MXPA06010016A - Ion channel modulators - Google Patents

Abstract

The invention relates to compounds, compositions comprising the compounds, and methods of using the compounds and compound compositions. The compounds, compositions, and methods described herein can be used for the therapeutic modulation of ion channel function, and treatment of disease and disease symptoms, particularly those mediated by certain calcium channel subtype targets.

Description

ION CHANNEL MODULATORS Background of the Invention All cells depend on the regulated movement of inorganic ions through cell membranes to perform essential physiological functions. Electrical excitability, synaptic plasticity, and signal transduction are examples of processes in which changes in ion concentration play a critical role. In general, the ion channels that allow these changes are protein pores consisting of one or multiple subunits, each containing two or more membrane coverage domains. Most ion channels have selectivity for specific ions, mainly Na +, K +, Ca2 +, or Cl ", by virtue of the physical preferences for size and charge.The electrochemical forces, instead of the active transport, lead the ions to Through the membranes, in this way a single channel can allow the passage of millions of ions per second.The opening of the channel, or "gate", is closely controlled by changes in voltage or by ligand binding, - depending on the The subclass of the canal The ion channels are attractive therapeutic targets because they are involved in many physiological processes, although the generation of drugs with Ref: 175184 specificity for particular channels in particular tissue types maintains a greater challenge. Voltage gate ion channels open in response to changes in membrane potential. For example, the depolarization of excitable cells such as neurons results in a transient influx of Na + ions, which propagate the nerve impulses. This change in Na + concentration is sensitive by voltage gate K + channels, which then allow an efflux of K + ions. The efflux of K + ions repolarizes the membrane. Other cell types depend on the voltage gate Ca2 + channels to generate action potentials. Voltage gate ion channels also perform important functions in non-excitable cells, such as the regulation of secretion, homeostatic, and mitogenic processes. The ligand gate ion channels can be opened by extracellular stimuli such as neurotransmitters (eg, glutamate, serotonin ', acetylcholine), or intracellular stimuli (eg, cAMP, Ca2 +, and phosphorylation). The Cavl family of voltage gate calcium channels consists of 4 major subtypes Cavl.l, Cav1.2, Cav1.3 and Cav1.4. These currents are found primarily in the skeletal muscle for Cavl.l, heart, smooth muscle, brain, pituitary and adrenal tissue for Cavl. 2, brain, pancreas, heart, kidney, ovaries and cochlea for Cav1.3 and in 'retina for Cav1.4. These currents require a strong depolarization for activation and are very durable. The subunit composition of the Cavl channels are defined by their subunit, which forms the pore and contains the voltage sensitive gates (ail.l, axl .2, axl .3 and a.l.4, also known as ls. , otic, L1?, and aiF respectively) and subunits ß, a2d and?. Genetic or pharmacological disturbances in the function of the ion channel can have dramatic clinical consequences. Long QT syndrome, epilepsy, cystic fibrosis, and episodic ataxia are some examples of inherited diseases that result from mutations in the ion channel subunits. Toxic side effects such as arrhythmia and stroke that are triggered by certain drugs are due to interference with the function of ion channels (Sirois, JE and, Atchison, WD, Neurotoxicology 1996; 17 (1): 63-84).; Keating, MT, Science 1996 272: 681-685). The drugs are useful for the therapeutic modulation of ion channel activity, and have applications in the treatment of many pathological conditions, including hypertension, angina pectoris, myocardial ischemia, overactivity of the bladder, alopecia, pain, heart failure, dysmenorrhea , type II diabetes, arrhythmia, graft rejection, stroke, seizures, epilepsy, infarction, gastric hypermobility, psychosis, cancer, muscular dystrophy, and narcolepsy (Coghlan, MJ, et al., J. Med. Chern., 2001, 44 : 1627-1653; Ackerman. M.J., and.Clapham, D.E. N. Eng. J. Med. 1997, 336: 1575-1586). The increasing number of ion channels identified and the understanding of their complexity help in future therapy efforts, which modify the function of the ion channel. Overactivity of the bladder (OAB) is characterized by storage symptoms such as urgency, frequency and nocturia with or without stimulation of incontinence, which results from the overactivity of the muscle in the bladder. OAB can lead to incontinence stimulation. The etiology of OAB and painful bladder syndrome is unknown, although alterations in nerves, smooth muscle and urothelium can cause OAB (Steers, W. Rev Urol, 4: S7-S18). There is evidence to suggest that the reduction of bladder overactivity can be indirectly effected by the inhibition of Cav2 and / or Cav1 channels.

Brief Description of the Invention The invention relates to heterocyclic compounds, compositions comprising the compounds, and methods of using the compounds and compositions of the compound. The compounds and compositions comprising them are useful for treating diseases or symptoms of diseases, including those mediated by or associated with ion channels. In one aspect it is a compound of the formula (AI) or a pharmaceutical salt thereof (AI) wherein, Ar 1 is cycloalkyl, aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more substituents; X is NR3, C (R3) 2, or O; Y is C = 0 or lower alkyl; R1 is Ar2 or lower alkyl optionally substituted with Ar2; each Ar2 is independently cycloalkyl, aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more substituents; q is 0, 1 or 2; each R2 is independently selected from (CH2) mC02R3, (CH2) mCOAr3, (CH2) mAr3, (CH2) 3Ar3, (CH2) nNR3R4 or (CH2) n0R4; each R3 is independently selected from H, or lower alkyl; each R4 is independently selected from H, lower alkyl or (CH2) pAr3; m is 1 or 2, n is 2 or 3 p is 0 or 1; each Ar3 is cycloalkyl, aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more substituents; each substituent 'for Ar1, Ar2 and Ar3 is independently selected from halogen, CN, N02, OR5, -.SR5, S (0) 2OR5, NR5R6, cycloalkyl, perfluoroalkyl C? -C2, '-perfluoroalkoxy C? -C2 / 1, 2-methylenedioxy, C (0) OR5, C (0) NR5R6, OC (0) NR5R6, NR5C (0) NR5R6, C (NR6) NR5R6, NR5C (NR6) NR5R6, S (0) 2NR5R6, R7, C (0) R7, NR5C (0) R7, S (0) R7, OR S (0) 2R7; each R5 is independently selected from hydrogen or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C 1 -C 4 alkoxy, NH 2, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino or C 3 -C 6 cycloalkyl; each R6 is independently selected from hydrogen, (CH2) pAr4, or lower alkyl, optionally substituted with one or more substituents independently selected from halogen, OH, C? -C4 alkoxy, NH2, C? -C4 alkylamino, dialkylamino C? -C4 or C3-C6 cycloalkyl; each R7 is independently selected from (CH2) pAr4 or • lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C? -C4 alkoxy, NH2, C? -C alkylamino, C? -C dialkylamino or C3 cycloalkyl -C6; and each Ar4 is independently selected from C3-Ce, aryl or heteroaryl cycloalkyl, each optionally substituted with one to three substituents independently selected from halogen, OH, Cx-C alkoxy, NH2, Ci- C4 alkylamino, C1-C4 dialkylamino or , 2-methylenedioxy. In another aspect, the compounds are those of any of the formulas herein (including any combination thereof): wherein, Ar 1 is aryl or heteroaryl, each optionally substituted with one or more substituents; X is NR3; and Y is C = 0; wherein, R1 is aryl or heteroaryl, each optionally substituted with one or more substituents; Wherein, each R2 is independently (CH ^ mAr3; and each Ar3 is heteroaryl optionally substituted with one or more substituents; wherein, Ar3 is a heteroaryl comprising a five membered ring having carbon atoms and 1, 2 or 3 selected heteroatoms of N, O and S, optionally substituted with one or more substituents; wherein, Ar3 is pyrrolidinyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, benzimidazolyl, benzoxazolyl, or benzthiazolyl, each optionally substituted with one or more substituents; wherein each R2 is- (CH2) nNR3R4, wherein each R4 is independently (CH2) PAr3; wherein R3 is H; wherein the compound of the formula Al is a compound delineated in any of the tables herein, or a pharmaceutical salt thereof. In one aspect it is a compound of the formula (Bl) or a pharmaceutical salt thereof wherein, Ar 1 is cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of H, halogen, amino, hydroxy, cyano, nitro, carboxylate, alkyl, alkenyl, alkynyl, cycloalkyl, cyclohexyl, alkoxy, mono and di-alkyl amino, phenyl, carboxamide, haloalkyl, haloalkoxy, and alkanoyl; R1 is Ar2 or lower alkyl optionally substituted with Ar2; Ar2 is independently selected from cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of H, halogen, amino, hydroxy, cyano, nitro, carboxylate, alkyl, alkenyl, alkynyl, cycloalkyl, cyclohexyl, alkoxy, mono and dialkyl amino, phenyl, carboxamide, haloalkyl, haloalkoxy, and alkanoyl; q is 0, 1 or 2; each R2 is independently selected from (CH2) mC02R3, (CH2) mCOAr3, (CH2) mC0NR3R4, (CH2) mAr3, (CH2) 3Ar3, (CH2) nNR3R4 or (CH2) n0R4; each R3 is independently selected from H, or lower alkyl; each R4 is independently selected from H, lower alkyl or (CH2) pAr3; each Ar3 is cycloalkyl, aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more substituents, with the proviso that Ar3 is not piperidinyl, tetrahydroquinolinyl or tetrahydroisoquinolinyl; each Z is independently selected from 0 or NR3; each m is 1 or 2 each n is 2 or 3 each p is 0 or 1 each replaced by Ar1, Ar2 and Ar3 is independently selected from halogen, CN, N02, OR5, SR5, S (0) 20Rs, NR5R6, cycloalkyl , perfluoroalkyl Cx-C2, perfluoroalkoxy C? -C2, 1,2-methylenedioxy, C (0) 0R5, C (0) NR5Rs, 0C (0) NR5R6, NR5C (0) NR5R6, C (NRS) NR5R6, NR5C ( NR6) NR5R6, S (0) 2NR5R6, R7, C (0) R7, NR5C (0) R7, S (0) R7, or S (0) 2R7; each R5 is independently selected from hydrogen or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C? -C4 alkoxy / NH2, C? -C alkylamino, C? -C dialkylamino or C3-C6 cycloalkyl; each R6 is independently selected from hydrogen, (CH2) pAr4, or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C? -C4 alkoxy, NH2, C? -C4 alkylamino, C4-C4 dialkylamino or cycloalkyl C3-C3; each R7 is independently selected from (CH2) pAr4 or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C1-C4 alkoxy, NH2, C-C4 alkylamino, dialkylamino Ca-C4 or C3-C3 cycloalkyl; and each Ar4 is independently selected from C3-Cg cycloalkyl, aryl or heteroaryl, each optionally substituted with one to three substituents independently selected from halogen, OH, CX-C4 alkoxy, NH2, C? -C4 alkylamino / dialkylamino C? -C4 or 1 / 2- methylenedioxy. In another aspect, the compounds are those of any of the formulas herein (including any combination thereof): wherein, Ar 1 is cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of H, halogen, amino, hydroxy, cyano, nitro, carboxylate, alkyl, alkenyl, alkynyl, cycloalkyl, cyclohexyl, alkoxy, mono and di-alkyl amino, phenyl, carboxamide, haloalkyl, haloalkoxy, and alkanoyl; R1 is Ar2 or lower alkyl optionally substituted with Ar2; Ar2 is independently selected from cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of H, halogen, amino, hydroxy, cyano, nitro, carboxylate, alkyl, alkenyl, alkynyl, cycloalkyl, cyclohexyl, alkoxy, mono and dialkyl amino, phenyl, carboxamide, haloalkyl, haloalkoxy, and alkanoyl, - q is 0; each R2 is independently selected from (CH2) mC0R3, (CH2) mCOAr3, (CH2) mC0NR3R4, (CH2) 3Ar3, (CH2) nNR3R4 or (CH2) nOR4; each R3 is independently selected from H, or lower alkyl; each R4 is independently selected from H, lower alkyl or (CH2) pAr3; each Ar3 is cycloalkyl, aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more substituents, with the proviso that Ar3 is not piperidinyl, tetrahydroquinolinyl or tetrahydroisoquinolinyl; each Z is independently selected from O or NR3; each m is 1 or 2, each n is 2 or 3 each p is 0 or 1, each substituent for Ar1, Ar2 and Ar3 is independently selected from halogen, CN, N02, OR5, SR5, S (0) 2OR5, NR5R6, cycloalkyl, pe? Uoroalkyl C? -C2, perfluoroalkoxy C? -C2, 1,2-methylenedioxy, C (0) OR5, C (0) NR5R6, OC (0) NR5R6, NR5C (0) NR5R6, C (NRS) NR5R6, NR5C (NRe) NR5R6, S (0) 2NR5R6, R7, C (0) R7, NR5C (0) R7, S (0) R7, or S (0) 2R7; each R5 is independently selected from hydrogen or optionally substituted lower alkyl with one or more substituents independently selected from halogen, OH, C? -C4 alkoxy, NH2, C? -C4 alkylamino, C? 4 dialkylamino or cycloalkyl? -C?; each Rs is independently selected from hydrogen, (CH2) pAr4, or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C? -C4 alkoxy, NH2, C4-C4 alkylamino, C? -C dialkylamino or C3-C6 cycloalkyl; each R7 is independently selected from (CH2) pAr4 or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C? -C4 alkoxy, NH2, C? -C4 alkylamino / C? -C4 dialkylamino or C3-C3 cycloalkyl; and each Ar4 is independently selected from C3-C6 cycloalkyl, aryl or heteroaryl, each optionally substituted with one to three substituents independently selected from halogen, OH, CX-C4 alkoxy, NH2, C1-C4 alkylamino, dialkylamino C? -C4 or 1,2-methylenedioxy; wherein, Ar 1 is cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of H, halogen, amino, hydroxy, cyano, nitro, carboxylate, alkyl, alkenyl, alkynyl, cycloalkyl, cyclohexyl, alkoxy, mono and di-alkyl amino, phenyl, carboxamide, haloalkyl, haloalkoxy, and alkanoyl; R1 is Ar2 or lower alkyl optionally substituted with Ar2; Ar2 is independently selected from cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of H, halogen, amino, hydroxy, cyano, nitro, carboxylate, alkyl, alkenyl, alkynyl, cycloalkyl, cyclohexyl, alkoxy, mono and di-alkyl amino, phenyl, carboxamide, haloalkyl, haloalkoxy, and alkanoyl; q is 1; each R2 is independently selected from (CH2) mC02R3, (CH2) mCOAr3, (CEfeJmAr3, (CH2) 3Ar3, (CH2) nNR3R4 or (CH2) nOR4; each R3 is independently selected from H, or lower alkyl; each R4 is independently selected from H, lower alkyl or (CH2) pAr3; each Ar3 is cycloalkyl, aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more substituents, with the proviso that when R2 is (CH2) mAr3 and m is 1, then Ar3 is not ortho-dimethylaminophenyl, each Z is independently selected from O or NR3, each m is 1 or 2, each n is 2 or 3, each p is 0 or 1; each substituent for Ar1, Ar2 and Ar3 is independently selected from halogen, CN, N0, OR5, SR5, S (0) 2OR5, NR5R6, cycloalkyl, perfluoroalkyl C? -C2, perfluoroalkoxy C? -C2, 1,2-methylenedioxy, C (0) 0R5, C (0) NR5R6, OC (0) NR5R6, NR5C (0) NR5R6, C (NR6) NR5R6, NR5C (NR6) NR5R6, S (0) 2NR5R6, R7, C (0) R7, NR5C (0) R7, S (0) R7, or S (0) 2R7; each R5 is independently selected from hydrogen or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C? -C4 alkoxy, NH2, C? -C4 alkylamino, C? -C dialkylamino or C3-C6 cycloalkyl; each R6 is independently selected from hydrogen, (CH2) pAr4, or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, -C? -C4 alkoxy, NH, C? -C4 alkylamino, dialkylamino C? -C4 or C3-C6 cycloalkyl; each R7 is independently selected from (CH2) pAr4 or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C? -C4 alkoxy, NH2, C? -C alkylamino, C? -C4 dialkylamino or C3 cycloalkyl? C6; and each Ar4 is independently selected from C3-C6 cycloalkyl, aryl or heteroaryl, each optionally substituted with one to three substituents independently selected from halogen, OH, C? -C4 alkoxy, NH2, C? -C4 alkylamino, dialkylamino C? C or 1,2-methylenedioxy; wherein, Ar 1 is cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of H, halogen, amino, hydroxy, cyano, nitro, carboxylate, alkyl, alkenyl, alkynyl, cycloalkyl, cyclohexyl, alkoxy, mono and di-alkyl amino, phenyl, carboxamide, haloalkyl, haloalkoxy, and alkanoyl; Ra is Ar2 or lower alkyl optionally substituted with Ar2; Ar2 is independently selected from cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of H, halogen, amino, hydroxy, cyano, nitro, carboxylate, alkyl, alkenyl, alkynyl, cycloalkyl, cyclohexyl, alkoxy, mono and di-alkyl amine, phenyl, carboxamide, haloalkyl, haloalkoxy, and alkanoyl; q is 2; each R2 is independently selected from (CH2) mC02R3, (CH2) mCOAr3, (CH2) mC0NR3R4, (CH ^^ r3, (CH2) 3Ar3, (CH2) nNR3R4 or (CH2) n0R4; each R3 is independently selected from H, or lower alkyl, each R4 is independently selected from H, lower alkyl or (CH2) pAr3; each Ar3 is cycloalkyl, aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more substituents, each Z is independently selected from 0 or NR3; each-m is 1 or 2, each n is 2 or 3, each p is 0 or 1, each substituent for Ar1, Ar2 and Ar3 is independently selected from halogen, CN, N02, OR5, SR5, S (0) 2OR5, NR5R6, cycloalkyl, perfluoroalkyl C? -C2, perfluoroalkoxy C? -C2, 1,2-methylenedioxy, C (0) OR5, C (0) NR5R6, OC (0) NR5R6, NR5C (0) NR5R6, C ( NR6) NR5R6, NR5C (NR6) NR5R6, S (0) 2NR5Rd, R7, C (0) R7, NR5C (0) R7, S (0) R7, or S (0) 2R7; each R5 is independently selected from hydrogen or lower alkyl optionally substituted with one or more substituents inde independently selected from halogen, OH, C 1 -C 4 alkoxy, NH 2, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino or C 3 -C 6 cycloalkyl, each R 6 is independently selected from hydrogen, (CH 2) pAr 4, or optionally lower alkyl substituted with one or more substituents independently selected from halogen, OH, C? -C4 alkoxy, NH2, C? -C4 alkylamino, C? -C4 dialkylamino or C? C6 cycloalkyl; each R7 is independently selected from (CH2) pAr4 or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C? -C4 alkoxy, NH2, C? -C4 alkylamino, C? -C4 dialkylamino or C3 cycloalkyl? C6; and each Ar4 is independently selected from C3-Ce cycloalkyl, aryl or heteroaryl, each optionally substituted with one to three substituents independently selected from halogen, OH, C?-C4 alkoxy, NH2, C?-C alkylamino, dialkylamino. C? -C4 or 1,2-methylenedioxy; wherein, R2 is (CH2) mC02R3, (CH2) mCOAr3, or (CH2) mCONR3R4, and m is 2; wherein, R1 is Ar2 or lower alkyl substituted with Ar2, R2 is (CH2) mAr3, and m is 1, with the proviso that R1 is not furylmethyl or tetrahydrofurylmethyl; wherein, R1 is? r2 or lower alkyl substituted with Ar2, R2 is (CH2) mAr3, and m is 2, with the proviso that R1 is not furylmethyl or tetrahydrofurylmethyl; wherein, Ar1 and R1 are each optionally substituted aryl, and R2 is independently selected from (CH2) mAr3, (CH2) 3Ar3, (CH2) nNR3R4 or (CH2) nOR4; wherein, each R2 is independently selected from (CH2) mAr3, and each Ar3 is heteroaryl optionally substituted with one or more substituents; wherein, Ar 3 is heteroaryl having a ring of five carbon atom members and 1, 2 or 3 heteroatoms selected from N, O and S, optionally substituted with one or more substituents; wherein, Ar 3 is pyrrolidinyl, pyrazolyl, imidazolyl, thioimidazolyl, benzimidazolyl, or benzthioimidazolyl, each optionally substituted with one or more substituents; wherein, the compound of formula Bl is a compound delineated in any of the tables herein or a pharmaceutical salt thereof. One aspect is a method of treating a disease or symptoms of disease in a subject that includes administering to the subject an effective amount of a compound of the formula Cl or a pharmaceutical salt thereof: (C?) Wherein, Ar1 is cycloalkyl, aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more substituents; X is NR3, C (R3) 2, S, a bond u 0, or together with Y form -CH = CH-; Y is C = 0, a bond, or lower alkyl, or together with X form -CH = CH ~; R1 is Ar2, alkenyl, or lower alkyl optionally substituted with Ar2; each Ar2 is independently cycloalkyl, aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more substituents; q is 0, 1 or 2; each R2 is independently (CH2) mC02R3, (CH2) mCOAr3, (CH rAr3, (CH2) 3Ar3, (CH2) nNR3R4, (CH2) n0R4; (CH2) mCN; alkyl; alkynyl, (CR3R3) mC0NR3R4, Ar4, ( CR3R3) mN (R3) C (0) Ar3, or (CH2) mC (NOH) NH2; each R3 is independently H, or lower alkyl, each R4 is independently H, lower alkyl, alkoxy, (CH2) nNR5R6, or ( CH2) pAr3; m is 1 or 2, n is 2 or 3, p is 0 or 1, each Ar3 is cycloalkyl, aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more substituents, each substituent for Ar1, Ar2 and Ar3 is independently halogen, CN, N02, OR6, SR6, S (0) 20R5, NR5R6, cycloalkyl, perfluoroalkyl C? -C2, perfluoroalkoxy C? - C2 l 1,2-methylenedioxy, C (0) OR5, C (0) NR5R6, OC (0) NR5RG, NR5C (0) NR5R6, C (NR6) NR5R6, NR5C (NR6) NR5R6, S (0) 2NR5R6, R7, C (0) R7, NR5C (0) R7, S (0) R7, or S (0) 2R7: each R5 is independently hydrogen or lower alkyl optionally substituted with one or more substituents independently selected from halogen , OH, C 1 -C 4 alkoxy, NH 2, C 1 -C alkylamino, C 1 -C 4 dialkylamino or C 3 -C 6 cycloalkyl, each R 6 is independently hydrogen, (CH 2) pAr 4, or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C? -C alkoxy, NH2, C? -C alkylamino, C? -C dialkylamino or C3-Cd cycloalkyl; each R7 is independently (CH) pAr4 or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C? -C4 alkoxy, NH2, C? -C4 alkylamino, C? -C4 dialkylamino or C3-Ce cycloalkyl; and each Ar4 is independently C3-C6 cycloalkyl, heterocyclyl, aryl or heteroaryl, each optionally substituted with one to three substituents independently selected from halogen, OH, alkoxyC? -C4, NH2, C1-C4 alkylamino, dialkylamino C? C4 or 1,2-methylenedioxy. In another aspect, the methods are those of any of the formulas herein (including any combination thereof): wherein, Ar1 is aryl or heteroaryl, each optionally substituted with one or more substituents; X is NR3; And it is lower alkyl; R1 is aryl optionally substituted with one or more substituents; and each R2 is independently (CH2) mC02R3, (CH2) mCOAr3, (CH2) mCONR3R4, (CH2) mAr3, (CH2) 3Ar3, or (CH2) nNR3R4. wherein, Ar 1 is aryl or heteroaryl, each optionally substituted with one or more substituents; X is a link; And it is a link; R1 is aryl optionally substituted with one or more substituents; and each R2 is independently selected from (CH2) mC02R3, (CH2) mCOAr3, (CH2) mCONR3R4, (CH2) mAr3, (CH2) 3Ar3, (CH2) nNR3R4; wherein, each R2 is independently selected from (CH2) mAr3; wherein, each R2 is independently selected from (CH2) mAr3; and each Ar3 is heteroaryl optionally substituted with one or more substituents; wherein Ar3 is a heteroaryl comprising a five-membered ring having carbon atoms and 1, 2 or 3 heteroatoms selected from N, O and S, optionally substituted with one or more substituents; wherein Ar 3 is pyrrolidinyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, benzimidazolyl, benzoxazolyl, or benzthiazolyl, each optionally substituted with one or more substituents; wherein the compound of the formula Cl is a compound delineated in any of the Cl tables, or a pharmaceutical salt thereof; Another aspect is a method for modulating calcium channel activity comprising contacting a calcium channel with a compound of any of the formulas in the < I presented. Another aspect is a compound of formula Cl above, or a pharmaceutical salt thereof. Another aspect is a compound of the formula Cl or a pharmaceutical salt thereof, wherein, Ar 1 is cycloalkyl, aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more substituents, and each is linked to X by a carbon atom; X is CH2; Y is a bond, - R1 is Ar2, alkenyl, or lower alkyl optionally substituted with Ar2; each Ar2 is independently cycloalkyl, aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more substituents; q is 0, 1 or 2; each R2 is independently (CH2) mC02R3, (CH2) mCOAr3, or (CH2) mCONR3R4; each R3 is independently H, or lower alkyl; each R4 is independently H, lower alkyl, alkoxy, (CH2) nNR5R6, or (CH2) pAr3; m is 2; n is 2 or 3; p is O OR 1; each Ar3 is cycloalkyl, aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more substituents; each substituent for Ar1, Ar2 and Ar3 is independently halogen, CN, N02, OR6, SR6, S (0) 2OR5, NR5R6, cycloalkyl, perfluoroalkyl C? -C2, perfluoroalkoxy C? -C2, 1,2-methylenedioxy, C ( 0) OR5, C (0) NR5R6, OC (0) NR5R6, NR5C (0) NR5R6, C (NR6) NR5R6, NR5C (NR6) NR5R6, S (0) 2NR5R6, R7, C (0) R7, NR5C ( 0) R7, S (0) R7, or S (0) 2R7; each R5 is independently hydrogen - or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C 1 -C 4 alkoxy, NH 2, C 1 -C 4 alkylamino, C 1 -C 6 dialkylamino or C 3 -C 6 cycloalkyl; each R6 is independently hydrogen, (CH2) pAr4, or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C 1 -C 4 alkoxy, NH 2, C 1 -C alkylamino, C 1 -C 4 dialkylamino or C 3 -C 6 cycloalkyl; each R7 is independently (CH2) pAr4 or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C 1 -C 4 alkoxy, NH 2, C 1 -C alkylamino, C 1 -C 6 dialkylamino or C 3 -C 6 cycloalkyl; and each Ar4 is independently C3-C6 cycloalkyl, heterocyclyl, aryl or heteroaryl, each optionally substituted with one to three substituents independently selected from halogen, OH, C1-C4 alkoxy, NH2, C? -C alkylamino, dialkylamino C? -C4 or 1, 2-methylenedioxy. In another aspect, the compounds are those of any of the formulas herein (including any combination thereof): wherein, Ar 1 is cycloalkyl, aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more substituents, and each is linked to X by a carbon atom; X is a link; And it is a link; R1 is Ar2; each Ar2 is independently cycloalkyl, aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more substituents; each R2 is 4-pyridylmethyl; wherein, Ar 1 is cycloalkyl, aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more substituents, and each is linked to X by a carbon atom, however, Ar 1 is not 4-pyridyl; X is a link; And it is a link; R1 is Ar2; each Ar2 is independently cycloalkyl, aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more substituents; and each R2 is 3-pyridylmethyl; wherein, Ar 1 is cycloalkyl, aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more substituents, and each is linked to X by a carbon atom; X is a link; And it is a link; R1 is Ar2; each Ar2 is independently cycloalkyl, aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more substituents; and each R2 is 2-pyridylmethyl; wherein: Ar 1 is cycloalkyl, aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more substituents; X is a link; And it is a link; R1 is Ar2; each Ar2 is independently cycloalkyl, aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more substituents; and each R2 is: wherein is NR3, S or 0. wherein, Ar1 is cycloalkyl, aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more substituents; X is a link; And it is a link; R1 is Ar2; each Ar2 is independently cycloalkyl, aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more substituents; each R2 is (CH ^ Ar3; and each Ar3 is aryl substituted with NH2, S (0) 20R3, COOH, or C (0) NH2 One aspect is a compound of the formula D- (I) or a pharmaceutical salt of the wherein R3 is Ar1 or ArXY where each Ar1 is cycloalkyl, aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more substituents, X is NR4, C (R4) 2, or 0; is C = 0 or lower alkyl, R1 is Ar2 or lower alkyl optionally substituted with Ar2, each Ar2 is independently cycloalkyl, aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more substituents, each R2 is independently selected from (CH2) ) mC (0) OR4, (CH2) mC (0) Ar3, (CH2) mC (0) NR4R5, (CH2) nNR4R5, (CH2) 3Ar3, or (CH2) mAr3; each R4 is independently selected from H, or lower alkyl, each R 5 is independently selected from H, lower alkyl or (CH 2) pAr 3, m is 1 or 2, n is 2 or 3 p is 0 or 1 each Ar 3 is cycloalkyl, aryl, heterocyclyl, or heteroary ilo, each optionally substituted with one or more substituents; each substituted by Ar1, Ar2 and Ar3 is independently selected from halogen, CN, N02, OR5, SR6, S (0) 2OR6, NR6R7, cycloalkyl, perfluoroalkyl 1.-C2, perfluoroalkoxy C-C2, 1,2-methylenedioxy, C (0) OR6, C (0) NR6R7, 0C (0) NR6R7, NR6C (0) NR6R7, C (NR6) NR6R7, NR6C (NR7) NR6R7, S (0) 2NR6R7, R8, C (0) R8, NRsC (0) R8, S (0) R8, or S (0) 2R8; each R6 is independently selected from hydrogen or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C-C4 alkoxy, NH2, C-C4 alkylamino, C-C4 dialkylamino or C3-C6 cycloalkyl; each R7 is independently selected from hydrogen, (CH2) gAr4, or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C? -C4 alkoxy, NH2, C? -C4 alkylamino, dialkylamino C? -C4 or C3-C3 cycloalkyl; each R8 is independently selected from (CH2) qAr4 or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C1-C4 alkoxy, NH2, C4-C4 alkylamino, C? -C dialkylamino or C3-C cycloalkyl J each Ar4 is independently selected from C3-C6 cycloalkyl, aryl or heteroaryl, each optionally substituted with one to three substituents independently selected from halogen, OH, CX-C4 alkoxy, NH2, C? -C4 alkylamino, dialkylamino CX-C4 or C3-C6 cycloalkyl; and q is 0 or 1. Another aspect is a compound of any of the formulas herein (including any combination thereof), wherein R3 is Ar1 and R1 is Ar2; wherein R3 is independently, aryl or heteroaryl, each optionally substituted with one or more substituents; and R1 is independently, aryl or heteroaryl, each optionally substituted with one or more substituents; wherein R2 is (CH2) mC (O) OR4, (CH2) mC (O) Ar3 or (CH2) mC (0) NR4R5; wherein R2 is (CH2) mAr3 and Ar3 is aryl or heteroaryl each optionally substituted with one or more substituents; wherein R2 is (CH2) mC (0) NRR5 and R5 is independently (CH2) pAr3, wherein Ar3 is aryl or heteroaryl, each optionally substituted with one or more substituents; wherein R2 is (CH2) nNR4R5 or (CH ^ mr3; wherein m is 2 and Ar3 is a heteroaryl comprising a five membered ring having carbon atoms and 1, 2 or 3 heteroatoms selected from N, O and S, optionally substituted with one or more substituents, wherein Ar3 is pyrrolidinyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, benzimidazolyl, benzoxazolyl, or benzthiazolyl, each optionally substituted with one or more substituents, or wherein the compound of the formula DI is a compound of any of the tables D- (1-6) One aspect is a compound of the formula E- (I) or a pharmaceutical salt thereof wherein, R3 is alkyl, alkoxyalkyl, Ar1 or ArXX-Y wherein, each Ar1 is independently cycloalkyl, aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more substituents; X is NR4, C (R4) 2, or O; Y is C = 0 or lower alkyl, -R1 is H, alkenyl, Ar2 or lower alkyl optionally substituted with Ar2 each Ar2 is independently cycloalkyl, aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more substituents; each R2 is independently selected from H, (CH2) mC (0) OR4, (CH2) mC (0) Ar3, (CH2) mC (0) NR4R5, (CH2) mC (O.) N (OR4) R5, ( CH2) mCH2OR4, Ar3, (CH2) nAr3; (CH2) nNRR5, or (CH ^^ 3, each R4 is independently selected from H, or lower alkyl, each R5 is independently selected from H, lower alkyl or (CH2) pAr3; m is 1 or 2; n is 2 or 3, p is 0 or 1, each Ar3 is cycloalkyl, aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more substituents, each substituent for Ar1, Ar2, and Ar3 is independently selected from halogen, CN, N02, OR6 , SR6, S (0) 2OR6, NR6R7, cycloalkyl, perfluoroalkyl C? -C2, perfluoroalkoxy C? -C2, 1,2-methylenedioxy, C (0) OR6, C (0) NR6R7, OC (0) NR6R7, NR6C ( 0) NR6R7, C (NR6) NR6R7, NR6C (NR7) NR6R7, S (0) 2NR6R7, R8, C (0) R8, NR6C (0) R8, S (0) R8, or S (0) 2R8; each R6 is independently selected from hydrogen or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C1-C4 alkoxy, NH2, C4-C4 alkylamino, C? -C dialkylamino or C3-Ce cycloalkyl; each R7 is independently selected from hydrogen, (CH2) qAr4, or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C? -C4 alkoxy, NH2, C? -C4 alkylamino, dialkylamino C? -C4 or C3-C6 cycloalkyl; each R8 is independently selected from (CH2) gAr4 or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C? -C4 alkoxy, NH2, C4-alkylamino, C? -C4 dialkylamino or C3-C6 cycloalkyl; each Ar4 is independently selected from C3-C6 cycloalkyl, aryl or heteroaryl, each optionally substituted with one to three substituents independently selected from halogen, OH, CX-C4 alkoxy, NH2, C? -C4 alkylamino, C? -C4 diakylamino or C3-C6 cycloalkyl; and q is O or 1. Another aspect is a compound of any of the formulas herein (including any combination thereof): wherein, R3 is Ar1 and R1 is Ar2; wherein, R3 is independently, aryl or heteroaryl, each optionally substituted with one or more substituents; and R1 is independently, aryl or heteroaryl, each optionally substituted with one or more substituents; wherein R2 is (CH2) mC (O) OR4, (CH2) mC (O) Ar3 or (CH2) mC (0) NRR5; wherein R2 is (CH ^ mAr3 and Ar3 is aryl or heteroaryl each optionally substituted with one or more substituents, wherein R2 is (CH2) mC (0) NR4R5 and R5 is independently, (CH2) pAr3, wherein Ar3 is aryl or heteroaryl, each optionally substituted with one or more substituents, wherein R2 is (CH2) nNR4R5 or (CH2ma3; or wherein the compound of the formula EI is any of those in the tables herein. One aspect is a method for treating a disease or symptoms of the disease in a subject comprising administering to the subject an effective amount of a compound of the formula F- (I) or a pharmaceutical salt thereof: wherein, Ar 1 is cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of H, halogen, amino, hydroxy, cyano, nitro, carboxylate, alkyl, alkenyl, alkynyl, cycloalkyl, cyclohexyl, alkoxy , mono and di-alkyl amin or, phenyl, carboxamide, haloalkyl, haloalkoxy, and alkanoyl; R1 is Ar2 or lower alkyl optionally substituted with Ar2; Ar2 is independently selected from cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of H, halogen, amino, hydroxy, cyano, nitro, carboxylate, alkyl, alkenyl, alkynyl, cycloalkyl, cyclohexyl, alkoxy, mono and di-alkyl amino, phenyl, carboxamide, haloalkyl, haloalkoxy, and alkanoyl; each R2 is independently selected from C02R3, COAr3, CONR3R4, Ar3, CH2NR3R4; each R3 is independently selected from H, or lower alkyl; each R4 is independently selected from H, lower alkyl, C (0) OR5, C (? rNR5R6, S (0) 2NR5R6, C (0) R7, S (0) 2R7 or (CH2) pAr3; each Ar3 is independently cycloalkyl , aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more substituents, each p is independently 0 or 1, each substituent for Ar3 is independently selected from halogen, CN, N02, OR5, SR5, S (O) 2OR5, NR5R6, cycloalkyl, perfluoroalkyl C? -C2, perfluoroalkoxy C? -C2, 1,2-methylenedioxy ,: C (0) OR5, C (0) NR5R6, 0C (0) NR5R6, NR5C (0) NR5R6, C (NR5 ) NR5R6, NR5C (NR6) NR5R6, S (0) 2NR5R6, R7, C (0) R7, NR6C (0) R7, S (0) R7, or S (0) 2R7: each R5 is independently selected from hydrogen or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C 1 -C 4 alkoxy, NH, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino or C 3 -C 6 cycloalkyl, each R 6 is independently selected from hydrogen, CH2) gAr4, or lower alkyl option ally substituted with one or more substituents independently selected from halogen, OH, C 1 -C 4 alkoxy, NH 2, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino or C 3 -C 6 cycloalkyl; each R7 is independently selected from (CH) gAr4 or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C1-C4 alkoxy, NH2, C?-C4 alkylamino, C-C4 dialkylamino or C3-C6 cycloalkyl; each Ar4 is independently selected from C3-C6 cycloalkyl, aryl or heteroaryl, each optionally substituted with one to three substituents independently selected from halogen, OH, CX-C alkoxy, NH2, C? -C4 alkylamino, dialkylamino C? -C4 or 1,2-methylenedioxy; and each q is independently 0 or 1. In other aspects, the methods are those having any of the formulas herein (including any combination thereof): wherein, each R2 is independently C0NR3R4, Ar3, CH2NR3R4; Wherein, Ar 1 is aryl or heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of H, halogen, amino, hydroxy, cyano, nitro, carboxylate, alkyl, alkenyl, alkynyl, cycloalkyl, cyclohexyl, alkoxy, mono and dialkyl amino, phenyl, carboxamide, haloalkyl, haloalkoxy, and alkanoyl; R1 is Ar2; and Ar2 is "independently aryl or heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of H, halogen, amino, hydroxy, cyano, nitro, carboxylate, alkyl, alkenyl, alkynyl, cycloalkyl, cyclohexyl, alkoxy, mono and di-alkyl amino, phenyl, carboxamide, haloalkyl, haloalkoxy, and alkanoyl; wherein, each R2 is independently Ar3; and each Ar3 is independently aryl or heteroaryl, each optionally substituted with one or more substituents; wherein, each Ar3 is independently heteroaryl, each optionally substituted with one or more substituents; wherein, each R2 is independently C0NR3R4, and each R4 is (CH2) pAr3; wherein, each Ar3 is independently aryl or heteroaryl, each optionally substituted with one or more substituents, - wherein, Ar3 is independently a nitrogen-containing heteroaryl, optionally substituted with one or more subs tituyentes; Wherein, each R2 is independently CH2NR3R4; and each R4 is (CH2) pAr3; Wherein, Ar3 is independently a nitrogen-containing heteroaryl, optionally substituted with one or more substituents. In one aspect it is a compound of the formula G- (I) or a pharmaceutical salt thereof wherein, Ar 1 is cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of H, halogen, amino, hydroxy, cyano, nitro, carboxylate, alkyl, alkenyl, alkynyl, cycloalkyl, cyclohexyl, alkoxy, mono and di-alkyl amino, phenyl, carboxamide, haloalkyl, haloalkoxy, and alkanoyl; R1 is Ar2 or lower alkyl optionally substituted with Ar2; Ar2 is independently selected from cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of H, halogen, amino, hydroxy, cyano, nitro, carboxylate, alkyl, alkenyl, alkynyl, cycloalkyl, cyclohexyl, alkoxy, mono and dialkylamino, phenyl, carboxamide, haloalkyl, haloalkoxy, and alkanoyl; each R2 is independently selected from C02R3", COAr3, CONR3R4, (CH2) mAr3, (CH2) nNR3R4 or CH20R4, each R3 is independently selected from H, or lower alkyl, each R4 is independently selected from H, lower alkyl, C ( 0) OR5, C (0) NR5R6, S (0) 2NR5R6, C (0) R7, S (0) 2R7 or (CH2) pAr3: each Ar3 is independently cycloalkyl, aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more substituents, each m is independently 0 or 1, each n is independently 1 or 2, each p is independently 0 or 1, each substituent for Ar3 is independently selected from halogen, CN, N02 / .OR5, SR5, S (0) 2OR5, NR5R6, cycloalkyl, perfluoroalkyl C? -C2, perfluoroalkoxy C? -C2, 1,2-methylenedioxy, C (0) OR5, C (0) NR5R6, 0C (0) NR5R6, NR5C (O) NR5R6 , C (NR5) NR5R6, NR5C (NR6) NR5R6, S (0) 2NR5R6, R7, C (0) R7, NR6C (0) R7, S (0) R7, or S (0) 2R7; each R5 is independently selected from hydrogen or lower alkyl, optionally substituted with one or more substituents independently selected from halogen, OH, C1-C4 alkoxy, NH2, C1-C4 alkylamino, dialkylamino C? -C or C3-C6 cycloalkyl; each R6 is independently selected from hydrogen, (CH2) gAr4, or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C3-C4 alkoxy, NH2, C4-4 alkylamino, C4-4 dialkylamino or C3-C3 cycloalkyl; each R7 is independently selected from (CH2) gAr4 or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C 1 -C 4 alkoxy, NH 2, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino or C 3 -C 3 cycloalkyl; each Ar4 is independently selected from C3-C6 cycloalkyl, aryl or heteroaryl, each optionally substituted with one to three substituents independently selected from halogen, OH, C? -C4 alkoxy, NH2, C-C4 alkylamino, dialkylamino C? -C4 or 1,2-methylenedioxy; and each q is independently 0 or 1. In another aspect, the compounds are those of any of the formulas herein (including any combination thereof) .- Where Ar1 is aryl or heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of H, halogen, amino, hydroxy, cyano, nitro, carboxylate, alkyl, alkenyl, alkynyl, cycloalkyl, cyclohexyl, alkoxy, mono and di-alkyl amino, phenyl, carboxamide, haloalkyl , haloalkoxy, and alkanoyl; R1 is Ar2; Ar2 is independently selected from "aryl or heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of H, halogen, amino, hydroxy, cyano, nitro, carboxylate, alkyl, alkenyl, alkynyl, cycloalkyl , cyclohexyl, alkoxy, mono and di-alkyl amino, phenyl, carboxamide, haloalkyl, haloalkoxy, and alkanoyl; and each R2 is independently selected from COAr3, CONR3R4, (CH2) mAr3, or (CH2) nNR3R4; Wherein, Ar1 is aryl, which may be optionally substituted with one or more substituents selected from the group consisting of H, halogen, amino, hydroxy, cyano, nitro, carboxylate, alkyl, alkenyl, alkynyl, cycloalkyl, cyclohexyl, alkoxy, mono and di-alkyl amino, phenyl, carboxamide, haloalkyl, haloalkoxy, and alkanoyl; Ar2 is independently aryl, which may be optionally substituted with one or more substituents selected from the group consisting of H, halogen, amino, hydroxy, cyano, nitro, carboxylate, alkyl, alkenyl, alkynyl, cycloalkyl, cyclohexyl, alkoxy, mono and di-alkyl amino, phenyl, carboxamide, haloalkyl, haloalkoxy, and alkanoyl; and each R2 is independently selected from (CH2) mAr3, or (CH2) nNR3R4; Wherein, each Ar3 is independently aryl or heteroaryl, each optionally substituted with one or more substituents; Wherein, each R4 is (CH2) pAr3; and each Ar3 is independently aryl or heteroaryl, each optionally substituted with one or more substituents; Wherein, each R2 is independently selected (CH2) nNR3R4; and each R4 is (CH2) pAr3; Wherein, R1 is para-chlorophenyl; Wherein, Ar1 is para-fluorophenyl; Wherein, the compound of formula G-I is a compound delineated in any of the tables herein, or a pharmaceutical salt thereof.

In one aspect it is a compound of the formula H- (I) or a pharmaceutical salt thereof wherein, Ar 1 is cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of H, halogen, amino, hydroxy, cyano, nitro, carboxylate, alkyl, alkenyl, alkynyl, cycloalkyl, cyclohexyl, alkoxy, mono and di-alkyl amino, phenyl, carboxamide, haloalkyl, haloalkoxy, and alkanoyl; X is NR3, C (R3) 2, or O; Y is C = 0 or lower alkyl; R1 is Ar2 or lower alkyl optionally substituted with Ar2; Ar2 is independently selected from cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of H, halogen, amino, hydroxy, cyano, nitro, carboxylate, alkyl, alkenyl, alkynyl, cycloalkyl, cyclohexyl, alkoxy, mono and di-alkyl amino, phenyl, carboxamide, haloalkyl, haloalkoxy, and alkanoyl; each R2 is independently selected from C02R3, COAr3, CONR3R4, (CH2) mAr3, CH2NR3R4 or CH2OR4; each R3 is independently selected from H, or lower alkyl; each R4 is independently selected from H, lower alkyl, C (0) OR5, C (0) NR5R6, S (0) 2NR5R6, C (0) R7, S (0) 2R7 or (CH2) pAr3; each -Ar3 is independently cycloalkyl, aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more substituents; each m is independently 0 or 1; each p is independently 0 or 1; each substituent for Ar3 is independently selected from halogen, CN, N02, OR5, SR5, S (0) 2OR5, NR5RG, cycloalkyl, perfluoroalkyl! -C2, perfluoroalkoxy C? -C2, 1,2-methylenedioxy, C (0) OR5 , C (0) NR5R6, OC (0) NR5R6, NR5C (O) NR5R6, C (NR5) NR5R6, NR5C (NR6) NR5R6, S (0) 2NR5R6, R7, C (0) R7, NR6C (0) R7 , S (0) R7, or S (0) 2R7; each R5 is independently selected from hydrogen or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C? -C4 alkoxy, NH2, C? -C alkylamino, C? -C4 dialkylamino or C3-Cd cycloalkyl; each R6 is independently selected from hydrogen, (CH2) gAr, or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C? -C4 alkoxy, NH2, C? alkylamino, dialkylamino C? -C or C3-C3 cycloalkyl; each R7 is independently selected from (CH2) qAr4 or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C? -C4 alkoxy, NH2, C? -C4 alkylamino, C4-C4 dialkylamino or C3-C6 cycloalkyl; each Ar4 is independently selected from C3-C6 cycloalkyl, aryl or heteroaryl, each optionally substituted with one to three substituents independently selected from halogen, OH, Ci-C4 alkoxy, NH2, C? -C4 alkylamino, dialkylamino C? or C? , 2-methylenedioxy; and each q is independently 0 or 1. In another aspect, the compounds are those of any of the formulas herein (including any combination thereof): wherein, Ar1 is aryl or heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of H, halogen, amino, hydroxy, cyano, nitro, carboxylate, alkyl, alkenyl, alkynyl, cycloalkyl, cyclohexyl, alkoxy, mono and di-alkyl-amino, phenyl, carboxamide, haloalkyl, haloalkoxy, and alkanoyl; X is NR3; Y is C = 0 or lower alkyl; R1 is Ar2; Ar2 is independently aryl or heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of H, halogen, amino, hydroxy, cyano, nitro, carboxylate, alkyl, alkenyl, alkynyl, cycloalkyl, cyclohexyl , alkoxy, mono and di-alkyl amino, phenyl, carboxamide, haloalkyl, haloalkoxy, and alkanoyl; and each R2 is independently COAr3, C0NR3R4, (CH ^ m r3, or CH2NR3R4; Y is C = 0; and Ar2 is independently aryl which may be optionally substituted with one or more substituents selected from the group consisting of H, halogen, amino, hydroxy, cyano, nitro, carboxylate, alkyl, alkenyl, alkynyl, cycloalkyl, cyclohexyl, alkoxy, mono and di-alkyl amino, phenyl, carboxamide, haloalkyl, haloalkoxy, and alkanoyl; Wherein, Y is lower alkyl; R1 is Ar2; Ar 2 is independently aryl or heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of H, halogen, amino, hydroxy, cyano, nitro, carboxylate, alkyl, alkenyl, alkynyl, cycloalkyl, cyclohexyl , alkoxy, mono and di-alkyl amino, phenyl, carboxamide, haloalkyl, haloalkoxy, and alkanoyl; Wherein, each R2 is independently CONR3R4 or CH2NR3R4; Wherein, each R 2 is independently (CH 4 mAr 3; wherein, Ar 3 is heteroaryl optionally substituted with one or more substituents; wherein, each R 4 is independently (CH 2) PAr 3; wherein the compound of the formula HI is a delineated compound; in any of the tables herein, or a pharmaceutical salt thereof An aspect is a compound of the formula J- (I) or a pharmaceutical salt thereof j-) wherein, Ar1 is cycloalkyl, aryl, heterocyclyl, or heteroaryl, "each optionally substituted with one or more substituents; R1 is? r2 or optionally substituted lower alkyl each Ar2 is independently selected from cycloalkyl, aryl, heterocyclyl, or heteroaryl each optionally substituted with one or more substituents, each R2 is independently (CH2) mC02R3, (CH2) mC0Ar3, (CH2) mC0NR3R4, (CH ^^ r3; (CH2) n0R3; (CH2) nAr3 or (CH2) nNR3R4 each R3 is independently selected from H, or lower alkyl, each R4 is independently selected from H, lower alkyl, C (0) 0R ?, C (0) NR5R6, S (0) 2NR5R6, C (0) R7, S (0) 2) R7 or (CH2) pAr3; or each R3 and R4 are taken together with the nitrogen compound which is bonded to form a 4-7 membered heterocyclic ring wherein one carbon atom in each heterocyclic ring is optionally an NR4, 0 or S and each heterocyclic ring is optionally substituted with one or more alkyl groups inf Each Ar3 is independently cycloalkyl, aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more substituents; each m is independently 0 or 1, each n is independently 1 or 2 each p is independently 0 or 1, each substituent for Ar3 is independently selected from halogen, CN, N02, OR5, SR5, S (0) 2OR5, NR5R6, cycloalkyl , perfluoroalkyl C? -C2, perfluoroalkoxy C? -C2, 1,2-methylenedioxy, C (0) 0R5, C (0) NR5R6, OC (0) NR5R6, NR5C (0) NR5R6, C (NR5) NR5R6, NR5C (NR6) NR5R6, S (0) 2NR5R6, R7, C (0) R7, NR6C (0) R7, S (0) R7, or S (0) 2R7; each R5 is independently selected from hydrogen or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C? -C alkoxy, NH2, C? -C alkylamino, C? -C dialkylamino or C3-Ce cycloalkyl; each R6 is independently selected from hydrogen, (CH2) pAr4, or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C? -C4 alkoxy, NH2, C? -C alkylamino, dialkylamino C? -C or C3-C6 cycloalkyl; each R7 is independently selected from (CH2) pAr4 or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C 1 -C 4 alkoxy, NH 2, C 1 -C alkylamino, C 1 -C 4 dialkylamino or C 3 -C 6 cycloalkyl,. and each Ar4 is independently selected from C3-C3 cycloalkyl, aryl or heteroaryl, each optionally substituted with one to three substituents independently selected from halogen, OH, alkoxy. C? ~ C, NH2, C -C4 alkylamino, dialkylamino C? -C4 or- 1,2-methylenedioxy. Other aspects are those compounds (of any of the formulas herein (including any combination thereof): wherein each R2 is independently (CH2) mC02R3, (CH2) mC0Ar3, (CH2) raCONR3R4, (CH2) nAr3 or (CH2) nNR3R4; Wherein, R 1 is C 2 -C 2 alkyl substituted with Ar 2; and Ar2 is optionally substituted with one or more substituents; Wherein, R1 is Ar2; Ar2 is optionally substituted with one more substituents; Wherein, R2 is (CH2) raC (0) OR3 > (CH2) raC (0) Ar3 or (CH2) mC (O) NR3R4 and each m is independently 0 or 1; and each Ar3 is optionally substituted with one or more substituents; wherein, R2 is (CH2) nNR3R4 and n is 1; wherein, R2 is (CH2) nNR3R4 and n is 2; wherein, R2 is (CH2) raAr3 and m is 0; and Ar3 is optionally substituted with one or more substituents; wherein, R2 is (CH2) mAr3 and m is 1; and Ar3 is optionally substituted with one or. more substituents; wherein, each Ar1, Ar2, Ar3 and Ar4 is independently selected from cycloalkyl, phenyl, naphthyl, acenaphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, furyl, thienyl, pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl , isoxazolyl, isotriazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, trityanil, indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo ^ - [b] furanyl, benzo [b] thiophenyl, lH-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, tetrahydro-isoquinolinyl, isoquinolinyl, tetrahydro-quinoline, cinnolinyl, phthalazinyl , quinazolinyl, quinoxalinyl, naphthyridinyl, peridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, or phenoxazinyl, each optionally substituted with one or more substituents; Wherein, the compound is of the formula J- (I): wherein, Ar 1 is aryl or heteroaryl each optionally substituted with one to three substituents; R1 is Ar2; each Ar2 is independently selected from aryl or heteroaryl each optionally substituted with one to three substituents; R2 is (CH2) nNR3R4 and n is 1 wherein each R4 is independently selected from H, lower alkyl, C (0) 0R5, C (0) NR5Rs, S (0) 2NR5R6, C (0) R7, S (0 ) 2) R7 or (CH2) pAr3; or each R3 and R4 are taken together with the nitrogen compound which is bonded to form a 4-7 membered heterocyclic ring wherein, one carbon atom in each heterocyclic ring is optionally an NR4, 0 or S and each heterocyclic ring it is optionally substituted with one or two lower alkyl groups; each p is independently 0 or 1; and each Ar3 is independently selected from aryl or heteroaryl, each optionally substituted with one to three substituents; wherein the compound is of the formula J- (I): wherein, Ar 1 is aryl or heteroaryl each optionally substituted with one to three substituents; R1 is Ar2; each Ar2 is independently selected from aryl or heteroaryl each optionally substituted with one to three substituents; R2 is (CH2) nNR3R4 and n is 2 wherein each R4 is independently selected from H, lower alkyl, C (0) 0R5, C (0) NR5R6, S (0) 2NR5R6, C (0) R7, S (0 ) 2) R7 or (CH2) pAr3; or each R3 and R4 are taken together with the nitrogen compound which is bonded to form a 4-7 membered heterocyclic ring wherein, one carbon atom in each heterocyclic ring is optionally an NR4, 0 or S and each heterocyclic ring it is optionally substituted with one or two lower alkyl groups; each p is independently 0 or 1; and each Ar3 is independently selected from aryl or heteroaryl, each optionally substituted with one to three substituents; Where the compound is of the formula J- (I): wherein, Ar 1 is aryl or heteroaryl each optionally substituted with one to three substituents; R1 is Ar2; each? r2 is independently selected from heterocyclyl or heteroaryl each optionally substituted with one to three substituents; R2 is (CH2) mAr3 and m is 0; each Ar3 is independently selected from aryl or heteroaryl, each optionally substituted with one to three substituents; each substituent for Ar1, Ar2 and Ar3 is independently selected from halogen, OR5, NR5R6, perfluoroalkyl C? -C2, perfluoroalkoxy C? -C2, 1,2-methylenedioxy; each R 5 is independently selected from hydrogen or lower alkyl optionally substituted with one or more substituents selected from halogen, OH, C x C alkoxy, NH 2, C 1 -C 4 alkylamino, C 4 -C 4 dialkylamino; each R6 is independently selected from hydrogen, (CH2) pAr4 or lower alkyl optionally substituted with one or more substituents selected from halogen, OH, C? -C4 alkoxy, NH2, C4 alkylamino, C? -C4 dialkylamino; each p is independently 0 or 1; and each Ar4 is independently selected from aryl or heteroaryl, each optionally substituted with one to three substituents independently selected from halogen, OH, 1-C4 alkoxy, NH2, C? -C alkylamino, dialkylamino C? -C4, perfluoroalkyl C? C2 / perfluoroalkoxy C? -C2, 1,2-methylenedioxy; Where the compound is of the formula J- (I): wherein, Ar 1 is aryl or heteroaryl each optionally substituted with one to three substituents; R1 is Ar2; each Ar2 is independently selected from heterocyclyl or heteroaryl each optionally substituted with one to three substituents; R2 is (CH2) mAr3 and m is 1; each Ar3 is independently selected from aryl or heteroaryl, each optionally substituted with one to three substituents; each substituent for Ar1, Ar2 and Ar3 is independently selected from halogen, OR5, NR5R6, perfluoroalkyl C? -C2, perfluoroalkoxy C? -C2, 1,2-methylenedioxy; each R5 is independently selected from hydrogen or lower alkyl optionally substituted with one or more substituents selected from halogen, OH, C? -C4 alkoxy, NH2, C? -C4 alkylamino, C? -C4 dialkylamino; each R6 is independently selected from hydrogen, (CH) pAr4 or lower alkyl optionally substituted with one or more substituents selected from halogen, OH, C? -C4 alkoxy, NH2, C? -C4 alkylamino, dialkylamino C? -C; each p is independently 0 or 1; and each Ar4 is independently selected from aryl or heteroaryl, each optionally substituted with one to three independently selected substituents halogen, OH, C? -C4 alkoxy, NH2, C? -C4 alkylamino, dialkylamino C? -C4, perfluoroalkyl C? -C2, perfluoroalkoxy C? -C2, 1,2-methylenedioxy; Where the compound is "of the formula J - (.I): wherein, Ar 1 is phenyl substituted with one to three substituents; R1 is Ar2 and Ar2 phenyl substituted with one to three substituents; R2 is (CH2) nNR3R4 and n is 1; each R3 is independently selected from H or lower alkyl; each R4 is (CH2) pAr3; each p is independently 0 or 1; each Ar3 is independently selected from aryl or heteroaryl, each optionally substituted with one to three substituents; each substituent for Ar1, Ar2 and Ar3 is independently selected from halogen, OR5, NR5R6, perfluoroalkyl C? -C2, perfluoroalkoxy C? -C2, 1,2-methylenedioxy; each R5 is independently selected from hydrogen or lower alkyl optionally substituted with one or more substituents selected from halogen, OH, C? -C4 alkoxy, NH2, C? -C4 alkylamino, C? -C4 dialkylamino; each R6 is independently selected from hydrogen, (CH2) pAr4 or lower alkyl optionally substituted with one or more substituents selected from halogen, OH, C-C alkoxy, NH2, C? -C4 alkylamino, dialkylamino C? -C4; and each Ar4 is independently selected from aryl or heteroaryl, each optionally substituted with one to three independently selected substituents halogen, OH, C? -C4 alkoxy, NH2, C? -C4 alkylamino, dialkylamino C? -C4, perfluoroalkyl C? C2, C 1 -C 2 perfluoroalkoxy, 1,2-methylenedioxy; - Where the compound is of the formula J- (I): wherein, Ar 1 is phenyl substituted with one to three substituents; R1 is Ar2 and Ar2 phenyl substituted with one to three substituents; R2 is (CH2) nNR3R4 and n is 1; each R3 and R4 are taken together with the nitrogen compound which is bonded to form a 4-7 membered heterocyclic ring wherein, one carbon atom in each heterocyclic ring is optionally an NR4, 0 or S and each heterocyclic ring is optionally substituted with one or two lower alkyl groups; each substituent for Ar1 and Ar2 is independently selected from halogen, OR5, NR5R6, perfluoroalkyl C? -C2, perfluoroalkoxy C? -C2, 1,2-methylenedioxy each R5 is independently selected from hydrogen or lower alkyl optionally substituted with one or more substituents selected from halogen, OH, C-C4 alkoxy, NH2, C? -C4 alkylamino, dialkylamino C? -C4; each R6 is independently selected from hydrogen, (CH2) pAr4 or lower alkyl optionally substituted with one or more substituents selected from halogen, OH, C? -C4 alkoxy, NH, C? -C alkylamino, C? -C4 dialkylamino; each p is independently 0 or 1; and each Ar4 is independently selected from aryl or heteroaryl, each optionally substituted with one to three independently selected substituents halogen, OH, C? -C4 alkoxy, NH2, C? -C4 alkylamino, dialkylamino C? -C4, perfluoroalkyl C? C2, C 1 -C 2 perfluoroalkoxy, 1,2-methylenedioxy; Wherein the compound is of the formula J- (I): wherein, Ar 1 is phenyl substituted with one to three substituents; R1 is Ar2 and Ar2 phenyl substituted with one to three substituents; R2 is (CH ^ Ar3 and m is 0, each Ar3 is benzimidazol-2-yl optionally substituted with one to three substituents; each substituent for Ar1, Ar2 and Ar3 is each independently selected from halogen, OR5, NR5R6, perfluoroalkyl C? -C2, perfluoroalkoxy C? -C2, 1,2-methylenedioxy, each R5 is independently selected from hydrogen or lower alkyl optionally substituted with one or more substituents selected from halogen, OH, C? -C4 alkoxy, NH2, alkylamino C? C4, C? -C4 dialkylamino, each R6 is independently selected from hydrogen, (CH2) PAr4 or lower alkyl optionally substituted with one or more substituents selected from halogen, OH, C? -C4 alkoxy, NH2, C? -C4 alkylamino? , dialkylamino C? -C4, each p is independently 0 or 1, and each? r4 is independently selected from aryl or heteroaryl, each optionally substituted with one to three independently selected substituents halogen, OH, C -Ci alkoxy, NH2 , C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino, C 1 -C 2 perfluoroalkyl, C 1 -C 2 perfluoroalkoxy, 1,2-methylenedioxy; or wherein the compound of the formula J- (I) is any of those in the table J-I herein. Another aspect is a method for treating a disease mediated by calcium channel Caví or symptoms of the disease in a subject comprising administering to the subject an effective amount of a compound, or pharmaceutical salt (or composition thereof) of any of the formulas of the present . Another aspect is a method for modulating (eg, inhibiting, agonizing, antagonizing) calcium channel activity including contacting a compound, or pharmaceutically acceptable salt thereof, of any of the formulas herein (or composition thereof). ) with a calcium channel. In the methods herein, the calcium channel can be Caví (for example, Cav1.2 or Cav1.3). The Caví calcium channel that mediates the disease or symptoms of the disease can be a disease of the nervous system or symptom of the disease or it can be cardiovascular disease or symptom of the disease.

Another aspect is a method for treating a disease mediated or symptom of the disease in a subject comprising administering to the subject an effective amount of a compound, or pharmaceutical salt, - (or composition thereof) of any of the formulas herein. The disease or symptom of the disease is angina, hypertension, congestive heart failure, myocardial ischemia, atrial fibrillation, diabetes mellitus, urinary incontinence, overload bladder, lung disease, cognitive function or nervous system disorder; Where, the disease or symptom of the disease is modulated by the Caví calcium channel; Where the disease or symptom of the disease is modulated by the calcium channel Caví .2 or Caví .3; Where the disease or symptom of the disease is angina, hypertension, congestive heart failure, myocardial ischemia, arrhythmia, diabetes, urinary incontinence, stroke, pain, traumatic brain injury, or a neuronal disorder. Another aspect is a composition that includes a compound of any of the formulas of the present, or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The composition may also include an additional therapeutic agent. Another aspect is a method for making a compound of any of the formulas herein, which include reacting an intermediate delineated herein with a reagent to provide a compound of any of the formulas herein as defined herein. Another aspect is a method for modulating (eg, inhibiting, antagonizing, agonizing) the activity in a calcium channel in a subject in need thereof comprising administering to the subject an effective amount of a compound of any of the formulas of the present invention. , or pharmaceutically acceptable salt thereof, or composition thereof.

In another aspect, the invention relates to a composition comprising a compound of any of the formulas herein, an additional therapeutic agent, and a pharmaceutically acceptable carrier. The additional therapeutic agent can be a cardiovascular disease agent and / or a disease agent of the nervous system. A disease agent of the nervous system refers to a disease agent of the peripheral nervous system (PNS) and / or disease agent of the central nervous system (CNS). Yet another aspect of this invention relates to a method of treating a subject (e.g., mammal, human, horse, dog, cat) having a disease or symptom of the disease (including, but not limited to, angina, hypertension). , congestive heart failure, myocardial ischemia, atrial fibrillation, diabetes mellitus, urinary incontinence, overactive bladder, lung disease, cognitive function, or a nervous system disorder). The method includes administering to the subject (which includes a subject identified as needing such treatment) an effective amount of a compound described herein, or a composition described herein to produce such an effect. It identifies a subject who needs such treatment may be in the judgment of a subject or a professional "in health care and may be subjective (for example, opinion) or objective (for example, measured by a test method or Yet another aspect of this invention relates to a method of treating a subject (e.g., mammal, human, horse, dog, cat) having a disease mediated by the ion channel or symptom of the disease (which includes , but not limited to angina, hypertension, congestive heart failure, myocardial ischemia, atrial fibrillation, diabetes mellitus, urinary incontinence, overactive bladder, lung disease, cognitive function, or a nervous system disorder.) The method includes administering the subject ( including a subject identified as needing such treatment) an effective amount of a compound described herein, or a composition described herein to produce such an effect. Identifying a subject that needs such treatment can be in the judgment of a subject or a health care professional and can be subjective (for example, opinion) or objective (for example, measured by a method of testing or diagnosis) . The invention also relates to a method for making a compound described herein, the method includes any of the reactions or reagents as outlined in the reaction schemes or examples herein. Alternatively, the method includes taking any of the intermediate compounds described herein and reacting this with one or more chemical reagents in one or more steps to produce a compound described herein. Also within the scope of this invention is a packaged product ": The packaged product includes a container, one of the above compounds in the container, and a legend (e.g., a label or an insert) associated with the container and indicating the administration of the compound to treat a disorder associated with modulation in the ion channel In other embodiments, the compounds, compositions, and methods delineated herein are any of the compounds of the tables herein or methods included therein.

The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and from the claims.

Detailed Description of the Description As used herein, the term "halo" refers to any radical of fluorine, chlorine, bromine or iodine. The term "alkyl" refers to a hydrocarbon chain which may be a straight chain or branched chain, which contains the indicated number of carbon atoms. For example, C? -C5 indicates that the group can have from 1 to 5 (inclusive) carbon atoms in it. The term "lower alkyl" refers to a Cx-C6 alkyl chain. The term "arylalkyl" refers to a portion in which a hydrogen atom is replaced by an aryl group.

The term "alkoxy" refers to an -O-alkyl radical.

The term "alkylene" refers to an alkyl divalent (that is, -R-). The term "alkylene dioxo" refers to a divalent species of the structure -O-R-O-, in which R represents an alkylene. The term "cycloalkyl" as used herein includes partially saturated and unsaturated cyclic hydrocarbon groups having 3 to 12 carbons, preferably 3 to 8 carbons, and more preferably 3 to 6 carbons. The term "aryl" refers to a 6-membered monocyclic hydrocarbon ring or multicyclic aromatic ring system of 10 to 14 members wherein 0, 1, 2, 3, or 4 atoms of each ring may be substituted by a substituent. Examples of the aryl groups include phenyl, naphthyl and the like. The term "heterocyclyl" refers to a non-aromatic 5-8 membered monocyclic, 8-12 membered bicyclic monocyclic, or 11-14 membered tricyclic ring system having 1-3 heteroatoms if it is monocyclic, 1-6 heteroatoms if is bicyclic, or 1-9 heteroatoms if tricyclic, the heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, 0, or S if it is monocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2 or 3 atoms of each ring can be replaced by a substituent. The term "heteroaryl" refers to a 5-8 membered aromatic monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1-3 heteroatoms if it is monocyclic, 1-6 heteroatoms if it is bicyclic, or 1-9 heteroatoms if tricyclic, the heteroatoms selected from O, N, or S (eg, carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, 0, or S if is monocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2, 3, or 4 atoms of each ring can be substituted by a substituent. The term "oxo" refers to an oxygen atom, which forms a carbonyl when bonded to a carbon, an N-oxide when bound to nitrogen, and a sulfoxide or sulfone when bonded to sulfur.

The term "acyl" refers to an alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heterocyclylcarbonyl, or heteroarylcarbonyl substituent, any of which may be further substituted by substituents. The term "substituents" refers to a group "substituted" on an alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl group at any atom of that group. Suitable substituents include, without halogen limitation, CN, N02, OR5, SR5, S (0) 20R5, NR5RS, perfluoroalkyl C? -C, perfluoroalkoxy C? -C2, 1,2-methylenedioxy, C (0) 0R5, C (0) NR5R6, 0C (0) NR5Rs, NR5C (0) NR5R6, C (NR6) NR5R6, NR? C (NR6) NR5R6, S (0) 2NR5R6, R7, C (0) R7, NR5C (0) R7 , S (0) R7, or S (0) 2R7. Each R 5 is independently hydrogen, C 1 -C 4 alkoyl or C 3 -C 6 cycloalkyl. Each Rs is independently hydrogen, C3-C6 cycloalkyl, aryl, heterocyclyl, heteroaryl, C? -C4 alkyl or C? -C4 alkyl substituted with C3-C6 cycloalkyl, aryl, heterocyclyl or heteroaryl. Each R7 is independently C3-C6 cycloalkyl, aryl, heterocyclyl, heteroaryl, C 1 -C 4 alkyl or C 1 -C 4 alkyl substituted with C 3 -C 6 cycloalkyl, aryl, heterocyclyl or heteroaryl. Each C3-Ce cycloalkyl, aryl, heterocyclyl, heteroaryl and C? -C alkyl in each R5, R6 and R7 can optionally be substituted with halogen, CN, C? -C4 alkyl, OH, C-C4 alkoxy, NH2, alkylamino C? ? -C4, dialkylamino C? -C4, perfluoroalkyl C? -C2, perfluoroalkoxy C? -C, or 1,2-methylenedioxy. In one aspect, the substituents in a group are independently hydrogen, hydroxyl, halogen, nitro, S03H, trifluoromethyl, trifluoromethoxy, straight or branched (C? -C6) alkyl, straight or branched C? -C6 alkoxy, O- benzyl, O-phenyl, phenyl, 1,2-methylenedioxy, carboxyl, morpholinyl, piperidinyl, amino or OC (0) NR5Rs. Each R5 and R6 is as described above. The term "treat" or "treatise" refers to administering a compound described herein to a subject for the purpose of curing, healing, alleviating, alleviating, altering, remedying, ameliorating, ameliorating or affecting a disease, the symptoms of the disease or predisposition towards the disease. "An effective amount" refers to an amount of a compound, which confers a therapeutic effect on the treated subject. The therapeutic effect can be objective (that is, it is measured by some test or marker) or subjective (ie, the subject gives an indication of or feels an effect).

An effective amount of the compound described above may be in the range from about 0.1 mg / Kg to about 500 mg / Kg. The effective dose also varies depending on the route of administration, as well as the possibility of co-use with other reagents. Representative compounds useful in the compositions and methods are delineated herein: Table A1 Table A1B Table A1C Table A1D Table B1A Table B18 Compound. "\" "GT ™" ("" "gri j ~? ¡J2 Table B1C Table C1B Table 01 C Compound No I A? B? I? C TafalaCID Compound No. | "Ar'-X-Y f R 'l ~~ R? Table C1E Table C1F Table C1 < 3 Table D-1 Table D-2 Table D-3 Table D-4 Table B-S Tafite D-ß TablaE ~ 1A Table E-IB Table E-1C Table E-1D Table E-1E, N-rAV-R2 AAA N AS b R Table E-1F Table E-1 < 5 ompueso No. f Ar1-X-Y R1 R * Table F-1 Table G-1A Table 0-1B Table G4C Table H4A Table H-1B Table H4C Table JM A ( Table J-1B Ion channel modulator compounds can be identified through both in vitro (e.g., cell-based and cell-free) and in vivo methods. Representative examples of these methods are described in the examples herein. The combinations of the substituents and variables descried by this invention are only those that result in the formation of the stable compounds. The term "stable", as used herein, refers to compounds in which sufficient stability is possessed to allow manufactures and which maintain the integrity of the compound for a sufficient period of time to be useful for the purpose detailed in present (e.g., therapeutic or prophylactic administration to a subject). The compounds delineated herein can be synthesized using conventional methods, as illustrated in the reaction scheme herein. In the reaction schemes in the present, at the time otherwise stated, the variables in the chemical formulas are as defined in other formulas herein. For example, Ar1, Ar3, R1, R2, R3 and R4 in the reaction schemes are defined as in any of the formulas herein, except where otherwise defined in the reaction schemes.

Reaction scheme Al of departure Treatment of the amine (I) under basic conditions (e.g., sodium acetate) with ethyl bromoacetate in the solvent provides amino acid ester (II). Treatment of (II) in the solvent with acetyl chloride provides (III). Imidazole (IV) is produced when (III) is treated with ethyl formate in the solvent under basic conditions. Saponification of ester (IV) under basic conditions gives imidazole (V). Treatment of (V) with N, 0-dimethylhydroxylamine under the amide bond forms conditions (for example, l-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride) in the solvent of the amide (VI). Treatment of amide (VI) under reducing conditions (eg, lithium aluminum hydride) in the solvent provides the aldehyde (VII). Treatment of (VII) with amine (VIII) under reducing conditions (eg, lithium aluminum hydride, THF) provides (IX). Treatment of (IX) with (X) gives the desired compound (XI).

Reaction scheme A2 The treatment of the carboxylic acid (V) with amine (VIII) under the amide bond forms conditions (e.g., l-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride) in the amide solvent (XII). Treatment of (XII) with (X) under basic conditions (for example, K2C03) in the solvent provides (XIII).

A3 reaction scheme püffi Y © s UR g u o VJlfl starting Reaction scheme A4 Reaction scheme Bl m («i (t Yj departed ^^ Treatment of the bromomethyl ketone (I) in the solvent, such as DMSO, with sodium azide affords the azidomethyl (II) ketone. Treatment of (II) with reducing conditions, such as palladium on carbon in aqueous HCl and H2 atmosphere, provides the amine (III). The reaction of (III) and isothiocyanate (IV) under basic conditions, such as sodium acid carbonate, in a solvent, such as ethanol, provides thioimidazole (V). The reaction of (V) and (VI) under basic condition, such as potassium carbonate, provides imidazole (VII).

Cl reaction scheme m Treatment of ethyl ester (I) with hydrazine in the solvent (e.g., ethanol) provides hydrazide (II). The treatment of (II) with thioisocyanate (III) under basic aqueous conditions gives triazole thiol (IV).

Reaction scheme C2 v > And ts a split group (for example, halogen) Treatment of (IV) with (V) under basic conditions (for example, K2C03 in acetone) gives (VI).

Reaction scheme C3 I 0 ». { X ki ?} And it is a g starting group C k? H) (par halle, halogen) Treatment of diethyl ethyl acetate (VII) with hydrazine in the solvent (e.g., ethanol) provides hydrazide (VIII). The treatment of (VIII) with basic conditions of aqueous thioisocyanate (III) gives triazole (IX) which again provides the aldehyde (X) during treatment with aqueous acidic conditions. Treatment of (X) with (V) under basic conditions (for example, 2C03 in acetone) provides (XIII).

Diagram of reaction D-I O O í,? ñ m cn > m Treatment of the bromomethyl compound with sodium azide affords the azidomethyl compound (I). Treatment of (I) under reducing conditions, such as palladium on carbon in aqueous HCl and H2 atmosphere, provides the amine (II). The treatment of (II) with isothiocyanate (III) "provides imidazole (IV). The alkylated imidazole N (Via) is produced from the reaction of (IV) with 3-bromo-propionate or 4-bromo-butyrate (V). Saponification of the ester (Via) gives the carboxylic acid (VIb).

Reaction scheme D-2 < V «Í) VHI) ÍBQ Alternatively, the imidazole (IV) was prepared by the following sequence. Treatment of diethyl ethyl acetate (VII) with hydrazine in the solvent (e.g., ethanol) provides hydrazide (VIII). The tratment of (VIII) with thioisocyanate (III) under basic aqueous conditions gives imidazole (IX) which again provides the aldehyde (X) under aqueous acidic conditions. The reductive amination of (X) and amine (XI) provides (IV).

Reaction scheme D-3 Reaction of the carboxylic acid (VIb) with the appropriately substituted amine under standard coupling procedures provides the desired amide (XII). Reduction of the amide under common reduction conditions (eg, diborane or lithium aluminum hydride) provides the corresponding amine (XIII). Alternatively, the treatment of (VIb) with the Weinreb reagent provides the amide (XIV). Treatment of the amide (XIV) under standard conditions with an organometallic reagent (e.g., lithium aryl or aryl magnesium halide) provides the ketone (XV). The reduction of the ketone under a variety of conditions provides the desired product (XVI).

Reaction scheme D-4 The ester treatment (Via) under standard reduction conditions (eg, lithium aluminum hydride) gives the alcohol (XVII). The treatment of (XVII) under conditions that form the standard ether (e.g., NaH, benzylbromide) gives (XVIII).

Reaction scheme D-5 ? VÍÍ5) (XIX) fXX) An alternative route to obtain heteroaryl derivatives is to react the activated acid of (VIb) with the appropriate substrate followed by cyclization to provide the desired product. For example as detailed in reaction scheme D-5, the reaction of the activated acid of (VIb) with benzene-1,2-diamine provides the amide intermediate (XIX), which is cyclized to provide the benzimidazole derivative (XX).

Reaction scheme E-l R-X ».-» ymtit _ar ^ # ** esH The treatment of ethyl ester (I) with hydrazine in the solvent (e.g., ethanol) provides hydrazide (II). The treatment of (II) with thioisocyanate (III) under basic aqueous conditions gives triazole thione (IV). N-alkylated triazole (Via) is produced from the reaction of (IV) with 3-bromo-proprionate or 4-bromobutyrate (V). Saponification of the ester (Via) gives the carboxylic acid (VIb).

Reaction scheme E-2 w Alternatively, the triazole (IV) was prepared by the following sequence. Treatment of diethyl ethyl acetate (VII) with hydrazine in the solvent (e.g., ethanol) provides hydrazide (VIII). The treatment of (VIII) with thioisocyanate (III) under basic aqueous conditions gives triazole (IX) which again provides the aldehyde (X) under aqueous acidic conditions. The reductive amination of (X) and amine (XI) provides (IV).

Reaction scheme E-3 t tm The reaction of carboxylic acid (VIb) with the appropriately substituted amine under standard coupling procedure provides the desired amide (VII). Reduction of the amide under common reduction conditions (eg, diborane or lithium aluminum hydride) provides the corresponding amine (VIII). Alternatively, treatment of (VIb) with the Weinreb reagent provides the amide (IX). Treatment of the amide (IX) under standard conditions with an organometallic reagent (e.g., aryl lithium or aryl magnesium halide) provides the ketone (X). The reduction of the ketone under a variety of conditions provides the desired product (XI).

Reaction scheme E-4 The ester treatment (VTa) under standard reduction conditions (for example, lithium aluminum hydride) gives the alcohol (XII). Treatment of (XII) under standard ether formation conditions (e.g., NaH, benzylbromide) gives (XIII).

Reaction scheme E-5 em XIV} An alternative route to obtain heteroaryl derivatives is to react the activated acid of (VIb) with the appropriate substrate followed by cyclization to provide the desired product. For example as detailed in Reaction Scheme E-5, the reaction of the activated acid of (VIb) with benzene-1,2-diamine provides the amide intermediate (XIV), which is cyclized to provide the benzimidazole derivative (XV) Reaction scheme G-I The treatment of an aryl nitrile with an alcohol under acidic conditions provides the alkoxy imidate intermediate, which is treated with the appropriate substituted amine under catalytic conditions (eg, ethanolic HCl, CuCl, Ln (III) ions) to provide amidine replaced (G-I) The treatment of amidine (GI) with a bromopyruvate or a 4-bromo-3-oxo-butyrate or a 5-bromo-oxo-pentanoate under basic conditions provides the imdiazole ester (G-IIa), which is hydrolysed to provide the corresponding acid derivative (G-IIb).

Reaction scheme G-2 The reaction of the acid (G-IIb) with the appropriately substituted amine under the standard coupling procedure provides the desired amide (G-III). Reduction of the amide with common reducing agents such as diborane or lithium aluminum hydride provides the corresponding amine (G-IV). Alternatively the treatment of the acid (G-IIb) with Weinreb reagent provides amide (G-V). Treatment of the amide under standard condition with an organometallic reagent (eg, aryl lithium or aryl magnesium halide) provides the ketone (G-VI). The reduction of the ketone under a variety of conditions provides the desired product (G-VII).

Reaction scheme G-3 * esarilooheieroarflo es- 0,1, 203 Alternatively treatment of amidine (G-I) with (G-X) provides the desired imidazole (G-VII).

Reaction scheme G-4 An alternative route to obtain heteroaryl derivatives is to react the activated acid of (G-Ilb) with the appropriate substrate followed by cyclization to provide the desired product. For example as detailed in Reaction Scheme G-4, the reaction of the activated acid of (G-IIb) with benzene-1,2-diamine provides the amide intermediate (G-VIII), which is cyclized to provide the benzimidazole derivative (G-IX).

Reaction scheme G-5 oja ons pte replaced can Ar The treatment of carboxylic acid (G-IIb) under standard reduction conditions (eg, lithium aluminum hydride) gives (G-XI). Treatment of (G-XI) under standard ether forms conditions (e.g., NaH, halo-R4) da (G-XII).

Reaction scheme H-l Treatment of an aryl nitrile with an alcohol under acidic conditions provides the alkoxy imidate intermediate, which is treated with the appropriate substituted amine under catalytic conditions (eg, ethanolic HCl, CuCl, Ln (III) ions) to provide the amidine H- (I) substituted. The treatment of amidine H- (I) with a bromopyruvate or 4-bromo-3-oxo-butyrate or a 5-bromo-oxo-pentanoate under basic conditions provides the imidiazole ester H- (lia), which is hydrolyzed to provide the corresponding acid derivative H- (Ilb).

Reaction scheme H-2 Reaction of the H- (Ilb) acid with the appropriately substituted amine under the standard coupling procedure provides the desired amide H- (III). Reduction of the amide with common reducing agents such as diborane or lithium aluminum hydride provides the corresponding amine H- (IV). Alternatively the treatment of the H- (Ilb) acid with the Weinreb reagent provides the amide H- (V). Treatment of the amide under standard condition with an organometallic reagent (ex aryl lithium or aryl magnesium halide) provides the ketone H- (VI). The reduction of the ketone under a variety of conditions provides the desired product H- (VII).

Reaction scheme H-3 * A ss art or hüíersarito p ss and 1 j? > o -w Alternatively the treatment of amidine H- (I) with H- (X) provides the desired imidazole H- (VII).

Reaction scheme H-4 An alternative route to obtain heteroaryl derivatives is to react the activated acid of H- (Ilb) with the appropriate substrate followed by cyclization to provide the desired product. For example as detailed in reaction scheme 4, the reaction of the activated acid of H- (Ilb) with benzene-1,2-diamine provides the amide intermediate H- (VIII), which is cyclized to provide the derivative of benzimidazole H- (IX).

Reaction scheme H-5 The treatment of carboxylic acid (H-IIa under standard reduction conditions (e.g., lithium condition reactions (e.g., NaH, halo-R4) gives H- (XII).

Reaction scheme J-I J-fttQ) «alkyl is 0,1 OR 2 The treatment of an aryl nitrile with an alcohol under acidic conditions provides the alkoxy imidate intermediate, which is treated with the appropriate substituted amine under catalytic conditions (eg, ethanolic HCl, CuCl, Ln (III) ions) to provide the amidine. replaced J- (I). The treatment of amidine J- (I) with a bromopyruvate, a 4-bromo-3-oxo-butyrate, a 5-bromo- -oxo-pentanoate or a 6-bromo-5-oxo-hexanoate under basic conditions provides the corresponding ester imidiazole J- (ly), which is hydrolyzed to provide the corresponding acid derivative J- (Hb). . "- Reaction scheme J-2 Reaction of the J- (Ilb) acid with the appropriately substituted amine under the standard coupling procedure provides the desired amide J- (III). The reduction of the amide with common reducing agents such as diborane or lithium aluminum hydride provides the corresponding amine J- (IV). Alternatively the treatment of the J- (Ilb) acid with the Weinreb reagent provides amide J- (V). Treatment of the amide under standard conditions with an organometallic reagent (eg aryl lithium or aryl magnesium halide) provides the ketone J- (VI). The reduction of the ketone under a variety of conditions that provide the desired product J- (VII).

Reaction scheme J-3 Mñ *% * res arto or heíerearito p es 0, 1, 203 Alternatively the treatment of amidine J- (I) with J- (X) provides the desired imidazole J- (VII).

Reaction scheme J-4 An alternative route to obtain heteroaryl derivatives is to react the activated acid of J- (Ilb) with the appropriate substrate ^ followed by cyclization to provide the desired product. For example as detailed in Reaction Scheme J-4, the reaction of the activated acid of J- (Ilb) - with benzene-1,2-diamine yields the amide intermediate J- (VIII), which is cyclized to provide the benzimidazole derivative J- (IX) • Reaction scheme J-5 aite The treatment of the carboxylic acid J- (Ilb) under standard reduction conditions (for example, lithium aluminum hydride) gives J- (XI). The treatment of J- (XI) under conditions of standard ether forms (e.g., NaH, halo-R4) gives J- (XII). The compounds are prepared essentially as described above in the general reaction schemes.

All references cited herein, whether in print, electronic, computer readable storage or otherwise, are expressly incorporated by reference in their entirety, including but not limited to, abstracts, articles, newspapers, publications, . texts, treaties, internet network sites, databases, patents, and patent publications. It will be understood that although the invention has been described in conjunction with the detailed description thereof, the following description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims. The synthesized compounds can be separated from the reaction mixture and then purified by a method such as column chromatography, high pressure liquid chromatography, or recrystallization. As can be appreciated by the skilled artisan, additional methods for synthesizing the compounds of the formulas herein will be apparent to those of ordinary skill in the art. Additionally, the various synthetic steps can be performed in an alternating sequence in order to give the desired compounds. Synthetic chemistry transformations and protective group methodologies (protection and deprotection) useful in the synthesis of the compounds described herein are known in the art and include, for example, those such as those described in R. Larock, Comprehensive Organic Transformations , 2nd. Ed., Wiley-VCH Publishers (1999); T. W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd. Ed., John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1999); and L. Paquette,. ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), and later editions thereof. The compounds of this invention may contain one or more asymmetric centers and thus be presented as racemates and racemic mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures. All of these isomeric forms of these compounds are expressly included in the present invention. The compounds of this invention may also be represented in multiple tautomeric forms, in such cases, the invention expressly includes all tautomeric forms of the compounds described herein (for example, alkylation of a ring system may result in alkylation at sites multiple, the invention expressly includes all these reaction products). Such isomeric forms of such compounds are expressly included in the present invention. All crystal forms of the compounds described herein are expressly included in the present invention. As used in this, the compounds of this invention, including the compounds of the formulas described herein, are defined to include pharmaceutically acceptable derivatives or prodrugs thereof. A "pharmaceutically acceptable derivative or prodrug" means any salt, ester, salt of an ester, or other pharmaceutically acceptable derivative of a compound of this invention which, during administration to a recipient, is capable of providing (directly or indirectly) the compound of this invention. Particularly favored derivatives and prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a mammal (e.g., by allowing an orally administered compound to be more rapidly absorbed in the blood) or that increase the release from the precursor compound to the biological compartment (for example, the brain or lymphatic system) in relation to the precursor species. Preferred prodrugs include derivatives wherein a group that increases aqueous solubility or active transport through the intestinal membrane is added to the structure of the formulas described herein. See, for example, Alexander, J. et al. Journal of Medicinal Chemistry 1988, 31, 318-322; Bundgaard, H. Design of Prodrugs; Elsevier: Amsterdam, 1985; pp 1-92; Bundgaard, H.; Nielsen, N.M. Journal of Medicinal Chemistry 1987, 30, 451-454; Bundgaard, H. A Textbook of Drug Design and Development; Harwood Academic Publ .: S itzerland, 1991; pp 113-191; Digenis, G. A. et al. Handbook of Experimental "Pharmacology 1975, 28, 86-112, Friis, GJ, Bundgaard, H. A Textbook of Drug Design and Development, 2 ed., Overseas Publ .: Amsterdam, 1996; pp 351-385"; Pitman, I. H. Medicinal Research Reviews 1981, 1, 189-214; Sinkula, A. A .; Yalkowsky Journal of Pharmaceutical Sciences 1975, 64, 181-210; Verbiscar, A. J.; Abood, L. G Journal of Medicinal Chemistry 1970, 13, 1176-1179; Stella, V. J.; Himmelstein, K. J. Journal of Medicinal Chemistry 1980, 23, 1275-1282; Bodor, N.; Kaminski, J. J. Annual Reports in Medicinal Chemistry 1987, 22, 303-313. The compounds of this invention can be modified by appropriate functionalities added to increase the selective biological properties. Such modifications are known in the art and include those that increase biological penetration in a given biological compartment (Eg, blood, lymphatic system, nervous system), increased oral availability, increased to allow administration by injection, altered metabolism and excretion ratio altered solubility.

The pharmaceutically acceptable salts of the compounds of this invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acid salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorrate, anforsulfonate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride , bromohydrate, iodohydrate, 2-hydroxyethane sulfonate, lactate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate , thiocyanate, tosylate and undecanoate. Other acids, such as oxalic, although not by themselves pharmaceutically acceptable, can be employed in the preparation of salts useful as intermediates for obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts. Suitable base salt derivatives include alkali metal salts (for example, sodium), alkaline earth metal (for example, magnesium), ammonium and N- (alkyl) 4+. This invention also divides the quaternization of any of the nitrogen-containing groups of the compounds described herein. The soluble or dispersible products in water or oil can be obtained by such quaternization. The compounds of the formulas described herein can, for example, be administered by injection, intravenously, intraarterially, subdermally, intraperitonally, intramuscularly, or subcutaneously; or orally, buccally, nasally, transmucosally, topically, in an ophthalmic preparation, - or by inhalation, with a dose in the range from about 0.5 to about 100 mg / kg of body weight, alternatively doses between 1 mg and 1000 mg / dose, every 4 to 120 hours, or in accordance with the requirements of the particular drug. The methods herein contemplate the administration of an effective amount of the compound or composition of compound to achieve the desired or established effect. Typically, the compositions of this invention will be administered from about 1 to about 6 times a day or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy. The amount of active ingredient that can be combined with the carrier materials to produce a single dose form will vary depending on the host treated and the particular mode of administration. A typical preparation will contain from about 5% to about 95% active compound (w / w). Alternatively, such preparations contain from about 20% to about 80% active compound. Lower or higher doses than those recited above may be required. The specific dose and treatment regimens for any particular patient will depend on a variety of factors, including the activity of the specific compound employed, age, body weight, general health status, sex, diet, time of administration, rate of excretion, combination of the drug, the severity and course of the disease, condition or symptoms, the patient's disposition to the disease, condition or -symptoms, and the judgment of the treating physician. During the improvement of the patient's condition, a maintenance dose of a compound, composition or combination of this invention may be administered, if necessary. Subsequently, the dose or frequency of administration, or both, can be reduced, as a function of the symptoms, to a level at which the improved condition is maintained when the symptoms have been alleviated to the desired level, the treatment would stop. Patients may, however, require intermittent treatment on a long-term basis on any recurrence of the symptoms of the disease. The compositions delineated herein include the compounds of the formulas delineated herein, as well as additional therapeutic agents present, in amounts effective to achieve a modulation of disease or symptoms of the disease, including disorders mediated by the ion channel or symptoms. of the same. References that include examples of additional therapeutic agents are: 1) Burger's Medicinal Chemistry &; Drug Discovery 6th edition, by Alfred Burger, Donald J. Abraham, ed., Volumes 1 through 6, Wiley Interscience Publication, NY, 2003; 2) Ion Channels and Disease by Francis M. Ashcroft, Academic Press, NY, 2000; and 3) Calcium Antagonists in Clinical Medicine 3rd edition, Murray Epstein, MD, FACP, ed. , Hanley & Belfus, Inc., Philadelphia, PA, 2002. Additional therapeutic agents include but are not limited to agents for the treatment of cardiovascular disease (eg, hypertension, angina, atrial fibrillation, stroke prevention, heart failure, acute myocardial ischemia, etc), metabolic disease (eg, syndrome X, diabetes, obesity), kidney or genital urinary disease (eg, glomerular nephritis, urinary incontinence, nephrotic syndrome), and their symptoms of the disease. Examples of additional therapeutic agents for the treatment of cardiovascular disease and symptoms of the disease including but not limited to antihypertensive agents, ACE inhibitors, angiotensin II receptor antagonists, statins, β-blockers, antioxidants, anti-inflammatory drugs, anti -trombotic, anti-coagulants or antiarrhythmics. Examples of additional therapeutic agents for the treatment of metabolic disease and symptoms of the disease include but are not limited to ACE inhibitors, angiotensin II antagonists, fibrates, thiazolidinediones or antidiabetic drugs of sulfonylurea. Examples of additional therapeutic agents for the treatment of urinary kidney and / or genital syndromes and their symptoms include but are not limited to alpha-1 adrenergic antagonists (eg, doxazosin), anti-muscarinic (eg, tolterodine), reuptake inhibitors, norepinephrine / serotonin (eg, duloxetine), tricyclic antidepressants (eg, doxepin, desipramine) or steroids. The term "pharmaceutically acceptable carrier or adjuvant" refers to a carrier or adjuvant that can be administered to a patient, together with a compound of this invention, and which does not destroy the pharmacological activity thereof and is non-toxic when administered in doses sufficient to administer a therapeutic amount of the compound. Carriers, adjuvants and pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchange, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) as -tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens or other similar polymer delivery matrices, whey proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, mixtures of partial glyceride of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium acid phosphate, potassium acid phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, substances based on cellulose, polyethylene glycol, sodium carboxymethyl cellulose io., polyacrylates, waxes, polyethylene polyoxypropylene blocking polymers, polyethylene glycol and lanolin. Cyclodextrins such as -, β-, and β-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-β-cyclodextrins, or other soluble derivatives may also be advantageously used to increase the administration of compounds of the formulas described herein. The pharmaceutical compositions of this invention can be administered orally, parenterally, by spray inhalation, topically, rectally, nasally, buccally, vaginally or by means of an implanted reservoir, preferably by oral administration or administration by injection. The pharmaceutical compositions of this invention may contain any of carriers, pharmaceutically acceptable non-toxic conventional adjuvants or vehicles. In some cases, the pH of the formulation can be adjusted with pharmaceutically acceptable acids, bases or buffer solutions to increase the stability of the formulated compound or its administration form. The term "parenteral" as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques. The pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleagenous suspension. This suspension can be formulated in accordance with techniques known in the art using suitable wetting or dispersing agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation can also be a suspension or sterile injectable solution in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the vehicles and acceptable solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspension medium. For this purpose, any soft fixed oil can be employed including synthetic mono or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms. such as emulsions and or suspensions. Other commonly used surfactants such as Tweens or Spans and / or other similar emulsifying or bioavailability enhancing agents that are commonly used in the manufacture of liquid, pharmaceutically acceptable solid or other dosage forms may also be used for the purposes of the formulation. The pharmaceutical compositions of this invention can be administered orally in any orally acceptable dosage form including, but not limited to, capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions. In the case of tablets for oral use, carriers that are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When the aqueous suspensions and / or emulsions are administered orally, the active ingredient can be suspended or dissolved in an oily phase is combined with emulsifiers and / or suspending agents. If desired, certain sweeteners and / or flavorings and / or coloring agents may be added. The pharmaceutical compositions of this invention can also be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing a compound of this invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and will therefore melt in the rectum to release the active components. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols. Topical administration of the pharmaceutical compositions of this invention is useful when the desired treatment involves areas or organs readily accessible by topical application. For topical application to the skin, the pharmaceutical composition may be formulated with an appropriate ointment containing the active components suspended or dissolved in a carrier. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petroleum, white gasoline, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical composition can be formulated with an appropriate cream or lotion containing the active compound suspended or dissolved in a carrier with appropriate emulsifying agents. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. The pharmaceutical compositions of this invention can also be applied topically in the lower intestinal tract by the rectal formulation of the suppository or in an appropriate enema formulation. Topically transdermal patches are also included in this invention. The pharmaceutical compositions of this invention can be administered by nasal spray or inhalation. Such compositions are prepared in accordance with techniques well known in the art of pharmaceutical formulation and can be prepared as solutions in saline, benzyl alcohol employed or other appropriate preservatives, absorption promoters to increase bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents known in the art.A composition having the compound of the present formulas and an additional agent (e.g., a therapeutic agent) can be administered using an implantable device. Implantable devices and related technologies are known in the art and are useful as delivery systems where a continuous supply, or prolonged release of compounds or compositions delineated herein, is desired. Additionally, the implantable device delivery system is useful for specific points of direction of release of compound or composition (eg, localized sites, organs) - Negrin et al., Biomaterials, 22 (6): 563 (2001). The extended release technology involves alternative release methods that can also be used in this invention. For example, sustained release formulations based on polymer technologies, sustained release techniques and encapsulation techniques (eg, polymeric, liposomal) can also be used for administration of the compounds and compositions delineated herein. Also within the invention is a patch for administering active chemotherapeutic combinations herein. The patch includes a layer of material (eg, polymeric, cloth, gauze, bandage) and the compound of the formulas herein as set forth herein. One side of the material layer may have a protective layer adhering to it to resist the passage of the compounds or compositions. The patch may additionally include an adhesive to hold the patch in place in a subject. The adhesive is a composition, including that of either natural or synthetic origin, which, when in contact with the subject's skin, temporarily adheres to the skin. It can be water resistant. The adhesive can be placed on the patch to keep it in contact with the subject's skin for an extended period of time. The adhesive can be made of a tack, or adhesive strength, such that it holds the device in place of the subject for incidental contact, however, during an affirmative act (e.g., tearing, peeling, or other intentional removal) the adhesive gives a way to the external pressure placed on the device or the adhesive by itself, and allows breaking the adhesion contact. The adhesive may be pressure sensitive, that is, it may allow the adhesive (and the device to adhere to the skin) to be placed against the skin by the application of pressure (e.g., pressing, rubbing) on the adhesive or device.

When the compositions of this invention comprise a combination of a compound of the formulas described herein and one or more additional therapeutic or prophylactic agents, both the additional compound and agent should be present at dose levels of between about 1 to 100% , And more preferably between about 5 to 95% of the dose normally administered in a monotherapy regimen. The additional agents can be administered separately, as part of a multiple dose regimen, from the compounds of this invention. Alternatively, those agents can be part of a single dose form, mixed together with the compounds of this invention in a simple composition. The invention will be further described in the following examples. It will be understood that these examples are for illustrative purposes only and are not construed as limiting this invention in any way.

EXAMPLE TO OOCYTE ASSAY Compounds representative of the formulas herein are separated by exclusion for activity against calcium channel targets in an assay essentially as described in Neuron, January 1997, 18 (11): 153-166, Lin et al. . to the; J. Neurosci, July 1, 2000, 20 (13): 4768-75, J. Pan and D. Lipsombe; and J. Neurosci., August 15, 2001, 21 (16): 5944-5951, W. Xu and D. Lipscombe, using a heterologous expression system of Xenopus oocyte. The assay is carried out in several calcium channels (for example, subfamily Cav1.2 or Cav1.3) therefore the modulation of the calcium channel is measured for each compound.

Example A2 HEK assay HEK-293T / 17 cells were transiently transfected in a similar manner as described in FuGENE 6 Package Insert Version 7, April 2002, Roche Applied Science, Indianapolis, IN. The cells are seeded at 2.5 x 10? cells in a 6-well plate of 2 L in an incubator overnight and reach a confluence of 30 ~ 40%. In a small sterile tube, sufficient serum-free medium is added as a diluent for the FuGENE transfection reagent (Roche Applied Science, Indianapolis, IN), to a total volume of 100 μL. 3 μL of FuGENE 6 reagent was added directly in this medium. The medium is gently covered to mix. 2 μg of DNA solution (0.8-2.0 μg / μL) is added to the previously diluted FuGENE 6 reagent. The DNA / Fugene 6 mixture is pipetted gently to mix the contents and incubate for about 15 minutes at room temperature. The complex mixture is then added to the HEK-293T / 17 cells, distributed around the well, and stirred to ensure uniform dispersion. The cells are returned to the incubator for 24 hrs. The transfected cells are then plated back to a density of 2.5X105 in a 35mm dish with 5 glass slides and grown in low serum (1%) medium for 24 hrs. The slides with isolated cells are then transferred into the chamber current and the calcium channel (eg type L, type N, etc.) or other currents to exclude by exclusion the counter are recorded from HEK-293T cells / 17 transiently transfected. The full-cell voltage clamp configuration of the patch clamp technique is employed to evaluate voltage-dependent calcium currents essentially as described by Thompson and Wong (1991) J. Physiol, 439: 671-689. To record the calcium channel currents (for example, type L, type N, etc.) for evaluation of the inhibitory potency of compounds (analysis of response to the study state concentration), five pulses of 20-30 ms of voltage are carried "in stages up to around +10 mV (the peak of the current voltage ratio) are administered at five Hz every 30 seconds from a waiting potential at -100mV. The evaluations of the compound are carried out essentially as described by Sah DW and Bean BP (1994) Mol Pharmacol 45 (l): 84-92.

Example A3 Formalin Test Compounds representative of the formulas herein are separated by exclusion for activity in the formalin test. The formalin test is widely used as a model of acute inflammatory and tonic pain (Dubuisson &Dennis, 1977 Pain 4: 161-174, Wheeler-Aceto et al, 1990, Pain 40: 229-238, Coderre et al, 1993 , Pain 52: 259-285). The test involves administration to the hind paw of the rat of dilute formalin solution followed by monitored behavioral signals (ie, kickback, stings and licks) during the "late phase" (11 to 60 minutes after injection) of the response to formalin that reflects both peripheral nerve activity and central sensitization. Sprague-Dawley rats, males (Harían, Indianapolis, IN) are used weighing approximately 225-300 g with n = 6-8 for each treatment group. Depending on the pharmacokinetic profile and route of administration, the vehicle- or dose of test compound is administered to each rat by an intaperitoneal or oral route 30-120 minutes before formalin. Each animal is acclimated to a chamber for 60 minutes before the administration of formalin, which is 50μL of a 5% solution injected subcutaneously on the surface of the plant of a hind paw using a 300μL microsyringe and a measuring needle 29. A mirror is placed at an angle behind the cameras to increase the views of the legs of the animals. The number of kickbacks (legs raised with or are agitation of the fast leg) and time consumed from the bite or licking of the injured hind leg are recorded for each rat for 2 continuous minutes every 5 minutes for a total of 60 minutes after the administration of formalin. A sample of terminal blood is harvested for concentration analysis, of compound in the plasma. Between the group comparisons of the total number of recums or the time consumed of pitting and / or licking during the early or late phase, they are conducted using a one-way analysis of variation (ANOVA). The p <; 0.05 is considered statistically important and p = 0.05-1.0 is considered evidence of a statistical trend. The data is presented graphically as means ± S.E.M. for each 5 minute interval of the experimental observation period of 60 minutes. The compounds are considered effective on the basis of their ability to inhibit the number of retreated or the time consumed from stinging and / or licking-during the late phase of the response to formalin. Compounds representative of the formulas herein are evaluated for activity against calcium channel targets. Compounds representative of the formulas herein are evaluated for activity against calcium channel targets.Example A4 Method A Compound Al (compound 1 of Reaction Scheme A5). { 2- [2- (lH-Benzoimidazol-2-yl) -ethylsulfanyl] -3-p-tolyl-3H-imidazol-4-ylmethyl} - (4-fluoro-phenyl) -amine Reaction Scheme A5 Part 1. Preparation of p-tolylaminoacetic acid ethyl ester A mixture of p-toluidine (16.6 g, 155 mmol), sodium acetate (16.5 g, 201.5 mmol) in ethanol (200 mL) was stirred and the bromoacetate of ethyl (16.5 mL, 155 mmol) was added at room temperature. The mixture was heated at 80 ° C for 1 hour then cooled to room temperature. The mixture was quenched with water and extracted with ethyl acetate. The organics were dried and concentrated under vacuum. The resulting residue was purified by chromatography (SiO2, 20% ethyl acetate in n-hexane to give the ethyl ester of p-tolylaminoacetic acid (23.9 g, 124 mmol) as a white solid.

Part 2. Preparation of the ethyl ester of (acetyl-p-tolyl-amino) -acetic acid A cooled solution of the p-tolylamino-acetic acid ethyl ester (23.9 g, 124 mmol) in THF (300 mL) was stirred and Acetyl chloride (10.5 mL, 148 mmol) was added slowly. The mixture was stirred for 1 hour and quenched with water and extracted with ethyl acetate. The organics were dried and concentrated under vacuum to give the ethyl ester of (acetyl-p-tolyl-amino) -acetic acid "(14.3 g, 96 mmol) as a white solid.

Part 3. Preparation of 2-mercapto-3-p-tolyl-3H-imidazole-4-carboxylic acid ethyl ester A solution of p-tolylaminoacetic acid ethyl ester (5.0 g, 21.3) and ethyl formate (5.3 g, 71.3 mmol) in benzene (10 mL) was cooled to 0 ° C and potassium ethoxide (21.3 mmol) was added. The mixture was placed in a refrigerator to stand overnight and extracted with water. To the aqueous solution was added potassium thiocyanate (2.14 g, 22.0 mmol) and concentrated aqueous HCl (4 mL). The mixture was heated for 2 hours at 60 ° C then cooled. The mixture was extracted with ethyl acetate. The organics were dried and concentrated under vacuum to give the ethyl ester of 2-mercapto-3-p-tolyl-3H-imidazole-4-carboxylic acid (1.7 g, 6.5 mmol) as a white solid.

Part 4. Preparation of 2-mercapto-3-p-tolyl-3H-imidazole-4-carboxylic acid A solution of 2-mercapto-3-p-tolyl-3H-imidazole-4-carboxylic acid ethyl ester (1.2 g, 4.6 mmol) in 1,4-dioxane (10 mL) was stirred and the lithium hydroxide hydrate (1 M, 10 mL) was added and the mixture was stirred at room temperature for 2 hours. The mixture was neutralized with 2N aqueous HCl and extracted with ethyl acetate.The organics were dried and concentrated in vacuo to give 2-mercapto-3-p-tolyl-3H-imidazole-4-carboxylic acid (1 g. 4.3 mmol) as a white solid.

Part 5. Preparation of 2-mercapto-3-p-tolyl-3H-imidazole-4-carboxylic acid methoxy-amide A mixture of 2-mercapto-3-p-tolyl-3H-imidazole-4-carboxylic acid (0.468 g, 2 mmol), l-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (0.382 g, 2 mmol) and N, 0-dimethylhydroxylamine (0.195 g, 2 mmol) in pyridine (4 mL) were added. heated at 40 ° C overnight. The mixture was cooled, quenched with water and extracted with ethyl acetate. The organics were dried, concentrated in vacuo to give the 2-mercapto-3-p-tolyl-3H-imidazole-4-carboxylic acid methoxy-methyl-amide (0.245 g, 0.88 mmol) as an oil.

Part 6. Preparation of 2-mercapto-3-p-tolyl-3H-imidazole-4-carbaldehyde A mixture of lithium aluminum hydride (0.10 g, 2.65 mmol) in tetrahydrofuran (10 mL) was stirred under nitrogen blanket at 0 ° C and 2-mercapto-3-p-tolyl-3H-imidazole-4-carboxylic acid methoxy-methyl-amide (0.245 g, 0.88 mmol) in THF (5 mL) was added. The mixture was allowed to warm to room temperature and stirred for 2 hours. The mixture was cooled to 0 ° C and quenched with 15% aqueous sodium bicarbonate and water, then extracted with ethyl acetate. The organics were dried and concentrated under vacuum to give 2-mercapto-3-p-tolyl-3H-imidazole-4-carbaldehyde (0.176 g, 0.80 mmol) as a solid.

Part 7. Preparation of 2-mercapto-3-p-tolyl-3H-imidazole-4-carboxylic acid (4-fluoro-phenyl) -amide A solution of 2-mercapto-3-p-tolyl-3H-imidazole -4-carbaldehyde (0.176 g, 0.80 mmol) and 4-fluoroaniline (0.80 mmol, 88 mgs) in DMF / acetic acid (10 μl: v / v, 3 mL) was stirred at room temperature for 1 hour. Sodium cyanoborohydride (0.76 g, 1.2 mmol) was added and the mixture was stirred overnight. The mixture was quenched with water and extracted with ethyl acetate. The organics were dried and concentrated to give a residue. Purification by chromatography (Si02, 5% methanol in methylene chloride) gives 2-mercapto-3-p-tolyl-3H-imidazole-4-carboxylic acid (4-fluoro-phenyl) -amide (0.05 g, 0.16 mmol) as a solid.

Part 8. Preparation of 2- [2- (lH-benzoimidazol-2-yl) -ethylsulfanyl] -3-p-tolyl-3H-imidazol-4-ylmethyl} - (4-fluorophenyl) -amine A mixture of the 2-mercapto-3-p-tolyl-3H-imidazole-4-carboxylic acid (4-fluoro-phenyl) -amide (0.05 g, 0.16 mmol)) and 2 - (Chloromethyl) benzimidazole (0.032 g, 0.19 mmol) in acetone (5 mL) was stirred and potassium carbonate (0.048 g, 0.35 mmol) was added. The mixture was heated at 40 ° C for 2 hours and cooled. The mixture was quenched with water and extracted with ethyl acetate. The organics were dried and concentrated under vacuum to give a solid. The solid was dissolved in diethyl ether and an ethereal HCl solution was added. The mixture was concentrated under vacuum to give 2- [2- (1H-benzoimidazol-2-yl) -ethylsulfanyl] -3-p-tolyl-3H-imidazol-4-ylmethyl} - (4-fluoro-phenyl) -amine (0.042 g, 0.08 mmol) as the HCl salt.

Method B Compound 2 (compound 2 of Reaction Scheme A2) 2- (lH-benzoimidazol-2-ylmethylsulfanyl) -3-p-tolyl-3H-imidazole-4-carboxylic acid (4-fluoro-phenyl) -amide Scheme Reaction A2 Part 1. Preparation of 2-mercapto-3-p-tolyl-3H-imidazole-4-carboxylic acid (4-fluoro-phenyl) -amide A mixture of 2-mercapto-3-p-tolyl-3H- acid imidazole-4-carboxylic acid (0.468 g, 2 mmol), l-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (0.382 g, 2 mmol) and 4-fluoroaniline (0.222 g, 2 mmol) in pyridine (4 mL) was heated at 40 ° C overnight. The mixture was cooled and quenched with water and extracted with ethyl acetate. The organics were dried, concentrated under vacuum to give 2-mercapto-3-p-tolyl-3H-imidazole-4-carboxylic acid (4-fluoro-phenyl) -amide (0.206 g, 0.63 mmol) as an oil .

Part 2. Preparation of 2- (lH-benzoimidazol-2-ylmethylsulfanyl) -3-p-tolyl-3H-imidazole-4-carboxylic acid (4-fluoro-phenyl) -amide To a solution of (4-fluoro) 2-mercapto-3-p-tolyl-3H-imidazole-4-carboxylic acid (phenyl) -amide (0.206 g, 0.63 mmol) and 2- (chloromethyl) benzimidazole (0.166 g, 1.00 mmol) in acetone (10 mL ) was stirred and potassium carbonate (0.191 g, 1.12 mmol) was added. The mixture was heated at 40 ° C for 2 hours and cooled. The mixture was quenched with water and extracted with ethyl acetate. The organics were dried and concentrated under vacuum to give a solid. La_ purification by chromatography (Si02, 20% acetone in n-hexane) gave 2- (lH-benzoimidazol-2-ylmethylsulfanyl) -3-p-tolyl-3H-imidazole-4-fluoro-phenyl) -amide. carboxylic acid (0.133 g, 0.29 mmol) as a white solid.

Example B4 Reaction scheme B2 Compound 1 (Compound 1 of Reaction Scheme B2) 2- [1- (4-Chloro-phenyl) -5- (4-fluoro-phenyl) -lH-imidazol-2-ylsulfanylmethyl] -lH-benzoimidazole Part 1. Preparation of 2-Azido-l- (4-fluoro-phenyl) -ethanone A solution of 2-bromo-l- (4-fluoro-phenyl) -ethanone (2.5 g, 11.5 mmol) in DMSO (15 L) at 10 ° C was stirred vigorously and sodium azide (0.94 g, 14.4 mmol) was added. The mixture was stirred for 1 hour then quenched with water (20 mL) and extracted with ethyl acetate (2 x 25 mL). The combined organic layers were washed with water (25 mL) and brine (25 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-azido-1- (4-fluoro-phenyl) - ethanone (1.7 g, 9.3 mmol) as a viscous yellow-red liquid.

Part 2. Preparation of 2-Amino-1- (4-fluoro-phenyl) -ethanone hydrochloride To a solution of 2-azido-1- (4-fluoro-phenyl) -ethanone (8.0 g, 44.7 mmol) in ethanol (125 mL) was added concentrated aqueous HCl (6 mL) and 10% Pd / C (10% mol). The mixture was stirred under a hydrogen (H2) atmosphere at 45 psi (3.1635 kg / cm2) for 1 hour. The mixture was filtered through celite and the celite cake was washed with copious amounts of methanol. The solvent was under reduced pressure and the semi-solid was triturated with diethyl ether, filtered and dried to give 2-amino-1- (4-fluoro-phenyl) -ethanone hydrochloride (5.0 g, 26.5 mmol) as a white solid. crystalline.

Part 3. Preparation of 1- (4-chloro-phenyl) -5- (4-fluoro-phenyl) -IH-imidazole-2-thiol A mixture of 2-amino-1- (4-fluorophenyl) -ethanone hydrochloride (5.0 g, 26.5 mmol), 4-chlorophenyl isothiocyanate (4.49 g, 26.5 mmol) and sodium acid carbonate (3.3 g, 39.7 mmol) in ethanol (100 mL) was heated at 90 ° C for 2 hours. The solvent was removed under reduced pressure. The resulting residue was resuspended in aqueous IN sodium hydroxide (50 mL) and heated at 100 ° C overnight. The hot mixture was filtered, cooled and acidified carefully with aqueous 6N HCl. The resulting mixture was filtered to give 1- (4-chloro-phenyl) -5- (4-fluoro-phenyl) -lH-imidazole-2-thiol (8.0 g, 26.3 mmol) as a yellow solid after drying.

Part 4. Preparation of 2- [1- (4-Chloro-phenyl) -5- (4-fluorophenyl) -lH-imidazol-2-yl-sulfanylmethyl] -lH-benzoimidazole A mixture of 1- (4-chloro- phenyl) -5- (4-fluoro-phenyl) -1H- -imidazole-2-thiol (4.0 g, 13.2 mmol), 2- (chloromethyl) benzimidazole (2.2 g, 13.2 mmol) and potassium carbonate (5.5 g, 39.6 mmol) in acetone (50 mL) was heated at 75 ° C until all the starting materials were consumed. The mixture was cooled and the solvent was removed under reduced pressure. The resulting residue was divided into 1: 1: 1 water / ethyl acetate / hexane. The brown solid was filtered, dried and re-suspended in a minimum amount of methanol. The methanolic mixture was filtered and dried to a white solid. The solid was resuspended in methanol and treated with ethereal 2N HCl until a solution was continued. The solution was diluted with a large amount of diethyl ether to promote precipitation, filtered and dried to give 2- [1- (4-chlorophenyl) -5- (4-fluoro-phenyl) -lH-imidazole- 2-yl-sulfanylmethyl] -1H-benzoimidazole (3.5 g, 7.4 mmol) as a white solid.

Example C4 Method CA Compound Cl (compound 1 in Reaction Scheme C4) Acid. { 5- [(4-Fluoro-phenylamino) -methyl] -4-p-tolyl-4H- [1,2,4] triazol-3-ylsulfanyl} -acetic Reaction Scheme C4 Part 1. Preparation of (4-Fluoro-phenylamino) -acetic acid ethyl ester A mixture of 4-fluoroaniline (10 g, 90 mmol), bromoacetate (15 g, 90 mmol), and sodium acetate (11 g, 135 mmol) in ethanol (200 mL) was heated to reflux for 2 hours. The cold reaction was cooled and concentrated under vacuum. The residue was diluted with water and extracted with ethyl acetate. The organics were dried and concentrated under vacuum to give (4-fluoro-phenylamino) -acetic acid ethyl ester (8.46 g, 42.9 mmol) as a white solid.

Part 2. Preparation of (4-Fluoro-phenylamino) -acetic acid hydrazide A mixture of ethyl ester of (4-fluoro-phenylamino) -acetic acid and hydrazine (8.23 g, 257 mmol) in ethanol (200 mL) was refluxed for 3 hours. The reaction was cooled and concentrated under vacuum. Trituration of the residue with n-hexane (75 mL) gave (4-fluoro-phenylamino) -acetic acid hydrazide (5.5 g, 30.20 mmol) as a white solid.

Part "3. Preparation of 5- [(4-Fluoro-phenylamino) -methyl] -4-p-tolyl-2,4-dihydro- [1,2,4] triazole-3-thione A mixture of acid hydrazide (4-fluoro-phenylamino) -acetic and p-toluenisothiocyanate (4.5 g, 30.20 mmol) in 2N aqueous sodium hydroxide (100 mL) was heated for several hours, then cooled.The solution was neutralized with 6N hydrochloric acid and extracted with ethyl acetate The organics were dried and concentrated in vacuo to give a brown residue, trituration of the residue with n-hexane (100 mL) gave 5 - [(4-fluoro-phenylamino) -methyl] -4-p. tolol-2, 4-dihydro- [1, 2, 4] triazole-3-thione (7.6 g, 24.2 mmol) as a white solid.

Part 4. Preparation of acid. { 5- [(4-Fluoro-phenylamino) -methyl] -4-p-tolyl-4H- [1,2,4] triazol-3-ylsulfanyl} -acetic To a mixture of 5- [(4-fluoro-phenylamino) -methyl] -4-p-tolyl-2,4-dihydro- [1,2,4] triazole-3-thione (0.30 gm, 0.95 mmol ), bromoacetic acid (0.13 gm, 0.95 mmol) and potassium carbonate (0.16 gm, 1.14 mmol) in acetone (6 mL) was heated at 40 C for 3 hours then cooled. The reaction was diluted with water and extracted with ethyl acetate. The organics were dried and concentrated under vacuum to give a residue. The residue was purified by chromatography on silica (20% methanol in methylene chloride) to give acid. { 5- [(4-Fluoro-phenylamino) -methyl] -4-p-tolyl-4H- [1,2,4] triazol-3-ylsulfanyl} - acetic (0.27 gm, 0.72 mmol) as a white solid.

Method CB Compound C2 (compound 2 in Reaction Scheme C5) N- (2-Chloro-phenyl) -2 -. { 5- [(4-f? Uoro-phenylamino) -methyl] -4-p-tolyl-4H- [1,2,4] triazol-3-ylsulfanyl} -acetamide Reaction scheme C5 Part 1. Preparation of N- (2-Chloro-phenyl) -2-. { 5- [(4-Fluoro-phenylamino) -methyl] -4-p-tolyl-4H- [1,2,4] triazol-3-ylsulfanyl} - acetamide To a mixture of 5- [(4-fluoro-phenylamino) -methyl] -4-p-tolyl-2,4-dihydro- [1,2,4] triazole-3-thione (0.30 gm, 0.95 mmol ), 2-bromo-N- (2-chloro-phenyl) -acetamide (0.24 gm, 0.95 mmol) and potassium carbonate (0.16 gm, 1.14 mmol) in acetone (6 mL) was heated at 40 C for 3 hours then cooled The reaction was diluted with water and extracted with ethyl acetate. The organics were dried and concentrated under vacuum to give a residue. The residue was purified by chromatography on silica (20% methanol in methylene chloride) to give N- (2-chloro-phenyl) -2-. { 5- [(4-Fluoro-phenylamino) -methyl] -4-p-tolyl-4H ~ [1,2,4] triazol-3-ylsulfanyl} -acetamide (0.10 gm, 0.20 mmol) as a white solid.

Method CC Compound C3 (compound 3 in Reaction Scheme C6) Reaction Scheme C6 [5- (lH-Benzoimidazol-2-ylmethylsulfanyl) -4-p-tolyl-4H- [1,2,4] triazol-3-ylmethyl] - (5-methyl-pyridin-2-yl) -amine Part 1. Preparation of diethoxy-acetic acid hydrazide A solution of ethyl dietoxyacetate (15.8 g, 90 mmol) ethanol (100 mL) was stirred and hydrazide (8.23 g, 257 mmol) was added. The mixture was refluxed for 2 hours, then cooled and concentrated under vacuum. The residue was diluted with water and extracted with ethyl acetate. The organics were dried and concentrated under vacuum to give diethoxy acetic acid hydrazide (10.53 g, 65 mmol) as a clear oil.

Part 2. Preparation of 5-diethoxymethyl-4-p-tolyl-2,4-dihydro- [1,2,4] triazole-3-thione p-Toluenisothiocyanate (9.7 g, 65 mmol) and diethoxy acid hydrazide Acetic acid (10.53 g, 65 mmol) was dissolved in aqueous 2N sodium hydroxide (100-ml) and heated for several hours then cooled. The solution was neutralized with 6N hydrochloric acid and extracted with ethyl acetate. ethyl. The organics were dried and concentrated under vacuum to give a yellow residue. Trituration of the residue with n-hexane (100 mL) gave 5-diethoxymethyl-4-p-tolyl-2, -dihydro- [1, 2, 4] triazole-3-thione (12.3 g, 42 mmol) as a solid yellow.

Part 3. Preparation of 5-thioxo-4-p-tolyl-4,5-dihydro-lH- [1,2,] triazole-3-carbaldehyde A solution of 5-diethoxymethyl-4-p-tolyl-2, - dihydro- [1,2,4] triazole-3-thione (5 g, 17 mmol) and aqueous 3N HCl (30 mL) in 1,4-dioxane (10 mL) was stirred and heated at 40 ° C for 2 hours. hours then it cooled. The mixture was quenched with water and extracted with ethyl acetate. The organics were dried and concentrated to give a residue. Purification by flash chromatography (Si02, 10% acetone in n-hexane) gave 5-thioxo-4-p-tolyl-4,5-dihydro-lH- [1,2,4] triazole-3-carbaldehyde (2.6 g , 11.8 mmol) as a yellow solid.

Part 4. Preparation of 5- (lH-Benzoimidazol-2-ylmethylsulfanyl) -4-p-tolyl-4H- [1,2,4] triazole-3-carbaldehyde • A solution of 5-thioxo-4-p-tolyl-4,5-dihydro-lH- [1,2,4] triazole-3-carbaldehyde (2.6 g, 1.8 mmol) and 2- (chloromethyl) benzimidazole (2.15 g, 12.9 mmol) in acetone (10 mL) was stirred and potassium carbonate (2.07 g, 15 mmol) was added. The mixture was heated to 40 C for 3 hours then cooled. The mixture was quenched with water and extracted with ethyl acetate. The organics were dried and concentrated to give a residue. Purification by flash chromatography (Si02, 30% acetone in n-hexane) gave. 5- (1H-benzoimidazol-2-ylmethylsulfanyl) -4-p-tolyl-4H- [1,2,4] triazole-3-carbaldehyde (2.50 g, 7.08 mmol) as a white solid.

Part 5. Preparation of [5- (lH-Benzoimidazol-2-ylmethylsulfanyl) -4-p-tolyl-4H- [1,2,4] triazol-3-ylmethyl] - (5-methyl-pyridin-2-yl) ) -amine A solution of 5- (lH-benzoimidazol-2-ylmethylsulfanyl) -4-p-tolyl-4H- [1,2,4] triazole-3-carbaldehyde (1.0 g, 4.56 mmol) and pyridine 2- amino-5-methyl (0.49 g, 4.56 mmol) in DMF / HOAc (10/1: w / w) (10 mL) was stirred at room temperature for 1 hour. Sodium cyanoborohydride (0.376 g, 6.0 mmol) was added and the mixture was stirred overnight. The mixture was quenched with water and extracted with ethyl acetate. The organics dried and concentrated to give a residue. Purification by flash chromatography (Si02, 30% acetone in n-hexane) gave [5- (lH-Benzoimidazol-2-ylmethylsulfanyl) -4-p-tolyl-4H- [1,2,4] triazol-3-ylmethyl ] - (5-methyl-pyridin-2-yl) -amine (0.108 g, 0.25 mmol) as a white opaque solid.

Example D-4 Compound D-15 3- (2- (ÍH-Benzo [d] imidazol-2-yl) ethyl) -5- (4-fluorophenyl) -1-p-tolyl-lH-imidazole-2 (3H ) -tiona Reaction Scheme D-6 Part 1. Preparation of 2-Azido-l- (4-fluoro-phenyl) -ethanone A solution of 2-bromo-l- (4-fluoro-phenyl) -ethanone (1 eq) in DMSO at 10 ° C is stirred vigorously and sodium azide (1.25 eq) is added. The mixture is stirred for 1 hour then quenched with water and extracted with ethyl acetate (2X). The combined organic layers are washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-azido-1- (4-fluoro-phenyl) -ethanone.

Part 2. Preparation of 2-Amino-1- (4-fluorophenyl) -ethanone hydrochloride To a solution of 2-azido-1- (4-fluoro-phenyl) -ethanone in ethanol is added concentrated HCl (aq) and % Pd / C (10% mol). The mixture is stirred under a hydrogen (H2) atmosphere at 45 psi (3.1635 kg / cm2) for 1 hour. The mixture is filtered through celite and the celite cake is washed with copious amounts of methanol. The solvent is removed under reduced pressure and the resulting residue is triturated with diethyl ether, filtered and dried to give 2-amino-1- (4-fluoro-phenyl) -ethanone hydrochloride.

Part 3. Preparation of 1- (4-Chloro-phenyl) -5- (4-fluoro-phenyl) -lH-imidazole-2-thiol A mixture of 2-amino-1- (4-fluoro-phenyl) hydrochloride -ethanone (1 eq), 4-chlorophenyl isothiocyanate (1 eq) and sodium acid carbonate (1.5 eq) in ethanol is heated at 90 ° C for 2 hours. The solvent is removed under reduced pressure. The resulting residue is resuspended in aqueous IN sodium hydroxide and heated at 100 ° C overnight. The hot mixture is filtered, cooled and acidified carefully with aqueous 6N HCl. The resulting mixture is filtered to give 1- (4-chloro-phenyl) -5- (4-fluoro-phenyl) -lH-imidazole-2-thiol.

Part 4. Preparation of 3- (5- (4-fluorophenyl) -1,2-dihydro-2-thioxo-1-p-tolylimidazol-3-yl) propanenitrile A mixture 5- (4-fluorophenyl) -lp-tolyl -lH-imidazole-2-thiol (1 eq) in dioxane is stirred and Triton B is added. The mixture is heated to 70 ° C and acrylonitrile (1 eq) is added and heated for 3 hours. The cold mixture is partitioned between aqueous 0.1N HCl and ethyl acetate. The organic layer is washed with water and brine, dried over sodium sulfate, filtered and the solvent is removed under reduced pressure. Flash chromatography (Si02) gave 3- (5- (4-fluorophenyl) -1,2-dihydro-2-thioxo-l-p-tolylimidazol-3-yl) propanenitrile.

Part 5. Preparation of 3- (1- (4-Chlorophenyl) -5- (4-fluorophenyl) -l, 2-dihydro-2-thioxoimidazol-3-yl) propionymidic acid ethyl ester A solution of propionitrile in 1 : 1 ethanol / diethylether is cooled in a water bath with ice and HCl (g) is carefully bubbled into the solution for 10-20 minutes. The reaction mixture is stirred at room temperature for 2-4 hours and the solvent is removed under reduced pressure to obtain 3- (1- (4-chlorophenyl) -5- (4-fluorophenyl) -1 ethyl ester, 2-dihydro-2-thioxoimidazol-3-yl) propionimide.

Part 6. Preparation of 3- (2- (IH-Benzo [d] imidazol-2-yl) ethyl) -5- (4-fluorophenyl) -lp-tolyl-lH-imidazol-2 (3H) -thione A mixture of ethyl ester of propionimidic acid and benzene-1,2-diamine in ethanol is stirred and heated to 60 ° C During the night the solvent is removed under reduced pressure, the residue is partitioned between ethyl acetate and saturated aqueous sodium bicarbonate The organic layer is dried over sodium sulfate, filtered and the solvent is removed under reduced pressure.

Purification by flash chromatography (Si02) followed by formation of HCl salt (methanol and 2M ethereal HCl) gave 3- (2- (lH-benzo [d] imidazol-2-yl) ethyl) -5- (4-) hydrochloride fluorophenyl) -1-p-tolyl-lH-imidazol-2 (3H) -thione.

Compound D-22 3- (1- (4-Chlorophenyl) -5- (4-fluorophenyl) -1,2-dihydro-2-thromoxoidazol-3-yl) propionic acid ethyl ester "Reaction scheme D-7 Preparation of 3- (1- (4-Chlorophenyl) -5- (4-fluorophenyl) -1,2-dihydro-2-thioxoimidazol-3-yl) propionic acid ethyl ester A "a solution 1- (4- chloro-phenyl) -5- (4-fluoro-phenyl) -1H-imidazole-2-thiol (1 eq) in DMF is added a 1M solution of lithium bis (trimethylsilyl) amide in THF (1 eq) and 3- Ethyl bromopropionate (1 eq) at room temperature The mixture is heated at 60 ° C for 2 hours and cooled to room temperature.The mixture is quenched with water and extracted with ethyl acetate.The organics7 are dried and concentrated under The residue is purified by chromatography on silica to give 3- (1- (4-chlorophenyl) -5- (4-fluorophenyl) -1,2-dihydro-2-thioxoimidazole-3-yl ethyl ester) propionic Compound D-26 3- (1- (4-Chlorophenyl) -5- (-fluorophenyl) -1,2-dihydro-2-thioxoimidazol-3-yl) -1- (pyrrolidin-1-yl) propan-1- ona Reaction scheme D-8 Part 1. Preparation of 3- (1- (4-Chlorophenyl) -5- (4-fluorophenyl) -1,2-dihydro-2-thioxoimidazol-3-yl) propionic acid A mixture of 3-ethyl ester (1- (4- chlorophenyl) -5- (4-fluorophenyl) -1,2-dihydro-2-thioxoimidazol-3-yl) propionic acid (1 eq) and lithium hydroxide hydrate (1.2 eq) is dissolved in 1, 4-dioxane: water (4/1: w / w) and allowed to stir at room temperature for 3 hours. The reaction mixture is neutralized with aqueous 2N HCl and extracted with ethyl acetate. The organics are dried and concentrated under vacuum to give 3- (1- (4-chlorophenyl) -5- (4-fluorophenyl) -1,2-dihydro-2-thioxoimidazol-3-yl) propionic acid.

Part 2. Preparation of 3- (1- (4-Chlorophenyl) -5- (4-fluorophenyl) -1,2-dihydro-2-thioxoimidazol-3-yl) -1- (pyrrolidin-1-yl) propan- 1-one To a solution of 3- (1- (4-chlorophenyl) -5- (4-fluorophenyl) -1,2-dihydro-2-thioxoimidazol-3-yl) propionic acid (1 eq), 1-3- (dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.7 eq) and morpholine (1.7 eq) in THF is stirred overnight at room temperature. The reaction was quenched with water and extracted with ethyl acetate. The organics are dried and concentrated under vacuum. The residue is purified by chromatography on silica to give 3- (1- (4-chlorophenyl) -5- (4-fluorophenyl) -1,2-dihydro-2-thioxoimidazol-3-yl) -1- (pyrrolidin-1). -il) ropan- 1-one.

Example E-4 Compound 3- [3- (2-Methoxy-phenyl) -5-thioxo-4-p-tolyl-4,5-dihydro- [1,2,4] triazol-1-yl] - acid propionic, ethyl ester Reaction scheme E-5 Part 1. Preparation of 5- (2-Methoxy-phenyl) -4-p-tolyl-4H- [1,2,4] triazole-3-thiol A mixture of 2-methoxybenzhydrazide (7.0 gm, 42 mmol) and isothiocyanate of p-tolyl (6.3 gm, 42 mmol) in ethanol (100 mL) was heated to reflux for one hour then cooled. The reaction mixture was filtered and the filter cake was washed with cold ethanol (50 mL). The filter cake was dissolved in aqueous 2N sodium hydroxide (100 mL) and heated overnight then cooled. The solution was neutralized with 6N hydrochloric acid and extracted with ethyl acetate. The organics were dried and concentrated under vacuum to give a white solid. Trituration of the solid with ethanol (100 mL) gave 5- (2-Methoxy-phenyl) -4-p-tolyl-4H- [1,2,4] triazole-3-thiol (11 gm, 37 mmol) as a solid white.

Part 2. Preparation of 3- [3- (2-Methoxy-phenyl) -5-thioxo-4-p-tolyl-4,5-dihydro- [1,2,4] triazol-1-yl] -propionic acid , ethyl ester To a solution of 5- (2-methoxy-phenyl) -4-p-tolyl-4H- [1, 2,4] triazole-3-thiol (0.9 g, 30.3 mmol) in DMF (100 mL) was added an IVM bis (trimethylsilyl) amide solution in THF (30.3 mL) and ethyl 3-bromopropionate ( 5.48 g, 30.3 mmol) at room temperature. The mixture was heated at 60 ° C for 1 hour and cooled to room temperature. The mixture was quenched with water and extracted with ethyl acetate. The organics were dried and concentrated under vacuum. The residue was purified by chromatography on silica (20% ethyl acetate in n-hexane) to give 3- [3- (2-methoxy-phenyl) -5-thioxo-4-p-tolyl-4,5-dihydro acid. - [1, 2,4] triazol-1-yl] -propionic, ethyl ester (10.08 g, 25.4 mmol) as a clear oil.

Compound E-2 3- [3- (2-Methoxy-phenyl) -5-thioxo-4-p-tolyl-4,5-dihydro- [1,2,4] triazol-1-yl] -1-morpholine -4-il-propan-1-one Reaction scheme E-6 Part 1. Preparation of 3- [3- (2-Methoxy-phenyl) -5-thioxo-4-p-tolyl'-4", 5-dihydro- [1,2,4] triazol-1-yl] acid -propionic A mixture of 3- [3- (2-methoxy-phenyl) -5-thioxo-4-p-tolyl-4,5-dihydro- [1, 2,4] triazol-1-yl] -propionic acid , ethyl ester (10.08 g, 25.4 mmol) and lithium hydroxide hydrate (1.28 g, 30.48 mmol) was dissolved in 1,4-dioxane: water (4/1: w / w) and allowed to stir at room temperature. for 3 hours The reaction mixture was neutralized with aqueous 2N HCl and extracted with ethyl acetate.The organics were dried and concentrated under vacuum to give 3- [3- (2-methoxy-phenyl) -5-thioxo- 4-p-tolyl-4,5-dihydro- [1,2,4] triazol-1-yl] -propionic acid (8.99 g, 24.4 mmol) as a white solid.

Part 2. Preparation of 3- [3- (2-Methoxy-phenyl) -5-thioxo-4-p-tolyl-4,5-dihydro- [1,2,4] triazol-1-yl] -1- morpholin-4-yl-propan-1-one To a solution of 3- [3- (2-methoxy-phenyl) -5-thioxo-4-p-tolyl-4,5-dihydro- [1,2, 4] triazol-1-yl] -propionic acid (0.50 g, 1.36 mmol, 1-3- (dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.388 g, 2.03 mmol) and morpholine (0.177 g, 2.03 mmol) in THF (15 mL) was stirred overnight at room temperature The reaction was quenched with water and extracted with ethyl acetate The organics were dried and concentrated under vacuum The residue was purified by chromatography on silica (20% acetone in n-hexane ) to give 3- [3- (2-methoxy-phenyl) -5-thioxo-4-p-tolyl-4,5-dihydro- [1,2,4] triazol-1-yl] -1-morpholine- 4-yl-propan-l-one (0.286 g, 0. 65 mmol) as a white solid.

Compound E-3 2- [2- (lH-Benzoimidazol-2-yl) -ethyl] -5- (2-methoxy-phenyl) -4-p-tolyl-2,4-dihydro- [1,2, 4] triazole-3-thione Reaction scheme E-7 Part 1. Preparation of 3- [3- (2-methoxy-phenyl) -5-thioxo-4-p-tolyl-4,5-dihydro- [1,2,4] triazol-1-yl] -propionitrile One mixture of 5- (2-methoxy-phenyl) -4-p-tolyl-2,4-dihydro- [1,2,4] triazole-3-thione (1.1 g, 3.7 mmol) in dioxane (6 mL) was stirred and Triton B (20 drops) was added. The mixture heated to 70 ° C and acrylonitrile (250 μL, 3.7 mmol) was added and heated 3 additional hours. The cold mixture was divided between Aqueous 0.1N HCl (10 mL) and ethyl acetate (20 mL). The organic layer was washed with water (10 mL) and brine (10 mL) and dried over sodium sulfate, filtered and the solvent was removed under reduced pressure to give a viscous yellow oil. Flash chromatography (Si02, 2: 3 ethyl acetate / hexane) gave 3- [3- (2-methoxy-phenyl) -5-thioxo-4-p-tolyl-4,5-dihydro- [1,2, 4] triazol-1-yl] -propionitrile (1 g, 2 ~ 8"mmol) as a white foam.

Part 2. Preparation of 3- [3- (2-Methoxy-phenyl) -5-thioxo-4-p-tolyl-4,5-dihydro- [1,2,4] triazole-1-ethyl ester il] -propionimide A solution of propionitrile (0.5 g, 1.4 mmol) in 1: 1 ethanol / diethylether (20 mL) was cooled in an ice water bath and HCl (g) was carefully bubbled into the solution for 10-20 minutes The reaction mixture was stirred at room temperature for 2-4 hours and the solvent was removed under reduced pressure to obtain 3- [3- (2-methoxy-phenyl) -5-thioxo-4-p- ethyl ester. tolyl-4, 5-dihydro- [1, 2,4] triazol-1-yl] -propionimide as a viscous yellow oil. The oil was used immediately without purification.

Part 3. Preparation of 2- [2- (lH-Benzoimidazol-2-yl) -ethyl] -5- (2-methoxy-phenyl) -4-p-tolyl-2,4-dihydro- [1,2, 4] triazole-3-thione A mixture of the ethyl ester of propionimidic acid and benzene-1,2-diamine (0.227 g, 2.1 mmol) in ethanol (10 mL) was stirred and heated at 60 ° C overnight. The solvent was removed under reduced pressure, the residue was partitioned between ethyl acetate. ethyl acetate (20 mL) and saturated aqueous sodium bicarbonate (10 mL). The organic layer was dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure. Flash chromatography (Si02, 1: 1 ethyl acetate / dichloromethane) gave a colorless oil. The oil was dissolved in methanol (2 mL) and treated with 2M ethereal HCl (10 mL). The solvent was removed under reduced pressure to provide the mono HCl salt of Compound E-3 (0.33 g) as a white solid.

Compound E-4- 5- (2-Methoxy-phenyl) -2- (2-pyridin-4-yl-ethyl) -4-p-tolyl-2,4-dihydro- [1,2,4] triazole-3 -tiona Reaction scheme E-8 Part 1. Preparation of 5- (2-Methoxy-phenyl) -2- (2-pyridin-4-yl-ethyl) -4-p-tolyl-2,4-dihydro- [1,2,4] triazole- 3-thione A mixture of 5- (2-methoxy-phenyl) -4-p-tolyl-2,4-dihydro- [1,2,4] triazole-3-thione (0.15 g, 0.50 mmol) in ethanol ( 10 mL) was stirred and 4-vinylpyridine (0.15 g, 1.0 mmol) was added. The mixture was heated overnight to reflux then cooled.

The cold mixture was concentrated under vacuum and the residue was diluted with ethyl acetate. The organics were washed with water (10 mL) and brine (10 mL) and dried over sodium sulfate, filtered and the solvent was removed under reduced pressure to give a viscous yellow oil. Flash chromatography (Si02, 20% ethyl acetate / hexane) gave 5- (2-methoxy-phenyl) -2- (2-pyridin-4-yl-ethyl) -4-p-tolyl-2,4-dihydro - [1,2,4] triazole-3-thione (0.04 g, 0.09 mmol) as a white solid.

Compound E-5 1- (4-Chloro-phenyl) -3- [3- (2-methoxy-phenyl) -5-thioxo-4-p-tolyl-4,5-dihydro- [1,2,4] triazol-1-yl] -propan-1-one Reaction scheme E-9 Part 1. Preparation of 1- (4-chloro-phenyl) -3- [3- (2-methoxy-phenyl) -5-thioxo-4-p-tolyl-4,5-dihydro- [1,2,4 ] triazol-1-yl] -propan-1-one To a solution of 5- (2-methoxy-phenyl) -4-p-tolyl-4H- [1,2,4] triazole-3-thiol (0.45 g , 1.5 mmol) in DMF (10 mL) was added a 1M solution of lithium bis (trimethylsilyl) amide in THF .. (1.5 mL) and beta-4-dichloropropiophenone (0.30 g, 1.5 mmol) at room temperature. The mixture was heated at 60 ° C for 1 hour and cooled to room temperature. The mixture was quenched with water and extracted with ethyl acetate. The organics were dried and concentrated under vacuum. The residue was purified by chromatography on silica (20% ethyl acetate in n-hexane) to give 1- (4-chloro-phenyl) -3- [3- (2-methoxy-phenyl) -5-thioxo-4- p-tolyl-4,5-dihydro- [1,2,4] triazol-1-yl] -propan-1-one (0.19"g, 0.41 mmol) as a white solid.

Example F-4 Compound F-1 2- (2-Methoxy-phenyl) -1-p-tolyl-1H-amidezole-4-carboxylic acid ethyl ester (Compound 1 in Reaction Scheme F-5) Scheme of F-5 reaction Part 1. Preparation of 2-Methoxy-Np-tolyl-benzamidine To a solution of sodium bis (trimethylsilyl) amide in THF (9.9 mL, 1M solution, 9.9 mmol) was slowly added at room temperature a solution of p-1. toluidine (1 g, 9.3 mmol) in dry THF (5 mL). After the mixture was stirred for 20 minutes, a solution of 2-methoxybenzonitrile (1.32 g, 9.9 mmol) in dry THF (5 mL) was added. The reaction mixture was stirred for 4 hours and quenched with water. The mixture was extracted with ethyl acetate three times. The combined organic layers were washed with water, brine, dried over anhydrous Na 2 SO, filtered and concentrated under vacuum to give 2-methoxy-N-p-tolyl-benzamidine as a red oil, which was used in the next step without further purification.

Part 2. Preparation of 4-Hydroxy-2- (2-methoxy-phenyl) -lp-tolyl-4,5-dihydro-1H-amidezole-4-carboxylic acid ethyl ester A mixture of 2-methoxy-Np- tolyl-benzamidine (340 mg, 1.5 mmol), NaHCO3, (378 mg, 4.5 mmol) in THE / water (4/1: w / w, 10 mL) was heated to reflux. A solution of ethyl bromopyruvate (0.19 mL, 1.5 mmol) in THF (2 mL) was added over 5 minutes. The reaction mixture was refluxed for 2 hours, cooled to room temperature, extracted with ethyl acetate three times. The combined organic layers were washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum to give 4-hydroxy-2- (2-methoxy-phenyl) -1-p-tolyl-4-ethyl ester. , 5-dihydro-1H-imidazole-4-carboxylic acid as a brown solid and was used without purification in the next step.

Part 3. Preparation of 2- (2-Methoxyphenyl) -lp-tolyl-1H-imidazole-4-carboxylic acid ethyl ester To 4-hydroxy-2- (2-methoxy-phenyl) ethyl ester flask -lp-tolyl-4,5-dihydro-lH-imidazole-4-carboxylic acid (5 g, 14.1 mmol) in dry toluene (50 mL) was added p-toluenesulfonic acid (268 mg, 1.4 mmol). The resulting mixture is - refluxed until the starting material was consumed.

The solvent was removed under vacuum and the resulting residue was partitioned between ethyl acetate and saturated aqueous NaHCO3. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over anhydrous Na 2 SO 4, filtered, concentrated in vacuo and worked up by chromatography on (Si0, 50% ethyl acetate in hexanes) to give ethyl ester of 2- (2-ethyl) acid. -methoxy-phenyl) -lp-tolyl-lH-imidazole-4-carboxylic acid (4.5 g, 13.4 mmol) as a solid.

F-2 (2- (2-methoxy-phenyl) -1- p -tolyl-lH-imidazole-4-carboxylic acid F-2 (4-fluoro-phenyl) -methyl-amide compound (Compound 2 in Reaction Scheme F-6) ) Reaction Scheme F-6 Part 1. Preparation of 2- (2-methoxy-phenyl) -1-p-tolyl-1H-imidazole-4-carboxylic acid To a solution of 2- (2-methoxy-phenyl) -lp- ethyl ester tolyl-lH-imidazole-4-carboxylic acid (4.5 g, 13.4 mmol) in methanol (10 mL) was added 2N aqueous NaOH (10 mL). The mixture was refluxed for 1 hour and cooled to room temperature. The solvents were partially removed under reduced pressure. The residue was acidified to pH 3, extracted with methylene chloride three times. The combined organic layers were washed with water, brine, dried over anhydrous Na 2 SO 4, filtered and concentrated under vacuum to 2- (2-methoxy-phenyl) -lp-tolyl-1H-imidazole-4-carboxylic acid (4.1 g, 13.4 mmol) as a solid.

Part 2. Preparation of 2- (2-Methoxy-phenyl) -1-p-tolyl-1H-imidazole-4-carboxylic (4-fluoro-phenyl) -amide To the flask containing 2- (2-methoxy) -amide phenyl) -1-p-tolyl-lH-imidazole-4-carboxylic acid (740 mg, 2.4 mmol), 4-fluoroaniline (0.23 L, 2.4 mmol) and l- [3- (dimethylamino) propyl] -3- hydrochloride ethylcarbodiimide (920 mg, 4.8 mmol). pyridine (10 mL) was added. The mixture was stirred at room temperature for 1 hour and the volatile organics were removed. The residue was partitioned between methylene chloride and water. The combined organic layers were washed with water, brine, dried over anhydrous Na 2 SO 4, filtered and concentrated in vacuo. Chromatography (Si02, 30% ethyl acetate in hexanes) gave 2- (2-methoxy-phenyl) -lp-tolyl-1H-imidazole-4-carboxylic acid (4-fluoro-phenyl) -amide (900 mg, 2.2 mmol) as a solid.

Compound F-3 (4-Fluoro-phenyl) - [2- (2-methoxy-phenyl) -lp-tolyl-lH-imidazol-4-ylmethyl] -amine (Compound 3 in reaction scheme F-7) Scheme Reaction F-7 To a solution of 2- (2-methoxy-phenyl) -lp-tolyl-lH-imidazole-4-carboxylic acid (4-fluoro-phenyl) -amide (250 mg, 0.62 mmol) in toluene (6 mL) was At room temperature, THF solution was added in complex with borane dimethylsulfide (1.25 mL, 2M solution, 2.5 mL). The mixture was refluxed overnight. Aqueous IN HCl was added to the cold reaction mixture. The mixture was refluxed for 30 minutes and cooled to room temperature. The solvents were partially removed under reduced pressure. The residue was neutralized with aqueous IN NaOH and extracted with methylene chloride three times. The organics were washed with water, brine, dried over anhydrous Na 2 SO 4, filtered and concentrated under vacuum. Chromatography (Si02, 30% ethyl acetate in hexanes) provided (4-fluoro-phenyl) - [2- (2-methoxy-phenyl) -1-p-tolyl-lH-imidazol-4-ylmethyl] -amine ( 210 mg, 0.54 mmol) as an oil.

Compound F-4 2- (2-Methoxy-phenyl) -1-p-tolyl-lH-imidazole-4-carboxylic acid methoxy-methyl-amide (Compound 4 in reaction scheme F-8) Reaction scheme F -8 Part 1 . Preparation of methoxy-methyl-amide 2- (2-methoxy-phenyl) -lp-tolyl-lH-imidazole-4-carboxylic acid To a solution of 2- (2-methoxy-phenyl) -1-p-tolyl-lH acid - imidazole-4-carboxylic acid (200 mg, 0.65 mmol) in methylene chloride (5 mL) was added chlorohydrate (dimethylamino) propyl] -3-ethylcarbodiimide (250 mg, 1.3 mmol), triethylamine (0.18 mL, 1.3 mmol) and N, 0-dimethylhydroxylamine hydrochloride (63 mg, 0.65 mmol). The mixture was stirred overnight. The mixture was applied to partition between methylene chloride and saturated aqueous NaHCO 3. The combined organic layers were washed with water, brine, dried over anhydrous Na 2 SO 4, filtered and concentrated under vacuum. Chromatography (SiO2, ethyl acetate) gave 2- (2-methoxy-phenyl) -1-p-tolyl-1H-imidazole-4-carboxylic acid methoxy-methyl (220 mg, 0.63 mmol) as an oil .

Part 2. Preparation of (4-Methoxy-phenyl) - [2- (2-methoxy-phenyl) -1-p-tolyl-1H-imidazol-4-yl] -methanone To a solution of methoxy-methyl-amide of the 2- (2-methoxy-phenyl) -lp-tolyl-lH-imidazole-4-carboxylic acid (110 mg, 0.31 mmol) in THF (2 mL) was slowly added with 4-methoxyphenylmagnesium bromide THF solution (0.63 mL, 0.5 M solution, 0.31 mmol). The mixture was stirred overnight. 0.5 M Additional 4-methoxyphenylmagnesium bromide in THF (0.63 mL, 0.31 mmol) was added and the mixture was stirred for 3 hours and quenched with water. The mixture was extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum, Reversed phase liquid chromatography followed by plate chromatography (Si02, 50% ethyl acetate in hexanes) provided the -methoxy-phenyl) - [2- (2-methoxy-phenyl) -lp-tolyl-lH-imidazol-4-yl] -methanone (9.1 mg, 0.04 mmol) as a foam.

Compound F-5 (4-Methoxy-phenyl) -2- (2-methoxy-pheny) -1-p-tolyl-lH-imidazole (Compound 5 in reaction scheme F-9) Reaction scheme F-9 YyOm *? Yyo * To a solution of 2-methoxy-N-p-tolyl-benzamidine (230 mg, 0.96 mmol) in acetonitrile (5 mL) was added NaHCO 3 (242 mg, 2.88 mmol). The mixture was heated to 50 ° C. A solution of 2-bromo-1- (4-methoxy-phenyl) -ethanone (220 mg, 0.96 mmol) in acetonitrile (2 mL) was added dropwise and the mixture was stirred at 50 ° C for 30 minutes and it was refluxed for 3 hours. The solvent was removed, the residue was applied to column chromatography (SiO2, 30% ethyl acetate in hexane) to give (4-methoxy-phenyl) -2- (2-methoxy-phenyl) -p-tolyl-1H- imidazole (320 mg, 0.86 mmol) as a solid.

Example G-4 Compounds representative of the formulas herein were evaluated for activity against calcium channel targets.

Compound G-1 [1- (4-Chloro-phenyl) -2- (4-fluoro-benzyl) -lH-imidazol-4-ylmethyl] - (4-fluoro-phenyl) -methyl-amine (Compound 1 in outline of reaction G-6) Reaction scheme G- 6 Part G-1. Preparation of N- (4-chloro-phenyl) -2- (4-fluorophenyl) -acetamidine A 4-chloroaniline (54.0 g, 424 mmol) in toluene (1000 L) at 0 ° C was added, dropwise, trimethylaluminum (2.0 M in toluene, 200 mL, 400 mmol) and the reaction was warmed at room temperature for 3 hours under nitrogen. A solution of 4-fluorophenylacetonitrile (31.8 g, 235 mmol) in toluene (20 mL) was added and the mixture was heated at 80 ° C overnight. The mixture was cooled to room temperature, treated with chloroform (200 ml) and SiO2, the thick mixture was stirred for 1 hour and emptied into a plug of Si02. Elution with 5:10:85 ammonium hydroxide: methanol: methylene chloride gave a light brown solid in vacuo. Recrystallization from ethyl acetate / hexanes gave N- (4-chloro-phenyl) -2- (4-fluoro-phenyl) -acetamidine (54.5 g, 207 mmol) as a white solid.

Part G-2. Preparation of 1- (4-chloro-phenyl) -2- (4-fluoro-benzyl) -4-hydroxy-4,5-dihydro-1H-imidazole-4-carboxylic acid ethyl ester A solution of N- ( 4-chloro-phenyl) -2- (4-fluoro-phenyl) -acetamidine (6.2 g, 24 mmol), ethyl bromopyruvate (10.1 g, 52 mmol), and sodium hydrogen carbonate (8.9 g, 106 mmol) in THF (100 mL) and water (100 mL) was refluxed 4 hours. The mixture was cooled to room temperature and extracted with diethyl ether. The organics were dried and concentrated in vacuo to give a dark brown oil. Recrystallization from ethyl acetate / hexanes gave 1- (4-chloro-phenyl) -2- (4-fluoro-benzyl) -hydroxy-4,5-dihydro-1H-imidazole-carboxylic acid ethyl ester ( 1.8 g, 4.7 mmol) as a light brown solid.

Part G-3. Preparation of 1- (4-chloro-phenyl) -2- (4-fluoro-benzyl) -1H-imidazole-4-carboxylic acid ethyl ester A solution of 1- (4-chlorophenyl) -ethyl ethyl ester - 2- (4-Fluoro-benzyl) -4-hydroxy-4,5-dihydro-1H-imidazole-4-carboxylic acid (1.8 g, 4.7 mmol) and p-toluenesulfonic acid monohydrate (0.2 g, 0.9 mmol) in toluene (20 mL) was refluxed 2 hours. The mixture was cooled to room temperature, the solvent was removed in vacuo, and the residue was partitioned between water and ethyl acetate. The organics were dried ~ and concentrated in vacuo to give a dark red oil which was purified by chromatography (Si02, 3% methanol in methylene chloride) to give ethyl ester of 1- (4-chloro-phenyl) -2- (4-fluoro-benzyl) -lH-imidazole-4-carboxylic acid (1.6 g, 4.4 mmol).

Part G-4. Preparation of 1- (4-chloro-phenyl) -2- (4-fluoro-benzyl) -1H-imidazole-4-carboxylic acid To a solution of 1- (4-chloro-phenyl) -2-ethyl ester - (4-Fluoro-benzyl) -lH-imidazole-4-carboxylic acid (1.6 g, 4.4 mmol) in 1,4-dioxane (15 mL) and water (15 mL) was added lithium hydroxide hydrate (0.4 g, 8.7 mmol) and the mixture was stirred at 40 ° C for 1 hour. More 1,4-dioxane was removed in vacuo, the residue was taken up in ethyl acetate / water, the aqueous was washed with ethyl acetate, acidified to pH 2 with aqueous 2N HCl and acid 1- (4-chloro). phenyl) -2- (4-fluoro-benzyl) -lH-imidazole-4-carboxylic acid (1 g, 2.7 mmol) was collected by filtration as the white HCl salt.

Part G-5. Preparation of 1- (4-Chloro-phenyl) -2- (4-fluoro-benzyl) -lH-imidazole-4-carboxylic acid (4-fluoro-phenyl) -methyl-amide A mixture of 1- (4 -chloro-phenyl) -2- (4-fluoro-benzyl) -lH-imidazole-4-carboxylic acid (0.4 g, 1.3 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.3 g, 1.5 mmol ) and 4-fluoro-N-methylaniline (0.2 g, 1.4 mmol) in methylene chloride (10 mL) was stirred at room temperature for 4 hours. The solvent was removed in vacuo, the residue was taken up in water and extracted with ethyl acetate. The organics were dried, concentrated in vacuo, and the residue was purified by chromatography (SiO2, 3% methanol in methylene chloride) to give 1- (4-chloro-phenyl) (4-fluoro-phenyl) -methyl-amide. ) -2- (4-fluoro-benzyl) -lH-imidazole-4-carboxylic acid (0.4 g, 0.9 mmol).

Part G-6. Preparation of [1- (4-Chloro-phenyl) -2- (4-fluoro-benzyl) -lH-imidazol-4-ylmethyl] - (4-fluoro-phenyl) -methyl-amine To a solution of (4- 1- (4-Chloro-phenyl) -2- (4-fluoro-benzyl) -lH-imidazole-4-carboxylic acid fluoro-phenyl) -methyl-amide (0.3 gm, 0.7 mmol) in THF (10 mL) At 0 ° C, borane-dimethylsulfide complex (2M in THF, 1.0 mL, 2.0 mmol) was added and the reaction was heated to reflux overnight. The mixture was cooled and diluted with methanolic HCl (10 mL), heated to reflux for 1 hour, cooled, and concentrated in vacuo. The residue was diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organics were dried and concentrated under vacuum to give an oil. Purification by chromatography (SiO 2, methanol in 3% methylene chloride) gave an oil which was taken up in ethanol and treated with HCl in ether to give 1- (4-chloro-phenyl) -2- (4-fluoro-benzyl) ) -lH-imidazol-4-ylmethyl] - (4-fluoro-phenyl) -methylamine (0.1 g, 0.2 mmol) as the opaque white HCl salt.

Compound G-2 2- [1- (4-Chloro-phenyl) -2- (4-fluoro-benzyl) -lH-imidazol-4-ylmethyl] -IH-benzoimidazole (Compound 2 in the G-7 reaction scheme ) Reaction scheme G-7 Parts G-l-5. Preparation of N- (2-Amino-phenyl) -2- [1- (4-chloro-phenyl) -2- (4-fluoro-benzyl) -lH-imidazol-4-yl] -acetamide The N- (2 -Amino-phenyl) -2- [1- (4-chloro-phenyl) -2- (4-fluorobenzyl) -lH-imidazol-4-yl] -acetamide was made as in Reaction scheme 6 replacing ethyl 4-bromoacetoacetate with ethyl bromopyruvate in Part 2 and 1,2-phenylenediamine by 4-fluoro-N-methylaniline in Part G-5.

Part G-6. Preparation of 2- [1- (4-Chloro-phenyl) -2- (4-fluorobenzyl) -lH-imidazol-4-ylmethyl] -lH-benzoimidazole A solution of N- (2-amino-phenyl) -2- [1- (4-Chloro-phenyl) -2- (4-fluoro-benzyl) -lH-imidazol-4-yl] -acetamide (3.8 g, 8.7 mmol) in glacial acetic acid (10 mL) was heated to 70 ° C for 0.5 hours. The mixture was cooled, added dropwise to saturated aqueous sodium hydrogen carbonate, the pH was adjusted to -14 with sodium hydroxide, extracted with ethyl acetate, and the organics were dried and concentrated in vacuo to give an oil . Treatment with HCl in ether followed by recrystallization from methanol / ether gave 2- [1- (4-chloro-phenyl) -2- (4-fluoro-benzyl) -lH-imidazol-4-ylmethyl] -1H -benzoimidazole (2.0 g, 4.8 mmol) as the white HCl salt.

Example H-4 Compounds representative of the formulas herein were evaluated for activity against calcium channel targets Compound H-1 Ethyl ester of 1- (4-chloro-phenyl) -2- acid. { [(4-fluorophenyl) -methyl-amino] -methyl} -lH-imidazole-4-carboxylic Reaction scheme H-6 Part H-l. Preparation of (4-Fluoro-phenylamino) -acetonitrile To a solution of 4-fluoroaniline (20.0 g, 180 mmol) in glacial acetic acid (250 mL) was added in portions paraformaldehyde (14.06 g) and potassium cyanide (14.06 g, 216 mmol) at 0 ° C. The mixture was allowed to stir at room temperature overnight and cooled. The mixture was neutralized with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organics dried and concentrated under vacuum. The resulting residue was purified by chromatography (SiO2, 10% ethyl acetate in n-hexane to give (4-fluoro-phenylamino) -acetonitrile (22.9 g, 153 mmol) as a yellow oil.

Part H-2. Preparation of [(4-Fluoro-phenyl) -methyl-amino] -acetonitrile To a thick solution of (4-fluoro-phenylamino) -acetonitrile (22.9 g, 153 mmol) and cesium carbonate (74.8 g, 229 mmol) in THF (200 mL) was added iodomethane (10.5 mL, 16 dmmol). The mixture was stirred for 3 hours at 40 ° C, cooled and quenched with water and extracted with ethyl acetate. The organics were dried and concentrated under vacuum to give [(4-fluoro-phenyl) -methyl-amino] -acetonitrile (22.3 g, 136 mmol) as an oil.

Part H-3. Preparation of N- (4-Chloro-phenyl) -2- [(4-fluorophenyl) -methyl-amino] -acetamidine To a solution of 4-chloroaniline (1.4 g, 11.0 mmol) in toluene (50 mL) was added trimethylaluminum (2M in toluene; 5.3 mL, 10.4 mmol) at 0 ° C under a blanket of nitrogen. The thick mixture was allowed to stir for 1 hour and added to a solution of [(4-fluoro-phenyl) -methyl-amino] -acetonitrile (1.0 g, 6.2 mmol) at room temperature. The mixture was heated to 80 ° C overnight, cooled and quenched with a thick mixture of a silica / chloroform mixture. The resulting mixture was filtered over a short pad of silica and washed with 10% methanol in methylene chloride. The combined fractions gave N- (4-chloro-phenyl) -2- [(4-fluoro-phenyl) -methyl-amino] -acetamidine (1.21 g, 4.18 mmol) as a yellow oil.

Part H-4. Preparation of ethyl ester of 1- (4-chloro-phenyl) -2- acid. { [(4-fluoro-phenyl) -methyl-amino] -methyl} -4-hydroxy-4,5-dihydro-lH-imidazole-4-carboxylic acid To a solution of N- (4-chloro-phenyl) -2- [(4-fluoro-phenyl) -methyl-amino] -acetamidine ( 1.21 g, 4.18 mmol) in THF (40 mL) was added sodium bicarbonate (0.70 g, 8.36 mmol) in water (10 mL) followed by slow addition of ethyl bromopyruvate (1.22 gm, 6.27 mmol) at 40 ° C. After the addition, the reaction was heated at 40 ° C for 2 hours and cooled. The mixture was diluted with water and extracted with ethyl acetate.

The organics were dried and concentrated under vacuum. The resulting residue was purified by chromatography (SiO2, 30% ethyl acetate in n-hexane) to give 1- (4-chloro-phenyl) -2- ethyl ester. { [(4-fluoro-phenyl) -methyl-amino] -methyl} -4-hydroxy-4,5-dihydro-lH-imidazole-4-carboxylic acid (0.74 g, 1.84 mmol) as a dark oil.

Part H-5. Preparation of ethyl ester of 1- (4-chloro-phenyl) -2- acid. { [(4-fluoro-phenyl) -methyl-amino] -methyl} -1H-imidazole-4-carboxylic acid A mixture of 1- (4-chloro-phenyl) -2- ethyl ester. { [(4-fluoro-phenyl) -methyl-amino] -methyl} 4-hydroxy-4,5-dihydro-1H-imidazole-4-carboxylic acid (0.74 gm, 1.84 mmol) and p-toluenesulfonic acid monohydrate (0.1 gm) in toluene (20 mL) was heated to reflux for 1 hour. The mixture was cooled, quenched with water and extracted with ethyl acetate. The organics were dried and concentrated under vacuum. The resulting residue was purified by chromatography (SiO2, 15% acetone in n-hexane) to give 1- (chloro-phenyl) -2- ethyl ester. { [(4-fluorophenyl) -methyl-amino] -methyl} -IH-imidazole-4-carboxylic acid (0.63 g, 1.62 mmol) as a white solid.

Compound H-2 and H-3 Phenylamide of 1- (4-chloro-phenyl) -2- acid. { [(4-fluoro-phenyl) -methyl-amino] -methyl} -lH-imidazole-4-carboxylic acid and [1- (4-chloro-phenyl) -4-phenylaminomethyl-lH-imidazol-2-ylmethyl] - (4-fluoro-phenyl) -methyl-amine Reaction scheme H-7 Part H-l. Preparation of 1- (4-chloro-phenyl) -2- acid. { [(4-fluoro-phenyl) -methyl-amino] -methyl} -IH-imidazole-4-carboxylic acid A solution of ethyl ester of 1- (4-chlorophenyl) -2- acid. { [(4-fluoro-phenyl) -methyl-amino] -methyl} -lH-imidazole-4-carboxylic acid (0.63 g, 1.62 mmol) and lithium hydroxide hydrate (0.14 g, 3.24 mmol) in a methanol / water mixture (2: 1 / p.-p) was heated at 50 ° C for 1 hour and cooled. The reaction mixture was concentrated under vacuum and diluted with aqueous 6N HCl until a pH of 6.5 was reached. The aqueous layer was extracted with ethyl acetate and the organics were dried, concentrated in vacuo to give 1- (4-chloro-phenyl) -2- acid. { [(4-fluoro-phenyl) -methyl-amino] -methyl} -IH-imidazole-4-carboxylic acid (0.41 g, 1.15 mmol) as a white solid.

Part H-2. Preparation of phenylamide of 1- (4-chlorophenyl) -2- acid. { [(4-fluoro-phenyl) -methyl-amino] -methyl} -lH-imidazole-4-carboxylic acid A mixture of 1- (4-chloro-phenyl) -2- acid. { [(4-fluorophenyl) -methyl-amino] -methyl} -lH-imidazole-4-carboxylic acid (0.36 g, 1.00 mmol) and 1- [3- (dimethylamino) propyl] -3-ethrbodiimide hydrochloride (0.28 g, 1.5 mmol) and aniline (0.09 g, 1 mmol) in pyridine (4 mL) was heated at 40 ° C overnight. The mixture was cooled, quenched with water and extracted with ethyl acetate. The organics were dried, concentrated under vacuum to 1- (4-chloro-phenyl) -2- phenylamide. { [(4-fluoro-phenyl) -methyl-amino] -methyl} -lH-imidazole-4-carboxylic acid (0.31 g, 0.71 mmol) as a solid.

Part H-3. Preparation of [1- (4-chloro-phenyl) -4-phenylaminomethyl-lH-imidazol-2-ylmethyl] - (4-fluoro-phenyl) -methyl-amine To a phenylamide solution. of l- (4-chloro-phenyl) -2- acid. { [(4-fluoro-phenyl) -methyl-amino] -methyl} -lH-imidazole-4-carboxylic acid (0.26 g, 0.6 mmol) in THF (15 mL) was added borane-dimethylsulfide complex (2M in THF, 0.9 mL) and allowed to stir overnight at reflux. The mixture was cooled and diluted with methanolic HCl (10 mL). The mixture was refluxed for 1 hour, cooled and concentrated under vacuum to give a residue. The residue was diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organics were dried and concentrated under vacuum to give a solid. Purification by chromatography (Si02, 40% acetone in n-hexane) gave [1- (4-chloro-phenyl) -4-phenylaminomethyl-lH-imidazol-2-ylmethyl] - (4-fluoro-phenyl) -methyl- amine (0.07 g, 0.17 mmol) as a white solid.

Compound H-4 [4- (lH-Benzoimidazol-2-ylmethyl) -1- (4-chloro-phenyl) -1H-imidazol-2-ylmethyl] - (4-fluoro-phenyl) -methyl-amine Reaction scheme H-8 Compound H-14 Part H-1. Preparation of (1- (4-Chloro-phenyl) -2-. {[[(4-fluoro-phenyl) -methyl-amino] -methyl] -1H-imidazol-4-yl) ethyl ester -acetic [1- (4-chloro-phenyl) -4-phenylaminomethyl-lH-imidazol-2-ylmethyl] - (4-fluoro-phenyl) -methyl-amine (1 eq.) and potassium carbonate (3 eq) is suspended in acetonitrile. The suspension is heated to 50 ° C and 4-bromo-3-oxo-butyric acid ethyl ester (1.5 eq.) In acetonitrile is slowly added dropwise. The reaction mixture is refluxed for 2 hours and cooled. The resulting residue is purified by chromatography (SiO2, ethyl acetate in hexane to give [1- (4-chloro-phenyl) -2- (2-methoxy-phenyl) -lH-imidazol-4-yl] ethyl ester. ] -acetic Part H-2. Preparation of (1- (4-Chloro-phenyl) -2- { [(4-fluoro-phenyl) -methyl-amino] -methyl} -IH-imidazol-4-yl) -acetic acid To a (1- (4-chlorophenyl) -2-. {[[(-fluoro-phenyl) -methyl-amino] -methyl] -lH-imidazol-4-yl) -acetic acid ethyl ester solution (1- (4-chlorophenyl) -2- { 1 eq.) In THF is added aqueous sodium hydroxide IN (5 eq). The mixture is stirred for 1 hour at 70 ° C and cooled. The reaction is diluted with water and the pH of the aqueous layer is adjusted to 6 using 6N aqueous sodium hydroxide. The aqueous phase is extracted with ethyl acetate, washed with water, dried and concentrated under vacuum to give (1- (4-chloro-phenyl) -2-. {[[(4-fluoro-phenyl) -methyl) acid. -amino] -methyl.}.-lH-imidazol-4-yl) -acetic acid. • Part H-3. "Preparation of N- (2-Amino-phenyl) -2- (1- (4-chloro-phenyl) -2- { [(4-fluoro-phenyl) -ethyl-amino] - methyl.}. - lH-imidazol-4-yl) -acetamide A mixture of (1- (4-chloro-phenyl) -2-. {[[(4-fluorophenyl) -methyl-amino] -methyl]. .lH-imidazol-4-yl) -acetic acid (1 eq.) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.2 eq.) and 1,2-phenylenediamine (1 eq.) in pyridine are stirred At room temperature overnight, the solvent is removed under vacuum, the resulting residue is diluted with water and extracted with ethyl acetate.The organics are dried, concentrated and the residue is purified by chromatography on silica gel (methanol in methylene chloride) to give N- (2-amino-phenyl) -2- (1- (4-chloro-phenyl) -2-. {[[(4-fluoro-phenyl) -ethylamino] -methyl}. -lH-imidazol-4-yl) -acetamide.

Part H-4. Preparation of [4- (lH-Benzoimidazol-2-ylmethyl) -1- (4-chloro-phenyl) -lH-imidazol-2-ylmethyl] - (4-fluoro-phenyl) -methyl-amine A solution of N- (2-amino-phenyl) -2 - (1- (4-chloro-phenyl) -2-. {[[(4-fluoro-phenyl) -ethyl-amino] -methyl]. -1H-imidazole-4 -yl) -acetamide (1 eq.) in glacial acetic acid has been heated at 70 ° C for 30 minutes. The mixture is cooled and saturated aqueous sodium bicarbonate solution is added. The pH is adjusted to 7 with sodium hydroxide pellets and the aqueous layer was extracted with ethyl acetate. The organics are dried and concentrated under vacuum to give a residue. The residue is treated with HCl in ether to give 2 - [1- (4-chloro-phenyl) -2- (2-methoxy-phenyl) -lH-imidazol-4-ylmethyl] -1H-benzoimidazole (0.44 gm, 0.98 mmol) as an HCl salt.

Example J-4 Compound 1 [1- (4- { 2- [1- (4-Chloro-phenyl) -2- (2-methoxy-phenyl) -lH-imidazol-4-yl] -ethyl.} . - (4-fluoro-phenyl) -methyl-amine Reaction scheme J-6 Part J-1. Preparation of N- (4-Chloro-phenyl) -2-methoxybenzamidine To a solution of 4-chloroaniline (25 g, 197 mmol) in THF (250 mL) at 0 ° C a 1M solution of sodium bis (trimethylsilyl) amide in THF (207 mL, 1.06 eq) was added dropwise over a period of 30 to 60 minutes. After the addition was complete, a solution of 2-methoxy benzonitrile (27.6 g, 209 mmol) in THF (125 mL) was added dropwise over a period of 15 to 30 minutes at room temperature and stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate, filtered and the solvent was removed under reduced pressure to give dark oil which solidified on standing. Titration with hexane and a minimum amount of ethyl acetate gave after filtration N- (4-chloro-phenyl) -2-methoxy-benzamidine (34 g, 131 mmol) as a gray solid.

Part J-2. Preparation of [1- (4-chloro-phenyl) -2- (2-methoxy-phenyl) -lH-imidazol-4-yl] -acetic acid ethyl ester A mixture at ~ 50 ° C of N- ( 4-chloro-phenyl) -2-methoxy-benzamidine (9 g, -34.6 mmol) and potassium hydrogen carbonate (10.38 g, 103.8 mmol, 3 eq) in acetonitrile (100 mL) was treated with a solution of 4-bromo-3-oxo-10-butyric acid ethyl ester (10 g, 48 mmol) in acetonitrile (50 mL) Drop by drop for 30 minutes. The reaction mixture was brought to reflux for 2 hours, cooled and filtered. Under vacuum the solvent was removed from the filtrate to give a dark oil. Flash chromatography (Si02, 50% ethyl acetate in . hexane) gave the ethyl ester of [1- (4-chloro-phenyl) -2- (2-methoxy-phenyl) -lH-imidazol-4-yl] -acetic acid (16 g, 17 mmol) as an oil viscous, dark.

Part J-3. Preparation of [1- (4-Chloro-phenyl) -2- (2-methoxy-phenyl) -lH-imidazol-4-yl] -acetic acid To a solution of the ethyl ester of [1- (4- chloro-phenyl) -2- (2-methoxy-phenyl) -lH-imidazol-4-yl] -acetic acid (1.5 g, 4.04 mmol) in THF. { 40 mL) was added aqueous IN sodium hydroxide (12 mL) and the mixture allowed to stir for 1 hour at 70 ° C and cooled. The reaction was quenched with water and adjusted to pH 6 with aqueous 6N sodium hydroxide and extracted with ethyl acetate. The combined organics were washed with water, dried and concentrated under vacuum to give [1- (4-chloro-phenyl) -2- (2-methoxy-phenyl) -IH-imidazol-4-yl] -acetic acid (0.49 g). g, 1.43 mmol) as a white solid.

Part J-4. Preparation of 2- [1- (4-Chloro-phenyl) -2- (2-methoxy-phenyl) -lH-imidazol-4-yl] -N- (4-fluoro-phenyl) -N-methyl-acetamide A mixture of [1- (4-chloro-phenyl) -2- (2-methoxy-phenyl) -lH-imidazol-4-yl] -acetic acid (0.25 g, 0.73 mmol) and 1- (3- hydrochloride) dimethylaminopropyl) -3-ethylcarbodiimide (0.28 g, 1.46 mmol) and 4-fluoro-N-methylaniline (0.082 mL, 0.73 mmol) in pyridine (3 mL) was stirred at room teature overnight. The solvent was removed in vacuo, the residue was diluted with water and extracted with ethyl acetate. The organics were dried, concentrated under reduced pressure and the residue was purified by chromatography (Si02, 3% methanol in methylene chloride) to give 2- [1- (4-chloro-phenyl) -2- (2-methoxy-phenyl) ) -lH-imidazol-4-yl] -N- (4-fluoro-phenyl) -N-methyl-acetamide (0.16 g, 0.36 mmol) as an oil.

Part J-5. Preparation of [1- (4-. {-2- [1- (4-Chloro-phenyl) -2- (2-methoxy-phenyl) -lH-imidazol-4-yl] -ethyl.} - (4 -fluoro-phenyl) -methylamine To a solution of 2- [1- (4-chloro-phenyl) -2- (2-methoxy-phenyl) -lH-imidazol-4-yl] -N- (4-fluoro- phenyl) -N-methyl-acetamide (0.07 g, 0.16 mmol.) in toluene (5 mL) at 0 ° C was added borane-dimethylsulfide complex (2M in THF, 0.16 mL, 0.31 mmol) and the reaction warmed The mixture was cooled and diluted with methanolic HCl (3 mL), refluxed for 1 hour, cooled and concentrated in vacuo, the residue was diluted with saturated aqueous sodium bicarbonate and extracted. with ethyl acetate The organics were dried, and concentrated in vacuo to give a white solid The solid was taken up in methanol and treated with HCl in ether to give [1- (4-. {2- 2- [1- ( 4-chloro-phenyl) -2- (2-methoxy-phenyl) -1H-imidazol-4-yl] -ethyl.} - (4-fluoro-phenyl) -methyl-amine (0.06 g, 0.013 mmol) as a white solid.

Compound J-2 2- [1- (4-Chloro-phenyl) -2- (2-methoxy-phenyl) -IH-imidazol-4-ylmethyl] -lH-benzoimidazole Reaction scheme J-7 Compound J-2 Part j-1. Preparation of N- (2-Amino-phenyl) -2- [1- (4-chloro-phenyl) -2- (2-methoxy-phenyl) -lH-imidazol-4-yl] -acetamide A mixture of acid [ 1- (4-Chloro-phenyl) -2- (2-methoxy-phenyl) -lH-imidazol-4-yl] -acetic acid (0.87 g, 2.56 mmol) and 1- (3-dimethylaminopropyl) -3- hydrochloride ethylcarbodiimide (0.73 g, 3.83 mmol) and 1,2-phenylenediamine (0.28 g, 2.56 mmol) in pyridine (5 mL) was stirred at room teature overnight. The solvent was removed in vacuo and treated with water and made basic with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organics were dried and concentrated to give N- (2-amino-phenyl) -2- [1- (4-chloro-phenyl) -2- (2-methoxy-phenyl) -lH-imidazol-4-yl] - acetamide (0.86 g, 1.99 mmol) as an oil.

Part J-2. Preparation of 2- [1- (4-Chloro-phenyl) -2- (2-methoxy-phenyl) -lH-imidazol-4-ylmethyl] -lH-benzoimidazole A solution of N- (2-amino-phenyl) - 2- [1- (4-Chloro-phenyl) -2- (2-methoxy-phenyl) -lH-imidazol-4-yl] -acetamide (0.86 g, 1.99 mmol) in glacial acetic acid (8 mL) was heated at 70 ° C for 30 minutes. The mixture was cooled and added dropwise to a saturated aqueous sodium bicarbonate and the pH adjusted to 7 with sodium hydroxide pellets. The mixture was extracted with ethyl acetate, the organics were dried and concentrated in vacuo to give an oil. Treatment of the oil with HCl in ether gave 2- [1- (4-chloro-phenyl) -2- (2-methoxy-phenyl) -lH-imidazol-4-ylmethyl] -lH-benzoimidazole (0.44 g, 0.98 mmol ) as a white solid.

Compound J-3 2- [2- (2-Methoxy-phenyl) -l-p-tolyl-lH-imidazol-4-ylmethoxymethyl] -1-methyl-lH-benzoimidazole Reaction Scheme J-8 Part J-1. Preparation of [2- (2-Methoxy-phenyl) -1-p-tolyl-lH-imidazol-4-yl] -methanol To a solution -78 ° C of 2- (2-methoxy-phenyl) ethyl ester ) -lp-tolyl-lH-imidazole-4-carboxylic acid (2.0 g, 6.0 mmol) in THF (10 mL) was added dropwise, aluminum, lithium aluminum hydride in ether (6.0 mL, 6.0 mmol). The mixture was warmed to room teature, stirred for 4 hours and quenched with three drops of methanol. The solvents were removed. The residue was partitioned between methylene chloride and water. The combined organic layers were washed with water, brine, dried over anhydrous Na 2 SO, filtered and concentrated under vacuum. Column chromatography (Si0, ethyl acetate) gave [2- (2-methoxy-phenyl) -l-p-tolyl-lH-imidazol-4-yl] -methanol (1.1 g, 3.7 mmol) as a solid.

Part J-2. Preparation of 2- [2- (2-methoxy-phenyl) -1-p-tolyl-lH-imidazol-4-ylmethoxymethyl] -1-methyl-lH-benzoimidazole To a solution of [2- (2-methoxy-phenyl) ) -1-b-tolyl-lH-imidazol-4-yl] -methanol (100 mg, 0.34 mmol) in THF (5 mL) was added NaH (15 mg, 0.34 mmol). The mixture was stirred at room temperature for 30 minutes and 2-chloromethyl-1-methyl-1H-benzoimidazole (61 mg, 0.34 mmol) was added.The mixture was refluxed for 1 hour, cooled to room temperature and The mixture was extracted with ether, the organic layer was washed with water, brine, dried over anhydrous Na 2 SO, filtered and concentrated in vacuo, column chromatography (SiO 2, ethyl acetate) gave 2- [ 2- (2-methoxy-phenyl) -1-p-tolyl-lH-imidazol-4-ylmethoxymethyl] -1-methyl-lH-benzoimidazole (86 mg, 0.20 mmol) as an oil. present are prepared in a similar manner as described above and in the General Reaction Schemes All references cited herein, whether in a printed, electronic, computer readable storage medium or otherwise, are expressly incorporated for references in its entirety, including but not limited to, summaries, articles, newspapers, publications, texts, treaties, internet network sites, databases, patents, and patent publications. It will be understood that although the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims It is noted that with this date, the best method known to the applicant to carry out the practice of said invention, is that which is clear from this description of the invention.

Claims (36)

Claims: Having described the invention as above, the content of the following claims is claimed as property.

1. A compound of the formula (AI) or a pharmaceutical salt thereof (AI) characterized in that, Ar 1 is cycloalkyl, aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more substituents; X is NR3, C (R3) 2, or 0; Y is C = 0 or lower alkyl; R1 is Ar2 or lower alkyl optionally substituted with Ar2; each Ar2 is independently cycloalkyl, aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more substituents; q is 0, 1 or 2; each R2 is independently selected from (CH2) mC02R3, (CH2) mC0Ar3, (CH2) mCONR3R4, (CH ^ ^ r3, (CH2) 3Ar3, (CH2) nNR3R4 or (CH2) n0R4; each R3 is independently selected from H, or lower alkyl; each R4 is independently selected from H, lower alkyl or (CH2) pAr3; m is 1 or 2 n is 2 or 3 p is 0 or 1, each Ar3 is cycloalkyl, aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more substituents; each substituent for Ar1, Ar2 and Ar3 is independently selected from halogen, CN, N0, OR5, SR5, S (0) 20R5, NR5R6, cycloalkyl, perfluoroalkyl Cx-C2, perfluoroalkoxy C? -C2, 1,2-methylenedioxy, C (0) OR5, C (0) NR5R6, OC (0) NR5R6, NR5C (0) NR5R6, C (NR6) NR5R6, NR5C (NR6) NR5R6, S (0) 2NR5R6, R7, C (0) R7, NR5C (0) R7, S (0) R7, or S (0) 2R7; each R5 is independently selected from hydrogen or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C3-C4 alkoxy, NH2, C1-C4 alkylamino, C1-C4 dialkylamino or C3-C6 cycloalkyl; each R6 is independently selected from hydrogen, (CH) pAr4, or lower alkyl, optionally substituted with one or more substituents independently selected from halogen, OH, alkoxy CL-C, NH2, C1-C4 alkylamino, C1-C4 dialkylamino or C3 cycloalkyl -C6; each R7 is independently selected from (CH2) pAr4 or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C 1 -C 4 alkoxy, NH 2, C 1 -C alkylamino, C 1 -C 4 dialkylamino or C 3 -C 6 cycloalkyl; and each Ar 4 is independently selected from C 3 -C 6 cycloalkyl, aryl or heteroaryl, each optionally substituted with one to three substituents independently selected from halogen, OH, Ci-C 4 alkoxy, NH 2, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino or 1,2-methylenedioxy.

2. A compound of the formula (Bl) or a pharmaceutical salt thereof characterized in that, Ar1 is cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of H, halogen, amino, hydroxy, cyano, nitro, carboxylate, alkyl, alkenyl, alkynyl, cycloalkyl, cyclohexyl, alkoxy, mono and di-alkyl amino, phenyl, carboxamide, haloalkyl, haloalkoxy, and alkanoyl; R1 is Ar2 or lower alkyl optionally substituted with Ar2; Ar2 is independently selected from cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of H, halogen, amino, hydroxy, cyano, nitro, carboxylate, alkyl, alkenyl, alkynyl, cycloalkyl, cyclohexyl, alkoxy, mono and dialkyl amino, phenyl, carboxamide, haloalkyl, haloalkoxy, and alkanoyl; q is 0, 1 or 2; each R2 is independently selected from (CH2) mC02R3, (CH2) mCOAr3, (CH2) mCONR3R4, (CH ^ pA3, (CH2) 3Ar3, (CH2) nNR3R4 or (CH2) nOR4; each R3 is independently selected from H, or lower alkyl, each R4 is independently selected from H, lower alkyl or (CH2) pAr3; each Ar3 is cycloalkyl, aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more substituents, with the proviso that Ar3 is not piperidinyl, tetrahydroquinolinyl or tetrahydroisoquinolinyl; each Z is independently selected from 0 or NR3, each m is 1 or 2, each n is 2 or 3 each p is 0 or 1 each substituent for Ar1, Ar2 and Ar3 is independently selected from halogen, CN, N02, OR5, SR5 , S (0) 2OR5, NR5R6, cycloalkyl, perfluoroalkyl C? -C2, perfluoroalkoxy Cx-C2, 1, 2-methylenedioxy, C (0) OR5, C (0) NR5R6, OC (0) NR5R6, NR5C (0) NR5R6, C (NR6) NR5R6, NR5C (NR6) NR5R6, S (0) 2NR5R6, R7, C (0) R7, NR5C (0) R7, S (0) R7, or S (0) 2R7; each R5 is independently selected from hydrogen or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C 1 -C 4 alkoxy, NH 2, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino or C 3 -Cg cycloalkyl; each R6 is independently selected from hydrogen, (CH2) pAr4 > or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C 1 -C 4 alkoxy, NH 2, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino or C 3 -CG cycloalkyl; each R7 is independently selected from (CH2) pAr4 or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C1-C4 alkoxy, NH2, C1-C4 alkylamino, C1-C4 dialkylamino or C3-Ce cycloalkyl; and each Ar 4 is independently selected from C 3 -C 6 cycloalkyl, aryl or heteroaryl, each optionally substituted with one to three substituents independently selected from halogen, OH, C 1 -C 4 alkoxy, NH 2, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino or 1,2-methylenedioxy.

3. A method for treating a disease or symptoms of disease in a subject, characterized in that it includes administering to the subject an effective amount of a compound of the formula Cl or a pharmaceutical salt thereof: AC? wherein, Ar 1 is cycloalkyl, aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more substituents; X is NR3, C (R3) 2, S, a bond or O, or together and with -CH = CH-; Y is C = 0, a bond, or lower alkyl, or together and with -CH = CH- forms; R1 is Ar2, alkenyl, or lower alkyl optionally substituted with Ar2; each Ar2 is independently cycloalkyl, aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more substituents; q is 0, 1 or 2; each R2 is independently (CH2) mC02R3, (CH2) mC0Ar3, (CH2) mCONR3R4, (CH2) mAr3, (CH2) nNR3R4, (CH2) nOR4; (CH2) mCN; I rent; alkynyl, (CR3R3) mCONR3R4, Ar4, (CR3R3) mN (R3) C (0) Ar3, or (CH2) mC (NOH) NH2; 'each R3 is independently H, or lower alkyl; each R4 is independently H, lower alkyl, alkoxy, (CH2) nNR5R6, or (CH2) pAr3; is 1 or 2, n is 2 or 3 p is 0 or 1, each Ar3 is cycloalkyl, aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more substituents; each substituent for Ar1, Ar2 and Ar3 is independently halogen, CN, N02, OR6, SR6, S (0) 2OR5, NR5R6, cycloalkyl, perfluoroalkyl C? -C2 / perfluoroalkoxy C? -C2, 1,2-methylenedioxy, C ( 0) OR5, C (0) NR5R6, OC (0) NR5R6, NR5C (0) NR5R6, C (NR6) NR5R6, NR5C (NR6) NR5R6, S (0) 2NR5R6, R7, C (0) R7, NR5C ( 0) R7, S (0) R7, or S (0) 2R7; each R5 is independently hydrogen or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C1-C4 alkoxy, NH2, C1-C4 alkylamino, C1-C4 dialkylamino or C3-C3 cycloalkyl; each R6 is independently hydrogen, (CH2) pAr4, or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C 1 -C 4 alkoxy, NH 2, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino or C 3 -C 6 cycloalkyl; each R7 is independently (CH2) pAr4 or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C1-C4 alkoxy, NH2, C1-C4 alkylamino, C1-C4 dialkylamino or C3-Ce cycloalkyl; and each Ar4 is independently C3-C6 cycloalkyl, heterocyclyl, aryl or heteroaryl, each optionally substituted with one to three substituents independently selected from halogen, OH, CL-C alkoxy, NH 2, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino or 1,2-methylenedioxy.

4. A compound of the formula Cl or a pharmaceutical salt thereof, (C characterized in that, Ar 1 is cycloalkyl, aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more substituents, and each is linked to X by a carbon atom, X is CH 2, Y is a bond, R 1 is Ar2, anynyl, or lower alkyl optionally substituted with Ar2, each Ar2 is independently "cycloalkyl, aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more substituents; q is 0, 1 or 2; each R2 is independently (CH2) ) mC02R3, (CH2) mCOAr3, or (CH2)? nCONR3R4, each R3 is independently H, or lower alkyl, each R4 is independently H, lower alkyl, alkoxy, (CH2) nNR5R6, or (CH2) pAr3; n is 2 or 3, p is 0 or 1, each Ar3 is cycloalkyl, aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more substituents, each substituent for Ar1, Ar2 and Ar3 is independently halogen, CN, N0 , OR6, SRS, S (0) 2OR5, NR5R6, cycloalkyl, perfluoroalkyl C? - C2, perfluoroalkoxy C? -C2 > , 1,2-methylenedioxy, C (0) OR5, C (0) NR5R6, 0C (0) NR5R6, NR5C (0) NRsR6, C (NRS) NR5R6, NRSC (NR6) NR5R6, S (0) 2NR5R6, R7 , C (0) R7, NR5C (0) R7, S (0) R7, or S (0) 2R7; each R 5 is independently hydrogen or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C 1 -C 4 alkoxy, NH, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino or C 3 -C 3 cycloalkyl; each R6 is independently hydrogen, (CH2) pAr4, or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C? -C4 alkoxy, NH2, C1-C4 alkylamino, C3-C4 dialkylamino or C3- cycloalkyl C6; each R7 is independently (CH2) pAr4 or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C? -C4 alkoxy, NH2, C1-C4 alkylamino, C1-C4 dialkylamino or C3-C6 cycloalkyl; and each Ar4 is independently C3-C6 cycloalkyl, heterocyclyl, aryl or heteroaryl, each optionally substituted with one to three substituents independently selected from halogen, OH, C1-C4 alkoxy, NH, C3-C4 alkylamino, dialkylamino C? -C4 or 1, 2-methylenedioxy.

5. A -compound of the formula (DI) _ or "a pharmaceutical salt thereof" characterized in that, R3 is Ar "1" or Arx-X-Y wherein, each Ar1 is cycloalkyl, aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more substituents; X is NR4, C (R4) 2, or O; Y is C = 0 or lower alkyl; R1 is Ar2 or lower alkyl optionally substituted with Ar2; each Ar2 is independently cycloalkyl, aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more substituents; each R2 is independently selected from (CH2) mC (0) OR4, (CH2) mC (0) Ar3, (CH2) mC (0) NR4R5, (CH2) nNR4R5, (CH2) 3Ar3, or (CH2) mAr3; each R4 is independently selected from H, or lower alkyl; each R5 is independently selected from H, lower alkyl or (CH2) pAr3; m is 1 or 2; n is 2 or 3; p is O or 1; each Ar3 is cycloalkyl, aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more substituents; each substituent for Ar1, Ar2 and Ar3 is independently selected from halogen, CN, N02, OR6, SR6, S (0) 20R6, NR6R7, cycloalkyl, perfluoroalkyl C? -C2 / perfluoroalkoxy C? -C2, 1,2-methylenedioxy, C (0) OR6, C (0) NR6R7, OC (0) NR6R7, NR6C (0) NR6R7, C (NR6) NR6R7, NR6C (NR7) NR6R7, "S (O) 2NR6R7, R8, C (0) R8 , ~ R6C (0) R8, S (0) R8, or S (0) 2R8; each R6 is independently selected from hydrogen or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C1-C4 alkoxy, NH2, C1-C4 alkylamino, C1-C4 dialkylamino or C3-C6 cycloalkyl, - each R7 is independently selected from hydrogen, (CH2) qAr4, or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C1 alkoxy -C4, NH2, C1-C4 alkylamino, C3-C4 dialkylamino or C3-C6 cycloalkyl; each R8 is independently selected from (CH2) gAr4 or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C1-C4 alkoxy, NH2, C1-C4 alkylamino, C1-C4 dialkylamino or C3-C6 cycloalkyl each Ar4 is independently selected from C3-C6 cycloalkyl, aryl or heteroaryl, each optionally substituted with one to three substituents independently selected from halogen, OH, C, C2 alkoxy, NH2, C4-4 alkylamino, C1-C4 dialkylamino or C3 cycloalkyl. C6; and q is 0 or 1.

6. A compound of the formula (El) or a pharmaceutical salt thereof characterized in that, R3 is alkyl, alkoxyalkyl, Ar1 or Ar1-X-Y wherein, each Ar1 is independently cycloalkyl, aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more substituents; X is NR4, C (R4) 2, or O; Y is C = 0 or lower alkyl; R1 is H, alkenyl, Ar2 or lower alkyl optionally substituted with Ar2 each Ar2 is independently cycloalkyl, aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more substituents; each R2 is independently selected from H, (CH2) mC (0) OR4, (CH2) mC (0) Ar3, (CH2) mC (0) NR4R5, (CH2) mC (O) N (OR4) R5, (CH2) ) mCH2OR4, Ar3, (CH2) nAr3; (CH2) nNR4R5, or (CH2) mAr3; each R4 is independently selected from H, or lower alkyl; each R5 is independently selected from H, lower alkyl or (CH2) pAr3; m is 1 or 2, n is 2 or 3 p is O or 1, each Ar 3 is cycloalkyl, aryl, heterocyclyl; or heteroaryl, each optionally substituted with one or more substituents; each substituent for Ar1, Ar2 and Ar3 is independently selected from halogen, CN, N02, OR6, SR6, S (0) 2OR6, NR6R7, cycloalkyl, perfluoroalkyl C? -C2, perfluoroalkoxy C? -C, 1,2-methylenedioxy, C (0) OR6, C (0) NR6R7, OC (0) NR6R7, NR6C (O) NR6R7, C (NR6) NR6R7, NR6C (NR7) NR6R7, S (0) 2NR6R7, R8, C (0) R8, NR6C (0) R8, S (0) R8, or S (0) 2R8; each R6 is independently selected from hydrogen or lower alkenyl optionally substituted with one or more substituents independently selected from halogen, OH, C1-C4 alkoxy, NH2, C1-C4 alkylamino, dialkylamino O.-C4 or cycloalkyl C3-C3; each R7 is independently selected from hydrogen, (CH2) qAr4, or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C1-C4 alkoxy, NH2, alkylamino 1.-C4, dialkylamino C1-C4 or cycloalkyl C3 -C6; each R8 is independently selected from (CH2) qAr4 or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C 1 -C 4 alkoxy, NH 2, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino or C 3 -C 6 cycloalkyl; each Ar4 is independently selected from C3-C6 cycloalkyl, aryl or heteroaryl, each optionally substituted with one to three substituents independently selected from halogen, OH, Ci-C alkoxy, NH2, C? -C alkylamino / C1-C4 dialkylamino or cycloalkyl C3-Ce; and q is O or 1.

7. A method for treating a disease or symptoms of the disease in a subject, characterized in that it comprises administering to the subject an effective amount of a compound of the formula (Fl) or a pharmaceutical salt thereof: < H) wherein, Ar 1 is cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of H, halogen, amino, hydroxy, cyano, nitro, carboxylate, alkyl, alkenyl, alkynyl, cycloalkyl, cyclohexyl, alkoxy, mono and di-alkyl amino, phenyl, carboxamide, haloalkyl, haloalkoxy, and alkanoyl; R1 is Ar2 or lower alkyl optionally substituted with Ar2; Ar2 is independently selected from cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of H, halogen, amino, hydroxy, cyano, nitro, carboxylate, alkyl, alkenyl, alkynyl, cycloalkyl, cyclohexyl, alkoxy, mono and di-alkyl amino, phenyl, carboxamide, haloalkyl, haloalkoxy, and alkanoyl; each R2 is independently selected from C02R3, COAr3, C0NR3R4, Ar3, CH2NR3R4; each R3 is independently selected from H, or lower alkyl; each R4 is independently selected from H, lower alkyl, C (0) OR5, C (0) NR5R6, S (0) 2NR5R6, C (0) R7, S (0) 2R7 or (CH2) pAr3; each Ar3 is independently cycloalkyl, aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more substituents; each p is independently 0_ó 1; each substituted by Ar3 is independently selected from halogen, CN, N02, OR5, SR5, S (0) 2OR5, NR5R6, cycloalkyl, perfluoroalkyl C? -C2, perfluoroalkoxy C? -C2, 1,2-methylenedioxy, C (0) ) 0R5, C (0) NR5R6, OC (0) NR5R6, NR5C (0) NR5Rs, C (NR5) NR5R6, NR5C (NR6) NR5R6, S (0) 2NR5R6, R7, C (0) R7, NR6C (0 ) R7, S (0) R7, or S (0) 2R7; each R5 is independently selected from hydrogen or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C 1 -C 4 alkoxy, NH 2, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino or C 3 -C 6 cycloalkyl; each R6 is independently selected from hydrogen, (CH2) gAr4, or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C1-C4 alkoxy, NH2, C1-C4 alkylamino, C1-C4 dialkylamino or C3- cycloalkyl C3; each R7 is independently selected from (CH2) qAr4 or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C1-C4 alkoxy, NH2, C1-C4 alkylamino, C1-C dialkylamino or C3-C6 cycloalkyl; each Ar4 is independently selected from C3-C6 cycloalkyl, aryl or heteroaryl, each optionally substituted with one to three substituents independently selected from halogen, OH, CX-C4 alkoxy, NH2, C1-C4 alkylamino, dialkylamino C? -C4 or , 2-methylenedioxy; and each q is independently 0 or 1.

8. A compound of the formula G- (I) or a pharmaceutical salt thereof characterized in that, Ar1 is cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of H, halogen, amino, hydroxy, cyano, nitro, carboxylate, alkyl, alkenyl, alkynyl, cycloalkyl, cyclohexyl, alkoxy, mono and di-alkyl amino, phenyl, carboxamide, haloalkyl, haloalkoxy, and alkanoyl ";" R1 is Ar2 or lower alkyl optionally substituted with Ar2; Ar2 is independently selected from cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of H, - halogen, amino, hydroxy, cyano, nitro, -carboxylate, alkyl, alkenyl, alkynyl, cycloalkyl, cyclohexyl, alkoxy, mono and di-alkyl amino, phenyl, carboxamide, haloalkyl, haloalkoxy, and alkanoyl; each R2 is independently selected from C02R3, COAr3, C0NR3R4, (CH2) mAr3, (CH2) nNR3R4 or CH2OR4; each R3 is independently selected from H, or lower alkyl; each R4 is independently selected from H, lower alkyl, C (0) OR5, C (0) NR5R6, S (0) 2NR5R6, C (0) R7, S (0) 2R7 or (CH2) pAr3; each Ar3 is independently cycloalkyl, aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more substituents; each m is independently 0 or 1, each n is independently 1 or 2 each p is independently 0 or 1, each substituted by Ar3 is independently selected from halogen, CN, N02, OR5, SR5, S (0) 2OR5, NR5R6, cycloalkyl, perfluoroalkyl C? -C2, perfluoroalkoxy C? -C2, 1,2-methylenedioxy, C (0) OR5, C (0) NR5R6, OC. (0) NR5R6, NR5C (0) NR5R6, C (NR5) NR5R6 , NR5C (NR6) NR5R6, S (0) 2NR5R6, R7, C (0) R7, NR6C (0) R7, S (0) R7, or S (0) 2R7; each R5 is independently selected from hydrogen or lower alkenyl optionally substituted with one or more substituents independently selected from halogen, OH, C -C 4 alkoxy, NH 2, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino or C 3 -C 6 cycloalkyl; each R6 is independently selected from hydrogen, (CH2) qAr4, or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C? -C4 alkoxy, NH2, C? -C4 alkylamino, dialkylamino C? -C4 or C3-C3 cycloalkyl; each R7 is independently selected from (GH2) qAr4 or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C? -C4 alkoxy, NH2, C? -C4 alkylamino, C? -C dialkylamino or C3 cycloalkyl? C6; each Ar4 is independently selected from C3-C6 cycloalkyl, aryl or heteroaryl, each • optionally. substituted with one to three substituents independently selected from halogen, OH, C 1 -C 4 alkoxy, NH 2, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino or 1,2 methylenedioxy; and each q is independently 0 or 1.

9. A method for treating a disease or symptoms of the disease in a subject in need of treatment, characterized in that it comprises administering to the subject an effective amount of a compound of the formula G- (I) or a pharmaceutical salt thereof: wherein, Ar 1 is cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of H, halogen, amino, hydroxy, cyano, nitro, carboxylate, alkyl, alkenyl, alkynyl, cycloalkyl, cyclohexyl, alkoxy, mono and di-alkyl amino, phenyl, carboxamide, haloalkyl, haloalkoxy, and alkanoyl; R1 is Ar2 or lower alkyl optionally substituted with Ar2; Ar2 is independently selected from cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of H, halogen, amino, hydroxy, cyano, nitro, carboxylate, alkyl, alkenyl, alkynyl, cycloalkyl, cyclohexyl, alkoxy, mono and dialkyl amino, phenyl, carboxamide, haloalkyl, haloalkoxy, and alkanoyl; each R2 is independently selected from C02R3, COAr3, CONR3R4, (CH2) mAr3, (CH2) nNR3R4 or CH20R4; each R3 is independently selected from H, or lower alkyl; each R4 is independently selected from H, lower alkyl, C (0) OR5, C (0) NR5R6, S (0) 2NR5R6, C (0) R7, S (0) 2R7 or (CH2) pAr3; each Ar3 is independently cycloalkyl, aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more substituents; each m is independently 0 or 1i each n is independently 1 or 2, each p is independently 0 or 1i each substituent for Ar3 is independently selected from halogen, CN, N02, OR5, SR5, S (0) 20R5, NR5R6, C 1 -C 2 perfluoroalkyl, C 1 -C 2 perfluoroalkoxy, 1,2-methylenedioxy, C (0) OR 5, -C (0) NR 5 R 6, OC (0) NR 5 R 6, NR 5 C (0) NR 5 R 6, C (NR 5) NR 5 RS , NR5C (NR6) NR5R6, S (0) 2NR5R6, R7, C (0) R7, NR6C (0) R7, S (0) R7, or S (0) 2R7; each R5 is independently selected from hydrogen or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C? -C4 alkoxy, NH2, C? -C4 alkylamino, C? -C dialkylamino or C3-C6 cycloalkyl; each R6 is independently selected from hydrogen, (CH2) qAr4, or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C? -C4 alkoxy, NH2, C4-C4 alkylamino, C? -C4 dialkylamino or cycloalkyl C3-C6; each R7 is independently selected from (CH2) qAr4 or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C? -C4 alkoxy, NH2, C? -C4 alkylamino, C4-C4 dialkylamino or C3-C6 cycloalkyl; each Ar4 is independently selected from C3-C6 cycloalkyl, aryl or heteroaryl, each optionally substituted with one to three substituents independently selected from halogen, OH, CX-C4 alkoxy, NH2, C? -C4 alkylamino, C4-4 dialkylamino or , 2-methylenedioxy; and each q is independently O or 1.

10. A compound of the formula H- (I) or a pharmaceutical salt thereof characterized in that, Ar1 is cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is optionally substituted with one. or more substituents selected from the group consisting of H, halogen, amino, hydroxy, cyano, nitro, carboxylate, alkyl, alkenyl, alkynyl, cycloalkyl, cyclohexyl, alkoxy, mono and di-alkyl amino, phenyl, carboxamide, haloalkyl, haloalkoxy , and alkanoyl; X is NR3, C (R3) 2, u 0; Y is C = 0 or lower alkyl; R1 is Ar2 or lower alkyl optionally substituted with Ar2; Ar2 is independently selected from cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of H, halogen, amino, hydroxy, cyano, nitro, carboxylate, alkyl, alkenyl, alkynyl, cycloalkyl, cyclohexyl, alkoxy, mono and di-alkyl amino, phenyl, carboxamide, haloalkyl, haloalkoxy, and alkanoyl; each R2 is independently selected from C02R3, COAr3, C0NR3R4, (CH) mAr3, CH2NR3R4 or CH20R4; each R3 is independently selected from H, or lower alkyl; each R4 is independently selected from H, lower alkyl, C (0) OR5, C (0) NR5R6, S (0) 2NR5R6, C (0) R7, S (0) 2R-7 or (CH2) pAr3; each Ar3 is independently cycloalkyl, aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more substituents; each m is independently 0 or 1; each p is independently 0 or 1; each substituent for Ar3 is independently selected from halogen, CN, N02, OR5, SR5, S (0) 20R5, NR5R6, cycloalkyl, perfluoroalkyl C? -C2, perfluoroalkoxy C? -C2, 1,2-methylenedioxy, C (0) 0R5, C (0) NR5R6, 0C (0) NR5R6, NR5C (O) NR5R6, C (NR5) NR5R6, NR5C (NR6) NR5R6, S (0) 2NR5R6, R7, C (0) R7, NR6C (0) R7, S (0) R7, or S (0) 2R7; each R5 is independently selected from hydrogen or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C-C4 alkoxy, NH2, C? -C4 alkylamino, C-C4 dialkylamino or C3-C6 cycloalkyl, - each R6 is independently selected from hydrogen, (CH2) gAr4, or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C? -C4 alkoxy, NH2, C? -C4 alkylamino, dialkylamino C? -C or C3-C6 cycloalkyl; each R7 is independently selected from (CH2) qAr4 or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C? -C4 alkoxy, NH2, C? -C4 alkylamino, C? -C dialkylamino or C3 cycloalkyl? C6; each -Ar4 is independently selected from C3-C6 cycloalkyl, aryl or heteroaryl, each optionally substituted with one to three substituents independently selected from halogen, OH, C?-C4 alkoxy, NH, C-C4 alkylamino, dialkylamino C-C4 or 1,2-methylenedioxy; and each q is independently 0 or 1.

11. A method for treating a disease or symptoms of the disease in a subject in need of treatment, characterized in that it comprises administering to the subject an effective amount of a compound of the formula H- (I) or a pharmaceutical salt thereof: wherein, Ar 1 is cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of H, halogen, amino, hydroxy, cyano, nitro, carboxylate, alkyl, alkenyl, alkynyl, cycloalkyl, cyclohexyl, alkoxy, mono and di-alkyl amino, phenyl, carboxamide, -haloalkyl, haloalkoxy, and alkanoyl; X is NR3, C (R3) 2, or O; • Y is C = 0 or lower alkyl; R1 is Ar2 or lower alkyl optionally substituted with? R2; Ar2 is independently selected from cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of H, halogen, amino, hydroxy, cyano, nitro, carboxylate, alkyl, alkenyl, alkynyl, cycloalkyl, cyclohexyl, alkoxy, mono and di-alkyl amino, phenyl, carboxamide, haloalkyl, haloalkoxy, and alkanoyl; each R is independently selected from C02R3, COAr3, C0NR3R4, (CH2) mAr3, CH2NR3R4 or CH20R4; each R3 is independently selected from H, or lower alkyl; each R4 is independently selected from H, lower alkyl, C (0) 0R5, C (0) NR5R6, S (0) 2NR5R6, C (0) R7, S (0) 2R7 or (CH2) pAr3; each Ar3 is independently cycloalkyl, aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more substituents; each m is independently 0 or 1; each p is independently 0 or 1; each substituent for Ar3 is independently selected from halogen, CN, N02, OR5, SR5, S (0) 2OR5, NR5R6, cycloalkyl, perfluoroalkyl C? -C2, perfluoroalkoxy C? -C2, 1,2-methylenedioxy, C (0) OR5, C (0) NR5R6, OC (0) NR5R6, NR5C (O) NR5R6, C (NR5) NR5R6, NR5C (NR6) NR5R6, S (0) 2NR5R6, R7, C (0) R7, NR6C (0) R7, S (0) R7, OR S (0) 2R7; each R5 is independently selected from hydrogen or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C 1 -C 4 alkoxy, NH 2, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino or C 3 -C 6 cycloalkyl; each R6 is independently selected from hydrogen, (CH2) qAr4, or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C1-C4 alkoxy, NH2, C alqu-C4 alkylamino, C?-C4 dialkylamino or cycloalkyl C3-C6; each R7 is independently selected from (CH2) qAr4 or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C-C4 alkoxy, NH2 / C? -C alkylamino, C? -C4 dialkylamino or C3-C6 cycloalkyl; each Ar 4 is independently selected from C 3 -C 6 cycloalkyl, aryl or heteroaryl, each optionally substituted with one to three substituents independently selected from halogen, OH, C 1 -C 4 alkoxy, NH 2, alkylamino C -C 4, dialkylamino C 4 -C 4 or 1,2-methylenedioxy; and each q is independently 0 or 1.

12. A compound of the formula J- (I) or a pharmaceutical salt thereof characterized in that Ara is cycloalkyl, aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more substituents; R1 is Ar2 or lower alkyl optionally substituted with Ar2; each? r2 is independently selected from cycloalkyl, aryl, heterocyclyl, or heteroaryl each optionally substituted with one or more substituents; each R2 is independently (CH2) mC02R3, (CH2) mCOAr3, (CH2) mCONR3R4, (CH2) mAr3; or (CH2) nNR3R4; each R3 is independently selected from H, or - _ lower alkyl; each R4 is independently selected from H, lower alkyl, C (0) OR5, C (0) NR5R6, S (0) 2NR5R6, C (0) R7, S (0) 2) R7 or (CH2) pAr3; or each R3 and R4 are taken together with the nitrogen atom to which they are bonded to form a 4-7 membered heterocyclic ring wherein, one carbon atom in each heterocyclic ring is optionally an NR4, O or S and each heterocyclic ring is optionally substituted with one or more lower alkyl groups; each Ar3 is independently cycloalkyl, aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more substituents; each m is independently 0 or 1; each n is independently 1 or 2; each p is independently O or 1; each substituent for Ar3 is independently selected from halogen, CN, N02, OR5, SR5, S (0) 2OR5, NR5R6, cycloalkyl, perfluoroalkyl C? -C2, perfluoroalkoxy C? -C2, 1,2-methylenedioxy, C (0) 0R5, C (0) NR5R6, 0C (0) NR5R6, NR5C (0) NR5R6, C (NR5) NRSR6, NR5C (NR6) NR5R6, S (0) 2NR5R6, R7, C (0) R7, NR6C (0) R7, S (0) R7, or S (0) 2R7; each R5 is independently selected from hydrogen or lower alkenyl optionally substituted with one or more substituents independently selected from halogen, OH, C 1 -C 4 alkoxy, NH, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino or C 3 -C 6 cycloalkyl; each R6 is independently selected from hydrogen, (CH2) pAr4, or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C? -C alkoxy, NH2, C? -C alkylamino, dialkylamino C? -C4 or C3-C6 cycloalkyl, - each R7 is independently selected from (CH) pAr4 or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C? -C4 alkoxy, NH2, C1-C4 alkylamino, dialkylamino C1-C4 or C3-C6 cycloalkyl; and each Ar4 is independently selected from C3-C6 cycloalkyl, aryl or heteroaryl, each optionally substituted with one to three substituents independently selected from halogen, OH, alkoxy C? C4, NH2, C1-C4 alkylamino, dialkylamino C? -C4 or 1,2-methylenedioxy.

13. The compound is of the formula J- (I) according to claim 12 characterized in that, Ar1 is aryl or heteroaryl each optionally substituted with one to three substituents; R1 is Ar2; each Ar2 is independently selected from aryl or heteroaryl each optionally substituted with one to three substituents; R2 is (CH2) nNR3R4 and n is 1 wherein each R4 is independently selected from H, lower alkyl, C (0) OR5, C (0) NR5R6, S (0) 2NR5R6, C (0) R7, S (0 ) 2) R7 or (CH2) pAr3; or each R3 and R4 are taken together with the nitrogen atom to which they are bonded to form a 4-7 membered heterocyclic ring wherein, one carbon atom in each heterocyclic ring is optionally an NR4, O or S and each heterocyclic ring it is optionally substituted with one or two lower alkyl groups; each p is independently 0 or 1; and each Ar3 is independently selected from aryl or heteroaryl, each optionally substituted with one to three substituents.

14. The compound according to any of claims 1-13, characterized in that it is -any of those in Tables A-J herein.

15. A method for inhibiting calcium channel activity, characterized in that it comprises contacting a compound according to any of claims 1 to 14 with the calcium channel.

16. A method for inhibiting calcium channel activity in a subject, characterized in that it comprises administering to the subject an effective amount of a compound according to any of claims 1 to 14.

17. A method for treating a disease mediated by the calcium channel in a subject, characterized in that it comprises administering to the subject an effective amount of a compound according to any of claims 1 to 14.

- - 18. The method according to any of claims 15-17, characterized in that the calcium channel is Cavl.

19. The method according to any of claims 15-17, characterized in that the calcium channel is Cav1.2 or Cav1.3. "

20. The method according to claim 17, characterized in that the disease mediated by the calcium channel Cavl or symptom of the disease is a cognitive function or disease of the nervous system or symptom of the disease.

21. The method according to claim 17, characterized in that the disease mediated by the calcium channel Cavl-2 or Cavl. 3 or symptom of the disease is a cognitive function or disease of the nervous system or symptom of the disease.

22. The method according to claim 17, characterized in that the disease mediated by the calcium channel Cavl or symptom of the disease is a cardiovascular disease or symptoms of the disease.

23. The method according to claim 17, characterized in that the disease mediated by the channel of - Calcium Cav1.2 or Cavl .3 or symptoms of the disease is a cardiovascular disease or symptom of the disease.

24. A method to treat angina, congestive heart failure, or myocardial ischemia mediated by the calcium channel Cavl in a. subject, characterized in that it comprises administering to the subject an effective amount of a compound according to any of claims 1 to 14.

25. The method according to claim 24, characterized in that the calcium channel Cavl is Cav1.2 or Cavl .3.

26. A method for treating urinary incontinence or overactive bladder mediated by the calcium channel Cavl in a subject, characterized in that it comprises administering to a subject an effective amount of a compound according to any of claims 1 to 1.

27. The method according to claim 26, characterized in that the calcium channel Cavl is Cav1.2 or Cav1.3.

28. A method for treating atrial fibrillation in the calcium channel Cavl in a subject, characterized in that it comprises administering to a subject an effective amount of a compound according to any of claims 1 to 14.

29. The method according to claim 28, characterized in that the calcium channel Cavl is Cav1.2 or Cavl .3.

30. A method for treating hypertension mediated by the calcium channel Cavl in a subject, characterized in that it comprises administering to the subject an effective amount of a compound according to any of claims 1 to 14.

31. The method according to claim 30, characterized in that the calcium channel Cavl is Cav1.2 or Cavl .3.

32. A method for making a compound according to any of claims 1-14, characterized in that it comprises reacting an intermediate compound delineated herein with a reagent to provide a compound according to any of claims 1-14 as defined at the moment.

33. A composition, characterized in that it comprises a compound according to any of claims 1-14 and a pharmaceutically acceptable carrier.

34. The composition according to claim 33, further characterized in that it comprises an additional therapeutic agent.

35. A method for treating a disease or symptom of the disease in a subject, characterized in that it comprises administering to the subject in need of such treatment an effective amount of a compound according to any of claims 1-14.

36. The method according to claim 35, characterized in that the disease or symptom of the disease is angina, hypertension, congestive heart failure, myocardial ischemia, atrial fibrillation, diabetes mellitus, urinary incontinence, overactive bladder, pulmonary disease, or cognitive function. Nervous system disorder.