Metalloenzyme inhibitor compounds

Abstract

Provided are compounds having metalloenzyme modulating activity, and methods of treating diseases, disorders, or symptoms mediated by these metalloenzymes.

Description

[0001] This application is a divisional application of Chinese invention patent application No. 201780087610.1, filed on December 22, 2017, entitled "Metallozyme Inhibitor Compound".

[0002] Cross-references to related applications

[0003] This application claims priority to U.S. Provisional Patent Application No. 62 / 440181, filed December 29, 2016, the entire contents of which are incorporated herein by reference. Technical Field

[0004] This application relates to compounds with metalloenzyme regulatory activity. Background Technology

[0005] Aldosterone is a steroid hormone secreted by the adrenal glands that binds to and activates the mineralocorticoid receptor (MR). In primary cells of the distal renal tubules and collecting ducts, MR activation leads to sodium and water retention accompanied by potassium excretion, causing plasma volume expansion and resulting in elevated blood pressure (BP). Excess aldosterone measured in circulation is called primary aldosteronism (PA), and it occurs when the renin-angiotensin-aldosterone system (RAAS) dysregulates aldosterone production. PA was initially found in patients with adrenal adenomas, and recent evidence suggests an increased prevalence associated with obesity. PA is a common cause of secondary hypertension, with a prevalence of 14% to 21% in patients with refractory hypertension (RHTN), a condition where blood pressure remains above target despite the simultaneous use of three different classes of antihypertensive medications, including diuretics. Recent studies have shown an association between excess aldosterone, RHTN, and obstructive sleep apnea (OSA), an association exacerbated by aldosterone-mediated fluid retention.

[0006] In several severe disease states, localized overproduction of aldosterone has been observed even without significant plasma elevations. In patients with chronic congestive heart failure (CHF), aldosterone levels in failing cardiac tissue are higher than in peripheral plasma. In animal models of kidney disease, it is hypothesized that localized aldosterone production in the renal cortex contributes to disease progression. In both states, locally elevated aldosterone levels exert detrimental effects through both MR-dependent and MR-independent mechanisms, including the production of reactive oxygen species and endothelial dysfunction, which leads to inflammation and stimulation of cell growth and proliferation, while upregulated collagen deposition results in fibrosis.

[0007] Antagonists of aldosterone (MR), including spironolactone and eplerenone, have been widely used to block the binding of aldosterone to MR. The combination of these drugs with angiotensin-converting enzyme (ACE) inhibitors and diuretics (RALES and EPHESUS trials) has demonstrated significant reductions in morbidity and mortality in patients with heart failure or myocardial infarction. Both drugs have side effects, including hyperkalemia, and non-selective spironolactone also causes gynecomastia through non-selective regulation of progesterone and androgen receptors. Furthermore, the elevation of renin and aldosterone is caused by MR antagonism, thus exacerbating the MR-independent (non-genomic) effects of aldosterone.

[0008] 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 harmful accumulation of aldosterone leading to the activation of MR-dependent inflammatory and fibrotic states. CYP11B2 is a mitochondrial cytochrome P450 enzyme that converts 11-deoxycorticosterone to aldosterone. Selective inhibition of CYP11B2 represents a promising therapeutic approach for aldosterone-related diseases.

[0009] The highly homologous metalloenzyme CYP11B1 (11-β-steroid hydroxylase) catalyzes the formation of cortisol, the major glucocorticoid, from 11-deoxycortisol. Given the high homology (93%) between CYP11B2 and CYP11B1, the development of selective CYP11B2 inhibitors has been a significant challenge. The inhibitor Osilodrostat (LCI-699) was developed as a CYP11B2 inhibitor for the treatment of hypertension, but was abandoned due to its potent inhibition of CYP11B1. This article describes a selective compound that blocks aldosterone production via CYP11B2 without inhibiting cortisol production via CYP11B1.

[0010] Organisms have developed sophisticated, specialized regulatory processes for the importation of metals, transporting them 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 bind metal ions to their active sites and utilize the metal as part of a catalytic process. More than one-third of all characterized enzymes are metalloenzymes.

[0011] The function of metalloenzymes is highly dependent on the presence of metal ions at their active sites. It is well known that agents that bind to and inactivate metal ions at their active sites significantly reduce enzyme activity. Nature employs the same strategy to reduce the activity of certain metalloenzymes during periods when enzyme activity is not required. For example, the protein TIMP (tissue inhibitor of metalloproteinases) binds to zinc ions at the active sites of various matrix metalloproteinases, thereby inhibiting enzyme activity. The pharmaceutical industry uses the 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 heme iron present at the active site of the target enzyme lanosterol demethylase, thereby inactivating the enzyme. Another example includes zinc-bound hydroxamic acid groups, which have been incorporated into most publicly disclosed matrix metalloproteinase and histone deacetylase inhibitors. Another example is zinc-bound carboxylic acid groups, which have been incorporated into most publicly disclosed angiotensin-converting enzyme inhibitors.

[0012] In the design of clinically safe and effective metalloenzyme inhibitors, it is desirable to use an appropriate metal-binding group for any specific target and clinical indication. If a weakly bound metal-binding group is used, the efficacy may be suboptimal. On the other hand, if a very tightly bound metal-binding group is used, the selectivity of the target enzyme for the relevant metalloenzyme may not be optimal. This lack of optimal selectivity due to unplanned inhibition of these off-target metalloenzymes can be a cause of clinical toxicity. One example of this clinical toxicity is the unplanned 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 due to the indiscriminate binding of the currently used 1-(1,2,4-triazole) to iron at the active sites of CYP2C9, CYP2C19, and CYP3A4. Another example of clinical toxicity is the joint pain observed in numerous clinical trials of matrix metalloproteinase inhibitors. This toxicity is thought to be related to the inhibition of off-target metalloenzymes, which is caused by the indiscriminate binding of isohydroxamic acid groups to zinc in the deoxyactive site.

[0013] Therefore, seeking metal-binding groups that can achieve a better balance between potency and selectivity remains an important goal and is of great significance in the development of therapeutics and methods to address unmet needs in the treatment and prevention of diseases, conditions, and symptoms. Summary of the Invention

[0014] This invention relates to compounds (e.g., any compound described herein; any chemical formula described herein), methods for modulating the activity of metalloenzymes, and methods for treating diseases, conditions, or symptoms thereof. Such methods may include the compounds described herein.

[0015] It should be understood that the embodiments of the invention with respect to the selection of preferred variables discussed below can be used alone or in combination with one or more embodiments of the invention or preferred variable options, as each combination is explicitly listed herein.

[0016] In one respect, compounds of formula I are provided:

[0017]

[0018] I,

[0019] Or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug, wherein:

[0020] A is N or CR 5 ;

[0021] W is N or CR 6 ;

[0022] X is N or CR 6 ;

[0023] Y is N or CR 6 ;

[0024] Z is N or CR 6 ;

[0025] The condition is that no more than two of W, X, Y, and Z are N;

[0026] R 1 It is hydrogen, halogen, cyano, acyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkyl, NR a R b NHSO2R c CH2NR a R b CH2NHSO2R d CO2R e COR f S(O)R d S(O)2R d CH2OR f , or CR e R f OH, where any R 1 It can be optionally replaced by one to three independent substituents R 7 replace;

[0027] R 2It is hydrogen, halogen, cyano, alkyl, or haloalkyl;

[0028] Or R 1 and R 2 Together with the atoms they are attached to, they form aryl, heterocyclic, or cycloalkyl rings;

[0029] R 3 It is hydrogen, halogen, cyano, acyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkyl, NR a R b NHSO2R c CH2NR a R b CH2NHSO2R d CO2R e COR f CH2OR f , or CR e R f OH;

[0030] R 4 It is an alkyl, cycloalkyl, haloalkyl, or heteroalkyl group;

[0031] R 5 It is hydrogen, alkyl, haloalkyl, heteroalkyl, or cycloalkyl;

[0032] Each occurrence of R 6 It can be independently hydrogen, halogen, cyano, haloalkyl, alkyl, cycloalkyl, alkoxy, haloalkyl or carboxyl;

[0033] Each occurrence of R 7 Independently halogenated, alkyl, alkoxy, haloalkyl, carboxyl, aryl, aryl substituted with one to three independent halogens, -(CH2) n C(O)NR g R h -S(O)2R i -CO2R j , or NR g R h ;

[0034] Each n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0035] Each occurrence of R a R b R c R d R e and R fIndependently, it can be hydrogen, acyl, alkoxyalkyl, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C(O)OC 1-6 Alkyl, C(O)C 1-6 Alkyl group, nitrogen-protecting group when attached to a nitrogen atom, or oxygen-protecting group when attached to an oxygen atom; or R a and R b Together with the atoms they are attached to, they form heterocyclic alkyl rings; or R e and R f Together with the atoms they are attached to, they form cycloalkyl rings; and

[0036] Each occurrence of R g R h R i and R j Independently 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 h Together with the atoms they are attached to, they form heterocyclic alkyl rings.

[0037] In some implementations, R 1 It is an aryl, heteroaryl, or heterocyclic alkyl group, wherein any R 1 It can be optionally replaced by one to three independent substituents R 7 replace.

[0038] In some implementations, R 1 It is an aryl, heteroaryl, or heterocyclic alkyl group, wherein any R 1 It can be optionally replaced by one to three independent substituents R 7 Replace, and each R 7 Independently halogenated, alkyl, alkoxy, haloalkyl, carboxyl, -(CH2) n C(O)NR g R h -S(O)2R i -CO2R j , or NR g R h And each R g and R h Independently hydrogen, alkyl, C(O)C 1-6 Alkyl, or R g and R h Together with the atoms they are attached to, they form heterocyclic alkyl rings.

[0039] In some implementations, R 1It 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 COR f , or CR e R f OH; or R 1 and R 2 Together with the atoms they are attached to, they form aromatic rings.

[0040] In some implementations, R 1 It 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 they are attached to, they form aromatic rings.

[0041] In some implementations, R 1 It is hydrogen, halogen, alkyl, haloalkyl, CH2NHSO2R d or NR a R b ;R a R b and R d It is independently hydrogen, alkyl, or haloalkyl.

[0042] In some implementations, R 1 It is an alkyl or haloalkyl group.

[0043] In some implementations, R 1 It is C 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

[0044] In some implementations, R 1 It is a haloalkyl group.

[0045] In some implementations, R 1 It is C 1-6 Halogenated alkyl groups.

[0046] In some implementations, R 1 It is a fluoroalkyl group. In some embodiments, R 1 It is C 1-6Fluoroalkyl. In some embodiments, R 1 It is C 1-3 Fluoroalkyl. In some embodiments, R 1 It is difluoromethyl or trifluoromethyl. In some embodiments, R 1 It is difluoromethyl. In some embodiments, R 1 It is trifluoromethyl.

[0047] In some implementations, R 2 It is hydrogen or alkyl.

[0048] In some implementations, R 2 Is it hydrogen or C? 1-6 alkyl.

[0049] In some implementations, R 2 Is it hydrogen or C? 1-3 alkyl.

[0050] In some implementations, R 2 It is an alkyl group. In some embodiments, R 2 It is C 1-6 Alkyl group. In some embodiments, R 2 It is C 1-3 Alkyl group. In some embodiments, R 2 It is hydrogen.

[0051] In some implementations, R 1 It is hydrogen and R 2 It is an alkyl group. In some embodiments, R 1 It is hydrogen and R 2 It is C 1-6 Alkyl group. In some embodiments, R 1 It is hydrogen and R 2 It is C 1-3 alkyl.

[0052] In some implementations, R 4 It is an alkyl or cycloalkyl group.

[0053] In some implementations, R 4 It is C 1-4 Alkyl or C 3-5 Cycloalkyl.

[0054] In some implementations, R 4 It is C 1-4 Alkyl group. In some embodiments, R 4 It is C 3-5 Cycloalkyl. In some embodiments, R 4 It is cyclopentyl. In some embodiments, R 4 It is cyclobutyl. In some embodiments, R4 It is cyclopropyl.

[0055] In some implementations, each R 6 It can be hydrogen, halogen, cyano, alkoxy, haloalkyl, or carboxyl.

[0056] In some implementations, each R 6 It can be hydrogen, halogen, or cyano group independently.

[0057] In some implementations, each R 6 It can be hydrogen, chlorine, fluorine or cyanide.

[0058] In some implementations, each R 6 It can be hydrogen, fluorine, or cyanide on its own.

[0059] In some implementations, each R 6 It can be hydrogen or halogen independently.

[0060] In some implementations, each R 6 It can be hydrogen, chlorine, or fluorine independently.

[0061] In some implementations, each R 6 It can be either hydrogen or fluorine.

[0062] In some implementations, each R 6 It can be either hydrogen or cyano.

[0063] In some implementations, each R 6 It is a halogen. In some implementations, each R 6 It is chlorine or fluorine. In some implementations, each R 6 It is fluorine. In some implementations, each R 6 It is a cyano group.

[0064] In some implementations, A is CR 5 And R 5 It is hydrogen, C 1-4 Alkyl or C 3-5 Cycloalkyl.

[0065] In some implementations, A is N.

[0066] In some implementations, no more than one of W, X, Y, and Z is N.

[0067] In some implementations, W, X, Y, and Z are each CR 6 .

[0068] In some implementations, Z is N.

[0069] In some embodiments, the compound of formula I is the same as the compound of formula Ia:

[0070]

[0071] Ia,

[0072] Or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R 1 R 2 R 4 R 6 A, X, and Z are as defined in this article.

[0073] In some embodiments, the compound of formula I is a compound of formula Ib:

[0074]

[0075] Ib,

[0076] Or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R 1 R 2 R 4 W, X, Y, and Z are as defined in this article.

[0077] In some embodiments, the compound of formula I is the compound of formula Ic:

[0078]

[0079] Ic,

[0080] Or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R 1 R 2 R 4 R 6 Z is as defined in this article.

[0081] In some embodiments, the compound of formula I is the compound of formula Id:

[0082]

[0083] ID

[0084] Or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R 1 R2 R 4 R 6 Z is as defined in this article.

[0085] In some embodiments, the compound of formula I is the compound of formula Ie:

[0086]

[0087] Ie,

[0088] Or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R 1 R 4 R 6 Z is as defined in this article.

[0089] In some embodiments, the compound of formula I is a compound of formula If:

[0090]

[0091] If,

[0092] Or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R 1 R 4 and R 6 As defined in this article.

[0093] In some embodiments, the compound of the aforementioned formula If is a compound of the following type:

[0094] Where R 4 It is an alkyl or cycloalkyl group; R 6 It is hydrogen or halogen, wherein at least one R 6 It is a halogen.

[0095] In some embodiments, the compound of the aforementioned formula If is a compound of the following type:

[0096] Where R 4 It is an alkyl or cycloalkyl group; R 6 It is halogen.

[0097] In some embodiments, the compound of the aforementioned formula If is a compound of the following type:

[0098] Where R 4 It is an alkyl or cycloalkyl group; R 6 It is hydrogen or halogen, wherein at least one R 6 It is halogen; R 1It is hydrogen, halogen, cyano, acyl, alkyl, haloalkyl, alkoxy, haloalkoxy, NR a R b NHSO2R c CH2NR a R b CH2NHSO2R d CO2R e COR f CH2OR f , or CR e R f OH.

[0099] In some embodiments, the compound of the aforementioned formula If is a compound of the following type:

[0100] Where R 4 It is an alkyl or cycloalkyl group; R 6 It is hydrogen or halogen, wherein at least one R 6 It is halogen; R 1 It is optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl.

[0101] In some embodiments, the compound of the aforementioned formula If is a compound of the following type:

[0102] Where R 1 It is an alkyl or haloalkyl group; R 4 It is an alkyl or cycloalkyl group; R 6 It is hydrogen or halogen, wherein at least one R 6 It is a halogen.

[0103] In some embodiments, the compound of the aforementioned formula If is a compound of the following type:

[0104] Where R 1 It is an alkyl or haloalkyl group; R 4 It is an alkyl or cycloalkyl group; R 6 It is halogen.

[0105] In some embodiments, the compound of formula I is the compound of formula Ig:

[0106]

[0107] Ig,

[0108] Or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R 1 R 4 and R 6 As defined in this article.

[0109] In some embodiments, the compound of formula Ig is the following compound:

[0110] Where R 4 It is an alkyl or cycloalkyl group; R 6 It is hydrogen or halogen, wherein at least one R 6 It is a halogen.

[0111] In some embodiments, the compound of formula Ig is the following compound:

[0112] Where R 4 It is an alkyl or cycloalkyl group; R 6 It is halogen.

[0113] In some embodiments, the compound of formula Ig is the following compound:

[0114] Where R 4 It is an alkyl or cycloalkyl group; R 6 It is hydrogen or halogen, wherein at least one R 6 It is halogen; R 1 It is hydrogen, halogen, cyano, acyl, alkyl, haloalkyl, alkoxy, haloalkoxy, NR a R b NHSO2R c CH2NR a R b CH2NHSO2R d CO2R e COR f CH2OR f , or CR e R f OH.

[0115] In some embodiments, the compound of formula Ig is the following compound:

[0116] Where R 4 It is an alkyl or cycloalkyl group; R 6 It is hydrogen or halogen, wherein at least one R 6 It is halogen; R 1 It is optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl.

[0117] On the other hand, compounds of formula I are provided:

[0118]

[0119] I,

[0120] Or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug, wherein:

[0121] A is N or CR 5 ;

[0122] W is N or CR 6 ;

[0123] X is N or CR 6 ;

[0124] Y is N or CR 6 ;

[0125] Z is N or CR 6 ;

[0126] The condition is that no more than two of W, X, Y, and Z are N;

[0127] R 1 It is hydrogen, halogen, cyano, acyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkyl, NR a R b NHSO2R c CH2NR a R b CR e R f NHSO2R d OR f SR f CO2R e COR f S(O)R d S(O)2R d CH2OR f , or CR e R f OH, where any R 1 It can be optionally replaced by one to three independent substituents R 7 replace;

[0128] R 2 It is hydrogen, halogen, cyano, alkyl, or haloalkyl;

[0129] Or R 1 and R 2 Together with the atoms they are attached to, they form aryl, heterocyclic, or cycloalkyl rings;

[0130] R 3It is hydrogen, halogen, cyano, acyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkyl, NR a R b NHSO2R c CH2NR a R b CH2NHSO2R d CO2R e COR f CH2OR f , or CR e R f OH;

[0131] R 4 It is an alkyl, cycloalkyl, haloalkyl, or heteroalkyl group;

[0132] R 5 It is hydrogen, cyano, alkyl, haloalkyl, heteroalkyl, or cycloalkyl;

[0133] Each occurrence of R 6 Independently hydrogen, halogen, cyano, haloalkyl, alkyl, cycloalkyl, alkoxy, haloalkyl, OR f Or carboxyl group;

[0134] Each occurrence of R 7 Independently halogenated, alkyl, alkoxy, haloalkyl, carboxyl, cycloalkyl, aryl, aryl substituted with one to three independent halogens, -(CH2) n C(O)NR g R h -S(O)2R i -CO2R j , or NR g R h ;

[0135] Each n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0136] Each occurrence of R a R b R c R d R e and R f Independently, it can be hydrogen, acyl, alkoxyalkyl, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C(O)OC 1-6 Alkyl, C(O)C 1-6 Alkyl group, nitrogen-protecting group when attached to a nitrogen atom, or oxygen-protecting group when attached to an oxygen atom; or Ra and R b Together with the atoms they are attached to, they form heterocyclic alkyl rings; or R e and R f Together with the atoms they are attached to, they form cycloalkyl rings; and

[0137] Each occurrence of R g R h R i and R j Independently 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 h Together with the atoms they are attached to, they form heterocyclic alkyl rings.

[0138] In some implementations, R 1 It is an aryl, heteroaryl, or heterocyclic alkyl group, wherein any R 1 It can be optionally replaced by one to three independent substituents R 7 replace.

[0139] In some implementations, R 1 It is an aryl, heteroaryl, or heterocyclic alkyl group, wherein any R 1 It can be optionally replaced by one to three independent substituents R 7 Replace, and each R 7 Independently, it can be halogen, alkyl, alkoxy, haloalkyl, carboxyl, or -(CH2). n C(O)NR g R h -S(O)2R i -CO2R j , or NR g R h And each R g and R h Independently hydrogen, alkyl, C(O)C 1-6 Alkyl, or R g and R h Together with the atoms they are attached to, they form heterocyclic alkyl rings.

[0140] In some implementations, R 1 It is hydrogen, halogen, cyano, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, NR a R b NHSO2R c CH2NR a R b CRe R f NHSO2R d SR f COR f , or CR e R f OH; or R 1 and R 2 Together with the atoms they are attached to, they form aromatic rings or cycloalkyl rings.

[0141] In some implementations, R 1 It is hydrogen, halogen, alkyl, alkenyl, haloalkyl, alkoxy, haloalkoxy, cycloalkoxy, aryl, NR a R b CR e R f NHSO2R d SR f , or CR e R f OH; or R 1 and R 2 Together with the atoms they are attached to, they form aromatic rings or cycloalkyl rings.

[0142] In some implementations, R 1 It is hydrogen, halogen, alkyl, haloalkyl, CR e R f NHSO2R d SR f , or NR a R b ;R a R b R d R e and R f It is independently hydrogen, alkyl, or haloalkyl.

[0143] In some implementations, R 1 It is SR f In some implementations, R 1 It is SR f ;R f It is hydrogen, alkyl, or haloalkyl.

[0144] In some implementations, R 1 It is an alkyl or haloalkyl group.

[0145] In some implementations, R 1 It is C 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

[0146] In some implementations, R 1It is a haloalkyl group.

[0147] In some implementations, R 1 It is C 1-6 Halogenated alkyl groups.

[0148] In some implementations, R 1 It is a fluoroalkyl group. In some embodiments, R 1 It is C 1-6 Fluoroalkyl. In some embodiments, R 1 It is C 1-3 Fluoroalkyl. In some embodiments, R 1 It is difluoromethyl or trifluoromethyl. In some embodiments, R 1 It is difluoromethyl. In some embodiments, R 1 It is trifluoromethyl.

[0149] In some implementations, R 2 It is hydrogen or alkyl.

[0150] In some implementations, R 2 Is it hydrogen or C? 1-6 alkyl.

[0151] In some implementations, R 2 Is it hydrogen or C? 1-3 alkyl.

[0152] In some implementations, R 2 It is an alkyl group. In some embodiments, R 2 It is C 1-6 Alkyl group. In some embodiments, R 2 It is C 1-3 Alkyl group. In some embodiments, R 2 It is hydrogen.

[0153] In some implementations, R 1 It is hydrogen and R 2 It is an alkyl group. In some embodiments, R 1 It is hydrogen and R 2 It is C 1-6 Alkyl group. In some embodiments, R 1 It is hydrogen and R 2 It is C 1-3 alkyl.

[0154] In some implementations, R 1 and R 2 Together with the atoms they are attached to, they form aromatic rings or cycloalkyl rings. In some embodiments, R 1 and R 2 Together with the atoms they are attached to, they form an aromatic ring. In some embodiments, R1 and R 2 Together with the atoms they are attached to, they form cycloalkyl rings.

[0155] In some implementations, R 4 It is an alkyl or cycloalkyl group.

[0156] In some implementations, R 4 It is C 1-4 Alkyl or C 3-5 Cycloalkyl.

[0157] In some implementations, R 4 It is C 1-4 Alkyl group. In some embodiments, R 4 It is C 3-5 Cycloalkyl. In some embodiments, R 4 It is cyclopentyl. In some embodiments, R 4 It is cyclobutyl. In some embodiments, R 4 It is cyclopropyl.

[0158] In some implementations, each R 6 It can be hydrogen, halogen, cyano, alkoxy, haloalkyl, or carboxyl.

[0159] In some implementations, each R 6 It can be hydrogen, halogen, or cyano group independently.

[0160] In some implementations, each R 6 It can be hydrogen, chlorine, fluorine or cyanide.

[0161] In some implementations, each R 6 It can be hydrogen, fluorine, or cyanide on its own.

[0162] In some implementations, each R 6 It can be hydrogen or halogen independently.

[0163] In some implementations, each R 6 It can be hydrogen, chlorine, or fluorine independently.

[0164] In some implementations, each R 6 It can be either hydrogen or fluorine.

[0165] In some implementations, each R 6 It can be either hydrogen or cyano.

[0166] In some implementations, each R 6 It is a halogen. In some implementations, each R 6 It is chlorine or fluorine. In some implementations, each R 6It is fluorine. In some implementations, each R 6 It is a cyano group.

[0167] In some implementations, A is CR 5 And R 5 It is hydrogen, cyano, C 1-4 Alkyl or C 3-5 Cycloalkyl.

[0168] In some implementations, A is N.

[0169] In some implementations, no more than one of W, X, Y, and Z is N.

[0170] In some implementations, W, X, Y, and Z are each independently CR 6 .

[0171] In some implementations, Z is N.

[0172] In some embodiments, the compound of formula I is the same as the compound of formula Ia:

[0173]

[0174] Ia,

[0175] Or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R 1 R 2 R 4 R 6 A, X, and Z are each defined independently as described in this paper.

[0176] In some embodiments, the compound of formula I is a compound of formula Ib:

[0177]

[0178] Ib,

[0179] Or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R 1 R 2 R 4 W, X, Y, and Z are each defined independently as described in this paper.

[0180] In some embodiments, the compound of formula I is the compound of formula Ic:

[0181]

[0182] Ic,

[0183] Or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R 1 R 2 R 4 R 6 Z and Z are defined independently as in this paper.

[0184] In some embodiments, the compound of formula I is the compound of formula Id:

[0185]

[0186] ID

[0187] Or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R 1 R 2 R 4 R 6 Z and Z are defined independently as in this paper.

[0188] In some embodiments, the compound of formula I is the compound of formula Ie:

[0189]

[0190] Ie,

[0191] Or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R 1 R 4 R 6 Z and Z are defined independently as in this paper.

[0192] In some embodiments, the compound of formula I is a compound of formula If:

[0193]

[0194] If,

[0195] Or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R 1 R 4 and R 6 Each is defined independently as described in this article.

[0196] In some embodiments, the compound of the aforementioned formula If is a compound of the following type:

[0197] Where R 4 It is an alkyl or cycloalkyl group; each R 6 Independently hydrogen or halogen, wherein at least one R 6 It is a halogen.

[0198] In some embodiments, the compound of the aforementioned formula If is a compound of the following type:

[0199] Where R 4 It is an alkyl or cycloalkyl group; each R 6 It is a halogen on its own.

[0200] In some embodiments, the compound of the aforementioned formula If is a compound of the following type:

[0201] Where R 4 It is an alkyl or cycloalkyl group; each R 6 It can be hydrogen, halogen, or cyano group independently.

[0202] In some embodiments, the compound of the aforementioned formula If is a compound that is: wherein R 4 It is C 1-4 Alkyl or C 3-5 cycloalkyl; each R 6 It can be hydrogen, halogen, or cyano group independently.

[0203] In some embodiments, the compound of the aforementioned formula If is a compound of the following type:

[0204] Where R 4 It is a cycloalkyl group; each R 6 It can be hydrogen, halogen, or cyano group independently.

[0205] In some embodiments, the compound of the aforementioned formula If is a compound of the following type:

[0206] Where R 4 It is C 3-5 cycloalkyl; each R 6 It can be hydrogen, halogen, or cyano group independently.

[0207] In some embodiments, the compound of the aforementioned formula If is a compound of the following type:

[0208] Where R 4 It is a cycloalkyl group; each R 6 It is a halogen on its own.

[0209] In some embodiments, the compound of the aforementioned formula If is a compound of the following type:

[0210] Where R4 It is C 3-5 cycloalkyl; each R 6 It is a halogen on its own.

[0211] In some embodiments, the compound of the aforementioned formula If is a compound of the following type:

[0212] Where R 4 It is an alkyl or cycloalkyl group; each R 6 Independently hydrogen, cyano, or halogen; R 1 It is hydrogen, halogen, cyano, acyl, alkyl, haloalkyl, alkoxy, haloalkoxy, NR a R b NHSO2R c CH2NR a R b CH2NHSO2R d CO2R e COR f CH2OR f , or CR e R f OH.

[0213] In some embodiments, the compound of the aforementioned formula If is a compound of the following type:

[0214] Where R 4 It is an alkyl or cycloalkyl group; each R 6 Independently hydrogen or halogen, wherein at least one R 6 It is halogen; R 1 It is hydrogen, halogen, cyano, acyl, alkyl, haloalkyl, alkoxy, haloalkoxy, NR a R b NHSO2R c CH2NR a R b CH2NHSO2R d CO2R e COR f CH2OR f , or CR e R f OH.

[0215] In some embodiments, the compound of the aforementioned formula If is a compound of the following type:

[0216] Where R 4 It is an alkyl or cycloalkyl group; each R 6 Independently hydrogen or halogen, wherein at least one R 6 It is halogen; R 1It is optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl.

[0217] In some embodiments, the compound of the aforementioned formula If is a compound of the following type:

[0218] Where R 1 It is an alkyl or haloalkyl group; R 4 It is an alkyl or cycloalkyl group; each R 6 Independently hydrogen or halogen, wherein at least one R 6 It is a halogen.

[0219] In some embodiments, the compound of the aforementioned formula If is a compound of the following type:

[0220] Where R 1 It is an alkyl or haloalkyl group; R 4 It is an alkyl or cycloalkyl group; each R 6 It is a halogen on its own.

[0221] In some embodiments, the compound of the aforementioned formula If is a compound of the following type:

[0222] Where R 1 It is an alkyl or haloalkyl group; R 4 It is an alkyl or cycloalkyl group; each R 6 It can be hydrogen, halogen, or cyano group independently.

[0223] In some embodiments, the compound of the aforementioned formula If is a compound of the following type:

[0224] Where R 1 It is a haloalkyl group; R 4 It is an alkyl or cycloalkyl group; each R 6 It can be hydrogen, halogen, or cyano group independently.

[0225] In some embodiments, the compound of the aforementioned formula If is a compound of the following type:

[0226] Where R 1 It is a haloalkyl group; R 4 It is C 1-4 Alkyl or C 3-5 Cycloalkyl; each R6 is independently hydrogen, halogen, or cyano.

[0227] In some embodiments, the compound of the aforementioned formula If is a compound of the following type:

[0228] Where R 1 It is a haloalkyl group; R 4 It is a cycloalkyl group; each R 6 It can be hydrogen, halogen, or cyano group independently.

[0229] In some embodiments, the compound of the aforementioned formula If is a compound of the following type:

[0230] Where R 1 It is a haloalkyl group; R 4 It is C 3-5 cycloalkyl; each R 6 It can be hydrogen, halogen, or cyano group independently.

[0231] In some embodiments, the compound of the aforementioned formula If is a compound of the following type:

[0232] Where R 1 It is a haloalkyl group; R 4 It is a cycloalkyl group; each R 6 It is a halogen on its own.

[0233] In some embodiments, the compound of the aforementioned formula If is a compound of the following type:

[0234] Where R 1 It is a haloalkyl group; R 4 It is C 3-5 cycloalkyl; each R 6 It is a halogen on its own.

[0235] In some embodiments, the compound of formula I is the compound of formula Ig:

[0236]

[0237] Ig,

[0238] Or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R 1 R 4 and R 6 Each is defined independently as described in this article.

[0239] In some embodiments, the compound of formula Ig is the following compound:

[0240] Where R 4 It is an alkyl or cycloalkyl group; each R 6 Independently hydrogen or halogen, wherein at least one R 6 It is a halogen.

[0241] In some embodiments, the compound of formula Ig is the following compound:

[0242] Where R 4 It is an alkyl or cycloalkyl group; each R 6 It is a halogen on its own.

[0243] In some embodiments, the compound of the aforementioned formula If is a compound of the following type:

[0244] Where R 4 It is an alkyl or cycloalkyl group; each R 6 It can be hydrogen, halogen, or cyano group independently.

[0245] In some embodiments, the compound of the aforementioned formula If is a compound of the following type:

[0246] Where R 4 It is C 1-4 Alkyl or C 3-5 Cycloalkyl; each R6 is independently hydrogen, halogen, or cyano.

[0247] In some embodiments, the compound of the aforementioned formula If is a compound of the following type:

[0248] Where R 4 It is a cycloalkyl group; each R 6 It can be hydrogen, halogen, or cyano group independently.

[0249] In some embodiments, the compound of the aforementioned formula If is a compound of the following type:

[0250] Where R 4 It is C 3-5 cycloalkyl; each R 6 It can be hydrogen, halogen, or cyano group independently.

[0251] In some embodiments, the compound of the aforementioned formula If is a compound of the following type:

[0252] Where R 4 It is a cycloalkyl group; each R 6 It can be either hydrogen or cyano.

[0253] In some embodiments, the compound of the aforementioned formula If is a compound of the following type:

[0254] Where R 4 It is C 3-5 cycloalkyl; each R 6 It can be either hydrogen or cyano.

[0255] In some embodiments, the compound of the aforementioned formula If is a compound of the following type:

[0256] Where R 4 It is a cycloalkyl group; each R 6 It is a halogen on its own.

[0257] In some embodiments, the compound of the aforementioned formula If is a compound of the following type:

[0258] Where R 4 It is C 3-5 cycloalkyl; each R 6 It is a halogen on its own.

[0259] In some embodiments, the compound of the aforementioned formula If is a compound of the following type:

[0260] Where R 4 It is an alkyl or cycloalkyl group; each R 6 Independently hydrogen, cyano, or halogen; R 1 It is hydrogen, halogen, cyano, acyl, alkyl, haloalkyl, alkoxy, haloalkoxy, NR a R b NHSO2R c CH2NR a R b CH2NHSO2R d CO2R e COR f CH2OR f , or CR e R f OH.

[0261] In some embodiments, the compound of formula Ig is the following compound:

[0262] Where R 4 It is an alkyl or cycloalkyl group; each R 6 Independently hydrogen or halogen, wherein at least one R 6 It is halogen; R 1 It is hydrogen, halogen, cyano, acyl, alkyl, haloalkyl, alkoxy, haloalkoxy, NR a R b NHSO2R c CH2NR a R b CH2NHSO2R d CO2R e COR f CH2OR f , or CR e R f OH.

[0263] In some embodiments, the compound of formula Ig is the following compound:

[0264] Where R 4 It is an alkyl or cycloalkyl group; each R 6 Independently hydrogen or halogen, wherein at least one R 6 It is halogen; R 1It is optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl.

[0265] In some embodiments, the compound of the aforementioned formula If is a compound of the following type:

[0266] Where R 1 It is an alkyl or haloalkyl group; R 4 It is an alkyl or cycloalkyl group; each R 6 It can be hydrogen, halogen, or cyano group independently.

[0267] In some embodiments, the compound of the aforementioned formula If is a compound of the following type:

[0268] Where R 1 It is an alkyl or haloalkyl group; R 4 It is C 1-4 Alkyl or C 3-5 Cycloalkyl; each R6 is independently hydrogen, halogen, or cyano.

[0269] In some embodiments, the compound of the aforementioned formula If is a compound of the following type:

[0270] Where R 1 It is a haloalkyl group; R 4 It is an alkyl or cycloalkyl group; each R 6 It can be hydrogen, halogen, or cyano group independently.

[0271] In some embodiments, the compound of the aforementioned formula If is a compound of the following type:

[0272] Where R 1 It is a haloalkyl group; R 4 It is C 1-4 Alkyl or C 3-5 Cycloalkyl; each R6 is independently hydrogen, halogen, or cyano.

[0273] In some embodiments, the compound of the aforementioned formula If is a compound of the following type:

[0274] Where R 1 It is a haloalkyl group; R 4 It is a cycloalkyl group; each R 6 It can be hydrogen, halogen, or cyano group independently.

[0275] In some embodiments, the compound of the aforementioned formula If is a compound of the following type:

[0276] Where R 1 It is a haloalkyl group; R 4 It is C 3-5 cycloalkyl; each R 6 It can be hydrogen, halogen, or cyano group independently.

[0277] In some embodiments, the compound of the aforementioned formula If is a compound of the following type:

[0278] Where R 1 It is a haloalkyl group; R 4 It is a cycloalkyl group; each R 6 It can be either hydrogen or cyano.

[0279] In some embodiments, the compound of the aforementioned formula If is a compound of the following type:

[0280] Where R 1 It is a haloalkyl group; R 4 It is C 3-5 cycloalkyl; each R 6 It can be either hydrogen or cyano.

[0281] In some embodiments, the compound of the aforementioned formula If is a compound of the following type:

[0282] Where R 1 It is a haloalkyl group; R 4 It is a cycloalkyl group; each R 6 It is a halogen on its own.

[0283] In some embodiments, the compound of the aforementioned formula If is a compound of the following type:

[0284] Where R 1 It is a haloalkyl group; R 4 It is C 3-5 cycloalkyl; each R 6 It is a halogen on its own.

[0285] In some embodiments, the compound of formula I is selected from the group consisting of:

[0286] 1-Cyclopropyl-6-fluoro-2-(pyridazin-4-yl)-1H-benzo[d]imidazolium (1);

[0287] 5-(1-Cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-carboxylonitrile (2);

[0288] 2-(6-chloropyridazine-4-yl)-1-cyclopropyl-6-fluoro-1H-benzo[d]imidazolium(3);

[0289] 1-Cyclopropyl-6-fluoro-2-(6-vinylpyridazin-4-yl)-1H-benzo[d]imidazolium(4);

[0290] 5-(1-Cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-carboxylic acid methyl ester (5);

[0291] 1-Cyclopropyl-2-(6-ethylpyridazin-4-yl)-6-fluoro-1H-benzo[d]imidazolium(6);

[0292] 1-(5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)-2,2,2-trifluoroethane-1-ol (7);

[0293] N-((5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methyl)propionamide (8);

[0294] (5-(1-Cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methyl)carbamate (9);

[0295] 4-(5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)morpholine(10);

[0296] 1-Cyclopropyl-6-fluoro-2-(6-(4-(4-fluorophenyl)piperazin-1-yl)pyridazin-4-yl)-1H-benzo[d]imidazolium (11);

[0297] 2-(5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)prop-2-ol (12);

[0298] 5-(1-Cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)-N-(tetrahydro-2H-pyran-4-yl)pyridazine-3-amine (13);

[0299] 4-(1-Cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)zoline (14);

[0300] 1-Cyclopropyl-6-fluoro-2-(6-methylpyridazin-4-yl)-1H-benzo[d]imidazolium (15);

[0301] N-(5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)ethanesulfonamide (16);

[0302] 2-(6-chloropyridazine-4-yl)-1-ethyl-1H-benzo[d]imidazol-6-carboxynitrile (17);

[0303] 2-(4-(5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)piperazin-1-yl)-N-isopropylacetamide (18);

[0304] 1-Cyclopropyl-5,6-Difluoro-2-(6-methylpyridazin-4-yl)-1H-benzo[d]imidazolium (19);

[0305] 2-(4-(5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)piperazin-1-yl)-1-(pyrrolidone-1-yl)ethyl-1-one (20);

[0306] 5-(1-Cyclopropyl-5,6-Difluoro-1H-Benz[d]imidazol-2-yl)-N-methylpyridazine-3-amine (21);

[0307] 2-(6-chloropyridazine-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole (22);

[0308] 1-Cyclopropyl-5,6-Difluoro-2-(6-Methoxypyridazin-4-yl)-1H-benzo[d]imidazolium (23);

[0309] 1-Cyclopropyl-5,6-Difluoro-2-(6-isopropoxypyridazin-4-yl)-1H-benzo[d]imidazolium (24);

[0310] 5-(1-Cyclopropyl-5,6-Difluoro-1H-Benz[d]imidazol-2-yl)-N,N-Dimethylpyridazine-3-amine (25);

[0311] 1-Ethyl-6-fluoro-2-(6-methylpyridazin-4-yl)-1H-indole (26);

[0312] 1-Cyclopropyl-5,6-Difluoro-2-(6-(2,2,2-trifluoroethoxy)pyridazin-4-yl)-1H-benzo[d]imidazolium (27);

[0313] 5-(1-Cyclopropyl-5,6-Difluoro-1H-Benz[d]imidazol-2-yl)-N-(2-methoxyethyl)pyridazine-3-amine (28);

[0314] 1-Cyclopropyl-2-(6-Methoxypyridazin-4-yl)-1H-benzo[d]imidazol-6-carboxynitrile (29);

[0315] 1-Cyclopropyl-6-fluoro-2-(6-methylpyridazin-4-yl)-1H-indole (30);

[0316] N-((5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methyl)ethanesulfonamide (31);

[0317] 5-(1-Cyclopropyl-5,6-Difluoro-1H-Benz[d]imidazol-2-yl)-N-(2,2,2-trifluoroethyl)pyridazine-3-amine (32);

[0318] 1-Cyclopropyl-2-(6-ethylpyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazolium (33);

[0319] 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-1H-benzo[d]imidazol-6-carboxynitrile (34);

[0320] 1-Cyclopropyl-2-(6-methylpyridazin-4-yl)-1H-benzo[d]imidazol-6-carboxynitrile (35);

[0321] 1-Cyclopropyl-5,6-Difluoro-2-(6-(4-methylpiperazin-1-yl)pyridazin-4-yl)-1H-benzo[d]imidazolium (36);

[0322] 1-(4-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)piperazin-1-yl)ethyl-1-one (37);

[0323] 1-Cyclopropyl-5,6-Difluoro-2-(6-(4-(methanesulfonyl)piperazin-1-yl)pyridazin-4-yl)-1H-benzo[d]imidazolium (38);

[0324] 4-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)piperazine-1-carboxylic acid tert-butyl ester (39);

[0325] 1-Ethyl-2-(6-methoxypyridazin-4-yl)-1H-benzo[d]imidazol-6-carboxynitrile (40);

[0326] 1-Ethyl-2-(6-ethylpyridazin-4-yl)-1H-benzo[d]imidazol-6-carboxynitrile (41);

[0327] 1-Cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazolium (42);

[0328] 2-(6-Cyclobutoxypyridazine-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazolium (43);

[0329] 1-Cyclopropyl-2-(6-(4,4-difluoropiperidin-1-yl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazolium (44);

[0330] 5-Chloro-3-cyclopropyl-2-(6-methylpyridazin-4-yl)-3H-imidazo[4,5-b]pyridine (45);

[0331] 1-Cyclopropyl-2-(6-(3,3-difluoropyrrolidone-1-yl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazolium(46);

[0332] 1-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)-2,2,2-trifluoroethane-1-ol (47);

[0333] 1-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)-N,N-dimethylpyrrolidine-3-amine (48);

[0334] 1-Cyclopropyl-5,6-Difluoro-2-(6-(4-fluorophenyl)pyridazin-4-yl)-1H-benzo[d]imidazolium (49);

[0335] 1-Cyclopropyl-5,6-Difluoro-2-(6-((4-fluorophenyl)ethynyl)pyridazin-4-yl)-1H-benzo[d]imidazolium (50);

[0336] 1-Cyclopropyl-5,6-Difluoro-2-(6-Isopropylpyridazin-4-yl)-1H-benzo[d]imidazolium (51);

[0337] N-((5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methyl)ethanesulfonamide (52);

[0338] 1-Cyclopropyl-5,6-Difluoro-2-(6-((1,1,1-trifluoroprop-2-yl)oxy)pyridazin-4-yl)-1H-benzo[d]imidazolium (53);

[0339] 3-Cyclopropyl-2-(6-methylpyridazin-4-yl)-3H-imidazo[4,5-b]pyridine-5-carboxylonitrile (54);

[0340] 1-Cyclopropyl-5,6-Difluoro-2-(pyridazin-4-yl)-1H-benzo[d]imidazolium (55);

[0341] 1-Cyclopropyl-5,6-Difluoro-2-(pyridazin-4-yl)-4-(trifluoromethyl)-1H-benzo[d]imidazolium (56);

[0342] 1-Cyclopropyl-2-(6-(2,2-difluoropropoxy)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazolium (57);

[0343] 1-Cyclopropyl-5,6-Difluoro-2-(5-Isopropylpyridazin-4-yl)-1H-benzo[d]imidazolium (58);

[0344] 1-Cyclopropyl-2-(6-Cyclopropylpyridazin-4-yl)-5,6-Difluoro-1H-benzo[d]imidazolium (59);

[0345] 2-(6-Chlorpyridazin-4-yl)-3-cyclopropyl-5-methoxy-3H-imidazo[4,5-b]pyridine (60);

[0346] 1-Cyclopropyl-5,6-difluoro-2-(6-(4-fluoro-2-methylphenyl)pyridazin-4-yl)-1H-benzo[d]imidazolium (61);

[0347] 1-Cyclopropyl-2-(6-(2,4-difluorophenyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazolium(62);

[0348] 1-Cyclopropyl-2-(6-(3,4-difluorophenyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazolium (63);

[0349] 1-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)ethyl-1-one (64);

[0350] 2-(6-Chlorpyridazin-4-yl)-1-ethyl-5,6-difluoro-1H-benzo[d]imidazolium (65);

[0351] 1-Cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-1H-benzo[d]imidazol-6-carboxynitrile (66);

[0352] 2-(6-(difluoromethyl)pyridazin-4-yl)-1-ethyl-5,6-difluoro-1H-benzo[d]imidazolium (67);

[0353] 2-(6-chloropyridazine-4-yl)-1-ethyl-1H-benzo[d]imidazol-6-carboxynitrile (68);

[0354] 2-(6-(difluoromethyl)pyridazin-4-yl)-1-ethyl-1H-benzo[d]imidazol-6-carboxynitrile (69);

[0355] 1-Cyclopropyl-2-(6-(1,1-difluoroethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazolium (70);

[0356] 1-Cyclopropyl-5,6-Difluoro-2-(6-(2,2,2-trifluoroethyl)pyridazin-4-yl)-1H-benzo[d]imidazolium (71);

[0357] 2-(6-Cyclopropylpyridazin-4-yl)-1-ethyl-5,6-difluoro-1H-benzo[d]imidazolium (72);

[0358] 5-Chloro-3-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-3H-imidazo[4,5-b]pyridine (73);

[0359] 1-Cyclopropyl-5,6-difluoro-2-(5-methylpyridazin-4-yl)-1H-benzo[d]imidazolium (74);

[0360] 1-Cyclopropyl-2-(6-Cyclopropylpyridazin-4-yl)-1H-benzo[d]imidazol-6-carboxynitrile (75);

[0361] 3-Cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-3H-imidazo[4,5-b]pyridine-5-carboxylonitrile (76);

[0362] N-((5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methyl)methanesulfonamide (77);

[0363] N-((5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methyl)-N-methylmethanesulfonamide (78);

[0364] N-((5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methyl)propane-2-sulfonamide (79);

[0365] 1-Cyclopropyl-5,6-Difluoro-2-(6-(Methylsulfonyl)pyridazin-4-yl)-1H-benzo[d]imidazolium (80);

[0366] 1-Cyclopropyl-2-(6-(ethylsulfonyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazolium (81);

[0367] 1-Cyclopropyl-5,6-difluoro-2-(6-(methylsulfinyl)pyridazin-4-yl)-1H-benzo[d]imidazolium (82);

[0368] 1-Cyclopropyl-2-(6-(ethylsulfinyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazolium (83);

[0369] 5-Chloro-3-cyclopropyl-2-(6-cyclopropylpyridazin-4-yl)-3H-imidazo[4,5-b]pyridine (84);

[0370] 1-Cyclopropyl-5,6-Difluoro-2-(6-(trifluoromethyl)pyridazin-4-yl)-1H-benzo[d]imidazolium (85);

[0371] 1-Cyclopropyl-2-(6-(trifluoromethyl)pyridazin-4-yl)-1H-benzo[d]imidazol-6-carboxynitrile (86);

[0372] 3-Cyclopropyl-2-(6-Cyclopropylpyridazin-4-yl)-3H-imidazo[4,5-b]pyridine-5-carboxylonitrile (87);

[0373] 2-((5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methyl)isothiazolidinyl-1,1-dioxide (88);

[0374] 3-Cyclopropyl-2-(6-(trifluoromethyl)pyridazin-4-yl)-3H-imidazo[4,5-b]pyridine-5-carboxylonitrile (89);

[0375] 1-Cyclopropyl-2-(6-methylpyridazin-4-yl)-6-(trifluoromethyl)-1H-benzo[d]imidazolium (90);

[0376] N-(1-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)ethyl)methanesulfonamide (91);

[0377] 1-Cyclopropyl-5,6-Difluoro-2-(6-(fluoromethyl)pyridazin-4-yl)-1H-benzo[d]imidazolium (92);

[0378] 1-Cyclopropyl-2-(5,6-Dimethylpyridazin-4-yl)-5,6-Difluoro-1H-benzo[d]imidazolium (93);

[0379] (5-(1-Cyclopropyl-5,6-Difluoro-1H-Benz[d]imidazol-2-yl)pyridazin-3-yl)methanol(94);

[0380] 5-Chloro-3-cyclopropyl-2-(6-(trifluoromethyl)pyridazin-4-yl)-3H-imidazo[4,5-b]pyridine (95);

[0381] N-(1-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)ethyl)ethanesulfonamide (96);

[0382] 2-(6-Butyridazin-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazolium (97);

[0383] 1-Cyclopropyl-6-methyl-2-(6-methylpyridazin-4-yl)-1H-benzo[d]imidazolium (98);

[0384] 1-Cyclopropyl-5,6-Difluoro-2-(3-methylpyridazin-4-yl)-1H-benzo[d]imidazolium (99);

[0385] 1-Cyclopropyl-2-(3,6-Dimethylpyridazin-4-yl)-5,6-Difluoro-1H-benzo[d]imidazolium (100);

[0386] 1-Cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-6,7-difluoro-1H-benzo[d]imidazolium (101);

[0387] 5-(1-Cyclopropyl-5,6-Difluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-thiol (102);

[0388] 2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1-methyl-1H-benzo[d]imidazolium(104);

[0389] 2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1-propyl-1H-benzo[d]imidazolium (105);

[0390] 4-(1-Cyclopropyl-5,6-Difluoro-1H-Benz[d]imidazol-2-yl)-5,6,7,8-Tetrahydrozoline(106);

[0391] 1-Cyclopropyl-2-(6-methylpyridazin-4-yl)-1H-benzo[d]imidazol-5-carboxynitrile (Ex. 107)

[0392] 1-Cyclobutyl-5,6-difluoro-2-(6-methylpyridazin-4-yl)-1H-benzo[d]imidazolium (108);

[0393] 1-Cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-1H-benzo[d]imidazol-6-ol (109);

[0394] 5-(1-Cyclopropyl-5,6-Difluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-carboxylic acid (110);

[0395] 1-Cyclopropyl-7-fluoro-2-(6-methylpyridazin-4-yl)-1H-benzo[d]imidazolium(111);

[0396] 5-Chloro-1-cyclopropyl-2-(6-methylpyridazin-4-yl)-1H-benzo[d]imidazolium (112);

[0397] 4-Chloro-1-cyclopropyl-2-(6-methylpyridazin-4-yl)-1H-benzo[d]imidazolium (113);

[0398] 1-Cyclopropyl-5,6-Difluoro-2-(6-(methoxymethyl)pyridazin-4-yl)-1H-benzo[d]imidazolium (114);

[0399] 5-(6-cyano-1-cyclopropyl-1H-benzo[d]imidazol-2-yl)pyridazine-3-carboxylic acid methyl ester (115);

[0400] 5-(6-cyano-1-cyclopropyl-1H-benzo[d]imidazol-2-yl)pyridazine-3-carboxylic acid (116);

[0401] 1-Cyclopropyl-2-(6-(cyclopropylmethoxy)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazolium (117);

[0402] 1-Cyclopropyl-2-(6-(2,2,2-trifluoroethoxy)pyridazin-4-yl)-1H-benzo[d]imidazol-6-carboxynitrile (118);

[0403] 6-Chloro-1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5-fluoro-1H-benzo[d]imidazolium (119);

[0404] 1-Cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5-fluoro-1H-benzo[d]imidazol-6-carboxynitrile (120);

[0405] 4-(1-Cyclopropyl-5,6-Difluoro-1H-benzo[d]imidazol-2-yl)-6,7-dihydro-5H-cyclopentano[c]pyridazine (121);

[0406] 1-Cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-6-fluoro-1H-benzo[d]imidazolium (122);

[0407] 1-Cyclopropyl-5,6-Difluoro-2-(6-(methylthio)pyridazin-4-yl)-1H-benzo[d]imidazolium (123);

[0408] 1-Cyclopropyl-5,6-Difluoro-2-(6-(isopropylthio)pyridazin-4-yl)-1H-benzo[d]imidazolium(124);

[0409] 1-Cyclopropyl-2-(6-((difluoromethyl)thio)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazolium (125);

[0410] 5-(1-Cyclopropyl-5,6-Difluoro-1H-Benzo[d]imidazol-2-yl)pyridazin-3-ol (126);

[0411] 1-Cyclopropyl-2-(6-(difluoromethoxy)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazolium (127);

[0412] 1-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)ethanol-1-ol(128);

[0413] 1-Cyclopropyl-5,6-Difluoro-2-(6-(1-fluoroethyl)pyridazin-4-yl)-1H-benzo[d]imidazolium (129);

[0414] 1-Cyclopropyl-5,6-difluoro-2-(6-((trifluoromethyl)thio)pyridazin-4-yl)-1H-benzo[d]imidazolium (130)

[0415] 1-Cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-1H-benzo[d]imidazolium (131);

[0416] 2-(6-(difluoromethyl)pyridazin-4-yl)-1-propyl-1H-benzo[d]imidazolium (132);

[0417] 1-Cyclopropyl-2-(6-(difluoromethoxy)pyridazin-4-yl)-1H-benzo[d]imidazol-6-carboxynitrile (133);

[0418] 1-Cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-1H-indol-3-carboxynitrile (134);

[0419] 2-(6-(difluoromethyl)pyridazin-4-yl)-1-methyl-1H-indole-3-carboxynitrile (135);

[0420] 1-Cyclopropyl-2-(6-(1-fluoroethyl)pyridazin-4-yl)-1H-benzo[d]imidazol-6-carboxynitrile (136); pharmaceutically acceptable salts, cocrystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically enriched derivatives and prodrugs thereof.

[0421] On the other hand, 2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (103), or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, is provided.

[0422] In one respect, the compound of formula I is a compound in which the compound inhibits (or is identified as inhibiting) aldosterone synthase (CYP11B2).

[0423] The compounds described herein include those that are identified as acquiring at least partial affinity for metalloenzymes through one or more of the following types of chemical interactions or bonds with a metal: σ bonds, covalent bonds, coordinate covalent bonds, ionic bonds, π bonds, δ bonds, or antibonding interactions. The compound may also acquire affinity for the metal through weaker interactions, such as van der Waals interactions, π-cation interactions, π-anion interactions, dipole-dipole interactions, and ion-dipole interactions. In one aspect, the compound is identified as interacting with the metal via a pyridazine moiety.

[0424] Methods for assessing metal-ligand binding interactions are known in the art, as illustrated in the references, including, for example, Lippard and Berg, “Principles of Bioinorganic Chemistry”, University Science Books, (1994); Basolo and Pearson John Wiley & Sons Inc, “Mechanisms of Inorganic Reactions”, 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, 107-109 (2008).

[0425] On the other hand, a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable carrier is provided.

[0426] On the other hand, a method for regulating the activity of metalloenzymes in a target is provided, comprising contacting the target with a compound of formula I under a quantity and conditions sufficient to regulate the activity of the metalloenzymes.

[0427] On the other hand, a method is provided for treating a subject who has or is susceptible to a condition or disease, wherein the subject has been identified as needing treatment for the condition or disease, the method comprising administering an effective amount of a compound or pharmaceutical composition of formula I to the subject in need, thereby subjecting the subject to treatment for the condition.

[0428] On the other hand, the objects are animals other than humans.

[0429] On the other hand, methods for treating subjects who have or are susceptible to metalloenzyme-related conditions or diseases are provided, including administering an effective amount of a compound of formula I or a pharmaceutical composition to the subject.

[0430] On the other hand, a method is provided for treating a subject who has or is susceptible to a metalloenzyme-related condition or disease, wherein the subject has been identified as needing treatment for the metalloenzyme-related condition or disease, the method comprising administering an effective amount of a compound or pharmaceutical composition of formula I to the subject in need, thereby subjecting the subject to treatment for the condition.

[0431] On the other hand, a method is provided for treating a subject who has or is susceptible to a metalloenzyme-mediated condition or disease, wherein the subject has been identified as needing treatment for the metalloenzyme-mediated condition or disease, the method comprising administering an effective amount of a compound or pharmaceutical composition of formula I to the subject in need to modulate (e.g., downregulate, inhibit) the metalloenzyme activity in the subject.

[0432] The methods described herein include those diseases or conditions mediated by any one of the following: aromatase (CYP19), cyclooxygenase family members, lanosterol demethylase (CYP51), nitric oxide synthase family members, thromboxane synthase (CYP5a), thyroid peroxidase, 17-α-hydroxylase / 17,20-lyase (CYP17), cytochrome P450 2A6 (CYP2A6), heme oxygenase, indoleamine 2,3-dioxygenase, retinoic acid hydroxylase (CYP26), vitamin D hydroxylase (CYP24), sterol 27-hydroxylase (CYP27), cytochrome P450 3A5 (CYP3A5), cholesterol 24-hydroxylase (CYP46), cytochrome P450 4F2 (CYP4F2), myeloperoxidase, or 11-β-hydroxylase (CYP11B1).

[0433] The methods described herein include those diseases or conditions that are cancer, cardiovascular disease, inflammatory disease, infectious disease, metabolic disease, ophthalmic disease, central nervous system (CNS) disease, urinary disease, or gastrointestinal disease.

[0434] The methods described in this article include diseases or conditions such as hypertension, refractory hypertension, conditions associated with primary or secondary hyperaldosteronism and adrenal hyperplasia, pulmonary 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 syndrome, coronary artery disease, fibrosis, diseases characterized by increased collagen formation, fibrosis, and matrix remodeling following hypertension, diseases characterized by fibrosis and matrix remodeling following endothelial cell dysfunction, and cardiovascular diseases such as atherosclerosis. Atrial fibrillation, kidney dysfunction, liver disease, non-alcoholic fatty liver disease, vascular disease, retinopathy, neuropathy, insulinopathy, endothelial dysfunction, myocardial fibrosis, vascular fibrosis, myocardial necrosis, vascular injury, myocardial infarction, left ventricular hypertrophy, vascular wall hypertrophy, endothelial thickening, arterial fibrinoid necrosis, kidney disease, diabetic nephropathy, glomerulosclerosis, glomerulonephritis, nephrotic syndrome, polycystic kidney disease, diabetes, metabolic syndrome, insulin resistance, sleep apnea, obstructive sleep apnea, muscular dystrophy, cirrhosis, non-alcoholic fatty liver disease, kidney disease, diabetic nephropathy, or stroke.

[0435] The methods described herein include those for identifying a subject as requiring a specific treatment. Identifying a subject requiring such treatment can be made by the subject or a healthcare professional and can be subjective (e.g., opinion) or objective (e.g., measurement via testing or diagnostic methods). Detailed Implementation

[0436] definition

[0437] To facilitate a better understanding of this invention, certain terms are defined herein.

[0438] As used herein, the term "treatment" of a disease includes the prevention, improvement, reduction, and / or management of the disease and / or symptoms that may lead to the disease. The terms "treatment" and "management" refer to methods of reducing or alleviating a disease and / or its accompanying symptoms. According to this disclosure, "treatment" includes preventing, blocking, inhibiting, weakening, protecting, modulating, reversing, and reducing the effects of a disease, such as its harmful effects.

[0439] As used herein, “inhibition” includes prevention, reduction, and cessation of progression. Note that “enzyme inhibition” (e.g., metalloenzyme inhibition) is distinguished and described below.

[0440] The term "regulation" refers to an increase or decrease in enzyme activity in response to exposure to compounds of this disclosure.

[0441] The terms "isolated," "purified," or "biopure" refer to substances that are substantially free of the components that normally accompany them in their 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 purity of the compound is at least 85%, more preferably at least 90%, even more preferably at least 95%, and most preferably at least 99%.

[0442] The terms “administration” or “application” refer to the means by which a compound is introduced into a target to achieve its intended function. Examples of possible routes of administration include injection (subcutaneous, intravenous, parenteral, intraperitoneal, intrathecal), topical, oral, inhalation, rectal, and transdermal administration.

[0443] The term "effective amount" refers to the amount of a compound that achieves the desired result within the necessary dosage and time period. The effective amount of a compound can vary depending on factors such as the subject's disease condition, age, and weight, as well as the compound's ability to elicit the desired response in the subject. Dosing regimens can be adjusted to provide the best therapeutic response. An effective amount is also the amount in which the beneficial therapeutic effect outweighs any toxic or harmful effects (e.g., side effects) of the inhibitory compound.

[0444] The phrases “systemic administration,” “systemic drug delivery,” “peripheral administration,” and “peripheral drug delivery” used here refer to the administration of a compound, drug, or other substance to the patient’s system, where it undergoes metabolism and other similar processes.

[0445] The term "therapeutic effective dose" refers to an amount of compound applied that is sufficient to prevent or, to some extent, alleviate the development of one or more symptoms of a disease or condition being treated.

[0446] The therapeutically effective amount (i.e., effective dose) of the compound can be from about 0.005 μg / kg body weight to about 200 mg / kg body weight, preferably from about 0.01 mg / kg body weight to about 200 mg / kg body weight, more preferably from about 0.015 mg / kg body weight to about 30 mg / kg body weight. In other embodiments, the therapeutically effective amount can be from about 1.0 pM to about 10 μM. Those skilled in the art will understand that certain factors can affect the dose required to effectively treat a subject, including but not limited to the severity of the disease or condition, prior treatment, the subject's overall health status and / or age, and other pre-existing conditions. Furthermore, treating a subject with a therapeutically effective amount of the compound can include monotherapy or preferably can include a series of treatments. In one example, a subject is treated with a compound at a concentration of about 0.005 μg / kg body weight 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, in the case of a chronic condition or disease, the subject can be treated daily for several years. It should also be understood that the effective dose of a compound used for treatment can be increased or decreased during a particular treatment.

[0447] The term "chirality" refers to molecules that are not superimposed on their mirror images, while the term "chirality" refers to molecules that are superimposed on their mirror images.

[0448] The term "diastereomer" refers to a stereoisomer with two or more asymmetric centers, whose molecules are not mirror images of each other.

[0449] The term "enantiomer" refers to two stereoisomers of a compound that are non-superimposable mirror images of each other. An equimolar mixture of two enantiomers is called a "racemic mixture" or "racemate".

[0450] The term "isomer" or "stereoisomer" refers to compounds with the same chemical composition but different spatial arrangements of atoms or groups.

[0451] The term "prodrug" refers to a compound having a portion that can be metabolized in vivo. Typically, prodrugs are metabolized in vivo by esterases or other mechanisms to become the active drug. Examples of prodrugs and their uses are well known in the art (see, for example, Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66:1-19). Prodrugs can be prepared in situ during the final isolation and purification of the compound, or by reacting the purified compound, either as a free acid or hydroxyl group, alone with a suitable esterifying agent. The hydroxyl group can be converted to an ester by treatment with a carboxylic acid. Examples of prodrug moieties include substituted and unsubstituted branched or unbranched lower alkyl ester moieties (e.g., propionates), lower alkenyl esters, di-lower alkylamino lower alkyl esters (e.g., dimethylaminoethyl ester), acylamino lower alkyl esters (e.g., acetoxymethyl ester), acyloxy lower alkyl esters (e.g., pivaloyloxymethyl ester), aryl esters (phenyl esters), aryl lower alkyl esters (e.g., benzyl esters), substituted (e.g., substituted with methyl, halogen, or methoxy) aryl and aryl lower alkyl esters, amides, lower alkylamides, di-lower alkylamides, and hydroxyamides. Preferred prodrug moieties are propionates and acyl esters. Prodrugs that are converted to their active form through other mechanisms in vivo are also included. In some aspects, the compounds disclosed herein are prodrugs of any general formula herein.

[0452] The term "object" refers to an animal, such as a mammal, including but not limited to primates (e.g., humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, etc. In some implementations, the object is humans.

[0453] In this application (including the claims), terms used without a quantifier mean "one or more". Thus, for example, reference to "sample" includes multiple samples unless the context clearly contradicts this (e.g., multiple samples), etc.

[0454] Throughout the specification and claims, unless the context otherwise requires, the words “comprising,” “including,” and “containing” are used in a non-exclusive sense.

[0455] As used herein, the term “about” when referring to a value means including variations based on specific amounts, such as ±20% in some embodiments, ±10% in some embodiments, ±5% in some embodiments, ±1% in some embodiments, ±0.5% in some embodiments, and ±0.1% in some embodiments, as such variations are suitable for performing the disclosed methods or using the disclosed compositions.

[0456] The term "inhibitor" as used herein refers to a molecule that exhibits inhibition of metalloenzyme activity. "Inhibition" as used herein means a reduction in metalloenzyme activity compared to the activity of the metalloenzyme in the absence of an inhibitor. In some embodiments, the term "inhibition" means a reduction in metalloenzyme activity of 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 means a reduction in metalloenzyme activity of about 5% to about 25%, about 25% to about 50%, about 50% to about 75%, or about 75% to 100%. In some embodiments, inhibition means a reduction in metalloenzyme activity of about 95% to 100%, for example, a reduction of 95%, 96%, 97%, 98%, 99%, or 100%. This reduction can be measured using a variety of techniques recognized by those skilled in the art. Specific tests for measuring individual activity are described below.

[0457] Furthermore, the compounds disclosed herein include alkenes having the following geometries: “Z” refers to the so-called “cis” (same-side) configuration, and “E” refers to the so-called “trans” (opposite-side) configuration. For the nomenclature of chiral centers, the terms “d” and “l” configurations are as defined in the IUPAC recommended specifications. Regarding the use of the terms diastereomer, racemate, epimer, and enantiomer, these will be used in their usual context to describe the stereochemistry of the formulation.

[0458] As used herein, the term "alkyl" refers to a straight-chain or branched hydrocarbon group containing 1 to 12 carbon atoms. The term "lower alkyl" refers to a C1 to C6 alkyl chain. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, tert-butyl, and n-pentyl. Alkyl groups may optionally be substituted with one or more substituents.

[0459] The term "haloalkyl" refers to an alkyl group that is substituted with one or more halogen substituents. Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, bromomethyl, chloromethyl, and 2,2,2-trifluoroethyl.

[0460] The term "alkenyl" refers to an unsaturated hydrocarbon chain, which can be straight or branched, containing 2 to 12 carbon atoms and at least one carbon-carbon double bond. The alkenyl group may optionally be substituted by one or more substituents.

[0461] The term "arylalinyl" refers to an unsaturated hydrocarbon chain, which can be straight or branched, containing 2 to 12 carbon atoms and at least one carbon-carbon double bond, wherein the alkenyl unit has one or more sp units. 2 The hybrid carbon is attached to the aryl moiety. The alkenyl group may optionally be substituted by one or more substituents.

[0462] The term "alkynyl" refers to an unsaturated hydrocarbon chain, which can be straight or branched, containing 2 to 12 carbon atoms and at least one carbon-carbon triple bond. The alkynyl group may optionally be substituted by one or more substituents.

[0463] The term "arylynyl" 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, wherein one or more sp-hybridized carbons of the ynyl unit are attached to the aryl moiety. The ynyl group may optionally be substituted by one or more substituents.

[0464] alkenyl sp 2 The sp carbon of the carbon group or alkynyl group can optionally be the linking point of the alkenyl or alkynyl group, respectively.

[0465] The term "alkoxy" refers to an -O-alkyl substituent.

[0466] The terms "halogen" and "halogenated" used here refer to -F, -Cl, -Br, or -I.

[0467] The term "alkylthio" refers to a -S-alkyl substituent.

[0468] The term "alkoxyalkyl" refers to an alkyl-O-alkyl substituent.

[0469] The term "haloalkoxy" refers to an -O-alkyl group substituted with one or more halogen substituents. Examples of haloalkoxy groups include trifluoromethoxy and 2,2,2-trifluoroethoxy.

[0470] The term "haloalkoxyalkyl" refers to an alkyl-O-alkyl group in which the alkyl group is substituted by one or more halogen substituents.

[0471] The term "haloalkylaminocarbonyl" refers to -C(O)-amino-alkyl, wherein the alkyl group is substituted by one or more halogen substituents.

[0472] The term "haloalkylthio" refers to a -S-alkyl group that is substituted with one or more halogen substituents. Examples of haloalkylthio groups include trifluoromethylthio and 2,2,2-trifluoroethylthio.

[0473] The term "haloalkyl carbonyl" refers to a -C(O)-alkyl group that is substituted with one or more halogen substituents. Examples of haloalkyl carbonyl groups include trifluoroacetyl.

[0474] The term "cycloalkyl" refers to a 3- to 8-membered monocyclic or 7- to 14-membered bicyclic system of a hydrocarbon having at least one saturated ring or at least one non-aromatic ring, wherein the non-aromatic ring may have a degree of unsaturation. The cycloalkyl group may optionally be substituted by one or more substituents. In one embodiment, 0, 1, 2, 3, or 4 atoms of each ring of the cycloalkyl group may be substituted by a substituent. Representative examples of cycloalkyl groups include cyclopropyl, cyclopentyl, cyclohexyl, cyclobutyl, cycloheptyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, etc.

[0475] The term "cycloalkoxy" refers to an -O-cycloalkyl substituent.

[0476] The term "cycloalkoxyalkyl" refers to an alkyl-O-cycloalkyl substituent.

[0477] The term "cycloalkylalkoxy" refers to an -O-alkyl-cycloalkyl substituent.

[0478] The term "cycloalkylaminocarbonyl" refers to a -C(O)-NH-cycloalkyl substituent.

[0479] The term "aryl" refers to a monocyclic, bicyclic, or tricyclic aromatic ring system of a hydrocarbon. The aryl group may optionally be substituted by one or more substituents. In one embodiment, 0, 1, 2, 3, 4, 5, or 6 atoms of each ring of the aryl group may be substituted by a substituent. Examples of aryl groups include phenyl, naphthyl, anthracene, fluorenyl, indene, azulel, etc.

[0480] The term "aryloxy group" refers to an -O-aryl substituent.

[0481] The term "arylalkoxy" refers to an -O-alkyl-aryl substituent.

[0482] The term "aryl alkylthio" refers to a -S-alkyl-aryl substituent.

[0483] The term "arylthioalkyl" refers to an alkyl-S-aryl substituent.

[0484] The term "arylalkylaminocarbonyl" refers to a -C(O)-amino-alkyl-aryl substituent.

[0485] The term "arylalkylsulfonyl" refers to -S(O)2-alkyl-aryl substituents.

[0486] The term "arylalkylsulfinyl" refers to -S(O)-alkyl-aryl substituents.

[0487] The term "aryloxyalkyl" refers to an alkyl-O-aryl substituent.

[0488] The term "alkylaryl" refers to an aryl-alkyl substituent.

[0489] The term "arylalkyl" refers to an alkyl-aryl substituent.

[0490] The term "heteroaryl" refers to an aromatic 5- to 8-membered monocyclic, 8- to 12-membered bicyclic, or 11- to 14-membered tricyclic system, having 1 to 4 heteroatoms if monocyclic, 1 to 6 heteroatoms if bicyclic, or 1 to 9 heteroatoms if tricyclic, wherein the heteroatoms are selected from O, N, or S, and the remaining ring atoms are carbon (with suitable hydrogen atoms unless otherwise specified). The heteroaryl group may optionally be substituted by one or more substituents. In one embodiment, 0, 1, 2, 3, or 4 atoms of each ring of the heteroaryl group may be substituted by a substituent. Examples of heteroaryl groups include pyridyl, furanyl, thiophene, pyrrole, oxazolyl, oxadiazolyl, imidazolyl, thiazolyl, isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridinyl, pyrazinyl, triazinyl, isoquinolinyl, indazole, etc.

[0491] The term "heteroarylalkyl" refers to an alkyl-heteroaryl substituent.

[0492] The term "heteroaryloxy" refers to an -O-heteroaryl substituent.

[0493] The term "heteroarylalkoxy" refers to an -O-alkyl-heteroaryl substituent.

[0494] The term "heteroaryloxyalkyl" refers to an alkyl-O-heteroaryl substituent.

[0495] The term "nitrogen-containing heteroaryl" refers to heteroaryl groups that, if monocyclic, have 1 to 4 cyclic nitrogen atoms; if bicyclic, have 1 to 6 cyclic nitrogen atoms; or if tricyclic, have 1 to 9 cyclic nitrogen atoms.

[0496] The term "heterocyclic alkyl" refers to a non-aromatic 3- to 8-membered monocyclic, 7- to 12-membered bicyclic, or 10- to 14-membered tricyclic system containing 1 to 3 heteroatoms in the monocyclic case, 1 to 6 heteroatoms in the bicyclic case, or 1 to 9 heteroatoms in the tricyclic case, wherein the heteroatoms are selected from O, N, S, B, P, or Si, and the non-aromatic system is fully saturated. The heterocyclic alkyl may optionally be substituted by one or more substituents. In one embodiment, 0, 1, 2, 3, or 4 atoms of each ring of the heterocyclic alkyl may be substituted by a substituent. Representative heterocyclic alkyl groups include piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,3-dioxolane, tetrahydrofuranyl, tetrahydrothiophenyl, thiirenyl, etc.

[0497] The term "heterocyclic alkyl alkyl" refers to an alkyl-heterocyclic alkyl substituent.

[0498] The term "alkylamino" refers to an amino substituent further replaced by one or two alkyl groups. The term "aminoalkyl" refers to an alkyl substituent further replaced by one or more amino groups. The term "hydroxyalkyl" or "hydroxyalkyl" refers to an alkyl substituent further replaced by one or more hydroxyl groups. The alkyl or aryl portion of alkylamino, aminoalkyl, mercaptoalkyl, hydroxyalkyl, mercaptoalkoxy, sulfonylalkyl, sulfonylaryl, alkylcarbonyl, and alkylcarbonylalkyl groups may optionally be substituted with one or more substituents.

[0499] The acids and bases that can be used in the methods described herein are known in the art. An acid catalyst is any acidic chemical that can be inorganic (e.g., hydrochloric acid, sulfuric acid, nitric acid, aluminum trichloride) or organic (e.g., camphorsulfonic acid, p-toluenesulfonic acid, acetic acid, ytterbium trifluoromethanesulfonate). The acid is used to promote the chemical reaction in a catalytic or stoichiometric amount. A base is any basic chemical that can be inorganic (e.g., sodium bicarbonate, potassium hydroxide) or organic (e.g., triethylamine, pyridine). The base is used to promote the chemical reaction in a catalytic or stoichiometric amount.

[0500] An alkylating agent is any reagent capable of alkylating the functional group in question (e.g., the oxygen atom of an alcohol, the nitrogen atom of an amino group). Alkylating agents are known in the art, included in the references cited herein, and include alkyl halides (e.g., methyl iodide, benzyl bromide, or benzyl chloride), alkyl sulfate salts (e.g., methyl sulfate), or other combinations of alkyl leaving groups known in the art. A leaving group is any stable substance that can be separated from the molecule during a reaction (e.g., elimination reaction, substitution reaction) and is known in the art, included in the references cited herein, and includes halides (e.g., I-, Cl-, Br-, F-), hydroxyl groups, alkoxy groups (e.g., -OMe, -Ot-Bu), acyloxy anions (e.g., -OAc, -OC(O)CF3), sulfonates (e.g., methanesulfonyl, toluenesulfonyl), acetamides (e.g., -NHC(O)Me), carbamates (e.g., N(Me)C(O)Ot-Bu), phosphonates (e.g., -OP(O)(OEt)2), water, or alcohols (proton condition), etc.

[0501] In some embodiments, substituents on any group (e.g., alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaryl, cycloalkyl, heterocycloalkyl) may be on any atom of that group, wherein any substituted group (e.g., alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaryl, cycloalkyl, heterocycloalkyl) may optionally be substituted by one or more substituents (which may be the same or different), each substituent replacing a hydrogen atom. Examples of suitable substituents include, but are not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, aryl, heteroaralkyl, halogen, haloalkyl, cyano, nitro, alkoxy, aryloxy, hydroxy, hydroxyalkyl, oxo (i.e., carbonyl), carboxyl, formyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkylcarbonyloxy, aryloxycarbonyl, heteroaroxy, heteroaroxycarbonyl, thio, mercapto, mercaptoalkyl, arylsulfonyl, amino, aminoalkyl, dialkylamino, alkylcarbonylamino, alkylaminocarbonyl, alkoxycarbonylamino, alkylamino , arylamino, diarylamino, alkylcarbonyl, or arylamino-substituted aryl; arylalkylamino, arylalkylaminocarbonyl, acylamino, alkylaminosulfonyl, arylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, imino, carboxamido, carbamido, carbamyl, thiourea, thiocyanate, sulfonylamino, sulfonylalkyl, sulfonylaryl, mercaptoalkoxy, N-hydroxymididine, or N'-aryl, N''-hydroxymididine.

[0502] The compounds disclosed herein can be prepared by methods known in the field of organic synthesis. If it is necessary to minimize competing byproducts, the reaction conditions should be optimized, and methods for optimizing reaction conditions are known in the art. Reaction optimization and scale-up can advantageously utilize 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.; Jähnisch, K et al., Angew. Chem. Int. Ed. Engl. 2004). 43 (406; and references therein). Those skilled in the art may determine additional reaction plans and schemes by using commercially available searchable database software such as SciFinder® (CAS Division of the American Chemical Society) and CrossFire Beilstein® (Elsevier MDL), or by using internet search engines such as Google or keyword databases such as the U.S. Patent and Trademark Office text database with appropriate keywords.

[0503] As will be understood by those skilled in the art, the methods for synthesizing the chemical formula compounds described herein will be readily apparent to those of ordinary skill in the art, and are included in the schemes and examples herein. Furthermore, various synthetic steps may be performed in an alternating or sequential order to obtain the desired compound. Additionally, the solvents, temperatures, reaction durations, etc., described herein are for illustrative purposes only, and those of ordinary skill in the art will recognize that variations in reaction conditions can produce the desired compounds of this disclosure.

[0504] The compounds described herein may also contain a linkage (e.g., a carbon-carbon bond) where bond rotation is restricted by a specific bond, such as by the presence of a ring or double bond. Therefore, all cis / trans and E / Z isomers are explicitly included in this disclosure. The compounds described herein may also be represented in a variety of tautomeric forms, in which case this disclosure explicitly includes all tautomeric forms of the compounds described herein, although only a single tautomeric form may be shown. All such isomers of these compounds are explicitly included in this disclosure. All crystalline and polymorphic forms of the compounds described herein are explicitly included in this disclosure. Extracts and fractions containing compounds of this disclosure are also illustrated. The term isomer is intended to include diastereomers, enantiomers, regioisomers, structural isomers, rotational isomers, tautomeric isomers, etc. For compounds containing one or more stereocenters, such as chiral compounds, the methods of this disclosure can be carried out with enantiomer-rich compounds, racemates, or mixtures of diastereomers.

[0505] The preferred enantiomer-rich compound has an enantiomer excess of 50% or more, more preferably 60%, 70%, 80%, 90%, 95%, 98%, or 99% or more of enantiomer excess. In a preferred embodiment, only one enantiomer or diastereomer of the chiral compound of the present invention is applied to cells or a target.

[0506] Treatment

[0507] In one aspect, a method for treating a subject who has or is susceptible to a condition or disease is provided, including administering an effective amount of a compound of formula I or a pharmaceutical composition to the subject.

[0508] In other respects, methods are provided for treating subjects who have or are susceptible to a condition or disease, wherein the subject has been identified as requiring treatment for a metalloenzyme-mediated condition or disease, the method comprising administering an effective amount of a compound or pharmaceutical composition of formula I to the subject in need, thereby subjecting the subject to treatment for the condition.

[0509] In one aspect, a method for regulating the activity of metalloenzymes in cells of a subject is provided, comprising contacting the subject with a compound of formula I in an amount and under conditions sufficient to regulate the activity of the metalloenzymes.

[0510] In one implementation, regulation is inhibition.

[0511] On the other hand, methods for treating subjects who have or are susceptible to metalloenzyme-mediated conditions or diseases are provided, including administering an effective amount of a compound of formula I or a pharmaceutical composition to the subject.

[0512] In other respects, methods are provided for treating subjects who have or are susceptible to metalloenzyme-mediated conditions or diseases, wherein the subjects have been identified as needing treatment for metalloenzyme-related conditions or diseases, the methods comprising administering an effective amount of a compound or pharmaceutical composition of formula I to the subject in need, thereby subjecting the subject to treatment for the condition.

[0513] In some implementations, methods for treating the disease, condition, or symptom are provided, where the condition is cancer, cardiovascular disease, endocrine disorder, inflammatory disease, infectious disease, gynecological disease, metabolic disease, ophthalmic disease, central nervous system (CNS) disease, urinary disease, or gastrointestinal disease. In some implementations, the disease is hypertension, refractory hypertension, conditions associated with primary or secondary aldosteronism and adrenal hyperplasia, pulmonary 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 syndrome, coronary artery disease, fibrosis, diseases characterized by increased collagen formation, fibrosis, and matrix remodeling following hypertension, diseases characterized by fibrosis and matrix remodeling following endothelial cell dysfunction, and cardiovascular diseases such as atherosclerosis. Atrial fibrillation, renal dysfunction, liver disease, non-alcoholic fatty liver disease, vascular disease, retinopathy, neuropathy, insulinopathy, endothelial dysfunction, myocardial fibrosis, vascular fibrosis, myocardial necrosis, vascular injury, myocardial infarction, left ventricular hypertrophy, vascular wall hypertrophy, endothelial thickening, arterial fibrinoid necrosis, kidney disease, diabetic nephropathy, glomerulosclerosis, glomerulonephritis, nephrotic syndrome, polycystic kidney disease, diabetes, metabolic syndrome, insulin resistance, sleep apnea, obstructive sleep apnea, muscular dystrophy, cirrhosis, non-alcoholic fatty liver disease, kidney disease, diabetic nephropathy, or stroke.

[0514] In some implementations, the object is a mammal, preferably a primate or a human.

[0515] In another embodiment, a method as described above is provided, wherein the effective amount of compound of formula I is as described above.

[0516] In another embodiment, a method as described above is provided, wherein the compound of formula I is administered intravenously, intramuscularly, subcutaneously, intraventricularly, orally, or topically.

[0517] In another embodiment, the method as described herein is provided, wherein the compound of formula I exhibits selectivity for the activity range of the target enzyme (e.g., aldosterone synthase (CYP11B2) IC50). 50 <1.0μM).

[0518] In other embodiments, the method described above is provided, wherein the compound of formula I is administered alone or in combination with one or more other therapeutic agents. In further embodiments, the additional therapeutic agents are anticancer agents, antifungal agents, cardiovascular therapeutic agents, anti-inflammatory agents, chemotherapeutic agents, anti-angiogenic agents, cytotoxic agents, antiproliferative agents, metabolic disease therapeutic agents, ophthalmic disease therapeutic agents, central nervous system (CNS) disease therapeutic agents, urinary disease therapeutic agents, or gastrointestinal disease therapeutic agents.

[0519] In some implementations, additional therapeutic agents are agents for treating hypertension, agents for treating primary aldosteronism, agents for treating kidney disease, agents for treating congestive heart failure, agents for treating atherosclerotic disorders, agents for treating diabetes, agents for treating obesity, or agents for treating metabolic diseases.

[0520] Other exemplary therapeutic agents include, but are not limited to, renin inhibitors, angiotensin-converting enzyme (ACE) inhibitors, dual inhibitors of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP), angiotensin II receptor blockers (ARBs), mineralocorticoid receptor antagonists (MRAs), neutral endopeptidase inhibitors (NEPs), enkephalinase inhibitors, calcium channel blockers, alpha-adrenergic blockers, beta-adrenergic blockers, diuretics (including loop diuretics), potassium channel activators, endothelin receptor antagonists, endothelin 1 receptor agonists, and soluble guanylate rings. Enzyme stimulants, 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.

[0521] Another object of this disclosure is the use of the compounds described herein (e.g., compounds of Formula I) in the preparation of medicaments for treating metalloenzyme-mediated conditions or diseases. Another object of this disclosure is the use of the compounds described herein (e.g., compounds of Formula I) for treating metalloenzyme-mediated conditions or diseases. Another object of this disclosure is the use of the compounds described herein (e.g., compounds of Formula I) in the preparation of agricultural compositions for treating or preventing metalloenzyme-mediated conditions or diseases in agricultural or agronomic environments.

[0522] Pharmaceutical Composition

[0523] In one aspect, a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable carrier is provided.

[0524] In another embodiment, a pharmaceutical composition is provided that further comprises additional therapeutic agents. In a further embodiment, the additional therapeutic agents are anticancer agents, antifungal agents, cardiovascular therapeutic agents, anti-inflammatory agents, chemotherapeutic agents, anti-angiogenic agents, cytotoxic agents, antiproliferative agents, metabolic disease agents, ophthalmic disease agents, central nervous system (CNS) disease agents, urinary disease agents, or gastrointestinal disease agents.

[0525] In some implementations, additional therapeutic agents are agents for treating hypertension, agents for treating primary aldosteronism, agents for treating kidney disease, agents for treating congestive heart failure, agents for treating atherosclerotic disorders, agents for treating diabetes, agents for treating obesity, or agents for treating metabolic diseases.

[0526] Other exemplary therapeutic agents include, but are not limited to, renin inhibitors, angiotensin-converting enzyme (ACE) inhibitors, dual inhibitors of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP), angiotensin II receptor blockers (ARBs), mineralocorticoid receptor antagonists (MRAs), neutral endopeptidase inhibitors (NEPs), enkephalinase inhibitors, calcium channel blockers, alpha-adrenergic blockers, beta-adrenergic blockers, diuretics (including loop diuretics), potassium channel activators, endothelin receptor antagonists, endothelin 1 receptor agonists, and soluble guanylate rings. Enzyme stimulants, 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.

[0527] In one aspect, a kit is provided comprising an effective amount of a unit dosage form of a compound of formula I, and instructions for administering the compound to a subject who has or is susceptible to a metalloenzyme-mediated disease or condition, including cancer, cardiovascular disease, endocrine disorders, inflammatory diseases, infectious diseases, gynecological diseases, metabolic diseases, ophthalmic diseases, central nervous system (CNS) diseases, urinary diseases, or gastrointestinal diseases. In other embodiments, the disease, condition, or symptom is hypertension, refractory hypertension, conditions associated with primary or secondary aldosteronism and adrenal hyperplasia, pulmonary 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 syndrome, coronary artery disease, fibrosis, diseases characterized by increased collagen formation, fibrosis, and matrix remodeling following hypertension, diseases characterized by fibrosis and matrix remodeling following endothelial cell dysfunction, and cardiovascular diseases such as atherosclerosis. Sclerosis, atrial fibrillation, renal dysfunction, liver disease, non-alcoholic steatohepatitis, vascular disease, retinopathy, neuropathy, insulinopathy, endothelial dysfunction, myocardial fibrosis, vascular fibrosis, myocardial necrosis, vascular injury, myocardial infarction, left ventricular hypertrophy, vascular wall hypertrophy, endothelial thickening, arterial fibrinoid necrosis, kidney disease, diabetic nephropathy, glomerulosclerosis, glomerulonephritis, nephrotic syndrome, polycystic kidney disease, diabetes, metabolic syndrome, insulin resistance, sleep apnea, obstructive sleep apnea, muscular dystrophy, cirrhosis, non-alcoholic fatty liver disease, kidney disease, diabetic nephropathy, or stroke.

[0528] The terms "pharmaceutically acceptable salt" or "pharmaceutically acceptable carrier" refer to a salt comprising an active compound, prepared using a relatively non-toxic acid or base, depending on the specific substituents present on the compound described herein. When the compounds of the present invention contain relatively acidic functional groups, a base addition salt can be obtained by contacting these compounds in their neutral form with a sufficient amount of a desired base, which may be pure or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts, or similar salts. When the compounds of the present invention contain relatively basic functional groups, an acid addition salt can be obtained by contacting these compounds in their neutral form with a sufficient amount of a desired acid, which may be pure or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, or phosphorous acid, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, succinic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid. Also included are amino acid salts such as arginine salts, and organic acid salts such as glucuronic acid or galacturonic acid (see, for example, Berge et al., Journal of Pharmaceutical Science 66:1-19 (1977)). Certain specific compounds of the present invention contain basic and acidic functional groups, which allow the compounds to be converted into basic addition salts or acid addition salts. Other pharmaceutically acceptable carriers known to those skilled in the art are applicable to this disclosure.

[0529] The neutral form of the compound can be re-obtained by contacting the salt with a base or acid and separating the parent compound in a conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but for the purposes of this disclosure, the salt and the parent form of the compound are equivalent.

[0530] In addition to the salt form, the present invention also provides compounds in prodrug form. The prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Furthermore, the prodrugs can be converted into the compounds of the present invention in an in vitro environment by chemical or biochemical methods. For example, when the prodrug is placed in a transdermal patch container containing suitable enzymes or chemical reagents, the prodrug can be slowly converted into the compounds of the present invention.

[0531] Some compounds of this disclosure may exist in both solvated and hydrated forms, including hydrated forms. Generally, the solvated form is equivalent to the non-solvated form and is intended to be included within the scope of this disclosure. Some compounds of this disclosure may exist in a variety of crystalline or amorphous forms. Generally, all physical forms are equivalent to the uses contemplated in this disclosure and are intended to fall within the scope of this disclosure.

[0532] This disclosure also provides pharmaceutical compositions comprising an effective amount of the compound described herein and a pharmaceutically acceptable carrier. In embodiments, the Formula I compound is administered to a subject using a pharmaceutically acceptable formulation, for example, after administration of the pharmaceutically acceptable formulation to the subject, the pharmaceutically acceptable formulation continuously delivers 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.

[0533] The actual dose level and administration time of the active ingredient in the pharmaceutical composition disclosed herein can be altered to obtain an effective amount of the active ingredient that achieves the desired therapeutic response for a specific patient, composition, and route of administration, and is non-toxic (or unacceptably toxic) to the patient.

[0534] In use, at least one compound according to the invention is administered to the recipient in an effective amount in a drug carrier via intravenous, intramuscular, subcutaneous, or intraventricular injection, or via oral or topical administration. According to this disclosure, the compounds of this disclosure can be administered alone or in combination with a second, different therapeutic agent. "In combination with" means administered substantially simultaneously or sequentially together. In one embodiment, the compounds of this disclosure are administered acutely. Thus, the compounds of the invention can be administered for short-term treatment, for example, for a duration of about one day to about one week. In another embodiment, the compounds of this disclosure can be administered for a longer period to improve chronic conditions, for example, depending on the duration of the condition to be treated, from about one week to several months.

[0535] As used herein, "effective amount" refers to the amount of the disclosed compound that, within a reasonable medical judgment, is high enough to significantly and positively alter the condition to be treated, but low enough to avoid serious side effects (in a reasonable benefit / risk ratio). The effective amount of the disclosed compound 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 concomitant treatments, and the specific compound used. For example, the therapeutically effective amount of the disclosed compound administered to a child or newborn will be proportionally reduced based on reasonable medical judgment. Therefore, the effective amount of the disclosed compound will be the minimum amount to provide the desired effect.

[0536] A decisive practical advantage of this disclosure is that the compounds can be conveniently administered, for example by intravenous, intramuscular, subcutaneous, oral, or intraventricular injection, or by topical application, for example, in the form of creams or gels. Depending on the route of administration, it may be necessary to coat the active ingredient containing the compounds of this disclosure in a material to protect the compound from enzymes, acids, and other natural conditions that could inactivate the compound. For administration of the compounds of the invention by means other than parenteral administration, the compound may be coated with or co-administered with a deactivating material.

[0537] This compound can be administered parenterally or intraperitoneally. It can also be prepared as a dispersant, for example, in glycerol, liquid polyethylene glycol and mixtures thereof, as well as in oils.

[0538] Some examples of substances that can be used as drug carriers are sugars, such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth gum; malt; gelatin; talc; stearic acid; magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and cocoa butter; polyols, such as propylene glycol, glycerol, sorbitol, mannitol, and polyethylene glycol; agar; alginic acid; pyrogen-free water; isotonic saline; and phosphate buffer solutions; skim milk powder; and other non-toxic compatible substances used in pharmaceutical formulations, such as vitamin C, estrogens, and echinacea. Wetting agents and lubricants, such as sodium dodecyl sulfate, as well as colorants, flavoring agents, lubricants, excipients, tableting agents, stabilizers, antioxidants, and preservatives may also be present. Solubilizers, including, for example, cremaphore and β-cyclodextrin, may also be used in the pharmaceutical compositions described herein.

[0539] Pharmaceutical compositions comprising the active compound (or its prodrug) of this disclosure can be prepared by conventional methods of mixing, dissolving, granulating, saccharifying, grinding, emulsifying, encapsulating, embedding, or lyophilizing. The compositions can be formulated in a conventional manner using one or more physiologically acceptable carriers, diluents, excipients, or adjuvants that facilitate the processing of the active compound into a pharmaceutically usable formulation.

[0540] The pharmaceutical compositions of this disclosure can be in forms suitable for virtually any route of administration, including, for example, local administration, ocular administration, oral administration, oral administration, systemic administration, nasal administration, injection administration, transdermal administration, rectal administration, vaginal administration, etc., or in forms suitable for administration by inhalation or blowing.

[0541] For topical administration, the active compound or prodrug can be formulated into solutions, gels, ointments, creams, suspensions, etc.

[0542] Systemic formulations include those designed for administration by injection, such as subcutaneous, intravenous, intramuscular, intrathecal, or intraperitoneal injection, as well as those designed for administration via the skin, mucosa, mouth, or respiratory tract.

[0543] Useful injectable formulations include sterile suspensions, solutions, or emulsions of active compounds in aqueous or oily carriers. The composition may also contain formulations such as suspending agents, stabilizers, and / or dispersants. Injectable formulations may be available in unit dosage forms (e.g., ampoules or multi-dose containers) and may contain added preservatives.

[0544] Alternatively, the injectable formulation may be provided in powder form for reconstitution with a suitable carrier prior to use, including but not limited to sterile pyrogen-free water, buffer solutions, dextrose solutions, etc. For this purpose, the active compound may be dried using any technique known in the art, such as lyophilization, and reconstituted prior to use.

[0545] For transmucosal drug delivery, a penetrant suitable for the barrier to be penetrated is used in the formulation. Such penetrants are known in the art.

[0546] For oral administration, the pharmaceutical composition may be in the form of lozenges, tablets, or capsules prepared by conventional methods with pharmaceutically acceptable excipients, such as binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone, or hydroxypropyl methylcellulose); 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 glycolate); or wetting agents (e.g., sodium dodecyl sulfate). Tablets may be coated using methods well known in the art, such as sugar coating or enteric coating.

[0547] Liquid formulations intended for oral administration may take the form of, for example, elixirs, solutions, syrups, or suspensions, or they may exist as dry products for reconstitution with water or other suitable carriers prior to use. These liquid formulations may be prepared using conventional methods with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives, or hydrogenated edible fats); emulsifiers (e.g., lecithin or gum arabic); non-aqueous carriers (e.g., almond oil, oily esters, ethanol, or graded vegetable oils); and preservatives (e.g., methylparaben, propylparaben, or sorbic acid). The formulations may also suitably contain buffer salts, preservatives, flavoring agents, coloring agents, and sweeteners.

[0548] As is well known, oral formulations can be appropriately formulated to provide controlled release of the active compound or prodrug.

[0549] For oral administration, the composition can be in the form of tablets or lozenges formulated in a conventional manner.

[0550] For rectal and vaginal administration, the active compound can be formulated as a solution (for retention enemas), a suppository, or an ointment containing a conventional suppository base such as cocoa butter or other glycerides.

[0551] For nasal administration or administration via inhalation or blowing, the active compound or prodrug can be conveniently delivered as an aerosol spray from a pressurized package or nebulizer using a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, fluorocarbons, carbon dioxide, or other suitable gases. In the case of pressurized aerosols, the dosage unit is determined by a valve that provides the delivery amount. Capsules and cartridges used in inhalers or blowers (e.g., capsules and cartridges made of gelatin) can be formulated into a powder mixture containing the compound and a suitable powder matrix such as lactose or starch.

[0552] Specific examples of aqueous suspension formulations suitable for nasal administration using commercially available nasal spray devices include the following components: an active compound or prodrug (0.5 mg / ml to 20 mg / ml); benzalkonium chloride (0.1 mg / ml to 0.2 mg / ml); polysorbate 80 (TWEEN® 80; 0.5 mg / ml to 5 mg / ml); sodium carboxymethyl cellulose or microcrystalline cellulose (1 mg / ml to 15 mg / ml); phenethyl alcohol (1 mg / ml to 4 mg / ml); and dextrose (20 mg / ml to 50 mg / ml). The final suspension pH can be adjusted to approximately pH 5 to pH 7, with a typical pH of approximately 5.5.

[0553] For ocular administration, the active compound or prodrug can be formulated into solutions, emulsions, suspensions, etc., suitable for ocular application. Various carriers suitable for ocular application of compounds are known in the art. Specific, non-limiting examples are described in U.S. Patent Nos. 6,261,547, 6,197,934, 6,056,950, 5,800,807, 5,776,445, 5,698,219, 5,521,222, 5,403,841, 5,077,033, 4,882,150, and 4,738,851, each of which is incorporated herein by reference in its entirety.

[0554] To prolong delivery, the active compound or prodrug can be formulated into a long-acting formulation for administration via implantation or intramuscular injection. The active ingredient can be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion-exchange resins, or as a microsoluble derivative such as a microsoluble salt. Alternatively, a transdermal delivery system can be used, employing an adhesive disc or patch designed to slowly release the active compound for transdermal absorption. For this purpose, a penetration enhancer can be used to facilitate the transdermal penetration of the active compound. Suitable transdermal patches are described in, for example, U.S. Patent Nos. 5,407,713, 5,352,456, 5,332,213, 5,336,168, 5,290,561, 5,254,346, 5,164,189, 5,163,899, 5,088,977, 5,087,240, 5,008,110, and 4,921,475, each of which is incorporated herein by reference in its entirety.

[0555] Alternatively, other drug delivery systems can be used. Liposomes and emulsions are well-known examples of delivery carriers that can be used to deliver active compounds or prodrugs. Certain organic solvents, such as dimethyl sulfoxide (DMSO), can also be used.

[0556] If desired, the pharmaceutical composition may be contained in a packaging or dispenser device, which may contain one or more unit dosage forms containing the active compound. The packaging may include, for example, metal or plastic foil, such as blister packs. The packaging or dispenser device may be accompanied by instructions for use.

[0557] The active compounds or prodrugs or combinations thereof disclosed herein are generally used in amounts that are effective in achieving the desired results, such as amounts that are effective in treating or preventing a specific disease being treated. The compound may be administered therapeutically to obtain a therapeutic benefit or prophylactically to obtain a preventative benefit. A therapeutic benefit is the eradication or improvement of the underlying condition being treated and / or the eradication or improvement of one or more symptoms associated with the underlying condition, resulting in the patient reporting an improvement in feeling or condition, although the patient may still be suffering from the underlying disease. For example, administering a compound to a patient with allergies provides a therapeutic benefit not only in eradicating or improving the underlying allergic reaction but also when the patient reports a reduction in the severity or duration of allergy-related symptoms after exposure to an allergen. As another example, therapeutic benefits for asthma include improved breathing after the onset of an asthma attack, or a reduction in the frequency or severity of asthma attacks. A therapeutic benefit also includes stopping or slowing the progression of the disease, whether or not improvement is achieved.

[0558] For prophylactic administration, the compound may be administered to patients at risk of developing one of the aforementioned diseases. Patients at risk of disease development may be those with characteristics that place them in a designated risk patient group, as defined by appropriate medical professionals or groups. Patients at risk may also be those who are normally or routinely exposed to environments where an underlying disease may occur, which can be treated with administration of a metalloenzyme inhibitor according to this disclosure. In other words, patients at risk are normally or routinely exposed to the disease or pathogenic conditions, or may be acutely exposed for a limited period of time. Alternatively, prophylactic administration may be used to avoid the development of symptoms in patients diagnosed with an underlying condition.

[0559] The amount of compound administered will depend on a variety of factors, including, for example, the specific indication being treated, the route of administration, whether the expected benefit is preventative or therapeutic, the severity of the indication being treated, the patient's age and weight, and the bioavailability of the specific active compound. Determining the effective dose is entirely within the capabilities of those skilled in the art.

[0560] The effective dose can initially be estimated based on in vitro assays. For example, an initial dose can be formulated for animals to achieve or exceed the IC50 concentration of the active compound in circulating blood or serum as measured in in vitro studies. 50 Examples include in vitro fungal MICs or MFCs and other in vitro assays described in the Examples section. Calculating the dose required to achieve such circulating blood or serum concentrations, taking into account the bioavailability of a particular compound, is entirely within the capabilities of a person skilled in the art. For guidance, refer to Fingl & Woodbury, “General Principles,” Goodman and Gilman's The Pharmaceutical Basis of Therapeutics, Chapter 1, pp. 1-46, latest edition, Pagamonon Press, and the references cited therein, which are incorporated herein by reference.

[0561] The initial dose can also be estimated based on in vivo data, such as animal models. Animal models used to test the efficacy of compounds in treating or preventing the aforementioned diseases are well known in the art.

[0562] Dosage is typically from about 0.0001 mg / kg / day or 0.001 mg / kg / day or 0.01 mg / kg / day to about 100 mg / kg / day, but can be higher or lower, depending in particular on the following factors: the activity of the compound, its bioavailability, the route of administration, and the various factors mentioned above. Dosage and intervals can be adjusted individually to provide plasma levels of the compound sufficient to maintain a therapeutic or preventative effect. In the case of local administration or selective uptake, such as local administration, the effective local concentration of the active compound may be independent of plasma concentration. Technicians will be able to optimize the effective local dose without excessive experimentation.

[0563] The compound can be administered once a day, several times a day, or even multiple times a day, depending on the indications being treated and the judgment of the prescribing physician.

[0564] Preferably, the compound will provide therapeutic or preventative benefits without causing substantial toxicity. The toxicity of the compound can be determined using standard pharmaceutical methods. The dose ratio between toxicity and therapeutic (or preventative) effect is the therapeutic index. Compounds with a high therapeutic index are preferred.

[0565] In any definition of a variable herein, the listing of chemical groups includes defining the variable as any single group or a combination of the listed groups. The description of embodiments for a variable herein includes that embodiment as any single embodiment, or a combination of that embodiment with any other embodiment or part thereof. The description of embodiments herein includes that embodiment as any single embodiment, or a combination of that embodiment with any other embodiment or part thereof.

[0566] Example

[0567] To provide a more complete understanding of the invention described herein, the following embodiments are presented. The embodiments described in this application are provided to illustrate the compounds, pharmaceutical compositions, and methods provided herein, and should not be construed as limiting their scope in any way.

[0568] General experimental procedures

[0569] The definitions of variables in the scheme structure described herein are equivalent to the definitions of variables in the corresponding positions in the formulas described herein. The example compounds listed in Table 2 were characterized by the HPLC and LCMS methods described in Table 1.

[0570] Table 1. HPLC and LCMS methods

[0571]

[0572] Common abbreviations:

[0573] ACN acetonitrile

[0574] br wide peak

[0575] d double peak

[0576] dd double peak

[0577] dba dibenzylidene acetone

[0578] DIPEA (diisopropylethylamine)

[0579] dppf1,1'-bis(diphenylphosphine)ferrocene

[0580] h hours

[0581] HRMS high-resolution mass spectrometry

[0582] HPLC (High Performance Liquid Chromatography)

[0583] LCMS (Liquid Chromatography and Mass Spectrometry)

[0584] MS mass spectrometry

[0585] MW microwave

[0586] m multiplet

[0587] min minutes

[0588] mL / ml

[0589] m / z mass-to-charge ratio

[0590] NMR nuclear magnetic resonance

[0591] ppm (parts per million)

[0592] rt or RT room temperature

[0593] s single peak

[0594] triple peak

[0595] TLC (Thin-Layer Chromatography)

[0596] Preparation of Int-1

[0597] plan:

[0598]

[0599] N-Cyclopropyl-5-fluoro-2-nitroaniline

[0600] Potassium carbonate (21.7 g, 157.23 mmol) was added to a stirred solution of 2,4-difluoro-1-nitrobenzene (25 g, 157.23 mmol) in potassium fluoride (9.12 g, 157.23 mmol) at room temperature under an inert atmosphere, followed by dropwise addition of cyclopropylamine (10.75 g, 188.68 mmol). The reaction mixture was stirred at room temperature for 2 h. After confirming the consumption of the starting material by thin-layer chromatography (TLC), 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 Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 5% EtOAc / hexane) to give N-cyclopropyl-5-fluoro-2-nitrobenzene (26 g, 132.65 mmol, 84%) as a yellow solid.

[0601] N 1 -Cyclopropyl-5-fluorobenzene-1,2-diamine (Int-1)

[0602] At room temperature and under an inert atmosphere, 10% Pd / C (50% wet basis, 2.4 g) was added to a stirred methanol (MeOH) (300 mL) solution of N-cyclopropyl-5-fluoro-2-nitroaniline (24 g, 122.45 mmol) on a 500 mL basis. The reaction mixture was stirred for 8 h at room temperature and under a hydrogen atmosphere (balloon pressure). After the starting material was consumed (as monitored by TLC), the reaction mixture was filtered through a diatomaceous earth pad and washed with methanol (100 mL). The filtrate was concentrated under reduced pressure to give N as a brown slurry. 1 -Cyclopropyl-5-fluorobenzene-1,2-diamineInt-1 (18g, 108.43mmol, 88%).

[0603] LC-MS: at 1.64 RT, m / z 166.8 [M+H] + (Purity 72.46%).

[0604] Preparation of Int-2

[0605] plan:

[0606]

[0607] (5-(1-Cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methanol

[0608] Sodium borohydride (152 mg, 4.01 mmol) was added 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 methanol / tetrahydrofuran (THF) (2:1, 15 mL) under an inert atmosphere at 0 °C. The reaction mixture was gradually warmed to room temperature and stirred for 4 h. After the starting material was consumed (as monitored by TLC), the reaction mixture was concentrated under reduced pressure. The mixture was diluted with water (25 mL) and extracted with EtOAc (2 × 40 mL). The combined organic extracts were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to give 5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-yl)methanol (130 mg, 0.46 mmol, 57%) as a brown solid, which could be used in the next step without further purification.

[0609] LC-MS: at 1.94 RT, m / z 284.9 [M+H] + (Purity 72.20%).

[0610] 5-(1-Cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-carboxaldehyde (Int-2)

[0611] At 0 °C and under an inert atmosphere, Dess-Martin reagent (DMP) (291 mg, 0.69 mmol) was added to a stirred solution of (130 mg, 0.46 mmol) in 10 mL of CH₂Cl₂. 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 terminated with 20 mL of saturated sodium bicarbonate solution and extracted with CH₂Cl₂ (2 × 20 mL). The combined organic extracts were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude substance was purified by silica gel column chromatography (elution buffer: 50% EtOAc / hexane) to obtain 5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-carboxaldehyde Int-2 (50 mg, 0.18 mmol, 39%) as a brown solid.

[0612] LC-MS: at 1.85 RT, m / z 282.9 [M+H] + (Purity 90.42%).

[0613] Preparation of Int-3

[0614] plan:

[0615]

[0616] (E)-5-(1-Cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-carboxaldehyde oxime

[0617] At room temperature and under an inert atmosphere, hydroxylamine hydrochloride (49 mg, 0.71 mmol) and potassium carbonate (98 mg, 0.71 mmol) were added to a stirred solution of 5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-carboxaldehyde Int-2 (100 mg, 0.35 mmol) in ethanol (EtOH) (2 mL). The reaction mixture was heated to 80 °C and stirred for 3 h. After the starting material was consumed (as monitored by TLC), the reaction mixture was concentrated under reduced pressure. The residue was diluted with water (40 mL) and stirred for 10 min. The precipitated solid was filtered, washed with water (10 mL), and dried under vacuum to give (E)-5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-carboxaldehyde oxime (70 mg, 0.23 mmol, 67%) as a grayish-white solid.

[0618] .

[0619] LC-MS: at 1.95 RT, m / z 297.9 [M+H] + (Purity 99.11%).

[0620] (5-(1-Cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methylamine(Int-3)

[0621] At room temperature and under an inert atmosphere, 10% Pd / C (50% wet basis, 25 mg) was added to a stirred ethanol (5 mL) solution of (E)-5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-carboxaldehyde oxime (70 mg, 0.23 mmol). The reaction mixture was evacuated and stirred for 5 h at room temperature and under a hydrogen atmosphere (balloon pressure). After the starting material was consumed (monitored by TCL), the reaction mixture was filtered through a diatomaceous earth pad and washed with MeOH / CH2Cl2 (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)methylamine Int-3 (50 mg, crude) as a grayish-white solid, which could be used in the next step without further purification.

[0622] LC-MS: at 1.62 RT, m / z 283.9 [M+H] + (Purity 64.40%).

[0623] Preparation of Int-4

[0624] plan:

[0625]

[0626] 3-(Ethylamino)-4-nitrobenzene

[0627] Potassium carbonate (3.32 g, 24.09 mmol) and ethylamine (70% aqueous solution, 2.17 g, 48.19 mmol) were added to a stirred solution of 3-fluoro-4-nitrobenzene (2 g, 12.05 mmol) in CH₂Cl₂ (250 mL) at room temperature and under an inert atmosphere. The reaction mixture was stirred at room temperature for 6 h. After the starting material was consumed (as monitored by TLC), the reaction mixture was stopped with water (60 mL) and extracted with EtOAc (2 × 60 mL). The combined organic extracts were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to give 3-(ethylamino)-4-nitrobenzene (1.9 g, crude) as a yellow solid, which could be used in the next step without further purification.

[0628]

[0629] LC-MS: at 4.10 RT, m / z 192.1 [M+H] + (Purity 98.96%).

[0630] 4-Amino-3-(ethylamino)benzonitrile (Int-4)

[0631] 10% Pd / C (50% wet basis, 190 mg) was added to a stirred ethanol (20 mL) solution of 1.9 g crude 3-(ethylamino)-4-nitrobenzene at room temperature and under an inert atmosphere. The reaction mixture was stirred for 5 h at room temperature and under a hydrogen atmosphere (balloon pressure). After the starting material was consumed (as monitored by TLC), the reaction mixture was filtered through a diatomaceous earth pad and washed with methanol (50 mL) and EtOAc (30 mL). The filtrate was concentrated under reduced pressure to give 4-amino-3-(ethylamino)benzonenitrile Int-4 (1.5 g crude) as a grayish-white solid, which could be used in the next step without further purification.

[0632] LC-MS: at 2.11 RT, m / z 161.9 [M+H] + (Purity 60.88%).

[0633] Preparation of Int-5

[0634] plan:

[0635]

[0636] N-Cyclopropyl-4,5-Difluoro-2-nitroaniline

[0637] Under an inert atmosphere, potassium carbonate (390 mg, 2.82 mmol) was added to potassium fluoride (164 mg, 2.82 mmol) containing 1,2,4-trifluoro-5-nitrobenzene (500 mg, 2.82 mmol), followed by dropwise addition of cyclopropylamine (0.23 mL, 3.39 mmol). The reaction mixture was stirred at 0 °C for 30 min. After the starting material was consumed (as monitored 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 Na₂SO₄ and concentrated under reduced pressure to give N-cyclopropyl-4,5-difluoro-2-nitrobenzylamine 2 (320 mg, crude) as a pale yellow solid, which could be used in the next step without further purification.

[0638] LC-MS: at 4.43 RT, m / z 215.4 [M+H] + (Purity 69.03%).

[0639] N 1 -Cyclopropyl-4,5-difluorobenzene-1,2-diamine (Int-5)

[0640] At room temperature and under an inert atmosphere, 10% Pd / C (50% wet basis, 30 mg) was added to a stirred solution of N-cyclopropyl-4,5-difluoro-2-nitroaniline (300 mg, 1.4 mmol) in 10 mL of EtOAc. The reaction mixture was stirred for 4 h at room temperature and under a hydrogen atmosphere (balloon pressure). After the starting material was consumed (as monitored by TLC), the reaction mixture was filtered through a diatomaceous earth pad and washed with methanol (15 mL) and EtOAc (10 mL). The filtrate was concentrated under reduced pressure to give N as a brown viscous paste. 1 -Cyclopropyl-4,5-difluorobenzene-1,2-diamineInt-5 (100 mg, crude) can be used in the next step without further purification.

[0641] LC-MS: at 2.12 RT, m / z 184.9 [M+H] + (Purity 83.53%).

[0642] Preparation of Int-6 and Int-7

[0643] plan:

[0644]

[0645] 3-(cyclopropylamino)-4-nitrobenzene

[0646] At room temperature and under an inert atmosphere, potassium carbonate (1.66 g, 12.05 mmol) was added to a stirred solution of 3-fluoro-4-nitrobenzene (1 g, 6.02 mmol) in CH₂Cl₂ (5 mL), followed by dropwise addition of cyclopropylamine (3.33 mL, 48.19 mmol). The reaction mixture was stirred at room temperature for 4 h. After the starting material was consumed (as monitored 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 Na₂SO₄ and concentrated under reduced pressure to give 3-(cyclopropylamino)-4-nitrobenzene (900 mg, crude) as a yellow solid, which could be used in the next step without further purification.

[0647]

[0648] LC-MS: at 3.25 RT, m / z 201.9 [MH] + (Purity 99.61%).

[0649] 4-Amino-3-(cyclopropylamino)benzonitrile (Int-6)

[0650] At room temperature and under an inert atmosphere, 10% Pd / C (50% wet basis, 500 mg) was added to a stirred ethanol (10 mL) solution of 3-(cyclopropylamino)-4-nitrobenzene (900 mg, 4.43 mmol). The reaction mixture was stirred for 5 h at room temperature and under a hydrogen atmosphere (balloon pressure). After the starting material was consumed (monitored by TLC), the reaction mixture was filtered through a diatomaceous earth pad and washed with EtOAc (30 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 20% EtOAc / hexane) to give 4-amino-3-(cyclopropylamino)benzonenitrile Int-6 (500 mg, 2.89 mmol, 65%) as a grayish-white solid.

[0651]

[0652] 1-Cyclopropyl-1H-benzo[d]imidazol-6-carboxynitrile (Int-7)

[0653] Under an inert atmosphere, a solution of 4-amino-3-(cyclopropylamino)benzonitrile Int-6 (500 mg, 2.89 mmol) in formic acid (5 mL) was heated to reflux and stirred for 5 h. After the feed was consumed (monitored by TLC), 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 ethyl acetate (2 × 30 mL). The combined organic extracts were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 50% EtOAc / hexane) to give 1-cyclopropyl-1H-benzo[d]imidazolium-6-carboxynitrile Int-7 (250 mg, 1.37 mmol, 56%) as a grayish-white solid.

[0654]

[0655] LC-MS: at 2.46 RT, m / z 184.0 [M+H] + (Purity 87.33%).

[0656] Preparation of Int-8

[0657] plan:

[0658]

[0659] 6-Chloro-N-cyclopropyl-3-nitropyridine-2-amine

[0660] Cyclopropylamine (3.7 mL, 52.08 mmol) was added to a stirred solution of 2,6-dichloro-3-nitropyridine (5 g, 26.04 mmol) in toluene (25 mL) under an inert atmosphere at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was then warmed to room temperature and stirred for 2 h. After the starting material was consumed (monitored 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 Na₂SO₄, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 10% EtOAc / hexane) to give 6-chloro-N-cyclopropyl-3-nitropyridine-2-amine (4 g, 18.77 mmol, 72%) as a pale yellow solid.

[0661]

[0662] 6-Chloro-N 2 -Cyclopropylpyridine-2,3-diamine (Int-8)

[0663] Iron (1.3 g, 23.47 mmol) and ammonium chloride (1.2 g, 23.47 mmol) were added to a stirred EtOH:water (1:1, 10 mL) solution of 6-chloro-N-cyclopropyl-3-nitropyridine-2-amine (1 g, 4.69 mmol) at room temperature and under an inert atmosphere. The reaction mixture was heated at 80 °C for 1 h. After the starting material was consumed (as monitored 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 Na₂SO₄, and concentrated under reduced pressure to give 6-chloro-N-cyclopropyl-3-nitropyridine-2-amine as a pale yellow solid. 2 -Cyclopropylpyridine-2,3-diamineInt-8 (700 mg, crude) can be used in the next step without further purification.

[0664] LC-MS: at 2.07 RT, m / z 183.9 [M+H] + (Purity 58.13%).

[0665] Preparation of Int-9

[0666] plan:

[0667]

[0668] N-Cyclopropyl-6-methoxy-3-nitropyridine-2-amine

[0669] Cyclopropylamine (3.69 mL, 53 mmol) was added to a stirred solution of 2-chloro-6-methoxy-3-nitropyridine (5 g, 26.5 mmol) in toluene (50 mL) under an inert atmosphere at 0 °C. The reaction mixture was stirred at 0 °C for 1 h and then warmed to room temperature and stirred for 6 h. After the starting material was consumed (as monitored 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 Na₂SO₄, and concentrated under reduced pressure. The crude product was ground with n-pentane to give N-cyclopropyl-6-methoxy-3-nitropyridine-2-amine (800 mg, 3.82 mmol, 83%) as a yellow solid.

[0670] N 2 -Cyclopropyl-6-methoxypyridine-2,3-diamine (Int-9)

[0671] At room temperature, iron powder (1.3 g, 24 mmol) and ammonium chloride (1.29 g, 23.9 mmol) were added to a stirred ethanol / water (1:1, 10 mL) solution of N-cyclopropyl-6-methoxy-3-nitropyridine-2-amine (1 g, 4.78 mmol). The reaction mixture was heated to 80 °C and maintained for 1 h. After the raw materials were consumed (monitored by TLC), the reaction mixture was filtered through a diatomaceous earth bed and the bed was washed with EtOAc (50 mL). The filtrate was concentrated under reduced pressure to give N as a black liquid. 2 -Cyclopropyl-6-methoxypyridine-2,3-diamineInt-9 (150 mg). The crude product can be used in the next step without further purification.

[0672]

[0673] LC-MS: at 2.11 RT, m / z 180.1 [M+H] + (Purity 75.36%)

[0674] Preparation of Int-10

[0675] plan:

[0676]

[0677] N-Ethyl-4,5-difluoro-2-nitroaniline

[0678] Potassium carbonate (3.1 g, 22.59 mmol) and ethylamine (559 mg, 12.42 mmol) were added to a stirred solution of 1,2,4-trifluoro-5-nitrobenzene (2 g, 11.29 mmol) in CH₂Cl₂ (10 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 h. After the starting material was consumed (monitored by TLC), the reaction mixture was diluted with water (100 mL) and extracted with CH₂Cl₂ (2 × 100 mL). The combined organic extracts were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (elution: 10% EtOAc / hexane) to give N-ethyl-4,5-difluoro-2-nitrobenzene (800 mg, 3.96 mmol, 35%) as a yellow solid.

[0679]

[0680] LC-MS: at 3.53 RT, m / z 203.1 [M+H] + (Purity 98.40%)

[0681] N 11-Ethyl-4,5-difluorophenyl-1,2-diamine (Int-10)

[0682] At room temperature and under an inert atmosphere, 10% Pd / C (500 mg, 500 mg, 50% wet basis) was added to a stirred solution of N-ethyl-4,5-difluoro-2-nitroaniline (800 mg, 3.96 mmol) in ethyl acetate (5 mL). The reaction mixture was stirred for 16 h at room temperature and under a hydrogen atmosphere (balloon pressure). After the feed was consumed (monitored by TLC), the reaction mixture was filtered through a diatomaceous earth bed and the bed was washed with EtOAc (50 mL). The filtrate was concentrated under reduced pressure to give N-ethyl-4,5-difluoro-2-nitroaniline as a black liquid. 1 -Ethyl-4,5-difluorophenyl-1,2-diamine Int-10 (500 mg, 2.90 mmol, 73%) can be used in the next step without further purification.

[0683]

[0684] LC-MS: m / z 173.2 [M+H] at 3.16 RT + (Purity 64.65%)

[0685] Preparation of Int-11

[0686] plan:

[0687]

[0688] 6-Chloro-N-ethyl-3-nitropyridine-2-amine

[0689] Ethylamine (1.35 mL) was added to a stirred solution of 2,6-dichloro-3-nitropyridine (2 g, 10.40 mmol) in toluene (8.5 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 (monitored 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 anhydrous Na₂SO₄, dried, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 2% EtOAc / hexane) to give 6-chloro-N-ethyl-3-nitropyridine-2-amine (800 mg, 3.98 mmol, 38%) as a yellow solid.

[0690]

[0691] LC-MS: m / z 202 [M+H] at 2.63 RT + (Purity 99.85%)

[0692] 6-Chloro-N2 -Ethylpyridine-2,3-diamine (Int-11)

[0693] At room temperature, iron powder (763.4 g, 13.68 mmol) and ammonium chloride (738.7 mg, 13.68 mmol) were added to a stirred ethanol / water (1:1, 20 mL) solution of 6-chloro-N-ethyl-3-nitropyridine-2-amine (550 mg, 2.73 mmol) (1:1, 20 mL). The reaction mixture was heated at 80 °C for 1 h. The 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 Na₂SO₄, and concentrated under reduced pressure to give 6-chloro-N-ethyl-3-nitropyridine-2-amine as a black solid. 2 -Ethylpyridine-2,3-diamine Int-11 (452 ​​mg). The crude product can be used in the next step without further purification.

[0694]

[0695] LC-MS: at 1.72 RT, m / z 172 [M+H] + (Purity 85.88%)

[0696] Preparation of Int-12

[0697] plan:

[0698]

[0699] 4,5-Difluoro-2-nitroaniline

[0700] At 0 °C and under an inert atmosphere, 15 mL of methanolic ammonia was added to a stirred methanolic ammonia solution of 1,2,4-trifluoro-5-nitrobenzene (5 g, 28.24 mmol) in 5 mL. The reaction mixture was heated to 90 °C and stirred for 2 h in a sealed tube. After the starting material was consumed (monitored by TLC), the reaction mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 2% EtOAc / hexane) to give 4,5-difluoro-2-nitrobenzylamine (800 mg, 4.59 mmol, 16%) as a pale yellow solid.

[0701]

[0702] LC-MS: at 2.49 RT, m / z 172.8 [MH] - (Purity 88.25%).

[0703] 4,5-Difluorobenzene-1,2-diamine (Int-12)

[0704] 10% Pd / C (50% wet basis, 200 mg) was added to a stirred methanol (15 mL) solution of 4,5-difluoro-2-nitroaniline (800 mg, 4.59 mmol) at room temperature and under an inert atmosphere. The reaction mixture was stirred for 3 h at room temperature under a hydrogen atmosphere (balloon pressure). After the starting material was consumed (as monitored by TLC), the reaction mixture was filtered through a diatomaceous earth pad and washed with methanol (15 mL) and CH2Cl2 (10 mL). The filtrate was concentrated under reduced pressure. The crude product was washed with n-hexane (15 mL) to give 4,5-difluorophenyl-1,2-diamine Int-12 (500 mg, 3.47 mmol, 80%) as a black solid.

[0705]

[0706] LC-MS: at 1.59 RT, m / z 145 [M+H] + (Purity 75.16%)

[0707] Preparation of Int-13

[0708] plan:

[0709]

[0710] 5-Chloro-N-cyclopropyl-3-nitropyridine-2-amine

[0711] At 0°C and under an inert atmosphere, the mixture is stirred... Cyclopropylamine (0.73 mL, 10.47 mmol) was added to a toluene (10 mL) solution of 2,5-dichloro-3-nitropyridine (1 g, 5.23 mmol). The reaction mixture was stirred at room temperature for 48 h. After the starting material was consumed (as monitored 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 Na₂SO₄ and concentrated under reduced pressure to give 5-chloro-N-cyclopropyl-3-nitropyridine-2-amine (700 mg, 3.28 mmol, 63%) as an orange solid.

[0712]

[0713] LC-MS: at 3.03 RT, m / z 214 [M+H] + (Purity 98.66%)

[0714] 5-Chloro-N 2-Cyclopropylpyridine-2,3-diamine (Int-13)

[0715] At room temperature, iron powder (262 mg, 4.69 mmol) and ammonium chloride (253 mg, 4.69 mmol) were added to a stirred ethanol / water (1:1, 20 mL) solution of 5-chloro-N-cyclopropyl-3-nitropyridine-2-amine (200 mg, 0.938 mmol) (1:1, 20 mL). The reaction mixture was heated to 80 °C and stirred for 3 h. After the starting material was consumed (monitored by TLC), the reaction mixture was filtered through a diatomaceous earth mat 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-cyclopropyl-3-nitropyridine-2-amine as a black solid. 2 -Cyclopropylpyridine-2,3-diamineInt-13 (120 mg). The crude product can be used in the next step without further purification.

[0716]

[0717] LC-MS: at 1.87 RT, m / z 183.9 [M+H] + (Purity 88.05%)

[0718] Preparation of Int-14

[0719] plan:

[0720]

[0721] N-Cyclopropyl-2-fluoro-6-nitroaniline

[0722] Cyclopropylamine (0.13 mL, 1.89 mmol) was added to a stirred ethanol (2 mL) solution of 1,2-difluoro-3-nitrobenzene (200 mg, 1.26 mmol) at room temperature and under an inert atmosphere, and the mixture was stirred for 16 h. After the starting material was consumed (monitored 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 Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 5% EtOAc / hexane) to give N-cyclopropyl-2-fluoro-6-nitrobenzene (200 mg, 1.02 mmol, 81%) as a yellow viscous paste.

[0723]

[0724] LC-MS: at 3.28 RT, m / z 197.0 [M+H] + (Purity 99.89%)

[0725] N 1 -Cyclopropyl-6-fluorobenzene-1,2-diamine (Int-14)

[0726] At room temperature and under an inert atmosphere, 10% Pd / C (50% wet basis, 30 mg) was added to a stirred solution of N-cyclopropyl-2-fluoro-6-nitroaniline (200 mg, 1.02 mmol) in ethyl acetate (5 mL). The reaction mixture was stirred at room temperature and under a hydrogen atmosphere (balloon pressure) for 4 h. After the feed was consumed (monitored by TLC), the reaction mixture was filtered through a diatomaceous earth bed and the bed was washed with EtOAc (15 mL). The filtrate was concentrated under reduced pressure to give N as a colorless, viscous slurry. 1 -Cyclopropyl-6-fluorobenzene-1,2-diamineInt-14 (160 mg). The crude product can be used in the next step without further purification.

[0727]

[0728] Preparation of Int-15

[0729] plan:

[0730]

[0731] 4,5-Difluoro-N-methyl-2-nitroaniline

[0732] Methylamine (2M, 28.25 mL, 56.5 mmol) was added dropwise to a stirred solution of 1,2,4-trifluoro-5-nitrobenzene (5 g, 28.25 mmol) in THF (50 mL) at -20 °C under an inert atmosphere, and the mixture was stirred for 2 h at the same temperature. After the starting material was consumed (monitored by TLC), the reaction mixture was terminated with brine (50 mL) and extracted with EtOAc (2 × 100 mL). The combined organic extracts were dried over anhydrous Na₂SO₄ 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-nitrobenzylamine (1.1 g, 5.85 mmol, 20%) as a pale yellow solid.

[0733]

[0734] 4,5-Difluoro-N 1 1,2-Methylbenzene-1,2-diamine (Int-15)

[0735] 10% Pd / C (50% wet basis, 250 mg) was added to a stirred solution of 4,5-difluoro-N-methyl-2-nitroaniline (1 g, 5.32 mmol) in ethyl acetate (15 mL) at room temperature and under an inert atmosphere. The reaction mixture was stirred for 3 h at room temperature and under a hydrogen atmosphere (balloon pressure). After the feed was consumed (as monitored by TLC), the reaction mixture was filtered through a diatomaceous earth bed 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 as a brown slurry. 1 1,2-Methylbenzene-1,2-diamine Int-15 (700 mg). The crude product can be used in the next step without further purification.

[0736]

[0737] LC-MS: at 2.20 RT, m / z 158.8 [M+H] + (Purity 99.55%)

[0738] Preparation of Int-16

[0739] plan:

[0740]

[0741] 4,5-Difluoro-2-nitro-N-propylaniline

[0742] At room temperature and under an inert atmosphere, potassium carbonate (5.07 g, 36.72 mmol) and 1-aminopropane (3.48 mL, 42.37 mmol) were added dropwise to a stirred solution of 1,2,4-trifluoro-5-nitrobenzene (5 g, 28.25 mmol) in THF (150 mL) and stirred for 16 h. After the starting material was consumed (monitored 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 Na₂SO₄ 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.

[0743]

[0744] 4,5-Difluoro-N 1 1,2-Propylphenyl-1,2-diamine (Int-16)

[0745] At room temperature and under an inert atmosphere, 10% Pd / C (50% wet basis, 150 mg) was added to a stirred solution of 4,5-difluoro-2-nitro-N-propylaniline (500 mg, 2.31 mmol) in ethyl acetate (10 mL). The reaction mixture was stirred at room temperature and under a hydrogen atmosphere (balloon pressure) for 4 h. After the feed was consumed (monitored by TLC), the reaction mixture was filtered through a diatomaceous earth bed and the bed was washed with methanol (20 mL). The filtrate was concentrated under reduced pressure to give 4,5-difluoro-N-propylaniline as a brown slurry. 1 -Propylphenyl-1,2-diamine Int-16 (350 mg). The crude product can be used in the next step without further purification.

[0746]

[0747] LC-MS: at 2.88 RT, m / z 186.9 [M+H] + (Purity 89.94%)

[0748] Preparation of Int-17

[0749] plan:

[0750]

[0751] 3-(cyclopropylamino)-4-nitrophenol

[0752] Cyclopropylamine (726 mg, 12.74 mmol) was added to a stirred THF solution of 3-fluoro-4-nitrophenol (1 g, 6.37 mmol) in a sealed tube under an inert atmosphere. The reaction mixture was heated to 80 °C and stirred for 6 h. After the starting material was consumed (monitored 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 Na₂SO₄ 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.

[0753]

[0754] LC-MS: at 2.51 RT, m / z 194.9 [M+H] + (Purity 99.35%)

[0755] 4-Amino-3-(cyclopropylamino)phenol (Int-17)

[0756] At room temperature and under an inert atmosphere, 10% Pd / C (50% wet basis, 250 mg) was added to a stirred solution of 3-(cyclopropylamino)-4-nitrophenol (1 g, 5.15 mmol) in ethyl acetate (10 mL). The reaction mixture was stirred at room temperature and under a hydrogen atmosphere (balloon pressure) for 4 h. After the starting material was consumed (as monitored by TLC), the reaction mixture was filtered through a diatomaceous earth bed and the bed was washed with methanol (30 mL). The filtrate was concentrated under reduced pressure to give 4-amino-3-(cyclopropylamino)phenol Int-17 (600 mg) as a brown slurry. The crude product could be used in the next step without further purification.

[0757]

[0758] LC-MS: at 1.09 RT, m / z 164.8 [M+H] + (Purity 74.22%)

[0759] Preparation of Int-18

[0760] plan:

[0761]

[0762] N-Cyclopropyl-5-methyl-2-nitroaniline

[0763] Triethylamine (1.35 mL, 9.68 mmol) was added to a stirred solution of 2-fluoro-4-methyl-1-nitrobenzene (500 mg, 3.22 mmol) in THF (5 mL) under an inert atmosphere, followed by the addition of cyclopropylamine (919 mg, 16.13 mmol). The reaction mixture was heated to 60 °C and stirred for 16 h. After the starting material was consumed (monitored 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 Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 5% EtOAc / hexane) to give N-cyclopropyl-5-methyl-2-nitrobenzene (500 mg, 2.6 mmol, 80%) as a yellow solid.

[0764]

[0765] LC-MS: at 3.35 RT, m / z 192.9 [M+H] + (Purity 99.53%).

[0766] N 1 -Cyclopropyl-5-methylphenyl-1,2-diamine (Int-18)

[0767] 10% Pd / C (50% wet basis, 50 mg) was added to a stirred solution of N-cyclopropyl-5-methyl-2-nitroaniline (150 mg, 0.78 mmol) in ethyl acetate (1 mL) at room temperature and under an inert atmosphere. The reaction mixture was stirred for 3 h at room temperature and under a hydrogen atmosphere (balloon pressure). After the feed was consumed (as monitored by TLC), the reaction mixture was filtered through a diatomaceous earth bed and the bed was washed with ethyl acetate (15 mL). The filtrate was concentrated under reduced pressure to give N as a black solid. 1 -Cyclopropyl-5-methylphenyl-1,2-diamine Int-18 (120 mg). The crude product can be used in the next step without further purification.

[0768]

[0769] LC-MS: at 2.49 RT, m / z 162.9 [M+H] + (Purity 81.92%)

[0770] Preparation for Int-19

[0771] plan:

[0772]

[0773] N-Cyclopropyl-2-nitro-5-(trifluoromethyl)aniline

[0774] Potassium carbonate (1.32 g, 9.57 mmol) and cyclopropylamine (1.09 g, 19.14 mmol) were added to a stirred solution of 2-fluoro-1-nitro-4-(trifluoromethyl)benzene (1 g, 4.78 mmol) in CH2Cl2 (40 mL) at 0 °C under an inert atmosphere. The reaction mixture was gradually warmed to room temperature and stirred for 16 h. After the starting material was consumed (monitored by TLC), the reaction mixture was diluted with ice-cold water (30 mL) and extracted with CH2Cl2 (2 × 40 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 5% EtOAc / hexane) to give N-cyclopropyl-2-nitro-5-(trifluoromethyl)aniline (1 g, 4.06 mmol, 85%) as a yellow solid.

[0775]

[0776] LC-MS: at 4.33 RT, m / z 245.0 [MH] - (Purity 78.90%).

[0777] N 1-Cyclopropyl-5-(trifluoromethyl)benzene-1,2-diamine (Int-19)

[0778] At room temperature and under an inert atmosphere, 10% Pd / C (50% wet basis, 100 mg) was added to a stirred methanol (20 mL) solution of N-cyclopropyl-2-nitro-5-(trifluoromethyl)aniline (1 g, 4.06 mmol). The reaction mixture was stirred for 3 h at room temperature and under a hydrogen atmosphere (balloon pressure). After the feed was consumed (monitored by TLC), the reaction mixture was filtered through a diatomaceous earth bed and the bed was washed with methanol (20 mL). The filtrate was concentrated under reduced pressure to give N as a brown slurry. 1 -Cyclopropyl-5-(trifluoromethyl)benzene-1,2-diamineInt-19 (700 mg). The crude product can be used in the next step without further purification.

[0779] Preparation of Int-20

[0780] plan:

[0781]

[0782] N-Cyclopropyl-2,3-Difluoro-6-nitroaniline

[0783] Cyclopropylamine (1.61 g, 28.25 mmol) was added to a stirred solution of 1,2,3-trifluoro-4-nitrobenzene (1 g, 28.25 mmol) in ethanol (100 mL) at room temperature and under an inert atmosphere, and the mixture was stirred for 48 h to allow the reaction to proceed. After the starting material was consumed (monitored 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 Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 5% EtOAc / hexane) to give N-cyclopropyl-2,3-difluoro-6-nitrobenzene (3 g, 14.0 mmol, 50%) as a yellow solid.

[0784]

[0785] LC-MS: at 4.06 RT, m / z 213.4 [MH] + (Purity 99.81%)

[0786] N 1 -Cyclopropyl-5,6-difluorobenzene-1,2-diamine (Int-20)

[0787] At room temperature and under an inert atmosphere, 10% Pd / C (50% wet basis, 100 mg) was added to a stirred solution of N-cyclopropyl-2,3-difluoro-6-nitroaniline (1 g, 4.67 mmol) in ethyl acetate (10 mL). The reaction mixture was stirred for 2 h at room temperature and under a hydrogen atmosphere (balloon pressure). After the feed was consumed (as monitored by TLC), the reaction mixture was filtered through a diatomaceous earth bed and the bed was washed with ethyl acetate (20 mL). The filtrate was concentrated under reduced pressure to give N as a black solid. 1 -Cyclopropyl-5,6-difluorobenzene-1,2-diamine Int-20 (700 mg). The crude product can be used in the next step without further purification.

[0788]

[0789] LC-MS: at 2.60 RT, m / z 185.0 [M+H] + (Purity 67.33%)

[0790] Preparation of Int-21

[0791] plan:

[0792]

[0793] N-Cyclobutyl-4,5-difluoro-2-nitroaniline

[0794] Potassium carbonate (1.17 g, 8.47 mmol) was added to a stirred THF (20 mL) solution of 1,2,4-trifluoro-5-nitrobenzene (1 g, 5.65 mmol) under an inert atmosphere, followed by the addition of cyclobutylamine (0.58 mL, 6.78 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 6 h. After the starting material was consumed (monitored 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 Na₂SO₄ and concentrated under reduced pressure. The solution was obtained by silica gel column chromatography (eluting with 5% EtOAc / hexane) to give N-cyclobutyl-4,5-difluoro-2-nitrobenzene (450 mg, 1.97 mmol, 35%) as a yellow solid.

[0795]

[0796] LC-MS: at 2.90 RT, m / z 229.0 [M+H] + (Purity 97.77%)

[0797] N 1-Cyclobutyl-4,5-difluorobenzene-1,2-diamine (Int-21)

[0798] 10% Pd / C (50% wet basis, 45 mg) was added to a stirred solution of N-cyclobutyl-4,5-difluoro-2-nitroaniline (450 mg, 1.97 mmol) in ethyl acetate (10 mL) at room temperature and under an inert atmosphere. The reaction mixture was stirred for 3 h at room temperature and under a hydrogen atmosphere (balloon pressure). After the feed was consumed (as monitored by TLC), the reaction mixture was filtered through a diatomaceous earth bed and the bed was washed with ethyl acetate (15 mL). The filtrate was concentrated under reduced pressure to give N as a black solid. 1 -Cyclobutyl-4,5-difluorobenzene-1,2-diamineInt-21 (350 mg). This crude substance can be used in the next step without further purification.

[0799]

[0800] LC-MS: at 2.92 RT, m / z 199.0 [M+H] + (Purity 83.44%)

[0801] Preparation of Int-22

[0802] plan:

[0803]

[0804] 4-(cyclopropylamino)-3-nitrobenzene

[0805] Potassium carbonate (1.66 g, 12.05 mmol) was added to a stirred solution of 4-fluoro-3-nitrobenzene (1 g, 6.02 mmol) in CH₂Cl₂ (5 mL) under an inert atmosphere at 0 °C, followed by the dropwise addition of cyclopropylamine (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 (as monitored 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 Na₂SO₄ and concentrated under reduced pressure to give 4-(cyclopropylamino)-3-nitrobenzene (1.1 g) as a yellow solid. The crude product could be used in the next step without further purification.

[0806]

[0807] LC-MS: at 2.88 RT, m / z 202.0 [MH] - (Purity 99.48%).

[0808] 3-Amino-4-(cyclopropylamino)benzonitrile (Int-22)

[0809] 10% Pd / C (50% wet basis, 350 mg) was added to a stirred ethanol (40 mL) solution of 1.1 g crude 4-(cyclopropylamino)-3-nitrobenzene at room temperature and under an inert atmosphere. The reaction mixture was stirred for 3 h at room temperature and under a hydrogen atmosphere (balloon pressure). After the feed was consumed (as monitored by TLC), the reaction mixture was filtered through a diatomaceous earth bed and the bed was washed with ethyl acetate (20 mL). The filtrate was concentrated under reduced pressure to give 900 mg of 3-amino-4-(cyclopropylamino)benzonezene Int-22 as a yellow solid. The crude substance could be used in the next step without further purification.

[0810]

[0811] LC-MS: at 2.40 RT, m / z 173.9 [M+H] + (Purity 84.82%)

[0812] Preparation of Int-23

[0813] plan:

[0814]

[0815] 1-Chloro-2,5-difluoro-4-nitrobenzene

[0816] Potassium carbonate (715 mg, 5.18 mmol) and cyclopropylamine (305 mg, 5.18 mmol) were added to a stirred CH₂Cl₂ (10 mL) solution of 1-chloro-2,5-difluoro-4-nitrobenzene (500 mg, 2.59 mmol) under an inert atmosphere at 0 °C. The reaction mixture was stirred at room temperature for 24 h. After the starting material was consumed (as monitored by TLC), the reaction mixture was diluted with water (20 mL) and extracted with CH₂Cl₂ (2 × 20 mL). The combined organic extracts were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to give 1-chloro-2,5-difluoro-4-nitrobenzene (400 mg, 1.73 mmol, 67%) as a yellow solid.

[0817]

[0818] 5-Chloro-N 1 -Cyclopropyl-4-fluorobenzene-1,2-diamine (Int-23)

[0819] 10% Pd / C (50% wet basis, 100 mg) was added to a stirred EtOAc (10 mL) solution of 1-chloro-2,5-difluoro-4-nitrobenzene (400 mg, 1.74 mmol) at room temperature and under an inert atmosphere. The reaction mixture was evacuated and stirred for 5 h at room temperature and under a hydrogen atmosphere (balloon pressure). After the feed was consumed (monitored by TLC), the reaction mixture was filtered through a diatomaceous earth bed and the bed was washed with EtOAc (40 mL). The filtrate was concentrated under reduced pressure to give 5-chloro-N as a grayish-white solid. 1 -Cyclopropyl-4-fluorobenzene-1,2-diamineInt-23 (280 mg, 1.40 mmol, 81%).

[0820]

[0821] Preparation of Int-24

[0822] plan:

[0823]

[0824] 4-Chloro-N-cyclopropyl-2-nitroaniline

[0825] Cyclopropylamine (2.6 g, 45.71 mmol) was added dropwise to 4-chloro-1-fluoro-2-nitrobenzene (2 g, 11.43 mmol) at 10 °C under an inert atmosphere. The reaction mixture was gradually warmed to room temperature and stirred for 5 h. After the starting material was consumed (monitored 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 Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 3% to 5% EtOAc / hexane) to give 4-chloro-N-cyclopropyl-2-nitrobenzene (2.08 g, 0.98 mmol, 83%) as a yellow solid.

[0826]

[0827] LC-MS: at 2.85 RT, m / z 213.1 [M+H] + (Purity 99.81%)

[0828] 4-Chloro-N 1 -Cyclopropylphenyl-1,2-diamine (Int-24)

[0829] Raney nickel (500 mg) was added to a stirred solution of 4-chloro-N-cyclopropyl-2-nitroaniline (1 g, 4.72 mmol) in methanol-ammonia (2 M, 50 mL) at room temperature and under an inert atmosphere. The reaction mixture was stirred for 4 h at room temperature and under a hydrogen atmosphere (balloon pressure). After the feed was consumed (monitored by TLC), the reaction mixture was filtered through a diatomaceous earth bed 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 as a brown liquid. 1 -Cyclopropylphenyl-1,2-diamine Int-24 (700 mg). The crude product can be used in the next step without further purification.

[0830]

[0831] LC-MS: at 2.15 RT, m / z 183.1 [M+H] + (Purity 87.51%)

[0832] Preparation of Int-25

[0833] plan:

[0834]

[0835] 3-Chloro-N-cyclopropyl-2-nitroaniline

[0836] Cyclopropylamine (0.78 mL, 11.4 mmol) was added dropwise to 1-chloro-3-fluoro-2-nitrobenzene (500 mg, 2.85 mmol) under an inert atmosphere and stirred for 4 h. After the starting material was consumed (monitored 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 Na₂SO₄ and concentrated under reduced pressure to give 3-chloro-N-cyclopropyl-2-nitrobenzylamine (500 mg) as a yellow solid. The crude product could be used in the next step without further purification.

[0837]

[0838] LC-MS: at 2.74 RT, m / z 213.1 [M+H] + (Purity 98.57%)

[0839] 3-Chloro-N 1 -Cyclopropylphenyl-1,2-diamine (Int-25)

[0840] Iron powder (157 mg, 2.83 mmol) was added to a stirred solution of 2 mL of acetic acid containing 200 mg crude 3-chloro-N-cyclopropyl-2-nitroaniline at room temperature and under an inert atmosphere. The reaction mixture was heated to 80 °C and stirred for 1 h. After the starting material was consumed (as monitored by TLC), the reaction mixture was terminated with 20 mL of saturated NaHCO3 solution and extracted with EtOAc (2 × 20 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 3-chloro-N-cyclopropyl-2-nitroaniline as a brown paste. 1 -Cyclopropylphenyl-1,2-diamine Int-25 (200 mg). The crude product can be used in the next step without further purification.

[0841] LC-MS: at 2.47 RT, m / z 183.0 [M+H] + (Purity 43.71%)

[0842] Preparation of Int-26

[0843] plan:

[0844]

[0845] 4-Isopropyl-2-(trifluoromethyl) Azoxyl-5(2H)-one

[0846] Trifluoroacetic anhydride (72 mL) was added dropwise to DL-valine (30 g, 256.41 mmol) at room temperature. The reaction mixture was heated to reflux and stirred for 8 h. After the starting material was consumed (monitored by TLC), the reaction mixture was diluted with water (100 mL) and extracted with CH2Cl2 (250 mL). The combined organic extracts were dried over anhydrous Na2SO4 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 could be used in the next step without further purification.

[0847]

[0848] LC-MS: at 2.94 RT, m / z 193.9 [MH] - (Purity 75.69%).

[0849] Diethyl 2-((4-isopropyl-5-oxo-2-(trifluoromethyl)-2,5-dihydrooxazol-2-yl)methyl)malonate

[0850] Under an inert atmosphere, at 0 °C, diethyl 2-methylenemalonate (47.63 g, crude) and triethylamine (48.2 mL, 346.14 mmol) were added to a stirred solution of 4-isopropyl-2-(trifluoromethyl)oxazol-5(2H)-one (45 g, crude) in CH2Cl2 (450 mL). The reaction mixture was warmed to room temperature and stirred for 16 h. After the starting material was consumed (monitored by TLC), the reaction mixture was diluted with water (150 mL) and extracted with CH2Cl2 (2 × 250 mL). The combined organic extracts were dried over anhydrous Na2SO4 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 substance could be used in the next step without further purification.

[0851] LC-MS: at 3.70 RT, m / z 368.1 [M+H] + (Purity 82.98%)

[0852] 3-Oxo-6-(trifluoromethyl)-2,3,4,5-tetrahydropyridazine-4-carboxylic acid ethyl ester

[0853] At room temperature and under an inert atmosphere, hydrazine hydrochloride (23.16 g, 340.59 mmol) was added to a stirred solution of 25 g crude 2-((4-isopropyl-5-oxo-2-(trifluoromethyl)-2,5-dihydrooxazol-2-yl)methyl)malonic acid (200 mL) in acetic acid. The reaction mixture was heated to reflux and stirred for 3 h. After the starting material was consumed (monitored by TLC), the reaction mixture was alkalized with saturated sodium bicarbonate solution and extracted with EtOAc (2 × 250 mL). The combined organic extracts were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (elution: 30% to 40% EtOAc / hexane) to give ethyl 3-oxo-6-(trifluoromethyl)-2,3,4,5-tetrahydropyridazine-4-carboxylate (15 g, 63.55 mmol) as a pale yellow liquid.

[0854] LC-MS: at 2.19 RT, m / z 237.0 [MH] - (Purity 87.20%).

[0855] 3-Hydroxy-6-(trifluoromethyl)pyridazine-4-carboxylic acid ethyl ester

[0856] Under an inert atmosphere, at 0 °C, a solution of bromine (5.03 g, 31.51 mmol) in acetic acid (40 mL) was added to a stirred solution of ethyl 3-oxo-6-(trifluoromethyl)-2,3,4,5-tetrahydropyridazine-4-carboxylate (7.5 g, 31.51 mmol). The reaction mixture was warmed to room temperature and stirred for 1 h. After the starting material was consumed (monitored by TLC), the reaction mixture was alkalized with saturated sodium bicarbonate solution and extracted with EtOAc (2 × 200 mL). The combined organic extracts were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (elution: 30% to 40% EtOAc / hexane) to give ethyl 3-hydroxy-6-(trifluoromethyl)pyridazine-4-carboxylate (2.5 g, 10.59 mmol, 34%) as a grayish-white solid.

[0857]

[0858] LC-MS: at 2.03 RT, m / z 235.0 [MH] - (Purity 98.67%).

[0859] 3-Chloro-6-(trifluoromethyl)pyridazine-4-carboxylic acid ethyl ester

[0860] Phosphorus trichloride (19.6 mL, 211.86 mmol) was added 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) 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 (as monitored by TLC), the reaction mixture was alkalized with sodium bicarbonate solution (100 mL) and extracted with EtOAc (2 × 200 mL). The combined organic extracts were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (elution: 15% to 20% EtOAc / hexane) to give ethyl 3-chloro-6-(trifluoromethyl)pyridazine-4-carboxylate (3 g, 11.81 mmol, 55%) as a pale yellow liquid.

[0861]

[0862] LC-MS: at 3.61 RT, m / z 255.4 [M+H] + (Purity 98.51%).

[0863] 6-(trifluoromethyl)pyridazine-4-carboxylic acid ethyl ester

[0864] Triethylamine (0.5 mL) and 10% Pd / C (50% wet basis, 100 mg) were added to a stirred ethanol (10 mL) solution of ethyl 3-chloro-6-(trifluoromethyl)pyridazine-4-carboxylate (500 mg, 1.96 mmol) at room temperature and under an inert atmosphere. The headspace of the reaction was briefly placed under vacuum and rapidly purged with hydrogen. The reaction mixture was stirred at room temperature under a hydrogen atmosphere (balloon pressure) for 1 h. After the starting material was consumed (monitored by TLC), the reaction mixture was filtered through a diatomaceous earth pad and washed with EtOAc (50 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 30% EtOAc / hexane) to give ethyl 6-(trifluoromethyl)pyridazine-4-carboxylate (300 mg, 1.36 mmol, 69%) as a grayish-white solid.

[0865]

[0866] LC-MS: at 3.09 RT, m / z 221.1 [M+H] + (Purity 92.69%).

[0867] 6-(trifluoromethyl)pyridazine-4-carboxylic acid (Int-26)

[0868] At 0 °C, lithium hydroxide (171.6 g, 4.09 mmol) was added to a stirred mixture of ethyl 6-(trifluoromethyl)pyridazine-4-carboxylic acid (300 mg, 1.36 mmol) in THF:water (4:1, 5 mL). The reaction mixture was gradually warmed to room temperature and stirred for 1 h. After the starting material was consumed (monitored by TLC), the volatiles were concentrated under reduced pressure. The residue was then acidified with concentrated HCl (pH 3 to pH 4) and extracted with EtOAc (2 × 30 mL). The combined organic extracts were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The resulting solid was washed with n-pentane (10 mL) and dried under vacuum to give 6-(trifluoromethyl)pyridazine-4-carboxylic acid Int-26 (210 mg) as a grayish-white solid. The crude product could be used in the next step without further purification.

[0869]

[0870] LC-MS: at 3.79 RT, m / z 191.0 [MH] - (Purity 94.51%).

[0871] Preparation of Int-27

[0872] plan:

[0873]

[0874] 1-Cyclopropyl-5,6-difluoro-2-(6-vinylpyridazin-4-yl)-1H-benzo[d]imidazole

[0875] At room temperature and under an inert atmosphere, 1,4-dioxane (3 mL) of 2-(6-chloropyridazine-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole Ex.22 (150 mg, 0.50 mmol) in 1,4-dioxane (3 mL) and water (0.5 mL) was added to a stirred solution of 2-(6-chloropyridin-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole Ex.22 (150 mg, 0.50 mmol). The reaction mixture was degassed with argon for 10 min. Pd(dppf)Cl2 (4 mg, 0.005 mmol) was added at room temperature, and the mixture was degassed with argon for 10 min. The reaction mixture was heated to 80 °C and stirred for 5 h. After the starting material was consumed (monitored by TLC), the volatiles were concentrated under reduced pressure. The crude substance was purified by silica gel column chromatography (elution buffer: 50% EtOAc / hexane) to obtain 1-cyclopropyl-5,6-difluoro-2-(6-vinylpyridazin-4-yl)-1H-benzimidazole (70 mg, 0.23 mmol, 48%) as a grayish-white solid.

[0876]

[0877] 5-(1-Cyclopropyl-5,6-Difluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-carboxaldehyde (Int-27)

[0878] Under an inert atmosphere at 0°C, acetone containing 1-cyclopropyl-5,6-difluoro-2-(6-vinylpyridazin-4-yl)-1H-benzimidazole (300 mg, 1.00 mmol) was stirred. t Sodium periodate (430 mg, 2.01 mmol) and osmium tetroxide (1 M solution, 6 mL) were added to a BuOH:water (1:1:1, 18 mL) solution. The reaction mixture was warmed to room temperature and stirred for 1 h. After the starting material was consumed (monitored by TLC), the reaction mixture was filtered through a diatomaceous earth bed and the bed was washed with EtOAc (100 mL). The organic layer was washed with water (100 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 2% MeOH / CH2Cl2) to obtain a black solid. 5-(1-Cyclopropyl-5,6-Difluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-carboxaldehyde Int-27 (200 mg). The crude product can be used without further purification.

[0879]

[0880] Preparation of Int-28

[0881] plan:

[0882]

[0883] (E)-5-(1-Cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-carboxaldehyde oxime

[0884] At room temperature and under an inert atmosphere, hydroxylamine hydrochloride (276 mg, 4 mmol) and potassium carbonate (552 mg, 4 mmol) were added to a stirred ethanol (10 mL) solution of 5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-carboxaldehyde Int-27 (600 mg, 2 mmol). The reaction mixture was heated to 80 °C and stirred for 3 h. After the starting material was consumed (as monitored by TLC), the reaction mixture was concentrated under reduced pressure. The residue was diluted with water (70 mL) and extracted with CH2Cl2 (100 mL × 3). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was washed with n-hexane (20 mL) and dried under vacuum to obtain (E)-5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-carboxaldehyde oxime (500 mg, 1.58 mmol, 79%) as a grayish-white solid.

[0885]

[0886] LC-MS: at 2.33 RT, m / z 315.9 [M+H] + (Purity 97.99%).

[0887] (5-(1-Cyclopropyl-5,6-Difluoro-1H-Benz[d]imidazol-2-yl)pyridazin-3-yl)methylamine (Int-28)

[0888] Sodium hydroxide (190 mg, 4.76 mmol) and 10% Pd / C (500 mg, 1.58 mg, wet basis, 150 mg) were added to a stirred ethanol (10 mL) solution of (E)-5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-carboxaldehyde oxime (500 mg, 1.58 mmol) at room temperature and under an inert atmosphere. The reaction mixture was stirred for 3 h at room temperature and under a hydrogen atmosphere (balloon pressure). After the starting material was consumed (as monitored by TLC), the reaction mixture was filtered through a diatomaceous earth pad. The filtrate was concentrated under reduced pressure. The residue was diluted with CH2Cl2 (80 mL) and washed with water (50 mL). The organic layer was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to give (5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methylamine Int-28 (400 mg, 1.32 mmol, 84%) as a grayish-white solid. The crude product could be used in the next step without further purification.

[0889]

[0890] LC-MS: at 1.91 RT, m / z 301.9 [M+H] + (Purity 95.51%).

[0891] Preparation of Int-29

[0892] plan:

[0893]

[0894] 6-(difluoromethyl)pyridazine-4-carboxylic acid (Int-29) was prepared from alanine and difluoroacetic anhydride (DFAA) in a manner similar to Int-26.

[0895] Preparation of Int-30

[0896] plan:

[0897]

[0898] 1-(5-(1-Cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)ethyl-1-one oxime

[0899] Under an inert atmosphere, hydroxylamine hydrochloride (75 mg, 1.08 mmol) and potassium carbonate (149 mg, 1.08 mmol) were added to a stirred solution of 1-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)ethyl-1-one Ex.64 (170 mg, 0.54 mmol) in 10 mL of EtOH. The reaction mixture was heated to 80 °C and stirred for 3 h. After the starting material was consumed (monitored by TLC), the volatiles were concentrated under reduced pressure. The residue was diluted with water (30 mL) and extracted with CH2Cl2 (2 × 40 mL). The combined organic extracts were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to give 100 mg of 1-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)ethyl-1-one oxime as a grayish-white solid. The crude product could be used in the next step without further purification.

[0900]

[0901] LC-MS: at 2.52 RT, m / z 329.9 [M+H] + (Purity 86.46%).

[0902] 1-(5-(1-Cyclopropyl-5,6-Difluoro-1H-Benz[d]imidazol-2-yl)pyridazin-3-yl)ethyl-1-amine (Int-30)

[0903] Sodium hydroxide (37 mg, 0.91 mmol) and 10% Pd / C (50% wet basis, 80 mg) were added to a stirred ethanol (10 mL) solution of 1-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)ethyl-1-one oxime (100 mg, crude) at room temperature and under an inert atmosphere. The reaction mixture was stirred for 8 h at room temperature and under a hydrogen atmosphere (balloon pressure). After the feedstock was consumed (monitored by TLC), the reaction mixture was filtered through a diatomaceous earth mat and the mat was washed with MeOH (20 mL). The filtrate was concentrated under reduced pressure. The residue was diluted with water (20 mL) and extracted with CH2Cl2 (2 × 30 mL). The combined organic extracts were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to give 1-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)ethyl-1-amine Int-30 (80 mg) as a grayish-white solid. The crude product was ready for use without further purification.

[0904] LC-MS: at 1.71 RT, m / z 315.9 [M+H] + (Purity 85.70%).

[0905] Example 1

[0906] plan:

[0907]

[0908] N-(2-(cyclopropylamino)-4-fluorophenyl)pyridazine-4-carboxamide

[0909] At room temperature and under an inert atmosphere, N was stirred. 1 To a solution of cyclopropyl-5-fluorophenyl-1,2-diamine Int-1 (300 mg, 1.81 mmol) in N,N-dimethylformamide (DMF) (3 mL), pyridazine-4-carboxylic acid (224 mg, 1.81 mmol), N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethylammonium N-oxide hexafluorophosphate (HATU) (824 mg, 2.17 mmol), and diisopropylethylamine (1.26 mL, 7.23 mmol) were added. The reaction mixture was stirred at room temperature for 8 h. After the starting material was consumed (as monitored 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 Na₂SO₄ and concentrated under reduced pressure. The crude substance was purified by silica gel column chromatography (elution buffer: 50% EtOAc / hexane) to obtain N-(2-(cyclopropylamino)-4-fluorophenyl)pyridazine-4-carboxamide (220 mg, 0.81 mmol, 44%) as a brown solid.

[0910]

[0911] LC-MS: at 2.66 RT, m / z 272.9 [M+H] + (Purity 89.14%).

[0912] 1-Cyclopropyl-6-fluoro-2-(pyridazin-4-yl)-1H-benzo[d]imidazolium (Ex 1)

[0913] A solution of N-(2-(cyclopropylamino)-4-fluorophenyl)pyridazin-4-carboxamide (150 mg, 0.55 mmol) in acetic acid (3 mL) was heated to 100 °C and stirred for 8 h under an inert atmosphere. After the starting material was consumed (monitored 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 Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 5% MeOH / CH₂Cl₂) to give a grayish-white solid of 1-cyclopropyl-6-fluoro-2-(pyridazin-4-yl)-1H-benzo[d]imidazolium Ex 1 (68 mg, 0.27 mmol, 48%).

[0914]

[0915] LC-MS: at 2.98 RT, m / z 255.0 [M+H] + (Purity 97.13%).

[0916] HPLC: 98.24%.

[0917] Example 2 and Example 3

[0918] plan:

[0919]

[0920] 6-Chloro-N-(2-(cyclopropylamino)-4-fluorophenyl)pyridazine-4-carboxamide

[0921] At room temperature and under an inert atmosphere, N was stirred. 1 To a DMF (3 mL) solution of cyclopropyl-5-fluorophenyl-1,2-diamine Int-1 (500 mg, 3.01 mmol), 6-chloropyridazine-4-carboxylic acid (475 mg, 3.01 mmol), HATU (1.37 g, 3.61 mmol), and diisopropylethylamine (2.2 mL, 12.04 mmol) were added. The reaction mixture was stirred at room temperature for 4 h. After the starting material was consumed (monitored by TLC), the reaction mixture was terminated with ice-cold water (30 mL) and extracted with EtOAc (2 × 30 mL). The combined organic extracts were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (elution: 20% EtOAc / hexane) to give 6-chloro-N-(2-(cyclopropylamino)-4-fluorophenyl)pyridazine-4-carboxamide (550 mg, 1.79 mmol, 60%) as a brown solid.

[0922]

[0923] LC-MS: at 3.00 RT, m / z 305.0 [MH] + (Purity 83.53%).

[0924] 2-(6-Chlorpyridazin-4-yl)-1-cyclopropyl-6-fluoro-1H-benzo[d]imidazolium (Ex.3)

[0925] Trifluoroacetic acid (0.6 mL) was added dropwise to a stirred solution of 6-chloro-N-(2-(cyclopropylamino)-4-fluorophenyl)pyridazin-4-carboxamide (550 mg, 1.79 mmol) in 10 mL of CH₂Cl₂ at room temperature under an inert atmosphere. The reaction mixture was stirred at room temperature for 16 h. After the starting material was consumed (monitored by TLC), 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 Na₂SO₄, 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 Ex.3 (200 mg, 0.69 mmol, 38%) as a grayish-white solid.

[0926]

[0927] LC-MS: at 2.59 RT, m / z 288.9 [M+H] + (Purity 98.16%).

[0928] HPLC: 98.76%.

[0929] 5-(1-Cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-carboxylonitrile (Ex.2);

[0930] Zn(CN)₂ (24 mg, 0.21 mmol) was added to a stirred DMF (1 mL) solution of 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-6-fluoro-1H-benzo[d]imidazole Ex.₂ (100 mg, 0.35 mmol) at room temperature and under an inert atmosphere. The reaction mixture was degassed under argon for 10 min. Pd₂(dba)₃ (16 mg, 0.02 mmol) and Pd(dppf)Cl₂ (13 mg, 0.02 mmol) were added at room temperature, and the reaction mixture was degassed under argon for 5 min. The reaction mixture was heated to 100 °C and stirred for 2 h. After the starting material was consumed (monitored by TLC), the reaction mixture was diluted with EtOAc (40 mL), filtered through a diatomaceous earth mat, and the diatomaceous earth bed was washed with EtOAc (15 mL). The organic layer was washed with water (20 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude substance was purified by silica gel column chromatography (elution buffer: 40% EtOAc / hexane) to obtain 5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-carboxylonite Ex.2 (30 mg, 0.11 mmol, 31%) as a grayish-white solid.

[0931]

[0932] LC-MS: at 2.92 RT, m / z 279.8 [M+H] + (Purity 99.44%).

[0933] HPLC: 99.21%.

[0934] Example 4

[0935] plan:

[0936]

[0937] 1-Cyclopropyl-6-fluoro-2-(6-vinylpyridazin-4-yl)-1H-benzo[d]imidazolium (Ex.4)

[0938] At room temperature and under an inert atmosphere, potassium carbonate (431 mg, 3.12 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-diazepineborane (160 mg, 1.04 mmol) were added to a stirred solution of 1,4-dioxane (15 mL) and water (2 mL). The reaction mixture was degassed under argon for 15 min. Pd(dppf)Cl2·CH2Cl2 (8.5 mg, 0.01 mmol) was added to the mixture at room temperature. The reaction mixture was heated to 80 °C and stirred for 4 h. After the starting material was consumed (monitored by TLC), the reaction mixture was diluted with EtOAc (60 mL), filtered through a diatomaceous earth mat, and the diatomaceous earth bed was washed with EtOAc (15 mL). The organic layer was washed with water (20 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (elution: 40% EtOAc / hexane) to give 1-cyclopropyl-6-fluoro-2-(6-vinylpyridazin-4-yl)-1H-benzimidazole (150 mg, 0.53 mmol, 51%) as a grayish-white solid.

[0939]

[0940] LC-MS: at 2.43 RT, m / z 280.9 [M+H] + (Purity 93.90%).

[0941] HPLC: 95.00%.

[0942] Example 5

[0943] plan:

[0944]

[0945] 5-(1-Cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-carboxylic acid methyl ester (Ex. 5)

[0946] At room temperature, in a steel reactor, sodium acetate (171 mg, 2.08 mmol), 1,1'-ferrocene diyl-bis(diphenylphosphine) (19 mg, 0.03 mmol), and palladium(II) acetate (7.8 mg, 0.03 mmol) were added to a stirred MeOH solution of 2-(6-chloropyridazine-4-yl)-1-cyclopropyl-6-fluoro-1H-benzo[d]imidazole Ex.3 (200 mg, 0.69 mmol) (3 mL). The steel reactor was filled with CO gas (15 bar pressure). The resulting reaction mixture was stirred at 50 °C for 2 h. After the feedstock was consumed (monitored by TLC), the reaction mixture was filtered through a diatomaceous earth bed and the bed was washed with methanol (30 mL). The filtrate was concentrated under reduced pressure. The crude substance was purified by silica gel column chromatography (elution buffer: 50% EtOAc / hexane) to obtain methyl 5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-carboxylic acid as a grayish-white solid, Ex.5 (70 mg, 0.22 mmol, 32%).

[0947]

[0948] LC-MS: at 2.36 RT, m / z 312.9 [M+H] + (Purity 95.19%).

[0949] HPLC: 99.01%.

[0950] Example 6

[0951] plan:

[0952]

[0953] 1-Cyclopropyl-2-(6-ethylpyridazin-4-yl)-6-fluoro-1H-benzo[d]imidazolium (Ex. 6)

[0954] Triethylamine (catalytic amount) and 10% Pd / C (50% wet basis, 20 mg) were added to a stirred ethyl acetate (8 mL) solution of 1-cyclopropyl-6-fluoro-2-(6-vinylpyridazin-4-yl)-1H-benzo[d]imidazole Ex.4 (70 mg, 0.25 mmol) at room temperature and under an inert atmosphere. The reaction mixture was evacuated and stirred at room temperature under a hydrogen atmosphere (balloon pressure) for 3 h. After the starting material was consumed (monitored by TLC), the reaction mixture was filtered through a diatomaceous earth bed and the 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 / CH2Cl2) to give 1-cyclopropyl-2-(6-ethylpyridazin-4-yl)-6-fluoro-1H-benzo[d]imidazole Ex.6 (50 mg, 0.18 mmol, 67%) as a grayish-white solid.

[0955]

[0956] LC-MS: at 2.37 RT, m / z 282.9 [M+H] + (Purity 98.84%).

[0957] HPLC: 98.29%.

[0958] Example 7

[0959] plan:

[0960]

[0961] 1-(5-(1-Cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)-2,2,2-trifluoroethane-1-ol (Ex. 7)

[0962] Trimethyl(trifluoromethyl)silane (0.05 mL, 0.35 mmol) was added to a stirred solution of 5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-carboxaldehyde Int-2 (50 mg, 0.18 mmol) in THF (3 mL) under an inert atmosphere. Cesium fluoride (81 mg, 0.53 mmol) was added and the mixture was stirred at room temperature for 16 h to allow the reaction to proceed. After the starting material was consumed (monitored by TLC), the reaction mixture was terminated with a saturated ammonium chloride solution (15 mL) and extracted with EtOAc (2 × 15 mL). The combined organic extracts were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude substance was purified by silica gel column chromatography (elution buffer: 5% MeOH / CH2Cl2) to obtain 1-(5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)-2,2,2-trifluoroethane-1-ol Ex.7 (15 mg, 0.04 mmol, 24%) as a grayish-white solid.

[0963]

[0964] LC-MS: at 2.59 RT, m / z 352.9 [M+H] + (Purity 96.11%).

[0965] HPLC: 93.29%.

[0966] Example 8

[0967] plan:

[0968]

[0969] N-((5-(1-Cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methyl)propionamide (Ex.8)

[0970] Under an inert atmosphere, propionyl chloride (0.05 mL, 0.59 mmol) and triethylamine (0.14 mL, 0.1 mmol) were added to a stirred solution of (140 mg, 0.49 mmol) methylamine Int-3 in CH2Cl2 (5 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 3 h. After the starting material was consumed (as monitored by TLC), the reaction mixture was diluted with water (20 mL) and extracted with CH2Cl2 (2 × 20 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude substance was purified by preparative high performance liquid chromatography (HPLC) to obtain N-((5-(1-cyclopropyl-6-fluoro-1H-benzis[d]imidazol-2-yl)pyridazin-3-yl)methyl)propionamide (40 mg, 0.12 mmol, 24%) as a white solid.

[0971]

[0972] LC-MS: at 2.07 RT, m / z 340.1 [M+H] + (Purity 99.22%).

[0973] HPLC: 99.08%.

[0974] Example 9

[0975] plan:

[0976]

[0977] (5-(1-Cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methyl)carbamate (Ex.9)

[0978] Under an inert atmosphere, ethyl chloroformate (0.05 mL, 0.53 mmol) and triethylamine (0.12 mL, 0.88 mmol) were added to a stirred solution of (125 mg, 0.44 mmol) methylamine Int-3 in THF (6 mL) 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 Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by preparative HPLC to obtain ethyl (5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methyl)carbamate Ex.9 (40 mg, 0.11 mmol, 26%) as a grayish-white solid.

[0979]

[0980] LC-MS: at 2.33 RT, m / z 356.1 [M+H] + (Purity 98.62%).

[0981] HPLC: 99.15%.

[0982] Example 10

[0983] plan:

[0984]

[0985] 4-(5-(1-Cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)morpholine (Ex. 10)

[0986] Under an inert atmosphere, triethylamine (0.11 mL, 0.78 mmol) and morpholine (0.07 mL, 0.78 mmol) were added to a stirred ethanol (0.9 mL) solution of 2-(6-chloropyridazine-4-yl)-1-cyclopropyl-6-fluoro-1H-benzo[d]imidazolium Ex.3 (150 mg, 0.52 mmol). The reaction mixture was heated to 90 °C and stirred for 16 h. After the starting material was consumed (as monitored by TLC), the reaction mixture was terminated with saturated ammonium chloride solution (20 mL) and extracted with CH2Cl2 (2 × 20 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude substance was purified by silica gel column chromatography (elution buffer: 100% EtOAc) to obtain 4-(5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)morpholine Ex.10 (40 mg, 0.12 mmol, 23%) as a grayish-white solid.

[0987]

[0988] LC-MS: at 2.33 RT, m / z 340.0 [M+H] + (Purity 97.11%).

[0989] HPLC: 97.09%.

[0990] Example 11

[0991] plan:

[0992]

[0993] 1-Cyclopropyl-6-fluoro-2-(6-(4-(4-fluorophenyl)piperazin-1-yl)pyridazin-4-yl)-1H-benzo[d]imidazolium (Ex. 11)

[0994] Under an inert atmosphere, triethylamine (0.036 mL, 0.26 mmol) and 1-(4-fluorophenyl)piperazine (47 mg, 0.26 mmol) were added to a stirred solution of 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-6-fluoro-1H-benzo[d]imidazole Ex.3 (50 mg, 0.17 mmol) in EtOH (0.3 mL). The reaction mixture was stirred at 90 °C for 7 h. After the starting material was consumed (monitored by TLC), the evaporation was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (elution: 90% EtOAc / hexane) to give 1-cyclopropyl-6-fluoro-2-(6-(4-(4-fluorophenyl)piperazin-1-yl)pyridazin-4-yl)-1H-benzo[d]imidazole Ex.11 (40 mg, 0.09 mmol, 53%) as a grayish-white solid.

[0995]

[0996] LC-MS: at 2.38 RT, m / z 433.1 [M+H] + (Purity 99.63%).

[0997] HPLC: 96.82%.

[0998] Example 12

[0999] plan:

[1000]

[1001] 5-(1-Cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-carboxaldehyde (Int-2)

[1002] Under an inert atmosphere at 0 °C, 1-cyclopropyl-6-fluoro-2-(6-vinylpyridazin-4-yl)-1H-benzo[d]imidazolium Ex.4 (600 mg, 2.14 mmol) was stirred in an acetone:tert-butanol mixture. t Sodium periodate (912 mg, 4.28 mmol) and osmium tetroxide (2.5 wt% in toluene, 3 mL) were added to a solution of BuOH:water (1:1:1, 30 mL). The reaction mixture was stirred at 0 °C for 5 h. After the starting material was consumed (monitored 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-carboxaldehyde Int-2 (400 mg, 1.41 mmol, 66%) as a brown solid.

[1003]

[1004] 1-[5-(1-Cyclopropyl-6-fluoro1H-1,3-benzodiazol-2-yl)pyridazin-3-yl]ethanol-1-ol

[1005] At -78 °C and under an inert atmosphere, magnesium methyl bromide (2M in diethyl ether, 0.35 mL, 0.70 mmol) was added dropwise to a stirred solution of 5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-carboxaldehyde Int-2 (200 mg, 0.70 mmol) in 6 mL of THF. The reaction mixture was stirred at -78 °C for 1 h. After the starting material was consumed (as monitored by TLC), the reaction mixture was terminated with saturated ammonium chloride solution (20 mL) and extracted with EtOAc (2 × 30 mL). The combined organic extracts were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude substance was purified by silica gel column chromatography (elution buffer: 2% to 3% MeOH / CH2Cl2) to obtain 1-[5-(1-cyclopropyl-6-fluoro-1H-1,3-benzodiazol-2-yl)pyridazin-3-yl]ethyl-1-ol (150 mg, 0.50 mmol, 71%) as a brown solid.

[1006]

[1007] 1-(5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)ethyl-1-one

[1008] At 0 °C and under an inert atmosphere, Dysmart reagent (213 mg, 0.51 mmol) was added to a stirred solution of 1-[5-(1-cyclopropyl-6-fluoro-1H-1,3-benzodiazol-2-yl)pyridazin-3-yl]ethane-1-ol (100 mg, 0.33 mmol) in 10 mL of CH2Cl2. The reaction mixture was warmed to room temperature and stirred for 3 h. After the starting material was consumed (as monitored by TLC), the reaction mixture was terminated with 20 mL of saturated sodium bicarbonate solution and extracted with CH2Cl2 (2 × 50 mL). The organic layer was washed with 20 mL of saturated sodium bicarbonate, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude substance was purified by silica gel column chromatography (elution buffer: 2% to 3% MeOH / CH2Cl2) to obtain 1-(5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)ethyl-1-one (80 mg, 0.27 mmol, 81%) as a grayish-white solid.

[1009]

[1010] 2-(5-(1-Cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)prop-2-ol (Ex. 12)

[1011] Magnesium methyl bromide (2 M in diethyl ether, 0.1 mL, 0.20 mmol) was added dropwise to a stirred solution of 1-(5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)ethyl-1-one (60 mg, 0.20 mmol) in 2 mL of THF under an inert atmosphere at -78 °C. The reaction mixture was stirred at -78 °C for 1 h. After the starting material was consumed (as monitored by TLC), the reaction mixture was terminated with saturated ammonium chloride solution (20 mL) and extracted with EtOAc (2 × 30 mL). The combined organic extracts were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by preparative HPLC to obtain 2-(5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)prop-2-ol Ex.12 (15 mg, 0.05 mmol, 24%) as a grayish-white solid.

[1012]

[1013] LC-MS: at 2.19 RT, m / z 313 [M+H] + (Purity 95.83%).

[1014] HPLC: 95.47%.

[1015] Example 13

[1016] plan:

[1017]

[1018] 5-(1-Cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)-N-(Tetrahydro-2H-pyran-4-yl)pyridazin-3-amine (Ex. 13)

[1019] At room temperature and under an inert atmosphere, triethylamine (0.2 mL, 1.56 mmol) and tetrahydro-2H-pyran-4-amine (105 mg, 1.04 mmol) were added to a stirred solution of 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-6-fluoro-1H-benzo[d]imidazolium Ex.3 (150 mg, 0.52 mmol) in EtOH (1.5 mL). The reaction mixture was stirred under reflux for 16 h. After the starting material was consumed (monitored by TLC), the evaporation was 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 Ex.13 (40 mg, 0.11 mmol, 22%) as a grayish-white solid.

[1020]

[1021] LC-MS: at 1.74 RT, m / z 354 [M+H] + (Purity 97.97%).

[1022] HPLC: 97.95%.

[1023] Example 14

[1024] plan:

[1025]

[1026] N-(2-(cyclopropylamino)-4-fluorophenyl)cenline-4-carboxamide

[1027] At 0°C and under an inert atmosphere, N was stirred. 1 To a DMF (5 mL) solution of cyclopropyl-5-fluorophenyl-1,2-diamine Int-1 (500 mg, 3.01 mmol), cinnamyl-4-carboxylic acid (524 mg, 3.01 mmol), HATU (1.71 g, 4.51 mmol), and diisopropylethylamine (1 mL, 6.02 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), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to give N-(2-(cyclopropylamino)-4-fluorophenyl)cinnamyl-4-carboxamide (500 mg, crude) as a brown solid, which could be used in the next step without further purification.

[1028] LC-MS: at 2.71 RT, m / z 322.9 [M+H] + (Purity 38.30%).

[1029] 4-(1-Cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)cenline (Ex. 14)

[1030] At room temperature and under an inert atmosphere, 4 mL of 6N HCl was added to a stirred EtOH solution of N-(2-(cyclopropylamino)-4-fluorophenyl)-cinnamoline-4-carboxamide (400 mg, 1.24 mmol) in 5 mL. The reaction mixture was stirred at 80 °C for 1 h. After the starting material was consumed (as monitored by TLC), the reaction mixture was diluted with 20 mL of saturated sodium bicarbonate solution and extracted with CH2Cl2 (2 × 20 mL). The combined organic extracts were dried over anhydrous Na2SO4 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)-cinnamoline Ex.14 (160 mg, 0.52 mmol, 43%) as a grayish-white solid.

[1031]

[1032] LC-MS: at 2.59 RT, m / z 304.9 [M+H] + (Purity 99.51%).

[1033] HPLC: 99.30%.

[1034] Example 15

[1035] plan:

[1036]

[1037] N-(2-(cyclopropylamino)-4-fluorophenyl)-6-methylpyridazine-4-carboxamide

[1038] N2 was added to a stirred DMF (3 mL) solution of 174 mg (1.0 mmol) of 6-methylpyridazine-4-carboxylic acid at 0 °C under an inert atmosphere. 1-Cyclopropyl-5-fluorophenyl-1,2-diamine Int-1 (166 mg, 1.0 mmol), HATU (570 mg, 1.5 mmol), and diisopropylethylamine (1.38 mL, 4 mmol). The reaction mixture was stirred at room temperature for 16 h. After the starting material was consumed (monitored 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 Na2SO4, and concentrated under reduced pressure to give N-(2-(cyclopropylamino)-4-fluorophenyl)-6-methylpyridazine-4-carboxamide (250 mg, crude) as a brown solid.

[1039] LC-MS: at 3.53 RT, m / z 287.2 [M+H] + (Purity 54.60%).

[1040] 1-Cyclopropyl-6-fluoro-2-(6-methylpyridazin-4-yl)-1H-benzo[d]imidazolium (Ex. 15)

[1041] At room temperature and under an inert atmosphere, 3.5 mL of 6N HCl was added to a stirred solution of N-(2-(cyclopropylamino)-4-fluorophenyl)-6-methylpyridazin-4-carboxamide (250 g, 0.87 mmol) in 1.5 mL of EtOH. The reaction mixture was stirred at 80 °C for 2 h. After the starting material was consumed (monitored by TLC), the reaction mixture was diluted with 20 mL of saturated sodium carbonate solution and extracted with EtOAc (2 × 20 mL). The combined organic extracts were washed with 20 mL of water and 20 mL of brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 4% to 5% MeOH / CH₂Cl₂) to give 1-cyclopropyl-6-fluoro-2-(6-methylpyridazin-4-yl)-1H-benzo[d]imidazole Ex. 15 (80 mg, 0.29 mmol, 34%) as a grayish-white solid.

[1042]

[1043] LC-MS: at 2.19 RT, m / z 268.9 [M+H] + (Purity 95.85%).

[1044] HPLC: 97.59%.

[1045] Example 16

[1046] plan:

[1047]

[1048] N-(5-(1-Cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)ethanesulfonamide (Ex. 16)

[1049] Ethanesulfonamide (57 mg, 0.52 mmol) and cesium carbonate (283 mg, 0.86 mmol) were added to a stirred solution of 2-(6-chloropyridazine-4-yl)-1-cyclopropyl-6-fluoro-1H-benzo[d]imidazole Ex.3 (100 mg, 0.34 mmol) in 1,4-dioxane (4 mL), and the mixture was purged under argon for 5 min. Then, Pd(OAc)2 (7.8 mg, 0.004 mmol) and 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (Xanthphos) (30 mg, 0.05 mmol) were added to the reaction mixture. The reaction mixture was heated to 120 °C and stirred for 16 h. After the starting material was consumed (monitored by TLC), the reaction mixture was diluted with water (50 mL) and extracted with 10% MeOH:CH2Cl2 (2 × 50 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (elution: 2% to 3% MeOH / CH2Cl2) to give N-(5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)ethanesulfonamide Ex. 16 (30 mg, 0.08 mmol, 24%) as a colorless paste.

[1050]

[1051] LC-MS: at 2.04 RT, m / z 362 [M+H] + (Purity 95.41%).

[1052] HPLC: 94.11%.

[1053] Example 17

[1054] plan:

[1055]

[1056] 6-Chloro-N-(4-cyano-2-(ethylamino)phenyl)pyridazine-4-carboxamide

[1057] Under an inert atmosphere, 6-chloropyridazine-4-carboxylic acid (316 mg, 2 mmol), HATU (1.14 g, 3 mmol), and diisopropylethylamine (1.38 mL, 8 mmol) were added to a stirred DMF (6 mL) solution of 4-amino-3-(ethylamino)benzonitrile Int-4 (322 mg, 2 mmol). The reaction mixture was stirred at room temperature for 16 h. After the starting material was consumed (as monitored 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 conditions and concentrated under reduced pressure to give 6-chloro-N-(4-cyano-2-(ethylamino)phenyl)pyridazine-4-carboxamide (350 mg, crude) as a grayish-white solid.

[1058] LC-MS: at 2.07 RT, m / z 300.1 [MH] - (Purity 18.03%)

[1059] 2-(6-Chlorpyridazin-4-yl)-1-ethyl-1H-benzo[d]imidazol-6-carboxynitrile (Ex. 17)

[1060] Trifluoroacetic acid (TFA) (1 mL) was added to a stirred solution of 3 mL of 6-chloro-N-(4-cyano-2-(ethylamino)phenyl)pyridazin-4-carboxamide (350 mg, 1.16 mmol) in CH₂Cl₂ at room temperature under an inert atmosphere. The reaction mixture was stirred at room temperature for 6 h. After the starting material was consumed (as monitored 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) and brine (20 mL), dried over anhydrous Na₂SO₄, 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]imidazolium-6-carboxynitrile Ex.17 (25 mg, 0.08 mmol, 7.5%) as a grayish-white solid.

[1061]

[1062] LC-MS: at 3.50 RT, m / z 284.2 [M+H] + (Purity 99.67%).

[1063] HPLC: 99.48%.

[1064] Example 18

[1065] plan:

[1066]

[1067] 2-(4-(5-(1-Cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)piperazin-1-yl)-N-isopropylacetamide (Ex. 18)

[1068] 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) were added to a stirred EtOH (2 mL) solution of 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-6-fluoro-1H-benzisin-1-yl)acetamide under an inert atmosphere at room temperature. The reaction mixture was stirred under reflux for 16 h. After the starting material was consumed (as monitored by TLC), the evaporation was evaporated under reduced pressure. The crude substance was purified by preparative HPLC to obtain 2-(4-(5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)piperazin-1-yl)-N-isopropylacetamide Ex.18 (12 mg, 0.02 mmol, 14%) as a grayish-white solid.

[1069]

[1070] LC-MS: at 3.76 RT, m / z 438.4 [M+H] + (Purity 94.38%).

[1071] HPLC: 94.23%.

[1072] Example 19

[1073] plan:

[1074]

[1075] N-(2-(cyclopropylamino)-4,5-difluorophenyl)-6-methylpyridazine-4-carboxamide

[1076] At 0°C and under an inert atmosphere, N was stirred. 1To a DMF (3 mL) solution of cyclopropyl-4,5-difluorophenyl-1,2-diamine Int-5 (184 mg, 1.0 mmol), 6-methylpyridazine-4-carboxylic acid (174 mg, 1.0 mmol), HATU (570 mg, 1.5 mmol), and diisopropylethylamine (1.38 mL, 4.0 mmol) were added. The reaction mixture was stirred at room temperature for 16 h. After the starting material was consumed (monitored by TLC), the reaction mixture was terminated 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 Na₂SO₄, and concentrated under reduced pressure to give N-(2-(cyclopropylamino)-4,5-difluorophenyl)-6-methylpyridazine-4-carboxamide (220 mg, crude) as a brown paste.

[1077] LC-MS: at 3.78 RT, m / z 305.2 [M+H] + (Purity 44.76%).

[1078] 1-Cyclopropyl-5,6-difluoro-2-(6-methylpyridazin-4-yl)-1H-benzo[d]imidazolium (Ex. 19)

[1079] At room temperature and under an inert atmosphere, 3.5 mL of 6N HCl was added to a stirred solution of N-(2-(cyclopropylamino)-4,5-difluorophenyl)-6-methylpyridazin-4-carboxamide (220 mg, 0.72 mmol) in 1.5 mL of EtOH. The reaction mixture was stirred at 80 °C for 2 h. After the starting material was consumed (as monitored by TLC), the reaction mixture was diluted with 100 mL of saturated sodium carbonate solution and extracted with EtOAc (2 × 100 mL). The combined organic extracts were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (elution: 3% to 5% MeOH / CH₂Cl₂) to give 1-cyclopropyl-5,6-difluoro-2-(6-methylpyridazin-4-yl)-1H-benzo[d]imidazole Ex. 19 (60 mg, 0.20 mmol, 29%) as a grayish-white solid.

[1080]

[1081] LC-MS: at 2.32 RT, m / z 286.9 [M+H] + (Purity 99.57%).

[1082] HPLC: 99.70%.

[1083] Example 20

[1084] plan:

[1085]

[1086] 4-(2-ethoxy-2-oxoethyl)piperazine-1-carboxylic acid tert-butyl ester

[1087] Potassium carbonate (3.71 g, 26.8 mmol) and ethyl bromoacetate (1.2 mL, 10.8 mmol) were added to a stirred DMF (14 mL) solution of piperazine-1-carboxylic acid tert-butyl ester (2 g, 10.7 mmol) at room temperature and under an inert atmosphere. The reaction mixture was stirred at room temperature for 16 h. After the starting material was consumed (as monitored 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 Na₂SO₄ and concentrated under reduced pressure to give 4-(2-ethoxy-2-oxoethyl)piperazine-1-carboxylic acid tert-butyl ester (2.8 g, 10.29 mmol, 95%) as a yellow oil.

[1088]

[1089] 2-(4-tert-Butoxycarbonyl)piperazin-1-yl)acetic acid

[1090] At 0 °C, lithium hydroxide (1.29 g, 30.8 mmol) was added to a stirred solution of tert-butyl 4-(2-ethoxy-2-oxoethyl)piperazine-1-carboxylic acid (2.8 g, 10.29 mmol) in a mixture of THF:MeOH:water (3:1:1, 30 mL). The reaction mixture was gradually warmed to room temperature and stirred for 3 h. After the starting material was consumed (monitored by TLC), the volatiles were concentrated under reduced pressure. The residue was then acidified to pH 4 to pH 5 with 5% citric acid solution and extracted with EtOAc (2 × 100 mL). The combined organic extracts were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to give 2-(4-tert-butyloxycarbonyl)piperazine-1-yl)acetic acid (200 mg, crude) as a yellow oil, which could be used in the next step without further purification.

[1091] LC-MS: at 1.06 RT, m / z 245.1 [MH] + (Purity 71.81%).

[1092] 4-(2-oxo-2-(pyrrolidone-1-yl)ethyl)piperazine-1-carboxylic acid tert-butyl ester

[1093] At room temperature and under an inert atmosphere, pyrrolidine (0.2 mL, 2.45 mmol), HATU (1.1 g, 3.07 mmol), and diisopropylethylamine (1.5 mL, 8.19 mmol) were added to a stirred solution of 2-(4-tert-butyloxycarbonyl)piperazin-1-yl)acetic acid (500 mg, 2.04 mmol) in CH2Cl2 (15 mL). The reaction mixture was stirred at room temperature for 16 h. After the starting material was consumed (monitored by TLC), the reaction mixture was diluted with water (30 mL) and extracted with CH2Cl2 (2 × 30 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (elution: 2% MeOH / CH2Cl2) to give tert-butyl 4-(2-oxo-2-(pyrrolidine-1-yl)ethyl)piperazin-1-carboxylic acid as a brown solid (100 mg, 0.33 mmol, 16%).

[1094]

[1095] 4-(2-oxo-2-(pyrrolidone-1-yl)ethyl)piperazin-1-yl 2,2,2-trifluoroacetate

[1096] Trifluoroacetic acid (0.5 mL) was added dropwise to a stirred solution of tert-butyl 4-(2-oxo-2-(pyrrolidone-1-yl)ethyl)piperazin-1-carboxylic acid (100 mg, 0.33 mmol) in 1 mL of CH₂Cl₂ under an inert atmosphere at room temperature. The reaction mixture was stirred at room temperature for 1 h. After the starting material was consumed (monitored by TLC), volatiles were removed under reduced pressure. The crude product was washed with diethyl ether (2 × 5 mL) to give 120 mg of 4-(2-oxo-2-(pyrrolidone-1-yl)ethyl)piperazin-1-yl 2,2,2-trifluoroacetate (TFA salt) as a white solid.

[1097]

[1098] 2-(4-(5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)piperazin-1-yl)-1-(pyrrolidone-1-yl)acet-1-one (Ex. 20)

[1099] At room temperature and under an inert atmosphere, triethylamine (0.14 mL, 1.04 mmol) and 4-(2-oxo-2-(pyrrolidine-1-yl)ethyl)piperazin-1-yl 2,2,2-trifluoroacetate (34 mg, 0.17 mmol) were added to a stirred EtOH (2 mL) solution of 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-6-fluoro-1H-benzisin-1-yl)-2,2,2-trifluoroacetate. The reaction mixture was stirred at 80 °C for 32 h. After the starting material was consumed (monitored by TLC), the evaporation was evaporated under reduced pressure. The crude substance was purified by preparative HPLC to obtain 2-(4-(5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)piperazin-1-yl)-1-(pyrrolidone-1-yl)ethyl-1-one Ex.20 (20 mg, 0.041 mmol, 13%) as a grayish-white solid.

[1100]

[1101] LC-MS: at 1.74 RT, m / z 450.2 [M+H] + (Purity 97.66%).

[1102] HPLC: 97.81%.

[1103] Examples 21 and 22

[1104] plan:

[1105]

[1106] 6-Chloro-N-(2-(cyclopropylamino)-4,5-difluorophenyl)pyridazine-4-carboxamide

[1107] At room temperature and under an inert atmosphere, N was stirred. 1To a DMF (10 mL) solution of cyclopropyl-4,5-difluorophenyl-1,2-diamine Int-5 (1 g, 5.43 mmol), 6-chloropyridazine-4-carboxylic acid (1.03 g, 6.52 mmol), HATU (2.48 g, 6.52 mmol), and diisopropylethylamine (3.9 mL, 21.72 mmol) were added. The reaction mixture was stirred at room temperature for 16 h. After the starting material was consumed (monitored 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 Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (elution: 0% to 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.

[1108]

[1109] 2-(6-Chlorpyridazin-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole (Ex. 22)

[1110] At room temperature and under an inert atmosphere, 10.5 mL of 6N HCl was added to a stirred EtOH solution of 700 mg (2.16 mmol) of 6-chloro-N-(2-(cyclopropylamino)-4,5-difluorophenyl)pyridazin-4-carboxamide (700 mg, 2.16 mmol). The reaction mixture was stirred at 70 °C for 30 min. After the starting material was consumed (monitored by TLC), the reaction mixture was diluted with 50 mL of saturated sodium bicarbonate solution and extracted with EtOAc (2 × 50 mL). The combined organic extracts were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (elution: 20% to 30% EtOAc / hexane) to give 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole Ex.22 (280 mg, 0.91 mmol, 42%) as a grayish-white solid.

[1111]

[1112] LC-MS: at 2.52 RT, m / z 306.9 [M+1] + (99.86% purity).

[1113] HPLC: 99.51%.

[1114] 5-(1-Cyclopropyl-5,6-Difluoro-1H-benzo[d]imidazol-2-yl)-N-methylpyridazin-3-amine (Ex. 21)

[1115] 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazolium Ex. 22 (600 mg, 1.96 mmol) was dissolved in 2 M methylamine solution (2 M, in diethyl ether, 3 mL) and the reaction mixture was stirred at room temperature for 16 h. After the starting material was consumed (monitored 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 Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (elution: 2% to 3% MeOH / CH2Cl2) to give 5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-N-methylpyridazin-3-amine Ex. 21 (50 mg, 0.16 mmol, 8%) as a light green solid.

[1116]

[1117] LC-MS: at 1.76 RT, m / z 301.9 [M+1] + (98.78% purity).

[1118] HPLC: 99.48%.

[1119] Example 23

[1120] plan:

[1121]

[1122] 1-Cyclopropyl-5,6-difluoro-2-(6-methoxypyridazin-4-yl)-1H-benzo[d]imidazolium (Ex. 23)

[1123] Sodium methoxide (53 mg, 0.98 mmol) was added to a stirred solution of 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole Ex. 22 (100 mg, 0.32 mmol) in 5 mL of MeOH at room temperature and under an inert atmosphere. The reaction mixture was stirred at 70 °C for 2 h. After the starting material was consumed (as monitored by TLC), the volatiles were evaporated under reduced pressure. The residue was diluted with water (10 mL) and extracted with CH2Cl2 (2 × 10 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude substance was purified by silica gel column chromatography (elution buffer: 40% EtOAc / hexane) to obtain 1-cyclopropyl-5,6-difluoro-2-(6-methoxypyridazin-4-yl)-1H-benzo[d]imidazole Ex.23 (40 mg, 0.13 mmol, 41%) as a grayish-white solid.

[1124] LC-MS: at 2.30 RT, m / z 302.9 [M+H] + (99.80% purity).

[1125] HPLC: 99.68%.

[1126] Example 24

[1127] plan:

[1128]

[1129] 1-Cyclopropyl-5,6-Difluoro-2-(6-isopropoxypyridazin-4-yl)-1H-benzo[d]imidazolium (Ex. 24)

[1130] Under an inert atmosphere, sodium hydride (55%, in mineral oil, 20 mg, 0.46 mmol) was added in portions to a stirred solution of 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole Ex. 22 (70 mg, 0.23 mmol) in DMF (0.5 mL). The reaction mixture was stirred at 0 °C for 30 min. Propanol (27.5 mg, 0.46 mmol) was added to the reaction mixture at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. After the starting material was consumed (as monitored by TLC), the reaction mixture was terminated with ice-cold water (20 mL) and extracted with EtOAc (2 × 20 mL). The combined organic extracts were washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude substance was purified by silica gel column chromatography (elution buffer: 5% EtOAc / hexane) to obtain 1-cyclopropyl-5,6-difluoro-2-(6-isopropoxypyridazin-4-yl)-1H-benzimidazole Ex.24 (30 mg, 0.09 mmol, 40%) as a grayish-white solid.

[1131]

[1132] LC-MS: at 2.88 RT, m / z 330.9 [M+H] + (93.72% purity).

[1133] HPLC: 95.25%.

[1134] Example 25

[1135] plan:

[1136]

[1137] 5-(1-Cyclopropyl-5,6-Difluoro-1H-benzo[d]imidazol-2-yl)-N,N-Dimethylpyridazin-3-amine (Ex. 25)

[1138] 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazolium Ex. 22 (60 mg, 0.19 mmol) was dissolved in 2M dimethylamine solution (2M, in THF, 3 mL) and the reaction mixture was stirred for 16 h. After the starting material was consumed (monitored 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 Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (elution: 2% to 3% MeOH / CH2Cl2) to give 5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-N,N-dimethylpyridazin-3-amine Ex. 25 (16 mg, 0.05 mmol, 26%) as a grayish-white solid.

[1139]

[1140] LC-MS: at 1.81 RT, m / z 316.1 [M+1] + (98.32% purity).

[1141] HPLC: 95.98%.

[1142] Example 26

[1143] plan:

[1144]

[1145] 2-Bromo-1-ethyl-6-fluoro-1H-indole

[1146] Potassium carbonate (476 mg, 3.50 mmol) was added to a stirred DMF (2 mL) solution of 2-bromo-6-fluoro-1H-indole (250 mg, 1.16 mmol) under an inert atmosphere, followed by the addition of iodoethane (364 mg, 2.33 mmol). The reaction mixture was stirred at room temperature for 4 h. After the starting material was consumed (as monitored 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 Na₂SO₄ and concentrated under reduced pressure to give 2-bromo-1-ethyl-6-fluoro-1H-indole (280 mg, crude) as a yellow solid.

[1147]

[1148] 1-Ethyl-6-fluoro-2-(6-methylpyridazin-4-yl)-1H-indole (Ex. 26)

[1149] 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)boric acid (214 mg, 1.24 mmol) and sodium carbonate solution (2 M, 0.5 mL) were added, and the mixture was purged under argon for 10 min. Then, Pd(dppf)Cl2 (60 mg, 0.08 mmol) was added to the reaction mixture, and the mixture was stirred in a sealed tube at 80 °C for 16 h. The reaction progress was monitored 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 Na2SO4, and concentrated under reduced pressure. The crude substance was purified by silica gel column chromatography (elution buffer: 2% MeOH / CH2Cl2) to obtain 1-ethyl-6-fluoro-2-(6-methylpyridazin-4-yl)-1H-indole Ex. 26 (50 mg, 0.19 mmol, 20%) as a yellow solid.

[1150]

[1151] LC-MS: at 2.73RT, m / z 256 [M+H] + (98.24% purity).

[1152] HPLC: 97.70%.

[1153] Example 27

[1154] plan:

[1155]

[1156] 1-Cyclopropyl-5,6-difluoro-2-(6-(2,2,2-trifluoroethoxy)pyridazin-4-yl)-1H-benzo[d]imidazolium (Ex. 27)

[1157] Under an inert atmosphere, sodium hydride (55%, in mineral oil, 20 mg, 0.46 mmol) was added in portions to a stirred solution of 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole Ex. 22 (70 mg, 0.23 mmol) in 0.5 mL of DMF. The reaction mixture was stirred at 0 °C for 30 min. 2,2,2-trifluoroethane-1-ol (46 mg, 0.46 mmol) was added to the reaction mixture at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. After the starting material was consumed (monitored by TLC), the reaction mixture was terminated with ice-cold water (20 mL) and extracted with EtOAc (2 × 20 mL). The combined organic extracts were washed with water (10 mL) and brine (10 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude substance was purified by silica gel column chromatography (elution buffer: 30% EtOAc / hexane) to obtain 1-cyclopropyl-5,6-difluoro-2-(6-(2,2,2-trifluoroethoxy)pyridazin-4-yl)-1H-benzo[d]imidazole Ex.27 (50 mg, 0.13 mmol, 62%) as a grayish-white solid.

[1158]

[1159] LC-MS: at 3.18 RT, m / z 370.9 [M+1] + (99.73% purity).

[1160] HPLC: 98.32%.

[1161] Example 28

[1162] plan:

[1163]

[1164] 5-(1-Cyclopropyl-5,6-Difluoro-1H-benzo[d]imidazol-2-yl)-N-(2-methoxyethyl)pyridazine-3-amine (Ex. 28)

[1165] At room temperature and under an inert atmosphere, 2-methoxyethyl-1-amine (0.5 mL, 75.11 mmol) and diisopropylethylamine (0.5 mL) were added to a solution of 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole Ex. 22 (50 mg, 0.16 mmol) in THF (0.5 mL). The reaction mixture was stirred at 110 °C for 16 h. After the starting material was consumed (as monitored 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 Na2SO4 and concentrated under reduced pressure. The crude product was washed with CH2Cl2:hexane (1:9, 10 mL) to obtain 5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-N-(2-methoxyethyl)pyridazine-3-amine Ex. 28 (40 mg, 0.13 mmol, 92%) as a pale yellow solid.

[1166]

[1167] LC-MS: at 1.80 RT, m / z 346 [M+H] + (97.27% purity).

[1168] HPLC: 97.05%.

[1169] Example 29

[1170] plan:

[1171]

[1172] N-(4-cyano-2-(cyclopropylamino)phenyl)-6-methoxypyridazine-4-carboxamide

[1173] At room temperature and under an inert atmosphere, 6-methoxypyridazine-4-carboxylic acid (281 mg, 1.72 mmol), HATU (720 mg, 1.89 mmol), and diisopropylethylamine (0.8 mL, 5.17 mmol) were added to a stirred DMF solution of 4-amino-3-(cyclopropylamino)benzylnitrile Int-6 (300 mg, 1.72 mmol) in 5 mL. The reaction mixture was stirred at room temperature for 16 h. After the starting material was consumed (as monitored 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 Na₂SO₄ 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 could be used in the next step without further purification.

[1174] 1-Cyclopropyl-2-(6-Methoxypyridazin-4-yl)-1H-benzo[d]imidazol-6-carboxynitrile (Ex. 29)

[1175] Trifluoroacetic acid (0.5 mL) was added dropwise to a stirred solution of N-(4-cyano-2-(cyclopropylamino)phenyl)-6-methoxypyridazine-4-carboxamide (300 mg, crude) in 10 mL of CH₂Cl₂ under an inert atmosphere at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. After the starting material was consumed (monitored by TLC), volatiles were removed under reduced pressure. The residue was diluted with water (5 mL), alkalized with saturated sodium carbonate solution (20 mL), and extracted with CH₂Cl₂ (2 × 20 mL). The combined organic extracts were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude substance was purified by silica gel column chromatography (elution buffer: 2% MeOH / CH2Cl2) to obtain 1-cyclopropyl-2-(6-methoxypyridazin-4-yl)-1H-benzo[d]imidazol-6-carboxynitrile Ex.29 (40 mg, 0.13 mmol, 14% (two steps)) as a light yellow solid.

[1176]

[1177] LC-MS: at 2.25 RT, m / z 291.9 [M+H] + (95.84% purity).

[1178] HPLC: 97.16%.

[1179] Example 30

[1180] plan:

[1181]

[1182] 1-(2,2-Dibromovinyl)-4-fluoro-2-nitrobenzene

[1183] Carbon tetrabromide (5.8 g, 17.75 mmol) and triphenylphosphine (9.3 g, 35.50 mmol) were added to a stirred solution of 4-fluoro-2-nitrobenzaldehyde (2 g, 11.83 mmol) in CH₂Cl₂ (100 mL) under an inert atmosphere at 0 °C. The reaction mixture was stirred at 5 °C for 2 h. The reaction progress 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 product) as a brown solid, which could be used in the next step without further purification.

[1184] 2-(2,2-Dibromovinyl)-5-fluoroaniline

[1185] At room temperature and under an inert atmosphere, SnCl₂·H₂O (11.1 g, 46.29 mmol) was added to a stirred solution of 1-(2,2-dibromovinyl)-4-fluoro-2-nitrobenzene (3.2 g, 9.87 mmol) in 20 mL of EtOH. The reaction mixture was stirred under reflux for 2 h. The reaction progress was monitored by TLC; the volatiles were concentrated under reduced pressure. The resulting residue was alkalized to approximately pH 10 with potassium carbonate solution and extracted with EtOAc (2 × 50 mL). The combined organic extracts were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (elution: 10% EtOAc / hexane) to give 2-(2,2-dibromovinyl)-5-fluoroaniline (2.1 g, 7.14 mmol, 72%) as a brown solid.

[1186] LC-MS: at 3.34 RT, m / z 295.6 [M+2H] + (96.98% purity).

[1187] N-(2-(2,2-dibromovinyl)-5-fluorophenyl)methanesulfonamide

[1188] At 0 °C and under an inert atmosphere, pyridine (0.54 mL, 6.80 mmol) and methanesulfonyl chloride (0.38 mL, 5.10 mmol) were added to a stirred solution of 2-(2,2-dibromovinyl)-5-fluoroaniline (1 g, 3.40 mmol) in CH₂Cl₂ (10 mL). The reaction mixture was stirred at room temperature for 16 h. The reaction progress was monitored by TLC; the reaction mixture was terminated with NaHSO₄ solution and extracted with EtOAc (2 × 50 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 10% EtOAc / hexane) to give N-(2-(2,2-dibromovinyl)-5-fluorophenyl)methanesulfonamide (1.1 g, 2.94 mmol, 87%) as a brown solid.

[1189]

[1190] 2-Bromo-6-fluoro-1H-indole

[1191] At room temperature and under an inert atmosphere, a 1 M TBAF solution in THF (1 mL) was added to a stirred solution of N-(2-(2,2-dibromovinyl)-5-fluorophenyl)methanesulfonamide (200 mg, 0.53 mmol) in 2 mL of THF. The reaction mixture was stirred in a microwave at 100 °C for 5 min. The reaction progress was monitored by TLC; 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 Na₂SO₄ and concentrated under reduced pressure to give 2-bromo-6-fluoro-1H-indole 5 (100 mg, crude) as a brown solid, which could be used in the next step without further purification.

[1192] LC-MS: at 3.34 RT, m / z 295.6 [M+2H] + (96.98% purity).

[1193] 2-Bromo-1-cyclopropyl-6-fluoro-1H-indole

[1194] At room temperature and under an inert atmosphere, cyclopropylboronic acid (321 mg, 3.73 mmol), sodium carbonate (571 mg, 5.60 mmol), copper acetate (371 mg, 1.86 mmol), and bipyridine (291 mg, 1.86 mmol) were added to a stirred solution of 2-bromo-6-fluoro-1H-indole 5 (400 mg, 1.86 mmol) in 1,2-dichloroethane (5 mL). The reaction mixture was stirred in a sealed tube at 80 °C for 16 h. The reaction progress was monitored 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 Na₂SO₄, and concentrated under reduced pressure. The crude substance was purified by silica gel column chromatography (elution buffer: 10% EtOAc / hexane) to obtain 2-bromo-1-cyclopropyl-6-fluoro-1H-indole (300 mg, 1.19 mmol, 63%) as a brown solid.

[1195]

[1196] 1-Cyclopropyl-6-fluoro-2-(6-methylpyridazin-4-yl)-1H-indole (Ex. 30)

[1197] 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-dioxacyclopentaborane-2-yl)pyridazine (261 mg, 1.19 mmol) and sodium carbonate solution (2 M, 0.5 mL) were added, and the mixture was purged under argon for 10 min. Then, Pd(dppf)Cl2 (58 mg, 0.08 mmol) was added to the reaction mixture, and the mixture was stirred in a sealed tube at 80 °C for 16 h. The reaction progress was monitored 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 Na2SO4, and concentrated under reduced pressure. The crude substance was purified by silica gel column chromatography (elution buffer: 2% MeOH / CH2Cl2) to obtain 1-cyclopropyl-6-fluoro-2-(6-methylpyridazin-4-yl)-1H-indole Ex. 30 (36 mg, 0.13 mmol, 17%) as a light yellow solid.

[1198]

[1199] LC-MS: at 2.78 RT, m / z 267.9 [M+H] + (98.96% purity).

[1200] HPLC: 97.98%.

[1201] Example 31

[1202] plan:

[1203]

[1204] N-((5-(1-Cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methyl)ethanesulfonamide (Ex. 31)

[1205] At 0 °C and under an inert atmosphere, ethanesulfonyl chloride (16 mg, 0.12 mmol) and triethylamine (0.03 mL, 0.21 mmol) were added to a THF (2 mL) solution of (30 mg, 0.10 mmol) of (5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methyl)ethanesulfonamide Ex. 31 (15 mg, 0.04 mmol, 38%). The reaction mixture was stirred at room temperature for 1 h. After the starting material was consumed (monitored 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 Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give N-((5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methyl)ethanesulfonamide Ex. 31 (15 mg, 0.04 mmol, 38%) as a white solid.

[1206]

[1207] LC-MS: at 2.21RT, m / z 376 [M+H] + (99.12% purity).

[1208] HPLC: 98.34%.

[1209] Example 32

[1210] plan:

[1211]

[1212] 5-(1-Cyclopropyl-5,6-Difluoro-1H-Benz[d]imidazol-2-yl)-N-(2,2,2-trifluoroethyl)pyridazine-3-amine (Ex. 32)

[1213] 2,2,2-trifluoroethyl-1-amine (1.2 mL) was added to a stirred NMP (1.2 mL) solution of 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole Ex.22 (80 mg, 0.26 mmol) at room temperature and under an inert atmosphere. The reaction mixture was stirred in a microwave at 130 °C for 6 h. After the starting material was consumed (as monitored 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 Na2SO4 and concentrated under reduced pressure. The crude substance was purified by silica gel column chromatography (elution buffer: 3% MeOH / CH3Cl2) to obtain 5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-N-(2,2,2-trifluoroethyl)pyridazine-3-amine Ex. 32 (15 mg, 0.04 mmol, 15%) as a light yellow solid.

[1214]

[1215] LC-MS: at 2.21RT, m / z 370 [M+H] + (97.23% purity).

[1216] HPLC: 97.15%.

[1217] Example 33

[1218] plan:

[1219]

[1220] 1-Cyclopropyl-5,6-difluoro-2-(6-vinylpyridazin-4-yl)-1H-benzo[d]imidazole

[1221] At room temperature and under an inert atmosphere, to a stirred solution of 2-(6-chloropyridazine-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole Ex.22 (150 mg, 0.50 mmol) in 1,4-dioxane (3 mL) and water (0.5 mL), add vinylboronic acid pinacol ester (76 mg, 0.50 mmol) and potassium carbonate (203 mg, 1.47 mmol). The reaction mixture was degassed with argon for 10 min, and Pd(dppf)Cl2 (4 mg, 0.005 mmol) was added. The reaction mixture was then degassed with argon for another 10 min. The reaction mixture was heated to 80 °C and stirred for 5 h. After the starting material was consumed (monitored by TLC), the volatiles were concentrated under reduced pressure. The crude substance was purified by silica gel column chromatography (elution buffer: 50% EtOAc / hexane) to obtain 1-cyclopropyl-5,6-difluoro-2-(6-vinylpyridazin-4-yl)-1H-benzimidazole (70 mg, 0.23 mmol, 48%) as a grayish-white solid.

[1222]

[1223] 1-Cyclopropyl-2-(6-ethylpyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (Ex. 33)

[1224] At room temperature and under an inert atmosphere, 10% Pd / C (20 mg) and triethylamine (catalytic amount) were added to a 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). The reaction mixture was stirred at room temperature under a hydrogen atmosphere (balloon pressure) for 5 h. After the starting material was consumed (monitored by TLC), the reaction mixture was filtered through a diatomaceous earth pad and washed, 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 / CH2Cl2) to give 1-cyclopropyl-2-(6-ethylpyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole Ex. 33 (35 mg, 0.11 mmol, 50%) as a grayish-white solid.

[1225]

[1226] LC-MS: at 2.51 RT, m / z 300.9 [M+H] + (98.98% purity).

[1227] HPLC: 97.01%.

[1228] Example 34

[1229] plan:

[1230]

[1231] 2-(6-Chlorpyridazin-4-yl)-1-cyclopropyl-1H-benzo[d]imidazol-6-carboxynitrile (Ex. 34)

[1232] At room temperature and under an inert atmosphere, phosphoric acid chloride (POCl3) (0.38 mL, 4.13 mmol) was added to a stirred solution of 1-cyclopropyl-2-(6-methoxypyridazin-4-yl)-1H-benzo[d]imidazolium-6-carboxynitrile Ex.29 (60 mg, 0.20 mmol). The reaction mixture was heated to 100 °C and stirred for 2 h. After the starting material was consumed (monitored by TLC), the reaction mixture was alkalized with saturated sodium carbonate solution (30 mL) and extracted with EtOAc (2 × 30 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 50% EtOAc / hexane) to give 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-1H-benzo[d]imidazolium-6-carboxynitrile Ex.34 (10 mg, 0.03 mmol, 16%) as a white solid.

[1233]

[1234] LC-MS: at 3.28 RT, m / z 296.2 [M+H] + (96.40% purity).

[1235] HPLC: 96.31%.

[1236] Example 35

[1237] plan:

[1238]

[1239] 3-Cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-carboxynitrile

[1240] At room temperature and under an inert atmosphere, 1,1'-carbonyldiimidazole (CDI) (702 mg, 4.33 mmol) was added to a stirred DMF (10 mL) solution of 4-amino-3-(cyclopropylamino)benzylnitrile Int-6 (500 mg, 2.89 mmol). The reaction mixture was stirred at room temperature for 16 h. After the starting material was consumed (monitored 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 Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 30% to 40% EtOAc / hexane) to give 3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazolium-5-carboxynitrile (200 mg, 1.00 mmol, 35%) as a grayish-white solid.

[1241]

[1242] 2-Bromo-1-cyclopropyl-1H-benzo[d]imidazol-6-carboxynitrile

[1243] At room temperature and under an inert atmosphere, phosphoryl bromide (1.2 g, 4.02 mmol) was added to a stirred solution of 2-bromo-3-cyclopropyl-2,3-dihydro-1H-benzo[d]imidazolium-5-carboxynitrile (200 mg, 1.0 mmol) in 1,2-dichloroethane (DCE) (4 mL). The reaction mixture was heated to 80 °C and stirred for 16 h. After the starting material was consumed (as monitored by TLC), the reaction mixture was diluted with water (20 mL), alkalized with saturated sodium carbonate solution (30 mL), and extracted with CH2Cl2 (2 × 30 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 2-bromo-3-cyclopropyl-2,3-dihydro-1H-benzo[d]imidazolium-5-carboxynitrile (50 mg, 0.20 mmol, 19%) as a white solid, which could be used in the next step without further purification.

[1244] LC-MS: at 2.52 RT, m / z 261.8 [M+] + (96.21% purity).

[1245] 1-Cyclopropyl-2-(6-methylpyridazin-4-yl)-1H-benzo[d]imidazol-6-carboxynitrile (Ex. 35)

[1246] At room temperature and under an inert atmosphere, 3-methyl-5-(4,4,5,5-tetramethyl-1H-benzo[d]imidazolium-5-carboxynitrile (100 mg, 0.38 mmol) and 2M sodium carbonate aqueous solution (0.3 mL, 0.64 mmol) were added to a stirred solution of 1,4-dioxane (3 mL) at room temperature and an inert atmosphere. The reaction mixture was degassed with argon for 10 min, and Pd(dppf)Cl2 (23 mg, 0.03 mmol) was added. The mixture was then degassed with argon for another 10 min. The reaction mixture was heated to 90 °C and stirred for 16 h. After the starting material was consumed (monitored by TLC), the volatiles were concentrated under reduced pressure. The crude substance was purified by silica gel column chromatography (elution buffer: 50% EtOAc / hexane) to obtain 1-cyclopropyl-2-(6-methylpyridazin-4-yl)-1H-benzo[d]imidazolium-6-carboxynitrile Ex. 35 (20 mg, 0.07 mmol, 12%) as a grayish-white solid.

[1247]

[1248] LC-MS: at 2.02 RT, m / z 275.9 [M+H] + (99.65% purity).

[1249] HPLC: 99.26%.

[1250] Example 36

[1251] plan:

[1252]

[1253] 1-Cyclopropyl-5,6-Difluoro-2-(6-(4-methylpiperazin-1-yl)pyridazin-4-yl)-1H-benzo[d]imidazolium (Ex. 36)

[1254] A solution of 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazolium Ex. 22 (50 mg, 0.16 mmol) in 1-methylpiperazine (0.5 mL) was stirred at 130 °C for 3 h under an inert atmosphere. After the starting material was consumed (monitored 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 Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (elution: 5% MeOH / CH2Cl2) to give 1-cyclopropyl-5,6-difluoro-2-(6-(4-methylpiperazin-1-yl)pyridazin-4-yl)-1H-benzo[d]imidazolium Ex. 36 (25 mg, 0.06 mmol, 41%) as a pale yellow solid.

[1255]

[1256] LC-MS: at 1.71 RT, m / z 371 [M+H] + (98.46% purity).

[1257] HPLC: 97.35%.

[1258] Example 37

[1259] plan:

[1260]

[1261] 1-Cyclopropyl-5,6-Difluoro-2-(6-(piperazin-1-yl)pyridazin-4-yl)-1H-benzo[d]imidazolium

[1262] Trifluoroacetic acid (0.6 mL) was added to a stirred solution of 2 mL CH₂Cl₂ containing 200 mg (0.43 mmol) of 4-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)piperazine-1-carboxylic acid tert-butyl ester Ex.39, under an inert atmosphere at 0 °C. The reaction mixture was warmed to room temperature and stirred for 1 h. After the starting material was consumed (as monitored by TLC), 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 Na₂SO₄ and concentrated under reduced pressure. The crude product was washed with diethyl ether: n-pentane (1:1, 2×2 mL) to give 1-cyclopropyl-5,6-difluoro-2-(6-(piperazin-1-yl)pyridazin-4-yl)-1H-benzis[d]imidazole (90 mg, crude product) as a brown solid, which can be used in the next step without further purification.

[1263] LC-MS: at 1.78 RT, m / z 357 [M+H] + (98.01% purity).

[1264] 1-(4-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)piperazin-1-yl)acet-1-one (Ex. 37)

[1265] Triethylamine (0.05 mL, 0.42 mmol) and acetyl chloride (0.01 mL, 0.14 mmol) were added to a stirred solution of 1-cyclopropyl-5,6-difluoro-2-(6-(piperazin-1-yl)pyridazin-4-yl)-1H-benzi[d]imidazole (50 mg, 0.14 mmol) in CH2Cl2 (1 mL) under an inert atmosphere. The reaction mixture was stirred at 0 °C for 10 min. After the starting material was consumed (as monitored by TLC), the reaction mixture was diluted with saturated sodium bicarbonate solution (20 mL) and extracted with CH2Cl2 (2 × 20 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude substance was purified by silica gel column chromatography (elution buffer: 5% MeOH / CH2Cl2) to obtain 1-(4-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)piperazin-1-yl)ethyl-1-one Ex. 37 (14 mg, 0.03 mmol, 25%) as a light yellow solid.

[1266]

[1267] LC-MS: at 1.57 RT, m / z 399.1 [M+H] + (93.31% purity).

[1268] HPLC: 92.89%.

[1269] Example 38

[1270] plan:

[1271]

[1272] 1-Cyclopropyl-5,6-difluoro-2-(6-(4-(methanesulfonyl)piperazin-1-yl)pyridazin-4-yl)-1H-benzo[d]imidazolium (Ex. 38)

[1273] Under an inert atmosphere, triethylamine (0.05 mL, 0.42 mmol) and methanesulfonyl chloride (0.01 mL, 0.14 mmol) were added to a stirred solution of 1-cyclopropyl-5,6-difluoro-2-(6-(piperazin-1-yl)pyridazin-4-yl)-1H-benzi[d]imidazole (50 mg, 0.14 mmol) in CH2Cl2 (1 mL). The reaction mixture was stirred for 10 min. After the starting material was consumed (monitored by TLC), the reaction mixture was diluted with saturated sodium bicarbonate solution (20 mL) and extracted with CH2Cl2 (2 × 20 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude substance was purified by silica gel column chromatography (elution buffer: 5% MeOH / CH2Cl2) to obtain 1-cyclopropyl-5,6-difluoro-2-(6-(4-(methanesulfonyl)piperazin-1-yl)pyridazin-4-yl)-1H-benzo[d]imidazolium Ex. 38 (14 mg, 0.03 mmol, 25%) as a light yellow solid.

[1274]

[1275] LC-MS: at 2.09 RT, m / z 435.1 [M+H] + (98.86% purity).

[1276] HPLC: 97.10%.

[1277] Example 39

[1278] plan:

[1279]

[1280] 4-(5-(1-Cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)piperazine-1-carboxylic acid tert-butyl ester (Ex. 39)

[1281] At room temperature and under an inert atmosphere, tert-butyl piperazine-1-carboxylic acid (729 mg, 3.97 mmol) was added to a stirred solution of 2-(6-chloropyridazine-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole Ex. 22 (200 mg, 0.65 mmol) in dimethyl sulfoxide (DMSO) (4 mL). The reaction mixture was stirred at 130 °C for 3 h. After the starting material was consumed (as monitored 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) and brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 5% MeOH / CH2Cl2) to give Ex. 39 (230 mg, 0.50 mmol, 77%) as a brown solid.

[1282]

[1283] LC-MS: at 2.52 RT, m / z 457.1 [M+H] + (97.87% purity).

[1284] HPLC: 95.78%.

[1285] Examples 40 and 41

[1286] plan:

[1287]

[1288] 6-Chloro-N-(4-cyano-2-(ethylamino)phenyl)pyridazine-4-carboxamide

[1289] Under an inert atmosphere, 4-amino-3-(ethylamino)benzylnitrile Int-4 (104 mg, 0.64 mmol), HATU (369.9 mg, 0.97 mmol), and diisopropylethylamine (0.45 mL, 2.59 mmol) were added to a stirred DMF (2 mL) solution of 6-chloropyridazine-4-carboxylic acid (100 mg, 0.64 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 h. After the starting material was consumed (as monitored by TLC), the reaction mixture was diluted with an aqueous ammonium chloride solution (30 mL) and extracted with EtOAc (2 × 30 mL). The combined organic extracts were dried over anhydrous Na₂SO₄ 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.

[1290] LC-MS: at 2.07 RT, m / z 300.9 [M] + (36.25% purity).

[1291] 1-Ethyl-2-(6-methoxypyridazin-4-yl)-1H-benzo[d]imidazol-6-carboxynitrile (Ex. 40)

[1292] Trifluoroacetic acid (0.4 mL) was added to a stirred solution of 6-chloro-N-(4-cyano-2-(ethylamino)phenyl)pyridazin-4-carboxamide (100 mg, 0.33 mmol) in CH2Cl2 (1.6 mL) under an inert atmosphere at 0 °C. The reaction mixture was stirred at 0 °C for 6 h. After the starting material was consumed (as monitored by TLC), the reaction mixture was diluted with saturated sodium bicarbonate solution (20 mL) and extracted with EtOAc (2 × 30 mL). The combined organic extracts were washed with water (20 mL) and brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was ground with diethyl ether (2 × 10 mL) and n-pentane (2 × 10 mL) to give 1-ethyl-2-(6-methoxypyridazin-4-yl)-1H-benzo[d]imidazolium-6-carboxynitrile Ex. 40 (25 mg, 0.09 mmol, 26%) as a grayish-white solid.

[1293]

[1294] LC-MS: at 2.15 RT, m / z 279.8 [M+H] + (98.27% purity).

[1295] HPLC: 98.65%.

[1296] 2-(6-Chlorpyridazin-4-yl)-1-ethyl-1H-benzo[d]imidazol-6-carboxynitrile (Ex. 17)

[1297] At room temperature and under an inert atmosphere, phosphoryl chloride (0.57 mL, 6.09 mmol) was added to a stirred solution of 1-ethyl-2-(6-methoxypyridazin-4-yl)-1H-benzo[d]imidazol-6-carboxynitrile Ex. 40 (85 mg, 0.30 mmol). The reaction mixture was heated to 100 °C and maintained for 2 h. After the starting material was consumed (monitored by TLC), the reaction mixture was alkalized with an aqueous sodium carbonate solution (20 mL) and extracted with EtOAc (2 × 20 mL). The combined organic extracts were washed with water (10 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude product was ground with diethyl ether (2 × 5 mL) and n-pentane (2 × 5 mL) to give 2-(6-chloropyridazin-4-yl)-1-ethyl-1H-benzo[d]imidazol-6-carboxynitrile Ex. 17 (100 mg, crude product) as a pale yellow paste, which could be used in the next step without further purification.

[1298] 1-Ethyl-2-(6-vinylpyridazin-4-yl)-1H-benzo[d]imidazol-6-carboxynitrile

[1299] At room temperature and under an inert atmosphere, pinacol vinylborate (70 mg, 0.46 mmol) and potassium carbonate (190 mg, 1.37 mmol) were added to a stirred solution of 2-(6-chloropyridazine-4-yl)-1-ethyl-1H-benzo[d]imidazol-6-carboxynitrile Ex. 17 (130 mg, 0.46 mmol) in 1,4-dioxane (3 mL) and water (0.5 mL). The reaction mixture was degassed with argon for 10 min. At room temperature, Pd(dppf)Cl2 (3.7 mg, 0.005 mmol) was added, and the mixture was degassed with argon for another 10 min. The reaction mixture was heated to 80 °C and stirred for 4 h. After the starting material was consumed (monitored 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]imidazol-6-carboxynitrile (110 mg, crude product) as a brown paste.

[1300] LC-MS: at 2.18 RT, m / z 275.9 [M+H] + (78.16% purity).

[1301] 1-Ethyl-2-(6-ethylpyridazin-4-yl)-1H-benzo[d]imidazol-6-carboxynitrile (Ex. 41)

[1302] At room temperature and under an inert atmosphere, 10% Pd / C (50% wet basis, 20 mg) and triethylamine (0.005 mL, 0.04 mmol) were added to a solution of 1-ethyl-2-(6-vinylpyridazin-4-yl)-1H-benzo[d]imidazol-6-carboxynitrile (110 mg, 0.40 mmol) in EtOAc (5 mL). The reaction mixture was stirred at room temperature under a hydrogen atmosphere (balloon pressure) for 2 h. After the starting material was consumed (as monitored by TLC), the reaction mixture was filtered through a diatomaceous earth pad 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]imidazol-6-carboxynitrile Ex. 41 (4 mg, 14.44 mmol, 4%) as a grayish-white solid.

[1303]

[1304] LC-MS: at 2.12 RT, m / z 277.9 [M+H] + (96.23% purity).

[1305] HPLC: 96.66%.

[1306] Example 42

[1307] plan:

[1308]

[1309] 1-Cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (Ex. 42)

[1310] At 0 °C and under an inert atmosphere, (diethylamino)sulfur trifluoride (DAST) (0.09 mL, 0.66 mmol) was added to a stirred CH2Cl2 (5 mL) solution of 5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-carboxaldehyde Int-27 (100 mg, 0.33 mmol). The reaction mixture was warmed to room temperature and stirred for 1 h. After the starting material was consumed (monitored by TLC), the reaction mixture was diluted with saturated sodium carbonate solution (20 mL) and extracted with CH2Cl2 (2 × 20 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (elution: 50% EtOAc / hexane) to give 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazolium Ex.42 (40 mg, 0.12 mmol, 37%) as a brown solid.

[1311]

[1312] LC-MS: at 3.53 RT, m / z 323.3 [M+H] + (98.91% purity).

[1313] HPLC: 99.33%.

[1314] Example 43

[1315] plan:

[1316]

[1317] 2-(6-Cyclobutoxypyridazine-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole (Ex. 43)

[1318] Sodium hydride (60%, in mineral oil, 16.3 mg, 0.41 mmol) was added fractionally to a stirred DMF (2 mL) solution of 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole Ex. 22 (50 mg, 0.16 mmol) in mineral oil. The reaction mixture was stirred at 0 °C for 10 min. Cyclobutanol (141 mg, 0.20 mmol) was then added to the reaction mixture at 0 °C. The reaction mixture was warmed to room temperature and stirred for 1 h. After the starting material was consumed (as monitored by TLC), the reaction mixture was terminated with ice-cold water (20 mL) and extracted with EtOAc (2 × 20 mL). The combined organic extracts were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude substance was purified by silica gel column chromatography (elution buffer: 3% MeOH / CH2Cl2) to obtain 2-(6-cyclobutoxypyridazine-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole Ex.43 (45 mg, 0.13 mmol, 57%) as a grayish-white solid.

[1319]

[1320] LC-MS: at 2.61 RT, m / z 343 [M+H] + (95.30% purity).

[1321] HPLC: 95.28%.

[1322] Example 44

[1323] plan:

[1324]

[1325] 1-Cyclopropyl-2-(6-(4,4-difluoropiperidin-1-yl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazolium (Ex. 44)

[1326] At room temperature and under an inert atmosphere, 4,4-difluoropiperidine (59 mg, 0.49 mmol) was added to a stirred solution of 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole Ex. 22 (100 mg, 0.32 mmol) in DMSO (2 mL). The reaction mixture was heated to 120-130 °C and stirred for 16 h. After the starting material was consumed (as monitored 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 Na₂SO₄ and concentrated under reduced pressure. The crude substance was purified by silica gel column chromatography (elution buffer: 50% to 60% EtOAc / hexane) to obtain 1-cyclopropyl-2-(6-(4,4-difluoropiperidin-1-yl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole Ex.44 (40 mg, 0.10 mmol, 32%) as a grayish-white solid.

[1327]

[1328] LC-MS: at 2.98 RT, m / z 392.1 [M+H] + (93.89% purity).

[1329] HPLC: 92.05%.

[1330] Example 45

[1331] plan:

[1332]

[1333] 6-Methylpyridazine-4-carboxylic acid

[1334] Sodium hydroxide (395 mg, 9.80 mmol) and 10% Pd / C (50% wet basis, 150 mg) were added to a stirred solution of 3-chloro-6-methylpyridazine-4-carboxylic acid 1 (500 mg, 2.90 mmol) in 50 mL of MeOH at room temperature and under an inert atmosphere. The reaction mixture was stirred at room temperature under a hydrogen atmosphere (balloon pressure) for 1 h. After the starting material was consumed (as monitored by TLC), the reaction mixture was filtered through a diatomaceous earth pad. The filtrate was concentrated under reduced pressure, and 6N HCl was added to bring the pH to approximately 6 and concentrated under reduced pressure to give 6-methylpyridazine-4-carboxylic acid (410 mg, crude) as a yellow liquid, which could be used in the next step without further purification.

[1335]

[1336] N-(6-chloro-2-(cyclopropylamino)pyridin-3-yl)-6-methylpyridazine-4-carboxamide

[1337] At room temperature and under an inert atmosphere, 6-chloro-N 2 To a DMF (5 mL) solution of cyclopropylpyridine-2,3-diamine Int-8 (400 mg, 2.18 mmol), compounds 6-methylpyridazine-4-carboxylic acid (362 mg, 2.62 mmol), HATU (996 mg, 2.62 mmol), and diisopropylethylamine (1.6 mL, 8.75 mmol) were added. The reaction mixture was stirred at room temperature for 16 h. After the starting material was consumed (monitored 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 Na₂SO₄ 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 could be used in the next step without further purification.

[1338] LC-MS: at 2.06 RT, m / z 303.9 [M+H] + (93.73% purity).

[1339] 5-Chloro-3-cyclopropyl-2-(6-methylpyridazin-4-yl)-3H-imidazo[4,5-b]pyridine (Ex. 45)

[1340] At 0 °C and under an inert atmosphere, 6N HCl (3 mL) was added to a stirred EtOH (2 mL) solution of N-(6-chloro-2-(cyclopropylamino)pyridin-3-yl)-6-methylpyridazin-4-carboxamide (100 mg, 0.33 mmol). The reaction mixture was stirred at room temperature for 1 h. After the starting material was consumed (monitored 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 Na₂SO₄ 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 Ex. 45 (12 mg, 0.04 mmol, 10%) as a brown solid.

[1341]

[1342] LC-MS: at 2.03 RT, m / z 285.9 [M+H] + (98.73% purity).

[1343] HPLC: 95.65%.

[1344] Example 46

[1345] plan:

[1346]

[1347] 1-Cyclopropyl-2-(6-(3,3-difluoropyrrolidone-1-yl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazolium (Ex. 46)

[1348] At room temperature and under an inert atmosphere, 3,3-difluoropyrrolidine hydrochloride (70 mg, 0.50 mmol) and triethylamine (0.06 mL, 0.49 mmol) were added to a stirred solution of 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazolium Ex.22 (100 mg, 0.32 mmol) in DMSO (2 mL). The reaction mixture was heated to 130 °C and stirred for 48 h. After the starting material was consumed (as monitored 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 Na2SO4 and concentrated under reduced pressure. The crude substance was purified by preparative HPLC to obtain 1-cyclopropyl-2-(6-(3,3-difluoropyrrolidone-1-yl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole Ex.46 (15 mg, 0.04 mmol, 12%) as a grayish-white solid.

[1349]

[1350] LC-MS: at 2.80 RT, m / z 378.1 [M+H] + (97.60% purity).

[1351] HPLC: 99.55%.

[1352] Example 47

[1353] plan:

[1354]

[1355] 1-(5-(1-Cyclopropyl-5,6-Difluoro-1H-Benz[d]imidazol-2-yl)pyridazin-3-yl)-2,2,2-trifluoroethane-1-ol (Ex. 47)

[1356] Trimethyl(trifluoromethyl)silane (47 mg, 0.33 mmol) was added to a stirred THF (1 mL) solution of 5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-carboxaldehyde Int-27 (50 mg, 0.16 mmol) in 0 °C under an inert atmosphere. 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 (monitored by TLC), the reaction mixture was terminated at 0 °C with 1 N HCl solution (5 mL) and extracted with EtOAc (2 × 15 mL). The combined organic extracts were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude substance was purified by silica gel column chromatography (elution buffer: 50% EtOAc / hexane) to obtain 1-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)-2,2,2-trifluoroethane-1-ol Ex.47 (10 mg, 0.03 mmol, 16%) as a brown solid.

[1357]

[1358] LC-MS: at 2.69 RT, m / z 371 [M+H] + (95.24% purity).

[1359] HPLC: 95.69%.

[1360] Example 48

[1361] plan:

[1362]

[1363] 1-(5-(1-Cyclopropyl-5,6-Difluoro-1H-Benz[d]imidazol-2-yl)pyridazin-3-yl)-N,N-Dimethylpyrrolidine-3-amine (Ex. 48)

[1364] Under an inert atmosphere, triethylamine (0.116 mL, 0.84 mmol) and 1-(3-(dimethylamino)-1,5-pyrrolidine-1-yl)-2,2,2-trifluoroethane-1-one (120 mg, 0.56 mmol) were added to a stirred solution of 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole Ex.22 (115 mg, 0.37 mmol) in DMSO (2 mL) were added. The reaction mixture was stirred at 90 °C for 5 h. After the starting material was consumed (as monitored by TLC), the reaction mixture was diluted with ice water (10 mL) and extracted with EtOAc (2 × 10 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude substance was purified by silica gel column chromatography (elution buffer: 5% to 10% MeOH / CH2Cl2) to obtain 1-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)-N,N-dimethylpyrrolidine-3-amine Ex.48 (10 mg, 0.02 mmol, 7%) as a grayish-white solid.

[1365]

[1366] LC-MS: at 2.06 RT, m / z 385.1 [M+H] + (97.17% purity).

[1367] HPLC: 98.58%.

[1368] Example 49

[1369] plan:

[1370]

[1371] 1-Cyclopropyl-5,6-difluoro-2-(6-(4-fluorophenyl)pyridazin-4-yl)-1H-benzo[d]imidazolium (Ex. 49)

[1372] Pd(PPh3)2Cl2 (11.5 mg, 0.01 mmol) and sodium carbonate (86.4 mg, 0.81 mmol) were purged under argon for 5 min at room temperature in a mixture of 1,4-dimethoxyethane (DME):water (4:1, 1.25 mL). 3-(6-chloropyridazin-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazolium Ex.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 h. After the starting material was consumed (monitored by TLC), the reaction mixture was diluted with water (20 mL) and extracted with CH2Cl2 (2 × 20 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude substance was purified by silica gel column chromatography (elution buffer: 2% MeOH / CH2Cl2) to obtain 1-cyclopropyl-5,6-difluoro-2-(6-(4-fluorophenyl)pyridazin-4-yl)-1H-benzo[d]imidazole Ex. 49 (40 mg, 0.10 mmol, 48%) as a grayish-white solid.

[1373]

[1374] LC-MS: at 2.58RT, m / z 367 [M+H] + (98.75% purity).

[1375] HPLC: 98.72%.

[1376] Example 50

[1377] plan:

[1378]

[1379] 1-Cyclopropyl-5,6-difluoro-2-(6-((4-fluorophenyl)ethynyl)pyridazin-4-yl)-1H-benzo[d]imidazolium (Ex. 50)

[1380] At room temperature and under an inert atmosphere, 1-ethynyl-4-fluorobenzene (40 mg, 0.32 mmol) and potassium carbonate (90 mg, 0.65 mmol) were added to a stirred solution of 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole Ex.22 (100 mg, 0.32 mmol) in N,N-dimethylacetamide (DMA) (3 mL). The reaction mixture was degassed with argon for 10 minutes. At room temperature, Pd2(dba)3 (14.8 mg, 0.01 mmol) and 2-(dicyclohexylphosphine)-2',4',6'-triisopropylbiphenyl (X-phos) (8 mg, 0.01 mmol) were added, and the mixture was degassed with argon for another 5 minutes. The reaction mixture was heated to 80 °C and stirred for 2 h. After the raw materials were consumed (monitored 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 Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (elution: 30% EtOAc / hexane) to give 1-cyclopropyl-5,6-difluoro-2-(6-((4-fluorophenyl)ethynyl)pyridazin-4-yl)-1H-benzo[d]imidazolium Ex. 50 (50 mg, 0.13 mmol, 39%) as a brown solid.

[1381]

[1382] LC-MS: at 4.58 RT, m / z 391.3 [M+H] + (97.94% purity).

[1383] HPLC: 96.14%.

[1384] Example 51

[1385] plan:

[1386]

[1387] 1-Cyclopropyl-5,6-Difluoro-2-(6-(prop-1-en-2-yl)pyridazin-4-yl)-1H-benzo[d]imidazolium

[1388] To a stirred solution of 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazolium Ex.22 (120 mg, 0.40 mmol) in 1,4-dioxane (3.2 mL) and water (0.8 mL), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxane-pentaborane (219 mg, 1.17 mmol) and sodium carbonate (164.6 mg, 1.56 mmol) were added, and the mixture was purged with argon at room temperature for 10 min. Pd(PPh3)4 (23 mg, 0.02 mmol) was added to the reaction mixture. The reaction mixture was stirred at 110 °C for 8 h. After the starting materials were consumed (as monitored by TLC), the reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The crude product was ground with n-pentane (2 × 5 mL) to obtain 1-cyclopropyl-5,6-difluoro-2-(6-(prop-1-en-2-yl)pyridazin-4-yl)-1H-benzimidazole (100 mg, crude product) as a grayish-white solid, which can be used in the next step without further purification.

[1389] LC-MS: at 2.38 RT, m / z 313.1 [M+H] + (94.08% purity).

[1390] 1-Cyclopropyl-5,6-Difluoro-2-(6-isopropylpyridazin-4-yl)-1H-benzo[d]imidazolium (Ex. 51)

[1391] At room temperature and under an inert atmosphere, triethylamine (0.04 mL), sodium hydroxide (25 mg, 0.64 mmol), and 10% Pd / C (50% wet basis, 30 mg) were added to a stirred ethyl acetate (5 mL) solution of 1-cyclopropyl-5,6-difluoro-2-(6-(prop-1-en-2-yl)pyridazin-4-yl)-1H-benzis[d]imidazole (100 mg, 0.32 mmol). The reaction mixture was stirred at room temperature under a hydrogen atmosphere (balloon pressure) for 1 h. After the starting material was consumed (as monitored by TLC), the reaction mixture was filtered through a diatomaceous earth bed and the bed was washed with EtOAc (20 mL). The filtrate was concentrated under reduced pressure. The crude product was washed with n-pentane (2×2 mL) and diethyl ether (2×2 mL) to give 1-cyclopropyl-5,6-difluoro-2-(6-isopropylpyridazin-4-yl)-1H-benzo[d]imidazolium Ex. 51 (55 mg, 0.17 mmol, 55%) as a grayish-white solid.

[1392]

[1393] LC-MS: at 2.31 RT, m / z 315.1 [M+H] +(97.95% purity).

[1394] HPLC: 99.16%.

[1395] Example 52

[1396] plan:

[1397]

[1398] N-((5-(1-Cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methyl)ethanesulfonamide (Ex. 52)

[1399] Triethylamine (0.19 mL, 0.79 mmol) and ethanesulfonyl chloride (65.7 mg, 0.51 mmol) were added to a stirred solution of (140 mg, 0.46 mmol) of methylamine in CH2Cl2 (4 mL) at room temperature and under an inert atmosphere. The reaction mixture was stirred at room temperature for 1 h. After the starting material was consumed (as monitored by TLC), the reaction mixture was diluted with water (20 mL) and extracted with CH2Cl2 (2 × 20 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude substance was purified by preparative HPLC to obtain N-((5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methyl)ethanesulfonamide Ex.52 (18 mg, 0.04 mmol, 10%) as a white solid.

[1400]

[1401] LC-MS: at 2.32 RT, m / z 394 [M+H] + (99.29% purity).

[1402] HPLC: 98.78%.

[1403] Example 53

[1404] plan:

[1405]

[1406] 1-Cyclopropyl-5,6-difluoro-2-(6-((1,1,1-trifluoroprop-2-yl)oxy)pyridazin-4-yl)-1H-benzo[d]imidazolium (Ex. 53)

[1407] Under an inert atmosphere, sodium hydride (60%, in mineral oil, 24.5 mg, 0.61 mmol) was added in portions to a stirred solution of 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole Ex. 22 (75 mg, 0.24 mmol) in 2.25 mL of DMF. The reaction mixture was stirred at 0 °C for 10 min. Then, 1,1,1-trifluoroprop-2-ol (34 mg, 0.30 mmol) was added to the reaction mixture at 0 °C. The reaction mixture was warmed to room temperature and stirred for 1 h. After the starting material was consumed (as monitored by TLC), the reaction mixture was terminated with ice water (20 mL) and extracted with EtOAc (2 × 20 mL). The combined organic extracts were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude substance was purified by silica gel column chromatography (elution buffer: 3% MeOH / CH2Cl2) to obtain 1-cyclopropyl-5,6-difluoro-2-(6-((1,1,1-trifluoroprop-2-yl)oxy)pyridazin-4-yl)-1H-benzo[d]imidazolium Ex. 53 (60 mg, 0.15 mmol, 84%) as a brown solid.

[1408]

[1409] LC-MS: at 2.76 RT, m / z 385.1 [M+H] + (97.88% purity).

[1410] HPLC: 97.83%.

[1411] Example 54

[1412] plan:

[1413]

[1414] 3-Cyclopropyl-2-(6-methylpyridazin-4-yl)-3H-imidazo[4,5-b]pyridine-5-carboxylonitrile (Ex. 54)

[1415] Zinc cyanide (61.5 mg, 0.52 mmol) and Pd(PPh3)4 (30.3 mg, 0.02 mmol) were added to a stirred solution of 5-chloro-3-cyclopropyl-2-(6-methylpyridazin-4-yl)-3H-imidazo[4,5-b]pyridine Ex. 45 (75 mg, 0.26 mmol) in DMF (0.8 mL) at room temperature. The mixture was purged with argon for 10 min and then heated to 170 °C and held for 4.5 h. After the starting material was consumed (monitored by TLC), the reaction mixture was diluted with ice water (20 mL) and extracted with EtOAc (2 × 20 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by preparative HPLC to obtain 3-cyclopropyl-2-(6-methylpyridazin-4-yl)-3H-imidazo[4,5-b]pyridine-5-carboxylonite Ex.54 (25 mg, 0.09 mmol, 35%) as a grayish-white solid.

[1416]

[1417] LC-MS: at 1.88 RT, m / z 276.9 [M+H] + (98.98% purity).

[1418] HPLC: 95.03%.

[1419] Example 55

[1420] plan:

[1421]

[1422] N-(2-(cyclopropylamino)-4,5-difluorophenyl)pyridazine-4-carboxamide

[1423] At room temperature and under an inert atmosphere, N was stirred. 1 To a DMF (3 mL) solution of cyclopropyl-4,5-difluorophenyl-1,2-diamine Int-5 (300 mg, 1.63 mmol), pyridazine-4-carboxylic acid (202 mg, 1.63 mmol), HATU (743 mg, 1.95 mmol), and diisopropylethylamine (1.1 mL, 6.52 mmol) were added. The reaction mixture was stirred at room temperature for 16 h. After the starting material was consumed (monitored 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 Na₂SO₄ and concentrated under reduced pressure to give N-(2-(cyclopropylamino)-4,5-difluorophenyl)pyridazine-4-carboxamide (250 mg, crude) as a grayish-white solid, which could be used in the next step without further purification.

[1424] LC-MS: at 2.34 RT, m / z 291 [M+H] + (96.97% purity).

[1425] 1-Cyclopropyl-5,6-Difluoro-2-(pyridazin-4-yl)-1H-benzo[d]imidazolium (Ex. 55)

[1426] At room temperature and under an inert atmosphere, 2 mL of 6N HCl was added to a stirred EtOH solution of N-(2-(cyclopropylamino)-4,5-difluorophenyl)pyridazin-4-carboxamide (200 mg, 0.68 mmol) in 4 mL. The reaction mixture was stirred at 70 °C for 1 h. After the starting material was consumed (as monitored by TLC), the reaction mixture was diluted with 20 mL of saturated sodium bicarbonate solution and extracted with EtOAc (2 × 20 mL). The combined organic extracts were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude product was washed with n-pentane (2 × 5 mL) to give 1-cyclopropyl-5,6-difluoro-2-(pyridazin-4-yl)-1H-benzo[d]imidazolium Ex. 55 (120 mg, 0.44 mmol, 64%) as a grayish-white solid.

[1427]

[1428] LC-MS: at 2.21RT, m / z 272.9 [M+H] + (99.23% purity).

[1429] HPLC: 99.54%.

[1430] Example 56

[1431] plan:

[1432]

[1433] 1-Cyclopropyl-5,6-Difluoro-2-(pyridazin-4-yl)-4-(trifluoromethyl)-1H-benzo[d]imidazolium (Ex. 56)

[1434] Zinc trifluoromethyl sulfinate (243 mg, 0.73 mmol) was added to a stirred DMSO (1.5 mL) solution of 1-cyclopropyl-5,6-difluoro-2-(pyridazin-4-yl)-1H-benzo[d]imidazole Ex. 55 (100 mg, 0.36 mmol) at room temperature and under an inert atmosphere. TBHP (141 mg, 1.10 mmol) was added at 0 °C. The reaction mixture was stirred at 50 °C for 16 h. After the starting material was consumed (as monitored by TLC), the reaction mixture was alkalized with saturated sodium bicarbonate solution (20 mL) and extracted with CH2Cl2 (2 × 20 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give 1-cyclopropyl-5,6-difluoro-2-(pyridazin-4-yl)-4-(trifluoromethyl)-1H-benzo[d]imidazolium Ex.56 (19 mg, 0.05 mmol, 15%) as a grayish-white solid.

[1435]

[1436] LC-MS: at 2.75 RT, m / z 340.9 [M+H] + (91.67% purity).

[1437] HPLC: 91.79%.

[1438] Example 57

[1439] plan:

[1440]

[1441] 1-Cyclopropyl-2-(6-(2,2-difluoropropoxy)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazolium (Ex. 57)

[1442] Under an inert atmosphere, sodium hydride (60%, in mineral oil, 16.2 mg, 0.40 mmol) was added in portions to a stirred solution of 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole Ex. 22 (50 mg, 0.16 mmol) in 1.5 mL of DMF, and the mixture was stirred for 5 minutes. 2,2-Difluoroprop-1-ol (18.8 mg, 0.19 mmol) was added to the reaction mixture and stirred at room temperature for 1 h. After the starting material was consumed (as monitored by TLC), the reaction mixture was terminated with ice-cold water (20 mL) and extracted with EtOAc (2 × 20 mL). The combined organic extracts were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude product was washed with CH2Cl2:n-pentane (5:95, 10 mL) to give 1-cyclopropyl-2-(6-(2,2-difluoropropoxy)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazolium Ex. 57 (45 mg, 0.12 mmol, 82%) as a grayish-white solid.

[1443]

[1444] LC-MS: at 3.08 RT, m / z 367 [M+H] + (96.40% purity).

[1445] HPLC: 94.40%.

[1446] Example 58

[1447] plan:

[1448]

[1449] 1-Cyclopropyl-5,6-Difluoro-2-(5-isopropylpyridazin-4-yl)-1H-benzo[d]imidazolium (Ex. 58)

[1450] At room temperature and under an inert atmosphere, zinc isopropyl sulfinate (205 mg, 0.73 mmol) was added to a stirred solution of 1-cyclopropyl-5,6-difluoro-2-(pyridazin-4-yl)-1H-benzo[d]imidazolium Ex. 55 (100 mg, 0.37 mmol) in DMSO (1 mL). Then, tert-butyl hydroperoxide (70%, in water, 142 mg, 1.1 mmol) was added at 0 °C. The reaction mixture was gradually warmed to room temperature and then heated to 50 °C and held for 16 h. After the starting material was consumed (monitored by TLC), the reaction mixture was alkalized with saturated NaHCO3 solution (pH approximately 8) and extracted with EtOAc (2 × 30 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude substance was purified by silica gel column chromatography (elution buffer: 70% EtOAc / hexane), then ground with n-pentane (2 × 4 mL) and dried under vacuum to obtain 1-cyclopropyl-5,6-difluoro-2-(5-isopropylpyridazin-4-yl)-1H-benzo[d]imidazole Ex. 58 (15 mg, 0.05 mmol, 13%) as a grayish-white solid.

[1451]

[1452] LC-MS: at 2.70 RT, m / z 315.0 [M+H] + (95.37% purity).

[1453] HPLC: 92.84%.

[1454] Example 59

[1455] plan:

[1456]

[1457] 1-Cyclopropyl-2-(6-Cyclopropylpyridazin-4-yl)-5,6-Difluoro-1H-benzo[d]imidazole (Ex. 59)

[1458] Cyclopropylboronic acid (24 mg, 0.27 mmol) and cesium carbonate (186 mg, 0.57 mmol) were added to a stirred toluene / water (3:1, 2 mL) solution of 2-(6-chloropyridazine-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole Ex. 22 (70 mg, 0.22 mmol) and the mixture was purged under argon for 10 min. Pd(dppf)Cl2 (18.6 mg, 0.02 mmol) was added to the reaction mixture, and the mixture was further degassed for 5 min. The reaction was heated to 110 °C and held for 16 h, then cooled. After the starting material was consumed (monitored 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 Na2SO4, and concentrated under reduced pressure. The crude substance was purified by silica gel column chromatography (elution buffer: 30% EtOAc / hexane) to obtain 1-cyclopropyl-2-(6-cyclopropylpyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole Ex.23 (8 mg, 0.02 mmol, 11%) as a light yellow solid.

[1459]

[1460] LC-MS: at 2.22RT, m / z 313.1 [M+H] + (93.72% purity).

[1461] HPLC: 96.07%.

[1462] Example 60

[1463] plan:

[1464]

[1465] 6-Chloro-N-(2-(cyclopropylamino)-6-methoxypyridin-3-yl)pyridazine-4-carboxamide

[1466] N2 was added to a stirred DMF (10 mL) solution of 6-chloropyridazine-4-carboxylic acid (500 mg, 3.16 mmol) under an inert atmosphere at 0 °C. 2Cyclopropyl-6-methoxypyridine-2,3-diamine Int-9 (566 mg, 3.16 mmol), HATU (1.8 g, 4.74 mmol), and diisopropylethylamine (2.19 mL, 12.64 mmol) were used. The reaction mixture was stirred at room temperature for 16 h. After the starting material was consumed (monitored 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) and brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 30% to 40% EtOAc / hexane) to give 6-chloro-N-(2-(cyclopropylamino)-6-methoxypyridine-3-yl)pyridazine-4-carboxamide (225 mg, 0.70 mmol, 22%) as a grayish-white solid.

[1467]

[1468] 2-(6-Chlorpyridazin-4-yl)-3-cyclopropyl-5-methoxy-3H-imidazo[4,5-b]pyridine (Ex. 60)

[1469] Under an inert atmosphere, 6N HCl (2 mL) was added to a stirred solution of 6-chloro-N-(2-(cyclopropylamino)-6-methoxypyridin-3-yl)pyridazin-4-carboxamide (150 mg, 0.47 mmol) in EtOH (3.5 mL). The reaction mixture was stirred at 80 °C for 1 h. After the starting material was consumed (monitored 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 Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (elution: 60% to 70% EtOAc / hexane) to give 2-(6-chloropyridazin-4-yl)-3-cyclopropyl-5-methoxy-3H-imidazo[4,5-b]pyridine Ex. 60 (35 mg, 0.11 mmol, 22%) as a brown solid.

[1470]

[1471] LC-MS: at 1.85 RT, m / z 302.1 [M+H] + (95.67% purity).

[1472] HPLC: 94.24%.

[1473] Example 61

[1474] plan:

[1475]

[1476] 1-Cyclopropyl-5,6-difluoro-2-(6-(4-fluoro-2-methylphenyl)pyridazin-4-yl)-1H-benzo[d]imidazolium (Ex. 61)

[1477] In a sealed tube, 42 mg (0.27 mmol) of (4-fluoro-2-methylphenyl)boronic acid and 72.5 mg (0.68 mmol) were added to a stirred solution of 2-(6-chloropyridazine-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole Ex. 22 (70 mg, 0.22 mmol) in DME / EtOH (2:1, 0.9 mL), and the mixture was purged under argon for 10 min. Trans-bis-(triphenylphosphine)palladium-II dichloride (8 mg, 0.01 mmol) was added to the reaction mixture, and the mixture was stirred at 80 °C for 16 h. After the starting materials were consumed (monitored by TLC), the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude substance was purified by silica gel column chromatography (elution buffer: 20% EtOAc / hexane) to obtain 1-cyclopropyl-5,6-difluoro-2-(6-(4-fluoro-2-methylphenyl)pyridazin-4-yl)-1H-benzo[d]imidazole Ex.61 (45 mg, 0.11 mmol, 51%) as a grayish-white solid.

[1478]

[1479] LC-MS: at 2.60 RT, m / z 381.1 [M+H] + (97.81% purity).

[1480] HPLC: 96.11%.

[1481] Example 62

[1482] plan:

[1483]

[1484] 1-Cyclopropyl-2-(6-(2,4-difluorophenyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (Ex. 62)

[1485] To a stirred solution of 2-(6-chloropyridazine-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole Ex. 22 (70 mg, 0.22 mmol) in DME:EtOH (2:1, 0.9 mL), (2,4-difluorophenyl)boronic acid (43 mg, 0.27 mmol) and sodium carbonate (72.5 mg, 0.68 mmol) were added, and the mixture was purged under argon for 10 min. Trans-bis-(triphenylphosphine)palladium-II dichloride (8 mg, 0.01 mmol) was added to the reaction mixture, and the mixture was stirred in a sealed tube at 80 °C for 16 h. After the starting material was consumed (monitored by TLC), the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude substance was purified by silica gel column chromatography (elution buffer: 20% EtOAc / hexane) to obtain 1-cyclopropyl-2-(6-(2,4-difluorophenyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole Ex.62 (45 mg, 0.11 mmol, 51%) as a grayish-white solid.

[1486]

[1487] LC-MS: at 2.61 RT, m / z 385.1 [M+H] + (96.45% purity).

[1488] HPLC: 96.95%.

[1489] Example 63

[1490] plan:

[1491]

[1492] 1-Cyclopropyl-2-(6-(3,4-difluorophenyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (Ex. 63)

[1493] In a sealed tube, 3,4-difluorophenyl)boronic acid (43 mg, 0.27 mmol) and sodium carbonate (75.5 mg, 0.68 mmol) were added to a stirred solution of 2-(6-chloropyridazine-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole Ex. 22 (70 mg, 0.22 mmol) in DME / EtOH (2:1, 0.9 mL). The mixture was then purged under argon for 10 min. Trans-bis-(triphenylphosphine)palladium-II dichloride (8 mg, 0.01 mmol) was added to the reaction mixture, and the mixture was stirred at 80 °C for 16 h. After the starting material was consumed (monitored by TLC), the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude substance was purified by silica gel column chromatography (elution buffer: 20% EtOAc / hexane) to obtain 1-cyclopropyl-2-(6-(3,4-difluorophenyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole Ex.63 (45 mg, 0.11 mmol, 51%) as a grayish-white solid.

[1494]

[1495] LC-MS: at 2.62 RT, m / z 385 [M+H] + (98.32% purity).

[1496] HPLC: 98.68%.

[1497] Examples 64 and 70

[1498] plan:

[1499]

[1500] 1-Cyclopropyl-2-(6-(1-ethoxyvinyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole

[1501] At room temperature, tributyl(1-ethoxyvinyl)stanane (0.26 mL, 0.78 mmol) and Pd(dppf)Cl2·CH2Cl2 (53 mg, 0.06 mmol) were added to a stirred DMF (4 mL) solution of 2-(6-chloropyridazine-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole Ex.22 (200 mg, 0.65 mmol) and the mixture was degassed under argon for 10 min. The reaction mixture was stirred at 100 °C for 16 h. After the starting material was consumed (as monitored by TLC), the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (40 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude substance was purified by silica gel column chromatography (elution buffer: 30% EtOAc / hexane) to obtain 1-cyclopropyl-2-(6-(1-ethoxyvinyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (180 mg, 0.52 mmol, 81%) as a light brown semi-solid.

[1502] LC-MS: at 3.10 RT, m / z 343.1 [M+H] + (81.31% purity).

[1503] 1-(5-(1-Cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)ethyl-1-one (Ex. 64)

[1504] At room temperature, 2.5N HCl (2 mL) was added to a stirred solution of 1-cyclopropyl-2-(6-(1-ethoxyvinyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (180 mg, 0.52 mmol) in acetone (3 mL). The reaction mixture was stirred at room temperature for 6 h. After the starting material was consumed (monitored by TLC), the volatiles were evaporated under reduced pressure. The residue was diluted with CH2Cl2 (40 mL) and washed with saturated sodium bicarbonate solution (30 mL) and brine (30 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 1-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole-2-yl)pyridazin-3-yl)ethyl-1-one Ex. 64 (110 mg, 0.35 mmol, 69%) as a light brown solid.

[1505]

[1506] LC-MS: at 2.65 RT, m / z 315.0 [M+H] + (95.59% purity).

[1507] HPLC: 93.77%.

[1508] 1-Cyclopropyl-2-(6-(1,1-difluoroethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazolium (Ex. 70)

[1509] A solution of 1-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl) ethyl-1-one Ex. 70 (110 mg, 0.35 mmol) in DAST (3 mL) was stirred at room temperature for 16 h under an inert atmosphere. After the starting material was consumed (monitored by TLC), the reaction mixture was terminated with saturated sodium bicarbonate solution (30 mL) and extracted with EtOAc (40 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 50% EtOAc / hexane), and further purified by preparative HPLC to give 1-cyclopropyl-2-(6-(1,1-difluoroethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazolium Ex. 70 (45 mg, 0.13 mmol, 41%) as a grayish-white solid.

[1510]

[1511] LC-MS: at 2.99 RT, m / z 337.0 [M+H] + (99.31% purity).

[1512] HPLC: 99.50%.

[1513] Example 65

[1514] plan:

[1515]

[1516] 6-Chloro-N-(2-(ethylamino)-4,5-difluorophenyl)pyridazine-4-carboxamide

[1517] At 0°C and under an inert atmosphere, N was stirred. 1To a solution of ethyl-4,5-difluorophenyl-1,2-diamine Int-10 (500 mg, 2.9 mmol) in EtOAc (15 mL), 6-chloropyridazine-4-carboxylic acid (505 mg, 3.19 mmol), triethylamine (0.8 mL, 5.81 mmol), and propylphosphonic anhydride (50%, in EtOAc, 4.5 mL, 7.26 mmol) were added. The reaction mixture was stirred at room temperature for 5 h. After the starting material was consumed (monitored by TLC), the reaction mixture was terminated with saturated sodium bicarbonate solution (50 mL) and extracted with EtOAc (2 × 60 mL). The combined organic extracts were washed with water (70 mL) and brine (70 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude substance was purified by silica gel column chromatography (elution buffer: 15% EtOAc / hexane) to obtain 6-chloro-N-(2-(ethylamino)-4,5-difluorophenyl)pyridazine-4-carboxamide (500 mg, 1.60 mmol, 55%) as a yellow solid.

[1518]

[1519] LC-MS: at 2.69 RT, m / z 312.9 [M+H] + (96.47% purity).

[1520] 2-(6-Chlorpyridazin-4-yl)-1-ethyl-5,6-difluoro-1H-benzo[d]imidazole (Ex. 65)

[1521] At room temperature and under an inert atmosphere, 6N HCl (6 mL) was added to a stirred ethanol (4 mL) solution of 400 mg, 1.28 mmol, of 6-chloro-N-(2-(ethylamino)-4,5-difluorophenyl)pyridazin-4-carboxamide (400 mg, 1.28 mmol). The reaction mixture was stirred at 50 °C for 15 min. After the starting material was consumed (as monitored by TLC), the reaction mixture was poured into a saturated sodium bicarbonate solution (40 mL) and extracted with EtOAc (2 × 50 mL). The combined organic extracts were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude product (100 mg) was purified by preparative HPLC to give 2-(6-chloropyridazin-4-yl)-1-ethyl-5,6-difluoro-1H-benzo[d]imidazolium Ex. 65 (30 mg, 0.10 mmol, 29%) as a grayish-white solid.

[1522]

[1523] LC-MS: at 2.58 RT, m / z 294.9 [M+H] + (98.60% purity).

[1524] HPLC: 99.85%.

[1525] Example 66

[1526] plan:

[1527]

[1528] 1-Cyclopropyl-2-(6-vinylpyridazin-4-yl)-1H-benzo[d]imidazol-6-carboxynitrile

[1529] At room temperature, in a sealed tube, a solution of 2-(6-chloropyridazine-4-yl)-1-cyclopropyl-1H-benzo[d]imidazol-6-carboxynitrile Ex.34 (200 mg, 0.67 mmol) in 1,4-dioxane (5 mL) and water (1.5 mL) was added to a mixture of vinylboronic acid pinacol ester (313 mg, 2.03 mmol) and potassium carbonate (374 mg, 2.71 mmol). The reaction mixture was degassed with argon for 10 minutes. Pd(dppf)Cl was then added to the mixture at room temperature. 2. CH2Cl2 (5.3 mg, 0.006 mmol) was applied, and the mixture was degassed with argon for an additional 10 minutes. The reaction mixture was heated to 100 °C and stirred for 16 h. After the starting material was consumed (monitored by TLC), the reaction mixture was diluted with ice-cold water (20 mL) and extracted with CH2Cl2 (2 × 20 mL). The combined organic extracts were washed with water (20 mL) and brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give 1-cyclopropyl-2-(6-vinylpyridazin-4-yl)-1H-benzo[d]imidazol-6-carboxynitrile (200 mg) as a brown, thick paste. The crude product could be used in the next step without further purification.

[1530] LC-MS: at 2.27 RT, m / z 288 [M+H] + (73.7% purity).

[1531] 1-Cyclopropyl-2-(6-Formylpyridazin-4-yl)-1H-Benzo[d]imidazol-6-carboxynitrile

[1532] Sodium periodate (29.68 mg, 0.13 mmol) was added to a stirred solution of 1-cyclopropyl-2-(6-vinylpyridazin-4-yl)-1H-benzo[d]imidazolium-6-carboxynitrile (200 mg, crude) in tert-butanol (0.5 mL), acetone (0.5 mL), and water (0.5 mL), followed by the addition of osmium tetroxide (0.1 M, in toluene, 4 mL). The reaction mixture was gradually warmed to room temperature and stirred for 2 h. After the starting material was consumed (monitored by TLC), the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2 × 10 mL). The combined organic extracts were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to give 1-cyclopropyl-2-(6-formylpyridazin-4-yl)-1H-benzo[d]imidazolium-6-carboxynitrile (200 mg, crude) as an orange solid. The crude product can be used in the next step without further purification.

[1533] LC-MS: at 1.78 RT, m / z 308.1 [M+H2O] + (8.32% purity).

[1534] 1-Cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-1H-benzo[d]imidazol-6-carboxynitrile (Ex. 66)

[1535] At 0 °C and under an inert atmosphere, DAST (223 mg, 1.38 mmol) was added to a stirred CH2Cl2 (10 mL) solution of 1-cyclopropyl-2-(6-formylpyridazin-4-yl)-1H-benzo[d]imidazol-6-carboxynitrile (200 mg, crude). The reaction mixture was warmed to room temperature and stirred for 2 h. After the starting material was consumed (monitored by TLC), the reaction mixture was diluted with saturated sodium carbonate solution (20 mL) and extracted with CH2Cl2 (2 × 20 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 30% EtOAc / hexane), and further purified by preparative HPLC to give 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-1H-benzo[d]imidazolium-6-carboxynitrile Ex. 66 (15 mg, 0.05 mmol, 7%) as a brown solid.

[1536]

[1537] LC-MS: at 2.52 RT, m / z 312 [M+H] + (98.91% purity).

[1538] HPLC: 99.83%.

[1539] Example 67

[1540] plan:

[1541]

[1542] 1-Ethyl-5,6-difluoro-2-(6-vinylpyridazin-4-yl)-1H-benzo[d]imidazolium

[1543] In a sealed tube at room temperature and under an inert atmosphere, 12 mL of 1,4-dioxane (400 mg, crude) of 2-(6-chloropyridazin-4-yl)-1-ethyl-5,6-difluoro-1H-benzi[d]imidazole Ex. 65 and 4 mL of water were added to a stirred solution of 1,4-dioxane (419 mg, 2.72 mmol) and potassium carbonate (563 mg, 4.08 mmol). The reaction mixture was degassed with argon for 20 minutes. Pd(dppf)Cl₂ was then added at room temperature. CH2Cl2 (11 mg, 0.013 mmol) was added, and the mixture was degassed with argon for an additional 10 minutes. The reaction mixture was heated to 80 °C and stirred for 5 h. After the starting material was consumed (monitored by TLC), the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 × 60 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (elution: 2% MeOH / CH2Cl2) to give 1-ethyl-5,6-difluoro-2-(6-vinylpyridazin-4-yl)-1H-benzo[d]imidazole (100 mg, crude product) as a grayish-white solid.

[1544]

[1545] LC-MS: at 2.47 RT, m / z 287 [M+H] + (96.16% purity).

[1546] 5-(1-Ethyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-carboxaldehyde

[1547] At 0°C, acetone was added to stirred 1-ethyl-5,6-difluoro-2-(6-vinylpyridazin-4-yl)-1H-benzo[d]imidazole (100 mg, crude product): tSodium periodate (149 mg, 0.69 mmol) and osmium tetroxide (0.1 M, in toluene, 2 mL) were added to a solution of BuOH:water (1:1:1, 6 mL). The reaction mixture was heated to room temperature and stirred for 3 h. After the starting material was consumed (monitored by TLC), the reaction mixture was filtered through a diatomaceous earth bed and the bed was washed with EtOAc (30 mL). The filtrate was concentrated under reduced pressure. The residue was diluted with water (20 mL) and extracted with CH2Cl2 (2 × 30 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 5-(1-ethyl-5,6-difluoro-1H-benzo[d]imidazol-2-ylpyridazine-3-carboxaldehyde (100 mg, crude) as a brown solid. The crude substance could be used in the next step without further purification.

[1548]

[1549] LC-MS: at 1.87 RT, m / z 289 [M+H] + (70.81% purity).

[1550] 2-(6-(difluoromethyl)pyridazin-4-yl)-1-ethyl-5,6-difluoro-1H-benzo[d]imidazole (Ex. 67)

[1551] At 0 °C and under an inert atmosphere, DAST (0.09 mL, 0.69 mmol) was added to a stirred CH2Cl2 (8 mL) solution of 5-(1-ethyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-carboxaldehyde (100 mg, crude). The reaction mixture was warmed to room temperature and stirred for 3 h. After the starting material was consumed (monitored by TLC), the reaction mixture was terminated with ice-cold water (20 mL) and extracted with CH2Cl2 (2 × 30 mL). The combined organic extracts were washed with saturated sodium bicarbonate solution (30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 10% EtOAc / hexane) to give 2-(6-(difluoromethyl)pyridazin-4-yl)-1-ethyl-5,6-difluoro-1H-benzo[d]imidazolium Ex.67 (30 mg, 0.09 mmol, 28%) as a grayish-white solid.

[1552]

[1553] LC-MS: at 2.69 RT, m / z 311.0 [M+H] + (98.69% purity).

[1554] HPLC: 98.72%.

[1555] Examples 68 and 69

[1556] plan:

[1557]

[1558] 6-Chloro-N-(4-cyano-2-(ethylamino)phenyl)pyridazine-4-carboxamide

[1559] Under an inert atmosphere, at 0 °C, 6-chloropyridazine-4-carboxylic acid (210 mg, 1.32 mmol), triethylamine (0.34 mL, 2.48 mmol), and propylphosphonic anhydride (50%, in EtOAc, 1.97 mL, 3.10 mmol) were added to a stirred solution of 4-amino-3-(ethylamino)benzylnitrile Int-4 (200 mg, 1.24 mmol) in 10 mL of EtOAc. The reaction mixture was stirred at room temperature for 5 h. After the starting material was consumed (monitored by TLC), the reaction mixture was terminated with saturated sodium bicarbonate solution (30 mL) and extracted with EtOAc (2 × 30 mL). The combined organic extracts were washed with water (40 mL) and brine (40 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude substance was purified by silica gel column chromatography (elution buffer: 20% EtOAc / hexane) to obtain 6-chloro-N-(4-cyano-2-(ethylamino)phenyl)pyridazine-4-carboxamide (250 mg, 0.83 mmol, 67%) as a yellow solid.

[1560]

[1561] 2-(6-Chlorpyridazin-4-yl)-1-ethyl-1H-benzo[d]imidazol-6-carboxynitrile (Ex. 68)

[1562] Trifluoroacetic acid (0.2 mL) was added to a stirred solution of 6-chloro-N-(4-cyano-2-(ethylamino)phenyl)pyridazin-4-carboxamide (50 mg, 0.16 mmol) in CH2Cl2 (2 mL) under an inert atmosphere at 0 °C. The reaction mixture was stirred at room temperature for 6 h. After the starting material was consumed (monitored by TLC), the volatiles were evaporated under reduced pressure. The residue was terminated with saturated sodium bicarbonate solution (20 mL) and extracted with CH2Cl2 (2 × 20 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (elution: 20% EtOAc / hexane) to give 2-(6-chloropyridazin-4-yl)-1-ethyl-1H-benzo[d]imidazolium-6-carboxynitrile Ex.68 (35 mg, 0.12 mmol, 74%) as a grayish-white solid.

[1563]

[1564] LC-MS: at 2.34 RT, m / z 284 [M+H] + (97.52% purity).

[1565] HPLC: 97.70%.

[1566] 1-Ethyl-2-(6-vinylpyridazin-4-yl)-1H-benzo[d]imidazol-6-carboxynitrile

[1567] Under an inert atmosphere, a mixture of 1,4-dioxane (6 mL) and water (2 mL) of 2-(6-chloropyridazin-4-yl)-1-ethyl-1H-benzo[d]imidazol-6-carboxynitrile Ex. 68 (170 mg, 0.60 mmol) was added to a stirred solution of 1,4-dioxane (6 mL) and water, followed by the addition of vinylboronic acid pinacol ester (185 mg, 1.20 mmol) and potassium carbonate (248.69 mg, 1.80 mmol). The reaction mixture was degassed under argon for 20 min. Pd(dppf)Cl2·CH2Cl2 (4.9 mg, 0.06 mmol) was added to the mixture at room temperature. The reaction mixture was heated to 80 °C and stirred for 5 h. After the starting material was consumed (as monitored by TLC), the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 × 30 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude substance was purified by silica gel column chromatography (elution buffer: 1% to 2% MeOH / CH2Cl2) to obtain 1-ethyl-2-(6-vinylpyridazin-4-yl)-1H-benzo[d]imidazol-6-carboxynitrile (100 mg, 0.36 mmol, 61%) as a grayish-white solid.

[1568]

[1569] LC-MS: at 2.23 RT, m / z 276.1 [M+H] + (95.18% purity).

[1570] 1-Ethyl-2-(6-formylpyridazin-4-yl)-1H-benzo[d]imidazol-6-carboxynitrile

[1571] Under an inert atmosphere at 0°C, acetone was added to a stirred mixture of 1-ethyl-2-(6-vinylpyridazin-4-yl)-1H-benzo[d]imidazol-6-carboxynitrile (100 mg, 0.36 mmol): tSodium periodate (154.9 mg, 0.72 mmol) and osmium tetroxide (1%, in toluene, 2 mL) were added to a solution of BuOH:water (1:1:1, 6 mL). The reaction mixture was stirred at room temperature for 5 h. After the starting material was consumed (monitored by TLC), the reaction mixture was filtered through a diatomaceous earth bed and the bed was washed with EtOAc (20 mL). The filtrate was concentrated under reduced pressure. The residue was diluted with water (20 mL) and extracted with CH2Cl2 (2 × 30 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 1-ethyl-2-(6-formylpyridazin-4-yl)-1H-benzo[d]imidazolium-6-carboxynitrile (100 mg, crude) as a thick slurry. The crude substance could be used in the next step without further purification.

[1572] LC-MS: at 1.65 RT, m / z 278.1 [M+H] + (43.82% purity).

[1573] 2-(6-(difluoromethyl)pyridazin-4-yl)-1-ethyl-1H-benzo[d]imidazol-6-carboxynitrile (Ex. 69)

[1574] DAST (0.09 mL, 0.72 mmol) was added to a stirred CH2Cl2 (4 mL) solution of 1-ethyl-2-(6-formylpyridazin-4-yl)-1H-benzo[d]imidazol-6-carboxynitrile (100 mg, crude) under an inert atmosphere at 0 °C. The reaction mixture was warmed to room temperature and stirred for 5 h. After the starting material was consumed (monitored by TLC), the reaction mixture was poured into ice-cold water (20 mL) and extracted with CH2Cl2 (2 × 30 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (elution: 10% EtOAc / hexane) to give 2-(6-(difluoromethyl)pyridazin-4-yl)-1-ethyl-1H-benzo[d]imidazol-6-carboxynitrile Ex.69 (30 mg, 0.10 mmol) as a grayish-white solid.

[1575]

[1576] LC-MS: at 2.41RT, m / z 300.0 [M+H] + (99.41% purity).

[1577] HPLC: 99.68%.

[1578] Example 71

[1579] plan:

[1580]

[1581] 1-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)-2,2,2-trifluoroethane-1-ol

[1582] Cesium fluoride (202.6 mg, 1.33 mmol) was added to a stirred DME (5 mL) solution of 5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-carboxaldehyde Int-27 (400 mg, 1.33 mmol) at 0 °C under an inert atmosphere, and the mixture was stirred for 15 min. TMS-CF3 (284 mg, 1.99 mmol) was added to the reaction mixture at 0 °C. The reaction mixture was warmed to room temperature and stirred for 16 h. After the starting material was consumed (monitored by TLC), the reaction mixture was terminated with 20 mL of 1 N HCl solution, alkalized with 20 mL of saturated sodium bicarbonate solution, and extracted with EtOAc (2 × 60 mL). The combined organic extracts were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (elution buffer: 40% EtOAc / hexane) to obtain 1-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)-2,2,2-trifluoroethane-1-ol (160 mg, 0.43 mmol, 32%) as a grayish-white solid.

[1583]

[1584] LC-MS: at 2.76 RT, m / z 371.1 [M+H] + (75.32% purity).

[1585] O-(1-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)-2,2,2-trifluoroethyl)S-methyl xanthate (carbonodithioate)

[1586] Under an inert atmosphere, sodium hydride (60%, in mineral oil, 21.6 mg, 0.54 mmol) was added in portions to a stirred solution of 1-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)-2,2,2-trifluoroethane-1-ol (100 mg, 0.27 mmol) in 5 mL of THF, and the mixture was stirred for 30 min. Carbon disulfide (41 mg, 0.54 mmol) was added to the reaction mixture at 0 °C and stirred for 30 min, followed by the addition of methyl iodine (76 mg, 0.54 mmol) at 0 °C and stirring continued for 2 h. After the starting material was consumed (monitored by TLC), the reaction mixture was terminated with saturated ammonium chloride solution (15 mL) and extracted with EtOAc (2 × 30 mL). The combined organic extracts were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to give O-(1-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)-2,2,2-trifluoroethyl)S-methyl xanthate (100 mg), a black, thick paste. The crude product could be used in the next step without further purification.

[1587]

[1588] LC-MS: at 3.63 RT, m / z 461.1 [M+H] + (77.86% purity).

[1589] 1-Cyclopropyl-5,6-difluoro-2-(6-(2,2,2-trifluoroethyl)pyridazin-4-yl)-1H-benzo[d]imidazolium (Ex. 71)

[1590] At room temperature and under an inert atmosphere, AIBN (5.3 mg, 0.032 mmol) and tributyltinane (95 mg, 0.32 mmol) were added to a stirred solution of O-(1-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)-2,2,2-trifluoroethyl)S-methyl xanthate (100 mg, 0.21 mmol) in toluene (5 mL). The reaction mixture was heated to 60 °C and stirred for 3 h. After the starting material was consumed (as monitored by TLC), the reaction mixture was terminated with saturated ammonium chloride solution (20 mL) and extracted with EtOAc (2 × 30 mL). The combined o...

Claims

1. A compound of formula I: I， Or its pharmaceutically acceptable salt; wherein 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 ; The condition is that no more than two of W, X, Y, and Z are N; R 1 It is hydrogen, halogen, cyano, acyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkyl, NR a R b NHSO2R c CH2NR a R b CH2NHSO2R d CO2R e COR f S(O)R d S(O)2R d CH2OR f , or CR e R f OH, where any R 1 It can be optionally replaced by one to three independent substituents R 7 replace; R 2 It is hydrogen, halogen, cyano, alkyl, or haloalkyl; Or R 1 and R 2 Together with the atoms they are attached to, they form aryl, heterocyclic, or cycloalkyl rings; R 3 It is hydrogen, halogen, cyano, acyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkyl, NR a R b NHSO2R c CH2NR a R b CH2NHSO2R d CO2R e COR f CH2OR f , or CR e R f OH; R 4 It is an alkyl, cycloalkyl, haloalkyl, or heteroalkyl group; R 5 It is hydrogen, alkyl, haloalkyl, heteroalkyl, or cycloalkyl; Each occurrence of R 6 It can be independently hydrogen, halogen, cyano, haloalkyl, alkyl, cycloalkyl, alkoxy, haloalkyl or carboxyl; Each occurrence of R 7 Independently halogenated, alkyl, alkoxy, haloalkyl, carboxyl, aryl, aryl substituted with one to three independent halogens, -(CH2) n C(O)NR g R h -S(O)2R i -CO2R j , or NR g R h , Each n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; Each occurrence of R a R b R c R d R e and R f Independently, it can be hydrogen, acyl, alkoxyalkyl, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C(O)OC 1-6 Alkyl, C(O)C 1-6 Alkyl group, nitrogen-protecting group when attached to a nitrogen atom, or oxygen-protecting group when attached to an oxygen atom; or R a and R b Together with the atoms they are attached to, they form heterocyclic alkyl rings; or R e and R f Together with the atoms they are attached to, they form cycloalkyl rings; and Each occurrence of R g R h R i and R j Independently 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 h Together with the atoms they are attached to, they form heterocyclic alkyl rings.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 It 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 COR f , or CR e R f OH; or R 1 and R 2 Together with the atoms they are attached to, they form aromatic rings.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 It 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 they are attached to, they form aromatic rings.

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein: R 1 It is hydrogen, halogen, alkyl, haloalkyl, CH2NHSO2R d , or NR a R b ;and R a R b and R d It is independently hydrogen, alkyl, or haloalkyl.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 It is a haloalkyl group.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R 2 It is hydrogen or alkyl.

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 It is hydrogen and R 2 It is an alkyl group.

8. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R 4 It is an alkyl or cycloalkyl group.

9. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R 4 It is C 1-4 Alkyl or C 3-5 Cycloalkyl.

10. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein each R 6 It can be hydrogen, halogen, cyano, alkoxy, haloalkyl, or carboxyl.

11. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein each R 6 It can be hydrogen, halogen, or cyano group independently.

12. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein A is a CR 5 And R 5 It is hydrogen, C 1-4 Alkyl or C 3-5 Cycloalkyl.

13. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein A is N.

14. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein no more than one of W, X, Y and Z is N.

15. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein W, X, Y, and Z are each independently CR 6 .

16. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein Z is N.

17. The compound according to claim 1, wherein the compound is a compound of formula Ia: Ia, Or its pharmaceutically acceptable salt.

18. The compound of claim 17 or a pharmaceutically acceptable salt thereof, wherein A is N.

19. The compound according to claim 1, wherein the compound is a compound of formula Ib: Ib, Or its pharmaceutically acceptable salt.

20. The compound according to claim 1, wherein the compound is a compound of formula Ic: Ic, Or its pharmaceutically acceptable salt.

21. The compound according to claim 1, wherein the compound is a compound of formula Id: ID Or its pharmaceutically acceptable salt.

22. The compound according to claim 1, wherein the compound is a compound of formula Ie: Ie, Or its pharmaceutically acceptable salt.

23. The compound according to claim 1, wherein the compound is a compound of the formula If: If, Or its pharmaceutically acceptable salt.

24. The compound of claim 23 or a pharmaceutically acceptable salt thereof, wherein R 1 It is a haloalkyl group.

25. The compound of claim 24 or a pharmaceutically acceptable salt thereof, wherein each R 6 It is a halogen on its own.

26. The compound according to claim 1, wherein the compound is a compound of formula Ig: Ig, Or its pharmaceutically acceptable salt.

27. The compound according to claim 1, wherein the compound is selected from: 1-Cyclopropyl-6-fluoro-2-(pyridazin-4-yl)-1H-benzo[d]imidazolium (1); 5-(1-Cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-carboxylonitrile (2); 2-(6-chloropyridazine-4-yl)-1-cyclopropyl-6-fluoro-1H-benzo[d]imidazolium(3); 1-Cyclopropyl-6-fluoro-2-(6-vinylpyridazin-4-yl)-1H-benzo[d]imidazolium(4); 5-(1-Cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-carboxylic acid methyl ester (5); 1-Cyclopropyl-2-(6-ethylpyridazin-4-yl)-6-fluoro-1H-benzo[d]imidazolium(6); 1-(5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)-2,2,2-trifluoroethane-1-ol (7); N-((5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methyl)propionamide (8); (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]imidazolium (11); 2-(5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)prop-2-ol (12); 5-(1-Cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)-N-(tetrahydro-2H-pyran-4-yl)pyridazine-3-amine (13); 4-(1-Cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)zoline (14); 1-Cyclopropyl-6-fluoro-2-(6-methylpyridazin-4-yl)-1H-benzo[d]imidazolium (15); N-(5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)ethanesulfonamide (16); 2-(6-chloropyridazine-4-yl)-1-ethyl-1H-benzo[d]imidazol-6-carboxynitrile (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]imidazolium (19); 2-(4-(5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)piperazin-1-yl)-1-(pyrrolidone-1-yl)ethyl-1-one (20); 5-(1-Cyclopropyl-5,6-Difluoro-1H-Benz[d]imidazol-2-yl)-N-methylpyridazine-3-amine (21); 2-(6-chloropyridazine-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]imidazolium (23); 1-Cyclopropyl-5,6-Difluoro-2-(6-isopropoxypyridazin-4-yl)-1H-benzo[d]imidazolium (24); 5-(1-Cyclopropyl-5,6-Difluoro-1H-Benz[d]imidazol-2-yl)-N,N-Dimethylpyridazine-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]imidazolium (27); 5-(1-Cyclopropyl-5,6-Difluoro-1H-Benz[d]imidazol-2-yl)-N-(2-methoxyethyl)pyridazine-3-amine (28); 1-Cyclopropyl-2-(6-Methoxypyridazin-4-yl)-1H-benzo[d]imidazol-6-carboxynitrile (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-Benz[d]imidazol-2-yl)-N-(2,2,2-trifluoroethyl)pyridazine-3-amine (32); 1-Cyclopropyl-2-(6-ethylpyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazolium (33); 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-1H-benzo[d]imidazol-6-carboxynitrile (34); 1-Cyclopropyl-2-(6-methylpyridazin-4-yl)-1H-benzo[d]imidazol-6-carboxynitrile (35); 1-Cyclopropyl-5,6-Difluoro-2-(6-(4-methylpiperazin-1-yl)pyridazin-4-yl)-1H-benzo[d]imidazolium (36); 1-(4-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)piperazin-1-yl)ethyl-1-one (37); 1-Cyclopropyl-5,6-Difluoro-2-(6-(4-(methanesulfonyl)piperazin-1-yl)pyridazin-4-yl)-1H-benzo[d]imidazolium (38); 4-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)piperazine-1-carboxylic acid tert-butyl ester (39); 1-Ethyl-2-(6-methoxypyridazin-4-yl)-1H-benzo[d]imidazol-6-carboxynitrile (40); 1-Ethyl-2-(6-ethylpyridazin-4-yl)-1H-benzo[d]imidazol-6-carboxynitrile (41); 1-Cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazolium (42); 2-(6-Cyclobutoxypyridazine-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazolium (43); 1-Cyclopropyl-2-(6-(4,4-difluoropiperidin-1-yl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazolium (44); 5-Chloro-3-cyclopropyl-2-(6-methylpyridazin-4-yl)-3H-imidazo[4,5-b]pyridine (45); 1-Cyclopropyl-2-(6-(3,3-difluoropyrrolidone-1-yl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazolium(46); 1-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)-2,2,2-trifluoroethane-1-ol (47); 1-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)-N,N-dimethylpyrrolidine-3-amine (48); 1-Cyclopropyl-5,6-Difluoro-2-(6-(4-fluorophenyl)pyridazin-4-yl)-1H-benzo[d]imidazolium (49); 1-Cyclopropyl-5,6-Difluoro-2-(6-((4-fluorophenyl)ethynyl)pyridazin-4-yl)-1H-benzo[d]imidazolium (50); 1-Cyclopropyl-5,6-Difluoro-2-(6-Isopropylpyridazin-4-yl)-1H-benzo[d]imidazolium (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-trifluoroprop-2-yl)oxy)pyridazin-4-yl)-1H-benzo[d]imidazolium (53); 3-Cyclopropyl-2-(6-methylpyridazin-4-yl)-3H-imidazo[4,5-b]pyridine-5-carboxylonitrile (54); 1-Cyclopropyl-5,6-Difluoro-2-(pyridazin-4-yl)-1H-benzo[d]imidazolium (55); 1-Cyclopropyl-5,6-Difluoro-2-(pyridazin-4-yl)-4-(trifluoromethyl)-1H-benzo[d]imidazolium (56); 1-Cyclopropyl-2-(6-(2,2-difluoropropoxy)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazolium (57); 1-Cyclopropyl-5,6-Difluoro-2-(5-Isopropylpyridazin-4-yl)-1H-benzo[d]imidazolium (58); 1-Cyclopropyl-2-(6-Cyclopropylpyridazin-4-yl)-5,6-Difluoro-1H-benzo[d]imidazolium (59); 2-(6-Chlorpyridazin-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]imidazolium (61); 1-Cyclopropyl-2-(6-(2,4-difluorophenyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazolium(62); 1-Cyclopropyl-2-(6-(3,4-difluorophenyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazolium (63); 1-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)ethyl-1-one (64); 2-(6-Chlorpyridazin-4-yl)-1-ethyl-5,6-difluoro-1H-benzo[d]imidazolium (65); 1-Cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-1H-benzo[d]imidazol-6-carboxynitrile (66); 2-(6-(difluoromethyl)pyridazin-4-yl)-1-ethyl-5,6-difluoro-1H-benzo[d]imidazolium (67); 2-(6-chloropyridazine-4-yl)-1-ethyl-1H-benzo[d]imidazol-6-carboxynitrile (68); 2-(6-(difluoromethyl)pyridazin-4-yl)-1-ethyl-1H-benzo[d]imidazol-6-carboxynitrile (69); 1-Cyclopropyl-2-(6-(1,1-difluoroethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazolium (70); 1-Cyclopropyl-5,6-Difluoro-2-(6-(2,2,2-trifluoroethyl)pyridazin-4-yl)-1H-benzo[d]imidazolium (71); 2-(6-Cyclopropylpyridazin-4-yl)-1-ethyl-5,6-difluoro-1H-benzo[d]imidazolium (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]imidazolium (74); 1-Cyclopropyl-2-(6-Cyclopropylpyridazin-4-yl)-1H-benzo[d]imidazol-6-carboxynitrile (75); 3-Cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-3H-imidazo[4,5-b]pyridine-5-carboxylonitrile (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]imidazolium (80); 1-Cyclopropyl-2-(6-(ethylsulfonyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazolium (81); 1-Cyclopropyl-5,6-difluoro-2-(6-(methylsulfinyl)pyridazin-4-yl)-1H-benzo[d]imidazolium (82); 1-Cyclopropyl-2-(6-(ethylsulfinyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazolium (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]imidazolium (85); 1-Cyclopropyl-2-(6-(trifluoromethyl)pyridazin-4-yl)-1H-benzo[d]imidazol-6-carboxynitrile (86); 3-Cyclopropyl-2-(6-Cyclopropylpyridazin-4-yl)-3H-imidazo[4,5-b]pyridine-5-carboxylonitrile (87); 2-((5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methyl)isothiazolidinyl-1,1-dioxide (88); 3-Cyclopropyl-2-(6-(trifluoromethyl)pyridazin-4-yl)-3H-imidazo[4,5-b]pyridine-5-carboxylonitrile (89); 1-Cyclopropyl-2-(6-methylpyridazin-4-yl)-6-(trifluoromethyl)-1H-benzo[d]imidazolium (90); And its pharmaceutically acceptable salts.

28. A compound of formula I: I， Or its pharmaceutically acceptable salt; wherein 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 ; The condition is that no more than two of W, X, Y, and Z are N; R 1 It is hydrogen, halogen, cyano, acyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkyl, NR a R b NHSO2R c CH2NR a R b CR e R f NHSO2R d OR f SR f CO2R e COR f S(O)R d S(O)2R d CH2OR f , or CR e R f OH, where any R 1 It can be optionally replaced by one to three independent substituents R 7 replace; R 2 It is hydrogen, halogen, cyano, alkyl, or haloalkyl; Or R 1 and R 2 Together with the atoms they are attached to, they form aryl, heterocyclic, or cycloalkyl rings; R 3 It is hydrogen, halogen, cyano, acyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkyl, NR a R b NHSO2R c CH2NR a R b CH2NHSO2R d CO2R e COR f CH2OR f , or CR e R f OH; R 4 It is an alkyl, cycloalkyl, haloalkyl, or heteroalkyl group; R 5 It is hydrogen, cyano, alkyl, haloalkyl, heteroalkyl, or cycloalkyl; Each occurrence of R 6 Independently hydrogen, halogen, cyano, haloalkyl, alkyl, cycloalkyl, alkoxy, haloalkyl, OR f Or carboxyl group; Each occurrence of R 7 Independently halogenated, alkyl, alkoxy, haloalkyl, carboxyl, cycloalkyl, aryl, aryl substituted with one to three independent halogens, -(CH2) n C(O)NR g R h -S(O)2R i -CO2R j , or NR g R h , Each n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; Each occurrence of R a R b R c R d R e and R f Independently, it can be hydrogen, acyl, alkoxyalkyl, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C(O)OC 1-6 Alkyl, C(O)C 1-6 Alkyl group, nitrogen-protecting group when attached to a nitrogen atom, or oxygen-protecting group when attached to an oxygen atom; or R a and R b Together with the atoms they are attached to, they form heterocyclic alkyl rings; or R e and R f Together with the atoms they are attached to, they form cycloalkyl rings; and Each occurrence of R g R h R i and R j Independently 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 h Together with the atoms they are attached to, they form heterocyclic alkyl rings.

29. The compound of claim 28 or a pharmaceutically acceptable salt thereof, wherein R 1 It is hydrogen, halogen, cyano, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, NR a R b NHSO2R c CH2NR a R b CR e R f NHSO2R d SR f COR f , or CR e R f OH; or R 1 and R 2 Together with the atoms they are attached to, they form aromatic rings or cycloalkyl rings.

30. The compound of claim 28 or a pharmaceutically acceptable salt thereof, wherein R 1 It is hydrogen, halogen, alkyl, alkenyl, haloalkyl, alkoxy, haloalkoxy, cycloalkoxy, aryl, NR a R b CR e R f NHSO2R d SR f , or CR e R f OH; or R 1 and R 2 Together with the atoms they are attached to, they form aromatic rings or cycloalkyl rings.

31. The compound of claim 28 or a pharmaceutically acceptable salt thereof, wherein: R 1 It is hydrogen, halogen, alkyl, haloalkyl, CR e R f NHSO2R d SR f , or NR a R b ;and R a R b R d R e and R f It is independently hydrogen, alkyl, or haloalkyl.

32. The compound of claim 28 or a pharmaceutically acceptable salt thereof, wherein R 1 It is a haloalkyl group.

33. The compound according to any one of claims 28 to 32, or a pharmaceutically acceptable salt thereof, wherein R 2 It is hydrogen or alkyl.

34. The compound of claim 28 or a pharmaceutically acceptable salt thereof, wherein R 1 It is hydrogen, R 2 It is an alkyl group.

35. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 28 to 32, wherein R 4 It is an alkyl or cycloalkyl group.

36. The compound according to any one of claims 28 to 32, or a pharmaceutically acceptable salt thereof, wherein R 4 It is C 1-4 Alkyl or C 3-5 Cycloalkyl.

37. The compound according to any one of claims 28 to 32, or a pharmaceutically acceptable salt thereof, wherein each R 6 It can be hydrogen, halogen, cyano, alkoxy, haloalkyl, or carboxyl.

38. The compound according to any one of claims 28 to 32, or a pharmaceutically acceptable salt thereof, wherein each R 6 It can be hydrogen, halogen, or cyano group independently.

39. The compound according to any one of claims 28 to 32, or a pharmaceutically acceptable salt thereof, wherein A is a CR 5 And R 5 It is hydrogen, C 1-4 Alkyl or C 3-5 Cycloalkyl.

40. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 28 to 32, wherein A is N.

41. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 28 to 32, wherein no more than one of W, X, Y and Z is N.

42. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 28 to 32, wherein W, X, Y and Z are each independently CR 6 .

43. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 28 to 32, wherein Z is N.

44. The compound according to claim 28, wherein the compound is a compound of formula Ia: Ia, Or its pharmaceutically acceptable salt.

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

46. ​​The compound according to claim 28, wherein the compound is a compound of formula Ib: Ib, Or its pharmaceutically acceptable salt.

47. The compound according to claim 28, wherein the compound is a compound of formula Ic: Ic, Or its pharmaceutically acceptable salt.

48. The compound according to claim 28, wherein the compound is a compound of formula Id: ID Or its pharmaceutically acceptable salt.

49. The compound according to claim 28, wherein the compound is a compound of formula Ie: Ie, Or its pharmaceutically acceptable salt.

50. The compound according to claim 28, wherein the compound is a compound of formula If: If, Or its pharmaceutically acceptable salt.

51. The compound of claim 50 or a pharmaceutically acceptable salt thereof, wherein R 1 It is a haloalkyl group.

52. The compound of claim 50 or a pharmaceutically acceptable salt thereof, wherein R 6 It is a halogen on its own.

53. The compound according to claim 28, wherein the compound is a compound of formula Ig: Ig, Or its pharmaceutically acceptable salt.

54. A compound selected from: 1-Cyclopropyl-6-fluoro-2-(pyridazin-4-yl)-1H-benzo[d]imidazolium (1); 5-(1-Cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-carboxylonitrile (2); 2-(6-chloropyridazine-4-yl)-1-cyclopropyl-6-fluoro-1H-benzo[d]imidazolium(3); 1-Cyclopropyl-6-fluoro-2-(6-vinylpyridazin-4-yl)-1H-benzo[d]imidazolium(4); 5-(1-Cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-carboxylic acid methyl ester (5); 1-Cyclopropyl-2-(6-ethylpyridazin-4-yl)-6-fluoro-1H-benzo[d]imidazolium(6); 1-(5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)-2,2,2-trifluoroethane-1-ol (7); N-((5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methyl)propionamide (8); (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]imidazolium (11); 2-(5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)prop-2-ol (12); 5-(1-Cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)-N-(tetrahydro-2H-pyran-4-yl)pyridazine-3-amine (13); 4-(1-Cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)zoline (14); 1-Cyclopropyl-6-fluoro-2-(6-methylpyridazin-4-yl)-1H-benzo[d]imidazolium (15); N-(5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)ethanesulfonamide (16); 2-(6-chloropyridazine-4-yl)-1-ethyl-1H-benzo[d]imidazol-6-carboxynitrile (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]imidazolium (19); 2-(4-(5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)piperazin-1-yl)-1-(pyrrolidone-1-yl)ethyl-1-one (20); 5-(1-Cyclopropyl-5,6-Difluoro-1H-Benz[d]imidazol-2-yl)-N-methylpyridazine-3-amine (21); 2-(6-chloropyridazine-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]imidazolium (23); 1-Cyclopropyl-5,6-Difluoro-2-(6-isopropoxypyridazin-4-yl)-1H-benzo[d]imidazolium (24); 5-(1-Cyclopropyl-5,6-Difluoro-1H-Benz[d]imidazol-2-yl)-N,N-Dimethylpyridazine-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]imidazolium (27); 5-(1-Cyclopropyl-5,6-Difluoro-1H-Benz[d]imidazol-2-yl)-N-(2-methoxyethyl)pyridazine-3-amine (28); 1-Cyclopropyl-2-(6-Methoxypyridazin-4-yl)-1H-benzo[d]imidazol-6-carboxynitrile (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-Benz[d]imidazol-2-yl)-N-(2,2,2-trifluoroethyl)pyridazine-3-amine (32); 1-Cyclopropyl-2-(6-ethylpyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazolium (33); 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-1H-benzo[d]imidazol-6-carboxynitrile (34); 1-Cyclopropyl-2-(6-methylpyridazin-4-yl)-1H-benzo[d]imidazol-6-carboxynitrile (35); 1-Cyclopropyl-5,6-Difluoro-2-(6-(4-methylpiperazin-1-yl)pyridazin-4-yl)-1H-benzo[d]imidazolium (36); 1-(4-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)piperazin-1-yl)ethyl-1-one (37); 1-Cyclopropyl-5,6-Difluoro-2-(6-(4-(methanesulfonyl)piperazin-1-yl)pyridazin-4-yl)-1H-benzo[d]imidazolium (38); 4-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)piperazine-1-carboxylic acid tert-butyl ester (39); 1-Ethyl-2-(6-methoxypyridazin-4-yl)-1H-benzo[d]imidazol-6-carboxynitrile (40); 1-Ethyl-2-(6-ethylpyridazin-4-yl)-1H-benzo[d]imidazol-6-carboxynitrile (41); 1-Cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazolium (42); 2-(6-Cyclobutoxypyridazine-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazolium (43); 1-Cyclopropyl-2-(6-(4,4-difluoropiperidin-1-yl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazolium (44); 5-Chloro-3-cyclopropyl-2-(6-methylpyridazin-4-yl)-3H-imidazo[4,5-b]pyridine (45); 1-Cyclopropyl-2-(6-(3,3-difluoropyrrolidone-1-yl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazolium(46); 1-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)-2,2,2-trifluoroethane-1-ol (47); 1-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)-N,N-dimethylpyrrolidine-3-amine (48); 1-Cyclopropyl-5,6-Difluoro-2-(6-(4-fluorophenyl)pyridazin-4-yl)-1H-benzo[d]imidazolium (49); 1-Cyclopropyl-5,6-Difluoro-2-(6-((4-fluorophenyl)ethynyl)pyridazin-4-yl)-1H-benzo[d]imidazolium (50); 1-Cyclopropyl-5,6-Difluoro-2-(6-Isopropylpyridazin-4-yl)-1H-benzo[d]imidazolium (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-trifluoroprop-2-yl)oxy)pyridazin-4-yl)-1H-benzo[d]imidazolium (53); 3-Cyclopropyl-2-(6-methylpyridazin-4-yl)-3H-imidazo[4,5-b]pyridine-5-carboxylonitrile (54); 1-Cyclopropyl-5,6-Difluoro-2-(pyridazin-4-yl)-1H-benzo[d]imidazolium (55); 1-Cyclopropyl-5,6-Difluoro-2-(pyridazin-4-yl)-4-(trifluoromethyl)-1H-benzo[d]imidazolium (56); 1-Cyclopropyl-2-(6-(2,2-difluoropropoxy)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazolium (57); 1-Cyclopropyl-5,6-Difluoro-2-(5-Isopropylpyridazin-4-yl)-1H-benzo[d]imidazolium (58); 1-Cyclopropyl-2-(6-Cyclopropylpyridazin-4-yl)-5,6-Difluoro-1H-benzo[d]imidazolium (59); 2-(6-Chlorpyridazin-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]imidazolium (61); 1-Cyclopropyl-2-(6-(2,4-difluorophenyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazolium(62); 1-Cyclopropyl-2-(6-(3,4-difluorophenyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazolium (63); 1-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)ethyl-1-one (64); 2-(6-Chlorpyridazin-4-yl)-1-ethyl-5,6-difluoro-1H-benzo[d]imidazolium (65); 1-Cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-1H-benzo[d]imidazol-6-carboxynitrile (66); 2-(6-(difluoromethyl)pyridazin-4-yl)-1-ethyl-5,6-difluoro-1H-benzo[d]imidazolium (67); 2-(6-chloropyridazine-4-yl)-1-ethyl-1H-benzo[d]imidazol-6-carboxynitrile (68); 2-(6-(difluoromethyl)pyridazin-4-yl)-1-ethyl-1H-benzo[d]imidazol-6-carboxynitrile (69); 1-Cyclopropyl-2-(6-(1,1-difluoroethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazolium (70); 1-Cyclopropyl-5,6-Difluoro-2-(6-(2,2,2-trifluoroethyl)pyridazin-4-yl)-1H-benzo[d]imidazolium (71); 2-(6-Cyclopropylpyridazin-4-yl)-1-ethyl-5,6-difluoro-1H-benzo[d]imidazolium (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]imidazolium (74); 1-Cyclopropyl-2-(6-Cyclopropylpyridazin-4-yl)-1H-benzo[d]imidazol-6-carboxynitrile (75); 3-Cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-3H-imidazo[4,5-b]pyridine-5-carboxylonitrile (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]imidazolium (80); 1-Cyclopropyl-2-(6-(ethylsulfonyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazolium (81); 1-Cyclopropyl-5,6-difluoro-2-(6-(methylsulfinyl)pyridazin-4-yl)-1H-benzo[d]imidazolium (82); 1-Cyclopropyl-2-(6-(ethylsulfinyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazolium (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]imidazolium (85); 1-Cyclopropyl-2-(6-(trifluoromethyl)pyridazin-4-yl)-1H-benzo[d]imidazol-6-carboxynitrile (86); 3-Cyclopropyl-2-(6-Cyclopropylpyridazin-4-yl)-3H-imidazo[4,5-b]pyridine-5-carboxylonitrile (87); 2-((5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methyl)isothiazolidinyl-1,1-dioxide (88); 3-Cyclopropyl-2-(6-(trifluoromethyl)pyridazin-4-yl)-3H-imidazo[4,5-b]pyridine-5-carboxylonitrile (89); 1-Cyclopropyl-2-(6-methylpyridazin-4-yl)-6-(trifluoromethyl)-1H-benzo[d]imidazolium (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]imidazolium (92); 1-Cyclopropyl-2-(5,6-Dimethylpyridazin-4-yl)-5,6-Difluoro-1H-benzo[d]imidazolium (93); (5-(1-Cyclopropyl-5,6-Difluoro-1H-Benz[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-Butyridazin-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazolium (97); 1-Cyclopropyl-6-methyl-2-(6-methylpyridazin-4-yl)-1H-benzo[d]imidazolium (98); 1-Cyclopropyl-5,6-Difluoro-2-(3-methylpyridazin-4-yl)-1H-benzo[d]imidazolium (99); 1-Cyclopropyl-2-(3,6-Dimethylpyridazin-4-yl)-5,6-Difluoro-1H-benzo[d]imidazolium (100); 1-Cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-6,7-difluoro-1H-benzo[d]imidazolium (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-1H-benzo[d]imidazole (103); 2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1-methyl-1H-benzo[d]imidazolium(104); 2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1-propyl-1H-benzo[d]imidazolium (105); 4-(1-Cyclopropyl-5,6-Difluoro-1H-Benz[d]imidazol-2-yl)-5,6,7,8-Tetrahydrozoline(106); 1-Cyclopropyl-2-(6-methylpyridazin-4-yl)-1H-benzo[d]imidazol-5-carboxynitrile (Ex. 107) 1-Cyclobutyl-5,6-difluoro-2-(6-methylpyridazin-4-yl)-1H-benzo[d]imidazolium (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]imidazolium(111); 5-Chloro-1-cyclopropyl-2-(6-methylpyridazin-4-yl)-1H-benzo[d]imidazolium (112); 4-Chloro-1-cyclopropyl-2-(6-methylpyridazin-4-yl)-1H-benzo[d]imidazolium (113); 1-Cyclopropyl-5,6-Difluoro-2-(6-(methoxymethyl)pyridazin-4-yl)-1H-benzo[d]imidazolium (114); 5-(6-cyano-1-cyclopropyl-1H-benzo[d]imidazol-2-yl)pyridazine-3-carboxylic acid methyl ester (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]imidazolium (117); 1-Cyclopropyl-2-(6-(2,2,2-trifluoroethoxy)pyridazin-4-yl)-1H-benzo[d]imidazol-6-carboxynitrile (118); 6-Chloro-1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5-fluoro-1H-benzo[d]imidazolium (119); 1-Cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5-fluoro-1H-benzo[d]imidazol-6-carboxynitrile (120); 4-(1-Cyclopropyl-5,6-Difluoro-1H-benzo[d]imidazol-2-yl)-6,7-dihydro-5H-cyclopentano[c]pyridazine (121); 1-Cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-6-fluoro-1H-benzo[d]imidazolium (122); 1-Cyclopropyl-5,6-Difluoro-2-(6-(methylthio)pyridazin-4-yl)-1H-benzo[d]imidazolium (123); 1-Cyclopropyl-5,6-Difluoro-2-(6-(isopropylthio)pyridazin-4-yl)-1H-benzo[d]imidazolium(124); 1-Cyclopropyl-2-(6-((difluoromethyl)thio)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazolium (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]imidazolium (127); 1-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)ethanol-1-ol(128); 1-Cyclopropyl-5,6-Difluoro-2-(6-(1-fluoroethyl)pyridazin-4-yl)-1H-benzo[d]imidazolium (129); 1-Cyclopropyl-5,6-difluoro-2-(6-((trifluoromethyl)thio)pyridazin-4-yl)-1H-benzo[d]imidazolium (130) 1-Cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-1H-benzo[d]imidazolium (131); 2-(6-(difluoromethyl)pyridazin-4-yl)-1-propyl-1H-benzo[d]imidazolium (132); 1-Cyclopropyl-2-(6-(difluoromethoxy)pyridazin-4-yl)-1H-benzo[d]imidazol-6-carboxynitrile (133); 1-Cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-1H-indol-3-carboxynitrile (134); 2-(6-(difluoromethyl)pyridazin-4-yl)-1-methyl-1H-indole-3-carboxynitrile (135); 1-Cyclopropyl-2-(6-(1-fluoroethyl)pyridazin-4-yl)-1H-benzo[d]imidazol-6-carboxynitrile (136); And its pharmaceutically acceptable salts.

55. A compound selected from: 1-Cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazolium (42); 3-Cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-3H-imidazo[4,5-b]pyridine-5-carboxylonitrile (76); 1-Cyclopropyl-2-(6-(trifluoromethyl)pyridazin-4-yl)-1H-benzo[d]imidazol-6-carboxynitrile (86); And its pharmaceutically acceptable salts.

56. Use of the compound of any one of claims 1 to 55 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inhibiting the activity of metalloenzymes, wherein the compound or a pharmaceutically acceptable salt thereof is in contact with the metalloenzyme.

57. The use according to claim 56, wherein the contact is performed in vivo.

58. The use according to claim 56, wherein the contact is performed in vitro.

59. The use according to claim 56, wherein the metalloenzyme comprises a metal atom, said metal atom being iron, zinc, heme iron, manganese, magnesium, iron sulfide clusters, nickel, molybdenum, or copper.

60. The use according to claim 56, wherein the metalloenzyme is a member of the cytochrome P450 family, cyclooxygenase, and nitric oxide synthase.

61. The use according to claim 56, wherein the metalloenzyme is aldosterone synthase (CYP11B2).

62. The use according to claim 56, wherein the metalloenzyme is an 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-α-hydroxylase / 17,20-lyase (CYP17), cytochrome P450 2A6 (CYP2A6), heme oxygenase, indoleamine 2,3-dioxygenase, retinoic acid hydroxylase (CYP26), vitamin D hydroxylase (CYP24), sterol 27-hydroxylase (CYP27), cytochrome P450 3A5 (CYP3A5), cholesterol 24-hydroxylase (CYP46), cytochrome P450 4F2 (CYP4F2), myeloperoxidase, and 11-β-hydroxylase (CYP11B1).

63. The use according to claim 56, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a human subject.

64. Use of the compound of any one of claims 1 to 55 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for regulating the activity of metalloenzymes in a target.

65. Use of any compound of claims 1 to 55 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a person suffering from or susceptible to a condition or disease, wherein the person has been identified as requiring treatment of the condition or disease.

66. Use of the compound of any one of claims 1 to 55 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a person suffering from or susceptible to a metalloenzyme-related condition or disease.

67. Use of any compound of claims 1 to 55 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a person suffering from or susceptible to a metalloenzyme-related condition or disease, wherein the person has been identified as requiring treatment for the metalloenzyme-related condition or disease, and the person is receiving treatment for the condition or disease.

68. Use of any compound of claims 1 to 55 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a subject suffering from or susceptible to a metalloenzyme-mediated condition or disease, wherein the subject has been identified as requiring treatment of a metalloenzyme-mediated condition or disease, and the metalloenzyme activity in the subject is regulated.

69. The use according to any one of claims 65 to 68, wherein the condition or disease is mediated 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-α-hydroxylase / 17,20-lyase (CYP17), cytochrome P450 2A6 (CYP2A6), heme oxygenase, indoleamine 2,3-dioxygenase, retinoic acid hydroxylase (CYP26), vitamin D hydroxylase (CYP24), sterol 27-hydroxylase (CYP27), cytochrome P450 3A5 (CYP3A5), cholesterol 24-hydroxylase (CYP46), cytochrome P450 4F2 (CYP4F2), myeloperoxidase, or 11-β-hydroxylase (CYP11B1).

70. The use according to any one of claims 65 to 68, wherein the condition or disease is cancer, cardiovascular disease, endocrine disease, inflammatory disease, infectious disease, gynecological disease, metabolic disease, ophthalmic disease, central nervous system (CNS) disease, urinary disease, or gastrointestinal disease.

71. The use according to claim 70, wherein the condition or disease is hypertension, refractory hypertension, conditions associated with primary or secondary hyperaldosteronism and adrenal hyperplasia, pulmonary 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 syndrome, coronary artery disease, fibrosis, diseases characterized by increased collagen formation, fibrosis and matrix remodeling after hypertension, diseases characterized by fibrosis and matrix remodeling after endothelial cell dysfunction, and heart disease. Vascular diseases, kidney dysfunction, liver disease, non-alcoholic fatty liver disease, vascular diseases, retinopathy, neuropathy, insulinopathy, endothelial dysfunction, myocardial fibrosis, vascular fibrosis, myocardial necrosis, vascular injury, myocardial infarction, left ventricular hypertrophy, vascular wall hypertrophy, endothelial thickening, arterial fibrinoid necrosis, kidney disease, diabetic nephropathy, glomerulosclerosis, glomerulonephritis, nephrotic syndrome, polycystic kidney disease, diabetes, metabolic syndrome, insulin resistance, sleep apnea, obstructive sleep apnea, muscular dystrophy, cirrhosis, non-alcoholic fatty liver disease, kidney disease, diabetic nephropathy, or stroke.

72. The use according to claim 71, wherein the cardiovascular disease is atherosclerosis or atrial fibrillation.

73. The use according to claim 68, wherein the metalloenzyme activity in the object is downregulated or inhibited.

74. The use according to claim 65, wherein the object is an animal other than a human.

75. A pharmaceutical composition comprising the compound of any one of claims 1 to 55 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

76. The pharmaceutical composition of claim 75, further comprising an additional therapeutic agent.

77. The pharmaceutical composition of claim 75, further comprising an additional therapeutic agent, said therapeutic agent being an anticancer agent, antifungal agent, cardiovascular therapeutic agent, anti-inflammatory agent, chemotherapeutic agent, anti-angiogenic agent, cytotoxic agent, antiproliferative agent, metabolic disease therapeutic agent, ophthalmic disease therapeutic agent, central nervous system (CNS) disease therapeutic agent, urinary disease therapeutic agent, or gastrointestinal disease therapeutic agent.

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