Metalloenzyme inhibitor compounds

Abstract

To provide metalloenzyme inhibitor compounds.SOLUTION: Provided are compounds having metalloenzyme modulating activity, and methods of treating diseases, disorders or symptoms thereof mediated by such metalloenzymes.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 62 / 789,832, filed January 8, 2019, which is hereby incorporated by reference in its entirety. [Background technology]

[0002] background Aldosterone is a steroid hormone secreted by the adrenal gland that binds to and activates the mineralocorticoid receptor (MR). Activation of MR in the chief cells of the distal and collecting tubules of the kidney leads to retention of sodium and water and excretion of potassium, resulting in an increase in plasma volume and blood pressure (BP). Excessively elevated circulating levels of aldosterone are called primary aldosteronism (PA), which arises from dysregulation of aldosterone production by the renin-angiotensin-aldosterone system (RAAS). PA was first identified in patients with adrenal adenomas, and recent evidence suggests that its prevalence increases with obesity. PA is a common cause of secondary hypertension, with the prevalence of PA ranging from 14 to 21% in patients with treatment-resistant hypertension (RHTN), defined as failure to achieve target blood pressure despite simultaneous use of three different classes of antihypertensive drugs (including a diuretic). Recent studies have demonstrated an association between aldosterone excess, RHTN, and obstructive sleep apnea (OSA), which is exacerbated by aldosterone-mediated fluid retention.

[0003] In several severe pathological conditions, local overproduction of aldosterone has been identified in the absence of significant increases in plasma volume. In patients with chronic congestive heart failure (CHF), aldosterone concentrations in failing cardiac tissue are higher than those in peripheral plasma. In animal models of renal disease, local production of aldosterone in the renal cortex is thought to contribute to disease progression. In both of these conditions, elevated local aldosterone concentrations contribute to deleterious effects through both MR-dependent and MR-independent mechanisms, including reactive oxygen species generation and endothelial dysfunction leading to inflammation, and stimulation of cell growth and proliferation with upregulation of collagen deposition leading to fibrosis.

[0004] To block the binding of aldosterone to the MR, MR antagonists such as spironolactone and eplerenone are widely used. It has been demonstrated that the combination of these drugs with angiotensin-converting enzyme (ACE) inhibitors and diuretics significantly reduces morbidity and mortality in patients with heart failure or myocardial infarction (RALES and EPHESUS studies). Both drugs have side effects such as hyperkalemia, and nonselective spironolactone also induces gynecomastia by nonselectively modulating progesterone and androgen receptors. Furthermore, the MR-independent (nongenomic) action of aldosterone is exacerbated by the rise in renin and aldosterone as a result of MR antagonism.

[0005] Unlike MR antagonists, inhibition of CYP11B2 (aldosterone synthase), a key enzyme in aldosterone biosynthesis, should provide the beneficial effects of antagonizing MR without causing the deleterious accumulation of aldosterone that leads to the activation of MR-independent inflammatory and fibrotic states. CYP11B2 is a cytochrome P450 enzyme in mitochondria that converts 11-deoxycorticosterone to aldosterone. Selective inhibition of CYP11B2 is a promising treatment for aldosterone-related diseases.

[0006] The highly homologous metalloenzyme CYP11B1 (11-β-steroid-hydroxylase) catalyzes the production of 11-deoxycortisol to the major glucocorticoid, cortisol. Given the high homology between CYP11B2 and CYP1IB1 (93%), developing selective CYP11B2 inhibitors has been a considerable challenge. The inhibitor Osilodrostat (LCI-699) was developed as a CYP11B2 inhibitor for the treatment of hypertension, but its strong inhibition of CYP1IB1 led to the abandonment of this treatment. Herein, we describe selective compounds that inhibit the production of aldosterone by CYP11B2 without inhibiting cortisol production by CYP11B1.

[0007] Living organisms have developed tightly controlled processes to take up specific metals, transport them to intracellular storage sites, and finally to the site of use. One of the most important functions of metals such as zinc and iron in biological systems is to activate metalloenzymes. Metalloenzymes are enzymes that bind a metal ion to the enzyme's active site and utilize the metal as part of a catalytic process. Over one-third of all characterized enzymes are metalloenzymes.

[0008] The function of metalloenzymes is highly dependent on the presence or absence of a metal ion at the active site of the enzyme. It is well known that drugs that bind and inactivate the metal ion at the active site dramatically reduce the activity of the enzyme. Nature also utilizes this same strategy to reduce the activity of certain metalloenzymes during periods when enzyme activity is undesirable. For example, the protein TIMPs (tissue inhibitors of metalloproteinases) suppress enzyme activity by binding to zinc ions at the active site of various matrix metalloproteinase enzymes. The pharmaceutical industry has used this same strategy to design therapeutic drugs. For example, the azole antifungal drugs fuconazole and voriconazole contain a 1-(1,2,4-triazole) group that binds to the heme iron present at the active site of the target enzyme lanosterol demethylase, thereby inactivating the enzyme. Other examples include the zinc-binding hydroxamic acid group that has been incorporated into most published inhibitors of matrix metalloproteinases and histone deacetylases. Another example is the zinc-binding carboxylic acid group that is incorporated into most published angiotensin-converting enzyme inhibitors.

[0009] In designing clinically safe and effective metalloenzyme inhibitors, it is important to use the metal binding group that is most suitable for the specific target and clinical indication. The use of weakly binding metal binding groups may result in suboptimal efficacy. On the other hand, the use of very tightly binding metal binding groups may result in suboptimal selectivity of the target enzyme over related metalloenzymes. Suboptimal selectivity may result in clinical toxicity due to unintentional inhibition of these off-target metalloenzymes.

[0010] One example of this type of clinical toxicity is the unintended inhibition of human drug metabolizing enzymes, including CYP2C9, CYP2C19, and CYP3A4, by currently available azole antifungal drugs, such as fluconazole and voriconazole. This off-target inhibition is believed to be primarily due to indiscriminate binding of the currently available 1-(1,2,4-triazoles) to the iron in the active sites of CYP2C9, CYP2C19, and CYP3A4. Another example is the arthralgia observed in many clinical trials of matrix metalloproteinase inhibitors. This toxicity is believed to be related to off-target metalloenzyme inhibition due to indiscriminate binding of the hydroxamic acid group to zinc in the off-target active sites. Summary of the Invention [Problem to be solved by the invention]

[0011] Thus, the search for metal binding groups that can exhibit a better balance of potency and selectivity remains an important goal that would be useful in achieving therapeutic agents and methods that address current unmet needs in the treatment and prevention of diseases, disorders, and symptoms thereof. [Means for solving the problem]

[0012] BRIEF SUMMARY OF THE INVETION The present invention is directed to compounds (e.g., any of those delineated herein), methods of modulating the activity of metalloenzymes, and methods of treating diseases, disorders, or symptoms thereof, which may include the compounds herein.

[0013] With regard to the selection of preferred variables, it is understood that the embodiments of the invention described below can be employed alone or in combination with one or more embodiments or selection of preferred variables of the invention, as if each combination were expressly recited herein.

[0014] In one embodiment, a compound of formula I:

[0015] [ka] or a pharma- ceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein: W, X, Y, and Z each independently represent N or CR 1 and; Q, T, U, and V are each independently N or CR 2 and; A is N or CR 3 and; with the proviso that no more than two of W, X, Y, and Z are N; and no more than two of Q, T, U, and V are N; R 1 are each independently hydrogen, halogen, cyano, acyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, (CR e R f ) n NR a R b , (CR e R f ) n NR c S(O2)R d , (CR e R f ) n NR c CO2R d , CO2R e , C.O.R. f , or (CR e R f ) n OR f ;R 1 Each of the groups has 1 to 3 independent substituents R 7 may be optionally substituted with; R 2are each independently hydrogen, halogen, cyano, acyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, (CR e R f ) n NR a R b , (CR e R f ) n NR c S(O2)R d , (CR e R f ) n NR c CO2R d , N(S(O2)R d )2, CO2R e , C.O.R. f , or (CR e R f ) n OR f ;R 2 Each of the groups has 1 to 3 independent substituents R 7 may be optionally substituted with; R 3 is hydrogen, cyano, alkyl, haloalkyl, heteroalkyl, or cycloalkyl; R 4 is hydrogen, alkyl, cycloalkyl, haloalkyl, or heteroalkyl; Each n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; R 7 each independently represents a halogen, an alkyl, an alkoxy, a haloalkyl, a carboxyl, an aryl, an aryl substituted with 1 to 3 independent halogens, -(CR e R f ) n C(O)NR a R b , -S(O)2R d , -CO2R e , or NR a R b and; R a , R b , R c , R d , R e , and R f are each independently hydrogen, acyl, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxyalkyl, C(O)OC 1~6 Alkyl, C(O)OH, C(O)C 1~6 Alkyl, S(O2)C 1~6 alkyl, S(O2)aryl, S(O2)heteroaryl, a nitrogen protecting group (if attached to a nitrogen atom), or an oxygen protecting group (if attached to an oxygen atom); or R a and R b together with the atoms to which they are attached form a heterocycloalkyl ring; or R e and R f together with the atoms to which they are attached form a cycloalkyl ring; or R c and R d together with the atoms to which they are attached form a heterocycloalkyl ring.

[0016] In certain embodiments, among W, X, Y, and Z, N is not more than one.

[0017] In certain embodiments, W, X, Y, and Z are each CR 1 It is.

[0018] In certain embodiments, W and Y are each CR 1 It is.

[0019] In certain embodiments, Z is N. In certain embodiments, Z is CR 1 It is.

[0020] In certain embodiments, X is N. In certain embodiments, X is CR 1 It is.

[0021] In certain embodiments, W, X, and Y are each CR 1 and Z is N.

[0022] In certain embodiments, N is no more than one of Q, T, U, and V.

[0023] In certain embodiments, at least one of Q, T, U, and V is N.

[0024] In certain embodiments, Q, T, U, and V are each CR 2 It is.

[0025] In certain embodiments, Q and V are each CR 2 It is.

[0026] In certain embodiments, T and U are each CR 2 It is.

[0027] In certain embodiments, T is N; U is CR 2 In certain embodiments, U is N; T is CR 2 It is.

[0028] In certain embodiments, one of T and U is N and the other is CR 2 It is.

[0029] In certain embodiments, Q and V are each CR 2 One of T and U is N, and the other is CR 2 It is.

[0030] In certain embodiments, T is N.

[0031] In certain embodiments, U is N.

[0032] In certain embodiments, Q, U, and V are each CR 2 and T is N.

[0033] In certain embodiments, Q, T, and V are each CR 2 ;U is N.

[0034] In certain embodiments, W, X, Y, and Z are each CR 1 Q and V are CR 2 one of T and U is N and the other is CR 2 In certain embodiments, W, X, Y, and Z are each CR 1 Q, U, and V are CR 2 and T is N. In certain embodiments, W, X, Y, and Z are each CR 1 Q, T, and V are CR 2 ;U is N.

[0035] In certain embodiments, W, X, and Y are each CR 1 Z is N; Q and V are each CR 2 one of T and U is N and the other is CR 2 In certain embodiments, W and Y are each CR 1 Z is N; Q, U, and V are each CR 2 and T is N. In certain embodiments, W, X, and Y are each CR 1 Z is N; Q, T, and V are each CR 2 ;U is N.

[0036] In certain embodiments, W, X, Y, and Z are each CR 1 Q, T, U, and V are CR 2 It is.

[0037] In certain embodiments, A is CR 3 and R 3 is hydrogen, C 1~4 Alkyl or C 3~5 It is cycloalkyl.

[0038] In certain embodiments, A is N.

[0039] In certain embodiments, R 1 are each independently hydrogen, halogen, cyano, alkyl, alkoxy, haloalkyl, or haloalkoxy.

[0040] In certain embodiments, R 1 are each independently hydrogen, halogen, or cyano.

[0041] In certain embodiments, R 1 are each independently hydrogen, fluoro, chloro, or cyano.

[0042] In certain embodiments, R 1 are each independently hydrogen or cyano. In certain embodiments, R 1 are each independently hydrogen or halogen. In certain embodiments, R 1 are each independently hydrogen or chloro. 1 are each independently hydrogen or fluoro.

[0043] In certain embodiments, at least one R 1 is halogen or cyano. In certain embodiments, at least one R 1 is fluoro, chloro, or cyano. In certain embodiments, at least one R 1 is chloro or cyano. In certain embodiments, at least one R 1 is fluoro or cyano. In certain embodiments, at least one R 1 is halogen. In certain embodiments, at least one R 1 is fluoro or chloro. In certain embodiments, at least one R 1 is fluoro. In certain embodiments, at least one R 1In certain embodiments, at least one R 1 is cyano.

[0044] In certain embodiments, R 2 are each independently hydrogen, halogen, cyano, acyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, (CR e R f ) n NR a R b , (CR e R f ) n NR c S(O2)R d , (CR e R f ) n NR c CO2R d , CO2R e , C.O.R. f , or (CR e R f ) n OR f It is.

[0045] In certain embodiments, R 2 are each independently hydrogen, halogen, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, (CR e R f ) n NR c S(O2)R d , or CO2R e It is.

[0046] In certain embodiments, R 2 are each independently hydrogen, halogen, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, or (CR e R f ) n NR c S(O2)R d It is.

[0047] In certain embodiments, R2 are each independently hydrogen, haloalkyl, or NHS(O2)R d ;R d is alkyl.

[0048] In certain embodiments, R 2 are each independently hydrogen, halogen, or C 1~3 Alkoxy, Cyano, C 1~3 Alkyl, N(S(O2)C 1~3 alkyl)2, NHS(O2)C 1~3 Alkyl, COH, C 1~3 Haloalkyl, or C 1~3 In certain embodiments, R 2 are each independently hydrogen, halogen, or C 1~3 Alkoxy, Cyano, C 1~3 Alkyl, NHS(O2)C 1~3 Alkyl, C 1~3 Haloalkyl, or C 1~3 In certain embodiments, R 2 are independently hydrogen, NHS(O2)C 1~3 Alkyl or C 1~3 It is haloalkyl.

[0049] In certain embodiments, R 2 are each independently hydrogen, fluoro, or C 1~3 Alkoxy, Cyano, C 1~3 Alkyl, NHS(O2)Me, N(S(O2)Me)2, CO2H, C 1~3 Haloalkyl, or C 1~3 In certain embodiments, R 2 are each independently hydrogen, fluoro, or C 1~3 Alkoxy, Cyano, C 1~3 Alkyl, NHS(O2)Me, C 1~3 Haloalkyl, or C 1~3 In certain embodiments, R 2 are each independently hydrogen, NHS(O2)Me, or C 1~3 It is haloalkyl.

[0050] In certain embodiments, R 2 are each independently hydrogen, fluoro, methoxy, cyano, methyl, ethyl, NHS(O2)Me, N(S(O2)Me)2, CO2H, difluoromethyl, trifluoromethyl, trifluoromethoxy, or difluoromethoxy. 2 are each independently hydrogen, fluoro, methoxy, cyano, methyl, ethyl, NHS(O2)Me, CO2H, difluoromethyl, trifluoromethyl, trifluoromethoxy, or difluoromethoxy. 2 are each independently hydrogen, NHS(O2)Me, or difluoromethyl.

[0051] In certain embodiments, at least one R 2 is hydrogen, halogen, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, or (CR e R f ) n NR c S(O2)R d In certain embodiments, at least one R 2 is halogen, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, or (CR e R f ) n NR c S(O2)R d In certain embodiments, at least one R 2 is hydrogen, halogen, cyano, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkoxy, or NHS(O2)C 1~3 In certain embodiments, at least one R 2 is halogen, cyano, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy, C 1~3Haloalkoxy, or NHS(O2)C 1~3 It is an alkyl.

[0052] In certain embodiments, at least one R 2 is hydrogen, fluoro, cyano, methyl, ethyl, methoxy, difluoromethyl, trifluoromethyl, trifluoromethoxy, difluoromethoxy, or NHS(O2)Me. In certain embodiments, at least one R 2 is fluoro, cyano, methyl, ethyl, methoxy, difluoromethyl, trifluoromethyl, trifluoromethoxy, difluoromethoxy, or NHS(O2)Me. 2 is hydrogen, fluoro, cyano, ethyl, methoxy, trifluoromethyl, difluoromethoxy, or NHS(O2)Me. In certain embodiments, at least one R 2 is fluoro, cyano, ethyl, methoxy, trifluoromethyl, difluoromethoxy, or NHS(O2)Me. In certain embodiments, at least one R 2 is hydrogen, difluoromethoxy, or NHS(O2)Me. In certain embodiments, at least one R 2 is difluoromethoxy or NHS(O2)Me.

[0053] In certain embodiments, R 3 is hydrogen, cyano, alkyl, haloalkyl, heteroalkyl, or cycloalkyl. In certain embodiments, R 3 is hydrogen, alkyl, haloalkyl, heteroalkyl, or cycloalkyl. In certain embodiments, R 3 is alkyl, haloalkyl, heteroalkyl, or cycloalkyl. In certain embodiments, R 3 is alkyl, haloalkyl, or cycloalkyl. In certain embodiments, R 3 is alkyl or cycloalkyl. In certain embodiments, R 3 is alkyl. In certain embodiments, R 3is alkyl or cycloalkyl. In certain embodiments, R 3 is C 1~3 Alkyl or C 3~5 It is cycloalkyl.

[0054] In certain embodiments, R 4 is alkyl or cycloalkyl. In certain embodiments, R 4 is C 1~4 Alkyl or C 3~5 In certain embodiments, R 4 is ethyl or cyclopropyl.

[0055] In certain embodiments, R 4 is C 1~4 In certain embodiments, R 4 is C 3~5 In certain embodiments, R 4 is cyclopentyl. In certain embodiments, R 4 is cyclobutyl. In certain embodiments, R 4 is cyclopropyl.

[0056] In certain embodiments, R 4 is C 1~4 In certain embodiments, R 4 is methyl. In certain embodiments, R 4 is ethyl. In certain embodiments, R 4 is n-propyl. In certain embodiments, R 4 is i-propyl. In certain embodiments, R 4 is n-butyl. In certain embodiments, R 4 is i-butyl. In certain embodiments, R 4 is t-butyl.

[0057] In certain embodiments, R 1 are each independently hydrogen, halogen, or cyano; R 2are each independently hydrogen, halogen, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, or (CR e R f ) n NR c S(O2)R d ;R 4 is cyclopropyl.

[0058] In certain embodiments, R 1 are each independently hydrogen or cyano; R 2 are each independently hydrogen, halogen, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, or (CR e R f ) n NR c S(O2)R d ;R 4 is cyclopropyl.

[0059] In certain embodiments, R 1 are each independently hydrogen or halogen; R 2 are each independently hydrogen, halogen, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, or (CR e R f ) n NR c S(O2)R d ;R 4 is cyclopropyl.

[0060] In certain embodiments, R 1 are each independently a halogen; R 2 are each independently hydrogen, halogen, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, or (CR e R f ) n NR c S(O2)R d ;R 4 is cyclopropyl.

[0061] In certain embodiments, R 1are each independently hydrogen, chloro, fluoro, or cyano; R 2 are each independently hydrogen, chloro, fluoro, cyano, methyl, trifluoromethyl, difluoromethylmethoxy, trifluoromethoxy, difluoromethoxy, or NHS(O2)CH3; R 4 is cyclopropyl.

[0062] In certain embodiments, R 1 are each independently hydrogen or cyano; R 2 are each independently hydrogen, chloro, fluoro, cyano, methyl, trifluoromethyl, difluoromethylmethoxy, trifluoromethoxy, difluoromethoxy, or NHS(O2)CH3; R 4 is cyclopropyl.

[0063] In certain embodiments, R 1 are each independently hydrogen, chloro, or fluoro; R 2 are each independently hydrogen, chloro, fluoro, cyano, methyl, trifluoromethyl, difluoromethylmethoxy, trifluoromethoxy, difluoromethoxy, or NHS(O2)CH3; R 4 is cyclopropyl.

[0064] In certain embodiments, the compound of formula I is a compound of formula Ia:

[0065] [ka] or a pharma- ceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; R 4 , W, X, Y, Z, T, U, and V are as defined herein.

[0066] In certain embodiments, the compound of formula I is a compound of formula Ib:

[0067] [ka] or a pharma- ceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; R 1 , R 2 , R 4 , Z, T, and U are as defined herein.

[0068] In certain embodiments, the compound of formula I is a compound of formula Ic:

[0069] [ka] or a pharma- ceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; R 1 , R 4 , T, and U are as defined herein.

[0070] In certain embodiments, the compound of formula I is a compound of formula Id:

[0071] [ka] or a pharma- ceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; R 1 , R 4 , T, and U are as defined herein.

[0072] In certain embodiments, the compound of formula I is a compound of formula Ie:

[0073] [ka] or a pharma- ceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; R 1 , R 2 , R 4 and Z are as defined herein.

[0074] In certain embodiments of the compound of formula Ie, Z is CR 1 or N;R 1 are each independently hydrogen, halogen, or cyano; R 2 is hydrogen, halogen, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, or (CR e R f ) n NR c S(O2)R d ;R 4 is cyclopropyl.

[0075] In certain embodiments of the compound of formula Ie, Z is CR 1 ;R 1 are each independently hydrogen, halogen, or cyano; R 2 is hydrogen or haloalkyl; R 4 is cyclopropyl.

[0076] In certain embodiments of compounds of formula Ie, Z is N; R 1 are each independently hydrogen, halogen, or cyano; R 2 is hydrogen or haloalkyl; R 4 is cyclopropyl.

[0077] In certain embodiments, the compound of formula I is a compound of formula If:

[0078] [ka] or a pharma- ceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; R 1 , R 2 , R 4 and Z are as defined herein.

[0079] In certain embodiments of compounds of formula If, Z is CR 1 or N;R 1 are each independently hydrogen, halogen, or cyano; R 2 is hydrogen, halogen, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, or (CR e R f ) n NR c S(O2)R d ;R 4 is cyclopropyl.

[0080] In certain embodiments of the compound of formula If, Z is CR 1 ;R 1 are each independently hydrogen, halogen, or cyano; R 2 is hydrogen or haloalkyl; R 4 is cyclopropyl.

[0081] In certain embodiments of the compound of formula If, Z is N; R 1 are each independently hydrogen, halogen, or cyano; R 2 is hydrogen or haloalkyl; R 4 is cyclopropyl.

[0082] In certain embodiments, the compound of formula I is a compound of formula Ig:

[0083] [ka] or a pharma- ceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; R 1 , R 2 , R 4 and Z are as defined herein.

[0084] In certain embodiments of compounds of formula Ig, Z is CR 1 or N;R 1 are each independently hydrogen, halogen, or cyano; R 2 are each independently hydrogen, halogen, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, or (CR e R f ) n NR c S(O2)R d ;R 4 is cyclopropyl.

[0085] In certain embodiments of the compound of formula Ig, Z is CR 1 ;R 1 are each independently hydrogen, halogen, or cyano; R 2 are each independently hydrogen, halogen, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, or (CR e R f ) n NR c S(O2)R d ;R 4 is cyclopropyl.

[0086] In certain embodiments, the compound of formula I is a compound of formula Ih:

[0087] [ka] or a pharma- ceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; R 1 , R 2, and R 4 is as defined herein.

[0088] In certain embodiments of compounds of formula Ih, R 1 are each independently hydrogen, halogen, or cyano; R 2 are each independently hydrogen, halogen, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, or (CR e R f ) n NR c S(O2)R d ;R 4 is cyclopropyl.

[0089] In certain embodiments, the compound of formula I is a compound of formula Ii:

[0090] [ka] or a pharma- ceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; R 1 , R 2 , and R 4 is as defined herein.

[0091] In certain embodiments of the compound of formula Ii, R 1 are each independently hydrogen, halogen, or cyano; R 2 are each independently hydrogen, halogen, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, or (CR e R f ) n NR c S(O2)R d ;R 4 is cyclopropyl.

[0092] In certain embodiments, the compound of formula I is a compound of formula Ij:

[0093] [ka] or a pharma- ceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; R 1 and R 2 is as defined herein.

[0094] In certain embodiments of compounds of formula Ij, R 1 are each independently hydrogen, halogen, or cyano; R 2 are each independently hydrogen, halogen, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, or (CR e R f ) n NR c S(O2)R d It is.

[0095] In certain embodiments, the compound of formula I is a compound selected from the group consisting of the following compounds: 1'-Cyclopropyl-6'-fluoro-1'H-1,2-bibenzo[d]imidazole (1); 1'-Cyclopropyl-6',7'-difluoro-1'H-1,2-bibenzo[d]imidazole (2); 1'-Cyclopropyl-4,5,6'-trifluoro-1'H-1,2'-bibenzo[d]imidazole (3); 1'-Cyclopropyl-5,6,6'-trifluoro-1'H-1,2'-bibenzo[d]imidazole (4); 1'-Cyclopropyl-6'-fluoro-5,6-dimethoxy-1'H-1,2'-bibenzo[d]imidazole (5); 1'-Cyclopropyl-6'-fluoro-1'H-[1,2'-bibenzo[d]imidazole]-5-carbonitrile (6); 1'-Cyclopropyl-6'-fluoro-1'H-[1,2'-bibenzo[d]imidazole]-6-carbonitrile (7); 1'-Cyclopropyl-6'-fluoro-5-methyl-1'H-1,2'-bibenzo[d]imidazole (8); 1'-Cyclopropyl-6'-fluoro-6-methyl-1'H-1 2'-bibenzo[d]imidazole (9); 1'-Cyclopropyl-5-ethyl-6'-fluoro-1'H-1,2'-bibenzo[d]imidazole (10); 1'-Cyclopropyl-6-ethyl-6'-fluoro-1'H-1,2'-bibenzo[d]imidazole (11); 1'-Cyclopropyl-6'-fluoro-5-methoxy-1'H-1,2'-bibenzo[d]imidazole (12); 1'-Cyclopropyl-6'-fluoro-6-methoxy-1'H-1,2'-bibenzo[d]imidazole (13); 1'-Cyclopropyl-6'-fluoro-4-methyl-1'H-1,2'-bibenzo[d]imidazole (14); 1'-Cyclopropyl-5,6,6',7'-tetrafluoro-1'H-1,2'-bibenzo[d]imidazole (15); 1'-Cyclopropyl-5',6'-difluoro-1'H-1,2'-bibenzo[d]imidazole (16); 1'-Cyclopropyl-5,5',6,6'-tetrafluoro-1'H-1,2'-bibenzo[d]imidazole (17); 1'-Cyclopropyl-5,6'-difluoro-1'H-1,2'-bibenzo[d]imidazole (18); 1'-Cyclopropyl-6,6'-difluoro-1'H-1,2'-bibenzo[d]imidazole (19); 1'-Cyclopropyl-6'-fluoro-5-(trifluoromethyl)-1'H-1,2'-bibenzo[d]imidazole (20); 1'-Cyclopropyl-6'-fluoro-6-(trifluoromethyl)-1'H-1,2'-bibenzo[d]imidazole (21); 1'-Ethyl-5,6-difluoro-1'H-[1,2'-bibenzo[d]imidazole]-6'-carbonitrile (22); 1'-Cyclopropyl-5',6'-difluoro-1'H-[1,2'-bibenzo[d]imidazole]-5-carbonitrile (23); 1'-Cyclopropyl-5',6'-difluoro-1'H-[1,2'-bibenzo[d]imidazole]-6-carbonitrile (24); 1'-Cyclopropyl-5,6-difluoro-1'H-[1,2'-bibenzo[d]imidazole]-6'-carbonitrile (25); 6'-Chloro-1'-cyclopropyl-5,6-difluoro-1'H-1,2'-bibenzo[d]imidazole (26); 1'-Cyclopropyl-6'-fluoro-5-(trifluoromethoxy)-1'H-1,2'-bibenzo[d]imidazole (27); 1'-Cyclopropyl-6'-fluoro-6-(trifluoromethoxy)-1'H-1,2'-bibenzo[d]imidazole (28); 5-Chloro-3-cyclopropyl-2-(5,6-difluoro-1H-benzo[d]imidazol-1-yl)-3H-imidazo[4,5-b]pyridine (29); N-(1'-cyclopropyl-6',7'-difluoro-1'H-[1,2'-bibenzo[d]imidazol]-5-yl)-N-(methylsulfonyl)methanesulfonamide (30); N-(1'-cyclopropyl-6',7'-difluoro-1'H-[1,2'-bibenzo[d]imidazol]-5-yl)methanesulfonamide (31); 3-Cyclopropyl-2-(5,6-difluoro-1H-benzo[d]imidazol-1-yl)-3H-imidazo[4,5-b]pyridine-5-carbonitrile (32); N-(1'-cyclopropyl-6',7'-difluoro-1'H-[1,2'-bibenzo[d]imidazol]-6-yl)methanesulfonamide (33); 1-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-1H-imidazo[4,5-b]pyridine (34); 1-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-1H-imidazo[4,5-c]pyridine (35); 3-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-3H-imidazo[4,5-c]pyridine (36); 3-Cyclopropyl-2-(3H-imidazo[4,5-c]pyridin-3-yl)-3H-imidazo[4,5-b]pyridine-5-carbonitrile (37); 3-Cyclopropyl-2-(1H-imidazo[4,5-c]pyridin-1-yl)-3H-imidazo[4,5-b]pyridine-5-carbonitrile (38); 1-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-1H-imidazo[4,5-c]pyridine-6-carboxylic acid (39); 1-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-6-(difluoromethyl)-1H-imidazo[4,5-c]pyridine (40); 3-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-6-(difluoromethyl)-3H-imidazo[4,5-c]pyridine (41); 1-Cyclopropyl-2-(3H-imidazo[4,5-c]pyridin-3-yl)-1H-benzo[d]imidazole-6-carbonitrile (42); 1-Cyclopropyl-2-(1H-imidazo[4,5-c]pyridin-1-yl)-1H-benzo[d]imidazole-6-carbonitrile (43); 1'-Cyclopropyl-5',6'-difluoro-1'H-[1,2'-bibenzo[d]imidazole]-5-carboxylic acid (Ex. 44); N-(1'-cyclopropyl-5',6'-difluoro-1'H-[1,2'-bibenzo[d]imidazol]-6-yl)methanesulfonamide (45); N-(1'-cyclopropyl-5',6'-difluoro-1'H-[1,2'-bibenzo[d]imidazol]-5-yl)methanesulfonamide (46); N-(6'-cyano-1'-cyclopropyl-1'H-[1,2'-bibenzo[d]imidazol]-5-yl)methanesulfonamide (47); N-(6'-cyano-1'-cyclopropyl-1'H-[1,2'-bibenzo[d]imidazol]-6-yl)methanesulfonamide (48); 1'-Cyclopropyl-5-(difluoromethoxy)-1'H-[1,2'-bibenzo[d]imidazole]-6'-carbonitrile (49); 1'-Cyclopropyl-6-(difluoromethoxy)-1'H-[1,2'-bibenzo[d]imidazole]-6'-carbonitrile (50); 1'-Cyclopropyl-5',6'-difluoro-1'H-[1,2'-bibenzo[d]imidazole]-6-carboxylic acid (51); 1'-Cyclopropyl-5-(difluoromethoxy)-5',6'-difluoro-1'H-1,2'-bibenzo[d]imidazole (52); 1'-Cyclopropyl-6-(difluoromethoxy)-5',6'-difluoro-1'H-1,2'-bibenzo[d]imidazole (53); and pharma-ceutically acceptable salts, co-crystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically enriched derivatives, and prodrugs thereof.

[0096] In one embodiment, the compounds of formula I are compounds that inhibit (or are determined to inhibit) aldosterone synthase (CYP11B2).

[0097] Compounds herein include compounds that have been identified to gain affinity with at least a portion of a metalloenzyme by forming one or more of the following types of chemical interactions or bonds with the metal: sigma bonds, covalent bonds, coordinate-covalent bonds, ionic bonds, pi bonds, delta bonds, or back-donor interactions. The compounds may also gain affinity through weaker interactions with the metal, such as van der Waals interactions, cation-pi interactions, anion-pi interactions, dipole-dipole interactions, ion-dipole interactions. In one embodiment, the compounds have been identified to bind and interact with the metal through a pyrimidine moiety.

[0098] Methods for evaluating metal-ligand binding interactions are known in the art and are exemplified in references such as "Principles of Bioinorganic Chemistry" by Lippard and Berg, University Science Books, (1994); "Mechanisms of Inorganic Reactions" by Basolo and Pearson John Wiley & Sons Inc; 2nd edition (September 1967); "Biological Inorganic Chemistry" by Ivano Bertini, Harry Gray, Ed Stiefel, Joan Valentine, University Science Books (2007); Xue et al. "Nature Chemical Biology", vol. 4, no. 2, 107-109 (2008).

[0099] In another embodiment, there is provided a pharmaceutical composition comprising a compound of formula I and a pharma- ceutically acceptable carrier.

[0100] In another aspect, a method of modulating metalloenzyme activity in a subject is provided, comprising contacting the subject with a compound of formula I in an amount and under conditions sufficient to modulate the activity of the metalloenzyme.

[0101] In another aspect, there is provided a method of treating a subject suffering from or susceptible to a disorder or disease, and determined to be in need of treatment for said disorder or disease, comprising administering to said subject in need thereof an effective amount of a compound of formula I or a pharmaceutical composition such that said disorder in said subject is treated.

[0102] In other embodiments, the subject is a non-human animal.

[0103] In another aspect, there is provided a method for treating a subject suffering from or susceptible to a metalloenzyme-associated disorder or disease, comprising administering to the subject an effective amount of a compound of formula I or a pharmaceutical composition.

[0104] In another aspect, there is provided a method of treating a subject suffering from or susceptible to a metalloenzyme-associated disorder or disease and determined to be in need of treatment for a metalloenzyme-associated disorder or disease, comprising administering to said subject in need thereof an effective amount of a compound of formula I or a pharmaceutical composition such that said disorder in said subject is treated.

[0105] In another aspect, there is provided a method of treating a subject suffering from or susceptible to a metalloenzyme-mediated disorder or disease, and determined to be in need of treatment for a metalloenzyme-mediated disorder or disease, comprising administering to said subject in need thereof an effective amount of a compound of formula I or a pharmaceutical composition such that metalloenzyme activity in said subject is modulated (e.g., downregulated, inhibited).

[0106] The methods herein include those in which the disease or disorder is characterized by a function of an enzyme that is involved in the regulation of aromatase (CYP19), a member of the cyclooxygenase family, lanosterol demethylase (CYP51), a member of the nitric oxide synthase family, thromboxane synthase (CYP5a), iodide peroxidase, 17-alpha hydroxylase / 17,20-lyase (CYP17), cytochrome P450 2A6 (CYP2A6), heme oxygenase, indoleamine-2,3-dioxygenase, retinoic acid hydroxylase (CYP26), vitamin D hydroxylase (CYP24), sterol 27-hydroxylase (CYP27), cytochrome P450 3A5 (CYP3A5), cholesterol 24-hydroxylase (CYP46), cytochrome P450 The methods include those mediated by either 4F2 (CYP4F2), myeloperoxidase, or 11-β-hydroxylase (CYP11B1).

[0107] The methods herein include methods wherein the disease or disorder is cancer, a cardiovascular disease, an inflammatory disease, an infectious disease, a metabolic disease, an ophthalmic disease, a central nervous system (CNS) disease, a urological disease, or a gastrointestinal disease.

[0108] The methods herein include, for example, treating or preventing a disease or disorder, including hypertension, resistant hypertension, pathological conditions associated with primary or secondary aldosteronism and adrenal hyperplasia, pulmonary arterial hypertension, heart failure, diastolic dysfunction, left ventricular diastolic dysfunction, diastolic heart failure, systolic dysfunction, systolic heart failure, hypokalemia, renal failure, chronic renal failure, restenosis, nephropathy, post-myocardial infarction, coronary artery disease, fibrosis, diseases characterized by increased collagen formation, fibrosis and matrix remodeling after hypertension, fibrosis and matrix remodeling after endothelial cell dysfunction, cardiovascular diseases, e.g., atherosclerosis, atrial fibrillation, renal insufficiency, liver disease, non-alcoholic steatohepatitis, vascular disease, retinopathy, neuropathy, insulin dysregulation, endothelial cell dysfunction, myocardial fibrosis, vascular fibrosis, myocardial necrotic lesions, and the like. In some embodiments, the condition is a chronic kidney disease (CKD), a metabolic disorder (ILD), a vascular disease (VEGF), a vascular endothelial disorder ...

[0109] The methods described herein include methods in which a subject has been determined to be in need of a particular treatment described herein. The determination that a subject is in need of such treatment can be determined by the subject or a medical professional and can be subjective (e.g., opinion) or objective (e.g., measurable by a test or diagnostic method). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0110] Detailed Description definition In order that the present invention may be more readily understood, for convenience, certain terms are first defined herein.

[0111] As used herein, the term "treating" a disorder includes preventing, ameliorating, mitigating, and / or managing the disorder and / or conditions that may cause the disorder. The terms "treating" and "treatment" refer to a method of alleviating or abating a disease and / or its associated symptoms. According to the present disclosure, the term "treating" includes preventing a disorder, blocking a disorder, inhibiting a disorder, attenuating a disorder, protecting against a disorder, modulating a disorder, reversing the effects of a disorder, and, for example, reducing the occurrence of deleterious effects of a disorder.

[0112] The term "inhibiting" as used herein includes preventing, reducing, and halting. It should be noted that this is distinct from "enzyme inhibition" (e.g., metalloenzyme inhibition), which will be described later.

[0113] The term "modulate" refers to increasing or decreasing the activity of an enzyme in response to exposure to a compound of the present disclosure.

[0114] The terms "isolated," "purified," or "biologically pure" refer to material that is substantially or essentially free from components that normally accompany it in its natural state. Purity and homogeneity are typically determined using analytical chemistry techniques such as polyacrylamide gel electrophoresis or high performance liquid chromatography. In particular embodiments, the compounds are at least 85% pure, more preferably at least 90%, more preferably at least 95%, and most preferably at least 99% pure.

[0115] The term "administration" or "administering" includes any route by which a compound is introduced into a subject so that it can perform its intended function. Examples of routes of administration that can be used include injection (subcutaneous, intravenous, parenteral, intraperitoneal, intrathecal), topical, oral, inhalation, rectal, and transdermal routes.

[0116] The term "effective amount" includes an effective amount, administered at the dosage required for the period of time required to achieve the desired result. The effective amount of a compound may vary depending on factors such as the subject's condition, age, and weight, and the ability of the compound to induce a desired response in the subject. Dosage regimens can be adjusted to obtain an optimal therapeutic response. An effective amount is also an amount in which any toxic or adverse effects (e.g., side effects) of the inhibitor compound are outweighed by the therapeutically beneficial effects.

[0117] As used herein, the phrases "systemic administration," "administered systemically," "peripheral administration," and "administered peripherally" refer to administration of a compound, drug, or other substance so that it enters the patient's body, i.e., enters metabolic and other similar processes.

[0118] The term "therapeutically effective amount" refers to that amount of the compound being administered sufficient to prevent the occurrence of, or alleviate to some extent, one or more symptoms of the condition or disorder being treated.

[0119] A therapeutically effective amount of a compound (i.e., an effective dosage) can range from about 0.005 μg / kg body weight to about 200 mg / kg body weight, preferably from about 0.01 mg / kg to about 200 mg / kg body weight, more preferably from about 0.015 mg / kg to about 30 mg / kg body weight. In other embodiments, a therapeutically effective amount can range from about 1.0 pM to about 10 μM. Those skilled in the art will appreciate that the dosage required to effectively treat a subject can be influenced by certain factors, including, but not limited to, the severity of the disease or disorder, previous treatments, general health and / or age of the subject, and existing diseases. Furthermore, treatment of a subject with a therapeutically effective amount of a compound can include a single treatment or, preferably, a series of treatments. In one example, a subject is treated with a compound in the range of about 0.005 μg / kg body weight to about 200 mg / kg body weight once a day for about 1 to 10 weeks, preferably 2 to 8 weeks, more preferably about 3 to 7 weeks, and even more preferably about 4, 5, or 6 weeks. In another example, where a subject has a chronic condition or illness, daily treatment can be administered for several years. It will also be understood that the effective dosage of the compound used in the treatment can be increased or decreased during the course of a particular treatment.

[0120] The term "chiral" refers to a molecule that has the property of not being superimposable on its mirror image counterpart, while the term "achiral" refers to a molecule that is superimposable on its mirror image counterpart.

[0121] The term "diastereomer" refers to a stereoisomer with two or more centers of asymmetricity and whose molecules are not mirror images of one another.

[0122] The term "enantiomers" refers to two stereoisomers of a compound that are non-superimposable mirror images of one another. An equimolar mixture of two enantiomers is called a "racemic mixture" or a "racemate."

[0123] The term "isomers" or "stereoisomers" refers to compounds which have identical chemical constitution but differ in the arrangement of the atoms or groups in space.

[0124] The term "prodrug" includes compounds having a moiety that can be metabolized in vivo. Generally, prodrugs are metabolized in vivo by esterases or other mechanisms to become active drugs. Examples of prodrugs and their uses are well known in the art (see, for example, Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66: 1-19). Prodrugs can be prepared in situ during the final isolation and purification of the compound, or can be prepared separately by reacting the purified compound in its free acid form or a hydroxyl group with a suitable esterifying agent.

[0125] Hydroxyl groups can be converted to esters by treatment with a carboxylic acid. Examples of prodrug moieties include substituted and unsubstituted branched or unbranched lower alkyl ester moieties (e.g., propionate esters), lower alkenyl esters, di-lower alkyl-amino lower alkyl esters (e.g., dimethylaminoethyl esters), acylamino lower alkyl esters (e.g., acetyloxymethyl esters), acyloxy lower alkyl esters (e.g., pivaloyloxymethyl esters), aryl esters (phenyl esters), aryl-lower alkyl esters (e.g., benzyl esters), substituted (e.g., with methyl, halo, or methoxy substituents) aryl and aryl-lower alkyl esters, amides, lower-alkyl amides, di-lower alkyl amides, and hydroxyamides. Preferred prodrug moieties are propionate esters and acyl esters. Prodrugs that are converted to active forms in vivo via other mechanisms are also included. In some embodiments, the compounds of the present disclosure are prodrugs represented by any of the formulas herein.

[0126] The term "subject" refers to animals, such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, and the like. In certain embodiments, the subject is a human.

[0127] As used in this application, including the claims, the terms "a," "an," and "the" mean "one or more." Thus, for example, "a sample" encompasses a plurality of samples unless the context clearly indicates otherwise (e.g., a plurality of samples), and so forth.

[0128] Throughout this specification and the claims, the words "comprise", "comprises" and "comprising" are used in their non-exclusive sense, unless the context requires otherwise.

[0129] The term "about" as used herein in reference to a value is meant to encompass variations from the stated amount, in some embodiments ±20%, in some embodiments ±10%, in some embodiments ±5%, in some embodiments ±1%, in some embodiments ±0.5%, and in some embodiments ±0.1%, as appropriate for practicing the disclosed methods or using the disclosed compositions.

[0130] The word "inhibitor" as used herein refers to a molecule that exhibits activity that inhibits a metalloenzyme. "Inhibit" as used herein means reducing the activity of the metalloenzyme compared to the activity of the metalloenzyme in the absence of the inhibitor.

[0131] In some embodiments, the term "inhibit" refers to reducing metalloenzyme activity by at least about 5%, at least about 10%, at least about 20%, at least about 25%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 95%. In other embodiments, inhibit refers to reducing metalloenzyme activity by about 5% to about 25%, about 25% to about 50%, about 50% to about 75%, or about 75% to 100%. In some embodiments, inhibit refers to reducing metalloenzyme activity by about 95% to 100%, e.g., reducing activity by 95%, 96%, 97%, 98%, 99%, or 100%. Such reductions can be measured using a variety of techniques that one of skill in the art would recognize. Specific tests for measuring individual activities are described below.

[0132] Additionally, the compounds of the present disclosure include olefins of both geometric configurations: "Z" refers to what is referred to as the "cis" (same side) configuration and "E" refers to what is referred to as the "trans" (opposite side) configuration. The terms "d" and "l" configurations for the nomenclature of asymmetric centers are as defined by the IUPAC recommendations. With regard to the use of the terms diastereomers, racemates, epimers, and enantiomers, they are used in their normal context to describe the stereochemistry of the formulations.

[0133] The term "alkyl" as used herein refers to a straight or branched chain hydrocarbon group having 1 to 12 carbon atoms. The term "lower alkyl" refers to a C1 to C6 alkyl chain. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, tert-butyl, and n-pentyl. An alkyl group may be optionally substituted with one or more substituents.

[0134] The term "haloalkyl" refers to an alkyl group substituted with one or more halo substituents. Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, bromomethyl, chloromethyl, and 2,2,2-trifluoroethyl.

[0135] The term "alkenyl" refers to an unsaturated hydrocarbon chain, which may be straight or branched, containing 2 to 12 carbon atoms and at least one carbon-carbon double bond. Alkenyl groups may be optionally substituted with one or more substituents.

[0136] The term "arylalkenyl" refers to an aryl group containing 2 to 12 carbon atoms and at least one carbon-carbon double bond, and having an alkenyl unit sp 2 It refers to an unsaturated hydrocarbon chain, which may be straight or branched, in which one or more hybridized carbons are attached to an aryl moiety. An alkenyl group may be optionally substituted with one or more substituents.

[0137] The term "alkynyl" refers to an unsaturated hydrocarbon chain, which may be straight or branched, containing 2 to 12 carbon atoms and at least one carbon-carbon triple bond. Alkynyl groups may be optionally substituted with one or more substituents.

[0138] The term "arylalkynyl" refers to an unsaturated hydrocarbon chain, which may be straight or branched, containing 2 to 12 carbon atoms and at least one carbon-carbon triple bond, in which one or more sp hybridized carbons of the alkynyl unit are attached to an aryl moiety. The alkynyl group may be optionally substituted with one or more substituents.

[0139] Alkenyl and alkynyl groups sp 2 or sp carbon may optionally be the point of attachment of an alkenyl or alkynyl group, respectively.

[0140] The term "alkoxy" refers to an --O-alkyl substituent.

[0141] The term "halogen", "hal" or "halo" as used herein means -F, -Cl, -Br, or -I.

[0142] The term "alkylthio" refers to an --S-alkyl substituent.

[0143] The term "alkoxyalkyl" refers to an -alkyl-O-alkyl substituent.

[0144] The term "haloalkoxy" refers to an -O-alkyl that is substituted with one or more halo substituents. Examples of haloalkoxy groups include trifluoromethoxy and 2,2,2-trifluoroethoxy.

[0145] The term "haloalkoxyalkyl" refers to -alkyl-O-alkyl', where the alkyl' is substituted with one or more halo substituents.

[0146] The term "haloalkylaminocarbonyl" refers to -C(O)-amino-alkyl, in which the alkyl is substituted with one or more halo substituents.

[0147] The term "haloalkylthio" refers to an -S-alkyl substituted with one or more halo substituents. Examples of haloalkylthio groups include trifluoromethylthio and 2,2,2-trifluoroethylthio.

[0148] The term "haloalkylcarbonyl" refers to -C(O)-alkyl substituted with one or more halo substituents. Examples of haloalkylcarbonyl groups include trifluoroacetyl.

[0149] The term "cycloalkyl" refers to a 3- to 8-membered monocyclic or 7- to 14-membered bicyclic hydrocarbon ring system having at least one saturated ring or at least one non-aromatic ring, which non-aromatic ring may contain some degree of unsaturation.

[0150] Cycloalkyl groups may be optionally substituted with one or more substituents. In one embodiment, 0, 1, 2, 3, or 4 atoms of each ring of a cycloalkyl group may be substituted with a substituent. Representative examples of cycloalkyl groups include cyclopropyl, cyclopentyl, cyclohexyl, cyclobutyl, cycloheptyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, and the like.

[0151] The term "cycloalkoxy" refers to an --O-cycloalkyl substituent.

[0152] The term "cycloalkoxyalkyl" refers to an -alkyl-O-cycloalkyl substituent.

[0153] The term "cycloalkylalkoxy" refers to an --O-alkyl-cycloalkyl substituent.

[0154] The term "cycloalkylaminocarbonyl" refers to a -C(O)-NH-cycloalkyl substituent.

[0155] The term "aryl" refers to a hydrocarbon monocyclic, bicyclic, or tricyclic aromatic ring system. An aryl group may be optionally substituted with one or more substituents. In one embodiment, 0, 1, 2, 3, 4, 5, or 6 atoms of each ring of an aryl group may be substituted with a substituent. Examples of aryl groups include phenyl, naphthyl, anthracenyl, fluorenyl, indenyl, azulenyl, and the like.

[0156] The term "aryloxy" refers to an --O-aryl substituent.

[0157] The term "arylalkoxy" refers to an -O-alkyl-aryl substituent.

[0158] The term "arylalkylthio" refers to an -S-alkyl-aryl substituent.

[0159] The term "arylthioalkyl" refers to an -alkyl-S-aryl substituent.

[0160] The term "arylalkylaminocarbonyl" refers to a -C(O)-amino-alkyl-aryl substituent.

[0161] The term "arylalkylsulfonyl" refers to an -S(O)2-alkyl-aryl substituent.

[0162] The term "arylalkylsulfinyl" refers to an -S(O)-alkyl-aryl substituent.

[0163] The term "aryloxyalkyl" refers to an -alkyl-O-aryl substituent.

[0164] The term "alkylaryl" refers to an -aryl-alkyl substituent.

[0165] The term "arylalkyl" refers to an -alkyl-aryl substituent.

[0166] The term "heteroaryl" refers to an aromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1-4 ring heteroatoms in the case of a monocyclic ring, 1-6 heteroatoms in the case of a bicyclic ring, or 1-9 heteroatoms in the case of a tricyclic ring, the heteroatoms being selected from O, N, or S, with the remaining ring atoms being carbon (with appropriate hydrogen atoms unless otherwise specified). Heteroaryl groups may be optionally substituted with one or more substituents. In one embodiment, 0, 1, 2, 3, or 4 atoms of each ring of a heteroaryl group may be substituted with a substituent. Heteroaryl groups include pyridyl, furanyl, thienyl, pyrrolyl, oxazolyl, oxadiazolyl, imidazolyl, thiazolyl, isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, isoquinolinyl, indazolyl, and the like.

[0167] The term "heteroarylalkyl" refers to an -alkyl-heteroaryl substituent.

[0168] The term "heteroaryloxy" refers to an --O-heteroaryl substituent.

[0169] The term "heteroarylalkoxy" refers to an -O-alkyl-heteroaryl substituent.

[0170] The term "heteroaryloxyalkyl" refers to an -alkyl-O-heteroaryl substituent.

[0171] The term "nitrogen-containing heteroaryl" refers to a heteroaryl group having 1 to 4 nitrogen ring heteroatoms if monocyclic, 1 to 6 nitrogen ring heteroatoms if bicyclic, or 1 to 9 nitrogen ring heteroatoms if tricyclic.

[0172] The term "heterocycloalkyl" refers to a non-aromatic 3-8 membered monocyclic, 7-12 membered bicyclic, or 10-14 membered tricyclic ring system containing 1-3 heteroatoms in the case of a monocyclic ring, 1-6 heteroatoms in the case of a bicyclic ring, or 1-9 heteroatoms in the case of a tricyclic ring, the heteroatoms being selected from O, N, S, B, P, or Si, and the non-aromatic ring system being fully saturated. Heterocycloalkyl groups may be optionally substituted with one or more substituents. In one embodiment, 0, 1, 2, 3, or 4 atoms of each ring of a heterocycloalkyl group may be substituted with a substituent. Representative heterocycloalkyl groups include piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,3-dioxolane, tetrahydrofuranyl, tetrahydrothienyl, thiirenyl, and the like.

[0173] The term "heterocycloalkylalkyl" refers to an -alkyl-heterocycloalkyl substituent.

[0174] The term "alkylamino" refers to an amino substituent further substituted with one or two alkyl groups. The term "aminoalkyl" refers to an alkyl substituent further substituted with one or more amino groups. The terms "hydroxyalkyl" or "hydroxylalkyl" refer to an alkyl substituent further substituted with one or more hydroxyl groups. The alkyl or aryl portions of alkylamino, aminoalkyl, mercaptoalkyl, hydroxyalkyl, mercaptoalkoxy, sulfonylalkyl, sulfonylaryl, alkylcarbonyl, and alkylcarbonylalkyl may be optionally substituted with one or more substituents.

[0175] Acids and bases useful in the methods herein are known in the art. Acid catalysts are any acidic chemicals and can be inorganic (e.g., hydrochloric acid, sulfuric acid, nitric acid, aluminum trichloride) or organic (e.g., camphorsulfonic acid, p-toluenesulfonic acid, acetic acid, ytterbium trifluoromethanesulfonate) in nature. Acids are useful in catalytic or stoichiometric amounts to promote chemical reactions. Bases are any basic chemicals and can be inorganic (e.g., sodium bicarbonate, potassium hydroxide) or organic (e.g., triethylamine, pyridine) in nature. Bases are useful in catalytic or stoichiometric amounts to promote chemical reactions.

[0176] An alkylating agent is any reagent capable of alkylating a functional group of interest (e.g., the oxygen atom of an alcohol, the nitrogen atom of an amino group). Alkylating agents are known in the art, including the references cited herein, and include alkyl halides (e.g., methyl iodide, benzyl bromide or chloride), alkyl sulfates (e.g., methyl sulfate), or other alkyl group-leaving group combinations known in the art. Leaving groups are any stable chemical species that can be cleaved from a molecule during a reaction (e.g., abstraction, substitution, etc.) and are known in the art, including the references cited herein, and include halides (e.g., I-, Cl-, Br-, F-), hydroxy, alkoxy (e.g., -OMe, -Ot-Bu), acyloxy anions (e.g., -OAc, -OC(O)CF3), sulfonates (e.g., mesyl, tosyl), acetamides (e.g., -NHC(O)Me), carbamates (e.g., N(Me)C(O)Ot-Bu), phosphonates (e.g., -OP(O)(OEt)2), water, or alcohols (protic conditions), and the like.

[0177] In certain embodiments, substituents of any group (e.g., alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, heterocycloalkyl, etc.) may be located on any atom of the group, and any group that is optionally substituted (e.g., alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, heterocycloalkyl, etc.) may be optionally substituted with one or more substituents (which may be the same or different), each replacing a hydrogen atom. Examples of suitable substituents include, but are not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halogen, haloalkyl, cyano, nitro, alkoxy, aryloxy, hydroxyl, hydroxylalkyl, oxo (i.e., carbonyl), carboxyl, formyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkylcarbonyloxy, aryloxycarbonyl, heteroaryloxy, heteroaryloxycarbonyl, thio, mercapto, mercaptoalkyl, arylsulfonyl, amino, aminoalkyl, dialkylamino. , alkylcarbonylamino, alkylaminocarbonyl, alkoxycarbonylamino, alkylamino, arylamino, diarylamino, alkylcarbonyl, or arylamino-substituted aryl, arylalkylamino, aralkylaminocarbonyl, amido, alkylaminosulfonyl, arylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, imino, carboxamido, carboxamido, carbamyl, thioureido, thiocyanato, sulfamido, sulfonylalkyl, sulfonylaryl, mercaptoalkoxy, N-hydroxyamidinyl, or N'-aryl, N"-hydroxyamidinyl.

[0178] The compounds of the present disclosure can be prepared by means known in the art of organic synthesis. Methods for optimizing reaction conditions to minimize competing by-products, if necessary, are known in the art. Reaction optimization and scale-up can advantageously utilize high speed parallel synthesis equipment and computer-controlled microreactors (see, for example, Design And Optimization in Organic Synthesis, 2001). nd Edition, Carlson R, Ed, 2005; Elsevier Science Ltd.; Jahnisch, K et al, Angew. Chem. Int. Ed. Engl. 2004 43: 406; and references contained therein). Additional reaction schemes and procedures can be determined by those skilled in the art by performing appropriate keyword searches using commercially available structure-searchable database software, such as SciFinder® (CAS division of the American Chemical Society) and CrossFire Beilstein® (Elsevier MDL), or Internet search engines, such as Google® or keyword databases such as the US Patent and Trademark Office text database.

[0179] Those skilled in the art will appreciate that methods of synthesis of compounds represented by the formulae set forth herein, including those described in the schemes and examples herein, will be apparent to those skilled in the art. Additionally, the various synthetic steps may be performed in alternative sequences or orders to obtain the desired compounds. Additionally, those skilled in the art will recognize that the solvents, temperatures, reaction times, and the like listed herein are for illustrative purposes only, and that variations in reaction conditions may be used to produce the desired compounds of the present disclosure.

[0180] The compounds herein may also include bonds (e.g., carbon-carbon bonds) with restricted rotation about a particular bond, for example due to the presence of a ring or double bond. Thus, all cis / trans and E / Z isomers are expressly included in the present disclosure. The compounds herein may also be represented in multiple tautomeric forms, in which case the present disclosure expressly includes all tautomeric forms of the compounds described herein, even if only a single tautomeric form may be represented. All such isomeric forms of the compounds herein are expressly included in the present disclosure. All crystal forms and polymorphs of the compounds described herein are expressly included in the present disclosure. Extracts and fractions containing the compounds of the present disclosure are also incorporated. The term isomer is intended to include stereoisomers, enantiomers, positional isomers, structural isomers, rotamers, tautomers, and the like. In the case of compounds containing one or more stereocenters, e.g., asymmetric compounds, the methods of the disclosure can be carried out with compounds enriched in one enantiomer, a racemate, or a mixture of diastereomers.

[0181] Preferred enantiomerically enriched compounds have an enantiomeric excess of 50% or greater, more preferably the compounds have an enantiomeric excess of greater than 60%, greater than 70%, greater than 80%, greater than 90%, greater than 95%, greater than 98%, or greater than 99% or more. In preferred embodiments, only one enantiomer or diastereomer of the asymmetric compounds of the present disclosure is administered to a cell or subject. Treatment method In one aspect, there is provided a method for treating a subject suffering from or susceptible to a disorder or disease, comprising administering to the subject an effective amount of a compound of formula I or a pharmaceutical composition.

[0182] In another aspect, there is provided a method of treating a subject suffering from or susceptible to a disorder or disease, and determined to be in need of treatment for a metalloenzyme-mediated disorder or disease, comprising administering to said subject in need thereof an effective amount of a compound of formula I or a pharmaceutical composition such that said disorder in said subject is treated.

[0183] In one aspect, a method of modulating metalloenzyme activity in a cell of a subject is provided, comprising contacting the subject with a compound of formula I in an amount and under conditions sufficient to modulate the metalloenzyme activity.

[0184] In one embodiment, the modulation is inhibition.

[0185] In another aspect, there is provided a method for treating a subject suffering from or susceptible to a metalloenzyme-mediated disorder or disease, comprising administering to the subject an effective amount of a compound of formula I or a pharmaceutical composition.

[0186] In another aspect, there is provided a method of treating a subject suffering from or susceptible to a metalloenzyme-mediated disorder or disease, and determined to be in need of treatment for a metalloenzyme-mediated disorder or disease, comprising administering to said subject in need thereof an effective amount of a compound of formula I or a pharmaceutical composition such that said disorder in said subject is treated.

[0187] In certain embodiments, methods are provided for treating a disease, disorder, or a symptom thereof, wherein the disorder is cancer, a cardiovascular disease, an endocrine disease, an inflammatory disease, an infectious disease, a gynecological disease, a metabolic disease, an ophthalmological disease, a central nervous system (CNS) disease, a urological disease, or a gastrointestinal disease. In certain embodiments, the disease is hypertension, resistant hypertension, pathological conditions associated with primary or secondary aldosteronism and adrenal hyperplasia, pulmonary arterial hypertension, heart failure, diastolic dysfunction, left ventricular diastolic dysfunction, diastolic heart failure, systolic dysfunction, systolic heart failure, hypokalemia, renal failure, chronic renal failure, restenosis, nephropathy, post-myocardial infarction, coronary artery disease, fibrosis, diseases characterized by increased collagen formation, fibrosis and matrix remodeling after hypertension, fibrosis and matrix remodeling after endothelial cell dysfunction, cardiovascular diseases such as atherosclerosis, atrial fibrillation, renal insufficiency, liver disease, non-alcoholic steatohepatitis, vascular disease, retinopathy, neuropathy, insulin dyscrasia, endothelial cell dysfunction, myocardial fibrosis, vascular fibrosis, myocardial necrotic lesions, vasculitis, myocardial infarction, left ventricular hypertrophy, vascular wall hypertrophy, intimal thickening, fibrinoid necrosis of arteries, kidney disease, diabetic nephropathy, glomerulosclerosis, glomerulonephritis, nephritic syndrome , polycystic kidney disease, diabetes, metabolic syndrome, insulin resistance, sleep apnea, obstructive sleep apnea, muscular dystrophy, cirrhosis, non-alcoholic fatty liver disease, kidney disease, diabetic nephropathy, or stroke.

[0188] In certain embodiments, the subject is a mammal, preferably a primate or a human.

[0189] In another embodiment, there is provided a method as described above, wherein the effective amount of the compound of formula I is as described above.

[0190] In other embodiments, there is provided a method as described above, wherein the compound of formula I is administered intravenously, intramuscularly, subcutaneously, intracerebroventricularly, orally, or topically.

[0191] In other embodiments, the methods described herein include those in which the compound of formula I exhibits selectivity for the range of activity of the target enzyme (e.g., IC 200 for aldosterone synthase (CYP11B2) 50 <1.0μM).

[0192] In other embodiments, methods are provided as described above, wherein a compound of formula I is administered alone or in combination with one or more other therapies. In further embodiments, the additional therapeutic agent is an anti-cancer agent, an anti-fungal agent, a cardiovascular agent, an anti-inflammatory agent, a chemotherapeutic agent, an anti-angiogenic agent, a cytotoxic agent, an anti-proliferative agent, an agent for treating a metabolic disease, an ophthalmologic disease agent, an agent for treating a central nervous system (CNS) disease, an agent for treating a urological disease, or an agent for treating a gastrointestinal disease.

[0193] In certain embodiments, the additional therapeutic agent is an agent for treating hypertension, an agent for treating primary aldosteronism, an agent for treating renal disease, an agent for treating congestive heart failure, an agent for treating an atherosclerotic condition, an agent for treating diabetes, an agent for treating obesity, or an agent for treating a metabolic disease.

[0194] Exemplary additional therapeutic agents include, but are not limited to, renin inhibitors, angiotensin-converting enzyme (ACE) inhibitors, dual inhibitors of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP), angiotensin II receptor blockers (ARBs), mineralocorticoid receptor antagonists (MRAs), neutral endopeptidase inhibitors (NEPs), neprilysin inhibitors, calcium antagonists, alpha-adrenergic blockers, beta-adrenergic blockers, diuretics (including loop diuretics), potassium channel activators, endothelin receptor antagonists, endothelin 1 receptor antagonists, soluble guanylate cyclase inhibitors, and the like. These include enzyme stimulators, vasodilators, HMG-CoA reductase inhibitors, niacin and niacin receptor agonists, Niemann-Pick C1-like 1 (NPC1L1) inhibitors, insulin or insulin analogues, biguanides (e.g., metformin), sulfonylureas, peroxisome proliferator-activated receptor (PPAR) agonists and partial agonists (including PPARγ agonists and other PPAR ligands), dipeptidyl peptidase-4 (DPP4) inhibitors, glucagon-like peptide 1 (GLP-1), GLP-1 receptor agonists, and sodium-glucose cotransporter 2 (SGLT2) inhibitors.

[0195] Another object of the disclosure is the use of a compound described herein (e.g., a compound of Formula I) in the manufacture of a medicament for use in treating a metalloenzyme-mediated disorder or disease. Another object of the disclosure is the use of a compound described herein (e.g., a compound of Formula I) in the manufacture of an agricultural composition for use in treating or preventing a metalloenzyme-mediated disorder or disease in an agricultural or agrarian environment. Pharmaceutical Compositions In one aspect, there is provided a pharmaceutical composition comprising a compound of formula I and a pharma- ceutically acceptable carrier.

[0196] In another embodiment, a pharmaceutical composition is provided further comprising an additional therapeutic agent, hi further embodiments, the additional therapeutic agent is an anti-cancer agent, an anti-fungal agent, a cardiovascular agent, an anti-inflammatory agent, a chemotherapeutic agent, an anti-angiogenic agent, a cytotoxic agent, an anti-proliferative agent, an agent for treating a metabolic disease, an agent for treating an ophthalmic disease, an agent for treating a central nervous system (CNS) disease, an agent for treating a urological disease, or an agent for treating a gastrointestinal disease.

[0197] In certain embodiments, the additional therapeutic agent is an agent for treating hypertension, an agent for treating primary aldosteronism, an agent for treating renal disease, an agent for treating congestive heart failure, an agent for treating an atherosclerotic condition, an agent for treating diabetes, an agent for treating obesity, or an agent for treating a metabolic disease.

[0198] Exemplary additional therapeutic agents include, but are not limited to, renin inhibitors, angiotensin-converting enzyme (ACE) inhibitors, dual inhibitors of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP), angiotensin II receptor blockers (ARBs), mineralocorticoid receptor antagonists (MRAs), neutral endopeptidase inhibitors (NEPs), neprilysin inhibitors, calcium antagonists, alpha-adrenergic blockers, beta-adrenergic blockers, diuretics (including loop diuretics), potassium channel activators, endothelin receptor antagonists, endothelin 1 receptor antagonists, soluble guanylate cyclase inhibitors, and the like. These include enzyme stimulators, vasodilators, HMG-CoA reductase inhibitors, niacin and niacin receptor agonists, Niemann-Pick C1-like 1 (NPC1L1) inhibitors, insulin or insulin analogues, biguanides (e.g., metformin), sulfonylureas, peroxisome proliferator-activated receptor (PPAR) agonists and partial agonists (including PPARγ agonists and other PPAR ligands), dipeptidyl peptidase-4 (DPP4) inhibitors, glucagon-like peptide 1 (GLP-1), GLP-1 receptor agonists, and sodium-glucose cotransporter 2 (SGLT2) inhibitors.

[0199] In one aspect, a kit is provided that includes an effective amount of a compound of formula I in unit dosage form together with instructions for administering the compound to a subject suffering from or susceptible to a metalloenzyme-mediated disease or disorder, such as cancer, cardiovascular disease, endocrine disease, inflammatory disease, infectious disease, gynecological disease, metabolic disease, ophthalmology disease, central nervous system (CNS) disease, urological disease, or gastrointestinal disease. In certain embodiments, the disorder, disease, or symptom thereof is hypertension, resistant hypertension, pathological conditions associated with primary or secondary aldosteronism and adrenal hyperplasia, pulmonary arterial hypertension, heart failure, diastolic dysfunction, left ventricular diastolic dysfunction, diastolic heart failure, systolic dysfunction, systolic heart failure, hypokalemia, renal failure, chronic renal failure, restenosis, nephropathy, post-myocardial infarction, coronary artery disease, fibrosis, diseases characterized by increased collagen formation, fibrosis and matrix remodeling following hypertension, fibrosis and matrix remodeling following endothelial cell dysfunction, cardiovascular disease, e.g., atherosclerosis. The conditions include, for example, diabetes, atrial fibrillation, renal insufficiency, liver disease, non-alcoholic steatohepatitis, vascular disease, retinopathy, neuropathy, insulin abnormalities, endothelial cell dysfunction, myocardial fibrosis, vascular fibrosis, myocardial necrotic lesions, vasculitis, myocardial infarction, left ventricular hypertrophy, vascular wall hypertrophy, intimal thickening, arterial fibrinoid necrosis, kidney disease, diabetic nephropathy, glomerulosclerosis, glomerulonephritis, nephritic syndrome, polycystic kidney disease, diabetes, metabolic syndrome, insulin resistance, sleep apnea, obstructive sleep apnea, muscular dystrophy, liver cirrhosis, non-alcoholic fatty liver disease, kidney disorder, diabetic nephropathy, or stroke.

[0200] The term "pharmaceutical acceptable salt" or "pharmaceutical acceptable carrier" is intended to include salts of active compounds prepared with relatively low toxicity acids or bases, depending on the specific substituents present in the compounds described herein. When a compound of the present disclosure contains a relatively highly acidic functional group, a base addition salt can be obtained by contacting such a compound in neutral form with a sufficient amount of a desired base, either neat or in a suitable inert solvent. Examples of pharmaceutical acceptable base addition salts include sodium salts, potassium salts, calcium salts, ammonium salts, organic amino salts, or magnesium salts, or similar salts. When a compound of the present disclosure contains a relatively highly basic functional group, a base addition salt can be obtained by contacting such a compound in neutral form with a sufficient amount of a desired acid, either neat or in a suitable inert solvent. Examples of pharma- ceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphate, dihydrogenphosphate, sulfuric, monohydrogensulfuric, hydroiodic, or phosphoric acid, as well as those derived from relatively less toxic organic acids such as acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, etc. Also included are salts of alginates and similar amino acids and salts of glucuronic or galactunoric acids and similar organic acids (see, e.g., Berge et al., Journal of Pharmaceutical Science 66:1-19 (1977)). Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. Other pharma- ceutically acceptable carriers known to those of ordinary skill in the art are suitable for the present disclosure.

[0201] The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound and the various salt forms differ in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for purposes of this disclosure.

[0202] In addition to salt forms, the present disclosure provides compounds in prodrug form. Prodrugs of the compounds described herein are compounds that undergo easy chemical changes under physiological conditions to provide the compounds of the present disclosure. Furthermore, prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present disclosure by placing them in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

[0203] Certain compounds of the present disclosure can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, solvated forms are equivalent to unsolvated forms and are intended to be included within the scope of the present disclosure. Certain compounds of the present disclosure can exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the use envisioned by the present disclosure and are intended to be included within the scope of the present disclosure.

[0204] The present disclosure also provides pharmaceutical compositions comprising an effective amount of the compound described herein and a pharma- ceutical acceptable carrier.In one embodiment, the compound of formula I is administered to a subject using a pharma- ceutical acceptable formulation, for example, a pharma- ceutical acceptable formulation that provides sustained delivery of the compound to the subject for at least 12 hours, 24 hours, 36 hours, 48 ​​hours, 1 week, 2 weeks, 3 weeks, or 4 weeks after administering the pharma- ceutical acceptable formulation to the subject.

[0205] Actual dosage levels and time course of administration of the active ingredients in the pharmaceutical compositions of the present disclosure can be varied to provide for a particular patient, composition, and method of administration an amount of active ingredient effective to achieve the desired therapeutic response without toxicity (or unacceptable toxicity) to the patient.

[0206] In use, at least one compound according to the present disclosure is administered in a pharmaceutical carrier by intravenous, intramuscular, subcutaneous, or intracerebroventricular injection, or by oral administration or topical application in a pharma- ceutical effective amount to a subject in need thereof. According to the present disclosure, the compounds of the present disclosure can be administered alone or in combination with a second, different therapeutic. The term "in combination with" means together, substantially simultaneously, or sequentially. In one embodiment, the compounds of the present disclosure are administered acutely. Thus, the compounds of the present disclosure can be administered for short-term treatment, for example, from about one day to about one week. In other embodiments, the compounds of the present disclosure can be administered for long-term, for example, from about one week to several months, depending on the condition to be treated, to ameliorate chronic disorders.

[0207] As used herein, "pharmaceutical effective amount" refers to an amount of the compound of the present disclosure that is high enough to significantly improve the condition to be treated, within the scope of sound medical judgment, but low enough to avoid serious side effects (at a reasonable benefit / risk ratio). The pharmaceutical effective amount of the compound of the present disclosure will vary depending on the specific goal to be achieved, the age and health of the patient to be treated, the severity of the underlying disease, the duration of treatment, the nature of the concomitant therapy, and the specific compound employed. For example, the therapeutically effective amount of the compound of the present disclosure administered to a child or neonate will be reduced accordingly, in accordance with sound medical judgment. Thus, the effective amount of the compound of the present disclosure is the minimum amount that will produce the desired effect.

[0208] The clear practical advantage of the present disclosure is that the compound can be administered in a convenient form, for example, by intravenous, intramuscular, subcutaneous, oral, or intracerebroventricular injection route, or by local application such as cream or gel. Depending on the administration route, the active ingredient including the compound of the present disclosure may need to be coated with some material to protect the compound of the present disclosure from the action of enzymes, acids, and other natural conditions that may inactivate the compound of the present disclosure. In order to administer the compound of the present disclosure by a method other than parenteral administration, the compound of the present disclosure can be coated with or administered together with a material to prevent inactivation.

[0209] The compounds can be administered parenterally or intraperitoneally.For example, dispersions can be formulated in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils.

[0210] Some examples of substances which can serve as pharmaceutical carriers include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, cellulose acetate; powdered tragancanth; malt; gelatin; talc; stearic acid; magnesium stearate; calcium sulfate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and cocoa butter; polyols such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; agar; alginic acid; pyrogen-free water; isotonic saline; and phosphate buffers; nonfat dry milk; as well as other compatible nontoxic substances used in pharmaceutical formulations, such as vitamin C, estrogen, and echinacea. Coloring agents, flavorings, lubricants, excipients, tableting agents, stabilizers, antioxidants, and preservatives can also be present, as well as wetting agents and lubricants such as sodium lauryl sulfate. Solubilizing agents, such as cremaphore and β-cyclodextrin, can also be used in the pharmaceutical compositions herein.

[0211] Pharmaceutical compositions containing the active compound (or its prodrug) of the present disclosure can be manufactured using conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing processes. The compositions can be formulated in a conventional manner using one or more physiologically acceptable carriers, diluents, excipients, or adjuvants that facilitate the processing of the active compound into a medicament usable preparation.

[0212] The pharmaceutical compositions that are the subject of this disclosure can be in a form suitable for virtually any mode of administration, including, for example, topical, ocular, oral, buccal, systemic, nasal, injectable, transdermal, rectal, vaginal, and the like, or in a form suitable for administration by inhalation or insufflation.

[0213] For topical administration, the active compounds or prodrugs can be formulated as solutions, gels, ointments, creams, suspensions, and the like.

[0214] Systemic formulations include those designed for administration by injection, e.g., subcutaneous, intravenous, intramuscular, intrathecal, or intraperitoneal injection, as well as those designed for transdermal, transmucosal, oral, or pulmonary administration.

[0215] Useful injectable preparations include sterile suspensions, solutions, or emulsions of the active compound in an aqueous or oily vehicle. The compositions may also contain formulating agents, such as suspending, stabilizing, and / or dispersing agents. Injectable preparations may also be provided in unit dosage form (e.g., in ampoules or in multi-dose containers) and may contain added preservatives.

[0216] Alternatively, the injectable formulations may be provided in powder form for reconstitution before use with a suitable solvent, including but not limited to sterile pyrogen-free water, buffer, dextrose solution, etc. To this end, the active compound may be dried by any known technique, such as lyophilization, and reconstituted prior to use.

[0217] For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation, and such penetrants are known in the art.

[0218] For oral administration, the pharmaceutical compositions can take the form of, for example, lozenges, tablets, or capsules formulated by conventional means with pharma- ceutically acceptable excipients, such as: binders (e.g., pregelatinized maize starch, polyvinylpyrrolidone, or hydroxypropylmethylcellulose); fillers (e.g., lactose, microcrystalline cellulose, or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrants (e.g., potato starch or sodium starch glycolate); and / or wetting agents (e.g., sodium lauryl sulfate). Tablets can be coated, for example, with sugar or enteric coatings by methods well known in the art.

[0219] Liquid preparations for oral administration can take the form of, for example, elixirs, liquid preparations, syrups, or suspension preparations, or can be provided as dry products that are prepared with water or a suitable solvent before use. Such liquid preparations can be formulated using conventional means with pharma- ceutically acceptable additives, such as: suspending agents (e.g., sorbitol syrup, cellulose derivatives, or hydrogenated edible fats); emulsifying agents (e.g., lecithin or gum arabic); non-aqueous solvents (e.g., almond oil, oily esters, ethyl alcohol, or fractionated vegetable oils); and preservatives (e.g., methyl or propyl p-hydroxybenzoate or sorbic acid). The preparations can further contain, if appropriate, buffer salts, preservatives, flavoring agents, coloring agents, and sweetening agents.

[0220] Preparations for oral administration can be suitably formulated so as to give controlled release of the active compound or prodrug, as is known in the art.

[0221] For buccal administration, the compositions can take the form of tablets or lozenges formulated in conventional manner.

[0222] For rectal and vaginal administration routes, the active compounds can be formulated as solution preparations (for retention enemas), suppositories, or ointments containing conventional suppository bases such as cocoa butter or other glycerides.

[0223] For nasal administration or administration by inhalation or insufflation, the active compound or prodrug can be conveniently delivered in the form of an aerosol spray from a pressurized pack or nebulizer using a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, fluorocarbons, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Capsules and cartridges (e.g., capsules and cartridges composed of gelatin) for use in an inhaler or insufflator can be formulated to contain a powder mix of the compound and a suitable powder base, such as lactose or starch.

[0224] A specific example of an aqueous suspension formulation suitable for nasal administration using a commercially available nasal spray contains the following ingredients: active compound or prodrug (0.5-20 mg / mL); benzalkonium chloride (0.1-0.2 mg / mL); polysorbate 80 (TWEEN® 80; 0.5-5 mg / mL); sodium carboxymethylcellulose or microcrystalline cellulose (1-15 mg / mL); phenylethanol (1-4 mg / mL); and dextrose (20-50 mg / mL). The pH of the final suspension formulation can be adjusted to a range of about pH 5 to about pH 7, with a typical pH being about pH 5.5.

[0225] For intraocular administration, the active compound or prodrug can be formulated into a solution formulation, emulsion formulation, suspension formulation, etc. suitable for intraocular administration. A variety of solvents suitable for administering compounds intraocularly are known in the art. Non-limiting examples are described in U.S. Patent No. 6,261,547; U.S. Patent No. 6,197,934; U.S. Patent No. 6,056,950; U.S. Patent No. 5,800,807; U.S. Patent No. 5,776,445; U.S. Patent No. 5,698,219; U.S. Patent No. 5,521,222; U.S. Patent No. 5,403,841; U.S. Patent No. 5,077,033; U.S. Patent No. 4,882,150; and U.S. Patent No. 4,738,851, each of which is incorporated herein by reference in its entirety.

[0226] For long-term delivery of the active compound or prodrug, it can be formulated as a depot preparation for administration by implantation or intramuscular injection. The active ingredient can be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or with ion exchange resins, or as a poorly soluble derivative, e.g., as a poorly soluble salt. Alternatively, a transdermal delivery system can be used, which is manufactured as a circular adhesive disc or patch that slowly releases the active compound so that it is absorbed through the skin. For this purpose, a permeation enhancer can be used to promote the percutaneous penetration of the active compound. Suitable transdermal patches are described, for example, in U.S. Pat. Nos. 5,407,713; 5,352,456; 5,332,213; 5,336,168; 5,290,561; 5,254,346; 5,164,189; 5,163,899; 5,088,977; 5,087,240; 5,008,110; and 4,921,475, the entire contents of each of which are incorporated herein by reference.

[0227] Alternatively, other pharmaceutical delivery systems can be employed. Liposomes and emulsions are well-known examples of delivery vehicles that can be used to deliver active compounds or prodrugs. Certain organic solvents, such as dimethylsulfoxide (DMSO), can also be used.

[0228] The pharmaceutical compositions can, if desired, be presented in a pack or dispenser device which can contain one or more unit dosage forms containing the active compound. The pack can, for example, comprise metal or laminated plastic, such as a blister pack. The pack or dispenser device can be accompanied by instructions for administration.

[0229] The active compounds or prodrugs or compositions thereof of the present disclosure will generally be used in an amount effective to achieve the intended result, for example, an amount effective to treat or prevent the specific disease to be treated. The compounds can be administered therapeutically to achieve a therapeutic effect, or prophylactically to achieve a prophylactic effect. By therapeutic effect, it is meant that the underlying disorder to be treated is eradicated or ameliorated, and / or one or more symptoms associated with the underlying disorder are eradicated or ameliorated, such that the patient reports an improved feeling or condition, regardless of whether the patient may still be afflicted by the underlying disorder. For example, a therapeutic effect is achieved when administering a compound to a patient suffering from an allergy not only eradicates or improves the underlying allergic reaction, but also when the patient reports a reduction in the severity or duration of symptoms associated with the allergy after exposure to an allergen. As another example, a therapeutic effect related to asthma may include improved breathing after an asthma attack has developed, or a reduction in the frequency or severity of asthma attacks. Benefits of treatment also include halting or slowing the progression of the disease, regardless of whether improvement is realized.

[0230] In the case of prophylactic administration, the compound can be administered to a patient at risk of developing one of the above-mentioned diseases. A patient at risk of developing a disease can be a patient with characteristics defined by an appropriate medical professional or group that place the patient in a group called at-risk patients. A patient at risk can also be a patient who is commonly or routinely exposed to an environment that may cause the development of an underlying disease treatable by administering a metalloenzyme inhibitor according to the present disclosure. In other words, a patient at risk can be a patient who is commonly or routinely exposed to a condition that causes a disease or illness, or who is acutely exposed within a limited time period. Alternatively, prophylactic administration can be performed to avoid the onset of symptoms in a patient diagnosed with an underlying disorder.

[0231] The amount of compound administered will vary depending on a variety of factors, such as the particular indication to be treated, the method of administration (whether the desired effect is prophylactic or therapeutic), the severity of the indication to be treated, as well as the age and weight of the patient, the bioavailability of the particular active compound, etc. The determination of an effective dosage is well within the capabilities of one of ordinary skill in the art.

[0232] Effective doses can be estimated initially by in vitro testing. For example, initial dosages for use in animals can be formulated to achieve circulating or serum concentrations of the active compound, as measured in in vitro tests (e.g., in vitro MIC or MFC against fungi and other in vitro tests described in the Examples section), that reach or exceed the IC50 of the specific compound. It is well within the ability of one of ordinary skill in the art to calculate doses to achieve such circulating or serum concentrations, taking into account the bioavailability of a specific compound. For guidance, see Fingl & Woodbury, "General Principles," In: Goodman and Gilman's The Pharmaceutical Basis of Therapeutics, Chapter 1, pp. 1-46, latest edition, Pagamon Press, and references cited therein, which are incorporated herein by reference.

[0233] Initial doses can also be estimated from in vivo data, such as animal models. Animals useful for testing the effectiveness of compounds in treating or preventing the various diseases mentioned above are well known in the art.

[0234] Dosages will typically be in the range of about 0.0001 or 0.001 or 0.01 mg / kg / day to about 100 mg / kg / day, but may be higher or lower depending on, among other factors, the activity of the compound, its bioavailability, the method of administration, and the various factors discussed above. Dosages and administration intervals can be individually adjusted to obtain sufficient plasma concentrations of the compound to maintain therapeutic or prophylactic efficacy. In the case of local administration or selective uptake, e.g., local topical administration, the effective local concentration of the active compound may not be related to the plasma concentration. One of skill in the art will be able to optimize effective local dosages without undue experimentation.

[0235] The compounds may be administered once a day, several or more times a day, or even multiple times a day, depending, among other things, on the indication being treated and the judgment of the prescribing physician.

[0236] Preferably, the compounds will exhibit therapeutic or prophylactic effects without exhibiting substantial toxicity. The toxicity of the compounds can be determined using standard pharmaceutical procedures. The ratio of the dose exhibiting toxic effects and the dose exhibiting therapeutic (or prophylactic) effects is the therapeutic index. Disclosed compounds exhibiting high therapeutic indices are preferred.

[0237] The recitation of a listing of chemical groups in any definition of a variable herein includes a definition of that variable as any single group or combination of listed groups. The recitation of an embodiment of a variable herein includes a definition of that embodiment as any single embodiment or in combination with any other embodiment or portion thereof. EXAMPLES

[0238] Working Example In order that the invention described herein may be more fully understood, the following examples are set forth. The examples described in this application are provided to illustrate the compounds, pharmaceutical compositions, and methods provided herein, and should not be construed as limiting the scope thereof in any way. General experimental procedure The definitions of variables in the structures in the schemes herein correspond to the variables at the corresponding positions in the formulas described herein. The example compounds listed in Table 2 were characterized by the HPLC and LCMS methods shown in Table 1.

[0239] [Table 1] Common abbreviations: ACN Acetonitrile br Broad d double line dd double double line dba Dibenzylideneacetone DIPEA Diisopropylethylamine dppf 1,1'-ferrocenediyl-bis(diphenylphosphine) h time HRMS high resolution mass spectrometry HPLC High Performance Liquid Chromatography LCMS Liquid Chromatography and Mass Spectrometry MS mass spectrometry MW Microwave m multiplet min minutes mL Milliliters m / z mass-to-charge ratio NMR nuclear magnetic resonance ppm parts per million rt or RT Room temperature s single line t triple line TLC Thin layer chromatography. Preparation of Int-1

[0240] [ka]

[0241] N-Cyclopropyl-5-fluoro-2-nitroaniline To 2,4-difluoro-1-nitrobenzene (25 g, 157.23 mmol) were added potassium fluoride (9.12 g, 157.23 mmol) and potassium carbonate (21.7 g, 157.23 mmol), followed by dropwise addition of cyclopropanamine (10.75 g, 188.68 mmol) under inert atmosphere at room temperature, and the reaction was stirred for 2 h. Once the starting material was consumed (by TLC), the reaction mixture was diluted with water (200 mL) and extracted with EtOAc (2×200 mL). The organic extracts were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 5% EtOAc / hexane) to give N-cyclopropyl-5-fluoro-2-nitroaniline 2 (26 g, 132.65 mmol, 84%) as a yellow solid. 1 H NMR (500MHz, CDCl3): δ 8.20 (dd, J = 9.3, 6.1 Hz, 1H), 6.95 (dd, J = 11.4, 2.7 Hz, 1H), 6.45-6.39 (m, 1H), 2.59-2.53 (m, 1H), 0.97-0.92 (m, 2H), 0.71-0.65 (m, 2H) N 1 -Cyclopropyl-5-fluorobenzene-1,2-diamine To a stirred solution of N-cyclopropyl-5-fluoro-2-nitroaniline (24 g, 122.45 mmol) in methanol (300 mL) was added 10% Pd / C (50% wet, 2.4 g) at room temperature under an inert atmosphere. The reaction mixture was stirred at room temperature under a hydrogen atmosphere (balloon pressure) for 8 h. Once the starting material was consumed (by TLC), the reaction mixture was filtered through a pad of Celite and washed with methanol (100 mL). The filtrate was concentrated under reduced pressure to give N 1-Cyclopropyl-5-fluorobenzene-1,2-diamine (18 g, 108.43 mmol, 88%) was obtained as a brown syrup. 1 H NMR (400MHz, DMSO-d6): δ 6.52 (dd, J = 11.6, 2.8 Hz, 1H), 6.45 (dd, J = 8.4, 6.0 Hz, 1H), 6.18 (td, J = 8.5, 2.9 Hz, 1H), 5.28 (s, 1H), 4.30 (brs, 2H), 2.36-2.28 (m, 1H), 0.74-0.68 (m, 2H), 0.42-0.37 (m, 2H) LC-MS: m / z 166.8 [M+H] + , RT=1.64 (purity 72.46%) 1-Cyclopropyl-6-fluoro-1,3-dihydro-2H-benzo[d]imidazol-2-one N 1 To a stirred solution of 1,1'-cyclopropyl-5-fluorobenzene-1,2-diamine (1 g, 6.02 mmol) in THF (20 mL), 1,1'-carbonyldiimidazole (1.46 g, 9.04 mmol) was added at room temperature under inert atmosphere and the reaction mixture was stirred for 16 h. Once the starting material was consumed (by TLC), the reaction mixture was diluted with EtOAc (60 mL) and washed with 1N HCl (10 mL). The organic layer was separated, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give 1-cyclopropyl-6-fluoro-1,3-dihydro-2H-benzo[d]imidazol-2-one (1 g) as a black solid. The crude product was used in the next step without further purification. 1 H NMR (400MHz, CDCl3): δ 9.75 (brs, 1H), 7.00-6.93 (m, 2H), 6.81-6.74 (m, 1H), 2.92-2.84 (m, 1H), 1.16-1.12 (m, 2H), 1.06-1.01 (m, 2H) 2-Bromo-1-cyclopropyl-6-fluoro-1H-benzo[d]imidazole (Int-1) Phosphoryl bromide (5.97 g, 20.83 mmol) was added to a stirred solution of 1-cyclopropyl-6-fluoro-1,3-dihydro-2H-benzo[d]imidazol-2-one (1 g, crude) in toluene (30 mL) at room temperature under inert atmosphere. The reaction mixture was heated to 110° C. and stirred for 16 h. Once the starting material was consumed (by TLC), the reaction mixture was diluted with CHCl (50 mL) and warm water (50 mL) and stirred for 30 min. The reaction mixture was then basified to pH 10 with aqueous NaCO and extracted with CHCl (2×50 mL). The organic extracts were combined, washed with water (30 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 30% EtOAc / hexanes) to give 2-bromo-1-cyclopropyl-6-fluoro-1H-benzo[d]imidazole Int-1 (600 mg, 2.35 mmol, 39% (2 steps)) as a pale yellow syrup. 1 H NMR (500MHz, CDCl3): δ 7.60 (dd, J = 8.7, 4.9 Hz, 1H), 7.22 (dd, J = 8.7, 2.3 Hz, 1H), 7.00 (td, J = 9.3, 2.6 Hz, 1H), 3.25-3.18 (m, 1H), 1.33-1.28 (m, 2H), 1.18-1.13 (m, 2H) LC-MS: m / z 254.9 [M+H] + , RT=2.49 (purity 95.00%) Preparation of Int-2

[0242] [ka]

[0243] N-Cyclopropyl-2,3-difluoro-6-nitroaniline Cyclopropanamine (3.22 g, 56.5 mmol) was added dropwise to a stirred solution of 1,2,3-trifluoro-4-nitrobenzene (10 g, 56.5 mmol) in ethanol (200 mL) at room temperature under inert atmosphere and stirred for 16 h. Once the starting material was consumed (by TLC), the volatiles were removed under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (eluent: 10% EtOAc / hexanes) to give N-cyclopropyl-2,3-difluoro-6-nitroaniline (8 g, 37.38 mmol, 66%) as a pale yellow viscous syrup. 1 H NMR (500MHz, DMSO-d6): δ 7.96-7.91 (m, 1H), 7.75 (brs, 1H), 6.87-6.80 (m, 1H), 3.03-2.97 (m, 1H), 0.78-0.72 (m, 2H), 0.68-0.63 (m, 2H) N 1 -Cyclopropyl-5,6-difluorobenzene-1,2-diamine A stirred solution of N-cyclopropyl-2,3-difluoro-6-nitroaniline (8 g, 37.38 mmol) in ethyl acetate (200 mL) was added to 10% Pd / C (50% wet, 2 g) at room temperature under an inert atmosphere. The reaction mixture was stirred at room temperature under a hydrogen atmosphere (balloon pressure) for 6 h. Once the starting material was consumed (by TLC), the reaction mixture was filtered through a pad of Celite and washed with methanol (60 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 10% EtOAc / hexane) to give N 1 -Cyclopropyl-5,6-difluorobenzene-1,2-diamine (4.3 g, 23.37 mmol, 62%) was obtained as a brown viscous syrup. 1H NMR (400MHz, DMSO-d6): δ 6.55-6.46 (m, 1H), 6.32-6.26 (m, 1H), 4.69 (s, 2H), 4.54 (brs, 1H), 2.73-2.65 (m, 1H), 0.58-0.52 (m, 2H), 0.48-0.42 (m, 2H) LC-MS: m / z 185.0 [M+H] + , RT=2.97 (purity 61.14%) 1-Cyclopropyl-67-difluoro-1,3-dihydro-2H-benzo[d]imidazol-2-one N 1 To a stirred solution of 1,1'-cyclopropyl-5,6-difluorobenzene-1,2-diamine (500 mg, 2.72 mmol) in THF (10 mL) was added 1,1'-carbonyldiimidazole (660 mg, 4.08 mmol) at room temperature under inert atmosphere and stirred for 16 h. Once the starting material was consumed (by TLC), the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2 x 30 mL). The organic extracts were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give 1-cyclopropyl-6,7-difluoro-1,3-dihydro-2H-benzo[d]imidazol-2-one (600 mg) as a brown viscous syrup. The crude product was used in the next step without further purification. LC-MS: m / z 208.9 [MH] - , RT=2.80 (purity 47.16%) and m / z 208.9 [MH] - , RT=4.05 (purity 33.71%) 2-Bromo-1-cyclopropyl-6,7-difluoro-1H-benzo[d]imidazole (Int-2) Phosphoryl bromide (3.29 g, 11.43 mmol) was added to a stirred solution of 1-cyclopropyl-6,7-difluoro-1,3-dihydro-2H-benzo[d]imidazol-2-one (600 mg, crude) in toluene (10 mL) at room temperature under inert atmosphere. The reaction mixture was heated to 100 °C and stirred for 16 h. Once the starting material was consumed (by TLC), the reaction mixture was quenched with saturated NaHCO3 to pH 8 and extracted with EtOAc (2 x 30 mL). The organic extracts were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 10% EtOAc / hexane) to give 2-bromo-1-cyclopropyl-6,7-difluoro-1H-benzo[d]imidazole Int-2 (100 mg, 0.37 mmol, 13% (2 steps)) as an off-white solid. 1 H NMR (500MHz, DMSO-d6): δ 7.42 (dd, J = 8.8, 3.6 Hz, 1H), 7.32-7.24 (m, 1H), 3.56-3.50 (m, 1H), 1.28-1.16 (m, 4H) LC-MS: m / z 272.8 [M+H] + , RT=3.30 (purity 73.30%) Preparation of Int-3

[0244] [ka]

[0245] 3-Methyl-2-nitroaniline Aqueous ammonium hydroxide (30%, 10 mL) was added to a stirred solution of 1-fluoro-3-methyl-2-nitrobenzene (1 g, 6.45 mmol) in ethanol (10 mL) in a sealed tube at 0° C. The reaction mixture was heated to 80° C. and stirred for 24 h. Once the starting material was consumed (by TLC), the reaction mixture was diluted with water (40 mL) and extracted with Et2O (2×40 mL). The organic extracts were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give 3-methyl-2-nitroaniline (1.2 g) as a pale yellow solid. The crude product was used in the next step without further purification. LC-MS: m / z 153.0 [M+H] + , RT=2.15 (purity 36.85%) 3-Methylbenzene-1,2-diamine To a stirred solution of 3-methyl-2-nitroaniline (1.2 g, crude product) in methanol (15 mL) was added 10% Pd / C (50% wet, 150 mg) at room temperature under an inert atmosphere. The reaction mixture was stirred at room temperature under a hydrogen atmosphere (balloon pressure) for 2 h. Once the starting material was consumed (by TLC), the reaction mixture was filtered through a pad of Celite and washed with methanol (40 mL). The filtrate was concentrated under reduced pressure to give 3-methylbenzene-1,2-diamine (900 mg) as a brown solid. The crude product was used in the next step without further purification. 4-Methyl-1H-benzo[d]imidazole (Int-3) A stirred solution of 3-methylbenzene-1,2-diamine (900 mg, crude) in formic acid (5 mL) was heated to 90 °C under inert atmosphere and stirred for 16 h. Once the starting material was consumed (by TLC), the reaction mixture was basified to pH 8 with saturated Na2CO3 solution and extracted with EtOAc (2 x 40 mL). The organic extracts were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 2% MeOH / CH2Cl2) to give 4-methyl-1H-benzo[d]imidazole Int-3 (120 mg, 0.91 mmol, 14%, overall yield for three steps) as a pale yellow solid. 1H NMR (400MHz, CD3OD): δ 8.12 (s, 1H), 7.45-7.39 (m, 1H), 7.15 (t, J = 7.7 Hz, 1H), 7.05 (d, J = 7.3 Hz, 1H), 2.57 (s, 3H) Preparation of Int-4

[0246] [ka]

[0247] N-Cyclopropyl-4,5-difluoro-2-nitroaniline To a mixture of 1,2,4-trifluoro-5-nitrobenzene (500 mg, 2.82 mmol) in potassium fluoride (164 mg, 2.82 mmol) was added dropwise potassium carbonate (390 mg, 2.82 mmol) and cyclopropanamine (0.23 mL, 3.39 mmol) at 0° C. under inert atmosphere. The reaction mixture was stirred at 0° C. for 30 min. Once the starting material was consumed (by TLC), the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2×20 mL). The organic extracts were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give N-cyclopropyl-4,5-difluoro-2-nitroaniline (320 mg) as a pale yellow solid. The crude product was used in the next step without further purification. LC-MS: m / z 215.4 [M+H] + , RT=4.43 (purity 69.03%) N 1 -Cyclopropyl-4,5-difluorobenzene-1,2-diamine A stirred solution of N-cyclopropyl-4,5-difluoro-2-nitroaniline (300 mg, crude product) in ethyl acetate (10 mL) was added to 10% Pd / C (50% wet, 30 mg) at room temperature under an inert atmosphere. The reaction mixture was stirred at room temperature under a hydrogen atmosphere (balloon pressure) for 4 h. Once the starting material was consumed (by TLC), the reaction mixture was filtered through a pad of Celite and washed with methanol (15 mL) and EtOAc (10 mL). The filtrate was concentrated under reduced pressure to give N1 -Cyclopropyl-4,5-difluorobenzene-1,2-diamine (100 mg) was obtained as a brown viscous syrup. The crude product was used in the next step without further purification. LC-MS: m / z 184.9 [M+H] + , RT=2.12 (purity 83.53%) 1-Cyclopropyl-5,6-difluoro-1,3-dihydro-2H-benzo[d]imidazol-2-one N 1 A stirred solution of 1,1'-cyclopropyl-4,5-difluorobenzene-1,2-diamine (500 mg, crude) in THF (10 mL) was added with 1,1'-carbonyldiimidazole (430 mg, 2.64 mmol) at room temperature under inert atmosphere and stirred for 16 h. Once the starting material was consumed (by TLC), the reaction mixture was diluted with EtOAc (60 mL) and washed with 1N HCl (10 mL). The organic layer was separated, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give 1-cyclopropyl-5,6-difluoro-1,3-dihydro-2H-benzo[d]imidazol-2-one (500 mg, crude) as a black solid. The crude product was used in the next step without further purification. 2-Bromo-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole (Int-4) Phosphoryl bromide (2.73 g, 9.52 mmol) was added to a stirred solution of 1-cyclopropyl-5,6-difluoro-1,3-dihydro-2H-benzo[d]imidazol-2-one (500 mg, crude) in toluene (20 mL) at room temperature under inert atmosphere. The reaction mixture was heated to 80° C. and stirred for 16 h. Once the starting material was consumed (by TLC), the reaction mixture was diluted with water (20 mL), heated to 40° C., and stirred for 30 min. The mixture was basified with saturated Na2CO3 solution (30 mL) and extracted with CHCl2 (2×30 mL). The organic extracts were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 10% EtOAc / hexane) to give 2-bromo-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole Int-4 (300 mg, 1.09 mmol, 46% (2 steps)) as a brown solid. 1 H NMR (400 MHz, DMSO-d6): δ 7.13-7.69 (m, 2H), 3.38-3.33 (m, 1H), 1.29-1.21 (m, 2H), 1.11-1.03 (m, 2H) Preparation of Int-5 Scheme:

[0248] [ka]

[0249] 3-(Ethylamino)-4-nitrobenzonitrile To a stirred solution of 3-fluoro-4-nitrobenzonitrile (2 g, 12.05 mmol) in CHCl (250 mL), potassium carbonate (3.32 g, 24.09 mmol) and ethylamine (2.17 g of 70% aqueous solution, 48.19 mmol) were added at room temperature under an inert atmosphere. The reaction mixture was stirred at room temperature for 6 h. Once the starting material was consumed (by TLC), the reaction mixture was quenched with water (60 mL) and extracted with EtOAc (2×60 mL). The organic extracts were combined, dried over anhydrous NaSO, and concentrated under reduced pressure to give 3-(ethylamino)-4-nitrobenzonitrile (1.9 g) as a yellow solid. The crude product was used in the next step without further purification. 1 H NMR (500MHz, DMSO-d6): δ 8.22-8.10 (m, 2H), 7.58 (brs, 1H), 7.00 (d, J = 8.7 Hz, 1H), 3.48-3.38 (m, 2H), 1.21 (t, J = 6.9 Hz, 3H) LC-MS: m / z 192.1 [M+H] + , RT=4.10 (purity 98.96%) 4-Amino-3-(ethylamino)benzonitrile (Int-5) A stirred solution of 3-(ethylamino)-4-nitrobenzonitrile (1.9 g, crude) in ethanol (20 mL) was added to 10% Pd / C (50% wet, 190 mg) at room temperature under an inert atmosphere. The reaction mixture was stirred at room temperature under a hydrogen atmosphere (balloon pressure) for 5 h. Once the starting material was consumed (by TLC), the reaction mixture was filtered through a pad of Celite and washed with methanol (50 mL) and EtOAc (30 mL). The filtrate was concentrated under reduced pressure to give 4-amino-3-(ethylamino)benzonitrile Int-5 (1.5 g) as an off-white solid. The crude product was used in the next step without further purification. LC-MS: m / z 161.9 [M+H] + , RT=2.11 (purity 60.88%) Preparation of Int-6 Scheme:

[0250] [ka]

[0251] 3-(Cyclopropylamino)-4-nitrobenzonitrile A stirred solution of 3-fluoro-4-nitrobenzonitrile (1 g, 6.02 mmol) in CHCl (5 mL) was added dropwise with potassium carbonate (1.66 g, 12.05 mmol) and cyclopropanamine (3.33 mL, 48.19 mmol) at room temperature under an inert atmosphere. The reaction mixture was stirred at room temperature for 4 h. Once the starting material was consumed (by TLC), the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2×40 mL). The organic extracts were combined, dried over anhydrous NaSO and concentrated under reduced pressure to give 3-(cyclopropylamino)-4-nitrobenzonitrile (900 mg) as a yellow solid. The crude product was used in the next step without further purification. 1 H NMR (400MHz, CDCl3): δ 8.24 (d, J = 8.7 Hz, 1H), 8.07 (brs, 1H), 7.64 (d, J = 1.7 Hz, 1H), 6.93 (dd, J = 8.7, 1.7 Hz, 1H), 2.62-2.57 (m, 1H), 1.03-0.97 (m, 2H), 0.72-0.67 (m, 2H) LC-MS: m / z 201.9 [MH] - , RT=3.25 (purity 99.61%) 4-Amino-3-(cyclopropylamino)benzonitrile (Int-6) A stirred solution of 3-(cyclopropylamino)-4-nitrobenzonitrile (900 mg, crude) in ethanol (10 mL) was added to 10% Pd / C (50% wet, 500 mg) at room temperature under inert atmosphere. The reaction mixture was stirred at room temperature under hydrogen atmosphere (balloon pressure) for 5 h. Once the starting material was consumed (by TLC), the reaction mixture was filtered through a pad of Celite and washed with EtOAc (30 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 20% EtOAc / hexane) to give 4-amino-3-(cyclopropylamino)benzonitrile Int-6 (500 mg, 2.89 mmol, 48% (2 steps)) as an off-white solid. 1 H NMR (400MHz, DMSO-d6): δ 6.93 (d, J = 1.9 Hz, 1H), 6.87 (dd, J = 8.0, 1.9 Hz, 1H), 6.55 (d, J = 8.0 Hz, 1H), 5.49 (s, 2H), 5.43 (s, 1H), 2.40-2.34 (m, 1H), 0.77-0.71 (m, 2H), 0.42-0.37 (m, 2H) Preparation of Int-7

[0252] [ka]

[0253] 5-Chloro-N-cyclopropyl-2-nitroaniline Triethylamine (2.38 mL, 17.09 mmol) and cyclopropanamine (0.43 mL, 6.27 mmol) were added to a stirred solution of 4-chloro-2-fluoro-1-nitrobenzene (1 g, 5.7 mmol) in THF (20 mL) at room temperature under inert atmosphere. The reaction mixture was heated to 80° C. and stirred for 16 h. Once the starting material was consumed (by TLC), the reaction mixture was diluted with ice-cold water (40 mL) and extracted with EtOAc (2×40 mL). The organic extracts were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 2% EtOAc / hexane) to give 5-chloro-N-cyclopropyl-2-nitroaniline (1 g, 4.72 mmol, 83%) as a yellow solid. 1 H NMR (400MHz, DMSO-d6): δ 8.08 (d, J = 9.2 Hz, 2H), 7.37 (d, J = 2.3 Hz, 1H), 6.79 (dd, J = 9.2, 2.3 Hz, 1H), 2.69-2.63 (m, 1H), 0.92-0.86 (m, 2H), 0.68-0.61 (m, 2H) LC-MS: m / z 213.2 [M+H] + , RT=4.68 (purity 97.21%) 5-Chloro-N 1 -Cyclopropylbenzene-1,2-diamine (Int-7) To a stirred solution of 5-chloro-N-cyclopropyl-2-nitroaniline (250 mg, 1.27 mmol) in ethanol / water mixture (1:1, 10 mL), iron powder (356 mg, 6.38 mmol) and ammonium chloride (341 mg, 6.38 mmol) were added at room temperature. The reaction mixture was heated to 80° C. and stirred for 5 h. Once the starting material was consumed (by TLC), the reaction mixture was filtered through a pad of Celite and washed with ethanol (30 mL). The filtrate was concentrated under reduced pressure to give 5-chloro-N 1 -Cyclopropylbenzene-1,2-diamine Int-7 (200 mg) was obtained as a brown syrup. The crude product was used in the next step without further purification. 1 H NMR (500MHz, DMSO-d6): δ 6.69 (d, J = 2.3 Hz, 1H), 6.50-6.40 (m, 2H), 5.28 (brs, 1H), 4.64 (brs, 2H), 2.37-2.30 (m, 1H), 0.75-0.69 (m, 2H), 0.42-0.37 (m, 2H) LC-MS: m / z 182.9 [M+H] + , RT=2.85 (purity 86.58%) Preparation of Int-8

[0254] [ka]

[0255] 6-Chloro-N-cyclopropyl-3-nitropyridin-2-amine (2) (LNB No: SVC-MA1601-094) Cyclopropylamine (3.7 mL, 52.08 mmol) was added to a stirred solution of 2,6-dichloro-3-nitropyridine (5 g, 26.04 mmol) in toluene (25 mL) at 0 °C under inert atmosphere. The reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was warmed to room temperature and stirred for 2 h. Once the starting material was consumed (by TLC), the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The organic extracts were combined, washed with saturated brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 10% EtOAc / hexane) to give 6-chloro-N-cyclopropyl-3-nitropyridin-2-amine (4 g, 18.77 mmol, 72%) as a pale yellow solid. 1 H NMR (500 MHz, CDCl3): δ 8.34 (d, J = 8.7 Hz, 2H), 6.66 (d, J = 8.7 Hz, 1H), 3.10-3.05 (m, 1H), 0.97-0.93 (m, 2H), 0.67-0.64 (m, 2H) 6-Chloro-N2 -Cyclopropylpyridine-2,3-diamine (Int-8) To a stirred solution of 6-chloro-N-cyclopropyl-3-nitropyridin-2-amine (1 g, 4.69 mmol) in ethanol / water (1:1, 10 mL), iron powder (1.3 g, 23.47 mmol) and ammonium chloride (1.2 g, 23.47 mmol) were added at room temperature. The reaction mixture was heated at 80° C. for 1 h. Once the starting material was consumed (by TLC), the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2×20 mL). The organic extracts were combined, washed with saturated brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give 6-chloro-N 2 -Cyclopropylpyridine-2,3-diamine Int-8 (700 mg, crude) was obtained as a pale yellow solid, which was used in the next step without further purification. LC-MS: m / z 183.9 [M+H] + , RT=2.07 (purity 58.13%) Example 1

[0256] [ka]

[0257] 1'-Cyclopropyl-6'-fluoro-1'H-1,2'-bibenzo[d]imidazole (Ex.1) 2-Bromo-1-cyclopropyl-6-fluoro-1H-benzo[d]imidazole To a stirred solution of Int-1 (150 mg, 0.59 mmol) in DMSO (5 mL) was added 1H-benzo[d]imidazole (139 mg, 1.18 mmol) and potassium carbonate (243 mg, 1.76 mmol) at room temperature under an inert atmosphere. The reaction mixture was heated to 100° C. and stirred for 16 h. Once the starting material was consumed (by TLC), the reaction mixture was diluted with ice-cold water (20 mL) and extracted with EtOAc (2×30 mL). The organic extracts were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 30% EtOAc / hexane) to give 1'-cyclopropyl-6'-fluoro-1'H-1,2'-bibenzo[d]imidazole Ex.1 (90 mg, 0.31 mmol, 52%) as an off-white solid. 1 H NMR (500MHz, DMSO-d6): δ 8.90 (s, 1H), 7.87-7.82 (m, 2H), 7.77 (dd, J = 8.8, 4.8 Hz, 1H), 7.55 (dd, J = 9.0, 2.6 Hz, 1H), 7.43-7.36 (m, 2H), 7.23-7.17 (m, 1H), 3.73-3.68 (m, 1H), 1.02-0.96 (m, 2H), 0.65-0.61 (m, 2H) LC-MS: m / z 292.9 [M+H] + , RT=2.96 (purity 99.33%) HPLC: 99.03% Example 2

[0258] [ka]

[0259] 1'-Cyclopropyl-6',7'-difluoro-1'H-1,2'-bibenzo[d]imidazole (Ex.2) 2-Bromo-1-cyclopropyl-6,7-difluoro-1H-benzo[d]imidazole To a stirred solution of Int-2 (100 mg, 0.37 mmol) in DMSO (2 mL) was added potassium carbonate (152 mg, 1.1 mmol) and 1H-benzo[d]imidazole (87 mg, 0.73 mmol) at room temperature under an inert atmosphere. The reaction mixture was heated to 100 °C and stirred for 16 h. Once the starting material was consumed (by TLC), the reaction mixture was diluted with water (15 mL) and extracted with CHCl (2 x 20 mL). The organic extracts were combined, dried over anhydrous NaSO and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 30% EtOAc / hexane) to give 1'-cyclopropyl-6',7'-difluoro-1'H-1,2'-bibenzo[d]imidazole Ex.2 (20 mg, 0.06 mmol, 17%) as a white solid. 1 H NMR (500MHz, DMSO-d6): δ 8.88 (s, 1H), 7.89-7.82 (m, 2H), 7.58 (dd, J = 8.8, 3.3 Hz, 1H), 7.44-7.35 (m, 3H), 3.94-3.87 (m, 1H), 0.97-0.92 (m, 2H), 0.74-0.70 (m, 2H) LC-MS: m / z 310.9 [M+H] + , RT=3.21 (purity 97.98%) HPLC: 92.97% Example 3

[0260] [ka]

[0261] 1'-Cyclopropyl-4,5,6'-trifluoro-1'H-1,2'-bibenzo[d]imidazole (Ex.3) To a stirred solution of 4,5-difluoro-1H-benzo[d]imidazole (241 mg, 1.57 mmol) in DMSO (5 mL), potassium carbonate (325 mg, 2.35 mmol) was added at room temperature under inert atmosphere and stirred for 15 min. 2-Bromo-1-cyclopropyl-6-fluoro-1H-benzo[d]imidazole Int-1 (200 mg, 0.78 mmol) was added at room temperature and the reaction mixture was heated to 100° C. and stirred for 16 h. Once the starting material was consumed (by TLC), the reaction mixture was diluted with ice-cold water (25 mL). The precipitated solid was filtered and dried under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (eluent: 20% EtOAc / hexane) to give 1'-cyclopropyl-4,5,6'-trifluoro-1'H-1,2'-bibenzo[d]imidazole Ex.3 (120 mg, 0.36 mmol, 47%) as an off-white solid. The structure was further confirmed by 2D NMR (NOESY, DQFCOSY). 1 H NMR (400MHz, DMSO-d6): δ 9.03 (s, 1H), 7.78 (dd, J = 8.8, 4.8 Hz, 1H), 7.73-7.67 (m, 1H), 7.57 (dd, J = 9.0, 2.4 Hz, 1H), 7.53-7.44 (m, 1H), 7.25-7.18 (m, 1H), 3.73-3.65 (m, 1H), 1.04-0.98 (m, 2H), 0.69-0.63 (m, 2H) LC-MS: m / z 328.9 [M+H] + , RT=3.31 (purity 99.92%) HPLC: 99.82% Example 4

[0262] [ka]

[0263] 1'-Cyclopropyl-5,6,6'-trifluoro-1'H-1,2'-bibenzo[d]imidazole (Ex.4) To a solution of 5,6-difluoro-1H-benzo[d]imidazole (241 mg, 1.57 mmol) in DMSO (5 mL) was added potassium carbonate (325 mg, 2.35 mmol) at room temperature under inert atmosphere and stirred for 15 min. Then 2-bromo-1-cyclopropyl-6-fluoro-1H-benzo[d]imidazole Int-1 (200 mg, 0.78 mmol) was added at room temperature and the reaction mixture was heated to 100° C. and stirred for 16 h. Once the starting material was consumed (by TLC), the reaction mixture was diluted with ice-cold water (30 mL). The precipitated solid was filtered and dried under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (eluent: 20% EtOAc / hexane) to give 1'-cyclopropyl-5,6,6'-trifluoro-1'H-1,2'-bibenzo[d]imidazole Ex.4 (120 mg, 0.36 mmol, 47%) as a white solid. 1 H NMR (400MHz, DMSO-d6): δ 8.98 (s, 1H), 7.98-7.92 (m, 2H), 7.78 (dd, J = 8.8, 4.9 Hz, 1H), 7.56 (dd, J = 9.0, 2.4 Hz, 1H), 7.23-7.18 (m, 1H), 3.72-3.67 (m, 1H), 1.03-0.97 (m, 2H), 0.69-0.64 (m, 2H) LC-MS: m / z 328.9 [M+H] + , RT=3.09 (purity 99.22%) HPLC: 99.79% Example 5

[0264] [ka]

[0265] 1'-Cyclopropyl-6'-fluoro-5,6-dimethoxy-1'H-1,2'-bibenzo[d]imidazole (Ex.5) 2-Bromo-1-cyclopropyl-6-fluoro-1H-benzo[d]imidazole To a stirred solution of Int-1 (100 mg, 0.39 mmol) in DMSO (2 mL) was added potassium carbonate (164 mg, 1.18 mmol) and 5,6-dimethoxy-1H-benzo[d]imidazole (70 mg, 0.39 mmol) at room temperature under an inert atmosphere. The reaction mixture was heated to 80° C. and stirred for 16 h. Once the starting material was consumed (by TLC), the reaction mixture was diluted with water (25 mL) and extracted with EtOAc (2×20 mL). The organic extracts were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 40% EtOAc / hexane) to give 1'-cyclopropyl-6'-fluoro-5,6-dimethoxy-1'H-1,2'-bibenzo[d]imidazole Ex.5 (100 mg, 0.28 mmol, 72%) as an off-white solid. 1 H NMR (500MHz, DMSO-d6): δ8.64 (s, 1H), 7.77 (dd, J = 8.7, 4.9 Hz, 1H), 7.54 (dd, J = 9.0, 2.3 Hz, 1H), 7.36 (d, J = 2.6 Hz, 2H), 7.22-7.16 (m, 1H), 3.85 (s, 3H), 3.78 (s, 3H), 3.69-3.65 (m, 1H), 0.99-0.93 (m, 2H), 0.63-0.58 (m, 2H) LC-MS: m / z 353.0 [M+H] + , RT=2.13 (purity 98.91%) HPLC: 98.37% Examples 6 and 7

[0266] [ka]

[0267] 1'-Cyclopropyl-6'-fluoro-1'H-[1,2'-bibenzo[d]imidazole]-5-carbonitrile (Ex.6) and 1'-cyclopropyl-6'-fluoro-1'H-[1,2'-bibenzo[d]imidazole]-6-carbonitrile (Ex.7) To a stirred solution of 1H-benzo[d]imidazole-5-carbonitrile (111 mg, 0.78 mmol) in DMSO (5 mL) were added potassium carbonate (162 mg, 1.18 mmol) and 2-bromo-1-cyclopropyl-6-fluoro-1H-benzo[d]imidazole Int-1 (100 mg, 0.39 mmol) at room temperature under inert atmosphere. The reaction mixture was heated to 100° C. and stirred for 16 h. Once the starting material was consumed (by TLC), the reaction mixture was diluted with ice-cold water (25 mL) and extracted with EtOAc (2×25 mL). The organic extracts were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 2% MeOH / CH2Cl2) and then by preparative HPLC to give 1'-cyclopropyl-6'-fluoro-1'H-[1,2'-bibenzo[d]imidazole]-5-carbonitrile Ex.6 (30 mg, 0.09 mmol, 24%) and 1'-cyclopropyl-6'-fluoro-1'H-[1,2'-bibenzo[d]imidazole]-6-carbonitrile Ex.7 (30 mg, 0.09 mmol, 24%) as off-white solids, respectively. The structures of the two species were confirmed by 2D NMR (NOESY, DQFCOSY) analysis. Analysis data of Ex.6: 1 H NMR (400MHz, CD3OD): δ 8.96 (s, 1H), 8.28 (s, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.80-7.72 (m, 2H), 7.52 (dd, J = 8.7, 2.4 Hz, 1H), 7.19 (td, J = 9.3, 2.1 Hz, 1H), 3.67-3.60 (m, 1H), 1.07-1.00 (m, 2H), 0.72-0.66 (m, 2H) LC-MS: m / z 317.9 [M+H] +, RT=2.35 (purity 99.53%) HPLC: 98.79% Analysis data of Ex.7: 1 H NMR (400MHz, CD3OD): δ 9.03 (s, 1H), 8.29 (s, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.79-7.73 (m, 2H), 7.51 (dd, J = 8.7, 2.5 Hz, 1H), 7.18 (td, J = 9.3, 2.4 Hz, 1H), 3.69-3.64 (m, 1H), 1.09-1.04 (m, 2H), 0.73-0.68 (m, 2H) LC-MS: m / z 317.9 [M+H] + , RT=2.35 (purity 98.07%) HPLC: 97.16% Example 8 and Example 9

[0268] [ka]

[0269] 1'-Cyclopropyl-6'-fluoro-5-methyl-1'H-1,2'-bibenzo[d]imidazole (Ex.8) and 1'-cyclopropyl-6'-fluoro-6-methyl-1'H-1,2'-bibenzo[d]imidazole (Ex.9) 2-Bromo-1-cyclopropyl-6-fluoro-1H-benzo[d]imidazole To a stirred solution of Int-1 (100 mg, 0.39 mmol) and 5-methyl-1H-benzo[d]imidazole (103 mg, 0.78 mmol) in DMSO (5 mL) was added potassium carbonate (162 mg, 1.18 mmol) at room temperature under an inert atmosphere. The reaction mixture was heated to 90° C. and stirred for 16 h. Once the starting material was consumed (by TLC), the reaction mixture was diluted with water (25 mL) and extracted with EtOAc (2×25 mL). The organic extracts were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 2% MeOH / CHCl) and then by preparative HPLC to give 1'-cyclopropyl-6'-fluoro-5-methyl-1'H-1,2'-bibenzo[d]imidazole Ex.8 (40 mg, 0.13 mmol, 33%) and 1'-cyclopropyl-6'-fluoro-6-methyl-1'H-1,2'-bibenzo[d]imidazole Ex.9 (40 mg, 0.13 mmol, 33%) as off-white solids, respectively. The structures of these two species were confirmed by 2D NMR (NOESY, DQFCOSY). Analysis data for Ex.8: 1 H NMR (400MHz, CD3OD): δ 8.69 (s, 1H), 7.72 (dd, J = 8.8, 4.7 Hz, 1H), 7.64-7.60 (m, 2H), 7.50 (dd, J = 8.7, 2.4 Hz, 1H), 7.30 (dd, J = 8.3, 0.9 Hz, 1H), 7.21-7.13 (m, 1H), 3.64-3.58 (m, 1H), 2.52 (s, 3H), 1.03-0.98 (m, 2H), 0.68-0.63 (m, 2H) LC-MS: m / z 306.9 [M+H] + , RT=2.95 (99.99% purity) HPLC: 99.46% Analysis data of Ex.9: 1H NMR (400MHz, CD3OD): δ 8.66 (s, 1H), 7.76-7.68 (m, 2H), 7.56-7.49 (m, 2H), 7.28 (dd, J = 8.3, 1.1 Hz, 1H), 7.21-7.14 (m, 1H), 3.64-3.58 (m, 1H), 2.50 (s, 3H), 1.05-0.98 (m, 2H), 0.69-0.63 (m, 2H) LC-MS: m / z 306.9 [M+H] + , RT=2.96 (purity 99.92%) HPLC: 99.77% Examples 10 and 11

[0270] [ka]

[0271] 1'-Cyclopropyl-5-ethyl-6'-fluoro-1'H-1,2'-bibenzo[d]imidazole (Ex.10) and 1'-cyclopropyl-6-ethyl-6'-fluoro-1'H-1,2'-bibenzo[d]imidazole (Ex.11) 2-Bromo-1-cyclopropyl-6-fluoro-1H-benzo[d]imidazole Int-1 (100 mg, 0.39 mmol) in DMSO (5 mL) was stirred while adding 5-ethyl-1H-benzo[d]imidazole hydrochloride 1 (143 mg, 0.78 mmol) and potassium carbonate (162 mg, 1.18 mmol) at room temperature under inert atmosphere. The reaction mixture was heated to 90° C. and stirred for 16 h. Once the starting material was consumed (by TLC), the reaction mixture was diluted with water (25 mL) and extracted with EtOAc (2×25 mL). The organic extracts were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 2% MeOH / CH2Cl2) and then by preparative HPLC to give 1'-cyclopropyl-5-ethyl-6'-fluoro-1'H-1,2'-bibenzo[d]imidazole Ex.10 (30 mg, 0.09 mmol, 15%) and 1'-cyclopropyl-6-ethyl-6'-fluoro-1'H-1,2'-bibenzo[d]imidazole Ex.11 (30 mg, 0.09 mmol, 15%), respectively, as off-white solids. The structures of the two species were confirmed by 2D NMR (NOESY, DQFCOSY). Analysis data of Ex.10: 1 H NMR (400MHz, CD3OD): δ 8.70 (s, 1H), 7.72 (dd, J = 8.9, 4.6 Hz, 1H), 7.66-7.63 (m, 2H), 7.50 (dd, J = 8.7, 2.3 Hz, 1H), 7.33 (dd, J = 8.0, 1.4 Hz, 1H), 7.21-7.13 (m, 1H), 3.64-3.58 (m, 1H), 2.83 (q, J = 7.5 Hz, 2H), 1.33 (t, J = 7.6 Hz, 3H), 1.04-0.98 (m, 2H), 0.70-0.63 (m, 2H) LC-MS: m / z 320.9 [M+H] + , RT=3.19 (purity 99.96%) HPLC: 99.86% Analytical data of Ex.11: 1 H NMR (400MHz, CD3OD): δ 8.68 (s, 1H), 7.74 (t, J = 2.3 Hz, 1H), 7.72 (t, J = 2.3 Hz, 1H), 7.56 (s, 1H), 7.51 (dd, J = 8.7, 2.4 Hz, 1H), 7.32 (dd, J = 8.3, 1.3 Hz, 1H), 7.21-7.14 (m, 1H), 3.64-3.58 (m, 1H), 2.80 (q, J = 7.7 Hz, 2H), 1.28 (t, J = 7.6 Hz, 3H), 1.05-0.98 (m, 2H), 0.70- 0.63 (m, 2H) LC-MS: m / z 321.0 [M+H] + , RT=3.16 (purity 99.97%) HPLC: 99.83% Example 12 and Example 13

[0272] [ka]

[0273] 1'-Cyclopropyl-6'-fluoro-5-methoxy-1'H-1,2'-bibenzo[d]imidazole (Ex.12) and 1'-cyclopropyl-6'-fluoro-6-methoxy-1'H-1,2'-bibenzo[d]imidazole (Ex.13) (LNB No: SVC-MA1530-065) To a stirred solution of 5-methoxy-1H-benzo[d]imidazole (116 mg, 0.78 mmol) in DMSO (2.5 mL), potassium carbonate (162 mg, 1.18 mmol) was added at room temperature under inert atmosphere and the mixture was stirred for 15 min. 2-Bromo-1-cyclopropyl-6-fluoro-1H-benzo[d]imidazole Int-1 (100 mg, 0.39 mmol) was added at room temperature and the reaction mixture was heated to 100 °C and stirred for 16 h. Once the starting material was consumed (by TLC), the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The organic extracts were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 5% MeOH / CH2Cl2) and then by preparative HPLC to obtain 1'-cyclopropyl-6'-fluoro-5-methoxy-1'H-1,2'-bibenzo[d]imidazole Ex.12 (20 mg, 0.06 mmol, 15%) and 1'-cyclopropyl-6'-fluoro-6-methoxy-1'H-1,2'-bibenzo[d]imidazole Ex.13 (40 mg, 0.12 mmol, 30%), respectively, as white solids. The structures of these two species were confirmed by 2D NMR (NOESY, DQFCOSY). Analytical data of Ex.12: 1 H NMR (400MHz, CD3OD): δ 8.69 (s, 1H), 7.71 (dd, J = 9.0, 4.6 Hz, 1H), 7.67-7.62 (m, 1H), 7.49 (dd, J = 8.8, 2.3 Hz, 1H), 7.33 (d, J = 2.4 Hz, 1H), 7.20-7.15 (m, 1H), 7.08 (dd, J = 9.0, 2.4 Hz, 1H), 3.90 (s, 3H), 3.64-3.59 (m, 1H), 1.06-1.00 (m, 2H), 0.69-0.64 (m, 2H) LC-MS: m / z 323.1 [M+H] + , RT=2.32 (purity 98.58%) HPLC: 98.16% Analysis data of Ex.13: 1 H NMR (400MHz, CD3OD): δ 8.62 (s, 1H), 7.76-7.68 (m, 2H), 7.51 (dd, J = 8.7, 2.3 Hz, 1H), 7.24 (d, J = 2.3 Hz, 1H), 7.21-7.14 (m, 1H), 7.06 (dd, J = 8.9, 2.4 Hz, 1H), 3.84 (s, 3H), 3.64- 3.59 (m, 1H), 1.06-1.00 (m, 2H), 0.70-0.65 (m, 2H) LC-MS: m / z 323.0 [M+H] + , RT=2.29 (purity 98.70%) HPLC: 99.58% Example 14

[0274] [ka]

[0275] 1'-Cyclopropyl-6'-fluoro-4-methyl-1'H-1,2'-bibenzo[d]imidazole (Ex.14) To a stirred solution of 2-bromo-1-cyclopropyl-6-fluoro-1H-benzo[d]imidazole Int-1 (120 mg, 0.47 mmol) and 4-methyl-1H-benzo[d]imidazole Int-3 (74 mg, 0.56 mmol) in DMSO (5 mL) was added potassium carbonate (195 mg, 1.41 mmol) at room temperature under an inert atmosphere. The reaction mixture was heated to 110° C. and stirred for 16 h. Once the starting material was consumed (by TLC), the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2×20 mL). The organic extracts were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 50% EtOAc / hexane) to give 1'-cyclopropyl-6'-fluoro-4-methyl-1'H-1,2'-bibenzo[d]imidazole Ex.14 (60 mg, 0.2 mmol, 41%) as a pale yellow solid. The structure was confirmed by 2D NMR (NOESY, DQFCOSY). 1 H NMR (500MHz, CD3OD): δ 8.70 (s, 1H), 7.72 (dd, J = 8.7, 4.8 Hz, 1H), 7.56-7.48 (m, 2H), 7.33 (t, J = 7.8 Hz, 1H), 7.24 (d, J = 7.3 Hz, 1H), 7.17 (td, J = 9.3, 2.5 Hz, 1H), 3.64-3.57 (m, 1H), 2.70 (s, 3H), 1.02-0.95 (m, 2H), 0.67-0.62 (m, 2H) LC-MS: m / z 306.9 [M+H] + , RT=2.71 (purity 98.35%) HPLC: 98.43% Example 15

[0276] [ka]

[0277] 1'-Cyclopropyl-5,6,6',7'-tetrafluoro-1'H-1,2'-bibenzo[d]imidazole (Ex.15) 2-Bromo-1-cyclopropyl-6,7-difluoro-1H-benzo[d]imidazole To a stirred solution of Int-2 (60 mg, 0.22 mmol) and 5,6-difluoro-1H-benzo[d]imidazole (41 mg, 0.26 mmol) in DMSO (2 mL) was added potassium carbonate (91 mg, 0.66 mmol) at room temperature under an inert atmosphere. The reaction mixture was heated to 80° C. and stirred for 16 h. Once the starting material was consumed (by TLC), the reaction mixture was diluted with water (15 mL) and extracted with EtOAc (2×15 mL). The organic extracts were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 40% EtOAc / hexane) to give 1'-cyclopropyl-5,6,6',7'-tetrafluoro-1'H-1,2'-bibenzo[d]imidazole Ex.15 (20 mg, 0.06 mmol, 26%) as a pale yellow solid. 1 H NMR (400MHz, CD3OD): δ 8.84 (s, 1H), 7.83 (dd, J = 10.0, 7.1 Hz, 1H), 7.73 (dd, J = 10.3, 7.2 Hz, 1H), 7.55-7.49 (m, 1H), 7.33-7.24 (m, 1H), 3.87-3.80 (m, 1H), 1.09-1.02 (m, 2H), 0.80-0.73 (m, 2H) LC-MS: m / z 347.0 [M+H] + , RT=2.65 (purity 98.94%) HPLC: 95.27% Example 16

[0278] [ka]

[0279] 1'-Cyclopropyl-5',6'-difluoro-1'H-1,2'-bibenzo[d]imidazole (Ex.16) 2-Bromo-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole To a stirred solution of Int-4 (100 mg, 0.36 mmol) in DMSO (5 mL) was added potassium carbonate (152 mg, 1.09 mmol) and 1H-benzo[d]imidazole (86.5 mg, 0.73 mmol) at room temperature under an inert atmosphere. The reaction mixture was stirred at 100° C. for 16 h. Once the starting material was consumed (by TLC), the reaction mixture was diluted with water (15 mL) and extracted with EtOAc (2×20 mL). The organic extracts were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 30% EtOAc / hexane) to give 1'-cyclopropyl-5',6'-difluoro-1'H-1,2'-bibenzo[d]imidazole Ex.16 (80 mg, 0.25 mmol, 70%) as a white solid. 1 H NMR (400MHz, DMSO-d6): δ 8.91 (s, 1H), 7.95-7.70 (m, 4H), 7.47-7.30 (m, 2H), 3.75-3.69 (m, 1H), 1.07-0.91 (m, 2H), 0.69-0.58 (m, 2H) LC-MS: m / z 310.9 [M+H] + , RT=2.89 (purity 99.83%) HPLC: 98.92% Example 17

[0280] [ka]

[0281] 1'-Cyclopropyl-5,5',6,6'-tetrafluoro-1'H-1,2'-bibenzo[d]imidazole (Ex.17) 2-Bromo-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole To a stirred solution of Int-4 (100 mg, 0.36 mmol) in DMSO (5 mL), 5,6-difluoro-1H-benzo[d]imidazole (113 mg, 0.73 mmol) and potassium carbonate (152 mg, 1.09 mmol) were added at room temperature under an inert atmosphere. The reaction mixture was stirred at 100° C. for 16 h. Once the starting material was consumed (by TLC), the reaction mixture was diluted with ice-cold water (30 mL) and extracted with EtOAc (2×30 mL). The organic extracts were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Purification by silica gel column chromatography (eluent: 3% MeOH / CH2Cl2) afforded 1'-cyclopropyl-5,5',6,6'-tetrafluoro-1'H-1,2'-bibenzo[d]imidazole Ex. 17 (80 mg, 0.23 mmol, 63%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ 8.98 (s, 1H), 8.00-7.90 (m, 2H), 7.90-7.82 (m, 2H), 3.72- 3.70 (m, 1H), 1.04-0.95 (m, 2H), 0.73-0.59 (m, 2H) LC-MS: m / z 347.0 [M+H] + , RT=3.22 (purity 98.67%) HPLC: 95.00% Example 18 and Example 19

[0282] [ka]

[0283] 1'-Cyclopropyl-5,6'-difluoro-1'H-1,2'-bibenzo[d]imidazole (Ex.18) and 1'-cyclopropyl-6,6'-difluoro-1'H-1,2'-bibenzo[d]imidazole (Ex.19) 2-Bromo-1-cyclopropyl-6-fluoro-1H-benzo[d]imidazole To a stirred solution of Int-1 (150 mg, 0.59 mmol) in DMSO (5 mL) was added 5-fluoro-1H-benzo[d]imidazole (160 mg, 1.17 mmol) and potassium carbonate (244 mg, 1.76 mmol) at room temperature under inert atmosphere. The reaction mixture was stirred at 100° C. for 16 h. Once the starting material was consumed (by TLC), the reaction mixture was diluted with ice-cold water (30 mL) and extracted with EtOAc (2×30 mL). The organic extracts were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 3% MeOH / CH2Cl2) and then by preparative HPLC to give 1'-cyclopropyl-5,6'-difluoro-1'H-1,2'-bibenzo[d]imidazole Ex.18 (60 mg, 0.19 mmol, 33%) and 1'-cyclopropyl-6,6'-difluoro-1'H-1,2'-bibenzo[d]imidazole Ex.19 (40 mg, 0.13 mmol, 22%), respectively, as off-white solids. The structures of these two species were confirmed by 2D NMR (NOESY, COSY). Analysis data of Ex.18 1 H NMR (400MHz, DMSO-d6): δ 8.98 (s, 1H), 7.88 (dd, J = 8.9, 4.8 Hz, 1H), 7.77 (dd, J = 8.8, 4.9 Hz, 1H), 7.67 (dd, J = 9.4, 2.4 Hz, 1H), 7.56 (dd, J = 9.0, 2.4 Hz, 1H), 7.30-7.25 (m, 1H), 7.23-7.17 (m, 1H), 3.73-3.68 (m, 1H), 1.09-0.91 (m, 2H), 0.72-0.51 (m, 2H) LC-MS: m / z 310.9 [M+H] + , RT=2.91 (purity 99.79%) HPLC: 99.67% Analysis data of Ex.19 1H NMR (400MHz, DMSO-d6): δ 8.98 (s, 1H), 7.84 (dd, J = 8.9, 4.8 Hz, 1H), 7.77 (dd, J = 8.8, 4.9 Hz, 1H), 7.67 (dd, J = 9.4, 2.4 Hz, 1H), 7.56 (dd, J = 9.0, 2.4 Hz, 1H), 7.28-7.15 (m, 2H), 3.73-3.67 (m, 1H), 1.05-0.99 (m, 2H), 0.67-0.62 (m, 2H) LC-MS: m / z 310.9 [M+H] + , RT=2.93 (purity 99.87%) HPLC: 99.58% Example 20 and Example 21

[0284] [ka]

[0285] 1'-Cyclopropyl-6'-fluoro-5-(trifluoromethyl)-1'H-1,2'-bibenzo[d]imidazole (Ex.20) and 1'-cyclopropyl-6'-fluoro-6-(trifluoromethyl)-1'H-1,2'-bibenzo[d]imidazole (Ex.21) 2-Bromo-1-cyclopropyl-6-fluoro-1H-benzo[d]imidazole To a stirred solution of Int-1 (150 mg, 0.60 mmol) in DMSO (5 mL) was added 5-(trifluoromethyl)-1H-benzo[d]imidazole (131 mg, 0.70 mmol) and potassium carbonate (243 mg, 1.76 mmol) at room temperature under inert atmosphere. The reaction mixture was stirred at 90° C. for 16 h. Once the starting material was consumed (by TLC), the reaction mixture was diluted with ice-cold water (50 mL) and extracted with EtOAc (2×50 mL). The organic extracts were combined, washed with water (50 mL), saturated brine (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 30% EtOAc / hexane) and then by preparative HPLC to give 1'-cyclopropyl-6'-fluoro-5-(trifluoromethyl)-1'H-1,2'-bibenzo[d]imidazole B-397 (40 mg, 0.11 mmol, 38%) and 1'-cyclopropyl-6'-fluoro-6-(trifluoromethyl)-1'H-1,2'-bibenzo[d]imidazole B-421 (40 mg, 0.11 mmol, 38%), respectively, as off-white solids. The structures of both species were confirmed by 2D NMR analysis (NOESY, DQFCOSY). Analytical data of Ex.20: 1 H NMR (400 MHz, CD3OD): δ 8.91 (s, 1H), 8.15 (s, 1H), 7.97 (d, J = 8.5 Hz, 1H), 7.77-7.70 (m, 2H), 7.52 (dd, J = 8.7, 2.4 Hz, 1H), 7.21-7.16 (m, 1H), 3.67-3.60 (m, 1H), 1.07-1.00 (m, 2H), 0.70-0.65 (m, 2H) LC-MS: m / z 360.9 [M+H] + , RT=3.34 (purity 99.60%) HPLC: 99.64% Analytical data of Ex.21: 1H NMR (400MHz, CD3OD): δ 9.01 (s, 1H), 8.19 (s, 1H), 8.02 (d, J = 8.5 Hz, 1H), 7.80-7.71 (m, 2H), 7.52 (dd, J = 8.7, 2.4 Hz, 1H), 7.21-7.16 (m, 1H), 3.69-3.63 (m, 1H), 1.13-0.97 (m, 2H), 0.77-0.60 (m, 2H) LC-MS: m / z 361.0 [M+H] + , RT=3.32 (purity 99.79%) HPLC: 99.53% Example 22

[0286] [ka]

[0287] 3-Ethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrile 4-Amino-3-(ethylamino)benzonitrile To a stirred solution of Int-5 (500 mg, 3.10 mmol) in THF (10 mL) was added 1,1'-carbonyldiimidazole (750 mg, 4.05 mmol) at 0 °C under inert atmosphere. The reaction mixture was slowly warmed to room temperature and stirred for 16 h. Once the starting material was consumed (by TLC), the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The organic extracts were combined, washed with water (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 50-60% EtOAc / hexanes) to give 3-ethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrile (280 mg, 1.49 mmol, 50%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.39 (brs, 1H), 7.69 (s, 1H), 7.44 (dd, J = 8.0, 1.5 Hz, 1H), 7.12 (d, J = 8.2 Hz, 1H), 3.88-3.82 (m, 2H), 1.19 (t, J = 7.2 Hz, 3H) LC-MS: m / z 188.1 [M+H] + , RT=2.87 (purity 99.10%) 2-Bromo-l-ethyl-1H-benzo[d]imidazole-6-carbonitrile To a stirred solution of phosphoryl bromide (153 mg, 0.53 mmol) in 1,2-dichloroethane (5 mL) was added 3-ethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrile (50 mg, 0.26 mmol) at room temperature under inert atmosphere. The reaction mixture was heated to reflux and heated for 36 h. Once the starting material was consumed (by TLC), the reaction mixture was diluted with ice-cold water (20 mL), neutralized to pH 7 with saturated sodium carbonate solution, and extracted with EtOAc (2×20 mL). The organic extracts were combined, washed with water (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give 2-bromo-1-ethyl-1H-benzo[d]imidazole-6-carbonitrile (65 mg) as an off-white solid. The crude product was used in the next step without further purification. LC-MS: m / z 250.2 [M+H] + , RT=3.55 (purity 50.03%) 1'-Ethyl-5,6-difluoro-1'H-[1,2'-bibenzo[d]imidazole]-6'-carbonitrile (Ex.22) To a stirred solution of 2-bromo-1-ethyl-1H-benzo[d]imidazole-6-carbonitrile (65 mg, crude product) in DMSO (2 mL) were added 5,6-difluoro-1H-benzo[d]imidazole (48 mg, 0.31 mmol) and potassium carbonate (107 mg, 0.78 mmol) at room temperature under inert atmosphere. The reaction mixture was heated to 80° C. and stirred for 6 h. Once the starting material was consumed (by TLC), the reaction mixture was diluted with ice-cold water (20 mL) and extracted with EtOAc (2×20 mL). The organic extracts were combined, washed with water (20 mL), saturated brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 50–60% EtOAc / hexanes) and further triturated with CH3CN (2 × 20 mL) to give 1'-ethyl-5,6-difluoro-1'H-[1,2'-bibenzo[d]imidazole]-6'-carbonitrile Ex. 22 (15 mg, 0.04 mmol, 18%) as an off-white solid. 1 H NMR (400 MHz, CD3OD): δ 8.70 (s, 1H), 8.26 (s, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.80-7.70 (m, 2H), 7.66 (dd, J = 9.9, 7.0 Hz, 1H), 4.37-4.31 (m, 2H), 1.37 (t, J = 7.3 Hz, 3H) LC-MS: m / z 323.9 [M+H] + , RT=2.83 (purity 97.05%) HPLC: 99.02% Example 23 and Example 24

[0288] [ka]

[0289] 1'-Cyclopropyl-5',6'-difluoro-1'H-[1,2'-bibenzo[d]imidazole]-5-carbonitrile (Ex.23) and 1'-cyclopropyl-5',6'-difluoro-1'H-[1,2'-bibenzo[d]imidazole]-6-carbonitrile (Ex.24) 2-Bromo-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole To a stirred solution of Int-4 (125 mg, 0.45 mmol) in DMSO (4 mL) was added 1H-benzo[d]imidazole-5-carbonitrile (98 mg, 0.68 mmol) and potassium carbonate (190 mg, 1.37 mmol) at room temperature under an inert atmosphere. The reaction mixture was heated to 90 °C and stirred for 16 h. Once the starting material was consumed (by TLC), the reaction mixture was diluted with ice water (50 mL) and extracted with EtOAc (2 x 50 mL). The organic extracts were combined, washed with water (50 mL), saturated brine (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 2% MeOH / CHCl) and then by preparative HPLC to give 1'-cyclopropyl-5',6'-difluoro-1'H-[1,2'-bibenzo[d]imidazole]-5-carbonitrile Ex.23 (40 mg, 0.12 mmol, 26%) and 1'-cyclopropyl-5',6'-difluoro-1'H-[1,2'-bibenzo[d]imidazole]-6-carbonitrile Ex.24 (40 mg, 0.12 mmol, 26%), respectively, as off-white solids. The structures of these two species were confirmed by 2D NMR analysis (NOESY, DQFCOSY). Analytical data of Ex.23: 1 H NMR (400 MHz, DMSO-d6): δ 9.14 (s, 1H), 8.44 (s, 1H), 8.06 (d, J = 8.41 Hz, 1H), 7.93- 7.81 (m, 3H), 3.74-3.69 (m, 1H), 1.10-0.96 (m, 2H), 0.75-0.61 (m, 2H) LC-MS: m / z 336.0 [M+H] +, RT=2.93 (purity 98.56%) HPLC: 98.26% Analytical data of Ex.24: 1 H NMR (400 MHz, DMSO-d6): δ 9.17 (s, 1H), 8.40 (s, 1H), 8.04 (d, J = 8.3 Hz, 1H), 7.92 (dd, J = 10.9, 7.4 Hz, 1H), 7.87 (dd, J = 10.4, 7.3 Hz, 1H), 7.81 (dd, J = 8.3, 1.6 Hz, 1H), 3.81-3.68 (m, 1H), 1.09-0.93 (m, 2H), 0.74-0.62 (m, 2H) LC-MS: m / z 335.9 [M+H] + , RT=2.94 (purity 96.57%) HPLC: 97.57% Example 25

[0290] [ka]

[0291] 3-Cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrile 4-Amino-3-(cyclopropylamino)benzonitrile To a stirred solution of Int-6 (500 mg, 2.89 mmol) in THF (10 mL) was added 1,1'-carbonyldiimidazole (702 mg, 4.33 mmol) at room temperature under an inert atmosphere. The reaction mixture was slowly warmed to room temperature and stirred for 16 h. Once the starting material was consumed (by TLC), the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The organic extracts were combined, washed with water (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 30-40% EtOAc / hexanes) to give 3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrile (200 mg, 1.00 mmol, 35%) as an off-white solid. 1 H NMR (500 MHz, DMSO-d6): δ 11.29 (brs, 1H), 7.55 (s, 1H), 7.45 (dd, J = 8.0, 1.3 Hz, 1H), 7.09 (d, J = 8.1 Hz, 1H), 2.91-2.85 (m, 1H), 1.05-1.00 (m, 2H), 0.92-0.83 (m, 2H) 2-Bromo-1-cyclopropyl-1H-benzo[d]imidazole-6-carbonitrile To a stirred solution of 3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrile (200 mg, 1.0 mmol) in 1,2-dichloroethane (4 mL) was added phosphoryl bromide (1.2 g, 4.02 mmol) at room temperature under inert atmosphere. The reaction mixture was heated to 80° C. and stirred for 16 h. Once the starting material was consumed (by TLC), the reaction mixture was diluted with water (20 mL), basified with saturated sodium carbonate solution (30 mL), and extracted with CHCl (2×30 mL). The organic extracts were combined, dried over anhydrous NaSO, and concentrated under reduced pressure to give 2-bromo-1-cyclopropyl-1H-benzo[d]imidazole-6-carbonitrile (50 mg) as a white solid. The crude product was used in the next step without further purification. LC-MS: m / z 261.8[M+] + , RT=2.52 (purity 96.21%) 1'-Cyclopropyl-5,6-difluoro-1'H-[1,2'-bibenzo[d]imidazole]-6'-carbonitrile (Ex.25) To a stirred solution of 2-bromo-1-cyclopropyl-1H-benzo[d]imidazole-6-carbonitrile (100 mg, 0.38 mmol) in DMSO (3 mL) were added potassium carbonate (106 mg, 0.76 mmol) and 5,6-difluoro-1H-benzo[d]imidazole (59 mg, 0.38 mmol) at room temperature under an inert atmosphere. The reaction mixture was heated to 80° C. and stirred for 16 h. Once the starting material was consumed (by TLC), the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2×20 mL). The organic extracts were combined, washed with water (30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 30-40% EtOAc / hexane) to give 1'-cyclopropyl-5,6-difluoro-1'H-[1,2'-bibenzo[d]imidazole]-6'-carbonitrile Ex.25 (20 mg, 0.06 mmol, 16%) as an off-white solid. 1H NMR (400 MHz, CD3OD): δ 8.94 (s, 1H), 8.21 (s, 1H), 7.96-7.89 (m, 2H), 7.75 (dd, J = 10.2, 7.2 Hz, 1H), 7.71 (dd, J = 8.4, 1.5 Hz, 1H), 3.79-3.73 (m, 1H), 1.23-1.14 (m, 2H), 0.84- 0.71 (m, 2H) LC-MS: m / z 336.0 [M+H] + , RT=2.96 (purity 97.43%) HPLC: 98.95% Example 26

[0292] [ka]

[0293] 6-Chloro-1-cyclopropyl-1,3-dihydro-2H-benzo[d]imidazol-2-one 5-Chloro-N 1 To a stirred solution of Int-7 (200 mg, 1.09 mmol) in THF (10 mL), 1,1'-carbonyldiimidazole (267 mg, 1.65 mmol) was added at room temperature under inert atmosphere and the mixture was stirred for 16 h. Once the starting material was consumed (by TLC), the reaction mixture was acidified with 1N HCl solution (20 mL) and extracted with EtOAc (2 x 20 mL). The organic extracts were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give 6-chloro-1-cyclopropyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (150 mg) as a brown solid. The crude product was used in the next step without further purification. 1 H NMR (400 MHz, DMSO-d6): δ 7.15 (s, 1H), 7.04-6.99 (m, 1H), 6.96-6.88 (m, 1H), 2.87- 2.78 (m, 1H), 1.06-0.96 (m, 2H), 0.88-0.74 (m, 2H) 2-Bromo-6-chloro-1-cyclopropyl-1H-benzo[d]imidazole To a stirred solution of 6-chloro-1-cyclopropyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (150 mg, crude) in toluene (10 mL), phosphoryl bromide (825 mg, 2.88) was added at room temperature under inert atmosphere. The reaction mixture was heated to 80° C. and stirred for 16 h. Once the starting material was consumed (by TLC), the reaction mixture was diluted with CHCl (20 mL), hot water (20 mL) was added, and the mixture was stirred for 30 min. The reaction mixture was basified to pH 10 with aqueous NaCO and extracted with CHCl (2×20 mL). The organic extracts were combined, washed with water (20 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 10% EtOAc / hexanes) to give 2-bromo-6-chloro-1-cyclopropyl-1H-benzo[d]imidazole (80 mg, 0.30 mmol, 41%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ 7.63 (s, 1H), 7.58 (d, J = 8.7 Hz, 1H), 7.24 (dd, J = 8.6, 2.1 Hz, 1H), 3.36-3.30 (m, 1H), 1.27-1.18 (m, 2H), 1.10-1.02 (m, 2H) 6'-Chloro-1'-cyclopropyl-5,6-difluoro-1'H-1,2'-bibenzo[d]imidazole (Ex.26) To a stirred solution of 2-bromo-6-chloro-1-cyclopropyl-1H-benzo[d]imidazole (80 mg, 0.30 mmol) in DMSO (5 mL) was added potassium carbonate (123 mg, 0.88 mmol) and 5,6-difluoro-1H-benzo[d]imidazole (92 mg, 0.59 mmol) at room temperature under an inert atmosphere. The reaction mixture was heated to 80° C. and stirred for 16 h. Once the starting material was consumed (by TLC), the reaction mixture was diluted with ice-cold water (20 mL) and extracted with EtOAc (2×20 mL). The organic extracts were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 2% MeOH / CH2Cl2) to give 6'-chloro-1'-cyclopropyl-5,6-difluoro-1'H-1,2'-bibenzo[d]imidazole Ex.26 (30 mg, 0.08 mmol, 29%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ 8.99 (s, 1H), 7.98-7.96 (m, 2H), 7.79 (s, 1H), 7.77 (d, J = 7.0 Hz, 1H), 7.40-7.34 (m, 1H), 3.74-3.68 (m, 1H), 1.08-0.99 (m, 2H), 0.72-0.62 (m, 2H) LC-MS: m / z 344.9 [M+H] + , RT=2.71 (purity 96.05%) HPLC: 93.47% Example 27 and Example 28

[0294] [ka]

[0295] 1'-Cyclopropyl-6'-fluoro-5-(trifluoromethoxy)-1'H-1,2'-bibenzo[d]imidazole (Ex.27) and 1'-cyclopropyl-6'-fluoro-6-(trifluoromethoxy)-1'-1,2'-bibenzo[d]imidazole (Ex.28) 2-Bromo-1-cyclopropyl-6-fluoro-1H-benzo[d]imidazole To a stirred solution of Int-1 (100 mg, 0.39 mmol) in DMSO (4 mL) was added 5-(trifluoromethoxy)-1H-benzo[d]imidazole (80 mg, 0.40 mmol) and potassium carbonate (108 mg, 0.78 mmol) at room temperature under inert atmosphere. The reaction mixture was heated to 80° C. and stirred for 24 h. Once the starting material was consumed (by TLC), the reaction mixture was diluted with ice-cold water (20 mL) and extracted with EtOAc (2×20 mL). The organic extracts were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 20-30% EtOAc / hexane) to give 1'-cyclopropyl-6'-fluoro-5-(trifluoromethoxy)-1H-1,2'-bibenzo[d]imidazole Ex.27 (20 mg, 0.05 mmol, 14%) and 1'-cyclopropyl-6'-fluoro-6-(trifluoromethoxy)-1'H-1,2'-bibenzo[d]imidazole Ex.28 (20 mg, 0.05 mmol, 14%) as off-white solids, respectively. The structures of these two species were confirmed by 2D NMR (NOESY, DQFCOSY). Analytical data of Ex.27: 1 H NMR (400 MHz, CD3OD): δ 8.88 (s, 1H), 7.87 (d, J = 8.9 Hz, 1H), 7.78-7.68 (m, 2H), 7.51 (dd, J = 8.7, 2.3 Hz, 1H), 7.40 (dd, J = 8.9, 1.4 Hz, 1H), 7.19-7.17 (m, 1H), 3.66-3.61 (m, 1H), 1.07-1.00 (m, 2H), 0.71-0.63 (m, 2H) LC-MS: m / z 377.0 [M+H] + , RT=3.36 (purity 96.14%) HPLC: 92.27% Analytical data for Ex.28: 1H NMR (400 MHz, CD3OD): δ 8.89 (s, 1H), 7.92 (d, J = 8.8 Hz, 1H), 7.81-7.77 (m, 1H), 7.75 (dd, J = 8.9, 4.6 Hz, 1H), 7.51 (dd, J = 8.7, 2.4 Hz, 1H), 7.41-7.37 (m, 1H), 7.21-7.14 (m, 1H), 3.68-3.61 (m, 1H), 1.08-1.04 (m, 2H), 0.74-0.68 (m, 2H) LC-MS: m / z 377.0 [M+H] + , RT=3.34 (purity 98.88%) HPLC: 96.61% Example 29

[0296] [ka]

[0297] 5-Chloro-3-cyclopropyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one 6-Chloro-N 2 To a stirred solution of Int-8 (300 mg, 1.64 mmol) in THF (5 mL), 1,1'-carbonyldiimidazole (398 mg, 2.46 mmol) was added at room temperature under inert atmosphere and the mixture was stirred for 16 h. Once the starting material was consumed (by TLC), the reaction mixture was diluted with 1N HCl (10 mL) and extracted with EtOAc (2 x 10 mL). The organic extracts were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give 5-chloro-3-cyclopropyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (200 mg, crude) as a black solid. The crude product was used in the next step without further purification. 2-Bromo-5-chloro-3-cyclopropyl-3H-imidazo[4,5-b]pyridine Phosphoryl bromide (1.09 g, 3.82 mmol) was added to a stirred solution of 5-chloro-3-cyclopropyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (200 mg, crude) in toluene (10 mL) at room temperature under inert atmosphere. The reaction mixture was heated to 80° C. and stirred for 16 h. Once the starting material was consumed (by TLC), the reaction mixture was diluted with CHCl (10 mL), warm water (10 mL) and the mixture was stirred for 30 min. The reaction mixture was basified to pH 10 with aqueous NaCO and extracted with CHCl (2×10 mL). The organic extracts were combined, washed with water (20 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 10% EtOAc / hexanes) to give 2-bromo-5-chloro-3-cyclopropyl-3H-imidazo[4,5-b]pyridine (70 mg, 0.25 mmol, 27% (2 steps)) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ8.07 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 3.40-3.32 (m, 1H), 1.26-1.19 (m, 4H) 5-Chloro-3-cyclopropyl-2-(5,6-difluoro-1H-benzo[d]imidazol-1-yl)-3H-imidazo[4,5-b]pyridine (Ex.29) To a stirred solution of 2-bromo-5-chloro-3-cyclopropyl-3H-imidazo[4,5-b]pyridine (70 mg, 0.25 mmol) in DMSO (5 mL) was added potassium carbonate (107 mg, 0.77 mmol) and 5,6-difluoro-1H-benzo[d]imidazole (79 mg, 0.51 mmol) at room temperature under inert atmosphere. The reaction mixture was stirred at 80° C. for 16 h. Once the starting material was consumed (by TLC), the reaction mixture was diluted with ice-cold water (20 mL) and extracted with EtOAc (2×30 mL). The organic extracts were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 2% MeOH / CH2Cl2) to give 5-chloro-3-cyclopropyl-2-(5,6-difluoro-1H-benzo[d]imidazol-1-yl)-3H-imidazo[4,5-b]pyridine Ex.29 (50 mg, 0.14 mmol, 56%) as an off-white solid. 1 H NMR (400MHz, DMSO-d6): δ 9.01 (s, 1H), 8.24 (d, J = 9.2 Hz, 1H), 8.03-7.96 (m, 2H), 7.49 (dd, J = 9.0 Hz, 1H), 3.68-3.61 (m, 1H), 1.08-1.01 (m, 2H), 0.82-0.77 (m, 2H) LC-MS: m / z 345.9 [M+H] + , RT=3.03 (purity 99.62%) HPLC: 99.87% Example 30

[0298] [ka]

[0299] 1'-Cyclopropyl-6',7'-difluoro-5-nitro-1'H-1,2'-bibenzo[d]imidazole and 1'-cyclopropyl-6',7'-difluoro-6-nitro-1'-1,2'-bibenzo[d]imidazole 2-Bromo-1-cyclopropyl-6,7-difluoro-1H-benzo[d]imidazole To a stirred solution of Int-2 (200 mg, 0.73 mmol) in DMSO (2 mL) was added 5-nitro-1H-benzo[d]imidazole (120 mg, 0.73 mmol) and potassium carbonate (305 mg, 2.21 mmol) at room temperature under inert atmosphere. The reaction mixture was heated to 100 °C and stirred for 16 h. Once the starting material was consumed (by TLC), the reaction mixture was diluted with ice-cold water (30 mL) and extracted with EtOAc (2 x 20 mL). The organic extracts were combined, washed with water (15 mL), saturated brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product (approximately 180 mg).

[0300] This material was combined with another batch (200 mg crude) and purified by silica gel column chromatography (eluent: 20% EtOAc / hexanes) to give 1'-cyclopropyl-6',7'-difluoro-5-nitro-1'H-1,2'-bibenzo[d]imidazole (80 mg, 0.22 mmol, 15%) and a mixture of isomers (180 mg), respectively, as off-white solids. The pure regioisomers (80 mg) were used in the next step. The structures were confirmed in the final step. 1 H NMR (500 MHz, CDCl3): δ 8.86 (d, J= 2.3 Hz, 1H), 8.59 (s, 1H), 8.39 (dd, J= 9.0, 2.0 Hz, 1H), 7.97 (d, J = 8.7 Hz, 1H), 7.56-7.52 (m, 1H), 7.26-7.22 (m, 1H), 3.69-3.65 (m, 1H), 1.19-1.13 (m, 2H), 0.81-0.76 (m, 2H) LC-MS: m / z 356 [M+H] + , RT=3.14 (purity 97.14%) 1'-Cyclopropyl-6',7'-difluoro-1'H-[1,2'-bibenzo[d]imidazol]-5-amine A stirred solution of 1'-cyclopropyl-6',7'-difluoro-5-nitro-1'H-1,2'-bibenzo[d]imidazole (80 mg, 0.22 mmol) in ethyl acetate (5 mL) was added to 10% Pd / C (15 mg) at room temperature under an inert atmosphere. The reaction mixture was stirred at room temperature under a hydrogen atmosphere (balloon pressure) for 6 h. Once the starting material was consumed (by TLC), the reaction mixture was filtered through a pad of Celite and washed with methanol (30 mL). The filtrate was concentrated under reduced pressure to give 1'-cyclopropyl-6',7'-difluoro-1'H-[1,2'-bibenzo[d]imidazol]-5-amine (60 mg, 0.18 mmol, 82%) as a brown solid. LC-MS: m / z 325.9 [M+H] + , RT=2.38 (purity 96.51%) N-(1'-cyclopropyl-6',7'-difluoro-1'H-[1,2'-bibenzo[d]imidazol]-5-yl)-N-(methylsulfonyl)methanesulfonamide (Ex.30) To a stirred solution of 1'-cyclopropyl-6',7'-difluoro-1'H-[1,2'-bibenzo[d]imidazol]-5-amine (60 mg, 0.18) in CHCl (3 mL) was added triethylamine (0.05 mL, 0.36 mmol) and methanesulfonyl chloride (0.02 mL, 0.22 mmol) at 0 °C under an inert atmosphere. The reaction mixture was slowly warmed to room temperature and stirred for 30 min. Once the starting material was consumed (by TLC), the reaction mixture was diluted with water (20 mL) and extracted with CHCl (2 x 20 mL). The organic extracts were combined, dried over anhydrous NaSO and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: EtOAc) to give N-(1'-cyclopropyl-6',7'-difluoro-1'H-[1,2'-bibenzo[d]imidazol]-5-yl)-N-(methylsulfonyl)methanesulfonamide Ex.30 (40 mg, 0.08 mmol, 54%) as an off-white solid. The structure was further confirmed by 2D NMR (NOESY, DQFCOSY). 1H NMR (500 MHz, DMSO-d6): δ 9.04 (s, 1H), 8.09 (s, 1H), 7.96 (d, J = 8.7 Hz, 1H), 7.59 (dd, J = 8.7, 3.5 Hz, 1H), 7.55 (dd, J = 8.7, 2.3 Hz, 1H), 7.43-7.37 (m, 1H), 3.95-3.92 (m, 1H), 3.59 (s, 6H), 1.02-0.97 (m, 2H), 0.80-0.78 (m, 2H) LC-MS: m / z 481.9 [M+H] + , RT=2.85 (purity 98.72%) HPLC: 96.03% Example 31 and Example 33

[0301] [ka]

[0302] 1'-Cyclopropyl-6',7'-difluoro-5-nitro-1'H-1,2'-bibenzo[d]imidazole and 1'-cyclopropyl-6',7'-difluoro-6-nitro-1'H-1,2'-bibenzo[d]imidazole 2-Bromo-1-cyclopropyl-6,7-difluoro-1H-benzo[d]imidazole To a stirred solution of Int-2 (200 mg, 0.73 mmol) in DMSO (2 mL) was added 5-nitro-1H-benzo[d]imidazole (120 mg, 0.73 mmol) and potassium carbonate (305 mg, 2.21 mmol) at room temperature under inert atmosphere. The reaction mixture was heated to 100° C. and stirred for 16 h. Once the starting material was consumed (by TLC), the reaction mixture was diluted with ice-cold water (30 mL) and extracted with EtOAc (2×20 mL). The organic extracts were combined, washed with water (15 mL), saturated brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product (approximately 180 mg).

[0303] This material was combined with another batch (200 mg crude product) and purified by silica gel column chromatography (eluent: 20% EtOAc / hexanes) to give 1'-cyclopropyl-6',7'-difluoro-5-nitro-1'H-1,2'-bibenzo[d]imidazole (80 mg, 0.22 mmol, 15%) and a mixture of isomers (180 mg), respectively, as white solids, which were used in the next step without further purification. 1'-Cyclopropyl-6',7'-difluoro-1'H-[1,2'-bibenzo[d]imidazol]-5-amine and 1'-cyclopropyl-6',7'-difluoro-1'H-[1,2'-bibenzo[d]imidazol]-6-amine A stirred solution of 1'-cyclopropyl-6',7'-difluoro-5-nitro-1'H-1,2'-bibenzo[d]imidazole and 1'-cyclopropyl-6',7'-difluoro-6-nitro-1'H-1,2'-bibenzo[d]imidazole (180 mg, mixture of isomers) in ethyl acetate (12 mL) was added to 10% Pd / C (40 mg) at room temperature under an inert atmosphere. The reaction mixture was stirred at room temperature under a hydrogen atmosphere (balloon pressure) for 6 h. Once the starting material was consumed (by TLC), the reaction mixture was filtered through a Celite pad and the Celite bed was washed with methanol (30 mL). The filtrate was concentrated under reduced pressure to give 1'-cyclopropyl-6',7'-difluoro-1'H-[1,2'-bibenzo[d]imidazol]-5-amine and 1'-cyclopropyl-6',7'-difluoro-1'H-[1,2'-bibenzo[d]imidazol]-6-amine (130 mg, mixture of isomers) as a brown solid. N-(1'-cyclopropyl-6',7'-difluoro-1'H-[1,2'-bibenzo[d]imidazol]-5-yl)methanesulfonamide (Ex.31) and N-(1'-cyclopropyl-6',7'-difluoro-1'H-[1,2'-bibenzo[d]imidazol]-6-yl)methanesulfonamide (Ex.33) To a stirred solution of 1'-cyclopropyl-6',7'-difluoro-1'H-[1,2'-bibenzo[d]imidazol]-5-amine (130 mg, mixture of isomers) in CHCl (8 mL) was added triethylamine (0.11 mL, 0.5 mmol) and methanesulfonyl chloride (0.03 mL, 0.24 mmol) under inert atmosphere at 0° C. The reaction mixture was stirred at 0° C. for 30 min. Once the starting material was consumed (by TLC), the reaction mixture was diluted with water (20 mL) and extracted with CHCl (2×20 mL). The organic extracts were combined, dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 50% EtOAc / hexane) and then by chiral preparative HPLC to give N-(1'-cyclopropyl-6',7'-difluoro-1'H-[1,2'-bibenzo[d]imidazol]-5-yl)methanesulfonamide Ex.31 (30 mg, 0.07 mmol, 19%) and N-(1'-cyclopropyl-6',7'-difluoro-1'H-[1,2'-bibenzo[d]imidazol]-6-yl)methanesulfonamide Ex.32 (30 mg, 0.07 mmol, 19%), respectively, as pale yellow solids. The structures of these two species were confirmed by 2D NMR (NOESY, DQFCOSY). Analytical data of Ex.31: 1 H NMR (500 MHz, DMSO-d6): δ 9.70 (brs, 1H), 8.87 (s, 1H), 7.82 (d, J = 8.7 Hz, 1H), 7.65 (d, J = 1.7 Hz, 1H), 7.56 (dd, J = 9.0, 3.8 Hz, 1H), 7.40-7.37 (m, 1H), 7.28 (dd, J = 8.7, 2.3 Hz, 1H), 3.90-3.86 (m, 1H), 2.97 (s, 3H), 1.02-0.91 (m, 2H), 0.73-0.71 (m, 2H) LC-MS: m / z 404.0 [M+H] + , RT=2.57 (purity 99.65%) HPLC: 98.78% Analytical data of Ex.33: 1 H NMR (500 MHz, DMSO-d6): δ 9.66 (brs, 1H), 8.83 (s, 1H), 7.78 (d, / = 8.7 Hz, 1H), 7.74 (s, 1H), 7.56 (dd, J = 8.7, 3.5 Hz, 1H), 7.40-7.35 (m, 1H), 7.26 (dd, J = 8.7, 1.7 Hz, 1H), 3.94- 3.78 (m, 1H), 2.94 (s, 3H), 0.99-0.92 (m, 2H), 0.74-0.72 (m, 2H) LC-MS: m / z 404.0 [M+H] + , RT=2.51 (purity 99.34%) HPLC: 99.25% Example 32

[0304] [ka]

[0305] 3-Cyclopropyl-2-(5,6-difluoro-1H-benzo[d]imidazol-1-yl)-3H-imidazo[4,5-b]pyridine-5-carbonitrile (Ex.32) To a stirred solution of 5-chloro-3-cyclopropyl-2-(5,6-difluoro-1H-benzo[d]imidazol-1-yl)-3H-imidazo[4,5-b]pyridine Ex.29 (100 mg, 0.28 mmol) in DMF (2 mL) in a sealed tube, zinc cyanide (34 mg, 0.28 mmol) and Pd(PPh3)4 (34 mg, 0.02 mmol) were added at room temperature and the mixture was purged with argon for 10 min. The reaction mixture was heated to 100 °C and stirred for 16 h. Once the starting material was consumed (by TLC), the reaction mixture was diluted with ice-cold water (20 mL) and extracted with EtOAc (2 x 20 mL). The organic extracts were combined, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give 3-cyclopropyl-2-(5,6-difluoro-1H-benzo[d]imidazol-1-yl)-3H-imidazo[4,5-b]pyridine-5-carbonitrile Ex.32 (40 mg, 0.11 mmol, 41%) as an off-white solid. 1 H NMR (500 MHz, DMSO-d6): δ 9.12 (s, 1H), 8.39 (d, J = 8.1 Hz, 1H), 8.09 (dd, J = 10.4, 7.0 Hz, 1H), 8.01-7.98 (m, 2H), 3.81-3.71 (m, 1H), 1.18-1.07 (m, 2H), 0.91-0.83 (m, 2H) LC-MS: m / z 336.9 [M+H] + , RT=2.87 (purity 98.89%) HPLC: 99.49% Example 34

[0306] [ka]

[0307] 1-(1-Cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-1H-imidazo[4,5-b]pyridine (Ex.34) 2-Bromo-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole To a stirred solution of Int-4 (100 mg, 0.36 mmol) in DMSO (1 mL) was added 1H-imidazo[4,5-b]pyridine (52 mg, 0.44 mmol) and potassium carbonate (152 mg, 1.10 mmol) at room temperature under inert atmosphere. The reaction mixture was stirred at 90° C. for 16 h. Once the starting material was consumed (by TLC), the reaction mixture was diluted with ice-cold water (20 mL) and extracted with EtOAc (2×50 mL). The organic extracts were combined, washed with water (20 mL), saturated brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 2% MeOH / CH2Cl2) to give 1-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-1H-imidazo[4,5-b]pyridine Ex.34 (60 mg, 0.19 mmol, 52%) as a pale yellow solid. The structure was further confirmed by 2D NMR (NOESY, DQFCOSY). 1 H NMR (400 MHz, DMSO-d6): δ 9.18 (s, 1H), 8.59 (dd, J = 4.8, 1.6 Hz, 1H), 8.31 (dd, J = 8.2, 1.6 Hz, 1H), 7.90-7.84 (m, 2H), 7.46 (dd, J = 8.2, 4.8 Hz, 1H), 3.78-3.55 (m, 1H), 1.10-0.94 (m, 2H), 0.75-0.57 (m, 2H) LC-MS: m / z 311.9 [M+H] + , RT=2.37 (purity 98.26%) HPLC: 96.30% Example 35 and Example 36

[0308] [ka]

[0309] 1-(1-Cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-1H-imidazo[4,5-c]pyridine (Ex.35) and 3-(1-cyclopropyl-5,6-difluoro-1H-benzo[N]imidazol-2-yl)-3H-imidazo[4,5-c]pyridine (Ex.36) 2-Bromo-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole To a stirred solution of Int-4 (150 mg, 0.55 mmol) in DMSO (2 mL) was added 1H-imidazo[4,5-c]pyridine (98 mg, 0.83 mmol) and potassium carbonate (229 mg, 1.66 mmol) at room temperature under inert atmosphere. The reaction mixture was heated to 100° C. and stirred for 16 h. Once the starting material was consumed (by TLC), the reaction mixture was diluted with ice-cold water (20 mL) and extracted with EtOAc (2×20 mL). The organic extracts were combined, washed with water (20 mL), saturated brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give 1-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-1H-imidazo[4,5-c]pyridine Ex.35 (32 mg, 0.1 mmol, 19%) as an off-white solid and 3-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-3H-imidazo[4,5-c]pyridine Ex.36 (28 mg, 0.09 mmol, 16%) as an off-white solid, respectively. The structures were confirmed by 2D NMR (NOESY, DQFCOSY). B-510 Analysis Data: 1 H NMR (400 MHz, CD3OD): δ 9.12 (s, 1H), 9.91 (s, 1H), 8.53 (d, J = 5.6 Hz, 1H), 7.91 (dd, J = 5.6, 0.8 Hz, 1H), 7.72 (dd, J = 10.0, 7.0 Hz, 1H), 7.66 (dd, J = 10.4, 7.3 Hz, 1H), 3.74-3.68 (m, 1H), 1.12-1.06 (m, 2H), 0.75-0.69 (m, 2H) LC-MS: m / z 311.9 [M+H] + , RT=2.29 (purity 99.86%) HPLC: 99.93% B-511 Analysis Data: 1 H NMR (400 MHz, CD3OD): δ 9.22 (s, 1H), 9.08 (s, 1H), 8.55 (d, J = 5.6 Hz, 1H), 7.91 (dd, J = 5.6, 0.8 Hz, 1H), 7.72 (dd, J = 10.0, 7.0 Hz, 1H), 7.66 (dd, J = 10.4, 7.3 Hz, 1H), 3.74-3.68 (m, 1H), 1.16-1.05 (m, 2H), 0.78-0.71 (m, 2H) LC-MS: m / z 311.9 [M+H] + , RT=2.26 (purity 99.79%) HPLC: 99.74% Example 37 and Example 38

[0310] [ka]

[0311] 5-Chloro-3-cyclopropyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one 6-Chloro-N 2To a stirred solution of Int-8 (300 mg, 1.64 mmol) in THF (5 mL), 1,1'-carbonyldiimidazole (398 mg, 2.46 mmol) was added at room temperature under inert atmosphere and the mixture was stirred for 16 h. Once the starting material was consumed (by TLC), the reaction mixture was quenched with 1N HCl (10 mL) and extracted with EtOAc (2 x 10 mL). The organic extracts were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give 5-chloro-3-cyclopropyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (200 mg, crude) as a black solid. The crude product was used in the next step without further purification. 2-Bromo-5-chloro-3-cyclopropyl-3H-imidazo[4,5-b]pyridine Phosphoryl bromide (1.09 g, 3.82 mmol) was added to a stirred solution of 5-chloro-3-cyclopropyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (200 mg, crude) in toluene (10 mL) at room temperature under inert atmosphere. The reaction mixture was heated to 80° C. and stirred for 16 h. Once the starting material was consumed (by TLC), the reaction mixture was diluted with CHCl (10 mL) and warm water (10 mL) and stirred for 30 min. The reaction mixture was basified to pH 10 with aqueous NaCO and extracted with CHCl (2×10 mL). The organic extracts were combined, washed with water (20 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 10% EtOAc / hexanes) to give 2-bromo-5-chloro-3-cyclopropyl-3H-imidazo[4,5-b]pyridine (70 mg, 0.25 mmol, 27% (2 steps)) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ 8.07 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 3.40-3.32 (m, 1H), 1.26-1.19 (m, 4H) 5-Chloro-3-cyclopropyl-2-(3H-imidazo[4,5-c]pyridin-3-yl)-3H-imidazo[4,5-b]pyridine To a stirred solution of 2-bromo-5-chloro-3-cyclopropyl-3H-imidazo[4,5-b]pyridine (500 mg, 1.83 mmol) in DMSO (5 mL) was added 3H-imidazo[4,5-c]pyridine (219 mg, 1.83 mmol) and potassium carbonate (761 mg, 5.51 mmol) at room temperature under an inert atmosphere. The reaction mixture was heated to 80° C. and stirred for 16 h. Once the starting material was consumed (by TLC), the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2×30 mL). The organic extracts were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 5% MeOH / CH2Cl2) to give 5-chloro-3-cyclopropyl-2-(3H-imidazo[4,5-c]pyridin-3-yl)-3H-imidazo[4,5-b]pyridine and regioisomers (350 mg) as off-white solids. 1 H NMR (500 MHz, DMSO-d6): δ 9.20-9.15 (m, 1H), 9.08 (s, 1H), 8.55 (d, J = 5.2 Hz, 1H), 8.29-8.23 (m, 1H), 8.00-7.86 (m, 1H), 7.52-7.48 (m, 1H), 3.77-3.67 (m, 1H), 1.09-0.99 (m, 2H), 0.87-0.76 (m, 2H) 3-Cyclopropyl-2-(3H-imidazo[4,5-c]pyridin-3-yl)-3H-imidazo[4,5-b]pyridine-5-carbonitrile (Ex. 37) and 3-cyclopropyl-2-(1H-imidazo[4,5-c]pyridin-1-yl)-3H-imidazo[4,5-b]pyridine-5-carbonitrile (Ex. 38) To a stirred solution of 5-chloro-3-cyclopropyl-2-(3H-imidazo[4,5-c]pyridin-3-yl)-3H-imidazo[4,5-c]pyridine and regioisomers (175 mg, mixture of isomers) in DMF (2.5 mL) in a microwave vessel, zinc cyanide (132 mg, 1.13 mmol) was added under inert atmosphere at room temperature and the mixture was flushed with argon for 15 min. To this reaction mixture was added Pd(PPh3)4 (65 mg, 0.06 mmol). The vessel was sealed, irradiated at 150 °C and stirred for 1 h. Once the starting material was consumed (by TLC), the reaction mixture was diluted with ice-cold water (20 mL) and extracted with EtOAc (2 x 20 mL). The organic extracts were combined, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 3% MeOH / CH2Cl2) to give a mixture of isomers (85 mg) as a pale yellow solid.

[0312] This material was combined with another batch (85 mg) and purified by preparative HPLC to give 3-cyclopropyl-2-(3H-imidazo[4,5-c]pyridin-3-yl)-3H-imidazo[4,5-b]pyridine-5-carbonitrile Ex.37 (10 mg, 0.03 mmol) and 3-cyclopropyl-2-(1H-imidazo[4,5-c]pyridin-1-yl)-3H-imidazo[4,5-b]pyridine-5-carbonitrile Ex.38 (30 mg, 0.1 mmol). The structures of both species were confirmed by 2D NMR (NOESY, DQFCOSY). Analytical data of Ex.37: 1 H NMR (400 MHz, CD3OD): δ 9.44 (d, J = 0.9 Hz, 1H), 9.27 (s, 1H), 8.58 (d, J = 5.6 Hz, 1H), 8.28 (d, J = 8.2 Hz, 1H), 7.93 (dd, J = 5.6, 1.0 Hz, 1H), 7.88 (d, J = 8.2 Hz, 1H), 3.80-3.75 (m, 1H), 1.30-1.23 (m, 2H), 1.00-0.94 (m, 2H) LC-MS: m / z 301.9 [M+H] + , RT=1.92 (purity 95.35%) HPLC: 98.60% Analytical data for Ex.38: 1 H NMR (400 MHz, CD3OD): δ 9.12 (m, 2H), 8.57 (d, J = 5.8 Hz, 1H), 8.28 (d, J = 8.3 Hz, 1H), 8.14 (dd, J = 5.8, 1.0 Hz, 1H), 7.89 (d, J = 8.3 Hz, 1H), 3.77-3.72 (m, 1H), 1.23-1.19 (m, 2H), 0.94-0.88 (m, 2H) LC-MS: m / z 301.9 [M+H] + , RT=1.91 (purity 99.31%) HPLC: 99.25% Example 39

[0313] [ka]

[0314] 6-Chloro-1H-imidazo[4,5-c]pyridine To 6-chloropyridine-3,4-diamine (2 g, 13.99 mmol) was added formic acid (20 mL) under inert atmosphere at room temperature. The reaction mixture was heated to 120° C. and stirred for 16 h. Once the starting material was consumed (by TLC), the reaction mixture was basified with saturated NaHCO3 solution (100 mL) and extracted with EtOAc (2×100 mL). The organic extracts were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give 6-chloro-1H-imidazo[4,5-c]pyridine (2 g) as a light brown solid. The crude product was used in the next step without further purification. LC-MS: m / z 151.9 [MH] - , RT=6.38 (purity 59.98%) 6-Chloro-1-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-1H-imidazo[4,5-c]pyridine 2-Bromo-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole To a stirred solution of Int-4 (1.5 g, 5.49 mmol) in DMSO (15 mL) was added 6-chloro-1H-imidazo[4,5-c]pyridine (841 mg, 5.49 mmol) and potassium carbonate (2.27 g, 16.48 mmol) at room temperature under an inert atmosphere. The reaction mixture was heated to 80° C. and stirred for 16 h. Once the starting material was consumed (by TLC), the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2×40 mL). The organic extracts were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 40-50% EtOAc / hexanes) to give 6-chloro-1-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-1H-imidazo[4,5-c]pyridine and related regioisomers (750 mg, mixture of isomers) as an off-white solid, which was used in the next step without further purification. LC-MS: m / z 346.4 [M+H] + , RT=3.58 (purity 96.38%) 1-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-1H-imidazo[4,5-c]pyridine-6-carboxylate methyl To a stirred solution of 6-chloro-1-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-1H-imidazo[4,5-c]pyridine and regioisomers (500 mg, mixture) in methanol (30 mL) were added sodium acetate (356 mg, 4.35 mmol), dppf (40 mg, 0.07 mmol), followed by Pd(OAc)2 (49 mg, 0.07 mmol) at room temperature under inert atmosphere. CO gas was bubbled through the reaction mixture at 200 psi pressure and the reaction was heated to 100 °C and stirred for 28 h. Once the starting material was consumed (by TLC), the reaction mixture was diluted with EtOAc (80 mL) and washed with water (30 mL). The organic extracts were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 100% EtOAc) to give 1-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-1H-imidazo[4,5-c]pyridine-6-carboxylate (170 mg, 0.46 mmol, 32%) as a light brown solid. The structure was confirmed by 2D NMR (NOESY, gDQFCOSY). 1 H NMR (400 MHz, DMSO-d6): δ 9.29 (s, 1H), 9.24 (d, J = 1.0 Hz, 1H), 8.61 (d, J = 1.0 Hz, 1H), 7.99 (dd, J = 10.9, 7.4 Hz, 1H), 7.89 (dd, J = 10.4, 7.3 Hz, 1H), 3.90 (s, 3H), 3.77-3.71 (m, 1H), 1.06-1.00 (m, 2H), 0.74-0.68 (m, 2H) LC-MS: m / z 370.1 [M+H] + , RT=2.50 (purity 96.82%) 1-(1-Cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-1H-imidazo[4,5-c]pyridine-6-carboxylic acid (Ex.39) To a stirred solution of 1-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-1H-imidazo[4,5-c]pyridine-6-carboxylate (30 mg, 0.08 mmol) in a mixture of THF (0.4 mL) and water (0.3 mL), barium hydroxide octahydrate (51 mg, 0.16 mmol) was added at room temperature and the mixture was stirred for 3 h. Once the starting material was consumed (by TLC), the reaction mixture was quenched with dry ice. The resulting solid was filtered and the filtrate was lyophilized to give 1-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-1H-imidazo[4,5-c]pyridine-6-carboxylic acid Ex.39 (16 mg, 0.04 mmol, 57%) as an off-white solid. 1 H NMR (400 MHz, THF+D2O): δ 9.19 (brs, 1H), 8.92 (s, 1H), 8.56-8.40 (m, 1H), 7.78-7.54 (m, 2H), 3.78-3.76 (m, 1H), 1.05-1.01 (m, 2H), 0.58-0.54 (m, 2H) LC-MS: m / z 356.2 [M+H] + , RT=1.75 (purity 95.96%) HPLC: 97.81% Example 40

[0315] [ka]

[0316] 6-Chloro-1H-imidazo[4,5-c]pyridine To 6-chloropyridine-3,4-diamine (2 g, 13.99 mmol) was added formic acid (20 mL) at room temperature under inert atmosphere. The reaction mixture was heated to 120° C. and stirred for 16 h. Once the starting material was consumed (by TLC), the reaction mixture was basified with saturated NaHCO3 solution (100 mL) and extracted with EtOAc (2×100 mL). The organic extracts were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give 6-chloro-1H-imidazo[4,5-c]pyridine (2 g) as a light brown solid. The crude product was used in the next step without further purification. LC-MS: m / z 151.9 [MH] - , RT=6.38 (purity 59.98%) 6-Chloro-1-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-1H-imidazo[4,5-c]pyridine 2-Bromo-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole To a stirred solution of Int-4 (2.5 g, 9.16 mmol) in DMSO (25 mL) was added 6-chloro-1H-imidazo[4,5-c]pyridine (1.4 g, crude product) and potassium carbonate (3.79 g, 27.47 mmol) at room temperature under an inert atmosphere. The reaction mixture was heated to 90° C. and stirred for 16 h. Once the starting material was consumed (by TLC), the reaction mixture was poured into water (100 mL) and extracted with EtOAc (2×100 mL). The organic extracts were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 1-2% MeOH / CH2Cl2) to give the main 6-chloro-1-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-1H-imidazo[4,5-c]pyridine isomer (1.2 g, 3.47 mmol) and the minor 2a isomer (500 mg, 1.45 mmol), respectively, as off-white solids. Analytical data for the main isomer: 1H NMR (400 MHz, DMSO-d6): δ 9.23 (s, 1H), 9.04 (d, J = 0.8 Hz, 1H), 8.03 (d, J = 0.8 Hz, 1H), 7.94-7.85 (m, 2H), 3.78-3.72 (m, 1H), 1.08-1.02 (m, 2H), 0.77-0.72 (m, 2H) LC-MS: m / z 345.9 [M+H] + , RT=2.83 (purity 97.53%) Analytical data for minor isomers: 1 H NMR (400 MHz, DMSO-d6): δ 9.11 (s, 1H), 8.98 (d, J = 0.8 Hz, 1H), 7.99 (d, J = 1.0 Hz, 1H), 7.95-7.83 (m, 2H), 3.75-3.69 (m, 1H), 1.06-0.99 (m, 2H), 0.76-0.69 (m, 2H) LC-MS: m / z 345.9 [M+H] + RT=2.84 (purity 76.09%) 1-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-6-vinyl-1H-imidazo[4,5-c]pyridine In a sealed test tube, 6-chloro-1-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-1H-imidazo[4,5-c]pyridine (major isomer) (200 mg, 0.58 mmol) in 1,4-dioxane (4 mL) was stirred while 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (178 mg, 1.16 mmol) and aqueous potassium carbonate (2 M, 0.6 mL) were added at room temperature and the mixture was purged with argon for 5 min. To this reaction mixture was added Pd(OAc)2 (20 mg, 0.03 mmol) and X-Phos (41 mg, 0.09 mmol), and the mixture was degassed again under argon for 5 min. The reaction mixture was heated to 80 °C and stirred for 16 h. Once the starting material was consumed (by TLC), the reaction mixture was poured into water (20 mL) and extracted with EtOAc (2×30 mL). The organic extracts were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 2% MeOH / CHCl2) to give 1-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-6-vinyl-1H-imidazo[4,5-c]pyridine (90 mg, 0.27 mmol, 46%) as a yellow solid. 1 H NMR (400 MHz, CDCl3): δ 9.19 (d, J = 0.8 Hz, 1H), 8.41 (s, 1H), 7.72 (d, J = 0.7 Hz, 1H), 7.63 (dd, J = 10.1, 7.3 Hz, 1H), 7.43 (dd, J = 9.4, 6.9 Hz, 1H), 6.93 (dd, J = 17.3, 10.7 Hz, 1H), 6.30 (dd, J = 17.3, 1.2 Hz, 1H), 5.50 (dd, J = 10.7, 1.2 Hz, 1H), 3.46-3.41 (m, 1H), 1.17-1.11 (m, 2H), 0.76-0.70 (m, 2H) LC-MS: m / z 338.1 [M+H] + , RT=2.70 (96.65% purity) 1-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-1H-imidazo[4,5-c]pyridine-6-carbaldehyde To a stirred solution of 1-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-6-vinyl-1H-imidazo[4,5-c]pyridine (60 mg, 0.18 mmol) in tert-butanol / acetone / water (1:1:1, 3.6 mL) was added sodium periodate (76 mg, 0.36 mmol) under an inert atmosphere at 0° C., followed by dropwise addition of osmium tetroxide (1M in toluene, 1.2 mL). The reaction mixture was allowed to warm slowly to room temperature and stirred for 1 h. Once the starting material was consumed (by TLC), the reaction mixture was filtered through a pad of Celite and washed with EtOAc (20 mL). The filtrate was extracted with EtOAc (2×10 mL). The organic extracts were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give 1-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-1H-imidazo[4,5-c]pyridine-6-carbaldehyde (60 mg) as an off-white solid, which was used crude in the next step without further purification. 1 H NMR (400 MHz, DMSO-d6): δ 10.14 (s, 1H), 9.36 (d, J = 0.8 Hz, 1H), 9.33 (s, 1H), 8.48 (d, J = 1.0 Hz, 1H), 7.98 (dd, J = 10.9, 7.4 Hz, 1H), 7.88 (dd, J = 10.4, 7.3 Hz, 1H), 3.79-3.71 (m, 1H), 1.06-1.00 (m, 2H), 0.76-0.70 (m, 2H) LC-MS: m / z 339.9 [M+H] + , RT=2.55 (purity 81.70%) 1-(1-Cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-6-(difluoromethyl)-1H-imidazo[4,5-c]pyridine (Ex.40) To a stirred solution of 1-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-1H-imidazo[4,5-c]pyridine-6-carbaldehyde (60 mg, crude product) in CHCl (3 mL) was added diethylaminosulfur trifluoride (0.05 mL, 0.35 mmol) at 0° C. under an inert atmosphere. The reaction mixture was slowly warmed to room temperature and stirred for 1 h. Once the starting material was consumed (by TLC), the reaction mixture was basified with saturated NaHCO solution (20 mL) and extracted with EtOAc (2×20 mL). The organic extracts were combined, dried over anhydrous NaSO and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 20-30% EtOAc / hexane) to give 1-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-6-(difluoromethyl)-1H-imidazo[4,5-c]pyridine Ex.40 (25 mg, 0.07 mmol, 39% (2 steps)) as an off-white solid. The structure was further confirmed by 2D NMR analysis (NOESY, DQFCOSY). 1 H NMR (400 MHz, DMSO-d6): δ 9.27-9.21 (m, 2H), 8.23 ​​(s, 1H), 7.95 (dd, J = 10.8, 7.4 Hz, 1H), 7.88 (dd, J = 10.4, 7.3 Hz, 1H), 7.28-6.95 (m, 1H), 3.77-3.71 (m, 1H), 1.08-1.00 (m, 2H), 0.76-0.68 (m, 2H) LC-MS: m / z 362.2 [M+H] + , RT=2.36 (purity 96.77%) HPLC: 96.68% Chiral HPLC (purity): 100.00%; R t =12.25min (Chiralpak IA, 250×4.6mm, 5μm); Mobile phase (A) 0.1%DEA / n-hexane (B) DCM:MeOH (50:50) (A:B=85:15); Flow rate: 1.0mL / min) Example 41

[0317] [ka]

[0318] 1-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-6-vinyl-1H-imidazo[4,5-c]pyridine In a sealed tube, 6-chloro-1-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-1H-imidazo[4,5-c]pyridine (by-product isomer) (200 mg, 0.58 mmol) in 1,4-dioxane (5 mL) was stirred while 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (178 mg, 1.16 mmol) and aqueous potassium carbonate (2 M, 0.6 mL) were added at room temperature, and the mixture was purged with argon for 5 min. Pd(OAc)2 (20 mg, 0.03 mmol) and X-Phos (41 mg, 0.09 mmol) were added, and the mixture was degassed with argon for 5 min. The reaction mixture was heated to 80 °C and stirred for 16 h. Once the starting material was consumed (by TLC), the reaction mixture was poured into water (20 mL) and extracted with EtOAc (2×30 mL). The organic extracts were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 2% MeOH / CHCl2) to give 1-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-6-vinyl-1H-imidazo[4,5-c]pyridine (120 mg, 0.35 mmol, 61%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3): δ 9.14 (d, J = 1.0 Hz, 1H), 8.50 (s, 1H), 7.84 (d, J = 0.8 Hz, 1H), 7.61 (dd, J = 10.1, 7.2 Hz, 1H), 7.43 (dd, J = 9.5, 6.9 Hz, 1H), 6.99 (dd, J = 17.3, 10.7 Hz, 1H), 6.26 (dd, J = 17.4, 1.3 Hz, 1H), 5.50 (dd, J = 10.7, 1.2 Hz, 1H), 3.49-3.44 (m, 1H), 1.16-1.10 (m, 2H), 0.78-0.72 (m, 2H) LC-MS: m / z 338.1 [M+H] + , RT=2.74 (purity 96.95%) 1-(1-Cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-1H-imidazo[4,5-c]pyridine-6-carbaldehyde To a stirred solution of 1-(1-cyclopropyl-56-difluoro-1H-benzo[d]imidazol-2-yl)-6-vinyl-1H-imidazo[4,5-c]pyridine (120 mg, 0.36 mmol) in tert-butanol / acetone / water (1:1:1, 7.2 mL) was added sodium periodate (152 mg, 0.71 mmol) followed by dropwise addition of osmium tetroxide (1M in toluene, 2.4 mL) at 0° C. under an inert atmosphere. The reaction mixture was allowed to warm slowly to room temperature and stirred for 1 h. Once the starting material was consumed (by TLC), the reaction mixture was filtered through a pad of Celite and washed with EtOAC (10 mL). The filtrate was extracted with EtOAc (2×20 mL). The organic extracts were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give 1-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-1H-imidazo[4,5-c]pyridine-6-carbaldehyde (120 mg) as a brown solid, which was used crude in the next step without further purification. 1H NMR (400 MHz, DMSO-d6): δ 10.15 (s, 1H), 9.41 (d, J = 1.0 Hz, 1H), 9.32 (s, 1H), 8.42 (d, J = 0.8 Hz, 1H), 7.97-7.87 (m, 2H), 3.80-3.75 (m, 1H), 1.06-1.02 (m, 2H), 0.77-0.71 (m, 2H) LC-MS: m / z 339.9 [M+H] + , RT=2.49 (purity 77.00%) 3-(1-Cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-6-(difluoromethyl)-3H-imidazo[4,5-c]pyridine (Ex.41) To a stirred solution of 1-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-1H-imidazo[4,5-c]pyridine-6-carbaldehyde (120 mg, crude product) in CHCl (6 mL) was added diethylaminosulfur trifluoride (0.09 mL, 0.71 mmol) at 0° C. under an inert atmosphere. The reaction mixture was slowly warmed to room temperature and stirred for 90 min. Once the starting material was consumed (by TLC), the reaction mixture was basified with saturated NaHCO solution (100 mL) and extracted with CHCl (2×20 mL). The organic extracts were combined, dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 20-30% EtOAc / hexane) to give 3-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-6-(difluoromethyl)-3H-imidazo[4,5-c]pyridine Ex.41 (55 mg, 0.15 mmol, 43% (2 steps)) as a pale yellow solid. The structure was further confirmed by 2D NMR analysis (NOESY, DQFCOSY). 1H NMR (400 MHz, DMSO-d6): δ9.33-9.25 (m, 2H), 8.19 (s, 1H), 7.95-7.86 (m, 2H), 7.30-6.96 (m, 1H), 3.80-3.74 (m, 1H), 1.08-1.00 (m, 2H), 0.79-0.70 (m, 2H) LC-MS: m / z 361.9 [M+H] + , RT=2.78 (purity 97.33%) HPLC: 98.97% Chiral HPLC (purity): 100.00%; R t =20.73min (Chiralpak IA, 250×4.6mm, 5μm); Mobile phase (A) 0.1%DEA / n-hexane (B) DCM:MeOH (50:50) (A:B=85:15); Flow rate: 1.0mL / min) Example 42 and Example 43

[0319] [ka]

[0320] 3-Cyclopropyl-2-oxo-2,3-dihydro-1-benzo[d]imidazole-5-carbonitrile 4-Amino-3-(cyclopropylamino)benzonitrile A solution of Int-6 (4 g, 23.12 mmol) in THF (80 mL) was added to 1,1-carbonyldiimidazole (5.62 g, 34.68 mmol) with stirring at 0° C. under inert atmosphere. The reaction mixture was slowly warmed to room temperature and stirred for 16 h. Once the starting material was consumed (by TLC), the reaction mixture was diluted with EtOAc (50 mL). The organic extracts were combined and washed with 1N HCl solution (20 mL), water (50 mL), and saturated brine (50 mL). The organic layer was separated, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 40% EtOAc / hexanes) to give 3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrile (3.8 g, 19.07 mmol, 83%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ 11.30 (s, 1H), 7.54 (d, J = 1.3 Hz, 1H), 7.45 (dd, J = 8.1, 1.6 Hz, 1H), 7.08 (dd, 7= 8.1, 0.4 Hz, 1H), 2.89-2.82 (m, 1H), 1.07-0.98 (m, 2H), 0.92-0.84 (m,2H) LC-MS: m / z 200.2 [M+H] + , RT=1.73 (purity 99.76%) 2-Bromo-1-cyclopropyl-1H-benzo[d]imidazole-6-carbonitrile To a stirred solution of 3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrile (3.8 g, 19.09 mmol) in 1,2-dichloroethane (250 mL) was added phosphoryl bromide (10.95 g, 38.19 mmol) in small portions at 0° C. under inert atmosphere. The reaction mixture was heated to 95° C. and stirred for 16 h. Additional phosphoryl bromide (5.47 g, 19.09 mmol) was then added at 0° C. The reaction mixture was heated to 95° C. and stirred for an additional 16 h. Once the starting material was consumed (by TLC), the reaction mixture was poured into ice-cold water (50 mL), basified to pH 8 with saturated NaHCO3 solution, and extracted with EtOAc (2×100 mL). The organic extracts were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 20% EtOAc / hexanes) to give 2-bromo-1-cyclopropyl-1H-benzo[d]imidazole-6-carbonitrile (2.8 g, 10.68 mmol, 56%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ 8.18 (dd, J = 1.6, 0.6 Hz, 1H), 7.77 (dd, J = 8.3, 0.6 Hz, 1H), 7.64 (dd, J = 8.3, 1.6 Hz, 1H), 3.45-3.38 (m, 1H), 1.32-1.26 (m, 2H), 1.16-1.12 (m, 2H) LC-MS: m / z 261.7 [M+H] + , RT=2.52 (purity 95.12%) 1-Cyclopropyl-2-(3H-imidazo[4,5-c]pyridin-3-yl)-1H-benzo[b]imidazole-6-carbonitrile (Ex. 42) and 1-cyclopropyl-2-(1H-imidazo[4,5-c]pyridin-1-yl)-1H-benzo[d]imidazole-6-carbonitrile (Ex. 43) To a stirred solution of 2-bromo-1-cyclopropyl-1H-benzo[d]imidazole-6-carbonitrile (225 mg, 0.86 mmol) in DMSO (2.5 mL) was added 37-imidazo[4,5-c]pyridine (102 mg, 0.86 mmol) and potassium carbonate (355 mg, 2.58 mmol) at room temperature under inert atmosphere. The reaction mixture was stirred at 80° C. for 16 h. Once the starting material was consumed (by TLC), the reaction mixture was diluted with ice-cold water (50 mL) and extracted with EtOAc (2×20 mL). The organic extracts were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 5% MeOH / CHCl) and then by chiral preparative HPLC to give 1-cyclopropyl-2-(3H-imidazo[4,5-c]pyridin-3-yl)-1H-benzo[d]imidazole-6-carbonitrile Ex.42 (25 mg, 0.08 mmol, 10%) and 1-cyclopropyl-2-(1H-imidazo[4,5-c]pyridin-1-yl)-1H-benzo[d]imidazole-6-carbonitrile Ex.43 (55 mg, 0.18 mmol, 21%), respectively, as off-white solids. The structures were confirmed by 2D NMR (NOESY, DQFCOSY). Analytical data for Ex.42: 1 H NMR (400 MHz, DMSO-d6): δ 9.32 (d, J = 0.9 Hz, 1H), 9.23 (s, 1H), 8.55 (d, J = 5.5 Hz, 1H), 8.31 (d, J = 1.0 Hz, 1H), 7.95 (d, J = 8.3 Hz, 1H), 7.89 (dd, J = 5.5, 0.9 Hz, 1H), 7.76 (dd, J = 8.4, 1.5 Hz, 1H), 3.88-3.81 (m, 1H), 1.15-1.09 (m, 2H), 0.83-0.77 (m, 2H) LC-MS: m / z 300.9 [M+H] + , RT=2.13 (purity 99.85%) HPLC: 99.77% Chiral HPLC (purity): 95.01%; R t =10.29min (Chiralpak IA, 250×4.6mm, 5μm); Mobile phase (A) 0.1%DEA / n-hexane (B) DCM:MeOH (50:50) (A:B=75:25); Flow rate: 1.0mL / min) Analytical data of Ex.43: 1 H NMR (400 MHz, DMSO-d6): δ 9.16 (d, J = 1.0 Hz, 1H), 9.12 (s, 1H), 8.55 (d, J = 5.5 Hz, 1H), 8.32 (dd, J = 1.5, 0.6 Hz, 1H), 7.98 (dd, J = 5.6, 1.1 Hz, 1H), 7.94 (dd, J = 8.4, 0.6 Hz, 1H), 7.76 (dd, J = 8.4, 1.6 Hz, 1H), 3.84-3.78 (m, 1H), 1.12-1.06 (m, 2H), 0.79-0.74 (m, 2H) LC-MS: m / z 300.9 [M+H] + , RT=2.15 (purity 99.84%) HPLC: 99.68% Chiral HPLC (purity): 100.00%; R t =9.10min (Chiralpak IA, 250×4.6mm, 5pm); Mobile phase (A) 0.1%DEA / n-hexane (B) DCM:MeOH (50:50) (A:B=75:25); Flow rate: 1.0mL / min) Example 44 and Example 51

[0321] [ka]

[0322] Methyl 1'-cyclopropyl-5',6'-difluoro-1'-[1,2'-bibenzo[d]imidazole]-5-carboxylate and Methyl 1'-cyclopropyl-5',6'-difluoro-1'-[1,2'-bibenzo[d]imidazole]-6-carboxylate 2-Bromo-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole To a stirred solution of Int-4 (500 mg, 1.83 mmol) in DMSO (5 mL) was added 1H-benzo[d]imidazole-6-methyl carboxylate (323 mg, 1.83 mmol) and potassium carbonate (654 mg, 5.49 mmol) at room temperature under an inert atmosphere. The reaction mixture was heated to 80° C. and stirred for 16 h. Once the starting material was consumed (by TLC), the reaction mixture was diluted with water (70 mL) and extracted with EtOAc (2×30 mL). The organic extracts were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 5% MeOH / CHCl) and then by chiral preparative HPLC to give methyl 1'-cyclopropyl-5',6'-difluoro-1'H-[1,2'-bibenzo[d]imidazole]-5-carboxylate (200 mg, 0.54 mmol, 30%) and methyl 1'-cyclopropyl-5',6'-difluoro-1'H-[1,2'-bibenzo[d]imidazole]-6-carboxylate (200 mg, 0.54 mmol, 30%), respectively, as off-white solids. The structures were confirmed by 2D NMR (NOESY, DQFCOSY). Analytical data for methyl 1'-cyclopropyl-5',6'-difluoro-1'H[1,2'-bibenzo[d]imidazole]-5-carboxylate: 1 H NMR (500 MHz, DMSO-d6): δ 9.07 (s, 1H), 8.40 (d, J = 0.9 Hz, 1H), 8.06-8.03 (m, 1H), 7.99-7.96 (m, 1H), 7.92-7.84 (m, 2H), 3.91 (s, 3H), 3.75-3.70 (m, 1H), 1.04-0.99 (m, 2H), 0.69-0.65 (m, 2H) LC-MS: m / z 369.0 [M+H] + , RT=2.98 (purity 99.80%) HPLC: 99.18% Chiral HPLC (purity): 100.00%; R t=11.09min (Chiralpak IA, 250×4.6mm, 5μm); Mobile phase (A) 0.1%DEA / n-hexane (B) DCM:MeOH (50:50) (A:B=75:25); Flow rate: 1.0mL / min) Analytical data for methyl 1'-cyclopropyl-5',6'-difluoro-1'H-[1,2'-bibenzo[d]imidazole]-6-carboxylate: 1 H NMR (500 MHz, DMSO-d6): δ 9.15 (s, 1H), 8.49 (s, 1H), 8.02-7.99 (m, 1H), 7.98-7.93 (m, 2H), 7.86 (dd, J = 10.3, 7.3 Hz, 1H), 3.88 (s, 3H), 3.76-3.71 (m, 1H), 1.04-1.01 (m, 2H), 0.70-0.65 (m, 2H) LC-MS: m / z 369.0 [M+H] + , RT=2.97 (purity 96.73%) HPLC: 99.00% Chiral HPLC (purity): 100.00%; R t =6.11min (Chiralpak IA, 250×4.6mm, 5μm); Mobile phase (A) 0.1%DEA / n-hexane (B) DCM:MeOH (50:50) (A:B=75:25); Flow rate: 1.0mL / min) 1'-Cyclopropyl-5',6'-difluoro-1'H-[1,2'-bibenzo[d]imidazole]-5-carboxylic acid (Ex.44) To a stirred solution of methyl 1'-cyclopropyl-5',6'-difluoro-1'H-[1,2'-bibenzo[d]imidazole]-5-carboxylate (50 mg, 0.13 mmol) in a mixture of THF (1 mL) and water (0.5 mL), barium hydroxide octahydrate (128 mg, 0.41 mmol) was added at room temperature and the mixture was stirred for 16 h. Once the starting material was consumed (by TLC), the reaction mixture was quenched with dry ice. The resulting solid was filtered and the filtrate was concentrated under reduced pressure. The crude product was triturated with CHCl (2×3 mL), n-pentane (2×10 mL) and lyophilized to give 1'-cyclopropyl-5',6'-difluoro-1'H-[1,2'-bibenzo[d]imidazole]-5-carboxylic acid Ex. 44 (35 mg, 0.1 mmol, 73%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ 9.01 (s, 1H), 8.36 (d, J = 0.9 Hz, 1H), 8.02 (dd, J = 8.6, 1.4 Hz, 1H), 7.92-7.82 (m, 3H), 3.75-3.70 (m, 1H), 1.04-0.98 (m, 2H), 0.69-0.64 (m, 2H) LC-MS: m / z 355.2 [M+H] + , RT=2.16 (purity 98.43%) HPLC: 98.50% 1'-Cyclopropyl-5',6'-difluoro-1'H-[1,2'-bibenzo[d]imidazole]-6-carboxylic acid (Ex.51) To a stirred solution of 1'-cyclopropyl-5',6'-difluoro-1'H-[1,2'-bibenzo[d]imidazole]-6-methyl carboxylate (160 mg, 0.43 mmol) in a mixture of THF (3 mL) and water (1.5 mL), barium hydroxide octahydrate (411 mg, 1.3 mmol) was added at room temperature and the mixture was stirred for 24 h. Additional barium hydroxide octahydrate (411 mg, 1.3 mmol) was then added at room temperature and stirred for another 24 h. Once the starting material was consumed (by TLC), the reaction mixture was quenched with dry ice. The reaction mixture was filtered through a pad of Celite and the Celite bed was washed with THF / water / methanol (1:1:1, 12 mL). The filtrate was concentrated under reduced pressure. The crude product was lyophilized and triturated again with 2% MeOH / CH2Cl2 (6 mL) to give 1'-cyclopropyl-5',6'-difluoro-1'H-[1,2'-bibenzo[d]imidazole]-6-carboxylic acid Ex. 51 (28 mg, 0.08 mmol, 19%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ 13.05 (brs, 1H), 9.13 (s, 1H), 8.48 (d, J = 1.0 Hz, 1H), 8.01-7.94 (m, 2H), 7.93-7.82 (m, 2H), 3.76-3.71 (m, 1H), 1.07-1.01 (m, 2H), 0.71-0.64 (m, 2H) LC-MS: m / z 355.2 [M+H] + , RT=2.13 (purity 94.55%) HPLC: 93.56% Example 45 and Example 46

[0323] [ka]

[0324] 1'-Cyclopropyl-5',6'-difluoro-5-nitro-1'H-1,2'-bibenzo[d]imidazole 2-Bromo-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole To a stirred solution of Int-4 (500 mg, 1.84 mmol) in DMSO (5 mL), 5-nitro-1H-benzo[d]imidazole (451 mg, 2.77 mmol) and potassium carbonate (764 mg, 5.53 mmol) were added at room temperature under inert atmosphere. The reaction mixture was heated to 100° C. and stirred for 16 h. Once the starting material was consumed (by TLC), the reaction mixture was poured into ice-cold water (60 mL). The resulting solid was filtered. The residue was purified by silica gel column chromatography (eluent: 20% EtOAc / hexane) to give 1′-cyclopropyl-5′,6′-difluoro-5-nitro-1′H-1,2′-bibenzo[d]imidazole (620 mg, mixture of isomers) as a pale yellow solid. The mixture was used in the next step without further purification. 1'-Cyclopropyl-5',6'-difluoro-1'H-[1,2'-bibenzo[d]imidazol]-5-amine A solution of 1'-cyclopropyl-5',6'-difluoro-5-nitro-1'H-1,2'-bibenzo[d]imidazole (100 mg, mixture) in a mixture of ethyl acetate / methanol (1:1, 20 mL) was stirred while 10% Pd / C (50% wet, 25 mg) was added at room temperature under an inert atmosphere. The reaction mixture was stirred at room temperature under a hydrogen atmosphere (balloon pressure) for 4 h. Once the starting material was consumed (by TLC), the reaction mixture was filtered through a Celite pad and the Celite bed was washed with methanol (20 mL). The filtrate was concentrated under reduced pressure to give 1'-cyclopropyl-5',6'-difluoro-1'H-[1,2'-bibenzo[d]imidazole]-5-amine and regioisomers (60 mg, mixture of isomers) as a brown syrup. The crude product was used in the next step without further purification. LC-MS: m / z 326.0 [M+H] + , RT=2.36 (purity 88.53%) N-(1'-cyclopropyl-5',6'-difluoro-1'-[1,2'-bibenzo[d]imidazol]-5-yl)methanesulfonamide (Ex. 46) and N-(1'-cyclopropyl-5',6'-difluoro-1'H-[1,2'-bibenzo[d]imidazol]-6-yl)methanesulfonamide (Ex. 45) To a stirred solution of 1'-cyclopropyl-5',6'-difluoro-1'H-[1,2'-bibenzo[d]imidazol]-5-amine and regioisomers (300 mg, crude) in CHCl (30 mL) was added triethylamine (0.13 mL, 0.92 mmol) followed by methanesulfonyl chloride (0.06 mL, 0.74 mmol) under inert atmosphere at 0 °C and stirred at 0 °C for 1 h. Once the starting material was consumed (by TLC), the reaction mixture was quenched with saturated NaHCO solution (20 mL) and extracted with CHCl (2 x 20 mL). The organic extracts were combined, dried over anhydrous NaSO and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 30% MeOH / CH2Cl2) and then by chiral preparative HPLC to obtain Ex.46 (42 mg, 0.1 mmol) and Ex.45 (31 mg, 0.08 mmol), respectively, as pale yellow solids. The structures were confirmed by 2D NMR (NOESY, gDQFCOSY) analysis. Analytical data for Ex.46: 1 H NMR (500 MHz, DMSO -d6): δ 9.72 (s, 1H), 8.91 (s, 1H), 7.90-7.80 (m, 3H), 7.67 (d, J = 1.8 Hz, 1H), 7.29 (dd, J = 8.7, 1.8 Hz, 1H), 3.74-3.69 (m, 1H), 2.99 (s, 3H), 1.06-0.99 (m, 2H), 0.69-0.61 (m, 2H) LC-MS: m / z 404.0 [M+H] + , RT=2.51 (purity 99.13%) HPLC: 98.74% Chiral HPLC (purity): 100.00%; R t=14.73min (Chiralpak IA, 250×4.6mm, 5μm); Mobile phase (A) 0.1%DEA / n-hexane (B) DCM:MeOH (50:50) (A:B=75:25); Flow rate: 1.0mL / min) Analytical data of Ex.45: 1 H NMR (500 MHz, DMSO-d6): δ 9.77 (s, 1H), 8.87 (s, 1H), 7.90-7.83 (m, 2H), 7.79 (d, J = 8.3 Hz, 1H), 7.74 (d, J = 1.8 Hz, 1H), 7.27 (dd, J = 8.7, 1.8 Hz, 1H), 3.73-3.66 (m, 1H), 2.95 (s, 3H), 1.05-0.98 (m, 2H), 0.69-0.65 (m, 2H) LC-MS: m / z 403.9 [M+H] + , RT=2.46 (purity 96.45%) HPLC: 96.12% Chiral HPLC (purity): 100.00%; R t =7.82min (Chiralpak IA, 250×4.6mm, 5μm); Mobile phase (A) 0.1%DEA / n-hexane (B) DCM:MeOH (50:50) (A:B=75:25); Flow rate: 1.0mL / min) Example 47 and Example 48

[0325] [ka]

[0326] 3-Cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrile 4-Amino-3-(cyclopropylamino)benzonitrile To a stirred solution of Int-6 (4 g, 23.12 mmol) in THF (80 mL) was added 1,1-carbonyldiimidazole (5.62 g, 34.68 mmol) at 0° C. under inert atmosphere. The reaction mixture was slowly warmed to room temperature and stirred for 16 h. Once the starting material was consumed (by TLC), the reaction mixture was diluted with EtOAc (50 mL). The organic extracts were combined and washed with 1N HCl solution (20 mL), water (50 mL), and saturated brine (50 mL). The organic layer was separated, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 40% EtOAc / hexanes) to give 3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrile (3.8 g, 19.07 mmol, 83%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ 11.30 (s, 1H), 7.54 (d, J = 1.3 Hz, 1H), 7.45 (dd, J = 8.1, 1.6 Hz, 1H), 7.08 (dd, J = 8.1, 0.4 Hz, 1H), 2.89-2.82 (m, 1H), 1.07-0.98 (m, 2H), 0.92-0.84 (m, 2H) LC-MS: m / z 200.2 [M+H] + , RT=1.73 (purity 99.76%) 2-Bromo-1-cyclopropyl-1H-benzo[d]imidazole-6-carbonitrile Phosphoryl bromide (10.95 g, 38.19 mmol) was added in small portions to a stirred solution of 3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrile (3.8 g, 19.09 mmol) in 1,2-dichloroethane (250 mL) at 0° C. under inert atmosphere. The reaction mixture was heated to 95° C. and stirred for 16 h. Then, additional phosphoryl bromide (5.47 g, 19.09 mmol) was added at 0° C. The reaction mixture was heated to 95° C. and stirred for another 16 h. Once the starting material was consumed (by TLC), the reaction mixture was poured into ice-cold water (50 mL), basified to pH 8 with saturated NaHCO3 solution, and extracted with EtOAc (2×100 mL). The organic extracts were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 20% EtOAc / hexanes) to give 2-bromo-1-cyclopropyl-1H-benzo[d]imidazole-6-carbonitrile (2.8 g, 10.68 mmol, 56%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ 8.18 (dd, J = 1.6, 0.6 Hz, 1H), 7.77 (dd, J = 8.3, 0.6 Hz, 1H), 7.64 (dd, J = 8.3, 1.6 Hz, 1H), 3.45-3.38 (m, 1H), 1.32-1.26 (m, 2H), 1.16-1.12 (m, 2H) LC-MS: m / z 261.7 [M+H] + , RT=2.52 (purity 95.12%) 1'-Cyclopropyl-5-nitro-1'H-[1,2'-bibenzo[d]imidazole]-6'-carbonitrile To a stirred solution of 2-bromo-1-cyclopropyl-1H-benzo[d]imidazole-6-carbonitrile (1 g, 3.82 mmol) in DMSO (10 mL) was added 5-nitro-1H-benzo[d]imidazole (622 mg, 3.82 mmol) and potassium carbonate (1.58 g, 11.45 mmol) at room temperature under inert atmosphere. The reaction mixture was heated to 90° C. and stirred for 16 h. Once the starting material was consumed (by TLC), the reaction mixture was poured into ice-cold water (30 mL) and extracted with EtOAc (2×40 mL). The organic extracts were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 2% MeOH / CH2Cl2) to give 1'-cyclopropyl-5-nitro-1'H-[1,2'-bibenzo[d]imidazole]-6'-carbonitrile and regioisomers (550 mg, mixture of isomers) as pale yellow solids. LC-MS: m / z 345.0 [M+H] + , RT=2.84 (purity 85.04%) 5-Amino-1'-cyclopropyl-1'H-[1,2'-bibenzo[d]imidazole]-6'-carbonitrile A stirred solution of 1'-cyclopropyl-5-nitro-1'H-[1,2'-bibenzo[d]imidazole]-6'-carbonitrile (450 mg, 1.31 mmol) in a mixture of ethyl acetate (80 mL) and methanol (80 mL) was added to 10% Pd / C (50% wet, 112 mg) at room temperature under inert atmosphere. The reaction mixture was stirred at room temperature under hydrogen atmosphere (balloon pressure) for 2 h. Once the starting material was consumed (by TLC), the reaction mixture was filtered through a pad of Celite and washed with EtOAc (100 mL). The filtrate was concentrated under reduced pressure to give 5-amino-1'-cyclopropyl-1'H-[1,2'-bibenzo[d]imidazole]-6'-carbonitrile and regioisomers (400 mg) as light brown solids. The crude product was used in the next step without further purification. LC-MS: m / z 315.0 [M+H] + , RT=2.12 (purity 58.42%) N-(6'-cyano-1'-cyclopropyl-1'H-[1,2'-bibenzo[d]imidazol]-5-yl)methanesulfonamide (Ex. 47) and N-(6'-cyano-1'-cyclopropyl-1'H-[1,2'-bibenzo[d]imidazol]-6-yl)methanesulfonamide (Ex. 48) To a stirred solution of 5-amino-1'-cyclopropyl-1'H-[1,2'-bibenzo[d]imidazole]-6'-carbonitrile and regioisomers (400 mg, crude) in CHCl (10 mL) was added triethylamine (0.27 mL, 1.91 mmol) under inert atmosphere at 0° C., followed by dropwise addition of a solution of methanesulfonyl chloride (0.07 mL, 0.95 mmol) in CHCl (2 mL) and stirred at 0° C. for 30 min. Once the starting material was consumed (by TLC), the reaction mixture was quenched with saturated NaHCO solution (30 mL) and extracted with CHCl (2×20 mL). The organic extracts were combined, dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 2% MeOH / CH2Cl2) and then by chiral preparative HPLC to give N-(6'-cyano-1'-cyclopropyl-1'H-[1,2'-bibenzo[d]imidazol]-5-yl)methanesulfonamide Ex.47 (110 mg, 0.28 mmol) and N-(6'-cyano-1'-cyclopropyl-1'H-[1,2'-bibenzo[d]imidazol]-6-yl)methanesulfonamide Ex.48 (50 mg, 0.13 mmol), respectively, as yellow solids. The structures were confirmed by 2D NMR (NOESY, DQFCOSY). Analytical data of Ex.47: 1H NMR (400 MHz, DMSO-d6): δ 9.73 (brs, 1H), 8.99 (s, 1H), 8.28 (d, J = 1.0 Hz, 1H), 7.95- 7.89 (m, 2H), 7.73 (dd, J = 8.3, 1.4 Hz, 1H), 7.68 (d, J = 1.9 Hz, 1H), 7.31 (dd, J = 8.7, 1.9 Hz, 1H), 3.84-3.77 (m, 1H), 2.99 (s, 3H), 1.14-1.07 (m, 2H), 0.77-0.71 (m, 2H) LC-MS: m / z 393.0 [M+H] + , RT=2.30 (purity 96.63%) HPLC: 95.50% KIRAL HPLC (purity): 98.00%; R t =18.80min (Chiralpak IA, 250×4.6mm, 5μm); mobile phase (A) 0.1% DEA / n-hexahydrobenzene (B) DCM:MeOH (50:50) (A:B=75:25); flow rate: 1.0mL / min) Analysis of Ex.48: 1 H NMR (400 MHz, DMSO-d6): δ 9.80 (s, 1H), 8.94 (s, 1H), 8.29 (d, J = 0.8 Hz, 1H), 7.93- 7.86 (m, 2H), 7.80 (d, J = 8.7 Hz, 1H), 7.74 (dd, J = 8.3, 1.4 Hz, 1H), 7.29 (dd, J = 8.7, 2.0 Hz, 1H), 3.83-3.75 (m, 1H), 2.96 (s, 3H), 1.14-1.07 (m, 2H), 0.79-0.72 (m, 2H) LC-MS: m / z 393.1 [M+H] + , RT=2.26 (purity 99.05%) HPLC: 97.73% KIRAL HPLC (purity): 100.00%; R t=11.19min (Chiralpak IA, 250×4.6mm, 5μm); Mobile phase (A) 0.1% DEAinn-hexane (B) DCM:MeOH (50:50) (A:B=75:25); Flow rate: 1.0mL / min) Example 49 and Example 50

[0327] [ka]

[0328] 5-Hydroxy-1H-benzo[d]imidazole-1-carboxylate tert-Butyl Ethyldiisopropylamine (1.43 mL, 8.21 mmol) and di-tert-butyl dicarbonate (1.88 mL, 8.21 mmol) were added to a stirred solution of 1H-benzo[d]imidazol-5-ol (1 g, 7.46 mmol) in 1,4-dioxane (30 mL) at room temperature under inert atmosphere. The reaction mixture was heated to 80° C. and stirred for 1 h. Once the starting material was consumed (by TLC), the reaction mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 1% MeOH / CH2Cl2) to give tert-butyl 5-hydroxy-1H-benzo[d]imidazole-1-carboxylate (1 g, 4.27 mmol, 57%) as a colorless syrup. 1 H NMR (400 MHz, DMSO-d6): δ 9.68-9.37 (m, 1H), 8.54-8.37 (m, 1H), 7.75-7.46 (m, 1H), 7.37-7.02 (m, 1H), 6.91-6.77 (m, 1H), 1.65-1.62 (m, 9H) LC-MS: m / z 232.9 [MH] - , RT=2.31 (purity 56.96%) 5-(Difluoromethoxy)-1H-benzo[d]imidazole To a stirred solution of tert-butyl 5-hydroxy-1H-benzo[d]imidazole-1-carboxylate (1.2 g, 5.13 mmol) in DMF (48 mL) was added sodium 2-chloro-2,2-difluoroacetate (1.56 g, 10.26 mmol) and potassium carbonate (2.12 g, 15.38 mmol) at room temperature under inert atmosphere. The reaction mixture was heated to 100° C. and stirred for 20 h. Once the starting material was consumed (by TLC), the reaction mixture was poured into ice-cold water (100 mL) and extracted with EtOAc (2×40 mL). The organic extracts were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 2% MeOH / CHCl2) to give 5-(difluoromethoxy)-1H-benzo[d]imidazole (100 mg, 0.35 mmol, 11%) as a light brown semi-solid. LC-MS: m / z 184.9 [M+H] + , RT=1.87 (purity 53.46%) 3-Cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrile 4-Amino-3-(cyclopropylamino)benzonitrile To a stirred solution of Int-6 (4 g, 23.12 mmol) in THF (80 mL) was added 1,1'-carbonyldiimidazole (5.62 g, 34.68 mmol) at 0 °C under inert atmosphere. The reaction mixture was slowly warmed to room temperature and stirred for 16 h. Once the starting material was consumed (by TLC), the reaction mixture was diluted with EtOAc (50 mL). The organic extracts were combined and washed with 1N HCl solution (20 mL), water (50 mL), and saturated brine (50 mL). The organic layer was separated, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 40% EtOAc / hexanes) to give 3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrile (3.8 g, 19.07 mmol, 83%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.30 (s, 1H), 7.54 (d, J = 1.3 Hz, 1H), 7.45 (dd, J = 8.1, 1.6 Hz, 1H), 7.08 (dd, J = 8.1, 0.4 Hz, 1H), 2.89-2.82 (m, 1H), 1.07-0.98 (m, 2H), 0.92-0.84 (m, 2H) LC-MS: m / z 200.2 [M+H] + , RT=1.73 (purity 99.76%) 2-Bromo-1-cyclopropyl-1H-benzo[d]imidazole-6-carbonitrile Phosphoryl bromide (10.95 g, 38.19 mmol) was added in small portions to a stirred solution of 3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrile (3.8 g, 19.09 mmol) in 1,2-dichloroethane (250 mL) under inert atmosphere at 0° C. The reaction mixture was heated to 95° C. and stirred for 16 h. Additional phosphoryl bromide (5.47 g, 19.09 mmol) was then added at 0° C. The reaction mixture was heated to 95° C. and stirred for another 16 h. Once the starting material was consumed (by TLC), the reaction mixture was poured into ice-cold water (50 mL), basified to pH ∼8 with saturated NaHCO3 solution, and extracted with EtOAc (2×100 mL). The organic extracts were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 20% EtOAc / hexanes) to give 2-bromo-1-cyclopropyl-1H-benzo[d]imidazole-6-carbonitrile (2.8 g, 10.68 mmol, 56%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ 8.18 (dd, J = 1.6, 0.6 Hz, 1H), 7.77 (dd, J = 8.3, 0.6 Hz, 1H), 7.64 (dd, J = 8.3, 1.6 Hz, 1H), 3.45-3.38 (m, 1H), 1.32-1.26 (m, 2H), 1.16-1.12 (m, 2H) LC-MS: m / z 261.7 [M+H] + , RT=2.52 (purity 95.12%) 1'-Cyclopropyl-5-(difluoromethoxy)-1'H-[1,2'-bibenzo[d]imidazole]-6'-carbonitrile (Ex. 49) and 1'-cyclopropyl-6-(difluoromethoxy)-1'H-[1,2'-bibenzo[d]imidazole]-6'-carbonitrile (Ex. 50) To a stirred solution of 5-(difluoromethoxy)-1H-benzo[d]imidazole (150 mg, 0.57 mmol) in DMSO (1.5 mL) were added 2-bromo-1-cyclopropyl-1H-benzo[d]imidazole-6-carbonitrile (105 mg, 0.57 mmol) and potassium carbonate (237 mg, 1.72 mmol) at room temperature under inert atmosphere. The reaction mixture was heated to 100° C. and stirred for 16 h. Once the starting material was consumed (by TLC), the reaction mixture was poured into ice-cold water (20 mL) and extracted with EtOAc (2×20 mL). The organic extracts were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 2% MeOH / CHCl) and then by chiral preparative HPLC to give 1'-cyclopropyl-5-(difluoromethoxy)-1'H-[1,2'-bibenzo[d]imidazole]-6'-carbonitrile Ex.49 (25 mg, 0.07 mmol) and 1'-cyclopropyl-6-(difluoromethoxy)-1'H-[1,2'-bibenzo[d]imidazole]-6'-carbonitrile Ex.50 (25 mg, 0.07 mmol), respectively, as off-white solids. The structures of the two species were confirmed by 2D NMR (NOESY, DQFCOSY) analysis. Analytical data of Ex.49: 1H NMR (400 MHz, CDCl3): δ8.54 (s, 1H), 7.98-7.92 (m, 2H), 7.87 (d, J = 7.9 Hz, 1H), 7.69 (d, J = 2.0 Hz, 1H), 7.65 (dd, J = 8.3, 1.5 Hz, 1H), 7.29 (d, J = 2.1 Hz, 1H), 6.78-6.39 (m, 1H), 3.58-3.50 (m, 1H), 1.29-1.22 (m, 2H), 0.84-0.78 (m, 2H) LC-MS: m / z 366.2 [M+H] + , RT=2.42 (purity 99.51%) HPLC: 98.15% KIRAL HPLC (purity): 100.00%; R t =12.05min (Chiralpak IA, 250×4.6mm, 5μm); mobile phase (A) 0.1% DEA / n-hexahydrobenzene (B) DCM:MeOH (50:50) (A:B=80:20); flow rate: 1.0mL / min) Analysis of Ex.50: 1 H NMR (400 MHz, CDCl3): δ 8.51 (s, 1H), 7.96 (dd, J = 1.5, 0.8 Hz, 1H), 7.90-7.89 (m, 1H), 7.88-7.87 (m, 1H), 7.76 (d, J = 2.0 Hz, 1H), 7.65 (dd, J = 8.3, 1.6 Hz, 1H), 7.27-7.23 (m, 1H), 6.78-6.39 (m, 1H), 3.57-3.50 (m, 1H), 1.28-1.22 (m, 2H), 0.84-0.78 (m, 2H) LC-MS: m / z 366.2 [M+H] + , RT=2.41 (purity 99.66%) HPLC: 99.16% KIRAL HPLC (purity): 100.00%; R t=9.80min (Chiralpak IA, 250x4.6mm, 5μm); Mobile phase (A) 0.1%DEA / n-hexane (B) DCM:MeOH (50:50) (A:B=80:20); Flow rate: 1.0mL / min) Example 52 and Example 53

[0329] [ka]

[0330] 1'-Cyclopropyl-5-(difluoromethoxy)-5',6'-difluoro-1'H-1,2'-bibenzo[d]imidazole (Ex. 52) and 1'-cyclopropyl-6-(difluoromethoxy)-5',6'-difluoro-1'H-1,2'-bibenzo[b]imidazole (Ex. 53). 2-Bromo-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole To a stirred solution of Int-4 (178 mg, 0.65 mmol) in DMSO (2 mL) was added 5-(difluoromethoxy)-1H-benzo[d]imidazole (120 mg, 0.65 mmol) and potassium carbonate (270 mg, 1.96 mmol) at room temperature under inert atmosphere. The reaction mixture was heated to 100° C. and stirred for 16 h. Once the starting material was consumed (by TLC), the reaction mixture was diluted with ice-cold water (20 mL) and extracted with EtOAc (2×20 mL). The organic extracts were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 2% MeOH / CHCl) and then by chiral preparative HPLC to give 1'-cyclopropyl-5-(difluoromethoxy)-5',6'-difluoro-1'H-1,2'-bibenzo[d]imidazole Ex.52 (15 mg, 0.04 mmol, 6%) and 1'-cyclopropyl-6-(difluoromethoxy)-5',6'-difluoro-1'H-1,2'-bibenzo[d]imidazole Ex.53 (15 mg, 0.04 mmol, 6%), respectively, as off-white solids. The structures were confirmed by 2D NMR (NOESY, COSY) analysis. Analytical data of Ex.52: 1 H NMR (400 MHz, DMSO-d6): δ 8.99 (s, 1H), 7.93-7.81 (m, 3H), 7.66 (d, J = 2.3 Hz, 1H), 7.50-7.09 (m, 2H), 3.75-3.69 (m, 1H), 1.06-0.98 (m, 2H), 0.71-0.64 (m, 2H) LC-MS: m / z 377.0 [M+H] + , RT=3.16 (purity 99.27%) HPLC: 99.64% KIRAL HPLC (purity): 100.00%; R t =9.02min (Chiralpak IA, 250×4.6mm, 5μm); mobile phase (A) 0.1% DEA / n-hexahydrobenzene (B) DCM:MeOH (50:50) (A:B=80:20); flow rate: 1.0mL / min) Analysis of Ex.53: 1 H NMR (400 MHz, DMSO-d6): δ 8.95 (s, 1H), 7.95-7.82 (m, 3H), 7.70 (d, J = 2.3 Hz, 1H), 7.43-7.04 (m, 2H), 3.74-3.69 (m, 1H), 1.05-0.97 (m, 2H), 0.69-0.63 (m, 2H) LC-MS: m / z 377.0 [M+H] + , RT=3.13 (purity 99.36%) HPLC: 99.74% KIRAL HPLC (purity): 99.50%; R t =10.96min (Chiralpak IA, 250x4.6mm, 5μm); mobile phase (A) 0.1% DEA / n-hexahydrobenzene (B) DCM:MeOH (50:50) (A:B=80:20); flow rate: 1.0mL / min) Example 54: Metalloenzyme activity V79-4 cells expressing recombinant andrenodoxin and andrenodoxin reductase together with either recombinant human CYP11B2 or CYP11B1 were generated as previously described (LaSala et al 2009 Anal Bioch 394:56-61). Enzyme-enriched microsomal fractions were prepared from cell lysates and the IC values ​​of inhibitors were determined. 50 The enzymes were used as the enzyme source for determining the Km values. The Km values ​​of the substrates were experimentally determined for 11-deoxycorticosterone (substrate for CYP11B2) and 11-deoxycortisol (substrate for CYP11B1). Enzyme tests for screening inhibitors were performed at the Km of each substrate using microsomes enriched for CYP11B2 and CYP11B1 enzymes. The products of the enzymatic reaction, aldosterone (for CYP11B2) or cortisol (for CYP11B1), were measured by LC-MS. The tests were performed under conditions that resulted in less than 20% turnover of the substrate. The IC of the inhibitors was determined. 50 was calculated by measuring the production of product in the absence of inhibitor or in the presence of various concentrations of inhibitor. t ) was defined as 100% activity in each data set. The product (P b ) was defined as 0% activity in each data set. The percentage of activity in the presence of each inhibitor was calculated according to the formula: Activity (%) = (PP b ) / (P t -P b ) (P = product produced in the presence of inhibitor). IC 50 Values ​​were defined as the concentration of inhibitor that reduced activity by 50% relative to control reactions without inhibitor.

[0331] [Table 2]

[0332] [Table 3]

[0333] [Table 4]

[0334] [Table 5]

[0335] [Table 6]

[0336] [Table 7]

[0337] [Table 8]

[0338] [Table 9] The results in Table 2 demonstrate that the compounds of formula I are potent inhibitors of CYP11B2, and many of the compounds of formula I exhibit significant selective inhibition of CYP11B2 over CYP11B1. References The contents of all references cited throughout this application (including literature references, issued patents, published patent applications, and co-pending patent applications) are hereby expressly incorporated by reference in their entirety. Doctrine of Equivalents Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the scope of the following claims.

Claims

1. Compounds of Formula I: 【Chemistry 1】 (In the formula: W, X, Y, and Z are each independently N or CR. １ and Q, T, U, and V are each independently N or CR. ２ and A is N or CR ３ and with the proviso that no more than two of W, X, Y, and Z are N; and no more than two of Q, T, U, and V are N; R １ are each independently hydrogen, halogen, cyano, acyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, (CR ｅ R ｆ ) ｎ N.R. ａ R ｂ , (CR ｅ R ｆ ) ｎ N.R. ｃ S (O ２ ) R ｄ , (CR ｅ R ｆ ) ｎ N.R. ｃ CO ２ R ｄ , CO ２ R ｅ , C.O.R. ｆ , or (CR ｅ R ｆ ) ｎ OR ｆ and R １ Each of the groups is independently 1 to 3 substituents R ７ may be optionally substituted with; R ２ are each independently hydrogen, halogen, cyano, acyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, (CR ｅ R ｆ ) ｎ N.R. ａ R ｂ , (CR ｅ R ｆ ) ｎ N.R. ｃ S (O ２ ) R ｄ , (CR ｅ R ｆ ) ｎ N.R. ｃ CO ２ R ｄ , N(S(O ２ ) R ｄ ) ２ , CO ２ R ｅ , C.O.R. ｆ , or (CR ｅ R ｆ ) ｎ OR ｆ and R ２ Each of the groups is independently 1 to 3 substituents R ７ may be optionally substituted with; R ３ is hydrogen, cyano, alkyl, haloalkyl, heteroalkyl, or cycloalkyl; R ４ is hydrogen, alkyl, cycloalkyl, haloalkyl, or heteroalkyl; Each n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; R ７ are each independently a halogen, an alkyl, an alkoxy, a haloalkyl, a carboxyl, an aryl, an aryl substituted with 1 to 3 independent halogens, -(CR ｅ R ｆ ) ｎ C(O)NR ａ R ｂ , -S(O) ２ R ｄ , -CO ２ R ｅ , or NR ａ R ｂ and R ａ , R ｂ , R ｃ , R ｄ , R ｅ , and R ｆ are each independently hydrogen, acyl, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxyalkyl, C(O)OC １～６ Alkyl, C(O)OH, C(O)C １～６ Alkyl, S(O ２ ) C １～６ Alkyl, S(O ２ ) aryl, S(O ２ ) heteroaryl, a nitrogen protecting group if attached to a nitrogen atom, or an oxygen protecting group if attached to an oxygen atom; or ａ and R ｂ together with the atoms to which they are attached form a heterocycloalkyl ring; or R ｅ and R ｆ together with the atoms to which they are attached form a cycloalkyl ring; or R ｃ and R ｄ together with the atom to which they are attached form a heterocycloalkyl ring) or a pharma- ceutically acceptable salt thereof.

2. 10. The compound of claim 1, having the formula Ia: 【Chemistry 2】 or a pharma- ceutically acceptable salt thereof.

3. A compound according to claim 1 or 2, having the formula I-b: 【Chemistry 3】 or a pharma- ceutically acceptable salt thereof.

4. A compound according to any one of claims 1 to 3, having the formula I-c: 【Chemistry 4】 or a pharma- ceutically acceptable salt thereof.

5. A compound according to any one of claims 1 to 3, having the formula I-d: 【Chemistry 5】 or a pharma- ceutically acceptable salt thereof.

6. A compound according to any one of claims 1 to 3, having the formula Ie: 【Chemistry 6】 or a pharma- ceutically acceptable salt thereof.

7. A compound according to any one of claims 1 to 3, having the formula If: 【Chemistry 7】 or a pharma- ceutically acceptable salt thereof.

8. A compound according to any one of claims 1 to 3, having the formula I-g: 【Chemistry 8】 or a pharma- ceutically acceptable salt thereof.

9. A compound according to any one of claims 1 to 4, having the formula Ih: 【Chemistry 9】 or a pharma- ceutically acceptable salt thereof.

10. A compound according to any one of claims 1 to 4, having the formula I-i: 【Chemistry 10】 or a pharma- ceutically acceptable salt thereof.

11. A compound according to any one of claims 1 to 4, having the formula I-j: 【Chemistry 11】 or a pharma- ceutically acceptable salt thereof.

12. R １ The compound according to any one of claims 1 to 11, or a pharma- ceutically acceptable salt thereof, wherein each of the is independently hydrogen, halogen, cyano, alkyl, alkoxy, haloalkyl, or haloalkoxy.

13. R １ The compound according to any one of claims 1 to 12, or a pharma- ceutically acceptable salt thereof, wherein each of is independently hydrogen, halogen, or cyano.

14. At least one R １ The compound according to any one of claims 1 to 13, or a pharma- ceutically acceptable salt thereof, wherein is halogen or cyano.

15. R ２ are each independently hydrogen, halogen, cyano, acyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, (CR ｅ R ｆ ) ｎ N.R. ａ R ｂ , (CR ｅ R ｆ ) ｎ N.R. ｃ S (O ２ ) R ｄ , (CR ｅ R ｆ ) ｎ N.R. ｃ CO ２ R ｄ , CO ２ R ｅ , C.O.R. ｆ , or (CR ｅ R ｆ ) ｎ OR ｆ 15. The compound according to any one of claims 1 to 14, wherein:

16. R ２ are each independently hydrogen, halogen, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, (CR ｅ R ｆ ) ｎ N.R. ｃ S (O ２ ) R ｄ , or CO ２ R ｅ 16. The compound according to any one of claims 1 to 15, wherein:

17. R ２ are each independently hydrogen, halogen, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, or (CR ｅ R ｆ ) ｎ N.R. ｃ S (O ２ ) R ｄ 17. The compound according to any one of claims 1 to 16, wherein:

18. R ２ are each independently hydrogen, haloalkyl, or NHS(O ２ ) R ｄ and R ｄ The compound according to any one of claims 1 to 17, or a pharma- ceutically acceptable salt thereof, wherein is alkyl.

19. At least one R ２ is hydrogen, halogen, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, or (CR ｅ R ｆ ) ｎ N.R. ｃ S (O ２ ) R ｄ 18. The compound according to any one of claims 1 to 17, wherein:

20. R ４ The compound according to any one of claims 1 to 10 or 12 to 20, or a pharma- ceutically acceptable salt thereof, wherein: is alkyl or cycloalkyl.

21. R ４ is C １～４ Alkyl or C ３～５ 21. The compound according to any one of claims 1 to 10 or 12 to 20, or a pharma- ceutically acceptable salt thereof, which is cycloalkyl.

22. R ４ is ethyl or cyclopropyl, or a pharma- ceutically acceptable salt thereof.

23. 23. The compound of any one of claims 1 or 12-22, or a pharma- ceutically acceptable salt thereof, wherein A is N.

24. 24. The compound according to any one of claims 1, 2, or 12 to 23, wherein among W, X, Y, and Z, N is one or less, or a pharma- ceutically acceptable salt thereof.

25. W, X, Y, and Z are CR １ 24. The compound according to any one of claims 1, 2, or 12 to 23, which is: or a pharma- ceutically acceptable salt thereof.

26. 25. The compound of any one of claims 1-3, 6-8, or 12-24, or a pharma- ceutically acceptable salt thereof, wherein Z is N.

27. Z is CR １ 25. The compound according to any one of claims 1 to 3, 6 to 8, or 12 to 24, which is: or a pharma- ceutically acceptable salt thereof.

28. The compound according to any one of claims 1 to 5 or 12 to 27, wherein among Q, T, U, and V, N is one or less, or a pharma- ceutically acceptable salt thereof.

29. Q, T, U, and V are CRs ２ 28. The compound according to any one of claims 1 or 12 to 27, wherein:

30. T and U are CR ２ 28. The compound according to any one of claims 1 to 5 or 12 to 27, or a pharma- ceutically acceptable salt thereof.

31. T is N and U is CR ２ 29. The compound according to any one of claims 1 to 5 or 12 to 28, or a pharma- ceutically acceptable salt thereof.

32. U is N and T is CR ２ 29. The compound according to any one of claims 1 to 5 or 12 to 28, or a pharma- ceutically acceptable salt thereof.

33. R １ are each independently hydrogen, halogen, or cyano; R ４ or a pharma- ceutically acceptable salt thereof.

34. R １ are each independently hydrogen, halogen, or cyano; R ２ are each independently hydrogen, halogen, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, or (CR ｅ R ｆ ) ｎ N.R. ｃ S (O ２ ) R ｄ and R ４ is cyclopropyl; or a pharma- ceutically acceptable salt thereof.

35. R １ are each independently hydrogen or cyano; R ２ are each independently hydrogen, halogen, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, or (CR ｅ R ｆ ) ｎ N.R. ｃ S (O ２ ) R ｄ and R ４ or a pharma- ceutically acceptable salt thereof. The compound of any one of claims 1-13, 15, 16, or 20-32, wherein:

36. R １ are each independently hydrogen or halogen; R ２ are each independently hydrogen, halogen, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, or (CR ｅ R ｆ ) ｎ N.R. ｃ S (O ２ ) R ｄ and R ４ or a pharma- ceutically acceptable salt thereof. The compound of any one of claims 1-13, 15, 16, or 20-32, wherein:

37. R １ are each independently a halogen; R ２ are each independently hydrogen, halogen, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, or (CR ｅ R ｆ ) ｎ N.R. ｃ S (O ２ ) R ｄ and R ４ or a pharma- ceutically acceptable salt thereof. The compound according to any one of claims 1 to 16 or 20 to 32, wherein:

38. R １ are each independently hydrogen, chloro, fluoro, or cyano; R ２ are each independently hydrogen, chloro, fluoro, cyano, methyl, trifluoromethyl, difluoromethylmethoxy, trifluoromethoxy, difluoromethoxy, or NHS(O ２ ) CH ３ and R ４ is cyclopropyl; or a pharma- ceutically acceptable salt thereof.

39. R １ are each independently hydrogen or cyano; R ２ are each independently hydrogen, chloro, fluoro, cyano, methyl, trifluoromethyl, difluoromethylmethoxy, trifluoromethoxy, difluoromethoxy, or NHS(O ２ ) CH ３ and R ４ or a pharma- ceutically acceptable salt thereof. The compound of any one of claims 1-13, 15-17, or 20-32, wherein:

40. R １ are each independently hydrogen, chloro, or fluoro; R ２ are each independently hydrogen, chloro, fluoro, cyano, methyl, trifluoromethyl, difluoromethylmethoxy, trifluoromethoxy, difluoromethoxy, or NHS(O ２ ) CH ３ and R ４ or a pharma- ceutically acceptable salt thereof. The compound of any one of claims 1-13, 15-17, or 20-32, wherein:

41. 2. The compound of claim 1 , 1'-Cyclopropyl-6'-fluoro-1'H-1,2-bibenzo[d]imidazole (1); 1'-Cyclopropyl-6',7'-difluoro-1'H-1,2-bibenzo[d]imidazole (2); 1'-Cyclopropyl-4,5,6'-trifluoro-1'H-1,2'-bibenzo[d]imidazole (3); 1'-Cyclopropyl-5,6,6'-trifluoro-1'H-1,2'-bibenzo[d]imidazole (4); 1'-Cyclopropyl-6'-fluoro-5,6-dimethoxy-1'H-1,2'-bibenzo[d]imidazole (5); 1'-Cyclopropyl-6'-fluoro-1'H-[1,2'-bibenzo[d]imidazole]-5-carbonitrile (6); 1'-Cyclopropyl-6'-fluoro-1'H-[1,2'-bibenzo[d]imidazole]-6-carbonitrile (7); 1'-Cyclopropyl-6'-fluoro-5-methyl-1'H-1,2'-bibenzo[d]imidazole (8); 1'-Cyclopropyl-6'-fluoro-6-methyl-1'H-12'-bibenzo[d]imidazole (9); 1'-Cyclopropyl-5-ethyl-6'-fluoro-1'H-1,2'-bibenzo[d]imidazole (10); 1'-Cyclopropyl-6-ethyl-6'-fluoro-1'H-1,2'-bibenzo[d]imidazole (11); 1'-Cyclopropyl-6'-fluoro-5-methoxy-1'H-1,2'-bibenzo[d]imidazole (12); 1'-Cyclopropyl-6'-fluoro-6-methoxy-1'H-1,2'-bibenzo[d]imidazole (13); 1'-Cyclopropyl-6'-fluoro-4-methyl-1'H-1,2'-bibenzo[d]imidazole (14); 1'-Cyclopropyl-5,6,6',7'-tetrafluoro-1'H-1,2'-bibenzo[d]imidazole (15); 1'-Cyclopropyl-5',6'-difluoro-1'H-1,2'-bibenzo[d]imidazole (16); 1'-Cyclopropyl-5,5',6,6'-tetrafluoro-1'H-1,2'-bibenzo[d]imidazole (17); 1'-Cyclopropyl-5,6'-difluoro-1'H-1,2'-bibenzo[d]imidazole (18); 1'-Cyclopropyl-6,6'-difluoro-1'H-1,2'-bibenzo[d]imidazole (19); 1'-Cyclopropyl-6'-fluoro-5-(trifluoromethyl)-1'H-1,2'-bibenzo[d]imidazole (20); 1'-Cyclopropyl-6'-fluoro-6-(trifluoromethyl)-1'H-1,2'-bibenzo[d]imidazole (21); 1'-Ethyl-5,6-difluoro-1'H-[1,2'-bibenzo[d]imidazole]-6'-carbonitrile (22); 1'-Cyclopropyl-5',6'-difluoro-1'H-[1,2'-bibenzo[d]imidazole]-5-carbonitrile (23); 1'-Cyclopropyl-5',6'-difluoro-1'H-[1,2'-bibenzo[d]imidazole]-6-carbonitrile (24); 1'-Cyclopropyl-5,6-difluoro-1'H-[1,2'-bibenzo[d]imidazole]-6'-carbonitrile (25); 6'-Chloro-1'-cyclopropyl-5,6-difluoro-1'H-1,2'-bibenzo[d]imidazole (26); 1'-Cyclopropyl-6'-fluoro-5-(trifluoromethoxy)-1'H-1,2'-bibenzo[d]imidazole (27); 1'-Cyclopropyl-6'-fluoro-6-(trifluoromethoxy)-1'H-1,2'-bibenzo[d]imidazole (28); 5-Chloro-3-cyclopropyl-2-(5,6-difluoro-1H-benzo[d]imidazol-1-yl)-3H-imidazo[4,5-b]pyridine (29); N-(1'-cyclopropyl-6',7'-difluoro-1'H-[1,2'-bibenzo[d]imidazol]-5-yl)-N-(methylsulfonyl)methanesulfonamide (30); N-(1'-cyclopropyl-6',7'-difluoro-1'H-[1,2'-bibenzo[d]imidazol]-5-yl)methanesulfonamide (31); 3-Cyclopropyl-2-(5,6-difluoro-1H-benzo[d]imidazol-1-yl)-3H-imidazo[4,5-b]pyridine-5-carbonitrile (32); N-(1'-cyclopropyl-6',7'-difluoro-1'H-[1,2'-bibenzo[d]imidazol]-6-yl)methanesulfonamide (33); 1-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-1H-imidazo[4,5-b]pyridine (34); 1-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-1H-imidazo[4,5-c]pyridine (35); 3-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-3H-imidazo[4,5-c]pyridine (36); 3-Cyclopropyl-2-(3H-imidazo[4,5-c]pyridin-3-yl)-3H-imidazo[4,5-b]pyridine-5-carbonitrile (37); 3-Cyclopropyl-2-(1H-imidazo[4,5-c]pyridin-1-yl)-3H-imidazo[4,5-b]pyridine-5-carbonitrile (38); 1-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-1H-imidazo[4,5-c]pyridine-6-carboxylic acid (39); 1-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-6-(difluoromethyl)-1H-imidazo[4,5-c]pyridine (40); 3-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-6-(difluoromethyl)-3H-imidazo[4,5-c]pyridine (41); 1-Cyclopropyl-2-(3H-imidazo[4,5-c]pyridin-3-yl)-1H-benzo[d]imidazole-6-carbonitrile (42); 1-Cyclopropyl-2-(1H-imidazo[4,5-c]pyridin-1-yl)-1H-benzo[d]imidazole-6-carbonitrile (43); 1'-Cyclopropyl-5',6'-difluoro-1'H-[1,2'-bibenzo[d]imidazole]-5-carboxylic acid (Ex. 44); N-(1'-cyclopropyl-5',6'-difluoro-1'H-[1,2'-bibenzo[d]imidazol]-6-yl)methanesulfonamide (45); N-(1'-cyclopropyl-5',6'-difluoro-1'H-[1,2'-bibenzo[d]imidazol]-5-yl)methanesulfonamide (46); N-(6'-cyano-1'-cyclopropyl-1'H-[1,2'-bibenzo[d]imidazol]-5-yl)methanesulfonamide (47); N-(6'-cyano-1'-cyclopropyl-1'H-[1,2'-bibenzo[d]imidazol]-6-yl)methanesulfonamide (48); 1'-Cyclopropyl-5-(difluoromethoxy)-1'H-[1,2'-bibenzo[d]imidazole]-6'-carbonitrile (49); 1'-Cyclopropyl-6-(difluoromethoxy)-1'H-[1,2'-bibenzo[d]imidazole]-6'-carbonitrile (50); 1'-Cyclopropyl-5',6'-difluoro-1'H-[1,2'-bibenzo[d]imidazole]-6-carboxylic acid (51); 1'-Cyclopropyl-5-(difluoromethoxy)-5',6'-difluoro-1'H-1,2'-bibenzo[d]imidazole (52); 1'-Cyclopropyl-6-(difluoromethoxy)-5',6'-difluoro-1'H-1,2'-bibenzo[d]imidazole (53); or a pharma- ceutically acceptable salt thereof.

42. 42. A method of inhibiting metalloenzyme activity comprising contacting a compound according to any one of claims 1 to 41 with a metalloenzyme.

43. 43. The method of claim 42, wherein said contacting is in vivo.

44. 43. The method of claim 42, wherein said contacting is in vitro.

45. 43. The method of claim 42, wherein the metalloenzyme comprises a metal atom that is iron, zinc, heme iron, manganese, magnesium, iron-sulfur cluster, nickel, molybdenum, or copper.

46. 43. The method of claim 42, wherein the metalloenzyme is a member of an enzyme class selected from the cytochrome P450 family, cyclooxygenases, and nitric oxide synthases.

47. 43. The method of claim 42, wherein the metalloenzyme is aldosterone synthase (CYP11B2).

48. The metalloenzymes include aromatase (CYP19), members of the cyclooxygenase family, lanosterol demethylase (CYP51), members of the nitric oxide synthase family, thromboxane synthase (CYP5a), iodide peroxidase, 17-alpha hydroxylase / 17,20-lyase (CYP17), cytochrome P450 2A6 (CYP2A6), heme oxygenase, indoleamine 2,3-dioxygenase, retinoic acid hydroxylase (CYP26), vitamin D hydroxylase (CYP24), sterol 27-hydroxylase (CYP27), cytochrome P450 3A5 (CYP3A5), cholesterol 24-hydroxylase (CYP46), cytochrome P450 43. The method of claim 42, wherein said enzymes are 4F2 (CYP4F2), myeloperoxidase, and 11-β-hydroxylase (CYP11B1).

49. 43. The method of claim 42, further comprising administering the compound to a human subject.

50. 13. A method of modulating metalloenzyme activity in a subject, comprising contacting the subject with a compound of claim 1 in an amount and under conditions sufficient to modulate metalloenzyme activity.

51. A method of treating a subject suffering from or susceptible to a disorder or disease and determined to be in need of treatment for said disorder or disease, comprising administering to said subject in need thereof an effective amount of a compound of claim 1.

52. 13. A method of treating a subject suffering from or susceptible to a metalloenzyme-associated disorder or disease, comprising administering to the subject an effective amount of a compound of claim 1.

53. A method of treating a subject suffering from or susceptible to a metalloenzyme-associated disorder or disease, and determined to be in need of treatment for the metalloenzyme-associated disorder or disease, comprising administering to the subject in need thereof an effective amount of a compound of claim 1 such that the disorder or disease in the subject is treated.

54. A method of treating a subject suffering from or susceptible to a metalloenzyme-mediated disorder or disease, and determined to be in need of treatment for the metalloenzyme-mediated disorder or disease, comprising administering to the subject in need thereof an effective amount of a compound of claim 1 such that metalloenzyme activity in the subject is modulated (e.g., downregulated, inhibited).

55. The disorder or disease may be mediated by any of the following: aromatase (CYP19), members of the cyclooxygenase family, lanosterol demethylase (CYP51), members of the nitric oxide synthase family, thromboxane synthase (CYP5a), iodide peroxidase, 17-alpha hydroxylase / 17,20-lyase (CYP17), cytochrome P450 2A6 (CYP2A6), heme oxygenase, indoleamine 2,3-dioxygenase, retinoic acid hydroxylase (CYP26), vitamin D hydroxylase (CYP24), sterol 27-hydroxylase (CYP27), cytochrome P450 3A5 (CYP3A5), cholesterol 24-hydroxylase (CYP46), cytochrome P450 55. The method of any one of claims 51 to 54, mediated by 4F2 (CYP4F2), myeloperoxidase, or 11-β-hydroxylase (CYP11B1).

56. 56. The method of any one of claims 51 to 55, wherein the disorder or disease is cancer, a cardiovascular disease, an endocrine disease, an inflammatory disease, an infectious disease, a gynecological disease, a metabolic disease, an ophthalmological disease, a central nervous system (CNS) disease, a urological disease, or a gastrointestinal disease.

57. The disorders or diseases include hypertension, resistant hypertension, pathological conditions associated with primary or secondary aldosteronism and adrenal hyperplasia, pulmonary arterial hypertension, heart failure, diastolic dysfunction, left ventricular diastolic dysfunction, diastolic heart failure, systolic dysfunction, systolic heart failure, hypokalemia, renal failure, chronic renal failure, restenosis, nephropathy, post-myocardial infarction, coronary artery disease, fibrosis, diseases characterized by increased collagen formation, fibrosis and matrix remodeling after hypertension, fibrosis and matrix remodeling after endothelial cell dysfunction, cardiovascular diseases such as atherosclerosis, atrial fibrillation, renal insufficiency, liver disease, non-small cell lung disease, osteoporosis ... The method according to any one of claims 51 to 56, wherein the condition is alcoholic steatohepatitis, vascular disease, retinopathy, neuropathy, insulin abnormalities, endothelial cell dysfunction, myocardial fibrosis, vascular fibrosis, myocardial necrotic lesions, vasculitis, myocardial infarction, left ventricular hypertrophy, vascular wall hypertrophy, intimal thickening, arterial fibrinoid necrosis, kidney disease, diabetic nephropathy, glomerulosclerosis, glomerulonephritis, nephritic syndrome, polycystic kidney disease, diabetes, metabolic syndrome, insulin resistance, sleep apnea, obstructive sleep apnea, muscular dystrophy, liver cirrhosis, non-alcoholic fatty liver disease, kidney disorder, diabetic nephropathy, or stroke.

58. 42. A pharmaceutical composition comprising a compound according to any one of claims 1 to 41 and a pharma- ceutically acceptable carrier.

59. 59. The pharmaceutical composition of claim 58, further comprising an additional therapeutic agent.

60. 59. The pharmaceutical composition of claim 58, further comprising an additional therapeutic agent that is an anti-cancer agent, an anti-fungal agent, a cardiovascular agent, an anti-inflammatory agent, a chemotherapeutic agent, an anti-angiogenic agent, a cytotoxic agent, an anti-proliferative agent, an agent for treating a metabolic disease, an agent for treating an ophthalmic disease, an agent for treating a central nervous system (CNS) disease, an agent for treating a urological disease, or an agent for treating a gastrointestinal disease.

61. 52. The method of claim 51, wherein the subject is a non-human animal.

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