) receptor-mediated response and efficacy of cannabinoid CB(2) receptor inverse agonist, JTE-907, in cutaneous inflammation in mice. Eur J Pharmacol. 2005 Sep 27;520(l-3): 164-71.

[00322] Van Sickle MD, Duncan M, Kingsley PJ, Mouihate A, Urbani P, Mackie K, Stella N, Makriyannis A, Piomelli D, Davison JS, Marnett LJ, Di Marzo V, Pittman QJ, Patel KD, Sharkey KA. Identification and functional characterization of brainstem cannabinoid CB2 receptors. Science. 2005 Oct 14;310(5746):329-32.

[00323] Walczak JS, Pichette V, Leblond F, Desbiens K, Beaulieu P. Behavioral, pharmacological and molecular characterization of the saphenous nerve partial ligation: a new model of neuropathic pain. Neuroscience. 2005;132(4):1093- 102.

[00324] Whiteside GT, Lee GP, Valenzano KJ. The role of the cannabinoid CB2 receptor in pain transmission and therapeutic potential of small molecule CB2 receptor agonists. Curr Med Chem. 2007; 14(8):917-36.

[00325] Wotherspoon G, Fox A, Mclntyre P, Colley S, Bevan S, Winter J. Peripheral nerve injury induces cannabinoid receptor 2 protein expression in rat sensory neurons. Neuroscience. 2005;135(l):235-45.

[00326] Yoshihara S, Morimoto H, Yamada Y, Abe T, Arisaka O. Cannabinoid receptor agonists inhibit sensory nerve activation in guinea pig airways. Am J Respir Crit Care Med. 2004 Nov 1; 170(9): 941-6.

[00327] Zhang J, Hoffert C, Vu HK, Groblewski T, Ahmad S, O'Donnell D. Induction of CB2 receptor expression in the rat spinal cord of neuropathic but not inflammatory chronic pain models. Eur J Neurosci. 2003 Jun;17(12):2750-4.