Metalloenzyme Inhibitor Compounds

Abstract

Provided are compounds that have activity modulating metalloenzymes, as well as methods for treating diseases, disorders, or symptoms thereof mediated by such metalloenzymes. [Solution] There is provided a compound represented by the following general formula I, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof: JPEG2023071692000207.jpg33170 Specific examples include 1-cyclopropyl-6-fluoro-2-(pyridazin-4-yl)-1H-benzo[d]imidazole and 5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-carbonitrile.

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 / 440,181, filed December 29, 2016, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] Aldosterone is a steroid hormone secreted by the adrenal gland that binds to and activates mineralocorticoid receptors (MRs). In primary cells of the distal convoluted tubule and collecting duct, activation of renal MRs leads to sodium and water retention through potassium excretion, resulting in plasma volume expansion and elevated blood pressure (BP). Excess aldosterone measured in the circulation is called primary aldosteronism (PA) and occurs when aldosterone production is dysregulated by the renin-angiotensin-aldosterone system (RAAS). PA was first identified in patients with adrenal adenomas, and recent evidence suggests that its prevalence increases in association with obesity. PA is a common cause of secondary hypertension, with a prevalence ranging from 14 to 21% in patients with resistant hypertension (RHTN), a condition defined as BP remaining above target despite the concurrent use of three antihypertensive drugs from different classes, including a diuretic. Recent studies have demonstrated a link between excess aldosterone, RHTN, and obstructive sleep apnea (OSA), which is exacerbated by aldosterone-mediated fluid retention.

[0003] Local overproduction of aldosterone has been noted in several severe disease states, even when significant plasma increases are not observed. In patients with chronic congestive heart failure (CHF), aldosterone levels 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 postulated to contribute to disease progression. In both of these conditions, local elevated aldosterone levels contribute to deleterious effects, including inflammation, generation of reactive oxygen species leading to stimulation of cell growth and proliferation, and endothelial dysfunction, via both MR-dependent and MR-independent mechanisms, and upregulate collagen deposition, leading to fibrosis.

[0004] MR antagonists, including spironolactone and eplerenone, are widely used to block the effects of aldosterone binding to the MR. Significant reductions in morbidity and mortality in patients with heart failure or myocardial infarction have been demonstrated with these agents in combination with angiotensin-converting enzyme (ACE) inhibitors and diuretics (RALES & EPHESUS trials). Side effects, including hyperkalemia, are seen with both agents, and nonselective spironolactone can also lead to gynecomastia due to nonselective modulation of progesterone and androgen receptors. Furthermore, because elevations in renin and aldosterone result from MR antagonism, the MR-independent (nongenomic) effects of aldosterone are amplified.

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

[0006] The highly homologous metalloenzyme CYP11B1 (11-β-steroid hydroxylase) catalyzes the formation of the primary glucocorticoid, cortisol, from 11-deoxycortisol. Given the high degree of homology between CYP11B2 and CYP11B1 (93%), the development of selective CYP11B2 inhibitors is a significant challenge. The inhibitor osilodrostat (LCI-699) was developed as a CYP11B2 inhibitor for treating hypertension but was discontinued due to its potent inhibition of CYP11B1. Described herein are selective compounds that block aldosterone production via CYP11B2 without inhibiting cortisol production via CYP11B1.

[0007] Organisms have developed tightly regulated processes for the specific import of metals and their delivery to intracellular storage sites and ultimately to sites of use. One of the most useful functions of metals, such as zinc and iron, in biological systems is to enable the activity of metalloenzymes. Metalloenzymes are enzymes that incorporate metal ions into the enzyme active site and utilize the metal as part of a catalytic process. More than one-third of all characterized enzymes are metalloenzymes.

[0008] The function of metalloenzymes is highly dependent on the presence of metal ions in the enzyme's active site. It is well established that agents that bind to and inactivate active-site metal ions dramatically reduce enzyme activity. Nature employs this same strategy to reduce the activity of certain metalloenzymes during periods when enzyme activity is undesirable. For example, the protein TIMP (tissue inhibitor of metalloproteases) binds to zinc ions in the active sites of various matrix metalloprotease enzymes, thereby halting enzyme activity. The pharmaceutical industry employs this same strategy in the design of therapeutic agents. For example, the azole antifungal agents fluconazole and voriconazole contain a 1-(1,2,4-triazole) group that binds to the heme iron present in the active site of the target enzyme lanosterol demethylase, thereby inactivating the enzyme. Another example involves the zinc-binding hydroxamic acid group incorporated into most published inhibitors of matrix metalloproteases and histone deacetylases. Another example is the zinc-binding carboxylic acid group incorporated into most published angiotensin-converting enzyme inhibitors.

[0009] In designing clinically safe and effective metalloenzyme inhibitors, it is desirable to use metal-binding groups appropriate for any particular target and clinical indication. If weakly binding metal-binding groups are utilized, efficacy may be suboptimal. On the other hand, if very tightly binding metal-binding groups are utilized, selectivity of the target enzyme relative to related metalloenzymes may be suboptimal. Lack of ideal selectivity can lead to clinical toxicity due to unintended inhibition of these off-target metalloenzymes. One example of such clinical toxicity is the unintended inhibition of human drug-metabolizing enzymes, such as CYP2C9, CYP2C19, and CYP3A4, by currently available azole antifungal agents, such as fluconazole and voriconazole. This off-target inhibition is believed to be primarily caused by indiscriminate binding of currently available 1-(1,2,4-triazoles) to iron at the active sites of CYP2C9, CYP2C19, and CYP3A4. Another example of this is the joint pain observed in many clinical trials of matrix metalloproteinase inhibitors. This toxicity is thought to be related to inhibition of off-target metalloenzymes, due to indiscriminate binding of the hydroxamic acid group to zinc in the off-target active site. [Prior art documents] [Patent documents]

[0010] [Patent Document 1] U.S. Patent No. 6,261,547 [Patent Document 2] U.S. Patent No. 6,197,934 [Patent Document 3] U.S. Patent No. 6,056,950 [Patent Document 4] U.S. Patent No. 5,800,807 [Patent Document 5] U.S. Patent No. 5,776,445 [Patent Document 6] U.S. Patent No. 5,698,219 [Patent Document 7] U.S. Patent No. 5,521,222 [Patent Document 8] U.S. Patent No. 5,403,841 [Patent Document 9] U.S. Patent No. 5,077,033 [Patent Document 10] U.S. Patent No. 4,882,150 [Patent Document 11] U.S. Patent No. 4,738,851 [Patent Document 12] U.S. Patent No. 5,407,713 [Patent Document 13] U.S. Patent No. 5,352,456 [Patent Document 14] U.S. Patent No. 5,332,213 [Patent Document 15] U.S. Patent No. 5,336,168 [Patent Document 16] U.S. Patent No. 5,290,561 [Patent Document 17] U.S. Patent No. 5,254,346 [Patent Document 18] U.S. Patent No. 5,164,189 [Patent Document 19] U.S. Patent No. 5,163,899 [Patent Document 20] U.S. Patent No. 5,088,977 [Patent Document 21] U.S. Patent No. 5,087,240 [Patent Document 22] U.S. Patent No. 5,008,110 [Patent Document 23] U.S. Patent No. 4,921,475 [Non-patent literature]

[0011] [Non-Patent Document 1] Lippard and Berg, "Principles of Bioinorganic Chemistry," University Science Books (1994) [Non-patent document 2] Basolo and Pearson, "Mechanisms of Inorganic Reactions," John Wiley & Sons Inc., 2nd ed. (September 1967) [Non-patent document 3] Ivano Bertini, Harry Gray, Ed Stiefel, Joan Valentine, "Biological Inorganic Chemistry," University Science Books (2007); Xue et al., "Nature Chemical Biology," Vol. 4, No. 2, pp. 107-109 (2008) [Non-patent document 4] Berge et al. (1977) "Pharmaceutical Salts," J. Pharm. Sci. 66:1-19 [Non-Patent Document 5] Design and Optimization in Organic Synthesis, 2nd Edition, Carlson R, ed., 2005, Elsevier Science Ltd. [Non-patent document 6] Jahnisch, K. et al., Angew. Chem. Int. Ed. Engl. 2004, 43:406 [Non-Patent Document 7] "General Principles" from Goodman and Gilman's "The Pharmaceutical Basis of Therapeutics" by Fingl & Woodbury, Chapter 1, pp. 1-46, latest edition, Pagamon Press Summary of the Invention [Problem to be solved by the invention]

[0012] Therefore, the search for metal binding groups that can achieve a better balance of potency and selectivity remains an important goal and may be crucial in realizing therapeutic agents and methods that address currently unmet needs in the treatment and prevention of diseases, disorders, and their symptoms.

[0013] The present invention is directed to compounds (e.g., any of those depicted herein, any of the formulas depicted herein), methods of modulating the activity of metalloenzymes, and methods of treating diseases, disorders, or symptoms thereof. The methods may involve the compounds described herein.

[0014] With respect to the selection of preferred variables, it is understood that the embodiments of the invention discussed below may be used alone or in combination with one or more embodiments of the invention or selection of preferred variables, each combination being expressly recited herein.

[0015] In one embodiment, Formula I

[0016] [ka]

[0017] (In the formula, A is N or CR 5 and W is N or CR 6 and X is N or CR 6 and Y is N or CR 6 and Z is N or CR 6 and However, under the condition that no more than two of W, X, Y, and Z are N, R 1 is hydrogen, halogen, cyano, acyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, NR a R b , NHSO2R c , CH2NR a R b , CH2NHSO2R d , CO2R e , C.O.R.f , S(O)R d , S(O)2R d , CH2OR f or CR e R f OH and any R 1 is 1 to 3 independent substituents R 7 and optionally substituted R 2 is hydrogen, halogen, cyano, alkyl or haloalkyl; or R 1 and R 2 together with the atoms to which they are attached form an aryl, heterocycloalkyl, or cycloalkyl ring; R 3 is hydrogen, halogen, cyano, acyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, NR a R b , NHSO2R c , CH2NR a R b , CH2NHSO2R d , CO2R e , C.O.R. f , CH2OR f or CR e R f OH, R 4 is alkyl, cycloalkyl, haloalkyl, or heteroalkyl; R 5 is hydrogen, alkyl, haloalkyl, heteroalkyl, or cycloalkyl; R 6 is independently at each occurrence hydrogen, halogen, cyano, haloalkyl, alkyl, cycloalkyl, alkoxy, haloalkyl, or carboxyl; R 7Each occurrence of is independently selected from halogen, alkyl, alkoxy, haloalkyl, carboxyl, aryl, aryl substituted with 1 to 3 independent halogens, -(CH2)nC(O)NR g R h , -S(O)2R i , -CO2R j or NR g R h and each n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; R a , R b , R c , R d , R e and R f each occurrence independently represents hydrogen, acyl, alkoxyalkyl, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C(O)OC 1~6 Alkyl, C(O)C 1~6 alkyl, 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, R g , R h , R i and R j each occurrence independently represents hydrogen, acyl, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C(O)OC 1~6 Alkyl, C(O)C 1~6 alkyl, or R g and R htogether with the atom to which they are attached form a heterocycloalkyl ring), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0018] In one embodiment, R 1 is aryl, heteroaryl, or heterocycloalkyl, and any R 1 is 1 to 3 independent substituents R 7 and may be optionally substituted.

[0019] In one embodiment, R 1 is aryl, heteroaryl, or heterocycloalkyl, and any R 1 is 1 to 3 independent substituents R 7 and each R may be optionally substituted. 7 are independently halogen, alkyl, alkoxy, haloalkyl, carboxyl, -(CH2)nC(O)NR g R h , -S(O)2R i , -CO2R j or NR g R h and each R g and R h are independently hydrogen, alkyl, C(O)C 1~6 alkyl, or R g and R h together with the atoms to which they are attached form a heterocycloalkyl ring.

[0020] In one embodiment, R 1 is hydrogen, halogen, cyano, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, NR a R b , NHSO2R c , CH2NR a R b , CH2NHSO2R d , C.O.R. f or CRe R f OH or R 1 and R 2 together with the atoms to which they are attached form an aryl ring.

[0021] In one embodiment, R 1 is hydrogen, halogen, alkyl, alkenyl, haloalkyl, alkoxy, haloalkoxy, cycloalkoxy, aryl, NR a R b , CH2NHSO2R d or CR e R f OH or R 1 and R 2 together with the atoms to which they are attached form an aryl ring.

[0022] In one embodiment, R 1 is hydrogen, halogen, alkyl, haloalkyl, CH2NHSO2R d or NR a R b and R a , R b and R d is independently hydrogen, alkyl, or haloalkyl.

[0023] In one embodiment, R 1 is alkyl or haloalkyl.

[0024] In one embodiment, R 1 is C 1~6 Alkyl or C 1~6 It is haloalkyl.

[0025] In one embodiment, R 1 is haloalkyl.

[0026] In one embodiment, R 1 is C 1~6 It is haloalkyl.

[0027] In one embodiment, R 1is fluoroalkyl. In certain embodiments, R 1 is C 1~6 In one embodiment, R 1 is C 1~3 In one embodiment, R 1 is difluoromethyl or trifluoromethyl. 1 is difluoromethyl. In one embodiment, R 1 is trifluoromethyl.

[0028] In one embodiment, R 2 is hydrogen or alkyl.

[0029] In one embodiment, R 2 is hydrogen or C 1~6 It is alkyl.

[0030] In one embodiment, R 2 is hydrogen or C 1~3 It is alkyl.

[0031] In one embodiment, R 2 is alkyl. In one embodiment, R 2 is C 1~6 In one embodiment, R 2 is C 1~3 In one embodiment, R 2 is hydrogen.

[0032] In one embodiment, R 1 is hydrogen and R 2 is alkyl. In one embodiment, R 1 is hydrogen and R 2 is C 1~6 In one embodiment, R 1 is hydrogen and R 2 is C 1~3 It is alkyl.

[0033] In one embodiment, R 4 is alkyl or cycloalkyl.

[0034] In one embodiment, R 4 is C 1~4 Alkyl or C 3~5 It is cycloalkyl.

[0035] In one embodiment, R 4 is C 1~4 In one embodiment, R 4 is C 3~5 In one embodiment, R 4 is cyclopentyl. In one embodiment, R 4 is cyclobutyl. In one embodiment, R 4 is cyclopropyl.

[0036] In some embodiments, each R 6 are independently hydrogen, halogen, cyano, alkoxy, haloalkyl, or carboxyl.

[0037] In some embodiments, each R 6 are independently hydrogen, halogen, or cyano.

[0038] In some embodiments, each R 6 are independently hydrogen, chloro, fluoro or cyano.

[0039] In some embodiments, each R 6 are independently hydrogen, fluoro or cyano.

[0040] In some embodiments, each R 6 are independently hydrogen or halogen.

[0041] In some embodiments, each R 6 are independently hydrogen, chloro or fluoro.

[0042] In some embodiments, each R 6 is independently hydrogen or fluoro.

[0043] In some embodiments, each R 6 are independently hydrogen or cyano.

[0044] In some embodiments, each R 6 is halogen. In one embodiment, each R 6 is chloro or fluoro. In certain embodiments, each R 6 is fluoro. In certain embodiments, each R 6 is cyano.

[0045] In one embodiment, A is CR 5 and R 5 is hydrogen, C 1~4 Alkyl or C 3~5 It is cycloalkyl.

[0046] In certain embodiments, A is N.

[0047] In some embodiments, not more than one of W, X, Y, and Z is N.

[0048] In one embodiment, W, X, Y, and Z are each CR 6 is.

[0049] In certain embodiments, Z is N.

[0050] In certain embodiments, the compound of formula I has formula Ia

[0051] [ka]

[0052] (In the formula, R 1 , R 2 , R 4 , R 6 , A, X, and Z are as defined herein), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0053] In certain embodiments, the compound of formula I has formula Ib

[0054] [ka]

[0055] (In the formula, R 1 , R 2 , R 4 , W, X, Y and Z are as defined herein), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug thereof.

[0056] In certain embodiments, the compound of formula I has formula Ic

[0057] [ka]

[0058] (In the formula, R 1 , R 2 , R 4 , R 6 and Z are as defined herein), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0059] In certain embodiments, the compound of formula I has the formula Id

[0060] [ka]

[0061] (In the formula, R 1 , R 2 , R 4 , R 6and Z are as defined herein), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0062] In certain embodiments, the compound of formula I has the formula Ie

[0063] [ka]

[0064] (In the formula, R 1 , R 4 , R 6 and Z are as defined herein), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0065] In certain embodiments, the compound of formula I has the formula If

[0066] [ka]

[0067] (In the formula, R 1 , R 4 and R 6 is as defined herein), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0068] In certain embodiments, the aforementioned compound of formula If is R 4 is alkyl or cycloalkyl, and R 6 is hydrogen or halo, and at least one R 6 is a halo compound.

[0069] In certain embodiments, the aforementioned compound of formula If is R 4is alkyl or cycloalkyl, and R 6 is a halo compound.

[0070] In certain embodiments, the aforementioned compound of formula If is R 4 is alkyl or cycloalkyl, and R 6 is hydrogen or halo, and at least one R 6 is the halo, and R 1 is hydrogen, halogen, cyano, acyl, alkyl, haloalkyl, alkoxy, haloalkoxy, NR a R b , NHSO2R c , CH2NR a R b , CH2NHSO2R d , CO2R e , C.O.R. f , CH2OR f or CR e R f It is a compound in which OH.

[0071] In certain embodiments, the aforementioned compound of formula If is R 4 is alkyl or cycloalkyl, and R 6 is hydrogen or halo, and at least one R 6 is the halo, and R 1 is an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, or an optionally substituted heterocycloalkyl.

[0072] In certain embodiments, the aforementioned compound of formula If is R 1 is alkyl or haloalkyl, and R 4 is alkyl or cycloalkyl, and R 6 is hydrogen or halo, and at least one R 6 is a halo compound.

[0073] In certain embodiments, the aforementioned compound of formula If is R 1 is alkyl or haloalkyl, and R4 is alkyl or cycloalkyl, and R 6 is a halo compound.

[0074] In certain embodiments, the compound of formula I has the formula Ig

[0075] [ka]

[0076] (In the formula, R 1 , R 4 and R 6 is as defined herein), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0077] In certain embodiments, the aforementioned compounds of formula Ig are 4 is alkyl or cycloalkyl, and R 6 is hydrogen or halo, and at least one R 6 is a halo compound.

[0078] In certain embodiments, the aforementioned compounds of formula Ig are 4 is alkyl or cycloalkyl, and R 6 is a halo compound.

[0079] In certain embodiments, the aforementioned compounds of formula Ig are 4 is alkyl or cycloalkyl, and R 6 is hydrogen or halo, and at least one R 6 is the halo, and R 1 is hydrogen, halogen, cyano, acyl, alkyl, haloalkyl, alkoxy, haloalkoxy, NR a R b , NHSO2R c , CH2NR a R b , CH2NHSO2R d , CO2R e , C.O.R.f , CH2OR f or CR e R f It is a compound in which OH.

[0080] In certain embodiments, the aforementioned compounds of formula Ig are 4 is alkyl or cycloalkyl, and R 6 is hydrogen or halo, and at least one R 6 is the halo, and R 1 is an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, or an optionally substituted heterocycloalkyl.

[0081] In another embodiment, Formula I

[0082] [ka]

[0083] (In the formula, A is N or CR 5 and W is N or CR 6 and X is N or CR 6 and Y is N or CR 6 and Z is N or CR 6 and However, under the condition that no more than two of W, X, Y, and Z are N, R 1 is hydrogen, halogen, cyano, acyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, NR a R b , NHSO2R c , CH2NR a R b , C.R.e R f NHSO2R d , OR f , S.R. f , CO2R e , C.O.R. f , S(O)R d , S(O)2R d , CH2OR f or CR e R f OH and any R 1 is 1 to 3 independent substituents R 7 and optionally substituted R 2 is hydrogen, halogen, cyano, alkyl or haloalkyl; or R 1 and R 2 together with the atoms to which they are attached form an aryl, heterocycloalkyl, or cycloalkyl ring; R 3 is hydrogen, halogen, cyano, acyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, NR a R b , NHSO2R c , CH2NR a R b , CH2NHSO2R d , CO2R e , C.O.R. f , CH2OR f or CR e R f OH, R 4 is alkyl, cycloalkyl, haloalkyl, or heteroalkyl; R 5 is hydrogen, cyano, alkyl, haloalkyl, heteroalkyl, or cycloalkyl; R 6 Each occurrence of is independently selected from hydrogen, halogen, cyano, haloalkyl, alkyl, cycloalkyl, alkoxy, haloalkyl, ORf or carboxyl, R 7 Each occurrence of is independently selected from halogen, alkyl, alkoxy, haloalkyl, carboxyl, cycloalkyl, aryl, aryl substituted with 1 to 3 independent halogens, -(CH2)nC(O)NR g R h , -S(O)2R i , -CO2R j or NR g R h and each n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; R a , R b , R c , R d , R e and R f each occurrence independently represents hydrogen, acyl, alkoxyalkyl, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C(O)OC 1~6 Alkyl, C(O)C 1~6 alkyl, 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, R g , R h , R i and R j each occurrence independently represents hydrogen, acyl, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C(O)OC 1~6 Alkyl, C(O)C 1~6 alkyl, or R g and R htogether with the atom to which they are attached form a heterocycloalkyl ring), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0084] In one embodiment, R 1 is aryl, heteroaryl, or heterocycloalkyl, and any R 1 is 1 to 3 independent substituents R 7 and may be optionally substituted.

[0085] In one embodiment, R 1 is aryl, heteroaryl, or heterocycloalkyl, and any R 1 is 1 to 3 independent substituents R 7 and each R may be optionally substituted. 7 are independently halogen, alkyl, alkoxy, haloalkyl, carboxyl, -(CH2)nC(O)NR g R h , -S(O)2R i , -CO2R j or NR g R h and each R g and R h are independently hydrogen, alkyl, C(O)C 1~6 alkyl, or R g and R h together with the atoms to which they are attached form a heterocycloalkyl ring.

[0086] In one embodiment, R 1 is hydrogen, halogen, cyano, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, NR a R b , NHSO2R c , CH2NR a R b , C.R. e R f NHSO2R d, S.R. f , C.O.R. f or CR e R f OH or R 1 and R 2 together with the atoms to which they are attached form an aryl or cycloalkyl ring.

[0087] In one embodiment, R 1 is hydrogen, halogen, alkyl, alkenyl, haloalkyl, alkoxy, haloalkoxy, cycloalkoxy, aryl, NR a R b , C.R. e R f NHSO2R d , S.R. f or CR e R f OH or R 1 and R 2 together with the atoms to which they are attached form an aryl or cycloalkyl ring.

[0088] In one embodiment, R 1 is hydrogen, halogen, alkyl, haloalkyl, CR e R f NHSO2R d , S.R. f or NR a R b and R a , R b , R d , R e and R f is independently hydrogen, alkyl, or haloalkyl.

[0089] In one embodiment, R 1 is SR f In one embodiment, R 1 is SR f and R f is hydrogen, alkyl or haloalkyl.

[0090] In one embodiment, R 1 is alkyl or haloalkyl.

[0091] In one embodiment, R 1 is C 1~6 Alkyl or C 1~6 It is haloalkyl.

[0092] In one embodiment, R 1 is haloalkyl.

[0093] In one embodiment, R 1 is C 1~6 It is haloalkyl.

[0094] In one embodiment, R 1 is fluoroalkyl. In certain embodiments, R 1 is C 1~6 In one embodiment, R 1 is C 1~3 In one embodiment, R 1 is difluoromethyl or trifluoromethyl. 1 is difluoromethyl. In one embodiment, R 1 is trifluoromethyl.

[0095] In one embodiment, R 2 is hydrogen or alkyl.

[0096] In one embodiment, R 2 is hydrogen or C 1~6 It is alkyl.

[0097] In one embodiment, R 2 is hydrogen or C 1~3 It is alkyl.

[0098] In one embodiment, R 2 is alkyl. In one embodiment, R 2 is C 1~6 In one embodiment, R 2 is C 1~3 In one embodiment, R2 is hydrogen.

[0099] In one embodiment, R 1 is hydrogen and R 2 is alkyl. In one embodiment, R 1 is hydrogen and R 2 is C 1~6 In one embodiment, R 1 is hydrogen and R 2 is C 1~3 It is alkyl.

[0100] In one embodiment, R 1 and R 2 together with the atoms to which they are attached form an aryl or cycloalkyl ring. 1 and R 2 together with the atoms to which they are attached form an aryl ring. 1 and R 2 together with the atoms to which they are attached form a cycloalkyl ring.

[0101] In one embodiment, R 4 is alkyl or cycloalkyl.

[0102] In one embodiment, R 4 is C 1~4 Alkyl or C 3~5 It is cycloalkyl.

[0103] In one embodiment, R 4 is C 1~4 In one embodiment, R 4 is C 3~5 In one embodiment, R 4 is cyclopentyl. In one embodiment, R 4 is cyclobutyl. In one embodiment, R 4 is cyclopropyl.

[0104] In some embodiments, each R6 are independently hydrogen, halogen, cyano, alkoxy, haloalkyl, or carboxyl.

[0105] In some embodiments, each R 6 are independently hydrogen, halogen, or cyano.

[0106] In some embodiments, each R 6 are independently hydrogen, chloro, fluoro or cyano.

[0107] In some embodiments, each R 6 are independently hydrogen, fluoro or cyano.

[0108] In some embodiments, each R 6 are independently hydrogen or halogen.

[0109] In some embodiments, each R 6 are independently hydrogen, chloro or fluoro.

[0110] In some embodiments, each R 6 is independently hydrogen or fluoro.

[0111] In some embodiments, each R 6 are independently hydrogen or cyano.

[0112] In some embodiments, each R 6 is halogen. In one embodiment, each R 6 is chloro or fluoro. In certain embodiments, each R 6 is fluoro. In certain embodiments, each R 6 is cyano.

[0113] In one embodiment, A is CR 5 and R 5 is hydrogen, cyano, C 1~4 Alkyl or C 3~5 It is cycloalkyl.

[0114] In certain embodiments, A is N.

[0115] In some embodiments, not more than one of W, X, Y, and Z is N.

[0116] In one embodiment, W, X, Y, and Z are each independently CR 6 is.

[0117] In certain embodiments, Z is N.

[0118] In certain embodiments, the compound of formula I has formula Ia

[0119] [ka]

[0120] (In the formula, R 1 , R 2 , R 4 , R 6 , A, X and Z are each independently as defined herein), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug thereof.

[0121] In certain embodiments, the compound of formula I has formula Ib

[0122] [ka]

[0123] (In the formula, R 1 , R 2 , R 4 , W, X, Y and Z are each independently as defined herein), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug thereof.

[0124] In certain embodiments, the compound of formula I has formula Ic

[0125] [ka]

[0126] (In the formula, R 1 , R 2 , R 4 , R 6 and Z are each independently as defined herein), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0127] In certain embodiments, the compound of formula I has the formula Id

[0128] [ka]

[0129] (In the formula, R 1 , R 2 , R 4 , R 6 and Z are each independently as defined herein), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0130] In certain embodiments, the compound of formula I has the formula Ie

[0131] [ka]

[0132] (In the formula, R 1 , R 4 , R 6and Z are each independently as defined herein), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0133] In certain embodiments, the compound of formula I has the formula If [ka]

[0134] (In the formula, R 1 , R 4 and R 6 and each independently are defined herein), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0135] In certain embodiments, the aforementioned compound of formula If is R 4 is alkyl or cycloalkyl, and each R 6 are independently hydrogen or halo, and at least one R 6 is a halo compound.

[0136] In certain embodiments, the aforementioned compound of formula If is R 4 is alkyl or cycloalkyl, and each R 6 are independently halo.

[0137] In certain embodiments, the aforementioned compound of formula If is R 4 is alkyl or cycloalkyl, and each R 6 are independently hydrogen, halo, or cyano.

[0138] In certain embodiments, the aforementioned compound of formula If is R 4 is C 1~4 Alkyl or C 3~5 cycloalkyl, and each R 6are independently hydrogen, halo, or cyano.

[0139] In certain embodiments, the aforementioned compound of formula If is R 4 is cycloalkyl, and each R 6 are independently hydrogen, halo, or cyano.

[0140] In certain embodiments, the aforementioned compound of formula If is R 4 But C 3~5 cycloalkyl, and each R 6 are independently hydrogen, halo, or cyano.

[0141] In certain embodiments, the aforementioned compound of formula If is R 4 is cycloalkyl, and each R 6 are independently halo.

[0142] In certain embodiments, the aforementioned compound of formula If is R 4 But C 3~5 cycloalkyl, and each R 6 are independently halo.

[0143] In certain embodiments, the aforementioned compound of formula If is R 4 is alkyl or cycloalkyl, and each R 6 are independently hydrogen, cyano, or halo, and R 1 is hydrogen, halogen, cyano, acyl, alkyl, haloalkyl, alkoxy, haloalkoxy, NR a R b , NHSO2R c , CH2NR a R b , CH2NHSO2R d , CO2R e , C.O.R. f , CH2OR f or CR e R f It is a compound in which OH.

[0144] In certain embodiments, the aforementioned compound of formula If is R 4 is alkyl or cycloalkyl, and each R 6 are independently hydrogen or halo, and at least one R 6 is the halo, and R 1 is hydrogen, halogen, cyano, acyl, alkyl, haloalkyl, alkoxy, haloalkoxy, NR a R b , NHSO2R c , CH2NR a R b , CH2NHSO2R d , CO2R e , C.O.R. f , CH2OR f or CR e R f It is a compound in which OH.

[0145] In certain embodiments, the aforementioned compound of formula If is R 4 is alkyl or cycloalkyl, and each R 6 are independently hydrogen or halo, and at least one R 6 is the halo, and R 1 is an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, or an optionally substituted heterocycloalkyl.

[0146] In certain embodiments, the aforementioned compound of formula If is R 1 is alkyl or haloalkyl, and R 4 is alkyl or cycloalkyl, and each R 6 are independently hydrogen or halo, and at least one R 6 is a halo compound.

[0147] In certain embodiments, the aforementioned compound of formula If is R 1 is alkyl or haloalkyl, and R 4 is alkyl or cycloalkyl, and each R 6 are independently halo.

[0148] In certain embodiments, the aforementioned compound of formula If is R 1 is alkyl or haloalkyl, and R 4 is alkyl or cycloalkyl, and each R 6 are independently hydrogen, halo, or cyano.

[0149] In certain embodiments, the aforementioned compound of formula If is R 1 is haloalkyl, and R 4 is alkyl or cycloalkyl, and each R 6 are independently hydrogen, halo, or cyano.

[0150] In certain embodiments, the aforementioned compound of formula If is R 1 is haloalkyl, and R 4 But C 1~4 Alkyl or C 3~5 cycloalkyl, and each R 6 are independently hydrogen, halo, or cyano.

[0151] In certain embodiments, the aforementioned compound of formula If is R 1 is haloalkyl, and R 4 is cycloalkyl, and each R 6 are independently hydrogen, halo, or cyano.

[0152] In certain embodiments, the aforementioned compound of formula If is R 1 is haloalkyl, and R 4 But C 3~5 cycloalkyl, and each R 6 are independently hydrogen, halo, or cyano.

[0153] In certain embodiments, the aforementioned compound of formula If is R 1 is haloalkyl, and R 4 is cycloalkyl, and each R 6 are independently halo.

[0154] In certain embodiments, the aforementioned compound of formula If is R 1 is haloalkyl, and R 4 But C 3~5 cycloalkyl, and each R 6 are independently halo.

[0155] In certain embodiments, the compound of formula I has the formula Ig

[0156] [ka]

[0157] (In the formula, R 1 , R 4 and R 6 are each independently as defined herein), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0158] In certain embodiments, the aforementioned compounds of formula Ig are 4 is alkyl or cycloalkyl, and each R 6 are independently hydrogen or halo, and at least one R 6 is a halo compound.

[0159] In certain embodiments, the aforementioned compounds of formula Ig are 4 is alkyl or cycloalkyl, and each R 6 are independently halo.

[0160] In certain embodiments, the aforementioned compound of formula If is R 4 is alkyl or cycloalkyl, and each R 6 are independently hydrogen, halo, or cyano.

[0161] In certain embodiments, the aforementioned compound of formula If is R 4 But C 1~4 Alkyl or C3~5 cycloalkyl, and each R 6 are independently hydrogen, halo, or cyano.

[0162] In certain embodiments, the aforementioned compound of formula If is R 4 is cycloalkyl, and each R 6 are independently hydrogen, halo, or cyano.

[0163] In certain embodiments, the aforementioned compound of formula If is R 4 But C 3~5 cycloalkyl, and each R 6 are independently hydrogen, halo, or cyano.

[0164] In certain embodiments, the aforementioned compound of formula If is R 4 is cycloalkyl, and each R 6 are independently hydrogen or cyano.

[0165] In certain embodiments, the aforementioned compound of formula If is R 4 But C 3~5 cycloalkyl, and each R 6 are independently hydrogen or cyano.

[0166] In certain embodiments, the aforementioned compound of formula If is R 4 is cycloalkyl, and each R 6 are independently halo.

[0167] In certain embodiments, the aforementioned compound of formula If is R 4 But C 3~5 cycloalkyl, and each R 6 are independently halo.

[0168] In certain embodiments, the aforementioned compound of formula If is R 4 is alkyl or cycloalkyl, and each R 6 are independently hydrogen, cyano, or halo, and R 1is hydrogen, halogen, cyano, acyl, alkyl, haloalkyl, alkoxy, haloalkoxy, NR a R b , NHSO2R c , CH2NR a R b , CH2NHSO2R d , CO2R e , C.O.R. f , CH2OR f or CR e R f It is a compound in which OH.

[0169] In certain embodiments, the aforementioned compounds of formula Ig are 4 is alkyl or cycloalkyl, and each R 6 are independently hydrogen or halo, and at least one R 6 is the halo, and R 1 is hydrogen, halogen, cyano, acyl, alkyl, haloalkyl, alkoxy, haloalkoxy, NR a R b , NHSO2R c , CH2NR a R b , CH2NHSO2R d , CO2R e , C.O.R. f , CH2OR f or CR e R f It is a compound in which OH.

[0170] In certain embodiments, the aforementioned compounds of formula Ig are 4 is alkyl or cycloalkyl, and each R 6 are independently hydrogen or halo, and at least one R 6 is the halo, and R 1 is an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, or an optionally substituted heterocycloalkyl.

[0171] In certain embodiments, the aforementioned compound of formula If is R 1is alkyl or haloalkyl, and R 4 is alkyl or cycloalkyl, and each R 6 are independently hydrogen, halo, or cyano.

[0172] In certain embodiments, the aforementioned compound of formula If is R 1 is alkyl or haloalkyl, and R 4 But C 1~4 Alkyl or C 3~5 cycloalkyl, and each R 6 are independently hydrogen, halo, or cyano.

[0173] In certain embodiments, the aforementioned compound of formula If is R 1 is haloalkyl, and R 4 is alkyl or cycloalkyl, and each R 6 are independently hydrogen, halo, or cyano.

[0174] In certain embodiments, the aforementioned compound of formula If is R 1 is haloalkyl, and R 4 But C 1~4 Alkyl or C 3~5 cycloalkyl, and each R 6 are independently hydrogen, halo, or cyano.

[0175] In certain embodiments, the aforementioned compound of formula If is R 1 is haloalkyl, and R 4 is cycloalkyl, and each R 6 are independently hydrogen, halo, or cyano.

[0176] In certain embodiments, the aforementioned compound of formula If is R 1 is haloalkyl, and R 4 But C 3~5 cycloalkyl, and each R 6 are independently hydrogen, halo, or cyano.

[0177] In certain embodiments, the aforementioned compound of formula If is R 1 is haloalkyl, and R 4 is cycloalkyl, and each R 6 are independently hydrogen or cyano.

[0178] In certain embodiments, the aforementioned compound of formula If is R 1 is haloalkyl, and R 4 But C 3~5 cycloalkyl, and each R 6 are independently hydrogen or cyano.

[0179] In certain embodiments, the aforementioned compound of formula If is R 1 is haloalkyl, and R 4 is cycloalkyl, and each R 6 are independently halo.

[0180] In certain embodiments, the aforementioned compound of formula If is R 1 is haloalkyl, and R 4 But C 3~5 cycloalkyl, and each R 6 are independently halo.

[0181] In one embodiment, the compound of formula I is 1-Cyclopropyl-6-fluoro-2-(pyridazin-4-yl)-1H-benzo[d]imidazole (1); 5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-carbonitrile (2); 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-6-fluoro-1H-benzo[d]imidazole (3); 1-Cyclopropyl-6-fluoro-2-(6-vinylpyridazin-4-yl)-1H-benzo[d]imidazole (4); Methyl 5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-carboxylate (5); 1-Cyclopropyl-2-(6-ethylpyridazin-4-yl)-6-fluoro-1H-benzo[d]imidazole (6); 1-(5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)-2,2,2-trifluoroethan-1-ol (7); N-((5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methyl)propionamide (8); Ethyl ((5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methyl)carbamate (9); 4-(5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)morpholine (10); 1-Cyclopropyl-6-fluoro-2-(6-(4-(4-fluorophenyl)piperazin-1-yl)pyridazin-4-yl)-1H-benzo[d]imidazole (11); 2-(5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)propan-2-ol (12); 5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)-N-(tetrahydro-2H-pyran-4-yl)pyridazin-3-amine (13); 4-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)cinnoline (14); 1-Cyclopropyl-6-fluoro-2-(6-methylpyridazin-4-yl)-1H-benzo[d]imidazole (15); N-(5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)ethanesulfonamide (16); 2-(6-chloropyridazin-4-yl)-1-ethyl-1H-benzo[d]imidazole-6-carbonitrile (17); 2-(4-(5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)piperazin-1-yl)-N-isopropylacetamide (18); 1-Cyclopropyl-5,6-difluoro-2-(6-methylpyridazin-4-yl)-1H-benzo[d]imidazole (19); 2-(4-(5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)piperazin-1-yl)-1-(pyrrolidin-1-yl)ethan-1-one (20); 5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-N-methylpyridazin-3-amine (21); 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole (22); 1-Cyclopropyl-5,6-difluoro-2-(6-methoxypyridazin-4-yl)-1H-benzo[d]imidazole (23); 1-Cyclopropyl-5,6-difluoro-2-(6-isopropoxypyridazin-4-yl)-1H-benzo[d]imidazole (24); 5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-N,N-dimethylpyridazin-3-amine (25); 1-Ethyl-6-fluoro-2-(6-methylpyridazin-4-yl)-1H-indole (26); 1-Cyclopropyl-5,6-difluoro-2-(6-(2,2,2-trifluoroethoxy)pyridazin-4-yl)-1H-benzo[d]imidazole (27); 5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-N-(2-methoxyethyl)pyridazin-3-amine (28); 1-Cyclopropyl-2-(6-methoxypyridazin-4-yl)-1H-benzo[d]imidazole-6-carbonitrile (29); 1-Cyclopropyl-6-fluoro-2-(6-methylpyridazin-4-yl)-1H-indole (30); N-((5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methyl)ethanesulfonamide (31); 5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-N-(2,2,2-trifluoroethyl)pyridazin-3-amine (32); 1-Cyclopropyl-2-(6-ethylpyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (33); 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-1H-benzo[d]imidazole-6-carbonitrile (34); 1-Cyclopropyl-2-(6-methylpyridazin-4-yl)-1H-benzo[d]imidazole-6-carbonitrile (35); 1-Cyclopropyl-5,6-difluoro-2-(6-(4-methylpiperazin-1-yl)pyridazin-4-yl)-1H-benzo[d]imidazole (36); 1-(4-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)piperazin-1-yl)ethan-1-one (37); 1-Cyclopropyl-5,6-difluoro-2-(6-(4-(methylsulfonyl)piperazin-1-yl)pyridazin-4-yl)-1H-benzo[d]imidazole (38); tert-Butyl 4-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)piperazine-1-carboxylate (39); 1-Ethyl-2-(6-methoxypyridazin-4-yl)-1H-benzo[d]imidazole-6-carbonitrile (40); 1-Ethyl-2-(6-ethylpyridazin-4-yl)-1H-benzo[d]imidazole-6-carbonitrile (41); 1-Cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (42); 2-(6-cyclobutoxypyridazin-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole (43); 1-Cyclopropyl-2-(6-(4,4-difluoropiperidin-1-yl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (44); 5-chloro-3-cyclopropyl-2-(6-methylpyridazin-4-yl)-3H-imidazo[4,5-b]pyridine (45); 1-Cyclopropyl-2-(6-(3,3-difluoropyrrolidin-1-yl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (46); 1-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)-2,2,2-trifluoroethan-1-ol (47); 1-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)-N,N-dimethylpyrrolidin-3-amine (48); 1-Cyclopropyl-5,6-difluoro-2-(6-(4-fluorophenyl)pyridazin-4-yl)-1H-benzo[d]imidazole (49); 1-Cyclopropyl-5,6-difluoro-2-(6-((4-fluorophenyl)ethynyl)pyridazin-4-yl)-1H-benzo[d]imidazole (50); 1-Cyclopropyl-5,6-difluoro-2-(6-isopropylpyridazin-4-yl)-1H-benzo[d]imidazole (51); N-((5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methyl)ethanesulfonamide (52); 1-Cyclopropyl-5,6-difluoro-2-(6-((1,1,1-trifluoropropan-2-yl)oxy)pyridazin-4-yl)-1H-benzo[d]imidazole (53); 3-Cyclopropyl-2-(6-methylpyridazin-4-yl)-3H-imidazo[4,5-b]pyridine-5-carbonitrile (54); 1-Cyclopropyl-5,6-difluoro-2-(pyridazin-4-yl)-1H-benzo[d]imidazole (55); 1-Cyclopropyl-5,6-difluoro-2-(pyridazin-4-yl)-4-(trifluoromethyl)-1H-benzo[d]imidazole (56); 1-Cyclopropyl-2-(6-(2,2-difluoropropoxy)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (57); 1-Cyclopropyl-5,6-difluoro-2-(5-isopropylpyridazin-4-yl)-1H-benzo[d]imidazole (58); 1-Cyclopropyl-2-(6-cyclopropylpyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (59); 2-(6-chloropyridazin-4-yl)-3-cyclopropyl-5-methoxy-3H-imidazo[4,5-b]pyridine (60); 1-Cyclopropyl-5,6-difluoro-2-(6-(4-fluoro-2-methylphenyl)pyridazin-4-yl)-1H-benzo[d]imidazole (61); 1-Cyclopropyl-2-(6-(2,4-difluorophenyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (62); 1-Cyclopropyl-2-(6-(3,4-difluorophenyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (63); 1-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)ethan-1-one (64); 2-(6-chloropyridazin-4-yl)-1-ethyl-5,6-difluoro-1H-benzo[d]imidazole (65); 1-Cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-1H-benzo[d]imidazole-6-carbonitrile (66); 2-(6-(difluoromethyl)pyridazin-4-yl)-1-ethyl-5,6-difluoro-1H-benzo[d]imidazole (67); 2-(6-chloropyridazin-4-yl)-1-ethyl-1H-benzo[d]imidazole-6-carbonitrile (68); 2-(6-(difluoromethyl)pyridazin-4-yl)-1-ethyl-1H-benzo[d]imidazole-6-carbonitrile (69); 1-Cyclopropyl-2-(6-(1,1-difluoroethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (70); 1-Cyclopropyl-5,6-difluoro-2-(6-(2,2,2-trifluoroethyl)pyridazin-4-yl)-1H-benzo[d]imidazole (71); 2-(6-cyclopropylpyridazin-4-yl)-1-ethyl-5,6-difluoro-1H-benzo[d]imidazole (72); 5-chloro-3-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-3H-imidazo[4,5-b]pyridine (73); 1-Cyclopropyl-5,6-difluoro-2-(5-methylpyridazin-4-yl)-1H-benzo[d]imidazole (74); 1-Cyclopropyl-2-(6-cyclopropylpyridazin-4-yl)-1H-benzo[d]imidazole-6-carbonitrile (75); 3-Cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-3H-imidazo[4,5-b]pyridine-5-carbonitrile (76); N-((5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methyl)methanesulfonamide (77); N-((5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methyl)-N-methylmethanesulfonamide (78); N-((5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methyl)propane-2-sulfonamide (79); 1-Cyclopropyl-5,6-difluoro-2-(6-(methylsulfonyl)pyridazin-4-yl)-1H-benzo[d]imidazole (80); 1-Cyclopropyl-2-(6-(ethylsulfonyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (81); 1-Cyclopropyl-5,6-difluoro-2-(6-(methylsulfinyl)pyridazin-4-yl)-1H-benzo[d]imidazole (82); 1-Cyclopropyl-2-(6-(ethylsulfinyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (83); 5-chloro-3-cyclopropyl-2-(6-cyclopropylpyridazin-4-yl)-3H-imidazo[4,5-b]pyridine (84); 1-Cyclopropyl-5,6-difluoro-2-(6-(trifluoromethyl)pyridazin-4-yl)-1H-benzo[d]imidazole (85); 1-Cyclopropyl-2-(6-(trifluoromethyl)pyridazin-4-yl)-1H-benzo[d]imidazole-6-carbonitrile (86); 3-Cyclopropyl-2-(6-cyclopropylpyridazin-4-yl)-3H-imidazo[4,5-b]pyridine-5-carbonitrile (87); 2-((5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methyl)isothiazolidine 1,1-dioxide (88); 3-Cyclopropyl-2-(6-(trifluoromethyl)pyridazin-4-yl)-3H-imidazo[4,5-b]pyridine-5-carbonitrile (89); 1-Cyclopropyl-2-(6-methylpyridazin-4-yl)-6-(trifluoromethyl)-1H-benzo[d]imidazole (90); N-(1-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)ethyl)methanesulfonamide (91); 1-Cyclopropyl-5,6-difluoro-2-(6-(fluoromethyl)pyridazin-4-yl)-1H-benzo[d]imidazole (92); 1-Cyclopropyl-2-(5,6-dimethylpyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (93); (5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methanol (94); 5-chloro-3-cyclopropyl-2-(6-(trifluoromethyl)pyridazin-4-yl)-3H-imidazo[4,5-b]pyridine (95); N-(1-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)ethyl)ethanesulfonamide (96); 2-(6-butylpyridazin-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole (97); 1-Cyclopropyl-6-methyl-2-(6-methylpyridazin-4-yl)-1H-benzo[d]imidazole (98); 1-Cyclopropyl-5,6-difluoro-2-(3-methylpyridazin-4-yl)-1H-benzo[d]imidazole (99); 1-Cyclopropyl-2-(3,6-dimethylpyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (100); 1-Cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-6,7-difluoro-1H-benzo[d]imidazole (101); 5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-thiol (102); 2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1-methyl-1H-benzo[d]imidazole (104); 2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1-propyl-1H-benzo[d]imidazole (105); 4-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-5,6,7,8-tetrahydrocinnoline (106); 1-Cyclopropyl-2-(6-methylpyridazin-4-yl)-1H-benzo[d]imidazole-5-carbonitrile (Example 107); 1-Cyclobutyl-5,6-difluoro-2-(6-methylpyridazin-4-yl)-1H-benzo[d]imidazole (108); 1-Cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-1H-benzo[d]imidazol-6-ol (109); 5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-carboxylic acid (110); 1-Cyclopropyl-7-fluoro-2-(6-methylpyridazin-4-yl)-1H-benzo[d]imidazole (111); 5-chloro-1-cyclopropyl-2-(6-methylpyridazin-4-yl)-1H-benzo[d]imidazole (112); 4-chloro-1-cyclopropyl-2-(6-methylpyridazin-4-yl)-1H-benzo[d]imidazole (113); 1-Cyclopropyl-5,6-difluoro-2-(6-(methoxymethyl)pyridazin-4-yl)-1H-benzo[d]imidazole (114); Methyl 5-(6-cyano-1-cyclopropyl-1H-benzo[d]imidazol-2-yl)pyridazine-3-carboxylate (115); 5-(6-cyano-1-cyclopropyl-1H-benzo[d]imidazol-2-yl)pyridazine-3-carboxylic acid (116); 1-Cyclopropyl-2-(6-(cyclopropylmethoxy)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (117); 1-Cyclopropyl-2-(6-(2,2,2-trifluoroethoxy)pyridazin-4-yl)-1H-benzo[d]imidazole-6-carbonitrile (118); 6-chloro-1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5-fluoro-1H-benzo[d]imidazole (119); 1-Cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5-fluoro-1H-benzo[d]imidazole-6-carbonitrile (120); 4-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-6,7-dihydro-5H-cyclopenta[c]pyridazine (121); 1-Cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-6-fluoro-1H-benzo[d]imidazole (122); 1-Cyclopropyl-5,6-difluoro-2-(6-(methylthio)pyridazin-4-yl)-1H-benzo[d]imidazole (123); 1-Cyclopropyl-5,6-difluoro-2-(6-(isopropylthio)pyridazin-4-yl)-1H-benzo[d]imidazole (124); 1-Cyclopropyl-2-(6-((difluoromethyl)thio)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (125); 5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-ol (126); 1-Cyclopropyl-2-(6-(difluoromethoxy)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (127); 1-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)ethan-1-ol (128); 1-Cyclopropyl-5,6-difluoro-2-(6-(1-fluoroethyl)pyridazin-4-yl)-1H-benzo[d]imidazole (129); 1-Cyclopropyl-5,6-difluoro-2-(6-((trifluoromethyl)thio)pyridazin-4-yl)-1H-benzo[d]imidazole (130) 1-Cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-1H-benzo[d]imidazole (131); 2-(6-(difluoromethyl)pyridazin-4-yl)-1-propyl-1H-benzo[d]imidazole (132); 1-Cyclopropyl-2-(6-(difluoromethoxy)pyridazin-4-yl)-1H-benzo[d]imidazole-6-carbonitrile (133); 1-Cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-1H-indole-3-carbonitrile (134); 2-(6-(difluoromethyl)pyridazin-4-yl)-1-methyl-1H-indole-3-carbonitrile (135); A compound selected from the group consisting of 1-cyclopropyl-2-(6-(1-fluoroethyl)pyridazin-4-yl)-1H-benzo[d]imidazole-6-carbonitrile (136), pharmaceutically acceptable salts, co-crystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically enriched derivatives, and prodrugs thereof.

[0182] In another aspect, there is provided 2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (103), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0183] In one embodiment, the compounds of formula I are compounds that inhibit (or are identified as inhibiting) aldosterone synthase (CYP11B2).

[0184] The compounds herein include compounds identified as achieving affinity for metalloenzymes at least in part through the formation of one or more of the following types of chemical interactions or bonds to the metal: sigma, covalent, coordinate covalent, ionic, pi, delta, or reverse bond interactions. The compounds may also achieve affinity through weaker interactions with the metal, such as van der Waals interactions, pi-cation interactions, pi-anion interactions, dipole-dipole interactions, and ion-dipole interactions. In one aspect, the compounds are identified as having a bonding interaction with the metal via a pyridazine moiety.

[0185] Methods for assessing metal-ligand binding interactions are known in the art as exemplified by references including, for example, Lippard and Berg, "Principles of Bioinorganic Chemistry," University Science Books (1994); Basolo and Pearson, "Mechanisms of Inorganic Reactions," John Wiley & Sons Inc; 2nd Edition (September 1967); Ivano Bertini, Harry Gray, Ed Stiefel, Joan Valentine, "Biological Inorganic Chemistry," University Science Books (2007); Xue et al., "Nature Chemical Biology," Vol. 4, No. 2, pp. 107-109 (2008).

[0186] In another aspect, there is provided a pharmaceutical composition comprising a compound of Formula I and a pharmaceutically acceptable carrier.

[0187] In another aspect, a method of modulating the activity of a metalloenzyme 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.

[0188] In another aspect, there is provided a method of treating a subject suffering from or susceptible to a disorder or disease, wherein the subject has been identified as in need of treatment for the 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 subject is treated for said disorder.

[0189] In another embodiment, the subject is a non-human animal.

[0190] In another aspect, a method of treating a subject suffering from or susceptible to a metalloenzyme-associated disorder or disease is provided, comprising administering to the subject an effective amount of a compound of formula I or a pharmaceutical composition.

[0191] In another aspect, there is provided a method of treating a subject suffering from or susceptible to a metalloenzyme-associated disorder or disease, wherein the subject has been identified as 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 subject is treated for said disorder.

[0192] In another aspect, there is provided a method of treating a subject suffering from or susceptible to a disorder or disease mediated by a metalloenzyme, wherein the subject has been identified as in need of treatment for a disorder or disease mediated by a metalloenzyme, comprising administering to said subject in need thereof an effective amount of a compound of formula I or a pharmaceutical composition such that the activity of the metalloenzyme in said subject is modulated (e.g., downregulated, inhibited).

[0193] The methods herein include those wherein the disease or disorder is characterized by a phenotype of aromatase (CYP19), a member of the cyclooxygenase family, lanosterol demethylase (CYP51), a member of the nitric oxide synthase family, thromboxane synthase (CYP5a), thyroid peroxidase, 17-alpha hydroxylase / 17,20-lyase (CYP17), cytochrome P4502A6 (CYP2A6), heme oxygenase, indoleamine 2, 3-dioxygenase, retinoic acid hydroxylase (CYP26), vitamin D hydroxylase (CYP24), sterol 27-hydroxylase (CYP27), cytochrome P4503A5 (CYP3A5), cholesterol 24-hydroxylase (CYP46), cytochrome P4504F2 (CYP4F2), myeloperoxidase, or 11-beta-hydroxylase (CYP11B1).

[0194] The methods herein include those 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 urinary disease, or a gastrointestinal disease.

[0195] The methods herein are directed to treating diseases or disorders including hypertension, resistant hypertension, pathological conditions associated with primary or secondary hyperaldosteronism 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 conditions, coronary heart 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 function In some embodiments, the method is characterized by a condition in which the condition is a cardiac disorder, liver disease, non-alcoholic steatohepatitis, vascular disease, retinopathy, neuropathy, dysinsulinism, endothelial dysfunction, myocardial fibrosis, vascular fibrosis, myocardial necrotic lesions, vascular injury, myocardial infarction, left ventricular hypertrophy, vascular wall hypertrophy, endothelial 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, cirrhosis, non-alcoholic fatty liver disease, nephropathy, diabetic nephropathy, or stroke.

[0196] The methods envisioned herein include methods in which a subject is identified as needing a particular, defined treatment. Identification of a subject as needing such treatment may be the judgment of the subject or a health care professional and may be subjective (e.g., opinion) or objective (e.g., measurable by a test or diagnostic method). [Means for solving the problem]

[0197] definition In order that the present invention may be more readily understood, for convenience, certain terms are first defined here.

[0198] As used herein, the term "treating" a disorder includes preventing, ameliorating, alleviating, and / or responding to the disorder and / or conditions that may cause the disorder. The terms "treating" and "treatment" refer to a method of alleviating or attenuating a disease and / or its associated symptoms. According to the present disclosure, "treating" includes preventing, blocking, inhibiting, attenuating, protecting against, modulating, reversing, and reducing the occurrence of an effect, e.g., a deleterious effect, of a disorder.

[0199] As used herein, "inhibiting" encompasses preventing, suppressing, and halting the progression. Note that "enzyme inhibition" (e.g., metalloenzyme inhibition) is distinct and is described below.

[0200] The term "modulate" refers to increasing or decreasing the activity of an enzyme in response to exposure to a compound of the present disclosure.

[0201] The terms "isolated," "purified," or "biologically pure" refer to material that is substantially or essentially free from components that normally accompany it as found in the natural state. Purity and homogeneity are typically determined using analytical chemistry techniques, such as polyacrylamide gel electrophoresis or high performance liquid chromatography. In particular, in embodiments, the compounds are at least 85% pure, more preferably at least 90% pure, more preferably at least 95% pure, and most preferably at least 99% pure.

[0202] The terms "administration" or "administering" include routes of introducing a compound into a subject to perform its intended function. Examples of routes of administration that may be used include injection (subcutaneous, intravenous, parenteral, intraperitoneal, intrathecal), topical, oral, inhalation, rectal, and transdermal.

[0203] The term "effective amount" includes an amount effective, at dosages and for periods of time necessary, to achieve the desired result. An effective amount of a compound may vary according to factors such as the disease state, age, and weight of the subject, and the ability of the compound to elicit a desired response in the subject. Dosage regimens can be adjusted to obtain the optimal therapeutic response. An effective amount is also one in which any toxic or adverse effects (e.g., side effects) of the inhibitor compound are outweighed by the therapeutically beneficial effects.

[0204] As used herein, the phrases "systemic administration," "administered systemically," "peripheral administration," and "administered peripherally" refer to the administration of a compound, drug, or other material so that it enters the patient's entire body and is therefore subject to metabolism and other similar processes.

[0205] The term "therapeutically effective amount" refers to that amount of the compound being administered sufficient to prevent the onset of the condition or disorder being treated or to alleviate to some extent one or more of the symptoms.

[0206] A therapeutically effective amount of a compound (i.e., an effective dosage) can range from about 0.005 μg / kg to 200 mg / kg, preferably from about 0.01 mg / kg to about 200 mg / kg, and 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. One of skill in the art will recognize that certain factors, including, but not limited to, the severity of the disease or disorder, previous treatments, the subject's general health and / or age, and other diseases present, can affect the dosage required to effectively treat a subject. Furthermore, treatment of a subject with a therapeutically effective amount of a compound can include a single treatment or, preferably, can include a series of treatments. In one example, a subject is treated with a compound in the range of about 0.005 μg / kg to about 200 mg / kg body weight once daily 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, a subject may be treated daily for several years in the setting of a chronic condition or disease. It is also recognized that the effective dosage of the compound used for treatment may increase or decrease over the course of a particular treatment.

[0207] The term "chiral" refers to a molecule that has the property of not being superimposable on its mirror image partner, while the term "achiral" refers to a molecule that is superimposable on its mirror image partner.

[0208] The term "diastereoisomer" refers to a stereoisomer with two or more centers of dissymmetry and whose molecules are not mirror images of one another.

[0209] The term "enantiomer" refers to a compound of two stereoisomers that are non-superimposable mirror images of one another. An equimolar mixture of two enantiomers is called a "racemic mixture" or "racemate."

[0210] The term "isomers" or "stereoisomers" refers to compounds that have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.

[0211] The term "prodrug" includes compounds having a moiety that can be metabolized in vivo. Typically, prodrugs are metabolized in vivo by esterases or other mechanisms to active drugs. Examples of prodrugs and their uses are well known in the art (see, e.g., 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 a compound, or by separately reacting the free acid form or a hydroxyl of the purified compound with a suitable esterifying agent. 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 ester), lower alkenyl ester, di-lower alkyl-amino lower alkyl ester (e.g., dimethylaminoethyl ester), acylamino lower alkyl ester (e.g., acetyloxymethyl ester), acyloxy lower alkyl ester (e.g., pivaloyloxymethyl ester), aryl ester (phenyl ester), aryl-lower alkyl ester (e.g., benzyl ester), substituted (e.g., with methyl, halo, or methoxy substituents) aryl and aryl-lower alkyl ester, amide, lower-alkyl amide, di-lower alkyl amide, and hydroxyamide. Preferred prodrug moieties are propionate ester and acyl ester. Prodrugs that are converted to active forms in vivo by other mechanisms are also included. In an embodiment, the compounds of the present disclosure are prodrugs of any of the formulas herein.

[0212] The term "subject" refers to animals, e.g., mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, etc. In certain embodiments, the subject is a human.

[0213] The terms "a," "an," and "the" as used in this application, including the claims, refer to "one or more." Thus, for example, reference to "a sample" includes multiple samples unless the context clearly indicates otherwise (e.g., multiple samples, etc.).

[0214] Throughout this specification and the claims, the words "comprise", "comprises" and "comprising" are used in an open-ended sense unless the context requires otherwise.

[0215] As used herein, the term "about," when referring to a value, is meant to encompass such variations of, 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% from the specified amount, as appropriate for performing the disclosed methods or using the disclosed compositions.

[0216] The use of the term "inhibitor" herein is intended to refer to a molecule that exhibits inhibitory activity against a metalloenzyme. As used herein, "inhibit" refers to reducing the activity of a metalloenzyme compared to the activity of the metalloenzyme without the inhibitor. In some embodiments, the term "inhibit" refers to reducing the activity of a metalloenzyme 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, inhibition refers to reducing the activity of a metalloenzyme by about 5% to about 25%, about 25% to about 50%, about 50% to about 75%, or about 75% to 100%. In some embodiments, inhibition refers to reducing the activity of a metalloenzyme by about 95% to 100%, e.g., reducing activity by 95%, 96%, 97%, 98%, 99%, or 100%. Such a decrease can be measured using a variety of techniques that will be appreciated by those skilled in the art. Particular assays for measuring individual activity are described below.

[0217] Additionally, compounds of the present disclosure include olefins having the configuration "Z" refers to what is referred to as the "cis" (same side) configuration, while "E" refers to what is referred to as the "trans" (opposite side) configuration. With regard to the nomenclature of chiral centers, the terms "d" and "l" configurations are as defined by the IUPAC Recommendations. With regard to the use of the terms diastereoisomers, racemates, epimers, and enantiomers, these are used in their normal context to describe the stereochemistry of the preparations.

[0218] As used herein, the term "alkyl" refers to a straight or branched chain hydrocarbon group containing 1 to 12 carbon atoms. The term "lower alkyl" refers to a C1-C6 alkyl chain. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, tert-butyl, and n-pentyl. Alkyl groups may be optionally substituted with one or more substituents.

[0219] The term "haloalkyl" refers to an alkyl group that is substituted with one or more halo substituents. Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, bromomethyl, chloromethyl, and 2,2,2-trifluoroethyl.

[0220] The term "alkenyl" refers to an unsaturated hydrocarbon chain that may be straight or branched and contains from 2 to 12 carbon atoms and at least one carbon-carbon double bond. Alkenyl groups can be optionally substituted with one or more substituents.

[0221] The term "arylalkenyl" refers to an aryl group containing 2 to 12 carbon atoms and at least one carbon-carbon double bond, and one or more sp groups in the alkenyl unit. 2 It refers to an unsaturated hydrocarbon chain, which may be straight or branched, in which a hybridized carbon is attached to an aryl moiety. An alkenyl group may be optionally substituted with one or more substituents.

[0222] The term "alkynyl" refers to an unsaturated hydrocarbon chain, which may be straight or branched, containing from 2 to 12 carbon atoms and at least one carbon-carbon triple bond. Alkynyl groups can be optionally substituted with one or more substituents.

[0223] 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.

[0224] sp of alkenyl and alkynyl groups 2 or sp carbon, respectively, can optionally be the point of attachment of an alkenyl or alkynyl group.

[0225] The term "alkoxy" refers to an --O-alkyl substituent.

[0226] As used herein, the terms "halogen," "hal," or "halo" mean -F, -Cl, -Br, or -I.

[0227] The term "alkylthio" refers to an --S-alkyl substituent.

[0228] The term "alkoxyalkyl" refers to an -alkyl-O-alkyl substituent.

[0229] The term "haloalkoxy" refers to an -O-alkyl substituted by one or more halo substituents. Examples of haloalkoxy groups include trifluoromethoxy and 2,2,2-trifluoroethoxy.

[0230] The term "haloalkoxyalkyl" refers to -alkyl-O-alkyl', wherein the alkyl' is substituted with one or more halo substituents.

[0231] The term "haloalkylaminocarbonyl" refers to -C(O)-amino-alkyl, wherein the alkyl is substituted by one or more halo substituents.

[0232] The term "haloalkylthio" refers to an -S-alkyl substituted by one or more halo substituents. Examples of haloalkylthio groups include trifluoromethylthio and 2,2,2-trifluoroethylthio.

[0233] The term "haloalkylcarbonyl" refers to a -C(O)-alkyl substituted by one or more halo substituents. Examples of haloalkylcarbonyl groups include trifluoroacetyl.

[0234] The term "cycloalkyl" refers to a hydrocarbon 3- to 8-membered monocyclic or 7- to 14-membered bicyclic ring system having at least one saturated ring or at least one non-aromatic ring, where the non-aromatic ring may have some degree of unsaturation. 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 by a substituent. Representative examples of cycloalkyl groups include cyclopropyl, cyclopentyl, cyclohexyl, cyclobutyl, cycloheptyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, and the like.

[0235] The term "cycloalkoxy" refers to an --O-cycloalkyl substituent.

[0236] The term "cycloalkoxyalkyl" refers to an -alkyl-O-cycloalkyl substituent.

[0237] The term "cycloalkylalkoxy" refers to an --O-alkyl-cycloalkyl substituent.

[0238] The term "cycloalkylaminocarbonyl" refers to a -C(O)-NH-cycloalkyl substituent.

[0239] 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 by a substituent. Examples of aryl groups include phenyl, naphthyl, anthracenyl, fluorenyl, indenyl, azulenyl, and the like.

[0240] The term "aryloxy" refers to an --O-aryl substituent.

[0241] The term "arylalkoxy" refers to an --O-alkyl-aryl substituent.

[0242] The term "arylalkylthio" refers to an -S-alkyl-aryl substituent.

[0243] The term "arylthioalkyl" refers to an -alkyl-S-aryl substituent.

[0244] The term "arylalkylaminocarbonyl" refers to a -C(O)-amino-alkyl-aryl substituent.

[0245] The term "arylalkylsulfonyl" refers to an -S(O)2-alkyl-aryl substituent.

[0246] The term "arylalkylsulfinyl" refers to an -S(O)-alkyl-aryl substituent.

[0247] The term "aryloxyalkyl" refers to an -alkyl-O-aryl substituent.

[0248] The term "alkylaryl" refers to an -aryl-alkyl substituent.

[0249] The term "arylalkyl" refers to an -alkyl-aryl substituent.

[0250] 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 if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, wherein the heteroatoms are selected from O, N, or S, and the remaining ring atoms are carbon (with appropriate hydrogen atoms unless otherwise specified). Heteroaryl groups can 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 can be substituted by a substituent. Examples of heteroaryl groups include pyridyl, furanyl, thienyl, pyrrolyl, oxazolyl, oxadiazolyl, imidazolylthiazolyl, isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, isoquinolinyl, indazolyl, and the like.

[0251] The term "heteroarylalkyl" refers to an -alkyl-heteroaryl substituent.

[0252] The term "heteroaryloxy" refers to an --O-heteroaryl substituent.

[0253] The term "heteroarylalkoxy" refers to an --O-alkyl-heteroaryl substituent.

[0254] The term "heteroaryloxyalkyl" refers to an -alkyl-O-heteroaryl substituent.

[0255] The term "nitrogen-containing heteroaryl" refers to a heteroaryl group having 1 to 4 ring nitrogen heteroatoms if monocyclic, 1 to 6 ring nitrogen heteroatoms if bicyclic, or 1 to 9 ring nitrogen heteroatoms if tricyclic.

[0256] The term "heterocycloalkyl" refers to a non-aromatic 3- to 8-membered monocyclic, 7- to 12-membered bicyclic, or 10- to 14-membered tricyclic ring system containing 1 to 3 heteroatoms if monocyclic, 1 to 6 heteroatoms if bicyclic, or 1 to 9 heteroatoms if tricyclic, wherein the heteroatoms are selected from O, N, S, B, P, or Si, and the non-aromatic ring system is fully saturated. Heterocycloalkyl groups can 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 can be substituted by a substituent. Representative heterocycloalkyl groups include piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,3-dioxolane, tetrahydrofuranyl, tetrahydrothienyl, thiirenyl, and the like.

[0257] The term "heterocycloalkylalkyl" refers to an -alkyl-heterocycloalkyl substituent.

[0258] The term "alkylamino" refers to an amino substituent that is further substituted with one or two alkyl groups. The term "aminoalkyl" refers to an alkyl substituent that is further substituted with one or more amino groups. The terms "hydroxyalkyl" or "hydroxylalkyl" refer to an alkyl substituent that is 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.

[0259] Acids and bases useful in the methods herein are known in the art. Acid catalysts are any acidic chemicals that may be inorganic in nature (e.g., hydrochloric acid, sulfuric acid, nitric acid, aluminum trichloride) or organic in nature (e.g., camphorsulfonic acid, p-toluenesulfonic acid, acetic acid, ytterbium triflate). Acids are useful in catalytic or stoichiometric amounts to promote chemical reactions. Bases are any basic chemicals that may be inorganic in nature (e.g., sodium bicarbonate, potassium hydroxide) or organic in nature (e.g., triethylamine, pyridine). Bases are useful in catalytic or stoichiometric amounts to promote chemical reactions.

[0260] An alkylating agent is any reagent capable of affecting alkylation of a desired functional group (e.g., the oxygen atom of an alcohol, the nitrogen atom of an amino group). Alkylating agents are known in the art, including those 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 depart from a molecule during a reaction (e.g., elimination reaction, substitution reaction), and are known in the art, including those 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)CF), 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)), water or alcohols (protonated state), and the like.

[0261] In certain embodiments, a substituent on any group (e.g., alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, heterocycloalkyl) can 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) can be optionally substituted with one or more substituents (which can be the same or different), each replacing a hydrogen atom. Examples of suitable substituents are 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, Examples include, but are not limited to, alkylaminocarbonyl, alkoxycarbonylamino, alkylamino, arylamino, diarylamino, alkylcarbonyl or arylamino substituted aryl, arylalkylamino, aralkylaminocarbonyl, amido, alkylaminosulfonyl, arylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, imino, carboxamido, carbamido, carbamyl, thioureido, thiocyanato, sulfamido, sulfonylalkyl, sulfonylaryl, mercaptoalkoxy, N-hydroxyamidinyl or N'-aryl, N''-hydroxyamidinyl.

[0262] The compounds of the present disclosure can be made by organic synthesis means known in the art. Methods for optimizing reaction conditions and, if necessary, minimizing competing by-products are known in the art. Reaction optimization and scaling can be advantageously achieved using high-speed parallel synthesis equipment and computer-controlled microreactors (e.g., Design and Optimization in Organic Synthesis, 2nd Edition, Carlson R, ed., 2005, Elsevier Science Ltd.; Jahnisch, K et al., Angew. Chem. Int. Ed. Engl. 2004, 43:406, and references therein). Additional reaction schemes and protocols can be determined by those skilled in the art using commercially available structure-searchable database software, such as SciFinder® (CAS Division of the American Chemical Society) and CrossFire Beilstein® (Elsevier MDL), or by keyword searches using internet search engines such as Google®, or keyword databases, such as the U.S. Patent and Trademark Office text database.

[0263] As one of ordinary skill in the art will recognize, methods for synthesizing compounds of the formulae herein, including the schemes and examples herein, will be apparent to one of ordinary skill in the art. Moreover, the various synthetic steps can be performed in an alternate sequence or order to obtain the desired compounds. Furthermore, solvents, temperatures, reaction durations, and the like depicted herein are for illustrative purposes only, and one of ordinary skill in the art, understanding variations in the reaction conditions, will be able to produce the desired compounds of the present disclosure.

[0264] The compounds herein may also contain linkages (e.g., carbon-carbon bonds), and bond rotation is limited to that particular linkage, where the limitation arises, for example, from 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 such instances, the present disclosure expressly includes all tautomeric forms of the compounds described herein, even though only a single tautomeric form may be represented. All such isomeric forms of such compounds herein are expressly included in the present disclosure. All crystalline forms and polymorphs of the compounds described herein are expressly included in the present disclosure. Extracts and fractions containing compounds of the present disclosure are also embodied. The term isomer is intended to include diastereoisomers, enantiomers, positional isomers, structural isomers, rotamers, tautomers, and the like. For compounds containing one or more stereocenters, e.g., chiral compounds, the methods of the disclosure can be carried out on enantiomerically enriched compounds, racemates, or mixtures of diastereoisomers.

[0265] Preferred enantiomerically enriched compounds have an enantiomeric excess of 50% or greater, and more preferably, the compounds have an enantiomeric excess of 60%, 70%, 80%, 90%, 95%, 98%, or 99% or greater. In preferred embodiments, only one enantiomer or diastereoisomer of a chiral compound of the present disclosure is administered to a cell or subject.

[0266] Treatment method In one aspect, a method of treating a subject suffering from or susceptible to a disorder or disease is provided, comprising administering to the subject an effective amount of a compound of formula I or a pharmaceutical composition.

[0267] In another aspect, there is provided a method of treating a subject suffering from or susceptible to a disorder or disease, wherein the subject has been identified as in need of treatment for a disorder or disease mediated by a metalloenzyme, comprising administering to said subject in need thereof an effective amount of a compound of formula I or a pharmaceutical composition such that said subject is treated for said disorder.

[0268] In one aspect, a method of modulating the activity of a cellular metalloenzyme 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.

[0269] In one embodiment, the modulation is inhibition.

[0270] In another aspect, there is provided a method of treating a subject suffering from or susceptible to a disorder or disease mediated by a metalloenzyme, comprising administering to the subject an effective amount of a compound of formula I or a pharmaceutical composition.

[0271] In another aspect, there is provided a method of treating a subject suffering from or susceptible to a disorder or disease mediated by a metalloenzyme, wherein the subject has been identified as in need of treatment for a disorder or disease mediated by a metalloenzyme, comprising administering to said subject in need thereof an effective amount of a compound of formula I or a pharmaceutical composition such that said subject is treated for said disorder.

[0272] In one embodiment, a method is provided for treating a disease, disorder, or a symptom thereof, wherein the disorder is cancer, a cardiovascular disease, an endocrine disorder, an inflammatory disease, an infectious disease, a gynecological disease, a metabolic disease, an ophthalmological disease, a central nervous system (CNS) disease, a urinary disease, or a gastrointestinal disease. In one embodiment, the disease is hypertension, resistant hypertension, pathological conditions associated with primary or secondary hyperaldosteronism 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 conditions, coronary heart disease, fibrosis, diseases characterized by increased collagen formation, fibrosis and matrix remodeling after hypertension, matrix remodeling after fibrosis and endothelial dysfunction, cardiovascular diseases such as atherosclerosis, atrial fibrillation, renal dysfunction, and the like. The conditions include: liver dysfunction, liver disease, non-alcoholic steatohepatitis, vascular disease, retinopathy, neuropathy, dysinsulinism, endothelial dysfunction, myocardial fibrosis, vascular fibrosis, myocardial necrotic lesions, vascular damage, myocardial infarction, left ventricular hypertrophy, vascular wall hypertrophy, endothelial 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, cirrhosis, non-alcoholic fatty liver disease, kidney damage, diabetic nephropathy, or stroke.

[0273] In certain embodiments, the subject is a mammal, preferably a primate or a human.

[0274] 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.

[0275] In another embodiment there is provided a method, as described above, wherein the compound of formula I is administered intravenously, intramuscularly, subcutaneously, intracerebroventricularly, orally or topically.

[0276] In another embodiment there is provided a method, as described herein, wherein a compound of formula I is administered in an amount that is selectivity of its spectrum of activity against a target enzyme (e.g., IC of aldosterone synthase (CYP11B2) 50<1.0 μM).

[0277] In another embodiment, there is provided a method as described above, wherein the compound of Formula I is administered alone or in combination with one or more other therapeutic agents, 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 a metabolic disease, an agent for an ophthalmology disease, an agent for a central nervous system (CNS) disease, an agent for a urological disease, or an agent for a gastrointestinal disease.

[0278] In certain embodiments, the additional therapeutic agent is an agent that treats hypertension, an agent that treats primary aldosteronism, an agent that treats renal disease, an agent that treats congestive heart failure, an agent that treats an atherosclerotic condition, an agent that treats diabetes, an agent that treats obesity, or an agent that treats a metabolic disease.

[0279] Exemplary additional therapeutic agents include 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 channel blockers, alpha-adrenergic blockers, beta-adrenergic blockers, diuretics (including loop diuretics), potassium channel activators, endothelin receptor antagonists, endothelin 1 receptor agonists, soluble guanylate cyclase stimulators These include, but are not limited to, drugs, vasodilators, HMG-CoA reductase inhibitors, niacin and niacin receptor agonists, Niemann-Pick C1-like 1 (NPC1L1) inhibitors, insulin or insulin analogs, 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.

[0280] Another object of the present 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 disorder or disease mediated by a metalloenzyme. Another object of the present disclosure is the use of a compound described herein (e.g., a compound of Formula I) for use in treating a disorder or disease mediated by a metalloenzyme. Another object of the present disclosure is the use of a compound described herein (e.g., a compound of Formula I) in the manufacture of an agrochemical composition for use in treating or preventing a disorder or disease mediated by a metalloenzyme in an agricultural or field setting.

[0281] Pharmaceutical Composition In one aspect, a pharmaceutical composition is provided comprising a compound of Formula I and a pharmaceutically acceptable carrier.

[0282] In another embodiment, there is provided a pharmaceutical composition 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 a metabolic disease, an agent for an ophthalmology disease, an agent for a central nervous system (CNS) disease, an agent for a urological disease, or an agent for a gastrointestinal disease.

[0283] In certain embodiments, the additional therapeutic agent is an agent that treats hypertension, an agent that treats primary aldosteronism, an agent that treats renal disease, an agent that treats congestive heart failure, an agent that treats an atherosclerotic condition, an agent that treats diabetes, an agent that treats obesity, or an agent that treats a metabolic disease.

[0284] Exemplary additional therapeutic agents include 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 channel blockers, alpha-adrenergic blockers, beta-adrenergic blockers, diuretics (including loop diuretics), potassium channel activators, endothelin receptor antagonists, endothelin 1 receptor agonists, soluble guanylate cyclase stimulators These include, but are not limited to, drugs, vasodilators, HMG-CoA reductase inhibitors, niacin and niacin receptor agonists, Niemann-Pick C1-like 1 (NPC1L1) inhibitors, insulin or insulin analogs, 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.

[0285] In one aspect, a kit is provided comprising 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 disease or disorder mediated by a metalloenzyme, including cancer, cardiovascular disease, endocrine disease, inflammatory disease, infectious disease, gynecological disease, metabolic disease, ophthalmological disease, central nervous system (CNS) disease, urinary disease, or gastrointestinal disease. In other embodiments, the disease, disorder, or symptom thereof is hypertension, resistant hypertension, pathological conditions associated with primary or secondary hyperaldosteronism 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 conditions, coronary heart disease, fibrosis, diseases characterized by increased collagen formation, fibrosis and matrix remodeling after hypertension, fibrosis and matrix remodeling after endothelial dysfunction, cardiovascular diseases such as atherosclerosis, atrial fibrillation, and the like. fibrillation, renal insufficiency, liver disease, non-alcoholic steatohepatitis, vascular disease, retinopathy, neuropathy, dysinsulinism, endothelial dysfunction, myocardial fibrosis, vascular fibrosis, myocardial necrotic lesions, vascular damage, myocardial infarction, left ventricular hypertrophy, vascular wall hypertrophy, endothelial 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, cirrhosis, non-alcoholic fatty liver disease, kidney damage, diabetic nephropathy or stroke.

[0286] The term "pharmaceutically acceptable salt" or "pharmaceutically acceptable carrier" is intended to include salts of active compounds prepared with relatively non-toxic acids or bases, depending on the particular substituents found in the compounds described herein. When a compound of the present disclosure contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salts, or similar salts. When a compound of the present disclosure contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydroiodic, or phosphorous acids, as well as salts derived from relatively non-toxic organic acids such as acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, and methanesulfonic acids. Also included are salts of amino acids, e.g., arginate, and salts of organic acids such as glucuronic or galacturonic acid (see, e.g., Berge et al., Journal of Pharmaceutical Science 66:1-19 (1977)). Certain compounds of the present disclosure contain both basic and acidic functionalities that convert the compounds into base or acid addition salts. Other pharmaceutically acceptable carriers known to those of ordinary skill in the art are suitable for the present disclosure.

[0287] The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and separating the parent compound by conventional means. The parent form of the compound may differ from the various salt forms with respect to certain physical properties, such as solubility in polar solvents, but the salts are otherwise equivalent to the parent form of the compound for purposes of this disclosure.

[0288] In addition to salt forms, the present disclosure provides compounds in prodrug form. Prodrugs of the compounds described herein are compounds that readily undergo chemical changes under physiological conditions to yield 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 when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

[0289] Certain compounds of the present disclosure may 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 encompassed within the scope of the present disclosure. Certain compounds of the present disclosure may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent to the uses envisioned by the present disclosure and are intended to be within the scope of the present disclosure.

[0290] The present disclosure also provides a pharmaceutical composition comprising an effective amount of a compound described herein and a pharmaceutically acceptable carrier. In some embodiments, the compound of formula I is administered to a subject using a pharmaceutically acceptable formulation, for example, a pharmaceutically acceptable formulation that provides continuous 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 the pharmaceutically acceptable formulation is administered to the subject.

[0291] Actual dosage levels and course of administration of the active ingredients in the pharmaceutical compositions of the present disclosure may be varied to provide for a particular patient, composition, and mode of administration an amount of the active ingredient effective to achieve the desired therapeutic response without toxicity (or unacceptable toxicity) to the patient.

[0292] In use, at least one compound according to the present disclosure is administered in a pharmaceutically effective amount in a pharmaceutical carrier by intravenous, intramuscular, subcutaneous, or intracerebroventricular injection, or orally, or by topical application to a subject in need thereof. According to the present disclosure, the compound of the present disclosure can be administered alone or together with a second, different therapeutic agent. "Together" means together, substantially simultaneously, or sequentially. In one embodiment, the compound of the present disclosure is administered within a short period of time. Thus, the compound of the present disclosure can be administered for short-term treatment, for example, from about one day to about one week. In another embodiment, the compound of the present disclosure can be administered for a longer period of time, for example, from about one week to several months, depending on the condition being treated, to ameliorate chronic disorders.

[0293] As used herein, a "pharmaceutically effective amount" refers to a compound of the present disclosure that is high enough to significantly improve the condition being treated, but low enough to avoid serious side effects (at a reasonable benefit / risk ratio), within the bounds of good medical practice. The pharmaceutically effective amount of a compound of the present disclosure will vary depending on the specific goal to be achieved, the age and physical condition of the patient being treated, the severity of the underlying disease, the duration of treatment, the nature of concurrent treatments, and the specific compound used. For example, the therapeutically effective amount of a compound of the present disclosure administered to a child or neonate will be proportionally reduced, in accordance with good medical practice. Thus, an effective amount of a compound of the present disclosure is the minimum amount that will achieve the desired effect.

[0294] A clear practical advantage of the present disclosure is that the compounds can be administered in a convenient manner, for example, by intravenous, intramuscular, subcutaneous, oral, or intracerebroventricular injection, or by topical application, for example, as a cream or gel. Depending on the route of administration, the active ingredient, including the compounds of the present disclosure, may need to be coated with a material that protects the compound from the action of enzymes, acids, and other natural conditions that may inactivate the compound. To administer the compounds of the present disclosure by other than parenteral administration, the compounds may be coated with or administered together with a material that prevents inactivation.

[0295] The compounds may be administered parenterally or intraperitoneally.Dispersions may also be prepared, for example, in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils.

[0296] Some examples of substances that 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, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; stearic acid; magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and theobroma oil; polyols, such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; agar; alginic acid; pyrogen-free water; isotonic saline; and phosphate buffer; skim milk powder; and other non-toxic, compatible substances used in pharmaceutical formulations, such as vitamin C, estrogen, and echinacea. Wetting agents and lubricants, such as sodium lauryl sulfate, may also be present, as may colorants, flavorings, lubricants, excipients, tableting agents, stabilizers, antioxidants, and preservatives. For example, solubilizing agents including cremaphores and beta-cyclodextrins may be used in the pharmaceutical compositions herein.

[0297] Pharmaceutical compositions containing the active compounds (or prodrugs thereof) of the present disclosure can be manufactured by conventional mixing, dissolving, granulating, dragee-making, pulverizing, 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 auxiliaries that facilitate processing of the active compounds into pharmaceutically usable preparations.

[0298] The pharmaceutical compositions of the presently disclosed subject matter may be in virtually any form suitable for any mode of administration, including, for example, topical, ocular, oral, buccal, systemic, nasal, infusion, transdermal, rectal, vaginal, etc., or in a form suitable for administration by inhalation or insufflation.

[0299] For topical administration, the active compounds or prodrugs may be formulated as solutions, gels, ointments, creams, suspensions, and the like.

[0300] 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.

[0301] Useful injectable preparations include sterile suspensions, solutions, or emulsions of the active compound in aqueous or oily vehicles. The compositions may also contain formulating agents, such as suspending agents, stabilizing agents, and / or dispersing agents. Preparations for injection may be presented in unit dosage form (e.g., in ampoules or multi-dose containers) and may contain added preservatives.

[0302] Alternatively, the injectable formulations can be provided in powder form for reconstitution before use with a suitable vehicle including, but not limited to, sterile pyrogen-free water, buffer, dextrose solution, etc. To this end, the active compound can be dried by any technique known in the art, such as lyophilization, and reconstituted prior to use.

[0303] For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.

[0304] For oral administration, the pharmaceutical compositions may take the form of, for example, lozenges, tablets, or capsules prepared by conventional means with pharmaceutically 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), or wetting agents (e.g., sodium lauryl sulfate). Tablets can be coated, for example, with sugar coatings or enteric coatings, by methods well known in the art.

[0305] Liquid preparations for oral administration may take the form of, for example, elixirs, solutions, syrups, or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means using pharmaceutically acceptable additives, such as suspending agents (e.g., sorbitol syrup, cellulose derivatives, or hydrogenated edible fats), emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol, or fractionated vegetable oils), and preservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic acid). The preparations may also contain buffer salts, preservatives, flavoring agents, coloring agents, and sweetening agents, as appropriate.

[0306] Preparations for oral administration can be suitably formulated to achieve controlled release of the active compound or prodrug, as is well known.

[0307] For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

[0308] For rectal and vaginal administration, the active compounds may be formulated as solutions (for retention enemas), suppositories containing conventional suppository bases such as cocoa butter or other glycerides, or ointments.

[0309] 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 pressurized packs or a 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 for use in an inhaler or insufflator (e.g., capsules and cartridges comprised of gelatin) can be formulated containing a powder mix of the compound and a suitable powder base, such as lactose or starch.

[0310] A specific example of an aqueous suspension formulation suitable for nasal administration using a commercially available nasal spray device 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 can be adjusted to a range of about pH 5 to pH 7, with a pH of about pH 5.5 being typical.

[0311] For intraocular administration, the active compound or prodrug can be formulated as a solution, emulsion, suspension, etc., suitable for administration to the eye. A variety of vehicles suitable for administering compounds to the eye 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.

[0312] For long-term delivery, the active compound or prodrug can be formulated as an implantable preparation for administration by implant or intramuscular injection.The active ingredient can be formulated with a suitable polymeric or hydrophobic material (for example, as an emulsion in an acceptable oil), or with an ion exchange resin, or as a sparingly soluble derivative, for example, as a sparingly soluble salt.Alternatively, a transdermal delivery system can be used, which is manufactured as an adhesive disk or patch that slowly releases the active compound for transdermal absorption.To this end, a penetration enhancer can be used to promote transdermal penetration of the active compound. Suitable transdermal patches are described, for example, in U.S. Pat. No. 5,407,713, U.S. Pat. No. 5,352,456, U.S. Pat. No. 5,332,213, U.S. Pat. No. 5,336,168, U.S. Pat. No. 5,290,561, U.S. Pat. No. 5,254,346, U.S. Pat. No. 5,164,189, U.S. Pat. No. 5,163,899, U.S. Pat. No. 5,088,977, U.S. Pat. No. 5,087,240, U.S. Pat. No. 5,008,110, and U.S. Pat. No. 4,921,475, each of which is incorporated herein by reference in its entirety.

[0313] Alternatively, other drug delivery systems may be used. 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 dimethyl sulfoxide (DMSO), may also be used.

[0314] 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 plastic foil, such as a blister pack. The pack or dispenser device can be accompanied by instructions for administration.

[0315] The active compounds or prodrugs of the present disclosure, or compositions thereof, are typically used in an amount effective to achieve the intended result, e.g., an amount effective to treat or prevent the particular disease being treated. Compounds can be administered therapeutically to achieve a therapeutic benefit or prophylactically to achieve a prophylactic benefit. Therapeutic benefit refers to the eradication or amelioration of the underlying disorder being treated and / or the eradication or amelioration of one or more symptoms associated with the underlying disorder, such that the patient reports a perceived improvement or an improved condition, even though the patient may still be afflicted by the underlying disorder. For example, therapeutic benefit is achieved when administering a compound to a patient suffering from an allergy not only eradicates or ameliorates the underlying allergic response, 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, therapeutic benefit for asthma includes an improvement in breathing after the onset of an asthma attack or a reduction in the frequency or severity of asthma episodes. Therapeutic benefit also includes halting or slowing the progression of the disease, regardless of whether improvement is achieved.

[0316] For prophylactic administration, the compound may be administered to a patient at risk of developing one of the previously described diseases. A patient at risk of developing a disease may have characteristics that classify the patient into a designated risk patient group as defined by an appropriate medical professional or group. An at-risk patient may also be a patient who is typically or routinely in a situation where the onset of an underlying disease treatable by administration of a metalloenzyme inhibitor according to the present disclosure may occur. In other words, an at-risk patient is a patient who is typically or routinely exposed to a disease- or illness-causing condition or who may be briefly exposed for a limited period of time. Alternatively, prophylactic administration may be applied to patients diagnosed with an underlying disorder to avoid the onset of symptoms.

[0317] The amount of compound administered will depend on a variety of factors, including, for example, the particular indication being treated, the mode of administration, whether the desired benefit is prophylactic or therapeutic, the severity of the indication being treated, as well as the age and weight of the patient, the bioavailability of the particular active compound, etc. Determination of an effective dosage is well within the capabilities of one of ordinary skill in the art.

[0318] Effective dosages can be initially estimated from in vitro assays. For example, initial dosages used in animals can be formulated to achieve circulating or serum concentrations of the active compound at or above the IC50 of the particular compound as measured in an in vitro assay, such as the in vitro fungal MIC or MFC, or other in vitro assays described in the Examples section. Calculating dosages to achieve such circulating or serum concentrations, taking into account the bioavailability of a particular compound, is well within the capabilities of one of ordinary skill in the art. For guidance, see "General Principles," Chapter 1, pages 1-46, of "Goodman and Gilman's The Pharmaceutical Basis of Therapeutics," by Fingl & Woodbury, latest edition, Pagamon Press, and the references therein, which are incorporated herein by reference.

[0319] Initial dosages can also be estimated from in vivo data, for example, animal models. Animal models useful for testing the efficacy of compounds to treat or prevent the various diseases mentioned above are well known in the art.

[0320] Dosages typically range from 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, bioavailability, mode of administration, and various factors discussed above. Dosage amounts and intervals can be adjusted individually to achieve plasma levels of the compound sufficient to maintain therapeutic or prophylactic effect. In cases of local administration or selective absorption, e.g., local topical administration, the effective local concentration of the active compound may not be related to plasma concentration. One of ordinary skill in the art can optimize an effective local dosage without undue experimentation.

[0321] Compounds may be administered once per day, a few or several times per day, or even multiple times per day, depending upon, among other things, the indication being treated and the judgment of the prescribing physician.

[0322] Preferably, the compound provides therapeutic or prophylactic benefit without causing substantial toxicity. The toxicity of a compound can be determined using standard pharmaceutical procedures. The dose ratio between toxic and therapeutic (or prophylactic) effect is the therapeutic index. Compounds that exhibit high therapeutic indices are preferred.

[0323] The description of a chemical group in any definition of a variable herein includes definitions of that variable as either a single group or a combination of the listed groups. The description of an embodiment of a variable herein includes that embodiment as either a single embodiment or in combination with any other embodiment or sub-combination thereof. The description of an embodiment herein includes that embodiment as either a single embodiment or in combination with any other embodiment or sub-combination thereof. [Example]

[0324] 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 presented to illustrate the compounds, pharmaceutical compositions and methods provided herein, and should not be construed in any way as limiting the scope thereof.

[0325] General Experimental Procedure The definitions of variables in the structures in the schemes herein are equivalent to the definitions of the corresponding positions in the formulas described herein. The example compounds shown in Table 2 were characterized by the HPLC and LCMS methods described in Table 1.

[0326] [Table 1]

[0327] Common abbreviations: ACN Acetonitrile br Wide d doublet dd Double of doublets 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 mL milliliter m / z mass-to-charge ratio NMR nuclear magnetic resonance ppm parts per million rt or RT room temperature s singlet t triplet TLC thin layer chromatography

[0328] Preparation of Intermediate-1 Scheme:

[0329] [ka]

[0330] N-Cyclopropyl-5-fluoro-2-nitroaniline To a stirred solution of 2,4-difluoro-1-nitrobenzene (25 g, 157.23 mmol) in potassium fluoride (9.12 g, 157.23 mmol) was added dropwise potassium carbonate (21.7 g, 157.23 mmol) followed by cyclopropanamine (10.75 g, 188.68 mmol) at room temperature under an inert atmosphere. The reaction mixture was stirred at room temperature for 2 hours. After thin-layer chromatography (TLC) showed that the starting material was consumed, the reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (EtOAc) (2 × 200 mL). The combined organic extracts were dried over anhydrous NaSO 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 (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).

[0331] N 1 -Cyclopropyl-5-fluorobenzene-1,2-diamine (Intermediate-1) To a stirred solution of N-cyclopropyl-5-fluoro-2-nitroaniline (24 g, 122.45 mmol) in methanol (MeOH) (300 mL) was added 10% Pd / C (50% aqueous, 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 hours. After 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 and N 1 -Cyclopropyl-5-fluorobenzene-1,2-diamine intermediate-1 (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 (br s, 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] at retention time 1.64 + (72.46% purity).

[0332] Preparation of Intermediate-2 Scheme:

[0333] [ka]

[0334] (5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methanol To a stirred solution of methyl 5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-carboxylate (250 mg, 0.8 mmol) in a 2:1 mixture of methanol / tetrahydrofuran (THF) (15 mL) was added sodium borohydride (152 mg, 4.01 mmol) under an inert atmosphere at 0° C. The reaction mixture was gradually warmed to room temperature and stirred for 4 hours. After the starting material was consumed (by TLC), the reaction mixture was concentrated under reduced pressure. The residue was diluted with water (25 mL) and extracted with EtOAc (2×40 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure to give (5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methanol (130 mg, 0.46 mmol, 57%) as a brown solid, which was used in the next step without further purification. LC-MS: m / z 284.9[M+H] at retention time 1.94 + (72.20% purity).

[0335] 5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-carbaldehyde (Intermediate-2) To a stirred solution of (5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methanol (130 mg, 0.46 mmol) in CHCl (10 mL) under an inert atmosphere at 0 °C was added Dess-Martin periodinane (DMP) (291 mg, 0.69 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 2 h. After the starting material was consumed (by TLC), the reaction mixture was quenched with saturated sodium bicarbonate solution (20 mL) and extracted with CHCl (2 × 20 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 50% EtOAc / hexane) to give 5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-carbaldehyde intermediate-2 (50 mg, 0.18 mmol, 39%) as a brown solid. 1 H NMR (500MHz, CDCl3): δ 10.50 (s, 1H), 10.06 (d, J = 2.0 Hz, 1H), 8.64 (d, J = 2.3 Hz, 1H), 7.80 (dd, J = 8.8, 4.8 Hz, 1H), 7.34 (dd, J = 8.4, 2.3 Hz, 1H), 7.13 (td, J = 9.3, 2.3 Hz, 1H), 3.73-3.69 (m, 1H), 1.37-1.31 (m, 2H), 0.90-0.85 (m, 2H). LC-MS: m / z 282.9 [M+H] at retention time 1.85 + (90.42% purity).

[0336] Preparation of Intermediate-3 Scheme:

[0337] [ka]

[0338] (E)-5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-carbaldehyde oxime To a stirred solution of 5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-carbaldehyde intermediate-2 (100 mg, 0.35 mmol) in ethanol (EtOH) (2 mL) was added hydroxylamine hydrochloride (49 mg, 0.71 mmol) and potassium carbonate (98 mg, 0.71 mmol) at room temperature under an inert atmosphere. The reaction mixture was heated to 80° C. and stirred for 3 hours. After the starting material was consumed (by TLC), the reaction mixture was concentrated under reduced pressure. The residue was diluted with water (40 mL) and stirred for 10 minutes. The precipitated solid was filtered, washed with water (10 mL), and evaporated to dryness in vacuo to give (E)-5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-carbaldehyde oxime (70 mg, 0.23 mmol, 67%) as an off-white solid. 1H NMR (500MHz, DMSO-d6): δ 12.25 (s, 1H), 9.81 (s, 1H), 8.56 (s, 1H), 8.48 (s, 1H), 7.80 (dd, J = 8.7, 4.9 Hz, 1H), 7.55 (dd, J = 9.0, 1.7 Hz, 1H), 7.20 (td, J = 9.8, 2.3 Hz, 1H), 3.95-3.89 (m, 1H), 1.20-1.16 (m, 2H), 0.84-0.79 (m, 2H). LC-MS: m / z 297.9 [M+H] at retention time 1.95 + (99.11% purity).

[0339] (5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methanamine (Intermediate-3) To a stirred solution of (E)-5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-carbaldehyde oxime (70 mg, 0.23 mmol) in ethanol (5 mL) was added 10% Pd / C (50% aqueous, 25 mg) at room temperature under an inert atmosphere. The reaction mixture was evacuated and stirred under a hydrogen atmosphere (balloon pressure) at room temperature for 5 hours. After the starting material was consumed (by TLC), the reaction mixture was filtered through a pad of Celite and washed with MeOH / CHCl (10:1, 20 mL). The filtrate was concentrated under reduced pressure to give (5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methanamine intermediate-3 (50 mg, crude) as an off-white solid, which was used in the next step without further purification. LC-MS: m / z 283.9[M+H] at retention time 1.62 + (Purity 64.40%).

[0340] Preparation of Intermediate-4 Scheme:

[0341] [ka]

[0342] 3-(Ethylamino)-4-nitrobenzonitrile To a stirred solution of 3-fluoro-4-nitrobenzonitrile (2 g, 12.05 mmol) in CHCl (250 mL) was added potassium carbonate (3.32 g, 24.09 mmol) and ethylamine (70% aqueous solution, 2.17 g, 48.19 mmol) under an inert atmosphere at room temperature. The reaction mixture was stirred at room temperature for 6 hours. After the starting material was consumed (by TLC), the reaction mixture was quenched with water (60 mL) and extracted with EtOAc (2 × 60 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure to give 3-(ethylamino)-4-nitrobenzonitrile (1.9 g, crude) as a yellow solid, which was used in the next step without further purification. 1 H NMR (500MHz, DMSO-d6): δ 8.22-8.10 (m, 2H), 7.58 (br s, 1H), 7.00 (br d, J = 8.7 Hz, 1H), 3.48-3.38 (m, 2H), 1.21 (br t, J = 6.9 Hz, 3H). LC-MS: m / z 192.1 [M+H] at retention time 4.10 + (98.96% purity).

[0343] 4-Amino-3-(ethylamino)benzonitrile (Intermediate-4) To a stirred solution of 3-(ethylamino)-4-nitrobenzonitrile (1.9 g, crude) in ethanol (20 mL) was added 10% Pd / C (50% aqueous, 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 hours. After 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 intermediate-4 (1.5 g, crude) as an off-white solid, which was used in the next step without further purification. LC-MS: m / z 161.9[M+H] at retention time 2.11 +(Purity 60.88%).

[0344] Preparation of Intermediate-5 Scheme:

[0345] [ka]

[0346] N-Cyclopropyl-4,5-difluoro-2-nitroaniline To 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) under an inert atmosphere at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. After the starting material was consumed (by TLC), the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 × 20 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure to give N-cyclopropyl-4,5-difluoro-2-nitroaniline 2 (320 mg, crude) as a pale yellow solid, which was used in the next step without further purification. LC-MS: m / z 215.4[M+H] with retention time 4.43 + (Purity 69.03%).

[0347] N 1 -Cyclopropyl-4,5-difluorobenzene-1,2-diamine (Intermediate-5) To a stirred solution of N-cyclopropyl-4,5-difluoro-2-nitroaniline (300 mg, 1.4 mmol) in EtOAc (10 mL) was added 10% Pd / C (50% aqueous, 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 hours. After 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 and N 1-Cyclopropyl-4,5-difluorobenzene-1,2-diamine intermediate-5 (100 mg, crude) was obtained as a brown viscous syrup and used in the next step without further purification. LC-MS: m / z 184.9[M+H] at retention time 2.12 + (Purity 83.53%).

[0348] Preparation of Intermediate-6 and Intermediate-7 Scheme:

[0349] [ka]

[0350] 3-(Cyclopropylamino)-4-nitrobenzonitrile To a stirred solution of 3-fluoro-4-nitrobenzonitrile (1 g, 6.02 mmol) in CHCl (5 mL) was added dropwise potassium carbonate (1.66 g, 12.05 mmol) and cyclopropanamine (3.33 mL, 48.19 mmol) under an inert atmosphere at room temperature. The reaction mixture was stirred at room temperature for 4 hours. After the starting material was consumed (by TLC), the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2 × 40 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure to give 3-(cyclopropylamino)-4-nitrobenzonitrile (900 mg, crude) as a yellow solid, which 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 (br s, 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 [M−H] at retention time 3.25 + (99.61% purity).

[0351] 4-Amino-3-(cyclopropylamino)benzonitrile (Intermediate-6) To a stirred solution of 3-(cyclopropylamino)-4-nitrobenzonitrile (900 mg, 4.43 mmol) in ethanol (10 mL) was added 10% Pd / C (50% aqueous, 500 mg) at room temperature under an inert atmosphere. The reaction mixture was stirred at room temperature under a hydrogen atmosphere (balloon pressure) for 5 hours. After 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 material was purified by silica gel column chromatography (eluent: 20% EtOAc / hexane) to give 4-amino-3-(cyclopropylamino)benzonitrile intermediate-6 (500 mg, 2.89 mmol, 65%) 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).

[0352] 1-Cyclopropyl-1H-benzo[d]imidazole-6-carbonitrile (Intermediate-7) A solution of 4-amino-3-(cyclopropylamino)benzonitrile Intermediate-6 (500 mg, 2.89 mmol) in formic acid (5 mL) was heated to reflux under an inert atmosphere and stirred for 5 h. After the starting material was consumed (by TLC), the volatiles were removed under reduced pressure. The residue was diluted with water (10 mL), neutralized with saturated sodium bicarbonate solution (20 mL), and extracted with EtOAc (2 × 30 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 50% EtOAc / hexane) to afford 1-cyclopropyl-1H-benzo[d]imidazole-6-carbonitrile Intermediate-7 (250 mg, 1.37 mmol, 56%) as an off-white solid. 1 H NMR (500MHz, DMSO-d6): δ 8.50 (s, 1H), 8.21 (d, J = 0.9 Hz, 1H), 7.82 (d, J = 8.1 Hz, 1H), 7.62 (dd, J = 8.4, 1.4 Hz, 1H), 3.59-3.54 (m, 1H), 1.15-1.05 (m, 4H). LC-MS: m / z 184.0 [M+H] at retention time 2.46 + (87.33% purity).

[0353] Preparation of Intermediate-8 Scheme:

[0354] [ka]

[0355] 6-chloro-N-cyclopropyl-3-nitropyridin-2-amine To a stirred solution of 2,6-dichloro-3-nitropyridine (5 g, 26.04 mmol) in toluene (25 mL) was added cyclopropylamine (3.7 mL, 52.08 mmol) under an inert atmosphere at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was warmed to room temperature and stirred for 2 h. After the starting material was consumed (by TLC), the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 × 50 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 10% EtOAc / hexane) to afford 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)

[0356] 6-Chloro-N 2 -Cyclopropylpyridine-2,3-diamine (Intermediate-8) To a stirred solution of 6-chloro-N-cyclopropyl-3-nitropyridin-2-amine (1 g, 4.69 mmol) in EtOH:water (1:1, 10 mL) was added iron (1.3 g, 23.47 mmol) and ammonium chloride (1.2 g, 23.47 mmol) under an inert atmosphere at room temperature. The reaction mixture was heated to 80° C. for 1 h. After the starting material was consumed (by TLC), the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2×20 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give 6-chloro-N 2 -Cyclopropylpyridine-2,3-diamine intermediate-8 (700 mg, crude) was obtained as a pale yellow solid and used in the next step without further purification. LC-MS: m / z 183.9[M+H] at retention time 2.07 + (Purity 58.13%).

[0357] Preparation of Intermediate-9 Scheme:

[0358] [ka]

[0359] N-Cyclopropyl-6-methoxy-3-nitropyridin-2-amine To a stirred solution of 2-chloro-6-methoxy-3-nitropyridine (5 g, 26.5 mmol) in toluene (50 mL) was added cyclopropylamine (3.69 mL, 53 mmol) under an inert atmosphere at 0 °C. The reaction mixture was stirred at 0 °C for 1 h, warmed to room temperature, and stirred for 6 h. After the starting material was consumed (by TLC), the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 × 50 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude material was triturated with n-pentane to give N-cyclopropyl-6-methoxy-3-nitropyridin-2-amine (800 mg, 3.82 mmol, 83%) as a yellow solid.

[0360] N 2 -Cyclopropyl-6-methoxypyridine-2,3-diamine (Intermediate-9) To a stirred solution of N-cyclopropyl-6-methoxy-3-nitropyridin-2-amine (1 g, 4.78 mmol) in ethanol / water (1:1, 10 mL) at room temperature was added iron powder (1.3 g, 24 mmol) and ammonium chloride (1.29 g, 23.9 mmol). The reaction mixture was heated to 80° C. for 1 h. After the starting material was consumed (by TLC), the reaction mixture was filtered through a pad of Celite, and the Celite bed was washed with EtOAc (50 mL). The filtrate was concentrated under reduced pressure to afford N 2 -Cyclopropyl-6-methoxypyridine-2,3-diamine Intermediate-9 (150 mg) was obtained as a black liquid, which was used crude in the next step without further purification. 1 H NMR (400 MHz, DMSO-d6): δ 6.71 (d, J = 7.9 Hz, 1H), 5.78 (d, J = 7.9 Hz, 1H), 4.09-4.06 (m, 2H), 3.84-3.81 (m, 1H), 3.70 (s, 3H), 2.77-2.68 (m, 1H), 0.69-0.61 (m, 2H), 0.43-0.37 (m, 2H) LC-MS: m / z 180.1 [M+H] with retention time 2.11 + (75.36% purity)

[0361] Preparation of Intermediate-10 Scheme:

[0362] [ka]

[0363] N-Ethyl-4,5-difluoro-2-nitroaniline To a stirred solution of 1,2,4-trifluoro-5-nitrobenzene (2 g, 11.29 mmol) in CHCl (10 mL) at room temperature, potassium carbonate (3.1 g, 22.59 mmol) and ethanamine (559 mg, 12.42 mmol) were added. The reaction mixture was stirred at room temperature for 16 h. After the starting material was consumed (by TLC), the reaction mixture was diluted with water (100 mL) and extracted with CHCl (2 × 100 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 10% EtOAc / hexane) to give N-ethyl-4,5-difluoro-2-nitroaniline (800 mg, 3.96 mmol, 35%) as a yellow solid. 1 H NMR (500 MHz, DMSO-d6): δ 8.19 (brs, 1H), 8.13 (dd, J = 11.0, 8.7 Hz, 1H), 7.14 (dd, J = 13.9, 7.0 Hz, 1H), 3.40-3.33 (m, 2H), 1.20 (t, J = 7.2Hz, 3H) LC-MS: m / z 203.1 [M+H] with retention time 3.53 + (98.40% purity)

[0364] N 1 -Ethyl-4,5-difluorobenzene-1,2-diamine (Intermediate-10) To a stirred solution of N-ethyl-4,5-difluoro-2-nitroaniline (800 mg, 3.96 mmol) in ethyl acetate (5 mL) was added 10% Pd / C (50% aqueous, 500 mg) at room temperature under an inert atmosphere. The reaction mixture was stirred at room temperature under a hydrogen atmosphere (balloon pressure) for 16 hours. After the starting material was consumed (by TLC), the reaction mixture was filtered through a pad of Celite and the bed was washed with EtOAc (50 mL). The filtrate was concentrated under reduced pressure and N 1 -ethyl-4,5-difluorobenzene-1,2-diamine Intermediate-10 (500 mg, 2.90 mmol, 73%) was obtained as a black liquid, which was used in the next step without further purification. 1 H NMR (500 MHz, DMSO-d6): δ 6.47 (dd, J = 12.8, 8.1 Hz, 1H), 6.30 (dd, J = 13.3, 8.1 Hz, 1H), 4.64 (br s, 2H), 4.44 (t, J = 5.2 Hz, 1H), 3.00-2.94 (m, 2H), 1.17 (t, J = 7.2 Hz, 3H) LC-MS: m / z 173.2 [M+H] with retention time 3.16 + (64.65% purity)

[0365] Preparation of Intermediate-11 Scheme:

[0366] [ka]

[0367] 6-chloro-N-ethyl-3-nitropyridin-2-amine To a stirred solution of 2,6-dichloro-3-nitropyridine (2 g, 10.40 mmol) in toluene (8.5 mL) was added ethylamine (1.35 mL) under an inert atmosphere at 0 °C. The reaction mixture was warmed to room temperature and stirred for 3 h. After the starting material was consumed (by TLC), the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 × 50 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 2% EtOAc / hexane) to afford 6-chloro-N-ethyl-3-nitropyridin-2-amine (800 mg, 3.98 mmol, 38%) as a yellow solid. 1 H NMR (500 MHz, DMSO-d6): δ 8.70 (brs, 1H), 8.40 (d, J = 7.5 Hz, 1H), 6.75 (d, J = 8.1 Hz, 1H), 3.55-3.50 (m, 2H), 1.18 (t, J = 7.0 Hz, 3H) LC-MS: m / z 202 [M+H] with retention time 2.63 + (99.85% purity)

[0368] 6-Chloro-N 2 -Ethylpyridine-2,3-diamine (Intermediate-11) To a stirred solution of 6-chloro-N-ethyl-3-nitropyridin-2-amine (550 mg, 2.73 mmol) in ethanol / water (1:1, 20 mL) at room temperature was added iron powder (763.4 g, 13.68 mmol) and ammonium chloride (738.7 mg, 13.68 mmol). The reaction mixture was heated to 80° C. for 1 h. After the starting material was consumed (by TLC), the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2×30 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give 6-chloro-N 2 -Ethylpyridine-2,3-diamine Intermediate-11 (452 ​​mg) was obtained as a black solid, which was used crude in the next step without further purification. 1H NMR (500 MHz, DMSO-d6): δ 6.67 (d, J = 7.5 Hz, 1H), 6.33 (d, J = 8.1 Hz, 1H), 5.85 (brs, 1H), 4.88 (br s, 2H), 3.37-3.25 (m, 2H), 1.15 (t, J = 7.0 Hz, 3H) LC-MS: m / z 172 [M+H] with retention time 1.72 + (85.88% purity)

[0369] Preparation of Intermediate-12 Scheme:

[0370] [ka]

[0371] 4,5-Difluoro-2-nitroaniline To a stirred solution of 1,2,4-trifluoro-5-nitrobenzene (5 g, 28.24 mmol) in methanol (5 mL) was added methanolic ammonia (15 mL) at 0 °C under an inert atmosphere. The reaction mixture was heated to 90 °C and stirred in a sealed tube for 2 h. After the starting material was consumed (by TLC), the reaction mixture was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 2% EtOAc / hexane) to give 4,5-difluoro-2-nitroaniline (800 mg, 4.59 mmol, 16%) as a pale yellow solid. 1 H NMR (500 MHz, CDCl3): δ 8.00 (dd, J = 10.4, 8.7 Hz, 1H), 6.60 (dd, J = 11.0, 6.4 Hz, 1H), 6.09 (brs, 2H) LC-MS: m / z 172.8 [M−H] at retention time 2.49 - (88.25% purity)

[0372] 4,5-Difluorobenzene-1,2-diamine (Intermediate-12) To a stirred solution of 4,5-difluoro-2-nitroaniline (800 mg, 4.59 mmol) in methanol (15 mL) was added 10% Pd / C (50% aqueous, 200 mg) at room temperature under an inert atmosphere. The reaction mixture was stirred at room temperature under a hydrogen atmosphere (balloon pressure) for 3 hours. After the starting material was consumed (by TLC), the reaction mixture was filtered through a pad of Celite and washed with methanol (15 mL) and CHCl (10 mL). The filtrate was concentrated under reduced pressure. The crude material was washed with n-hexane (15 mL) to give 4,5-difluorobenzene-1,2-diamine Intermediate-12 (500 mg, 3.47 mmol, 80%) as a black solid. 1 H NMR (500 MHz, DMSO-d6): δ 6.47-6.41 (m, 2H), 4.55 (brs, 4H) LC-MS: m / z 145 [M+H] at retention time 1.59 + (75.16% purity)

[0373] Preparation of Intermediate-13 Scheme:

[0374] [ka]

[0375] 5-Chloro-N-cyclopropyl-3-nitropyridin-2-amine To a stirred solution of 2,5-dichloro-3-nitropyridine (1 g, 5.23 mmol) in toluene (10 mL) was added cyclopropylamine (0.73 mL, 10.47 mmol) under an inert atmosphere at 0 °C. The reaction mixture was stirred at room temperature for 48 h. After the starting material was consumed (by TLC), the reaction mixture was diluted with water (40 mL) and extracted with EtOAc (2 × 60 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure to give 5-chloro-N-cyclopropyl-3-nitropyridin-2-amine (700 mg, 3.28 mmol, 63%) as an orange solid. 1H NMR (400 MHz, CDCl3): δ 8.45 (d, J = 2.5 Hz, 1H), 8.41 (d, J = 2.4 Hz, 1H), 8.18 (br s, 1H), 3.05-2.97 (m, 1H), 0.98-0.91 (m, 2H), 0.68-0.62 (m, 2H) LC-MS: m / z 214 [M+H] with retention time 3.03 + (98.66% purity)

[0376] 5-Chloro-N 2 -Cyclopropylpyridine-2,3-diamine (Intermediate-13) To a stirred solution of 5-chloro-N-cyclopropyl-3-nitropyridin-2-amine (200 mg, 0.938 mmol) in ethanol / water (1:1, 20 mL) at room temperature was added iron powder (262 mg, 4.69 mmol) and ammonium chloride (253 mg, 4.69 mmol). The reaction mixture was heated to 80° C. and stirred for 3 h. After the starting material was consumed (by TLC), the reaction mixture was filtered through a pad of Celite and washed with EtOAc. The filtrate was diluted with water (30 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 5-chloro-N 2 -Cyclopropylpyridine-2,3-diamine Intermediate-13 (120 mg) was obtained as a black solid, which was used crude in the next step without further purification. 1 H NMR (500 MHz, DMSO-d6): δ 7.35 (d, J = 1.7 Hz, 1H), 6.67 (d, J = 2.3 Hz, 1H), 6.00 (br s, 1H), 5.02 (br s, 2H), 2.72-2.63 (m, 1H), 0.68-0.63 (m, 2H), 0.41-0.37 (m, 2H) LC-MS: m / z 183.9 [M+H] at retention time 1.87 + (88.05% purity)

[0377] Preparation of Intermediate-14 Scheme:

[0378] [ka]

[0379] N-Cyclopropyl-2-fluoro-6-nitroaniline To a stirred solution of 1,2-difluoro-3-nitrobenzene (200 mg, 1.26 mmol) in ethanol (2 mL) was added cyclopropanamine (0.13 mL, 1.89 mmol) at room temperature under an inert atmosphere and stirred for 16 h. After the starting material was consumed (by TLC), the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 × 20 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 5% EtOAc / hexane) to give N-cyclopropyl-2-fluoro-6-nitroaniline (200 mg, 1.02 mmol, 81%) as a yellow viscous syrup. 1 H NMR (400 MHz, CDCl3): δ 7.93 (dt, J = 8.8, 1.5 Hz, 1H), 7.82 (brs, 1H), 7.24-7.19 (m, 1H), 6.63-6.58 (m, 1H), 3.12-3.07 (m, 1H), 0.87-0.79 (m, 2H), 0.67-0.61 (m, 2H) LC-MS: m / z 197.0 [M+H] at retention time 3.28 + (99.89% purity)

[0380] N 1 -Cyclopropyl-6-fluorobenzene-1,2-diamine (Intermediate-14) To a stirred solution of N-cyclopropyl-2-fluoro-6-nitroaniline (200 mg, 1.02 mmol) in ethyl acetate (5 mL) was added 10% Pd / C (50% aqueous, 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 hours. After the starting material was consumed (by TLC), the reaction mixture was filtered through a pad of Celite and the bed was washed with EtOAc (15 mL). The filtrate was concentrated under reduced pressure to afford N 1 -Cyclopropyl-6-fluorobenzene-1,2-diamine Intermediate-14 (160 mg) was obtained as a colorless viscous syrup, which was used crude in the next step without further purification. 1 H NMR (500 MHz, DMSO-d6): δ 6.61-6.51 (m, 1H), 6.40-6.24 (m, 3H), 4.89 (br s, 2H), 2.62-2.58 (m, 1H), 0.49-0.38 (m, 4H)

[0381] Preparation of Intermediate-15 Scheme:

[0382] [ka]

[0383] 4,5-Difluoro-N-methyl-2-nitroaniline To a stirred solution of 1,2,4-trifluoro-5-nitrobenzene (5 g, 28.25 mmol) in THF (50 mL) under an inert atmosphere at −20° C., methanamine (2 M in THF, 28.25 mL, 56.5 mmol) was added dropwise and stirred at the same temperature for 2 h. After the starting material was consumed (by TLC), the reaction mixture was quenched with brine (50 mL) and extracted with EtOAc (2×100 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 3% EtOAc / hexane) to give 4,5-difluoro-N-methyl-2-nitroaniline (1.1 g, 5.85 mmol, 20%) as a pale yellow solid. 1 H NMR (400 MHz, CDCl3): δ 8.06 (dd, J = 10.7, 8.4 Hz, 2H), 6.61 (dd, J = 12.5, 6.7 Hz, 1H), 3.01 (d, J = 5.1 Hz, 3H)

[0384] 4,5-Difluoro-N 1 -Methylbenzene-1,2-diamine (Intermediate-15) To a stirred solution of 4,5-difluoro-N-methyl-2-nitroaniline (1 g, 5.32 mmol) in ethyl acetate (15 mL) was added 10% Pd / C (50% aqueous, 250 mg) at room temperature under an inert atmosphere. The reaction mixture was stirred at room temperature under a hydrogen atmosphere (balloon pressure) for 3 hours. After the starting material was consumed (by TLC), the reaction mixture was filtered through a pad of Celite and the bed was washed with methanol (30 mL). The filtrate was concentrated under reduced pressure to give 4,5-difluoro-N-methyl-2-nitroaniline. 1 -methylbenzene-1,2-diamine Intermediate-15 (700 mg) was obtained as a brown syrup, which was used crude in the next step without further purification. 1 H NMR (500 MHz, DMSO-d6): δ 6.48 (dd, J = 12.5, 8.4 Hz, 1H), 6.28 (dd, J = 13.3, 8.1 Hz, 1H), 4.71 (s, 1H), 4.59 (br s, 2H), 2.66 (d, J = 5.2Hz, 3H) LC-MS: m / z 158.8 [M+H] at retention time 2.20 + (99.55% purity)

[0385] Preparation of Intermediate-16 Scheme:

[0386] [ka]

[0387] 4,5-Difluoro-2-nitro-N-propylaniline To a stirred solution of 1,2,4-trifluoro-5-nitrobenzene (5 g, 28.25 mmol) in THF (150 mL) was added dropwise potassium carbonate (5.07 g, 36.72 mmol) and propan-1-amine (3.48 mL, 42.37 mmol) under an inert atmosphere at room temperature and stirred for 16 h. After the starting material was consumed (by TLC), the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 × 100 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 3% EtOAc / hexane) to give 4,5-difluoro-2-nitro-N-propylaniline (600 mg, 2.77 mmol, 10%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6): δ 8.25 (br s, 1H), 8.14 (dd, J = 11.3, 8.7 Hz, 1H), 7.17 (dd, J = 13.7, 7.2 Hz, 1H), 3.35-3.26 (m, 2H), 1.68-1.56 (m, 2H), 0.93 (t, J = 7.4 Hz, 3H)

[0388] 4,5-Difluoro-N 1 -Propylbenzene-1,2-diamine (Intermediate-16) To a stirred solution of 4,5-difluoro-2-nitro-N-propylaniline (500 mg, 2.31 mmol) in ethyl acetate (10 mL) was added 10% Pd / C (50% aqueous, 150 mg) under an inert atmosphere at room temperature. The reaction mixture was stirred under a hydrogen atmosphere (balloon pressure) at room temperature for 4 hours. After the starting material was consumed (by TLC), the reaction mixture was filtered through a pad of Celite and the bed was washed with methanol (20 mL). The filtrate was concentrated under reduced pressure to give 4,5-difluoro-N-propylaniline. 1 -propylbenzene-1,2-diamine Intermediate-16 (350 mg) was obtained as a brown syrup, which was used crude in the next step without further purification. 1H NMR (500 MHz, DMSO-d6): δ 6.48 (dd, J = 12.8, 8.1 Hz, 1H), 6.30 (dd, J = 13.3, 8.1 Hz, 1H), 4.66 (s, 2H), 4.47 (br t, J = 4.6 Hz, 1H), 2.96-2.88 (m, 2H), 1.62-1.54 (m, 2H), 0.95 (t, J = 7.5 Hz, 3H) LC-MS: m / z 186.9 [M+H] at retention time 2.88 + (89.94% purity)

[0389] Preparation of Intermediate-17 Scheme:

[0390] [ka]

[0391] 3-(Cyclopropylamino)-4-nitrophenol To a stirred solution of 3-fluoro-4-nitrophenol (1 g, 6.37 mmol) in THF (20 mL) in a sealed tube under an inert atmosphere at room temperature, cyclopropanamine (726 mg, 12.74 mmol) was added. The reaction mixture was heated to 80 °C and stirred for 6 h. After 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 combined organic extracts were 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 3-(cyclopropylamino)-4-nitrophenol (1.2 g, 6.18 mmol, 75%) as a yellow solid. 1H NMR (500 MHz, DMSO-d6): δ 10.86 (br s, 1H), 8.15 (br s, 1H), 7.97 (d, J = 9.3 Hz, 1H), 6.61 (d, J = 1.7 Hz, 1H), 6.22 (dd, J = 9.3, 2.3 Hz, 1H), 2.57-2.55 (m, 1H), 0.91-0.82 (m, 2H), 0.67-0.57 (m, 2H) LC-MS: m / z 194.9 [M+H] at retention time 2.51 + (99.35% purity)

[0392] 4-Amino-3-(cyclopropylamino)phenol (Intermediate-17) To a stirred solution of 3-(cyclopropylamino)-4-nitrophenol (1 g, 5.15 mmol) in ethyl acetate (10 mL) was added 10% Pd / C (50% aqueous, 250 mg) at room temperature under an inert atmosphere. The reaction mixture was stirred at room temperature under a hydrogen atmosphere (balloon pressure) for 4 hours. After the starting material was consumed (by TLC), the reaction mixture was filtered through a pad of Celite, and the bed was washed with methanol (30 mL). The filtrate was concentrated under reduced pressure to give 4-amino-3-(cyclopropylamino)phenol Intermediate-17 (600 mg) as a brown syrup. The crude product was used in the next step without further purification. 1 H NMR (500 MHz, DMSO-d6): δ 8.18 (brs, 1H), 6.37-6.29 (m, 2H), 5.86 (dd, J = 8.1, 2.3 Hz, 1H), 4.92 (s, 1H), 3.81 (brs, 2H), 2.27-2.25 (m, 1H), 0.69-0.62 (m, 2H), 0.41-0.35 (m, 2H) LC-MS: m / z 164.8 [M+H] at retention time 1.09 + (74.22% purity)

[0393] Preparation of Intermediate-18 Scheme:

[0394] [ka]

[0395] N-Cyclopropyl-5-methyl-2-nitroaniline To a stirred solution of 2-fluoro-4-methyl-1-nitrobenzene (500 mg, 3.22 mmol) in THF (5 mL) was added triethylamine (1.35 mL, 9.68 mmol) followed by cyclopropanamine (919 mg, 16.13 mmol) at room temperature under an inert atmosphere. The reaction mixture was heated to 60 °C and stirred for 16 h. After 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 combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 5% EtOAc / hexane) to give N-cyclopropyl-5-methyl-2-nitroaniline (500 mg, 2.6 mmol, 80%) as a yellow solid. 1 H NMR (500 MHz, CDCl3): δ 8.10 (brs, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.07 (s, 1H), 6.50 (d, J = 8.8 Hz, 1H), 2.58-2.55 (m, 1H), 2.37 (s, 3H), 0.94-0.88 (m, 2H), 0.67-0.62 (m, 2H). LC-MS: m / z 192.9 [M+H] at retention time 3.35 + (99.53% purity).

[0396] N 1 -Cyclopropyl-5-methylbenzene-1,2-diamine (Intermediate-18) To a stirred solution of N-cyclopropyl-5-methyl-2-nitroaniline (150 mg, 0.78 mmol) in ethyl acetate (1 mL) was added 10% Pd / C (50% aqueous, 50 mg) at room temperature under an inert atmosphere. The reaction mixture was stirred at room temperature under a hydrogen atmosphere (balloon pressure) for 3 hours. After the starting material was consumed (by TLC), the reaction mixture was filtered through a pad of Celite and the bed was washed with ethyl acetate (15 mL). The filtrate was concentrated under reduced pressure to afford N 1 -Cyclopropyl-5-methylbenzene-1,2-diamine Intermediate-18 (120 mg) was obtained as a black solid, which was used crude in the next step without further purification. 1 H NMR (500 MHz, DMSO-d6): δ 6.60 (s, 1H), 6.41 (d, J = 8.1 Hz, 1H), 6.24 (br d, J = 7.5 Hz, 1H), 4.91 (s, 1H), 4.21 (br s, 2H), 2.32-2.30 (m, 1H), 2.14 (s, 3H), 0.71-0.64 (m, 2H), 0.41-0.35 (m, 2H) LC-MS: m / z 162.9 [M+H] with retention time 2.49 + (81.92% purity)

[0397] Preparation of Intermediate-19 Scheme:

[0398] [ka]

[0399] N-Cyclopropyl-2-nitro-5-(trifluoromethyl)aniline To a stirred solution of 2-fluoro-1-nitro-4-(trifluoromethyl)benzene (1 g, 4.78 mmol) in CHCl (40 mL) under an inert atmosphere at 0 °C, potassium carbonate (1.32 g, 9.57 mmol) and cyclopropanamine (1.09 g, 19.14 mmol) were added. The reaction mixture was gradually warmed to room temperature and stirred for 16 h. After the starting material was consumed (by TLC), the reaction mixture was diluted with ice-cold water (30 mL) and extracted with CHCl (2 × 40 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 5% EtOAc / hexane) to give N-cyclopropyl-2-nitro-5-(trifluoromethyl)aniline (1 g, 4.06 mmol, 85%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6): δ 8.25 (d, J = 8.9 Hz, 1H), 8.13 (brs, 1H), 7.62 (d, J = 1.0 Hz, 1H), 7.04 (dd, J = 8.8, 1.8 Hz, 1H), 2.76-2.69 (m, 1H), 0.95-0.87 (m, 2H), 0.69-0.63 (m, 2H) LC-MS: retention time 4.33, m / z 245.0 [M−H] - (78.90% purity)

[0400] N 1 -Cyclopropyl-5-(trifluoromethyl)benzene-1,2-diamine (Intermediate-19) To a stirred solution of N-cyclopropyl-2-nitro-5-(trifluoromethyl)aniline (1 g, 4.06 mmol) in methanol (20 mL) was added 10% Pd / C (50% aqueous, 100 mg) at room temperature under an inert atmosphere. The reaction mixture was stirred at room temperature under a hydrogen atmosphere (balloon pressure) for 3 hours. After the starting material was consumed (by TLC), the reaction mixture was filtered through a pad of Celite and the bed was washed with methanol (20 mL). The filtrate was concentrated under reduced pressure and N 1-Cyclopropyl-5-(trifluoromethyl)benzene-1,2-diamine Intermediate-19 (700 mg) was obtained as a brown syrup, which was used crude in the next step without further purification.

[0401] Preparation of Intermediate-20 Scheme:

[0402] [ka]

[0403] N-Cyclopropyl-2,3-difluoro-6-nitroaniline To a stirred solution of 1,2,3-trifluoro-4-nitrobenzene (1 g, 28.25 mmol) in ethanol (100 mL) was added cyclopropanamine (1.61 g, 28.25 mmol) at room temperature under an inert atmosphere, and the reaction was stirred for 48 h. After the starting material was consumed (by TLC), the reaction mixture was diluted with ice-cold water (50 mL) and extracted with EtOAc (2 × 60 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 5% EtOAc / hexane) to give N-cyclopropyl-2,3-difluoro-6-nitroaniline (3 g, 14.0 mmol, 50%) as a yellow solid. 1 H NMR (500 MHz, DMSO-d6): δ 7.95-7.91 (m, 1H), 7.75 (brs, 1H), 6.85-6.80 (m, 1H), 3.02-2.98 (m, 1H), 0.79-0.72 (m, 2H), 0.67-0.65 (m, 2H) LC-MS: m / z 213.4 [M−H] at retention time 4.06 + (99.81% purity)

[0404] N 1 -Cyclopropyl-5,6-difluorobenzene-1,2-diamine (Intermediate-20) To a stirred solution of N-cyclopropyl-2,3-difluoro-6-nitroaniline (1 g, 4.67 mmol) in ethyl acetate (10 mL) was added 10% Pd / C (50% aqueous, 100 mg) at room temperature under an inert atmosphere. The reaction mixture was stirred at room temperature under a hydrogen atmosphere (balloon pressure) for 2 hours. After the starting material was consumed (by TLC), the reaction mixture was filtered through a pad of Celite and the bed was washed with ethyl acetate (20 mL). The filtrate was concentrated under reduced pressure and N 1 -Cyclopropyl-5,6-difluorobenzene-1,2-diamine Intermediate-20 (700 mg) was obtained as a black solid, which was used crude in the next step without further purification. 1 H NMR (500 MHz, DMSO-d6): δ 6.55-6.47 (m, 1H), 6.33-6.27 (m, 1H), 4.70 (br s, 2H), 4.54 (br s, 1H), 2.74-2.66 (m, 1H), 0.59-0.52 (m, 2H), 0.48-0.43 (m, 2H) LC-MS: m / z 185.0 [M+H] at retention time 2.60 + (67.33% purity)

[0405] Preparation of Intermediate-21 Scheme:

[0406] [ka]

[0407] N-Cyclobutyl-4,5-difluoro-2-nitroaniline To a stirred solution of 1,2,4-trifluoro-5-nitrobenzene (1 g, 5.65 mmol) in THF (20 mL) was added potassium carbonate (1.17 g, 8.47 mmol) followed by cyclobutanamine (0.58 mL, 6.78 mmol) under an inert atmosphere at 0 °C. The reaction mixture was gradually warmed to room temperature and stirred for 6 h. After the starting material was consumed (by TLC), the reaction mixture was diluted with ice-cold water (50 mL) and extracted with EtOAc (2 × 60 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 5% EtOAc / hexane) to afford N-cyclobutyl-4,5-difluoro-2-nitroaniline (450 mg, 1.97 mmol, 35%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6): δ 8.18-8.08 (m, 2H), 7.00 (dd, J = 13.4, 7.0 Hz, 1H), 4.16-4.07 (m, 1H), 2.48-2.39 (m, 2H), 2.06-1.94 (m, 2H), 1.83-1.69 (m, 2H) LC-MS: m / z 229.0 [M+H] at retention time 2.90 + (97.77% purity)

[0408] N 1 -Cyclobutyl-4,5-difluorobenzene-1,2-diamine (Intermediate-21) To a stirred solution of N-cyclobutyl-4,5-difluoro-2-nitroaniline (450 mg, 1.97 mmol) in ethyl acetate (10 mL) was added 10% Pd / C (50% aqueous, 45 mg) at room temperature under an inert atmosphere. The reaction mixture was stirred at room temperature under a hydrogen atmosphere (balloon pressure) for 3 hours. After the starting material was consumed (by TLC), the reaction mixture was filtered through a pad of Celite and the bed was washed with ethyl acetate (15 mL). The filtrate was concentrated under reduced pressure and N 1 -cyclobutyl-4,5-difluorobenzene-1,2-diamine Intermediate-21 (350 mg) was obtained as a black solid, which was used crude in the next step without further purification. 1 H NMR (500 MHz, CDCl3): δ 6.52 (dd, J = 11.3, 8.0 Hz, 1H), 6.33 (dd, J = 12.1, 7.1 Hz, 1H), 3.86-3.76 (m, 1H), 3.40-3.18 (m, 3H), 2.52-2.39 (m, 2H), 1.91-1.78 (m, 4H) LC-MS: m / z 199.0 [M+H] with retention time 2.92 + (83.44% purity)

[0409] Preparation of Intermediate-22 Scheme:

[0410] [ka]

[0411] 4-(Cyclopropylamino)-3-nitrobenzonitrile To a stirred solution of 4-fluoro-3-nitrobenzonitrile (1 g, 6.02 mmol) in CHCl (5 mL) under an inert atmosphere at 0 °C, potassium carbonate (1.66 g, 12.05 mmol) was added dropwise, followed by cyclopropanamine (3.33 mL, 48.19 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 4 h. After the starting material was consumed (by TLC), the reaction mixture was poured into water (30 mL) and extracted with EtOAc (2 × 50 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure to give 4-(cyclopropylamino)-3-nitrobenzonitrile (1.1 g) as a yellow solid. The crude material was used in the next step without further purification. 1 H NMR (400 MHz, CDCl3): δ 8.49 (d, J = 1.9 Hz, 1H), 8.41 (brs, 1H), 7.66-7.63 (m, 1H), 7.40 (d, J = 9.0 Hz, 1H), 2.68-2.61 (m, 1H), 1.04-0.98 (m, 2H), 0.75-0.70 (m, 2H) LC-MS: m / z 202.0 [M−H] at retention time 2.88 - (99.48% purity)

[0412] 3-Amino-4-(cyclopropylamino)benzonitrile (Intermediate-22) To a stirred solution of 4-(cyclopropylamino)-3-nitrobenzonitrile (1.1 g, crude) in ethanol (40 mL) was added 10% Pd / C (50% aqueous, 350 mg) at room temperature under an inert atmosphere. The reaction mixture was stirred at room temperature under a hydrogen atmosphere (balloon pressure) for 3 hours. After the starting material was consumed (by TLC), the reaction mixture was filtered through a pad of Celite, and the bed was washed with ethyl acetate (20 mL). The filtrate was concentrated under reduced pressure to give 3-amino-4-(cyclopropylamino)benzonitrile Intermediate-22 (900 mg) as a yellow solid. The crude material was used in the next step without further purification. 1 H NMR (400 MHz, CDCl3): δ 7.18 (dd, J = 8.2, 1.8 Hz, 1H), 7.00 (d, J = 8.3 Hz, 1H), 6.92 (d, J = 1.9 Hz, 1H), 4.41 (br s, 1H), 3.24 (br s, 2H), 2.51-2.43 (m, 1H), 0.85-0.78 (m, 2H), 0.59-0.53 (m, 2H) LC-MS: m / z 173.9 [M+H] at retention time 2.40 + (84.82% purity)

[0413] Preparation of Intermediate-23 Scheme:

[0414] [ka]

[0415] 1-chloro-2,5-difluoro-4-nitrobenzene To a stirred solution of 1-chloro-2,5-difluoro-4-nitrobenzene (500 mg, 2.59 mmol) in CHCl (10 mL) under an inert atmosphere at 0 °C, potassium carbonate (715 mg, 5.18 mmol) and cyclopropanamine (305 mg, 5.18 mmol) were added. The reaction mixture was stirred at room temperature for 24 h. After the starting material was consumed (by TLC), the reaction mixture was diluted with water (20 mL) and extracted with CHCl (2 × 20 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure to give 1-chloro-2,5-difluoro-4-nitrobenzene (400 mg, 1.73 mmol, 67%) as a yellow solid. 1 H NMR (500 MHz, CDCl3): δ 7.97 (d, J = 9.3 Hz, 2H), 7.37 (d, J = 6.4 Hz, 1H), 2.57-2.54 (m, 1H), 1.00-0.91 (m, 2H), 0.71-0.59 (m, 2H)

[0416] 5-Chloro-N 1 -Cyclopropyl-4-fluorobenzene-1,2-diamine (Intermediate-23) To a stirred solution of 1-chloro-2,5-difluoro-4-nitrobenzene (400 mg, 1.74 mmol) in EtOAc (10 mL) at room temperature under an inert atmosphere was added 10% Pd / C (50% aqueous, 100 mg). The reaction mixture was evacuated and stirred at room temperature under a hydrogen atmosphere (balloon pressure) for 5 hours. After the starting material was consumed (by TLC), the reaction mixture was filtered through a pad of Celite and the bed was washed with EtOAc (40 mL). The filtrate was concentrated under reduced pressure to give 5-chloro-N 1 -cyclopropyl-4-fluorobenzene-1,2-diamine Intermediate-23 (280 mg, 1.40 mmol, 81%) was obtained as an off-white solid. 1H NMR (500 MHz, DMSO-d6): δ 6.68 (d, J = 7.5 Hz, 1H), 6.47 (d, J = 11.6 Hz, 1H), 5.16 (br s, 1H), 4.96 (br s, 2H), 2.34-2.27 (m, 1H), 0.74-0.67 (m, 2H), 0.42-0.28 (m, 2H)

[0417] Preparation of Intermediate-24 Scheme:

[0418] [ka]

[0419] 4-Chloro-N-cyclopropyl-2-nitroaniline To 4-chloro-1-fluoro-2-nitrobenzene (2 g, 11.43 mmol) was added dropwise cyclopropanamine (2.6 g, 45.71 mmol) under an inert atmosphere at 10 °C. The reaction mixture was gradually warmed to room temperature and stirred for 5 h. After the starting material was consumed (by TLC), the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2 × 50 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 3–5% EtOAc / hexane) to give 4-chloro-N-cyclopropyl-2-nitroaniline (2.08 g, 0.98 mmol, 83%) as a yellow solid. 1 H NMR (500 MHz, CDCl3): δ 8.16 (d, J = 2.2 Hz, 1H), 8.04 (br s, 1H), 7.42 (dd, J = 8.8, 2.2 Hz, 1H), 7.29 (d, J = 9.3 Hz, 1H), 2.61-2.55 (m, 1H), 0.96-0.90 (m, 2H), 0.69-0.63 (m, 2H) LC-MS: m / z 213.1 [M+H] at retention time 2.85 + (99.81% purity)

[0420] 4-Chloro-N 1 -Cyclopropylbenzene-1,2-diamine (Intermediate-24) To a stirred solution of 4-chloro-N-cyclopropyl-2-nitroaniline (1 g, 4.72 mmol) in methanolic ammonia (2 M, 50 mL) was added Raney nickel (500 mg) under an inert atmosphere at room temperature. The reaction mixture was stirred under a hydrogen atmosphere (balloon pressure) at room temperature for 4 hours. After the starting material was consumed (by TLC), the reaction mixture was filtered through a pad of Celite and the bed was washed with ethyl acetate (30 mL). The filtrate was concentrated under reduced pressure to give 4-chloro-N-cyclopropyl-2-nitroaniline (1 g, 4.72 mmol). 1 -Cyclopropylbenzene-1,2-diamine Intermediate-24 (700 mg) was obtained as a brown liquid, which was used crude in the next step without further purification. 1 H NMR (500 MHz, DMSO-d6): δ 6.70 (d, J = 8.3 Hz, 1H), 6.55-6.45 (m, 2H), 5.10 (s, 1H), 4.77 (br s, 2H), 2.31-2.29 (m, 1H), 0.72-0.65 (m, 2H), 0.41-0.34 (m, 2H) LC-MS: m / z 183.1 [M+H] at retention time 2.15 + (87.51% purity)

[0421] Preparation of Intermediate-25 Scheme:

[0422] [ka]

[0423] 3-chloro-N-cyclopropyl-2-nitroaniline To 1-chloro-3-fluoro-2-nitrobenzene (500 mg, 2.85 mmol) was added cyclopropanamine (0.78 mL, 11.4 mmol) dropwise under an inert atmosphere at room temperature and stirred for 4 hours. After the starting material was consumed (by TLC), the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2 × 30 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure to give 3-chloro-N-cyclopropyl-2-nitroaniline (500 mg) as a yellow solid. The crude product was used in the next step without further purification. 1 H NMR (400 MHz, CDCl3): δ 7.28-7.22 (m, 1H), 7.15 (dd, J = 8.5, 1.3 Hz, 1H), 6.80 (dd, J = 7.8, 1.3 Hz, 1H), 6.01 (br s, 1H), 2.54-2.46 (m, 1H), 0.88-0.82 (m, 2H), 0.60-0.55 (m, 2H). LC-MS: m / z 213.1 [M+H] with retention time 2.74 + (98.57% purity)

[0424] 3-Chloro-N 1 -Cyclopropylbenzene-1,2-diamine (Intermediate-25) To a stirred solution of 3-chloro-N-cyclopropyl-2-nitroaniline (200 mg, crude) in acetic acid (2 mL) was added iron powder (157 mg, 2.83 mmol) at room temperature under an inert atmosphere. The reaction mixture was heated to 80 °C and stirred for 1 h. After the starting material was consumed (by TLC), the reaction mixture was quenched with saturated NaHCO3 solution (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 3-chloro-N 1 -Cyclopropylbenzene-1,2-diamine Intermediate-25 (200 mg) was obtained as a brown syrup, which was used crude in the next step without further purification. LC-MS: m / z 183.0[M+H] at retention time 2.47 + (purity 43.71%)

[0425] Preparation of Intermediate-26 Scheme:

[0426] [ka]

[0427] 4-Isopropyl-2-(trifluoromethyl)oxazol-5(2H)-one To DL-valine (30 g, 256.41 mmol) was added trifluoroacetic anhydride (72 mL) dropwise at room temperature. The reaction mixture was heated to reflux and stirred for 8 hours. After the starting material was consumed (by TLC), the reaction mixture was diluted with water (100 mL) and extracted with CHCl (250 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure to give 4-isopropyl-2-(trifluoromethyl)oxazol-5(2H)-one 2 (45 g) as a pale yellow liquid. The crude product was used in the next step without further purification. 1 H NMR (400 MHz, CDCl3): δ 6.11-6.05 (m, 1H), 3.12-3.02 (m, 1H), 1.34 (d, J = 3.0 Hz, 3H), 1.32 (d, J = 3.0 Hz, 3H) LC-MS: m / z 193.9 [M−H] at retention time 2.94 - (75.69% purity)

[0428] Diethyl 2-((4-isopropyl-5-oxo-2-(trifluoromethyl)-2,5-dihydrooxazol-2-yl)methyl)malonate To a stirred solution of 4-isopropyl-2-(trifluoromethyl)oxazol-5(2H)-one (45 g, crude) in CHCl (450 mL) under an inert atmosphere at 0 °C, diethyl 2-methylenemalonate (47.63 g, crude) and triethylamine (48.2 mL, 346.14 mmol) were added. The reaction mixture was warmed to room temperature and stirred for 16 h. After the starting material was consumed (by TLC), the reaction mixture was diluted with water (150 mL) and extracted with CHCl (2 × 250 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure to give diethyl 2-((4-isopropyl-5-oxo-2-(trifluoromethyl)-2,5-dihydrooxazol-2-yl)methyl)malonate (50 g, crude) as a pale yellow solid. The crude product was used in the next step without further purification. LC-MS: m / z 368.1[M+H] at retention time 3.70 + (purity 82.98%)

[0429] Ethyl 3-oxo-6-(trifluoromethyl)-2,3,4,5-tetrahydropyridazine-4-carboxylate To a stirred solution of diethyl 2-((4-isopropyl-5-oxo-2-(trifluoromethyl)-2,5-dihydrooxazol-2-yl)methyl)malonate (25 g, crude) in acetic acid (200 mL) was added hydrazine hydrochloride (23.16 g, 340.59 mmol) at room temperature under an inert atmosphere. The reaction mixture was heated to reflux and stirred for 3 h. After the starting material was consumed (by TLC), the reaction mixture was basified with saturated sodium bicarbonate solution and extracted with EtOAc (2 × 250 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 30–40% EtOAc / hexanes) to give ethyl 3-oxo-6-(trifluoromethyl)-2,3,4,5-tetrahydropyridazine-4-carboxylate (15 g, 63.55 mmol) as a pale yellow liquid. LC-MS: retention time 2.19, m / z 237.0 [MH] - (purity 87.20%)

[0430] Ethyl 3-hydroxy-6-(trifluoromethyl)pyridazine-4-carboxylate To a stirred solution of ethyl 3-oxo-6-(trifluoromethyl)-2,3,4,5-tetrahydropyridazine-4-carboxylate (7.5 g, 31.51 mmol) in acetic acid (40 mL) was added a solution of bromine (5.03 g, 31.51 mmol) in acetic acid (35 mL) at 0 °C under an inert atmosphere. The reaction mixture was warmed to room temperature and stirred for 1 h. After the starting material was consumed (by TLC), the reaction mixture was basified with saturated sodium bicarbonate solution and extracted with EtOAc (2 × 200 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 30–40% EtOAc / hexanes) to afford ethyl 3-hydroxy-6-(trifluoromethyl)pyridazine-4-carboxylate (2.5 g, 10.59 mmol, 34%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ 14.16 (br s, 1H), 8.12 (s, 1H), 4.30 (q, J = 7.1 Hz, 2H), 1.29 (t, J = 7.2 Hz, 3H) LC-MS: m / z 235.0 [M−H] at retention time 2.03 - (98.67% purity)

[0431] Ethyl 3-chloro-6-(trifluoromethyl)pyridazine-4-carboxylate To a stirred solution of ethyl 3-hydroxy-6-(trifluoromethyl)pyridazine-4-carboxylate (5.0 g, 21.19 mmol) in 1,4-dioxane (50 mL) was added phosphoryl trichloride (19.6 mL, 211.86 mmol) under an inert atmosphere at 0 °C. The reaction mixture was heated to 100 °C and stirred for 4 h. After the starting material was consumed (by TLC), the reaction mixture was basified with sodium bicarbonate solution (100 mL) and extracted with EtOAc (2 × 200 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 15–20% EtOAc / hexanes) to give ethyl 3-chloro-6-(trifluoromethyl)pyridazine-4-carboxylate (3 g, 11.81 mmol, 55%) as a pale yellow liquid. 1 H NMR (500 MHz, CDCl3): δ 8.15 (s, 1H), 4.53 (q, J = 7.0 Hz, 2H), 1.47 (t, J = 7.2 Hz, 3H) LC-MS: m / z 255.4 [M+H] with retention time 3.61 + (98.51% purity)

[0432] Ethyl 6-(trifluoromethyl)pyridazine-4-carboxylate To a stirred solution of ethyl 3-chloro-6-(trifluoromethyl)pyridazine-4-carboxylate (500 mg, 1.96 mmol) in ethanol (10 mL) at room temperature under an inert atmosphere was added triethylamine (0.5 mL) and 10% Pd / C (50% aqueous, 100 mg). The headspace of the reaction was briefly evacuated and quickly refilled with hydrogen. The reaction mixture was stirred at room temperature under a hydrogen atmosphere (balloon pressure) for 1 hour. After the starting material was consumed (by TLC), the reaction mixture was filtered through a pad of Celite and washed with EtOAc (50 mL). The filtrate was concentrated under reduced pressure. The resulting crude material was purified by silica gel column chromatography (eluent: 30% EtOAc / hexanes) to afford ethyl 6-(trifluoromethyl)pyridazine-4-carboxylate (300 mg, 1.36 mmol, 69%) as an off-white solid. 1 H NMR (400 MHz, CDCl3): δ 9.85 (d, J = 1.8 Hz, 1H), 8.32 (d, J = 1.9 Hz, 1H), 4.53 (q, J = 7.2 Hz, 2H), 1.47 (t, J = 7.2 Hz, 3H) LC-MS: m / z 221.1 [M+H] with retention time 3.09 + (92.69% purity)

[0433] 6-(Trifluoromethyl)pyridazine-4-carboxylic acid (Intermediate-26) To a stirred solution of ethyl 6-(trifluoromethyl)pyridazine-4-carboxylate (300 mg, 1.36 mmol) in a 4:1 mixture of THF and water (5 mL) was added lithium hydroxide (171.6 g, 4.09 mmol) at 0 °C. The reaction mixture was gradually warmed to room temperature and stirred for 1 h. After the starting material was consumed (by TLC), the volatiles were concentrated under reduced pressure. The residue was then acidified using concentrated HCl (pH 3–4) and extracted with EtOAc (2 × 30 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure. The resulting solid was washed with n-pentane (10 mL) and evaporated to dryness to afford 6-(trifluoromethyl)pyridazine-4-carboxylic acid Intermediate-26 (210 mg) as an off-white solid. The crude material was used in the next step without further purification. 1 H NMR (400 MHz, DMSO-d6): δ 14.08 (brs, 1H), 9.83 (brs, 1H), 8.43 (brs, 1H) LC-MS: m / z 191.0 [M−H] at retention time 3.79 - (94.51% purity)

[0434] Preparation of Intermediate-27 Scheme:

[0435] [ka]

[0436] 1-Cyclopropyl-5,6-difluoro-2-(6-vinylpyridazin-4-yl)-1H-benzo[d]imidazole To a stirred solution of 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole (Example 22) (150 mg, 0.50 mmol) in 1,4-dioxane (3 mL) and water (0.5 mL) was added vinylboronic acid pinacol ester (76 mg, 0.50 mmol) and potassium carbonate (203 mg, 1.47 mmol) at room temperature under an inert atmosphere. The reaction mixture was degassed with argon for 10 minutes. Pd(dppf)Cl (4 mg, 0.005 mmol) was added at room temperature, and the mixture was degassed with argon for 10 minutes. The reaction mixture was heated to 80° C. and stirred for 5 hours. After the starting material was consumed (by TLC), the volatiles were concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 50% EtOAc / hexanes) to afford 1-cyclopropyl-5,6-difluoro-2-(6-vinylpyridazin-4-yl)-1H-benzo[d]imidazole (70 mg, 0.23 mmol, 48%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ 9.69 (s, 1H), 8.45 (s, 1H), 7.90-7.83 (m, 2H), 7.18-7.11 (m, 1H), 6.53 (d, J = 17.7 Hz, 1H), 5.82 (d, J = 11.4 Hz, 1H), 3.99-3.97 (m, 1H), 1.22-1.13 (m, 2H), 0.82-0.60 (m, 2H)

[0437] 5-(1-Cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-carbaldehyde (Intermediate-27) 1-Cyclopropyl-5,6-difluoro-2-(6-vinylpyridazin-4-yl)-1H-benzo[d]imidazole (300 mg, 1.00 mmol) in acetone: tTo a stirred solution of BuOH:water (1:1:1, 18 mL) under an inert atmosphere at 0 °C, sodium periodate (430 mg, 2.01 mmol) and osmium tetroxide (1 M solution, 6 mL) were added. The reaction mixture was warmed to room temperature and stirred for 1 h. After the starting material was consumed (by TLC), the reaction mixture was filtered through a pad of Celite, and the Celite bed was washed with EtOAc (100 mL). The organic layer was washed with water (100 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 2% MeOH / CHCl) to give 5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-carbaldehyde Intermediate-27 (200 mg) as a black solid. The crude product was used without further purification. 1 H NMR (500 MHz, DMSO-d6): δ 10.36 (s, 1H), 10.03 (s, 1H), 8.58 (s, 1H), 7.93-7.81 (m, 2H), 4.00-3.94 (m, 1H), 1.21-1.13 (m, 2H), 0.81-0.72 (m, 2H)

[0438] Preparation of Intermediate-28 Scheme:

[0439] [ka]

[0440] (E)-5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-carbaldehyde oxime To a stirred solution of 5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-carbaldehyde Intermediate-27 (600 mg, 2 mmol) in ethanol (10 mL) was added hydroxylamine hydrochloride (276 mg, 4 mmol) and potassium carbonate (552 mg, 4 mmol) at room temperature under an inert atmosphere. The reaction mixture was heated to 80 °C and stirred for 3 h. After the starting material was consumed (by TLC), the reaction mixture was concentrated under reduced pressure. The residue was diluted with water (70 mL) and extracted with CHCl (100 mL). The organic layer was dried over anhydrous NaSO and concentrated under reduced pressure. The crude material was washed with n-hexane (20 mL) and evaporated to dryness in vacuo to give (E)-5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-carbaldehyde oxime (500 mg, 1.58 mmol, 79%) as an off-white solid. 1 H NMR (500 MHz, DMSO-d6): δ 12.26 (s, 1H), 9.80 (d, J = 1.7 Hz, 1H), 8.56 (d, J = 2.3 Hz, 1H), 8.48 (s, 1H), 7.91-7.80 (m, 2H), 3.97-3.88 (m, 1H), 1.22-1.14 (m, 2H), 0.85-0.78 (m, 2H) LC-MS: m / z 315.9 [M+H] with retention time 2.33 + (97.99% purity)

[0441] (5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methanamine (Intermediate-28) To a stirred solution of (E)-5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-carbaldehyde oxime (500 mg, 1.58 mmol) in ethanol (10 mL) was added sodium hydroxide (190 mg, 4.76 mmol) and 10% Pd / C (50% aqueous, 150 mg) under an inert atmosphere at room temperature. The reaction mixture was stirred under a hydrogen atmosphere (balloon pressure) at room temperature for 3 hours. After the starting material was consumed (by TLC), the reaction mixture was filtered through a pad of Celite. The filtrate was concentrated under reduced pressure. The residue was diluted with CHCl (80 mL) and washed with water (50 mL). The organic layer was dried over anhydrous NaSO and concentrated under reduced pressure to give (5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-ylmethanamine Intermediate-28 (400 mg, 1.32 mmol, 84%) as an off-white solid. The crude material was used in the next step without further purification. 1 H NMR (500 MHz, DMSO-d6): δ 9.68 (d, J = 1.7 Hz, 1H), 8.35 (d, J = 1.7 Hz, 1H), 7.89-7.81 (m, 2H), 4.12 (s, 2H), 3.95-3.89 (m, 1H), 2.13 (brs, 2H), 1.27-1.14 (m, 2H), 0.79-0.66 (m, 2H) LC-MS: m / z 301.9 [M+H] at retention time 1.91 + (95.51% purity)

[0442] Preparation of Intermediate-29 Scheme:

[0443] [ka]

[0444] 6-(Difluoromethyl)pyridazine-4-carboxylic acid (Intermediate-29) was prepared in a similar manner to Intermediate-26 starting from alanine and difluoroacetic anhydride (DFAA).

[0445] Preparation of Intermediate-30 Scheme:

[0446] [ka]

[0447] 1-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)ethan-1-one oxime To a stirred solution of 1-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)ethan-1-one Example 64 (170 mg, 0.54 mmol) in EtOH (10 mL) under an inert atmosphere at 0 °C, hydroxylamine hydrochloride (75 mg, 1.08 mmol) and potassium carbonate (149 mg, 1.08 mmol) were added. The reaction mixture was heated to 80 °C and stirred for 3 h. After the starting material was consumed (by TLC), the volatiles were concentrated under reduced pressure. The residue was diluted with water (30 mL) and extracted with CHCl (2 × 40 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure to give 1-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)ethan-1-one oxime (100 mg) as an off-white solid. The crude product was used in the next step without further purification. 1 H NMR (500 MHz, DMSO-d6): δ 12.07 (s, 1H), 9.81 (d, J = 1.7 Hz, 1H), 8.63 (d, J = 1.7 Hz, 1H), 7.91-7.80 (m, 2H), 3.94-3.87 (m, 1H), 2.41 (s, 3H), 1.21-1.14 (m, 2H), 0.85-0.76 (m, 2H) LC-MS: m / z 329.9 [M+H] at retention time 2.52 + (86.46% purity)

[0448] 1-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)ethan-1-amine (Intermediate-30) To a stirred solution of 1-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)ethan-1-one oxime (100 mg, crude) in ethanol (10 mL) was added sodium hydroxide (37 mg, 0.91 mmol) and 10% Pd / C (50% aqueous, 80 mg) at room temperature under an inert atmosphere. The reaction mixture was stirred at room temperature under a hydrogen atmosphere (balloon pressure) for 8 hours. After the starting material was consumed (by TLC), the reaction mixture was filtered through a pad of Celite, and the Celite bed was washed with MeOH (20 mL). The filtrate was concentrated under reduced pressure. The residue was diluted with water (20 mL) and extracted with CHCl (2 × 30 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure to give 1-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)ethan-1-amine Intermediate-30 (80 mg) as an off-white solid. The crude product was used without further purification. LC-MS: m / z 315.9[M+H] at retention time 1.71 + (purity 85.70%)

[0449] Example 1 Scheme:

[0450] [ka]

[0451] N-(2-(cyclopropylamino)-4-fluorophenyl)pyridazine-4-carboxamide N 1To a stirred solution of 1-cyclopropyl-5-fluorobenzene-1,2-diamine intermediate-1 (300 mg, 1.81 mmol) in N,N-dimethylformamide (DMF) (3 mL) was added pyridazine-4-carboxylic acid (224 mg, 1.81 mmol), N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide (HATU) (824 mg, 2.17 mmol), and ethyldiisopropylamine (1.26 mL, 7.23 mmol) at room temperature under an inert atmosphere. The reaction mixture was stirred at room temperature for 8 hours. After the starting material was consumed (by TLC), the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2 × 30 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 50% EtOAc / hexanes) to afford N-(2-(cyclopropylamino)-4-fluorophenyl)pyridazine-4-carboxamide (220 mg, 0.81 mmol, 44%) as a brown solid. 1 H NMR (400MHz, DMSO-d6): δ 9.89 (s, 1H), 9.66 (dd, J = 2.2, 1.3 Hz, 1H), 9.47 (dd, J = 5.2, 1.1 Hz, 1H), 8.12 (dd, J = 5.3, 2.3 Hz, 1H), 7.13 (dd, J = 8.5, 6.4 Hz, 1H), 6.75 (dd, J = 11.9, 2.9 Hz, 1H), 6.43 (td, J = 8.5, 2.9 Hz, 1H), 6.12 (s, 1H), 2.38-2.32 (m, 1H), 0.77-0.71 (m, 2H), 0.47-0.40 (m, 2H). LC-MS: m / z 272.9 [M+H] at retention time 2.66 + (89.14% purity).

[0452] 1-Cyclopropyl-6-fluoro-2-(pyridazin-4-yl)-1H-benzo[d]imidazole (Example 1) N-(2-(cyclopropylamino)-4-fluorophenyl)pyridazine-4-carboxamide (150 mg, 0.55 mmol) in acetic acid (3 mL) was heated to 100 °C under an inert atmosphere and stirred for 8 h. After the starting material was consumed (by TLC), the reaction mixture was neutralized with saturated sodium bicarbonate solution (50 mL) and extracted with EtOAc (2 × 30 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 5% MeOH / CHCl) to give 1-cyclopropyl-6-fluoro-2-(pyridazin-4-yl)-1H-benzo[d]imidazole Example 1 (68 mg, 0.27 mmol, 48%) as an off-white solid. 1 H NMR (400MHz, DMSO-d6): δ 9.82 (dd, J = 2.2, 1.3 Hz, 1H), 9.45 (dd, J = 5.4, 1.1 Hz, 1H), 8.29 (dd, J = 5.4, 2.4 Hz, 1H), 7.79 (dd, J = 8.9, 4.9 Hz, 1H), 7.55 (dd, J = 9.1, 2.4 Hz, 1H), 7.22-7.15 (m, 1H), 3.94-3.87 (m, 1H), 1.22-1.16 (m, 2H), 0.78-0.73 (m, 2H). LC-MS: m / z 255.0 [M+H] at retention time 2.98 + (97.13% purity). HPLC: 98.24%.

[0453] Examples 2 and 3 Scheme:

[0454] [ka]

[0455] 6-chloro-N-(2-(cyclopropylamino)-4-fluorophenyl)pyridazine-4-carboxamide N 1To a stirred solution of 5-cyclopropyl-5-fluorobenzene-1,2-diamine intermediate-1 (500 mg, 3.01 mmol) in DMF (3 mL) was added 6-chloropyridazine-4-carboxylic acid (475 mg, 3.01 mmol), HATU (1.37 g, 3.61 mmol), and ethyldiisopropylamine (2.2 mL, 12.04 mmol) at room temperature under an inert atmosphere. The reaction mixture was stirred at room temperature for 4 hours. After the starting material was consumed (by TLC), the reaction mixture was quenched with ice-cold water (30 mL) and extracted with EtOAc (2 × 30 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 20% EtOAc / hexane) to afford 6-chloro-N-(2-(cyclopropylamino)-4-fluorophenyl)pyridazine-4-carboxamide (550 mg, 1.79 mmol, 60%) as a brown solid. 1 H NMR (500MHz, DMSO-d6): δ 9.96 (s, 1H), 9.63 (d, J = 1.4 Hz, 1H), 8.36 (d, J = 1.2 Hz, 1H), 7.13 (dd, J = 8.4, 6.7 Hz, 1H), 6.75 (dd, J = 11.7, 2.7 Hz, 1H), 6.43 (td, J = 8.5, 2.7 Hz, 1H), 6.14 (s, 1H), 2.37-2.33 (m, 1H), 0.77-0.73 (m, 2H), 0.46-0.42 (m, 2H). LC-MS: retention time 3.00, m / z 305.0 [M−H] + (83.53% purity).

[0456] 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-6-fluoro-1H-benzo[d]imidazole (Example 3) To a stirred solution of 6-chloro-N-(2-(cyclopropylamino)-4-fluorophenyl)pyridazine-4-carboxamide (550 mg, 1.79 mmol) in CHCl (10 mL) was added trifluoroacetic acid (0.6 mL) dropwise at room temperature under an inert atmosphere. The reaction mixture was stirred at room temperature for 16 hours. After the starting material was consumed (by TLC), the volatiles were removed under reduced pressure. The residue was diluted with EtOAc (50 mL) and washed with saturated sodium bicarbonate solution (20 mL). The organic layer was separated, dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 50% EtOAc / hexane) to give 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-6-fluoro-1H-benzo[d]imidazole Example 3 (200 mg, 0.69 mmol, 38%) as an off-white solid. 1 H NMR (500MHz, DMSO-d6): δ 9.82 (s, 1H), 8.46 (s, 1H), 7.81 (dd, J = 9.0, 4.9 Hz, 1H), 7.58 (dd, J = 9.0, 2.0 Hz, 1H), 7.21 (td, J = 9.3, 2.2 Hz, 1H), 3.97-3.93 (m, 1H), 1.22-1.17 (m, 2H), 0.83-0.79 (m, 2H). LC-MS: m / z 288.9 [M+H] with retention time 2.59 + (98.16% purity). HPLC: 98.76%.

[0457] 5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-carbonitrile (Example 2) To a stirred solution of 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-6-fluoro-1H-benzo[d]imidazole Example 2 (100 mg, 0.35 mmol) in DMF (1 mL) was added Zn(CN) (24 mg, 0.21 mmol) at room temperature under an inert atmosphere. The reaction mixture was degassed under argon for 10 minutes. Pd(dba) (16 mg, 0.02 mmol) and Pd(dppf)Cl (13 mg, 0.02 mmol) were added at room temperature, and the reaction mixture was degassed under argon for 5 minutes. The reaction mixture was heated to 100 °C and stirred for 2 hours. After the starting material was consumed (by TLC), the reaction mixture was diluted with EtOAc (40 mL), filtered through a pad of Celite, and the Celite bed was washed with EtOAc (15 mL). The organic layer was washed with water (20 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 40% EtOAc / hexanes) to give 5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-carbonitrile Example 2 (30 mg, 0.11 mmol, 31%) as an off-white solid. 1 H NMR (500MHz, DMSO-d6): δ 10.06 (d, J = 1.7 Hz, 1H), 8.92 (d, J = 1.7 Hz, 1H), 7.83 (dd, J = 8.7, 4.9 Hz, 1H), 7.59 (dd, J = 9.0, 2.0 Hz, 1H), 7.25-7.20 (m, 1H), 3.98-3.93 (m, 1H), 1.24-1.19 (m, 2H), 0.82-0.78 (m, 2H). LC-MS: m / z 279.8 [M+H] with retention time 2.92 + (99.44% purity). HPLC: 99.21%.

[0458] Example 4 Scheme:

[0459] [ka]

[0460] 1-Cyclopropyl-6-fluoro-2-(6-vinylpyridazin-4-yl)-1H-benzo[d]imidazole (Example 4) To a stirred solution of 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-6-fluoro-1H-benzo[d]imidazole (Example 3) (300 mg, 1.04 mmol) in a mixture of 1,4-dioxane (15 mL) and water (2 mL) was added potassium carbonate (431 mg, 3.12 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (160 mg, 1.04 mmol) at room temperature under an inert atmosphere. The reaction mixture was degassed under argon for 15 minutes. To this was added Pd(dppf)Cl.CHCl (8.5 mg, 0.01 mmol) at room temperature. The reaction mixture was heated to 80° C. and stirred for 4 hours. After the starting material was consumed (by TLC), the reaction mixture was diluted with EtOAc (60 mL) and filtered through a pad of Celite, washing the Celite bed with EtOAc (15 mL). The organic layer was washed with water (20 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 40% EtOAc / hexane) to give 1-cyclopropyl-6-fluoro-2-(6-vinylpyridazin-4-yl)-1H-benzo[d]imidazole Example 4 (150 mg, 0.53 mmol, 51%) as an off-white solid. 1 H NMR (500MHz, DMSO-d6): δ 9.68 (d, J = 1.7 Hz, 1H), 8.44 (d, J = 1.7 Hz, 1H), 7.78 (dd, J = 9.0, 4.9 Hz, 1H), 7.55 (dd, J = 9.0, 2.3 Hz, 1H), 7.21-7.09 (m, 2H), 6.52 (d, J = 17.6 Hz, 1H), 5.80 (d, J = 11.0 Hz, 1H), 3.97-3.93 (m, 1H), 1.20-1.14 (m, 2H), 0.77-0.72 (m, 2H). LC-MS: m / z 280.9 [M+H] with retention time 2.43+ (93.90% purity). HPLC: 95.00%.

[0461] Example 5 Scheme:

[0462] [ka]

[0463] Methyl 5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-carboxylate (Example 5) To a stirred solution of 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-6-fluoro-1H-benzo[d]imidazole Example 3 (200 mg, 0.69 mmol) in MeOH (3 mL) was added sodium acetate (171 mg, 2.08 mmol), 1,1'-ferrocenediyl-bis(diphenylphosphine) (19 mg, 0.03 mmol), and palladium(II) acetate (7.8 mg, 0.03 mmol) at room temperature in a steel bomb. The steel bomb was charged with CO gas (15 bar pressure). The resulting reaction mixture was stirred at 50 °C for 2 h. After the starting material was consumed (by TLC), the reaction mixture was filtered through a pad of Celite, and the Celite bed was washed with methanol (30 mL). The filtrate was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 50% EtOAc / hexanes) to give methyl 5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-carboxylate Example 5 (70 mg, 0.22 mmol, 32%) as an off-white solid. 1H NMR (500MHz, DMSO-d6): δ 10.04 (d, J = 2.0 Hz, 1H), 8.74 (d, J = 2.0 Hz, 1H), 7.82 (dd, J = 9.0, 4.9 Hz, 1H), 7.57 (dd, J = 9.1, 2.5 Hz, 1H), 7.21 (td, J = 9.3, 2.3 Hz, 1H), 4.03 (s, 3H), 3.99-3.95 (m, 1H), 1.23-1.18 (m, 2H), 0.82-0.78 (m, 2H). LC-MS: m / z 312.9 [M+H] at retention time 2.36 + (95.19% purity). HPLC: 99.01%.

[0464] Example 6 Scheme:

[0465] [ka]

[0466] 1-Cyclopropyl-2-(6-ethylpyridazin-4-yl)-6-fluoro-1H-benzo[d]imidazole (Example 6) To a stirred solution of 1-cyclopropyl-6-fluoro-2-(6-vinylpyridazin-4-yl)-1H-benzo[d]imidazole Example 4 (70 mg, 0.25 mmol) in ethyl acetate (8 mL) at room temperature under an inert atmosphere, triethylamine (catalyst) and 10% Pd / C (50% aqueous, 20 mg) were added. The reaction mixture was evacuated and stirred at room temperature under a hydrogen atmosphere (balloon pressure) for 3 hours. After the starting material was consumed (by TLC), the reaction mixture was filtered through a pad of Celite, and the Celite bed was washed with EtOAc (40 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 5% MeOH / CHCl) to give 1-cyclopropyl-2-(6-ethylpyridazin-4-yl)-6-fluoro-1H-benzo[d]imidazole Example 6 (50 mg, 0.18 mmol, 67%) as an off-white solid. 1 H NMR (400MHz, DMSO-d6): δ 9.66 (d, J = 2.1 Hz, 1H), 8.18 (d, J = 2.0 Hz, 1H), 7.78 (dd, J = 8.8, 4.9 Hz, 1H), 7.55 (dd, J = 9.0, 2.4 Hz, 1H), 7.22-7.14 (m, 1H), 3.95-3.90 (m, 1H), 3.07 (q, J = 7.6 Hz, 2H), 1.37 (t, J = 7.7 Hz, 3H), 1.21-1.15 (m, 2H), 0.77-0.71 (m, 2H). LC-MS: m / z 282.9 [M+H] with retention time 2.37 + (98.84% purity). HPLC: 98.29%.

[0467] Example 7 Scheme:

[0468] [ka]

[0469] 1-(5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)-2,2,2-trifluoroethan-1-ol (Example 7) To a stirred solution of 5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-carbaldehyde intermediate-2 (50 mg, 0.18 mmol) in THF (3 mL) was added trimethyl(trifluoromethyl)silane (0.05 mL, 0.35 mmol) under an inert atmosphere at 0 °C. Cesium fluoride (81 mg, 0.53 mmol) was added, and the reaction was stirred at room temperature for 16 h. After the starting material was consumed (by TLC), the reaction mixture was quenched with saturated ammonium chloride solution (15 mL) and extracted with EtOAc (2 × 15 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 5% MeOH / CH2Cl2) to give 1-(5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)-2,2,2-trifluoroethan-1-ol Example 7 (15 mg, 0.04 mmol, 24%) as an off-white solid. 1 H NMR (400MHz, CD3OD): δ 9.83 (d, J = 2.1 Hz, 1H), 8.57 (d, J = 2.1 Hz, 1H), 7.76 (dd, J = 8.9, 4.8 Hz, 1H), 7.52 (dd, J = 8.8, 2.3 Hz, 1H), 7.20-7.13 (m, 1H), 5.54 (q, J = 6.9 Hz, 1H), 3.90-3.85 (m, 1H), 1.33-1.20 (m, 2H), 0.87-0.79 (m, 2H). LC-MS: m / z 352.9 [M+H] with retention time 2.59 + (96.11% purity). HPLC: 93.29%.

[0470] Example 8 Scheme:

[0471] [ka]

[0472] N-((5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methyl)propionamide (Example 8) To a stirred solution of (5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methanamine Intermediate-3 (140 mg, 0.49 mmol) in CHCl (5 mL) under an inert atmosphere at 0 °C, propionyl chloride (0.05 mL, 0.59 mmol) and triethylamine (0.14 mL, 0.1 mmol) were added. The reaction mixture was stirred at 0 °C for 3 h. After the starting material was consumed (by TLC), the reaction mixture was diluted with water (20 mL) and extracted with CHCl (2 × 20 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure. The crude material was purified by preparative high performance liquid chromatography (HPLC) to give N-((5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methyl)propionamide Example 8 (40 mg, 0.12 mmol, 24%) as a white solid. 1 H NMR (500MHz, DMSO-d6): δ 9.72 (d, J = 1.4 Hz, 1H), 8.60 (br t, J = 5.1 Hz, 1H), 8.13 (d, J = 1.4 Hz, 1H), 7.79 (dd, J = 8.7, 4.9 Hz, 1H), 7.54 (dd, J = 9.0, 2.0 Hz, 1H), 7.18 (td, J = 9.8, 2.3 Hz, 1H), 4.67 (d, J = 6.1 Hz, 2H), 3.89-3.84 (m, 1H), 2.22 (q, J = 7.5 Hz, 2H), 1.25-1.16 (m, 2H), 1.04 (t, J = 7.7 Hz, 3H), 0.77-0.71 (m, 2H). LC-MS: m / z 340.1 [M+H] at retention time 2.07 + (99.22% purity). HPLC: 99.08%.

[0473] Example 9 Scheme:

[0474] [ka]

[0475] Ethyl ((5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methyl)carbamate (Example 9) To a stirred solution of (5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methanamine Intermediate-3 (125 mg, 0.44 mmol) in THF (6 mL) was added ethyl chloroformate (0.05 mL, 0.53 mmol) and triethylamine (0.12 mL, 0.88 mmol) under an inert atmosphere at 0 °C. The reaction mixture was warmed to room temperature and stirred for 3 h. After the starting material was consumed (by TLC), the reaction mixture was diluted with saturated ammonium chloride solution (20 mL) and extracted with EtOAc (2 × 20 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure. The crude material was purified by preparative HPLC to afford ethyl ((5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methyl)carbamate Example 9 (40 mg, 0.11 mmol, 26%) as an off-white solid. 1 H NMR (400MHz, DMSO-d6): δ 9.75 (d, J = 2.1 Hz, 1H), 8.18 (d, J = 2.0 Hz, 1H), 7.93 (br t, J = 6.0 Hz, 1H), 7.79 (dd, J = 8.9, 4.9 Hz, 1H), 7.55 (dd, J = 9.1, 2.4 Hz, 1H), 7.22-7.15 (m, 1H), 4.60 (d, J = 6.1 Hz, 2H), 4.03 (q, J = 7.1 Hz, 2H), 3.91-3.84 (m, 1H), 1.22-1.16 (m, 5H), 0.78-0.73 (m, 2H). LC-MS: m / z 356.1 [M+H] with retention time 2.33 + (98.62% purity). HPLC: 99.15%.

[0476] Example 10 Scheme:

[0477] [ka]

[0478] 4-(5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)morpholine (Example 10) To a stirred solution of 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-6-fluoro-1H-benzo[d]imidazole Example 3 (150 mg, 0.52 mmol) in ethanol (0.9 mL) was added triethylamine (0.11 mL, 0.78 mmol) and morpholine (0.07 mL, 0.78 mmol) at room temperature under an inert atmosphere. The reaction mixture was heated to 90 °C and stirred for 16 h. After the starting material was consumed (by TLC), the reaction mixture was quenched with saturated ammonium chloride solution (20 mL) and extracted with CHCl (2 × 20 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 100% EtOAc) to give 4-(5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)morpholine Example 10 (40 mg, 0.12 mmol, 23%) as an off-white solid. 1 H NMR (500MHz, DMSO-d6): δ 9.14 (s, 1H), 7.81-7.71 (m, 2H), 7.53 (br d, J = 7.8 Hz, 1H), 7.16 (br t, J = 7.1 Hz, 1H), 3.93-3.91 (m, 1H), 3.83-3.61 (m, 8H), 1.18-1.16 (m, 2H), 0.75-0.73 (m, 2H). LC-MS: m / z 340.0 [M+H] at retention time 2.33 + (97.11% purity). HPLC: 97.09%.

[0479] Example 11 Scheme:

[0480] [ka]

[0481] 1-Cyclopropyl-6-fluoro-2-(6-(4-(4-fluorophenyl)piperazin-1-yl)pyridazin-4-yl)-1H-benzo[d]imidazole (Example 11) To a stirred solution of 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-6-fluoro-1H-benzo[d]imidazole Example 3 (50 mg, 0.17 mmol) in EtOH (0.3 mL) was added triethylamine (0.036 mL, 0.26 mmol) and 1-(4-fluorophenyl)piperazine (47 mg, 0.26 mmol) at room temperature under an inert atmosphere. The reaction mixture was stirred at 90° C. for 7 hours. After the starting material was consumed (by TLC), the volatiles were evaporated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 90% EtOAc / hexanes) to afford 1-cyclopropyl-6-fluoro-2-(6-(4-(4-fluorophenyl)piperazin-1-yl)pyridazin-4-yl)-1H-benzo[d]imidazole Example 11 (40 mg, 0.09 mmol, 53%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.13 (d, J = 1.6 Hz, 1H), 7.80 (d, J = 1.5 Hz, 1H), 7.77 (dd, J = 8.9, 4.9 Hz, 1H), 7.54 (dd, J = 9.1, 2.4 Hz, 1H), 7.20-7.14 (m, 1H), 7.12-7.02 (m, 4H), 3.96-3.92 (m, 1H), 3.89-3.83 (m, 4H), 3.28-3.24 (m, 4H), 1.21-1.15 (m, 2H), 0.78-0.72 (m, 2H) LC-MS: m / z 433.1 [M+H] at retention time 2.38 + (99.63% purity). HPLC: 96.82%.

[0482] Example 12 Scheme:

[0483] [ka]

[0484] 5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-carbaldehyde (Intermediate-2) 1-Cyclopropyl-6-fluoro-2-(6-vinylpyridazin-4-yl)-1H-benzo[d]imidazole Example 4 (600 mg, 2.14 mmol) in acetone:tert-butanol ( tTo a stirred solution of BuOH:water (1:1:1, 30 mL) under an inert atmosphere at 0 °C, sodium periodate (912 mg, 4.28 mmol) and osmium tetroxide (2.5 wt% in toluene, 3 mL) were added. The reaction mixture was stirred at 0 °C for 5 h. After the starting material was consumed (by TLC), the reaction mixture was filtered and the filter was washed with EtOAc (2 × 30 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 90% EtOAc / hexane) to give 5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-carbaldehyde intermediate-2 (400 mg, 1.41 mmol, 66%) as a brown solid. 1 H NMR (500 MHz, CDCl3): δ 10.52 (s, 1H), 10.08 (s, 1H), 8.65 (s, 1H), 7.81 (dd, J = 9.0, 4.9 Hz, 1H), 7.35 (dd, J = 8.4, 2.3 Hz, 1H), 7.17-7.12 (m, 1H), 3.78-3.67 (m, 1H), 1.39-1.30 (m, 2H), 0.94-0.82 (m, 2H)

[0485] 1-[5-(1-cyclopropyl-6-fluoro-1H-1,3-benzodiazol-2-yl)pyridazin-3-yl]ethan-1-ol To a stirred solution of 5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-carbaldehyde intermediate-2 (200 mg, 0.70 mmol) in THF (6 mL) was added dropwise methylmagnesium bromide (2 M in diethyl ether, 0.35 mL, 0.70 mmol) under an inert atmosphere at −78° C. The reaction mixture was stirred at −78° C. for 1 h. After the starting material was consumed (by TLC), the reaction mixture was quenched with saturated ammonium chloride solution (20 mL) and extracted with EtOAc (2×30 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 2-3% MeOH / CH2Cl2) to give 1-[5-(1-cyclopropyl-6-fluoro-1H-1,3-benzodiazol-2-yl)pyridazin-3-yl]ethan-1-ol (150 mg, 0.50 mmol, 71%) as a brown solid. 1 H NMR (500 MHz, DMSO-d6): δ 9.72 (s, 1H), 8.34 (s, 1H), 7.79 (dd, J = 9.0, 4.9 Hz, 1H), 7.55 (dd, J = 9.0, 2.0 Hz, 1H), 7.23-7.14 (m, 1H), 5.78 (d, J = 4.6 Hz, 1H), 5.16-5.05 (m, 1H), 3.95-3.90 (m, 1H), 1.52 (d, J = 6.7 Hz, 3H), 1.25-1.15 (m, 2H), 0.77-0.75 (m, 2H)

[0486] 1-(5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)ethan-1-one To a stirred solution of 1-[5-(1-cyclopropyl-6-fluoro-1H-1,3-benzodiazol-2-yl)pyridazin-3-yl]ethan-1-ol (100 mg, 0.33 mmol) in CHCl (10 mL) was added Dess-Martin periodinane (213 mg, 0.51 mmol) under an inert atmosphere at 0 °C. The reaction mixture was warmed to room temperature and stirred for 3 h. After the starting material was consumed (by TLC), the reaction mixture was quenched with saturated sodium bicarbonate solution (20 mL) and extracted with CHCl (2 × 50 mL). The organic layer was washed with saturated sodium bicarbonate solution (20 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 2-3% MeOH / CH2Cl2) to give 1-(5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)ethan-1-one (80 mg, 0.27 mmol, 81%) as an off-white solid. 1 H NMR (500 MHz, DMSO-d6): δ 10.04 (s, 1H), 8.64 (s, 1H), 7.82 (dd, J = 9.0, 4.9 Hz, 1H), 7.57 (dd, J = 9.0, 2.0 Hz, 1H), 7.23-7.11 (m, 1H), 4.02-3.91 (m, 1H), 2.87 (s, 3H), 1.20-1.15 (m, 2H), 0.79-0.76 (m, 2H)

[0487] 2-(5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)propan-2-ol (Example 12) To a stirred solution of 1-(5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)ethan-1-one (60 mg, 0.20 mmol) in THF (2 mL) was added dropwise methylmagnesium bromide (2 M in diethyl ether, 0.1 mL, 0.20 mmol) at −78° C. under an inert atmosphere. The reaction mixture was stirred at −78° C. for 1 h. After the starting material was consumed (by TLC), the reaction mixture was quenched with saturated ammonium chloride solution (20 mL) and extracted with EtOAc (2×30 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure. The crude material was purified by preparative HPLC to give 2-(5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)propan-2-ol Example 12 (15 mg, 0.05 mmol, 24%) as an off-white solid. 1 H NMR (400 MHz, CD3OD): δ 9.65 (s, 1H), 8.57 (s, 1H), 7.73 (dd, J = 8.9, 4.8 Hz, 1H), 7.50 (dd, J = 8.8, 2.4 Hz, 1H), 7.21-7.08 (m, 1H), 3.91-3.76 (m, 1H), 1.71 (s, 6H), 1.30-1.18 (m, 2H), 0.83-0.76 (m, 2H) LC-MS: m / z 313 [M+H] with retention time 2.19 + (95.83% purity). HPLC: 95.47%.

[0488] Example 13 Scheme:

[0489] [ka]

[0490] 5-(1-Cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)-N-(tetrahydro-2H-pyran-4-yl)pyridazin-3-amine (Example 13) To a stirred solution of 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-6-fluoro-1H-benzo[d]imidazole Example 3 (150 mg, 0.52 mmol) in EtOH (1.5 mL) was added triethylamine (0.2 mL, 1.56 mmol) and tetrahydro-2H-pyran-4-amine (105 mg, 1.04 mmol) under an inert atmosphere at room temperature. The reaction mixture was stirred at reflux for 16 hours. After the starting material was consumed (by TLC), the volatiles were evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: EtOAc) to give 5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)-N-(tetrahydro-2H-pyran-4-yl)pyridazin-3-amine Example 13 (40 mg, 0.11 mmol, 22%) as an off-white solid. 1 H NMR (500 MHz, DMSO-d6): δ 9.01 (s, 1H), 7.74 (dd, J = 8.7, 4.9 Hz, 1H), 7.51 (dd, J = 9.1, 2.5 Hz, 1H), 7.41 (s, 1H), 7.18-7.11 (m, 1H), 7.07 (d, J = 7.2 Hz, 1H), 4.17-4.07 (m, 1H), 3.93-3.86 (m, 2H), 3.80-3.75 (m, 1H), 3.49-3.44 (m, 2H), 2.05-1.95 (m, 2H), 1.59-1.42 (m, 2H), 1.30-1.02 (m, 2H), 0.87-0.74 (m, 2H) LC-MS: m / z 354 [M+H] at retention time 1.74 + (97.97% purity). HPLC: 97.95%.

[0491] Example 14 Scheme:

[0492] [ka]

[0493] N-(2-(cyclopropylamino)-4-fluorophenyl)cinnoline-4-carboxamide N 1 To a stirred solution of N-cyclopropyl-5-fluorobenzene-1,2-diamine intermediate-1 (500 mg, 3.01 mmol) in DMF (5 mL) was added cinnoline-4-carboxylic acid (524 mg, 3.01 mmol), HATU (1.71 g, 4.51 mmol), and diisopropylethylamine (1 mL, 6.02 mmol) under an inert atmosphere at 0 °C. The reaction mixture was stirred at room temperature for 16 h. After the starting material was consumed (by TLC), the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 × 20 mL). The combined organic extracts were washed with water (20 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give N-(2-(cyclopropylamino)-4-fluorophenyl)cinnoline-4-carboxamide (500 mg, crude) as a brown solid, which was used in the next step without further purification. LC-MS: m / z 322.9[M+H] with retention time 2.71 + (Purity 38.30%).

[0494] 4-(1-Cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)cinnoline (Example 14) To a stirred solution of N-(2-(cyclopropylamino)-4-fluorophenyl)cinnoline-4-carboxamide (400 mg, 1.24 mmol) in EtOH (5 mL) was added 6 N HCl (4 mL) at room temperature under an inert atmosphere. The reaction mixture was stirred at 80 °C for 1 h. After the starting material was consumed (by TLC), the reaction mixture was diluted with saturated sodium bicarbonate solution (20 mL) and extracted with CHCl (2 × 20 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give 4-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)cinnoline Example 14 (160 mg, 0.52 mmol, 43%) as an off-white solid. 1H NMR (400 MHz, CD3OD): δ 9.69 (s, 1H), 8.65 (d, J = 8.2 Hz, 1H), 8.23 ​​(d, J = 8.5 Hz, 1H), 8.12-8.07 (m, 1H), 8.01-7.97 (m, 1H), 7.82-7.79 (m, 1H), 7.58 (dd, J = 8.8, 2.3 Hz, 1H), 7.25-7.18 (m, 1H), 3.76-3.71 (m, 1H), 0.98-0.93 (m, 2H), 0.65-0.54 (m, 2H) LC-MS: m / z 304.9 [M+H] with retention time 2.59 + (99.51% purity). HPLC: 99.30%.

[0495] Example 15 Scheme:

[0496] [ka]

[0497] N-(2-(cyclopropylamino)-4-fluorophenyl)-6-methylpyridazine-4-carboxamide A stirred solution of 6-methylpyridazine-4-carboxylic acid (174 mg, 1.0 mmol) in DMF (3 mL) was added to the flask under an inert atmosphere at 0 °C with N 1 N-cyclopropyl-5-fluorobenzene-1,2-diamine intermediate-1 (166 mg, 1.0 mmol), HATU (570 mg, 1.5 mmol), and diisopropylethylamine (1.38 mL, 4 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. After the starting material was consumed (by TLC), the reaction mixture was diluted with ammonium chloride solution (20 mL) and extracted with EtOAc (2 × 20 mL). The combined organic extracts were washed with water (20 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give N-(2-(cyclopropylamino)-4-fluorophenyl)-6-methylpyridazine-4-carboxamide (250 mg, crude) as a brown solid. LC-MS: m / z 287.2[M+H] with retention time 3.53 + (Purity 54.60%).

[0498] 1-Cyclopropyl-6-fluoro-2-(6-methylpyridazin-4-yl)-1H-benzo[d]imidazole (Example 15) To a stirred solution of N-(2-(cyclopropylamino)-4-fluorophenyl)-6-methylpyridazine-4-carboxamide (250 g, 0.87 mmol) in EtOH (1.5 mL) was added 6 N HCl (3.5 mL) at room temperature under an inert atmosphere. The reaction mixture was stirred at 80° C. for 2 hours. After the starting material was consumed (by TLC), the reaction mixture was diluted with saturated sodium carbonate solution (20 mL) and extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water (20 mL), brine (20 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 4-5% MeOH / CH2Cl2) to give 1-cyclopropyl-6-fluoro-2-(6-methylpyridazin-4-yl)-1H-benzo[d]imidazole Example 15 (80 mg, 0.29 mmol, 34%) as an off-white solid. 1 H NMR (400 MHz, CD3OD): δ 9.64 (s, 1H), 8.21 (s, 1H), 7.74 (dd, J = 9.0, 4.6 Hz, 1H), 7.51 (dd, J = 8.8, 2.1 Hz, 1H), 7.19-7.13 (m, 1H), 3.89-3.83 (m, 1H), 2.84 (s, 3H), 1.31-1.23 (m, 2H), 0.86-0.79 (m, 2H) LC-MS: m / z 268.9 [M+H] with retention time 2.19 + (95.85% purity). HPLC: 97.59%.

[0499] Example 16 Scheme:

[0500] [ka]

[0501] N-(5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)ethanesulfonamide (Example 16) To a stirred solution of 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-6-fluoro-1H-benzo[d]imidazole (Example 3) (100 mg, 0.34 mmol) in 1,4-dioxane (4 mL) was added ethanesulfonamide (57 mg, 0.52 mmol) and cesium carbonate (283 mg, 0.86 mmol), and the mixture was purged under argon for 5 minutes. Pd(OAc) (7.8 mg, 0.004 mmol) and Xantphos (30 mg, 0.05 mmol) were then added to the reaction mixture. The reaction mixture was heated to 120 °C and stirred for 16 hours. After the starting material was consumed (by TLC), the reaction mixture was diluted with water (50 mL) and extracted with 10% MeOH:CHCl (2 × 50 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 2-3% MeOH / CH2Cl2) to afford N-(5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)ethanesulfonamide Example 16 (30 mg, 0.08 mmol, 24%) as a colorless syrup. 1 H NMR (400 MHz, CD3OD): δ 8.96 (brs, 1H), 8.45 (brs, 1H), 7.76-7.73 (m, 1H), 7.50 (dd, J = 8.8, 2.3 Hz, 1H), 7.25-7.12 (m, 1H), 3.79-3.73 (m, 1H), 3.30-3.21 (m, 2H), 1.46-1.37 (m, 5H), 1.03-0.82 (m, 2H) LC-MS: m / z 362 [M+H] at retention time 2.04 + (95.41% purity). HPLC: 94.11%.

[0502] Example 17 Scheme:

[0503] [ka]

[0504] 6-chloro-N-(4-cyano-2-(ethylamino)phenyl)pyridazine-4-carboxamide To a stirred solution of 4-amino-3-(ethylamino)benzonitrile intermediate-4 (322 mg, 2 mmol) in DMF (6 mL) was added 6-chloropyridazine-4-carboxylic acid (316 mg, 2 mmol), HATU (1.14 g, 3 mmol), and ethyldiisopropylamine (1.38 mL, 8 mmol) at room temperature under an inert atmosphere. The reaction mixture was stirred at room temperature for 16 hours. After the starting material was consumed (by TLC), the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2 × 30 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure to give 6-chloro-N-(4-cyano-2-(ethylamino)phenyl)pyridazine-4-carboxamide (350 mg, crude) as an off-white solid. LC-MS: retention time 2.07, m / z 300.1 [MH] - (Purity 18.03%).

[0505] 2-(6-chloropyridazin-4-yl)-1-ethyl-1H-benzo[d]imidazole-6-carbonitrile (Example 17) To a stirred solution of 6-chloro-N-(4-cyano-2-(ethylamino)phenyl)pyridazine-4-carboxamide (350 mg, 1.16 mmol) in CHCl (3 mL) was added trifluoroacetic acid (TFA) (1 mL) at room temperature under an inert atmosphere. The reaction mixture was stirred at room temperature for 6 hours. After the starting material was consumed (by TLC), the reaction mixture was diluted with saturated sodium carbonate solution (30 mL) and extracted with EtOAc (2×30 mL). The combined organic extracts were washed with water (20 mL), brine (20 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give 2-(6-chloropyridazin-4-yl)-1-ethyl-1H-benzo[d]imidazole-6-carbonitrile Example 17 (25 mg, 0.08 mmol, 7.5%) as an off-white solid. 1 H NMR (400 MHz, CD3OD): δ 9.63 (d, J = 1.9 Hz, 1H), 8.27 (d, J = 1.8 Hz, 2H), 7.93 (dd, J = 8.4, 0.6 Hz, 1H), 7.69 (dd, J = 8.5, 1.4 Hz, 1H), 4.56-4.51 (m, 2H), 1.51 (t, J = 7.3 Hz, 3H) LC-MS: m / z 284.2 [M+H] at retention time 3.50 + (99.67% purity). HPLC: 99.48%.

[0506] Example 18 Scheme:

[0507] [ka]

[0508] 2-(4-(5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)piperazin-1-yl)-N-isopropylacetamide (Example 18) To a stirred solution of 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-6-fluoro-1H-benzo[d]imidazole Example 3 (56 mg, 0.19 mmol) in EtOH (2 mL) was added triethylamine (0.04 mL, 0.28 mmol) and N-isopropyl-2-(4-(2,2,2-trifluoroacetyl)-4,5-piperazin-1-yl)acetamide (60 mg, 0.27 mmol) at room temperature under an inert atmosphere. The reaction mixture was stirred at reflux for 16 hours. After the starting material was consumed (by TLC), the volatiles were evaporated under reduced pressure. The crude material was purified by preparative HPLC to give 2-(4-(5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)piperazin-1-yl)-N-isopropylacetamide Example 18 (12 mg, 0.02 mmol, 14%) as an off-white solid. 1 H NMR (400 MHz, CD3OD): δ 9.08 (s, 1H), 7.76 (s, 1H), 7.72 (dd, J = 8.9, 4.8 Hz, 1H), 7.50 (dd, J = 8.8, 2.5 Hz, 1H), 7.15 (dt, J = 9.3, 2.4 Hz, 1H), 4.13-4.02 (m, 1H), 3.87-3.81 (m, 4H), 3.34-3.31 (m, 1H), 3.10 (s, 2H), 2.73-2.69 (m, 4H), 1.28-1.23 (m, 2H), 1.20 (d, J = 6.7 Hz, 6H), 0.86-0.80 (m, 2H) LC-MS: m / z 438.4 [M+H] at retention time 3.76 + (94.38% purity). HPLC: 94.23%.

[0509] Example 19 Scheme:

[0510] [ka]

[0511] N-(2-(cyclopropylamino)-4,5-difluorophenyl)-6-methylpyridazine-4-carboxamide N 1 To a stirred solution of N-cyclopropyl-4,5-difluorobenzene-1,2-diamine intermediate-5 (184 mg, 1.0 mmol) in DMF (3 mL) was added 6-methylpyridazine-4-carboxylic acid (174 mg, 1.0 mmol), HATU (570 mg, 1.5 mmol), and diisopropylethylamine (1.38 mL, 4.0 mmol) under an inert atmosphere at 0 °C. The reaction mixture was stirred at room temperature for 16 h. After the starting material was consumed (by TLC), the reaction mixture was quenched with ammonium chloride solution (20 mL) and extracted with EtOAc (2 × 20 mL). The combined organic extracts were washed with water (20 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give N-(2-(cyclopropylamino)-4,5-difluorophenyl)-6-methylpyridazine-4-carboxamide (220 mg, crude) as a brown syrup. LC-MS: m / z 305.2[M+H] at retention time 3.78 + (Purity 44.76%).

[0512] 1-Cyclopropyl-5,6-difluoro-2-(6-methylpyridazin-4-yl)-1H-benzo[d]imidazole (Example 19) To a stirred solution of N-(2-(cyclopropylamino)-4,5-difluorophenyl)-6-methylpyridazine-4-carboxamide (220 mg, 0.72 mmol) in EtOH (1.5 mL) was added 6 N HCl (3.5 mL) at room temperature under an inert atmosphere. The reaction mixture was stirred at 80 °C for 2 h. After the starting material was consumed (by TLC), the reaction mixture was diluted with saturated sodium carbonate solution (100 mL) and extracted with EtOAc (2 × 100 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 3-5% MeOH / CHCl) to give 1-cyclopropyl-5,6-difluoro-2-(6-methylpyridazin-4-yl)-1H-benzo[d]imidazole Example 19 (60 mg, 0.20 mmol, 29%) as an off-white solid. 1 H NMR (400 MHz, CD3OD): δ 9.63 (d, J = 1.9 Hz, 1H), 8.20 (d, J = 2.1 Hz, 1H), 7.72 (dd, J = 10.1, 7.1 Hz, 1H), 7.62 (dd, J = 10.4, 7.3 Hz, 1H), 3.90-3.83 (m, 1H), 2.84 (s, 3H), 1.31-1.24 (m, 2H), 0.85-0.80 (m, 2H) LC-MS: m / z 286.9 [M+H] with retention time 2.32 + (99.57% purity). HPLC: 99.70%.

[0513] Example 20 Scheme:

[0514] [ka]

[0515] tert-Butyl 4-(2-ethoxy-2-oxoethyl)piperazine-1-carboxylate To a stirred solution of tert-butyl piperazine-1-carboxylate (2 g, 10.7 mmol) in DMF (14 mL) was added potassium carbonate (3.71 g, 26.8 mmol) and ethyl bromoacetate (1.2 mL, 10.8 mmol) at room temperature under an inert atmosphere. The reaction mixture was stirred at room temperature for 16 hours. After the starting material was consumed (by TLC), the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 × 50 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure to give tert-butyl 4-(2-ethoxy-2-oxoethyl)piperazine-1-carboxylate (2.8 g, 10.29 mmol, 95%) as a yellow oil. 1 H NMR (500MHz, DMSO-d6): δ 4.12-4.00 (m, 2H), 3.30 (s, 4H), 3.23 (s, 2H), 2.45 (t, J = 4.6 Hz, 4H), 1.39 (s, 9H), 1.18 (t, J = 7.1 Hz, 3H)

[0516] 2-(4-tert-butoxycarbonyl)piperazin-1-yl)acetic acid To a stirred solution of tert-butyl 4-(2-ethoxy-2-oxoethyl)piperazine-1-carboxylate (2.8 g, 10.29 mmol) in a mixture of THF:MeOH:water (3:1:1, 30 mL) was added lithium hydroxide (1.29 g, 30.8 mmol) at 0 °C. The reaction mixture was gradually warmed to room temperature and stirred for 3 h. After the starting material was consumed (by TLC), the volatiles were concentrated under reduced pressure. The residue was then acidified to pH 4-5 with 5% citric acid solution and extracted with EtOAc (2 × 100 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure to give 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)acetic acid (200 mg, crude) as a yellow oil, which was used in the next step without further purification. LC-MS: retention time 1.06, m / z 245.1 [MH] + (71.81% purity).

[0517] tert-Butyl 4-(2-oxo-2-(pyrrolidin-1-yl)ethyl)piperazine-1-carboxylate To a stirred solution of 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)acetic acid (500 mg, 2.04 mmol) in CHCl (15 mL) was added pyrrolidine (0.2 mL, 2.45 mmol), HATU (1.1 g, 3.07 mmol), and ethyldiisopropylamine (1.5 mL, 8.19 mmol) at room temperature under an inert atmosphere. The reaction mixture was stirred at room temperature for 16 h. After the starting material was consumed (by TLC), the reaction mixture was diluted with water (30 mL) and extracted with CHCl (2 × 30 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 2% MeOH / CH2Cl2) to give tert-butyl 4-(2-oxo-2-(pyrrolidin-1-yl)ethyl)piperazine-1-carboxylate (100 mg, 0.33 mmol, 16%) as a brown solid. 1 H NMR (500MHz, DMSO-d6): δ 3.43 (t, J = 6.7 Hz, 2H), 3.31 (s, 2H), 3.29-3.25 (m, 4H), 2.43 (brs, 4H), 1.87-1.82 (m, 2H), 1.78-1.71 (m, 2H), 1.39 (s, 9H), 1.29-1.23 (m, 2H)

[0518] 4-(2-oxo-2-(pyrrolidin-1-yl)ethyl)piperazin-1-yl 2,2,2-trifluoroacetate salt To a stirred solution of tert-butyl 4-(2-oxo-2-(pyrrolidin-1-yl)ethyl)piperazine-1-carboxylate (100 mg, 0.33 mmol) in CHCl (1 mL) was added dropwise trifluoroacetic acid (0.5 mL) at room temperature under an inert atmosphere. The reaction mixture was stirred at room temperature for 1 hour. After the starting material was consumed (by TLC), the volatiles were removed under reduced pressure. The crude product was washed with ether (2 × 5 mL) to give 4-(2-oxo-2-(pyrrolidin-1-yl)ethyl)piperazin-1-yl 2,2,2-trifluoroacetate salt (120 mg as the TFA salt) as a white solid. 1 H NMR (500 MHz, DMSO-d6): δ 3.72 (brs, 1H), 3.40-3.37 (m, 4H), 3.33-3.30 (m, 4H), 3.24 (s, 2H), 3.08 (brs, 4H), 1.92-1.85 (m, 2H), 1.81-1.76 (m, 2H)

[0519] 2-(4-(5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)piperazin-1-yl)-1-(pyrrolidin-1-yl)ethan-1-one (Example 20) To a stirred solution of 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-6-fluoro-1H-benzo[d]imidazole Example 3 (100 mg, 0.34 mmol) in EtOH (2 mL) was added triethylamine (0.14 mL, 1.04 mmol) and 4-(2-oxo-2-(pyrrolidin-1-yl)ethyl)piperazin-1-yl 2,2,2-trifluoroacetate salt (34 mg, 0.17 mmol) at room temperature under an inert atmosphere. The reaction mixture was stirred at 80° C. for 32 hours. After the starting material was consumed (by TLC), the volatiles were evaporated under reduced pressure. The crude material was purified by preparative HPLC to give 2-(4-(5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)piperazin-1-yl)-1-(pyrrolidin-1-yl)ethan-1-one Example 20 (20 mg, 0.041 mmol, 13%) as an off-white solid. 1 H NMR (400 MHz, CDCl3): δ 9.16 (s, 1H), 7.75-7.71 (m, 1H), 7.47 (s, 1H), 7.30 (dd, J = 8.6, 2.4 Hz, 1H), 7.11-7.06 (m, 1H), 3.87-3.85 (m, 4H), 3.63-3.57 (m, 1H), 3.53-3.43 (m, 4H), 3.28 (s, 2H), 2.83 (brs, 4H), 2.03-1.93 (m, 2H), 1.89-1.84 (m, 2H), 1.30-1.22 (m, 2H), 0.88-0.80 (m, 2H) LC-MS: m / z 450.2 [M+H] at retention time 1.74 + (97.66% purity). HPLC: 97.81%.

[0520] Examples 21 and 22 Scheme:

[0521] [ka]

[0522] 6-chloro-N-(2-(cyclopropylamino)-4,5-difluorophenyl)pyridazine-4-carboxamide N 1To a stirred solution of 1 g (5.43 mmol) of 1,2-cyclopropyl-4,5-difluorobenzene-1,2-diamine intermediate-5 in 10 mL of DMF was added 1.03 g (6.52 mmol), 2.48 g (6.52 mmol), and diisopropylethylamine (3.9 mL, 21.72 mmol) under an inert atmosphere at room temperature. The reaction mixture was stirred at room temperature for 16 hours. After the starting material was consumed (by TLC), the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2 × 30 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 0-2% MeOH / CH2Cl2) to give 6-chloro-N-(2-(cyclopropylamino)-4,5-difluorophenyl)pyridazine-4-carboxamide (800 mg, 2.46 mmol, 45%) as a brown solid. 1 H NMR (400 MHz, CDCl3): δ 9.50 (s, 1H), 7.95 (d, J = 1.6 Hz, 1H), 7.74 (brs, 1H), 7.37 (dd, J = 10.5, 8.5 Hz, 1H), 7.06 (dd, J = 12.4, 7.7 Hz, 1H), 4.16-4.03 (m, 1H), 2.51-2.40 (m, 1H), 0.83-0.75 (m, 2H), 0.56-0.47 (m, 2H)

[0523] 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole (Example 22) To a stirred solution of 6-chloro-N-(2-(cyclopropylamino)-4,5-difluorophenyl)pyridazine-4-carboxamide (700 mg, 2.16 mmol) in EtOH (7 mL) was added 6 N HCl (10.5 mL) at room temperature under an inert atmosphere. The reaction mixture was stirred at 70 °C for 30 min. After the starting material was consumed (by TLC), the reaction mixture was diluted with saturated sodium bicarbonate solution (50 mL) and extracted with EtOAc (2 × 50 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 20-30% EtOAc / hexane) to give 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole Example 22 (280 mg, 0.91 mmol, 42%) as an off-white solid. 1 H NMR (400 MHz, CDCl3): δ 9.78 (d, J = 1.9 Hz, 1H), 8.15 (d, J = 1.9 Hz, 1H), 7.60 (dd, J = 10.0, 7.2 Hz, 1H), 7.44 (dd, J = 9.5, 6.9 Hz, 1H), 3.70-3.62 (m, 1H), 1.41-1.33 (m, 2H), 0.93-0.84 (m, 2H) LC-MS: m / z 306.9 [M+1] at retention time 2.52 + (99.86% purity). HPLC: 99.51%.

[0524] 5-(1-Cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-N-methylpyridazin-3-amine (Example 21) 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole Example 22 (600 mg, 1.96 mmol) was dissolved in a 2M methylamine solution (2M in diethyl ether, 3 mL), and the reaction mixture was stirred at room temperature for 16 hours. After the starting material was consumed (by TLC), the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 × 50 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 2–3% MeOH / CHCl) to give 5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-N-methylpyridazin-3-amine Example 21 (50 mg, 0.16 mmol, 8%) as a pale green solid. 1 H NMR (400 MHz, CDCl3): δ 9.13 (d, J = 1.8 Hz, 1H), 7.57 (dd, J = 10.2, 7.3 Hz, 1H), 7.41 (dd, J = 9.7, 7.0 Hz, 1H), 7.20 (d, J = 1.8 Hz, 1H), 5.03 (d, J = 4.5 Hz, 1H), 3.59 (tt, J = 7.0, 3.6 Hz, 1H), 3.12 (d, J = 5.1 Hz, 3H), 1.32-1.24 (m, 2H), 0.87-0.80 (m, 2H) LC-MS: m / z 301.9 [M+1] at retention time 1.76 + (98.78% purity). HPLC: 99.48%.

[0525] Example 23 Scheme:

[0526] [ka]

[0527] 1-Cyclopropyl-5,6-difluoro-2-(6-methoxypyridazin-4-yl)-1H-benzo[d]imidazole (Example 23) To a stirred solution of 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole Example 22 (100 mg, 0.32 mmol) in MeOH (5 mL) was added sodium methoxide (53 mg, 0.98 mmol) at room temperature under an inert atmosphere. The reaction mixture was stirred at 70 °C for 2 hours. After the starting material was consumed (by TLC), the volatiles were evaporated under reduced pressure. The residue was diluted with water (10 mL) and extracted with CHCl (2 × 10 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 40% EtOAc / hexanes) to give 1-cyclopropyl-5,6-difluoro-2-(6-methoxypyridazin-4-yl)-1H-benzo[d]imidazole Example 23 (40 mg, 0.13 mmol, 41%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ 9.45 (s, 1H), 7.89-7.80 (m, 2H), 7.77 (s, 1H), 4.13 (s, 3H), 3.93-3.89 (m, 1H), 1.23-1.12 (m, 2H), 0.82-0.70 (m, 2H) LC-MS: m / z 302.9 [M+H] at retention time 2.30 + (99.80% purity). HPLC: 99.68%.

[0528] Example 24 Scheme:

[0529] [ka]

[0530] 1-Cyclopropyl-5,6-difluoro-2-(6-isopropoxypyridazin-4-yl)-1H-benzo[d]imidazole (Example 24) To a stirred solution of 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole Example 22 (70 mg, 0.23 mmol) in DMF (0.5 mL) was added sodium hydride (55% in mineral oil, 20 mg, 0.46 mmol) portionwise at 0° C. under an inert atmosphere. The reaction mixture was stirred at 0° C. for 30 minutes. To this reaction mixture was added propan-2-ol (27.5 mg, 0.46 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 hour. After the starting material was consumed (by TLC), the reaction mixture was quenched with ice-cold water (20 mL) and extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water (10 mL), brine (10 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 50% EtOAc / hexanes) to give 1-cyclopropyl-5,6-difluoro-2-(6-isopropoxypyridazin-4-yl)-1H-benzo[d]imidazole Example 24 (30 mg, 0.09 mmol, 40%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ 9.39 (s, 1H), 7.89-7.80 (m, 2H), 7.67 (s, 1H), 5.57-5.51 (m, 1H), 3.93-3.89 (m, 1H), 1.42 (d, J = 6.1 Hz, 6H), 1.20-1.11 (m, 2H), 0.86-0.68 (m, 2H) LC-MS: m / z 330.9 [M+H] at retention time 2.88 + (93.72% purity). HPLC: 95.25%.

[0531] Example 25 Scheme:

[0532] [ka]

[0533] 5-(1-Cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-N,N-dimethylpyridazin-3-amine (Example 25) 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole Example 22 (60 mg, 0.19 mmol) was dissolved in a 2M dimethylamine solution (2M in THF, 3 mL), and the reaction mixture was stirred for 16 h. After the starting material was consumed (by TLC), the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 × 50 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 2–3% MeOH / CHCl) to afford 5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-N,N-dimethylpyridazin-3-amine Example 25 (16 mg, 0.05 mmol, 26%) as an off-white solid. 1 H NMR (400 MHz, CDCl3): δ 9.08 (s, 1H), 7.58 (dd, J = 10.2, 7.3 Hz, 1H), 7.41 (dd, J = 9.7, 7.0 Hz, 1H), 7.32 (s, 1H), 3.62-3.57 (m, 1H), 3.28 (s, 6H), 1.29-1.23 (m, 2H), 0.87-0.77 (m, 2H) LC-MS: m / z 316.1 [M+1] at retention time 1.81 + (98.32% purity). HPLC: 95.98%.

[0534] Example 26 Scheme:

[0535] [ka]

[0536] 2-Bromo-1-ethyl-6-fluoro-1H-indole To a stirred solution of 2-bromo-6-fluoro-1H-indole (250 mg, 1.16 mmol) in DMF (2 mL) was added potassium carbonate (476 mg, 3.50 mmol) followed by iodoethane (364 mg, 2.33 mmol) at room temperature under an inert atmosphere. The reaction mixture was stirred at room temperature for 4 hours. After 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 combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure to give 2-bromo-1-ethyl-6-fluoro-1H-indole (280 mg, crude) as a yellow solid. 1 H NMR (400 MHz, CDCl3): δ 7.43 (dd, J = 8.6, 5.3 Hz, 1H), 6.98 (dd, J = 9.7, 2.3 Hz, 1H), 6.86-6.84 (m, 1H), 6.54 (d, J = 0.8 Hz, 1H), 4.21-4.16 (m, 2H), 1.34 (t, J = 7.2 Hz, 3H)

[0537] 1-Ethyl-6-fluoro-2-(6-methylpyridazin-4-yl)-1H-indole (Example 26) To a stirred solution of 2-bromo-1-ethyl-6-fluoro-1H-indole (200 mg, 0.83 mmol) in 1,4-dioxane (2 mL), (6-methylpyridazin-4-yl)boronic acid (214 mg, 1.24 mmol) and sodium carbonate solution (2 M, 0.5 mL) were added and purged under argon for 10 minutes. Pd(dppf)Cl (60 mg, 0.08 mmol) was then added to the reaction mixture, and the reaction mixture was stirred in a sealed tube at 80 °C for 16 hours. The progress of the reaction was monitored by TLC, and the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 × 20 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 2% MeOH / CH 2 Cl 2 ) to give 1-ethyl-6-fluoro-2-(6-methylpyridazin-4-yl)-1H-indole Example 26 (50 mg, 0.19 mmol, 20%) as a yellow solid. 1 H NMR (400 MHz, CD3OD): δ 9.25 (d, J = 2.0 Hz, 1H), 7.76 (d, J = 2.1 Hz, 1H), 7.61 (dd, J = 8.7, 5.3 Hz, 1H), 7.28 (dd, J = 10.1, 2.2 Hz, 1H), 6.96-6.90 (m, 2H), 4.35-4.30 (m, 2H), 2.77 (s, 3H), 1.29 (t, J = 7.2 Hz, 3H) LC-MS: m / z 256 [M+H] with retention time 2.73 + (98.24% purity) HPLC: 97.70%

[0538] Example 27 Scheme:

[0539] [ka]

[0540] 1-Cyclopropyl-5,6-difluoro-2-(6-(2,2,2-trifluoroethoxy)pyridazin-4-yl)-1H-benzo[d]imidazole (Example 27) To a stirred solution of 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole Example 22 (70 mg, 0.23 mmol) in DMF (0.5 mL) was added sodium hydride (55% in mineral oil, 20 mg, 0.46 mmol) portionwise at 0° C. under an inert atmosphere. The reaction mixture was stirred at 0° C. for 30 minutes. To this reaction mixture was added 2,2,2-trifluoroethan-1-ol (46 mg, 0.46 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 2 hours. After the starting material was consumed (by TLC), the reaction mixture was quenched with ice-cold water (20 mL) and extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water (10 mL), brine (10 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 30% EtOAc / hexanes) to afford 1-cyclopropyl-5,6-difluoro-2-(6-(2,2,2-trifluoroethoxy)pyridazin-4-yl)-1H-benzo[d]imidazole Example 27 (50 mg, 0.13 mmol, 62%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ 9.55 (s, 1H), 7.97 (s, 1H), 7.89-7.85 (m, 2H), 5.39-5.27 (m, 2H), 3.96-3.93 (m, 1H), 1.21-1.13 (m, 2H), 0.82-0.69 (m, 2H) LC-MS: m / z 370.9 [M+1] with retention time 3.18 + (99.73% purity). HPLC: 98.32%.

[0541] Example 28 Scheme:

[0542] [ka]

[0543] 5-(1-Cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-N-(2-methoxyethyl)pyridazin-3-amine (Example 28) To a stirred solution of 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole Example 22 (50 mg, 0.16 mmol) in THF (0.5 mL) was added 2-methoxyethan-1-amine (0.5 mL, 75.11 mmol) and ethyldiisopropylamine (0.5 mL) at room temperature under an inert atmosphere. The reaction mixture was stirred at 110 °C for 16 hours. After the starting material was consumed (by TLC), the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 × 50 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure. The crude material was washed with CH2Cl2:hexanes (1:9, 10 mL) to give 5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-N-(2-methoxyethyl)pyridazin-3-amine Example 28 (40 mg, 0.13 mmol, 92%) as a pale yellow solid. 1 H NMR (400 MHz, CDCl3): δ 9.12 (s, 1H), 7.56 (dd, J = 10.1, 7.2 Hz, 1H), 7.41 (dd, J = 9.7, 6.9 Hz, 1H), 7.22 (s, 1H), 5.21 (brs, 1H), 3.76-3.73 (m, 2H), 3.69-3.64 (m, 2H), 3.61-3.59 (m, 1H), 3.41 (s, 3H), 1.31-1.25 (m, 2H), 0.87-0.81 (m, 2H) LC-MS: m / z 346 [M+H] at retention time 1.80 + (97.27% purity). HPLC: 97.05%.

[0544] Example 29 Scheme:

[0545] [ka]

[0546] N-(4-cyano-2-(cyclopropylamino)phenyl)-6-methoxypyridazine-4-carboxamide To a stirred solution of 4-amino-3-(cyclopropylamino)benzonitrile Intermediate-6 (300 mg, 1.72 mmol) in DMF (5 mL) was added 6-methoxypyridazine-4-carboxylic acid (281 mg, 1.72 mmol), HATU (720 mg, 1.89 mmol), and ethyldiisopropylamine (0.8 mL, 5.17 mmol) at room temperature under an inert atmosphere. The reaction mixture was stirred at room temperature for 16 hours. After the starting material was consumed (by TLC), the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2 × 30 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure to give N-(4-cyano-2-(cyclopropylamino)phenyl)-6-methoxypyridazine-4-carboxamide (300 mg, crude) as a yellow liquid, which was used in the next step without further purification.

[0547] 1-Cyclopropyl-2-(6-methoxypyridazin-4-yl)-1H-benzo[d]imidazole-6-carbonitrile (Example 29) To a stirred solution of N-(4-cyano-2-(cyclopropylamino)phenyl)-6-methoxypyridazine-4-carboxamide (300 mg, crude) in CHCl (10 mL) under an inert atmosphere at 0° C., trifluoroacetic acid (0.5 mL) was added dropwise. The reaction mixture was stirred at 0° C. for 2 h. After the starting material was consumed (by TLC), the volatiles were removed under reduced pressure. The residue was diluted with water (5 mL), basified with saturated sodium carbonate solution (20 mL), and extracted with CHCl (2×20 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 2% MeOH / CH2Cl2) to give 1-cyclopropyl-2-(6-methoxypyridazin-4-yl)-1H-benzo[d]imidazole-6-carbonitrile Example 29 (40 mg, 0.13 mmol, 14% (over two steps)) as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d6): δ 9.48 (s, 1H), 8.32 (s, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.82 (s, 1H), 7.71 (dd, J = 8.4, 1.5 Hz, 1H), 4.14 (s, 3H), 4.01-3.85 (m, 1H), 1.23-1.14 (m, 2H), 0.87-0.77 (m, 2H) LC-MS: m / z 291.9 [M+H] at retention time 2.25 + (95.84% purity). HPLC: 97.16%.

[0548] Example 30 Scheme:

[0549] [ka]

[0550] 1-(2,2-Dibromovinyl)-4-fluoro-2-nitrobenzene To a stirred solution of 4-fluoro-2-nitrobenzaldehyde (2 g, 11.83 mmol) in CHCl (100 mL) under an inert atmosphere at 0° C. was added carbon tetrabromide (5.8 g, 17.75 mmol) and triphenylphosphine (9.3 g, 35.50 mmol). The reaction mixture was stirred at 5° C. for 2 h. The progress of the reaction was monitored by TLC, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give 1-(2,2-dibromovinyl)-4-fluoro-2-nitrobenzene (3.2 g, crude) as a brown solid, which was used in the next step without further purification.

[0551] 2-(2,2-dibromovinyl)-5-fluoroaniline To a stirred solution of 1-(2,2-dibromovinyl)-4-fluoro-2-nitrobenzene (3.2 g, 9.87 mmol) in EtOH (20 mL) was added SnCl2.H2O (11.1 g, 46.29 mmol) at room temperature under an inert atmosphere. The reaction mixture was stirred at reflux for 2 h. The reaction progress was monitored by TLC, and the volatiles were concentrated under reduced pressure. The resulting residue was basified with potassium carbonate solution to pH 10 and extracted with EtOAc (2 × 50 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 10% EtOAc / hexane) to give 2-(2,2-dibromovinyl)-5-fluoroaniline (2.1 g, 7.14 mmol, 72%) as a brown solid. LC-MS: m / z 295.6[M+2H] at retention time 3.34 + (Purity 96.98%)

[0552] N-(2-(2,2-dibromovinyl)-5-fluorophenyl)methanesulfonamide To a stirred solution of 2-(2,2-dibromovinyl)-5-fluoroaniline (1 g, 3.40 mmol) in CHCl (10 mL) under an inert atmosphere at 0 °C, pyridine (0.54 mL, 6.80 mmol) and mesyl chloride (0.38 mL, 5.10 mmol) were added. The reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC, and the reaction mixture was quenched with NaHSO solution and extracted with EtOAc (2 × 50 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 10% EtOAc / hexane) to give N-(2-(2,2-dibromovinyl)-5-fluorophenyl)methanesulfonamide (1.1 g, 2.94 mmol, 87%) as a brown solid. 1 H NMR (500 MHz, DMSO-d6): δ 9.57 (s, 1H), 7.69 (s, 1H), 7.59 (dd, J = 8.7, 6.4 Hz, 1H), 7.23 (dd, J = 10.4, 2.3 Hz, 1H), 7.14 (dt, J = 8.4, 2.3Hz, 1H), 3.06 (s, 3H)

[0553] 2-Bromo-6-fluoro-1H-indole To a stirred solution of N-(2-(2,2-dibromovinyl)-5-fluorophenyl)methanesulfonamide (200 mg, 0.53 mmol) in THF (2 mL) was added 1 M TBAF in THF (1 mL) at room temperature under an inert atmosphere. The reaction mixture was stirred in a microwave at 100° C. for 5 minutes. The progress of the reaction was monitored by TLC, and the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2×20 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give 2-bromo-6-fluoro-1H-indole 5 (100 mg, crude) as a brown solid, which was used in the next step without further purification. LC-MS: m / z 295.6[M+2H] at retention time 3.34 + (Purity 96.98%)

[0554] 2-Bromo-1-cyclopropyl-6-fluoro-1H-indole To a stirred solution of 2-bromo-6-fluoro-1H-indole 5 (400 mg, 1.86 mmol) in 1,2-dichloroethane (5 mL) was added cyclopropylboronic acid (321 mg, 3.73 mmol), sodium carbonate (571 mg, 5.60 mmol), copper acetate (371 mg, 1.86 mmol), and bipyridyl (291 mg, 1.86 mmol) under an inert atmosphere at room temperature. The reaction mixture was stirred in a sealed tube at 80 °C for 16 h. The progress of the reaction was monitored by TLC, and the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 × 20 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 10% EtOAc / hexanes) to afford 2-bromo-1-cyclopropyl-6-fluoro-1H-indole (300 mg, 1.19 mmol, 63%) as a brown solid. 1 H NMR (400 MHz, CDCl3): δ 7.39 (dd, J = 8.6, 5.4 Hz, 1H), 7.23 (dd, J = 10.1, 2.3 Hz, 1H), 6.88-6.83 (m, 1H), 6.51 (s, 1H), 3.14-3.09 (m, 1H), 1.27-1.19 (m, 2H), 1.13-1.08 (m, 2H)

[0555] 1-Cyclopropyl-6-fluoro-2-(6-methylpyridazin-4-yl)-1H-indole (Example 30) To a stirred solution of 2-bromo-1-cyclopropyl-6-fluoro-1H-indole (200 mg, 0.79 mmol) in 1,4-dioxane (5 mL), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazine (261 mg, 1.19 mmol) and sodium carbonate solution (2 M, 0.5 mL) were added and purged under argon for 10 minutes. Pd(dppf)Cl (58 mg, 0.08 mmol) was then added to the reaction mixture, and the reaction mixture was stirred in a sealed tube at 80 °C for 16 hours. The progress of the reaction was monitored by TLC, and the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 × 20 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 2% MeOH / CH2Cl2) to give 1-cyclopropyl-6-fluoro-2-(6-methylpyridazin-4-yl)-1H-indole Example 30 (36 mg, 0.13 mmol, 17%) as a pale yellow solid. 1 H NMR (400 MHz, CD3OD): δ 9.42 (d, J = 2.1 Hz, 1H), 7.97 (d, J = 2.1 Hz, 1H), 7.60 (dd, J = 8.7, 5.3 Hz, 1H), 7.37 (dd, J = 10.0, 2.4 Hz, 1H), 6.98 (s, 1H), 6.96-6.91 (m, 1H), 3.83-3.68 (m, 1H), 2.80-2.79 (m, 3H), 1.25-1.09 (m, 2H), 0.78-0.63 (m, 2H) LC-MS: m / z 267.9 [M+H] at retention time 2.78 + (98.96% purity) HPLC: 97.98%

[0556] Example 31 Scheme:

[0557] [ka]

[0558] N-((5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methyl)ethanesulfonamide (Example 31) To a stirred solution of (5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methanamine Intermediate-3 (30 mg, 0.10 mmol) in THF (2 mL) was added ethanesulfonyl chloride (16 mg, 0.12 mmol) and triethylamine (0.03 mL, 0.21 mmol) under an inert atmosphere at 0 °C. The reaction mixture was stirred at room temperature for 1 h. After the starting material was consumed (by TLC), the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 × 20 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure. The crude material was purified by preparative HPLC to afford N-((5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methyl)ethanesulfonamide Example 31 (15 mg, 0.04 mmol, 38%) as a white solid. 1 H NMR (400 MHz, CD3OD): δ 9.73 (s, 1H), 8.52 (s, 1H), 7.78-7.74 (m, 1H), 7.53 (dd, J = 8.9, 2.4 Hz, 1H), 7.20-7.14 (m, 1H), 4.71 (s, 2H), 3.87-3.82 (m, 1H), 3.24-3.19 (m, 2H), 1.47-1.31 (m, 5H), 0.89-0.80 (m, 2H) LC-MS: m / z 376 [M+H] with retention time 2.21 + (99.12% purity). HPLC: 98.34%.

[0559] Example 32 Scheme:

[0560] [ka]

[0561] 5-(1-Cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-N-(2,2,2-trifluoroethyl)pyridazin-3-amine (Example 32) To a stirred solution of 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole Example 22 (80 mg, 0.26 mmol) in NMP (1.2 mL) was added 2,2,2-trifluoroethan-1-amine (1.2 mL) at room temperature under an inert atmosphere. The reaction mixture was stirred in a microwave at 130° C. for 6 hours. After the starting material was consumed (by TLC), the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2×20 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 3% MeOH / CH2Cl2) to give 5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-N-(2,2,2-trifluoroethyl)pyridazin-3-amine Example 32 (15 mg, 0.04 mmol, 15%) as a pale yellow solid. 1 H NMR (400 MHz, CDCl3): δ 9.28 (s, 1H), 7.59 (dd, J = 10.1, 7.2 Hz, 1H), 7.44 (dd, J = 9.6, 7.0 Hz, 1H), 7.37 (s, 1H), 5.09 (t, J = 6.0 Hz, 1H), 4.43-4.30 (m, 2H), 3.66-3.60 (m, 1H), 1.36-1.29 (m, 2H), 0.91-0.84 (m, 2H) LC-MS: m / z 370 [M+H] with retention time 2.21 + (97.23% purity). HPLC: 97.15%.

[0562] Example 33 Scheme:

[0563] [ka]

[0564] 1-Cyclopropyl-5,6-difluoro-2-(6-vinylpyridazin-4-yl)-1H-benzo[d]imidazole To a stirred solution of 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole (Example 22) (150 mg, 0.50 mmol) in 1,4-dioxane (3 mL) and water (0.5 mL) was added vinylboronic acid pinacol ester (76 mg, 0.50 mmol) and potassium carbonate (203 mg, 1.47 mmol) at room temperature under an inert atmosphere. The reaction mixture was degassed with argon for 10 minutes, Pd(dppf)Cl (4 mg, 0.005 mmol) was added, and the reaction mixture was degassed with argon for an additional 10 minutes. The reaction mixture was heated to 80 °C and stirred for 5 hours. After the starting material was consumed (by TLC), the volatiles were concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 50% EtOAc / hexanes) to afford 1-cyclopropyl-5,6-difluoro-2-(6-vinylpyridazin-4-yl)-1H-benzo[d]imidazole (70 mg, 0.23 mmol, 48%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ 9.69 (s, 1H), 8.45 (s, 1H), 7.90-7.83 (m, 2H), 7.18-7.11 (m, 1H), 6.53 (d, J = 17.7 Hz, 1H), 5.82 (d, J = 11.4 Hz, 1H), 3.99-3.97 (m, 1H), 1.22-1.13 (m, 2H), 0.82-0.60 (m, 2H)

[0565] 1-Cyclopropyl-2-(6-ethylpyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (Example 33) To a stirred solution of 1-cyclopropyl-5,6-difluoro-2-(6-vinylpyridazin-4-yl)-1H-benzo[d]imidazole (70 mg, 0.23 mmol) in EtOAc (3 mL) was added 10% Pd / C (20 mg) and triethylamine (catalytic amount) at room temperature under an inert atmosphere. The reaction mixture was stirred at room temperature under a hydrogen atmosphere (balloon pressure) for 5 hours. After the starting material was consumed (by TLC), the reaction mixture was filtered through a pad of Celite, and the pad was washed with methanol (30 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 2% MeOH / CHCl) to give 1-cyclopropyl-2-(6-ethylpyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole Example 33 (35 mg, 0.11 mmol, 50%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ 9.65 (s, 1H), 8.17 (s, 1H), 7.89-7.81 (m, 2H), 3.95-3.91 (m, 1H), 3.10-3.04 (m, 2H), 1.36 (t, J = 7.6 Hz, 3H), 1.24-1.12 (m, 2H), 0.79-0.64 (m, 2H) LC-MS: m / z 300.9 [M+H] at retention time 2.51 + (98.98% purity). HPLC: 97.01%.

[0566] Example 34 Scheme:

[0567] [ka]

[0568] 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-1H-benzo[d]imidazole-6-carbonitrile (Example 34) A stirred solution of 1-cyclopropyl-2-(6-methoxypyridazin-4-yl)-1H-benzo[d]imidazole-6-carbonitrile Example 29 (60 mg, 0.20 mmol) in phosphoryl chloride (POCl) (0.38 mL, 4.13 mmol) was added under an inert atmosphere at room temperature. The reaction mixture was heated to 100 °C and stirred for 2 h. After the starting material was consumed (by TLC), the reaction mixture was basified with saturated sodium carbonate solution (30 mL) and extracted with EtOAc (2 × 30 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 50% EtOAc / hexane) to give 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-1H-benzo[d]imidazole-6-carbonitrile Example 34 (10 mg, 0.03 mmol, 16%) as a white solid. 1 H NMR (400 MHz, CD3OD): δ 9.82 (s, 1H), 8.47 (s, 1H), 8.26 (s, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.68 (dd, J = 8.4, 1.5 Hz, 1H), 3.95-3.90 (m, 1H), 1.36-1.29 (m, 2H), 0.94-0.84 (m, 2H) LC-MS: m / z 296.2 [M+H] at retention time 3.28 + (96.40% purity). HPLC: 96.31%.

[0569] Example 35 Scheme:

[0570] [ka]

[0571] 3-Cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrile To a stirred solution of 4-amino-3-(cyclopropylamino)benzonitrile intermediate-6 (500 mg, 2.89 mmol) in THF (10 mL) was added 1,1'-carbonyldiimidazole (CDI) (702 mg, 4.33 mmol) at room temperature under an inert atmosphere. The reaction mixture was stirred at room temperature for 16 h. After the starting material was consumed (by TLC), the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 × 20 mL). The combined organic extracts were 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: 30–40% EtOAc / hexanes) to afford 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)

[0572] 2-Bromo-1-cyclopropyl-1H-benzo[d]imidazole-6-carbonitrile To a stirred solution of 2-bromo-3-cyclopropyl-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrile (200 mg, 1.0 mmol) in 1,2-dichloroethane (DCE) (4 mL) was added phosphoryl bromide (1.2 g, 4.02 mmol) at room temperature under an inert atmosphere. The reaction mixture was heated to 80 °C and stirred for 16 h. After 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 combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure to give 2-bromo-3-cyclopropyl-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrile (50 mg, 0.20 mmol, 19%) as a white solid, which was used in the next step without further purification. LC-MS: m / z 261.8[M+] at retention time 2.52 + (96.21% purity).

[0573] 1-Cyclopropyl-2-(6-methylpyridazin-4-yl)-1H-benzo[d]imidazole-6-carbonitrile (Example 35) To a stirred solution of 2-bromo-3-cyclopropyl-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrile (100 mg, 0.38 mmol) in 1,4-dioxane (3 mL) was added 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazine (126.9 mg, 0.57 mmol) and 2 M aqueous sodium carbonate (0.3 mL, 0.64 mmol) under an inert atmosphere at room temperature. The reaction mixture was degassed under argon for 10 minutes, and Pd(dppf)Cl (23 mg, 0.03 mmol) was added, and the mixture was degassed under argon for an additional 10 minutes. The reaction mixture was heated to 90 °C and stirred for 16 hours. After the starting material was consumed (by TLC), the volatiles were concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 50% EtOAc / hexanes) to give 1-cyclopropyl-2-(6-methylpyridazin-4-yl)-1H-benzo[d]imidazole-6-carbonitrile Example 35 (20 mg, 0.07 mmol, 12%) as an off-white solid. 1 H NMR (400 MHz, CD3OD): δ 9.68 (d, J = 1.8 Hz, 1H), 8.26 (s, 2H), 7.91 (d, J = 8.5 Hz, 1H), 7.68 (dd, J = 8.4, 1.4 Hz, 1H), 3.94-3.90 (m, 1H), 2.86 (s, 3H), 1.36-1.25 (m, 2H), 0.90-0.81 (m, 2H) LC-MS: m / z 275.9 [M+H] at retention time 2.02 + (99.65% purity). HPLC: 99.26%.

[0574] Example 36 Scheme:

[0575] [ka]

[0576] 1-Cyclopropyl-5,6-difluoro-2-(6-(4-methylpiperazin-1-yl)pyridazin-4-yl)-1H-benzo[d]imidazole (Example 36) A solution of 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole Example 22 (50 mg, 0.16 mmol) in 1-methylpiperazine (0.5 mL) was stirred at 130 °C for 3 hours under an inert atmosphere. After the starting material was consumed (by TLC), the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 × 20 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 5% MeOH / CHCl) to give 1-cyclopropyl-5,6-difluoro-2-(6-(4-methylpiperazin-1-yl)pyridazin-4-yl)-1H-benzo[d]imidazole Example 36 (25 mg, 0.06 mmol, 41%) as a pale yellow solid. 1 H NMR (400 MHz, CDCl3): δ 9.13 (s, 1H), 7.57 (dd, J = 10.2, 7.3 Hz, 1H), 7.46 (s, 1H), 7.41 (dd, J = 9.6, 7.0 Hz, 1H), 3.86-3.74 (m, 4H), 3.63-3.57 (m, 1H), 2.64-2.52 (m, 4H), 2.37 (s, 3H), 1.30-1.25 (m, 2H), 0.85-0.81 (m, 2H) LC-MS: m / z 371 [M+H] at retention time 1.71 + (98.46% purity). HPLC: 97.35%.

[0577] Example 37 Scheme:

[0578] [ka]

[0579] 1-Cyclopropyl-5,6-difluoro-2-(6-(piperazin-1-yl)pyridazin-4-yl)-1H-benzo[d]imidazole To a stirred solution of tert-butyl 4-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)piperazine-1-carboxylate Example 39 (200 mg, 0.43 mmol) in CHCl (2 mL) under an inert atmosphere at 0° C. was added trifluoroacetic acid (0.6 mL). The reaction mixture was warmed to room temperature and stirred for 1 h. After the starting material was consumed (by TLC), the volatiles were removed under reduced pressure. The residue was neutralized with saturated sodium bicarbonate solution (20 mL) and extracted with EtOAc (2×20 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure. The crude was washed with ether:n-pentane (1:1, 2 × 2 mL) to give 1-cyclopropyl-5,6-difluoro-2-(6-(piperazin-1-yl)pyridazin-4-yl)-1H-benzo[d]imidazole (90 mg, crude) as a brown solid, which was used in the next step without further purification. LC-MS: m / z 357[M+H] at retention time 1.78 + (98.01% purity).

[0580] 1-(4-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)piperazin-1-yl)ethan-1-one (Example 37) To a stirred solution of 1-cyclopropyl-5,6-difluoro-2-(6-(piperazin-1-yl)pyridazin-4-yl)-1H-benzo[d]imidazole (50 mg, 0.14 mmol) in CHCl (1 mL) under an inert atmosphere at 0 °C was added triethylamine (0.05 mL, 0.42 mmol) and acetyl chloride (0.01 mL, 0.14 mmol). The reaction mixture was stirred at 0 °C for 10 min. After the starting material was consumed (by TLC), the reaction mixture was diluted with saturated sodium bicarbonate solution (20 mL) and extracted with CHCl (2 × 20 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 5% MeOH / CH2Cl2) to give 1-(4-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)piperazin-1-yl)ethan-1-one Example 37 (14 mg, 0.03 mmol, 25%) as a pale yellow solid. 1 H NMR (400 MHz, CDCl3): δ 9.20 (s, 1H), 7.57 (dd, J = 10.1, 7.2 Hz, 1H), 7.49 (s, 1H), 7.42 (dd, J = 9.6, 6.9 Hz, 1H), 3.94-3.89 (m, 2H), 3.84-3.78 (m, 2H), 3.75-3.70 (m, 2H), 3.69-3.64 (m, 2H), 3.64-3.59 (m, 1H), 2.18 (s, 3H), 1.32-1.26 (m, 2H), 0.86-0.81 (m, 2H) LC-MS: m / z 399.1 [M+H] at retention time 1.57 + (93.31% purity). HPLC: 92.89%.

[0581] Example 38 Scheme:

[0582] [ka]

[0583] 1-Cyclopropyl-5,6-difluoro-2-(6-(4-(methylsulfonyl)piperazin-1-yl)pyridazin-4-yl)-1H-benzo[d]imidazole (Example 38) To a stirred solution of 1-cyclopropyl-5,6-difluoro-2-(6-(piperazin-1-yl)pyridazin-4-yl)-1H-benzo[d]imidazole (50 mg, 0.14 mmol) in CHCl (1 mL) under an inert atmosphere at 0 °C, triethylamine (0.05 mL, 0.42 mmol) and mesyl chloride (0.01 mL, 0.14 mmol) were added. The reaction mixture was stirred for 10 min. After the starting material was consumed (by TLC), the reaction mixture was diluted with saturated sodium bicarbonate solution (20 mL) and extracted with CHCl (2 × 20 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 5% MeOH / CH2Cl2) to afford 1-cyclopropyl-5,6-difluoro-2-(6-(4-(methylsulfonyl)piperazin-1-yl)pyridazin-4-yl)-1H-benzo[d]imidazole Example 38 (14 mg, 0.03 mmol, 25%) as a pale yellow solid. 1 H NMR (400 MHz, CDCl3): δ 9.22 (s, 1H), 7.57 (dd, J = 10.1, 7.2 Hz, 1H), 7.51 (s, 1H), 7.42 (dd, J = 9.6, 6.9 Hz, 1H), 3.96-3.91 (m, 4H), 3.65-3.60 (m, 1H), 3.43-3.38 (m, 4H), 2.84 (s, 3H), 1.34-1.24 (m, 2H), 0.91-0.80 (m, 2H) LC-MS: m / z 435.1 [M+H] with retention time 2.09 + (98.86% purity). HPLC: 97.10%.

[0584] Example 39 Scheme:

[0585] [ka]

[0586] tert-Butyl 4-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)piperazine-1-carboxylate (Example 39) To a stirred solution of 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole Example 22 (200 mg, 0.65 mmol) in dimethyl sulfoxide (DMSO) (4 mL) was added tert-butyl piperazine-1-carboxylate (729 mg, 3.97 mmol) at room temperature under an inert atmosphere. The reaction mixture was stirred at 130 °C for 3 hours. After the starting material was consumed (by TLC), the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2 × 30 mL). The combined organic extracts were washed with water (20 mL), brine (20 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 5% MeOH / CHCl) to give Example 39 (230 mg, 0.50 mmol, 77%) as a brown solid. 1 H NMR (400 MHz, CDCl3): δ 9.17 (s, 1H), 7.57 (dd, J = 10.0, 7.2 Hz, 1H), 7.47 (s, 1H), 7.41 (dd, J = 9.7, 6.9 Hz, 1H), 3.78-3.75 (m, 4H), 3.64-3.58 (m, 5H), 1.50 (s, 9H), 1.31-1.26 (m, 2H), 0.86-0.81 (m, 2H) LC-MS: m / z 457.1 [M+H] at retention time 2.52 + (97.87% purity). HPLC: 95.78%.

[0587] Examples 40 and 41 Scheme:

[0588] [ka]

[0589] 6-chloro-N-(4-cyano-2-(ethylamino)phenyl)pyridazine-4-carboxamide To a stirred solution of 6-chloropyridazine-4-carboxylic acid (100 mg, 0.64 mmol) in DMF (2 mL) was added 4-amino-3-(ethylamino)benzonitrile Intermediate-4 (104 mg, 0.64 mmol), HATU (369.9 mg, 0.97 mmol), and ethyldiisopropylamine (0.45 mL, 2.59 mmol) under an inert atmosphere at room temperature. The reaction mixture was stirred at room temperature for 16 h. After the starting material was consumed (by TLC), the reaction mixture was diluted with aqueous ammonium chloride (30 mL) and extracted with EtOAc (2 × 30 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure to give 6-chloro-N-(4-cyano-2-(ethylamino)phenyl)pyridazine-4-carboxamide (90 mg, crude) as a yellow solid. LC-MS: m / z 300.9[M] at retention time 2.07 + (36.25% purity).

[0590] 1-Ethyl-2-(6-methoxypyridazin-4-yl)-1H-benzo[d]imidazole-6-carbonitrile (Example 40) To a stirred solution of 6-chloro-N-(4-cyano-2-(ethylamino)phenyl)pyridazine-4-carboxamide (100 mg, 0.33 mmol) in CHCl (1.6 mL) under an inert atmosphere at 0° C. was added trifluoroacetic acid (0.4 mL). The reaction mixture was stirred at 0° C. for 6 h. After the starting material was consumed (by TLC), the reaction mixture was diluted with saturated sodium carbonate solution (20 mL) and extracted with EtOAc (2×30 mL). The combined organic extracts were washed with water (20 mL), brine (20 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude material was triturated with ether (2×10 mL) and n-pentane (2×10 mL) to afford 1-ethyl-2-(6-methoxypyridazin-4-yl)-1H-benzo[d]imidazole-6-carbonitrile Example 40 (25 mg, 0.09 mmol, 26%) as an off-white solid. 1 H NMR (400 MHz, CD3OD): δ 9.27 (d, J = 1.9 Hz, 1H), 8.24 (s, 1H), 7.91 (dd, J = 8.4, 0.6 Hz, 1H), 7.68 (dd, J = 8.5, 1.4 Hz, 1H), 7.59 (s, 1H), 4.53-4.49 (m, 2H), 4.22 (s, 3H), 1.48 (t, J = 7.3 Hz, 3H) LC-MS: m / z 279.8 [M+H] at retention time 2.15 + (98.27% purity). HPLC: 98.65%.

[0591] 2-(6-chloropyridazin-4-yl)-1-ethyl-1H-benzo[d]imidazole-6-carbonitrile (Example 17) A stirred solution of 1-ethyl-2-(6-methoxypyridazin-4-yl)-1H-benzo[d]imidazole-6-carbonitrile (Example 40, 85 mg, 0.30 mmol) in phosphoryl chloride (0.57 mL, 6.09 mmol) was added under an inert atmosphere at room temperature. The reaction mixture was heated to 100° C. for 2 hours. After the starting material was consumed (by TLC), the reaction mixture was basified with aqueous sodium carbonate (20 mL) and extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water (10 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude material was triturated with ether (2 × 5 mL) and n-pentane (2 × 5 mL) to afford 2-(6-chloropyridazin-4-yl)-1-ethyl-1H-benzo[d]imidazole-6-carbonitrile Example 17 (100 mg, crude) as a pale yellow syrup, which was used in the next step without further purification.

[0592] 1-Ethyl-2-(6-vinylpyridazin-4-yl)-1H-benzo[d]imidazole-6-carbonitrile To a stirred solution of 2-(6-chloropyridazin-4-yl)-1-ethyl-1H-benzo[d]imidazole-6-carbonitrile (Example 17) (130 mg, 0.46 mmol) in 1,4-dioxane (3 mL) and water (0.5 mL) was added vinyl pinacol borate (70 mg, 0.46 mmol) and potassium carbonate (190 mg, 1.37 mmol) at room temperature under an inert atmosphere. The reaction mixture was degassed under argon for 10 minutes. To this was added Pd(dppf)Cl (3.7 mg, 0.005 mmol) at room temperature, and the mixture was degassed for an additional 10 minutes under argon. The reaction mixture was heated to 80° C. and stirred for 4 hours. After the starting material was consumed (by TLC), the reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give 1-ethyl-2-(6-vinylpyridazin-4-yl)-1H-benzo[d]imidazole-6-carbonitrile (110 mg, crude) as a brown syrup. LC-MS: m / z 275.9[M+H] at retention time 2.18 + (78.16% purity).

[0593] 1-Ethyl-2-(6-ethylpyridazin-4-yl)-1H-benzo[d]imidazole-6-carbonitrile (Example 41) To a stirred solution of 1-ethyl-2-(6-vinylpyridazin-4-yl)-1H-benzo[d]imidazole-6-carbonitrile (110 mg, 0.40 mmol) in EtOAc (5 mL) was added 10% Pd / C (50% aqueous, 20 mg) and triethylamine (0.005 mL, 0.04 mmol) at room temperature under an inert atmosphere. The reaction mixture was stirred at room temperature under a hydrogen atmosphere (balloon pressure) for 2 hours. After 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 concentrated under reduced pressure. The crude product was purified by preparative HPLC to give 1-ethyl-2-(6-ethylpyridazin-4-yl)-1H-benzo[d]imidazole-6-carbonitrile Example 41 (4 mg, 14.44 mmol, 4%) as an off-white solid. 1 H NMR (400 MHz, CD3OD): δ 9.51 (d, J = 2.0 Hz, 1H), 8.26 (s, 1H), 8.06 (d, J = 2.1 Hz, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.69 (dd, J = 8.5, 1.4 Hz, 1H), 4.55-4.50 (m, 2H), 3.21-3.15 (m, 2H), 1.53-1.45 (m, 6H) LC-MS: m / z 277.9 [M+H] at retention time 2.12 + (96.23% purity). HPLC: 96.66%.

[0594] Example 42 Scheme:

[0595] [ka]

[0596] 1-Cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (Example 42) To a stirred solution of 5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-carbaldehyde Intermediate-27 (100 mg, 0.33 mmol) in CHCl (5 mL) under an inert atmosphere at 0 °C, was added (diethylamino)sulfur trifluoride (DAST) (0.09 mL, 0.66 mmol). The reaction mixture was warmed to room temperature and stirred for 1 h. After the starting material was consumed (by TLC), the reaction mixture was diluted with saturated sodium carbonate solution (20 mL) and extracted with CHCl (2 × 20 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 50% EtOAc / hexanes) to give 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole Example 42 (40 mg, 0.12 mmol, 37%) as a brown solid. 1 H NMR (400 MHz, DMSO-d6): δ 9.99 (s, 1H), 8.55 (s, 1H), 7.93-7.85 (m, 2H), 7.42 (t, J = 54.5 Hz, 1H), 4.01-3.97 (m, 1H), 1.25-1.13 (m, 2H), 0.84-0.72 (m, 2H) LC-MS: m / z 323.3 [M+H] with retention time 3.53 + (98.91% purity). HPLC: 99.33%.

[0597] Example 43 Scheme:

[0598] [ka]

[0599] 2-(6-Cyclobutoxypyridazin-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole (Example 43) To a stirred solution of 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole Example 22 (50 mg, 0.16 mmol) in DMF (2 mL) was added sodium hydride (60% in mineral oil, 16.3 mg, 0.41 mmol) portionwise at 0 °C under an inert atmosphere. The reaction mixture was stirred at 0 °C for 10 minutes. Then, cyclobutanol (141 mg, 0.20 mmol) was added to the reaction mixture at 0 °C. The reaction mixture was warmed to room temperature and stirred for 1 hour. After the starting material was consumed (by TLC), the reaction mixture was quenched with ice-cold water (20 mL) and extracted with EtOAc (2 × 20 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 3% MeOH / CH2Cl2) to give 2-(6-cyclobutoxypyridazin-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole Example 43 (45 mg, 0.13 mmol, 57%) as an off-white solid. 1 H NMR (400 MHz, CDCl3): δ 9.42 (s, 1H), 7.59 (dd, J = 10.1, 7.2 Hz, 1H), 7.47 (s, 1H), 7.44-7.40 (m, 1H), 5.53-5.48 (m, 1H), 3.62-3.57 (m, 1H), 2.67-2.50 (m, 2H), 2.31-2.08 (m, 2H), 1.99-1.83 (m, 1H), 1.78-1.73 (m, 1H), 1.37-1.24 (m, 2H), 0.89-0.77 (m, 2H) LC-MS: m / z 343 [M+H] with retention time 2.61 + (95.30% purity). HPLC: 95.28%.

[0600] Example 44 Scheme:

[0601] [ka]

[0602] 1-Cyclopropyl-2-(6-(4,4-difluoropiperidin-1-yl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (Example 44) To a stirred solution of 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole (Example 22) (100 mg, 0.32 mmol) in DMSO (2 mL) was added 4,4-difluoropiperidine (59 mg, 0.49 mmol) at room temperature under an inert atmosphere. The reaction mixture was heated to 120-130 °C and stirred for 16 h. After 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 combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 50-60% EtOAc / hexanes) to afford 1-cyclopropyl-2-(6-(4,4-difluoropiperidin-1-yl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole Example 44 (40 mg, 0.10 mmol, 32%) as an off-white solid. 1 H NMR (400 MHz, CD3OD): δ 9.09 (s, 1H), 7.82 (s, 1H), 7.72-7.68 (m, 1H), 7.62-7.57 (m, 1H), 3.99-3.92 (m, 4H), 3.86-3.83 (m, 1H), 2.19-2.00 (m, 4H), 1.27-1.19 (m, 2H), 0.87-0.76 (m, 2H) LC-MS: m / z 392.1 [M+H] at retention time 2.98 + (93.89% purity). HPLC: 92.05%.

[0603] Example 45 Scheme:

[0604] [ka]

[0605] 6-Methylpyridazine-4-carboxylic acid To a stirred solution of 3-chloro-6-methylpyridazine-4-carboxylic acid 1 (500 mg, 2.90 mmol) in MeOH (50 mL) was added sodium hydroxide (395 mg, 9.80 mmol) and 10% Pd / C (50% aqueous, 150 mg) under an inert atmosphere at room temperature. The reaction mixture was stirred at room temperature under a hydrogen atmosphere (balloon pressure) for 1 hour. After the starting material was consumed (by TLC), the reaction mixture was filtered through a pad of Celite. The filtrate was concentrated under reduced pressure, and 6N HCl was added until the pH was approximately 6. Concentration under reduced pressure afforded 6-methylpyridazine-4-carboxylic acid (410 mg, crude) as a yellow liquid, which was used in the next step without further purification. 1 H NMR (500 MHz, DMSO-d6): δ 9.24 (s, 1H), 7.69 (s, 1H), 2.62 (s, 3H)

[0606] N-(6-chloro-2-(cyclopropylamino)pyridin-3-yl)-6-methylpyridazine-4-carboxamide 6-Chloro-N 2To a stirred solution of N-cyclopropylpyridine-2,3-diamine intermediate-8 (400 mg, 2.18 mmol) in DMF (5 mL) was added compound 6-methylpyridazine-4-carboxylic acid (362 mg, 2.62 mmol), HATU (996 mg, 2.62 mmol), and ethyldiisopropylamine (1.6 mL, 8.75 mmol) at room temperature under an inert atmosphere. The reaction mixture was stirred at room temperature for 16 hours. After the starting material was consumed (by TLC), the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2 × 30 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure to give N-(6-chloro-2-(cyclopropylamino)pyridin-3-yl)-6-methylpyridazine-4-carboxamide (200 mg, 0.66 mmol, 30%) as a black solid, which was used in the next step without further purification. LC-MS: m / z 303.9[M+H] at retention time 2.06 + (93.73% purity).

[0607] 5-Chloro-3-cyclopropyl-2-(6-methylpyridazin-4-yl)-3H-imidazo[4,5-b]pyridine (Example 45) To a stirred solution of N-(6-chloro-2-(cyclopropylamino)pyridin-3-yl)-6-methylpyridazine-4-carboxamide (100 mg, 0.33 mmol) in EtOH (2 mL) was added 6N HCl (3 mL) under an inert atmosphere at 0° C. The reaction mixture was stirred at room temperature for 1 hour. After the starting material was consumed (by TLC), the reaction mixture was diluted with saturated sodium bicarbonate solution (20 mL) and extracted with EtOAc (2×20 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give 5-chloro-3-cyclopropyl-2-(6-methylpyridazin-4-yl)-3H-imidazo[4,5-b]pyridine Example 45 (12 mg, 0.04 mmol, 10%) as a brown solid. 1H NMR (400 MHz, CD3OD): δ 9.67 (s, 1H), 8.26 (s, 1H), 8.12 (d, J = 8.4 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 3.83-3.78 (m, 1H), 2.84 (s, 3H), 1.29-1.25 (m, 2H), 0.94-0.92 (m, 2H) LC-MS: m / z 285.9 [M+H] at retention time 2.03 + (98.73% purity). HPLC: 95.65%.

[0608] Example 46 Scheme:

[0609] [ka]

[0610] 1-Cyclopropyl-2-(6-(3,3-difluoropyrrolidin-1-yl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (Example 46) To a stirred solution of 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole (Example 22) (100 mg, 0.32 mmol) in DMSO (2 mL) was added 3,3-difluoropyrrolidine hydrochloride (70 mg, 0.50 mmol) and triethylamine (0.06 mL, 0.49 mmol) at room temperature under an inert atmosphere. The reaction mixture was heated to 130 °C and stirred for 48 hours. After 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 combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure. The crude material was purified by preparative HPLC to afford 1-cyclopropyl-2-(6-(3,3-difluoropyrrolidin-1-yl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole Example 46 (15 mg, 0.04 mmol, 12%) as an off-white solid. 1H NMR (400 MHz, CD3OD): δ 9.10 (s, 1H), 7.72-7.68 (m, 1H), 7.62-7.57 (m, 1H), 7.49 (d, J = 1.8 Hz, 1H), 4.03 (t, J = 12.9 Hz, 2H), 3.90-3.77 (m, 3H), 2.69-2.54 (m, 2H), 1.30-1.22 (m, 2H), 0.86-0.80 (m, 2H) LC-MS: m / z 378.1 [M+H] at retention time 2.80 + (97.60% purity). HPLC: 99.55%.

[0611] Example 47 Scheme:

[0612] [ka]

[0613] 1-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)-2,2,2-trifluoroethan-1-ol (Example 47) To a stirred solution of 5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-carbaldehyde Intermediate-27 (50 mg, 0.16 mmol) in THF (1 mL) was added trimethyl(trifluoromethyl)silane (47 mg, 0.33 mmol) under an inert atmosphere at 0 °C. Cesium fluoride (76 mg, 0.50 mmol) was added to the reaction mixture at 0 °C. The reaction mixture was stirred at room temperature for 2 h. After the starting material was consumed (by TLC), the reaction mixture was quenched with 1 N HCl solution (5 mL) at 0 °C and extracted with EtOAc (2 × 15 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 50% EtOAc / hexanes) to give 1-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)-2,2,2-trifluoroethan-1-ol Example 47 (10 mg, 0.03 mmol, 16%) as a brown solid. 1 H NMR (400 MHz, CD3OD): δ 9.83 (s, 1H), 8.58 (s, 1H), 7.75-7.71 (m, 1H), 7.67-7.63 (m, 1H), 5.60-5.52 (m, 1H), 3.94-3.81 (m, 1H), 1.35-1.21 (m, 2H), 0.93-0.78 (m, 2H) LC-MS: m / z 371 [M+H] with retention time 2.69 + (95.24% purity). HPLC: 95.69%.

[0614] Example 48 Scheme:

[0615] [ka]

[0616] 1-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)-N,N-dimethylpyrrolidin-3-amine (Example 48) To a stirred solution of 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole Example 22 (115 mg, 0.37 mmol) in DMSO (2 mL) was added triethylamine (0.116 mL, 0.84 mmol) and 1-(3-(dimethylamino)-1,5-pyrrolidin-1-yl)-2,2,2-trifluoroethan-1-one (120 mg, 0.56 mmol) under an inert atmosphere at 0° C. The reaction mixture was stirred at 90° C. for 5 hours. After the starting material was consumed (by TLC), the reaction mixture was diluted with ice-cold water (10 mL) and extracted with EtOAc (2×10 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 5-10% MeOH / CHCl) to afford 1-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)-N,N-dimethylpyrrolidin-3-amine Example 48 (10 mg, 0.02 mmol, 7%) as an off-white solid. 1 H NMR (400 MHz, CD3OD): δ 9.01 (s, 1H), 7.72-7.67 (m, 1H), 7.61-7.57 (m, 1H), 7.44 (s, 1H), 3.96-3.93 (m, 1H), 3.86-3.81 (m, 2H), 3.62-3.55 (m, 1H), 3.45-3.37 (m, 1H), 3.09-2.99 (m, 1H), 2.38 (s, 6H), 2.08-1.95 (m, 1H), 1.32-1.20 (m, 3H), 0.87-0.78 (m, 2H) LC-MS: m / z 385.1 [M+H] at retention time 2.06 + (97.17% purity). HPLC: 98.58%.

[0617] Example 49 Scheme:

[0618] [ka]

[0619] 1-Cyclopropyl-5,6-difluoro-2-(6-(4-fluorophenyl)pyridazin-4-yl)-1H-benzo[d]imidazole (Example 49) Pd(PPh)Cl (11.5 mg, 0.01 mmol) and sodium carbonate (86.4 mg, 0.81 mmol) in 1,4-dimethoxyethane (DME):water (4:1, 1.25 mL) were purged under argon at room temperature for 5 minutes. 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole Example 22 (50 mg, 0.16 mmol) and (4-fluorophenyl)boronic acid (25.1 mg, 0.17 mmol) were added to the reaction mixture at room temperature. The reaction mixture was stirred in a sealed tube at 80 °C for 12 hours. After the starting material was consumed (by TLC), the reaction mixture was diluted with water (20 mL) and extracted with CHCl (2 × 20 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 2% MeOH / CH2Cl2) to give 1-cyclopropyl-5,6-difluoro-2-(6-(4-fluorophenyl)pyridazin-4-yl)-1H-benzo[d]imidazole Example 49 (40 mg, 0.10 mmol, 48%) as an off-white solid. 1 H NMR (400 MHz, CD3OD): δ 9.75 (s, 1H), 8.68 (s, 1H), 8.32-8.18 (m, 2H), 7.76-7.72 (m, 1H), 7.67-7.62 (m, 1H), 7.35 (t, J = 8.8 Hz, 2H), 3.98-3.93 (m, 1H), 1.32-1.25 (m, 2H), 0.90-0.84 (m, 2H) LC-MS: m / z 367 [M+H] at retention time 2.58 +(98.75% purity). HPLC: 98.72%.

[0620] Example 50 Scheme:

[0621] [ka]

[0622] 1-Cyclopropyl-5,6-difluoro-2-(6-((4-fluorophenyl)ethynyl)pyridazin-4-yl)-1H-benzo[d]imidazole (Example 50) To a stirred solution of 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole (Example 22) (100 mg, 0.32 mmol) in N,N-dimethylacetamide (DMA) (3 mL) was added 1-ethynyl-4-fluorobenzene (40 mg, 0.32 mmol) and potassium carbonate (90 mg, 0.65 mmol) at room temperature under an inert atmosphere. The reaction mixture was degassed with argon for 10 minutes. Pd2(dba)3 (14.8 mg, 0.01 mmol) and X-phos (8 mg, 0.01 mmol) were added at room temperature, and the mixture was degassed with argon for an additional 5 minutes. The reaction mixture was heated to 80 °C and stirred for 2 hours. After the starting material was consumed (by TLC), the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 × 20 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 30% EtOAc / hexane) to give 1-cyclopropyl-5,6-difluoro-2-(6-((4-fluorophenyl)ethynyl)pyridazin-4-yl)-1H-benzo[d]imidazole Example 50 (50 mg, 0.13 mmol, 39%) as a brown solid. 1H NMR (400 MHz, DMSO-d6): δ 9.81 (s, 1H), 8.49 (s, 1H), 7.91-7.84 (m, 2H), 7.84-7.76 (m, 2H), 7.38 (t, J = 9.0 Hz, 2H), 4.01-3.93 (m, 1H), 1.24-1.16 (m, 2H), 0.85-0.71 (m, 2H) LC-MS: m / z 391.3 [M+H] at retention time 4.58 + (97.94% purity). HPLC: 96.14%.

[0623] Example 51 Scheme:

[0624] [ka]

[0625] 1-Cyclopropyl-5,6-difluoro-2-(6-(prop-1-en-2-yl)pyridazin-4-yl)-1H-benzo[d]imidazole To a stirred solution of 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole (Example 22) (120 mg, 0.40 mmol) in 1,4-dioxane (3.2 mL) and water (0.8 mL) was added 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (219 mg, 1.17 mmol) and sodium carbonate (164.6 mg, 1.56 mmol), and the mixture was purged with argon at room temperature for 10 minutes. Pd(PPh3)4 (23 mg, 0.02 mmol) was added to the reaction mixture. The reaction mixture was heated at 110 °C for 8 hours. After the starting material was consumed (by TLC), the reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The crude material was triturated with n-pentane (2 × 5 mL) to afford 1-cyclopropyl-5,6-difluoro-2-(6-(prop-1-en-2-yl)pyridazin-4-yl)-1H-benzo[d]imidazole (100 mg, crude) as an off-white solid, which was used in the next step without further purification. LC-MS: m / z 313.1[M+H] at retention time 2.38 + (94.08% purity).

[0626] 1-Cyclopropyl-5,6-difluoro-2-(6-isopropylpyridazin-4-yl)-1H-benzo[d]imidazole (Example 51) To a stirred solution of the compound 1-cyclopropyl-5,6-difluoro-2-(6-(prop-1-en-2-yl)pyridazin-4-yl)-1H-benzo[d]imidazole (100 mg, 0.32 mmol) in ethyl acetate (5 mL) was added triethylamine (0.04 mL), sodium hydroxide (25 mg, 0.64 mmol), and 10% Pd / C (50% aqueous, 30 mg) at room temperature under an inert atmosphere. The reaction mixture was stirred at room temperature under a hydrogen atmosphere (balloon pressure) for 1 hour. After the starting material was consumed (by TLC), the reaction mixture was filtered through a pad of Celite, and the Celite bed was washed with EtOAc (20 mL). The filtrate was concentrated under reduced pressure. The crude material was washed with n-pentane (2×2 mL) and ether (2×2 mL) to give 1-cyclopropyl-5,6-difluoro-2-(6-isopropylpyridazin-4-yl)-1H-benzo[d]imidazole Example 51 (55 mg, 0.17 mmol, 55%) as an off-white solid. 1 H NMR (400 MHz, CD3OD): δ 9.63 (s, 1H), 8.22 (s, 1H), 7.73-7.69 (m, 1H), 7.64-7.60 (m, 1H), 3.91-3.86 (m, 1H), 3.49-3.31 (m, 1H), 1.47 (d, J = 7.0 Hz, 6H), 1.31-1.20 (m, 2H), 0.86-0.73 (m, 2H) LC-MS: m / z 315.1 [M+H] with retention time 2.31 + (97.95% purity). HPLC: 99.16%.

[0627] Example 52 Scheme:

[0628] [ka]

[0629] N-((5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methyl)ethanesulfonamide (Example 52) To a stirred solution of (5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methanamine (140 mg, 0.46 mmol) in CHCl (4 mL) was added triethylamine (0.19 mL, 0.79 mmol) and ethanesulfonyl chloride (65.7 mg, 0.51 mmol) at room temperature under an inert atmosphere. The reaction mixture was stirred at room temperature for 1 h. After the starting material was consumed (by TLC), the reaction mixture was diluted with water (20 mL) and extracted with CHCl (2 × 20 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure. The crude material was purified by preparative HPLC to afford N-((5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methyl)ethanesulfonamide Example 52 (18 mg, 0.04 mmol, 10%) as a white solid. 1 H NMR (400 MHz, CD3OD): δ 9.72 (s, 1H), 8.52 (s, 1H), 7.76-7.70 (m, 1H), 7.66-7.61 (m, 1H), 4.71 (s, 2H), 3.88-3.82 (m, 1H), 3.24-3.19 (m, 2H), 1.43-1.33 (m, 5H), 0.86-0.79 (m, 2H) LC-MS: m / z 394 [M+H] at retention time 2.32 + (99.29% purity). HPLC: 98.78%.

[0630] Example 53 Scheme:

[0631] [ka]

[0632] 1-Cyclopropyl-5,6-difluoro-2-(6-((1,1,1-trifluoropropan-2-yl)oxy)pyridazin-4-yl)-1H-benzo[d]imidazole (Example 53) To a stirred solution of 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole Example 22 (75 mg, 0.24 mmol) in DMF (2.25 mL) was added sodium hydride (60% in mineral oil, 24.5 mg, 0.61 mmol) in portions at 0 °C under an inert atmosphere. The reaction mixture was stirred at 0 °C for 10 minutes. 1,1,1-trifluoropropan-2-ol (34 mg, 0.30 mmol) was then added to the reaction mixture at 0 °C. The reaction mixture was warmed to room temperature and stirred for 1 hour. After the starting material was consumed (by TLC), the reaction mixture was quenched with ice-cold water (20 mL) and extracted with EtOAc (2 × 20 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 3% MeOH / CH2Cl2) to afford 1-cyclopropyl-5,6-difluoro-2-(6-((1,1,1-trifluoropropan-2-yl)oxy)pyridazin-4-yl)-1H-benzo[d]imidazole Example 53 (60 mg, 0.15 mmol, 84%) as a brown solid. 1 H NMR (400 MHz, CDCl3): δ 9.54 (s, 1H), 7.63 (s, 1H), 7.62-7.58 (m, 1H), 7.45-7.41 (m, 1H), 6.15-6.04 (m, 1H), 3.69-3.42 (m, 1H), 1.64 (d, J = 6.3 Hz, 3H), 1.36-1.24 (m, 2H), 0.92-0.81 (m, 2H) LC-MS: m / z 385.1 [M+H] at retention time 2.76 + (97.88% purity). HPLC: 97.83%.

[0633] Example 54 Scheme:

[0634] [ka]

[0635] 3-Cyclopropyl-2-(6-methylpyridazin-4-yl)-3H-imidazo[4,5-b]pyridine-5-carbonitrile (Example 54) To a stirred solution of 5-chloro-3-cyclopropyl-2-(6-methylpyridazin-4-yl)-3H-imidazo[4,5-b]pyridine (Example 45) (75 mg, 0.26 mmol) in DMF (0.8 mL) was added zinc cyanide (61.5 mg, 0.52 mmol) and Pd(PPh) (30.3 mg, 0.02 mmol) at room temperature. The mixture was purged with argon for 10 minutes and then heated to 170 °C for 4.5 hours. After 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 combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure. The crude material was purified by preparative HPLC to afford 3-cyclopropyl-2-(6-methylpyridazin-4-yl)-3H-imidazo[4,5-b]pyridine-5-carbonitrile Example 54 (25 mg, 0.09 mmol, 35%) as an off-white solid. 1 H NMR (400 MHz, CDCl3): δ 9.75 (s, 1H), 8.19 (d, J = 8.2 Hz, 1H), 8.01 (s, 1H), 7.72 (d, J = 8.2 Hz, 1H), 3.70-3.64 (m, 1H), 2.90 (s, 3H), 1.41-1.36 (m, 2H), 1.06-0.81 (m, 2H) LC-MS: m / z 276.9 [M+H] at retention time 1.88 + (98.98% purity). HPLC: 95.03%.

[0636] Example 55 Scheme:

[0637] [ka]

[0638] N-(2-(cyclopropylamino)-4,5-difluorophenyl)pyridazine-4-carboxamide N 1 To a stirred solution of N-cyclopropyl-4,5-difluorobenzene-1,2-diamine intermediate-5 (300 mg, 1.63 mmol) in DMF (3 mL) was added pyridazine-4-carboxylic acid (202 mg, 1.63 mmol), HATU (743 mg, 1.95 mmol), and ethyldiisopropylamine (1.1 mL, 6.52 mmol) at room temperature under an inert atmosphere. The reaction mixture was stirred at room temperature for 16 hours. After the starting material was consumed (by TLC), the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2 × 30 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure to give N-(2-(cyclopropylamino)-4,5-difluorophenyl)pyridazine-4-carboxamide (250 mg, crude) as an off-white solid, which was used in the next step without further purification. LC-MS: m / z 291[M+H] at retention time 2.34 + (96.97% purity).

[0639] 1-Cyclopropyl-5,6-difluoro-2-(pyridazin-4-yl)-1H-benzo[d]imidazole (Example 55) To a stirred solution of N-(2-(cyclopropylamino)-4,5-difluorophenyl)pyridazine-4-carboxamide (200 mg, 0.68 mmol) in EtOH (4 mL) was added 6 N HCl (2 mL) at room temperature under an inert atmosphere. The reaction mixture was stirred at 70° C. for 1 hour. After the starting material was consumed (by TLC), the reaction mixture was diluted with saturated sodium bicarbonate solution (20 mL) and extracted with EtOAc (2×20 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure. The crude material was washed with n-pentane (2×5 mL) to give 1-cyclopropyl-5,6-difluoro-2-(pyridazin-4-yl)-1H-benzo[d]imidazole Example 55 (120 mg, 0.44 mmol, 64%) as an off-white solid. 1 H NMR (400 MHz, CD3OD): δ 9.81 (s, 1H), 9.41 (dd, J = 5.4, 1.3 Hz, 1H), 8.33 (dd, J = 5.5, 2.3 Hz, 1H), 7.4-7.69 (m, 1H), 7.65-7.61 (m, 1H), 3.87-3.84 (m, 1H), 1.30-1.24 (m, 2H), 0.88-0.73 (m, 2H) LC-MS: m / z 272.9 [M+H] with retention time 2.21 + (99.23% purity). HPLC: 99.54%.

[0640] Example 56 Scheme:

[0641] [ka]

[0642] 1-Cyclopropyl-5,6-difluoro-2-(pyridazin-4-yl)-4-(trifluoromethyl)-1H-benzo[d]imidazole (Example 56) To a stirred solution of 1-cyclopropyl-5,6-difluoro-2-(pyridazin-4-yl)-1H-benzo[d]imidazole (Example 55) (100 mg, 0.36 mmol) in DMSO (1.5 mL) was added zinc trifluoromethanesulfinate (243 mg, 0.73 mmol) at room temperature under an inert atmosphere. To this was added TBHP (141 mg, 1.10 mmol) at 0° C. The reaction mixture was stirred at 50° C. for 16 hours. After the starting material was consumed (by TLC), the reaction mixture was basified with saturated sodium bicarbonate solution (20 mL) and extracted with CHCl (2×20 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure. The crude material was purified by preparative HPLC to afford 1-cyclopropyl-5,6-difluoro-2-(pyridazin-4-yl)-4-(trifluoromethyl)-1H-benzo[d]imidazole Example 56 (19 mg, 0.05 mmol, 15%) as an off-white solid. 1 H NMR (500 MHz, CD3OD): δ 9.85 (s, 1H), 9.44 (dd, J = 5.2, 1.2 Hz, 1H), 8.38 (dd, J = 5.2, 2.3 Hz, 1H), 8.06 (dd, J = 9.3, 7.0 Hz, 1H), 3.92-3.86 (m, 1H), 1.38-1.20 (m, 2H), 0.89-0.83 (m, 2H) LC-MS: m / z 340.9 [M+H] at retention time 2.75 + (91.67% purity) HPLC: 91.79%

[0643] Example 57 Scheme:

[0644] [ka]

[0645] 1-Cyclopropyl-2-(6-(2,2-difluoropropoxy)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (Example 57) To a stirred solution of 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole (Example 22) (50 mg, 0.16 mmol) in DMF (1.5 mL) was added sodium hydride (60% in mineral oil, 16.2 mg, 0.40 mmol) in portions at 0 °C under an inert atmosphere, and the mixture was stirred for 5 minutes. 2,2-Difluoropropan-1-ol (18.8 mg, 0.19 mmol) was added to the reaction mixture, which was stirred at room temperature for 1 hour. After the starting material was consumed (by TLC), the reaction mixture was quenched with ice-cold water (20 mL) and extracted with EtOAc (2 × 20 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure. The crude material was washed with CHCl:n-pentane (5:95, 10 mL) to give 1-cyclopropyl-2-(6-(2,2-difluoropropoxy)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole Example 57 (45 mg, 0.12 mmol, 82%) as an off-white solid. 1 H NMR (400 MHz, CDCl3): δ 9.53 (s, 1H), 7.65 (d, 1H), 7.60 (dd, J = 10.0, 7.3 Hz, 1H), 7.43 (dd, J = 9.7, 6.9 Hz, 1H), 4.80 (t, J = 12.1 Hz, 2H), 3.67-3.58 (m, 1H), 1.80 (t, J = 18.6 Hz, 3H), 1.39-1.27 (m, 2H), 0.92-0.76 (m, 2H) LC-MS: m / z 367 [M+H] with retention time 3.08 + (96.40% purity) HPLC: 94.40%

[0646] Example 58 Scheme:

[0647] [ka]

[0648] 1-Cyclopropyl-5,6-difluoro-2-(5-isopropylpyridazin-4-yl)-1H-benzo[d]imidazole (Example 58) To a stirred solution of 1-cyclopropyl-5,6-difluoro-2-(pyridazin-4-yl)-1H-benzo[d]imidazole (Example 55) (100 mg, 0.37 mmol) in DMSO (1 mL) was added zinc isopropylsulfinate (205 mg, 0.73 mmol) at room temperature under an inert atmosphere. tert-Butyl hydroperoxide (70% in water, 142 mg, 1.1 mmol) was then added at 0°C. The reaction mixture was gradually warmed to room temperature and then heated to 50°C for 16 hours. After the starting material was consumed (by TLC), the reaction mixture was basified with saturated NaHCO3 solution (pH approx. 8) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 70% EtOAc / hexanes), followed by trituration with n-pentane (2×4 mL) and vacuum drying to afford 1-cyclopropyl-5,6-difluoro-2-(5-isopropylpyridazin-4-yl)-1H-benzo[d]imidazole Example 58 (15 mg, 0.05 mmol, 13%) as an off-white solid. 1 H NMR (400 MHz, CD3OD): δ 9.48 (d, J = 0.8 Hz, 1H), 9.31 (d, J = 1.0 Hz, 1H), 7.71 (dd, J = 10.1, 7.1 Hz, 1H), 7.61 (dd, J = 10.5, 7.3 Hz, 1H), 3.62-3.56 (m, 1H), 3.27-3.20 (m, 1H), 1.33 (d, J = 7.0 Hz, 6H), 1.08-1.03 (m, 2H), 0.73-0.68 (m, 2H) LC-MS: m / z 315.0 [M+H] at retention time 2.70 + (95.37% purity) HPLC: 92.84%

[0649] Example 59 Scheme:

[0650] [ka]

[0651] 1-Cyclopropyl-2-(6-cyclopropylpyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (Example 59) To a stirred solution of 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole (Example 22) (70 mg, 0.22 mmol) in toluene / water (3:1, 2 mL) was added cyclopropylboronic acid (24 mg, 0.27 mmol) and cesium carbonate (186 mg, 0.57 mmol) in a sealed tube, and the mixture was purged under argon for 10 minutes. Pd(dppf)Cl (18.6 mg, 0.02 mmol) was added to the reaction mixture, which was further degassed for 5 minutes. The reaction was heated to 110 °C for 16 hours and then cooled. After the starting material was consumed (by TLC), the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 × 20 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 30% EtOAc / hexanes) to afford 1-cyclopropyl-2-(6-cyclopropylpyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole Example 59 (8 mg, 0.02 mmol, 11%) as a pale yellow solid. 1 H NMR (400 MHz, CDCl3): δ 9.57 (s, 1H), 7.81 (s, 1H), 7.59 (dd, J = 10.2, 7.3 Hz, 1H), 7.43 (dd, J = 9.7, 7.0 Hz, 1H), 3.67-3.60 (m, 1H), 2.32-2.24 (m, 1H), 1.35-1.27 (m, 4H), 1.25-1.19 (m, 2H), 0.86-0.80 (m, 2H) LC-MS: m / z 313.1 [M+H] at retention time 2.22 + (93.72% purity) HPLC: 96.07%

[0652] Example 60 Scheme:

[0653] [ka]

[0654] 6-chloro-N-(2-(cyclopropylamino)-6-methoxypyridin-3-yl)pyridazine-4-carboxamide A stirred solution of 6-chloropyridazine-4-carboxylic acid (500 mg, 3.16 mmol) in DMF (10 mL) was added to the flask under an inert atmosphere at 0 °C with N 2 N-cyclopropyl-6-methoxypyridine-2,3-diamine intermediate-9 (566 mg, 3.16 mmol), HATU (1.8 g, 4.74 mmol), and diisopropylethylamine (2.19 mL, 12.64 mmol) were added. The reaction mixture was stirred at room temperature for 16 h. After the starting material was consumed (by TLC), the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 × 20 mL). The combined organic extracts were washed with water (20 mL), brine (20 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 30–40% EtOAc / hexanes) to afford 6-chloro-N-(2-(cyclopropylamino)-6-methoxypyridin-3-yl)pyridazine-4-carboxamide (225 mg, 0.70 mmol, 22%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ 9.91 (s, 1H), 9.62 (s, 1H), 8.35 (s, 1H), 7.33 (d, J = 8.2 Hz, 1H), 6.50 (d, J = 2.4 Hz, 1H), 6.00 (d, J = 8.0 Hz, 1H), 3.82 (s, 3H), 2.73-2.70 (m, 1H), 0.73-0.64 (m, 2H), 0.52-0.40 (m, 2H)

[0655] 2-(6-chloropyridazin-4-yl)-3-cyclopropyl-5-methoxy-3H-imidazo[4,5-b]pyridine (Example 60) To a stirred solution of 6-chloro-N-(2-(cyclopropylamino)-6-methoxypyridin-3-yl)pyridazine-4-carboxamide (150 mg, 0.47 mmol) in EtOH (3.5 mL) was added 6 N HCl (2 mL) under an inert atmosphere at 0 °C. The reaction mixture was stirred at 80 °C for 1 h. After the starting material was consumed (by TLC), the reaction mixture was diluted with saturated sodium carbonate solution (20 mL) and extracted with EtOAc (2 × 20 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 60-70% EtOAc / hexanes) to afford 2-(6-chloropyridazin-4-yl)-3-cyclopropyl-5-methoxy-3H-imidazo[4,5-b]pyridine Example 60 (35 mg, 0.11 mmol, 22%) as a brown solid. 1 H NMR (400 MHz, CD3OD): δ 8.28 (s, 1H), 7.42 (s, 1H), 7.33 (d, J = 8.3 Hz, 1H), 6.03 (d, J = 8.3 Hz, 1H), 3.90 (s, 3H), 2.79-2.74 (m, 1H), 0.77-0.68 (m, 2H), 0.53-0.47 (m, 2H) LC-MS: m / z 302.1 [M+H] at retention time 1.85 + (95.67% purity) HPLC: 94.24%

[0656] Example 61 Scheme:

[0657] [ka]

[0658] 1-Cyclopropyl-5,6-difluoro-2-(6-(4-fluoro-2-methylphenyl)pyridazin-4-yl)-1H-benzo[d]imidazole (Example 61) To a stirred solution of 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole (Example 22) (70 mg, 0.22 mmol) in DME / EtOH (2:1, 0.9 mL) was added (4-fluoro-2-methylphenyl)boronic acid (42 mg, 0.27 mmol) and sodium carbonate (72.5 mg, 0.68 mmol) in a sealed tube, and the mixture was purged under argon for 10 minutes. trans-Dichlorobis-(triphenylphosphine)-II (8 mg, 0.01 mmol) was added to the reaction mixture, and the reaction mixture was stirred at 80 °C for 16 hours. After the starting material was consumed (by TLC), the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 20% EtOAc / hexanes) to afford 1-cyclopropyl-5,6-difluoro-2-(6-(4-fluoro-2-methylphenyl)pyridazin-4-yl)-1H-benzo[d]imidazole Example 61 (45 mg, 0.11 mmol, 51%) as an off-white solid. 1 H NMR (400 MHz, CDCl3): δ 9.81 (s, 1H), 8.14 (s, 1H), 7.60 (dd, J = 10.1, 7.2 Hz, 1H), 7.49 (dd, J = 8.34, 5.83 Hz, 1H), 7.44 (dd, J = 9.6, 6.9 Hz, 1H), 7.11-7.03 (m, 2H), 3.71-3.63 (m, 1H), 2.46 (s, 3H), 1.37-1.30 (m, 2H), 0.93-0.87 (m, 2H) LC-MS: m / z 381.1 [M+H] at retention time 2.60 + (97.81% purity) HPLC: 96.11%

[0659] Example 62 Scheme:

[0660] [ka]

[0661] 1-Cyclopropyl-2-(6-(2,4-difluorophenyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (Example 62) To a stirred solution of 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole (Example 22) (70 mg, 0.22 mmol) in DME:EtOH (2:1, 0.9 mL) was added (2,4-difluorophenyl)boronic acid (43 mg, 0.27 mmol) and sodium carbonate (75.5 mg, 0.68 mmol), and the mixture was purged under argon for 10 minutes. trans-Dichlorobis-(triphenylphosphine)-II (8 mg, 0.01 mmol) was added to the reaction mixture, and the reaction mixture was stirred in a sealed tube at 80 °C for 16 hours. After the starting material was consumed (by TLC), the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 20% EtOAc / hexanes) to afford 1-cyclopropyl-2-(6-(2,4-difluorophenyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole Example 62 (45 mg, 0.11 mmol, 51%) as an off-white solid. 1 H NMR (400 MHz, CDCl3): δ 9.79 (s, 1H), 8.51 (s, 1H), 8.36-8.29 (m, 1H), 7.62 (dd, J = 10.2, 7.3 Hz, 1H), 7.44 (dd, J = 9.6, 7.0 Hz, 1H), 7.16-7.10 (m, 1H), 7.03-6.97 (m, 1H), 3.71-3.64 (m, 1H), 1.38-1.32 (m, 2H), 0.92-0.87 (m, 2H) LC-MS: m / z 385.1 [M+H] with retention time 2.61 + (96.45% purity) HPLC: 96.95%

[0662] Example 63 Scheme:

[0663] [ka]

[0664] 1-Cyclopropyl-2-(6-(3,4-difluorophenyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (Example 63) To a stirred solution of 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole (Example 22) (70 mg, 0.22 mmol) in DME / EtOH (2:1, 0.9 mL) was added (3,4-difluorophenyl)boronic acid (43 mg, 0.27 mmol) and sodium carbonate (75.5 mg, 0.68 mmol) in a sealed tube, and the mixture was purged under argon for 10 minutes. trans-Dichlorobis-(triphenylphosphine)-II (8 mg, 0.01 mmol) was added to the reaction mixture, and the reaction mixture was stirred at 80 °C for 16 hours. After the starting material was consumed (by TLC), the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 20% EtOAc / hexanes) to afford 1-cyclopropyl-2-(6-(3,4-difluorophenyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole Example 63 (45 mg, 0.11 mmol, 51%) as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 9.79 (s, 1H), 8.43 (s, 1H), 8.14-8.09 (m, 1H), 7.96-7.90 (m, 1H), 7.62 (dd, J = 10.0, 7.3 Hz, 1H), 7.46 (dd, J = 9.5, 6.9 Hz, 1H), 7.36 (dd, J = 17.9, 8.7 Hz, 1H), 3.79-3.66 (m, 1H), 1.39-1.29 (m, 2H), 0.93-0.82 (m, 2H) LC-MS: m / z 385 [M+H] at retention time 2.62 + (98.32% purity) HPLC: 98.68%

[0665] (Example 64 and Example 70) Scheme:

[0666] [ka]

[0667] 1-Cyclopropyl-2-(6-(1-ethoxyvinyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole To a stirred solution of 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole (Example 22) (200 mg, 0.65 mmol) in DMF (4 mL) was added tributyl(1-ethoxyvinyl)stannane (0.26 mL, 0.78 mmol) and Pd(dppf)Cl.CHCl (53 mg, 0.06 mmol) at room temperature, and th...

Claims

1. Formula I 【Chemistry 1】 (In the formula, A is N or CR 5 and W is N or CR 6 and X is N or CR 6 and Y is N or CR 6 and Z is N or CR 6 and However, up to two of W, X, Y, and Z must be N. R 1 is hydrogen, halogen, cyano, acyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, NR a R b , N.H.S.O. 2 R c , C.H. 2 NR a R b , C.H. 2 NHSO 2 R d , CO 2 R e , C.O.R. f , S(O)R d , S(O) 2 R d , C.H. 2 OR f Or CR e R f OH and R 2 is hydrogen, halogen, cyano, alkyl or haloalkyl; or R 1 and R 2 together with the atoms to which they are attached form an aryl, heterocycloalkyl, or cycloalkyl ring; R 3 is hydrogen, halogen, cyano, acyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, NR a R b , N.H.S.O. 2 R c , C.H. 2 NR a R b , C.H. 2 NHSO 2 R d , CO 2 R e , C.O.R. f , C.H. 2 OR f or CR e R f OH, R 4 is cycloalkyl or haloalkyl; R 5 is hydrogen, alkyl, haloalkyl, heteroalkyl or cycloalkyl; R 6 each occurrence is independently hydrogen, halogen, cyano, haloalkyl, alkyl, cycloalkyl, alkoxy, haloalkyl, or carboxyl; R a , R b , R c , R d , R e and R f each occurrence independently represents hydrogen, acyl, alkoxyalkyl, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C(O)OC 1～6 Alkyl, C(O)C 1～6 an alkyl group, 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, Each of R1, R2, R3, R4, R5, R6, Ra, Rb, Rc, Rd, Re, and Rf is unsubstituted), or a pharma- ceutically acceptable salt thereof.

2. The compound according to claim 1, or a pharma- ceutically acceptable salt thereof, wherein R1 is hydrogen, halogen, cyano, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, NRaRb, NHSO2Rc, CH2NRaRb, CH2NHSO2Rd, CORf or CReRfOH, or R1 and R2 together with the atoms to which they are attached form an aryl ring.

3. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein R1 is hydrogen, halogen, alkyl, alkenyl, haloalkyl, alkoxy, haloalkoxy, cycloalkoxy, aryl, NRaRb, CH2NHSO2Rd or CReRfOH, or R1 and R2 together with the atoms to which they are attached form an aryl ring.

4. R 1 is hydrogen, halogen, alkyl, haloalkyl, CH 2 NHSO 2 R d or NR a R b ; 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein R3, Rb, and Rd are independently hydrogen, alkyl, or haloalkyl.

5. The compound of claim 1, or a pharma- ceutical acceptable salt thereof, wherein R1 is haloalkyl.

6. The compound according to any one of claims 1 to 5, or a pharma- ceutically acceptable salt thereof, wherein R2 is hydrogen or alkyl.

7. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein R1 is hydrogen and R2 is alkyl.

8. The compound according to any one of claims 1 to 7, or a pharma- ceutically acceptable salt thereof, wherein R4 is cycloalkyl.

9. The compound according to any one of claims 1 to 7, or a pharma- ceutically acceptable salt thereof, wherein R4 is C3-5 cycloalkyl.

10. The compound of any one of claims 1 to 9, or a pharma- ceutically acceptable salt thereof, wherein each R6 is independently hydrogen, halogen, cyano, alkoxy, haloalkyl, or carboxyl.

11. The compound of any one of claims 1 to 9, or a pharma- ceutically acceptable salt thereof, wherein each R6 is independently hydrogen, halogen or cyano.

12. The compound according to any one of claims 1 to 11, or a pharma- ceutically acceptable salt thereof, wherein A is CR5 and R5 is hydrogen, C1-4 alkyl or C3-5 cycloalkyl.

13. The compound of any one of claims 1 to 11, or a pharma- ceutically acceptable salt thereof, wherein A is N.

14. The compound of any one of claims 1 to 13, or a pharma- ceutically acceptable salt thereof, wherein not more than one of W, X, Y and Z is N.

15. The compound according to any one of claims 1 to 13, or a pharma- ceutically acceptable salt thereof, wherein W, X, Y and Z are each independently CR6.

16. The compound of any one of claims 1 to 14, or a pharma- ceutically acceptable salt thereof, wherein Z is N.

17. The compound of claim 1a 【Chemistry 2】 2. The compound of claim 1, which is:

18. The compound of claim 16, or a pharma- ceutically acceptable salt thereof, wherein A is N.

19. The compound of claim 1 【Chemistry 3】 2. The compound of claim 1, which is:

20. The compound of claim 1, 【Chemistry 4】 2. The compound of claim 1, which is:

21. The compound of claim 1, 【Chemistry 5】 2. The compound of claim 1, which is:

22. The compound of claim 1, 【Chemistry 6】 2. The compound of claim 1, which is:

23. The compound of claim 22, wherein the compound has the formula If 【Chemistry 7】 2. The compound of claim 1, which is:

24. The compound of claim 23, or a pharma- ceutically acceptable salt thereof, wherein R1 is haloalkyl.

25. The compound of claim 24, or a pharma ceutically acceptable salt thereof, Wherein each R6 is independently halogen.

26. The compound of claim 1, 【Chemistry 8】 2. The compound of claim 1, which is:

27. 1-Cyclopropyl-6-fluoro-2-(pyridazin-4-yl)-1H-benzo[d]imidazole (1); 5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-carbonitrile (2); 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-6-fluoro-1H-benzo[d]imidazole (3); 1-Cyclopropyl-6-fluoro-2-(6-vinylpyridazin-4-yl)-1H-benzo[d]imidazole (4); Methyl 5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-carboxylate (5); 1-Cyclopropyl-2-(6-ethylpyridazin-4-yl)-6-fluoro-1H-benzo[d]imidazole (6); 1-(5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)-2,2,2-trifluoroethan-1-ol (7); N-((5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methyl)propionamide (8); Ethyl ((5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methyl)carbamate (9); 4-(5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)morpholine (10); 1-Cyclopropyl-6-fluoro-2-(6-(4-(4-fluorophenyl)piperazin-1-yl)pyridazin-4-yl)-1H-benzo[d]imidazole (11); 2-(5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)propan-2-ol (12); 5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)-N-(tetrahydro-2H-pyran-4-yl)pyridazin-3-amine (13); 4-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)cinnoline (14); 1-Cyclopropyl-6-fluoro-2-(6-methylpyridazin-4-yl)-1H-benzo[d]imidazole (15); N-(5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)ethanesulfonamide (16); 2-(4-(5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)piperazin-1-yl)-N-isopropylacetamide (18); 1-Cyclopropyl-5,6-difluoro-2-(6-methylpyridazin-4-yl)-1H-benzo[d]imidazole (19); 2-(4-(5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)piperazin-1-yl)-1-(pyrrolidin-1-yl)ethan-1-one (20); 5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-N-methylpyridazin-3-amine (21); 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole (22); 1-Cyclopropyl-5,6-difluoro-2-(6-methoxypyridazin-4-yl)-1H-benzo[d]imidazole (23); 1-Cyclopropyl-5,6-difluoro-2-(6-isopropoxypyridazin-4-yl)-1H-benzo[d]imidazole (24); 5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-N,N-dimethylpyridazin-3-amine (25); 1-Cyclopropyl-5,6-difluoro-2-(6-(2,2,2-trifluoroethoxy)pyridazin-4-yl)-1H-benzo[d]imidazole (27); 5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-N-(2-methoxyethyl)pyridazin-3-amine (28); 1-Cyclopropyl-2-(6-methoxypyridazin-4-yl)-1H-benzo[d]imidazole-6-carbonitrile (29); 1-Cyclopropyl-6-fluoro-2-(6-methylpyridazin-4-yl)-1H-indole (30); N-((5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methyl)ethanesulfonamide (31); 5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-N-(2,2,2-trifluoroethyl)pyridazin-3-amine (32); 1-Cyclopropyl-2-(6-ethylpyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (33); 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-1H-benzo[d]imidazole-6-carbonitrile (34); 1-Cyclopropyl-2-(6-methylpyridazin-4-yl)-1H-benzo[d]imidazole-6-carbonitrile (35); 1-Cyclopropyl-5,6-difluoro-2-(6-(4-methylpiperazin-1-yl)pyridazin-4-yl)-1H-benzo[d]imidazole (36); 1-(4-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)piperazin-1-yl)ethan-1-one (37); 1-Cyclopropyl-5,6-difluoro-2-(6-(4-(methylsulfonyl)piperazin-1-yl)pyridazin-4-yl)-1H-benzo[d]imidazole (38); tert-Butyl 4-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)piperazine-1-carboxylate (39); 1-Cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (42); 2-(6-cyclobutoxypyridazin-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole (43); 1-Cyclopropyl-2-(6-(4,4-difluoropiperidin-1-yl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (44); 5-Chloro-3-cyclopropyl-2-(6-methylpyridazin-4-yl)-3H-imidazo[4,5-b]pyridine (45); 1-Cyclopropyl-2-(6-(3,3-difluoropyrrolidin-1-yl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (46); 1-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)-2,2,2-trifluoroethan-1-ol (47); 1-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)-N,N-dimethylpyrrolidin-3-amine (48); 1-Cyclopropyl-5,6-difluoro-2-(6-(4-fluorophenyl)pyridazin-4-yl)-1H-benzo[d]imidazole (49); 1-Cyclopropyl-5,6-difluoro-2-(6-((4-fluorophenyl)ethynyl)pyridazin-4-yl)-1H-benzo[d]imidazole (50); 1-Cyclopropyl-5,6-difluoro-2-(6-isopropylpyridazin-4-yl)-1H-benzo[d]imidazole (51); N-((5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methyl)ethanesulfonamide (52); 1-Cyclopropyl-5,6-difluoro-2-(6-((1,1,1-trifluoropropan-2-yl)oxy)pyridazin-4-yl)-1H-benzo[d]imidazole (53); 3-Cyclopropyl-2-(6-methylpyridazin-4-yl)-3H-imidazo[4,5-b]pyridine-5-carbonitrile (54); 1-Cyclopropyl-5,6-difluoro-2-(pyridazin-4-yl)-1H-benzo[d]imidazole (55); 1-Cyclopropyl-5,6-difluoro-2-(pyridazin-4-yl)-4-(trifluoromethyl)-1H-benzo[d]imidazole (56); 1-Cyclopropyl-2-(6-(2,2-difluoropropoxy)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (57); 1-Cyclopropyl-5,6-difluoro-2-(5-isopropylpyridazin-4-yl)-1H-benzo[d]imidazole (58); 1-Cyclopropyl-2-(6-cyclopropylpyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (59); 2-(6-chloropyridazin-4-yl)-3-cyclopropyl-5-methoxy-3H-imidazo[4,5-b]pyridine (60); 1-Cyclopropyl-5,6-difluoro-2-(6-(4-fluoro-2-methylphenyl)pyridazin-4-yl)-1H-benzo[d]imidazole (61); 1-Cyclopropyl-2-(6-(2,4-difluorophenyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (62); 1-Cyclopropyl-2-(6-(3,4-difluorophenyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (63); 1-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)ethan-1-one (64); 1-Cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-1H-benzo[d]imidazole-6-carbonitrile (66); 1-Cyclopropyl-2-(6-(1,1-difluoroethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (70); 1-Cyclopropyl-5,6-difluoro-2-(6-(2,2,2-trifluoroethyl)pyridazin-4-yl)-1H-benzo[d]imidazole (71); 5-Chloro-3-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-3H-imidazo[4,5-b]pyridine (73); 1-Cyclopropyl-5,6-difluoro-2-(5-methylpyridazin-4-yl)-1H-benzo[d]imidazole (74); 1-Cyclopropyl-2-(6-cyclopropylpyridazin-4-yl)-1H-benzo[d]imidazole-6-carbonitrile (75); 3-Cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-3H-imidazo[4,5-b]pyridine-5-carbonitrile (76); N-((5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methyl)methanesulfonamide (77); N-((5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methyl)-N-methylmethanesulfonamide (78); N-((5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methyl)propane-2-sulfonamide (79); 1-Cyclopropyl-5,6-difluoro-2-(6-(methylsulfonyl)pyridazin-4-yl)-1H-benzo[d]imidazole (80); 1-Cyclopropyl-2-(6-(ethylsulfonyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (81); 1-Cyclopropyl-5,6-difluoro-2-(6-(methylsulfinyl)pyridazin-4-yl)-1H-benzo[d]imidazole (82); 1-Cyclopropyl-2-(6-(ethylsulfinyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (83); 5-Chloro-3-cyclopropyl-2-(6-cyclopropylpyridazin-4-yl)-3H-imidazo[4,5-b]pyridine (84); 1-Cyclopropyl-5,6-difluoro-2-(6-(trifluoromethyl)pyridazin-4-yl)-1H-benzo[d]imidazole (85); 1-Cyclopropyl-2-(6-(trifluoromethyl)pyridazin-4-yl)-1H-benzo[d]imidazole-6-carbonitrile (86); 3-Cyclopropyl-2-(6-cyclopropylpyridazin-4-yl)-3H-imidazo[4,5-b]pyridine-5-carbonitrile (87); 2-((5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methyl)isothiazolidine 1,1-dioxide (88); 3-Cyclopropyl-2-(6-(trifluoromethyl)pyridazin-4-yl)-3H-imidazo[4,5-b]pyridine-5-carbonitrile (89); 1-Cyclopropyl-2-(6-methylpyridazin-4-yl)-6-(trifluoromethyl)-1H-benzo[d]imidazole (90) 2. The compound of claim 1, selected from the group consisting of: and pharma- ceutically acceptable salts thereof.

28. Formula I 【Chemistry 9】 (In the formula, A is N or CR 5 ; W is N or CR 6 ; X is N or CR 6 ; Y is N or CR 6 ; Z is N or CR 6 ; However, up to two of W, X, Y, and Z must be N. R1 is hydrogen, halogen, cyano, acyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, NRaRb, NHSO2Rc, CH2NRaRb, CReRfNHSO2Rd, ORf, SRf, CO2Re, CORf, S(O)Rd, S(O)2Rd, CH2ORf or CReRfOH; R2 is hydrogen, halogen, cyano, alkyl or haloalkyl; or R 1 and R 2 together with the atoms to which they are attached form an aryl, heterocycloalkyl, or cycloalkyl ring; R3 is hydrogen, halogen, cyano, acyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, NRaRb, NHSO2Rc, CH2NRaRb, CH2NHSO2Rd, CO2Re, CORf, CH2ORf or CReRfOH; R 4 is cycloalkyl or haloalkyl; R 5 is hydrogen, cyano, alkyl, haloalkyl, heteroalkyl or cycloalkyl; R 6 at each occurrence is independently hydrogen, halogen, cyano, haloalkyl, alkyl, cycloalkyl, alkoxy, haloalkyl, OR f , or carboxyl; R a , R b , R c , R d , R e and R f each occurrence are independently hydrogen, acyl, alkoxyalkyl, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C(O)OC 1-6 alkyl, C(O)C 1-6 alkyl, 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 atom to which they are attached form a heterocycloalkyl ring, or R e and R f together with the atom to which they are attached form a cycloalkyl ring; Each of R1, R2, R3, R4, R5, R6, Ra, Rb, Rc, Rd, Re, and Rf is unsubstituted), or a pharma- ceutically acceptable salt thereof.

29. The compound of claim 28, or a pharma- ceutically acceptable salt thereof, wherein R1 is hydrogen, halogen, cyano, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, NRaRb, NHSO2Rc, CH2NRaRb, CReRfNHSO2Rd, SRf, CORf or CReRfOH, or R1 and R2 together with the atoms to which they are attached form an aryl or cycloalkyl ring.

30. The compound of claim 28, or a pharma- ceutically acceptable salt thereof, wherein R1 is hydrogen, halogen, alkyl, alkenyl, haloalkyl, alkoxy, haloalkoxy, cycloalkoxy, aryl, NRaRb, CReRfNHSO2Rd, SRf or CReRfOH, or R1 and R2 together with the atoms to which they are attached form an aryl or cycloalkyl ring.

31. The compound according to claim 30, wherein R 1 is hydrogen, halogen, alkyl, haloalkyl, CR e R f NHSO 2 R d , SR f or NR a R b ; 29. The compound of claim 28, or a pharma- ceutically acceptable salt thereof, wherein Ra, Rb, Rd, Re, and Rf are independently hydrogen, alkyl, or haloalkyl.

32. The compound of claim 28, or a pharma- ceutically acceptable salt thereof, wherein R1 is haloalkyl.

33. The compound according to any one of claims 28 to 32, or a pharma- ceutically acceptable salt thereof, wherein R2 is hydrogen or alkyl.

34. The compound of claim 28, or a pharma- ceutically acceptable salt thereof, wherein R1 is hydrogen and R2 is alkyl.

35. The compound of any one of claims 28 to 34, or a pharma- ceutically acceptable salt thereof, wherein R4 is cycloalkyl.

36. The compound of any one of claims 28 to 34, or a pharma- ceutically acceptable salt thereof, wherein R4 is C3-5 cycloalkyl.

37. The compound of any one of claims 28 to 36, or a pharma- ceutically acceptable salt thereof, wherein each R6 is independently hydrogen, halogen, cyano, alkoxy, haloalkyl, or carboxyl.

38. The compound of any one of claims 28 to 36, or a pharma- ceutically acceptable salt thereof, wherein each R6 is independently hydrogen, halogen or cyano.

39. The compound according to any one of claims 28 to 38, or a pharma- ceutically acceptable salt thereof, wherein A is CR5 and R5 is hydrogen, C1-4 alkyl or C3-5 cycloalkyl.

40. The compound of any one of claims 28 to 38, or a pharma- ceutically acceptable salt thereof, wherein A is N.

41. The compound of any one of claims 28 to 40, or a pharma- ceutically acceptable salt thereof, wherein not more than one of W, X, Y, and Z is N.

42. The compound according to any one of claims 28 to 41, or a pharma- ceutically acceptable salt thereof, wherein W, X, Y and Z are each independently CR6.

43. 42. The compound of any one of claims 28 to 41, or a pharma- ceutically acceptable salt thereof, wherein Z is N.

44. The compound of formula Ia 【Chemistry 10】 29. The compound of claim 28, which is:

45. The compound of claim 44, or a pharma- ceutically acceptable salt thereof, wherein A is N.

46. ​​The compound of claim 1, 【Chemistry 11】 29. The compound of claim 28, which is:

47. The compound of claim 47, wherein the compound is of formula Ic 【Chemistry 12】 29. The compound of claim 28, which is:

48. The compound of claim 1, 【Chemistry 13】 29. The compound of claim 28, which is:

49. The compound of claim 1, wherein the compound is of formula Ie 【Chemistry 14】 29. The compound of claim 28, which is:

50. The compound of claim 1, 【Chemistry 15】 29. The compound of claim 28, which is:

51. The compound of claim 50, or a pharma- ceutically acceptable salt thereof, wherein R1 is haloalkyl.

52. The compound of claim 50, or a pharma ceutically acceptable salt thereof, Wherein R6 is independently a halogen.

53. The compound of claim 1, 【Chemistry 16】 29. The compound of claim 28, which is:

54. 1-Cyclopropyl-6-fluoro-2-(pyridazin-4-yl)-1H-benzo[d]imidazole (1); 5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-carbonitrile (2); 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-6-fluoro-1H-benzo[d]imidazole (3); 1-Cyclopropyl-6-fluoro-2-(6-vinylpyridazin-4-yl)-1H-benzo[d]imidazole (4); Methyl 5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-carboxylate (5); 1-Cyclopropyl-2-(6-ethylpyridazin-4-yl)-6-fluoro-1H-benzo[d]imidazole (6); 1-(5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)-2,2,2-trifluoroethan-1-ol (7); N-((5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methyl)propionamide (8); Ethyl ((5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methyl)carbamate (9); 4-(5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)morpholine (10); 1-Cyclopropyl-6-fluoro-2-(6-(4-(4-fluorophenyl)piperazin-1-yl)pyridazin-4-yl)-1H-benzo[d]imidazole (11); 2-(5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)propan-2-ol (12); 5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)-N-(tetrahydro-2H-pyran-4-yl)pyridazin-3-amine (13); 4-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)cinnoline (14); 1-Cyclopropyl-6-fluoro-2-(6-methylpyridazin-4-yl)-1H-benzo[d]imidazole (15); N-(5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)ethanesulfonamide (16); 2-(4-(5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)piperazin-1-yl)-N-isopropylacetamide (18); 1-Cyclopropyl-5,6-difluoro-2-(6-methylpyridazin-4-yl)-1H-benzo[d]imidazole (19); 2-(4-(5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)piperazin-1-yl)-1-(pyrrolidin-1-yl)ethan-1-one (20); 5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-N-methylpyridazin-3-amine (21); 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole (22); 1-Cyclopropyl-5,6-difluoro-2-(6-methoxypyridazin-4-yl)-1H-benzo[d]imidazole (23); 1-Cyclopropyl-5,6-difluoro-2-(6-isopropoxypyridazin-4-yl)-1H-benzo[d]imidazole (24); 5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-N,N-dimethylpyridazin-3-amine (25); 1-Cyclopropyl-5,6-difluoro-2-(6-(2,2,2-trifluoroethoxy)pyridazin-4-yl)-1H-benzo[d]imidazole (27); 5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-N-(2-methoxyethyl)pyridazin-3-amine (28); 1-Cyclopropyl-2-(6-methoxypyridazin-4-yl)-1H-benzo[d]imidazole-6-carbonitrile (29); 1-Cyclopropyl-6-fluoro-2-(6-methylpyridazin-4-yl)-1H-indole (30); N-((5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methyl)ethanesulfonamide (31); 5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-N-(2,2,2-trifluoroethyl)pyridazin-3-amine (32); 1-Cyclopropyl-2-(6-ethylpyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (33); 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-1H-benzo[d]imidazole-6-carbonitrile (34); 1-Cyclopropyl-2-(6-methylpyridazin-4-yl)-1H-benzo[d]imidazole-6-carbonitrile (35); 1-Cyclopropyl-5,6-difluoro-2-(6-(4-methylpiperazin-1-yl)pyridazin-4-yl)-1H-benzo[d]imidazole (36); 1-(4-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)piperazin-1-yl)ethan-1-one (37); 1-Cyclopropyl-5,6-difluoro-2-(6-(4-(methylsulfonyl)piperazin-1-yl)pyridazin-4-yl)-1H-benzo[d]imidazole (38); tert-Butyl 4-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)piperazine-1-carboxylate (39); 1-Cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (42); 2-(6-cyclobutoxypyridazin-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole (43); 1-Cyclopropyl-2-(6-(4,4-difluoropiperidin-1-yl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (44); 5-Chloro-3-cyclopropyl-2-(6-methylpyridazin-4-yl)-3H-imidazo[4,5-b]pyridine (45); 1-Cyclopropyl-2-(6-(3,3-difluoropyrrolidin-1-yl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (46); 1-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)-2,2,2-trifluoroethan-1-ol (47); 1-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)-N,N-dimethylpyrrolidin-3-amine (48); 1-Cyclopropyl-5,6-difluoro-2-(6-(4-fluorophenyl)pyridazin-4-yl)-1H-benzo[d]imidazole (49); 1-Cyclopropyl-5,6-difluoro-2-(6-((4-fluorophenyl)ethynyl)pyridazin-4-yl)-1H-benzo[d]imidazole (50); 1-Cyclopropyl-5,6-difluoro-2-(6-isopropylpyridazin-4-yl)-1H-benzo[d]imidazole (51); N-((5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methyl)ethanesulfonamide (52); 1-Cyclopropyl-5,6-difluoro-2-(6-((1,1,1-trifluoropropan-2-yl)oxy)pyridazin-4-yl)-1H-benzo[d]imidazole (53); 3-Cyclopropyl-2-(6-methylpyridazin-4-yl)-3H-imidazo[4,5-b]pyridine-5-carbonitrile (54); 1-Cyclopropyl-5,6-difluoro-2-(pyridazin-4-yl)-1H-benzo[d]imidazole (55); 1-Cyclopropyl-5,6-difluoro-2-(pyridazin-4-yl)-4-(trifluoromethyl)-1H-benzo[d]imidazole (56); 1-Cyclopropyl-2-(6-(2,2-difluoropropoxy)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (57); 1-Cyclopropyl-5,6-difluoro-2-(5-isopropylpyridazin-4-yl)-1H-benzo[d]imidazole (58); 1-Cyclopropyl-2-(6-cyclopropylpyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (59); 2-(6-chloropyridazin-4-yl)-3-cyclopropyl-5-methoxy-3H-imidazo[4,5-b]pyridine (60); 1-Cyclopropyl-5,6-difluoro-2-(6-(4-fluoro-2-methylphenyl)pyridazin-4-yl)-1H-benzo[d]imidazole (61); 1-Cyclopropyl-2-(6-(2,4-difluorophenyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (62); 1-Cyclopropyl-2-(6-(3,4-difluorophenyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (63); 1-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)ethan-1-one (64); 1-Cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-1H-benzo[d]imidazole-6-carbonitrile (66); 1-Cyclopropyl-2-(6-(1,1-difluoroethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (70); 1-Cyclopropyl-5,6-difluoro-2-(6-(2,2,2-trifluoroethyl)pyridazin-4-yl)-1H-benzo[d]imidazole (71); 5-Chloro-3-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-3H-imidazo[4,5-b]pyridine (73); 1-Cyclopropyl-5,6-difluoro-2-(5-methylpyridazin-4-yl)-1H-benzo[d]imidazole (74); 1-Cyclopropyl-2-(6-cyclopropylpyridazin-4-yl)-1H-benzo[d]imidazole-6-carbonitrile (75); 3-Cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-3H-imidazo[4,5-b]pyridine-5-carbonitrile (76); N-((5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methyl)methanesulfonamide (77); N-((5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methyl)-N-methylmethanesulfonamide (78); N-((5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methyl)propane-2-sulfonamide (79); 1-Cyclopropyl-5,6-difluoro-2-(6-(methylsulfonyl)pyridazin-4-yl)-1H-benzo[d]imidazole (80); 1-Cyclopropyl-2-(6-(ethylsulfonyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (81); 1-Cyclopropyl-5,6-difluoro-2-(6-(methylsulfinyl)pyridazin-4-yl)-1H-benzo[d]imidazole (82); 1-Cyclopropyl-2-(6-(ethylsulfinyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (83); 5-Chloro-3-cyclopropyl-2-(6-cyclopropylpyridazin-4-yl)-3H-imidazo[4,5-b]pyridine (84); 1-Cyclopropyl-5,6-difluoro-2-(6-(trifluoromethyl)pyridazin-4-yl)-1H-benzo[d]imidazole (85); 1-Cyclopropyl-2-(6-(trifluoromethyl)pyridazin-4-yl)-1H-benzo[d]imidazole-6-carbonitrile (86); 3-Cyclopropyl-2-(6-cyclopropylpyridazin-4-yl)-3H-imidazo[4,5-b]pyridine-5-carbonitrile (87); 2-((5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methyl)isothiazolidine 1,1-dioxide (88); 3-Cyclopropyl-2-(6-(trifluoromethyl)pyridazin-4-yl)-3H-imidazo[4,5-b]pyridine-5-carbonitrile (89); 1-Cyclopropyl-2-(6-methylpyridazin-4-yl)-6-(trifluoromethyl)-1H-benzo[d]imidazole (90); N-(1-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)ethyl)methanesulfonamide (91); 1-Cyclopropyl-5,6-difluoro-2-(6-(fluoromethyl)pyridazin-4-yl)-1H-benzo[d]imidazole (92); 1-Cyclopropyl-2-(5,6-dimethylpyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (93); (5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methanol (94); 5-Chloro-3-cyclopropyl-2-(6-(trifluoromethyl)pyridazin-4-yl)-3H-imidazo[4,5-b]pyridine (95); N-(1-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)ethyl)ethanesulfonamide (96); 2-(6-Butylpyridazin-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole (97); 1-Cyclopropyl-6-methyl-2-(6-methylpyridazin-4-yl)-1H-benzo[d]imidazole (98); 1-Cyclopropyl-5,6-difluoro-2-(3-methylpyridazin-4-yl)-1H-benzo[d]imidazole (99); 1-Cyclopropyl-2-(3,6-dimethylpyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (100); 1-Cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-6,7-difluoro-1H-benzo[d]imidazole (101); 5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-thiol (102); 4-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-5,6,7,8-tetrahydrocinnoline (106); 1-Cyclopropyl-2-(6-methylpyridazin-4-yl)-1H-benzo[d]imidazole-5-carbonitrile (Example 107); 1-Cyclobutyl-5,6-difluoro-2-(6-methylpyridazin-4-yl)-1H-benzo[d]imidazole (108); 1-Cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-1H-benzo[d]imidazol-6-ol (109); 5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-carboxylic acid (110); 1-Cyclopropyl-7-fluoro-2-(6-methylpyridazin-4-yl)-1H-benzo[d]imidazole (111); 5-Chloro-1-cyclopropyl-2-(6-methylpyridazin-4-yl)-1H-benzo[d]imidazole (112); 4-Chloro-1-cyclopropyl-2-(6-methylpyridazin-4-yl)-1H-benzo[d]imidazole (113); 1-Cyclopropyl-5,6-difluoro-2-(6-(methoxymethyl)pyridazin-4-yl)-1H-benzo[d]imidazole (114); Methyl 5-(6-cyano-1-cyclopropyl-1H-benzo[d]imidazol-2-yl)pyridazine-3-carboxylate (115); 5-(6-cyano-1-cyclopropyl-1H-benzo[d]imidazol-2-yl)pyridazine-3-carboxylic acid (116); 1-Cyclopropyl-2-(6-(cyclopropylmethoxy)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (117); 1-Cyclopropyl-2-(6-(2,2,2-trifluoroethoxy)pyridazin-4-yl)-1H-benzo[d]imidazole-6-carbonitrile (118); 6-Chloro-1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5-fluoro-1H-benzo[d]imidazole (119); 1-Cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5-fluoro-1H-benzo[d]imidazole-6-carbonitrile (120); 4-(1-Cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-6,7-dihydro-5H-cyclopenta[c]pyridazine (121); 1-Cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-6-fluoro-1H-benzo[d]imidazole (122); 1-Cyclopropyl-5,6-difluoro-2-(6-(methylthio)pyridazin-4-yl)-1H-benzo[d]imidazole (123); 1-Cyclopropyl-5,6-difluoro-2-(6-(isopropylthio)pyridazin-4-yl)-1H-benzo[d]imidazole (124); 1-Cyclopropyl-2-(6-((difluoromethyl)thio)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (125); 5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-ol (126); 1-Cyclopropyl-2-(6-(difluoromethoxy)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (127); 1-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)ethan-1-ol (128); 1-Cyclopropyl-5,6-difluoro-2-(6-(1-fluoroethyl)pyridazin-4-yl)-1H-benzo[d]imidazole (129); 1-Cyclopropyl-5,6-difluoro-2-(6-((trifluoromethyl)thio)pyridazin-4-yl)-1H-benzo[d]imidazole (130) 1-Cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-1H-benzo[d]imidazole (131); 1-Cyclopropyl-2-(6-(difluoromethoxy)pyridazin-4-yl)-1H-benzo[d]imidazole-6-carbonitrile (133); 1-Cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-1H-indole-3-carbonitrile (134); 1-Cyclopropyl-2-(6-(1-fluoroethyl)pyridazin-4-yl)-1H-benzo[d]imidazole-6-carbonitrile (136) and pharma- ceutically acceptable salts thereof.

55. 1-Cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (42). 3-Cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-3H-imidazo[4,5-b]pyridine-5-carbonitrile (76), 1-Cyclopropyl-2-(6-(trifluoromethyl)pyridazin-4-yl)-1H-benzo[d]imidazole-6-carbonitrile (86) and pharma- ceutically acceptable salts thereof.

56. A pharmaceutical composition for use in treating a subject suffering from or susceptible to a disorder or disease associated with a metalloenzyme, comprising an effective amount of a compound described in any one of claims 1 to 55 or a pharmaceutical salt thereof.

57. The disorder or disease is characterized by an oxidative stress disorder (OSD) induced by aromatase (CYP19), a member of the cyclooxygenase family, lanosterol demethylase (CYP51), a member of the nitric oxide synthase family, thromboxane synthase (CYP5a), thyroid peroxidase, 17-alpha hydroxylase / 17,20-lyase (CYP17), cytochrome P4502A6 (CYP2A6), heme oxygenase, or indoleamine 2,3-dihydroxylase.

57. The pharmaceutical composition of claim 56, wherein the cytotoxicity of CYP450 is mediated by cytochrome P450 3A5 (CYP3A5), cholesterol 24-hydroxylase (CYP46), cytochrome P450 4F2 (CYP4F2), myeloperoxidase or 11-beta-hydroxylase (CYP11B1).

58. The pharmaceutical composition of claim 56 or 57, 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 urinary disease or a gastrointestinal disease.

59. The disorder or disease is hypertension, resistant hypertension, pathological conditions associated with primary or secondary hyperaldosteronism 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 state, coronary heart 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 59. The pharmaceutical composition according to any one of claims 56 to 58, wherein the condition is steatohepatitis, vascular disease, retinopathy, neuropathy, dysinsulinemia, endothelial dysfunction, myocardial fibrosis, vascular fibrosis, myocardial necrotic lesions, vascular damage, myocardial infarction, left ventricular hypertrophy, vascular wall hypertrophy, endothelial 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, cirrhosis, non-alcoholic fatty liver disease, kidney damage, diabetic nephropathy, or stroke.

60. A pharmaceutical composition comprising a compound according to any one of claims 1 to 55, or a pharmaceutical salt thereof, and a pharma- ceutical acceptable carrier.

61. The pharmaceutical composition of claim 60, further comprising an additional therapeutic agent.

62. The pharmaceutical composition of claim 60, further comprising an additional therapeutic agent which 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 a metabolic disease, an agent for an ophthalmic disease, an agent for a central nervous system (CNS) disease, an agent for a urological disease, or an agent for a gastrointestinal disease.

63. The pharmaceutical composition of claim 56, wherein the subject is an animal other than a human.

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