Benzimidazole and pyridylimidazole derivatives

BACKGROUND OF THE INVENTION

[0001] 1. Field of the Invention

[0002] This invention relates to benzimidazole and pyridylimidazole derivatives, and, more specifically, to such derivatives that bind with high selectively and/or high affinity to the benzodiazepine site of GABAA receptors. This invention also relates to pharmaceutical compositions comprising such compounds and to the use of such compounds in the treatment of central nervous system (CNS) diseases.

[0003] 2. Description of the Related Art

[0004] The GABAA receptor superfamily represents one of the classes of receptors through which the major inhibitory neurotransmitter, γ-aminobutyric acid, or GABA, acts. Widely, although unequally, distributed throughout the mammalian brain, GABA mediates many of its actions through a complex of proteins called the GABAA receptor, which causes alteration in chloride conductance and membrane polarization. In addition to being the site of neurotransmitter action, a number of drugs including the anxiolytic and sedating benzodiazepines bind to this receptor. The GABAA receptor comprises a chloride channel that generally, but not invariably, opens in response to GABA, allowing chloride to enter the cell. This, in turn, effects a slowing of neuronal activity through hyperpolarization of the cell membrane potential.

[0005] GABAA receptors are composed of five protein subunits. A number of cDNAs for these GABAA receptor subunits have been cloned and their primary structures determined. While these subunits share a basic motif of 4 membrane-spanning helices, there is sufficient sequence diversity to classify them into several groups. To date at least 6α, 3β, 3γ, 1ε, 1δ and 2ρ subunits have been identified. Native GABAA receptors are typically composed of 2α, 2β, and 1γ. Various lines of evidence (such as message distribution, genome localization and biochemical study results) suggest that the major naturally occurring receptor combinations are α1β2γ2, α2β3γ2, α3β3γ2, and α5β3γ2 (Mohler et al. Neuroch. Res. 1995; 20(5):631-36).

[0006] The GABAA receptor binding sites for GABA (2 per receptor complex) are formed by amino acids from the α and β subunits. Amino acids from the α and γ subunits together form one benzodiazepine site per receptor. Benzodiazepines exert their pharmacological actions by interacting with the benzodiazepine binding sites associated with the GABAA receptor. In addition to the benzodiazepine site (sometimes referred to as the benzodiazepine or BDZ receptor), the GABAA receptor contains sites of interaction for several other classes of drugs. These include a steroid binding site, a picrotoxin site, and a barbiturate site. The benzodiazepine site of the GABAA receptor is a distinct site on the receptor complex that does not overlap with the site of interaction for other classes of drugs that bind to the receptor or for GABA (see, e.g., Cooper, et al., The Biochemical Basis of Neuropharmacology, 6th ed., 1991, pp. 145-148, Oxford University Press, New York).

[0007] In a classic allosteric mechanism, the binding of a drug to the benzodiazepine site increases the affinity of the GABA receptor for GABA. Benzodiazepines and related drugs that enhance the ability of GABA to open GABAA receptor channels are known as agonists or partial agonists depending on the level of GABA enhancement. Other classes of drugs, such as β-carboline derivatives, that occupy the same site and negatively modulate the action of GABA are called inverse agonists. A third class of compounds exists which occupy the same site as both the agonists and inverse agonists and yet have little or no effect on GABA activity. These compounds will, however, block the action of agonists or inverse agonists and are thus referred to as GABAA receptor antagonists.

[0008] The important allosteric modulatory effects of drugs acting at the benzodiazepine site were recognized early, and the distribution of activities at different subtype receptors has been an area of intense pharmacological discovery. Agonists that act at the benzodiazepine site are known to exhibit anxiolytic, sedative, and hypnotic effects, while compounds that act as inverse agonists at this site elicit anxiogenic, cognition enhancing, and proconvulsant effects. While benzodiazepines have enjoyed long pharmaceutical use as anxiolytics, these compounds are known to exhibit a number of unwanted side effects. These may include cognitive impairment, sedation, ataxia, potentiation of ethanol effects, and a tendency for tolerance and drug dependence.

[0009] GABAA selective ligands may also act to potentiate the effects of certain other CNS active compounds. For example, there is evidence that selective serotonin reuptake inhibitors (SSRIs) may show greater antidepressant activity when used in combination with GABAA selective ligands than when used alone.

SUMMARY OF THE INVENTION

[0010] This invention provides benzimidazole and pyridylimidazole derivatives that bind to the benzodiazepine site of GABAA receptors, including human GABAA receptors. Preferred compounds of the invention bind with high selectivity and/or high affinity to GABAA receptors. Preferred compounds act as agonists, antagonists or inverse agonists of such receptors. As such, they are useful in the treatment of various CNS disorders.

[0011] The invention provides compounds of Formula I (shown below), and pharmaceutical compositions comprising compounds of Formula I.

[0012] The invention provides methods for synthesizing compounds of Formula I.

[0013] The invention further provides methods of treating patients suffering from certain CNS disorders with an effective amount of a compound of the invention. The patient may be a human or other mammal. Treatment of humans, domesticated companion animals (pets) or livestock animals suffering from certain CNS disorders with an effective amount of a compound of the invention is encompassed by the invention.

[0014] In a separate aspect, the invention provides methods of potentiating the actions of other CNS active compounds. These methods comprise administering an effective amount of a compound of the invention in conjunction with the administration of another CNS active compound.

[0015] Additionally this invention relates to the use of compounds of Formula I as probes for the localization of GABAA receptors in tissue sections.

[0016] In a first aspect, the invention provides compounds of Formula I

[0017] and the pharmaceutically acceptable salts thereof.

[0018] In this aspect, Z1 is nitrogen or CR1; Z2 is nitrogen or CR2; Z3 is nitrogen or CR3; and Z4 is nitrogen or CR4; provided that no more than two of Z1 Z2, Z3, and Z4 are nitrogen. Further in Formula I,

[0019] R1, R2, R3, and R4 are independently selected from

[0020] i) hydrogen, halogen, hydroxy, nitro, cyano, amino, haloalkyl, and haloalkoxy,

[0021] ii) alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl, (cycloalkyl)alkyl, —NH(R10), —N(R10)(R11) hydroxyalkyl, aminoalkyl, (R10)NHalkyl-, (R10)(R11)Nalkyl-, alkanoyl, alkoxycarbonyl, (heterocycloalkyl)alkyl, alkylsulfonyl, alkylthio, mono- or dialkylaminocarbonyl, heterocycloalkyl, aryl, and heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 of R20, wherein R10 and R11 are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, (cycloalkyl)alkyl, aryl, arylalkyl, alkanoyl, and mono and dialkylaminoalkyl; and

[0022] iii) a group of the formula:

[0023] where G is a bond, alkyl, —O—, —C(═O)—, or —CH2C(═O)—, and RA is a saturated, partially unsaturated, or aromatic carbocycle, consisting of 1 ring or 2 fused, pendant, or spiro rings, each ring containing 0, 1, or 2 heteroatoms independently chosen from N, S, and O, said saturated, partially unsaturated, or aromatic carbocycle is optionally substituted with 1, 2, 3, or 4 of R20,

[0024] iv) a group of the formula

[0025] where J is N, CH, or C-alkyl, and RB and RC are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, aryl, arylalkyl, alkanoyl, heteroaryl, and mono and dialkylaminoalkyl, each of which is optionally substituted by 1 or 2 substituents independently chosen from halogen, hydroxy, cyano, amino, nitro, alkoxy, and alkyl; RB and RC and the atom to which they are attached form a 4- to 10-membered monocyclic or bicyclic ring, which may contain:

[0026] a) one or more double bonds,

[0027] b) one or more of oxo, O, S, SO, SO2, or N—RD wherein RD is hydrogen, Ar1, alkyl, cycloalkyl, heterocycloalkyl, or Ar1alkyl; wherein Ar1 is aryl or heteroaryl, each of which is optionally substituted by 1 or 2 substituents independently chosen from halogen, hydroxy, cyano, amino, nitro, alkoxy, and alkyl,

[0028] c) one or more substituents R20;

[0029] v) —OC(═O)RE, —C(═O)ORE, —C(═O)NH2, —C(═O)NHRE, —C(═O)NRERF, —S(O)nRE, —S(O)nNH2, —S(O)nNHRE, —S(O)nNRERF, —NHC(═O)RE, —C(═NRE)RF, —HC═N—OH, —HC═N(alkoxy), —HC═N(alkyl), —NREC(═O)RF, —NHS(O)mRE, and —NRES(O)mRF, where m is 0, 1 or 2, and RE and RF are independently selected at each occurrence from alkyl, cycloalkyl, heterocycloalkyl, alkoxy, mono- or dialkylamino, aryl, or heteroaryl each of which is optionally substituted by 1, 2, or 3 of R30,

[0030] R20, in this aspect of the invention, is independently selected at each occurrence from the group consisting of: halogen; hydroxy; nitro; cyano; amino; alkyl; alkoxy optionally substituted with amino or mono- or dialkylamino; cycloalkyl; cycloalkylalkyl; cycloalkylalkoxy; alkenyl; alkynyl; haloalkyl; oxo; haloalkoxy; mono- and dialkylamino; aminoalkyl; and mono- and dialkylaminoalkyl.

[0031] R30 is independently selected at each occurrence from halogen, hydroxy, nitro, cyano, amino, alkyl, alkoxy optionally substituted with amino or mono- or dialkylamino, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, heterocycloalkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, oxo, mono- and dialkylamino, aminoalkyl, and mono- and dialkylaminoalkyl.

[0032] R5 represents hydrogen or haloalkyl; or

[0033] R5 represents alkyl, cycloalkyl, or (cycloalkyl)alkyl, each of which may contain one or more double or triple bonds, and each of which is optionally substituted with 1, 2, or 3 of R30, or R5 represents aryl, arylalkyl, heteroaryl, or heteroarylalkyl each of which is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of haloalkyl, amino, —NH(R10), —N(R10) (R11), carboxamido, (R10)NHcarbonyl, (R10) (R11)Ncarbonyl, halogen, hydroxy, nitro, cyano, amino, alkyl, alkoxy optionally substituted with amino or mono- or dialkylamino, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, heterocycloalkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, aminoalkyl, and mono- and dialkylaminoalkyl.

[0034] Q represents —C(R6) (R7) or oxygen, with the proviso that Q is not oxygen when X2 is nitrogen.

[0035] R6 and R7 independently represent hydrogen, fluorine, or alkyl.

[0036] The group:

[0037] represents a 5 to 7 membered heteroaryl or heterocycloalkyl ring containing up to 4 heteroatoms selected from nitrogen, sulfur, and oxygen, said 5 to 7 membered heteroaryl or heterocycloalkyl ring is substituted at each carbon atom by R, and substituted at each nitrogen atom available for substitution by R′.

[0038] R is independently chosen at each occurrence from hydrogen, halogen, amino, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, (cycloalkyl)alkyl, haloalkyl, haloalkoxy, carboxamido, and 3- to 7-membered carbocyclic or heterocyclic groups which are saturated, unsaturated, or aromatic, which may be further substituted with one or more substituents independently selected from halogen, oxo, hydroxy, alkyl, and alkoxy.

[0039] R′ is independently chosen at each occurrence from alkyl, hydrogen, cycloalkyl, cycloalkyl(alkyl), and 3- to 7-membered carbocyclic or heterocyclic groups which are saturated, unsaturated, or aromatic, which 3- to 7-membered carbocyclic or heterocyclic groups are optionally substituted with one or more substituents independently selected from halogen, oxo, hydroxy, alkyl, and alkoxy.

[0040] X1 and X2 independently represent nitrogen, carbon or CH.

[0041] Y is nitrogen, oxygen, carbon, —CH—, —CH2—, or absent.

[0042] W represents aryl or heteroaryl, wherein the aryl or heteroaryl group is optionally substituted with up to 4 groups independently selected from R30, —CO2H, —C(═O)ORE, —C(═O)NHRE, —C(═O)NRERF, —C(O)RE, and —S(O)mRE, —ORE, where R30 and RE are as defined above and m is 0, 1, or 2.

DETAILED DESCRIPTION

[0043] In addition to the compounds and salts of Formula I, described above, the invention further provides compounds of Formula I wherein

[0044] R1, R2, R3, and R4 are independently selected from

[0045] i) hydrogen, halogen, hydroxy, nitro, cyano, amino, halo(C1-C6) alkyl, and halo(C1-C6)alkoxy,

[0046] ii) (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl, (C2-C6)alkenyl, alkynyl, ((C3-C8)cycloalkyl) (C1-C4)alkyl, —NH(R10), —N(R10)(R11), hydroxy(C1-C6)alkyl, amino(C1-C6)alkyl, (R10)NH(C1-C6)alkyl, (R10) (R11)N(C1-C6)alkyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylsulfonyl, (C1-C6)alkylthio, mono- or di(C1-C6)alkylaminocarbonyl, heterocycloalkyl, (heterocycloalkyl) C1-C4alkyl, aryl, and heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 of R20, wherein R10 and R11 are independently selected from the group consisting of (C1-C6)alkyl, (C2-C6)alkenyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl, (C3-C8) cycloalkylalkyl, aryl, aryl(C1-C6)alkyl, (C1-C6)alkanoyl, and mono and di (C1-C6) alkylaminoalkyl;

[0047] iii) a group of the formula:

[0048] where G is (C1-C6)alkyl, —O—, —C(═O)—, or —CH2C(═O)—, and

[0049] RA is a saturated, partially unsaturated, or aromatic carbocycle, consisting of 1 ring or 2 fused, pendant, or spiro rings, each ring consisting of from 3 to 8 ring atoms, and each ring containing 0, 1, or 2 heteroatoms independently chosen from N, S, and O; said saturated, partially unsaturated, or aromatic carbocycle is optionally substituted with 1, 2, 3, or 4 of R20,

[0050] iv) a group of the formula

[0051] where J is N, CH, or C—(C1-C6)alkyl and RB and RC are independently selected from the group consisting of hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-CG)alkoxy, (C3-C8) cycloalkyl, (C3-C8cycloalkyl) (C1-C4)alkyl, heterocycloalkyl, aryl, aryl(C1-C4)alkyl, (C1-C6) alkanoyl, heteroaryl, and mono and di(C1-C6)alkylamino(C1-C6)alkyl, each of which is optionally substituted by 1 or 2 substituents independently chosen from halogen, hydroxy, cyano, amino, nitro, C1-C6alkoxy, and C1-C6alkyl; or RB and RC and the atom to which they are attached form a 4- to 10-membered monocyclic or bicyclic ring, which may contain

[0052] a) one or more double bonds

[0053] b) one or more of oxo, O, S, SO, SO2, and N—RD wherein RD is hydrogen, Ar1, (C1-C6) alkyl, (C3-C8) cycloalkyl, heterocycloalkyl, or Ar1(C1-C6)alkyl; wherein Ar1 is aryl or heteroaryl, each of which is optionally substituted by 1 or 2 substituents independently chosen from halogen, hydroxy, cyano, amino, nitro, C1-C6alkoxy, and C1-C6alkyl;

[0054] c) one or more substituents R20;

[0055] v) —OC(═O)RE, —C(═O)ORE, —C(═O)NH2, —C(═O)NHRE, —C(═O)NRERF, —S(O)nRE, —S(O)nNH2, —S(O)nNHRE, —S(O)NHRERF, —NHC(═O)RE, —C(═NRE)RF, —HC═N—OH, —HC═N(C1-C6alkoxy), —HC═N(C1-C6alkyl), —NREC(═O)RF, —NHS(O)mRE, and —NRES(O)mRF, where m is 0, 1 or 2, and RE and RF are independently selected at each occurrence from (C1-C6)alkyl, (C3-C8)cycloalkyl, heterocycloalkyl, (C1-C6)alkoxy, mono- and di(C1-C6)alkylamino, aryl, and heteroaryl each of which is optionally substituted by 1, 2, or 3 of R30.

[0056] R20 is independently selected at each occurrence from the group consisting of halogen; hydroxy; nitro; cyano; amino; (C1-C6)alkyl; (C1-C6)alkoxy optionally substituted with amino or mono- or di(C1-C6)alkylamino; (C3-C8)cycloalkyl; (C3-C8)cycloalkyl(C1-C4) alkyl; (C3-C8)cycloalkyl (C1-C4) alkoxy; (C2-C6) alkenyl; (C2-C6)alkynyl; halo(C1-C6)alkyl; halo(C1-C6)alkoxy; oxo; mono- and di(C1-C6)alkylamino; amino(C1-C6)alkyl; and mono- and di(C1-C6) alkylamino (C1-C6) alkyl.

[0057] R30 is independently selected at each occurrence from halogen, hydroxy, nitro, cyano, amino, (C1-C6)alkyl, (C1-C6)alkoxy optionally substituted with amino or mono- or di(C1-C6)alkylamino, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C4)alkyl, (C3-C8)cycloalkyl(C1-C4)alkoxy, heterocycloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, oxo, mono- and di(C1-C6)alkylamino, amino(C1-C6)alkyl, and mono- and di(C1-C6) alkylamino (C1-C6) alkyl.

[0058] R5 represents hydrogen or halo (C1-C6) alkyl; or

[0059] R5 represents (C1-C6)alkyl, (C3-C8)cycloalkyl, or (C3-C8cycloalkyl) (C1-C4)alkyl, each of which may contain one or more double or triple bonds, and each of which is optionally substituted with 1, 2, or 3 of R30, or

[0060] R5 represents aryl, aryl(C1-C4)alkyl, heteroaryl, or heteroaryl(C1-C4)alkyl each of which is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of: halo (C1-C6) alkyl, amino, NH(R10), N(R10) (R11), carboxamido, NH(R10) carbonyl, N(R10) (R11) carbonyl, halogen, hydroxy, nitro, cyano, amino, (C1-C6)alkyl, (C1-C6)alkoxy optionally substituted with amino or mono- or di(C1-C6)alkylamino, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C4)alkyl, (C3-C8)cycloalkyl(C1-C4)alkoxy, heterocyclo(C1-C4)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, halo(C1-C6) alkyl, halo (C1-C6) alkoxy, amino (C1-C6) alkyl, and mono- and di (C1-C6) alkylamino (C1-C6) alkyl;

[0061] Q represents —C(R6) (R7) or oxygen, with the proviso that Q is not oxygen when X2 is nitrogen;

[0062] R6 and R7 independently represent hydrogen, fluorine, or C1-C6alkyl; and

[0063] the group:

[0064] represents a 5 to 7 membered heteroaryl or heterocycloalkyl ring containing up to 4 heteroatoms selected from nitrogen, sulfur, and oxygen, said 5 to 7 membered heteroaryl or heterocycloalkyl ring is substituted at each carbon atom by R, and is substituted at each nitrogen atom available for substitution by R′;

[0065] R is independently chosen at each occurrence from hydrogen, halogen, amino, C1-C6alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, C1-C6alkoxy, (C3-C8)cycloalkyl, (C3-C8cycloalkyl) (C1-C4)alkyl, halo(C1-C6)alkyl, haloalkoxy, carboxamido, and 3- to 7-membered carbocyclic or heterocyclic groups which are saturated, unsaturated, or aromatic, which may be further substituted with one or more substituents independently selected from halogen, oxo, hydroxy, C1-4alkyl, and —O(C1-4alkyl);

[0066] R′ is independently chosen at each occurrence from hydrogen, C1-C6alkyl, C3-C8cycloalkyl, C3-C8cycloalkyl(C1-C4alkyl), and 3- to 7-membered carbocyclic or heterocyclic groups which are saturated, unsaturated, or aromatic, which 3- to 7-membered carbocyclic or heterocyclic groups are optionally substituted with one or more substituents independently selected from halogen, oxo, hydroxy, C1-4alkyl, and —O(C1-4alkyl); and

[0067] X1, X2, W, and Y are as defined for Formula I, above.

[0068] Such compounds will be referred to as compounds of Formula IA.

[0069] A particular aspect of the invention is directed to compounds and pharmaceutically acceptable salts of Formula II

[0070] In Formula II, the variables Z1, Z2, Z3, Z4, R5, Q, X1, X2, and W carry the definition set forth for Formula I, or more preferably, for Formula IA;

[0071] X3 and X4 are independently selected from the group consisting of carbon, CR, N, O, S, NH, and N(C1-C6)alkyl; provided that at least one of X1, X2, X3, and X4 is carbon or CR; and

[0072] R is independently chosen at each occurrence from hydrogen, halogen, amino, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, carboxamido, and 3- to 7-membered carbocyclic or heterocyclic groups which are saturated, unsaturated, or aromatic, which may be further substituted with one or more substituents independently selected from halogen, oxo, hydroxy, C1-4alkyl, and —O(C1-4alkyl).

[0073] The invention is particularly directed to compounds of Formula I, Formula IA, and Formula II, in which Z1 is CR1, Z2 is CR2, Z3 is CR3, and Z4 is CR4.

[0074] The invention is also directed to compounds of Formula I, Formula IA, and Formula II, in which one, and only one, of Z1, Z2, Z3, and Z4 is nitrogen.

[0075] Another particular aspect of the invention provides compounds of Formula I, Formula IA, and Formula II, in which Z, is CR1, Z4 is CR4, and only one, of Z2 and Z3 is nitrogen.

[0076] The invention is further directed to compounds of Formula I, Formula IA, and Formula II wherein:

[0077] i) X2 is carbon; and Q is oxygen;

[0078] ii) X2 is N; and Q is C(R6) (R7);

[0079] iii) X2 is carbon; and Q is C(R6) (R7);

[0080] iv) X1 is carbon; X2 is N; and Q is C(R6) (R7)

[0081] v) X1 is nitrogen; X2 is carbon; and Q is C(R6) (R7); or wherein

[0082] vi) Q is C(R6) (R7)

[0083] For each of i) through vi) preferred compounds are those where Z1 is CR1, Z2 is CR2, Z3 is CR3, and Z4 is CR4. For each of i) through vi) preferred compounds are those in which one, and only one, of Z1, Z2, Z3, and Z4 is nitrogen. For each of i) through vi)compounds in which Z1 is CR1, and only one, of Z2 and Z3 is nitrogen are particularly preferred.

[0084] In another aspect, the invention provides compounds of Formula III and Formula IV:

[0085] wherein R, R1, R2, R3, R4, R5, Q, and W carry the definitions set forth for Formula I, or more preferably for Formula IA.

[0086] Particular compounds of Formula III included in the invention are those wherein Q is C(R6) (R7).

[0087] Preferred compounds of Formula IV include those where R6 and R7 are hydrogen, methyl or fluoro and the other is ethyl, or where one of R6 and R7 is hydrogen, methyl or fluoro and the other is ethyl.

[0088] Other compounds of the invention include compounds of Formula III or Formula IV, wherein R is independently selected at each occurrence from the group consisting of:

[0089] i) hydrogen, halogen, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, and

[0090] ii) phenyl and pyridyl each of which is optionally substituted with up to 3 substituents independently chosen from halogen, hydroxy, C1-4alkyl, and —O(C1-4alkyl). Q (in Formula III) is C(R6) (R7)

[0091] In Formula III and IV, R1, R2, R3, and R4 are independently selected from hydrogen, halogen, hydroxy, nitro, cyano, amino, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, heterocycloalkyl, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, mono or di(C1-C6)alkylamino, amino(C1-C6)alkyl, and mono- and di(C1-C6) alkylamino (C1-C6) alkyl;

[0092] R5 represents hydrogen, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C3-C8) cycloalkyl (C1-C6) alkyl, phenyl, benzyl, thiophenyl, thiazoyl, pyridyl, imidazolyl, pyrazolyl, or pyrimidinyl;

[0093] R6 and R7 independently represent hydrogen, fluorine, or C1-C6 alkyl; and

[0094] W represents phenyl, thienyl, thiazoyl, pyridyl, imidazolyl, oxazolyl, triazolyl, tetrazolyl, pyrazolyl, isoxazolyl, or pyrimidinyl, each of which is optionally substituted with up to 4 R30 groups, where R30 carries the definition set forth for Formula I, or more preferably R30 carries the definition set forth for Formula IA.

[0095] Particularly included in the invention are compounds of Forumula III and Formula IV in which wherein R, R1, R2, R3, R4, R5, Q, and W carry the definition set forth for Formula I, or more preferably for Formula IA, and

[0096] W represents a 6-membered aryl or heteroaryl groups, wherein the 6-membered aryl or heteroaryl group is optionally substituted with up to 4 groups independently selected from R30, —CO2H, —C(═O)ORE, —C(═O)NHRE, —C(═O)NRERF, —C(O)RE, —S(O)nRE, and —ORE or wherein

[0097] W represents a 5-membered heteroaryl group, wherein the 5-membered heteroaryl group is optionally substituted with up to 4 groups independently selected from R30, —CO2H, —C(═O)ORE, —C(═O)NHRE, —C(═O)NRERF, —C(O)RE, —S(O)mRE, and —ORE.

[0098] In these embodiments of the invention m is 0, 1, or 2, and RE carries the definition set forth for Formula I, or more preferably RE carries the definition set forth for Formula IA and R30 carries the definition set forth above with respect to Formula IA.

[0099] In another aspect, the compounds of Formula III or Formula IV are those in which one of R2 or R3 carries the definition set forth for Formula I, or more preferably for Formula IA.

[0100] In this aspect of the invention,

[0101] R is independently selected at each occurrence from the group consisting of hydrogen, halogen, and (C1-C2)alkyl;

[0102] R1, R4, and the other of R2 and R3 are independently selected from hydrogen, halogen, hydroxy, nitro, cyano, amino, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, mono or di(C1-C6)alkylamino, amino(C1-C6)alkyl, and mono- and di (C1-C6) alkylamino (C1-C6) alkyl;

[0103] R5 represents (C1-C6)alkyl; and

[0104] Q (in Formula III) is CH2, and R6 and R7 in Formula IV are hydrogen; and

[0105] W represents phenyl, furanyl, thienyl, thiazoyl, pyridyl, imidazolyl, oxazolyl, triazolyl, tetrazolyl, pyrazolyl, isoxazolyl, pyrimidinyl, benzimidazolyl, quinolinyl, isoquinolinyl each of which is optionally substituted with up to 4 R30 groups, where R30 carries the definition set forth for Formula I, or more preferably R30 carries the definition set forth for Formula IA.

[0106] Still other preferred W groups are 4-pyrimidinyl, 5-halo-2-pyrimidinyl, 3,6-dihalopyrimidin-2-yl, and 2,6-, 4,6-, and 5,6-dihalopyridin-2-yl. Other preferred W groups are phenyl substituted with one or two independently selected C1-C2 alkyl, C1-C2 alkoxy, amino, halogen, trifluoromethyl, or cyano groups. Still other preferred W groups are 2-thiazolyl groups carrying one or two independently selected C1-C2 alkyl, amino, (C1-C3) alkyl, hydroxy, (C1-C3)alkyl, or trifluoromethyl groups.

[0107] Another aspect of the invention includes compounds of Formula III or Formula IV wherein

[0108] R is independently selected at each occurrence from the group consisting of hydrogen, halogen, and (C1-C2)alkyl;

[0109] R1, R4, and one of R2 and R3 are independently selected from hydrogen, halogen, trifluoromethyl, C1-C2 alkyl, and cyano;

[0110] the other of R2 and R3 carries the definition set forth for Formula I, or more preferably for Formula IA; and

[0111] R5 represents (C1-C6)alkyl, and preferably C2-C4 alkyl. Preferably R1 and R4 are hydrogen;

[0112] Preferred R groups are independently selected from hydrogen and C1-C3 alkyl, more preferably hydrogen and methyl, and most preferably are hydrogen.

[0113] More preferred R5 groups are ethyl and n-propyl.

[0114] In this aspect,

[0115] Q (in Formula III) is CH2, and R6 and R7 in Formula IV are hydrogen; and

[0116] W, is phenyl, pyridyl, or thiazolyl, each which is optionally substituted by one or more substituents independently chosen from halogen, cyano, hydroxy, oxo, C1-C2haloalkyl, C1-C2alkyl, and C1-C2 alkoxy, or more preferably

[0117] W is 2-thiazolyl, 2-pyrimidinyl, 3-fluorophenyl, or 6-fluoro-2-pyridinyl. Such compounds will be referred to as compounds of Formula III-A and Formula IV-A.

[0118] A particular aspect of the invention provides compounds of Formula III-A and Formula IV-A, wherein:

[0119] one of R2 and R3 is chosen from hydrogen, halogen, hydroxy, nitro, cyano, amino, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, mono or di(C1-C6)alkylamino, amino(C1-C6)alkyl, and mono- and di (C1-C6)alkylamino(C1-C6)alkyl;

[0120] the other of R2 and R3 is chosen from

[0121] i) hydrogen, halogen, hydroxy, nitro, cyano, amino, halo(C1-C6)alkyl, and halo(C1-C6)alkoxy, and

[0122] ii) C1-C6alkyl, C1-C6alkoxy, C3-C8cycloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C8cycloalkyl)C1-C4alkyl, —NH(R10), —N(R10) (R11) (R10)NH(C1-C6)alkyl, (R10) (R11)N(C1-C6)alkyl, (heterocycloalkyl)alkyl, and heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 of R20; and

[0123] R20carries the definition set forth for Formula I, or more preferably R20 carries the definition set forth with respect to Formula IA.

[0124] In this aspect, preferred compounds of Formula III-A and IV-A include those where one of R2 and R3 is hydrogen, halogen, hydroxy, nitro, cyano, amino, C1-C3 alkyl, C1-C2 alkoxy, cyclopropyl, cyclopropylmethyl, trifluromethyl, or mono- or di(C1-C2)alkylamino, and the other is hydrogen, halogen, or C1-C3 alkyl, preferably hydrogen or methyl. More preferred compounds of Formula IV-A include those where R2 is hydrogen, halogen, more preferably fluoro or chloro, cyano, amino, C1-C2 alkyl or C1-C2 alkoxy and R3 is hydrogen or methyl. Other more preferred compounds of Formula IV-A include those where R2 is hydrogen, methyl, or ethyl, and R3 is hydrogen, halogen, preferably fluoro or chloro, cyano, amino, or C1-C3 alkoxy.

[0125] Another aspect of the invention provides compounds of Formula III-A and Formula IV-A, wherein:

[0126] one of R2 and R3 is chosen from hydrogen, halogen, hydroxy, nitro, cyano, amino, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, mono or di(C1-C6)alkylamino, amino(C1-C6)alkyl, and mono- and di (C1-C6)alkylamino(C1-C6)alkyl;

[0127] the other of R2 and R3 is chosen from

[0128] where J is N, CH, or C-(C1-C6)alkyl and

[0129] RB and RC are independently selected from the group consisting of hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, C3-C8)cycloalkyl, and (C3-C8cycloalkyl) (C1-C4)alkyl; or

[0130] RB and RC and the atom to which they are attached form a 4-to 10-membered monocyclic or bicyclic ring, which may contain

[0131] a) one or more double bonds,

[0132] b) one or more of oxo, O, S, SO, SO2, and N—RD wherein RD is hydrogen or (C1-C6)alkyl;

[0133] c) one or more of R20; and

[0134] R20 carries the definition set forth with respect to Formula I, or more preferably R20 carries the definition set forth for R20 Formula IA.

[0135] The invention also provides compounds of Formula III-A and Formula IV-A, wherein:

[0136] one of R2 and R3 is chosen from hydrogen, halogen, hydroxy, nitro, cyano, amino, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, mono or di(C1-C6)alkylamino, amino(C1-C6)alkyl, and mono- and di(C1-C6)alkylamino(C1-C6)alkyl;

[0137] the other of R2 and R3 is a group of the formula:

[0138] where G is a bond or C1-C2alkyl;

[0139] RA is a saturated, partially unsaturated, or aromatic carbocycle, consisting of 1 ring or 2 fused, pendant, or spiro rings, each ring containing 0, 1, or 2 heteroatoms independently chosen from N, S, and O, said saturated, partially unsaturated, or aromatic carbocycle is optionally substituted with 1, 2, 3, or 4 of R20; and

[0140] R20 carries the definition set forth for Ra in Formula I, or more preferably R20 carries the definition set forth for R20 in Formula IA R20.

[0141] Preferably RA is chosen from phenyl, pyrrolyl, pyrazolyl, thiazolyl, isoxazolyl, triazolyl, tetrazolyl, oxadiazolyl, and oxazolyl each of which is optionally substituted with 1, 2, 3, or 4 of R20.

[0142] Other compounds of the invention are compounds of Formula III-A and Formula IV-A, wherein:

[0143] one of R2 and R3 is chosen from hydrogen, halogen, hydroxy, nitro, cyano, amino, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl (C1-C6)alkyl, halo (C1-C6) alkyl, halo (C1-C6) alkoxy, mono or di (C1-C6)alkylamino, amino (C1-C6) alkyl, and mono- and di(C1-C6)alkylamino(C1-C6)alkyl; and

[0144] the other of R2 and R3 is —HC═N—OH or —HC═N(C1-C6alkoxy).

[0145] Another aspect of the invention is directed to compounds of Formula I, Formula IA and Formula II wherein

[0146] one and only one of Z, is CR1, Z4 is CR4, either Z2 or Z3 is nitrogen; and

[0147] i) W represents a 5-membered heteroaryl group, and the 5-membered heteroaryl group is optionally substituted with up to 4 groups independently selected from R30, —CO2H, —C(═O)ORE, —C(═O)NHRE, —C(═O)NRERF, —C(O)RE, and —S(O)mRE, —ORE; or

[0148] ii) W represents a 6-membered aryl or heteroaryl group, wherein the 6-membered aryl or heteroaryl group is optionally substituted with up to 4 groups independently selected from R30, —CO2H, —C(═O)ORE, —C(═O)NHRE, —C(═O)NRERF, —C(O)RE, and —S(O)mRE, —ORE; where

[0149] R30 and RE carry the definitions set forth for those groups in Formula I, or preferably for Formula IA, and m is 0, 1, or 2.

[0150] Thus, the invention includes compounds represented by Formula V and Formula VI

[0151] wherein R, R1, R2, R3, R4, R5, and Q carry the definitions set forth for Formula I, or more preferably for Formula IA, and W is a 5-membered heteroaryl group as described above.

[0152] The invention further includes compounds of Formula V and Formula VI wherein

[0153] R is independently selected at each occurrence from the group consisting of

[0154] i) hydrogen, halogen, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, and

[0155] ii) phenyl and pyridyl each of which is optionally substituted with up to 3 substituents independently chosen from halogen, hydroxy, C1-4alkyl, and —O(C1-4alkyl);

[0156] R1, R2, R3, and R4, are independently selected from hydrogen, halogen, hydroxy, nitro, cyano, amino, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, heterocycloalkyl, halo(C1-C6)alkyl, halo (C1-C6) alkoxy, mono or di (C1-C6)alkylamino, amino (C1-C6) alkyl, and mono- and di (C1-C6) alkylamino (C1-C6) alkyl;

[0157] R5 represents hydrogen, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C3-C8) cycloalkyl (C1-C6) alkyl, phenyl, benzyl, thiophenyl, thiazoyl, pyridyl, imidazolyl, pyrazolyl, or pyrimidinyl;

[0158] R6 and R7 independently represent hydrogen, fluorine, or C1-C6 alkyl;

[0159] W represents either a 5-membered heteroaryl group chosen from thienyl, thiazolyl, imidazolyl, oxazolyl, triazolyl, tetrazolyl, pyrazolyl, or isoxazolyl each of which is optionally substituted with up to 4 R30 groups; or

[0160] W represents a 6-membered aryl or heteroaryl group chosen from phenyl, pyrimidinyl, pyridyl, pyridizinyl, or pyrazinyl, each of which is optionally substituted with up to 4 R30 groups; and

[0161] R30 is as defined for Formula I, or preferably as defined for Formula IA.

[0162] Preferred compounds of Formula V an VI include those where R2 and R3 independently represent hydrogen, halogen, preferably fluoro or chloro, C1-C3 alkyl, cyclopropyl, cyclopropylmethyl, C1-C3 alkoxy, trifluoromethyl, nitro, cyano, amino, or mono-or di(C1-C3) alkylamino. Other preferred R2 and R3 groups are mono- or di(C1-C3)alkylamino(C2-C3)alkoxy, morpholinyl(C2-C3)alkoxy, piperidin-1-yl(C2-C3)alkoxy, and piperazin-1-yl(C2-C3)alkoxy.

[0163] In another aspect, the invention is directed to compounds of Formula V and Formula VI wherein:

[0164] R is independently selected at each occurrence from the group consisting of hydrogen, halogen, and (C1-C2) alkyl; and

[0165] R1 and R4 are independently selected from hydrogen, halogen, hydroxy, nitro, cyano, amino, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, halo(C1-C6)alkyl, halo (C1-C6) alkoxy, mono or di (C1-C6)alkylamino, amino (C1-C6) alkyl, and mono- and di (C1-C6)alkylamino(C1-C6)alkyl.

[0166] In this aspect of the invention, R2 (Formula V) and R3 (Formula VI) carry the definitions set forth with respect to Formula I, or more preferably for Formula IA;

[0167] R5 represents (C1-C6)alkyl, preferably ethyl or n-propyl;

[0168] R6 and R7 are hydrogen;

[0169] W represents a 5-membered heteroaryl group chosen from furanyl, thienyl, thiazoyl, imidazolyl, oxazolyl, triazolyl, tetrazolyl, pyrazolyl, or isoxazolyl, each of which is optionally substituted with up to 4 R30 groups, or

[0170] W represents a 6-membered aryl or heteroaryl group chosen from phenyl, pyrimidinyl, pyridyl, pyridizinyl, or pyrazinyl each of which is optionally substituted with up to 4 R30 groups; and

[0171] R30 is as defined for Formula I, or more preferably for Formula IA.

[0172] Compounds of this aspect of the invention will be referred to as compounds of Formula V-A and Formula VI-A.

[0173] Preferred R groups are hydrogen and C1-C3 alkyl, more preferably hydrogen and methyl, and most preferably hydrogen.

[0174] Preferred R1 and R4 groups for this aspect of the invention include hydrogen, halogen, trifluoromethyl, C1-C2 alkyl, and cyano. Preferably R1 and R4 are hydrogen. More preferably R, R1, and R4 are all hydrogen.

[0175] Preferred compounds of this aspect of the invention in which W is a 5-membered heteroaryl group include those wherein W is thiazolyl which is optionally substituted by one or more substituents independently chosen from halogen, cyano, hydroxy, oxo, C1-C2haloalkyl, C1-C2alkyl, and C1-C2 alkoxy. Other preferred compounds are those wherein W is 2-thiazolyl.

[0176] Preferred compounds of this aspect in which W is a 6-membered heteroaryl group include those wherein W is phenyl or pyridyl, each of which is optionally substituted by one or more substituents independently chosen from halogen, cyano, hydroxy, oxo, C1-C2haloalkyl, C1-C2alkyl, and C1-C2 alkoxy. Also preferred are compounds wherein W is 2-pyrimidinyl, 3-fluorophenyl, or 6-fluoro-2-pyridinyl.

[0177] Still other preferred W groups are 4-pyrimidinyl, 5-halo-2-pyrimidinyl, 3,6-dihalopyrimidin-2-yl, and 2,6-, 4,6-, and 5,6-dihalopyridin-2-yl. Other preferred W groups are phenyl substituted with one or two independently selected C1-C2 alkyl, C1-C2 alkoxy, amino, halogen, trifluoromethyl, or cyano groups. Still other preferred W groups are 2-thiazolyl groups carrying one or two independently selected C1-C2 alkyl, amino, (C1-C3) alkyl, hydroxy, (C1-C3)alkyl, or trifluoromethyl groups.

[0178] Other aspects of the invention include compounds of Formula V-A and Formula VI-A wherein

[0179] R2 (for Formula V-A) or R3 (for Formula VI-A) is chosen from

[0180] i) hydrogen, halogen, hydroxy, nitro, cyano, amino, halo(C1-C6)alkyl, and halo(C1-C6)alkoxy,

[0181] ii) C1-C6alkyl, C1-C6alkoxy, C3-C8cycloalkyl, C2-C6alkenyl, C1-C6alkynyl, (C3-C8cycloalkyl)C1-C4alkyl, —NH(R10), —N(R10)(R11), (R10NH(C1-C6)alkyl, (R10) (R11)N(C1-C6)alkyl, (heterocycloalkyl) C1-C4alkyl, and heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 of R20, where R20 carries the definition set forth for compounds of Formula I, or preferably for compounds of Formula IA.

[0182] Another aspect of the invention is directed to compounds of Formula V-A and Formula VI-A wherein R2 (for Formula V-A) or R3 (for Formula VI-A) is chosen from hydrogen, halogen, hydroxy, nitro, cyano, amino, halo(C1-C6)alkyl, and halo(C1-C6)alkoxy.

[0183] Further aspects of the invention include compounds of Formula V-A and Formula VI-A wherein R2 (for Formula V-A) or R3 (for Formula VI-A) is a group of the formula

[0184] where J is N, CH, or C—(C1-C6)alkyl and

[0185] RB and RC are independently selected from the group consisting of hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, C3-C8)cycloalkyl, and (C3-C8cycloalkyl) (C1-C4)alkyl; or

[0186] RB and RC and the atom to which they are attached form a 4-to 10-membered monocyclic or bicyclic ring, which may contain a) one or more double bonds, b) one or more of oxo, O, S, SO, SO2, and N—RD wherein RD is hydrogen or (C1-C6)alkyl; and/or c) one or more substituents R20, where R20 carries the definition set forth for compounds of Formula I, or more preferably that set forth for compounds of Formula IA.

[0187] Also provided by the invention are compounds of Formula V-A and Formula VI-A wherein R2 (for Formula V-A) or R3 (for Formula VI-A) is a group of the formula

[0188] where G is a bond or C1-C2alkyl; and RA is a saturated, partially unsaturated, or aromatic carbocycle consisting of 1 ring or 2 fused, pendant, or spiro rings, each ring containing 0, 1, or 2 heteroatoms independently selected from N, S, and O, where the saturated, partially unsaturated, or aromatic carbocycle is optionally substituted with 1, 2, 3, or 4 of R20. Preferred compounds of this class are those where RA is chosen from phenyl, pyrrolyl, pyrazolyl, thiazolyl, isoxazolyl, triazolyl, tetrazolyl, oxadiazolyl, and oxazolyl each of which is optionally substituted with 1, 2, 3, or 4 of R20. R20 carries the definition set forth for compounds of Formula I, or more preferably that set forth for compounds of Formula IA.

[0189] The invention also includes compounds of Formula V-A and Formula VI-A wherein R2 (for Formula V-A) or R3 (for Formula VI-A) is —HC═N—OH or —HC═N(C1-C6alkoxy).

[0190] Other benzimidazole and pyridylimidazole compounds of the invention are represented by Formula X-Formula XVIII, below.

[0191] The variables Z1, Z2, Z3, Z4, R, Q, and W, which appear in Formulae X-XVIII carry the definition set forth for Formula I, or more preferably for Formula IA.

[0192] Compounds of Formulae X-XVIII wherein Z1 is CF1, Z2 is CR2, Z3 is CR3, and Z4 is CR4 are preferred. Compounds of Formulae X-XVIII wherein one and only one Z1, Z2, Z3, Z4 is nitrogen are also preferred. Compounds of Formulae X-XVIII wherein one and only one Z1, Z2, Z3, Z4 is nitrogen, and either Z2 or Z3 is nitrogen are particularly preferred.

[0193] Particularly embodied in the invention are compounds of Formulae X-XVIII wherein Q (when present) is C(R6) (R7). Preferably R6 and R7 are hydrogen.

[0194] Other embodiments of the invention are directed to compounds of Formulae X-XVIII wherein W represents a 5-membered heteroaryl group, and the 5-membered heteroaryl group is optionally substituted with up to 4 groups independently selected from R30, —CO2H, —C(═O)ORE, —C(═O)NHRE, —C(═O)NRERF, —C(O)RE, and —S(O)mRE, —ORE, where R30 and RE are as defined above and m is 0, 1, or 2. Preferred compounds of this class are compounds wherein wherein Z1 is CR1, Z2 is CR2, Z3 is CR3, and Z4 is CR4 or wherein one and only one Z1, Z2, Z3, Z4 is nitrogen are also preferred; compounds of this class wherein one and only one Z1, Z2, Z3, Z4 is nitrogen, and either Z2 or Z3 is nitrogen are particularly preferred.

[0195] This invention provides benzimidazole and pyridylimidazole derivatives, preferred examples of which bind with high affinity to the benzodiazepine site of GABAA receptors, including human GABAA receptors. The affinity of compounds of Formula I for the benzodiazepine site may be determined using a GABAA receptor binding assay, such as the assay presented in Example 53. Preferred compounds of Formula I that bind with high affinity to the benzodiazepine site of the GABAA receptor exhibit Ki values of less than 1 μM in that assay. Very high affinity compounds of the invention exhibit Ki values of less than 100 nM or more preferably less than 10 nM in the assay presented in Example 53. Without wishing to be bound to any particular theory, it is believed that the interaction of the compounds of Formula I with the benzodiazepine site results in the pharmaceutical utility of these compounds.

[0196] Benzimidazole and pyridylimidazole derivatives that bind with high selectivity to the benzodiazepine site of GABAA receptors, including human GABAA receptors, are also included in this invention. Preferred compounds of Formula I which exhibit high selectivity (or high specificity) exhibit affinity for the benzodiazepine site of the GABA receptor that is at least 10-fold greater, and preferably 100-fold greater, than the affinity exhibited at any other membrane-bound receptor which is a known drug target. More preferred compounds of Formula I do not exhibit a binding affinity at any other membrane-bound receptor which is a known drug target that is less than 1 micromolar. Membrane-bound receptors that are known drug targets include, but are not limited to dopamine receptors, CRF receptors, bradykinin receptors, NPY receptors, beta-adrenergic receptors, capsaicin receptors, galanin receptors, MCH receptors, melanocortin receptors, and neurokinin receptors. Binding affinities for membrane-bound receptors which are known drug targets may be determined via radioligand binding assays which are generally well known in the art.

[0197] The invention further comprises methods of treating patients in need of such treatment with an amount of a compound of the invention sufficient to alter the symptoms of a CNS disorder. Compounds of the inventions that act as agonists at α2β3γ2 and α3β3γ2 receptor subtypes are useful in treating anxiety disorders such as panic disorder, obsessive compulsive disorder and generalized anxiety disorder; stress disorders including post-traumatic stress, and acute stress disorders. Compounds of the inventions that act as agonists at α2β3γ2 and α3β3β2 receptor subtypes are also useful in treating depressive or bipolar disorders and in treating sleep disorders. Compounds of the invention that act as inverse agonists at the α5β3γ2 receptor subtype or α1β2γ2 and α5β3γ2 receptor subtypes are useful in treating cognitive disorders including those resulting from Down Syndrome, neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, and stroke related dementia. Compounds of the invention that act as inverse agonists at the α5β3γ2 are particularly useful in treating cognitive disorders through the enhancement of memory, and particularly short-term memory, in memory-impaired patients. Compounds of the invention that act as agonists at the α1β2γ2 receptor subtype are useful in treating convulsive disorders such as epilepsy. Compounds that act as antagonists at the benzodiazepine site are useful in reversing the effect of benzodiazepine overdose and in treating drug and alcohol addiction.

[0198] The diseases and/ or disorders that can also be treated using compounds and compositions according to the invention include:

[0199] Depression, e.g. depression, atypical depression, bipolar disorder, depressed phase of bipolar disorder.

[0200] Anxiety, e.g. general anxiety disorder (GAD), agoraphobia, panic disorder +/− agoraphobia, social phobia, specific phobia, Post traumatic stress disorder, obsessive compulsive disorder (OCD) dysthymia, adjustment disorders with disturbance of mood and anxiety, separation anxiety disorder, anticipatory anxiety acute stress disorder, adjustment disorders, cyclothymia.

[0201] Sleep disorders, e.g. sleep disorders including primary insomnia, circadian rhythm sleep disorder, dyssomnia NOS, parasomnias, including nightmare disorder, sleep terror disorder, sleep disorders secondary to depression and/or anxiety or other mental disorders, substance induced sleep disorder.

[0202] Cognition Impairment, e.g. cognition impairment, memory impairment, short-term memory impairment, Alzheimer's disease, Parkinson's disease, mild cognitive impairment (MCI), age-related cognitive decline (ARCD), stroke, traumatic brain injury, AIDS associated dementia, and dementia associated with depression, anxiety or psychosis.

[0203] Attention Deficit Disorder, e.g. attention deficit disorder (ADD), and attention deficit and hyperactivity disorder (ADHD).

[0204] Speech disorders, e.g. stuttering, including motor tic, clonic stuttering, dysfluency, speech blockage, dysarthria, Tourete syndrome or logospasm.

[0205] Psychosis e.g. schizophrenia, hallucinatory disorders

[0206] The invention also provides pharmaceutical compositions comprising one or more compounds of the invention together with a pharmaceutically acceptable carrier or excipient, for treating disorders responsive to GABAA receptor modulation, e.g., treatment of anxiety, depression, sleep disorders or cognitive impairment by GABAA receptor modulation. Pharmaceutical compositions include packaged pharmaceutical compositions comprising a container holding a therapeutically effective amount of at least one GABAA receptor modulator as described supra and instructions (e.g., labeling) indicating the contained GABAA receptor ligand is to be used for treating a disorder responsive to GABAA receptor modulation in the patient.

[0207] In a separate aspect, the invention provides a method of potentiating the actions of other CNS active compounds, which comprises administering an effective amount of a compound of the invention in combination with another CNS active compound. Such CNS active compounds include, but are not limited to the following: for anxiety, serotonin receptor (e.g. 5-HT1A) agonists and antagonists; for anxiety and depression, neurokinin receptor antagonists or corticotropin releasing factor receptor (CRF1) antagonists; for sleep disorders, melatonin receptor agonists; and for neurodegenerative disorders, such as Alzheimer's dementia, nicotinic agonists, muscarinic agents, acetylcholinesterase inhibitors and dopamine receptor agonists. Particularly the invention provides a method of potentiating the antidepressant activity of selective serotonin reuptake inhibitors (SSRIs) by administering an effective amount of a GABA agonist compound of the invention in combination with an SSRI.

[0208] Combination administration can be carried out in a fashion analogous to that disclosed in Da-Rocha, et al., J. Psychopharmacology (1997) 11(3) 211-218; Smith, et al., Am. J. Psychiatry (1998) 155(10) 1339-45; or Le, et al., Alcohol and Alcoholism (1996) 31 Suppl. 127-132. Also see, the discussion of the use of the GABAA receptor ligand 3-(5-methylisoxazol-3-yl)-6-(1-methyl-1,2,3-triazol-4-yl) methyloxy-1,2,4-triazolo [3,4-a]phthalzine in combination with nicotinic agonists, muscarinic agonists, and acetylcholinesterase inhibitors, in PCT International publications Nos. WO 99/47142, WO 99/47171, and WO 99/47131, respectively. Also see in this regard PCT International publication No. WO 99/37303 for its discussion of the use of a class of GABAA receptor ligands, 1,2,4-triazolo[4,3-b]pyridazines, in combination with SSRIs.

[0209] The present invention also pertains to methods of inhibiting the binding of benzodiazepine compounds, such as RO15-1788, or GABA to the GABAA receptors which methods involve contacting a solution containing compound of the invention with cells expressing GABAA receptors, wherein the compound is present at a concentration sufficient to inhibit benzodiazepine binding or GABA binding to GABAA receptors in vitro. This method includes inhibiting the binding of benzodiazepine compounds to GABAA receptors in vivo, e.g., in a patient given an amount of a compound of Formula I that would be sufficient to inhibit the binding of benzodiazepine compounds or GABA to GABAA receptors in vitro. In one embodiment, such methods are useful in treating benzodiazepine drug overdose. The amount of a compound that would be sufficient to inhibit the binding of a benzodiazepine compound to the GABAA receptor may be readily determined via a GABAA receptor binding assay, such as the assay described in Example 53. The GABAA receptors used to determine in vitro binding may be obtained from a variety of sources, for example from preparations of rat cortex or from cells expressing cloned human GABAA receptors.

[0210] The invention also provides methods for altering the signal-transducing activity, particularly the chloride ion conductance of GABAA receptors, said method comprising exposing cells expressing such receptors to an effective amount of a compound of the invention. This method includes altering the signal-transducing activity of GABAA receptors in vivo, e.g., in a patient given an amount of a compound of Formula I that would be sufficient to alter the signal-transducing activity of GABAA receptors in vitro. The amount of a compound that would be sufficient to alter the signal-transducing activity of GABAA receptors may be determined via a GABAA receptor signal transduction assay, such as the assay described in Example 54. The cells expressing the GABA receptors in vivo may be, but are not limited to, neuronal cells or brain cells. Such cells may be contacted with compounds of the invention through contact with a body fluid containing the compound, for example through contact with cerebrospinal fluid. Alteration of the signal-transducing activity of GABAA receptors in vitro may be determined from a detectable change in the electrophysiology of cells exprssing GABAA receptors, when such cells are contacted with an compound of the invention in the presence of GABA. For example, a change in the electrophysiology of cells expressing GABAA receptors may be detected using a voltage-clamp assay performed on oocytes injected with GABAA receptor mRNA. Such an assay is shown in Example 54.

[0211] Intracellular recording or patch-clamp recording may be used to quantitate changes in electrophysiology of cells. A reproducible change in behavior of an animal given a compound of the invention may also be used to indicate that changes in the electrophysiology of the animal's cells expressing GABAA receptors has occurred.

[0212] The GABAA receptor ligands provided by this invention and labeled derivatives thereof are also useful as standards and reagents in determining the ability of a potential pharmaceutical to bind to the GABAA receptor. Radiolabeled derivatives the GABAA receptor ligands provided by this invention are also useful as radiotracers for positron emission tomography (PET) imaging or for single photon emission computerized tomography (SPECT).

[0213] More particularly compounds of the invention may be used for demonstrating the presence of GABAA receptors in cell or tissue samples. This may be done by preparing a plurality of matched cell or tissue samples, at least one of which is prepared as an experimental sample and at least one of which is prepared as a control sample. The experimental sample is prepared by contacting (under conditions that permit binding of RO15-1788 to GABAA receptors within cell and tissue samples) at least one of the matched cell or tissue samples that has not previously been contacted with any compound or salt of the invention with an experimental solution comprising the detectably-labeled preparation of the selected compound or salt at the first measured molar concentration. The control sample is prepared in the same manner as the experimental sample and also contains an unlabelled preparation of the same compound or salt of the invention at a greater molar concentration.

[0214] The experimental and control samples are then washed to remove unbound detectably-labeled compound. The amount of remaining bound detectably-labeled compound is then measured and the amount of detectably-labeled compound in the experimental and control samples is compared. A comparison that indicates the detection of a greater amount of detectable label in the at least one washed experimental sample than is detected in any of control samples demonstrates the presence of GABAA receptors in that experimental sample.

[0215] The detectably-labeled compound used in this procedure may be labeled with a radioactive label or a directly or indirectly luminescent label. When tissue sections are used in this procedure and the detectably-labeled compound is radiolabeled, the bound, labeled compound may be detected autoradiographically to generate an autoradiogram. The amount of detectable label in an experimental or control sample may be measured by viewing the autoradiograms and comparing the exposure density of the autoradiograms.

[0216] The invention provides a method for preparing a compound of Formula A

[0217] which comprises reacting a compound of Formula B

[0218] with a compound of Formula C

[0219] In Formula A and C, above Z1, Z2, Z3, Z4, and R5 carry the definitions forth for Formula I, or more preferably Z1, Z2, Z3, Z4, and R5 carry the definitions forth for Formula Ia.

[0220] R6 and R7 independently represent hydrogen, fluorine, or alkyl.

[0221] R in Formula B, above, is independently chosen at each occurrence from hydrogen, halogen, amino, C1-C6alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, C1-C6alkoxy, (C3-C8)cycloalkyl, (C3-C8cycloalkyl) (C1-C4)alkyl, halo(C1-C6)alkyl, haloalkoxy, carboxamido, and 3- to 7-membered carbocyclic or heterocyclic groups which are saturated, unsaturated, or aromatic, which may be further substituted with one or more substituents independently selected from halogen, oxo, hydroxy, C1-4alkyl, and —O(C1-4alkyl)

[0222] W in Formula B represents aryl or heteroaryl, wherein the aryl or heteroaryl group is optionally substituted with up to 4 groups independently selected from R30, —CO2H, —C(═O)ORE, —C(═O)NHRE, —C(═O)NRERF, —C(O)RE, and —S(O)mRE, —ORE, where R30 and RE are as for Formula I or preferably as defined for Formula Ia and m is 0, 1, or 2. This process will be referred to as Process 1.

[0223] In particular embodiments the invention includes a process of preparing a compound of Formula A as described above wherein: Z1 is CR1, Z2 is CR2, Z3 is CR3, and Z4 is CR4.

[0224] R is independently selected at each occurrence from the group consisting of hydrogen, halogen, and (C1-C2)alkyl;

[0225] R1, R4, and one of R2 and R3 are independently selected from hydrogen, halogen, hydroxy, nitro, cyano, amino, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, halo (C1-C6) alkyl, halo (C1-C6) alkoxy, mono or di (C1-C6)alkylamino, amino (C1-C6) alkyl, and mono- and di (C1-C6)alkylamino(C1-C6)alkyl.

[0226] The other of R2 and R3 carries the definition set forth for Formula I, or preferably that set forth for Formula Ia, or in certain preferred embodiments this group is chosen from

[0227] i) hydrogen, halogen, hydroxy, nitro, cyano, amino, halo(C1-C6)alkyl, and halo(C1-C6)alkoxy,

[0228] ii) C1-C6alkyl, C1-C6alkoxy, C3-C8cycloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C8cycloalkyl) C1-C4alkyl, —NH(R10), —N(R10) (R11), (R10)NH(C1-C6)alkyl, (R10) (R11)N(C1-C6)alkyl, (heterocycloalkyl)C1-C4alkyl, and heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 of R20.

[0229] In certain preferred embodiments R, R1, and R4 are all hydrogen.

[0230] R5 represents (C1-C6)alkyl. Preferred definitions of R5 include ethyl and n-propyl.

[0231] R6 and R7 are hydrogen.

[0232] W represents phenyl, furanyl, thienyl, thiazolyl, imidazolyl, oxazolyl, triazolyl, tetrazolyl, pyrazolyl, isoxazolyl, pyrimidinyl, benzimidazolyl, quinolinyl, isoquinolinyl each of which is optionally substituted with up to 4 R30 groups, where R30 is as defined in the above process. Preferred W groups include, 2-thiazolyl, 2-pyrimidinyl, 3-fluorophenyl, or 6-fluoro-2-pyridinyl.

[0233] In other preferred embodiments the invention is directed to a process, as described as for Process 1, wherein Z1 is CR1; one and only one of Z2 or Z3 is nitrogen; Z4 is CR4.

[0234] R1 and R4 may carry the definition set forth in Process 1. Preferred definitions of R1 and R4 include hydrogen, halogen, trifluoromethyl, C1-C2 alkyl, and cyano.

[0235] In certain preferred embodiments R, R1, and R4 are all hydrogen.

[0236] R2 or R3 (for whichever one of Z2 or Z3 is CR2 or CR3) is chosen from

[0237] i) hydrogen, halogen, hydroxy, nitro, cyano, amino, halo(C1-C6)alkyl, and halo(C1-C6)alkoxy,

[0238] ii) C1-C6alkyl, C1-C6alkoxy, C3-C8cycloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C8cycloalkyl) C1-C4alkyl, —NH(R10), —N(RO) (R11), (R10)NH(C1-C6)alkyl, (R10) (R11)N(C1-C6)alkyl, (heterocycloalkyl)C1-C4alkyl, and heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 of R20.

[0239] R5 represents (C1-C6)alkyl. Preferred definitions of R5 include ethyl and n-propyl.

[0240] R6 and R7 are hydrogen.

[0241] W represents a 5-membered heteroaryl group, the 5-membered heteroaryl group is optionally substituted with up to 4 groups independently selected from R30, —CO2H, —C(═O)ORE, —C(═O)NHRE, —C(═O)NRERF, —C(O)RE, and —S(O)mRE, —ORE, where R30 and RE are as defined above and m is 0, 1, or 2; or

[0242] W represents a 6-membered aryl or heteroaryl group, wherein the 6-membered aryl or heteroaryl group is optionally substituted with up to 4 groups independently selected from R30, —CO2H, —C(═O)ORE, —C(═O)NHRE, —C(═O)NRERF, —C(O)RE, and —S(O)mRE, —ORE, where R30 and RE are as defined above and m is 0, 1, or 2.

[0243] When W represents a 5-membered heteroaryl group W is preferably thiazolyl, thienyl, imidazolyl, oxazolyl, triazolyl, tetrazolyl, pyrazolyl, or isoxazolyl, each of which is optionally substituted by one or more substituents independently chosen from halogen, cyano, hydroxy, oxo, C1-C2haloalkyl, C1-C2alkyl, and C1-C2 alkoxy. Unsubstituted 2-thiazolyl is a particularly preferred W group.

[0244] When W represents a 6-membered aryl or heteroaryl group, W is preferably phenyl, pyrimidinyl, pyridyl, pyrazinyl, or pyridizinyl, each of which is optionally substituted by one or more substituents independently chosen from halogen, cyano, hydroxy, oxo, C1-C2haloalkyl, C1-C2alkyl, and C1-C2 alkoxy. Particularly preferred W groups include 2-pyrimidinyl, 3-fluorophenyl, or 6-fluoro-2-pyridinyl.

[0245] In this process the reactants B and C are generally combined in a polar aprotic solvent, such as THF, DMF, or 1,4-dioxane, at temperatures ranging from 0-100 degrees C. A reducing agent such as NaH or other base, for example sodium hydroxide, potassium butoxide, potassium carbonate, or cesium carbonate, is then added, and the reaction is allowed to proceed. Choice of solvent, reaction temperature, and reducing agent will depend on the identity of the reactants B and C, but will be readily determined by a worker of ordinary skill in the art of chemical synthesis. Scheme I, step 4, provides further illustration of this process.

[0246] Chemical Description and Terminology

[0247] Formula I includes, but is not limited to the subformulae exemplified as Formula Ia, Formulae II-VI and Formulae X-XVIII and their pharmaceutically acceptable acid and base addition salts.

[0248] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings or animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. As used herein, “pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Those skilled in the art will recognize a wide variety of non-toxic pharmaceutically acceptable addition salts.

[0249] Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfamic, sulfinic, phosphoric, nitric and the like; and the salts prepared from organic acids such as alkanoic such as acetic, HOOC—(CH2)n-ACOOH where n is 0-4, and the like, tartaric, maleic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, malefic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, HOOC—(CH2)n—COOH where n is 0-4, and the like. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., p. 1418 (1985).

[0250] The invention includes hydrates of compounds of Formula I.

[0251] The invention includes all crystalline forms of the compounds of Formula I. Certain crystalline forms may be preferred.

[0252] The present invention also encompasses the acylated prodrugs of the compounds of Formula I. Those skilled in the art will recognize various synthetic methodologies that may be employed to prepare non-toxic pharmaceutically acceptable addition salts and acylated prodrugs of the compounds encompassed by Formula I. The invention further encompasses all enantiomers and diastereomers of the disclosed compounds. Those of ordinary skill in the art will readily recognize methods by which mixtures of enantiomers and diasteromers may be resolved. The definition of Formula I as used in herein include possible isomers, such as tautomers and rotamers.

[0253] The compounds herein described may have one or more asymmetric centers or planes. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms (racemates), by asymmetric synthesis, or by synthesis from optically active starting materials. Resolution of the racemates can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral HPLC column. Many geometric isomers of olefins, C═N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral (enantiomeric and diastereomeric), and racemic forms, as well as all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated.

[0254] When any variable occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0 to 3 R*, (where R* indicates any variable group such as R) then said group may optionally be substituted with up to three R* groups and R* at each occurrence is selected independently from the definition of R′. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

[0255] When any group, such as an aryl group, heteroaryl group, carbocyclic group, heterocyclic group, or monocylic or bicyclic ring is said to be “optionally substituted by one or more substituents” that group may contain 0 or from 1 to the maximum number of substituents allowable without exceeding the valency of the atoms of the substituted group. Preferably such groups are substituted with 0 or from 1 to 4 substituents, and more preferably such groups are substituted with 0 or from 1 to 3 substituents. Preferably such groups are not substituted with more that one oxo substituent.

[0256] A dash “—” that is not between two letters or symbols is used to indicate a point of attachement for a substituent. For example —C(═O)NH2 is attached through the carbon atom.

[0257] As used herein, “alkyl” is intended to include both branched and straight-chain aliphatic hydrocarbon groups, having the specified number of carbon atoms. Alkyl groups of 2 or more carbon atoms may contain double or triple bonds. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl. Preferred alkyl groups are C1-C6 alkyl groups. “C1-C6 alkyl” indicates alkyl groups having from 1 to about 6 carbon atoms.

[0258] As used herein, “alkoxy” represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, 2-butoxy, t-butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy, n-hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy. “C1-C6 alkoxy” indicates alkoxy groups having from 1 to about 6 carbon atoms.

[0259] “Alkenyl” is intended to include hydrocarbon chains of either a straight or branched configuration comprising one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl and propenyl. Alkenyl groups typically will have 2 to about 8 carbon atoms, more typically 2 to about 6 carbon atoms.

[0260] “Alkynyl” is intended to include hydrocarbon chains of either a straight or branched configuration comprising one or more triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl and propynyl. Alkynyl groups typically will have 2 to about 8 carbon atoms, more typically 2 to about 6 carbon atoms.

[0261] “Aryl” refers to aromatic groups having 1 or more rings, wherein the members of the aromatic ring or rings are carbon. When indicated such groups may be substituted. Preferred aryl groups include optionally substituted phenyl and optionally substituted naphthyl.

[0262] The term “Cycloalkyl” is intended to include saturated ring groups, having the specified number of carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. Cycloalkyl groups typically will have 3 to about 8 ring members.

[0263] In the term “1(cycloalkyl)alkyl”, Cycloalkyl and alkyl are as defined above and the point of attachment is on the alkyl group. This term encompasses, but is not limited to, cyclopropylmethyl, cyclohexylmethyl, cyclohexylmethyl.

[0264] As used herein, “haloalkyl” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen atoms (for example —CvFw where v=1 to 3 and w=1 to (2v+1). Examples of haloalkyl include, but are not limited to, trifluoromethyl, difluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.

[0265] As used herein, “haloalkoxy” indicates a haloalkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy and trichloromethoxy.

[0266] As used herein the term “heteroaryl” is intended to mean a stable 5-to 7-membered monocyclic or 7-to 10-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S. It is preferred that the total number of S and O atoms in the heteroaryl group is not more than 1.

[0267] Examples of heteroaryl groups include, but are not limited to, pyrimidinyl, pyridyl, quinolinyl, benzothienyl, indolyl, pryidazinyl, pyazinyl, isoindolyl, isoquinolyl, quinazolinyl, quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, thienyl, thiazolyl, indolizinyl, indazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzoisoxolyl, dihydro-benzodioxinyl, furanyl, pyrrolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, oxazolopyridinyl, imidazopyridinyl, isothiazolyl, naphthyridinyl, cinnolinyl, carbazolyl, beta-carbolinyl, isochromanyl, chromanonyl, chromanyl, tetrahydroisoquinolinyl, isoindolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isobenzothienyl, benzoxazolyl, pyridopyridinyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, purinyl, benzodioxolyl, triazinyl, phenoxazinyl, phenothiazinyl, pteridinyl, benzothiazolyl, imidazopyridinyl, imidazothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl, dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl, coumarinyl, isocoumarinyl, chromanyl, tetrahydroquinolinyl, dihydroquinolinyl, dihydroquinolinonyl, dihydroisoquinolinonyl, dihydrocoumarinyl, dihydroisocoumarinyl, isoindolinonyl, benzodioxanyl, benzoxazolinonyl, pyrrolyl N-oxide, pyrimidinyl N-oxide, pyridazinyl N-oxide, pyrazinyl N-oxide, quinolinyl N-oxide, indolyl N-oxide, indolinyl N-oxide, isoquinolyl N-oxide, quinazolinyl N-oxide, quinoxalinyl N-oxide, phthalazinyl N-oxide, imidazolyl N-oxide, isoxazolyl N-oxide, oxazolyl N-oxide, thiazolyl N-oxide, indolizinyl N-oxide, indazolyl N-oxide, benzothiazolyl N-oxide, benzimidazolyl N-oxide, pyrrolyl N-oxide, oxadiazolyl N-oxide, thiadiazolyl N-oxide, triazolyl N-oxide, tetrazolyl N-oxide, benzothiopyranyl S-oxide, and benzothiopyranyl S,S-dioxide.

[0268] Preferred heteroaryl groups include imidazolyl, pyrrolyl, pyridyl, thiazolyl, pyrazolyl, thiazolyl, isoxazolyl, triazolyl, tetrazolyl, oxadiazolyl, pyrimidinyl, and oxazolyl.

[0269] The term “heterocycloalkyl” is intended to include saturated ring groups having at least 1 heteroatom. Heterocycloalkyl groups typically include 3 to 8 ring atoms, preferably 5 to 7 ring atoms. Heterocycloalkyl groups typically have from 1 to 3 heteroatoms selected from N, S, and 0 with remaining ring atoms being carbon. Preferably not more than one S atom and one 0 atom is present in a heterocycloalkyl group. Preferred heterocycloalkyl groups include morpholinyl, piperidinyl, piperazinyl, thiomorpholinyl, and pyrrolidinyl.

[0270] The phrase “monocyclic or bicyclic ring” refers to saturated, partially unsaturated, or aromatic rings or ring systems, which optionally contain from 1 to 4 heteroatoms independently chosen from N, S, and O with remaining ring members being carbon. Preferred monocyclic and bicyclic rings are saturated and partially unsaturated rings or ring systems.

[0271] The term “oxo” indicates a carbonyl group. When an oxo group appears as a substituent the allowed valence of the substituted position is not exceeded.

[0272] Pharmaceutical Compositions

[0273] The compounds of general Formulas I may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. Oral administration in the form of a pill, capsule, elixir, syrup, lozenge, troche, or the like is particularly preferred. The term parenteral as used herein includes subcutaneous injections, intradermal, intravascular (e.g., intravenous), intramuscular, spinal, intrathecal injection or like injection or infusion techniques. In addition, there is provided a pharmaceutical formulation comprising a compound of general Formula I and a pharmaceutically acceptable carrier. One or more compounds of general Formula I may be present in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants and if desired other active ingredients. The pharmaceutical compositions containing compounds of general Formula I may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.

[0274] Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monosterate or glyceryl distearate may be employed.

[0275] Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.

[0276] Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

[0277] Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol.

[0278] Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

[0279] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.

[0280] Pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monoleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monoleate. The emulsions may also contain sweetening and flavoring agents.

[0281] Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

[0282] The compounds of general Formulas I may also be administered in the form of suppositories, e.g., for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.

[0283] Compounds of general Formulas I may be administered parenterally in a sterile medium. The drug, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle.

[0284] For administration to non-human animals, the composition may also be added to the animal feed or drinking water. It will be convenient to formulate these animal feed and drinking water compositions so that the animal takes in an appropriate quantity of the composition along with its diet. It will also be convenient to present the composition as a premix for addition to the feed or drinking water.

[0285] Dosage levels of the order of from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 0.5 mg to about 7 g per patient per day). The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient.

[0286] Frequency of dosage may also vary depending on the compound used and the particular disease treated. However, for treatment of most disorders, a dosage regimen of 4 times daily or less is preferred. For the treatment of anxiety, depression, or cognitive impairment a dosage regimen of 1 or 2 times daily is particularly preferred. For the treatment of sleep disorders a single dose that rapidly reaches effective concentrations is desirable.

[0287] It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease undergoing therapy.

[0288] Preferred compounds of the invention will have certain pharmacological properties. Such properties include, but are not limited to high solubility (preferably 500 ng/ ml or more) in aqueous solutions, oral bioavailability, low toxicity, low serum protein binding, lack of clinically relevant EKG effects, and desirable in vitro and in vivo half-lifes. Penetration of the blood brain barrier for compounds used to treat CNS disorders is necessary, while low brain levels of compounds used to treat periphereal disorders are often preferred.

[0289] Assays may be used to predict these desirable pharmacological properties. Assays used to predict bioavailability include transport across human intestinal cell monolayers, including Caco-2 cell monolayers. Toxicity to cultured hepatocyctes may be used to predict compound toxicity. Penetration of the blood brain barrier of a compound in humans may be predicted from the brain levels of the compound in laboratory animals given the compound intravenously.

[0290] Serum protein binding may be predicted from albumin binding assays. Such assays are described in a review by Oravcova, et al. (Journal of Chromatography B (1996) volume 677, pages 1-27).

[0291] Compound half-life is inversely proportional to the frequency of dosage of a compound. In vitro half-lifes of compounds may be predicted from assays of microsomal half-life as described by Kuhnz and Gieschen (Drug Metabolism and Disposition, (1998) volume 26, pages 1120-1127).

EXAMPLES

[0292] Preparation of Compounds

[0293] Representative procedures suitable for the preparation of compounds of Formula I are outlined in Schemes I-X, which are not to be construed as limiting the invention in scope or spirit to the specific reagents and conditions shown in them. Those having skill in the art will recognize that the reagents and conditions may be varied and additional steps employed to produce compounds encompassed by the present invention. In some cases, protection of reactive functionalities may be necessary to achieve the desired transformations. In general, such need for protecting groups, as well as the conditions necessary to attach and remove such groups, will be apparent to those skilled in the art of organic synthesis. Unless otherwise stated in the schemes below, the variables, e.g., Z1, Z2, Z3, Z4, R5, R2, R3 and W, are as defined in Formula I.

[0294] Scheme I illustrates a route to selected compounds of Formula 6 via coupling of chloromethyl compounds 4 and aryl imidazoles 5. In Step 1, aryl and heteroaryl halides of formula 1 are reacted with appropriate amines in the presence of base to obtain amino adducts of formula 2. In Step 2, reduction of the nitro group in compounds of formula 2 yields diamines 3. In Step 3, diamines of formula 3 are reacted with 2-chloro-acetimidic acid methyl ester hydrochloride or a similar electrophile such as 2-chloro-1,1,1-trimethoxy-ethane or chloroacetic acid anhydride. In Step 4, chloromethyl compounds of formula 4 are reacted with aryl and heteroaryl imidazoles of formula 5 in the presence of base and solvent to obtain compounds of formula 6. Depending on the particular nature of 5, a stronger or weaker base may be selected to facilitate the reaction in Step 4.

[0295] Scheme II illustrates the synthesis of compounds of formula 10 from diamines 3. In Step 1, reaction of malonyl dichloride with ethyl vinyl ether provides 7. In Step 2, treatment of 7with triethyl orthoformate in the presence of acid yields 8. Compound 8 is reacted in Step 3 with a variety of aryl and heteroaryl hydrazines to obtain compounds of formula 9 as a mixture with the undesired regioisomer. As illustrated in Steps 4 and 5, compounds of formula 9 can be hydrolyzed to the corresponding acids and coupled with compounds of formula 3 to obtain, following cyclization in refluxing acetic acid, compounds of formula 10. As described in subsequent schemes and examples, compounds of formula 9 may also be directly coupled to compounds of formula 3 in the presence of trimethylaluminum. Depending on the particular example and reaction conditions selected, cyclization may occur without need for heating in acetic acid as described in Step 5.

[0296] Scheme III illustrates a method for preparing compounds of formula 21 and 22. Step 1 encompasses hydrolysis of compounds of formula 11 to the corresponding acids followed by dimerization in the presence of a suitable coupling reagent such as 1,1′-carbonyldiimidazole to form compounds of formula 12. In Step 2, deacylation of compounds of formula 12 is accomplished by heating with concentrated sulfuric acid to obtain compounds of formula 13. Heating of compounds of formula 13 with ammonium hydroxide in Step 3 results in formation of compounds of formula 14. Nitration of compounds of formula 14 in Step 4 is accomplished using nitric acid to obtain compounds of formula 15. Compounds of formula 15 are converted to the corresponding chlorides 16 in Step 5 by heating with phosphorous oxychloride. In Step 6,chlorides 16 are reacted with ammonia followed by heating with phosphorous oxychloride to obtain 2-chloropyridines 17, which are subsequently reduced to diamines 18 in Step 7. In Step 8, diamines 18 are reacted with esters of formula 19 in the presence of trimethylaluminum followed by heating in acetic acid to obtain compounds of formula 20. Depending on the particular example and reaction conditions selected, cyclization may occur without need for heating in acetic acid. Step 9 illustrates alkylation of compounds of formula 20 with ethyl iodide in the presence of base to obtain a mixture of compounds of formula 21 and 22. Those skilled in the art will realize that alternate alkylating agents may be employed to obtain similar compounds bearing different RS groups.

[0297] Scheme IV illustrates a variation of Scheme III for specifically preparing compounds of formula 22. In Step 1,compounds of formula 16 are reacted with ethyl amine to form the amino adducts which are subsequently converted to 2-chloropyridines 23 by reaction with phosphorous oxychloride.

[0298] Those skilled in the art will realize that numerous other suitable amines of formula R5NH2 may be employed in Step 1 to yield other variants of Formula I. In Steps 2 and 3, hydrogenation of compounds of formula 23 to diamines of formula 24 followed by trimethylaluminum-facilitated coupling and cyclization in acetic acid provides compounds of formula 22. Depending on the particular example and reaction conditions selected, cyclization may occur without need for heating in acetic acid

[0299] Scheme V illustrates a route employing a protecting group strategy for preparing pyrazole compounds of formula 29. In Step 1, pyrazole 25 is reacted with di-tert-butyldicarbonate in the presence of 4-dimethylaminopyridine to obtain 26. Reaction with glyoxal and ammonium hydroxide provides 27. Reaction of 27 with chloromethyl compounds of formula 4 in the presence of base provides compounds of formula 28. Deprotection of compounds of formula 28 with acid in Step 4 provides pyrazoles of formula 29.

[0300] Scheme VI provides a route for preparing thiazole compounds of formula 33. Step 1 involves bromination of ketoesters of formula 30 to form x-bromoketones of formula 31. In Step 2,compounds of formula 31 are reacted with thioformamide to obtain thiazoles of formula 32. Condensation of 32 with 3 in Step 3 in the presence of trimethylaluminum provides compounds of formula 33. Depending on the particular reactants and conditions employed in Step 3, the product mixture may require heating in a suitable solvent such as acetic acid to enhance formation of 33.

[0301] Scheme VII provides routes to several heterocyclic systems via common intermediate 35. In Step 1, compounds of formula 34 are reacted with compounds of formula 4 at low temperature in the presence of a suitable base such as lithium diisopropylamide to form compounds of formula 35. Rxn 1 illustrates conversion of ketones of formula 35 to isoxazole derivatives of formula 36 by reaction of compounds of formula 35 with tris(dimethylamino)methane followed by treatement with hydroxylamine. In Rxn 2, compounds of formula 35 are reacted with tris(dimethylamino)methane followed by treatment with hydrazine acetate to obtain pyrazoles 37. In Rxn 3 and 4, compounds of formula 35 are brominated to form a-bromoketones 38 that are subsequently reacted with thioformamide to obtain thiazoles of formula 39. Rxn 5 illustrates the synthesis of pyrazoles of formulas 40 and 41 by reaction of compounds of formula 35 with tris(dimethylamino)methane followed by treatment with methyl hydrazine.

[0302] Scheme VIII provides a route for preparation of tetrazoles of formula 44. In Step 1, aryl and heteroaryl tetrazoles of formula 42 are heated with bis(tributyltin) oxide to form stannanes of formula 43. In Step 2, heating compounds of formula 43 with compounds of formula 4 in a suitable solvent such as toluene gives compounds of formula 44.

[0303] Scheme IX illustrates the synthesis of triazoles of formula 50. In Step 1, aryl and heteroaryl hydrazines are reacted with 1,3,5-triazine 45 to obtain triazoles of formula 46. In Step 2, heating compounds of formula 46 with formaldehyde provides alcohols of formula 47. In Step 3, alcohols of formula 47 are converted to the corresponding chlorides by treatment with thionyl chloride. The chlorides are subsequently converted to nitriles 48 by the action of tetraethyl ammonium cyanide.

[0304] Cyanides 48 are hydrolyzed in Step 4 to carboxylic acids 49. In Step 5, carboxylic acids of formula 49 are coupled with diamines 3 in the presence of EDCI [1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride] or other suitable coupling reagents followed by heating in acetic acid to complete cyclization of the intermediate amino amides to compounds of formula 50.

[0305] Scheme X illustrates two routes for the synthesis of imidazoles of formula 52, which are intermediates in the synthesis of selected compounds of Formula I. In Step 1, aryl and heteroaryl aldehydes are treated with glyoxal and ammonium hydroxide to form imidazoles of formula 52. In Step 1′, imidazole 53 is treated with butyl lithium followed by tri-n-butyltin chloride to obtain compounds of formula 54, which must be handled with care to avoid decomposition. In Step 2′, compounds of formula 54 are utilized in palladium cross-coupling reactions with aryl and heteroaryl halides to obtain compounds of formula 55. Subsequent treatment of compounds of formula 55 with acid in Step 3′ provides compounds of formula 52.

[0306] The invention is illustrated further by the following examples, which are not to be construed as limiting the invention in scope or spirit to the specific procedures described in them. Additional compounds encompassed by this invention beyond the accompanying Examples may be prepared using methods known to those skilled in the art of chemical synthesis. Those having skill in the art will recognize that the starting materials may be varied and additional steps employed to produce compounds encompassed by the present inventions, as demonstrated by the following examples. In some cases, protection of reactive functionalities may be necessary to achieve some the desired transformations. In general, such need for protecting groups, as well as the conditions necessary to attach and remove such groups, will be apparent to those skilled in the art of organic synthesis.

[0307] Preparation of Starting Materials and Intermediates

[0308] The starting materials and various intermediates may be obtained from commercial sources, prepared from commercially available organic compounds, or prepared using known synthetic methods. Representative examples of methods suitable for preparing intermediates of the invention are set forth below.

Example 1

[0309] Synthesis of 1-Propyl-2-{[2-(2-fluoropyrid-6-yl)-1H-imidazol-1-yl]methyl}-5-cyano-1H-benzimidazole

[0310] 1. Preparation of 4-n-Propylamino-3-nitrobenzonitrile

[0311] To a stirring suspension of 4-chloro-3-nitrobenzonitrile (7.30 g, 40 mmol) in isopropanol (30 mL) is added n-propylamine (9.87 mL, 120 mmol). The mixture is stirred at room temperature for 5 h, and the solid is then collected by filtration to give 4-n-propylamino-3-nitrobenzonitrile as a yellow solid. 1H NMR (CDCl3) δ 8.51 (1H, q), 8.42(1H, br s), 7.60(1H, m), 6.91(1H, d), 3.33(2H, q), 1.84-1.74(2H, m), 1.07(3H, t). LRMS 206.3 (MH+).

[0312] 2. Preparation of 3-Amino-4-n-propylaminobenzonitrile

[0313] To a Parr bottle containing 4-n-propylamino-3-nitrobenzonitrile (7.63 g, 37.2 mmol) in ethyl acetate (38 mL) is added 5% Pd/C (50% wet, 633 mg). The Parr bottle is sealed in a mechanical shaker, evacuated, and then purged with nitrogen followed by hydrogen. The system is pressurized to 50 PSI of hydrogen at room temperature and mechanical shaking engaged. After 2 hours, shaking is stopped, and the system purged with nitrogen prior to opening the vessel. The reaction mixture is filtered through celite, concentrated in vacuo, and the obtained solid recrystallized by dissolving in ethyl acetate (15 mL), heating, and adding hexanes (15 mL), to give 3-Amino-4-n-propylaminobenzonitrile as gray crystals. 1H NMR (CDCl3) δ 7.14(1H, dd), 6.92(1H, d), 6.56(1H, d), 3.98(1H, br s), 3.30(2H, br s), 3.12(2H, t), 1.75-1.65(2H, m), 1.03(3H, t). LRMS calcd 175.23, found 176.2 (MH+).

[0314] 3. Preparation of 1-Propyl-2-{[2-(2-fluoropyrid-6-yl)-1H-imidazol-1-yl]methyl}-5-cyano-1H-benzimidazole

[0315] Method A

[0316] (A) Preparation of 1-n-Propyl-2-chloromethyl-5-cyanobenzimidazole Hydrochloride

[0317] i) A solution of 3-amino-4-n-propylaminobenzonitrile (7.38 g, 42.1 mmol) and ethyl chloroacetimidate hydrochloride (9.92 g, 63.2 mmol) in ethanol (100 mL) is heated at reflux for 17 h, then cooled and concentrated to give 1-n-Propyl-2-chloromethyl-5-cyanobenzimidazole hydrochloride. Prior to use in the next step, this material is converted to free base by adding aqueous bicarbonate and extracting with dichloromethane, drying (Na2SO4), and concentrating.

[0318] ii) Alternatively, chloroacetylchloride rather than ethyl chloroacetimidate can by used: To a solution of 3-amino-4-n-propylaminobenzonitrile (5.15 g, 29.4 mmol) and triethylamine (4.51 mL) in ethyl acetate (52 mL) at room temperature, chloroacetyl chloride (2.57 mL) is added slowly. After stirring the reaction mixture for 30 minutes at room temperature, acetic acid (5 mL) is added and the reaction mixture heated to reflux. After heating for 20 h, the reaction mixture is cooled to room temperature and diluted with water (50 mL). The organic solution is washed twice with 1.0 M sodium hydroxide (2×50 mL), then washed with an aqueous solution of 0.25 M KH2PO4 (50 mL), followed by brine (50 mL). The organic layer is dried (sodium sulfate), concentrated in vacuo, and the solid recrystallized by heating in ethyl acetate (20 mL), adding hexane (40 mL) and cooling to room temperature with stirring to afford 1-n-Propyl-2-chloromethyl-5-cyanobenzimidazole as brown crystals. 1H NMR (CDCl3): δ 8.08 (d, J=0.8 Hz, 1H), 7.57 (dd, J=1.65, 8.52 Hz, 1H), 7.45 (d, J=8.24 Hz, 1H), 7.26 (s, 1H), 4.84 (s, 2H), 4.24 (t, J=7.6 Hz, 2H), 1.94 (pentet, J=7.4. 7.6 Hz, 2H), 1.03 (t, J=7.4 Hz, 3H).

[0319] (B) Preparation of 1-Propyl-2-{[2-(2-fluoropyrid-6-yl)-1H-imidazol-1-yl]methyl}-5-cyano-1H-benzimidazole

[0320] To a stirring suspension of sodium hydride (2.25 g of 60% in oil) in DMF (10 mL) at 0° a solution of 2-Fluoro-6-(1H-imidazol-2-yl)-pyridine (7.7 g, 47.2 mmol) in DMF (20 mL) is added. After stirring for 5 minutes, a solution of 1-n-Propyl-2-chloromethyl-5-cyanobenzimidazole (11 g, 47.2 mmol) and sodium iodide (20 mg) in DMF (80 mL) is added. The reaction mixture is stirred for 6 h, gradually warmed to room temperature. The reaction mixture is cooled, water added, the solid collected, rinsed with water and dried to afford the title compound, 1-Propyl-2-{[2-(2-fluoropyrid-6-yl)-1H-imidazol-1-yl]methyl}-5-cyano-1H-benzimidazole.

[0321] Method B

[0322] Trimethylaluminum (0.54 mL of 2.0M in toluene, 1.09 mmol) is added dropwise to a solution of 3-Amino-4-propylaminobenzonitrile (152 mg; 0.87 mmol) in dichloromethane (10 mL), and the mixture was stirred at room temperature for lhr. A solution of [2-(2-Fluoropyridin-6-yl)-imidazol-1-yl] acetic acid methyl ester (102 mg; 0.43 mmol) in dichloromethane (5 mL) is added all at once, and the mixture heated at reflux for 16 hr. The brown solution is cooled to room temperature and treated dropwise with methanol (1 mL) then water (2 mL) and stirred at room temperature for 15 min. Anhydrous sodium sulfate is added until the gel becomes solid, the mixture is diluted with dichloromethane (100 mL) and filtered through celite. The filtrate is concentrated to give a brown oil which is dissolved in acetic acid (7 mL) and heated at 1000 for 72 hr. The mixture is cooled to room temperature and concentrated. The residue is dissolved in ethyl acetate (15 mL), washed with saturated aqueous NaHCO3 (1×50 mL), then brine (1×50 mL), dried (MgSO4), and concentrated, and the residue purified by preparative thin layer chromatography to give 1-n-Propyl-2-{[2-(2-fluoropyrid-6-yl)-1H-imidazol-1-yl]methyl}-5-cyano-1H-benzimidazole as a light brown semi-solid (57 mg).

[0323] Method C

[0324] A solution of [2-(6-Fluoropyridin-2-yl)-imidazol-1-yl]acetic acid hydrochloride (274 mg; 1.06 mmol) and triethylamine (0.15 mL; 1.06 mmol) in dichloromethane (10 mL) is treated dropwise with oxalyl chloride (0.64 mL of a 2M solution in dichloromethane; 1.27 mmol), and the resulting suspension stirred at room temperature for 2 hr.

[0325] The mixture is concentrated and the residue suspended in dichloromethane (10 mL). A solution of 3-Amino-4-propylaminobenzonitrile (185 mg; 1.06 mmol) in dichloromethane (5 mL) is added and the mixture stirred at room temperature for 16 hr, then concentrated. The residue is dissolved in acetic acid (10 mL) and heated at 1000 for lhr. The mixture is cooled to room temperature, concentrated, taken up in ethyl acetate (150 mL) washed with saturated aqueous NaHCO3 (50 mL)and then washed with brine (50 mL), dried (MgSO4), and concentrated to give the crude product as a waxy brown solid (338 mg). This crude product is slurried with diethyl ether (ca. 4 mL) and a few drops of methanol, then filtered to give 1-n-Propyl-2-{[2-(2-fluoropyrid-6-yl)-1H-imidazol-1-yl]methyl}-5-cyano-1H-benzimidazole as a pale brown solid (230 mg).

[0326]

1
H NMR (399.96 MHz, CDCl3): δ 8.17(dd, J=2.0, 7.6 Hz, 1H, H-18), 8.05(s, 1H, H-4), 7.88(q, J=8.0 Hz, 1H, H-19), 7.52(d, J=8.4 Hz, 1H, H-6), 7.41(d, J=8.4 Hz, 1H, H-7), 7.21(s, 1H, H-14), 7.18(s, 1H, H-15), 6.28(s, 2H, H-13), 4.28(t, J=7.6 Hz, 2H, H-10), 1.68(dt, J=7.6 Hz, 2H, H-11), 0.84(t, J=7.6 Hz, 3H, H-12).

[0327]

13
C NMR (100.57 MHz, CDCl3, 1H decoupled at 399. 957 MHz): δ, 162.36(d, JC-F=239.6 Hz), 152.53, 148.69(d, JC-F=13.0 Hz), 142.36(d, JC-F=7.6 Hz), 142.31, 142.28, 138.42, 129.96, 126.55, 125.31, 124.23, 120.27(d, JC-F=3.8 Hz), 119.96, 111.23, 108.52(d, JC-F=35.9 Hz), 105.70, 46.10, 44.57, 23.43, 11.27.

Example 2

[0328] Synthesis of 1-Ethyl-2-{[2-(3-fluorophenyl)-pyrazol-3-yl]methyl}-5-cyano-1H-benzimidazole

[0329] 1. Preparation of 1-(3-Fluorophenyl)-5-carboxymethylpyrazole

[0330] To a stirring solution of ethyl vinyl ether (340 mL, 3.55 mol) in diethyl ether (200 mL), cooled in an ice bath, is added dropwise a solution of malonyl dichloride (69 mL, 0.71 mol) in ether (20 mL). Stirring is continued at 0° C. for 2 h, then a solution of triethylamine (196 mL) and ethanol (350 mL) in ether (210 mL) is added with cooling. More ether is added to further precipitate triethylamine hydrochloride, the mixture is then filtered, and the filtrate concentrated. The residue is taken up in ethanol (710 mL), then triethyl orthoformate (177 mL, 1.07 mol) and concentrated HCl (5 mL) is added. The mixture is stirred overnight then concentrated. To the residue is added ethanol (500 mL) and 3-Fluorophenylhydrazine hydrochloride (27.6 g, 0.17 mol). The mixture is heated at reflux for 2 h, then cooled and concentrated. Ethyl acetate is added, the mixture is washed with aqueous bicarbonate, then with water, dried (Na2SO4), concentrated, and the residue purified by silica gel chromatography. Ethanol (20 mL) and 1 N NaOH (100 mL) are added, and heated at reflux for 1 h. The mixture is cooled and washed with ethyl acetate. The aqueous layer is cooled and acidified, the solid collected by filtration, rinsed well with water and dried to give 1-(3-Fluorophenyl)-5-carboxymethylpyrazole as a gold solid. 1H NMR (CDCl3): δ 7.68 (d, J=1.8 Hz, 1H), 7.41-7.48 (m, 1H), 7.10-7.26 (m, 3H), 6.44 (d, J=2.1 Hz, 1H), 3.77 (s, 2H). LCMS: 221.2 (MH+), 219.2 (MH−).

[0331] 2. Preparation of 1-Ethyl-2-{[2-(3-fluorophenyl)-pyrazol-3-yl]methyl}-5-cyano-1H-benzimidazole

[0332] To a stirring solution of 3-amino-4-ethylaminobenzonitrile (887 mg, 5.5 mmol) and 1-(3-Fluorophenyl)-5-carboxymethylpyrazole (1.10 g, 5 mmol) in pyridine (5 mL) is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.15 g, 6 mmol). The mixture is stirred at room temperature for 17.5 h, then concentrated. The residue is cooled in an ice bath, aqueous HCl is added with stirring, the precipitate is collected by filtration, rinsed well with water and dried. The solid is added to acetic acid (75 mL) and heated at reflux for 5.5 h. The mixture is cooled, concentrated, and purified by silica gel chromatography to give 1-Ethyl-2-{[2-(3-fluorophenyl)-pyrazol-3-yl]methyl}-5-cyano-1H-benzimidazole. The product is converted to the mesylate salt in acetone. 1H NMR (CDCl3): δ 8.17 (s, 1H), 7.89 (d, J=8.52 Hz, 1H), 7.68-7.75 (m 1H), 7.44-7.54 (m, 2H), 7.37-7.40 (m, 1H), 7.21-7.28 (m, 1H), 6.35 (d, J=1.65 Hz, 1H), 4.65 (s, 2H), 4.29 (q, J=7.14 Hz, 2H), 2.34 (s, 3H), 1.19 (t, J=7.14 Hz, 3H). LCMS 346.0 (MH+), 344.4 (MH−)

Example 3

[0333] Synthesis of 1-Ethyl-2-{[1-(3-fluorophenyl)-1,2,4-triazol-5-yl]methyl}-5-cyano-1H-benzimidazole

[0334] 1. Preparation of 1-(3-Fluorophenyl)-1,2,4-triazole

[0335] A mixture of 1,3,5-triazine (1 g, 12.3 mmol) and 3-Fluorophenylhydrazine hydrochloride (2 g, 12.3 mmol) in ethanol (20 mL) is heated at reflux overnight. After concentrating, ethyl acetate is added, the mixture is washed with aqueous bicarbonate followed by saturated aqueous sodium chloride, dried (MgSO4), and concentrated to give 1.8 g of crude 1-(3-Fluorophenyl)-1,2,4-triazole. 1H NMR (CDCl3): δ 8.57 (s, 1H), 8.12 (s, 1H), 7.46-7.51 (m, 3H), 7.08-7.15 (m, 1H). LCMS 164.1 (MH+).

[0336] 2. Preparation of 1-(3-Fluorophenyl)-5-hydroxymethyl-1,2,4-triazole

[0337] A mixture of the crude 1-(3-Fluorophenyl)-1,2,4-triazole and formaldehyde (10 mL of 37 wt % in water) is heated at 150° C. in a sealed tube for 48 h. After cooling the reaction vessel, the reaction mixture is extracted with dichloromethane, dried (MgSO4), concentrated, and the residue purified using silica gel chromatography to afford 1-(3-Fluorophenyl)-5-hydroxymethyl-1,2,4-triazole. 1H NMR (CDCl3): δ 8.02 (s, 1H), 7.42-7.53 (m, 3H), 7.22-7.29 (m, 1H), 4.81 (s, 2H). LCMS 194.2 (MH−).

[0338] 3. Preparation of 1-(3-Fluorophenyl)-5-cyanomethyl-1,2,4-triazole

[0339] 1-(3-Fluorophenyl)-5-hydroxymethyl-1,2,4-triazole (1.7 g) is treated with thionyl chloride (10 mL) in dichloromethane (20 mL) at room temperature overnight. The solvent is then removed. To the residue is added acetonitrile (20 mL), tetraethylammonium cyanide (2.75 g, 17.6 mmol), and triethylamine (2.5 mL, 17.6 mmol). The mixture is stirred at room temperature for 2 h. The mixture is diluted with ethyl acetate, washed with aqueous bicarbonate, and then with saturated aqueous sodium chloride, dried (Na2SO4), concentrated and the residue purified by silica gel chromatography to give crude 1-(3-Fluorophenyl)-5-cyanomethyl-1,2,4-triazole. 1H NMR (CDCl3): δ 8.06 (s, 1H), 7.52-7.62 (m, 1H), 7.20-7.30 (m, 3H), 3.98 (s, 2H). LCMS 203.0 (MH+), 201.2 (MH−).

[0340] 4. Preparation of 1-(3-Fluorophenyl)-5-carboxymethyl-1,2,4-triazole

[0341] Crude 1-(3-Fluorophenyl)-5-cyanomethyl-1,2,4-triazole (0.9 g) is taken up in ethanol (50 mL) and cooled in an ice bath. HCl gas is bubbled through for 0.5 h. Water (10 mL) is added and the mixture heated at 65° C. for 2 h. After cooling, most of the ethanol is removed on a roto-evaporator, 3 N NaOH (25 mL) and ethanol (25 mL) are then added. The solution is heated at reflux for 2 h, cooled, and then extracted with diethyl ether (3×). The aqueous layer is acidified to pH 2, extracted with ethyl acetate. The organic layer is washed with saturated aqueous sodium chloride, dried (Na2SO4), and concentrated to give 1-(3-Fluorophenyl)-5-carboxymethyl-1,2,4-triazole. 1H NMR (CDCl3): δ 8.08 (s, 1H), 7.50-7.57 (m, 1H), 7.22-7.32 (m, 3H), 4.01 (s, 2H).

[0342] 5. Preparation of 1-Ethyl-2-{[1(3-fluorophenyl)-1,2,4-triazol-5-yl]methyl}-5-cyano-1H-benzimidazole

[0343] Using the procedure described in Example 2, Step 2, 1-(3-fluorophenyl)-5-carboxymethyl-1,2,4-triazole is converted to 1-Ethyl-2-{[1-(3-fluorophenyl)-1,2,4-triazol-5-yl]methyl}-5-cyano-1H-benzimidazole. 1H NMR (CDCl3): δ 8.03 (s, 1H); 8.01 (s, 1H) 7.42-7.56 (m, 5H); 7.22 (m, 1H); 4.51 (s, 2H); 4.43 (q, 2H); 1.45 (t, 3H). LCMS 347.3 (MH+).

Example 4

[0344] Synthesis of 1-Propyl-2-[(5-phenyl-1H-tetrazol-1-yl)methyl]-1H-benzimidazole

[0345] 1. Preparation of 2-(Tri-n-butyltin)-5-phenyl -1H-tetrazole

[0346] A mixture of 5-phenyl-1H-tetrazole (200 mg, 1.22 mmol) and bis(tri-n-butyltin)oxide (0.31 mL, 0.61 mmol) in ethanol (2 mL) is heated at reflux for 10 minutes. The mixture is cooled, concentrated, and the crude 2-(Tri-n-butyltin)-5-phenyl -1H-tetrazole used directly.

[0347] 2. Preparation of 1-Propyl-2-[5-phenyl-1H-tetrazol-1-yl)methyl]-1H-benzimidazole

[0348] Crude 2-(tri-n-butyltin)-5-phenyl-1H-tetrazole (2.09 g, 4.8 mmol) and 1-propyl-2-chloromethylbenzimidazole (1.0 g, 4.8 mmol) are heated in toluene (5 mL) at reflux overnight. The solvent is removed in vacuo, the residue washed with hexane, and then purified by preparative chromatography to give 1-Propyl-2-[(5-phenyl-1H-tetrazol-1-yl)methyl]-1H-benzimidazole as the minor isomer. 1H NMR (CDCl3): δ 8.05-8.12 (m, 2H); 7.77 (m, 1H); 7.58-7.62 (m, 2H); 7.29-7.43 (m, 3H); 5.86 (5, 2H); 4.40 (t, 2 h); 1.85 (m, 2H); 1.01 (t, 3H).

Example 5

[0349] Synthesis of 1-Ethyl-2-{[2-(3-fluorophenyl)-pyrazol-3-yl]methyl}-5-acetyl-1H-benzimidazole

[0350] A mixture of 1-Ethyl-2-{[2-(3-fluorophenyl)-pyrazol-3-yl]methyl}-5-bromo-1H-benzimidazole (200 mg, 0.5 mmol), tributyl(1-ethoxyvinyl)tin (0.34 ml, 1.0 mmol), and tetrakis(triphenylphosphine)palladium(O) (29 mg) in toluene (10 mL) is heated at reflux for 1 h under argon. The solvent is removed in vacuo, the residue is then dissolved in 10% HCl (5 mL) and THF (5 mL). The mixture is stirred at room temperature for 0.5 h, then extracted with ethyl acetate. The aqueous layer is adjusted to pH 9, extracted with dichloromethane, and the organic layer dried (Na2SO4), concentrated, and the residue purified by preparative silica gel chromatography to give 1-Ethyl-2-{[2-(3-fluorophenyl)-pyrazol-3-yl]methyl}-5-acetyl-1H-benzimidazole. 1H NMR (CDCl3): δ 8.36 (d, 1H); 7.99 (dd, 1H); 7.645 (d, 1H); 7.25-7.49 (m, 4H); 7.14 (m, 1H); 6.21 (d, 1 h); 4.36 (s, 2H); 4.02 (g, 2H); 2.68 (s, 3H); 1.24 (t, 3H)

Example 6

[0351] Synthesis of 1-Ethyl-2-{[2-(3-fluorophenyl)-pyrazol-3-yl]methyl)-5-[1-(methoxyimino)ethyl]-1H-benzimidazole

[0352] A mixture of 1-Ethyl-2-{[2-(3-fluorophenyl)-pyrazol-3-yl]methyl}-5-acetyl-1H-benzimidazole (23 mg), methoxylamine hydrochloride (15 mg, 3 eq.), and sodium acetate (15 mg, 3 eq.) in methanol (1 mL) is stirred at room temperature overnight. The solvent is removed in vacuo and aqueous sodium bicarbonate added to pH 9, then extracted with ethyl acetate. The organic layer is dried (Na2SO4) and concentrated to give 1-Ethyl-2-([2-(3-fluorophenyl)-pyrazol-3-yl]methyl}-5-[1-(methoxyimino)ethyl]-1H-benzimidazole. 1H NMR (CDCl3): δ 7.94 (d, 1H); 7.73 (dd, 1H); 7.73 (dd, 1H); 7.63 (d, 1H); 7.52 (m, 1H); 7.38-7.40 (m, 3H); 7.27 (m 1H); 6.19 (d, 1H); 4.32 (s, 2H); 3.87-4.10 (m, 5H); 2.30 (s, 3H); 1.22 (t, 3H)

Example 7

[0353] Synthesis of 1-Ethyl-2-{[2-(2,5-difluorophenyl)-pyrazol-3-yl]methyl}-5-[5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl]-1H-benzimidazole

[0354] A mixture of 1-Ethyl-2-{[2-(2,5-difluorophenyl)-pyrazol-3-yl]methyl}-1H-benzimadol-5-carboxylate (152 mg) and 4-fluorobenzhydrazide (1.05 eq.) in phosphorous oxychloride (6 mL) is heated at reflux for 1.5 h. The mixture is cooled and concentrated, and then water (5 mL) is added to the residue. After adjusting to pH>7 with saturated aqueous bicarbonate, the solution is extracted with ethyl acetate (3×), and the combined organic layers are washed with water (2×) then with saturated aqueous sodium chloride, dried (MgSO4), concentrated, and the residue purified by preparative silica gel chromatography to give 1-Ethyl-2-{[2-(2,5-difluorophenyl)-pyrazol-3-yl]methyl}-5-[5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl]-1H-benzimidazole. LCMS MH+501.068.

Example 8

[0355] Synthesis of 1-Ethyl-2-{[2-(3-fluorophenyl)-1H-imidazol-1-yl]methyl}-5-(1,3,4-oxadiazol-2-yl)-1H-benzimidazole

[0356] A mixture of 1-ethyl-2-{[2-(3-fluorophenyl)-1H-imidazol-1-yl]methyl}-1H-benzimadol-5-hydrazide (177 mg), triethylorthoformate (8 mL) and acetic acid (2 mL) is heated at reflux for 5 h. The reaction is cooled, concentrated, and the residue purified by preparative silica gel chromatography to give 1-Ethyl-2-{[2-(3-fluorophenyl)-1H-imidazol-1-yl]methyl}-5-(1,3,4-oxadiazol-2-yl)-1H-benzimidazole, which was converted to the hydrochloride salt in ethyl acetate. 1H NMR (d6 DMSO): δ 9.32(s,1H), 8.19(s,1H), 8.03(d,1H), 7.97-7.95(m,2Hm), 7.87(d,1H), 7.72(m,1H), 7.66-7.60(m,2H), 7.54-7.50(m,1H), 5.99(s,2H), 4.34(q,2H), 1.31(t,3H), LCMS MH+389.4

Example 9

[0357] Synthesis of 1-Ethyl-2-{[2-(2,5-difluorophenyl)-1H-imidazol-1-yl]methyl}-5-amino-1H-benzimidazole

[0358] 1. Preparation of 4-Fluoro-3-nitroacetanilide

[0359] 4-Fluoro-3-nitroaniline (5.2 g) is treated with acetic anhydride (1.1 eq.) in dichloromethane at room temperature for 1 h. The reaction is concentrated, the residue taken up in dichloromethane and washed with aqueous sodium bicarbonate (2×) then with saturated aqueous sodium chloride, dried (MgSO4), and concentrated to give 4.7 g of crude 4-Fluoro-3-nitroacetanilide.

[0360] 2. Preparation of 3-Nitro-4-(ethylamino)acetanilide

[0361] A mixture of crude 4-Fluoro-3-nitroacetanilide (4.6 9), ethylamine (23 mL of 2M in THF), and potassium carbonate (3.5 g) in DMF (100 mL) is stirred at room temperature for 4 h, then heated at 60° C. for 5 h. The reaction is allowed to cool, water (150 mL) is added, and extracted with ethyl acetate (3×). The combined organic extracts are washed with water (3×), then washed with saturated aqueous sodium chloride, dried (MgSO4), and concentrated to give crude 3-Nitro-4-(ethylamino)acetanilide.

[0362] 3. Preparation of N-[3-Amino-4-(ethylamino)phenyl] acetamide

[0363] Crude 3-Nitro-4-(ethylamino)acetanilide (4.8 g), 10% Pd/C (0.5 g), methanol (50 mL) and ethyl acetate (200 mL) are placed in a Paar apparatus under hydrogen at 50 psi for 5 h. The mixture is filtered through Celite and concentrated to give 4 g of crude N-[3-Amino-4-(ethylamino)phenyl] acetamide

[0364] 4. Preparation of N-{2-{[2-(2,5-Difluorophenyl)-1H-imidazol-1-yl]methyl}-1-ethyl -1H-benzimidazol-5-yl} acetamide

[0365] Using the procedure described in Example 1 Method A, crude N-[3-amino-4-(ethylamino)phenyl] acetamide is converted to N-{2-[2-(2,5-Difluorophenyl)-1H-imidazol-1-yl]methyl)-1-ethyl -1H-benzimidazol-5-yl} acetamide.

[0366] 5. Preparation of 1-Ethyl-2-{[2-(2,5-difluorophenyl)-1H-imidazol-1-yl]methyl}-5-amino-1H-benzimidazole

[0367] Crude N-{1-Ethyl-2-{[2-(2,5-difluorophenyl)-1H-imidazol-1-yl]methyl}-1H-benzimidazol-5-yl} acetamide is treated with 10% aqueous HCl (20 mL) in methanol (10 mL) at reflux for 1.5 h. After cooling, the methanol is removed in vacuo, and the aqueous layer washed with ethyl acetate. The aqueous layer is adjusted to pH 10 with 3 N NaOH, then extracted with ethyl acetate (3×), and the combined organic extracts washed with water (2×) then saturated aqueous sodium chloride, dried (MgSO4), and concentrated to give 1-Ethyl-2-{[2-(2,5-difluorophenyl)-1H-imidazol-1-yl]methyl}-5-amino-1H-benzimidazole. LCMS MH+354.4.

Example 10

[0368] Synthesis of 1-Ethyl-2-{[2-(3-fluorophenyl)-pyrazol-3-yl]methyl}-5-(1,2,4-triazol-1-yl)-1H-benzimidazole

[0369] 1-Ethyl-2-{[2-(3-fluorophenyl)-pyrazol-3-yl]methyl}-5-amino-1H-benzimidazole (274 mg) is treated with N,N-dimethylformamide azine hydrochloride (1 eq) in toluene (10 mL) and methoxyethanol (10 mL) and refluxed for 6 h. After cooling and concentrating, the residue is treated with water and extracted with dichloromethane (2×). The aqueous layer is adjusted to pH 8 with aqueous sodium bicarbonate and extracted with dichloromethane (2×). The combined organic extracts are washed with saturated aqueous sodium chloride, dried (MgSO4) concentrated, purified by preparative silica gel chromatography, and triturated with ether to afford 1-Ethyl-2-{[2-(3-fluorophenyl)-pyrazol-3-yl]methyl}-5-(1,2,4-triazol-1-yl)-1H-benzimidazole, which is converted to the hydrochloride salt in ethyl acetate. LCMS MH+406.2.

Example 11

[0370] Synthesis of 1-ethyl-2-{[2-(2,5-difluorophenyl)-1H-imidazol-1-yl]methyl}-5-(1,2,3-triazol-1-yl-4-carboxylate)-1H-benzimidazole

[0371] 1. Preparation of 1-Ethyl-2-{[2-(2,5-difluorophenyl)-1H-imidazol-1-yl]methyl}-5-azido-1H-benzimidazole

[0372] To an ice-cold solution of 1-ethyl-2-{[2-(2,5-difluorophenyl)-1H-imidazol-1-yl]methyl}-5-amino-1H-benzimidazole (466 mg) in acetic acid (8 mL) a solution of sodium nitrite (1.1 eq) in water (4 mL) is added dropwise. After stirring at 0° C. for 1 h, a solution of sodium azide (1.3 eq) in water (5 mL) is added dropwise. Stirring is continued for 0.5 h at 0° C., and then at room temperature for 0.5 h. The reaction mixture is concentrated to ⅓ volume, water (10 mL) is added and then mixture is then extracted with ethyl acetate (3×). The combined organic layers are washed with aqueous sodium bicarbonate (2×), then washed with saturated aqueous sodium chloride, dried (MgSO4), and concentrated to give 641 mg of crude 1-Ethyl-2-{[2-(2,5-difluorophenyl)-1H-imidazol-1-yl]methyl}-5-azido-1H-benzimidazole.

[0373] 2. Preparation of 1-{2-[2-(2,5-Difluoro-phenyl)-imidazol-1-ylmethyl]-1-ethyl-1H-benzoimidazol-5-yl}-1H-[1,2,3]triazole-4-carboxylic acid ethyl ester

[0374] A mixture of crude 1-ethyl-2-{[2-(2,5-difluorophenyl)-1H-imidazol-1-yl]methyl}-5-azido-1H-benzimidazole (143 mg) and ethyl propiolate (1 eq.) in ethanol (10 mL) is heated at reflux for 6 h. The mixture is cooled, concentrated, and the residue purified by preparative silica gel chromatography to give 1-{2-[2-(2,5-Difluoro-phenyl)-imidazol-1-ylmethyl]-1-ethyl-1H-benzoimidazol-5-yl}-1H-[1,2,3]triazole-4-carboxylic acid ethyl ester. 1H NMR (CDCl3): δ 8.51 s,(1H), 8.05(s, 1H), 7.74(m,1H), 7.50-7.39(m,4H), 7.21-7.17(m,2H), 7.06(s,1H), 5.54(s,2H), 4.47(q,2H), 3.86(q,2H), 1.43(t,3H), 1.04(t,3H), LCMS MH+460.6.

Example 12

[0375] Synthesis of 1-ethyl-2-{[2-(2,5-difluorophenyl)-pyrazol-3-yl]methyl}-5-(1,2,3,4-tetrazol-1-yl)-1H-benzimidazole

[0376] 1-Ethyl-2-{[2-(2,5-difluorophenyl)-pyrazol-3-yl]methyl}-5-amino-1H-benzimidazole (104 mg) is treated with triethylorthoformate (4 eq) in acetic acid (10 mL) at reflux for 4 h. After concentrating the solution, acetic acid is re-added, sodium azide (4 eq ) added, and the mixture heated at 70° C. for 3 h. After cooling, water (15 mL) is added and the mixture concentrated. The residue is taken up in ethyl acetate, washed with aqueous sodium bicarbonate (2×) then saturated aqueous sodium chloride, dried (MgSO4), concentrated, and purified by preparative silica gel chromatography to give 1-ethyl-2-{[2-(2,5-difluorophenyl)-pyrazol-3-yl]methyl}-5-(1,2,3,4-tetrazol-1-yl)-1H-benzimidazole, which is converted to the hydrochloride salt in ethyl acetate. LCMS MH+ 395.018.

Example 13

[0377] Synthesis of 1-Ethyl-2-{[2-(2,5-difluorophenyl)-pyrazol-3-yl]methyl}-5-(5-methyl-oxazol-2-yl)-1H-benzimidazole

[0378] 1. Preparation of N-propargyl 1-ethyl-2-{[2-(2,5-difluorophenyl)-pyrazol-3-yl]methyl}-1H-benzimidazole-5-carboxamide

[0379] Oxalyl chloride (2.5 eq of 2M in dichloromethane) is added dropwise to a solution of 1-ethyl-2-{[2-(2,5-difluorophenyl)-pyrazol-3-yl]methyl}-1H-benzimidazole-5-carboxylate (368 mg) in DMF (5 drops) and dichlormethane (30 mL) at 0° C. The mixture is stirred at 0° C. for 0.5 h, then at room temperature for 1 h. The solution is concentrated, the residue taken up in DMF (30 ml), excess propargylamine added, and the mixture stirred for 6 h. Dilute aqueous sodium bicarbonate is added then extracted with dichloromethane (3×), the combined organic layers washed with saturated aqueous sodium chloride, dried (MgSO4), and concentrated to give 462 mg of crude N-propargyl 1-ethyl-2-{[2-(2,5-difluorophenyl)-pyrazol-3-yl]methyl}-1H-benzimidazole-5-carboxamide.

[0380] 2. Preparation of 1-Ethyl-2-{[2-(2,5-difluorophenyl)-pyrazol-3-yl]methyl}-5-(5-methyl-oxazol-2-yl)-1H-benzimidazole

[0381] A mixture of crude N-propargyl 1-ethyl-2-{[2-(2,5-difluorophenyl)-pyrazol-3-yl]methyl}-1H-benzimidazole-5-carboxamide (450 mg) and mercury(II) acetate (1 eq) is heated at reflux in acetic acid (15 mL) for 6 h. The mixture is concentrated, saturated aqueous potassium carbonate added and extracted with ethyl acetate (3×). The combined organic layers were washed with water then with saturated aqueous sodium chloride, dried (MgSO4), concentrated, and triturated with ether to give 1-ethyl-2-{[2-(2,5-difluorophenyl)-pyrazol-3-yl]methyl}-5-(5-methyl-oxazol-2-yl)-1H-benzimidazole, which is converted to the hydrochloride salt in ethyl acetate. 1H NMR (d6 DMSO): δ 8.16(s,1H), 8.09-9.0 m.(2H), 7.78(m,1H), 7.62(m,1H), 7.49-7.45(m,3H), 7.04(m,1H), 6.56(s,1H), 4.70(s,2H), 4.36(q,2H), 2.41(s,3H), 1.21(t,3H). LCMS MH+420.5.

Example 14

[0382] Synthesis of 2-{[2-(3-Fluorophenyl)-1H-imidazol-1-yl]methyl}-1-ethyl-5-(1,2,4-oxadiazol-3-yl)-1H-benzimidazole

[0383] 1. Preparation of 1-Ethyl-2-{[2-(2,5-difluorophenyl)-1H-imidazol-1-yl]methy-1H-benzimidazol}-5-carboxamide oxime l-Ethyl-2-{[2-(3-fluorophenyl)-1H-imidazol-1-yl]methyl}-5-cyano-1H-benzimidazole (340 mg) is added to a solution of hydroxylamine hydrochloride (137 mg, 2 eq) and triethylamine (0.3 mL, 2.2 eq) in methanol (3 mL), then heated at reflux for 2.5 h. The reaction is cooled, concentrated, water added, the solid collected and rinsed well with water and dried to give 305 mg of 1-Ethyl-2-{[2-(2,5-difluorophenyl)-1H-imidazol-1-yl]methy-1H-benzimidazol}-5-carboxamide oxime.

[0384] 2. Preparation of 1-Ethyl-2-{[2-(2,5-difluorophenyl)-1H-imidazol-1-yl]methy-1H-benzimidazol}-5-carboxamide oxime 1-Ethyl-2-{[2-(3-fluorophenyl)-1H-imidazol-1-yl]methy-1H-benzimidazol}-5-carboxamide oxime (161 mg) is treated with triethylorthoformate (3 mL) and boron trifluoride-THF complex (0.1 mL) at 100° C. for 2.5 h. 1N HCl (0.5 mL) is added to the hot mixture; the reaction is then cooled and concentrated. After cooling in an ice bath, aqueous sodium hydroxide is added. The solid is collected, rinsed with water, then ether and dried to give 1-Ethyl-2-{[2-(2,5-difluorophenyl)-1H-imidazol-1-yl]methy-1H-benzimidazol}-5-carboxamide oxime, which is converted to the methanesulfonate salt in acetone. Mp 183-186° C.

Example 15

[0385] Synthesis of 4-amino-3-ethylaminobenzonitrile

[0386] 1. 4-nitro-3-chlorobenzonitrile

[0387] To an ice cold solution of 4-amino-3-chlorobenzonitrile (1 g, 6.6 mmol) in concentrated HCl (2.5 mL) plus water (2.5 mL) a chilled solution of sodium nitrite (0.74 g, 1.62 eq) in water (3.6 mL) is added dropwise to maintain the reaction temperature <0° C. After stirring at 0° C. for 10 min, the mixture is added portion-wise to an ice cold solution of sodium nitrite (3.29 g, 7.22 eq) and copper(I) oxide (349 mg, 0.37 eq) in water 14.5 mL). Stirring is continued at 0° C. for 40 min, and then at room temperature for 0.5 h. The reaction mixture is extracted with dichloromethane (2×), the combined organic layers washed with saturated aqueous sodium chloride, dried (MgSO4), concentrated, and purified by silica gel chromatography to give 4-nitro-3-chlorobenzonitrile. 1H NMR (CDCl3): δ 7.96 (d, J=8.24 Hz, 1 h), 7.88 (d, J=1.65 Hz, 1H), 7.63 (dd, J=1.65, 8.24 Hz, 1H.

[0388] 2. Preparation of 4-Ethylamino-3-chloro benzonitrile

[0389] A mixture of 4-nitro-3-chlorobenzonitrile (0.74 g, 4.1 mmol), potassium carbonate (1.68 g, 12.2 mmol), and ethylamine(4 mL, 2M in THF) in DMF (2 mL) is stirred at ambient temperature for 3 h. Additional ethylamine (2.1 mL, 2M in THF) is added, the flask stoppered, and stirring continued an additional 15.5 h. Water (50 mL) is added and extracted 2× with ethyl acetate (50 mL), and the combined organic layers are washed with water, then brine, dried (MgSO4), and concentrated to give a mixture of 3-Ethylamine-4-nitrobenzonitrile and 4-Ethylamino-3-chloro benzonitrile which was carried forward without purification.

[0390] 3. Preparation of 4-Amino-3-ethylaminobenzonitrile

[0391] To a suspension of crude 4-ethylamino-3-chloro benzonitrile (above) in conc. HCl (4 mL) tin(II) chloride dihydrate (3.16 g) is added. After stirring at ambient temperature for 1.5 h, the mixture is poured onto ice and the solution mad alkaline with 10 N aq. NaOH. The aqueous solution is extracted 2× with dichloromethane, and the combined organic layers washed with brine, dried (MgSO4), and concentrated. Trituration with ether affords 4-Amino-3-ethylaminobenzonitrile as a white solid. 1H NMR (CDCl3): δ 7.00 (dd, J=1.65, 7.97 Hz, 1H), 6.83 (d, J=1.65 Hz, 1H), 6.67 (d, J=7.97 Hz, 1 h), 3.13 (q, J=7.14 Hz, 1.31 (t, J=7.14 Hz, 3H)

Example 16

[0392] Synthesis of 2-Fluoro-6-(1H-imidazol-2-yl)-pyridine

[0393] 1. Preparation of 2-Fluoropyridine-6-carboxaldehyde

[0394] Method A

[0395] 2-Fluoro-6-methylpyridine (14.4 g, 0.13 mol) and tert-butoxybis(dimethylamino)methane (Bredereck's reagent; 34.9 g, 0.20 mol) are heated at 140° C. for 24 h. The reaction is cooled and diluted with THF (100 mL). Sodium periodate (75 g) in water (400 mL) is added at 0-5° C., and the reaction mixture is then stirred for 24 h at room temperature. The precipitate is filtered through celite, and the filtrate extracted 5× with diethyl ether. The combined ether layers are washed with water, brine, and dried (MgSO4). Most of the solvent is removed by concentration at 0° C. (by keeping ice in the bath) to provide 2-Fluoropyridine-6-carboxaldehyde.

[0396] Method B

[0397] 2-Fluoropyridine-6-carboxaldehyde can also be prepared as follows: To a solution of diisopropylamine (6.54 mL, 1.2 equiv) in 30 mL of THF at 0 ° C. a solution of n-butyllithium (17.1 mL, 2.5M in hexanes) is added dropwise. Stirring is continued for 15 minutes at 0° C., the reaction is then cooled to −78° C. 2-Fluoro-6-methylpyridine (4.00 mL, 38.9 mmol) is added dropwise to the cold solution. The reaction mixture is stirred at −78° C. for 1 h and then quenched with DMF (4.52 mL, 1.5 equiv). The reaction is maintained at −78° C. for 30 minutes and then warmed to 0° C. The cold solution is added to a mixture of sodium periodate (24.9 g) in 120 mL of water at 0° C. The reaction mixture is allowed to gradually warm to room temperature over 1 h and then stirred at room temperature for 24 h. The reaction mixture is filtered through a plug of celite to remove the precipitate and the plug is washed with ether. The organic layer is separated, washed with aqueous sodium bicarbonate (1×40 mL), then with 0.25M KH2PO4 (1×40 mL) and then brine (1×40 mL). The organic solution is dried (NaSO4) and concentrated in vacuo.

[0398] 2. Preparation of 2-Fluoro-6-(1H-imidazol-2-yl)-pyridine

[0399] To a solution of the crude aldehyde from step 1, Method B (above) in methanol (12 mL) aqueous glyoxal (6.21 mL, 40 wt. % in water) is added dropwise. The solution is cooled to 0° C. and aqueous ammonium hydroxide (6.0 mL, 28 wt. % in water) is added. The reaction is allowed to warm to room temperature gradually over about an hour and then stirred another 3 h at room temperature. Most of the methanol is removed in vacuo, the reaction mixture diluted with water (10 mL) and extracted with ethyl acetate (30 mL). The organic layer is washed with brine (20 mL), diluted with hexanes (15 mL), passed through a plug of silica gel (¼ inch deep×¼ inch diameter), and the plug washed with more 2:1 ethyl acetate/hexanes (20 mL). The combined eluents are concentrated in vacuo to yield crude 2-Fluoro-6-(1H-imidazol-2-yl)-pyridine.

Example 17

[0400] Synthesis of 2-Fluoro-6-(1H-imidazol-2-yl)-pyridine acetic acid

[0401] 1. Preparation of [2-(6-fluoropyridin-2-yl)-imidazol-1-yl]acetic Acid Tert-Butyl Ester

[0402] A mixture of 2-Fluoro-6-(1H-imidazol-2-yl)pyridine (410 mg; 2.51 mmol), tert-butyl bromoacetate (539 mg; 2.76 mmol), potassium carbonate (520 mg; 3.77 mmol), and N,N-dimethylformamide (20 mL) is stirred at room temperature for 16 h. Water (60 mL) is added and the mixture extracted with ethyl acetate (3×70 mL). The organic extracts are washed with water (3×40 mL) and brine (1×40 mL), dried (MgSO4), and concentrated to give [2-(6-Fluoropyridin-2-yl)-imidazol-1-yl]acetic acid tert-butyl ester as an orange oil (630 mg). 1H NMR (CDCl3) δ 8.12 (dd,1H), 7.82(q,1H), 7.16(s,1H), 6.98(s,1H), 6.81(dd,1H), 5.14(s,2H), 1.44 s,(9H), LCMS: 276.1(M)

[0403] 2. Preparation of 2-Fluoro-6-(1H-imidazol-2-yl)-pyridine Acetic Acid

[0404] A solution of [2-(6-fluoropyridin-2-yl)-imidazol-1-yl]acetic acid tert-butyl ester (630 mg; 2.27 mmol) and trifluoroacetic acid (4 mL) in dichloromethane (4 mL) is stirred at room temperature for 5 hr. The reaction mixture is concentrated. The residue is treated with 3M HCl in ethyl acetate (10 mL) and the suspension stirred at room temperature for lhr. The precipitate is collected, washed with ethyl acetate, and dried to give 2-Fluoro-6-(1H-imidazol-2-yl)-pyridine acetic acid as a tan solid (581 mg), 1H NMR (d6DMSO) δ 8.35-8.26(m,2H), 7.83(s,1H), 7.76(s,1H), 7.44-7.41(m.1H), 5.40(s,2H). LCMS: 222.1(MH+).

Example 18

[0405] Synthesis of 2-{[2-(2,5-di-fluorophenyl)-1H-imidazol-1-yl]methyl}-1-ethyl-1H-imidazo[4,5-b]pyridine

[0406] 1. Preparation of 3-ethylamino-2-nitro-pyridine

[0407] Ice cold ethylamine (0.55 mL) was added to a solution of 3-fluoro-2-nitropyridine (400 mg, 2.8 mmol; prepared according to N. Ple and G. Queguiner, J. Heterocyclic Chem, 1989, 26, 475-476) in 2:1 DMF:THF (6 mL) at ambient temperature, and the mixture stirred for 0.75 h. Water was added, then extracted 2× with ethyl acetate. The combined organic layers were washed with water then with saturated aqueous sodium chloride, dried (MgSO4), and concentrated to give 3-ethylamino-2-nitro-pyridine as a gold solid. 1H NMR (CDCl3): δ 7.87 (d, 1 h0, 7.43 (dd, 1H), 7.35 (d, 1H), 3.38 (pentet, 2H), 1.4 (t, 3H). LCMS: 121.1(MH+—NO2)

[0408] 2. Preparation of 2-Amino-3-ethylaminopyridine

[0409] A mixture of 3-ethylamino-2-nitro-pyridine (400 mg), 10% palladium on carbon (40 mg) and 1:1 ethyl acetate:methanol (30 mL) were placed in a Parr apparatus under hydrogen (50 psi) for 50 min. The mixture was filtered through Celite, concentrated, and the product triturated with hexane to give 2-Amino-3-ethylaminopyridine as a brown solid. More material was recovered from the filtrate. 1H NMR (CDCl3): δ 7.59 (d, J=4.94 Hz, 1H), 6.81 (d, J=6.32 Hz, 1H), 6.71 (dd, J=4.94, 7.69 Hz, 1H), 3.12 (q, J=7.14 Hz, 2 h), 1.31 (t, J=7.14 Hz, 3H).

[0410] 3. Preparation of 2-{[2-(2,5-Difluorophenyl)-1H-imidazol-1-yl]methyl}-1-ethyl-1H-imidazo[4,5-b]pyridine 2-Amino-3-ethylaminopyridine (60 mg, 0.43 mmol) and methyl 1-carboxymethyl-2-(2,5-difluorophenyl)-imidazole (193 mg, . 0.76 mmol) were used according to Example 1 Method B to prepare 2-{[2-(2,5-Difluorophenyl)-1H-imidazol-1-yl]methyl}-1-ethyl-1H-imidazo[4,5-b]pyridine, which is converted to the hydrochloride salt in ethyl acetate. m.p. 214-216° C. LCMS MH+ 322.2, MH− 320.3.

Example 19

[0411] Synthesis of 2-{[2-(3-Fluorophenyl)-1H-imidazol-1-yl]methyl}-1-ethyl-3H-imidazo[4,5-c]pyridine

[0412] 1. Preparation of 3-Chloro-4-nitropyridine N-oxide

[0413] Aqueous hydrogen peroxide (30 mL of 30%) is added dropwise to an ice cold mixture of 3-chloropyridine (6.0 g, 53 mmol) in acetic anhydride (30 mL). The mixture is allowed to stir at ambient temperature for 24 h, water is then added and the mixture concentrated. The residue is taken up in concentrated sulfuric acid (10 mL) and fuming sulfuric acid (5 mL), and then cooled to 0° C. Concentrated nitric acid (24 mL) is added slowly, and the ice bath removed. The reaction is then heated at reflux for 2 h, icooled, and poured into ice water. Ammonium bicarbonate is added carefully until pH 8 is achieved, the solution is then extracted with dichloromethane. The organic layer is washed with water, dried (NaSO4), and concentrated to give 3-Chloro-4-nitropyridine N-oxide as a yellow solid. 1H NMR (CDCl3): δ 8.47 (d, J=4 Hz, H), 8.35 (dd, J=5, 12 Hz, 1H), 7.73 (ddd, J=4, 9, 12 Hz, 1H).

[0414] 2. Preparation of 3-Ethylamino-4-nitro-3-pyridine N-oxide

[0415] To an ice cold solution of 3-chloro-4-nitropyridine N-oxide (2.93 g, 16.8 mmol) in ethanol (30 mL) ethylamine (25 mL of 2M in THF) is added. The mixture is allowed to stir overnight at ambient temperature, then concentrated in vacuo to afford crude 3-Ethylamino-4-nitro-3-pyridine N-oxide as a yellow oil. 1H NMR (CDCl3): δ 8.01 (d, J=7 Hz, H), 7.91 (s, 1H), 7.45 (d, J=7 Hz, 1H), 3.31 (q, J=7 Hz, 2H), 1.40 (t, J=7 Hz, 3H) 3. Preparation of 3-Ethylamino-4-aminopyridine

[0416] Crude 3-ethylamino-4-nitro-3-pyridine N-oxide and 10% palladium on carbon (1 g) in methanol (30 mL) are placed in a Parr apparatus under hydrogen (60 psi) for 2 days. Additional 10% palladium on carbon (880 mg) is added and returned under hydrogen (60 psi) for 2 days. The mixture was filtered through Celite, concentrated, and the product triturated with hexane-ether to afford 1.3 g of 3-Ethylamino-4-aminopyridine. 1H NMR (d6-DMSO): δ 7.63 (d, J=6 Hz, 1H), 7.47 (s, 1H), 6.57 (d, J=6 Hz, 1H), 3.05 (q, J=7 Hz, 2H), 1.21 (t, J=7 Hz, 3H)

[0417] 4. Preparation of 2-{[2-(3-Fluorophenyl)-1H-imidazol-1-yl]methyl}-1-ethyl-3H-imidazo[4,5-c]pyridine 3-Ethylamino-4-aminopyridine (548 mg, 3.99 mmol) and methyl 1-carboxymethyl-2-(3-fluorophenyl)-imidazole (467 mg, 1.99 mmol) were used according to Example 1 Method B to prepare 2-{[2-(3-Fluorophenyl)-1H-imidazol-1-yl]methyl}-1-ethyl-3H-imidazo[4,5-c]pyridine. 1H NMR (CDCl3): δ 1.08(t, J=7 Hz, 3H), 3.89(q, J=7 Hz, 2H), 5.52(s, 2H), 7.04(s, 1H), 7.16-7.20(m, 2H), 7.37-7.50(m, 3H), 7.68(d, J=6 Hz, 1H), 8.47(d, J=6 Hz, 1H) 8.78(s, 1H).

Example 20

[0418] Synthesis of 3-fluoro-(1H-imidazol-2-yl)benzene

[0419] Saturated ammonium hydroxide solution (30 mL) is slowly added to a solution of 3-fluorobenzaldehyde (12.4 g, 100 mmol) and glyoxal (17.5 mL of 40% wt in water, 120 mmol) in methanol (100 mL) at ambient temperature. After stirring for 24 h, most of the solvent is removed at reduced pressure. Benzene is added and evaporated to remove residual water. The resulting dark oil is purified by chromatography on silica gel (2% MeOH/CH2Cl2) to obtain a tan solid. Trituration with ether/hexane provides 3-fluoro-(1H-imidazol-2-yl)benzene as a white solid. LRMS m/z (M+1) 163.2.

Example 21

[0420] Synthesis of 3-chloro-4-fluoro-(1H-imidazol-2-yl)benzene

[0421] A mixture of 3-chloro-4-fluoro-benzaldehyde (0.032 mol), glyoxal (40% in water, 0.038 mol) and ammonium hydroxide (28% in water, 0.16 mol) in MeOH (60 mL) is stirred at room temperature overnight. Solvent is removed in vacuo and the residue is partitioned between water and CH2Cl2. The organic layer is washed with brine, dried (Na2SO4), and concentrated. The residue is purified by column chromatography on silica gel eluting with CH2Cl2/MeOH (95/5) to afford 3-chloro-4-fluoro-(1H-imidazol-2-yl)benzene as a yellow solid. 1H NMR (CDCl3) δ 7.88 (dd, 1H), 7.70 (m, 1H), 7.19 (t, 1H), 7.17 (s, 2H). LRMS m/z (M+1) 197.0.

Example 22

[0422] Synthesis of 2,3,4-trifluoro-(1H-imidazol-2-yl)benzene

[0423] Saturated ammonium hydroxide solution (26 mL) is slowly added to a solution of 2,3,4-trifluorobenzaldehyde (5.0 g, 31.2 mmol) and glyoxal (10.75 mL of 40% wt in water, 93.7 mmol) in methanol (100 mL) at ambient temperature. After stirring for 24 h, most of the solvent is removed at reduced pressure. Benzene is added and evaporated to remove residual water. The resulting dark oil is purified by chromatography on silica gel (5% MeOH/CH2Cl2) to obtain a tan solid. Trituration with ether/hexane provides 2,3,4-trifluoro-(1H-imidazol-2-yl)benzene as a white solid. LRMS m/z (M+1) 199.10.

Example 23

[0424] Synthesis of 2-(1H-imidazol-2-yl)-thiazole

[0425] 1. Preparation of 1-ethoxymethyl-2-tributylstannanyl-1H-imidazole

[0426] 1.6 M n-BuLi (12.0 mL, 19.2 mmol) is slowly added to a solution of 1-ethoxymethyl-1H-imidazole [available via the procedure outlined in Tang, C. C.; Davalian, D.; Huang, P.; Breslow, R. J. Am. Chem. Soc. 1978, 100, 3918] (2.20 g, 17.4 mmol) in THF (30 mL) at −78° C. under N2. The reaction mixture is stirred at −78° C. for 20 min. whereupon tributyltin chloride (5.7 mL, 20.9 mmol) is slowly added. The reaction mixture is stirred at −78° C. for 10 min. and then warmed to room temperature. After stirring at room temperature for 1.5 h, the reaction mixture is concentrated in vacuo. The residue is triturated with hexanes and filtered, and the filtrate is concentrated in vacuo. The residue is again triturated with hexanes and filtered, and the filtrate concentrated in vacuo. The 1H NMR of the resulting oil indicates a 2:1 mixture of 1-ethoxymethyl-2-tributylstannanyl-1H-imidazole: 1-ethoxymethyl-1H-imidazole. This material is used in the next reaction without further purification. Selected 1H NMR resonances (400 MHz, CDCl3) δ 7.21 (s, 1H), 7.14 (s, 1H), 5.24 (s, 2H) ppm.

[0427] 2. Preparation of 2-(1-ethoxymethyl-1H-imidazol-2-yl)-thiazole

[0428] A solution of crude 1-ethoxymethyl-2-tributylstannanyl-1H-imidazole (previous experimental), 2-bromothiazole (1.05 mL, 11.6 mmol, 1.0 eq based on integration of 1H NMR of crude 1-ethoxymethyl-2-tributylstannanyl-1H-imidazole), and Pd (PPh3)4 (0.67 g, 0.58 mmol) in toluene (20 mL) is stirred at 80° C. for 18 h. After cooling to room temperature, the reaction mixture is poured into saturated aqueous NaHCO3 and extracted twice with CH2Cl2. The combined extracts are dried over Na2SO4 and concentrated in vacuo. The residue is purified by flash chromatography on silica gel, eluting with 2:1 hexanes-EtOAc (+0.5% Et3N). Fractions containing product are concentrated and resubjected to flash chromatography on silica gel. Elution with 2:1 hexanes-EtOAc (+0.5% Et3N) affords (26%) of 2-(1-ethoxymethyl-1H-imidazol-2-yl)-thiazole as a bright yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J 3.2 Hz, 1H), 7.33 (d, J=3.2 Hz, 1H), 7.20 (d, J=1.2 Hz, 1H), 7.15 (d, J=1.2 Hz, 1H) 6.03 (s, 2H), 3.56 (q, J=7.2 Hz, 2H), 1.17 (t, J=7.2 Hz, 3H) ppm.

[0429] 3. Preparation of 2-(1H-imidazol-2-yl)-thiazole

[0430] Concentrated HCl (10 ml) is added to a solution of 2-(1-ethoxymethyl-1H-imidazol-2-yl)-thiazole (940 mg, 4.49 mmol) in 24 mL of 1:1 EtOH-H2O at room temperature. The solution is stirred at reflux for 3 h. The reaction mixture is then cooled to 0° C. and made basic by the addition of about 12 mL of 10 N aqueous NaOH. The mixture is back titrated to approximately pH 4 using concentrated HCl. Solid NaHCO3 is added to the point of saturation and approximately pH 8. The mixture is then extracted twice using a mixture of THF and EtOAc. The combined extracts are dried over Na2SO4 and concentrated to an oily solid, which is triturated with a small amount of CH2Cl2. The solid is collected by filtration. The filtrate is concentrated, and the oily solid triturated once more with CH2Cl2. The second resultant solid is collected by filtration and combined with the solid first obtained. The product, 2-(1H-imidazol-2-yl)-thiazole, is obtained as a slightly off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 13.04 (br, 1H), 7.87 (d, J=3.2 Hz, 1H), 7.70 (d, J=3.2 Hz, 1H) 7.14 (br, 2H) ppm.

[0431] The compound of this example can be prepared essentially according to the procedures described in Example 21.

Example 24

[0432] Synthesis of 2-(1H-Imidazol-2-yl)-pyrimidine hydrochloride

[0433] A mixture of 2-Cyanopyrimidine (8.0 g, 76 mmol, prepared according to Liebigs Ann.Chem. 2, 1981, 333-341) and Aminoacetaldehyde dimethyl acetal (8 g, 76 mmol) is heated at 100° C. for 4 hours, cooled, and 100 mL of MeOH and 5 mL of concentrated HCl are added. The mixture is heated at reflux with stirring for 30 hours, cooled and evaporated to dryness in vacuo. 50 mL of i-PrOH is added to the residue and the mixture is heated at reflux with stirring for 30 minutes and cooled. The crystals are collected by filtration, washed with ether, and dried to give the title compound. 1H NMR (DMSO): δ 9.08 (d, 2H), 7.87 (s, 2H), 7.75 (t, 1H). LRMS calcd 146, found 147 (MH+).

Example 25

[0434] Synthesis of 2-(1H-Imidazol-2-yl)-thiazole-4-carbonitrile

[0435] 1) Preparation of 1-Dimethylsulfamoyl-1H-imidazole-2-carbothioic acid methoxymethyl-amide

[0436] To a solution of 1-Dimethylsulfamoyl-1-imidazole (2.0 g, 11.4 mmol) in 10 mL of anhydrous THF at −78° C. is added a solution of n-BuLi in Hexane (2.5 M, 4.6 mL) dropwise under N2. After the mixture is stirred at the same temperature for about one hour, Methoxymethyl isocyanate (1.2 g, 11.4 mmol) is added dropwise at −78° C. The reaction mixture is stirred at −78° C. for about 6 hours and slowly warmed to room temperature. After quenched with a saturated aqueous NH4Cl solution (20 mL), the mixture is extracted with Ethyl acetate (20 mL ×2). The extract is washed with water, dried and concentrated. The residue is purified on a silica gel column with 3% MeOH in CH2Cl2 as eluent to give the title compound. 1H NMR (CDCl3): δ 8.60 (br, 1H), 7.32 (d, 1H), 7.01 (d, 1H), 5.22 (d, 2H), 3.51 (s, 3H), 3.00 (d, 6H). LRMS calcd 278, found 279 (MH+).

[0437] 2) Preparation of 1H-Imidazole-2-carbothioic acid amide

[0438] A solution of 1-Dimethylsulfamoyl-1H-imidazole-2-carbothioic acid methoxymethyl-amide (1.0 g, 3.6 mmol) in Acetic acid (10 mL) and water (2 mL) is stirred at 50° C. overnight. After the volatiles are evaporated in vacuo, the residue is partitioned between Ethyl acetate (40 mL) and aqueous NaHCO3 (10 ML). The organic layer is separated, washed with water, dried and concentrated in vacuo to a solid (250 mg). 1H NMR (DMSO): δ 12.7 (s, 1H), 9.65 (s, 1H), 9.42 (s, 1H), 7.24 (s, 1H), 7.15 (s, 1H).

[0439] 3) Preparation of 2-(1H-Imidazole-2-yl)-thiazole-4-carboxylic Acid Ethyl Ester

[0440] A mixture of 1H-Imidazole-2-carbothioic acid amide (200 mg, 1.57 mmol) and Ethyl bromopyruvate (340 mg, 1.57 mmol) is heated at 75° C. for about 5 hours. After the volatiles are evaporated in vacuo, the residue is partitioned between Ethyl acetate (40 mL) and aqueous NaHCO3 (10 ML). The organic layer is separated, washed with water, dried and concentrated. The residue is purified on a silica gel column with 3% MeOH in CH2Cl2 as eluent to give 200 mg of the titled compound. 1H NMR (CDCl3): δ 8.15 (s, 1H), 7.20 (br, 1H), 7.10 (br, 1H), 4.33 (q, 2H), 1.23 (t, 3H). LRMS calcd 223, found 224 (MH+).

[0441] 4) Preparation of 2-(1H-Imidazole-2-yl)-thiazole-4-carboxylic Acid Amide

[0442] A solution of 2-(1H-Imidazole-2-yl)-thiazole-4-carboxylic acid ethyl ester (190 mg) in 5 mL of MeOH is saturated with NH3 gas, and heated at 60° C. in a sealed tube overnight. After cooled, the reaction mixture is transferred to a round bottle flask and evaporated in vacuo to a solid. LRMS calcd 194, found 195 (MH+).

[0443] 5) Preparation of 2-(1H-Imidazole-2-yl)-thiazole-4-carbonitrile

[0444] To a solution of 2-(1H-Imidazole-2-yl)-thiazole-4-carboxylic acid amide (120 mg) in 2 mL of anhydrous pyridine is added 0.25 mL of POCl3 dropwise at 0° C. The reaction mixture is stirred at the same temperature for 2 hours, poured into ice water, neutralized with solid NaHCO3, and extracted with 5% MeOH in CH2Cl2. The extract is washed with brine, dried and concentrated to a solid. 1H NMR (DMSO): δ 13.45 (br, 1H), 8.82 (s, 1H), 7.38 (s, 1H), 7.12 (s, 1H). LRMS calcd 176, found 177 (MH+).

Example 26

[0445] Synthesis of 2-[2-(6-fluoro-pyridin-2-yl)-imidazol-1-ylmethyl]-1-propyl-1-H-imidazo[4,5-c]pyridine

[0446] 1. Preparation of (3-nitro-pyridin-4-yl)-propyl-amine

[0447] To a solution of 4-chloro-3-nitro-pyridine(18.0 g, 114 mmol) in EtOH(300 ml) is added n-propylamine(46.9 ml, 568 mmol) slowly at 0° C. and the resulting yellow mixture is warmed to room temp. After stirring for 2 h, the reaction is concentrated in vacuo. The residue is purified by flash chromatography (eluent 50% Hex/EtOAc) to give (3-nitro-pyridin-4-yl)-propyl-amine as a yellow solid. 1H NMR (CDCl3) δ 9.16 (s, 1H), 8.25(d, J=6 Hz, 1H), 8.15(br s, 1H), 6.68(d, J=6 Hz, 1H), 3.29(q, J=6.8 Hz, 2H), 1.74 (sextet, J=7.2 Hz, 2H), 1.02(t, J=7.6 Hz, 3H). LRMS calcd 181.19, found 182.5 (MH+).

[0448] 2. Preparation of N-propyl-pyridine-3,4-diamine

[0449] A solution of (3-nitro-pyridin-4-yl)-propyl-amine(19.7 g, 109 mmol) in abs. MeOH(150 ml) is hydrogenated at room temp. and 50 psi in the presence of 10% palladium on carbon(1.9 g) for 15 h. Removal of catalyst, concentration of filtrate, and recrystallization the residue in dichloromethae-hexane yields N-propyl-pyridine-3,4-diamine as a tan solid. 1H NMR (DMSO-d6) δ 7.59 (s, 1H), 7.55(d, J=5.4 Hz, 1H), 6.30(d, J=5.4 Hz, 1H), 5.26(br s, 1H), 4.55(br s, 2H), 3.02(q, J=6.6 Hz, 2H), 1.56 (sextet, J=7.1 Hz, 2H), 0.92(t, 7.2 Hz, 3H). LRMS calcd 151.21, found 152.4 (MH+).

[0450] 3. Preparation of 2-[2-(6-fluoro-pyridin-2-yl)-imidazol-1-ylmethyl]-1-propyl-1-H-imidazo[4,5-c]pyridine

[0451] Trimethylaluminum (11 ml of 2.0M in toluene, 22.4 mmol) is added dropwise to a solution of N-propyl-pyridine-3,4-diamine(1.70 g, 11.2 mmol) in dichloromethane(50 ml), and the mixture is stirred for 30 minutes at room temperature. To this is added a solution of [2-(6-fluoro-pyridin-2-yl)-imidazol-1-yl]-acetic acid methyl ester (1.32 g, 5.61 mmol) in dichloromethane (10 ml) The mixture is heated at reflux for 18 hours. The resulting brown mixture is poured into ice-water and filtered through celite. The filtrate is extracted with dichloromethane and the combined extracts are washed with saturated brine, dried over anhydrous Na2SO4, filtered, concentrated in vacuo, and chromatographed on silica gel to afford 2-[2-(6-fluoro-pyridin-2-yl)-imidazol-1-ylmethyl]-1-propyl-1-H-imidazo[4,5-c]pyridine as a pale yellow solid. 1H NMR (CDCl3) δ 9.06(s, 1H), 8.42(d, J=5.6 Hz, 1H), 8.18(dd, J=2.1, 7.6 Hz, 1H), 7.88(dd, J=7.6, 8.4 Hz, 1H), 7.29(d, J=5.6 Hz, 1H), 7.22(s, 1H), 7.18(s, 1H), 6.88(dd, J=2.4, 8.4 Hz, 1H), 6.29 (s, 2H), 4.26(t, J=7.6 Hz, 2H), 1.68(sextet, J=7.2 Hz, 2H), 0.84(t, J=7.2 Hz, 3H). LRMS calcd 336.37, found 337.6 (MH+).

Example 27

[0452] Synthesis of 3-Ethyl-2-{[2-(1,3-thiazol-2-yl)-1H-imidazol-1-yl]methyl}-3H-imidazo[4,5-c]pyridine

[0453] 1. Preparation of 3-Chloro-4-nitro-pyridine-1-oxide

[0454] Aqueous 30% H2O2 (60 mL) is added dropwise to a magnetically stirred solution of 3-chloro-pyridine (12 g, 105 mmol) in acetic anhydride (60 mL) under cold conditions (0 to 10° C.). The resulting mixture is allowed to warm up to room temperature slowly and then stirred overnight at room temperature. The reaction mixture is quenched with water (50 mL), diluted with toluene and concentrated to obtain the crude N-oxide as an oil in near quantitative yield.

[0455] Fuming H2SO4 (25 mL) is added dropwise to a solution of crude 3-chloro-pyridine-1-oxide in concentrated H2SO4 (25 mL) under cold conditions (0° C.) with stirring. HNO3 (fuming, 90%, 60 mL) is added carefully to the above mixture with caution to keep the offset of any exotherm under control, and then allowed to warm to room temperature slowly. The resulting mixture is then heated at 120° C. for 4 h with stirring, cooled, poured into ice-cold water, and extracted with CHCl3. The combined organic phase is washed successively with saturated aqueous NaHCO3, water, brine, dried over Na2SO4, and concentrated in vacuo to afford 3-Chloro-4-nitro-pyridine-1-oxide as an yellow solid. 1H NMR (300 MHz, CDCl3): δ 8.31 (d, J=1.5 Hz, 1H), 8.13 (dd, J=1.5, 5.4 Hz, 1H), 7.95 (d, J=7.2 Hz, 1H)

[0456] 2. Preparation of 3-Ethylamino-4-nitro-pyridine-1-oxide

[0457] Anhydrous K2CO3 (19 g, 144.5 mmol) is suspended in a solution of 3-Chloro-4-nitro-pyridine-1-oxide (10 g, 57.8 mmol) in anhydrous acetonitrle (100 mL). Excess diethyl amine (2.0 M) in THF is added to the above suspension under cold conditions (ice-bath). After complete addition of diethyl amine, the reaction mixture is allowed to warm to room temperature and left stirring overnight. The reaction mixture is filtered to remove K2CO3 and the filtrate evaporated under reduced pressure to remove volatile solvents. The organic residue is subjected to chromatography, eluting with 30% EtOAc-hexanes to afford 3-Ethylamino-4-nitro-pyridine-1-oxide as an orange solid. 1H NMR (300 MHz, CDCl3): δ 8.0 1 (d, J=7.5 Hz, 1H), 7.91(s, 1H), 7.8 (brs, NH), 7.44 (d, J=7.2 Hz, 1H), 3.30 (t, J=7.2 Hz, 2H), 1.39 (t, J=7.2 Hz, 3H), m/z 184 [M+1]

[0458] 3. Preparation of N3-Ethyl-pyridine-3,4-diamine

[0459] A solution of 3-ethylamino-4-nitro-pyridine 1-oxide (1.5 g, 8.19 mmol), in methanol (30 mL) is hydrogenated over 10% Pd-C (1.5 g) at 50-60 psi for 48 h. The catalyst is removed by filtration through a pad of celite, and the solvent is evaporated under vacuum to afford N3-Ethyl-pyridine-3,4-diamine as an white solid. 1H NMR (300 MHz, CDCl3): δ 7.59 (s, 1H), 7.57 (d, J=2.4 Hz, 1H), 6.56 (d, J=5.4 Hz, 1H), 3.20 (t, J=7.2 Hz, 2H), 1.29 (t, J=7.2 Hz, 3H), m/z 138 [M+1]

[0460] 4. Preparation of N-(3-Ethylamino-pyridin-4-yl)-2-(2-thiazol-2-yl-imidazol-1-yl)-acetamide

[0461] A solution (2.0 M) of Me3Al (4.8 mL, 9.6 mmol) in toluene is added to a solution of the N3-ethyl-pyridine-3,4-diamine (1.06 g, 7.70 mmol) in anhydrous dichloromethane (40 mL) slowly under nitrogen, and the resulting mixture is stirred at room temperature for 1 h. (2-Thiazol-2-yl-imidazol-1-yl)-acetic acid methyl ester (860 mg, 3.85 mmol) is added to the above reaction mixture. The resulting suspension is refluxed overnight and then cooled to room temperature. The reaction mixture is decomposed with a few drops of MeOH. The resulting brown precipitate is suspended in 15% MeOH in CH2Cl2 (200 mL), subjected to sonication for 25 min, filtered through a pad of celite, and concentrated to afford a mixture of 3-Ethyl-2-{[2-(1,3-thiazol-2-yl)-1H-imidazol-1-yl]methyl}-3H-imidazo[4,5-c]pyridine and N-(3-ethylamino-pyridin-4-yl)-2-(2-thiazol-2-yl-imidazol-1-yl)-acetamide in a 2:1 ratio which is carried over to the next step without further purification. A portion of the crude residuei chromatographed over silica gel eluting with 7% MeOH-CH2Cl2 containing few drops of NH4OH to obtain an analytical sample of N-(3-ethylamino-pyridin-4-yl)-2-(2-thiazol-2-yl-imidazol-1-yl)-acetamide for characterization purposes. 1H NMR (300 MHz, CD3OD): δ 7.95 (s,1H), 7.87 (d, J=3.3 Hz, 1H), 7.79 (d, J=5.4 Hz, 1H), 7.61 (d, J=3.3 Hz, 1H), 7.42 (d, J=5.1 Hz, 1H), 7.33 (d, J=1.5 Hz, 1H) 7.12 (d, J=1.2 Hz, 1H), 5.51 (s, 2H), 3.20 (t, J=6.9 Hz, 2H), 1.23 (t, J=6.9 Hz, 3H); LRMS Calcd 328.38; found 329

[0462] 5. Preparation of 3-Ethyl-2-{[2-(1,3-thiazol-2-yl)-1H-imidazol-1-yl]methyl}-3H-imidazo[4,5-c]pyridine

[0463] The mixture (2:1) of the cyclized 3-Ethyl-2-{[2-(1,3-thiazol-2-yl)-1H-imidazol-1-yl]methyl}-3H-imidazo[4,5-c]pyridine and the intermediate N-(3-ethylamino-pyridin-4-yl)-2-(2-thiazol-2-yl-imidazol-1-yl)-acetamide obtained from the above Me3Al-mediated coupling conditions is dissolved in 30 mL of acetic acid and heated at 115° C. overnight with stirring. The next day, most of the AcOH is evaporated off under reduced pressure. The residue is diluted with 100 mL of CH2Cl2, washed with NaHCO3, water, brine, dried over Na2SO4, and concentrated. The crude product is purified by chromatography, eluting with 3% MeOH-CH2Cl2 containing few drops of NH4OH to afford 3-ethyl-2-{[2-(1,3-thiazol-2-yl)-1H-imidazol-1-yl]methyl}-3H-imidazo[4,5-c]pyridine as an white solid. 1H NMR (300 MHz, CD3OD): δ 8.87 (s, 1H), 8.30 (d, J=5.7 Hz, 1H), 7.75 (d, J=3.3 Hz, 1H), 7.57 (d, J=4.8 Hz, 1H), 7.52 (d, J=3.3 Hz, 1H), 7.39 (d, J=1.5 Hz, 1H), 7.18 (d, J=1.5 Hz, 1H), 6.29 (s, 2H), 4.52 (q, J=7.5 Hz, 2H), 1.44 (t, J=7.5 Hz, 3H); LRMS Calcd 310.38 found 311; Anal. Calcd for CHNS: C, 58.05, H 4.55, N 27.08. Found C 57.79; H, 4.38; N, 27.04.

Example 28

[0464] Synthesis of 3-ethyl-6-isopropyl-2-{[2-(1,3-thiazol-2-yl)-1H-imidazol-1-yl]methyl}-3H-imidazo[4,5-c]pyridine and 1-ethyl-6-isopropyl-2-{[2-(1,3-thiazol-2-yl)-1H-imidazol-1-yl]methyl}-1H-imidazo[4,5-c]pyridine

[0465] 1. Preparation of Isobutyrylacetic Acid

[0466]

[0467] A mixture of ethyl isobutyrylacetate (20.47 g, 129 mmol) and 1.5 M aq NaOH (250 mL) is stirred at room temperature overnight. The solution is then cooled to 0° C. and acidified to pH 1-2 by the slow addition of conc. HCl (˜35 mL). The solution is then saturated with NaCl and extracted thrice with EtOAc and once with CHCl3. The combined extracts are dried over Na2SO4 and concentrated to 14.46 g (86%) of isobutyrylacetic acid as an oil. 1H NMR (CDCl3, 300 MHz) reveals a mixture of keto and enol forms (˜4:1), in favor of the keto form. Keto form: δ 3.57 (s, 2H), 2.73 (sept, J=6.9 Hz, 1H), 1.16 (d, J=6.9 Hz, 6H) ppm. Enol form: 11.85 (s, 1H), 5.03 (s, 1H), 2.44 (sept, J=6.9 Hz, 1H) 1.10 (d, J=6.9 Hz, 6H) ppm.

[0468] 2. Preparation of 4-hydroxy-3-isobutyryl-6-isopropyl-pyran-2-one

[0469] To a solution of the isobutyrylacetic acid (14.45 g, 111 mmol) in THF (200 mL) at room temperature under N2 is added CDI (19.8 g, 122 mmol) in one portion. The yellow solution is stirred at room temperature for 20 h and then concentrated in vacuo. The residue is dissolved in CH2Cl2 and washed with 10% aq HCl (100 mL) followed by H2O (50 mL). The aqueous washes are reextracted once with CH2Cl2, and the combined extracts are dried over Na2SO4 and concentrated to provide 4-hydroxy-3-isobutyryl-6-isopropyl-pyran-2-one as a yellow oil. This material is sufficiently pure to be used without further purification in the next reaction. 1H NMR (CDCl3, 300 MHz) δ 17.02 (s, 1H), 5.92 (s, 1H), 3.94 (sept, J=6.9 Hz, 1H), 2.72 (sept, J=6.9 Hz, 1H), 1.25 (d, J=6.9 Hz, 6H), 1.16 (d, J=6.9 Hz, 6H) ppm.

[0470] 3. Preparation of 4-hydroxy-6-isopropyl-pyran-2-one

[0471] A solution of 4-hydroxy-3-isobutyryl-6-isopropyl-pyran-2-one (10.26 g, 45.8 mmol) in conc. H2SO4 (40 mL) is stirred at 130° C. for 15 min. The dark reaction mixture is then cooled to 0° C., and crushed ice (˜200 g) is added with stirring. The resulting solution is extracted thrice with Et2O, and the combined extracts are dried over Na2SO4 and concentrated. The crude material is purified by flash chromatography on silica gel. Gradient elution with 3:2 hexanes-EtOAc, 1:1 EtOAc-hexanes, 2:1 EtOAc-hexanes, and 3:1 EtOAc-hexanes affords 4-hydroxy-6-isopropyl-pyran-2-one as a light yellow solid. 1H NMR (CDCl3, 300 MHz) δ 11.2 (br, 1H), 6.00 (d, J=1.8 Hz, 1H), 5.58 (d, J=1.8 Hz, 1H), 2.73 (sept, J=6.9 Hz, 1H), 1.22 (d, J=6.9 Hz, 1H) ppm.

[0472] 4. Preparation of 4-hydroxy-6-isopropyl-1H-pyridin-2-one

[0473] A mixture of 4-hydroxy-6-isopropyl-pyran-2-one (4.82 g, 31.3 mmol) in conc. NH4OH (15 mL) is stirred at 100° C. in a sealed tube for 4 h. The solution is then transferred to a recovery flask and concentrated in vacuo. Toluene is used to azeotropically remove any remaining water. 4-Hydroxy-6-isopropyl-1H-pyridin-2-one is obtained as a tan powder. 1H NMR (DMSO-d6, 300 MHz) δ 10.96 (br s, 1H), 10.36 (br s, 1H), 5.59 (d, J=2.1 Hz, 1H), 5.33 (d, J=2.1 Hz, 1H), 2.64 (sept, J=6.9 Hz, 1H), 1.11 (d, J=6.9 Hz, 6H) ppm.

[0474] 5. Preparation of 4-hydroxy-6-isopropyl-3-nitro-1H-pyridin-2-one

[0475] A solution of 4-hydroxy-6-isopropyl-1H-pyridin-2-one (1.76 g, 11.5 mmol) in 55-60 mL of 50% aq HNO3 is stirred at 70° C. for 2.5 h. After cooling, the reaction mixture is poured into ice-cold H2O (−100 mL). The resulting solution is allowed to sit in the refrigerator for 3.5 days. The solid that precipitates is collected by filtration, washed with water, and dried to afford 4-hydroxy-6-isopropyl-3-nitro-1H-pyridin-2-one as yellow crystals. 1H NMR (DMSO-d6, 300 MHz) δ 12.30 (br s, 1H), 11.82 (br s, 1H), 5.82 (d, J=1.2 Hz, 1H), 2.71 (sept, J=6.9 Hz, 1H), 1.13 (d, J=6.9 Hz, 6H) ppm.

[0476] 6. Preparation of 4-chloro-6-isopropyl-3-nitro-1H-pyridin-2-one

[0477] To a suspension of 4-hydroxy-6-isopropyl-3-nitro-1H-pyridin-2-one (3.02 g, 15.2 mmol) in CH3CN (60 mL) at room temperature is added benzyltriethylammonium chloride (13.88 g, 61.0 mmol). The mixture is stirred at room temperature for 5-10 min, and then POCl3 (6.25 mL, 67.1 mmol) is added. The reaction mixture is stirred at room temperature for 15 min and then at reflux for 1 h. After cooling, the reaction mixture is concentrated in vacuo. The flask is then placed in an ice bath, and the residue treated with H2O (˜60 mL). The mixture is stirred for 4 h while slowly warming to rt. The solid that forms over this period of time is collected by filtration and then washed with H2O and a small amount of hexanes. 4-Chloro-6-isopropyl-3-nitro-1H-pyridin-2-one is obtained as a yellow solid. 1H NMR (CDCl3, 300 MHz) δ 13.13 (br s, 1H), 6.24 (s, 1H), 2.89 (sept, J=6.9 Hz, 1H), 1.31 (d, J=6.9 Hz, 6H) ppm.

[0478] 7. Preparation of 4-amino-6-isopropyl-3-nitro-1H-pyridin-2-one

[0479] A mixture of 4-chloro-6-isopropyl-3-nitro-1H-pyridin-2-one (700 mg, 3.23 mmol) in 6-7 mL of 7 N NH3 in MeOH is stirred at 100° C. in a sealed tube for 1.5 h. After cooling, the reaction mixture is concentrated in vacuo. The residue is suspended in H2O, filtered, washed with H2O, and dried, yielding 4-amino-6-isopropyl-3-nitro-1H-pyridin-2-one. 1H NMR (DMSO-d6, 300 MHz) δ 10.96 (br s, 1H), 8.15 (br s, 2H), 5.70 (d, J=0.9 Hz, 1H), 2.58 (sept, J=6.9 Hz, 1H), 1.11 (d, J=6.9 Hz, 6H) ppm.

[0480] 8. Preparation of 2-chloro-6-isopropyl-pyridin-4-ylamine

[0481] A mixture of 4-amino-6-isopropyl-3-nitro-1H-pyridin-2-one (555 mg, 2.81 mmol) in POC3 (10 mL) is stirred at reflux under N2 for 1.5 h. After cooling, the solution is concentrated in vacuo. The reaction flask is then placed in an ice bath, and crushed ice (˜20 g) is added to the residue. The mixture is swirled vigorously for several minutes and then stirred at room temperature for 30 min. The mixture is then extracted with EtOAc. The extract is washed with an additional 20 mL of H2O. The aqueous washes are reextracted once with EtOAc, and the combined extracts are dried over Na2SO4 and concentrated, yielding 2-chloro-6-isopropyl-pyridin-4-ylamine as an orange oil. This material is used without further purification. 1H NMR (DMSO-d6, 300 MHz) δ 7.27 (br s, 2H), 6.65 (s, 1H), 2.77 (sept, J=6.9 Hz, 1H), 1.13 (d, J=6.9 Hz, 6H) ppm.

[0482] 9. Preparation of 6-isopropyl-pyridine-3,4-diamine Hydrochloride

[0483] A solution of 2-chloro-6-isopropyl-pyridin-4-ylamine (684 mg, 3.17 mmol) in MeOH (10-15 mL) containing 10% Pd/C (˜70 mg) is stirred under an atmosphere of H2 (double stuffed balloon) for 5 h. The reaction mixture is then filtered through a pad of Celite using MeOH, and the filtrate is concentrated in vacuo. The residue is dissolved in a small amount of MeOH and further diluted with toluene. The solution is then concentrated in vacuo. This is repeated once more, affording 6-isopropyl-pyridine-3,4-diamine hydrochloride as an orange-yellow solid. 1H NMR (DMSO-d6, 300 MHz) δ 13.26 (br, 1H), 7.45, 7.40 (br m, 3H), 6.59 (s, 1H), 5.48 (br, 2H), 2.94 (sept, J=6.9 Hz, 1H), 1.19 (d, J=6.9 Hz, 6H) ppm.

[0484] 10. Preparation of 6-isopropyl-2-(2-thiazol-2-yl-imidazol-1-ylmethyl)-1H-imidazo[4,5-c]pyridine

[0485] To a mixture of 6-isopropyl-pyridine-3,4-diamine hydrochloride (265 mg, 1.41 mmol) in 1,2-dichloroethane (10 mL) at room temperature under N2 is added 2.0 M AlMe3 in toluene (2.12 mL, 4.24 mmol). The mixture is stirred at room temperature for 45 min and then treated with a solution of (2-thiazol-2-yl-imidazol-1-yl)-acetic acid methyl ester (252 mg, 1.13 mmol) in 1,2-dichloroethane (2 mL) via cannula, followed by a 1 mL rinse. The reaction mixture is then stirred at reflux for 20 h. After cooling, the reaction mixture is diluted with some MeOH (˜2 mL), followed by some water and then saturated aq NaHCO3. The resulting mixture is stirred vigorously for 15 min. The mixture is then extracted thrice with CHCl3 containing some (˜5%) MeOH. The combined extracts are dried over Na2SO4 and concentrated. The crude residue is then triturated with CHCl3, and the resulting mixture filtered. The solid is washed with a small amount of CHCl3 and dried, affording N-(4-amino-6-isopropyl-pyridin-3-yl)-2-(2-thiazol-2-yl-imidazol-1-yl)-acetamide as an off-white solid. 1H NMR (DMSO-d6, 300 MHz) δ 9.52 (s, 1H), 7.86 (s, 1H), 7.85 (d, J=3.3 Hz, 1H), 7.75 (d, J=3.6 Hz, 1H), 7.39 (s, 1H), 7.04 (d, J=0.9 Hz, 1H), 6.45 (s, 1H), 5.65 (s, 2H), 5.38 (s, 2H), 2.74 (sept, J=6.9 Hz, 1H), 1.13 (d, J=6.9 Hz, 6H) ppm. The filtrate is concentrated and further purified by flash chromatography on silica gel. Elution with 20:1 CHCl3-MeOH followed by 15:1 CHCl3-MeOH affords 6-isopropyl-2-(2-thiazol-2-yl-imidazol-1-ylmethyl)-1H-imidazo[4,5-c]pyridine (160 mg, 44%). 1H NMR (CDCl3, 300 MHz) δ 12.23 (br, 1H), 8.97 (br, 1H), 7.94 (d, J=2.7 Hz, 1H), 7.43 (d, J=3.3 Hz, 1H), 7.23 (br, 1H), 7.20 (d, J=0.9 Hz, 1H), 7.04 (s, 1H), 5.82 (s, 2H), 3.14 (sept, J=6.9 Hz, 1H), 1.30 (d, J=6.9 Hz, 6H) ppm.

[0486] 11. Preparation of 3-ethyl-6-isopropyl-2-{ [2-(1,3-thiazol-2-yl)-1H-imidazol-1-yl]methyl}-3H-imidazo[4,5-c]pyridine and 1-ethyl-6-isopropyl-2-{[2-(1,3-thiazol-2-yl)-1H-imidazol-1-yl]methyl}-1H-imidazo[4,5-c]pyridine

[0487] To a solution of 6-isopropyl-2-(2-thiazol-2-yl-imidazol-1-ylmethyl)-1H-imidazo[4,5-c]pyridine (160 mg, 0.493 mmol) in DMF (1.0 mL) at room temperature under N2 is added Cs2CO3 (168 mg, 0.518 mmol) followed by iodoethane (0.047 mL, 0.592 mmol). The mixture is stirred at room temperature for 1 h and then diluted with water and extracted twice with CH2Cl2. The combined extracts are dried over K2CO3 and concentrated. The residue is purified by preparative TLC, developing with 15:1 CHCl3-MeOH (+0.5% Et3N). The less polar (top) band affords 3-ethyl-6-isopropyl-2-{[2-(1,3-thiazol-2-yl)-1H-imidazol-1-yl]methyl}-3H-imidazo[4,5-c]pyridine. 1H NMR (CDCl3, 300 MHz) δ 8.70 (d, J=1.2 Hz, 1H), 7.83 (d, J=3.0 Hz, 1H), 7.53 (d, J=0.9 Hz, 1H) 7.39 (d, J=3.0 Hz, 1H), 7.18 (d, J=0.9 Hz, 1H), 7.14 (d, J=0.9 Hz, 1H), 6.32 (s, 2H), 4.32 (q, J=7.2 Hz, 2H), 3.18 (sept, J=6.9 Hz, 1H), 1.34 (d, J=6.9 Hz, 6H), 1.17 (t, J=7.2 Hz, 3H) ppm. The more polar (bottom) band affords 74 mg (43%) of 1-ethyl-6-isopropyl-2-{[2-(1,3-thiazol-2-yl)-1H-imidazol-1-yl]methyl}-1H-imidazo[4,5-c]pyridine. 1H NMR (CDCl3, 300 MHz) δ 9.01 (s, 1H), 7.83 (d, J=3.2 Hz, 1H), 7.38 (d, J=3.2 Hz, 1H), 7.15 (s, 1H), 7.12 (s, 1H), 7.09 (s, 1H), 6.32 (s, 2H), 4.21 (q, J=7.2 Hz, 2H), 3.17 (sept, J=6.8 Hz, 1H), 1.34 (d, J=6.8 Hz, 6H), 1.10 (t, J=7.2 Hz, 3H) ppm.

Example 29

[0488] Synthesis of 1-ethyl-6-isopropyl-2-{[2-(1,3-thiazol-2-yl)-1H-imidazol-1-yl]methyl}-1H-imidazo[4,5-c]pyridine

[0489] 1. Preparation of 4-ethylamino-6-isopropyl-3-nitro-1H-pyridin-2-one

[0490] To a mixture of 4-chloro-6-isopropyl-3-nitro-1H-pyridin-2-one (Example 28, step 6) (500 mg, 2.31 mmol) in CH3CN at room temperature is added EtNH2.HCl (565 mg, 6.92 mmol) followed by Et3N (1.29 mL, 9.23 mmol). The reaction mixture is then stirred in a sealed tube at 100° C. for 1.5 h. After cooling, the reaction mixture is diluted with CH2Cl2 and washed with H2O (2×25 mL). The aqueous washes are reextracted once with CH2Cl2, and the combined extracts are dried over Na2SO4 and concentrated to provide 4-ethylamino-6-isopropyl-3-nitro-1H-pyridin-2-one as a yellow-orange solid. The material is sufficiently pure to be used without further purification. 1H NMR (DMSO-d6, 400 MHz) δ 11.1 (br, 1H), 8.93 (m, 1H), 5.73 (s, 1H), 3.37 (dq, J=7.4, 6.8 Hz, 2H), 2.67 (sept, J=6.8 Hz, 1H), 1.17 (t, J=7.4 Hz, 3H), 1.15 (d, J=6.8 Hz, 6H) ppm.

[0491] 2. Preparation of (2-chloro-6-isopropyl-3-nitro-pyridin-4-yl)-ethyl-amine

[0492] A mixture of 4-ethylamino-6-isopropyl-3-nitro-1H-pyridin-2-one (520 mg, 2.31 mmol) in POCl3 is stirred at reflux for 1.5 h. After cooling, the solution is concentrated in vacuo. The reaction flask is then placed in an ice bath and crushed ice is added to the residue. The mixture is swirled vigorously for a few minutes and then stirred at 0° C. for 1 h. The mixture is then extracted with EtOAc. The extract is washed with additional H2O (20 mL) and brine (20 mL). The extract is dried over Na2SO4 and concentrated to afford (2-chloro-6-isopropyl-3-nitro-pyridin-4-yl)-ethyl-amine as a yellow solid. The material is sufficiently pure to be used without further purification. IH NMR (CDCl3, 400 MHz) δ 6.62 (br, 1H), 6.44 (s, 1H), 3.31 (m, 2H), 2.91 (sept, J=6.8 Hz, 1H), 1.33 (t, J=7.4 Hz, 3H), 1.26 (d, J=6.8 Hz, 6H) ppm.

[0493] 3. Preparation of N-ethyl-6-isopropyl-pyridine-3,4-diamine hydrochloride

[0494] A solution of (2-chloro-6-isopropyl-3-nitro-pyridin-4-yl)-ethyl-amine (0.56 g, 2.30 mmol) in MeOH (20 mL) containing 10% Pd/C (−50 mg) is stirred under and atmosphere of H2 for 3.5 h. The reaction mixture is then filtered through a pad of Celite using MeOH. The filtrate is concentrated in vacuo. Toluene is added to the residue and then removed in vacuo. This is repeated once more, yielding N4-ethyl-6-isopropyl-pyridine-3,4-diamine hydrochloride as a dark solid. 1H NMR (CD3OD, 400 MHz) δ 7.46 (s, 1H), 6.60 (s, 1H), 3.43 (q, J=7.4 Hz, 2H), 3.03 (sept, J=6.8 Hz, 1H), 1.35 (t, J=7.4 Hz, 3H), 1.33 (d, J=6.8 Hz, 6H) ppm.

[0495] 4. Preparation of 1-ethyl-6-isopropyl-2-{ [2-(1,3-thiazol-2-yl)-1H-imidazol-1-yl]methyl}-1H-imidazo[4,5-c]pyridine

[0496] To a suspension of N-ethyl-6-isopropyl-pyridine-3,4-diamine hydrochloride (126 mg, 0.582 mmol) in CH2Cl2 (5 mL) at room temperature under N2 is added 2.0 M AlMe3 in toluene (0.35 mL, 0.728 mmol). The dark solution is then stirred at room temperature for 45 min. Next, a solution of (2-Thiazol-2-yl-imidazol-1-yl)-acetic acid methyl ester (65 mg, 0.291 mmol) in CH2Cl2 (2 mL) is added via cannula followed by a 1 mL rinse. The reaction mixture is stirred at reflux overnight. After cooling, it is treated with MeOH (˜0.5 mL) and then diluted with 0.5 N NaOH and additional CH2Cl2. The mixture is stirred vigorously for 15 min and then extracted thrice with CH2Cl2 containing some (˜5%) MeOH. The combined extracts are dried over K2CO3 and concentrated to 156 mg of a crude mixture of the desired 1-ethyl-6-isopropyl-2-{[2-(1,3-thiazol-2-yl)-1H-imidazol-1-yl]methyl}-1H-imidazo[4,5-c]pyridine and N-(4-amino-6-isopropyl-pyridin-3-yl)-2-(2-thiazol-2-yl-imidazol-1-yl)-acetamide. This material is then dissolved in AcOH (6 mL), and the resulting solution is stirred at reflux for 5 h. After cooling, the reaction mixture is concentrated in vacuo. The residue is dissolved in CH2Cl2 and washed with 0.5 N NaOH. The aqueous layer is reextracted twice with CH2Cl2, and the combined extracts are dried over K2CO3 and concentrated. The crude material is purified by preparative TLC. Developing with 15:1 CHCl3 yields 1-ethyl-6-isopropyl-2-{[2-(1,3-thiazol-2-yl)-1H-imidazol-1-yl]methyl}-1H-imidazo[4,5-c] pyridine. 1H NMR (CDCl3, 400 MHz) δ 9.01 (s, 1H), 7.83 (d, J=3.2 Hz, 1H), 7.38 (d, J=3.2 Hz, 1H), 7.15 (s, 1H), 7.12 (s, 1H), 7.09 (s, 1H), 6.32 (s, 2H), 4.21 (q, J=7.2 Hz, 2H), 3.17 (sept, J=6.8 Hz, 1H), 1.34 (d, J=6.8 Hz, 6H), 1.10 (t, J=7.2 Hz, 3H) ppm.

Example 30

[0497] Synthesis of 1-ethyl-2-{[2-(1,3-thiazol-2-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]methyl}-1H-imidazo[4,5-c]pyridine

[0498] 1. Preparation of 2-(4-trifluoromethyl-1H-imidazol-2-yl)-thiazole

[0499] Analogous to the published procedure (J. Med. Chem. 2000, 43, 2165-2175), 1,1-dibromo-3,3,3-trifluoroacetone (4.47 g, 16.6 mmol) is added to a solution of NaOAc (2.72 g, 33.1 mmol) in H2O (15 mL). The resulting solution is stirred at 100° C. for 30 min and then allowed to cool to rt. Next, a solution of 2-thiazolecarboxaldehyde (1.5 g, 13.3 mmol) in MeOH (15 mL), containing conc. NH4OH (5 mL), is added. The reaction mixture is then stirred at room temperature for 20 h. It is then filtered, the solid washed with H2O, and dried. 2-(4-Trifluoromethyl-1H-imidazol-2-yl)-thiazole is obtained as an off-white fluffy solid. 1H NMR (DMSO-d6, 400 MHz) δ 13.81 (br, 1H), 7.97 (d, J=3.2 Hz, 1H), 7.94 (s, 1H), 7.87 (d, J=3.2 Hz, 1H) ppm.

[0500] 2. Preparation of (2-thiazol-2-yl-4-trifluoromethyl-imidazol-1-yl)-acetic Acid Methyl Ester

[0501] To a suspension of NaH (109 mg of a 60% dispersion in mineral oil, 2.74 mmol) in THF (10 mL) at 0° C. under N2 is added a solution of 2-(4-trifluoromethyl-1H-imidazol-2-yl)-thiazole (500 mg, 2.28 mmol) in THF (4 mL) via cannula, followed by a 1 mL rinse. The mixture is stirred at 0° C. for 30 min and then treated with methyl bromoacetate (0.28 mL, 2.97 mmol). The reaction mixture is stirred overnight while slowly warming to rt. It is then diluted with H2O (10 mL) and the resulting mixture stirred vigorously for 5 min. The mixture is further diluted with some brine and then extracted twice with EtOAc. The combined extracts are dried over Na2SO4 and concentrated. The crude material is purified by flash chromatography on silica gel. Elution with 4:1 hexanes-EtOAc followed by 3:1 hexanes-EtOAc affords unreacted 2-(4-trifluoromethyl-1H-imidazol-2-yl)-thiazole as well as (2-thiazol-2-yl-4-trifluoromethyl-imidazol-1-yl)-acetic acid methyl ester. 1H NMR (CDCl3, 400 MHz) δ 7.82 (d, J=3.2 Hz, 1H), 7.40 (d, J=3.2 Hz, 1H), 7.35 (s, 1H), 5.41 (s, 2H), 3.77 (s, 3H) ppm.

[0502] 3. Preparation of 1-ethyl-2-{[2-(1,3-thiazol-2-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]methyl}-1H-imidazo[4,5-c]pyridine

[0503] To a mixture of -ethyl-pyridine-3,4-diamine (94 mg, 0.687 mmol) in CH2Cl2 (5 mL) at room temperature under N2 is added 2.0 M AlMe3 in toluene (0.43 mL, 0.858 mmol), and the resulting mixture is stirred at room temperature for 1 h. Next, a solution of (2-thiazol-2-yl-4-trifluoromethyl-imidazol-1-yl)-acetic acid methyl ester (100 mg, 0.343 mmol) in CH2Cl2 is added via cannula. The reaction mixture is then stirred at reflux overnight. After cooling to rt, it is treated with MeOH (˜1 mL). The mixture is further diluted with 0.5 N aq NaOH (10 mL) and then stirred vigorously for 30 min. The mixture is then extracted thrice with CH2Cl2 containing some (˜5%) MeOH, and the combined extracts are dried over K2CO3 and concentrated. The crude mixture of 1-ethyl-2-{[2-(1,3-thiazol-2-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]methyl}-1H-imidazo[4,5-c] pyridine and N-(4-amino-pyridin-3-yl)-2-(2-thiazol-2-yl-4-trifluoromethyl-imidazol-1-yl)-acetamide is dissolved in AcOH (6 mL), and the resulting solution stirred at reflux overnight. The reaction mixture is then concentrated, and the residue is dissolved in CH2Cl2 and washed with 0.5 N aq NaOH. The aqueous layer is reextracted once with CH2Cl2, and the combined extracts are dried over K2CO3 and concentrated. The crude residue is purified by preparative TLC. Developing with 15:1 CHCl3—MeOH affords 1-ethyl-2-{[2-(1,3-thiazol-2-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]methyl}-1H-imidazo[4,5-c]pyridine. 1H NMR (CDCl3, 400 MHz) δ 9.10 (s, 1H), 8.47 (d, J=6.0 Hz, 1H), 7.88 (d, J=3.2 Hz, 1H), 7.58 (s, 1H), 7.48 (d, J=3.2 Hz, 1H), 7.31 (d, J=5.6 Hz, 1H), 6.37 (s, 2H), 4.31 (q, J=7.2 Hz, 2H), 1.24 (t, J=7.2 Hz, 3H) ppm.

Example 31

[0504] Synthesis of 3-ethyl-2-{[2-(6-fluoropyridin-2-yl)-1H-imidazol-1-yl]methyl}-6-propyl-3H-imidazo[4,5-c]pyridine

[0505] 1. Preparation of N-(4-amino-6-propyl-pyridin-3-yl)-acetamide

[0506] To a mixture of 6-propyl-pyridine-3,4-diamine hydrochloride (prepared from ethyl butyrylacetate as described in Example 28, steps 1-9) (187 mg, 1.00 mmol) in CH2Cl2 (4 mL) at 0° C. under N2 is added pyridine (0.24 mL, 3.00 mmol) followed by DMF (2 mL) (for solubility). Next, Ac2O (0.104 mL, 1.1 mmol) is added. The reaction mixture is stirred for 3 h while slowly warming to rt. It is then poured into saturatedd aq NaHCO3 and extracted thrice with CH2Cl2. The combined extracts are dried over K2CO3 and concentrated to 114 mg of crude N-(4-amino-6-propyl-pyridin-3-yl)-acetamide, which was used without further purification. 1H NMR (CDCl3, 300 MHz) δ 8.73 (br, 1H), 8.00 (s, 1H), 8.43 (s, 1H), 4.63 (br, 2H), 2.54 (m, 2H), 2.13 (s, 3H), 1.63 (sextet, J=7.2 Hz, 2H), 0.89 (t, J=7.2 Hz, 3H) ppm. Electrospray MS: m/z 194 [M+1].

[0507] 2. Preparation of N3-ethyl-6-propyl-pyridine-3,4-diamine

[0508] A solution of the crude N-(4-amino-6-propyl-pyridin-3-yl)-acetamide (114 mg, 0.59 mmol) in THF (2.5 mL) at 0° C. under N2 is treated with 0.5 M EtNMe2.AlH3 in toluene (2.4 mL, 1.18 mmol). The reaction mixture is stirred for 4 h while slowly warming to rt, whereupon it is treated with additional 0.5 M EtNMe2eAlH3 in toluene (2.4 mL, 1.18 mmol). After stirring at room temperature overnight, the reaction mixture is cooled to 0° C. and treated with moist Na2CO3. The mixture is diluted with CH2Cl2 and stirred vigorously for 15 min. It is then filtered through a pad of Celite, and the filtrate concentrated. The crude material is partially purified by preparative thin layer chromatography, developing with 15:1 CHCl3—MeOH (+1% Et3N). The band containing the desired N3-ethyl-6-propyl-pyridine-3,4-diamine does not separate well from the approximately 10% of the slightly more polar, unreacted N-(4-amino-6-propyl-pyridin-3-yl)-acetamide. Both bands are collected, and the mixture is carried into the next reaction. 1H NMR (CDCl3, 300 MHz) δ 7.74 (s, 1H), 6.42 (s, 1H), 4.10 (br, 1H), 3.67 (m, 1H), 3.10 (q, J=7.2 Hz, 2H), 2.56 (m, 2H), 1.67 (sextet, J=7.2 Hz, 2H), 1.25 (t, J=7.2 Hz, 3H), 0.91 (t, J=7.2 Hz, 3H) ppm. Electrospray MS: m/z 180 [M+1].

[0509] 3. Preparation of 3-ethyl-2-{[2-(6-fluoropyridin-2-yl)-1H-imidazol-1-yl]methyl}-6-propyl-3H-imidazo[4,5-c]pyridine

[0510] A solution of N3-ethyl-6-propyl-pyridine-3,4-diamine (82 mg, ˜0.45 mmol, contaminated with -10% of N-(4-amino-6-propyl-pyridin-3-yl)-acetamide) in 1,2-dichloroethane (4 mL) at room temperature under N2 is treated with 2.0 M AlMe3 (0.69 mL, 1.37 mmol). The resulting solution is stirred at room temperature for 30 min and then treated with a solution of [2-(6-fluoro-pyridin-2-yl)-imidazol-1-yl]-acetic acid methyl ester (97 mg, 0.41 mmol) in 1,2-dichloroethane via cannula, followed by a 1 mL rinse. The reaction mixture is then stirred at reflux overnight. After cooling, it is treated with MeOH (˜2 mL) and then further diluted with saturated aq NaHCO3 (˜10 mL) and some H2O. The mixture is stirred vigorously for 15 min and then extracted thrice with CHCl3 containing some (˜5%) MeOH. The combined extracts are dried over K2CO3 and concentrated. The crude material is purified by preparative thin layer chromatography. Developing with 15:1 CHCl3-MeOH yields 3-ethyl-2-{[2-(6-fluoropyridin-2-yl)-1H-imidazol-1-yl]methyl)-6-propyl-3H-imidazo[4,5-c]pyridine as an off-white solid. 1H NMR (CDCl3, 300 MHz) δ 8.70 (d, J=0.9 Hz, 1H), 8.17 (dd, J=8.0, 2.6 Hz, 1H), 7.89 (q, J=7.8 Hz, 1H), 7.47 (s, 1H), 7.22 (d, J=0.9 Hz, 1H), 7.18 (d, J=1.5 Hz, 1H), 6.88 (dd, J=8.6, 2.9 Hz, 1H), 6.27 (s, 2H), 4.42 (q, J=7.2 Hz, 2H), 2.86 (m, 2H), 1.78 (sextet, J=7.2 Hz, 2H), 1.30 (t, J=7.2 Hz, 3H), 0.97 (t, J=7.2 Hz, 3H) ppm. Electrospray MS: m/z 365 [M+1].

Example 32

[0511] Synthesis of 1-ethyl-2-{[2-(1,3-thiazol-2-yl)-1H-imidazol-1-yl]methyl}-6-(trifluoromethyl)-1H-imidazo[4,5-c]pyridine

[0512] 1. Preparation of 5-Nitro-2-trifluoromethyl-pyridin-4-ol

[0513] 25 mL of fuming H2SO4 under cold conditions (0° C.) is added dropwise to a stirred solution of 4-hydroxy-2-trifluoromethylpyridine [Chemistry of Heterocyclic Compounds 1997, 33, 995-996] (4 g, 24.5 mmol) in concentrated H2SO4 (10 mL). HNO3 (fuming, 90%, 25 mL) is added carefully to the above mixture with caution to keep the offset of any exotherm under control, and the reaction is allowed to warm to room temperature slowly. After heating at 120 (C for 6 h with stirring, the resulting mixture is cooled to room temperature, poured into ice-cold water maintaining the pH around 1 with the addition of 1ON NaOH solution, and then extracted with CHCl3. The combined organic phase is washed successively with saturated aqueous NaHCO3, water, brine, dried over Na2SO4, and concentrated in vacuo to afford 5-nitro-2-trifluoromethyl-pyridin-4-ol as an yellow solid. 1H NMR (300 MHz, CDCl3): δ 9.33 (s, 1H), 7.50 (s, 1H).

[0514] 2. Preparation of 4-Chloro-5-nitro-2-trifluoromethyl-pyridine

[0515] The crude 5-nitro-2-trifluoromethyl-pyridin-4-ol (3.4 g, 16.3 mmmol) was treated with PCl5 (5.2 g, 24.97 mmol) and POCl3 (7 mL, 24.49 mmol). The resulting mixture is heated at 80° C. for 18 h, cooled and poured into ice-cold water, and extracted with CH2Cl2. The combined organic phase is washed successively with saturated aqueous NaHCO3, water, brine, dried over Na2SO4, and concentrated in vacuo to afford 4-Chloro-5-nitro-2-trifluoromethyl-pyridine as an yellow oil. 1H NMR (300 MHz, CDCl3): δ 9.17 (s, 1H), 7.9 (s, 1H)

[0516] 3. Preparation of Ethyl-(5-nitro-2-trifluoromethyl-pyridin-4-yl)-amine

[0517] K2CO3 (4.15 g, 30.01 mmol), and 2.0 M solution of EtNH2 (15 mL, 30.01 mmol) in THF are added to a solution of 4-chloro-5-nitro-2-trifluoromethyl-pyridine (3.4 g, 15.0 mmol) in acetonitrile (30 mL) under cold conditions . The reaction is complete after stirring at 0° C. for 2 h. Usual work up affords ethyl-(5-nitro-2-trifluoromethyl-pyridin-4-yl)-amine as an yellow-orange viscous oil. 1H NMR (300 MHz, CDCl3): δ 9.24 (s, 1H), 7.09 (s, 1H), 3.45 (t, J=7.2 Hz, 2H), 1.42 (t, J=7.2 Hz, 3H).

[0518] 4. Preparation of N-Ethyl-6-trifluoromethyl-pyridine-3,4-diamine

[0519] Ethyl-(5-nitro-2-trifluoromethyl-pyridin-4-yl)-amine is hydrogenated under usual conditions to afford N4-ethyl-6-trifluoromethyl-pyridine-3,4-diamine. 1H NMR (300 MHz, CD3OD): δ 7.71 (s, 1H), 6.75 (s,1H), 3.28 (t, J=6.9 Hz, 2H), 1.31 (t, J=6.9 Hz, 3H).

[0520] 5. Preparation of 2-Chloromethyl-1-ethyl-6-trifluoromethyl-1H-imidazo[4,5-c]pyridine

[0521] The HCl salt of ethyl 2-chloro-acetimidate (3.90 g, 24.58 mmol) is added to a solution of N4-ethyl-6-trifluoromethyl-pyridine-3,4-diamine (1.44 g, 7.02 mmol) in EtOH (20 mL) and refluxed for 3 h. The reaction mixture is cooled to room temperature and concentrated under reduced pressure. The residue is diluted with CH2Cl2, washed with NaHCO3 solution, dried over Na2SO4, and concentrated to obtain 2-chloromethyl-1-ethyl-6-trifluoromethyl-1H-imidazo[4,5-c]pyridine. 1H NMR (300 MHz, CDCl3): δ 9.14 (s, 1H), 7.66 (s,1H), 7.26 (s, 1H), 4.87 (s, 2H) 4.40 (t, J=7.5 Hz, 2H), 1.58 (t, J=7.5 Hz, 3H).

[0522] 6. Preparation of 1-ethyl-2-{[2-(1,3-thiazol-2-yl)-1H-imidazol-1-yl]methyl}-6-(trifluoromethyl)-1H-imidazo[4,5-c]pyridine

[0523] A solution of 2-Chloromethyl-1-ethyl-6-trifluoromethyl-1H-imidazo[4,5-c]pyridine (1 g , 3.8 mmol) in anhydrous DMF (15 mL) were added K2CO3 (2.68 g, 19 mmol), and 2-(1H-imidazol-2-yl)-thiazole (555 mg, 3.8 mmol) and stirred at room temperature for 48 h. The crude residue after usual work up was purified eluting with 5% MeOH-CH2Cl2 containing few drops of NH4OH to afford1-ethyl-2-{[2-(1,3-thiazol-2-yl)-1H-imidazol-1-yl]methyl}-6-(trifluoromethyl)-1H-imidazo[4,5-c]pyridine (800 mg, 80%); 1H NMR (CD3OD): δ 8.83 (s, 1H), 8.14 (s, 1H), 7.71 (d, J=2.7 Hz, 1H), 7.53 (d, J=2.7 Hz, 1H), 7.45 (d, J=0.9 Hz, 1H), 7.19 (d, J=0.9 Hz, 1H), 6.30 (s, 2H), 4.54 (q, J=5.4 Hz, 2H), 1.46 (t, J=5.4 Hz, 3H); m/z 379[M+1]

Example 33

[0524] Synthesis of 3-ethyl-2-{[2-(1,3-thiazol-2-yl)-1H-imidazol-1-yl]methyl}-6-(trifluoromethyl)-3H-imidazo[4,5-c]pyridine

[0525] 1. Preparation of 5-Nitro-2-trifluoromethyl-pyridin-4-ylamine

[0526] Ammonia gas is bubbled through a solution of 2-trifluoromethyl-4-chloro-5-nitro-pyridine (4.12 g,18.23 mmol) in anhydrous THF at room temperature for 3 h. Removal of solvent under reduced pressure affords 5-nitro-2-trifluoromethyl-pyridin-4-ylamine (3.6 g, 96%); 1H NMR (300 MHz, CDCl3): δ 7.15 (s, 1H), 9.15 (s,1H).

[0527] 2. Preparation of 6-Trifluoromethyl-pyridine-3,4-diamine

[0528] Hyrogenation as described in the previous examples provides 6-trifluoromethyl-pyridine-3,4-diamine. 1H NMR (300 MHz, CDCl3) δ 6.95 (s, 1H), 8.01 (s,1H).

[0529] 3. Preparation of N3-ethyl-6-trifluoromethyl-pyridine-3,4-diamine

[0530] Cesium carbonate (3.1 g, 26.88 mmol) and ethyl iodide (1.76 g, 10.75 mmol) is added to a solution of 6-trifluoromethyl-pyridine-3,4-diamine (1.05 g, 8.96 mmol) in anhydrous DMF (12 mL). The mixture is heated in a sealed tube for 18 h, then cooled to room temperature, and diluted with EtOAc and water. Usual work up and purification by column chromatography, eluting with EtOAc-hexanes provides pure N3-Ethyl-6-trifluoromethyl-pyridine-3,4-diamine. 1H NMR (300 MHz, CDCl3): δ 7.95 (s, 1H); 6.95 (s, 1H) 3.21 (q, J=5.4 Hz, 2H), 1.35 (t, J=5.4 Hz, 3H)

[0531] 4. Preparation of 2-Chloromethyl-3-ethyl-6-trifluoromethyl-3H-imidazo[4,5-c]pyridine

[0532] 2-Chloromethyl-3-ethyl-6-trifluoromethyl-3H-imidazo[4,5-c]pyridine is made from N3-Ethyl 6-Trifluoromethyl-pyridine-3,4-diamine following the procedure described previously for the preparation of 2-Chloromethyl-1-ethyl-6-trifluoromethyl-1H-imidazo[4,5-c]pyridine. 1H NMR (300 MHz, CDCl3): δ 8.89 (s, 1H), 8.04 (s,1H), 4.87 (s, 2H), 4.45 (t, J=7.2 Hz, 2H), 1.59 (t, J=7.2 Hz, 3H)

[0533] 5. Preparation of 3-ethyl-2-{[2-(1,3-thiazol-2-yl)-1H-imidazol-1-yl]methyl}-6-(trifluoromethyl)-3H-imidazo[4,5-c]pyridine

[0534] As described previously for the preparation of 1-Ethyl-2-(2-thiazol-2-yl-imidazol-1-ylmethyl)-6-trifluoromethyl-1H-imidazo[4,5-c]pyridine, nucleophilic displacement of the 2-chloromethyl-3-ethyl-6-trifluoromethyl-3H-imidazo[4,5-c]pyridine with the same 2-(1H-imidazol-2-yl)-thiazole followed by usual work provides 3-ethyl-2-{[2-(1,3-thiazol-2-yl)-1H-imidazol-1-yl]methyl}-6-(trifluoromethyl)-3H-imidazo[4,5-c]pyridine. 1H NMR (CD3OD) δ 9.02 (s, 1H), 7.89 (s, 1H), 7.70 (d, J=3 Hz, 1H), 7.52 (d, J=3.3 Hz, 1H), 7.46 (d, J=1.5 Hz, 1H), 7.19 (d, J=1.5 Hz, 1H), 6.29 (s, 2H), 4.56 (q, J=7.5 Hz, 2H), 1.52 (t, J=7.5 Hz, 3H) m/z 379 [M+1]

Example 34

[0535] Synthesis of 3-ethyl-2-[(2-pyrimidin-2-yl-1H-imidazol-1-yl)methyl]-3H-imidazo[4,5-c]pyridine-4-carbonitrile

[0536] 1. Preparation of 3-Ethylamino-4-nitro-pyridine-2-carbonitrile

[0537] TMSCN (1.1 ml, 8.33 mmol) and dimethyl amino carbamoyl chloride (0.76 mL, 8.33 mmoL) are added to a solution of 3-ethylamino-4-nitro-pyridine-1-oxide (1 g, 6.94 mmol) in anhydrous DMF (10 mL) were added. The reaction mixture is stirred overnight at 80° C., cooled to room temperature, and diluted with CH2Cl2 and water. The combined organic layer is washed with water, brine, dried over Na2SO4, and concentrated. The residue is chromatographed eluting with 40% EtOAc-hexanes to afford 3-ethylamino-4-nitro-pyridine-2-carbonitrile as a yellow solid. 1H NMR (300 MHz, CD3OD): δ 7.82 (d, J=4.5 Hz, 1H), 7.50 (d, J=4.5 Hz, 1H), 3.70 (q, J=7.2 Hz, 2H), 1.39 (t, J=7.2 Hz, 3H).

[0538] 2. Preparation of 4-Amino-3-ethylamino-pyridine-2-carbonitrile

[0539] Hydrogenaton of 3-Ethylamino-4-nitro-pyridine-2-carbonitrile under conditions previously described provides 4-Amino-3-ethylamino-pyridine-2-carbonitrile. 1H NMR (300 MHz, CD3OD): δ 7.75 (d, J=5.4 Hz, 1H), 6.66 (d, J=5.4 Hz, 1H), 3.35 (q, J=7.2 Hz, 2H), 1.29 (t, J=7.2 Hz, 3H).

[0540] 3. Preparation of 2-Chloromethyl-3-ethyl-3H-imidazo[4,5-c]pyridine-4-carbonitrile

[0541] 2-Chloromethyl-3-ethyl-3H-imidazo[4,5-c]pyridine-4-carbonitrile is prepared from the reaction of 4-amino-3-ethylamino-pyridine-2-carbonitrile and 2-chloro acetimidate following the previously described procedure. 1H NMR (300 MHz, CDCl3): δ 8.55 (d, J=5.4 Hz, 1H), 7.84 (d, J=5.4 Hz, 1H) 4.98 (s, 2H), 3.41 (q, J=7.5 Hz, 2H), 1.23 (t, J=7.5 Hz, 3H).

[0542] 4. Preparation of 3-ethyl-2-[(2-pyrimidin-2-yl-1H-imidazol-1-yl)methyl]-3H-imidazo[4,5-c]pyridine-4-carbonitrile 3-ethyl-2-[(2-pyrimidin-2-yl-1H-imidazol-1-yl)methyl]-3H-imidazo[4,5-c]pyridine-4-carbonitrile is obtained from 2-chloromethyl-3-ethyl-3H-imidazo[4,5-c]pyridine-4-carbonitrile by nucleophilic displacement with 2-(1H-Imidazol-2-yl)-pyrimidine, as described previously, followed by usual work up. 1H NMR (300 MHz, CD3OD): δ 8.70 (d, J=5.1 Hz, 2H), 8.41 (d, J=5.4 Hz, 1H), 7.73 (d, J=5.1 Hz, 1H), 7.52 (d, J=1.2 Hz, 1H), 7.31 (d, J=1.2 Hz, 1H), 7.27 (t, J=4.5 Hz, 1H), 6.35 (s, 2H), 4.75 (q, J=7.5 Hz, 2H), 1.63 (t, J=7.2 Hz, 3H); m/z 331 [M+1]

Example 35

[0543] Synthesis of 1-(2-{[2-(6-fluoropyridin-2-yl)-1H-imidazol-1-yl]methyl}-1-propyl-1H-imidazo[4,5-c]pyridin-4-yl)ethanone

[0544] To the mixture of H2O (5 mL) and CH2Cl2 (5 mL) is added 1-Propyl-2-{[2-(2-fluoropyrid-6-yl)-1H-imidazol-1-yl]methyl}-5-aza-1H-benzimidazole (168 mg, 0.5 mmol), pyruvic acid (132 mg, 1.5 mmol), silver nitrate (7 mg, 0.04 mmol), (NH4)2S2O8 (342 mg, 1.5 mmol), and sulfuric acid (98%, 100 mg, 1.0 mmol). The mixture is heated to 40° C. for 2 hr, then cooled to room temperature. The aqueous solution is neutralized to pH 8 with saturated sodium bicarbonate solution and extracted with CH2Cl2. The combined organic layers are dried over Na2SO4 and solvent is removed to give a brown solid. Purification by preparative TLC provides ′1-(2-{[2-(6-fluoropyridin-2-yl)-1H-imidazol-1-yl]methyl}-1-propyl-1H-imidazo[4,5-c]pyridin-4-yl)ethanone as white solid. 1H NMR (CDCl3) d 8.48 (d, 1H), 8.12 (dd, 1H), 7.88 (q, 1H), 7.44 (d, 1H), 7.23 (d, 1H), 7.11 (d, 1H), 6.88 (dd, 1H), 6.40 (s, 2H) 4.22 (q, 2H), 2.84 (s, 3H), 1.58 (m, 2H), 0.74 (t, 3H).

Example 36

[0545] Synthesis of 1-(3-ethyl-2-([2-(1,3-thiazol-2-yl)-1H-imidazol-1-yl]methyl}-3H-imidazo[4,5-c]pyridin-6-yl)ethanone

[0546] 1. Preparation of 2,5-Dichloro-pyridine 1-oxide

[0547] A mixture of 2,5-Dichlropyridine (30 g, 0.2 mmol) and 3-Chloroperoxybenzoic acid (70%, 50 g, 0.2 mmol) in 500 mL of Dichloroethane is heated at 50° C. overnight. After cooling to −30° C., NH3 gas is bubbled into the reaction mixture for 5 minutes. The mixture is filtered, the solid is washed with dichloroethane (50 mL), and the filtrate is concentrated to a solid. The solid is mixed with 200 mL of Hexane and heated at reflux for 30 minutes. After cooling, the precipitate is collected by filtration, and dried to give the titled compound as a tan solid. 1H NMR (CDCl3): δ 8.40 (d, 1H), 7.44 (d, 1H), 7.22 (t, 1H).

[0548] 2. Preparation of 2,5-dichloro-4-nitro-pyridine 1-oxide

[0549] At 0° C., 30% oleum (13 mL) is added slowly to fuming HNO3 (22 mL) and the resulting mixture is added slowly to the solution of 2,5-dichloro-pyridine 1-oxide (5.2 g, 31 mmol) in concentrated H2SO4. After addition, the reaction mixture is warmed to room temperature over 1 hr, then heated to 80° C. for 2 hr. After cooling to room temperature, the mixture is poured into ice (120 g) and precipitate is formed gradually. The solid is collected by filtration and washed with water. The product is obtained as yellow solid. 1H NMR (CDCl3) δ 8.46 (s, 1H), 8.25 (s, 1H).

[0550] 3. Preparation of (6-Chloro-4-nitro-1-oxy-pyridin-3-yl)-ethylamine

[0551] To a solution of 2,5-Dichloro-4-nitro-pyridine 1-oxide (7 g, 33 mmol) in 100 mL of THF is added a solution of Ethylamine (2M, 50 mL) dropwise at ° C. The reaction mixture is warmed to room temperature and stirred overnight. The volatiles are evaporated in vacuo. The residue is purified on a silica gel column with 1% CH2Cl2 as eluent to give the title compound as an orange solid. 1H NMR (CDCl3): δ 8.24 (s, 1H), 8.06 (s, 1H), 7.62 (br, 1H), 3.25 (q, 2H), 1.38 (t, 3H)

[0552] 4. Preparation of 1-(5-ethylamino-4-nitro-pyridin-2-yl)-ethanone

[0553] (6-Chloro-4-nitro-1-oxy-pyridin-3-yl)ethyl-amine (700 mg, 3.2 mmol), tributyl-(1-ethoxy-vinyl)-stannane (1.75 g, 4.9 mmol), PdCl2(PPh3) 2 (350 mg, 0.5 mmol), and toluene (35 mL)o are added to a sealed tube; the mixture is degassed for 30 min. The reaction is heated to 75° C. for 16 hr and then cooled to room temperature. 6N HCl solution (20 mL) is added to the mixture is added and the reaction is stirred at room temperature for 1 hr. The reaction mixture is filtered through celite and the aqueous layer is neutralized to basic with saturated NaHCO3. The aqueous layer is extracted with ethyl acetate and the combined organic layers are dried over Na2SO4. The solvent is removed in vacuo. Purification by flash column provides the product as orange solid. 1H NMR (CDCl3) δ 8.70 (s, 1H), 8.48 (s, 1H), 7.96 (br, 1H), 3.55 (m, 2H), 2.65 (s, 3H), 0.92 (t, 3H). LRMS 210.1 (MH+).

[0554] 5. Preparation of 1-(4-amino-5-ethylamino-pyridin-2-yl)-ethanone

[0555] A mixture of 1-(5-ethylamino-4-nitro-pyridin-2-yl)-ethanone (310 mg, 1.5 mmol) and 10% Pd/C (50 mg) in ethanol (10 mL) is stirred under hydrogen for 1 hr. The mixture is filtered through Celite and concentrated in vacuo to give the product as yellow solid. 1H NMR (CD3OD) δ 7.61 (s, 1H), 7.30 (s, 1H), 3.26 (q, 2H), 2.53 (s, 3H), 0.90 (t, 3H). LRMS 180.5 (MH+).

[0556] 6. Preparation of 1-(3-ethyl-2-{[2-(1,3-thiazol-2-yl)-1H-imidazol-1-yl]methyl}-3H-imidazo[4,5-c]pyridin-6-yl)ethanone

[0557] A mixture of 1-(4-amino-5-ethylamino-pyridin-2-yl)-ethanone (54 mg, 0.3 mmol), (2-thiazol-2-yl-imidazol-1-yl)-acetic acid (61 mg, 0.3 mmol), EDCI (60 mg, 0.3 mmol), and pyridine (2 mL) is stirred at room temperature for 72 hr and then poured into water. The aqueous layer is extracted with ethyl acetate and the combined organic layers are dried over Na2SO4. Solvent is evaporated in vacuo and the residue is taken up in acetic acid (5 mL). The mixture is heated to ref lux for 16 hr and saturated NaHCO3 solution is added to neutralize the reaction. The aqueous solution is extracted with ethyl acetate and the combined organic layers are dried over Na2SO4. Solvent is removed in vacuo and purification by preparative TLC provides the product as white solid. 1H NMR (CDCl3) δ 8.79 (d, 2H), 8.47 (d, 1H), 7.83 (d, 1H), 7.40 (d, 1H), 7.19 (d, 1H), 7.15 (d, 1H), 6.39 (s, 2H), 4.02 (q, 2H), 2.77 (s, 3H), 1.86 (t, 3H). LRMS 353.2 (MH+).

Example 37

[0558] Synthesis of 1-Ethyl-2-(2-thiazol-2-yl-2H-pyrazol-3-ylmethyl)-1H-imidazo[4,5-c]pyridine

[0559] 1. Preparation of (2-Thiazol-2-yl-2H-pyrazol-3-yl)-acetic Acid Ethyl Ester

[0560] A mixture of thiazol-2-ylhydrazine (2.2 g, 19.1 mmol) and 3,5,5-triethoxy-pent-2-enoic acid ethyl ester (70% purity, 7.1 g, 19.1 mmol) is refluxed in acetic acid overnight. Acetic acid is removed. To the residue is added NaHCO3 (aq.) (40 mL) and ethyl acetate (100 mL). The insoluble material is filtered. The organic layer is dried and solvent removed. The crude is subjected to column separation (hexane/ethyl acetate 3:1) to give (2-thiazol-2-yl-2H-pyrazol-3-yl)-acetic acid ethyl ester as an oil.

[0561] 2. Preparation of 1-Ethyl-2-(2-thiazol-2-yl-2H-pyrazol-3-ylmethyl)-1H-imidazo[4,5-c]pyridine

[0562] Trimethylaluminum (2M in toluene) (1.4 mL, 2.85 mmol) is added dropwise under N2 to a solution of N -Ethyl-pyridine-3,4-diamine (156 mg, 1.14 mmol) in DCM (5 mL). The mixture is stirred at room temperature for 1 hour. A solution of thiazol-2-yl-2H-pyrazol-3-yl)-acetic acid ethyl ester (270 mg, 1.14 mmcl) in DCM (2 mL) is added. The mixture is reluxed for 25 hours. on cooling, the reaction is quenched with water added dropwise and DCM (20 mL) is added. The organic layer is separated and the aqueous layer is extracted with DCM (3×30 mL). The combined organic layers are dried and solvent removed. Acetic acid (10 ml)is added to the residue. The solution is refluxed for 3.5 h. Acetic acid is removed in vacuc and the residue is purified by PTLC (10% methanol in DCM) to give i-Ethyl-2-(2-thiazol-2-yl-2H-pyrazol-3-ylmethyl)-1H-imidazo[4,5-c]pyridine as a solid. 1H NMR (CDCl3) δ 9.00 (s, 1Hl), 8.43 (d, 1H), 7.63 (d, 1H), 7.43 (d, 1H), 7.15 (d, 1H), 7.06 (d, 1H), 6.25 (d, 1H), 4.99 (s, 2H), 4.25 (q, 2H), 1.36 (t, 3H)

Example 38

[0563] Synthesis of 1-Ethyl-2-[1-(2-thiazol-2-yl-2H-pyrazol-3-yl)-ethyl]-1H-imidazo[4,5-c]pyridine

[0564] 1. Preparation of 2-(2-Thiazol-2-yl-2H-pyrazol-3-yl)-propionic Acid Ethyl Ester

[0565] A mixture of (2-thiazol-2-yl-2H-pyrazol-3-yl)-acetic acid ethyl ester (100 mg, 0.42 mmol), methyl iodide (66 mg, 0.46 mmol) and cesium carbonate (151 mg, 0.46 mmol) in DMF (6 mL) is stirred at room temperature overnight. The reaction is quenched with NH4Cl (aq.) (6 mL) and ethyl acetate (30 mL). The organic layer is separated and the aqueous layer is extracted with ethyl acetate (3×30 mL). The combined organic layers are dried and the solvent removed. The crude is purified by PTLC (hexane/ethyl acetate 3:1) to give 2-(2-thiazol-2-yl-2H-pyrazol-3-yl)-propionic acid ethyl ester as an oil.

[0566] 2. Preparation of 1-Ethyl-2-[1-(2-thiazol-2-yl-2H-pyrazol-3-yl)-ethyl]-1H-imidazo[4,5-c]pyridine

[0567] Trimethylaluminum (2M in toluene) (0.5 mL, 1 mmol)) is added dropwise under N2 to a solution of N4-Ethyl-pyridine-3,4-diamine (44 mg, 0.32 mmol) in DCM (5 mL). The mixture is stirred at room temperature for 1 hour. A solution of thiazol-2-yl-2H-pyrazol-3-yl)-propionic acid ethyl ester in DCM (2 mL) is added. The mixture is reluxed for 3 days. On cooling, the reaction is quenched with water added dropwise and DCM (20 mL) is added. The organic layer is separated and the aqueous layer is extracted with DCM (3×30 mL). The combined organic layers are dried and the solvent removed. The residue is purified by PTLC (10% methanol in DCM) to give 1-ethyl-2-[1-(2-thiazol-2-yl-2H-pyrazol-3-yl)-ethyl]-1H-imidazo[4,5-c]pyridine as a solid. 1H NMR (CDCl3) δ 9.05 (s, 1H), 8.39 (d, 1H), 7.59 (d, 1H), 7.49 (d, 1H), 7.25 (d, 1H), 7.09 (d, 1H), 6.28 (d, 1H), 5.85 (q, 1H), 4.19 (q, 2H), 1.85 (d, 3H), 1.29 (t, 3H)

Example 39

[0568] Synthesis of 2-[2,4′]Bithiazolyl-51-ylmethyl-1-ethyl-1H-imidazo[4,5-c]pyridine

[0569] 1. Preparation of 4-Oxo-4-thiazol-2-yl-butyric Acid Ethyl Ester

[0570] To a stirred solution of 2-trimethylsilanyl-thiazole (2.6 g, 16.53 mmol) in DCM (30 mL) is added a solution of 3-chlorocarbonyl-propionic acid ethyl ester (5.4 g, 32.81 mmol)in DCM (10 mL). The mixture is stirred overnight at room temperature. To the mixture is added 5% NaHCO3 (30 mL) and mixture is stirred at room temperature for 20 minutes. The organic layer is separated and the aqueous lay is extracted with DCM (2×50 mL). The combined organic layers are dried and the solvent removed. The residue is separated by column (methylene chloride) to give 4-oxo-4-thiazol-2-yl-butyric acid ethyl ester.

[0571] 2. Preparation of 3-Bromo-4-oxo-4-thiazol-2-yl-butyric Acid Ethyl Ester

[0572] Phenyltrimethylammonium tribromide (3.4 g, 8.91 mmol) in DCM (20 mL) is added dropwise to a solution of 4-oxo-4-thiazol-2-yl-butyric acid ethyl ester (1.9 g, 8.91 mmol) in DCM (30 mL. The mixture is stirred overnight at room temperature. 5% NaHCO3 (40 mL) is added to the mixture. The organic layer is separated and the aqueous layer is extracted with DCM (2×40 mL). The combined organic layers are dried and solvent removed. The residue is purified by column (hexanes/ethyl acetate 3:1) to give 3-bromo-4-oxo-4-thiazol-2-yl-butyric acid ethyl ester.

[0573] 3. Preparation of [2,4′]Bithiazolyl-5′-yl-acetic Acid Ethyl Ester

[0574] To a solution of 3-bromo-4-oxo-4-thiazol-2-yl-butyric acid ethyl ester (2.2 g, 7.53 mmol) in 1,4-dioxane (40 mL) is added thioformamide (freshly made from formamide and P2S5 in 1,4-dioxane) (22.59 mmol). The mixture is refluxed overnight. The solvent is removed and NaHCO3 (aq.) (40 mL) and DCM (100 mL) are added to the residue. The organic layer is separated and the aqueous layer is extracted with DCM (2×40 mL). The combined organic layers are dried and solvent removed. The crude is purified by column (1% methanol n DCM) to give [2,4′]bithiazolyl-5′-yl-acetic acid ethyl ester.

[0575] 4. Preparation of 2-[2,4′]Bithiazolyl-5′-ylmethyl-1-ethyl-1H-imidazo[4,5-c]pyridine

[0576] Trimethylaluminum (2M in toluene)(2.2 mL, 4.4 mmol) is added dropwise under N2 yo a solution of N4-Ethyl-pyridine-3,4-diamine (237 mg, 1.73 mmol) in DCM (5 mL). The mixture is stirred at room temperature for 1 hour. A solution of [2,4′]bithiazolyl-5′-yl-acetic acid ethyl ester (440 mg, 1.73 mmol mmol) in DCM (2 mL) is added. The mixture is reluxed for 3 days. On cooling, the reaction is quenched with water added dropwise and DCM (40 mL) is added. The organic layer is separated and the aqueous layer is extracted with DCM (3×30 mL). The combined organic layers are dried and solvent removed. The residue is purified by PTLC (10% methanol in DCM) to give 2-[2,4′]bithiazolyl-5′-ylmethyl-1-ethyl-1H-imidazo[4,5-c]pyridine as a solid. 1H NMR (CDCl3) δ 9.05 (s, 1H0), 8.76 (s, 1H), 8.41 (d, 1H), 7.88 (d, 1H), 7.41 (d, 1H) 7.25 (d, 1H), 5.35 (s, 2H), 4.26 (q, 2H), 1.25 (t, 3H)

Example 40

[0577] Synthesis of 5-Bromo-1-ethyl-2-[3-(3-fluoro-phenyl)-isoxazol-4-ylmethyl]-1H-benzoimidazole

[0578] 1. Preparation of 3-(5-Bromo-1-ethyl-1H-benzoimidazol-2-yl)-1-(3-fluoro-phenyl)-propan-1-one

[0579] To a solution of 1-(3-fluoro-phenyl)-ethanone (0.55 g, 4.0 mmol) in THF (30 mL) at −78° C. under N2 is added LDA (2M in hexanes, 2.0 mL, 4.0 mmol). After 10 minutes, 5-bromo-2-chloromethyl-1-ethyl-1H-benzoimidazole (1 g, 3.65 mmol) in THF (5 mL) is added. The mixture is stirred at this temperature for an additional 1 hour and is gradually warmed to room temperature. The reaction is then quenched with saturated NH4Cl. The mixture is extracted with ethyl acetate (3×50 mL). Upon drying, the organic solvent is removed to give 3-(5-Bromo-1-ethyl-1H-benzoimidazol-2-yl)-1-(3-fluoro-phenyl)-propan-1-one as a yellow oil.

[0580] 2. Preparation of 5-Bromo-1-ethyl-2-[3-(3-fluoro-phenyl)isoxazol-4-ylmethyl]-1H-benzoimidazole

[0581] A mixture of 3-(5-Bromo-1-ethyl-1H-benzoimidazol-2-yl)-1(3-fluoro-phenyl)-propan-1-one (0.1 g, 0.27 mmol) and tris(dimethylamino)methane (0.077 g, 0.54 mmol) is heated at 60° C. in a sealed tube for 6 hours. The volatile material is removed in vacuo. To the residue is added EtOH (5 mL) and hydroxylamine (1.1 mmol). The mixture is heated at 120° C. for 2 hours. The solvent is removed. To the residue is added NaHCO3 (aq.) (10 mL) and DCM (30 mL). The organic layer is separated and the aqueous layer is extracted with DCM (2×15 mL). The combined organic layers are dried and the solvent removed. The crude is purified by PTLC (ethyl acetate/Hexanes 1:1) to give 5-Bromo-1-ethyl-2-[3-(3-fluoro-phenyl)-isoxazol-4-ylmethyl]-1H-benzoimidazole as a solid. 1H NMR (CDCl3) δ 8.40 (s, 1H), 7.88 (s, 1H), 7.31-7.52 (m, 4H), 7.18-7.22 (m, 2H), 4.14 (s, 2H), 4.04 (q, 2H), 1.18 (t, 3H).

Example 41

[0582] Synthesis of 5-Bromo-1-ethyl-2-[3-(3-fluoro-phenyl)-1H-pyrazol-4-ylmethyl]-1H-benzoimidazole

[0583] A mixture of 3-(5-Bromo-1-ethyl-1H-benzoimidazol-2-yl)-1-(3-fluoro-phenyl)-propan-1-one (0.1 g, 0.27 mmol) and tris(dimethylamino)methane (0.077 g, 0.54 mmol) is heated at 60° C. in a sealed tube for 6 hours. The volatile material is removed in vacuo. EtOH (5 mL) and hydrazine acetate (1.1 mmol) are added to the residue. The mixture is heated at 120° C. for 2 hours. The solvent is removed. NaHCO3 (aq.) (10 mL) and DCM (30 mL) are added to the residue. The organic layer is separated and the aqueous layer is extracted with DCM (2×15 mL). The combined organic layers are dried and the solvent removed. The crude is purified by PTLC (ethyl acetate/Hexanes 1:1) to give 5-bromo-1-ethyl-2-[3-(3-fluoro-phenyl)-1H-pyrazol-4-ylmethyl]-1H-benzoimidazole as a solid. LRMS: calcd 399.3, found [M+1] 401.0.

Example 42

[0584] Synthesis of 5-Bromo-1-ethyl-2-[3-(3-fluoro-phenyl)-1-methyl-1H-pyrazol-4-ylmethyl]-1H-benzoimidazole and 5-Bromo-1-ethyl-2-[5-(3-fluoro-phenyl)-1-methyl-1H-pyrazol-4-ylmethyl]-1H-benzoimidazole

[0585] A mixture of 3-(5-Bromo-1-ethyl-1H-benzoimidazol-2-yl)-1-(3-fluoro-phenyl)-propan-1-one (0.1 g , 0.27 mmol) and tris(dimethylamino)methane (0.077 g, 0.54 mmol) is heated at 60° C. in a sealed tube for 6 hours. The volatile material is removed in vacuo. EtOH (5 mL) and methyl hydrazine (1.1 mmol) are added to the residue. The mixture is heated at 120° C. for 2 hours. The solvent is removed. NaHCO3 (aq.) (10 mL) and DCM (30 mL) are added to the residue. The organic layer is separated and the aqueous layer is extracted with DCM (2×15 mL). The combined organic layers are dried and the solvent removed. The crude is purified by PTLC (ethyl acetate/Hexanes 1:1) to give 5-bromo-1-ethyl-2-[3-(3-fluoro-phenyl)-1-methyl-1H-pyrazol-4-ylmethyl]-1H-benzoimidazole and 5-bromo-1-ethyl-2-[5-(3-fluoro-phenyl)-1-methyl-1H-pyrazol-4-ylmethyl] -1H-benzoimidazole. 5-bromo-1-ethyl-2-[3-(3-fluoro-phenyl)-1-methyl-1H-pyrazol-4-ylmethyl]-1H-benzoimidazole: 1H NMR (CDCl3) δ 7.88 (s, 1H), 7.27-7.42 (m, 4H), 7.00-7.20 (m, 3H), 4.21 (s, 2H), 3.95 (t, 2H), 3.83 (s, 3H), 1.15 (t, 3H). 5-bromo-1-ethyl-2-[5-(3-fluoro-phenyl)-1-methyl-1H-pyrazol-4-ylmethyl]-1H-benzoimidazole: 1H NMR (CDCl3) δ 7.81 (s, 1H), 7.38-7.45 (m, 2H), 7.32 (dd, 1H), 7.00-7.18 (m, 4H), 4.00 (s, 2H), 3.90 (q, 2H), 3.78 (s, 3H), 1.15 (t, 3H).

Example 43

[0586] Synthesis of 5-Bromo-1-ethyl-2-[4-(3-fluoro-phenyl)-thiazol-5-ylmethyl]-1H-benzoimidazole

[0587] A mixture of 3-(5-bromo-1-ethyl-1H-benzoimidazol-2-yl)-1-(3-fluoro-phenyl)-propan-1-one (0.2 g, 0.53 mmol) and bromine (0.1 g, 0.62 mmol) is refluxed in 1,4-dioxane for 2 hours. Thioformamide (freshly made from formamide and P2S5 in 1,4-dioxane) (1.3 mmol) are added to the solution. The mixture is refluxed overnight. The solvent is removed and NaHCO3 (aq.) (15 mL) and DCM (40 mL) are added to the residue. The organic layer is separated and the aqueous layer is extracted with DCM (2×30 mL). The combined organic layers are dried and solvent removed. The crude is purified by PTLC (5% methanol in DCM) to give 5-bromo-1-ethyl-2-[4-(3-fluoro-phenyl)-thiazol-5-ylmethyl]-1H-benzoimidazole. 1H NMR (CDCl3) δ 8.78 (s, 1H), 7.91 (s, 1H), 7.38-7.48 (m, 4H), 7.11-7.19 (m, 2H), 4.59 (s, 2H), 3.90 (q, 2H), 1.12 (t, 3H).

Example 44

[0588] Synthesis of 1-[3-Ethyl-2-(2-thiazol-2-yl-imidazol-1-ylmethyl)-3H-benzoimidazol-5-yl]-ethanone

[0589] 1. Preparation of (5-Chloro-2-nitro-phenyl)-ethyl-amine

[0590] A mixture of 4-cloro-2-fluoronitrobenzene (5 g, 28.48 mmol), ethylamine (2M in THF, 24 mL, 48 mmol), and K2CO3 (7.9 g , 57 mmol)in acetonitrile (30 mL) is stirred at room temperature overnight. Solvent is removed. Ethyl acetate (80 mL) and brine (40 mL) are added to the residue. The organic layer is separated and the aqueous layer is extracted with ethyl acetate (2×50 mL). The combined organic layers are dried and solvent removed to give 5-chloro-2-nitro-phenyl)-ethyl-amine.

[0591] 2. Preparation of 1-(3-Ethylamino-4-nitro-phenyl)-ethanone

[0592] A mixture of 5-chloro-2-nitro-phenyl)-ethyl-amine (1 g, 4.98 mmol), tributyl-(1-ethoxyvinyl)stannane (2.7 g, 7.48 mmol) and dichlorobis(triphenylphosphine)palladium (II) (175 mg, 0.25 mmol) in toluene (80 mL) is heated at 100° C. in a sealed tube for 5 hours. On cooling, water (30 mL) and HCl (con. 30 mL) are added and the mixture is stirred at room temperature for 2 hours. The mixture is neutralized with NaOH (2 N) and extracted with DCM (3×50 mL). The combined organic layers are dried and solvent removed. The residue is purified by column (hexanes/ethyl acetate 3:1) to give -(3-ethylamino-4-nitro-phenyl)-ethanone.

[0593] 3. Preparation of 1-(4-Amino-3-ethylamino-phenyl)-ethanone

[0594] 10% Pd/C (100 mg) is added to a Parr bottle containing 1-(3-ethylamino-4-nitro-phenyl)-ethanone (0.98 g, 4.7 mmol) in ethanol (40 mL). The Parr bottle is sealed in a mechanical shaker, evacuated, and then purged with nitrogen followed by hydrogen. The system is pressurized to 50 PSI of hydrogen at room temperature and mechanical shaking engaged. After 2 hours, shaking is stopped, and the system purged with nitrogen prior to opening the vessel. The reaction mixture is filtered through celite, concentrated in vacuo, to give 1-(4-amino-3-ethylamino-phenyl)-ethanone.

[0595] 4. Preparation of 1-(2-Chloromethyl-3-ethyl-3H-benzoimidazol-5-yl)-ethanone

[0596] A mixture of 1-(4-amino-3-ethylamino-phenyl)-ethanone (300 mg, 1.69 mmol) and 2-chloroacetamidine hydrochloride (804 mg, 5.1 mmol) in acetonitrile (20 mL) is refluxed for 3 hours. Solvent is removed and the residue is treated with NaHCO3 (5%, 20 mL) and DCM (50 mL). The organic layer is separated and the aqueous layer is extracted with DCM (2×40 mL). The combined organic layers are dried and solvent removed to give 1-(2-Chloromethyl-3-ethyl-3H-benzoimidazol-5-yl)-ethanone.

[0597] 5. Preparation of 1-[3-Ethyl-2-(2-thiazol-2-yl-imidazol-1-ylmethyl)-3H-benzoimidazol-5-yl]-ethanone

[0598] A mixture of 1-(2-Chloromethyl-3-ethyl-3H-benzoimidazol-5-yl)-ethanone (150 mg, 0.63 mmol), 2-(1H-Imidazol-2-yl)-thiazole (95 mg, 0.63 mmol) and K2CO3 (262 mg, 1.9 mmol)in DMF (10 mL) is stirred at room temperature for 48 hours. Brine (6 mL) and DCM (20 mL) are added. The organic layer is separated and the aqueous layer is extracted with DCM (3×29 mL). The combined organic layers are dried and solvent removed. The residue is purified by PTLC (10% methanol in DCM) to give 1-[3-Ethyl-2-(2-thiazol-2-yl-imidazol-1-ylmethyl)-3H-benzoimidazol-5-yl]-ethanone as a solid. 1H NMR (CDCl3) δ 8.05 (d, 1H), 7.92 (dd, 1H), 7.87 (dd, 1H), 7.81 (dd, 1H), 7.40 (d, 1H), 7.20 (d, 1H), 7.14 (d, 1H), 6.17 (s, 2H), 4.33 (q, 2H), 2.67 (s, 3H), 1.13 (t, 3H).

Example 45

[0599] Synthesis of 1-Ethyl-2-[2-(1H-pyrazol-3-yl)-imidazol-1-ylmethyl]-1H-benzoimidazole-5-carbonitrile

[0600] 1. Preparation of 3-(1H-Imidazol-2-yl)-pyrazole-1-carboxylic Acid Tert-Butyl Ester

[0601] A mixture of 1H-Pyrazole-3-carbaldehyde (1 g, 10.4 mmol), di-tert-butyl dicarbonate (11.4 mmol) and N,N-dimethylpyridine (20 mg) in DCM (15 mL) and methanol (5 mL) is stirred at room temperature overnight. Solvent is removed. Glyoxal (6 mL) and ammonium hydroxid (8 mL) are added to the residue and the mixture is stirred at room temperature for 1.5 hours. Acetic acid is added dropwise o the mixture to pH˜7. Solvent is removed and DCM (50 mL) and brine (30 mL) are added to the residue. The organic layer is separated and the aqueous layer is extracted with DCM (2×40 mL). The combined organic layers are dried and solvent removed to give 3-(1H-imidazol-2-yl)-pyrazole-1-carboxylic acid tert-butyl ester.

[0602] 2. Preparation of 1-Ethyl-2-[2-(1H-pyrazol-3-yl)-imidazol-1-ylmethyl]-1H-benzoimidazole-5-carbonitrile

[0603] As described previously, nucleophilic displacement of 2-Chloromethyl-1-ethyl-1H-benzoimidazole-5-carbonitrile with 3-(1H-Imidazol-2-yl)-pyrazole-1-carboxylic acid tert-butyl ester followed by usual work-up provides 1-Ethyl-2-[2-(1H-pyrazol-3-yl)-imidazol-1-ylmethyl] -1H-benzoimidazole-5-carbonitrile; 1H NMR (CD3OD) δ 7.97 (s, 1H), 7.53 (brs, 1H), 7.46 (d, J=8.7 Hz, 1H) 7.35 (d, J=8.1 Hz, 1H), 6.97 (d, J=6.3 Hz, 2H), 6.79 (br s, 1H), 6.10 (s, 2H), 4.22 (q, J=7.2 Hz, 2H), 0.88 (t, J=7.2 Hz, 3H); m/z 318 [M+1].

Example 46

[0604] Synthesis of 4-(1-ethyl-2-{[2-(1,3-thiazol-2-yl)-1H-imidazol-1-yl]methyl}-1H-benzimidazol-5-yl)-2-methylbutan-2-ol

[0605] 1. Preparation of 4-(1-ethyl-2-{[2-(1,3-thiazol-2-yl)-1H-imidazol-1-yl]methyl}-1H-benzimidazol-5-yl)-2-methyl-1-but-3-yn-2-ol

[0606] Pd (PPh3)4 (15 mg, 0.013 mmol), CuI (5 mg, 0.026 mmol), and 2-methyl-but-3-yn-2-ol (250 μL, 2.6 mmol) are added to the solution of 1-ethyl-5-bromo-2-{[2-(1,3-thiazol-2-yl)-1H-imidazol-1-yl]methyl}-1H-benzimidazole (100 mg, 0.26 mmol) in i-Pr2NH(5 mL). The resulting mixture is heated to 100° C. for 20 hr. and then diluted with water. The aqueous layer is extracted with ethyl acetate. The combined organic layers are dried over Na2SO4 and solvent is removed to give a brown oil. Purification by ms5 preparative TLC provides 40 mg of product as yellow solid. LCMS 392.37 (MH+).

[0607] 2. Preparation of 4-(1-ethyl-2-{[2-(1,3-thiazol-2-yl)-1H-imidazol-1-yl]methyl}-1H-benzimidazol-5-yl)-2-methylbutan-2-ol

[0608] To a Parr bottle containing 4-(1-ethyl-2-{[2-(1,3-thiazol-2-yl)-1H-imidazol-1-yl]methyl}-1H-benzimidazol-5-yl)-2-methyl-1-but-3-yn-2-ol (40 mg, 0.1 mmol) in ethanol (10 mL) is added 10% Pd/C (50 mg). The Parr bottle is sealed in a mechanical shaker, evacuated, and then purged with nitrogen followed by hydrogen. The system is pressurized to 40 PSI of hydrogen at room temperature and mechanical shaking engaged. After 2 hours, shaking is stopped, and the system purged with nitrogen prior to opening the vessel. The reaction mixture is filtered through celite and concentrated in vacuo. The product is obtained as white solid. 1H NMR (CDCl3) δ 7.85 (d, 1H), 7.60 (s, 1H), 7.38 (d, 1H), 7.22 (m, 1H), 7.15 (m, 2H), 7.09 (s, 1H), 6.31 (s, 2H), 4.17 (q, 2H), 2.80 (m, 2H), 1.81 (m, 2H), 1.22 (d, 6H), 1.01 (t, 3H). LCMS 396.38 (MH+).

Example 47

[0609] Synthesis of 1-(1-ethyl-2-{[2-(1,3-thiazol-2-yl)-1H-imidazol-1-yl]methyl}-1H-benzimidazol-5-yl)-4-hydroxypentan-1-one

[0610] To the bi-layer system of 3 N HCl (5 mL) and CH2Cl2 is added 5-(1-ethyl-2-{[2-(1,3-thiazol-2-yl)-1H-imidazol-1-yl]methyl}-1H-benzimidazol-5-yl)-pent-4-yn-2-ol (107 mg, 0.27 mmol), Pdcl2 (5 mg, 0.028 mmol), and n-BU4NCl (17 mg, 0.056 mmol). The resulting mixture is stirred at room temperature for 72 hr, and then poured into saturated NaHCO3 solution. The aqueous layer is extracted with CH2Cl2 and the combined organic layers are dried over Na2SO4-Solvent is removed and purif ication by preparative TLC provides the product as white solid. 1H NMR (CDCl3) δ 8.44 (d, 1H), 7.80 (dd, 1H), 7.85 (d, 1H), 7.40 (d, 1H) F 7.36 (d, 1H), 7.18 (d, 1H), 7.14 (d, 1H), 6.36 (s, 2H), 4.27 (q, 2H), 3.86 (m, 1H), 3.19 (t, 2H), 1. 93 (m, 2H), 1. 25 (d, 3H), 1. 09 (t, 3H). LCMS 410.2 (MH+).

Example 48

[0611] Synthesis of 8-{[2-(6-Fluoropyridin-2-yl)-1H-imidazol-1-yl]methyl}-2,9-dimethyl-9H-purine

[0612] 1) Preparation of 6-Amino-4-chloro-2,N-dimethyl-5-nitropyrimidine

[0613] A solution of Methylamine (15.4 mL 1M in THF, diluted with 10 mL of hexane) is added dropwise to a solution of 4,6-Dichloro-2-methyl-5-nitropyrimidine (3.2 g, 15.4 mmol) in Hexane (30 mL). After addition, the reaction mixture is stirred at room temperature for one hour, and concentrated in vacuo to a solid. After the solid is dissolved in 50 mL of CH2Cl2, the resultant solution is washed with 0.1 N HCl (20 rmL) and water (20 mL), dried over Na2SO4 and concentrated to a yellow solid. 1H NMR (CDCl3) δ 7.7 (bs, 1H), 3.10 (d, 3H), 2.55 (s, 3H)

[0614] 2) Preparation of 2,N-Dimethyl-4,5-diaminopyrimidine

[0615] A mixture of 6-Amino-4-chloro-2,N-dimethyl-5-nitropyrimidine (1.0 g, 0.5 mmol), NaOH (40 mg, 1 mmol) and 1.0 g 10% Pd/C in 50 mL of 2% aqueous THF is hydrogenated at 50 PSI of hydrogen at room temperature overnight. The reaction mixture is filtered through celite, concentrated in vacuo, and the obtained solid is purified on a silica gel column eluting with 10/1/0.1 CH2Cl2/MeOH/NH4OH to give the title compound. 1H NMR (CDCl3) δ 7.64(s, 1H), 4.95 (bs, 1H), 3.02 (d, 3H), 2.45 (s, 3H), 1.90 (bs, 2H).

[0616] 3) Preparation of 8-chloromethyl-2,9-dimethyl-9H-purine

[0617] A solution of 2,N-Dimethyl-4,5-diaminopyrimidine (180 mg, 1.3 mmol) and ethyl chloroacetimidate hydrochloride (310 g, 2.0 mmol) in dichloroethane (10 mL) is heated at reflux for 17 h and cooled. The mixture is washed with aqueous NaHCO3, water, dried and concentrated to give 8-Chloromethyl-2,9-dimethyl-9H-purine.

[0618] 4) Preparation 8-{[2-(6-fluoropyridin-2-yl)-1H-imidazol-1-yl]methyl}-2,9-dimethyl-9H-purine

[0619] A mixture of 8-Chloromethyl-2,9-dimethyl-9H-purine (40 mg, 0.2 mmol), 2-Fluoro-6-(1H-imidazol-2-yl)-pyridine (40 mg, 0.25 mmol) and K2CO3 (55 mg, 0.4 mmol) in 2 mL of DMF is stirred at room temperature for four hours. The mixture is diluted with water (10 mL), and extracted with ethyl acetate three times. The combined extract is washed with brine, dried and concentrated. The residue is purified by preparative thin layer chromatography to give the title compound. 1H NMR(CDCl3): δ 8.92 (s, 1H), 8.18 (dd, 1H), 7.88 (q, 1H), 7.25 (s, 1H), 7.20 (s, 1H), 7.11 (s, 1H), 6.83 (dd, 1H), 6.22 (s, 2H), 3.89 (s, 3H), 2.8 (s, 3H). LRMS calcd 323, found 324 (MH+).

Example 49

[0620] The following compounds are prepared essentially according to the procedures in the previous examples.

[0621] a) 3-Methyl-2-(2-oxazol-2-yl-imidazol-1-ylmethyl)-3H-imidazo[4,5-c]pyridine

[0622] b) 3-Ethyl-2-(2-[1,3,4]oxadiazol-2-yl-imidazol-1-ylmethyl)-3H-imidazo[4,5-c]pyridine

[0623] c) 3-Ethyl-2-[2-(3-methyl-pyridin-2-yl)-imidazol-1-ylmethyl]-3H-imidazo[4,5-c]pyridine

Example 50

[0624] The compounds listed in tables 1-8 are prepared essentially according to the procedures set forth above in Schemes I-X and the preceding examples.

[0625] In tables 1-5 the designations X1, X2, W1, X5, W6, etc., on the substituents W1, R5, etc., indicate the point of attachment of the substituent to the parent structural formula. For example, R5 in compound number (hereinafter “Cmp. #”) 112 is an ethyl group; R5 in compound 134 is a cyclopropylmethyl group; and W1 in compound 132 is a 3-chlorophenyl group.

[0626] LC-MS data is provided for a number of the compounds in tables 1-5. The following HPLC method was used to obtain this data: YMC-pack pro C18 column, 33×4.6 mm(L×ID), 5 pm particle size. 3 min gradient from 5% to 95% B with 0.5 min hold at 95% B. Solvent A: 95% H2O-5%MeOH-0.05%TFA; Solvent B: 95%MeOH-5%H2O-0.05%TFA). Flow rate=2.0 ml/min. Injection volume=1 μl. MS (ES+): m/e 360 [MH]+. The LC data is given as HPLC retention times.

1TABLE 1

GC/FIDCmp. #R5W1MWRTMassor LC/MS100

302.37921.60303.1LC/MS101

316.4061.80317.1LC/MS102

316.4061.80317.1LC/MS103

320.36935.06GC/FID104

334.39615.07GC/FID105

334.39615.17GC/FID106

306.34255.12GC/FID107

320.36935.11GC/FID108

334.39615.10GC/FID109

100

334.39615.20GC/FID110

101

102

334.39615.21GC/FID111

103

104

324.33264.95GC/FID112

105

106

338.35944.95GC/FID113

107

108

352.38624.95GC/FID114

109

110

352.38625.05GC/FID115

111

112

354.81445.43GC/FID116

113

114

368.84125.42GC/FID117

115

116

368.84125.51GC/FID118

117

118

308.40745.27GC/FID119

119

120

322.43425.26GC/FID120

121

122

322.43425.37GC/FID121

123

124

356.34954.99GC/FID122

125

126

370.37634.98GC/FID123

127

128

384.40314.98GC/FID124

129

130

384.40315.07GC/FID125

131

132

367.24855.68GC/FID126

133

134

381.27535.67GC/FID127

135

136

395.30215.65GC/FID128

137

138

395.30215.74GC/FID129

139

140

322.79751.67323.1LC/MS130

141

142

336.82431.87337.3LC/MS131

143

144

350.85112.00351.1LC/MS132

145

146

350.85112.07351.3LC/MS133

147

148

330.43282.00331.3LC/MS134

149

150

328.4171.87329.2LC/MS135

151

152

348.42295.15GC/FID136

153

154

346.40715.28GC/FID137

155

156

348.42295.18GC/FID138

157

158

362.44975.32GC/FID139

159

160

346.40715.31GC/FID140

161

162

346.40715.31GC/FID141

163

164

366.4135.04GC/FID142

165

166

380.43985.18GC/FID143

167

168

364.39725.16GC/FID144

169

170

382.8685.47GC/FID145

171

172

380.85225.59GC/FID146

173

174

336.4615.33GC/FID147

175

176

334.44525.46GC/FID148

177

178

398.42995.04GC/FID149

179

180

396.41415.17GC/FID150

181

182

409.32895.68GC/FID151

183

184

423.35575.80GC/FID152

185

186

407.31315.81GC/FID153

187

188

364.87792.20365.2LC/MS154

189

190

378.90472.40379.3LC/MS155

191

192

362.86212.07363.3LC/MS

[0627]

2

TABLE 2

193

Cmp.

GC/FID or

#
R2
R5
W6
RT
LC/MS

156

194

195

196

9.18
GC/FID

157

197

198

199

8.67
GC/FID

158

200

201

202

10.56
GC/FID

159

203

204

205

9.39
GC/FID

160

206

207

208

8.87
GC/FID

161

209

210

211

10.91
GC/FID

162

212

213

214

9.12
GC/FID

163

215

216

217

8.61
LC/MS

164

218

219

220

10.46
GC/FID

165

221

222

223

8.98
GC/FID

166

224

225

226

8.49
GC/FID

167

227

228

229

10.28
GC/FID

168

230

231

232

9.77
GC/FID

169

233

234

235

9.17
GC/FID

170

236

237

238

11.41
LC/MS

171

239

240

241

8.75
GC/FID

172

242

243

244

8.31
GC/FID

173

245

246

247

9.97
GC/FID

174

248

249

250

9.04
GC/FID

175

251

252

253

8.55
GC/FID

176

254

255

256

10.36
GC/FID

177

257

258

259

9.81
GC/FID

178

260

261

262

9.21
GC/FID

179

263

264

265

11.49
GC/FID

180

266

267

268

9.64
GC/FID

181

269

270

271

9.05
GC/FID

182

272

273

274

11.22
LC/MS

183

275

276

277

10.86
GC/FID

184

278

279

280

10.08
GC/FID

185

281

282

283

12.97
GC/FID

186

284

285

286

9.85
GC/FID

187

287

288

289

9.23
GC/FID

188

290

291

292

11.52
GC/FID

[0628]

3

TABLE 3

293

GC/FID or

Cpd. #
R2
R5
W1
RT
LC/MS

189

294

295

296

6.17
GC/FID

190

297

298

299

6.02
GC/FID

191

300

301

302

6.32
GC/FID

192

303

304

305

6.15
GC/FID

193

306

307

308

6.37
GC/FID

194

309

310

311

6.20
GC/FID

195

312

313

314

6.40
GC/FID

196

315

316

317

1.32
LC/MS

197

318

319

320

6.52
GC/FID

198

321

322

323

6.36
GC/FID

199

324

325

326

6.77
GC/FID

200

327

328

329

6.60
GC/FID

201

330

331

332

6.37
GC/FID

202

333

334

335

6.22
GC/FID

203

336

337

338

1.40
LC/MS

204

339

340

341

6.50
GC/FID

205

342

343

344

6.66
GC/FID

206

345

346

347

6.51
GC/FID

207

348

349

350

7.15
GC/FID

208

351

352

353

6.91
GC/FID

209

354

355

356

7.13
GC/FID

210

357

358

359

6.91
GC/FID

211

360

361

362

5.64
GC/FID

212

363

364

365

5.47
GC/FID

213

366

367

368

5.92
GC/FID

214

369

370

371

5.75
GC/FID

215

372

373

374

1.13
LC/MS

216

375

376

377

5.71
GC/FID

217

378

379

380

5.91
GC/FID

218

381

382

383

5.74
GC/FID

219

384

385

386

6.05
GC/FID

220

387

388

389

5.89
GC/FID

221

390

391

392

5.99
GC/FID

222

393

394

395

5.82
GC/FID

223

396

397

398

6.11
GC/FID

224

399

400

401

5.96
GC/FID

225

402

403

404

6.09
GC/FID

226

405

406

407

5.94
GC/FID

227

408

409

410

6.11
GC/FID

228

411

412

413

5.96
GC/FID

229

414

415

416

6.33
GC/FID

230

417

418

419

6.18
GC/FID

231

420

421

422

6.33
GC/FID

232

423

424

425

6.19
GC/FID

233

426

427

428

6.21
GC/FID

234

429

430

431

6.07
GC/FID

235

432

433

434

5.81
GC/FID

236

435

436

437

5.64
GC/FID

237

438

439

440

6.29
GC/FID

238

441

442

443

6.13
GC/FID

239

444

445

446

5.97
GC/FID

240

447

448

449

5.82
GC/FID

241

450

451

452

6.51
GC/FID

242

453

454

455

6.36
GC/FID

243

456

457

458

6.42
GC/FID

244

459

460

461

6.26
GC/FID

245

462

463

464

6.52
GC/FID

246

465

466

467

6.38
GC/FID

247

468

469

470

6.34
GC/FID

248

471

472

473

6.19
GC/FID

249

474

475

476

6.45
GC/FID

250

477

478

479

6.32
GC/FID

251

480

481

482

6.71
GC/FID

252

483

484

485

2.18
LC/MS

253

486

487

488

6.28
GC/FID

254

489

490

491

6.12
GC/FID

255

492

493

494

7.38
GC/FID

256

495

496

497

7.11
GC/FID

257

498

499

500

1.48
LC/MS

258

501

502

503

7.95
GC/FID

259

504

505

506

6.34
GC/FID

260

507

508

509

6.18
GC/FID

261

510

511

512

6.47
GC/FID

262

513

514

515

6.32
GC/FID

263

516

517

518

6.10
GC/FID

264

519

520

521

5.95
GC/FID

265

522

523

524

6.15
GC/FID

266

525

526

527

6.00
GC/FID

267

528

529

530

7.43
GC/FID

268

531

532

533

7.15
GC/FID

269

534

535

536

7.74
GC/FID

270

537

538

539

7.41
GC/FID

271

540

541

542

6.65
GC/FID

272

543

544

545

6.50
GC/FID

273

546

547

548

6.23
GC/FID

274

549

550

551

6.08
GC/FID

275

552

553

554

6.30
GC/FID

276

555

556

557

6.15
GC/FID

[0629]

4

TABLE 4

558

GC/FID or

Cmp. #
R2
R5
W1
RT
Mass
LC/MS

277

559

560

561

7.12

GC/FID

278

562

563

564

6.77

GC/FID

279

565

566

567

7.17

GC/FID

280

568

569

570

6.82

GC/FID

281

571

572

573

7.10

GC/FID

282

574

575

576

6.77

GC/FID

283

577

578

579

7.30

GC/FID

284

580

581

582

6.92

GC/FID

285

583

584

585

7.53

GC/FID

286

586

587

588

7.07

GC/FID

287

589

590

591

7.79

GC/FID

288

592

593

594

7.28

GC/FID

289

595

596

597

7.29

GC/FID

290

598

599

600

6.92

GC/FID

291

601

602

603

7.86

GC/FID

292

604

605

606

7.34

GC/FID

293

607

608

609

7.77

GC/FID

294

610

611

612

7.29

GC/FID

295

613

614

615

1.44
472.4
LC/MS

296

616

617

618

1.56
508.4
LC/MS

297

619

620

621

2.02
468.5
LC/MS

298

622

623

624

7.84

GC/FID

299

625

626

627

6.41

GC/FID

300

628

629

630

1.32
410.3
LC/MS

301

631

632

633

6.59

GC/FID

302

634

635

636

6.35

GC/FID

303

637

638

639

6.54

GC/FID

304

640

641

642

6.29

GC/FID

305

643

644

645

6.61

GC/FID

306

646

647

648

6.37

GC/FID

307

649

650

651

6.76

GC/FID

308

652

653

654

6.50

GC/FID

309

655

656

657

6.58

GC/FID

310

658

659

660

6.34

GC/FID

311

661

662

663

6.72

GC/FID

312

664

665

666

6.47

GC/FID

313

667

668

669

6.74

GC/FID

314

670

671

672

6.50

GC/FID

315

673

674

675

6.78

GC/FID

316

676

677

678

6.52

GC/FID

317

679

680

681

7.05

GC/FID

318

682

683

684

6.74

GC/FID

319

685

686

687

7.13

GC/FID

320

688

689

690

2.14
480.5
LC/MS

321

691

692

693

6.96

GC/FID

322

694

695

696

6.67

GC/FID

323

697

698

699

6.49

GC/FID

324

700

701

702

6.26

GC/FID

325

703

704

705

7.13

GC/FID

326

706

707

708

6.77

GC/FID

327

709

710

711

6.65

GC/FID

328

712

713

714

6.42

GC/FID

329

715

716

717

7.39

GC/FID

330

718

719

720

7.00

GC/FID

331

721

722

723

7.26

GC/FID

332

724

725

726

6.90

GC/FID

333

727

728

729

1.99
456.5
LC/MS

334

730

731

732

2.06
492.5
LC/MS

335

733

734

735

7.00

GC/FID

336

736

737

738

6.71

GC/FID

337

739

740

741

7.31

GC/FID

338

742

743

744

2.45
545.6
LC/MS

339

745

746

747

7.86

GC/FID

340

748

749

750

2.65
550.7
LC/MS

341

751

752

753

7.14

GC/FID

342

754

755

756

6.81

GC/FID

343

757

758

759

9.51

GC/FID

344

760

761

762

8.54

GC/FID

345

763

764

765

11.94

GC/FID

346

766

767

768

1.48
547.7
LC/MS

347

769

770

771

7.22

GC/FID

348

772

773

774

6.83

GC/FID

349

775

776

777

7.44

GC/FID

350

778

779

780

7.04

GC/FID

351

781

782

783

6.83

GC/FID

352

784

785

786

6.56

GC/FID

353

787

788

789

6.84

GC/FID

354

790

791

792

6.58

GC/FID

355

793

794

795

9.63

GC/FID

356

796

797

798

8.64

GC/FID

357

799

800

801

1.05
497.6
LC/MS

358

802

803

804

9.16

GC/FID

359

805

806

807

7.61

GC/FID

360

808

809

810

7.17

GC/FID

361

811

812

813

7.02

GC/FID

362

814

815

816

6.72

GC/FID

363

817

818

819

1.05
459.5
LC/MS

364

820

821

822

6.79

GC/FID

[0630]

5

TABLE 5

823

Cpd.

GC/FID or

#
R2
R5
W1
MW
RT
Mass
LC/MS

365

824

825

826

413.5223
NA

366

827

828

829

431.5124
1.73
432.1
LC/MS

367

830

831

832

449.5025
1.67
450.4
LC/MS

368

833

834

835

447.9674
1.87
448.3
LC/MS

369

836

837

838

427.5491
1.87
428.4
LC/MS

370

839

840

841

445.5392
1.94
446.4
LC/MS

371

842

843

844

463.5293
1.87
464.4
LC/MS

372

845

846

847

461.9942
2.07
462.4
LC/MS

373

848

849

850

429.5213
2.87
430
LC/MS

374

851

852

853

447.5114
1.53
448.3
LC/MS

375

854

855

856

465.5015
1.47
466.5
LC/MS

376

857

858

859

463.9664
1.67
464.4
LC/MS

377

860

861

862

441.5759
2.07
442.6
LC/MS

378

863

864

865

459.566
2.13
460.3
LC/MS

379

866

867

868

477.5561
NA

380

869

870

871

441.5759
2.00
442.6
LC/MS

381

872

873

874

459.566
2.07
460.3
LC/MS

382

875

876

877

445.5883
1.73
446.4
LC/MS

383

878

879

880

463.5784
1.80
464.4
LC.MS

384

881

882

883

481.5685
1.73
482.2
LC/MS

385

884

885

886

480.0334
NA

386

887

888

889

455.6027
2.13
456.4
LC/MS

387

890

891

892

473.5928
NA

388

893

894

895

491.5829
2.13
492.4
LC/MS

389

896

897

898

490.0478
2.27
490.3
LC/MS

390

899

900

901

455.6027
2.13
456.4
LC/MS

391

902

903

904

473.5928
NA

392

905

906

907

491.5829
2.13
492.4
LC/MS

393

908

909

910

490.0478
2.27
490.5
LC/MS

394

911

912

913

483.6563
2.40
484.5
LC/MS

395

914

915

916

501.6464
2.47
502.3
LC/MS

396

917

918

919

519.6365
NA

397

920

921

922

518.1014
NA

398

923

924

925

485.5849
1.73
486.3
LC/MS

399

926

927

928

503.575
1.73
504.3
LC/MS

400

929

930

931

521.5651
NA

401

932

933

934

520.03
1.87
520.2
LC/MS

402

935

936

937

481.6405
2.34
482.5
LC/MS

403

938

939

940

499.6306
2.40
500.4
LC/MS

404

941

942

943

517.6207
2.34
518
LC/MS

405

944

945

946

516.0856
2.47
516.4
LC/MS

406

947

948

949

387.4845
1.47
388.5
LC/MS

407

950

951

952

405.4746
1.53
406.3
LC/MS

408

953

954

955

423.4647
1.47
424.2
LC/MS

409

956

957

958

413.5223
1.80
414.4
LC/MS

410

959

960

961

431.5124
1.87
432.1
LC/MS

411

962

963

964

449.5025
1.73
450.3
LC/MS

412

965

966

967

447.9674
1.93
448.5
LC/MS

413

968

969

970

415.5381
1.80
416.4
LC/MS

414

971

972

973

433.5282
1.87
434.5
LC/MS

415

974

975

976

451.5183
1.80
452.4
LC/MS

416

977

978

979

449.9832
2.00
450.3
LC/MS

417

980

981

982

415.5381
1.80
416.4
LC/MS

418

983

984

985

433.5282
1.87
434.5
LC/MS

419

986

987

988

433.5183
1.80
452.4
LC/MS

420

989

990

991

449.9832
2.00
450.3
LC/MS

421

992

993

994

429.5649
2.00
430.2
LC/MS

422

995

996

997

447.555
2.07
448.6
LC/MS

423

998

999

1000

465.5451
2.00
466.3
LC/MS

424

1001

1002

1003

464.01
2.20
464.4
LC/MS

425

1004

1005

1006

429.5649
1.93
430.2
LC/MS

426

1007

1008

1009

447.555
2.00
448.6
LC/MS

427

1010

1011

1012

465.5451
1.93
466.3
LC/MS

428

1013

1014

1015

464.01
2.13
464.4
LC/MS

429

1016

1017

1018

439.5601
2.00
440.7
LC/MS

430

1019

1020

1021

457.5502
2.07
458.4
LC/MS

431

1022

1023

1024

475.5403
NA

432

1025

1026

1027

474.0052
NA

433

1028

1029

1030

443.5917
2.13
444.6
LC/MS

434

1031

1032

1033

461.5818
2.20
462.4
LC/MS

435

1034

1035

1036

479.5719
NA

436

1037

1038

1039

478.0368
NA

437

1040

1041

1042

443.5917
2.13
444.6
LC/MS

438

1043

1044

1045

461.5818
2.20
462.4
LC/MS

439

1046

1047

1048

479.5719
NA

440

1049

1050

1051

478.0368
NA

441

1052

1053

1054

455.6027
2.20
456.4
LC/MS

442

1055

1056

1057

473.5928
NA

443

1058

1059

1060

491.5829
NA

444

1061

1062

1063

490.0478
2.34
490.3
LC/MS

445

1064

1065

1066

457.6185
2.34
458.4
LC/MS

446

1067

1068

1069

475.6086
NA

447

1070

1071

1072

493.5987
2.34
494.5
LC/MS

448

1073

1074

1075

492.0636
2.47
492.4
LC/MS

[0631]

6

TABLE 6

Cpd#
STRUCTURE
IUPAC NAME
NMR
MS (m/z)

449

1076

2-{[2-(3-fluorophenyl)-1H- imidazol-1-yl]methyl}-1-propyl-1H- benzimidazole
1H NMR(CDCl3): 7.80(m, 1H), 7.41-7.53(m, 3H), 7.29-7.31(m, 3H), 7.14-7.22(m, 2H), 7.06(d, 1H), 5.51(s, 2H), 3.69(t, 2H,), 1.43(m, 2H), 0.74(t, 3H)

450

1077

2-{[2-(2-fluorophenyl)-1H- imidazol-1-yl]methyl}-1-propyl-1H- benzimidazole
7.78(m, 1H), 7.66(m, 1H), 7.51 (m, 1H), 7.23-7.37(m, 5H), 7.17 (d, 1H), 7.03(d, 1H), 5.35(s, 2H), 3.68(t, 2H,), 1.40(m, 2H), 0.72(t, 3H)

451

1078

2-{[2-(4-fluorophenyl)-1H- imidazol-1-yl]methyl}-1-propyl-1H- benzimidazole
1H NMR(CDCl3): 7.80(m, 1H), 7.65-7.69(m, 2H), 7.18-7.32(m, 5H), 7.13(d, 1H), 7.04(d, 1H), 5.47 (s, 2H), 3.68(t, 2H,), 1.42 (m, 2H), 0.74(t, 3H)

452

1079

2-{[2-(3-chloro-4-fluorophenyl)- 1H-imidazol-1-yl]methyl}-1-propyl- 1H-benzimidazole
1H NMR(CDCl3): 7.76-7.81 (m, 2H), 7.56(m, 1H), 7.25-7.32(m, 4H), 7.14(d, 1H), 7.05(d, 1H), 5.46(s, 2H), 3.74(t, 2H,), 1.47 (m, 2H), 0.78(t, 3H)

453

1080

2-{[2-(2,5-difluorophenyl)-1H- imidazole-1-yl]methyl}-1-propyl-1H- benzimidazole
7.78(m, 1H), 7.38(m, 1H), 7.17-7.31 (in, 6H), 7.03 (d, 1H), 536 (s, 2H), 3.73(t, 2H,), 1.44(m, 2H), 0.76(t, 3H)

454

1081

6-chloro-2-{[2-(2-fluorophenyl)- 1H-imidazol-1-yl]methyl}-1-propyl- 1H-benzimidazole
1H NMR(CDCl3): 7.62-7.69(m, 2H), 7.51(m, 1H), 7.22-7.34(m, 4H), 7.18(d, 1H), 7.02(d, 1H), 5.34(s, 2H), 3.64(t, 2H,), 1.40 (m, 2H), 0.73(t, 3H)

455

1082

6-chloro-2-{[2-(3-fluorophenyl)- 1H-imidazol-1-yl]methyl}-1-propyl- 1H-benzimidazole
1H NMR(CDCl3): 7.69(d, 1H), 7.38-7.52(m, 3H), 7.15-7.29(m, 4H), 7.04(d, 1H), 5.48(s, 2H), 3.65(t, 2H), 1.42(m, 2H), 0.75 (t, 3H)

456

1083

6-chloro-2-{[2-(4-fluorophenyl)- 1H-imidazol-1-yl]methyl}-1-propyl- 1H-benzimidazole
1H NMR(CDCl3): 7.62-7.70(m, 3H), 7.13-7.28 (m, 5H), 7.02(d, 1H), 3.64(t, 2H), 1.41(m, 2H), 0.75(t, 3H)

457

1084

6-chloro-2-{[2-(3-chloro-4- fluorophenyl)-1H-imidazol-1- yl]methyl}-1-propyl-1H- benzimidazole
1H NMR(CDCl3): 7.75(dd, 1H), 7.69(dd, 1H), 7.55(m, 1H), 7.24-7.30(m, 3H), 7.15(d, 1H), 7.03 (d, 1H), 5.43(s, 2H,). 3.71(t, 2H), 1.47(in, 2H), 0.79(t, 3H)

458

1085

6-chloro-2-{[2-(2,5- difluorophenyl)-1H-imidazol-1- yl]methyl}-1-propyl-1H- benzimidazole
1H NMR(CDCl3): 7.67(d, 1H), 7.37(m, 1H), 7.17-7.29(m, 5H), 7.02(d, 1H), 5.34(s, 2H), 3.69(t, 2H), 1.43(m, 2H), 0.77(t, 3H)

459

1086

2-{[2-(3-fluorophenyl)-1H- imidazol-1-yl]methyl}-3-propyl-3H- imidazo[4,5-b]pyridine
1H NMR(CDCl3): 8.40(dd, 1H), 8.06(dd, 1H), 7.39-7.50(m, 3H), 7.15-7.29(m, 3H), 7.08(d, 1H), 5.52(s, 2H), 3.88(t, 2H,), 1.51 (m, 2H), 0.77(t, 3H)

460

1087

2-{[2-(2,5-difluorophenyl)-1H- imidazol-1-yl]methyl}-3-propyl-3H- imidazo[4,5-b]pyridine
1H NMR(CDCl3): 8.40(dd, 1H), 8.05(dd, IH), 7.38(m, 1H), 7.17-7.28(m, 4H), 7.08(d, 1H), 5.39 (s, 2H), 3.89(t, 2H), 1.50(m, 2H), 0.79(t, 3H)

461

1088

6-chloro-1-(cyclopropylmethyl)-2- {[2-(2,5-difluorophenyl)-1H- imidazol-1-yl]methyl}-1H- benzimidazole
1H NMR(CDCl3): 7.68(d, 1H), 7.38(m, 1H), 7.32(d, 1H), 7.19-7.28(m, 4H), 7.04(d, 1H), 5.36 (d, 2H), 3.62(d, 2H), 0.65(m, 1H), 0.46-0.51(m, 2H), 0.07-0.11 (m,2H)

462

1089

2-{[2-(2,5-difluorophenyl)-1H- imidazol-1-yl]methyl}-3-isobutyl- 3H-imidazo[4,5-b]pyridine
1H NMR(CDCl3): 8.38(dd, 1H), 8.04(dd, 1H), 7.38(m, 1H), 7 16-7.27(m, 4H), 7.09(d, 1H), 5.38 (s, 2H). 3.73(d, 2H), 1.98(m, 1H), 0.72(d, 6H)

463

1090

6-chloro-2-{[2-(2,5- difluorophenyl)-1H-imidazol-1- yl]inethyl}-1-ethyl-1H- benzimidazole
1H NMR(CDCl3): 7.67(d, 1H), 7.37(m, 1H), 7.17-7.30(m, 5H), 7.01(d, 1H), 5.35(s, 2H), 3.79 (q, 2H), 0.99(t, 3H)

464

1091

6-Chloro-1-ethyl-2-{[2-(3- fluorophenyl)-1H-imidazol-1- yl]methyl}-1H-benzimidazole
1H NMR(CDCl3): 7.69(d, 1H), 7.39-7.51(m, 3H), 7.16-7.30(m, 4H), 7.03(d, 1H), 5.49(s, 2H), 3.75(q, 2H), 0.98(t, 3H)

465

1092

2-{[2-(3-fluorophenyl)-1H- imidazol-1-yl]methyl}-3-methyl- 3H-imidazo+4,5-b]pyridine
1H NMR(CDCl3): 8.40(dd, 1H), 8.05(dd, 1H), 7.40-7.51(m, 3H), 7.13-7.29(m, 3H), 7.02(d, 1H), 5.53(s, 2H), 3.51(s, 3H)

466

1093

2-{[2-(2,5-difluorophenyl)-1H- imidazol-1-yl]methyl}-3-methyl- 3H-imidazo[4,5-b]pyridine
1H NMR(CDCl3): 8.40(dd, 1H), 8.03(dd, 1H), 7.36(m, 1H), 7.15-7.27(m, 4H), 7.03(d, 1H), 5.41 (s, 2H), 3.51(s, 3H)

467

1094

2-{[2-(3-chloro-4-fluorophenyl)- 1H-imidazol-1-yl]methyl}-3- methyl-3H-imidazo[4,5-b]pyridine

468

1095

3-(cyclopropylmethyl)-2-{[2-(2,5- difluorophenyl)-1H-imidazol-1- yl]methyl}-3H-imidazo[4,5- b]pyridine
1H NMR(CDCl3): 8.37(dd, 1H), 8.04(dd, 1H), 7.38(m, 1H), 7.09-7.28(m, 4H), 7.09(d, 1H), 5.42 (s, 2H), 3.83(d, 2H), 0.68(m, 1H), 0.38-0.43(m, 2H), 0.24-0.29 (m,2H)

469

1096

6-chloro-2-{[2-(3-chlorophenyl)- 1H-imidazol-1-yl[methyl}-1-ethyl- 1H-benzimidazole
1H NMR(CDCl3): 7.67-7.71(m, 2H), 7.45-7.56(m, 3H), 7.24-7.30 (m, 2H), 7.16(d, 2H), 7.04(d, 1H), 5.47(s, 2H), 3.76(q, 2H), 0.99(t, 3M)

470

1097

2-{[2-(3-chlorophenyl)-1H- imidazol-1-yl]methyl}-3- (cyclopropylmethyl)-3H- imidazo[4,5-b]pyridine
1H NMR(CDCl3): 8.39(dd, 1H), 8.06(dd, 1H), 7.68(m, 1H), 7.40-7.68(m, 3H), 7.27(m, 1H), 7.18 (d, 1H), 7.10(d, 1H), 5.53(s, 2H), 3.83(d, 2H), 0.73(m, 1H), 0.40-0.46(m, 2H), 0.24-0.28(m, 2H)

471

1098

6-chloro-2-{[2-(3-chlorophenyl)- 1H-imidazol-1-yl]methyl}-1- (cyclopropylmethyl)-1H- benzimidazole
1H NMR(CDCl3): 7.67-7.71(m, 2H), 7.42-7.56(m, 3H), 7.24-7.33 (m, 2H), 7.15(d, 1H), 7.06(d, 1H), 5.47(s, 2H), 3.58(d, 2H), 0.69(m, 1H), 0.47-0.53(m, 2H), 0.03-0.09(m, 2H)

472

1099

2-{[2-(3-chlorophenyl)-1H- imidazol-1-yl]methyl}-1-propyl-1H- benzimidazole
1H NMR(CDCl3): 7.79(m, 1H), 7.69(m, I H), 7.44-7.58(m, 3H), 7.27-7.30(m, 3H), 7.14(d, 1H), 7.07(d, 1H), 5.49(s, 2H), 3.69(t, 2H), 1.42(m, 2H), 0.75(t, 3H)

473

1100

2-{[2-(3-chlorophenyl)-1H- imidazol-1-yl]methyl}-3-ethyl-3H- imidazo[4,5-b]pyridine
1H NMR(CDCl3): 8.40(dd, 1H), 8.06(dd, 1H), 7.67(m, 1H), 7.43-7.57(m, 3H), 7.26(m, 1H), 7.19 (d, 1H), 7.08(d, 1H), 5.51(s, 2H), 4.00(q, 2H), 1.09(t, 3H)

474

1101

2-{[2-(3-chlorophenyl)-1H- imidazol-1-yl]methyl}-3-propyl-3H- imidazo[4,5-b]pyridine
1H NMR(CDCl3): 8.40(dd, 1H), 8.06(dd, 1H), 7.68(m, 1H), 7.43-7.56(m, 3H), 7.26(m, 1H), 7.18 (d, 1H), 7.09(d, 1H), 5.50(s, 2H), 3.89(t, 2H), 1.52(m, 2H), 0.79(t, 3H)

475

1102

1-ethyl-2-{[2-(3-fluorophenyl)-1H- imidazol-1-yl]methyl}-1H- benzimidazole-5-carbonitrile

346.3 [M + 1], 344.2 [M − 1]

476

1103

1-ethyl-2-{[2-(3-fluorophenyl)-1H- imidazol-1-yl]methyl}-5- (trifluoromethyl)-1H- benzimidazole

389.2 [M + 1]

477

1104

2-{[2-(2,5-difluorophenyl)-1H- imidazol-1-yl]methyl}-1-ethyl-5- (trifluoromethyl)-1H- benzimidazole

407.3 [M + 1]

478

1105

2-{[2-(3-fluorophenyl)-1H- imidazol-1-yl]methyl}-3-(2,2,2- trifluoroethyl)-3H-imidazo[4,5- b]pyridine

376.2 [M + 1]

479

1106

2-{[2-(2,5-difluorophenyl)-1H- imidazol-1-yl]methyl}-3-(2,2,2- trifluoroethyl)-3H-imidazo[4,5- b]pyridine

394.2 [M + 1]

480

1107

2-{[2-(3-chlorophenyl)-1H- imidazol-1-yl]methyl}-3-(2,2,2- trifluoroethyl)-3H-imidazo[4,5- b]pyridine

392.2 [M + 1]

481

1108

1-ethyl-5-(trifluoromethyl)-2-({2- [3-(trifluoromethyl)phenyl]-1H- imidazol-1-yI}methyl)-1H- benzimidazole
1H NMR(CDCl3): 8.09(d, 1H), 7.37-7.95(m, 6H), 7.19(d, 1H), 7.05(d, 1H), 5.49(s, 2H), 3.85 (q, 2H). 1.02(t, 3H)

482

1109

5-chloro-3-propyl-2-({2-13- (trifluoromethyl)phenyl]-1H- imidazol-1-yl}methyl)-3H- imidazo[4,5-b]pyridine
1H NMR(CDCl3): 7.60-7.97(m, 5H), 7.22-7.27(m, 2H), 7.09(d, 1H), 5.45(S, 2H), 3.85(t, 2H), 1.51(m, 2H), 0,76(t, 3H)

483

1110

3-(2,2,2-trifluoroethyl)-2-({2-[3- (trifluoromethyl)phenyl[-1H- imidazol-1-yl}methyl)-3H- imidazo[4,5-b]pyridine
1H NMR(CDCl3): 8.44(dd, 1H), 8.07(dd, 1H), 7.54-7.89(m, 4H), 7.24-7.34(m, 2H), 7.12(d, 1H), 5.51(s, 2H), 4.51(q, 2H)

484

1111

3-(cyclopropylmethyl)-2-({2-[3- (trifluoromethyl)phenyl]-1H- imidazol-1-yl}methyl)-3H- imidazo[4,5-b]pyridine
1H NMR(CDCl3): 8.39(dd, 1H), 7.60-8.03(m, 5H), 7.21-7.26(m, 2H), 7.11(d, 1H), 5.51(s, 2H), 3.84(d, 2H), 0.70(m, 1H), 0.44 (m, 2H), 0.24(m, 2H)

485

1112

3-isobutA-2-({2-[3- (trifluoromethyl)phenyl]-1H- imidazol-1-yl}methyl)-3H- imidazo[4,5-b]pyridine
1H NMR(CDCl3): 8.39(dd, 1H), 7.60-8.07(m, 5H), 7.21-7.26(m, 2H). 7.12(d, 1H), 5.49(s, 2H), 3.71(d, 2H), 1.98(m, 1H), 0,69 (d,6H)

486

1113

3-propyl-2-({2-[3- (trifluoromethyl)phenyl]-1H- imidazol-1-yI}methyl)-3H- imidazo[4,5-b]pyridine
1H NMR(CDCl3): 8.40(dd, 1H), 7.60-8.07(m, 5H), 7.21-7.26(m, 2H), 7.11(d, 1H), 5.49(s, 2H), 3.89(t, 2H), 1.51(m, 2H), 0.76 (t, 3H)

487

1114

1-propyl-2-({2-[3- (trifluoromethyl)phenyl]-1H- imidazol-1-yl}methyl)-1H- benzimidazole
1H NMR(CDCl3): 7.61-8.00(m, 5H), 7.09-7.31(m, 5H), 5.47(s, 2H), 3.69(t, 2H), 1.43(m, 2H), 0.73(t, 3H)

488

1115

6-chloro-1-(cyclopropylmethyl)-2- ({2-[3-(trifluoromethyl)phenyl]-1H- imidazol-1-yI}methyl)-1H- benzimidazole
1H NMR(CDCl3): 7.60-7.96(m, 5H), 7.05-7.31(m, 4H), 5.45(s, 2H), 3.58(d, 2H), 0.65(m, 1H), 0.47(m, 2H), 0.05(m, 2H)

489

1116

3-ethyl-2-({2-[3- (trifluoromethyl)phenyl]-1H- imidazol-1-yl}methyl)-3H- imidazo[4,5-b]pyridine
1H NMR(CDCl3): 8.40(dd, 1H), 7.60-8.06(m 5H), 7.21-7.28(m, 2H), 7.09(d, 1H), 5.49(s, 2H), 4.01(q, 2H), 1.09(t, 3H)

490

1117

ethyl 2-{[2-(3-chlorophenyl)-1H- imidazol-1-yl]methyl}-1-ethyl-1H- benzimidazole-5-carboxylate

491

1118

(2-{[2-(3-chlorophenyl)-1H- imidazol-1-yl]methyl}-1-ethyl-1H- benzimidazol-5-yl)methanol

492

1119

2-{[2-(3-chlorophenyl)-1H- imidazol-1-yl]methyl}-1-ethyl-5- [(4-methylpiperidin-1-yl)methyl]- 1H-benzimidazole

493

1120

2-{[2-(3-chlorophenyl)-1H- imidazol-1-yl]methyl}-1-ethyl-5- (morpholin-4-ylmethyl)-1H- benzimidazole

494

1121

2-{[2-(3-chlorophenyl)-1H- imidazol-1-yl]methyl}-1-ethyl-1H- benzimidazole-5-carboxylic acid

495

1122

1-ethyl-2-{[2-(3-fluorophenyl)-1H- imidazol-1-yl]methyl}-5- (morpholin-4-ylmethyl)-1H- benzimidazole

420.4 [M + 1]; 418.2 [M − 1]

496

1123

2-{[2-(3-chlorophenyl)-1H- imidazol-1-yl]methyl}-1-ethyl-1H- benzimidazole-5-carboxamide

497

1124

2-{[2-(3-chlorophenyl)-1H- imidazol-1-yl]methyl}-1-ethyl-N- methyl-1H-benzimidazole-5- carboxamide

498

1125

1-ethyl-2-{[2-(3-fluorophenyl)-1H- imidazol-1-yl]methyl}-1H- benzimidazole-5-carboxylic acid

365.1 [M + 1]

499

1126

1-ethyl-2-{[2-(3-fluorophenyl)-1H- imidazol-1-yl]methyl}-1H- benzimidazole-5-carboxamide

500

1127

2-{[2-(2,5-difluorophenyl)-1H- imidazol-1-yl]methyl}-1-ethyl-1H- benzimidazole-5-carboxylic acid

383.2 [M + 1]

501

1128

1-ethyl-2-{[2-(3-fluorophenyl)-1H- imidazol-1-yl]methyl}-5-[(4- methylpiperidin-1-yl)methyl]-1H- benzimidazole

432.4 [M + 1]

502

1129

2-{[2-(2,5-difluorophenyl)-1H- imidazol-1-yl]methyl}-N-[2- (dipropylamino)ethyl]-1-ethyl-1H- benzimidazole-5-carboxamide

509.5 [M + 1]

503

1130

5-fluoro-2-{[2-(4-flurophenyl)-1H imidazol-1-yl]methyl}-1-propyl-1H- benzimidazole
1H NMR(CDCl3): 7.65-7.71(m, 2H), 7.47(d, 1H), 7.03-7.23(m, 6H). 5.47(s, 2H), 3.65(t, 2H), 1.41(h, 2H), 0.71(t, 3H)

504

1131

2{[2-(3-chlorophenyl)-1H- imidazol-1-yl]methyl}-5-fluoro-1- propyl-1H-benzimidazole
1H NMR(CDCl3): 7.65(s, 1H), 7.41-7.53(m, 3H), 7.06-7.24(m, 5H), 5.47(s, 2H), 3.65(t, 2H), 1.47(h, 2H), 0.71(t, 3H)

505

1132

5-fluoro-2-{[2-(3-fluorophenyl)-1H imidazol-1-yl]methyl}-1-propyI-1H- benzimidazole
1H NMR(CDCl3): 7.35-7.47(m, 4H), 7.0-7.1(m, 5H), 5.47(s, 2H), 3.65(t, 2H), 1.35(h, 2H), 0.71(t, 3H)

506

1133

5-chloro-2-{[2-(2,5- difluorophenyl)-1H-imidazol-1- yl]methyl}-1-ethyl-1H- benzimidazole
1H NMR(CDCl3): 7.75(d, 1H), 7.37(m, 1H), 7.20-727(m, 5H), 7.02(d, 1H), 5.36(s, 2H), [0.99 T, 3H), 3.82(q, 2H)

507

1134

2-{[2-(2,5-difluorophenyl)-1H- imidazol-1-yl]methyl}-1-ethyl-5- fluoro-1H-benzimidazole
1H NMR(CDCl3): 7.43(m, 1H), 7.37(m, 1H), 7 19-7.25(m, 4H), 7.03-7.10(m, 2H), 5.35(s, 2H), 3.82(q, 2H), 1.00(t, 3H)

508

1135

5-chloro-2-{[2-(3-chlorophenyl)- 1H-imidazol-1-yl]methyl}-1-ethyl- 1H-benzimidazole
(L)-Tartrate salt 1H NMR (CD3OD): 7.24-7.59(m, 9H), 5.66(s, 2H), 4.51(s, 2H), 4.12 (q, 2H), 1.28(t, 3H)

509

1136

2-{[2-(3-chlorophenyl)-1H- imidazol-1-yl]methyl}-1-ethyl-1H- benzimidazole-5-carbonitrile
8.00(s, 1H), 7.38-7.72(m, 7H), 7.24(s, 1H), 5.71(s, 2H), 4.50 (s, 2H), 4.20(q, 2H), 1.22(t, 3H)

510

1137

2-{[2-(3-chlorophenyl)-1H- imidazol-1-yl]methyl}-1-ethyl-5- fluoro-1H-benzimidazole
(L)-Tartrate salt 1H NMR (CD3OD): 7.08-7.60(m, 9H), 5.66(s, 2H), 4.51(s, 2H), 4.12 (s, 2H), 1.18(t, 3H)

511

1138

2-{[2-(2,5-difluorophenyl)-1H- imidazol-1-yl]methyl}-1-ethyl-5- (4H-1,2,4-triazol-4-yl)-1H- benzimidazole
Hydrochloride 1H NMR(d6 DMSO): 9.57(2H, s), 8.11(1H, m), 8.01-7.99(1H, m), 7.86(1H, d), 7.78-7.74(1H, m), 7.66-7.52(3H, m), 5.95(2H, s), 4.31(2H, q), 1.26(3H, t)
406.5 [M + 1]

512

1139

2-{[2-(2,5-difluorophenyl)-1H- imidazol-1-yl]methyl}-1-ethyl-1H- benzimidazol-5-amine

354.4 [M + 1]

513

1140

1-ethyl-5-fluoro-2-{[2-(2- fluorophenyl)-1H-imidazol-1- yl]methyl}-1H-benzimidazole
(L)-Tartrate salt 1H NMR (CD3OD): 7.07-7.58(m, 9H), 5.53(s, 2H), 4.51(s, 2H), 4.03 (q, 2H), 1.07(t, 3H)

514

1141

1-ethyl-2-{[2-(3-fluorophenyl)-1H- imidazol-1-yl]methyl}-1H- benzimidazol-5-amine
1H NMR(CDCl3): 7.38-7.5(m, 4h), 7.15(t, 3H), 7.1(a, 1H), 7.05 (t, 2H), 6.7(d, 1H), 5.4(s, 2H), 3.70(q, 2H), 0.9(t, 3H)

515

1142

1-ethyl-2-{[2-(3-fluorophenyl)-1H- imidazol-1-yl]methyl}-5-(4H-1,2,4- triazol-4-yl)-1H-benzimidazole

388.2 [M + 1]

516

1143

1-ethyl-2-{[2-(3-fluorophenyl)-1H- imidazol-1-yl]methyl}-5-(2H- tetraazol-5-yI)-1H-benzimidazole

389.2 [M + 1]

517

1144

5-bromo-1-ethyl-2-{[2-(3- fluorophenyl)-1H-imidazol-1- yl]methyl}-1H-benzimidazole
1H NMR(CDCl3): 7.93(d, 1H), 7.39-7.52(m, 4H), 7.15-7.22(m, 3H), 7.025(d, 1H), 5.49(s, 2H), 3.76(q, 2H), 0.97(t, 3H)

518

1145

2-{[2-(2,5-difluorophenyl)-1H- imidazol-1-yl]methyl}-1-ethyl-1H- benzimidazole-5-carbonitrile
1H NMR(CDCl3): 8.09(d, 1H), 7.56(m, 1H), 7.33-7.40(m, 2H), 7.16-7.24(m, 3H), 7.04(d, 1H), 5.41(s, 2H), 3.89(q, 2H), 1.03(t, 3H)

519

1146

2-{[2-(3-bromophenyl)-1H- imidazol-1-yl]methyl}-1-ethyl-5- fluoro-1H-benzimidazole
Hydrochloride 1H NMR(d6- DMSO): 7.41-8.00(m, 8H), 7.18 (m, 1H), 5.92(s, 2H), 4.28(q, 2H), 1.27(t, 3H)

520

1147

2-{[2-(3-bromophenyl)-1H- imidazol-1-yl]methyl}-5-chloro-1- ethyl-1H-benzimidazole
Hydrochloride 1H NMR(d6- DMSO) 7.32-8.00(m, 9H), 5.95 (s, 2H), 4.29(q, 2H), 1.27(t, 3H)

521

1148

3-{1-[(1-ethyl-5-fluoro-1H- benzimidazol-2-yl)methyl]-1H- imidazol-2-yl}benzonitrile

346.11 [M + 1]

522

1149

1-ethyl-5-fluoro-2-{[2-(3- methylphenyl)-1H-imidazol-1- yl]methyl}-1H-benzimidazole

523

1150

1-ethyl-5-fluoro-2-{[2-(3- methoxyphenyl)-1H-imidazol-1- yl]methyl}-1H-benzimidazole

351.15 [M + 1]

524

1151

4-{1-[(1-ethyl-5-fluoro-1H- benzimidazol-2-yl)methyl]-1H- imidazol-2-yl}-2-fluorophenol

355.12 [M + 1]

525

1152

2-{[2-(3-bromophenyl)-1H- imidazol-1-yl]methyl}-1-ethyl-1H- benzimidazole-5-carbonitrile
1H NMR(CDCl3): 8.11(d, 1H), 7.81(s, 1H), 7.55-7.67(m, 3H), 7.35-7.41(m, 2H), 7.19(m, 1H), 7.04(d, 1H), 5.51(s, 2H), 3.84 (q, 2H), 1 04(t, 3H)

526

1153

2-{[2-(3-fluorophenyl)-1H- imidazol-1-yl]methyl}-1-propyl-1H- benzimidazole-5-carbonitrile

360.2 [M + 1]; 358.2 [M − 1]

527

1154

2-{[2-(3-chlorophenyl)-1H- imidazol-1-yl]methyl}-1-propyl-1H- benzimidazole-5-carbonitrile

376.2 [M + 1]; 374.2 [M − 1]

528

1155

2-{[2-(2,5-difluorophenyl)-1H- imidazol-1-yl]methyl}-1-propyl-1H- benzimidazole-5-carbonitrile

378.2 [M + 1]

529

1156

2-{[2-(3-chloro-4-fluorophenyl)- 1H-imidazol-1-yl]methyl}-1-propyl- 1H-benzimidazole-5-carbonitrile
394.4 [M + 1]; 392.1 [M − 1]

530

1157

2-{[2-(2,5-difluorophenyl)-1H- imidazol-1-yl]methyl}-1-ethyl-5- (methylsulfonyl)-1H- benzimidazole

531

1158

1-ethyl-5-(3-fluorophenyl)-2-{[2- (3-fluorophenyl)-1H-imidazol-1- yl]methyl}-1H-benzimidazole
1H NMR(CDCl3): 7.98(m, 1H), 7.27-7.54(m, 8H), 7 16-7.22(m, 2H), 701-7.07(m, 2H), 5.53(a, 2H), 3.82(q, 2H), 1.02(t, 3H)

532

1159

1-ethyl-2-{[2-(3-fluorophenyl)-1H- imidazol-1-yl]methyl}-5-thien-3-yl- 1H-benzimidazole
1H NMR(CDCl3): 8.0(m, 1H), 7.16-7.59(m, 10H), 7.07(d, 1H), 5.52(s, 2H), 3.81(q 2H), 1.01(t, 3H)

533

1160

5-bromo-2-{[2-(3-chlorophenyl)- 1H-imidazol-1-yl]methyl}-1-ethyl- 1H-benzimidazole
1H NMR(CDCl3): 7.93(d, 1H), 7.68(m, 1H), 7.40-7.57(m, 2H), 7.15-7.19(m, 2H), 7.03(d, 1H), 5.48(a, 2H), 3.77(q, 2H), 0.98(t, 3H)

534

1161

2-{[2-(3-cyanophenyl)-1H- imidazol-1-yl]methyl}-1-ethyl-1H- benzimidazole-5-carbonitrile

353.15 [M + 1]

535

1162

3-{1-[(1-ethyl-5-fluoro-1H- benzimidazol-2-yl)methyl]-1H- imidazol-2-yl}benzoic acid

364.10 [M + 1]

536

1163

1-ethyl-5-fluoro-2-{[2-(3-pyridin-4- ylphenyl)-1H-imidazol-1- yl]methyl}-1H-benzimidazole

398.18 [M + 1]

537

1164

2-{[2-(2,5-difluorophenyl)-1H- imidazol-1-yl]methyl}-1-ethyl-5- nitro-1H-benzimidazole
Hydrochloride 1H NMR(d6 DMSO): 8.42(IH, d), 8.17(1H, dd), 8.00(1H, s), 7.90(1H, s), 7.85(1H, d), 7.70(1H, m), 7.56-7.51(2H, m), 5.90(2H, s), 4.31(2H, q), 1.24(3H, t)
384.1 [M + 1]

538

1165

1-ethyl-2-{[2-(3-fluorophenyl)-1H- imidazol-1-yl]methyl}-5-nitro-1H- benzimidazole
1H NMR(d6 DMSO): 8.47(1H, d), 8.19(1H, dd), 8.00(1H, m), 7.96(1H, m), 7.88(1H, d), 771-7.50(4H, m), 5.98(2H, s), 4.35(2H, q), 1.30(3H, t)
366.2 [M + 1]

539

1166

2-{[2-(3-chlorophenyl)-1H- imidazol-1-yl]methyl}-1-ethyl-5- nitro-1H-benzimidazole

381.95 [M + 1]

540

1167

3-(1-{[1-ethyl-5-(methylsulfonyl)- 1H-benzimidazol-2-yl]methyl}-1H- imidazol-2-yl)benzonitrile

406.3 [M + 1]; 404.3 [M − 1]

541

1168

3-{1-[(1-ethyl-5-fluoro-1H- benzimidazol-2-yl)methyl]-1H- imidazol-2-yl}phenol

337.01 [M + 1]

542

1169

2-{[2-(3,4-difluorophenyl)-1H- imidazol-1-yl]methyl}-1-ethyl-1H- benzimidazole-5-carbonitrile

379.11 [M + 1]

543

1170

2-{[2-(5-bromo-2-fluorophenyl)- 1H-imidazol-1-yl]methyl}-1-ethyl- 1H-benzimidazole-5-carbonitrile

425.98 [M + 1]

544

1171

2-{[2-(2,5-difluorophenyl)-1H- imidazol-1-yl]methyl}-1-ethyl-5- (trifluoromethoxy)-1H- benzimidazole
1H NMR(CDCl3): 7.65(s, 1H), 7.18-7.41(m. 6H), 7.06(s, 1H), 5.35(s, 2H), 3.82(q, 2H), 1.0(t, 3H)

545

1172

5-chloro-1-ethyl-2-{[2-(3- fluorophenyl)-1H-imidazol-1- yl]methyl}-1H-benzimidazole
1H NMR(CDCl3): 7.22-7.60(m, 9H), 5.67(s, 2H), 4.49(s, 2H), 4.11(q, 2H), 1.16(t, 3H)

546

1173

3-{1-[(5-bromo-1-ethyl-1H- benzimidazol-2-yl)methyl]-1H- imidazol-2-yl}benzonitrile
Hydrochloride 1H NMR (CD3OD); 7.71-8.25(m, 9H), 6.18(s, 2H). 4.50(br s, 2H), 1.50 (br s, 3H)

547

1174

1-ethyl-2-{[2-(3-nitrophenyl)-1H- imidazol-1-yl]methyl}-1H- benzimidazole-5-carbonitrile

373.15 [M + 1]

548

1175

6-chloro-1-ethyl-2-{[2-(3- fluorophenyl)-1H-imidazol-1- yl]methyl}-1H-benzimidazole-5- carbonitrile

380.4 [M + 1]; 378.2 [M − 1]

549

1176

5-(3,5-difluorophenyl)-1-ethyl-2- {[2-(3-fluorophenyl)-1H-imidazol- 1-yl]methyl}-1H-benzimidazole
1H NMR(CDCl3): 7.96(d, 1H), 7.35-7.70(m, 6H), 7.06-7.23(m, 4H), 6.78(m, 1H), 5.52(s, 2H), 3.81(q, 2H), 1.00(t, 3H)

550

1177

3-(1-{[5-(3,5-difluorophenyl)-1- ethyl-1H-benzimidazol-2- yl]methyl}-1H-imidazol-2- yl)benzonitrile
1H NMR(CDCl3): 7.93-8.02(m, 2H), 7.37-7.77(m, 6H), 7.08-7.19 (m, 3H), 6.77(m, 1H), 5.49(s, 2H), 3.89(q, 2H), 1.10(t, 3H)

551

1178

1-(1-ethyl-2-{[2-(3-fluorophenyl)- 1H-imidazal-1-yl]methyl}-1H- benzimidazol-5-yl)ethanone
1H NMR(CDCl3): 8.40(S. 1H), 8.00(dd, 1H), 7.33-7.53(m, 4H), 7.17-7.22(m, 2H), 7.05(d, 1H), 5.53(s, 2H), 3.82(q, 2H), 2.67 (s, 3H), 1.01(t, 3H)

552

1179

5-(3,5-dimethylisoxazol-4-yl)-1- ethyl-2-{[2-(3-fluorophenyl)-1H- imidazol-1-yl]methyl}-1H- benzimidazole
1H NMR(CDCl3): 7.66(d, 1H), 7.34-7.54(m, 4H), 7.15-7.22(m, 3H), 7.06(d, 1H), 5.52(s, 2H), 3.83(q, 2H), 2.41(s, 3H), 2.28 (a, 3H), 1.02(s, 3H)

553

1180

1-ethyl-2-({2-[3- (trifluoromethoxy)phenyl]-1H- imidazol-1-yl}methyl)-1H- benzimidazole-5-carbonitrile

411.96 [M + 1]

554

1181

(1E)-1-(1-ethyl-2-{[2-(3- fluorophenyl)-1H-imidazol-1- yl]methyl}-1H-benzimidazol-5- yl)ethanone O-methyloxime
Syn and anti 1H NMR(CDCl3): 7.98(d, 1H), 7.94(d, 1H1), 7.75 (dd, 1H+H1), 7.14-7.22(m, 2H+H1), 7.32-7.52(m, 4H+H1), [7.03(d, 1H), 7.01(d, 1H1)], 5.49 (s, 2H+H1), [4.00(s, 2H), 3.86

#(s, 2H1)], 3.79(q, 2H+H1), [2.30 (s, 3H), 2.26(s, 3H1)], 0.98(t, 3H+H1)

555

1182

2-{[2-(2,5-difluorophenyl)-1H- imidazol-1-yl]methyl}-1-ethyl-5-[5- (trifluoromethyl)-1H-tetraazol-1- yl]-1H-benzimidazole

475.1 [M + 1]

556

1183

1-ethyl-2-{[2-(3-fluorophenyl)-1H- imidazol-1-yl]methyl}-1H- benzimidazole-5,6-dicarbonitrile

371.0 [M + 1]

557

1184

1-ethyl-2-[(2-pyridin-3-yl-1H- imidazol-1-yl)methyl]-1H- benzimidazole-5-carbonitrile
Dihydrochioride 1H NMR(d6 DMSO): 8.96(1H, s), 8.82(1H, d), 8.24(1H, d), 8.14(1H, s), 8.05(1H, d), 7.98(1H, d), 7.85(1H, d), 7.69-7.65(2H, m), 6.01(2H, s), 4.33(2H, q), 1.29(3H, t)

558

1185

1-ethyl-2-[(2-pyridin-2-yl-1H- imidazol-1-yl)methyl]-1H- benzimidazole-5-carbonitrile
Dihydrochloride 1H NMR(d6 DMSO): 8.55(1H, d), 8.41(1H, d), 8.10-7.98(4H, m), 7.85(1H, d), 7.64(1H, d), 7.54-7.51(1H, m), 6.39(2H, s), 4.45(2H, q), 1.41(3H, t)
329.4 [M + 1]

559

1186

1-ethyl-5-fluoro-2-{[2-(3- nitrophenyl)-1H-imidazol-1- yl]methyl}-1H-benzimidazole

365.99 [M + 1]

560

1187

1 -ethyl-2-{[2-(3-methylphenyl)- 1H-imidazol-1-yl]methyl}-1H- benzimidazole-5-carbonitrile

343.06 [M + 1]

561

1188

1-(3-{1-[(1 -ethyl-5-fluoro-1H- benzimidazol-2-yl)methyl]-1H- imidazol-2-yl}phenyl)ethanone

363.05 [M + 1]

562

1189

3-(1-{[5-(3,5-dimethylisoxazol-4- yl)-1-ethyl-1H-benzimidazol-2- yl]methyl}-1H-imidazol-2- yl)benzonitrile
1H NMR(CDCl3): 7.94-8.01(m, 2H), 7.75(m, 1H), 7.61-7.66(m, 2H), 7.38(dd, 1H), 7.18-7.22(m, 2H), 7.10(d, 1H), 5.49(s, 2H), 3.90(q, 2H), 2.42(s, 3H), 2.29(s, 3H), 1.12(t, 3H)

563

1190

2-{[2-(2,5-difluorophenyl)-1H- imidazol-1-yl]methyl}-1-ethyl-5- (1H-imidazol-2-yl)-1H- benzimidazole
Dihydrochloride 1H NMR(d6 DMSO): 8.43(1H, s), 8.13-8.11(2H, m), 7.99(1H, d), 7.89(1H, d), 7.79-7.75(3H, m), 7.60-7.51(3H, m), 5.95(2H, s), 4.31(2H, q), 1.26(3H, t)
405.3 [M + 1]

564

1191

1-ethyl-5-nitro-2-[(2-pyridin-2-yl- 1H-imidazol-1-yl)methyl]-1H- benzimidazole

349.1 [M + 1]

565

1192

2-{[2-(2,5-difluorophenyl)-1H- imidazol-1-yl]methyl}-1-ethyl-5-(1- ethyl-1H-imidazol-2-yl)-1H- benzimidazole

433.2 [M + 1]

566

1193

3-{1-[(5-acetyl-1-ethyl-1H- benzimidazol-2-yl)methyl]-1H- imidazol-2-yl}benzonitrile
1H NMR(CDCl3): 8.40(d,1H), 7.93-8.05(m, 3H), 7.76(m, 1H), 7.63(m, 1H), 7.37(dd, 1H), 7.21 (d, 1H), 7.09(d, 1H). 5.50(s, 2H), 3.91(q, 2H), 2.68(s, 3H), 1.11(t, 3H)

567

1194

1-ethyl-2-({2-[3- (trifluoromethyl)phenyl]-1H- imidazol-1-yl}methyl)-1H- benzimidazole-5-carbonitrile

396.06 [M + 1]

568

1195

1-ethyl-2-[(2-thien-2-yl-1H- imidazol-1-yl)methyl]-1H- benzimidazole-5-carbonitrile

334.04 [M + 1]

569

1196

3-(1-{[1-ethyl-5- (trifluoromethoxy)-1H- benzimidazol-2-yl]methyl}1H- imidazol-2-yl)benzonitrile

412.2 [M + 1]; 410.2 [M − 1]

570

1197

3-{1-[(1-ethyl-5-fluoro-1H- benzimidazol-2-yl)methyl]-1H- imidazol-2-yl}benzaldehyde

349.17 [M + 1]

571

1198

1-ethyl-2-{[2-(3-fluorophenyl)-1H- imidazol-1-yl]methyl}-N-methoxy- N-methyl-1H-benzimidazole-5- carboxamide
1H NMR(CDCl3): 8.19(d, 1H), 7.71(dd, 1H), 7.40-7.55(m, 3H), 7.32(dd, 1H), 7.16-7.23(m, 2H), 7.05(d, 1H), 5.53(s, 2H), 3.80 (q, 2H), 3.59(s, 3H), 3.41(s, 3H), 1.00(t, 3H)

572

1199

1-ethyl-2-{[2-(3-fluorophenyl)-1H- imidazol-1-yl]methyl}-5-(1 3,4- oxadiazol-2-yl)-1H- benzimidazole

573

1200

1-ethyl-2-{[2-(3-fluorophenyl)-1H- imidazol-1-yl]methyl}-5-(5-methyl- 1,3,4-oxadiazol-2-yl)-1H- benzimidazole
Hydrochloride 1H NMR(d6 DMSO): 8.11(1H, s), 8.00(1H, d), 7 95(1H, d), 7.90-7.82(2H, m), 7.74-7 72(1H,m), 7.64-7.58(2H, m), 7.53-7.49(1H, m), 5,96(2H, s), 4.329(2H, q), 2,56(3H, s), 1.30(3H, t)
403.3 [M + 1]

574

1201

1-ethyl-2-{[2-(3-fluorophenyl)-1H- imidazol-1-yl]methyl}-5-(5-methyl- 1,2,4-oxadiazol-3-yl)-1H- benzimidazole

403.8 [M + 1]; 401.4 [M − 1]

575

1202

1-ethyl-2-{[2-(3-fluorophenyl)-1H- imidazol-1-yl]methyl}-5- [(trifluoromethyl)sulfonyl]-1H- benzimidazole

453.8 [M + 1]; 451.2 [M − 1]

576

1203

1-(2-{[2-(3-chlorophenyl)-1H- imidazol-1-yl]methyl)-1-ethyl-1H- benzimidazol-5-yl)ethanone
1H NMR(CDCl3): (8.40(d, 1H), 8.01(dd, 1H), 7.68(m, 1H), 7.55 (m, 1H), 7.45-7.52(m, 2H), 7.35 (d, 1H), 7.17(d, 1H), 7.06(d,1H), 5.52(s, 2H), 3.85(q, 2H), 2.68 (s, 3H), 1.03(t, 3H)

577

1204

1-ethyl-2-{[2-(3-fluorophenyl)-1H- imidazol-1 -yl]methyl}-1H- benzimidazole-6-carbonitrile

346.2 [M + 1]; 344.3 [M − 1]

578

1205

methyl 3-{1-[(5-cyano-1-ethyl-1H- benzimidazol-2-yl)methyl]-1H- imidazol-2-yl}benzoate

386.17 [M + 1]

579

1206

1-ethyl-2-{[2-(3-fluorophenyl)-1H- imidazol-1-yl]methyl}-1H- imidazo[4,5-c]pyridine
1H NMR(CDCl3) 9.10(s, 1H), 8.44(d, 1H), 7.38-7.52(m, 3H), 7 18-7.20(m, 2H), 7.16(s, 1H), 7.04(d, 1H), 5.53(s, 2H), 3.79 (q, 2H), 1.00(t, 3H)

580

1207

379.05 [M + 1]

581

1208

2-{[2-(5-aminothien-3-yl)-1H- imidazol-1-yl]methyl}-1-ethyl-1H- benzimidazole-5-carbonitrile

397.12 [M + 1]

582

1209

1-ethyl-2-{[2-(3-nitrophenyl)-1H- imidazol-1-yl]methyl}-1H- benzimidazole-5-carboxamide

391.17 [M + 1]

583

1210

1-ethyl-2-{[2-(3-fluorophenyl)-1H- imidazol-1-yl]methyl}-5-(5-methyl- 1,3-oxazol-2-yl)-1H- benzimidazole
Hydrochloride 1H NMR(d6 DMSO): 8.05(1H, s), 7.99(1H, d), 7.97(1H, s), 7.88-7.86(1H, m), 7.76-7.72(2H, m), 7.65-7.59(2H, m), 7.54-7.51(1H, m), 6.99(1H, s), 5.9392H, s), 4.31(2H, q), 2.36(3H, s), 1.29(3H, t).
402.5 [M + 1]

584

1211

1-ethyl-2-{[2-(3-fluorophenyl)-1H- imidazol-1-yl]methyl}-5-(5-pyridin- 3-yl-1,3,4-oxadiazol-2-yl)-1H- benzimidazole
Hydrochloride 1H NMR(d6 DMSO): 9.36(1H, d), 8.84(1H, dd), 8.57(1H, m), 8.44(1H, s), 8.10(1H, dd), 8.03(1H, d), 7.98(1H, d), 7.90(1H, d), 7.75-7.51(5H, m), 5.99(2H, s), 4.35(2H, q), 1.33(3H, t).
466.5 [M + 1]

585

1212

(1E)-1-(2-{[2-(3-chlorophenyl)-1H- imidazol-1-yl]methyl}-1-ethyl-1H- benzimidazol-5-yl)ethanone oxime
1H NMR(CDCl3): 11.03(s, 1H), 7.81(s, 1H), 7.52-7.67(m, 4H), 7.40-7.45(m, 2H), 7.31(s, 1H), 7.07(s, 1H), 5.67(s, 2H,), 4.17 (q, 2H), 2.18(s, 3H), 1.16(t, 3H)

586

1213

(1E)-1-(2-{[2-(3-chlorophenyl)-1H- imidazol-1-yl]methyl}-1-ethyl-1H- benzimidazol-5-yl)ethanone O- methyloxime
Syn and anti 1H NMR(CDCl3): 7.99(dd, 1H), 7,95(dd, 1H1), 7.76(dd, 1H+H1), 7.65(m, 1H+H1), 7.44-7.57(m, 3H+H1), 7.27(d, 1H+H1), 7.15(d, 1H+H1), 7.04(d, 1H+H1), 5.49 (s, 2H+H1), 4.01(s, 3H), 3.87(s, 3H1), 3.80(q, 2H+H1), [2.30(s,

#3H), 2.27(a, 3H1)], 1.00(t, 3H+H1)

587

1214

(1E)-1-(2-{[2-(3-chlorophenyl)-1H- imidazol-1-yl]methyl}-1-ethyl-1H- benzimidazol-5-yl)ethanone O- ethyloxime
Syn and anti 1H NMR(CDCl3): 8.00(dd, 1H+H1), 7.76(dd, 1H+H1), 7.69(m, 1H+H1), 744-7.57(m, 3H+H1), 7.27(dd, 1H+H1), 7.15(d, 1H+H1), 7.04 (d, 1H), 7.03(d, 1H1), 5.49(s, 2H+H1), 4.26(q, 2H), 4.13(q, 2H1), 3.80(q, 2H+H1), 2.27(s,

#3H1), 1.34(t, 3H), 1.25(t, 3H1), 1.00(t, 3H+H1)

588

1215

1-ethyl-2-{[2-(6-fluoropyridin-2-yl)- 1H-imidazol-1-yl]methyl}-1H- benzimidazole-5-carbonitrile

347.07 [M + 1]

589

1216

1-ethyl-2-{[2-(3-fluorophenyl)-1H- imidazol-1-yl]methyl}-5-(1,2,4- oxadiazol-3-yl)-1H- benzimidazole

590

1217

1-ethyl-2-{[2-(6-methoxypyridin-2- yl)-1H-imidazol-1-yl]methyl}-1H- benzimidazole-5-carbonitrile

359.08 [M + 1]

591

1218

(1E)-1-(1-ethyl-2-{[2-(3- fluorophenyl)-1H-imidazol-1- yl]methyl}-1H-benzimidazol-5- yl)ethanone oxime
Hydrochloride 1H NMR(d6- DMSO): 11.10 S. 1H), 7.52-7.99 (m, 9H+H1), 5.923(s, 2H+H1): 4.30(q, 2H+H1), 2.18(s, 3H), 2.14(a, 3H1), 1.29(t, 3H+H1)

592

1219

(1E)-1-(1-ethyl-2-{[2-(3- fluorophenyl)-1H-imidazol-1- yl]methyl}-1H-benzimidazol-5- yl)ethanone O-ethyloxime
Hydrochloride 1H NMR(d6- DMSO): 7.52-7.99(m, 9H), 5.93 (s, 2H), 426(q, 2H), 4 14(q, 2H), 2.20(s, 3H), 1.23-1.29(m, 6H)

593

1220

1-(1-ethyl-2-{[2-(3-fluorophenyl)- 1H-imidazol-1-yl]methyl}-1H- benzimidazol-5-yl)propan-1-one
1H NMR(CDCl3): 8.42(d, 1H), 8.02(dd, 1H), 7.32-7.54(m, 4H), 7.17-7.24(m, 2H), 7.06(d, 1H), 5.53(s, 2H), 3.83(q, 2H), 3.09 (q, 2H), 1.27(t, 3H), 1.02(t, 3H)

594

1221

ethyl 1-(1-ethyl-2-{[2-(3- fluorophenyl)-1H-imidazol-1- yl]methyl}-1H-benzimidazol-5-yl)- 1H-1,2,3-triazole-4-carboxylate

595

1222

3-ethyl-2-{[2-(3-fluorophenyl)-1H- imidazol-1-yl]methyl}-3H- imidazo[4,5-c]pyridine

596

1223

1-(1-ethyl-2-{[2-(6-fluoropyridin-2- yl)-1H-imidazol-1-yl]methyl}-1H- benzimidazol-5-yl)ethanone

364.2 [M + 1]; 362.6 [M − 1]

597

1224

1-ethyl-2-{[2-(6-fluoropyridin-2-yl)- 1H-imidazol-1-yl]methyl}-5- (trifluoromethyl)-1H- benzimidazole

390.2 [M + 1]; 388.2 [M − 1]

598

1225

2-{[2-(6-fluoropyridin-2-yl)-1H- imidazol-1-yl]methyl}-1-propyl-1H- benzimidazole-5-carbonitrile
1H NMR(399.96MHz, CDCl3): d 8.17(dd, J=2.0, 7.6Hz, 1H), 8.05(s, 1H), 7.88(q, J=80Hz, 1H,), 7.52(d, J=8.4Hz, 1H), 7.41(d, J=8.4Hz, 1H), 7.21(s, 1H), 7.18(s, 1H), 6.28(s, 2H), 4.28(t, J=7.6Hz, 2H), 1.68(dt, J=7.6Hz, 2H), 0.84(t, J=7.6

#Hz, 3H)

361.2 [M + 1]; 359.2 [M − 1]

599

1226

1-ethyl-2-{[2-(3-fluorophenyl)-1H- imidazol-1-yl]methyl}-1H- imidazo[4,5-b]pyridine

322.2 [M + 1]; 320.3 [M − 1]

600

1227

2-{[2-(3-fluorophenyl)-1H- imidazol-1-yl]methyl}-1-propyl-1H- imidazo[4,5-c]pyridine
1H NMR(CDCl3): 9.11(s, 1H), 8.45(d, 1H), 7.38-7.52(m, 3H), 7.16-7.26(m, 3H) 7.06(s, 1H), 5.53(s, 2H), 3.71(t, 2H), 1.43(q 2H), 0.75(t, 3H)

601

1228

2-{[2-(3-chlorophenyl)-1H- imidazol-1-yl]methyl}-1-ethyl-5- isoxazol-5-yl-1H-benzimidazole
1H NMR(CDCl3): 8.30(d, 1H), 8.21(dd, 1H), 7.78(dd, 1H), 7.69 (m, 1H), 7.56(m, 1H), 7.45-7.48 (m, 2H), 7.39(dd, 1H), 7.17(d, 1H), 7.07(d, 1H), 6.53(d, 1HP, 5.52(s, 2H), 3.83(q, 2H), 1.03 (t,3H)

602

1229

1-(2-fluoroethyl)-2-{[2-(3- fluorophenyl)-1H-imidazol-1- yl]methyl}-1H-benzimidazole

339.2 [M + 1]

603

1230

2-{[2-(3-fluorophenyl)-1H- imidazol-1-yl]methyl}-1 -propyl-1H- imidazo[4,5-b]pyridine

336.2 [M + 1]; 334.2 [M − 1]

604

1231

2-{[2.(2,5-difluorophenyl)-1H- imidazol-1-yl]methyl}-1-ethyl-1H- imidazo[4,5-b]pyridine

605

1232

1-ethyl-2-[(2-{5- [hydroxy(oxido)amino]thien-3-yl}- 1H-imidazol-1-yl)methyl]-1H- benzimidazole-5-carbonitrile

606

1233

3-propyl-2-[(2-pyrimidin-2-yl-1H- imidazol-1-yl)methyl]-3H- imidazo[4,5-b]pyridine
(CDCl3) 8.46(d, 1H), 8.39(dd, 1H), 8.03(dd, 1H), 7.27(m, 5H), 6.37(s, 2H), 4.27(t, 2H), 1.70(p, 2H), 0.82(t, 3H)
320.4 [M + 1]

607

1234

3-ethyl-2-{[2-(2,3,4- trifluorophenyl)-1H-imidazol-1- yl]methyl}-3H-imidazo[4,5- bipyridine
(CDCl3) 8.40(dd, 1H), 8.02(dd, 1H), 7.36(dq, 1H), 725(dd, 1H), 7.22(d, 1H), 7.01(m, 2H), 5.38 (s, 2H), 4.03(q, 2H), 1.10(t, 3H)
358.2 [M + 1]

608

1235

3-propyl-2-[(2-thien-2-yl-1H- imidazol-1-yl)methyl]-3H- imidazo[4,5-b]pyridine
(CDCl3) 8.40(dd, 1H), 8.05(dd, 1H), 7.46(dd, 1H), 7.25(dd, 1H), 7.15(m, 2H), 7.03(d, 1H), 5.61 (s, 2H), 3.96(t, 2H), 1.55(p, 2H), 0.80(t, 3H)
324.3 [M + 1]

609

1236

3-ethyl-2-{[2-(1-methyl-1H- pyrazol-3-yl)-1H-imidazol-1- yl]methyl}-3H-imidazo[4,5- b]pyridine
(CDCl3)8.39(dd, 1H), 8.05(dd, 1H), 7.43(dd, 1H), 7.23(dd 1H), 7.10(dd, 1H), 7.04(dd, 1H) 6.91 (dd, 1H), 6.21(s, 2H), 4.33(q, 2H), 3.97(3, 3H), 1.13(t, 3H)
m/z 308.3 [M + 1]

610

1237

3-ethyl-2-{[2-(2-fluoro-5- methylphenyl)-1H-imidazol-1- yl]methyl}-3H-imidazo[4,5- b]pyridine
(CDCl3) 8.39(dd, J=4.8, 1.5 Hz, 1H), 8.05(dd, J=8.4, 1.5 Hz, 1H), 7.44(dd, J=6.6, 2.1 Hz, 1H), 7.25-7.30(m, 2H), 7.19 (d, J=1.5Hz, 1H), 7.12(dd, J=9.9, 8.7Hz, 1H), 7.04(d, J=1.5 Hz, 1H), 5.38(s, 2H), 3.96(q, J=

#7.2 Hz, 2H), 2.37(s, 3H), 1.03(t, J=7.2Hz, 3H)
336.2 [M + 1]

611

1238

3-ethyl-2-{[2-(5-fluoro-2- methylphenyl)-1H-imidazol-1- yl]methyl}-3H-imidazo[4,5- bipyridine
(CDCl3) 8.39(dd, J=4.6, 1.5 Hz, 1H), 8.04(dd, J=8.0, 1.5 Hz, 1H), 7.19-7.32(m, 3H), 7.07-7.13(m, 3H), 5.26(s, 2H), 3.98 (q, J=7.2Hz, 2H), 2.24(s, 3H), 1.11(t, J=7.2Hz, 3H)
m/z 336.2 [M + 1]

612

1239

2-{[2-(3-chloro-2,6- difluorophenyl)-1H-imidazol-1- yl]methyl}-3-ethyl-3H-imidazo[4,5- b]pyridine
(CDCl3) 8.40(dd, J=4.7, 1.5 Hz, 1H), 8.01(dd, J=8.0, 1.5 Hz, 1H), 7.52(m, 1H), 7.23-7.30 (m, 2H), 7.11(d, J=1.5Hz, 1H), 7.03(m, 1H), 5.34(s, 2H), 4.03 (q, J=7.2Hz, 2H), 1.10(t, J=7.2Hz, 3H)
m/z 374.2 [M + 1]

613

1240

3-ethyl-2-{[2-(2-methoxyphenyl)- 1H-imidazol-1-yl]methyl}-3H- imidazo[4,5-b]pyridine
(CDCl3) 8.38(dd, J=4.8, 1.5 Hz, 1H), 8.03(dd, J=8.1, 1.5 Hz, 1H), 7.46-7.57(m, 2H), 7.25 (m, 1H), 7.16(d, J=1.2Hz, 1H), 7.13(dt, J=7.5, 1.2Hz, 1H), 7.04(d, J=8.4Hz, 1H), 7.00(d, J=1.2Hz, 1H), 5.29(s, 2H), 3.90(q, J=7.2Hz, 2H), 3.84(s,

#3H), 0.98(t, J=7.2Hz, 3H)
m/z 334.2 [M + 1]

614

1241

3-ethyl-2-{[2-(2,4,5- trifluorophenyl)-1H-imidazol-1- yl]methyl}-3H-imidazo[4,5- b[pyridine
(CDCl3) 8.40(dd, J=4.6, 1.4 Hz, 1H), 8.04(dd, J=8.2, 1.5 Hz, 1H), 7.50(m, 1H), 7.25(dd, J=7.8, 5.1Hz, 1H), 7.21(d, J=1.5Hz, 1H), 7.14(m, 1H), 7.06 (d, J=1.5Hz, 1H), 5.37(s, 2H), 4.02(q, J=7.2Hz, 2H), 1.11(t, J=7.2Hz, 3H)
m/z 358.2 [M + 1]

615

1242

4-chloro-2-{[2-(6-fluoropyridin-2- yl)-1H-imidazol-1-yl]methyl}-6- methyl-1-propyl-1H-imidazo[4,5- c]pyridine
(CDCl3) 8.19(dd, J=6, 1.2Hz, 1H), 7.93(q, J=6Hz, 1H), 7.21(d, J=1Hz, 1H), 7.14(d, J=1Hz, 1H), 7.05(s, 1H), 6.93(dd, J=6, 2Hz, 1H), 6.38(s, 2H), 4.18(t, J=5.6Hz, 2H), 2.63(s, 3H), 1.57(sextet, J=5.4Hz, 2H),

#0.77(t, J=5.4Hz, 3H)
m/z 385 [M + 1}

616

1243

4-chloro-6-methyl-1-propyl-2-[(2- pyridin-2-yl-1H-imidazol-1- yl)methyl]-1H-imidazo[4,5- c]pyridine
(CD3OD) 8.02-7.98(m, 3H), 7.34(d, J=2Hz, 1H), 7.14(d, J=1.8Hz, 1H), 7.01(d, J=2Hz, 1H), 6.47(s, 1H), 6.12(s, 2H), 4.21(t, J=5.2Hz, 2H), 2.33(s, 3H), 1.68(sextet, J=5.4Hz, 2H), 0.86(t, J=5.4Hz, 3H)
m/z 367 [M + 1]

617

1244

3-ethyl-2-{[2-(5-fluoro-2- methoxyphenyl)-1H-imidazol-1- yl]methyl}-3H-imidazo[4,5- b]pyridine
(CDCl3) 8.39(dd, J=4.6, 1.4 Hz, 1H), 8.04(dd, J=8.0, 1.4 Hz, 1H), 7.15-7.32(m, 4H), 7.01 9.0, 4.5Hz, 1H), 5.30(s, 2H), (d, J=Hz, 1H), 6.96(dd J=3.95(q, J=7.2Hz, 2H), 3.80(s, 3H), 1.02(t, J=7.2Hz, 3H)
m/z 352.3 [M + 1]

618

1245

2-{[2-(6-fluoropyridin-2-yl)-1H- imidazol-1-yl]methyl}-5-methyl-3- propyl-3H-imidazo[4,5-b]pyridine
(CDCl3) 8.18(dd, J=7.8, 2.1 Hz, 1H), 7.84-7.92(m, 2H), 7.21 (d, J=1.2Hz, 1H), 7.18(d, J=1.2 Hz, 1H), 7.06(d, J=7.8Hz, 1H), 6.89(dd, J=8.1, 27Hz, 1H), 6.29(s, 2H), 4.29(t, J=7.5 Hz, 2H), 2.64(s, 3H), 1.72(m, 2H), 0.83(t, J=7.5Hz, 3H)

619

1246

3-ethyl-2-{[2-(2,3,5- trifluorophenyl)-1H-imidazol-1- yl]methyl}-3H-imidazo[4,5- b[pyridine
(CDCl3) 8.40(dd, J=4.8, 1.2 Hz, 1H), 8.04(dd, J=7.8, 1.2 Hz, 1H), 7.05-7.28(m, 5H), 5.40 (s, 2H), 4.04(q, J=7.3Hz, 2H), 1.10(t, J=7.3 Hz, 3H)

620

1247

2-{[2-(1H-benzimidazol-5-yl)-1H- imidazol-1-yl]methyl}-3-propyl-3H- imidazo[4,5-b]pyridine
(CDCl3): 8.38(d, 1H), 8.02(m, 2H), 7.96(s, 1H), 7.66(s, 1H), 7.42(d, 1H), 7.25(m, 2H), 5.56 (s, 2H), 5.29(1H), 3.87(t, 2H), 1.48(m, 2H), 0.68(t, 3H)
m/z 358 [M + 1]

621

1248

3-{1-[(3-ethyl-3H-imidazo[4,5- b]pyridin-2-yl)methyl]-1H- imidazol-2-yl}-4- fluorobenzonitrile
(CDCl3): 8.40(d, 1H), 796(m, 2H), 7.75(m, 1H), 7.31(m, 3H), 7.10(s, 1H), 5.38(s, 2H), 4.03 (q, 2H), 1.11(t, 3H)

622

1249

2-{[2-(2,6-difluoro-3- methylphenyl)-1H-imidazol-1- yl]methyl}-1-ethyl-1H- benzimidazole-5-carbonitrile
(CDCl3) 8.06(s,1H), 7.55(m, 1H), 7.37(dd, J=8.0, 1.2Hz, 1H), 7.32-7.26(m, 2H), 7.04(s, 1H), 6.94(t, J =8.8Hz, 1H), 5.34(s, 2H), 3.88(q, J=7.1Hz, 2H), 2.25 (S, 3H), 1.03(t, J=7.1Hz, 3H)
m/z 378 [M + 1]

623

1250

1-{1-[(3-ethyl-3H-imidazo[4,5- b]pyridin-2-yl)methyl]-1H- imidazol-2-yl}isoquinoline
(CDCl3) 9.11(d, 1H), 8.58(d, 1H), 8.37(dd, 1H), 8.02(dd, 1H) 7.86(dd, 1H), 7.51(m, 3H), 7.32 (d, 1H), 7.22(m, 2H), 6.11(s, 2H), 4.36(q, 2H), 1.11(t, 3H)
m/z 355.2 [M + 1]

624

1251

2-{[2-(2-fluoro-5-methylphenyl)- 1H-imidazol-1-yl]methyl}-1-propyl- 1H-imidazo[4,5-c]pyridine
(CDCl3) 9.07(s, 1H), 8.41{d, J=4.5Hz, 1H), 8.12(dd, J=5.1, 1.5 Hz, 1H), 7.28-7.24(m, 2H), 7.21(d, J=4.2Hz, 1H), 7.10(t, J=6.6Hz, 1H), 7.01(s, 1H), 5.37(s, 2H), 3.69(t, J=57Hz, 2H), 2.34(s, 3H), 1.40(sextet, J=5.7Hz, 2H), 0.74(t, J=5.7Hz, 3H)
m/z 350 [M + 1]

625

1252

1-ethyl-2-{[2-(2-fluoro-5- methylphenyl)-1H-imidazol-1- yl]methyl}-1H-imidazo[4,5- c]pyridine
(CDCl3) 9.09(s, 1H), 8.44(d, J=4.8Hz, 1H), 7.42(d, J=5.0Hz, 1H), 7.29-7.23(m, 3H), 7.12(t, J=6.3Hz, 1H), 7.00(s, 1H), 5.39(s, 2H), 3.81(q, J=5.4Hz, 2H), 2.36(s, 3H), 0.99(t, J=5.1Hz, 3H)
m/z 336 [M + 1]

626

1253

2-{[2-(3-chloro-2,6- difluorophenyl)-1H-imidazol-1- yl]methyl}-1-ethyl-1H-imidazo[4,5- c]pyridine
D6dmso) 9.42(s, 1H), 8.69(d, J=6.4Hz, 1H), 8.36(d, J=6.4Hz, 1H), 7.99-7.91(m, 2H), 7.75(s, 1H), 7.39(t, J=8Hz, 1H), 5.95(s, 2H), 4.43(q, J=7.2Hz, 2H), 1.25 (t, J=7.2Hz, 3H)
m/z 374 [M + 1]

627

1254

1-ethyl-2-(6-{1-[(1-ethyl-1H- imidazo[4,5-c]pyridin-2-yl)methyl]- 1H-imidazol-2-yl}pyridin-2-yl)-1H- imidazo[4,5-c]pyridine
(D6dmso) 9.57(s, 1H), 9.34(s, 1H), 8.74(d, J=6.8Hz, 1H), 8.63 (d, J=6.4Hz, 1H), 8.42(d, J=6.8Hz, 1H), 8.33(d, J=6.4Hz, 1H), 8.25(t, J=8Hz, 1H), 8.17(d, J=6.8Hz, 1H), 8.07(d, J=7.6Hz, 1H), 7.70(s, 1H), 7.46(s, 1H),

#6.32(s, 2H), 4.24-4.16(m, 4H), 0.97(t, J=7.2Hz, 3H), 0.89(t, J=7.2Hz, 3H)

628

1255

2-{[2-(2,6-difluoro-3- methylphenyl)-1H-imidazol-1- yl]methyl}-1-ethyl-1H-imidazo[4,5- c]pyridine
(d6 DMSO) 9.42(s, 1H), 8.69(d, J=6.4Hz, 1H), 8.37(d, J=6.8Hz, 1H), 8.08(s, 1H), 7.90(s, 1H), 7.67-7.61(m, 1H), 7.24(t, J=8.8Hz, 1H), 5.98(s, 2H), 4.44 (q, J=7.2Hz, 2H), 2.19(s, 3H), 1.27(t, J=7.2Hz, 3H)

629

1256

3-{1-[(3-ethyl-3H-imidazo[4,5- b]pyridin-2-yl)methyl]-1H- imidazol-2-yl}pyridin-2(1H)-one
(d6 DMSO) 12.00(br s, 1H), 8.28 (dd, J=5.2, 1.2Hz, 1H), 7.93(dd, J=8, 1.2Hz, 1H), 7.56(dd, J=6.8, 2Hz, 1H), 7.45(dd, J=6.8, 2Hz, 1H), 7.25(s, 1H), 7.20(dd, J=8, 4.8Hz, 1H), 6.98(s, 1H), 6.19(t, J=5.2Hz, 1H), 5.64(s, 2H), 4.14

#(q, J=7.2Hz, 2H), 1.07(t, J=7.2Hz, 3H)
m/z 319 [M − 1]

630

1257

2-{[2-(6-fluoropyridin-2-yl)-1H- imidazol-1-yl]methyl}-3,5- dimethyl-3H-imidazo[4,5- b]pyridine
(CDCl3) 8.16(dd, 1H), 7.88(m, 2H), 7.16(m, 2H), 7.06(d, 1H), 6.85(dd, 1H), 6.24(s, 2H), 3.85 (s, 3H), 2.62(s, 3H)

631

1258

8-{[2-(6-fluoropyridin-2-yl)-1H- imidazol-1-yl]methyl}-2,9- dimethyl-9H-purine
(CDCl3) 8.92(s, 1H), 8.18(dd, 1H), 7.88(q, 1H), 7.25(s, 1H), 7.20(s, 1H), 7.11(s, 1H), 6.83 (dd, 1H), 6.22(s, 2H), 3.89(s, 3H), 2.8(s, 3H)
m/z 324 [M + 1]

632

1259

2-{[2-(6-fluoropyridin-2-yl)-1H- imidazol-1-yl]methyl}-1,6- dimethyl-1H-imidazo[4,5- c]pyridine
(CDCl3) 8.91(s, 1H), 8.16(dd, J=7.6, 2.0Hz, 1H), 7.85(q, J=8.0Hz, 1H), 7.20(s, 1H), 7.18(s, 1H), 7.11(s, 1H), 6.84(dd, J=8.0, 2.8Hz, 1H), 6.22(s, 2H), 3.80(s, 3H), 2.66(s, 3H)
m/z 323 [M + 1]

633

1260

6-chloro-1-ethyl-2-}[2-(6- fluoropyridin-2-yl)-1H-imidazol-1- yl]methyl}-1H-benzimidazole
(CDCl3) 8.17(dd, 1H), 789(q, 1H), 7.25(s, 1H), 7.75(s, 1H), 7.26(m, 2H), 7.19(s, 1H), 7.17 (s, 1H), 6.89(dd, 1H), 6.28(s, 2H), 4.33(q, 2H), 1.20(s, 3H)
m/z 356 [M + 1]

634

1261

1-ethyl-2-{[2-(6-fluoropyridin-2-yl)- 1H-imidazol-1-yl]methyl}-6- (trifluoromethyl)-1H- benzimidazole
(CDCl3) 8.20(m, 1H), 7.87(m, 2H), 7.63(s, 1H), 7.48(d, 1H), 7.20(d, 2H), 6.85(dd, 1H), 6.25 (s, 2H), 4.38(q, 2H), 1.24(t, 3H)

635

1262

1-ethyl-2-{[2-(3-fluoropyridin-2-yl)- 1H-imidazol-1-yl]methyl}-6- (trifluoromethyl)-1H- benzimidazole
(CDCl3) 8.46(m, 1H), 7.84(d, 1H), 7.60(m, 2H), 7.52(d, 1H), 7.38(m, 1H), 7.25(s, 1H), 7.10 (s, 1H), 6.14(s, 2H), 4.35(q, 2H), 1.14(t, 3H)

636

1263

1-ethyl-2-{[2-(3-fluoropyridin-2-yl)- 1H-imidazol-1-yl]methyl}-6- methyl-1H-benzimidazole
(CDCl3) 8.48(dt, 1H), 7 59-7.66 (m, 2H), 7.36(m, 1H), 7.20(s, 1H), 7.08-7.11(m, 3H), 6.01(s, 2H), 4.18(q, 2H), 2.48(S. 3H), 1.07(s, 3H)

637

1264

6-chloro-1-ethyl-2-{[2-(3- fluoropyridin-2-yl)-1H-imidazol-1- yl]methyl}-1H-benzimidazole
(CDCl3) 8.48(dt, 1H), 7.74(s, 1H), 7.61(t, 1H), 7.37(m, 1H), 7.20(s, 1H), 7.23-7.26(m, 3H), 7.08(s, 1H), 6.01(s, 2H), 4.25 (q, 2H), 1.07(s, 3H)

638

1265

2-{[2-(3-fluoropyridin-2-yl)-1H- imidazol-1-yl]methyl}-1,6- dimethyl-1H-imidazo[4,5- c]pyridine
(CDCl3) 8.95(s, 1H), 8.45(dt, J=5.8, 1.8Hz, 1H), 7.61(m, 1H), 7.36(m, 1H), 7.27(s, 1H), 7.10 (s, 1H), 7.06(s, 1H), 6.06(s, 2H), 3.66(s, 3H), 2.67(s, 3H)
m/z 323 [M + 1]

639

1266

2-{[2-(3-fluorophenyl)-1H- imidazol-1-yl]methyl}-1H- benzimidazole

m/z 293 [M + 1]

640

1267

1-benzyl-2-{[2-(3-fluorophenyl)- 1H-imidazol-1-yl]methyl}-1H- benzimidazole

m/z 383 [M + 1]

641

1268

2-{[2-(6-fluoropyridin-2-yl)-1H- imidazol-1-yl]methyl}-1-methyl-6- (trifluoromethyl)-1H- benzimidazole
(CDCl3) 8.20(m, 1H), 7.87(m, 2H), 7.63(s, 1H), 7.48(d, 1H), 7.20(s, 2H), 6.84(dd, 1H), 6.25 (s, 2H), 3.92(s, 3H)

642

1269

4-(2-{[2-(3-fluarophenyl)-1H- imidazol-1-yl]methyl}-1H- benzimidazol-1-yl)-2- methylbutan-2-ol

m/z 379 [M + 1]

643

1270

1-ethyl-2-{[2-(3-fluoropyridin-2-yl)- 1H-imidazol-1-yl]methyl}-6- methyl-1H-imidazo[4,5-c]pyridine
(CDCl3) 8.96(s, 1H), 8.46(dt, 4.8, 1.4Hz, 1H), 7.61(m, 1H), 7.37(m, 1H), 7.24(d, J=1.2Hz, 1H), 7.10(s, 1H), 7.09(d, J=1.2 Hz, 1H), 6.06(s. 2H), 423(q, J=7.2Hz, 2H), 2.66(s, 3H), 1.10(t, J=7.2Hz, 3H)
m/z 337 [M + 1]

644

1271

2-{[2-(3-fluorophenyl)-1H- imidazol-1-yl]methyl}-1-methyl-6- (trifluoromethyl)-1H- benzimidazole

m/z 375 [M + 1]

645

1272

2-{[2-(3-fluoropyridin-2-yl)-1H- imidazol-1-yl]methyl}-1-methyl-6- (trifluoromethyl)-1H- benzimidazole
m/z 376 [M + 1]

646

1273

2-{[2-(3-fluorophenyl)-1H- imidazol-1-yl]methyl}-1,6- dimethyl-1H-imidazo[4,5- c]pyridine
(CDCl3) 8.95(s, 1H), 7 49-7.37 (m, 3H), 7.16(m, 2H), 7.06(s, 1H), 6.97(s, 1H), 5.50(s, 2H), 3.33(s, 3H), 2.66(s, 3H)
m/z 322 [M + 1]

647

1274

1-ethyl-2-{[2-(6-fluoropyridin-2-yl)- 1H-imidazol-1-yl]methyl}-6- methyl-1H-benzimidazole
(CDCl3) 8.15(dd, 1H), 7.87(q, 1H), 7.63(d, 1H), 7.08-7.17(m, 4H), 6.88(dd, 1H), 6.26(s, 1H), 4.27(q, 2H), 2.46(s, 1H), 1.16(t, 3H)

648

1275

1-(1-ethyl-2-{[2-(3-fluoropyridin-2- yl)-1H-imidazol-1-yl]methyl}-1H- benzimidazol-5-yl)ethanone
(CDCl3) 8.45(d, 1H), 8.38(s, 1H), 7.98(dd, 1H), 7.61(t, 1H), 7.37(m, 2H), 7.24(s, 1H), 7.21 (s, 1H), 6.08(s, 2H), 4.29(q, 2H), 2.66(s, 3H), 1.14(t, 3H)

649

1276

1-ethyl-2-{[2-(3-fluoropyridin-2-yl)- 1H-imidazol-1-yl]methyl}-1H- imidazo[4,5-c]pyridine
(CDCl3) 9.12(s, 1H), 8.45-8.49 (m, 2H), 7.620(t, 1H), 7.35-7.41 (m, 1H), 7.30(d, 1H), 7.27(s, 1H), 7.11(s, 1H), 6.13(s, 2H), 4.30(q, 2H), 1.12(t, 3H)

650

1277

1-ethyl-2-{[2-(3-fluoropyridin-2-yl)- 1H-imidazol-1-yl]methyl}-1H- benzimidazole-5-carbonitrile
(CDCl3) 8.45(d, 1H), 8.09(s, 1H), 7.62(t, 1H), 7.58(d, 1H), 7.42(s, 1H), 7.35-7.40(m, 2H), 7.09(s, 1H), 6.10(s, 2H), 4.32 (q, 2H), 112(t, 3H)

651

1278

5-chloro-1-ethyl-2-{[2-(3- fluoropyridin-2-yl)-1H-imidazol-1- yl]methyl}-1H-benzimidazole

m/z 356 [M + 1]

652

1279

1-ethyl-5-fluoro-2-{[2-(3- fluoropyridin-2-yl)-1H-imidazol-1- yl]methyl}-1H-benzimidazole

m/z 340 [M + 1]

653

1280

5-bromo-1-ethyl-2-{[2-(3- fluoropyridin-2-yl)-1H-imidazol-1- yl]methyl}-1H-benzimidazole
(CDCl3) 8.46(s, 1H), 7.90(s, 1H), 7.62(t, 1H), 7.32-7.42(m, 2H), 7.17-7.27(m, 2H), 7.06(s, 1H), 6.02(s, 2H), 4.22(q, 2H), 1.06(t, 3H)

654

1281

9-ethyl-8-{[2-(3-fluoropyridin-2-yl)- 1H-imidazol-1-yl]methyl}-2- methyl-9H-purine
(CDCl3) 8.96(s, 1H), 8.40(d, 1H), 7.59(m, 1H), 730(m, 2H), 7.12(s, 1H), 6.07(s, 2H), 4.30 (q, 2H), 2.78(s, 3H), 1.20(t, 3H)

655

1282

3-ethyl-2-{[2-(6-fluoropyridin-2-yl)- 1H-imidazol-1-yl]methyl}-3H- imidazo[4,5-c]pyridine
(CDCl3) 8.84(s, 1H), 8.47(d, J=5.7Hz, 1H), 8.20(dd, J=7.8, 3.0Hz, 1H), 7.91(q, J=8.1Hz, 1H), 7.28(s, 1H), 7.25(d, J=9.9 Hz, 2H), 6.91(dd, J=5.1, 3Hz, 1H), 6.35(s, 2H), 4.39(q, J=5.4Hz, 2H), 1.49(t, J=5.4Hz, 3H)
m/z 323 [M + 1]

656

1283

6-ethyl-2-{[2-(6-fluoropyridin-2-yl)- 1H-imidazol-1-yl]methyl}-1- methyl-1H-imidazo[4,5-c]pyridine
(CDCl3) 8.96(s, 1H), 817(br d, J=7.6Hz, 1H), 7.87(q, J=7.8 Hz, 1H), 7.21(s, 1H), 7.19(s, 1H), 7.12(s, 1H), 6.87(m, 1H), 6.24(s, 2H), 3.83(s, 3H), 2.95 (q, J=7.2Hz, 2H), 1.36(t, J=7.2Hz, 3H)
m/z 337 [M + 1]

657

1284

9-ethyl-8-{[2-(6-fluoropyridin-2-yl)- 1H-imidazol-1-yl]methyl}-2- methyl-9H-purine
(CDCl3) 8.96(s, 1H), 8.17(br d, J=76Hz, 1H), 7.87(q, J=7.8 Hz, 1H), 7.21(s, 1H), 7.19(s, 1H), 7.12(s, 1H), 6.87(m, 1H) 6.24(s, 2H), 3.83(s, 3H), 2.95 (q, J=7.2Hz, 2H), 1.36(t, J=7.2Hz, 3H)
m/z 337 [M + 1]

658

1285

1-ethyl-2-{[2-(1,3-thiazol-2-yl)-1H- imidazol-1-yl]methyl}-1H- benzimidazole-5-carbonitrile
(DMSO) 8.05(s, 1H), 7.80(d, 1H), 7.73(d, 1H), 7.65(d, 1H), 7.60(d, 1H), 7.48(s,1H), 7.10(s, 1H), 6.20(s, 2H), 4.40(q, 2H), 1.35(t, 3H)

659

1286

2-{[2-(6-fluoropyridin-2-yl)-1H- imidazol-1-yl]methyl}-3-methyl- 3H-imidazo[4,5-c]pyridine
(DMSO) 8.95(s, 1H), 8.22(d, J=5.4Hz, 1H), 7.99(m, 2H), 7.54 (s, 1H), 7.43(d, J=5.4Hz, 1H), 7.16(s, 1H), 7.0(br d, J=8.1 Hz, 1H), 6.08(s, 2H), 4.01(s, 3H)
m/z 3096 [M + 1]

660

1287

3-ethyl-2-{[2-(3-fluoropyridin-2-yl)- 1H-imidazol-1-yl]methyl}-3H- imidazo[4,5-c]pyridine
(CDCl3) 8.81(s, 1H), 8.46(m, 2H), 7.64(m, 2H), 7.36(m, 1H), 7.25(s, 1H), 7.12(s, 1H), 6.11 (s, 2H), 4.38(q, J=7.2Hz, 2H), 1.20(t, J=7.2Hz, 3H)
m/z 323 [M + 1]

661

1288

1-ethyl-2-{[2-(3-fluoropyridin-2-yl)- 1H-imidazol-1-yl]methyl}-5-thien- 3-yl-1H-benzimidazole

404.3

662

1289

1-(1-propyl-2-{[2-(6-fluoropyridin- 2-yl)-1H-imidazol-1-yl]methyl}-1H- benzimidazol-5-yl)ethanone
(CDCl3) 8.38(s, 1H), 8.18(dd, 1H), 8.00(d, 1H), 7.91(q, 1H), 7.39(d, 1H), 7.24(s, 1H), 7.18 (s, 1H), 6.89(dd, 1H), 6.31(s, 2H), 4.28(t, 2H), 2.67(s, 3H), 1.69(q, 2H), 0.88(t, 3H)

663

1290

1-ethyl-2-{[2-(1,3-thiazol-2-yl)-1H- imidazol-1-yl]methyl}-6- (trifluoromethyl)-1H- benzimidazole
(CD3Cl3) 7.87(m, 2H), 7.62(s, 1H), 7.55(d, 1H), 7.41(d, 1H), 7.18(s, 1H), 7.15(s, 1H), 6.37 (s, 2H), 4.30(q, 2H), 1.14(t, 3H)

664

1291

1-ethyl-2-[(2-pyrimidin-2-yl-1H- imidazol-1-yl)methyl]-6- (trifluoromethyl)-1H- benzimidazole
(CDCl3) 8.86(d, 2H), 7.85(d, 1H), 7.62(s, 1H), 7.55(d, 1H), 7.29(m, 2H), 7.16(s, 1H), 6.39 (s, 2H), 4.28(q, 2H), 1.18(t, 3H)

665

1292

2-({2-[6-(methylamino)pyridin-2- yl]-1H-imidazol-1-yl}methyl)-1- propyl-1H-benzimidazole-5- carbonitrile

m/z 372 [M + 1]

666

1293

1-ethyl-2-{[2-(2-furyl)-1H- imidazol-1 -yl]methyl}-6- (trifluoromethyl)-1H- benzimidazole

m/z 361 [M + 1]

667

1294

1-ethyl-2-{[2-(1,3-thiazol-2-yl)-1H- imidazol-1-yl]methyl}-5- (trifluoromethyl)-1H- benzimidazole
(CDCl3) 8.14(s, 1H), 7.84(d, 1H), 7.58(d, 1H), 7.40(m, 2H), 7.18(s, 1H), 7.15(s, 1H), 6.37 (s, 2H), 4.30(q, 2H), 1.12(t, 3H)

668

1295

1-ethyl-2-[(2-pyrimidin-2-yl-1H- imidazol-1-yl)methyl]-5- (trifluoromethyl)-1H- benzimidazole
(CDCl3) 8.85(d, 2H), 8.06(s, 1H)<7.54(d, 1H), 7.40(d, 1H), 7.28(m, 2H), 7.15(s, 1H), 6.38 (s, 2H), 4.27(q, 2H), 1.15(t, 3H)

669

1296

5,6-dichloro-1-ethyl-2-{[2-(1,3- thiazol-2-yl)-1H-imidazol-1- yl]methyl}-1H-benzimidazole
(CDCl3) 7.84(m, 2H), 7.44(s, 1H), 7.34(d, 1H), 7.14(m, 2H), 6.31(s, 2H), 4.20(q, 2H), 1.06(t, 3H)

670

1297

5,6-dichloro-1-ethyl-2-[(2- pyrimidin-2-yl-1H-imidazol-1- yl)methyl]-1H-benzimidazole
(CDCl3) 8.84(d, 2H), 7.84(s, 1H), 7.43(s, 1H), 7.26(m, 2H), 7.13(s, 1H), 6.33(s, 2H), 4.18 (q, 2H), 1.10(t, 3H)

671

1298

1-ethyl-2-{[2-(1H-pyrazol-3-yl)-1H- imidazol-1-yl]methyl}-1H- benzimidazole-5-carbonitrile
(CDCl3) 7.97(s, 1H), 753(br s, 1H), 7.46(d, J=8.7Hz, 1H), 7.35(d, J=8.1Hz, 1H), 6.97(d, J=6.3Hz, 2H), 6.79(br s, 1H), 6.10(s, 2H), 4.22(q, J=7.2Hz, 2H), 0.88(t, J=7.2Hz, 3H)
m/z318 [M + 1]

672

1299

1-ethyl-6-methyl-2-{[2-(1,3- thiazol-2-yl)-1H-imidazol-1- yl]methyl}-1H-benzimidazole
(CDCl3) 7.86(d, 1H), 7.65(d, 1H), 7.39(d, 1H), 7.14(d, 1H), 7.11(m, 3H), 6.31(s, 2H), 4.16 (q, 2H), 1.02(t, 3H)

673

1300

3-ethyl-2-{[2-(1,3-thiazol-2-yl)-1H- imidazol-1-yl]methyl}-5- (trifluoromethyl)-3H-imidazo[4,5- b]pyridine
(CD3OD) 8.03(d, J=8.4Hz, 1H), 7.72(d, J=3.3Hz, 1H), 7.65(d, J=8.1Hz, 1H), 7.55(d, J=3.3Hz, 1H), 7.46(d, J=1.5 Hz, 1H), 7.20(d, J=1.5Hz, 1H), 6.3(s, 2H), 4.56(q, J=6.9Hz, 2H), 1.49(t,, J=6.9Hz, 3H)

674

1301

1-ethyl-2-{[2-(1,3-thiazol-2-yl)-1H- imidazol-1-yl]methyl}-6- (trifluoromethyl)-1H-imidazo[4,5- c]pyridine
(CD3OD) 8.83(s, 1H), 8.14(s, 1H), 7.71(d, J=2.7Hz, 1H), 7.53(d, J=2.7Hz, 1H), 7.45(d, J=0.9Hz, 1H), 7.19(d, J=0.9 Hz, 1H) 6.30(s, 2H), 4.54(q, J=5.4Hz, 2H), 1.46(t, J=5.4Hz, 3H)
m/z 379 [M + 1]

675

1302

3-ethyl-2-{[2-(1,3-thiazol-2-yl)-1H- imidazol-1-yl]methyl}-6- (trifluoromethyl)-3H-imidazo[4,5- c]pyridine
(CD3OD) 9.02(s, 1H), 7.89(s, 1H), 7.70(d, J=3Hz, 1H), 7.52 (d, J=3.3Hz, 1H), 7.46(d, J=1.5Hz, 1H), 7.19(d, J=1.5Hz, 1H), 6.29(s, 2H), 4.56(q, J=7.5 Hz, 2H), 1.52(t, J=7.5Hz, 3H)
m/z 379 [M + 1]

676

1303

1-ethyl-5-fluoro-2-{[2-(1,3-thiazol- 2-yl)-1H-imidazol-1-yl]methyl}-1H- benzimidazole
(CDCl3) 7.88(d, 1H), 7.45(dd, 1H), 7.39(d, 1H), 7.23(dd, 1H), 7.18(s, 1H), 7.12(s, 1H), 7.06 (td, 1H)

677

1304

1,6-diethyl-2-{[2-(1,3-thiazol-2-yl)- 1H-imidazol-1-yl]methyl)-1H- imidazo[4,5-c]pyridine
(CDCl3) 9.01(d, J=1.2Hz, 1H), 7.85(d, J=3.6Hz, 1H), 7.40(d, J=3.0Hz, 1H), 7.16(d, J=1.5 Hz, 1H), 7.14(d, J=0.9Hz, 1H), 7.10(s, 1H), 6.34(s, 2H), 4.22 (q, J=7.2Hz, 2H), 2.93(q, J=7.2Hz, 2H), 1.35(t, J=7.2Hz, 3H), 1.10(t, J=7.2Hz, 3H)
m/z 339 [M + 1]

678

1305

1-(2-{[2-(6-fluoropyridin-2-yl)-1H- imidazol-1-yl]methyl}-1-propyl-1H- imidazo[4,5-c]pyridin-4- yl)ethanone
(CDCl3) 9.01(d, J=1.2Hz, 1H), 7.85(d, J=3.6Hz, 1H), 7.40(d, J=3.0Hz, 1H), 7.16(d, J=1.5 Hz, 1H), 7.14(d, J=0.9Hz, 1H), 7.10(s, 1H), 6.34(s, 2H), 4.22 (q, J=7.2Hz, 2H), 2.93(q, J=7.2Hz, 2H), 1.35(t, J=7.2Hz, 3H), 1.10(t, J=7.2Hz, 3H)
m/z 339 [M + 1]

679

1306

3-ethyl-2-{[2-(1,3-thiazol-2-yl)-1H- imidazol-1-yl]methyl}-3H- imidazo[4,5-c]pyridine
(CD3OD) 8.87(s, 1H), 8.30(d, J=5.7Hz, 1H), 7.75(d, J=3.3 Hz, 1H), 7.57(d, J=4.8Hz, 1H), 7.52(d,J=3.3Hz, 1H),7.39(d, J=1.5Hz, 1H), 7.18(d, J=1.5 Hz, 1H), 6.29(s, 2H), 4.52(q, J=7.5Hz, 2H), 1.44(t, J=7.5Hz, 3H)
m/z 311 [M + 1]

680

1307

1-ethyl-5-fluoro-6-methyl-2-{[2- (1,3-thiazol-2-yl)-1H-imiciazol-1- yl]methyl}-1H-benzimidazole
(CDCl3) 7.86(d, 1H), 7.40(m, 2H), 7.15(d, 1H), 7.11(d, 1H), 7.07(d, 1H), 6.30(s, 2H), 4.17 (q, 2H), 2.39(d, 3H), 1.03(t, 3H)

681

1308

4-(1-ethyl-2-{[2-(1,3-thiazol-2-yl)- 1H-imidazol-1-yl]methyl}-1H- benzimiciazol-5-yl)-2- methylbutan-2-ol
(CDCl3) 7.85(d, 1H), 7.60(s, 1H), 7.38(d, 1H), 7.22(m, 1H), 7.15(m, 2H), 7.09(s, 1H), 6.31 (s, 2H), 4.17(q, 2H), 2.80(m, 2H), 1.81(m, 2H), 1.22(d, 6H), 1.01(t, 3H)
m/z 396.3 [M + 1]

682

1309

1-(1-ethyl-2-{[2-(1,3-thiazol-2-yl)- 1H-imidazol-1-yl]methyl}-1H- benzimidazol-5-yl)-4- hydroxypentan-1-one
(CDCl3) 8.44 (d, 1H), 7.80(dd, 1H), 7.85(d, 1H), 7.40(d, 1H), 7.36(d, 1H), 7.18(d, 1H), 7.14 (d, 1H), 6.36(s, 2H), 4.27(q 2H), 3.86(m, 1H), 3.19(t, 2H), 1.93(m, 2H), 1.25(d, 3H), 1.09 (t, 3H)
m/z 410.2 [M + 1]

683

1310

1-ethyl-6-isobutyl-2-{[2-(1,3- thiazol-2-yl)-1H-imidazol-1- yl]methyl}-1H-imidazo[4,5- c]pyridine
(CDC13) 9.02(s, 1H), 7.85(d, 1H), 7.40(d, 1H), 7.18(s, 1H), 7.15(s, 1H), 7.06(s, 1H), 6.35 (s, 2H), 4.22(q, 2H), 2.75(d, 1H), 2.1(m, 1H), 1.10(t, 3H), 0.93(d, 6H)

684

1311

1-ethyl-6-isopropyl-2-{[2-(1,3- thiazol-2-yl)-1H-imidazol-1- yl]methyl}-1H-imidazo[4,5- c[pyridine
(CDCl3) 9.01(s, 1H), 7.83(d, J=3.2Hz, 1H), 7.38(d, J=3.2Hz, 1H), 7.15(s, 1H), 7.12(s, 1H), 7.09(s, 1H), 6.32(s, 2H), 4.21 (q, J=7.2Hz, 2H), 3.17(sept, J=6.8Hz, 1H), 1.34(d, J=6.8 Hz, 6H), 1.10(t, J=7.2Hz, 3H)
m/z 353 [M + 1]

685

1312

3-ethyl-6-isobutyl-2-{[2-(1,3- thiazol-2-yl)-1H-imidazol-1- yl]methyl}-3H-imidazo[4,5- c]pyridine
(CDCl3) 8.70(s, 1H), 7.85(d, 1H), 7.41(s, 1H), 7.40(d, 1H), 7.20(s, 1H), 7.15(s, 1H), 6.34 (s, 2H), 4.33(q, 2H), 2.75(d, 1H), 2.1(m, 1H), 1.19(t, 3H), 0.93(d, 6H)

686

1313

1-(1-ethyl-2-{[2-(1,3-thiazol-2-yl)- 1H-imidazol-1-yl]methyl}-1H- benzimidazol-6-yl)ethanone
(CDCl3) 8.05(d, 1H), 7.92(dd, 1H), 7.87(dd, 1H), 7.81(dd, 1H), 7.40(d, 1H), 7.20(d, 1H), 7.14 (d, 1H), 6.17(s, 2H), 4.33(q, 2H), 2.67(s, 3H), 1.13(t, 3H)

687

1314

4-(1-ethyl-2-{[2-(1,3-thiazol-2-yl)- 1H-imidazol-1-yl]methyl}-1H- benzimidazol-6-yl)-2- methylbutan-2-ol
(CDCl3) 7.88(d, 1H), 7.68(d, 1H), 7.39(d, 1H), 712-7.18(m, 3H), 7.09(d, 1H), 6.13(s, 2H), 4.19(q, 1H), 2.80-2.89(m, 2H), 1.80-1.89(m, 2H), 1.31(s, 6H), 1.06(t, 3H)

688

1315

1-ethyl-2-{[2-(1,3-thiazol-2-yl)-1H- imidazol-1-yl]methyl}-1H- benzimidazole-6-carbonitrile
(CD3OD) (2HCl Salt) 8.38(s, 1H), 7.98-8.01(m, 2H), 7.95(d, 1H), 7.87(d, 1H), 7.71(d, 2H), 6.50(s, 2H), 4.62(q, 2H), 1.62(t, 3H)

689

1316

1-ethyl-2-[(2-pyrimidin-2-yl-1H- imidazol-1-yl)methyl]-1H- benzimidazole-5-carbonitrile
(CD3OD) (2HCl Salt) 8.88(d, 2H), 8.08(d, 1H), 7.95(d, 1H), 7.93(d, 1H), 7.90(s, 1H), 7.73 (dd, 1H), 7.56(t, 1H), 6.60(s, 2H), 4.61(q, 2H), 1.63(t, 3H)

690

1317

1-ethyl-2-[(2-pyrimidin-2-yl-1H- imidazol-1-yl)methyl]-1H- benzimidazole-6-carbonitrile
(CDCl3) 8.85(d, 2H), 7.82(d, 1H), 7.69(d, 1H), 7.55(dd, 1H), 7.26-7.30(m, 2H), 7.18(d, 1H), 6.39(s, 2H), 4.29(q, 2H), 1.09(t, 3H)

691

1318

4-chloro-1-(1-ethyl-2-{[2-(1,3- thiazol-2-yl)-1H-imidazol-1- yl]methyl}-1H-benzimidazol-5-yl)- 4-methylpentan-1-one

m/z 442.2 [M − 1]444.1 [M + 1]

692

1319

1-ethyl-2-[(2-pyrimidin-2-yl-1H- imidazol-1-yl)methyl]-6- (trifluoromethyl)-1H-imidazo[4,5- c]pyridine
(CD3OD) 8.79(s, 1H), 8.70(d, J=5.1Hz, 1H), 8.17(a, 1H), 7.52 (d, J=1.2Hz, 1H), 7.31(d, J=1.2Hz, 1H), 7.27(t, J=5.1Hz, 1H), 6.63(s, 1H), 6.32(s, 2H), 4.57(q, J=7.5Hz, 2H), 1.50(t,, J=7.5Hz, 3H)
m/z 374 [M + 1]

693

1320

2-{1-[(5-acetyl-1-ethyl-1H- benzimidazol-2-yl)methyl]-1H- imidazol-2-yl}-1,3-thiazole-4- carbonitrile
(CDCl3+CD3OD) 8.29(s, 1H), 8.25(d, 1H), 7.97(dd, 1H), 7.52 (d, 1H), 7.42(s, 1H), 7.22(s 1H), 6.17(s, 2H), 4.44(q, 2H), 2.64(s, 3H), 1.43(t, 3H)
m/z 377 [M + 1]

694

1321

5-bromo-1-ethyl-2-[(2-pyrimidin-2- yl-1H-imidazol-1-yl)methyl]-1H- benzimidazole
(CDCl3) 8.85(d, 2H), 7.91(d, 1H), 7.39(dd, 1H), 7.27(t, 1H), 7.25(m, 1H), 7.19(d, 1H), 7.13 (d, 1H), 6.35(s, 2H), 4.20(q, 2H), 1.08(t, 3H)

695

1322

1-(3-ethyl-2-{[2-(1,3-thiazol-2-yl)- 1H-imidazol-1-yl]methyl}-3H- imidazo[4,5-c]pyridin-6- yl)ethanone
(CDCl3) 8.79(d, 2H), 8.47(d, 1H), 7.83(d, 1H), 7.40(d, 1H), 7.19(d, 1H), 7.15(d, 1H), 6.39 (s, 2H), 4.02(q, 2H), 2.77(s, 3H), 1.86(t, 3H)
m/z 353.2 [M + 1]

696

1323

3-ethyl-6-methyl-2-{[2-(1,3- thiazol-2-yl)-1H-imidazol-1- yl]methyl}-3H-imidazo[4,5- c]pyridine
(CDCl3)8.67(s, 1H), 7.83(d, J=3.0Hz, 1H), 7.5(s, 1H), 7.38(d, J=3.0Hz, 1H), 7.18(d, J=1.2 Hz, 1H), 7.14(d, J=1.2Hz, 1H), 6.33(s, 2H), 4.32(q, J=7.5Hz, 2H), 1.16(t, J=7.5Hz, 3H)
m/z 325 [M + 1]

697

1324

1-ethyl-5-pyridin-2-yl-2-[(2- pyrimidin-2-yl-1H-imidazol-1- yl)methyl]-1H-benzimidazole

m/z 382.2 [M + 1]

698

1325

1-ethyl-6-methyl-2-{[2-(1,3- thiazol-2-yl)-1H-imidazol-1- yl]methyl}-1H-imidazo[4,5- c]pyridine
(CDCl3) 8.96(d, J=0.9Hz, 1H), 7.84(d, J=33Hz, 1H), 7.39(d, J=3.0Hz, 1H), 7.16(d, J=0.9 Hz, 1H), 7.13(d, J=1.5Hz, 1H) 7.10(s, 1H), 6.33(s, 2H), 4.21 (q, J=7.2Hz, 2H), 2.66,(s, 2H), 1.09(t, J=7.2Hz, 3H)
m/z 325 [M + 1]

699

1326

6-(cyclopentylmethyl)-1-ethyl-2- {[2-(1,3-thiazol-2-yl)-1H-imidazol- 1-yl]methyl}-1H-imidazo[4,5- c]pyridine
(CDCl3) 9.01(s, 1H), 7.85(d, 1H), 7.41(d, 1H), 7.18(d, 1H), 7.15(d, 1H), 7.08(s, 1H), 6.36 (s, 2H), 4.22(q, 2H), 2.86(d, 2H), 2.25-2.40(m, 1H), 1.46-1.78 (m, 6H), 1.15 1.30(m, 2H), 1.08 (t, 3H)

700

1327

6-(cyclopentylmethyl)-3-ethyl-2- {[2-(1,3-thiazol-2-yl)-1H-imidazol- 1-yl]methyl}-3H-imidazo[4,5- c]pyridine
(CDCl3) 8.68(s, 1H), 7.84(d, 1H), 7.48(s, 1H), 7.41(d, 1H), 7.20(s, 1H), 7.15(s, 1H), 6.14 (s, 2H), 4.32(q, 2H), 2.88(d, 2H), 2.25-2.38(m, 1H), 1.45-72 (m, 6H), 1.16-1.33(m, 5H)

701

1328

3-ethyl-6-isopropyl-2-{[2-(1,3- thiazol-2-yl)-1H-imidazol-1- yl]methyl}-3H-imidazo[4,5- c]pyridine
(CDCl3) 8.70(d, J=1.2Hz, 1H), 7.83(d, J=3.0Hz, 1H), 7.53(d, J=0.9Hz, 1H), 7.39(d, J=3.0 Hz, 1H), 7.18(d, J=0.9Hz, 1H), 7.14(d, J=0.9Hz, 1H), 6.32(s, 2H), 4.32(q, J=7.2Hz, 2H), 3.18(sept, J=6.9Hz, 1H), 1.34 (d, J=6.9Hz, 6H), 1.17(t, J=
m/z 353 [M + 1]

702

1329

1-ethyl-2-[(2-pyrimidin-2-yl-1H- imidazol-1-yl)methyl]-1H- benzimidazole

m/z 305 [M + 1]

703

1330

6-chloro-1-ethyl-2-[(2-pyrimidin-2- yl-1H-imidazol-1-yl)methyl]-1H- benzimidazole
m/z 339 [M + 1]

704

1331

1-ethyl-6-methyl-2-[(2-pyrimidin- 2-yl-1H-imidazol-1-yl)methyl]-1H- benzimidazole

m/z 319 [M + 1]

705

1332

1-ethyl-5-fluoro-2-[(2-pyrimidin-2- yl-1H-imidazol-1-yl)methyl]-1H- benzimidazole

m/z 323 [M + 1]

706

1333

5-chIoro-1-ethyl-2-[(2-pyrimidin-2- yl-1H-imidazol-1-yl)methyl]-1H- benzimidazole

m/z 339 [M + 1]

707

1334

3-ethyl-6-propyl-2-{[2-(1,3-thiazol- 2-yl)-1H-imidazol-1-yl]methyl}-3H- midazo[4,5-c]pyridine
(CDCl3) 8.69(d, J=0.9Hz, 1H), 7.83(d, J=3.3Hz, 1H), 7.49(d, J=1.2Hz, 1H), 7.39(d, J=3.6 Hz, 1H), 7.18(d, J=0.9Hz, 1H), 7.14(d, J=1.5Hz, 1H), 6.33(s, 2H), 4.31(q, J=7.2Hz, 2H), 2.86(m, 2H), 1.78(sext, J=7.2 Hz, 2H), 1.17(t, J=7.2Hz, 3H),

#0.97(t, J=7.2Hz, 3H)
m/z 353 [M + 1]

708

1335

1-ethyl-6-propyl-2-{[2-(1,3-thiazol- 2-yl)-1H-imidazol-1-yl]methyl}-1H- imidazo[4,5-c]pyridine
(CDCl3) 9.00(d, J=0.9Hz, 1H), 7.84(d, J=3.0Hz, 1H), 7.39(d, J=3.3Hz, 1H), 7.16(d, J=1.5 Hz, 1H), 7.13(d, J=1.5Hz, 1H), 7.09(s, 1H), 6.33(s, 2H), 4.22 (q, J=7.2Hz, 2H), 2.86(m, 2H), 1.79(sext, J=7.2Hz, 2H), 1.09 (t, J=7.2Hz, 3H), 0.96(t, J=

#7.2Hz, 3H)
m/z 353 [M + 1]

709

1336

3,6-diethyl-2-{[2-(1,3-thiazol-2-yl)- 1H-imidazol-1-yl]methyl}-3H- imidazo[4,5-c]pyridine
(CDCl3) 8.69(d, J=0.9Hz, 1H), 7.84(d, J=3.6Hz, 1H), 7.51(s, 1H), 7.39(d, J=3.6Hz, 1H), 7.18(d, J=1.5Hz, 1H), 7.14(d, J=0.9Hz, 1H), 6.33(s, 2H), 4.32(q, J=7.2Hz, 2H), 2.93(q, J=7.2Hz, 2H), 1.34(t, J=7.2 Hz, 3H), 1.17(t, J=7.2Hz, 3H)
m/z 339 [M + 1]

710

1337

1-ethyl-5-fluoro-6-methyl-2-[(2- pyrimidin-2-yl-1H-imidazol-1- yl)methyl]-1H-benzimidazole

m/z 337.4 [M + 1]

711

1338

1-ethyl-2-{[2-(2-fluoro-6- methoxyphenyl)-1H-imidazol-1- yl]methyl}-1H-imidazo[4,5- c]pyridine
(CDCl3) 9.04(d, J=0.9Hz, 1H), 8.42(d, J=5.4Hz, 1H), 7.46-7.38(m, 1H), 7.25-7.22(m, 2H), 7.00(d, J=0.9Hz, 1H), 6.85-6.76(m, 2H), 5.31, 5.22(AB, J=15.3Hz, 2H), 3.85(q, J=7.2Hz, 2H), 3.77(s, 3H), 1.00(t, J=7.2 Hz, 3H)
m/z 352 [M + 1]

712

1339

1-ethyl-2-[(2-pyrimidin-2-yl-1H- imidazol-1-yl)methyl]-1H- imidazo[4,5-c]pyridine
(CDCl3) 9.09(s, 1H), 8.85(d, 2H), 8.46(d, 1H), 7.26-7.30(m, 3H), 7.16(1H), 6.39(s, 2H), 4.25 (q, 2H), 1.15(t, 3H)

713

1340

1-ethyl-6-methyl-2-[(2-pyrimidin- 2-yl-1H-imidazol-1-yl)methyl]-1H- imidazo[4,5-c]pyridine
(CDCl3) 8.95(d, J=1.2Hz, 1H), 8.84(d, J=4.8Hz, 2H), 7.27(t, J=5.1Hz, 1H), 7.25(d, J=1.2 Hz, 1H), 7.13(d, J=1.2 Hz 1H), 7.10(s, 1H), 6.35(s, 2H), 4.19 (q, J=7.2Hz, 2H), 2.65(s, 3H), 1.12(t, J=7.2Hz, 3H)
m/z 320 [M + 1]

714

1341

3-ethyl-2-[(2-pyrimdin-2-yl-1H- imidazol-1-yl)methyl]-3H- imidazo[4,5-c]pyridine
(DMSO) 8.94(s, 1H), 8.71(d, J=5.1Hz, 2H), 8.22(d, J=5.7 Hz, 1H), 7.53(d, J=1.2Hz, 1H), 7.43(d, J=5.4Hz, 1H), 7.31(t, J=4.5Hz, 1H), 7.17(d, J=1.2 Hz, 1H), 6.22(s, 2H), 4.46(q, J=7.5Hz, 2H), 1.39(t,, J=7.5 Hz, 3H)
m/z 306 [M + 1]

715

1342

3-ethyl-2-[(2-pyrimidin-2-yl-1H- imidazol-1-yl)methyl]-3H- imidazo[4,5-c]pyridine-4- carbonitrile
(CD3OD) 8.70(d, J=5.1Hz, 2 H), 8.41(d, J=5.4Hz, 1H), 7.73 (d, J=5.1Hz, 1H), 7.52(d, J=1.2Hz, 1H), 7.31(d, J=1.2 Hz, 1H), 7.27(t, J=4.5Hz, 1H) 6.35 (s, 2H), 4.75(q, J=7.5Hz, 2H), 1.63(t,, J=7.2Hz, 3H)
m/z 331 [M + 1]

716

1343

1-ethyl-6-isopropyl-2-[(2- pyrimidin-2-yl-1H-imidazol-1- yl)methyl]-1H-imidazo[4,5- c]pyridine
(CDCl3) 9.01(d, J=0.9Hz, 1H), 8.84(d, J=4.8Hz, 2H), 7.28(t, J=4.8Hz, 1H), 7.25(d, J=1.2 Hz, 1H), 7.13(d, J=0.9Hz, 1H), 7.10(d, J=0.9Hz, 1H), 6.35(s, 2H), 4.21(q, J=7.2Hz, 2H), 3.17(sept, J=6.9Hz, 1H), 1.34 (d, J=6.9Hz, 6H), 1.13(t, J=7.2Hz, 3H)
m/z 348 [M + 1]

717

1344

{1-ethyl-2-[(2-pyrimidin-2-yl-1H- imidazol-1-yl)methyl]-1H- benzimidazol-5- yl}(phenyl)methanone
(CDCl3) 8.84(d, 2H), 8.20(s, 1H), 7.80-7.90(m, 3H), 7.40-7.60 (m, 4H), 7.3(m, 3H), 7.18(s, 1H), 6.38(s, 2H), 4.25(q, 2H), 1.22(t, 3H)

718

1345

1-{1-ethyl-2-[(2-pyrimidin-2-yl-1H- imidazol-1-yl)methyl]-1H- benzimidazol-6-yl}ethanone
(CDCl3) 8.84(d, 2H), 8.03(s, 1H), 7.90(d, 1H), 7.78(d, 1H), 7.25-7.28(m, 2H), 7.18(s, 1H), 6.38(s, 2H), 4.48(q, 2H), 2.66 (s, 3H), 1.08(t, 3H)

719

1346

1-ethyl-6-fluoro-2-[(2-pyrimidin-2- yl-1H-imidazol-1-yl)methyl]-1H- benzimidazole
(CDCl3) 8.87(d, J=5.1Hz, 1H), 7.71(q, J=4.5Hz, 1H), 7.27 (m, 3H), 7.14(s, 1H), 7.03(m, 2H), 6.34(s, 2H), 4.18(q, J=7.5 Hz, 2H), 1.11(t,, J=7.5Hz, 3H)
m/z 323 [M + 1]

720

1347

1-ethyl-6-fluoro-2-{[2-(1,3-thiazol- 2-yl)-1H-imidazol-1-yl]methyl}-1H- benzimidazole
(CDCl3) 7.86(d, J=3.3Hz, 1H), 7.70(q, J=4.8Hz, 1H), 7.40(d, J=3Hz, 1H), 7.25(s, 1H), 7.16 (d, J=1.2Hz, 1H), 7.01(m, 2H), 6.32(s, 2H), 4.19(q, J=6.9 Hz, 2H), 1.06(t,, J=7.5Hz, 3H)
m/z 328 [M + 1]

721

1348

1-ethyl-5-phenyl-2-[(2-pyrimidin- 2-yl-1H-imidazol-1-yl)methyl]-1H- benzimidazole

m/z 381.5 [M + !]

722

1349

6-(cyclopentylmethyl)-1-ethyl-2- [(2-pyrimidin-2-yl-1H-imidazol-1- yl)methyl]-1H-imidazo[4,5- c]pyridine
(CDCl3) 9.00(s, 1H), 8.86(d, 2H), 7.25-7.31(m, 2H), 7.15(s, 1H), 7.08(s, 1H), 6.37(s, 2H), 4.20(q, 2H), 2.87(d, 2H), 2.25 2.40(m, 1H), 1.42-1.78(m, 6H), 1.15-1.30(m, 2H), 1.13(t, 3H)

723

1350

6-(cyclopentylmethyl)-3-ethyl-2- [(2-pyrimidin-2-yl-1H-imidazol-1- yl)methyl]-3H-imidazo[4,5- c]pyridine
(CDCl3) 8.85(d, 2H), 8.69(s, 1H), 7.47(s, 1H), 7.25-7.29(m, 2H), 7.18(s, 1H), 638(s, 2H), 4.30(q, 2H), 2.88(d, 2H), 2.22-2.39(m, 1H), 1.42-1.78(m, 6H), 1.20-1.33(m, 5H)

724

1351

1-ethyl-5-isopropyl-2-[(2- pyrimidin-2-yl-1H-imidazol-1- yl)methyl]-1H-benzimidazole
(CDCl3) 8.85(d, 2H), 7.63(d, 1H), 7.24(m, 2H), 7.21(m, 2H), 7.13(d, 1H), 6.33(s, 2H), 4.14 (q, 2H), 3.02(m, 1H), 1.29(d. 6H), 1.08(t, 3H)

725

1352

1-ethyl-6-(2-fluorophenyl)-2-[(2- pyrimidin-2-yl-1H-imidazol-1- yl)methyl]-1H-benzimidazole
(CDCl3) 8.87(d, J=4.8Hz, 2H), 7.85(d, J=8.4Hz, 1H), 7.48(m, 3H), 7.22(m, 6H), 6.39(s, 2H), 4.25(q, J=7.2Hz, 2H), 1.16(t, J=7.2Hz, 3H)
m/z 399 [M + 1]

726

1353

1-ethyl-2-{[2-(1,3-thiazol-2-yl)-1H- imidazol-1-yl]methyl}-6-[4- (trifluoromethyl)phenyl]-1H- benzimidazole
(DMSO) 7.95(m, 3H), 7.79(m, 3H), 7.70(d, J=3.3Hz, 1H), 7.59(d, J=8.7Hz, 1H) ,7.52(s, 1H), 7.48(s, 1H), 6.19(s, 2H), 4.43(q, J=7.2Hz, 2H), 1.34(t, J=7.2Hz, 3H)
m/z 454 [M + 1]

727

1354

1-ethyl-2-[(2-pyrimidin-2-yl-1H- imidazol-1-yl)methyl]-6-[4- (trifluoromethyl)phenyl]-1H- benzimidazole
(CDCl3) 8.87(d, J=4.8Hz, 2H), 8.00(s, 1H), 7.86(d, J=8.4Hz, 1H), 7.71(m, 3H), 7.52(m, 2H), 7.27(t, J=4.8Hz, 1H), 7.25(s, 1H), 7.17(s, 1H), 6.39(s, 2H), 4.28(q, J=6.9Hz, 2H), 1.16(t, J=6.9Hz, 3H)
m/z 449 [M + 1]

728

1355

6-isopropyl-3-propyl-2-{[2-(1,3- thiazol-2-yl)-1H-imidazol-1- yl]methyl}-3H-imidazo[4,5- c]pyridine
(CDCl3) 8.69(d, J=1.2Hz, 1H), 7.83(d, J=3.3Hz, 1H), 7.52(s, 1H), 7.39(d, 3.0Hz, 1H), 7.21 (d, J=1.5Hz, 1H), 7.13(d, J=0.9Hz, 1H), 6.33(s, 2H), 4.21 (m, 2H), 3.18(sept, J=6.9 Hz 1H), 1.61(sext, J=7.2Hz, 2H), 1.34(d, J=6.9Hz, 6H), 0.77(t,

#J=7.2 Hz, 3H)
m/z 367 [M + 1]

729

1356

6-isopropyl-1-propyl-2-{[2-(1,3- thiazol-2-yl)-1H-imidazol-1- yl]methyl}-1H-imidazo[4,5- c]pyridine
(CDCl3) 9.01(d, J=0.9Hz, 1H), 7.85(d, J=3.6Hz, 1H), 7.39(d, J=3.6Hz, 1H), 7.18(d, J=0.9 Hz, 1H), 7.12(d, J=0.9Hz, 1H), 7.07(s, 1H), 6.33(s, 2H), 4.10 (m, 2H), 3.16(sept, J=6.9Hz, 1H), 1.52(sext, J=7.2Hz, 2H), 1.34(d, J=6.9Hz, 6H), 0.75(t, J=7.2Hz, 3H)
m/z 367 [M + 1]

730

1357

3-ethyl-6-phenyl-2-{[2-(1,3- thiazol-2-yl)-1H-imidazol-1- yl]methyl}-3H-imidazo[4,5- c]pyridine
(CDCl3) 8.85(d, 1H), 8.08(d, 1H), 8.02(d, 1H), 7.99(m, 1H), 7.84(d, 1H), 7.48(m, 2H), 7.40 (m, 2H), 7.22(d, 1H), 7.17(d, 1H), 6.36(s, 2H), 4.38(q, 2H), 1.22(t, 3H)
m/z 387.4 [M + 1]

731

1358

3-(2-fluoroethyl)-2-[(2-pyrimidin-2- yl-1H-imidazol-1-yl)methyl]-3H- imidazo[4,5-c]pyridine
(CD3OD) 8.91(s, 1H), 8.69(d, J=5.1Hz, 2H), 8.28(d, J=5.7 Hz, 1H), 7.52(m, 2H), 7.30(s, 1H), 7.26(t, J=4.8Hz, 1H), 6.25(s, 2H)
m/z 324 [M + 1]

732

1359

3-(1-ethyl-2-{[2-(1,3-thiazol-2-yl)- 1H-imidazol-1-yl]methyl)-1H- benzimidazol-6-yl)benzonitrile
(DMSO) 8.24(s, 1H), 8.09(d, J=7.8Hz, 1H), 8.0(s. 1H), 7.76 (m, 2H), 7.61(m, 5H), 7.11(s, 1H), 6.18(s, 2H), 4.42(q, J=7.5 Hz, 2H), 1.34(t, J=7.5Hz, 3H)
m/z 411 [M + 1]

733

1360

3-{1-ethyl-2-[(2-pyrimidin-2-yl-1H- imidazol-1-yl)methyl]-1H- benzimidazol-6-yl}benzonitrile
(DMSO) 8.76(d, J=5.1Hz, 2H), 8.24(s, 1H), 8.07(d, J=8.4Hz, 1H), 7.99(s, 1H), 7.77(d, J=7.8 Hz, 1H), 7.64(t,, J=8.1Hz, 1H), 7.50(m, 3H), 7.34(t, J=4.8Hz, 1H), 7.17(s, 1H), 6.17(s, 2H), 4.42(q, J=6.9Hz, 2H), 1.34(t, J=6.0Hz, 3H)
m/z 406 [M + 1]

734

1361

1-ethyl-2-{[2-(1,3-thiazol-2-yl)-1H- imidazol-1-yl]methyl}-5- (trifluoromethoxy)-1H- benzimidazole
(CDCl3) 7.86(d, 1H), 7.66(s, 1H), 7.40(d, 1H), 7.33(d, 1H), 7.26(d, 2H), 7.14(s, 1H), 6.34 (s, 2H), 4.26(q, 2H), 1.10(t, 3H)
m/z 394 [M + 1]

735

1362

1-ethyl-2-[(2-pyrimidin-2-yl-1H- imidazol-1-yl)methyl]-5- (trifluoromethoxy)-1H- benzimidazole
(CDCl3) 8.84(d, 2H), 7.63(s, 1H), 7.25-7.28(m, 3H), 7.15(d, 2H), 6.35(s, 2H), 4.22(q, 2H), 1.13(t, 3H)

736

1363

3-ethyl-2-{[2-(6-fluoropyridin-2-yl)- 1H-imidazol-1-ylJmethyl}-6- isopropyl-3H-imidazo[4,5- c]pyridine
(CDCl3) 8.71(d, J=1.2Hz, 1H), 8.17(dd, J=7.7, 1.7Hz, 1H), 7.88(q, J=7.9Hz, 1H), 7.51(d, J=0.9Hz, 1H), 7.21(d, J=0.9 Hz, 1H), 7.18(d, J=1.5Hz, 1H), 6.88(dd, J=8.3, 2.0Hz, 1H), 6.26(s, 2H), 4.42(q, J=7.2Hz, 2H), 3.17(sept, J=6.9Hz, 1H),

#1.33(d, J=6.9Hz, 6H), 1.30(t, J=7.2Hz, 3H)
m/z 365 [M + 1]

737

1364

1-ethyl-2-{[2-(6-fluoropyridin-2-yl)- 1H-imidazol-1-yl]methyl}-6- isopropyl-1H-imidazo[4,5- c]pyridine
(CDCl3) 8.99(d, J=0.9Hz, 1H), 8.16(dd, J=7.8, 1.5Hz, 1H), 7.88(q, J=7.8Hz, 1H), 7.18(d, J=0.9Hz, 1H), 7.16(d, J=1.5 Hz, 1H), 7.11(d, 0.9Hz, 1H), 6.89(dd, J=7.8, 2.4Hz, 1H), 6.27(s, 2H), 4.33(q, J=7.2Hz, 2H), 3.17(sept, J=6.9Hz, 1H),

#1.35(d, J=6.9Hz, 6H), 1.23(t, J=7.2Hz, 3H)
m/z 365 [M + 1]

738

1365

3-ethyl-2-{[2-(6-fluoropyridin-2-yl)- 1H-imidazol-1-yl]methyl}-6-propyl- 3H-imidazo[4,5-c]pyridine
(CDCl3) 8.70(d, J=0.9Hz, 1H), 8.17(dd, J=8.0, 2.6Hz, 1H), 7.89(q, J=7.8Hz, 1H), 7.47(s, 1H), 7.22(d, J=0.9Hz, 1H), 7.18(d, J=1.5Hz, 1H), 6.88 (dd, J=8.6, 2.9Hz, 1H), 6.27(s, 2H), 4.42(q, J=7.2Hz, 2H), 2.86(m, 2H), 1.78(sextet, J=

#7.2Hz, 2H), 1.30(t, J=7.2Hz
m/z 365 [M + 1]

739

1366

(CD3OD) 8.60(d, J=4.5Hz, 1H), 8.09(s, 1H), 7.88(m, 4H), 7.68(d, J=8.4Hz, 1H), 7.57(d J=3.3Hz, 1H), 7.34(m, 2H), 7.15(s, 1H), 6.31(s, 2H), 4.45 (q, J=7.5Hz, 2H), 1.32(1, J=7.5Hz, 3H)
m/z 387 [M + 1]

740

1367

(CD3OD) 8.77(m, 2H), 8.14(s, 1H), 7.91(m, 2H), 7.81(d, J=8.4Hz, 1H), 7.62(d, J=8.4Hz, 1H), 7.45(s, 1H), 7.32(m, 4H), 6.30(s, 2H), 4.50(q, J=7.2Hz, 2H), 1.42(t, J=7.2Hz, 3H)
m/z 382 [M + 1]

741

1368

(CD3OD) 8.11(s, 1H), 7.78-7.91 (m, 3H), 7.55-7.62(m, 4H), 7.42 (d, J=1.5Hz, 1H), 6.25(s, 2H), 4.46(q, J=7.5Hz, 2H), 1.37(t, J=7.5Hz, 3H)
m/z 393 [M + 1]

742

1369

1-ethyl-2-{[2-(3-fluorophenyl)-1H- imidazol-1-yl]methyl}-1H- benzimidazole

321.3 [M + 1]

743

1370

2-{[2-(6-fluoropyridin-2-yl)-1H- imidazol-1-yl]methyl}-1-propyl-1H imidazo[4,5-b]pyridine
(HCl salt) H-1 NMR(dmso): 1.05 (t, 3H), 2.03(h, 2H), 4.62(t, 2H), 6.58(s, 2H), 7.24(d, 1H), 7.82(t, 1H), 7.95(s, 1H), 8.05(m, 2H), 8.25(q, 1H), 8.62(d, 1H), 8.93(d, 1H)
337 [M + 1]

744

1371

3-ethyl-5-fluoro-2-{[2-(3- fluorophenyl)-1H-imidazol-1- yl]methyl}-3H-imidazo[4,5- b]pyridine
dihydrochioride 1H NMR(d6 DMSO): 8.18(1H, t), 7.99(1H, d), 7.94(1H, d), 7.72-7.69(1H, m), 7.66-7.61(1H, m), 7.58-7.50(2H, m), 7.03(1H, d), 5.96(2H, s), 4.23(2H, q), 1.31(3H, s)
340.2 [M + 1]

745

1372

3-ethyl-2-{[2-(6-fluoropyridin-2-yl)- 1H-imidazol-1-yl]methyl}-3H- imidazo[4,5-b]pyridine

1
H NMR, δppm(CDCl3): 8.39(dd, 1H), 8.19(m, 1H), 8.02(dd, 1H), 7.89(m, 1H), 7.20-7.26(m, 3H), 6.89(m, 1H), 6.32(s, 2H), 4.47(q, 2H), 1.30(t, 3H)
323.3 [M + 1]

746

1373

1-ethyl-2-{[2-(6-fluoropyridin-2-yl)- 1H-imidazol-1-yl]methyl}-1H- imidazo[4,5-b]pyridine
(HCl salt) H-1 NMR(dmso): 1.63(t, 3H), 4.72(q, 2H), 6.58(s, 2H), 7.30(d, 1H), 7.82(m, 1H), 7.96(s, 1H), 8.03(m, 2H), 8.24(q, 1H), 8.60(d, 1H), 8.90(d, 1H)
323 [M + 1]

747

1374

2-{[2-(6-fluoropyridin-2-yl)-1H- imidazol-1-yl]methyl}-N,N- dimethyl-1-propyl-1H- benzimidazole-5-carboxamide
CDCl3. 8.17(d, J=7.42Hz, 1H), 7.85-7.92(m, 1H), 7.80(s, 1H), 7.34-7.42(m, 2H). 7.21(s, 1H), 7.15(s, 1H), 6.89(d, J=7.97Hz, 1H), 6.29(s, 2H), 4.21-4.26(m, 2H), 3.04-3.11(br d, 6H), 1.61-1.69 (m, 2H), 0.80(t, J=7.42Hz, 3H).

748

1375

2-{[2-(6-fluoropyridin-2-yl)-1H- imidazol-1-yl]methyl}-5-(5-methyl- 1,2,4-oxadiazol-3-yl)-1-propyl-1H- benzimidazole
d6-DMSO: 7.94-8.09(m, 3H), 7.82 (d, 1H), 7.76(d, 1H), 7.47(s, 1H), 7.18(s, 1H), 7.03(d, 1H), 6.15(s, 2H), 4.35(t, 2H), 2.65(s, 3H), 1.74-1.82(m, 2H), 0.94(t, 3H).
418.3 [M + 1]; 416.2 [M − 1]

749

1376

2-{[2-(6-fluoropyridin-2-yl)-1H- imidazol-1-yl]methyl)-5-(5-methyl- 1,3,4-oxadiazol-2-yl)-1-propyl-1H- benzimidazole
CDCl3: 8.36(s, 1H), 8.18(dd, 1H), 8.03(dd, 1H), 7.89(q, 1H), 7.44(d, 1H), 7.25(s, 1H), 7.17(s, 1H), 6.90 (dd, 1H), 6.33(s, 2H), 4.29(t, 2H), 2.59(s, 3H), 1.59-1.74(m, 2H), 0.82(1, 3H).
418.3 [M + 1]; 416.2 [M − 1]

750

1377

2-{[2-(2,5-difluorophenyl)-1H- imidazol-1-yl]methyl}-3-ethyl-5- fluoro-3H-imidazo[4,5-b]pyridine
hydrochloride 1H NMR(d6 DMSO): 8.15(1H, t), 8.08(1H, d), 7.99(1H, d), 7.76-7.72(1H, m) 7.62-7.50(2H, m) 7.02(1H, d), 5.92(2H, s), 4.20(2H, q), 1.26(3H, t)
358.2 [M + 1]

751

1378

3-{1-[(3-ethyl-5-fluoro-3H- imidazo[4,5-b]pyridin-2-yl)methyl]1H-imidazol-2-yl}benzonitrile
hydrochloride 1H NMR(d6 DMSO): 8.30(1H, s), 8.16(1H, dd), 8.11(1H, d), 8.04(1H, d), 8.00(1H, d), 7.96(1H, d), 7.74(1H, t), 7.03(1H, d), 5.97(2H, s), 4.22(2H, q), 1.30(3H, t)
347.3 [M + 1]

752

1379

2-{[2-(6-fluoropyridin-2-yl)-1H- imidazol-1-yl]methyl}-1-propyl-1H- imidazo[4,5-c]pyridine

1
H NMR(CDCl3) δ 9.06(s, 1H), 8.42(d, 1H), 8.18(d, 1H), 7.88 (dd, 1H) 7.28(d, 1H), 7.22(d, 1 H), 7.18(d, 1H), 6.88(d, 1H), 6.29 (s, 2H), 4.26(t, 2H) 1.69(q, 2H), 0.84(t, 3H)
m/e 337

753

1380

2-{[2-(6-fluoropyridin-2-yl)-1H- imidazol-1-yl]methyl)-1-isopropyl- 1H-imidazo[4,5-c]pyridine

1
H NMR(CDCl3) δ 9.03(s, 1H), 8.35(d, 1H, 8.14(d, 1H), 7.87 (dd, 1H), 7.42(d, 1H), 7.15(d, 1 H), 7.09(d, 1H), 6.87(d, 1H), 6.28 (s, 2H, 5.08(septet, 1H), 1.49(d, 6H)
m/e 337

754

1381

2-{[2-(6-fluoropyridin-2-yl)-1H- imidazol-1-yl]methyl}-1-isobutyl- 1H-imidazo[4,5-c]pyridine

1
H NMR(CDCl3) δ 9.03(s, 1H), 8.39(d, 1H), 8.15(d, 1H), 7.85 (dd, 1H), 7.27(d, 1H), 7.24(s, 1 H), 7.17(s, 1H), 6.85(d, 1H), 6.25 (s, 2H), 4.08(d, 2H), 2.09(septet, 1H), 0.85(d, 6H)
m/e 323.

755

1382

2-{[2-(6-fluoropyridin-2-yl)-1H- imidazol-1-yl]methyl}-5-(1,2,4- oxadiazol-3-yl)-1-propyl-1H- benzimidazole
Forinate d6-DMSO: 9.62(s, 1H), 7.99-8.09(m, 3H), 7.90(d, J=8.24 Hz, 1H), 7.79(d, J=8.79Hz, 1H), 7.52(s, 1H), 7.17(s, 1H), 7.02(d, J=7.41Hz, iN), 6.16(s, 2H), 4.34-4.39(m, 2H), 1.7-1.84(m, 2H), 0.92 (t, J=7.14Hz, 3H).

756

1383

{(2S)-1-[(2-{[2-(6-fluoropyridin-2- yl)-1H-isoidazol-1-yl]methyl)-1- propyl-1H-benzimidazol-5- yl)carbonyl]pyrrolidin-2- yl}methanol
CDCl3: 8.18(d, J=7.69Hz, 1H), 7.86-7.94(m, 2H), 7.51(d, J=8.52 Hz, 1H). 7.38(d, J=8.52Hz, 1H), 7.22(s, 1H), 7.17(s, 1H), 6.9(dd, J=2.75. 8.24Hz, 1H), 6.30(s, 2H), 4.43-4.46(m, 1H), 4.23-4.28(m, 2H), 3.76-3.79(m, 2H), 3.52-3.62

#(m, 2H), 2.16-2.19(m, 1H), 1.25-1.85(m, 5H), 0.82(t, J=7.23Hz, 2H).

757

1384

3-(cyclopropylmethyl)-2-{[2-(6- fluoropyridin-2-yl)-1H-imidazol-1- yl]methyl}-3H-imidazo[4,5- b]pyridine

1
H NMR, δppm(CDCl3): 8.37(dd, 1H), 8.18(dd, 1H), 8.01(dd, 1H), 7.88(m, 1H), 7.20-7.26(m, 3H), 6.87(dd, 1H), 6.31(s, 2H), 4.3 1(d, 2H), 1.22(m, 1H), 0.42-0.53(m, 4H)
349.3 [M + 1]

758

1385

2{[2-(6-fluoropyridin-2-yl)-1H- imidazol-1-yl]methyl}-3-propyl-3H- imidazo[4,5-b]pyridine

1
H NMR, δppm(CDCl3): 8.38(dd, 1H), 8.19(m, 1H), 8.02(dd, 1H), 7.89(m, 1H), 7.20-7.26(m, 3H), 6.88(m, 1H), 6.32(s, 2H), 4.35(t, 2H), 1.74(m, 2H), 0.85(t, 3H)
337.2 [M + 1]

759

1386

5-chloro-3-ethyl-2-{[2-(3- fluorophenyl)-1H-imidazol-1- yl]methyl}-3H-imidazo[4,5- b]pyridine

356.2 [M + 1]

760

1387

5-chloro-2-{[2-(2,5- difluorophenyl)-1H-imidazol-1- yl]methyl}-3-ethyl-3H-imidazo[4,5- b]pyridine
1H NMR(CDCl3): 7.96(1H, d), 7.38-7.34(1H, m), 7.26-7.17(4H, m), 7.04(1H, d), 5.37(1H, s), 3.96(2H, q), 1.06(3H, t)
374.2 [M + 1]

761

1388

2-{[2-(6-fluoropyridin-2-yl)-1H- imidazol-1-yl]methyl}-5-(1,3,4- oxadiazol-2-yl)-1-propyl-1H- benzimidazole
CDCl3: 8.45 9s, 1H), 8.43(s, 1H), 8.19(d, J=7.14Hz, 1H), 8.10(d, J=8.38Hz, 1H), 7.90(q, J=7.96Hz, 1H), 7.48(d, J=8.52Hz, 1H), 7.19 (s, 1H), 6.89-6.92(m, 1H), 6.33(s, 2H), 4.3(t, J=7.42Hz, 2H), 1.67-1.74 9m, 2H), 0.86(t, J=7.42Hz,

#3H)
404.6 [M + 1]; 402.3 [M − 1]

762

1389

1-ethyl-2-{[2-(6-fluoropyridin-2-yl)- 1H-imidazol-1-yl]methyl}-1H- imidazo[4,5-c]pyridine

1
H NMR(CDCl3) δ 8.82(s, 1H), 8.45(d, 1H), 8.18(d, 1H), 7.88 (dd, 1H), 7.65(d, 1H), 7.23(d, 1 H), 7.20(d, 1H), 6.88(d, 1H), 6.30 (s, 2H), 4.47(q, 2H), 1.33(t, 3H)
m/e 323

763

1390

2-{[2-(6-fluoropyridin-2-yl)-1H- imidazol-1-yl]methyl}-1-(2- methoxyethyl)-1H-imidazo[4,5- c]pyridine

1
H NMR(CDCl3) δ 9,.02(s, 1H), 8.41(d, 1H), 8.16(d, 1H), 7.84 (dd, 1H), 7.36(d, 1H), 7.25(d, 1 H), 7.21(d, 1H), 6.83(d, 1H), 6.18 (s, 2H), 4.57(t, 2H), 3.56(1,2H), 3.20(s, 3H)
m/e 353

764

1391

1-ethyl-4-fluoro-2-{[2-(3- fluorophenyl)-1H-imidazol-1- yl]methyl}-1H-imidazo[4,5- c]pyridine

1
H NMR(CDCl3): 7.97(1H, dd), 7.53-7.48(1H, m), 7.44-7.38(2H. m), 7.22-7.12(3H. m), 7.04(1H, s), 5.55(2H, s), 3.75(2H, q), 0.96(3H, t)
340.1 [M + 1]

765

1392

2-{[2-(6-fluoropyridin-2-yl)-1H- imidazol-1-yl]methyl}-3-isobutyl- 3H-imidazo[4,5-b]pyridine

1
H NMR, δppm(CDCl3): 8.38(dd, 1H), 8.18(dd, 1H), 8.01(dd, 1H), 7.88(m, 1H), 7.20-7.27(m, 3H), 6.87(dd, 1H), 6.29(s, 2H), 4.21(d, 2H), 2.27(m, 1H), 0.87(d, 6H)
351.3 [M + 1]

766

1393

2-{[2-(6-fluoropyridin-2-yl)-1H- imidazol-1-yl]methyl}-3-isopropyl- 3H-imidazo[4,5-b]pyridine

1
H NMR, δppm(CDCl3): 8.36(dd, 1H), 8.18(m, 1H), 8.00(dd, 1H), 7.90(m, 1H), 7.18-7.22(m, 2H), 7.13(d, 1H), 6.89(m, 1H), 6.32(s, 2H), 5.04(m, 1H), 1.63(d, 6H)
337.2 [M + 1]

767

1394

5-chloro-3-ethyl-2-{[2-(6- fluoropyridin-2-yl)-1H-imidazol-1- yl]methyl}-3H-imidazo[4,5- b]pyridine
1H NMR(CDCl3): 8.17(1H, dd), 7.94-7.84(2H, m), 7.23-7.20(3H, m), 6.89-6.85(1H, m), 6.27(2H, s), 4.45(2H, q), 1.31(3H, t)
357.2 [M + 1]

768

1395

5-chloro-2-{[2-(4-chloropyridin-2- yl)-1H-imidazol-1-yl]methyl}-3- ethyl-3H-imidazo[4,5-b]pyridine
1H NMR(CDCl3): 8.41(1H, d), 8.35(1H, dd), 7.94(1H, d), 7.26-7.17(4H, m), 6.36(2H, s), 4.36(2H, q), 1.22(3H, t)
373.2 (M)

769

1396

5-chloro-2-{[2-(6-chloropyridin-2- yl)-1H-imidazol-1-yl]methyl}-3- ethyl-3H-imidazo[4,5-b]pyridine
1H NMR(CDCl3): 8.22(1H, d), 7.94(1H, d), 7.75(1H, t), 7.29-7.20(4H, m), 6.31(2H, s), 4.45(2H, q), 1.30(3H, t)
373.3 (M)

770

1397

2-{[2-(6-fluoropyridin-2-yl)-1H- imidazol-1-yl]methyl}-1-isobutyl- 1H-imidazo[4,5-b]pyridine
(HCl salt) H-1 NMR(dmso): 1.05 (d, 6H), 2.40(h, 1H), 4.50(d, 2H), 6.57(s, 2H), 7.30(d, 1H), 7.82(m, 1H), 7.93(s, 1H), 8.03(m, 2H), 8.23(q, 1H), 8.62(d, 1H), 8.95(d, 1H)
351 [M + 1]

771

1398

1-(cyclopropylmethyl)-2-{[2-(6- fluoropyridin-2-yl)-1H-imidazol-1- yl]methyl}-1H-imidazo[4,5- b]pyridine
(free base) H-1 NMR(CDCl3): 0.30(m, 2H), 0.57(m, 2H), 1.05(m, 1H), 4.23(d, 2H), 6.38(s, 2H), 6.80(d, 1H), 7.08(s, 1H), 7.22(m, 1H), 7.39(s, 1H), 7.73(d, 1H), 7.90(q, 1H), 8.20(d, 1H), 8.58(d, 1H)
349 [M + 1]

772

1399

1-allyl-2-{[2-(6-fluoropyridin-2-yl)- 1H-imidazol-1-yl]methyl}-1H- imidazo]4,5-b]pyridine
(HCl) salt Melting point: 225-231 (decompose) H-1 NMR(dmso): 5.22-5.53(m, 4H), 6.21(m, 1H), 6.53(s, 2H), 7.24(d, 1H), 7.82(m, 1H), 7.95(s, 1H), 8.05(m, 2H), 8.25(q, 1H), 8.62(d, 1H), 8.82(d, 1H)
335 [M + 1]

773

1400

5-fluoro-2-{[2-(6-fluoropyridin-2- yl)-1H-imidazol-1-yl]methyl}-3- propyl-3H-imidazo[4,5-b]pyridine
hydrochloride 1H NMR(d6 DMSO). 8.42(1H, d), 8.26(1H, q), 8.10-8.05(2H, m), 7.96(1H, d), 7.36(1H, dd), 6.97(1H, d), 6.33(2H, s), 4.30(2H, t), 1.90-1.83(2H, m), 0.93(3H, t)

774

1401

1-(2-{[2-(2,5-difluorophenyl)-1H- imidazol-1-yl]methyl}-1-ethyl-1H- benzimidazol-5-yl)ethanone

1
H NMR, δppm(CDCl3): 8.39(dd, 1H), 8.01(dd, 1H), 7.34-7.41(m, 2H), 7.18-7.24(m, 3H), 7.04(d, 1H), 5.40(s, 2H), 3.88(q, 2H), 2.69(s, 3H), 1.03(s, 3H)
381.4 [M + 1]

775

1402

methyl 2-{[2-(6-fluoropyridin-2-yl)- 1H-imidazol-1-yl]methyl}-3-propyl- 3H-imidazo[4,5-b]pyridine-6- carboxylate
1H NMR(CDCl3): 9.05(1H, d), 8.62(1H, d), 8.19(1H, dd), 7.88(1H, q), 7.26-7.21(2H, m), 6.89-6.85(1H, m), 6.31(2H, s), 4.39(2H, t), 3.96(3H, s), 1.79-1.72(2H, m), 0.87(3H, t)
395.3 [M + 1]

776

1403

2-{[2-(6-fluoropyridin-2-yl)-1H- imidazol-1-yl]methyl}-6-(1 3,4- oxadiazol-2-yl)-3-propyl-3H- imidazo[4,5-b]pyridine
(KC 1084-78-2)
405.3 [M + 1]

777

1404

2-{[2-(6-fluoropyridin-2-yl)-1H- imidazol-1-yl]methyl}-6-(1,3,4- oxadiazol-2-yl)-1-propyl-1H- benzimidazole

1
H NMR(CDCl3) δ 8.46(s, 1H), 8.18-8.14(m, 2H), 7.95-7.83 (m, 3H), 7.24(d, 1H), 7.17(d, 1 H), 6.87(d, 1H), 6.31(s, 2H), 4.30 (t, 2H), 1.71(q, 2H), 0.85(t, 3H)
m/e 404

778

1405

2-{[2-(6-fluoropyridin-2-yl)-1H- imidazol-1-yl]methyl}-6-(5-methyl- 1,3,4-oxadiazol-2-yl)-1-propyl-1H- benzimidazole

1
H NMR(CDCl3) δ 8.17(d, 1H), 8.07(s, 1H), 7.91-7.80(m, 3H), 7.23(d, 1H), 7.16(d, 1H), 6.87 (d, 1H), 6.29(s, 2H), 4.28(t, 2H), 2.61(s, 3H), 1.69(q, 2H), 0.84(t, 3H)
m/e 418

779

1406

2-{[2-(3-fluorophenyl)-1H- imidazol-1-yl]methyl}-6-(1,2,4- oxadiazol-3-yl)-1-propyl-1H- benzimidazole

1
H NMR(CDCl3) δ 8.89(s, 1H), 8.15(s, 1H), 8.12-8.03(m, 1H), 7.81-7.73(m, 1H), 7.40-7.02 (m, 6H), 5.47(s, 2H), 3.82(t, 2H), 1.55(q, 2H), 0.79(t, 3H)
m/e 403

780

1407

2-{[2-(3-fluorophenyl)-1H- imidazol-1 -yl]methyl}-6-(5-methyl- 1,3,4-oxadiazol-2-yl)-1-propyl-1H- benzimidazole

1
H NMR(CDCl3) δ 8.04(s, 1H), 7.94-7.84(m, 2H), 7.50(7.39(m, 3H), 7.22-7.16(m, 2H), 7.08(d, 1H), 5.52(s, 2H), 3.76(t, 2H), 2.63(s, 3H), 1.47(q, 2H), 0.77(t, 3H)
m/e 417

781

1408

2-{[2-(3-fluorophenyl)-1H- imidazol-1-yl]methyl}-6-(1,3,4- oxadiazol-2-yl)-1-propyl-1H- benzimidazole

1
H NMR(CDCl3) δ 8.50(s, 1H), 8.15(d, 1H), 7.98-7.89(m, 2H), 7.56-7.39(m, 3H), 7.24-7.05 (m, 3H), 5.57(s, 2H), 3.78(s, 2H), 1.47(q, 2H), 0.80(t, 3H)
m/e 403

782

1409

2-{[2-(6-chloropyridin-2-yl)-1H- imidazol-1-yl]methyl}-6-(1,3,4- oxadiazol-2-yl)-3-propyl-3H- imidazo[4,5-b]pyridine
1H NMR(CDCl3): 9.14(1H, d), 8.63(1H, d), 8.51(1H, s), 8.26(1H, d), 7.76(1H, t), 7.28-7.24(3H, m), 6.36(2H, s), 4.42(2H, t), 1.81-1.74(2H, m), 0.88(3H, t)
421.3 [M + 1]

783

1410

2-{[2-(6-chloropyridin-2-yl)-1H- imidazol-1-yl]methyl}-1-propyl-1H- benzimidazole-5-carbonitrile
1H NMR(d6 DMSO): 8.02(1H, d, J=7.7Hz), 8.08(1H, s), 7.76(1H, t, J=8Hz), 7.55(1H, dd, J=8, 1.4 Hz), 7.428(1H, d, J=8.5Hz), 7.18-7.32(3H, m), 6.34(1H, s), 4.29(2H, t, J=8.7Hz), 1.66(2H, m), 0.81(3H, t, J=8.7Hz)
377.3 [M + 1]

784

1411

1-propyl-2-[(2-pyridin-2-yl-1H- imidazol-1-yl)methyl]-1H- benzimidazole-5-carbonitrile

785

1412

2-{[2-(6-fluoropyridin-2-yl)-1H- imidazol-1-yl]methyl}-5-{[(2S)-2- (methoxymethyl)pyrrolidin-1- yl]carbonyl}-1-propyl-1H- benzimidazole
CDCl3: 8.17(d,J=7.42Hz, 1H), 7.85-7.93(m, 2H), 7.51-7.53(m, 1H), 7.35(d, J=8.51Hz, 1H), 7.21 (s, 1H), 7.16(s, 1H), 6.89(dd, J=2.47, 7.97Hz, 1H), 6.28-6.3(m, 2H), 4.46(bs, 1H), 4.21-4.26(m,

#2H), 3.51-3.68(m, 4H), 3.40(s, 3H), 1.95-2.05(m, 4H), 1.62-1.72 (m, 2H), 0.81(t, J=7.42Hz, 3H).
475.2 [M + 1]; 477.2 [M − 1]

786

1413

2-{[2-(4-chloropyridin-2-yl)-1H- imidazol-1-yl]methyl}-1-propyl-1H- benzimidazole-5-carbonitrile
1H NMR(d6 DMSO): 8.42(1H, d, J=5Hz), 8.35(1H, s), 8.08(1H, s), 7.1-7.65(1H, m), 6.41(1H, s), 4.19(2H, t, J=7.4Hz), 1.57(2H, m), 0.78(3H, t, J=7.4Hz)
377.3 [M + 1]

787

1414

2-{[2-(6-fluoropyridin-2-yl)-1H- imidazol-1-yl]methyl}-1-propyl-5- [(2-pyridin-3-ylpiperidin-1- yl)carbonyl]-1H-benzimidazole
CDCl3: 8.61 9s, 1H), 8.52(d, J=4.67Hz, 1H), 8.15-8.18(m, 1H), 7.87-7.93(m, 1H), 7.85(s, 1H), 7.66(d J=7.69Hz, 1H), 7.30-7.45 (m, 3H), 7.21(s, 1H), 7.16(s, 1H), 6.88-6.91(m, 1H), 6.29(s, 2H),

#4.25(t, J=7.42Hz, 2H), 2.82-2.91
524.0 ]M + 1], 522.4 [M − 1]

788

1415

1-(2-{[2-(4-chloropyridin-2-yl)-1H- imidazol-1-yl]methyl}-1-ethyl-1H- benzimidazol-5-yl)ethanone

1
H NMR, δppm(CDCl3): 8.36-8.47(m, 3H), 8.01(dd, 1H), 7.38(d, 1H), 7.29(dd, 1H), 7.16-7.18(m, 2H), 6.43(s, 2H), 4.30(q, 2H), 2.68(s, 3H), 1.14(t, 3H)
380.3 [M + 1]

789

1416

1-(2-{[2-(6-chloropyridin-2-yl)-1H- imidazol-1-yl]methyl}-1-ethyl-1H- benzimidazol-5-yl)ethanone

1
H NMR, δppm(CDCl3): 8.40(d, 1H), 8.23(d, 1H), 8.01(dd, 1H), 7.77(t, 1H), 7.41(d, 1H), 7.30(d, 1H), 7.24(d, 1H), 7.18(d, 1H), 6.36(s, 2H), 4.41(q, 2H), 2.68(s, 3H), 1.25(t, 3H)
380.3 [M + 1]

790

1417

2-{[2-(3-fluorophenyl)-1H- imidazol-1-yl]methyl}-6-(5-methyl- 1,2,4-oxadiazol-3-yl)-1-propyl-1H- benzimidazole

1
H NMR(CDCl3) δ 8.03(d, 1H), 8.02(s, 1H), 7.85(d, 1H), 7.51-7.40(m, 3H), 7.21-7.16(m, 2H), 7.07(d, 1H), 5.52(s, 2H), 3.75(t, 2H), 2.67(s, 3H), 1.47(q, 2H), 0.76(t, 3H)
m/e 417

791

1418

6-(5-ethyl-1,2,4-oxadiazol-3-yl)-2- {[2-(3-fluorophenyl)-1H-imidazol- 1-yl]methyl}-1-propyl-1H- benzimidazole

1
H NMR(CDCl3) δ 8.05(d, 1H), 8.03(s, 1H), 7.85(d, 1H), 7.52-7.41(m, 3H), 7.21-7.17(m, 2H), 7.08(d, 1H), 5.52(s, 2H), 3.76(t, 2H), 3.00(q, 2H), 1.51-1.45(m, 5H), 0.77(t, 3H)
m/e 431

792

1419

2-{[2-(6-chloropyridin-2-yl)-1H- imidazol-1-yl]methyl}-1-propyl-1H- imidazo[4,5-c]pyridine
dihydrochioride 1H NMR(DMSO- d6) δ 9.32(s, 1H), 8.68(d, 1H), 8.47(d, 1H), 8.45(d, 1H), 8.09-8.03(m, 2H), 7.80(d, 1H), 7.54(d, 1H), 6.45(s, 2H), 4.61(t, 2H), 1.88(q, 2H), 0.95(t, 3H)
m/e 352

793

1420

2-{[2-(6-chloropyridin-2-yl)-1H- imidazol-1-yl]methy}-1-ethyl-1H- benzimidazole-5-carbonitrile
Mesylate d6-DMSO: 8.02-8.14(m, 3H), 7.97(s, 1H), 7.86(d, J=8.52 Hz, 1H), 7.77(s, 1H), 7.6(d, J=8.51Hz, 1H, 7.57(d, J=7.97Hz, 2H), 2.30(s, 3H), 1.39(t, J=7.14 Hz, 3H)
363.2 [M + 1]

794

1421

2-{[2-(4-chloropyridin-2-yl)-1H- imidazol-1-yl]methyl}-1-propyl-1H- imidazo[4,5-c]pyridine
dihydrochloride 1H NMR(DMSO- d6) δ 9.31(s, 1H), 8.66(d, 1H), 8.45(s, 1H), 8.41(d, 1H), 8.32(d, 1H), 7.86(d, 1H), 7.63(d, 1H), 7.52(d, 1H), 6.42(s, 2H), 4.55(t, 2 H), 1.91(q, 2H), 0.97(1, 3H)
m/e 353

795

1422

2-{[2-(6-fluoropyridin-2-yl)-1H- imidazol-1-yl]methyl}-6-(5-methyl- 1,3,4-oxadiazol-2-yl)-3-propyl-3H- imidazo[4,5-b]pyridine
1H NMR(CDCl3): 9.07(1H, d), 8.56(1H, d), 8.20(1H, dd), 7.88(1H, q), 7.26-7.2292H, m), 6.88(1H, dd), 6.3292H, s), 4.40(2H, t), 2.65(3H, s), 1.81-1.74(2H, m), 0.88(3H, 1)
419.3 [M + 1]

796

1423

2-{[2-(2-fluoropyridin-4-yl)-1H- imidazol-1-yl]methyl}-1-propyl-1H- benzimidazole-5-carbonitrile
1H NMR(CDCl3): 8.28(1H, d), 8.04(1H, s), 7.54-7.49(2H, m), 7.40(1H, d), 7.25-7.22(2H, m), 7.11(1H, s), 5.55(2H, s), 3.89(2H, t), 1.60-1.53(2H, m), 0.83(3H, t)
361.2 [M + 1]

797

1424

2-{[2-(6-ethoxypyridin-2-yl)-1H- imidazol-1-yl]methyl}-N,N- dimethyl-1-propyl-1H- benzimidazole-5-carboxamide
1H NMR(CDCl3): 8.49(1H, d), 8.10(1H, d), 7.88(1H, d), 7.71(1H, t), 7.13(1H, d), 7.00(1H, d), 6.74(1H, d), 6.45(2H, s), 4.27(2H, q), 4.08(2H, t), 3.15-3.06(611, br d), 1.48-1.35(5H, m), 0.67(3H, t)
434.6 [M + 1]

798

1425

2-{[2-(4-chloropyridin-2-yl)-1H- imidazol-1-yl]methyl}-3-ethyl-3H- imidazo[4,5-b]pyridine

1
H NMR, δppm(CDCl3): 8.44(dd, 1H), 8.39(m, 1H), 8.03(dd, 1H), 7.18-7.28(m, 5H), 6.41(s, 2H), 4.39(q, 2H), 1.20(t, 3H)
339.2 [M + 1]

799

1426

2-{[2-(6-chloropyridin-2-yl)-1H- imidazol-1-yl]methyl}-3-ethyl-3H- imidazo[4,5-b]pyridine

1
H NMR, δppm(CDCl3): 8.39(dd, 1H), 8.23(dd, 1H), 8.03(dd, 1H), 7.76(t, 1H), 7.19-7.29(m, 4H), 6.36(s, 2H), 4.48(q, 2H), 1.29(1, 3H)
339.2 [M + 1]

800

1427

3-(2-fluoroethyl)-2-{[2-(3- fluorophenyl)-1H-imidazol-1- yl]methyl}-3H-imidazo[4,5- b]pyridine
H-1 NMR(CDC13): 4.26(t, 1H), 4.35(t, 1H), 4.51(t, 1H), 4.67(s, 1H), 5.54(s, 2H), 7.09-7.45(m, 4H), 8.06(d, 1H), 8.36(d, 1H)
340 [M + 1]

801

1428

3-cyclopropyl-2-{[2-(6- fluoropyridin-2-yl)-1H-imidazol-1- yl]methyl}-3H-imidazo[4,5- b]pyridine
H-1 NMR(CDCl3): line list provided 1.20-1.24(m, 4H), 3.35 (m, 1H), 6.29(s, 2H), 6.79(d, 1H), 7.15(m, 3H), 7.82(q, 1H), 7.92(d, 1H), 8.15(d, 1H), 8.37(d, 1H)
355 [M + 1]

802

1429

2-{[2-(6-chloropyridin-2-yl)-1H- imidazol-l-yl]methyl}-3-(2- fluoroethyl)-3H-imidazo[4,5- b]pyridine
HCl salt H-1 NMR(dmso): line list provided 4.77(s, 2H), 4.90(m, 2H), 6.28(s, 2H), 7.24(m, 1H), 7.62 (d, 1H), 7.93(m, 2H), 8.12(m, 2H), 8.36(m, 2H)
357 [M + 1]

803

1430

1-(2-{[2-(6-fluoropyridin-2-yl)-1H- imidazol-1-yl]melhyl}-3-propyl-3H- imidazo[4,5-b]pyridin-6- yl)ethanone
1H NMR(CDCl3): 9.01(1H, d), 8.53(1H, d), 8.20-8.17(1H, m), 7.87(1H, q), 7.24-7.21(2H, m), 6.88-6.84(1H, m), 6.30(2H, s), 4.40(2H, t), 2.66(3H, s), 1.80-1.73(2H, m), 0.88(3H, t)
379.3 [M + 1]

804

1431

5-chloro-2-{[2-(6-fluoropyridin-2- yl)-1H-imidazol-1-yl]methyl}-3- propyl-3H-imidazo[4,5-b]pyridine
hydrochloride 1H NMR(d6 DMSO): 8.35(1H, dd), 8.24(1H, q), 8.02(1H, s), 7.95(1H, dd), 7.90(1H, s), 7.33(1H, dd), 7.28(1H, d), 7.26(1H, d), 6.32(2H, s), 4.33(2H, t), 1.90-1.85(2H, m), 0.94(3H, t)
371.3 [M + 1]

805

1432

2-{[2-(3-fluoropyridin-2-yl)-1H- imidazol-1-yl]methyl}-3-propyl-3H- imidazo[4,5-b]pyridine
dihydrochloride 1H NMR(d6 DMSO): 8.48-8.46(1H, m), 8,30(1H, dd), 8.12-8.03(2H, m), 7.96(1H, d), 7.90(1H, dd), 7.72-7.65(1H, m), 7.22(1H, dd), 6.18(2H, s), 4.27(2H, t), 1.83-1.75(2H, m), 0.87(3H, t)
337.2

806

1433

2-{[2-(3-fluoropyridin-2-yl)-1H- imidazol-1-yl]methyl}-1-propyl-1H- benzimidazole-5-carbonitrile
hydrochloride 1H NMR(d6 DMSO): 8.45(1H, m), 8.08-8.02(3H, m), 7.93(1H, s), 7.83(1H, d), 769-7.62(2H, m), 6.16(2H, s), 4.29(2H, t), 1.72-1.20(2H, m), 0.86(3H, t)
361.2 [M + 1]

807

1434

6-{1-[(1-propyl-1H-imidazo[4,5- c]pyridin-2-yl)methyl]-1H- imidazol-2-yl}pyridine-2- carbonitrile

1
H NMR(CDCl3) δ 9.03(s, 1H), 8.56(d, 1H), 8.44(d, 1H), 7.91 (dd, 1H), 7.60(d, 1H), 7.32(d, 1 H), 7.30(d, 1H), 7.25(d, 1H), 6.25 (s, 2H), 4.31(1, 2H), 1.78(q, 2H), 0.90(t, 3H)
m/e 344

808

1435

2{[2-(4-chloropyridin-2-yl)-1H- imidazol-1-yl]methyl}-3-propyl-3H- imidazo[4,5-b]pyridine

1
H NMR, δppm(CDCl3): 8.36-8.45(m, 3H), 8.03(dd, 1H), 7.18-7.29(m, 4H), 6.40(s, 2H), 4.28(t, 2H), 1.66(m, 2H), 0.81(1, 3H)

809

1436

2-{[2-(6-chloropyridin-2-yl)-1H- imidazol-1-yl]methyl}-3-propyl-3H- imidazo[4,5-b]pyridine

1
H NMR, δppm(CDCl3): 8.39(dd, 1H), 8.23(dd, 1H), 8.02(dd, 1H), 7.76(1, 1H), 7.19-7.29(m, 4H), 6.36(s, 2H), 4.34(1, 2H), 1.72(m, 2H), 0.83(t, 3H)

810

1437

2-{[2-(4-chloropyridin-2-yl)-1H- imidazol-1-yl]methyl}-3- cyclopropyl-3H-imidazo]4,5- b]pyridine
HCl salt H-1 NMR(DMSO): line list provided 1.24(m, 4H), 3.48(m, 1H), 6.43(s, 2H), 7.19(m, 1H), 7.67 (m, 1H), 7.86(d, 1H), 7.97(s, 1H), 8.06(s, 1H), 8.31(d, 1H), 8.56(d, 1H), 8.64(m, 1H)
351 [M + 1]; 349 [M − 1]

811

1438

2-{[2-(4-chloropyridin-2-yl)-1H- imidazol-1-yl]methyl}-3-(2- fluoroethyl)-3H-imidazo[4,5- b]pyridine
H-1 NMR(CDC13): 4.60-4.77(m, 2H), 4.81(s, 2H), 6.35(s, 2H), 7.20-7.25(m, 5H), 8.03(d, 1H), 8.38(m, 1H)
357 [M + 1]

812

1439

6-{1-[(3-propyl-3H-imidazo[4,5- b]pyridin-2-yl)methyl]-1H- imidazol-2-yl}pyridine-2- carbonitrile
1H NMR, dppm(CDCl3): 8.56(dd, 1H), 8.39(dd, 1H), 8.00(dd, 1H), 7.92(dd, 1H), 7.63(dd, 1H), 7.20-7.29(m, 3H), 6.32(s, 2H), 4.36(t, 2H), 1.80(m, 2H), 0.89(t, 3H) LC- MS: calcd: 343.39, found 344.1[M+1]

813

1440

6-{1-[(3-propyl-3H-imidazo[4,5- b]pyridin-2-yl)methyl]-1H- imidazol-2-yl}pyridine-2- carboxamide

1
H NMR, δppm(CDCl3): 8.88(s, 1H), 8.42(dd, 1H), 8.38(dd, 1H), 8.15(dd, 1H), 7.98(dd, 1H), 7.93(d, 1H), 7.22-7.27(m, 3H), 6.18(s, 2H), 5.67(s, 1H), 4.07(t, 2H), 1.54(m, 2H), 0.83(t, 3H)
362.2 [M + 1]

814

1441

3-propyl-2-({2-[6- (trifluoromethyl)pyridin-2-yl]-1H- imidazol-1-yl}methyl)-3H- imidazo[4,5-b]pyridine

1
H NMR, δppm(CDCl3): 8.53(d, 1H), 8.39(dd, 1H), 7.96-8.06(m, 2H), 7.64(dd, 1H), 7.20-7.27(m, 3H), 6.42(s, 2H), 4.26(t, 2H), 1.61(m, 2H), 0.72(t, 3H)
387.3 [M + 1]

815

1442

3-(2-fluoroethyl)-2{[2-(3- fluoropyridin-2-yl)-1H-imidazol-1- yl]methyl}-3H-imidazo[4,5- b]pyridine
H-1 NMR(CDCl3): line list provided 4.58-4.66(m, 2H), 4.75 (s, 2H), 6.03(s, 2H), 7.21-7.35(m, 4H), 7.57(m, 1H), 8.04(d, 1H), 8.41(m, 1H)
341 [M + 1]

816

1443

2-{[2-(3-fluorophenyl)-1H- imidazol-1-yl]methyl}-1-phenyl- 1H-benzimidazole
H-1 NMR(CDCl3): 5.38(s, 2H), 6.91-7.17(m, 8H), 7.22-7.45(m, 6H), 7.84(d, 1H)
369

817

1444

2-{[2-(6-fluoropyridin-2-yl)-1H- imidazol-1-yl]methyl}-1-phenyl- 1H-benzimidazole
H-1 NMR: 6.22(s, 2H), 6.78(m, 1H), 7.03-7.37(m, 9H), 7.65-7.92 (m, 3H)
368 [M − 1]

818

1445

3-allyl-2-{[2-(3-fluorophenyl)-1H- imidazol-1-yl]methyl}-3H- imidazo[4,5-b]pyridine
H-1 NMR(CDCl3): 4.59-4.62(m, 3H), 5.03(d, 1H), 5.43(s, 2H), 5.70 (m, 1H), 7.03(s, 1H), 7.17(m, 1H), 7.25(m, 2H), 7.43(m, 3H), 8.04(d, 1H), 8.40(d, 1H)
334 [M + 1]; 332 [M − 1]

819

1446

2-{[2-(6-fluoropyridin-2-yl)-1H- imidazol-1-yl]methyl}-1-propyl-5- [(4-pyridin-2-ylpiperazin-1- yl)carbonyl]-1H-benzimidazole
CDCl3: 8.15-8.2(m, 2H), 7.82-794 (m, 2H), 7.44-7.53(m, 1H), 7.35-7.44(m, 2H), 7.18(q, 2H), 6.88(d, 1H), 6.71(s, 1H), 6.65(s, 1H), 6.29 (s, 2H), 421-4.29(m, 2H), 3.53-4.0 (m, 8H), 1.53-1.71(m, 2H), 0.82(t, 3H)

820

1447

5-[(2-{[2-(6-fluoropyridn-2-yl)-1H- imidazol-1-yl]methyl}-1-propyl-1H- benzimidazol-5-yl)carbonyl]-2- oxa-5-azabicyclo[2.2.1]heptane
CDCl3: 8.18(d, 7.97Hz, 1Hz), 7.85 7.94(m, 2H), 7.52-7.54(m, 1H), 7.38-7.42(m, 1H), 7.17-7.26(m, 2H), 6.90(d, J=7.96Hz, 1H), 6.30 (s, 2H), 4.73-5.06(m, 1H), 4.56(d, 1H), 4.24-4.35(m, 2H), 4.04-4.10

#(m, 1H), 3.81-3.89(m, 1H), 3.51-3.7 (m, 2H, 1.96(s, 1H), 1.86(s, 1H), 1.64-1.71(m, 2H), 0.83(t, J=7.28 Hz, 3H).

821

1448

2-{[2-(2-fluorophenyl)-1H- imidazol-1-yl]methyl)-3-propyl-3H- imidazo[4,5-b]pyridine

1
H NMR, δppm(CDCl3): 8.39(dd, 1H), 8.03(dd, 1H), 7.65(m, 1H), 7.50(m, 1H), 7.20-7.35(m, 3H), 7.07(d, 1H), 5.38(s, 2H), 3.84(t, 2H), 1.46(m, 2H), 0.74(1, 3H)
336.2 [M + 1]

822

1449

2-{[2-(2-chlorophenyl)-1H- imidazol-1-yl]methyl}-3-propyl-3H- imidazo[4,5-b]pyridine

1
H NMR, δppm(CDCl3). 8.38(dd, 1H), 8.02(dd, 1H), 7.33-7.56(m, 4H), 7.19-7.27(m, 2H), 7.09(d, 1H), 5.30(s, 2H) 3.85(t, 2H), 1.50(m, 2H), 0.76(t, 3H)
352.2 [M + 1]

823

1450

3-propyl-2-({2-[2- (trifluoromethyl)phenyl]-1H- imidazol-1-yl}methyl)-3H- imidazo[4,5-b]pyridine

1
H NMR, δppm(CDCl3): 8.39(dd, 1H), 8.02(dd, 1H), 7.84(dd, 1H), 7.53-7.65(m, 2H), 7.45(m, 1H), 7.21-7.27(m, 2H), 7.09(d, 1H), 5.17(s, 2H), 3.93(t, 2H), 1.59(m, 2H), 0.80(t, 3H)
386.2 [M + 1]

824

1451

3-ethyl-2-{[2-(3-fluoropyridin-2-yl)- 1H-imidazol-1-yl]methyl}-3H- imidazo[4,5-b]pyridine

1
H NMR, δppm(CDCl3): 8.47(m, 1H), 8.40(dd, 1H), 8.04(dd, 1H), 7.62(m, 1H), 7.36(m, 1H), 7.23-7.28(m, 2H), 7.16(d, 1H), 6.10(s, 2H), 4.37(q, 2H), 1.19(t, 3H)
323.3 [M + 1]

825

1452

3-ethyl-2-{[2-(3-fluoropyridin-2-yl)- 1H-imidazol-1-yl]methyl}-6-(5- methyl-1,3,4-oxadiazol-2-yl)-3H- imidazo[4,5-b]pyridine
1H NMR(CDCl3): 9.08(1H, d), 8.58(1H, d), 8.45-8.43(1H, m), 7.65-7.59(1H, m), 7.39-7.30(2H, m), 7.18(1H, s), 6.14(2H, s), 4.43(2H, q), 2.66(3H, s), 1.23(3H, t)
405.3 [M + 1]

826

1453

1-allyl-2-{[2-(6-fluoropyridin-2-yl)- 1H-imidazol-1-yl]methyl}-1H- imidazo[4,5-c]pyridine

1
H NMR(CDC13) δ 9.05(s, 1H), 8.40(d, 1H), 8.14(d, 1H), 7.85 (dd, 1H), 7.26(d, 1H), 7.22(d, 1 H), 7.17(6.85(d, 1H), 6.19(s, 2 H), 5.82-5.70(m, 1H), 5.12(d, 1 H), 4.99-4.96(m, 2H), 4.82(d, 1 H)
m/e 335

827

1454

2-{[2-(6-fluoropyridin-2-yl)-1H- imidazol-1-yl]methyl}-1-prop-2- ynyl-1H-imidazo[4,5-c]pyridine

1
H NMR(CDCl3) δ 9.04(s, 1H), 8.46(d, 1H), 8.15(d, 1H), 7.86 (dd, 1H), 7.41(d, 1H), 7.26(d, 1 H), 7.21(d, 1H), 6.85(d, 1H), 6.23 (s, 2H), 5.21(d, 2H), 2.33-2.32 (m, 1H)
m/e 333

828

1455

2-{[2-(3-fluorophenyl)-1H- imidazol-1-yl]methyl}-3-prop-2- ynyl-3H-imidazo[4,5-b]pyridine
H-1 NMR(dmso): 3.47(s, 1H), 4.78(s, 2H), 5.65(s, 2H), 7.07-7.45 (m, 5H), 7.45(m, 2H), 8.07(m, 1H), 8.42(m, 1H)
332 [M + 1]; 330 [M − 1]

829

1456

2-{[2-(3-fluoropyridin-2-yl)-1H- imidazol-1-yl]methyl}-3-prop-2- ynyl-3H-imidazo[4,5-b]pyridine
HCl salt H-1 NMR(dmso): line list provided 3.51(s, 1H), 5.25(s, 2H), 6.25(s, 2H), 7.27(m, 1H), 7.72(m, 1H), 7.94-8.15(m, 4H), 8.35(m, 1H), 8.50(1H)
333 [M + 1]

830

1457

3-cyclopropyl-2-{12-(3- fluoropyridin-2-yl)-1H-imidazol-1- yl]methyl}-3H-imidazo[4,5- b]pyridine
HCl salt H-1 NMR(dmso): line list provided 1.19(m, 4H), 3.36(m, 2H), 6.24(s, 2H), 7.21(m, 1H), 7.70 (m, 1H), 7.88(d, 2H), 8.00(s, 1H), 8.07(m, 3H), 8.31(d, 1H), 8.52(d, 1H)
355 [M + 1]

831

1458

3-cyclopropyl-2-{[2-(3- fluorophenyl)-1H-imidazol-1- yl]methyl}-3H-imidazo[4,5- b]pyridine
HCl salt H-1 NMR(DMSO): line list provided 1.03-1.22(m, 4H), 3.37(m, 1H), 5.96(s, 2H), 7.22(m, 1H), 7.45-7.78(m, 4H), 7.95-8.03 (m, 3H), 8.37(d, 1H)
334 [M + 1]; 332 [M − 1]

832

1459

3-ethyl-2-({2-[6- (trifluoromethyl)pyridin-2-yl]-1H- imidazol-1-yl}methyl)-3H- imidazo[4,5-b]pyridine

1
H NMR, δppm(CDCl3): 8.52(d, 1H), 8.39(dd, 1H), 7.90-8.05(m, 2H), 7.64(d, 1H), 7.21-7.27(m, 3H), 6.42(s, 2H), 4.39(q, 2H), 1.17(t, 3H)
373.3 [M + 1]

833

1460

1-[1-ethyl-2-({2-[6- (trifluoromethyl)pyridin-2-yl]-1H- imidazol-1-yl}methyl)-1H- benzimidazol-5-yl]ethanone

1
H NMR, δppm(CDCl3): 8.52)d, 1H), 8.40(d, 1H), 7.99-8.03(m, 2H), 7.64(d, 1H), 7.40(d, 1H), 7.20-7.22(m, 2H), 6.41(s, 2H), 4.34(q, 2H), 2.68(s, 3H), 1.l5(t, 3H)
414.2 [M + 1]

834

1461

3-(2-fluoroethyl)-2-({2-[6- (trifluoromethyl)pyridin-2-yl]-1H- imidazol-1-yl}methyl)-3H- imidazo[4,5-b]pyridine
H-1 NMR(CDCl3): line list provided 4.60-4.81(m, 4H), 6.30 (s, 2H), 7.18-7.30(m, 3H), 7.54(d, 1H), 7.88-8.00(m, 2H), 8.33(d, 1H), 8.49(d, 1H)
391 [M + 1]; 389 [M − 1]

835

1462

3-allyl-2-{[2-(6-fluoropyridin-2-yl)- 1H-imidazol-1-yl]methyl}-3H- imidazo[4,5-b]pyridine
H-1 NMR(CDCl3): line list provided 4.87(d, 1H), 5.14(m, 3H), 5.87(m, 1H), 6.24(a, 2H), 6.86 (dd, 1H), 7.23(m, 3H), 7.84(m, 1H), 8.02(d, 1H), 8.15(m, 1H), 8.38(d, 1H)
335 [M + 1]; 333 [M − 1]

836

1463

6-{1-[(3-ethyl-3H-imidazo[4,5- b]pyridin-2-yl)methyl]-1H- imidazol-2-yl}pyridine-2- carbonitrile

1
H NMR, δppm(CDCl3): 8.56(dd, 1H), 8.40(dd, 1H), 8.01(dd, 1H), 7.93(t, 1H), 7.63(dd, 1H), 7.21-7.29(m, 3H), 6.33(s, 2H), 4.44(q, 2H), 1.35(t, 3H)
330.1 [M + 1]

837

1464

2-{[2-(6-fluoropyridin-2-yl)-1H- imidazol-1-yl]methyl}-N,N- dimethyl-1-propyl-1H- benzimidazole-6-carboxamide

1
H NMR(CDCl3) δ 8.17(d, 1H), 7.89(dd, 1H), 7.74(d, 1H), 7.49 (s, 1H), 7.30(d, 1H), 7.21(d, 1H), 7.15(d, 1H), 6.89(d, 1H), 6.29(s, 2H), 4.23(t, 2H), 3.07(br d, 6H), 1.66(q, 2H), 0.81(t, 3H)
m/e 407

838

1465

1-propyl-2-({2-[6- (trifluoromethyl)pyridin-2-yl]-1H- imidazol-1-yl}methyl)-1H- imidazo[4,5-c]pyridine

1
H NMR(CDCl3) δ 9.08(s, 1H), 8.52(d, 1H), 8.44(d, 1H), 7.99 (dd, 1H), 7.65(d, 1H), 7.29(d, 1 H), 7.26(d, 1H), 7.21(d, 1H), 6.40 (s, 2H), 4.19(t, 2H), 1.54(q, 2H), 0.71(t, 3H)
m/e 387

839

1466

2-{[2-(6-fluoropyridin-2-yl)-1H- imidazol-1-yl]methyl}-6- (morpholin-4-ylcarbonyl)-1-propyl 1H-benzimidazole

1
H NMR(CDCl3) δ 8.17(d, 1H), 7.88(dd, 1H), 7.75(d, 1H), 7.51 (s, 1H), 7.28-7.25(m, 1H), 7.21 (s, 1H), 7.16(s, 1H), 6.89(d, 1H), 6.29(s, 2H), 4.24(t, 2H), 3.69(br s, 8H), 1.67(q, 2H), 0.82(t, 3H)
m/e 449

840

1467

2-{[2-(6-fluoropyridin-2-yl)-1H- imidazol-1-yl]methyl}-1-propyl-6- [(4-pyridin-2-ylpiperazin-1- yl)carbonyl]-1H-benzimidazole

1
H NMR(CDC13) δ 8.19-8.16 (m, 2H), 7.88(dd, 1H), 7.77(d, 1 H), 7.53(s, 1H), 7.48(d, 1H), 7.32 (d, 1H), 7.26(d, 1H), 7.17(d, 1H), 6.89(d, 1H), 6.69-6.65(m, 2H), 6.30(s, 2H), 4.25(t, 2H), 3.59(br s, 8H), 1.67(q, 2H), 0.82(t, 3H)
m/e 525

841

1468

methyl-2-{[(6-fluropyridin-2-yl)- 1H-imidazol-1-yl]methyl}-1-propyl- 1H-benzimidazole-6-carboxylate

1
H NMR(CDCl3) δ 8.18(d, 1H), 8.09(s, 1H), 7.98-7.87(m, 2H), 7.76(d, 1H), 7.24(s, 1H), 7.17(s, 1H), 6.88(d, 1H), 6.31(s, 2H), 4.29(t, 2H), 3.94(s, 3H), 1.69(q, 2H), 0.85(t, 3H)4.
m/e 39

842

1469

1-(2-fluoroethyl)-2-{[2-(3- fluorophenyl)-1H-imidazol-1- yl]methyl}-1H-imidazo[4,5- c]pyridine
H-1 NMR(CDCl3): 4.02(t, 1H), 4.05(t, 1H), 4.32(t, 1H), 4.47(t, 1H), 5.58(s, 2H), 7.05-7.33(m, 5H), 7.44(m, 2H), 8.47(d, 1H), 9.10(s, 1H)
340 [M + 1]

843

1470

2-{[2-(4-chloro-1-methyl-1H- pyrazol-3-yl)-1H-imidazol-1- yl]methyl}-3-(2-fluoroethyl)-3H- imidazo[4,5-b]pyridine
H-1 NMR(CDCl3): line list provided 3.89(s, 3H), 4.55(s, 2H), 4.69(m, 1H), 4.71(m, 1H), 5.93(s, 2H), 7.11(s, 1H), 7.25(m, 2H), 7.47 (s, 1H), 8.04(d, 1H), 8.36(d, 1H)
360 [M + 1]

844

1471

(4S)-5-[(2-{[2-(6-fluoropyridin-2- yl)-1H-imidazol-1-yl]methyl)-1- propyl-1H-benzimidazol-6- yl)carbonyl]-2-oxa-5- azabicyclo[2.2.1]heptane

1
H NMR(CDCl3) δ 8.18(d, 1H), 7.89(dd, 1H), 7.78-7.72(m, 1H), 7.62(s, 1H), 7.42-7.33(m 1H), 7.22(s, 1H), 7.17(s, 1H), 6.89(d, 1H), 6.30(s, 2H), 5.06-4.51(m 2 H), 4.25(t, 2H), 4.11-3.48(m, 4H),

#1.96-1.87(m, 2H), 1.68(q, 2H), 0.83(t, 3H)
m/e 461

845

1472

1-propyl-2-[(2-pyrazin-2-yl-1H- imidazol-1-yl)methyl]-1H- imidazo[4,5-c]pyridine

1
H NMR(CDCl3) δ 9.58(s, 1H), 9.09(d, 1H), 8.61-8.42(m, 3H), 7.32-7.24(m, 3H), 6.33(s, 2H), 4.16(t, 2H), 1.63(q, 2H), 0.81(t, 3 H)
m/e 320

846

1473

3-ethyl-2-{[2-(2-methyl-1,3- thiazol-4-yl)-1H-imidazol-1- yl]methyl}-3H-imidazo[4,5- b]pyridine

1
H NMR, δppm(CDCl3): 8.40(dd, 1H), 8.05(dd, 1H), 7.88(s, 1H), 7.25(m, 1H), 7.11(d, 1H), 7.07(d, 1H), 6.29(s, 2H), 4.35(q, 2H), 2.78(s, 3H), 1.18(t, 3H)
325.2 [M + 1]

847

1474

1-(1-ethyl-2-{[2-(2-methyl-1,3- thiazol-4-yl)-1H-imidazol-1- yl]methyl}-1H-benzimidazol-5- yl)ethanone

1
H NMR, δppm(CDCl3): 8.41(d, 1H), 8.01(dd, 1H), 7.89(s, 1H), 7.38 6.30(s, 2H), 4.27(q, 2H), 2.79(s, 3H), 2.69(s, 3H), 1.12(t, 3H)
366.2 [M + 1]

848

1475

2-{[2-(3,5-difluorophenyl)-1H- imidazol-1-yl]methyl}-3-propyl-3H- imidazo[4,5-b]pyridine

1
H NMR, δppm(CDCl3): 8.41(dd, 1H), 8.06(dd, 1H), 7.19-7.29(m, 4H), 7.08(d, 1H), 6.93(m, 1H), 5.52(s, 2H), 3.96(t, 2H), 1.57(m, 3H), 0.82(t, 3H)
354.3 [M + 1]

849

1476

2-{[2-(3,5-difluoraphenyl)-1H- imidazol-1-yl]methyl}-3-ethyl-3H- imidazo[4,5-b]pyridine

1
H NMR, δppm(CDCl3): 8.41(dd, 1H), 8.06(dd, 1H), 7.19-7.31(m, 4H), 7.07(d, 1H), 6.93(m, 1H), 5.52(s, 2H), 4.05(q, 2H), 1.14(t, 3H).
340.3 [M + 1]

850

1477

3-propyl-2-{[2-(1,3-thiozol-2-yl)- 1H-imidazol-1-yl]methyl}-3H- imidazo[4,5-b]pyridine

1
H NMR, δppm(CDCl3): 8.40(dd, 1H), 8.05(dd, 1H), 7.86(d, 1H), 7.40(d, 1H), 7.25(d, 1H), 7.22(d, 1H), 7.15(d, 1H), 6.37(s, 2H), 4.27(t, 2H), 1.62(m, 2H), 0.78(t, 3H).
325.3 [M + 1]

851

1478

3-propyl-2-{[2-(2,4,5- trifluorophenyl)-1H-imidazol-1- yl]methyl}-3H-imidazo[4,5- b]pyridine

1
H NMR, δppm(CDCl3): 8.41(dd, 1H), 8.03(dd, 1H), 7.50(m, 1H), 7.22-7.29(m, 2H), 7.07-7.15(m, 2H), 5.37(s, 2H), 3.93(t, 2H), 1.53(m, 2H), 0.82(t, 3H).
372.2 [M + 1]

852

1479

2-{[2-(6-fluoropyridin-3-yl)-1H- imidazol-1-yl]methyl}-3-propyl-3H imidazo[4,5-b]pyridine
1H NMR(CDC13): 8.53-8.51(1H, m), 8.40(1H, dd), 8.16-8.14(1H, m), 8.03(1H, dd), 7.28-7.23(2H, m), 7.11(1H, d), 7.05(1h, dd), 5.46(2H, s), 4.00(2H, t), 1.65-1.59(2H, m), 0.84(3H, t)
337.1 [M + 1]

853

1480

2-{[2-(1,5-dimethyl-1H-pyrazol-3- yl)-1H-imidazol-1-yl]methyl}-3- propyl-3H-imidazo[4,5-b]pyridine
1H NMR(CDCl3): 8.37(1H, dd), 8.04(1H, dd), 7.22(1H, dd), 7.06(1H, d), 7.02(1H, d), 6.66(1H, s), 6.20(1H, s), 4.19(2H, t), 3.83(3H, s), 2.33(3H, s), 1.60-1.53(2H, m), 0.76(3H, t)
336.2 [M + 1]

854

1481

2-{[2-(3,4-difluorophenyl)-1H- imidazol-1-yl]methyl}-3-propyl-3H imidazo[4,5-b]pyridine
1H NMR(CDCl3): 8.38(1H, dd), 8.04(1H, dd), 7.56-7.50(1H, m), 7.41-7.36(1H, m), 7.30-7.21(2H, m), 7.15(1H, d), 7.04(1H, d), 5.4592H, s), 3.92(2H, t), 1.60-1.50(2H, m), 0.80(3H, t)
354.3 [M + 1]

855

1482

3-(2-fluoroethyl)-2-{[2-(3-fluoro-2- methylphenyl)-1H-imidazol-1- yl]methyl}-3H-imidazo[4,5- b]pyridine
H-1 NMR(CDCl3): 2.13(s, 3H), 4.14(m, 1H), 4.24(m, 1H), 4.48(m, 1H), 4.64(m, 1H), 5.29(s, 2H), 7.09 7.26(m, 6H), 8.02(d, 1H), 8.35(d, 1H)
354 [M + 1]

856

1483

2-{[2-(2,6-difluorophenyl)-1H- imidazol-1-yl]methyl}-3-(2- fluoroethyl)-3H-imidazo[4,5- b]pyridine
H-1 NMR(CDCl3): line list provided 4.14(t, 1H), 4.24(t, 1H), 4.46(t, 1H), 4.64(t, 1H), 5.40(s, 2H), 6.98(m, 2H), 7.11(s, 1H), 7.26 7.40(m, 3H), 8.01(d, 1H), 8.34(d, 1H)
358 [M + 1]

857

1484

3-(2-fluoroethyl)-2-{[2-(3-fluoro-4- methylphenyl)-1H-imidazol-1- yl]methyl}-3H-imidazo[4,5- b]pyridine
H-1 NMR(CDCl3): line list provided 2.35(s, 3H), 4.26(t, 1H), 4.35(t, 1H), 4.51(t, 1H), 4.67(t, 1H), 5.53(s, 2H), 7.07(s, 1H), 7.18 (s, 1H), 7.26-7.34(m, 4H), 8.07(d, 1H), 8.36(d, 1H)
354 [M + 1]

858

1485

3-ethyl-2-{[2-(3-fluorophenyl)-1H- imidazol-1-yl]methyl}-6-(5-methyl- 1,3,4-oxadiazol-2-yl)-3H- imidazo[4,5-b]pyridine
dihydrochloride 1H NMR(d6 DMSO): 9.96(1H, d), 8.50(1H, d), 7.98-7.91(2H, m), 7.72-7.50(4H, m), 6.01(2H s), 4.35(2H, q), 2.58(3H, s), 1.35(3H, t)
404.3 [M + 1]

859

1486

2-{[2-(2-methyl-1,3-thiazol-4-yl)- 1H-imidazol-1-yl]methyl}-3-propyl- 3H-imidazo[4,5-b]pyridine

1
H NMR, δppm(CDCl3): 8.40(dd, 1H), 8.05(dd, 1H), 7.91(s, 1H), 7.24(m, 1H), 7.11(d, 1H), 7.07(d, 1H), 6.30(s, 2H), 4.22(t, 2H), 2.78(s, 3H), 1.62(m, 2H), 0.79(t, 3H)
339.2 [M + 1]

860

1487

2-{[2-(2-methoxypyridin-3-yl)-1H- imidazol-1-yl]methyl}-3-propyl-3H- imidazo[4,5-b]pyridine

1
H NMR, δppm(CDCl3): 8.38(dd, 1H), 8.30(dd, 1H), 8.03(dd, 1H), 7.87(dd, 1H), 7.19-7.27(m, 2H), 7.01-7.05(m, 2H), 5.33(s, 2H), 3.97(s, 3H), 3.86(t, 2H), 1.47(m, 2H), 0.77(t, 3H)
349.3 [M + 1]

861

1488

2-{[2-(2,3-dichlorophenyl)-1H- imidazol-1-yl]methyl}-3-propyl-3H- imidazo[4,5-b]pyridine

1
H NMR, δppm(CDCl3): 8.38(dd, 1H), 8.02(dd, 1H), 7.59(dd, 1H), 7.39(dd, 1H), 7.21-7.29(m, 3H), 7.10(d, 1H), 5.29(s, 2H), 3.90(t, 2H), 1.53(m, 2H), 0.79(t, 3H).
386.3

862

1489

2-{[2-(2-fluoropyridin-3-yl)-1H- imidazol-1-yl]methyl}-3-propyl-3H- imidazo[4,5-b]pyridine

1
H NMR, δppm(CDCl3): 8.39(dd, 1H), 8.35(m, 1H), 8.12(m, 1H), 8.02(dd, 1H), 7.35(m, 1H), 7.22-7.29(m, 2H), 7.10(d, 1H), 5.43(s, 2H), 3.95(t, 2H), 1.54(m, 2H), 0.80(t, 3H).
337.2

863

1490

2-{[2-(2,3-difluorophenyl)-1H- imidazol-1-yl]methyl}-3-ethyl-3H- imidazo[4,5-b]pyridine

1
H NMR, δppm(CDCl3): 8.40(dd, 1H), 8.04(dd, 1H), 7.22-7.43(m, 5H), 7.08(d, 1H), 5.40(s, 2H), 3.99 (q, 2H), 1.05(t, 3H).
340.1

864

1491

2-{[2-(2,3-difluorophenyl)-1H- imidazol-1-yl]methyl}-3-propyl-3H imidazo[4,5-b]pyridine

1
H NMR, δppm(CDCl3). 8.39(dd, 1H), 8.03(dd, 1H), 7.22-7.42(m, 5H), 7.09(d, 1H), 5.39(s, 2H), 3.86(t, 2H), l.50(m, 2H), 0.78(t, 3H)
354.2

865

1492

2-{[2-(4-chloro-1-methyl-1H- pyrazol-3-yl)-1H-imidazol-1- yl]methyl}-3-propyl-3H- imidazo[4,5-b]pyridine
1H NMR(CDCl3): 8.38(1H, dd), 8.04(1H, dd), 7.52(1H, s), 7.26-7.21(2H, m), 7.05(1H, d), 5.98(2H, s), 4.15(2H, t), 3.94(3H, s), 1.62-1.52(2H, m), 0.80(3H, t)
356.2 [M + 1]

866

1493

3-cyclobutyl-2-{[2-(6-fluoropyridin- 2-yl)-1H-imidazol-1-yl]methyl}-3H- imidazo[4,5-b]pyridine
dihydrochloride 1H NMR(d6 DMSO): 8.39(1H, dd), 8.33(1H, dd), 8.25(1H, q), 8.03(1H, d), 7.95(1H, d), 7.87(1H, dd), 7.33(1H, dd), 7.21(1H, dd), 6.34(2H, s), 5.18(1H, m), 3.28-1.20(2H, m), 2.58-2.42(2H, m), 2.00-1.86(2H, m)
349.3 [M + 1]

867

1494

2-{1-[(3-propyl-3H-imidazo[4,5- b]pyridin-2-yl)methyl]-1H- imidazol-2-yl}isonicotinonitrile
dihydrochloride 1H NMR(d6 DMSO): 8.78(1H, s), 8.72(1H, d), 8.32(1H, dd), 7.99(1H, d), 7.93-7.86(3H, m), 7.21(1H, dd), 6.34(2H, s), 4.37(2H, t), 1.91-1.82(2H, m), 0.93(3H, t)
344.2 [M + 1]

868

1495

2-{1-[(1-propyl-1H-imidazo[4,5- c]pyridin-2-yl)methyl]-1H- imidazol-2-yl}isonicotinonitrile

1
H NMR(CDCl3) δ 9.07(s, 1H), 8.68(d, 1H), 8.60(s, 1H), 8.44(d, 1H), 7.45(d, 1H), 7.29(d, 1H), 7.26(d, 1H), 7.22(d, 1H), 6.37(s, 2H), 4.16(t, 2H), 1.63(q, 2H), 0.81(t, 3H)
m/e 344

869

1496

2-{[2-(2-methoxyphenyl)-1H- imidazol-1-yl]methyl}-3-propyl-3H imidazo[4,5-b]pyridine
dihydrochloride 1H NMR(d6 DMSO): 8.33(1H, dd), 8.02-7.99(2H, m), 7.93(1H, d), 7.65 7.59(1H, m), 7.51-7.48(1H, m), 7.29 7.21(2H, m), 7.11-7.06(1H, m), 5.75(2H, s), 4.12(2H, t), 3.64(3H, s), 1.69-1.61(2H, m), 0.74(3H, t).
348.3 [M + 1]

870

1497

2-{[2-(3-methoxyphenyl)-1H- imidazol-1-yl]methyl}-3-propyl-3H imidazo[4,5-b]pyridine
dihydrochioride 1H NMR(d6 DMSO): 8.35(1H, dd), 8.04-7.98(2H, m), 7.93(1H, d), 7.48(1H, 4.22(2H, t), 3.69(3H, s), 1.79-1.68(2H, m), 0.81(3H, t)
348.39 [M + 1]

871

1498

6-(1-{[3-(2-fluoroethyl)-3H- imidazo[4,5-b]pyridin-2-yl]methyl}1H-imidazol-2-yl)pyridine-2- carbonitrile
H-1 NMR(CDCl3): line list provided 4.74(m, 1H), 4.84-4.95 (m, 3H), 6.16(s, 2H), 7.19-7.28(m, 2H), 7.39(s, 1H), 7.54(d, 1H), 7.83 (t, 1H), 7.89(d, 1H), 8.34(m, 1H), 8.53(d, 1H)
348 [M + 1]

872

1499

2-{[2-(3,4-difluorophenyl)-1H- imidazol-1-yl]methyl}-3-(2- fluoroethyl)-3H-imidazo[4,5- b]pyridine
H-1 NMR(CDCl3): line list provided 4.33(t, 1H), 4.42(t, 1H), 4.56(t, 1H), 4.73(t, 1H), 5.51(s, 2H), 7.07(s, 1H), 7.18-7.26(m, 2H), 7.39(m, 1H), 7.55(m, 1H), 8.07(d, 1H), 8.37(s, 1H)
358 [M + 1]

873

1500

3-(2-fluoroethyl)-2-{[2-(2,4,5- trifluorophenyl)-1H-imidazol-1- yl]methyl}-3H-imidazo[4,5- b]pyridine
H-1 NMR(CDCl3): line list provided 4.23(t, 1H), 4.31(t, 1H), 4.50(t, 1H), 4.66(t, 1H), 5.40(s, 2H), 7.01-7.09(m, 2H), 7.20-7.26 (m, 2H), 7.43(m, 1H), 7.99(d, 1H), 8.32(d, 1H)
376 [M + 1]

874

1501

3-(2-fluoroethyl)-2-{[2-(5-fluoro-2- methylphenyl)-1H-imidazol-1- yl]methyl}-3H-imidazo]4,5- b]pyridine
H-1 NMR(CDCl3): line list provided 2.16(s, 3H), 4.19(t, 1H), 4.26(t, 1H), 4.49(t, 1H), 4.57(t, 1H), 5.28(s, 2H), 7.02-7.07(2H), 7.14(s, 1H), 7.21-7.26(m, 3H), 8.02(d, 1H), 8.35(d, 1H)
354

875

1502

1-propyl-2-{[2-(1,3-thiazol-2-yl)- 1H-imidazol-1-yl]methyl}-1H- imidazo[4,5-c]pyridine

1
H NMR(CDCl3) δ 9.07(s, 1H), 8.41(d, 1H), 7.82(d, 1H), 7.38(d, 1H), 7.25(d, 1H), 7.19(s, 1H), 7.12(s, 1H), 6.35(s, 2H), 4.14(t, 2 H), 1.53(q, 2H), 0.74(1, 3H)
m/e 325

876

1503

1-ethyl-2-{[2-(1,3-thiazol-2-yl)-1H- imidazol-1-yl]methyl}-1H- imidazo[4,5-c]pyridine

1
H NMR(CDCl3) δ 9.08(s, 1H), 8.43(d, 1H), 7.85(d, 1H), 7.38(d, 1H), 7.38-7.26(m, 1H), 7.17(s, 1 H), 7.14(s, 1H), 6.35(s, 2H), 4.25 (q, 2H), 1.11(t, 3H)
m/e 311

877

1504

2-{[2-(6-fluoropyridin-2-yl)-1H- imidazol-1-yl]methyl}-6-methyl-1- propyl-1H-imidazo[4,5-c]pyridine

1
H NMR(CDCl3) δ 8.93(s, 1H), 8.16(d, 1H), 7.87(dd, 1H), 7.20 (d, 1H), 7.16(d, 1H), 7.10(d, 1H), 6.87(d, 1H), 6.26(s, 2H), 4.19(t, 2H), 2.65(s, 3H), 1.65(q, 2H), 0.83(t, 3H)
m/e 351

878

1505

2-{[2-(3-fluorophenyl)-1H- imidazol-1-yl]methyl}-6-methyl-1- propyl-1H-imidazo[4,5-c]pyridine

1
H NMR(CDCl3) δ 8.95(s, 1H), 7.49-7.36(m, 3H), 7.19-7.15 (m, 2H), 7.04(m, 2H), 5.48(s, 2 H), 3.64(t, 2H), 2.64(s, 3H), 1.40 (q, 2H), 0.73(t, 3H)

879

1506

3-(cyclopropylmethyl)-2-{[2-(1,3- thiazol-2-yl)-1H-imidazol-1- yl]methyl}-3H-imidazo[4,5- b]pyridine
dihydrochloride 1H NMR(d6 DMSO): 8.35(1H, dd), 7.95(1H, dd), 7.90-7.87(2H, m), 7.81(1H, s), 7.52(1H, s), 7.27(1H, dd), 6.35(2H, s), 4.31(2H, d0, 1.42-1.38(1H, m), 0.55-0.52(4H, m)
335.1 [M − 1]

880

1507

2-{1-[(3-propyl-3H-imidazo[4,5- b]pyridin-2-yl)methyl]-1H- imidazol-2-yl]benzonitrile
dihydrochloride 1H NMR(d6 DMSO): 8.31(1H, d), 8.15(1H, s), 8.05-8.03(2H, m), 7.94-7.92(2H, m), 7.85-7.77(2H, m), 7.27-7.24(1H, m), 5.97(1H, s), 4.14(2H, t), 1.72 1.64(2H, m), 0.75(3H, t)
343.3 [M + 1]

881

1508

2-{[2-(5-methylisoxazol-3-yl)-1H- imidazol-1-yl]methyl}-3-propyl-3H imidazo[4,5-b]pyridine

1
H NMR, δppm(CDCl3): 8.39(dd, 1H), 8.04(dd, 1H), 7.19-7.27(m, 3H), 6.65(d, 1H), 6.10(s, 2H), 4.26(t, 2H), 1.63(m, 2H), 0.83(t, 3H)
323.2

882

1509

3-isopropyl-2-{[2-(1,3-thiazol-2- yl)-1H-imidazol-1-yl]methyl}-3H- imidazo[4,5-b]pyridine

1
H NMR, δppm(CDCl3): 8.37(dd, 1H), .8.02(dd, 1H) 7.84(d, 1H), 7.39(d, 1H), 7.11-7.23(m, 3H), 6.32(s, 2H), 4.92(m, 1H), 1.56(d, 6H)
325.4

883

1510

1-(1-ethyl-2-{[2-(1,3-thiazol-2-yl)- 1H-imidazol-1-yl]methyl}-1H- benzimidazol-5-yl)ethanone

1
H NMR, δppm(CDCl3): 8.39(d, 1H), .8.00(dd, 1H) 7.84(d, 1H), 7.39(d, 1H), 7.37(d, 1H), 7.18(d, 1H), 7.13(d, 1H), 6.35(s, 2H), 4.27(q, 2H), 2.67(s, 3H), 1.12(t, 3H)
352.2

884

1511

2-{[2-(2,3-difluorophenyl)-1H- imidazol-1-yl]methyl}-1-ethyl-1H- benzimidazole-5-carbonitrile

1
H NMR, δppm(CDCl3): 8.09(dd, 1H) 7.55(dd, 1H), 7.19-7.40(m, 5H), 7.04(d, 1H), 5.40(s, 2H), 3.86(q, 2H), 1.02(t, 3H)

885

1512

2-{[2-(5-fluoro-2-methylphenyl)- 1H-imidazol-1-yl]methyl}-3-propyl 3H-imidazo[4,5-b]pyridine

1
H NMR, δppm(CDCl3): 8.39(dd, 1H), 8.03(dd, 1H), 7.20-7.31(m, 3H), 7.07-7.13(m, 3H), 5.24(s, 2H), 3.88(t, 2H), 2.22(s, 3H), 1.54(m, 2H), 0.78(t, 3H)
350.3

886

1513

2-{[2-(2-fluoro-5-methylphenyl)- 1H-imidazol-1-yl]methyl}-3-propyl 3H-imidazo[4,5-b]pyridine

1
H NMR, δppm(CDCl3): 8.3 8(dd, 1H), 8.04(dd, 1H), 7.44(dd, 1H), 7.22-7.30(m, 2H), 7.19(d, 1H), 7.12(dd, 1H), 7.05(d, 1H), 5.37(s, 2H), 3.84(t, 2H), 2.36(s, 3H), 1.46(m, 2H), 0.76(1, 3H)
350.3

887

1514

2-{[2-(5-fluoro-2-methoxyphenyl)- 1H-imidazol-1-yl]methyl}-3-propyl 3H-imidazo[4,5-b]pyridine

1
H NMR, δppm(CDCl3): 8.39(dd, 1H), 8.03(dd, 1H), 7.15-7.32(m 4H), 7.03(d, 1H), 6.96(dd, 1H), 5.30(s, 2H), 3.84(t, 2H), 3.79(s, 3H), 1.46(m, 2H), 0.76(t, 3H)
366.2

888

1515

1-ethyl-2-({2-[3- (trifluoromethyl)phenyl]-1H- imidazol-1-yl}methyl)-1H- imidazo[4,5-c]pyridine
dihydrochloride 1H NMR(d6 DMSO): 10.02(1H, s), 8.70(1H, d), 8.37(1H, d), 8.08(1H, s), 7.97-7.94(3H, m), 7.82(1H, s), 7.75(1H, t), 6.09(2H, s), 4.45(2H, q), 1.32(3H, t).

889

1516

1-ethyl-2-{[2-(5-fluoro-2- methylphenyl)-1H-imidazol-1- yl]methyl}-1H-benzimidazole-5- carbonitrile
hydrochloride 1H NMR(d6 DMSO): 8.10(1H, s), 8.07(1H, d), 7.95(1H, d), 7.78(1H, d), 7.64(1H, dd), 7.52(1H, dd), 7.38-7.35(2H, m), 5.82(2H, s), 4.23(2H, q), 2.17(3H, s), 1.18(3H, t).

890

1517

2-{[2-(2,6-difluorophenyl)-1H- imidazol-1 -yl]methyl}-1-propyl-1H- imidazo[4,5-c]pyridine

1
H NMR(CDC13) δ 9.05(s, 1H), 8.43(d, 1H), 7.5-7.4(m, 1H), 7.27-7.23(m, 2H), 7.07-7.01(m, 3H), 5.34(s, 2H), 3.75(t, 2H), 1.47 (q, 2H), 0.77(t, 3H)
m/e 354

891

1518

2-{[2-(2,6-difluorophenyl)-1H- imidazol-1-yl]methyl}-1-ethyl-1H- imidazo[4,5-c]pyridine

1
H NMR(CDCl3) δ 9.05(s, 1H), 8.43(d, 1H), 7.52-7.42(m, 1H), 7.27-7.23(m, 2H), 7.08-7.01 (m, 3H), 5.35(s, 2H), 3.85(q, 2 H), 1.02(t, 3H)
m/e 340

892

1519

2-{[2-(3,4-difluorophenyl)-1H- imidazol-1-yl]methyl}-1-ethyl-1H- imidazo[4,5-c]pyridine

1
H NMR(CDCl3) δ 9.10(s, 1H), 8.46(d, 1H), 7.56-7.51(m, 1H), 7.42-7.30(m, 1H), 7.31-7.26 (m, 2H), 7.16(d, 1H), 7.03(d, 1 (t, 3H)
m/e 340

893

1520

2-{[2-(5-fluoro-2-methylphenyl)- 1H-imidazol-1-yl]methyl}-1-propyl- 1H-imidazo[4,5-c]pyridine

1
H NMR(CDCl3) δ 9.07(s, 1H), 8.43(d, 1H), 7.31-7.23(m, 3H), 7.12-7.04(m, 3H), 5.24(t, 2H), 3.73(t, 2H), 2.21(s, 3H), 1.49(q, 2H), 0.75(t, 3H)
m/e 350

894

1521

1-ethyl-2-{[2-(5-fluoro-2- methylphenyl)-1H-imidazol-1- yl]methyl}-1H-imidazo[4,5- c]pyridine

1
H NMR(CDCl3) δ 9.08(s, 1H), 8.44(d, 1H), 7.31-7.24(m, 3H), 7.12-7.04(m, 3H), 5.25(s, 1H), 3.83(q, 2H), 2.22(s, 3H), 1.06(t, 3H)
m/e 336

895

1522

2-{[2-(1,3-thiazol-2-yl)-1H- imidazol-1-yl]methyl}-3-(2,2,2- trifluoroethyl)-3H-imidazo[4,5- b]pyridine
H-1 NMR(CDCl3): line list provided 5.32(q, 2H), 6.19(s, 2H), 7.19(s, 1H), 7.26(m, 2H), 7.43(s, 1H), 7.79(d, 1H), 8.04(d, 1H), 8.41 (m, 1H)
365 [M + 1]

896

1523

2-{[2-(6-fluoropyridin-2-yl)-1H- imidazol-1-yl]methyl}-3-(2,2,2- trifluoroethyl)-3H-imidazo[4,5- b]pyridine
HCl salt H-1 NMR(CD3OD): 5.42 (q, 2H), 6.40(s, 2H), 7.24(d, 1H), 7.37(m, 1H), 7.90(m, 2H), 8.03(m, 2H), 8.22(m, 1H), 8.43(m, 1H)
377 [M + 1]

897

1524

2-{[2-(3,4-difluorophenyl)-1H- imidazol-1-yl]methyl)-3-ethyl-3H- imidazo[4,5-b]pyridine

1
H NMR, δppm(CDCl3): 8.39(dd, 1H), 8.04(dd, 1H), 7.54(m 1H), 7.40(m, 1H), 7.26-7.32(m, 2H), 7.16(d, 1H), 7.04(d, IN), 5.47(s, 2H), 4.02(q, 2H), 1.09(t, 3H)
340.2

898

1525

2-{[2-(1-methyl-1H-pyrazol-3-yl)- 1H-imidazol-1-yl]methyl)-3-propyl 3H-imidazo[4,5-b]pyridine
1H NMR(CDCl3): 8.38(1H, dd), 8.05(1H, dd), 7.42(1H, d), 7.23(1H, dd), 7.09(1H, d), 7.04(1H, d), 6.91(1H, d), 6.21(2H, s), 4.19(2H, t), 3.97(3H, s), 1.61-1.50(2H, m), 0.76(3H, t)
322.3 [M + 1]

899

1526

2-{[2-(2,3-difluorophenyl)-1H- imidazol-1-yl]methyl}-1-ethyl-1H- imidazo[4,5-c]pyridine
dihydrochioride 1H NMR(d6 DMSO): 9.44(1H, s), 8.70(1H, d), 8.37(1H, d), 8.04(1H, s), 7.89(1H, s), 7.73(1H, q), 7.49(1H, d), 7.37(1H, t), 6.05(2H, s), 4.44(2H, q), 1.30(3H, t)
340.2

900

1527

1-propyl-2-[(2-quinolin-2-yl-1H- imidazol-1-yl)methyl]-1H- benzimidazole-5-carbonitrile
dihydrochloride 1H NMR(d6 DMSO): 8.60(1H, d), 8.3591H, d), 8.02-7.99(2H, m), 7.88-7.85(2H, m), 7.79-7.60(5H, m), 6.54(2H, s), 4.47(2H, t), 1.85-1.77(2H, m), 0.89(3H, t)
393.4 [M + 1]

901

1528

2-{[2-(2,4-difluorophenyl)-1H- imidazol-1-yl]methyl}-3-ethyl-3H- imidazo[4,5-b]pyridine
dihydrochloride 1H NMR(d6 DMSO) 8.35-8.33(1H, m), 8.07-8.06(1H, m), 7.99-7.96(2H, m), 7.86 7.80(1H, m), 7.63-7.57(1H, m), 7.35-7.32(1H, m), 7.28-7.25(1H, m), 5.89(2H, s), 4.27(2H, q), 1.28(3H, t)
340.2 [M + 1]

902

1529

1-Propyl-2-(2-pyrimidin-2-yl- imidazol-1-ylmethyl)-1H- benzoimidazole-5-carbonitrile
dihydrochloride 1H NMR(d6 DMSO): 8.92(2H, d), 8.18(1H, d), 8.00-7.99(2H, m), 7.88(1H, dd), 7.65-7.62(2H, m), 6.46(2H, s), 4.42(2H, t), 1.93-1.84(2H, m), 0.97(3H, t)
344.2 [M + 1]

903

1530

3-ethyl-2-{[2-(2,3,6- trifluorophenyl)-1H-imidazol-1- yl]methyl}-3H-imidazo[4,5- b]pyridine

1
H NMR, δppm(CDCl3): 8.40(dd, 1H), 8.02(dd, 1H), 7.24-7.32(m, 3H), 7.11(d, 1H), 7.00(m, 1H), 5.36(s, 2H), 4.02(q, 2H), 1.09(t, 3H)
358.2

904

1531

3-propyl-2-[(2-thien-3-yl-1H- imidazol-1-yl)methyl]-3H- imidazo[4,5-b]pyridine

1
H NMR, δppm(CDCl3): 8.40(dd, 1H), 8.05(dd, 1H), 7.66(dd, 1H), 7.43-7.49(m, 2H), 7.25(dd, 1H), 7.14(d, 1H), 7.02(d, 1H), 5.55(s, 2H), 3.91(t, 2H), 1.51(m, 2H), 0.79(t, 3H)
324.3

905

1532

1-{1-ethyl-2-[(2-pyrimidin-2-yl-1H- imidazol-1-yl)methyl]-1H- benzimidazol-5-yl}ethanone

1
H NMR, δppm(CDCl3): 8.87(d, 2H), .8.41(dd, 1H), 8.02(dd, 1H), 7.40(dd, 1H), 7.26-7.31(m, 2H), 7.16(d, 1H), 6.40(s, 2H), 4.27(q, 2H), 2.69(s, 3H), 1.17(1, 3H)

906

1533

1-ethyl-2-{[2-(6-fluoropyridin-2-yl)- 1H-imidazol-1-yl]methyl}-6- methyl-1H-imidazo[4,5-c]pyridine

1
H NMR(CDCl3) δ 8.93(s, 1H), 8.16(d, 1H), 7.87(dd, 1H), 7.18 (d, 1H), 7.12(s, 1H), 6.87(d, 1H), 6.26(s, 2H), 4.30(q, 2H), 2.65(s, 3H), 1.22(t, 3H)
m/e 337

907

1534

1-ethyl-2-{[2-(3-fluorophenyl)-1H- imidazol-1-yl]methyl}-6-methyl- 1H-imidazo[4,5-c]pyridine
dihydrochloride 1H NMR(DMSO- d6) δ 9.28(s, 1H), 8.24(s, 1H), 8.23(d, 1H), 7.94(d, 1H), 7.69-7.48(m, 4H), 6.12(s, 2H), 4.39(q, 2H), 2.77(s, 3H), 1.35(t, 3H);
m/e 336

908

1535

3-ethyl-2-({2-[2-fluoro-5- (trifluoromethyl)phenyl]-1H- imidazol-1-yl}methyl)-3H- imidazo[4,5-b]pyridine
H-1 NMR(CDCl3): line list provided 1.08(1, 3H), 3.99(q, 2H), 5.38(s, 2H), 7.10(s, 1H), 7.22-7.39 (m, 2H), 7.75(m, 1H), 7.93(m, 1H), 8.02(d, 1H), 8.38(d, 1H)
390 (M + 1)

909

1536

2-{[2-(2-methylphenyl)-1H- imidazol-1-yl]methyl}-3-propyl-3H- imidazo[4,5-b]pyridine
H-1 NMR(CDCl3): line list provided 0.73(t, 3H), 1.49(m, 2H), 2.24(s, 3H), 3.81(m, 2H), 5.22(s, 2H), 7.10(s, 1H), 7.18-7.36(m, 6H), 8.02(d, 1H), 8.37(d, 1H)
332 [M + 1]

910

1537

6-{1-[(3-cyclopropyl-3H- imidazo[4,5-b]pyridn-2-yl)methyl]1H-imidazol-2-yl}pyridine-2- carbonitrile
H-1 NMR(CDC13): line list provided 1.28(m, 4H), 3.37(m, 1H) 3.48(s, 2H), 6.36(s, 2H), 7.15-7.28(m, 3H), 7.56(d, 1H), 7.86(m, 2H), 8.38(m, 1H), 8.54(d, 1H)
342 [M + 1]; 340 (M − 1)

911

1538

4-fluoro-3-{1-[(3-propyl-3H- imidazo[4,5-b]pyridin-2-yl)methyl]1H-imidazol-2-yl}benzonitrile
CDCl3: 8.38(dd, J=1.48, 4.81Hz, 1H), 7.98(dt, J=1.48, 7.35Hz, 2H), 7.72-7.78(m, 1H), 7.35(t, J=9.07Hz, 1H), 7.22-7.26(m, 2H), 7.11(d, J=11Hz, 1H), 5.37 (s, 2H), 3.93(t, J=7.69Hz, 2H), 1.54(dq, J=7.42, 7.69Hz, 2H),
361.2 [M + 1]

912

1539

1-propyl-2-({2-[3- (trifluoromethyl)phenyl]-1H- imidazol-1-yl}methyl)-1H- imidazo[4,5-c]pyridine
1H NMR(CDCl3): 9.09(1H, s), 8.43(1H, d), 7.93(1H, s), 7.84(1H, d), 7.72(1H, d), 7.62(1H, t), 7.25(1H,), 7.19(1H, d), 7.09(1H, d), 5.50(2H, s), 3.63(2H, t), 1.49-1.39(2H, m), 0.75(3H, t).

913

1540

2-{[2-(6-fluoropyridin-2-yl)-1H- imidazol-1-yl]methyl}-1-propyl-1H- benzimidazole-5-carbohydrazide
CD3OD: 8.10-8.29(m, 6H), 8.03 (S, 1H), 7.29(d, 1H), 6.4(s, 2H), 4.59-4.65(m, 2H), 2.0-2.12(m, 2H), 1.06-1.07(m, 3H).
394.3 [M + 1]

[0632]

7

TABLE 7

Cmp.

MS

#
STRUCTURE
IUPAC NAME
NMR
(m/z)

914

1541

1-ethyl-2-{[1-(3- fluorophenyl)-1H- pyrazol-5-yl]methyl}- 5-(morpholin-4- ylmethyl)-1H- benzimidazole

420.3 [M + 1]

915

1542

ethyl 1-ethyl-2-{[1-(3- fluorophenyl)-1H- pyrazol-5-yl]methyl}- 1H-benzimidazole-5- carboxylate

393.3 [M + 1]

916

1543

1-ethyl-2-{[1-(3- fluorophenyl)-1H- pyrazol-5-yl]methyl}- 1H-benzimidazole-5- carboxylic acid

365.2 [M + 1]

917

1544

N-[2-(dipropylamino)- ethyl]-1-ethyl-2-{[1- (3-fluorophenyl)-1H- pyrazol-5-yl]methyl}- 1H-benzimidazole-5- carboxamide

491.4 [M + 1]

918

1545

N,1-diethyl-2-{[1-(3- fluorophenyl)-1H- pyrazol-5-yl]methyl}- 1H-benzimidazole-5- carboxamide

392.3 [M + 1]

919

1546

1-ethyl-2-{[1-(3- fluorophenyl)-1H- pyrazol-5-yl]methyl}- N-phenyl-1H- benzimidazole-5- carboxamide

392.3 [M + 1]

920

1547

1-ethyl-2-{[1-(3- fluorophenyl)-1H- pyrazol-5-yl]methyl}- 5-[(4-methylpiperazin- 1-yl)methyl]-1H- benzimidazole
1H NMR(CDCl3): 7.65(d, 1H), 7.61(d, 1H), 7.45(m, 1H), 7.22-7.31 (m, 4H), 7.11(m, 1H), 6.16(d, 1H), 4.31(s, 2H), 3.96(q, 2H), 3.62(s, 2H),

# 2.40-2.60(m, 8H), 2.25 (s, 3H), 1.22(t, 3H)

921

1548

1-ethyl-5-[(4- ethylpiperazin-1- yl)methyl]-2-{[1- (3-fluorophenyl)-1H- pyrazol-5-yl]methyl}- 1H-benzimidazole
1H NMR(CDCl3): 7.65(d, 1H), 7.62(d, 1H), 7.45(m, 1H), 7.23-7.30 (m, 4H), 7.13(m, 1H), 6.16(d, 1H), 4.31(s, 2H), 3.96(q, 2H), 3.62(s, 2H),

# 2.40-2.60(m, 10H), 1.21 (t, 3H), 1.078(t, 3H)

922

1549

5-[(4-cyclopentyl- piperazin-1-yl)- methyl]-1-ethyl-2-{[1- (3-fluorophenyl)-1H- pyrazol-5-yl]methyl}- 1H-benzimidazole
1H NMR(CDCl3): 7.65(d, 1H), 7.61(d, 1H), 7.45(m, 1H), 7.22-7.31 (m, 4H), 7.13(m, 1H), 6.15(d, 1H), 4.31(s, 2H), 3.96(q, 2H), 3.63(s, 2H),

# 2.40-2.60(m, 9H), 1.31-1.90(m, 8H), 1.21(t, 3H.)

923

1550

5-[(4-cycloheptyl- piperazin-1-yl)- methyl]-1-ethyl-2-{[1- (3-fluorophenyl)-1H- pyrazol-5-yl]methyl}- 1H-benzimidazole

515.5 [M + 1]

924

1551

2-{[1-(3-chloro- phenyl)-1H-pyrazol- 5-yl]methyl}-1-ethyl- 5-(morpholin-4- ylmethyl)-1H- benzimidazole

436.3 [M +1]; 434.3 [M + 1]

925

1552

1′-[(1-ethyl-2-{[1- (3-fluorophenyl)-1H- pyrazol-5-yl]methyl}- 1H-benzimidazol-5- yl)methyl]-1,4′- bipiperidine
1H NMR(CDCl3): 7.63(d, 1H), 7.61(d, 1H), 7.44(m, 1H), 7.2307.31 (m, 4H), 7.13(m, 1H), 6.16(d, 1H), 4.31(s, 2H), 3.96(q, 2H), 3.61(s, 2H),

# 2.96(m, 2H), 2.50(m, 4H), 1.40-2.31(m, 13H), 1.23 (t, 3H)

926

1553

1-ethyl-2-{[1-(3- fluorophenyl)-1H- pyrazol-5-yl]methyl}- 5-[(4-pyrrolidin- 1-ylpiperidin-1-yl) methyl]-1H- benzimidazole

927

1554

1-ethyl-2-{[1-(3- fluorophenyl)-1H- pyrazol-5-yl]methyl}- 5-[(4-phenylpiperazin- 1-yl)methyl]-1H- benzimidazole
1H NMR(CDCl3): 7.69(d, 1H), 7.62(s, 1H), 7.45(m, 1H), 7.21-7.33 (m, 6H), 7.13(m, 1H), 6.82-6.94(m, 3H), 6.16 (d, 1H), 4.33(s, 2H),

# 3.97(q, 2H), 3.69(s, 2H), 3.15-3.23(m, 4H), 2.59-2.67(m, 4H), 1.21(t, 3H)

928

1555

2-{[1-(3-chloro- phenyl)-1H-pyrazol- 5-yl]methyl}-5-[(4- cycloheptylpiperazin- 1-yl)carbonyl]-1-ethyl- 1H-benzimidazole

545.4 [M +1]; 543.4 [M + 1]

929

1556

1-ethyl-2-{[1-(3- fluorophenyl)-1H- pyrazol-5-yl]methyl}- 1H-benzimidazole-5- carboxamide

930

1557

1-ethyl-5-fluoro-2-{[1- (3-fluorophenyl)-1H- pyrazol-5-yl]methyl}- 1H-benzimidazole
(L)-Tartrate salt 1H NMR (CD3OD): 7.67(s, 1H), 7.05-7.46 (m, 7H), 6.31(s, 1H), 4.53(s, 2H), 4.47(s, 2H), 4.14(q, 2H), 1.21(t, 3H)

931

1558

5-chloro-1-ethyl-2-{[1- (3-fluorophenyl)-1H- pyrazol-5-yl]methyl}- 1H-benzimidazole
(L)-Tartrate salt 1H NMR(d6-DMSO): 7.65(s, 1H), 7.21-7.58 (m, 7H), 6.26(s, 1H), 4.48(s, 2H), 4.30(s, 2H), 4.16(q, 2H), 1.15(t, 3H)

932

1559

5-bromo-1-ethyl-2- {[1-(3-fluorophenyl)- 1H-pyrazol-5-yl]- methyl}-1H- benzimidazole
(L)-Tartrate salt 1H NMR(d6-DMSO): 7.72(d, 1H), 7.65(d, 1H), 7.21-7.53(m, 6H), 6.26 (s, 1H), 4.48(s, 2H), 4.30(s, 2H), 4.16(q, 2H), 1.14(t, 3H)

933

1560

1-ethyl-2-{[1- (3-fluorophenyl)-1H- pyrazol-5-yl]methyl}- 5-phenyl-1H- benzimidazole
1H NMR(CDCl3): 7.96(d, 1H), 7.27-7.66 (m, 11H), 7.14(m, 1H), 6.21(d, 1H), 4.38(s, 2H), 4.01(q, 2H), 1.25(t, 3H)

934

1561

2-{[1-(2,5-difluoro- phenyl)-1H-pyrazol- 5-yl]methyl}-1-ethyl- 1H-benzimidazole-5- carbonitrile

364.2 [M + 1]

935

1562

2-{[1-(3-chloro- phenyl)-1H-pyrazol- 5-yl]methyl}-1-ethyl- 1H-benzimidazole-5- carbonitrile
1H NMR(CDCl3): 8.05(d, 1H), 7.36-7.65 (m, 7H), 6.21(d, 1H), 4.36(s, 2H), 4.02(q, 2H), 1.24(t, 3H)

936

1563

2-{[1-(2,5-difluoro- phenyl)-1H-pyrazol- 5-yl]methyl}-1-ethyl- 1H-benzimidazol-5- amine

354.2 [M + 1]

937

1564

2-{[1-(2,5-difluoro- phenyl)-1H-pyrazol- 5-yl]methyl}-1-ethyl- 5-(4H-1,2,4-triazol-4- yl)-1H-benzimidazole

405.95 [M + 1]

938

1565

1-ethyl-2-{[1- (3-fluorophenyl)-1H- pyrazol-5-yl]methyl}- 5-(1H-1,2,4-triazol-1- ylmethyl)-1H- benzimidazole

402.4 [M + 1]

939

1566

1-ethyl-2-{[1- (3-fluorophenyl)-1H- pyrazol-5-yl]methyl}- 5-(1H-tetraazol-1- ylmethyl)-1H- benzimidazole

403.2 [M +1]; 401.4 [M + 1]

940

1567

1-ethyl-2-{[1- (3-fluorophenyl)-1H- pyrazol-5-yl]methyl}- 5-(2H-tetraazol-2- ylmethyl)-1H- benzimidazole

403.4 [M +1]; 401.4 [M + 1]

941

1568

1-ethyl-2-{[1- (3-fluorophenyl)-1H- pyrazol-5-yl]methyl}- 5-[(methylthio)- methyl]-1H- benzimidazole

381.3 [M +1]; 379.3 [M + 1]

942

1569

2-{[1-(2,5-difluoro- phenyl)-1H-pyrazol- 5-yl]methyl}-1- ethyl-5-nitro- 1H-benzimidazole
Mesylate 1H NMR(d6 DMSO) 8.38(1H, d), 8.15-8.12 (1H, m), 7.77(1H, d), 7.71(1H, s), 7.51-7.34 (3H, m), 6.40(1H, s), 4.21(2H, q), 2.32(3H, s), 1.11(3H, t).

# 384.2 [M + 1]

943

1570

1-ethyl-2-{[1- (3-fluorophenyl)-1H- pyrazol-5-yl]methyl}- 5-(1,3-thiazol-5-yl)- 1H-benzimidazole
Hydrochloride 1H NMR(CD3OD): 9.725(s, 1H), 8.67(s, 1H), 8.13(s, 1H), 8.01-8.08 (m, 2H), 7.79(s, 1H), 7.21-7.57(m, 4H), 6.59 (d, 1H), 4.97(s, 2H),

# 4.50(q, 2H), 1.39(t, 3H)

944

1571

1-ethyl-2-{[1- (3-fluorophenyl)-1H- pyrazol-5-yl]methyl}- N-methoxy-N-methyl- 1H-benzimidazole-5- carboxamide
1H NMR(CDCl3): 8.13(d, 1H), 7.63-7.70 (m, 2H), 7.24-7.49 (m, 4H), 7.13(m, 1H), 6.19(d, 1H), 4.36(s, 2H), 4.00(q, 2H), 3.60(s, 3H),

# 3.40(s, H), 1.23(t, 3H)

945

1572

3-(1-ethyl-2-{[1- (3-fluorophenyl)- 1H-pyrazol-5-yl]- methyl}-1H- benzimidazol-5-yl)- benzonitrile
1H NMR(CDCl3): 7.84-7.92(m, 3H), 7.40-7.64(m, 6H), 7.26-7.33 (m, 2H), 7.14(m, 1H), 6.21(d, 1H), 4.37(s, 2H), 4.03(q, 2H), 1.26(t, 3H)

946

1573

N-[3-(1-ethyl-2-{[1- (3-fluorophenyl)- 1H-pyrazol-5-yl]- methyl}-1H- benzimidazol-5-yl)- phenyl]acetamide
1H NMR(CDCl3): 7.93(d, 1H), 7.26-7.72(m, 10H), 7.14(m, 1H), 6.20(d, 1H), 4.36(s, 2H), 4.01(q, 2H), 2.21(s, 3H), 1.24(t, 3H)

947

1574

1-ethyl-2-{[1-(3- fluorophenyl)-1H- pyrazol-5-yl]methyl}- 5-[4-(trifluoro- methoxy)phenyl]-1H- benzimidazole
1H NMR(CDCl3): 7.92(d, 1H), 7.27-7.65(m, 10H), 7.14(m, 1H), 6.20(d, 1H), 4.37(s, 2H), 4.08(q, 2H), 1.25(t, 3H)

948

1575

5-(3-chloro-4-fluoro- phenyl)-1-ethyl-2-{[1- (3-fluorophenyl)-1H- pyrazol-5-yl]methyl}- 1H-benzimidazole
1H NMR(CDCl3): 7.897(d, 1H), 7.63-7.66(m, 2H), 7.11-7.50 (m, 8H), 6.21(d, 1H), 4.36(s, 2H), 4.02(q, 2H), 1.25(t, 3H)

949

1576

1-ethyl-5-(3-fluoro- phenyl)-2-{[1- (3-fluorophenyl)-1H- pyrazol-5-yl]methyl}- 1H-benzimidazole
1H NMR(CDCl3): 7.95(d,1 H), 7.64(d, 1H), 7.27-7.53(m, 8H)/7.14 (m, 2H), 7.03(m, 1H), 6.20(d, 1H), 4.36(s, 2H), 4.02(q, 2H), 1.25(t, 3H)

950

1577

1-ethyl-2-{[1-(3- fluorophenyl)-1H- pyrazol-5-yl]methyl}- 5-pyridin-3-yl- 1H-benzimidazole
1H NMR(CDCl3): 8.90(d, 1H), 8.59(m, 1H), 7.90-7.95(m, 2H), 7.64 (d, 1H), 7.25-7.53 (m, 6H), 7.14(m, 1H), 6.21(d 1H), 4.37(s, 2H), 4.03(q 2H), 1.26(t, 3H)

951

1578

1-ethyl-2-{[1-(3- fluorophenyl)-1H- pyrazol-5-yl]methyl}- 5-pyridin-4-yl- 1H-benzimidazole
1H NMR(CDCl3): 8.67(d, 1H), 8.65(d, 1H), 8.03(d, 1H), 7.26-7.65 (m, 8H), 7.15(m, 1H), 6.21(d, 1H), 4.37(s, 2H), 4.03(q, 2H), 1.26(t, 3H)

952

1579

2-{[1-(2,5-difluoro- phenyl)-1H-pyrazol- 5-yl]methyl}-1-ethyl- 5-(methylidyne- lambda-5˜-azanyl)- 1H-benzimidazole
1H NMR(CDCl3): 7.70-7.67(2H, m), 7.31-7.14(5H, m), 6.16(1H, s), 4.28(2H, s), 4.02(2H, q), 1.22(3H, t)
364.1 [M + 1]

953

1580

N-(2-{[1-(2,5-difluoro- phenyl)-1H-pyrazol- 5-yl]methyl}-1-ethyl- 1H-benzimidazol- 5-yl)-2,2,2-tri- fluoroacetamide

449.96 [M + 1]

954

1581

2-{[1-(2,5-difluoro- phenyl)-1H-pyrazol- 5-yl]methyl}-1- ethyl-5-(1H-tetraazol- 1-yl)-1H- benzimidazole
1H NMR(DMSO): 10.07(s, 1H0, 8.07(s, 1H), 7.86(d, 1H), 7.79(d, 1H), 7.71(s, 1H), 7.36-7.57(m, 3H), 6.4 (s, 2H), 4.46(s, 2H), 4.21(q, 2H0, 1.14 (t, 3H)

955

1582

1-(1-ethyl-2-{[1-(3- fluorophenyl)-1H- pyrazol-5-yl]methyl}- 1H-benzimidazol- 5-yl)ethanol

956

1583

2-{[1-(3-chloro- phenyl)-1H-pyrazol- 5-yl]methyl}-1-ethyl- N-methoxy-N-methyl- 1H-benzimidazole-5- carboxamide
1H NMR(CDCl3): 8.13(d, 1H), 7.63-7.70 (m, 2H), 7.51(m, 1H), 7.31-7.41(m, 4H), 6.20 (d, 1H), 4.35(s, 2H), 4.00(q, 2H), 3.60(s, 3H),

# 3.40(s, 3H), 1.23(t, 3H)

957

1584

2-{[1-(2,5-difluoro- phenyl)-1H-pyrazol- 5-yl]methyl}-1-ethyl- 5-(5-methyl-1,3,4- oxadiazol-2-yl)-1H- benzimidazole

437.02 [M + 1]

958

1585

1-(2-{[1-(3-chloro- phenyl)-1H-pyrazol- 5-yl]methyl}-1-ethyl- 1H-benzimidazol- 5-yl)ethanone
1H NMR(CDCl3): 8.37(d, 1H), 8.03(dd, 1H), 7.65(d, 1H), 7.38-7.50(m, 5H), 6.24(d, 1H), 4.49(s, 2H), 4.03(q, 2H), 2.68(s, 3H), 1.24(t, 3H)

959

1586

2-{[1-(2,5-difluoro- phenyl)-1H-pyrazol- 5-yl]methyl}-1-ethyl- 5-[5-(trifluoromethyl)- 1H-tetraazol-1-yl]- 1H-benzimidazole

474.99 [M + 1]

960

1587

5-(3,5-difluorophenyl)- 1-ethyl-2-{[1- (3-fluorophenyl)-1H- pyrazol-5-yl]methyl}- 1H-benzimidazole
1H NMR(CDCl3): 7.91(d, 1H), 7.64(d, 1H), 7.27-7.50(m, 5H), 7.10-7.18(m, 3H), 6.77(m, 1H), 6.20(d, 1H), 4.36(s, 2H), 4.02(q, 2H), 1.25(t, 3H)

961

1588

(1Z)-1-(2-{[1-(3- chlorophenyl)-1H- pyrazol-5-yl]methyl}- 1-ethyl-1H- benzimidazol-5-yl)- ethanone O-methyloxime
1H NMR(CDCl3): 7.94(d, 1H), 7.73 (dd, 1H), 7.73(dd, 1H), 7.63(d, 1H), 7.52(m, 1H), 7.38-7.40(m, 3H), 7.27 (m, 1H), 6.19(d, 1H),

# 4.32(s, 2H), 3.87-4.10 (m, 5H), 2.30(s, 3H), 1.22(t, 3H.)

962

1589

2-{[1-(2,5-difluoro- phenyl)-1H-pyrazol- 5-yl]methyl}-1-ethyl- 5-(1,3,4-oxadiazol-2- yl)-1H-benzimidazole

425.10 [M + 1]

963

1590

(1E)-1-(1-ethyl-2-{[1- (3-fluorophenyl)- 1H-pyrazol-5-yl]- methyl}-1H- benzimidazol-5-yl)- ethanone oxime
1H NMR(CD3OD): 7.81(d, 1H), 7.64-7.68 (m, 2H), 7.42-7.53 (m, 2H), 7.16-7.32 (m, 3H), 6.28(d, 1H), 4.44(s, 2H), 4.12(q, 2H),

# 2.30(s, 3H), 1.23(t, 3H)

964

1591

(1E)-1-(1-ethyl-2-{[1- (3-fluorophenyl)- 1H-pyrazol-5-yl]- methyl}-1H- benzimidazol-5-yl)- ethanone O-ethyloxime
Syn and anti 1H NMR(CDCl3): 7.95(d, 1H+H1), 7.73(dd, 1H+H1), 7.63 (d, 1H+H1), 7.44 (m, 1H+H1), 7.24-7.33

# (m, 3H+H1), [6.18 (d, 1H+H1), 7.13 (d, 1H+H1)], 4.33 (s, 2H), [4.26(q, 2H), 4.13(q, 2H1)], 3.98 (q, 2H+2H1), [2.31 (s, 3H), 2.27(s, 3H1)], [1.35(t, 3H), 1.28(t, 3H1)], 1.22(t, 3H+H1)]

965

1592

2-{[1-(2,5-difluoro- phenyl)-1H-pyrazol- 5-yl]methyl}-1-ethyl- 5-(5-pyridin-3-yl- 1,3,4-oxadiazol- 2-yl)-1H- benzimidazole

# 1H NMR(d6 DMSO): 9.40(1H, s), 8.87(1H, s), 8.63(1H, d), 8.41(1H, s), 8.20(1H, d), 8.01(1H, d), 7.76(2H, m), 7.59(1H, m), 7.48-7.41(2H, m), 6.50 (1H, s), 4.61(2H, s), 4.31(2H, q), 1.19(3H, t)
484.5 [M + 1]

966

1593

2-(1-ethyl-2-{[1- (3-fluorophenyl)- 1H-pyrazol-5-yl]- methyl}-1H- benzimidazol-5-yl)-4- methoxybenzaldehyde
1H NMR(CDCl3): 9.86(s, 1H), 8.03(d, 1H), 7.26-7.78(m, 7H), 6.94-7.18(m, 3H), 6.22(dd, 1H), 4.38(s, 2H), 4.04(q, 2H), 3.91(s, 3H), 1.27(t, 3H)

967

1594

1-ethyl-2-{[1- (3-fluorophenyl)- 1H-pyrazol-5-yl]- methyl}-N,N- dimethyl-1H- benzimidazole-5- carboxamide
1H NMR(CDCl3): 7.78(s, 1H), 7.63(s, 1H), 7.10-7.48(m, 6H), 6.18 (s, 1H), 4.35(s, 2H), 4.00(q, 2H), 3.13(s, 3H), 3.05(s, 3H), 1.22(t, 3H)

968

1595

5-(3,5-dimethyl- isoxazol-4-yl)-1- ethyl-2-{[1-(3- fluorophenyl)-1H- pyrazol-5-yl]methyl}- 1H-benzimidazole
1H NMR(CDCl3): 7.62-7.64(m, 2H), 7.25-7.50(m, 4H), 7.11-7.18(m, 2H), 6.21(d, 1H), 4.36(s, 2H), 4.02(q, 2H), 2.42(s, 3H),

# 2.29(s, 3H), 1.26(t, 3H)

969

1596

5-bromo-2-{[1- (3-chlorophenyl)-1H- pyrazol-5-yl]methyl}- 1-ethyl-1H- benzimidazole
1H NMR(CDCl3): 7.87(d, 1H), 7.63(d, 1H), 7.50(m, 1H), 7.35-7.42(m, 4H), 7.18(d, 1H), 6.18(d, 1H), 4.31(s, 2H), 3.96(q, 2H), 1.21(t, 3H)

970

1597

2-{[1-(2,5-difluoro- phenyl)-1H-pyrazol- 5-yl]methyl}-1-ethyl- 5-(5-pyridin-4-yl- 1,3,4-oxadiazol-2-yl)- 1H-benzimidazole
Dihydrochloride 1H NMR(d6 DMSO): 8.98(2H, m), 8.43(1H, s), 8.35(2H, m), 8.19(1H, d), 7.99(1H, d), 7.75(1H, d), 7.59-7.5691H, m),

# 7.50-7.41(2H, m), 6.49 (1H, s), 4.58(2H, s), 4.30(2H, q), 1.19(3H, t)
484.5 [M + 1]

971

1598

(1E)-1-(2-{[1- (3-chlorophenyl)-1H- pyrazol-5-yl]methyl}- 1-ethyl-1H- benzimidazol-5-yl)- ethanone oxime
1H NMR(CDCl3): 10.92(br s, 1H), 8.58 (s, 1H), 7.52-7.64(m, 3H), 7.29(d, 1H), 6.20(d, 1H), 4.36(s, 2H), 3.97(q, 2H), 2.38(s, 3H), 1.21(t, 3H)

972

1599

(1E)-1-(2-{[1- (3-chlorophenyl)-1H- pyrazol-5-yl]methyl}- 1-ethyl-1H- benzimidazol-5-yl)- ethanone O- ethyloxime
Syn and anti 1H NMR(CDCl3): 7.95(d, 1H+H1), 7.73(dd, 1H+H1), 7.63(d, 1H+H1), 7.44(m, 1H+H1),

# 7.24-7.33(m, 3H+H1), [6.18(d, 1H+H1), 7.13(d, 1H+H1)], 4.33(s, 2H), [4.26(q, 2H), 4.13(q, 2H1)], 3.98(q, 2H+2H1), [2.31(s, 3H), 2.27(s, 3H1)], [1.35(t, 3H), 1.28(t, 3H1)], 1.22(t, 3H+H1)]

973

1600

(1E)-1-(2-{[1- (3-chlorophenyl)-1H- pyrazol-5-yl]methyl}- 1-ethyl-1H- benzimidazol-5- yl)ethanone O- (tert-butyl)oxime
Syn and anti 1H NMR(CDCl3): 8.00(d, 1H+H1), 7.75(dd, 1H+H1), 7.63(d, 1H+H1), 7.27(d, 1H+H1), 7.38-7.40(m, 3H+H1), 6.20(d, 1H) [6.18(d, 1H1)],

# 4.32(s, 2H+H1), 3.99(q, 2H+H1), 2.28(s, 3H), [2.27(s, 3H1]), 1.37(s, 9H), [1.32(s, 9H1]), 1.22(t, 3H, t3H)

974

1601

(1E)-1-(2-{[1- (3-chlorophenyl)-1H- pyrazol-5-yl]methyl}- 1-ethyl-1H- benzimidazol-5-yl)- ethanone O- tetrahydro-2H- pyran-2-yloxime
1H NMR(CDCl3): 7.95(d, 1H), 7.79 (dd, 1H), 7.63(d, 1H), 7.52(m, 1H), 7.37-7.40 (m, 3H), 7.26(dd, 1H), 6.19(d, 1H),

# 5.43(m, 1H), 4.32(s, 2H), 3.85-4.02(m, 4H), 3.66(m, 2H), 1.62-1.92(m, 4H), 1.22(t, 3H)

975

1602

(1-ethyl-2-{[1- (3-fluorophenyl)-1H- pyrazol-5-yl]methyl}- 1H-benzimidazol- 5-yl)acetonitrile
7.66(m, 1H), 7.63(d, 1H), 7.24-7.49(m, 5H), 7.13 (m, 1H), 6.17(d, 1H), 4.34(s, 2H), 3.99(q, 2H,), 3.87(s, 2H), 1.22(t, 3H)

976

1603

1-ethyl-2-{[1- (3-fluorophenyl)-1H- pyrazol-5-yl]methyl}- 5-(1,3,4-oxadiazol-2- yl)-1H-benzimidazole
1H NMR(d6 DMSO): 8.17(1H, s), 8.04-7.98 (2H, m), 7.71(1H, d), 7.55-7.50(2H, m), 7.45-7.43(1H, m), 7.29-

# 7.2491H, m), 6.40(1H, d), 4.77(2H, s), 4.36(2H, q), 2.58(3H, s), 1.24(3H, t)
403.6 [M + 1]

977

1604

1-ethyl-2-{[1- (3-fluorophenyl)-1H- pyrazol-5-yl]methyl}- 5-(5-methyl-1,3,4- oxadiazol-2-yl)-1H- benzimidazole
1H NMR(CD3OD): 8.79(s, 1H), 8.31(d, 1H), 7.69(s, 1H), 7.60(d, H), 7.46(dd, 1H), 7.30 (d, 2H), 7.16-7.20 (m, 1H), 6.37(s, 1H),

# 4.55(s, 2H), 4.20(q, 2H), 1.24(t, 3H)

978

1605

1-ethyl-2-{[1- (3-fluorophenyl)-1H- pyrazol-5-yl]methyl}- 1H-imidazo[4,5-c]- pyridine
1H NMR(CD3OD): 8.79(s, 1H), 8.31(d, 1H), 7.69(s, 1H), 7.60(d, H), 7.46(dd, 1H), 7.30 (d, 2H), 7.16-7.20 (m, 1H), 6.37(s, 1H), 4.55(s, 2H), 4.20(q, 2H),

# 1.24(t, 3H)

979

1606

1-ethyl-2-{[1- (3-fluorophenyl)-1H- pyrazol-5-yl]methyl}- 1H-benzimidazole- 6-carbonitrile

980

1607

1-(1-ethyl-2- {[1-(3-fluorophenyl)- 1H-pyrazol-5-yl]- methyl}-1H- benzimidazol-5- yl)propan-1-one

981

1608

2-{[1- (3-fluorophenyl)-1H- pyrazol-5-yl]methyl}- 1-(2-methoxyethyl)- 1H-benzimidazole- 5-carbonitrile

982

1609

2-{[1- (3-fluorophenyl)-1H- pyrazol-5-yl]methyl}- 1-(3-methoxypropyl)- 1H-benzimidazole- 5-carbonitrile

390.1 [M +1]; 388.3 [M + 1]

983

1610

1-(2-cyanoethyl)-2- {[1-(3-fluorophenyl)- 1H-pyrazol-5-yl]- methyl}-1H- benzimidazole-5- carbonitrile

371.3 [M + 1]

984

1611

1-ethyl-5-(5-ethyl- 1,3,4-oxadiazol- 2-yl)-2-{[1- (3-fluorophenyl)-1H- pyrazol-5-yl]methyl}- 1H-benzimidazole
1H NMR(d6DMSO): 8.17(1H, s), 8.01-7.94(2H, m), 7.71(1H, s), 7.53-7.51(2H, m), 7.44-7.42(1H, m), 7.28-7.24(1H, m), 6.39(1H, s),

# 4.73(2H, s), 4.33(2H, q), 2.94(2H, q), 1.32(3H, t), 1.23(3H, t)
417.5 [M + 1]

985

1612

5-(1-ethyl-2-{[1- (3-fluorophenyl)-1H- pyrazol-5-yl]methyl}- 1H-benzimidazol-5- yl)-1,3,4-oxadiazol-2- amine
1H NMR(d6DMSO): 8.17(1H, s), 8.01-7.94(2H, m), 7.71(1H, s), 7.53-7.51(2H, m), 7.44-7.42(1H, m), 7.28-7.24(1H, m), 6.39(1H, s),

# 4.73(2H, s), 4.33(2H, q), 2.94(2H, q), 1.32(3H, t), 1.23(3H, t)
417.5 [M + 1]

986

1613

2-[[1-(2,5-difluoro- phenyl)-1H-pyrazol- 5-yl](hydroxy)methyl]- 1-ethyl-1H- benzimidazole-5- carbonitrile
1H NMR(CDCl3): 7.93(d, 1H), 7.67(d, 1H), 7.55(dd, 1H), 7.40(dd, 1H): 7.24(m, 1H), 7.10-7.15 (m, 2H), 6.20(d, 1H), 6.01(s, 1H),

# 4.98(br, S, 1H): 4.04(q, 2H), 1.21(t, 3H)

987

1614

1-ethyl-2-{[1- (3-fluorophenyl)-1H- pyrazol-5-yl]methyl}- 1H-imidazo[4,5-b]- pyridine

322.3 [M +1]; 320.3 [M + 1]

988

1615

2-[[1-(2,5-difluoro- phenyl)-1H-pyrazol- 5-yl](fluoro)methyl]- 1-ethyl-1H- benzimidazole-5- carbonitrile
1H NMR(CDCl3): 8.07(d, 1H), 7.77(d, 1H), 7.60(dd, 1H), 7.47(dd, 1H), 7.11-7.23(m, 3H), 6.85[d, 1H, J(H, F)=47.4], 6.50(t, 1H),

# 4.27(m, 2H), 1.36(t, 3H)

989

1616

1-ethyl-2-{[1- (3-fluorophenyl)-1H- pyrazol-5-yl]methyl}- 5-(5-pyridin-3-yl- 1,3,4-oxadiazol-2-yl)- 1H-benzimidazole
1H NMR(d6DMSO): 9.41(1H, s), 8.88(1H, d), 8.67(1H, d), 8.46(1H, s), 8.25(1H, d), 8.10(1H, d), 7.81-7.72(2H, m), 7.55-7.46(3H, m),

# 7.30-7.26(1H, m), 6.43(1H, s), 4.84(2H, s), 4.40(2H, q), 1.27(3H, t)

990

1617

1-ethyl-2-{[1- (3-fluorophenyl)-1H- pyrazol-5-yl]methyl}- 5-isoxazol-5- yl-1H-benzimidazole
1H NMR(CDCl3): 8.30(d, 1H), 8.16(dd, 1H), 7.76(dd, 1H), 7.64(d, 1H), 7.38-7.50(m, 2H), 7.25-7.32(m, 2H), 7.14(m, 1H), 6.52(d, 1H),

# 6.21(d, 1H), 4.37(s, 2H), 4.01(q, 2H), 1.25(t, 3H)

991

1618

1-ethyl-2-[[1- (3-fluorophenyl)-1H- pyrazol-5-yl]- (hydroxy)methyl)-1H- benzimidazole-5- carbonitrile
1H NMR(CDCl3): 8.02(dd, 1H), 7.47-7.62(m, 5H), 7.39(d, 1H), 7.18(m, 1H), 6.12(d, 1H), 6.00(s, 1H), 5.05(brs, 1H), 3.83(q, 2H), 1.08(t, 3H)

992

1619

1-ethyl-2-{fluoro[1- (3-fluorophenyl)-1H- pyrazol-5-yl]- methyl}-1H- benzimidazole-5- carbonitrile
1H NMR(CDCl3): 8.12(dd, 1H), 7.73(d, 1H), 7.62 (dd, 1H), 7.44-7.53 (m, 2H), 7.31-7.39 (m, 2H), 7.17(m, 1H), 6.83(d, 1H, JH, F=46.8 MZ),

# 4.39(m, 2H), 1.43(t, 3H)

993

1620

methyl 5-[(5-cyano-1- ethyl-1H- benzimidazol-2-yl)- oxy]-1-(3-fluoro- phenyl)-1H-pyrazole- 4-carboxylate

406.3 [M + 1]

994

1621

2-[[1-(2,5-difluoro- phenyl)-1H- pyrazol-5-yl]- (difluoro)methyl]-1- ethyl-1H- benzimidazole-5- carbonitrile
1H NMR(CDCl3): 8.09(m, 1H), 7.84(M, 1H), 7.64(dd, 1H), 7.48(dd, 1H), 6.96-7.18(m, 3H), 6.85(d, 1H), 4.33(q, 2H), 1.38(t, 3H)

995

1622

1-ethyl-2-{[1- (3-fluorophenyl)-1H- pyrazol-5-yl]methyl}- 6-(1,3,4-oxadiazol-2- yl)-1H-benzimidazole

389.2 [M + 1]

996

1623

1-ethyl-2-{[1- (3-fluorophenyl)-1H- pyrazol-5-yl]methyl}- 6-(5-methyl-1,3,4- oxadiazol-2-yl)-1H- benzimidazole

403.3 [M + 1]

997

1624

1-(2-{[1- (3-fluorophenyl)-1H- pyrazol-5-yl]methyl}- 1H-benzimidazol- 1-yl)acetone

349.3 [M +1]; 347.2 [M + 1]

998

1625

2-{difluoro[1- (3-fluorophenyl)-1H- pyrazol-5-yl]methyl}- 1-ethyl-1H- benzimidazole-5- carbonitrile
1H NMR(CDCl3): 8.078(m, 1H), 7.80(m, 1H), 7.63(dd, 1H), 7.48(dd, 1H), 7.13-7.28(m, 3H), 6.99 (m, 1H), 6.81(d, 1H), 4.35(q, 2H), 1.39(t, 3H)

999

1626

2-{[1- (3-fluorophenyl)-1H- pyrazol-5-yl]methyl}- 1-(3-fluoropropyl)-1H- benzimidazole

353.2 [M +1]; 351.2 [M + 1]

1000

1627

1-(2-fluoroethyl)-2- {[1-(3-fluorophenyl)- 1H-pyrazol-5-yl]- methyl}-1H- benzimidazole

339.2 [M + 1]

1001

1628

4-(2-{[1- (3-fluorophenyl)-1H- pyrazol-5-yl]methyl}- 1H-benzimidazol-1- yl)butanenitrile

360.2 [M +1]; 358.3 [M + 1]

1002

1629

1-(1-ethyl-2-{[1- (3-fluorophenyl)-1H- pyrazol-5-yl]methyl}- 1H-benzimidazol-5- yl)-2,2,2-trifluoro- ethanone

417.2 [M + 1]

1003

1630

1-(2-{[1- (3-chlorophenyl)-1H- pyrazol-5-yl]methyl}- 1-ethyl-1H- benzimidazol-5-yl)- 2,2,2-trifluoroethanone

1004

1631

5-chloro-2-[[1-(2,5- difluorophenyl)-1H- pyrazol-5-yl]- (difluoro)methyl]-1- ethyl-1H- benzimidazole

1005

1632

(1E)-1-(1-ethyl-2-{[1- (3-fluorophenyl)-1H- pyrazol-5-yl]methyl}- 1H-benzimidazol-5- yl)ethanone O-(2- ethoxyethyl)oxime
1H NMR, δ ppm(CDCl3): 7.95(m, 1H), 7.72(dd, 1H), 7.63(d, 1H), 7.45(m, 1H), 7.11-7.31(m, 4H), 6.18(d, 1H), 4.34-

# 4.37(m, 4H), 3.98(q, 2H), 3.77(t, 2H), 3.58(q, 2H), 2.33(s, 3H), 1.18-1.26(m, 6H)

1006

1633

1-ethyl-2-{[1- (3-fluorophenyl)-1H- pyrazol-5-yl]methyl}- N,N-dimethyl- 1H-benzimidazole-6- carboxamide
1H NMR, δ ppm(CDCl3: 7.72(dd, 1H), 7.63(d, 1H), 7.40-7.49(m, 2H), 7.24-7.34(m, 3H), 7.13(d, 1H), 6.18(d, 1H), 4.35(s, 2H), 3.99(q, 2H),

# 3.13(s, 2H), 3.07(s, 3H), 1.23(t, 3H)

1007

1634

3-ethyl-2-{[1- (3-fluorophenyl)-1H- pyrazol-5-yl]methyl}- 3H-imidazo[4,5-b]- pyridine

1008

1635

2-{[1-(2,5-difluoro- phenyl)-1H-pyrazol-5- yl]methyl]-3-ethyl-3H- imidazo[4,5-b]- pyridine
1H NMR(CDCl3): 8.19(1H, d), 7.61(1H, d), 7.48-7.44(1H, m), 7.28-7.13(4H, m), 6.14(1H, m), 4.44(2H, s), 3.93(2H, q), 1.17(3H, t),
356.2 [M + 1]

1009

1636

4-chloro-1-ethyl-2-{[1- (3-fluorophenyl)-1H- pyrazol-5-yl]methyl}- 1H-imidazo[4,5-c]- pyridine
1H nmr(CDCl3): 8.19(1H, d), 7.61(1H, d), 7.48-7.44(1H, m), 7.28-7.13(4H, m), 6.14(1H, m), 4.44(2H, s), 3.93(2H, q), 1.17(3H, t)
356.2 [M + 1]

1010

1637

3-ethyl-2-{[1- (3-fluorophenyl)-1H- pyrazol-5-yl]methyl}- 5-methoxy-3H- imidazo[4,5-b]pyridine

392.3 [M + 1]

1011

1638

2-{[1- (3-fluorophenyl)-1H- pyrazol-5-yl]methyl)- 3-isopropyl-3H- imidazo[4,5-b]pyridine

1012

1639

1-(cyclopropylmethyl)- 2-{[1-(2,5-difluoro- phenyl)-1H-pyrazol-5- yl]methyl}-1H- imidazo[4,5-b]pyridine
H-1 NMR(CDCl3): 0.22(m, 2H), 0.54(m, 2H), 0.95(m, 1H), 3.84(d, 2H), 4.32(s, 2H), 6.18(s, 2H), 7.13-7.25(m, 4H), 7.65(m, 2H), 8.52(d, 1H)

# 366 [M + 1]

1013

1640

1-(cyclopropylmethyl)- 2-{[1-(3-fluoro- phenyl)-1H-pyrazol-5- yl]methyl}-1H- imidazo-[4,5-b]- pyridine
H-1 NMR(CDCl3): 0.22(m, 2H), 0.54(m, 2H), 0.95(m, 1H), 3.84(d, 2H), 4.32(s, 2H), 6.18(s, 2H), 7.13-7.25(m, 4H), 7.65(m, 2H), 8.52(d, 1H)

# 366 [M + 1]

1014

1641

2-{[1-(2,5-difluoro- phenyl)-1H-pyrazol-5- yl]methyl}-1-propyl- 1H-imidazo[4,5-b]- pyridine
H-1 NMR(CDCl3): 0.82(t, 3H), 1.62(h, 2H), 3.85(t, 2H), 4.33(s, 2H), 6.20(s, 1H), 7.05-7.25 (m, 4H), 7.82(m, 2H), 8.53(d, 1H)
354 [M + 1]

1015

1642

2-{[1- (3-fluorophenyl)-1H- pyrazol-5-yl]methyl}- 3-propyl-3H- imidazo[4,5-b]pyridine
(CDCl3) 8.43(dd, J=4.8, 1.5 Hz, 1H), 8.10(dd, J=8.0, 1.4 Hz, 1H), 7.64(d, J=2.1 Hz, 1H), 7.47(m, 1H), 7.23-7.34 (m, 3H), 7.12(m, 1H),

# 6.31(d, J=1.8 Hz, 1H), 4.60(s, 2H), 4.03(t, J=7.7 Hz, 2H), 1.65(m, 2H), 0.84(t, J=7.5 Hz,
m/z 366.2 [M + 1]

1016

1643

2-{[1- (3-fluorophenyl)-1H- pyrazol-5-yl]methyl}- 5-methyl-3-propyl- 3H-imidazo[4,5-b]- pyridine
(CDCl3) 7.85(d, J=7.8 Hz, 1H), 7.64(d, J=1.5 Hz, 1H), 7.43(m, 1H), 7.24-7.29(m, 2H), 7.12(m, 1H), 7.06(d, J=8.1 Hz, 1H),

# 6.22(d, J=1.5 Hz, 1H), 4.33(s, 2H), 4.01(t, J=7.5 Hz, 2H), 2.64(s, 3H), 1.67(m, 2H), 0.84(t, J=7.3 Hz, 3H)
m/z 350.3 [M + 1]

1017

1644

3-ethyl-2-({1-[3- (trifluoromethyl)- phenyl]-1H-pyrazol-5- yl}methyl)-3H- imidazo[4,5-b]pyridine
(CDCl3) 8.36(dd, J=4.8, 1.3 Hz, 1H), 7.98(dd, J=8.0, 1.3 Hz, 1H), 7.78(m, 1H), 7.56-7.72(m, 4H), 7.22(dd, J=8.1, 4.8 Hz, 1H),

# 6.29(d, J=1.5 Hz, 1H), 4.36(s, 2H), 4.17(q, J=7.2 Hz, 2H), 1.27(t, J=7.2 Hz, 3H)
m/z 372.2 [M + 1]

1018

1645

3-ethyl-2-{[1- (3-fluorophenyl)-1H- pyrazol-5-yl]methyl}- 5-methyl-3H- imidazo[4,5-b]pyridine
(CDCl3) 7.85(d, J=8.1 Hz, 1H), 7.64(d, J=1.8 Hz, 1H), 7.44(m, 1H), 7.24-7.29 (m, 2H), 7.13(m, 1H), 7.06(d, J=8.1 Hz, 1H),

# 6.21(d, J=1.5 Hz, 1H), 4.33(s, 2H), 4.12(q, J=7.3 Hz, 2H), 2.65(s, 3H), 1.25(t, J=7.3 Hz, 3H)
m/z 336.2 [M + 1]

1019

1646

3-ethyl-2-{[1- (6-fluoropyridin-2-yl)- 1H-pyrazol-5-yl]- methyl}-5-methyl-3H- imidazo[4,5-b]pyridine

m/z 337.2 [M + 1]

1020

1647

8-{[1-(6-fluoro- pyridin-2-yl)-1H- pyrazol-5-yl]methyl}- 2,9-dimethyl-9H- purine
(CDCl3) 8.81(s, 1H), 7.87(m, 2H), 7.69(d, 1H), 6.67(dd, 1H), 6.33(s, 1H), 4.86(s, 2H), 3.90(s, 3H), 2.79(s, 3H)

1021

1648

2-{[1-(6-fluoro- pyridin-2-yl)-1H- pyrazol-5-yl]methyl}- 1,6-dimethyl- 1H-imidazo[4,5-c]- pyridine
(CDCl3) 8.82(s, 1H), 7.88(m, 1H), 7.84(m, 1H), 7.67(s, 1H), 7.11(s, 1H), 6.69(m, 1H), 6.27,(s, 1H), 4.85(s, 2H), 3.81(s, 3H), 2.66(s, 3H)
m/z 323 [M + 1]

1022

1649

8-{[1-(3-fluoro- phenyl)-1H-pyrazol- 5-yl]methyl}-2,9- dimethyl-9H- purine
(CDCl3) 8.90(s, 1H), 7.63(d, 1H), 7.42(m, 1H), 7.26(m, 2H), 7.12(m, 1H), 6.16(d, 1H), 4.32(s, 2H), 3.60(s, 3H), 2.78(s, 3H)

1023

1650

2-{[1-(3-fluoro- phenyl)-1H-pyrazol- 5-yl]methyl}-1- methyl-6-(trifluoro- methyl)-1H- benzimidazole
(CDCl3) 7.79(d, 1H), 7.59(d, 2H), 7.54(m, 2H), 7.30(m, 2H), 7.16(m, 1H), 6.12(d, 1H), 4.38(s, 2H), 3.61(s, 3H),

1024

1651

9-ethyl-8-{[1- (6-fluoropyridin-2-yl)- 1H-pyrazol-5-yl]- methyl}-2-methyl-9H- purine
(CDCl3) 8.82(s, 1H), 7.88(m, 1H), 7.83(q, 1H), 7.69(d, 1H), 6.69(m, 1H), 6.35(s, 1H), 4.95(s, 2H), 4.44(q, 2H), 2.82(s, 3H), 1.52(t, 3H)

1025

1652

3-ethyl-2-{[1- (6-fluoropyridin-2-yl)- 1H-pyrazol-5-yl]- methyl}-3H- imidazo[4,5-c]pyridine
(CDCl3) 8.78(s, 1H), 8.38(d, J=3.9 Hz, 1H), 7.83-7.89(m, 2H), 7.66 (s, 1H), 7.56(d, J=3.9 Hz, 1H), 7.25(d, J=9.9 Hz, 1H),

# 6.70(d, J=9.9 Hz, 1H), 4.81(s, 2H), 4.39(q, J=5.4 Hz, 2H), 1.49(t, J=5.4 Hz, 3H)
m/z 323 [M + 1]

1026

1653

1-ethyl-2-{[1- (3-fluoropyridin-2-yl)- 1H-pyrazol-5-yl]- methyl}-6- methyl-1H- imidazo[4,5-c]pyridine
(CDCl3) 8.82(s, 1H), 8.28(br d, J=4.0 Hz, 1H), 7.70(d, J=1.6 Hz, 1H), 7.61(m, 1H), 7.35(m, 1H), 7.07(s, 1H), 6.23(s, 1H), 4.56(s, 2H),

# 4.09(q, J=7.2 Hz, 2H), 2.65(s, 3H), 1.25(t, J=7.2 Hz, 3H)
m/z 337 [M + 1]

1027

1654

2-{[1-(6-fluoro- pyridin-2-yl)-1H- pyrazol-5-yl]methyl}- 3-methyl-3H- imidazo[4,5-c]pyridine
(CDCl3) 8.78(br s, 1H), 8.38(br s, 1H), 7.87(m, 2H), 7.68(s, 1H), 7.55(br s, 1H), 7.25(s, 1H), 6.69(br d, J=7.5 Hz, 1H), 6.30(s, 2H),

# 4.88(s, 3H)
m/z 309.2 (M + 1]

1028

1655

6-ethyl-2-{[1- (3-fluoropyridin-2-yl)- 1H-pyrazol-5-yl]- methy)}-1-methyl- 1H-imidazo[4,5-c]- pyridine
(CDCl3) 8.86(s, 1H), 8.30(d, J=4.4 Hz, 1H), 7.71(s, 1H), 7.62(m, 1H), 7.36(m, 1H), 7.07(s, 1H), 6.18(s, 1H), 4.58(s, 2H), 3.64(s, 3H),

# 2.94(q, J=7.6 Hz, 2H), 1.36(t, J=7.6 Hz, 3H)
m/z 337 [M + 1]

1029

1656

2-{[1-(6-fluoro- pyridin-2-yl)-1H- pyrazol-5-yl]methyl}- 3,5-dimethyl-3H- imidazo[4,5-b]pyridine
(CDCl3) 8.86(s, 1H), 8.30(d, J=4.4 Hz, 1H), 7.71(s, 1H), 7.62(m, 1H), 7.36(m, 1H), 7.07(s, 1H), 6.18(s, 1H), 4.58(s, 2H), 3.64(s, 3H),

# 2.94(q, J=7.6 Hz, 2H), 1.36(t, J=7.6 Hz 3H)
m/z 337 [M + 1]

1030

1657

1-ethyl-2-{[1- (1,3-thiazol-2-yl)-1H- pyrazol-5-yl]methyl}- 1H-imidazo[4,5-c]- pyridine
(CDCl3) 9.00(s, 1H0, 8.43(d, 1H), 7.63(d, 1H), 7.43(d, 1H), 7.15(d, 1H), 7.06(d, 1H), 6.25(d, 1H), 4.99(s, 2H), 4.25(q, 2H), 1.36(t, 3H)

1031

1658

1-ethyl-2-{1-[1- (1,3-thiazol-2-yl)- 1H-pyrazol-5-yl]- ethyl}-1H- imidazo[4,5-c]pyridine
(CDCl3) 9.05(s, 1H), 8.39(d, 1H), 7.59(d, 1H), 7.49(d, 1H), 7.25(d, 1H), 7.09(d, 1H), 6.28(d, 1H), 5.85(q, 1H), 4.19(q, 2H), 1.85(d, 3H), 1.29(t, 3H)

1032

1659

1-ethyl-2-{[1- (1,3-thiazol-2-yl)- 1H-pyrazol-5-yl]- methyl}-6-(trifluoro- methyl)-1H- imidazo[4,5-c]pyridine
(CD3OD) 8.7(s, 1H), 8.17(s, 1H), 7.74(d, J=3.6 Hz, 1H), 7.33(d, J=3.6 Hz, 1H), 7.21(d, J=3.6 Hz, 1H), 7.21(d, J=3.6 Hz, 1H),

# 6.53(s, 1H), 5.01(s, 2H), 4.54(q, J=7.2 Hz, 2H), 1.52(t,, J=7.2 Hz, 3H)

1033

1660

3-ethyl-2-{[1- (1,3-thiazol-2-yl)- 1H-pyrazol-5-yl]- methyl}-3H- imidazo[4,5-c]pyridine
(CD3OD) 9.42(s, 1H), 8.44(d, J=6.6 Hz, 1H), 7.9(d, J=6.3 Hz, 1H), 7.7(s, 1H), 7.26(d, J=3.6 Hz, 1H), 7.20(d, J=3.6 Hz, 1H),

# 6.63(s, 1H), 5.09(s, 2H), 4.68(q, J=7.5 Hz, 2H), 1.62(t,, J=7.5 Hz, 3H)
m/z 311 [M + 1]

[0633]

8

TABLE 8

Cmp.

MS

#
STRUCTURE
IUPAC NAME
NMR
(m/z)

1035

1661

6-chloro-2-[(4-methyl-2-phenyl- 1H-imidazol-1-yl)methyl]-1- propyl-1H-benzimidazole
1H NMR(CDCl3): 7.62-7.71 (m, 3H), 7.45-7.53(m, 3H), 7.23-7.27(m, 2H), 6.74(q, 1H), 5.42(s, 2H), 3.59(t, 2H), 2.21(d, 3H,), 1.37(m, 2H), 0.70(t, 3H)

1036

1662

2-[(4-methyl-2-phenyl-1H- imidazol-1-yl)methyl]-1-propyl- 1H-benzimidazole
1M NMR(CDCl3): 7.80(m, 1H), 7.25-7.67(m, 8H), 6.74 (q, 1H), 5.43(s, 2H), 3.62(t, 2H), 2.20(d, 3H), 1.38(m, 2H,), 0.69(t, 3H)

1037

1663

6-chloro-2-{[4-chloro-2-(3- fluorophenyl)-1H-imidazol-1- yl]methyl}-1-propyl-1H- benzimidazole
1H NMR(CDCl3): 7.70(d, 1H), 7.37-7.50(m, 3H), 7.17-7.32(m, 3H), 6.96(s, 1H), 5.43(s, 2H), 3.70(t, 2H), 1.49 (m, 2H), 0.77(t, 3H)

1038

1664

2-[(4-methyl-2-phenyl-1H- imidazol-1-yl)methyl]-3-propyl- 3H-imidazo[4,5-b]pyridine
1H NMR(CDCl3): 8.39(dd, 1H), 8.06(dd, 1H), 7.63-7.65 (m, 2H), 7.45-7.55(m, 3H), 7.26(m, 1H), 6.77(q, 1H), 5.46(s, 2H), 3.82(t, 2H), 2.23 (d, 3H), 1.46(m, 2H), 0.73(t, 3H)

1039

1665

3-ethyl-2-{[2-(3-fluorophenyl)-4- methyl-1H-imidazol-1-yl]methyl}- 3H-imidazo[4,5-b]pyridine
1H NMR(CDCl3): 8.39(dd, 1H), 8.06(dd, 1H), 7.38-7.50 (m, 3H), 7.12-7.29(m, 2H), 6.77(q, 1H), 5.46(s, 2H), 3.98 (q, 2H), 2.22(d, 3H), 1.08(t, 3H)

1040

1666

2-{[2-(3-fluorophenyl)-4-methyl- 1H-imidazol-1-yl]methyl}-3- methyl-3H-imidazo[4,5-b]pyridine

1041

1667

2-{[2-(2,5-difluorophenyl)-4- methyl-1H-imidazol-1-yl]methyl}- 3-methyl-3H-imidazo[4,5- b]pyridine

1042

1668

3-(cyclopropylmethyl)-2-{[2-(2,5- difluorophenyl)-4-methyl-1H- imidazol-1-yl]methyl}-3H- imidazo[4,5-b]pyridine
1H NMR(CDCl3): 8.38(dd, 1H), 8.04(dd, 1H), 7.40(m, 1H), 7.15-7.27(m, 3H), 6.79 (d, 1H), 5.35(s, 2H), 3.82(d, 2H), 2.22 d, 3H), 0.75(m, 1H), 0.39-0.44(m, 2H), 0.23-0.28 (m, 2H)

1043

1669

1-ethyl-2-{[2-(3- fluorophenyl)-4-methyl-1H- imidazol-1-yl]methyl}-1H- benzimidazole-5- carbonitrile

m/z 360 [M + 1]

1044

1670

1-ethyl-2-{[2-(3- fluorophenyl)-5-methyl-1H- imidazol-1-yl]methyl}-1H- benzimidazole-5- carbonitrile

m/z 360 [M + 1]

1045

1671

2-[(2-methyl-4-phenyl-1,3- thiazol-5-yl)methyl]-1- propyl-1H-imidazo[4,5- c]pyridine
(CDCl3) 9.06(s, 1H), 8.39(d, J=5.6 Hz, 1H), 7.61(m, 2H), 7.47(m, 2H), 7.41(m, 1H), 7.20 (d, J=5.6 Hz, 1H), 4.54 (s, 2H), 3.77(t, J=7.6 Hz, 2H), 2.68(s, 3H),
m/z 349 [M + 1]

1046

1672

5-bromo-1-ethyl-2-{[3-(3- fluorophenyl)-1H-pyrazol-4- yl]methyl}-1H- benzimidazole

401.0 [M + 1]

1047

1673

5-bromo-1-ethyl-2-{[5-(3- fluorophenyl)isoxazol-4- yl]methyl}-1H- benzimidazole
(CDCl3) 8.40(s, 1H), 7.88(s, 1H), 7.31-7.52 (m, 4H), 7.18-7.22(m, 2H), 4.14(s, 2H), 4.04(q, 2H), 1.18(t, 3H)

1048

1674

5-bromo-1-ethyl-2-{[5-(3- fluorophenyl)-1-methyl-1H- pyrazol-4-yl]methyl}-1H- benzimidazole
(CDCl3) 7.81(s, 1H), 7.38-7.45(m, 2H), 7.32 (dd, 1H), 7.00-7.18(m, 4H), 4.00(s, 2H), 3.90(q, 2H), 3.78(s, 3H), 1.15(t, 3H)

1049

1675

5-bromo-1-ethyl-2-{[3-(3- fluorophenyl)-1-methyl-1H- pyrazol-4-yl]methyl}-1H- benzimidazole
(CDCL3) 7.88(s, 1H), 7.27-7.42(m, 4H), 7.00-7.20(m, 3H), 4.21(s, 2H), 3.95(t, 2H), 3.83(s, 3H), 1.15(t, 3H)

1050

1676

5-bromo-1-ethyl-2-{[4-(3- fluorophenyl)-1,3-thiazol-5- yl]methyl}-1H- benzimidazole
(CDCl3) 8.78(s, 1H), 7.91(s, 1H), 7.38-7.48 (m, 4H), 7.11-7.19(m, 2H), 4.59(s, 2H), 3.90(q, 2H), 1.12(t, 3H)

1051

1677

1-ethyl-2-{[4-(6- fluoropyridin-2-yl)-1,3- thiazol-5-yl]methyl}-6- methyl-1H-imidazo[4,5- c]pyridine
(CDCl3) 8.92(s, 1H), 8.75(s, 1H), 8.16(d, 1H), 7.90(dd, 1H), 7.08(s, 1H), 6.87(d, 1H), 5.28(s, 2H0, 4.32(q, 2H), 2.63 (s, 3H), 1.32(t, 3H)

1052

1678

2-{[3,5-bis-(3 fluorophenyl)isoxazol-4- yl]methyl}-1-ethyl-6- (trifluoromethyl)-1H- benzimidazole

m/z 484 [M + 1]

1053

1679

2-(2,4′-bi-1,3-thiazol-5′- ylmethyl)-1-ethyl-1H- imidazo[4,5-c]pyridine
(CDCl3) 9.05(s, 1H0, 8.76(s, 1H), 8.41(d, 1H), 7.88(d, 1H), 7.41(d, 1H), 7.25(d, 1H), 5.35(s, 2H), 4.26(q, 2H), 1.25(t, 3H)

1054

1680

1-ethyl-2-{[2-(1,3-thiazol-2- yl)-4-(trifluoromethyl)-1H- imidazol-1-yl]methyl}-1H- imidazo[4,5-c]pyridine
(CDCl3) 9.10(s, 1H), 8.47(d, J=6.0 Hz, 1H), 7.88(d, J=3.2 Hz, 1H), 7.58(s, 1H), 7.48(d, J=3.2 Hz, 1H), 7.31(d, J=5.6 Hz, 1H), 6.37(s, 2H), 4.31(q, J=7.2 Hz, 2H), 1.24(t, J=7.2 Hz, 3H)

# m/z 379 [M + 1]

1055

1681

3-ethyl-6-isopropyl-2-{[2- (1,3-thiazol-2-yl)-4- (trifluoromethyl)-1H- imidazol-1-yl]methyl}-3H- imidazo[4,5-c]pyridine
(CDCl3) 8.75(s, 1H), 7.87(d, J=3.3 Hz, 1H), 7.59(d, J=0.9 Hz, 1H),

# 7.54(s, 1H), 7.47(d, J=3.6 Hz, 1H), 6.32(s, 2H), 4.38(q, J=7.2 Hz, 2H), 3.21(sept, J=6.9 Hz, 1H), 1.35(d, J=6.9 Hz, 6H), 1.30(t, J=7.2 Hz
m/z 421 [M + 1]

1056

1682

1-ethyl-6-isopropyl-2-{[2- (1,3-thiazol-2-yl)-4- (trifluoromethyl)-1H- imidazol-1-yl]methyl}-1H- imidazo[4,5-c]pyridine
(CDCl3) 9.02(s, 1H), 7.88(d, J=2.7 Hz, 1H), 7.55(d, J=0.9 Hz, 1H), 7.48(d, J=3.3 Hz, 1H),

# 7.13(s, 1H), 6.34(s, 2H), 4.28(q, J=7.2 Hz, 2H), 3.20(sept, J=6.9 Hz, 1H), 1.36(d, J=6.9 Hz, 6H), 1.22(t, J=7.2 Hz,
m/z 421 [M + 1]

Example 51

[0634] Preparation of Radiolabeled Probe Compounds of the Invention

[0635] The compounds of the invention are prepared as radiolabeled probes by carrying out their synthesis using precursors comprising at least one atom that is a radioisotope. The radioisotope is preferably selected from of at least one of carbon (preferably 14C), hydrogen (preferably 3H), sulfur (preferably 35S), or iodine (preferably 125I). Such radiolabeled probes are conveniently synthesized by a radioisotope supplier specializing in custom synthesis of radiolabeled probe compounds. Such suppliers include Amersham Corporation, Arlington Heights, Ill.; Cambridge Isotope Laboratories, Inc. Andover, Mass.; SRI International, Menlo Park, Calif.; Wizard Laboratories, West Sacramento, Calif.; ChemSyn Laboratories, Lexena, Kans.; American Radiolabeled Chemicals, Inc., St. Louis, Mo.; and Moravek Biochemicals Inc., Brea, Calif.

[0636] Tritium labeled probe compounds are also conveniently prepared catalytically via platinum-catalyzed exchange in tritiated acetic acid, acid-catalyzed exchange in tritiated trifluoroacetic acid, or heterogeneous-catalyzed exchange with tritium gas. Such preparations are also conveniently carried out as a custom radiolabeling by any of the suppliers listed in the preceding paragraph using the compound of the invention as substrate. In addition, certain precursors may be subjected to tritium-halogen exchange with tritium gas, tritium gas reduction of unsaturated bonds, or reduction using sodium borotritide, as appropriate.

Example 52

[0637] Receptor Autoradiography

[0638] Receptor autoradiography (receptor mapping) is carried out in vitro as described by Kuhar in sections 8.1.1 to 8.1.9 of Current Protocols in Pharmacology (1998) John Wiley & Sons, New York, using radiolabeled compounds of the invention prepared as described in the preceding Example.

Example 53

[0639] Binding Assay

[0640] The high affinity and high selectivity of preferred compounds of the invention for the benzodiazepine site of the GABAA receptor can be confirmed using the binding assay described by Thomas and Tallman (J. Bio. Chem. 1981; 156:9838-9842, and J. Neurosci. 1983; 3:433-440).

[0641] Rat cortical tissue is dissected and homogenized in 25 volumes (w/v) of Buffer A (0.05 M Tris HCl buffer, pH 7.4 at 4 ° C.). The tissue homogenate is centrifuged in the cold (4° C.) at 20,000× g for 20 minutes. The supernatant is decanted, the pellet rehomogenized in the same volume of buffer, and centrifuged again at 20,000× g. The supernatant of this centrifugation step is decanted. The resulting pellet may be stored at −20° C. overnight. The pellet is then thawed and resuspended in 25 volumes of Buffer A (original wt/vol), centrifuged at 20,000× g and the supernatant decanted. This wash step is repeated once. The pellet is finally resuspended in 50 volumes of Buffer A.

[0642] Incubations contain 100 μl of tissue homogenate, 100 μl of radioligand, (0.5 nM 3H-Rol5-1788 [3H-Flumazenil], specific activity 80 Ci/mmol), and test compound or control (see below), and are brought to a total volume of 500 μl with Buffer A. Incubations are carried for 30 minutes at 4° C. and then rapidly filtered through Whatman GFB filters to separate free and bound ligand. Filters are washed twice with fresh Buffer A and counted in a liquid scintillation counter. Nonspecific binding (control) is determined by displacement of 3H Rol5-1788 with 10 μM Diazepam (Research Biochemicals International, Natick, Mass.). Data are collected in triplicate, averaged, and percent inhibition of total specific binding (Total Specific Binding=Total−Nonspecific) is calculated for each compound.

[0643] A competition binding curve may obtained with up to 11 points spanning the compound concentration range from 10−12M to 10−5M obtained per curve by the method described above for determining percent inhibition. Ki values are calculated according the Cheng-Prussof equation. Each of the compounds disclosed in Tables 6-8 was tested in this fashion and each was found to have a Ki of <4 μM. Preferred compounds of the invention exhibit Ki values of less than 100 nM and more preferred compounds of the invention exhibit Ki values of less than 10 nM.

Example 54

[0644] Electrophysiology

[0645] The following assay can be used to determine if a compound of the invention acts as an agonist, an antagonist, or an inverse agonist at the benzodiazepine site of the GABAA receptor.

[0646] Assays are carried out as described in White and Gurley (NeuroReport 6: 1313-1316, 1995) and White, Gurley, Hartnett, Stirling, and Gregory (Receptors and Channels 3: 1-5, 1995) with modifications. Electrophysiological recordings are carried out using the two electrode voltage-clamp technique at a membrane holding potential of −70 mV. Xenopus Laevis oocytes are enzymatically isolated and injected with non-polyadenylated cRNA mixed in a ratio of 4:1:4 for α, β and γ subunits, respectively. Of the nine combinations of α, β and γ subunits described in the White et al. publications, preferred combinations are α1β2γ2, α2β3γ2, α3β3γ2, and α5β3γ2. Preferably all of the subunit cRNAs in each combination are human clones or all are rat clones. The sequence of each of these cloned subunits is available from GENBANK, e.g., human α1, GENBANK accession no. X14766, human α2, GENBANK accession no. A28100; human α3, GENBANK accession no. A28102; human α5, GENBANK accession no. A28104; human 2, GENBANK accession no. NM 021911; human β3, GENBANK accession no. M82919 and accession no. Z20136; human γ2, GENBANK accession no. X15376; rat α1 GENBANK accession no. L08490, rat α2, GENBANK accession no. L08491; rat U3, GENBANK accession no. L08492; rat α5, GENBANK accession no. L08494; rat β2, GENBANK accession no. X15467; rat β3, GENBANK accession no. X15468; and rat Y2, GENBANK accession no. L08497. For each subunit combination, sufficient message for each constituent subunit is injected to provide current amplitudes of >10 nA when 1 μM GABA is applied.

[0647] Compounds are evaluated against a GABA concentration that evokes <10% of the maximal evokable GABA current (e.g. 1 μM-9 μM) Each oocyte is exposed to increasing concentrations of a compound being evaluated (test compound) in order to evaluate a concentration/effect relationship. Test compound efficacy is calculated as a percent-change in current amplitude: 100*((Ic/I)−1), where Ic is the GABA evoked current amplitude observed in the presence of test compound and I is the GABA evoked current amplitude observed in the absence of the test compound.

[0648] Specificity of a test compound for the benzodiazepine site is determined following completion of a concentration/effect curve. After washing the oocyte sufficiently to remove previously applied test compound, the oocyte is exposed to GABA+1 μM RO15-1788, followed by exposure to GABA+1 μM RO15-1788+test compound. Percent change due to addition of compound is calculated as described above. Any percent change observed in the presence of RO15-1788 is subtracted from the percent changes in current amplitude observed in the absence of 1 μM RO15-1788. These net values are used for the calculation of average efficacy and EC50 values by standard methods. To evaluate average efficacy and EC50 values, the concentration/effect data are averaged across cells and fit to the logistic equation.

[0649] It is to be understood that the foregoing describes preferred embodiments of the present invention and that modifications may be made therein without departing from the scope of the present invention as set forth in the following claims.

Benzimidazole and pyridylimidazole derivatives

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