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 Patent Application No. 201780087610.1, filed on December 22, 2017, entitled "Metalloenzyme Inhibitor Compounds".

[0002] Cross Reference to Related Applications

[0003] This application claims priority to U.S. Provisional Patent Application No. 62 / 440,181, filed on December 29, 2016. The entire contents of which are incorporated herein by reference. TECHNICAL FIELD

[0004] This application relates to compounds having metalloenzyme modulating activity. BACKGROUND

[0005] Aldosterone is a steroid hormone secreted from the adrenal glands that binds to and activates the mineralocorticoid receptor (MR). In primary cells of the distal tubule and collecting duct of the kidney, MR activation leads to retention of sodium and water with excretion of potassium, causing expansion of plasma volume, leading to elevated blood pressure (BP). Excess aldosterone, measured in the circulation, is termed primary aldosteronism (PA) and occurs when the renin-angiotensin-aldosterone system (RAAS) is dysregulated to produce aldosterone. PA was first discovered in patients with adrenal adenomas, and recent evidence suggests an increasing prevalence associated with obesity. PA is a common cause of secondary hypertension, with a prevalence of 14% to 21% of patients with resistant hypertension (RHTN), a condition in which blood pressure is higher than target values despite the concurrent use of 3 antihypertensive drugs of different classes, including diuretics. Recent studies have shown an association between excess aldosterone, RHTN, and obstructive sleep apnea (OSA), which is exacerbated by aldosterone-mediated fluid retention.

[0006] In several serious disease states, local excess production of aldosterone has been noted, even in the absence of significant plasma elevations. In patients with chronic congestive heart failure (CHF), aldosterone levels in failing heart tissue are higher than in peripheral plasma. In animal models of renal disease, local production of aldosterone in the renal cortex is hypothesized to contribute to disease progression. In both of these states, locally elevated aldosterone levels produce deleterious effects through MR-dependent and MR-independent mechanisms, including production of reactive oxygen species and endothelial dysfunction, which leads to inflammation and stimulation of cell growth and proliferation, while upregulated collagen deposition leads to fibrosis.

[0007] MR antagonists, including spironolactone and eplerenone, have been widely used to block the effects of aldosterone binding to MR. These drugs, in combination with angiotensin-converting enzyme (ACE) inhibitors and diuretics (RALES and EPHESUS trials), demonstrated a significant reduction 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 modulation of progesterone and androgen receptors. In addition, renin and aldosterone are elevated as a result of MR antagonism, thus the MR-independent (non-genomic) effects of aldosterone are exacerbated.

[0008] In contrast to MR antagonists, inhibition of the key enzyme in aldosterone biosynthesis, CYP11B2 (aldosterone synthase), should provide the beneficial effects of MR antagonism without the detrimental accumulation of aldosterone leading to activation of MR-dependent inflammatory and fibrotic states. CYP11B2 is a mitochondrial cytochrome P450 enzyme that converts 11-deoxycortisol to aldosterone. Selective inhibition of CYP11B2 represents a promising therapeutic approach to aldosterone-related diseases.

[0009] The highly homologous metalloenzyme CYP11B1 (11-beta-steroid-hydroxylase) catalyzes the formation of 11-deoxycortisol to the major glucocorticoid, cortisol. Given the high homology between CYP11B2 and CYP11B1 (93%), 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. Described herein are selective compounds that block aldosterone production through CYP11B2 without inhibiting cortisol production through CYP11B1.

[0010] Organisms have developed strict regulatory processes to import metals, transport them to intracellular storage sites, and ultimately to sites of use. One of the most useful functions of metals (e.g., zinc and iron) in biological systems is to make metalloenzymes active. Metalloenzymes are enzymes that bind a metal ion to the active site of the enzyme and utilize the metal as part of the catalytic process. Over one-third of the enzymes that have been characterized are metalloenzymes.

[0011] The function of metalloenzymes is highly dependent on the presence of a metal ion in the active site of the enzyme. It is well known that agents that bind to and inactivate the active site metal ion significantly reduce the activity of the enzyme. Nature employs the same strategy to reduce the activity of certain metalloenzymes during periods when the enzyme activity is not required. For example, the protein TIMP (tissue inhibitor of metalloproteinases) binds to the zinc ion in the active site of various matrix metalloproteinases, thereby preventing 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 the heme iron present in the active site of the target enzyme lanosterol demethylase, thereby inactivating the enzyme. Another example includes the zinc-binding hydroxamic acid group that has been incorporated into most of the matrix metalloproteinase and histone deacetylase inhibitors disclosed. Another example is the zinc-binding carboxylic acid group that has been incorporated into most of the angiotensin converting enzyme inhibitors disclosed.

[0012] In the design of clinically safe and effective metalloenzyme inhibitors, it is desirable to use an appropriate metal-binding group for any particular target and clinical indication. If a weakly binding metal-binding group is used, potency can be suboptimal. On the other hand, if a very tightly binding metal-binding group is used, the selectivity of the target enzyme for the relevant metalloenzyme can not be optimal. The lack of optimal selectivity can be a cause of clinical toxicity due to unplanned inhibition of these off-target metalloenzymes. One example of such 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 the iron in the active sites of CYP2C9, CYP2C19 and CYP3A4. Another example of clinical toxicity is the joint pain observed in many clinical trials of matrix metalloproteinase inhibitors. This toxicity is believed to be associated with the inhibition of off-target metalloenzymes due to the indiscriminate binding of the hydroxamic acid group to the zinc in the deoxy active site.

[0013] Accordingly, it remains an important goal to seek metal-binding groups that enable a better balance of potency and selectivity and are of significant interest in the realization of therapeutic agents and methods to address unmet needs in the treatment and prevention of diseases, disorders and symptoms. SUMMARY

[0014] The present invention relates to compounds (e.g., any of the compounds described herein; any of the chemical formulas described herein), methods of modulating metalloenzyme activity, and methods of treating a disease, disorder, or symptom thereof. The methods can include a compound herein.

[0015] It should be understood that the embodiments of the application discussed below with respect to preferred variable selections can be used alone or in combination with one or more embodiments of the application or preferred variable selections, as if each combination were explicitly listed herein.

[0016] In one aspect, provided is a compound of Formula I:

[0017]

[0018] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein:

[0019] A is N or CR 5 ;

[0020] W is N or CR 6 ;

[0021] X is N or CR 6 ;

[0022] Y is N or CR 6 ;

[0023] Z is N or CR 6 ;

[0024] provided that no more than two of W, X, Y, and Z are N;

[0025] R 1 is hydrogen, halogen, cyano, acyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, 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, wherein any R 1 may be optionally substituted with 1 to 3 independent substituents R 7 ;

[0026] R 2 is hydrogen, halogen, cyano, alkyl, or haloalkyl;

[0027] or R 1 and R 2 Together with the atoms they are attached to, they form aryl, heterocyclic, or cycloalkyl rings;

[0028] 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;

[0029] R 4 It is an alkyl, cycloalkyl, haloalkyl, or heteroalkyl group;

[0030] R 5 It is hydrogen, alkyl, haloalkyl, heteroalkyl, or cycloalkyl;

[0031] Each occurrence of R 6 It can be independently hydrogen, halogen, cyano, haloalkyl, alkyl, cycloalkyl, alkoxy, haloalkyl or carboxyl;

[0032] 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 ;

[0033] Each n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0034] Each occurrence of R a R b R c R d R e and R findependently hydrogen, acyl, alkoxyalkyl, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C(O)OC 1-6 alkyl, C(O)C 1-6 alkyl, a nitrogen protecting group when attached to a nitrogen atom, or an oxygen protecting group when attached to an oxygen atom; or R a and R b together with the atom to which they are attached form a heterocycloalkyl ring; or R e and R f together with the atom to which they are attached form a cycloalkyl ring; and

[0035] each occurrence of R g , R h , R i , and R j is 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 atom to which they are attached form a heterocycloalkyl ring.

[0036] In certain embodiments, R 1 is aryl, heteroaryl, or heterocycloalkyl, wherein any R 1 may be optionally substituted with 1 to 3 independent substituents R 7 .

[0037] In certain embodiments, R 1 is aryl, heteroaryl, or heterocycloalkyl, wherein any R 1 may be optionally substituted with 1 to 3 independent substituents R 7 , and each R 7 is independently halogen, alkyl, alkoxy, haloalkyl, carboxy, -(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 is independently hydrogen, alkyl, C(O)C 1-6 alkyl, or R g and R h together with the atom to which they are attached form a heterocycloalkyl ring.

[0038] In certain embodiments, R 1haloalkyl, alkoxy, haloalkoxy, 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 to which they are attached, form an aromatic ring.

[0039] In certain embodiments, R 1 is hydrogen, halo, alkyl, alkenyl, haloalkyl, alkoxy, haloalkoxy, cycloalkoxy, aryl, NR a R b , CH2NHSO2R d , or CR e R f OH; or R 1 and R 2 , together with the atoms to which they are attached, form an aromatic ring.

[0040] In certain embodiments, R 1 is hydrogen, halo, alkyl, haloalkyl, CH2NHSO2R d , or NR a R b ; R a , R b , and R d are independently hydrogen, alkyl, or haloalkyl.

[0041] In certain embodiments, R 1 is alkyl or haloalkyl.

[0042] In certain embodiments, R 1 is C 1-6 alkyl or C 1-6 haloalkyl.

[0043] In certain embodiments, R 1 is haloalkyl.

[0044] In certain embodiments, R 1 is C 1-6 haloalkyl.

[0045] In certain embodiments, R 1 is fluoroalkyl. In certain embodiments, R 1 is C 1-6 haloalkyl.fluoroalkyl. In certain embodiments, R 1 is C 1-3 fluoroalkyl. In certain embodiments, R 1 is difluoromethyl or trifluoromethyl. In certain embodiments, R 1 is difluoromethyl. In certain embodiments, R 1 is trifluoromethyl.

[0046] In certain embodiments, R 2 is hydrogen or alkyl.

[0047] In certain embodiments, R 2 is hydrogen or C 1-6 alkyl.

[0048] In certain embodiments, R 2 is hydrogen or C 1-3 alkyl.

[0049] In certain embodiments, R 2 is alkyl. In certain embodiments, R 2 is C 1-6 alkyl. In certain embodiments, R 2 is C 1-3 alkyl. In certain embodiments, R 2 is hydrogen.

[0050] In certain embodiments, R 1 is hydrogen and R 2 is alkyl. In certain embodiments, R 1 is hydrogen and R 2 is C 1-6 alkyl. In certain embodiments, R 1 is hydrogen and R 2 is C 1-3 alkyl.

[0051] In certain embodiments, R 4 is alkyl or cycloalkyl.

[0052] In certain embodiments, R 4 is C 1-4 alkyl or C 3-5 cycloalkyl.

[0053] In certain embodiments, R 4 is C 1-4 alkyl. In certain embodiments, R 4 is C 3-5 cycloalkyl. In certain embodiments, R 4 is cyclopentyl. In certain embodiments, R 4 is cyclobutyl. In certain embodiments, R4 is cyclopropyl.

[0054] In certain embodiments, each R 6 is independently hydrogen, halogen, cyano, alkoxy, haloalkyl, or carboxyl.

[0055] In certain embodiments, each R 6 is independently hydrogen, halogen, or cyano.

[0056] In certain embodiments, each R 6 is independently hydrogen, chloro, fluoro, or cyano.

[0057] In certain embodiments, each R 6 is independently hydrogen, fluoro, or cyano.

[0058] In certain embodiments, each R 6 is independently hydrogen or halogen.

[0059] In certain embodiments, each R 6 is independently hydrogen, chloro, or fluoro.

[0060] In certain embodiments, each R 6 is independently hydrogen or fluoro.

[0061] In certain embodiments, each R 6 is independently hydrogen or cyano.

[0062] In certain embodiments, each R 6 is halogen. In certain embodiments, each R 6 is chloro or fluoro. In certain embodiments, each R 6 is fluoro. In certain embodiments, each R 6 is cyano.

[0063] In certain embodiments, A is CR 5 and R 5 is hydrogen, C 1-4 alkyl, or C 3-5 cycloalkyl.

[0064] In certain embodiments, A is N.

[0065] In certain embodiments, no more than one of W, X, Y, and Z is N.

[0066] In certain embodiments, W, X, Y, and Z are each CR 6 .

[0067] In certain embodiments, Z is N.

[0068] In certain embodiments, the compound of Formula I is a compound of Formula I-a:

[0069]

[0070] or a pharmaceutically acceptable salt, co-crystal, 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 herein.

[0071] In certain embodiments, the compound of Formula I is a compound of Formula I-b:

[0072]

[0073] or a pharmaceutically acceptable salt, co-crystal, 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 herein.

[0074] In certain embodiments, the compound of Formula I is a compound of Formula I-c:

[0075]

[0076] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R 1 , R 2 , R 4 , R 6 , and Z are as defined herein.

[0077] In certain embodiments, the compound of Formula I is a compound of Formula I-d:

[0078]

[0079] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R 1 , R 2 , R 4 , R 6 , and Z are as defined herein.

[0080] In certain embodiments, the compound of Formula I is a compound of Formula I-e:

[0081]

[0082] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R 1 , R 4 , R 6 , and Z are as defined herein.

[0083] In certain embodiments, the compound of Formula I is a compound of Formula I-f:

[0084]

[0085] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R 1 , R 4 , and R 6 are as defined herein.

[0086] In certain embodiments, the foregoing compound of Formula I-f is a compound as follows:

[0087] wherein R 4 is alkyl or cycloalkyl; R 6 is hydrogen or halogen, wherein at least one R 6 is halogen.

[0088] In certain embodiments, the foregoing compound of Formula I-f is a compound as follows:

[0089] wherein R 4 is alkyl or cycloalkyl; R 6 is halogen.

[0090] In certain embodiments, the foregoing compound of Formula I-f is a compound as follows:

[0091] wherein R 4 is alkyl or cycloalkyl; R 6 is hydrogen or halogen, wherein at least one R 6 is halogen; R 1 is hydrogen, halogen, cyano, acyl, alkyl, haloalkyl, alkoxy, haloalkoxy, NR a R b , NHSO2R c , CH2NR a R b , CH2NHSO2R d , CO2R e , COR f , CH2OR for CR e R f OH.

[0092] In certain embodiments, the foregoing compounds of Formula I-f are compounds in which:

[0093] wherein R 4 is alkyl or cycloalkyl; R 6 is hydrogen or halogen, wherein at least one R 6 is halogen; R 1 is optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl.

[0094] In certain embodiments, the foregoing compounds of Formula I-f are compounds in which:

[0095] wherein R 1 is alkyl or haloalkyl; R 4 is alkyl or cycloalkyl; R 6 is hydrogen or halogen, wherein at least one R 6 is halogen.

[0096] In certain embodiments, the foregoing compounds of Formula I-f are compounds in which:

[0097] wherein R 1 is alkyl or haloalkyl; R 4 is alkyl or cycloalkyl; R 6 is halogen.

[0098] In certain embodiments, the compounds of Formula I are compounds of Formula I-g:

[0099]

[0100] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R 1 , R 4 , and R 6 are as defined herein.

[0101] In certain embodiments, the foregoing compounds of Formula I-g are compounds in which:

[0102] wherein R 4 is alkyl or cycloalkyl; R 6 is hydrogen or halogen, wherein at least one R 6 is halogen.

[0103] In certain embodiments, the foregoing compounds of Formula I-g are compounds in which:

[0104] R is alkyl or cycloalkyl; R is hydrogen or halogen, wherein at least one R is halogen; R is hydrogen, halogen, cyano, acyl, alkyl, haloalkyl, alkoxy, haloalkoxy, NR 4 6 R is hydrogen or halogen.

[0105] In certain embodiments, the foregoing compounds of Formula I-g are compounds in which:

[0106] R is alkyl or cycloalkyl; R is hydrogen or halogen, wherein at least one R is halogen; R is hydrogen, halogen, cyano, acyl, alkyl, haloalkyl, alkoxy, haloalkoxy, NR 4 6 R is hydrogen or halogen, wherein at least one R is halogen; R is hydrogen, halogen, cyano, acyl, alkyl, haloalkyl, alkoxy, haloalkoxy, NR 6 1 R is hydrogen, halogen, cyano, acyl, alkyl, haloalkyl, alkoxy, haloalkoxy, NR a R is hydrogen or halogen. b R is hydrogen or halogen. c R is hydrogen or halogen. a R is hydrogen or halogen. b R is hydrogen or halogen. d R is hydrogen or halogen. e R is hydrogen or halogen. f R is hydrogen or halogen. f R is hydrogen or halogen. e R is hydrogen or halogen. f R is hydrogen or halogen.

[0107] In certain embodiments, the foregoing compounds of Formula I-g are compounds in which:

[0108] R is alkyl or cycloalkyl; R is hydrogen or halogen, wherein at least one R is halogen; R is hydrogen, halogen, cyano, acyl, alkyl, haloalkyl, alkoxy, haloalkoxy, NR 4 6 R is hydrogen or halogen, wherein at least one R is halogen; R is hydrogen, halogen, cyano, acyl, alkyl, haloalkyl, alkoxy, haloalkoxy, NR 6 1 R is hydrogen, halogen, cyano, acyl, alkyl, haloalkyl, alkoxy, haloalkoxy, NR

[0109] In another aspect, provided are compounds of Formula I:

[0110]

[0111] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein:

[0112] A is N or CR 5 ;

[0113] W is N or CR 6 ;

[0114] X is N or CR 6 ;

[0115] Y is N or CR 6 ;

[0116] ​​​​​Z is N or CR 6 ;

[0117] provided that no more than two of W, X, Y, and Z are N;

[0118] R 1 is hydrogen, halogen, cyano, acyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, 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, wherein any R 1 may be optionally substituted with 1 to 3 independent substituents R 7 ;

[0119] R 2 is hydrogen, halogen, cyano, alkyl, or haloalkyl;

[0120] or R 1 and R 2 , together with the atoms to which they are attached, form an aryl, heterocycloalkyl, or cycloalkyl ring;

[0121] R 3 is hydrogen, halogen, cyano, acyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, NR a R b , NHSO2R c , CH2NR a R b , CH2NHSO2R d , CO2R e , COR f , CH2OR f , or CR e R f OH;

[0122] R4 is alkyl, cycloalkyl, haloalkyl, or heteroalkyl;

[0123] R 5 is hydrogen, cyano, alkyl, haloalkyl, heteroalkyl, or cycloalkyl;

[0124] each occurrence of R 6 is independently hydrogen, halogen, cyano, haloalkyl, alkyl, cycloalkyl, alkoxy, haloalkyl, OR f , or carboxyl;

[0125] each occurrence of R 7 is independently halogen, alkyl, alkoxy, haloalkyl, carboxyl, cycloalkyl, aryl, aryl substituted with 1 to 3 independent halogens, -(CH2) n C(O)NR g R h , -S(O)2R i , -CO2R j , or NR g R h ;

[0126] each n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

[0127] each occurrence of R a , R b , R c , R d , R e , and R f are independently hydrogen, acyl, alkoxyalkyl, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C(O)OC 1-6 alkyl, C(O)C 1-6 alkyl, a nitrogen protecting group when attached to a nitrogen atom, or an oxygen protecting group when attached to an oxygen atom; or R a and R b together with the atom to which they are attached form a heterocycloalkyl ring; or R e and R f together with the atom to which they are attached form a cycloalkyl ring; and

[0128] each occurrence of R g , R h , R i , and R j are 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 htogether with the atom to which they are attached form a heterocycloalkyl ring.

[0129] In certain embodiments, R 1 is aryl, heteroaryl, or heterocycloalkyl, wherein any R 1 may be optionally substituted with 1 to 3 independent substituents R 7 .

[0130] In certain embodiments, R 1 is aryl, heteroaryl, or heterocycloalkyl, wherein any R 1 may be optionally substituted with 1 to 3 independent substituents R 7 , and each R 7 is independently halogen, 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 is independently hydrogen, alkyl, C(O)C 1-6 alkyl, or R g and R h together with the atom to which they are attached form a heterocycloalkyl ring.

[0131] In certain embodiments, R 1 is hydrogen, halogen, cyano, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, NR a R b , NHSO2R c , CH2NR a R b , 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 atom to which they are attached form an aromatic ring or a cycloalkyl ring.

[0132] In certain embodiments, R 1 is hydrogen, halogen, alkyl, alkenyl, haloalkyl, alkoxy, haloalkoxy, cycloalkoxy, aryl, NR a R b , CR e Rf NHSO2R d , SR f , or CR e R f OH; or R 1 and R 2 , together with the atoms to which they are attached, form an aromatic ring or a cycloalkyl ring.

[0133] In certain embodiments, R 1 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 are independently hydrogen, alkyl, or haloalkyl.

[0134] In certain embodiments, R 1 is SR f . In certain embodiments, R 1 is SR f ; R f is hydrogen, alkyl, or haloalkyl.

[0135] In certain embodiments, R 1 is alkyl or haloalkyl.

[0136] In certain embodiments, R 1 is C 1-6 alkyl or C 1-6 haloalkyl.

[0137] In certain embodiments, R 1 is haloalkyl.

[0138] In certain embodiments, R 1 is C 1-6 haloalkyl.

[0139] In certain embodiments, R 1 is fluoroalkyl. In certain embodiments, R 1 is C 1-6 fluoroalkyl. In certain embodiments, R 1 is C 1-3 fluoroalkyl. In certain embodiments, R 1 is difluoromethyl or trifluoromethyl. In certain embodiments, R 1 is difluoromethyl. In certain embodiments, R1 It is trifluoromethyl.

[0140] In some implementations, R 2 It is hydrogen or alkyl.

[0141] In some implementations, R 2 Is it hydrogen or C? 1-6 alkyl.

[0142] In some implementations, R 2 Is it hydrogen or C? 1-3 alkyl.

[0143] 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.

[0144] 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.

[0145] 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, R 1 and R 2 Together with the atoms they are attached to, they form cycloalkyl rings.

[0146] In some implementations, R 4 It is an alkyl or cycloalkyl group.

[0147] In some implementations, R 4 It is C 1-4 Alkyl or C 3-5 Cycloalkyl.

[0148] In some implementations, R 4 It is C 1-4 Alkyl group. In some embodiments, R 4 It is C 3-5cycloalkyl. In certain embodiments, R 4 is cyclopentyl. In certain embodiments, R 4 is cyclobutyl. In certain embodiments, R 4 is cyclopropyl.

[0149] In certain embodiments, each R 6 is independently hydrogen, halogen, cyano, alkoxy, haloalkyl, or carboxyl.

[0150] In certain embodiments, each R 6 is independently hydrogen, halogen, or cyano.

[0151] In certain embodiments, each R 6 is independently hydrogen, chloro, fluoro, or cyano.

[0152] In certain embodiments, each R 6 is independently hydrogen, fluoro, or cyano.

[0153] In certain embodiments, each R 6 is independently hydrogen or halogen.

[0154] In certain embodiments, each R 6 is independently hydrogen, chloro, or fluoro.

[0155] In certain embodiments, each R 6 is independently hydrogen or fluoro.

[0156] In certain embodiments, each R 6 is independently hydrogen or cyano.

[0157] In certain embodiments, each R 6 is halogen. In certain embodiments, each R 6 is chloro or fluoro. In certain embodiments, each R 6 is fluoro. In certain embodiments, each R 6 is cyano.

[0158] In certain embodiments, A is CR 5 and R 5 is hydrogen, cyano, C 1-4 alkyl, or C 3-5 cycloalkyl.

[0159] In certain embodiments, A is N.

[0160] In certain embodiments, no more than one of W, X, Y, and Z is N.

[0161] In certain embodiments, W, X, Y, and Z are each independently CR 6 .

[0162] In certain embodiments, Z is N.

[0163] In certain embodiments, the compound of Formula I is a compound of Formula I-a:

[0164]

[0165]

[0166] or a pharmaceutically acceptable salt, co-crystal, 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 independently as defined herein.

[0167] In certain embodiments, the compound of Formula I is a compound of Formula I-b:

[0168]

[0169] or a pharmaceutically acceptable salt, co-crystal, 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 independently as defined herein.

[0170] In certain embodiments, the compound of Formula I is a compound of Formula I-c:

[0171]

[0172] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R 1 , R 2 , R 4 , R 6 and Z are each independently as defined herein.

[0173] In certain embodiments, the compound of Formula I is a compound of Formula I-d:

[0174]

[0175] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R 1 , R2 R 4 R 6 Z and Z are defined independently as in this paper.

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

[0177]

[0178] 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.

[0179] In some embodiments, the compound of formula I is a compound of formula If:

[0180]

[0181] 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.

[0182] In some embodiments, the compound of the aforementioned formula If is a compound of the following type:

[0183] 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.

[0184] In some embodiments, the compound of the aforementioned formula If is a compound of the following type:

[0185] Where R 4 It is an alkyl or cycloalkyl group; each R 6 Halogens are independent of each other.

[0186] In some embodiments, the compound of the aforementioned formula If is a compound of the following type:

[0187] Where R 4 It is an alkyl or cycloalkyl group; each R 6 It can be hydrogen, halogen, or cyano group independently.

[0188] In some embodiments, the compound of the aforementioned formula If is a compound that is: wherein R 4 It is C1-4 Alkyl or C 3-5 cycloalkyl; each R 6 It can be hydrogen, halogen, or cyano group independently.

[0189] In some embodiments, the compound of the aforementioned formula If is a compound of the following type:

[0190] Where R 4 It is a cycloalkyl group; each R 6 It can be hydrogen, halogen, or cyano group independently.

[0191] In some embodiments, the compound of the aforementioned formula If is a compound of the following type:

[0192] Where R 4 It is C 3-5 cycloalkyl; each R 6 It can be hydrogen, halogen, or cyano group independently.

[0193] In some embodiments, the compound of the aforementioned formula If is a compound of the following type:

[0194] Where R 4 It is a cycloalkyl group; each R 6 Halogens are independent of each other.

[0195] In some embodiments, the compound of the aforementioned formula If is a compound of the following type:

[0196] Where R 4 It is C 3-5 cycloalkyl; each R 6 Halogens are independent of each other.

[0197] In some embodiments, the compound of the aforementioned formula If is a compound of the following type:

[0198] 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.

[0199] In certain embodiments, the foregoing compounds of Formula I-f are compounds in which:

[0200] wherein R is alkyl or cycloalkyl; each R is independently hydrogen or halo, wherein at least one R is halo; R is optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl. 4 6 is hydrogen or halo, wherein at least one R is halo; R is optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl. 6 1 is hydrogen, halo, 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.

[0201] In certain embodiments, the foregoing compounds of Formula I-f are compounds in which:

[0202] wherein R is alkyl or cycloalkyl; each R is independently hydrogen or halo, wherein at least one R is halo; R is optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl. 4 6 is hydrogen or halo, wherein at least one R is halo; R is optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl. 6 1

[0203] In certain embodiments, the foregoing compounds of Formula I-f are compounds in which:

[0204] wherein R is alkyl or haloalkyl; R is alkyl or cycloalkyl; each R is independently hydrogen or halo, wherein at least one R is halo. 1 4 6 is hydrogen or halo, wherein at least one R is halo; R is optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl. 6

[0205] In certain embodiments, the foregoing compounds of Formula I-f are compounds in which:

[0206] wherein R is alkyl or haloalkyl; R is alkyl or cycloalkyl; each R is independently hydrogen or halo, wherein at least one R is halo. 1 4 6 is hydrogen or halo, wherein at least one R is halo; R is optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl. 1

[0207] In certain embodiments, the foregoing compounds of Formula I-f are compounds in which:

[0208] wherein R is alkyl or haloalkyl; R is alkyl or cycloalkyl; each R is independently hydrogen or halo, wherein at least one R is halo.​​​​​​​​​​​4 is alkyl or cycloalkyl; each R 6 is independently hydrogen, halo, or cyano.

[0209] In certain embodiments, the foregoing compounds of Formula I-f are compounds in which:

[0210] wherein R 1 is haloalkyl; R 4 is alkyl or cycloalkyl; each R 6 is independently hydrogen, halo, or cyano.

[0211] In certain embodiments, the foregoing compounds of Formula I-f are compounds in which:

[0212] wherein R 1 is haloalkyl; R 4 is C 1-4 alkyl or C 3-5 ycloalkyl; each R6is independently hydrogen, halo, or cyano.

[0213] In certain embodiments, the foregoing compounds of Formula I-f are compounds in which:

[0214] wherein R 1 is haloalkyl; R 4 is cycloalkyl; each R 6 is independently hydrogen, halo, or cyano.

[0215] In certain embodiments, the foregoing compounds of Formula I-f are compounds in which:

[0216] wherein R 1 is haloalkyl; R 4 is C 3-5 ycloalkyl; each R6is independently hydrogen, halo, or cyano. 6

[0217] In certain embodiments, the foregoing compounds of Formula I-f are compounds in which:

[0218] wherein R 1 is haloalkyl; R 4 is cycloalkyl; each R 6 is independently halo.

[0219] In certain embodiments, the foregoing compounds of Formula I-f are compounds in which:

[0220] wherein R 1 is haloalkyl; R 4 is C 3-5 ycloalkyl; each R6is independently hydrogen, halo, or cyano. 6

[0221] ​​In certain embodiments, the compound of Formula I is a compound of Formula I-g:

[0222]

[0223]

[0224] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R 1 , R 4 , and R 6 are each independently as defined herein.

[0225] In certain embodiments, the foregoing compound of Formula I-g is a compound as follows:

[0226] wherein R 4 is alkyl or cycloalkyl; each R 6 is independently hydrogen or halo, wherein at least one R 6 is halo.

[0227] In certain embodiments, the foregoing compound of Formula I-g is a compound as follows:

[0228] wherein R 4 is alkyl or cycloalkyl; each R 6 is independently halo.

[0229] In certain embodiments, the foregoing compound of Formula I-f is a compound as follows:

[0230] wherein R 4 is alkyl or cycloalkyl; each R 6 is independently hydrogen, halo, or cyano.

[0231] In certain embodiments, the foregoing compound of Formula I-f is a compound as follows:

[0232] wherein R 4 is C 1-4 alkyl or C 3-5 cycloalkyl; each R6 is independently hydrogen, halo, or cyano.

[0233] In certain embodiments, the foregoing compound of Formula I-f is a compound as follows:

[0234] wherein R 4 is cycloalkyl; each R 6 is independently hydrogen, halo, or cyano.

[0235] In certain embodiments, the foregoing compound of Formula I-f is a compound as follows:

[0236] wherein R 4 is C 3-5 cycloalkyl; each R 6 is independently hydrogen, halogen, or cyano.

[0237] In certain embodiments, the foregoing compounds of Formula I-f are compounds in which:

[0238] wherein R 4 is cycloalkyl; each R 6 is independently hydrogen or cyano.

[0239] In certain embodiments, the foregoing compounds of Formula I-f are compounds in which:

[0240] wherein R 4 is C 3-5 cycloalkyl; each R 6 is independently hydrogen or cyano.

[0241] In certain embodiments, the foregoing compounds of Formula I-f are compounds in which:

[0242] wherein R 4 is cycloalkyl; each R 6 is independently halogen.

[0243] In certain embodiments, the foregoing compounds of Formula I-f are compounds in which:

[0244] wherein R 4 is C 3-5 cycloalkyl; each R 6 is independently halogen.

[0245] In certain embodiments, the foregoing compounds of Formula I-f are compounds in which:

[0246] wherein R 4 is alkyl or cycloalkyl; each R 6 is independently hydrogen, cyano, or halogen; R 1 is hydrogen, halogen, cyano, acyl, alkyl, haloalkyl, alkoxy, haloalkoxy, NR a R b , NHSO2R c , CH2NR a R b , CH2NHSO2R d , CO2R e , COR f , CH2OR f , or CR e R f OH.

[0247] In some embodiments, the compound of formula Ig is the following compound:

[0248] 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.

[0249] In some embodiments, the compound of formula Ig is the following compound:

[0250] 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 an optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl.

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

[0252] 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.

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

[0254] 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.

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

[0256] Where R 1 It is a haloalkyl group; R4 is alkyl or cycloalkyl; each R 6 is independently hydrogen, halo, or cyano.

[0257] In certain embodiments, the foregoing compounds of Formula I-f are compounds in which:

[0258] wherein R 1 is haloalkyl; R 4 is C 1-4 alkyl or C 3-5 cycloalkyl; each R6is independently hydrogen, halo, or cyano.

[0259] In certain embodiments, the foregoing compounds of Formula I-f are compounds in which:

[0260] wherein R 1 is haloalkyl; R 4 is cycloalkyl; each R 6 is independently hydrogen, halo, or cyano.

[0261] In certain embodiments, the foregoing compounds of Formula I-f are compounds in which:

[0262] wherein R 1 is haloalkyl; R 4 is C 3-5 cycloalkyl; each R 6 is independently hydrogen, halo, or cyano. In certain embodiments, the foregoing compounds of Formula I-f are compounds in which:

[0263] wherein R 1 is haloalkyl; R 4 is cycloalkyl; each R 6 is independently hydrogen or cyano.

[0264] In certain embodiments, the foregoing compounds of Formula I-f are compounds in which:

[0265] wherein R 1 is haloalkyl; R 4 is C 3-5 cycloalkyl; each R 6 is independently hydrogen or cyano.

[0266] In certain embodiments, the foregoing compounds of Formula I-f are compounds in which:

[0267] wherein R 1 is haloalkyl; R 4 is cycloalkyl; each R 6 is independently halo.

[0268] In certain embodiments, the foregoing compounds of Formula I-f are compounds in which:

[0269] wherein R 1 is haloalkyl; R 4 is C 3-5 cycloalkyl; each R 6 is independently halogen.

[0270] In certain embodiments, the compound of Formula I is a compound selected from the group consisting of:

[0271] 1 -cyclopropyl-6-fluoro-2-(pyridazin-4-yl)- 1 H-benzo[d]imidazole (1);

[0272] 5-( 1 -cyclopropyl-6-fluoro- 1 H-benzo[d]imidazol-2-yl)pyridazine-3-carbonitrile (2);

[0273] 2-(6-chloropyridazin-4-yl)- 1 -cyclopropyl-6-fluoro- 1 H-benzo[d]imidazole (3);

[0274] 1 -cyclopropyl-6-fluoro-2-(6-vinylpyridazin-4-yl)- 1 H-benzo[d]imidazole (4);

[0275] 5-( 1 -cyclopropyl-6-fluoro- 1 H-benzo[d]imidazol-2-yl)pyridazine-3-carboxylic acid methyl ester (5);

[0276] 1 -cyclopropyl-2-(6-ethylpyridazin-4-yl)-6-fluoro- 1 H-benzo[d]imidazole (6);

[0277] 1 -(5-( 1 -cyclopropyl-6-fluoro- 1 H-benzo[d]imidazol-2-yl)pyridazin-3-yl)-2,2,2- trifluoroethan- 1 -ol (7); N-((5-( 1 -cyclopropyl-6-fluoro- 1 H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methyl)propanamide (8);

[0278] (5-( 1 -cyclopropyl-6-fluoro- 1 H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methyl) carbamic acid ethyl ester (9); 4-(5-( 1 -cyclopropyl-6-fluoro- 1 H-benzo[d]imidazol-2-yl)pyridazin-3-yl)morpholine (10);

[0279] 1 -cyclopropyl-6-fluoro-2-(6-(4-(4-fluorophenyl)piperazin- 1 -yl)pyridazin-4-yl)- 1 H- benzo[d]imidazole (11);

[0280] 2-(5-( 1 -cyclopropyl-6-fluoro- 1 H-benzo[d]imidazol-2-yl)pyridazin-3-yl)propan-2-ol (12);

[0281] 5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)-N-(tetrahydro-2H-pyran-4- yl)pyridazine-3 -amine (13);

[0282] 4-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)cinnoline (14);

[0283] 1-cyclopropyl-6-fluoro-2-(6-methylpyridazin-4-yl)-1H-benzo[d]imidazole (15);

[0284] N-(5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)ethane- sulfonamide (16);

[0285] 2-(6-chloropyridazin-4-yl)-1-ethyl-1H-benzo[d]imidazole-6-carbonitrile (17);

[0286] 2-(4-(5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)piperazin- 1-yl)-N-isopropylacetamide (18);

[0287] 1-cyclopropyl-5,6-difluoro-2-(6-methylpyridazin-4-yl)-1H-benzo[d]imidazole (19);

[0288] 2-(4-(5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)piperazin- 1-yl)-1-(pyrrolidin-1-yl)ethan-1-one (20);

[0289] 5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-N-methylpyridazine-3-amine (21);

[0290] 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole (22);

[0291] 1-cyclopropyl-5,6-difluoro-2-(6-methoxypyridazin-4-yl)-1H-benzo[d]imidazole (23);

[0292] 1-cyclopropyl-5,6-difluoro-2-(6-isopropoxypyridazin-4-yl)-1H-benzo[d]imidazole (24);

[0293] 5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-N,N-dimethylpyridazine-3- amine (25);

[0294] 1-ethyl-6-fluoro-2-(6-methylpyridazin-4-yl)-1H-indole (26);

[0295] 1 -cyclopropyl-5, 6-difluoro-2-(6-(2,2,2-trifluoroethoxy)pyridazin-4-yl)- 1 H- benzo[d]imidazole (27);

[0296] 5-(1 -cyclopropyl-5, 6-difluoro- 1 H-benzo[d]imidazol-2-yl)-N-(2-methoxyethyl)pyridaz in-3-amine (28);

[0297] 1 -cyclopropyl-2-(6-methoxypyridazin-4-yl)- 1 H-benzo[d]imidazole-6-carbonitrile (29);

[0298] 1 -cyclopropyl-6-fluoro-2-(6-methylpyridazin-4-yl)- 1 H-indole (30);

[0299] N-((5-(1 -cyclopropyl-6-fluoro- 1 H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methyl)ethane sulfonamide (31);

[0300] 5-(1 -cyclopropyl-5, 6-difluoro- 1 H-benzo[d]imidazol-2-yl)-N-(2,2,2-trifluoroethyl)pyridaz in-3-amine (32);

[0301] 1 -cyclopropyl-2-(6-ethylpyridazin-4-yl)-5, 6-difluoro- 1 H-benzo[d]imidazole (33);

[0302] 2-(6-chloropyridazin-4-yl)- 1 -cyclopropyl- 1 H-benzo[d]imidazole-6-carbonitrile (34);

[0303] 1 -cyclopropyl-2-(6-methylpyridazin-4-yl)- 1 H-benzo[d]imidazole-6-carbonitrile (35);

[0304] 1 -cyclopropyl-5, 6-difluoro-2-(6-(4-methylpiperazin- 1 -yl)pyridazin-4-yl)- 1 H- benzo[d]imidazole (36);

[0305] 1 -(4-(5-( 1 -cyclopropyl-5, 6-difluoro- 1 H-benzo[d]imidazol-2-yl)pyridazin-3-yl)piperazin- 1 - yl)ethan- 1 -one (37);

[0306] 1 -cyclopropyl-5, 6-difluoro-2-(6-(4-(methylsulfonyl)piperazin- 1 -yl)pyridazin-4-yl)- 1 H- benzo[d]imidazole (38);

[0307] 4-(5-( 1 -cyclopropyl-5, 6-difluoro- 1 H-benzo[d]imidazol-2-yl)pyridazin-3-yl)piperazine- 1 - carboxylate tert-butyl ester (39);

[0308] 1 -ethyl-2-(6-methoxypyridazin-4-yl)- 1 H-benzo [d] imidazole-6-carbonitrile (40);

[0309] 1 -ethyl-2-(6-ethylpyridazin-4-yl)- 1 H-benzo [d] imidazole-6-carbonitrile (41);

[0310] 1 -cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro- 1 H-benzo [d] imidazole (42);

[0311] 2-(6-cyclobutoxy-pyridazin-4-yl)- 1 -cyclopropyl-5,6-difluoro- 1 H-benzo [d] imidazole (43);

[0312] 1 -cyclopropyl-2-(6-(4,4-difluoropiperidin- 1 -yl)pyridazin-4-yl)-5,6-difluoro- 1 H-benzo [d] imidazole (44);

[0313] 5-chloro-3-cyclopropyl-2-(6-methylpyridazin-4-yl)-3H-imidazo[4,5-b]pyridine (45);

[0314] 1 -cyclopropyl-2-(6-(3,3-difluoropyrrolidin- 1 -yl)pyridazin-4-yl)-5,6-difluoro- 1 H-benzo [d] imidazole (46);

[0315] 1 -(5-( 1 -cyclopropyl-5,6-difluoro- 1 H-benzo [d] imidazol-2-yl)pyridazin-3-yl)-2,2,2- trifluoroethan- 1 -ol (47);

[0316] 1 -(5-( 1 -cyclopropyl-5,6-difluoro- 1 H-benzo [d] imidazol-2-yl)pyridazin-3-yl)-N,N- dimethylpyrrolidin-3-amine (48);

[0317] 1 -cyclopropyl-5,6-difluoro-2-(6-(4-fluorophenyl)pyridazin-4-yl)- 1 H-benzo [d] imidazole (49);

[0318] 1 -cyclopropyl-5,6-difluoro-2-(6-((4-fluorophenyl)ethynyl)pyridazin-4-yl)- 1 H-benzo [d] imidazole (50);

[0319] 1 -cyclopropyl-5,6-difluoro-2-(6-isopropylpyridazin-4-yl)- 1 H-benzo [d] imidazole (51);

[0320] N-((5-( 1 -cyclopropyl-5,6-difluoro- 1 H-benzo [d] imidazol-2-yl)pyridazin-3-yl)methyl)ethane sulfonamide (52);

[0321] 1-Cyclopropyl-5,6-Difluoro-2-(6-((1,1,1-trifluoroprop-2-yl)oxy)pyridazin-4-yl)-1H-benzo[d]imidazolium (53);

[0322] 3-Cyclopropyl-2-(6-methylpyridazin-4-yl)-3H-imidazo[4,5-b]pyridine-5-carboxylonitrile (54);

[0323] 1-Cyclopropyl-5,6-Difluoro-2-(pyridazin-4-yl)-1H-benzo[d]imidazolium (55);

[0324] 1-Cyclopropyl-5,6-Difluoro-2-(pyridazin-4-yl)-4-(trifluoromethyl)-1H-benzo[d]imidazolium (56);

[0325] 1-Cyclopropyl-2-(6-(2,2-difluoropropoxy)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazolium (57);

[0326] 1-Cyclopropyl-5,6-Difluoro-2-(5-Isopropylpyridazin-4-yl)-1H-benzo[d]imidazolium (58);

[0327] 1-Cyclopropyl-2-(6-Cyclopropylpyridazin-4-yl)-5,6-Difluoro-1H-benzo[d]imidazolium (59);

[0328] 2-(6-Chlorpyridazin-4-yl)-3-cyclopropyl-5-methoxy-3H-imidazo[4,5-b]pyridine (60);

[0329] 1-Cyclopropyl-5,6-difluoro-2-(6-(4-fluoro-2-methylphenyl)pyridazin-4-yl)-1H-benzo[d]imidazolium (61);

[0330] 1-Cyclopropyl-2-(6-(2,4-difluorophenyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazolium(62);

[0331] 1-Cyclopropyl-2-(6-(3,4-difluorophenyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazolium (63);

[0332] 1-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)ethyl-1-one (64);

[0333] 2-(6-Chlorpyridazin-4-yl)-1-ethyl-5,6-difluoro-1H-benzo[d]imidazolium (65);

[0334] 1 -cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)- 1 H-benzo[d]imidazole-6- carbonitrile (66);

[0335] 2-(6-(difluoromethyl)pyridazin-4-yl)- 1 -ethyl-5,6-difluoro- 1 H-benzo[d]imidazole (67);

[0336] 2-(6-chloropyridazin-4-yl)- 1 -ethyl- 1 H-benzo[d]imidazole-6-carbonitrile (68);

[0337] 2-(6-(difluoromethyl)pyridazin-4-yl)- 1 -ethyl- 1 H-benzo[d]imidazole-6-carbonitrile (69);

[0338] 1 -cyclopropyl-2-(6-( 1, 1 -difluoroethyl)pyridazin-4-yl)-5,6-difluoro- 1 H-benzo[d]imidazole (70);

[0339] 1 -cyclopropyl-5,6-difluoro-2-(6-(2,2,2-trifluoroethyl)pyridazin-4-yl)- 1 H-benzo[d]imidazole (71);

[0340] 2-(6-cyclopropylpyridazin-4-yl)- 1 -ethyl-5,6-difluoro- 1 H-benzo[d]imidazole (72);

[0341] 5-chloro-3-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-3H-imidazo[4,5- b]pyridine (73);

[0342] 1 -cyclopropyl-5,6-difluoro-2-(5-methylpyridazin-4-yl)- 1 H-benzo[d]imidazole (74);

[0343] 1 -cyclopropyl-2-(6-cyclopropylpyridazin-4-yl)- 1 H-benzo[d]imidazole-6-carbonitrile (75);

[0344] 3-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-3H-imidazo[4,5-b]pyridine-5- carbonitrile (76);

[0345] N-((5-( 1 -cyclopropyl-5,6-difluoro- 1 H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methyl)- N-methylmethanesulfonamide (78);

[0346] N-((5-( 1 -cyclopropyl-5,6-difluoro- 1 H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methyl)- N-methylmethanesulfonamide (78);

[0347] N-((5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methyl)propane-2- sulfonamide (79);

[0348] 1-cyclopropyl-5,6-difluoro-2-(6-(methylsulfonyl)pyridazin-4-yl)-1H-benzo[d]imidazole (80);

[0349] 1-cyclopropyl-2-(6-(ethylsulfonyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (81);

[0350] 1-cyclopropyl-5,6-difluoro-2-(6-(methylsulfinyl)pyridazin-4-yl)-1H-benzo[d]imidazole (82);

[0351] 1-cyclopropyl-2-(6-(ethylsulfinyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (83);

[0352] 5-chloro-3-cyclopropyl-2-(6-cyclopropylpyridazin-4-yl)-3H-imidazo[4,5-b]pyridine (84);

[0353] 1-cyclopropyl-5,6-difluoro-2-(6-(trifluoromethyl)pyridazin-4-yl)-1H-benzo[d]imidazole (85);

[0354] 1-cyclopropyl-2-(6-(trifluoromethyl)pyridazin-4-yl)-1H-benzo[d]imidazole-6-carbonitrile (86);

[0355] 3-cyclopropyl-2-(6-cyclopropylpyridazin-4-yl)-3H-imidazo[4,5-b]pyridine-5-carbonitrile (87);

[0356] 2-((5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methyl)isothiazolidine 1,1-dioxide (88);

[0357] 3-cyclopropyl-2-(6-(trifluoromethyl)pyridazin-4-yl)-3H-imidazo[4,5-b]pyridine-5-carbonitrile (89);

[0358] 1-cyclopropyl-2-(6-methylpyridazin-4-yl)-6-(trifluoromethyl)-1H-benzo[d]imidazole (90);

[0359] N-(1-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)ethyl)methanesulfonamide (91);

[0360] 1 -cyclopropyl-5, 6-difluoro-2-(6-(fluoromethyl)pyridazin-4-yl)- 1 H- benzo[d]imidazole (92);

[0361] 1 -cyclopropyl-2-(5, 6-dimethylpyridazin-4-yl)-5, 6-difluoro- 1 H- benzo[d]imidazole (93);

[0362] (5-(1 -cyclopropyl-5, 6-difluoro- 1 H-benzo[d]imidazol-2-yl)pyridazin-3- yl)methanol (94);

[0363] 5-chloro-3-cyclopropyl-2-(6-(trifluoromethyl)pyridazin-4-yl)-3H- imidazo[4,5-b]pyridine (95);

[0364] N-(1 -(5-(1 -cyclopropyl-5, 6-difluoro- 1 H-benzo[d]imidazol-2-yl)pyridazin-3- yl)ethyl)ethanesulfonamide (96);

[0365] 2-(6-butylpyridazin-4-yl)- 1 -cyclopropyl-5, 6-difluoro- 1 H-benzo[d]imidazole (97);

[0366] 1 -cyclopropyl-6-methyl-2-(6-methylpyridazin-4-yl)- 1 H-benzo[d]imidazole (98);

[0367] 1 -cyclopropyl-5, 6-difluoro-2-(3-methylpyridazin-4-yl)- 1 H-benzo[d]imidazole (99);

[0368] 1 -cyclopropyl-2-(3, 6-dimethylpyridazin-4-yl)-5, 6-difluoro- 1 H-benzo[d]imidazole (100);

[0369] 1 -cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-6, 7-difluoro- 1 H- benzo[d]imidazole (101);

[0370] 5-(1 -cyclopropyl-5, 6-difluoro- 1 H-benzo[d]imidazol-2-yl)pyridazin-3- thiol (102);

[0371] 2-(6-(difluoromethyl)pyridazin-4-yl)-5, 6-difluoro- 1 -methyl- 1 H- benzo[d]imidazole (104);

[0372] 2-(6-(difluoromethyl)pyridazin-4-yl)-5, 6-difluoro- 1 -propyl- 1 H- benzo[d]imidazole (105);

[0373] 4-(1 -cyclopropyl-5, 6-difluoro- 1 H-benzo[d]imidazol-2-yl)-5, 6, 7, 8- tetrahydrocinnoline (106);

[0374] 1 -cyclopropyl-2-(6-methylpyridazin-4-yl)- 1 H-benzo[d]imidazole-5-carbonitrile (Ex. 107)

[0375] 1 -cyclobutyl-5,6-difluoro-2-(6-methylpyridazin-4-yl)- 1 H-benzo[d]imidazole (108);

[0376] 1 -cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)- 1 H-benzo[d]imidazol-6-ol (109);

[0377] 5-( 1 -cyclopropyl-5,6-difluoro- 1 H-benzo[d]imidazol-2-yl)pyridazine-3-carboxylic acid (110);

[0378] 1 -cyclopropyl-7-fluoro-2-(6-methylpyridazin-4-yl)- 1 H-benzo[d]imidazole (111);

[0379] 5-chloro- 1 -cyclopropyl-2-(6-methylpyridazin-4-yl)- 1 H-benzo[d]imidazole (112);

[0380] 4-chloro- 1 -cyclopropyl-2-(6-methylpyridazin-4-yl)- 1 H-benzo[d]imidazole (113);

[0381] 1 -cyclopropyl-5,6-difluoro-2-(6-(methoxymethyl)pyridazin-4-yl)- 1 H-benzo[d]imidazole (114);

[0382] 5-(6-cyano- 1 -cyclopropyl- 1 H-benzo[d]imidazol-2-yl)pyridazine-3-carboxylic acid methyl ester (115);

[0383] 5-(6-cyano- 1 -cyclopropyl- 1 H-benzo[d]imidazol-2-yl)pyridazine-3-carboxylic acid (116);

[0384] 1 -cyclopropyl-2-(6-(cyclopropylmethoxy)pyridazin-4-yl)-5,6-difluoro- 1 H-benzo[d]imidazole (117);

[0385] 1 -cyclopropyl-2-(6-(2,2,2-trifluoroethoxy)pyridazin-4-yl)- 1 H-benzo[d]imidazole-6-carbonitrile (118);

[0386] 6-chloro- 1 -cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5-fluoro- 1 H-benzo[d]imidazole (119);

[0387] 1 -cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5-fluoro- 1 H-benzo[d]imidazole-6-carbonitrile (120);

[0388] 4-(1-Cyclopropyl-5,6-Difluoro-1H-benzo[d]imidazol-2-yl)-6,7-dihydro-5H-cyclopentano[c]pyridazine (121);

[0389] 1-Cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-6-fluoro-1H-benzo[d]imidazolium (122);

[0390] 1-Cyclopropyl-5,6-Difluoro-2-(6-(methylthio)pyridazin-4-yl)-1H-benzo[d]imidazolium (123);

[0391] 1-Cyclopropyl-5,6-Difluoro-2-(6-(isopropylthio)pyridazin-4-yl)-1H-benzo[d]imidazolium(124);

[0392] 1-Cyclopropyl-2-(6-((difluoromethyl)thio)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazolium (125);

[0393] 5-(1-Cyclopropyl-5,6-Difluoro-1H-Benzo[d]imidazol-2-yl)pyridazin-3-ol (126);

[0394] 1-Cyclopropyl-2-(6-(difluoromethoxy)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazolium (127);

[0395] 1-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)ethanol-1-ol(128);

[0396] 1-Cyclopropyl-5,6-Difluoro-2-(6-(1-fluoroethyl)pyridazin-4-yl)-1H-benzo[d]imidazolium (129);

[0397] 1-Cyclopropyl-5,6-difluoro-2-(6-((trifluoromethyl)thio)pyridazin-4-yl)-1H-benzo[d]imidazolium (130)

[0398] 1-Cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-1H-benzo[d]imidazolium (131);

[0399] 2-(6-(difluoromethyl)pyridazin-4-yl)-1-propyl-1H-benzo[d]imidazolium (132);

[0400] 1-Cyclopropyl-2-(6-(difluoromethoxy)pyridazin-4-yl)-1H-benzo[d]imidazol-6-carboxynitrile (133);

[0401] 1 -Cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-1 H-indole-3-carbonitrile (134);

[0402] 2-(6-(Difluoromethyl)pyridazin-4-yl)-1 -methyl-1 H-indole-3-carbonitrile (135);

[0403] 1 -Cyclopropyl-2-(6-(1 -fluoroethyl)pyridazin-4-yl)-1 H-benzo[d]imidazole-6- carbonitrile (136); pharmaceutically acceptable salts, co-crystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically- enriched derivatives, and prodrugs thereof.

[0404] In another aspect, there is provided 2-(6-(difluoromethyl)pyridazin-4-yl)-5,6- difluoro-1 H-benzo[d]imidazole (103), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically-enriched derivative, or prodrug thereof.

[0405] In one aspect, the compound of Formula I is a compound wherein the compound inhibits (or is identified to inhibit) aldosterone synthase (CYP11B2).

[0406] Compounds herein include those wherein the compound is identified to at least partially obtain affinity to a metalloenzyme by forming one or more than one chemical interaction or bond with the metal of the following types: a sigma bond, a covalent bond, a coordinate covalent bond, an ionic bond, a pi bond, a delta bond, or a backbonding interaction. The compound can also obtain affinity by weaker interactions with the metal, by, for example, van der Waals interactions, pi cation interactions, pi anion interactions, dipole-dipole interactions, ion-dipole interactions. In one aspect, the compound is identified to bond interact with the metal through the pyridazin moiety.

[0407] Methods for assessing metal-ligand binding interactions are known in the art, as exemplified in the references, including, for example, Lippard and Berg, "Principles of Bioinorganic Chemistry", University Science Books, (1994); Basolo and Pearson "Mechanisms of Inorganic Reactions" John Wiley & Sons Inc 2nd Edition (September 1967); Ivano Bertini, Harry Gray, Ed Stiefel, Joan Valentine "Biological Inorganic Chemistry", University Science Books (2007); Xue et al. "Nature Chemical Biology", vol. 4, no. 2, 107-109 (2008).

[0408] In another aspect, there is provided a pharmaceutical composition comprising a compound of Formula I and a pharmaceutically acceptable carrier.

[0409] In another aspect, there is provided a method of modulating metalloenzyme activity in a subject, comprising contacting the subject with a compound of Formula I in an amount and under conditions sufficient to modulate metalloenzyme activity.

[0410] In another aspect, there is provided a method of treating a subject suffering from or susceptible to a disorder or disease, wherein the subject has been identified as in need of treatment for the disorder or disease, comprising administering to the subject in need thereof an effective amount of a compound or pharmaceutical composition of Formula I, such that the subject receives treatment for the disorder.

[0411] In another aspect, the subject is an animal other than a human.

[0412] In another aspect, there is provided a method of treating a subject suffering from or susceptible to a metalloenzyme-related disorder or disease, comprising administering to the subject an effective amount of a compound of Formula I or a pharmaceutical composition.

[0413] In another aspect, there is provided a method of treating a subject suffering from or susceptible to a metalloenzyme-related disorder or disease, wherein the subject has been identified as in need of treatment for the metalloenzyme-related disorder or disease, comprising administering to the subject in need thereof an effective amount of a compound or pharmaceutical composition of Formula I, such that the subject receives treatment for the disorder.

[0414] In another aspect, there is provided a method of treating a subject suffering from or susceptible to a metalloenzyme-mediated disorder or disease, wherein the subject has been identified as in need of treatment for the metalloenzyme-mediated disorder or disease, comprising administering to the subject in need thereof an effective amount of a compound or pharmaceutical composition of Formula I, such that metalloenzyme activity in the subject is modulated (e.g., down-regulated, inhibited).

[0415] The methods herein include those wherein the disease or disorder in the method is one mediated by any one of aromatase (CYP19), a cyclooxygenase family member, lanosterol demethylase (CYP51), a nitric oxide synthase family member, thromboxyne synthase (CYP5a), thyroid peroxidase, 17-alpha hydroxylase / 17,20-lyase (CYP17), cytochrome P450 2A6 (CYP2A6), heme oxygenase, indoleamine 2,3-dioxygenase, retinoic acid hydroxylase (CYP26), vitamin D hydroxylase (CYP24), sterol 27-hydroxylase (CYP27), cytochrome P450 3A5 (CYP3A5), cholesterol 24-hydroxylase (CYP46), cytochrome P450 4F2 (CYP4F2), myeloperoxidase, or 11-beta-hydroxylase (CYP11B1).

[0416] The methods herein include those wherein the disease or disorder is a cancer, a cardiovascular disease, an inflammatory disease, an infectious disease, a metabolic disease, an ophthalmic disease, a central nervous system (CNS) disease, a urologic disease, or a gastrointestinal disease.

[0417] The methods herein include those wherein the disease or disorder is hypertension, resistant hypertension, disorders associated with primary or secondary aldosteronism and adrenal hyperplasia, pulmonary arterial hypertension, heart failure, diastolic dysfunction, left ventricular diastolic dysfunction, diastolic heart failure, systolic dysfunction, systolic heart failure, hypokalemia, renal failure, chronic renal failure, restenosis, nephropathy, post-myocardial infarction syndrome, coronary heart disease, fibrosis, a disease characterized by increased collagen formation after hypertension, fibrosis and matrix remodeling, a disease characterized by fibrosis and matrix remodeling after endothelial cell dysfunction, a cardiovascular disease such as atherosclerosis, atrial fibrillation, renal dysfunction, liver disease, nonalcoholic steatohepatitis, vascular disease, retinopathy, neuropathy, insulinopathy, endothelial dysfunction, myocardial fibrosis, vascular fibrosis, myocardial necrotic lesions, vascular injury, myocardial infarction, left ventricular hypertrophy, vascular wall hypertrophy, endothelial thickening, arterial fibrinoid necrosis, kidney disease, diabetic nephropathy, glomerular sclerosis, glomerulonephritis, nephrotic syndrome, polycystic kidney disease, diabetes, metabolic syndrome, insulin resistance, sleep apnea, obstructive sleep apnea, muscular dystrophy, cirrhosis, nonalcoholic fatty liver disease, kidney disease, diabetic nephropathy, or stroke.

[0418] The methods described herein include methods in which a subject is identified as in need of a particular said treatment. Identifying a subject in need of such treatment can be a judgment made by the subject or a health care professional, and can be subjective (e.g. opinion) or objective (e.g. measured by a test or diagnostic method). DETAILED DESCRIPTION

[0419] Definitions

[0420] In order that the application can be more readily understood, certain terms are first defined herein for convenience.

[0421] As used herein, the term“treatment” of a disease includes prevention, amelioration, palliation, and / or management of the disease and / or a condition that can lead to the disease. The terms“treatment” and“treating” refer to a method of alleviating or abating a disease and / or its symptoms. In accordance with the present disclosure,“treatment” includes prophylaxis, blocking, inhibiting, attenuating, protecting against, modulating, reversing, and reducing the effects of a disease, e.g., the deleterious effects of a disease.

[0422] As used herein,“inhibition” includes prevention, reduction, and cessation of progression. Note that“enzyme inhibition” (e.g., metalloenzyme inhibition) is distinguished and described below.

[0423] The term“modulation” refers to an increase or decrease in the activity of an enzyme in response to exposure to a compound of the disclosure.

[0424] The term“isolated,”“purified,” or“biologically pure” refers to material that is substantially free of components, which accompany the material in its natural state. Purity and homogeneity are typically determined using analytical chemistry techniques, e.g., polyacrylamide gel electrophoresis or high performance liquid chromatography. In particular embodiments, a compound is at least 85% pure, more preferably at least 90% pure, more preferably at least 95% pure, and most preferably at least 99% pure.

[0425] The term“administration” or“administering” includes routes of introducing a compound into a subject to achieve its intended function. Examples of routes of administration that can be used include injection (subcutaneous, intravenous, parenteral, intraperitoneal, intrathecal), topical, oral, inhalation, rectal, and transdermal.

[0426] The term“effective amount” includes an amount effective, at dosages and for periods of time necessary, to achieve a desired result. The effective amount of a compound can vary according to factors such as the disease condition, age, and weight of the subject, and the ability of the compound to elicit a desired response in the subject. Dosage regimens can be adjusted to provide the optimum therapeutic response. An effective amount is also one in which any toxic or detrimental effects (e.g., side effects) of the inhibitor compound are outweighed by the therapeutically beneficial effects.

[0427] The phrases "systemic administration," "systemic administration," "peripheral administration," and "peripheral administration" as used herein refer to the administration of a compound, drug, or other substance such that it enters the patient's system and thus is subject to metabolism and other similar processes.

[0428] The term "therapeutically effective amount" refers to the amount of a compound administered that is sufficient to prevent or to some extent alleviate the development of one or more symptoms of the disease or disorder being treated.

[0429] A therapeutically effective amount of a compound (i.e., an effective dose) can be from about 0.005 pg / 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, a therapeutically effective amount can be from about 1.0 pM to about 10 pM. Those skilled in the art will appreciate that certain factors can influence the dosage required to effectively treat a subject, including but not limited to the severity of the disease or disorder, previous treatments, the overall health and / or age of the subject, and the presence of other diseases. Moreover, treatment of a subject with a therapeutically effective amount of a compound can include a single treatment or, preferably, can include a series of treatments. In one example, a subject is treated with a compound from about 0.005 pg / kg body weight to about 200 mg / kg body weight once a day for about 1 week to 10 weeks, preferably 2 weeks to 8 weeks, more preferably about 3 weeks to 7 weeks, even more preferably about 4 weeks, 5 weeks, or 6 weeks. In another example, in the case of a chronic condition or disease, a subject can be treated daily for years of treatment. It will also be appreciated that the effective dosage of a compound used for treatment can increase or decrease over the course of a particular treatment.

[0430] The term "chiral" refers to molecules which have the property of not being superimposable on their mirror image, and the term "achiral" refers to molecules which are superimposable on their mirror image.

[0431] The term "diastereomer" refers to stereoisomers which have two or more asymmetric centers, and which are not mirror images of one another.

[0432] The term "enantiomer" refers to two stereoisomers of a compound which are mirror images of one another and which are not superimposable on one another. An equimolar mixture of two enantiomers is called a "racemic mixture" or "racemate."

[0433] The term "isomer" or "stereoisomer" refers to compounds which have the same chemical composition but different spatial arrangements of atoms or groups.

[0434] The term "prodrug" includes compounds, which can be metabolized in vivo to yield the active drug. Typically, the prodrug is metabolized in vivo by an esterase or other mechanism to produce the active drug. Examples of prodrugs and their use are well known in the art (see, e.g., Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66: 1-19). Prodrugs can be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound with a suitable esterifying agent. Hydroxyl groups can be converted to esters by treatment with a carboxylic acid. Examples of prodrug moieties include substituted and unsubstituted, branched and unbranched lower alkyl ester moieties (e.g., propionate), lower alkenyl esters, di-lower alkyl aminolower alkyl esters (e.g., dimethylaminoethyl ester), acylamino lower alkyl esters (e.g., acetyloxymethyl ester), acyloxy lower alkyl esters (e.g., pivaloyloxymethyl ester), aryl esters (phenyl ester), aryl-lower alkyl esters (e.g., benzyl ester), substituted (e.g., with methyl, halogen, or methoxy) aryl and aryl-lower alkyl esters, amides, lower alkyl amides, di-lower alkyl amides, and hydroxy amides. Preferred prodrug moieties are propionic acid ester and acyl ester. Prodrugs that are converted in vivo by other mechanisms are also included. In some aspects, the compounds of the present disclosure are prodrugs of any of the general formulae herein.

[0435] The term "subject" refers to an animal, such as a mammal, including but not limited to primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, and the like. In some embodiments, the subject is a human.

[0436] The term "comprising" (and related terms such as "comprise" and "comprises") is not used in a restrictive sense when used in the description or claims of this application. Thus, for example, reference to "a sample" includes a plurality of samples, unless the context clearly indicates otherwise (e.g., a plurality of samples), and the like.

[0437] Throughout this application the word "comprise" and variations of the word, such as "comprising", "comprises" and "comprised", are not used in a restrictive sense.

[0438] As used herein, the term "about" when used in reference to a value, refers to a variation of ±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 variation is appropriate to perform the disclosed methods or use the disclosed compositions.

[0439] The use of the word "inhibitor" herein means a molecule that exhibits inhibition of metalloenzyme activity. "Inhibition" herein refers to a decrease in the activity of a metalloenzyme as compared to the metalloenzyme activity in the absence of the inhibitor. In some embodiments, the term "inhibition" refers to a decrease 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 refers to a decrease in metalloenzyme activity of from about 5% to about 25%, from about 25% to about 50%, from about 50% to about 75%, or from about 75% to 100%. In some embodiments, inhibition refers to a decrease in metalloenzyme activity of from about 95% to 100%, e.g., a 95%, 96%, 97%, 98%, 99%, or 100% decrease in activity. Such decreases can be measured using various techniques recognized by those skilled in the art. Particular tests for measuring individual activities are described below.

[0440] Further, the compounds of the present disclosure include olefins having the following geometric configurations: "Z" refers to the so-called "cis" (same side) configuration, while "E" refers to the so-called "trans" (opposite side) configuration. In terms of nomenclature for chiral centers, the terms "d" and "l" configurations are as defined by the IUPAC Recommendations. With respect to the use of the terms diastereomer, racemate, epimer, and enantiomer, these will be used in their usual context to describe the stereochemistry of a formulation.

[0441] The term "alkyl," as used herein, refers to a straight or branched chain hydrocarbon group containing from 1 to 12 carbon atoms. The term "lower alkyl" refers to a C1to C6alkyl chain. Examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, t-butyl, and n-pentyl. The alkyl group can be optionally substituted with one or more substituents.

[0442] The term "haloalkyl" refers to an alkyl group substituted with one or more halogen substituents. Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, bromomethyl, chloromethyl, and 2,2,2-trifluoroethyl.

[0443] The term "alkenyl" refers to an unsaturated hydrocarbon chain that can be straight or branched, containing from 2 to 12 carbon atoms and at least one carbon-carbon double bond. The alkenyl group can be optionally substituted with one or more substituents.

[0444] The term "arylalkenyl" refers to an unsaturated hydrocarbon chain that can be straight or branched, containing from 2 to 12 carbon atoms and at least one carbon-carbon double bond, wherein the aryl unit is attached to the alkenyl unit through a sp 2 The heteroatom is attached to the aryl moiety through a sp2hybridized carbon. The alkenyl group can be optionally substituted with one or more substituents.

[0445] 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.

[0446] 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.

[0447] 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.

[0448] The term "alkoxy" refers to an -O-alkyl substituent.

[0449] The terms "halogen" and "halogenated" used here refer to -F, -Cl, -Br, or -I.

[0450] The term "alkylthio" refers to a -S-alkyl substituent.

[0451] The term "alkoxyalkyl" refers to an alkyl-O-alkyl substituent.

[0452] 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.

[0453] The term "haloalkoxyalkyl" refers to an alkyl-O-alkyl group in which the alkyl group is substituted by one or more halogen substituents.

[0454] The term "haloalkylaminocarbonyl" refers to -C(O)-amino-alkyl, wherein the alkyl group is substituted by one or more halogen substituents.

[0455] 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.

[0456] 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.

[0457] The term "cycloalkyl" refers to a hydrocarbon 3- to 8-membered monocyclic or 7- to 14-membered bicyclic ring system having at least one saturated ring or having at least one non-aromatic ring, which can have some degree of unsaturation. Cycloalkyl groups can be optionally substituted with one or more than one substituent. In one embodiment, 0, 1, 2, 3, or 4 atoms of each ring of the cycloalkyl group can be substituted with a substituent. Representative examples of cycloalkyl groups include cyclopropyl, cyclopentyl, cyclohexyl, cyclobutyl, cycloheptyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, and the like.

[0458] The term "cycloalkoxy" refers to an -O-cycloalkyl substituent.

[0459] The term "cycloalkoxyalkyl" refers to an -alkyl-O-cycloalkyl substituent.

[0460] The term "cycloalkylalkoxy" refers to an -O-alkyl-cycloalkyl substituent.

[0461] The term "cycloalkylaminocarbonyl" refers to a -C(O)-NH-cycloalkyl substituent.

[0462] The term "aryl" refers to a hydrocarbon monocyclic, bicyclic, or tricyclic aromatic ring system. Aryl groups can be optionally substituted with one or more than one substituent. In one embodiment, 0, 1, 2, 3, 4, 5, or 6 atoms of each ring of the aryl group can be substituted with a substituent. Examples of aryl groups include phenyl, naphthyl, anthryl, fluorenyl, indenyl, azulenyl, and the like.

[0463] The term "aryloxy" refers to an -O-aryl substituent.

[0464] The term "arylalkoxy" refers to an -O-alkyl-aryl substituent.

[0465] The term "arylalkylthio" refers to an -S-alkyl-aryl substituent.

[0466] The term "arythioalkyl" refers to an -alkyl-S-aryl substituent.

[0467] The term "arylalkylaminocarbonyl" refers to a -C(O)-amino-alkyl-aryl substituent.

[0468] The term "arylalkylsulfonyl" refers to a -S(O)2-alkyl-aryl substituent.

[0469] The term "arylalkylsulfinyl" refers to a -S(O)-alkyl-aryl substituent.

[0470] The term "aryloxyalkyl" refers to an -alkyl-O-aryl substituent.

[0471] The term "alkylaryl" refers to an -aryl-alkyl substituent.

[0472] The term "arylalkyl" refers to an -alkyl-aryl substituent.

[0473] The term "heteroaryl" refers to an aromatic 5- to 8-membered monocyclic, 8- to 12-membered bicyclic, or 11- to 14-membered tricyclic ring system, having 1 to 4 ring heteroatoms if monocyclic, 1 to 6 heteroatoms if bicyclic, or 1 to 9 heteroatoms if tricyclic, the heteroatoms selected from O, N, or S, with the remaining ring atoms being carbon (unless otherwise noted, with the appropriate hydrogen atoms). The heteroaryl group can be optionally substituted with one or more substituents. In one embodiment, 0, 1, 2, 3, or 4 atoms of each ring of the heteroaryl group can be substituted with a substituent. Examples of heteroaryl groups include pyridyl, furanyl, thienyl, pyrrolyl, oxazolyl, oxadiazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, isoquinolinyl, indazolyl, and the like.

[0474] The term "heteroarylalkyl" refers to an -alkyl-heteroaryl substituent.

[0475] The term "heteroaryloxy" refers to an -O-heteroaryl substituent.

[0476] The term "heteroarylalkoxy" refers to an -O-alkyl-heteroaryl substituent.

[0477] The term "heteroaryloxyalkyl" refers to an -alkyl-O-heteroaryl substituent.

[0478] The term "nitrogen-containing heteroaryl" refers to a heteroaryl group having 1 to 4 ring nitrogen heteroatoms if monocyclic; 1 to 6 ring nitrogen heteroatoms if bicyclic; or 1 to 9 ring nitrogen heteroatoms if tricyclic.

[0479] The term "heterocycloalkyl" refers to a non-aromatic 3- to 8-membered monocyclic, 7- to 12-membered bicyclic, or 10- to 14-membered tricyclic ring system containing 1 to 3 heteroatoms in the case of a monocyclic ring, 1 to 6 heteroatoms in the case of a bicyclic ring, or 1 to 9 heteroatoms in the case of a tricyclic ring, the heteroatoms selected from O, N, S, B, P, or Si, wherein the non-aromatic ring system is fully saturated. The heterocycloalkyl group can be optionally substituted with one or more substituents. In one embodiment, 0, 1, 2, 3, or 4 atoms of each ring of the heterocycloalkyl group can be substituted with a substituent. Representative heterocycloalkyl groups include piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,3-dioxolane, tetrahydrofuranyl, tetrahydrothiophenyl, thiirenyl, and the like.

[0480] The term "heterocycloalkylalkyl" refers to an -alkyl-heterocycloalkyl substituent.

[0481] The term "alkylamino" refers to an amino substituent further substituted with one or two alkyl groups. The term "aminoalkyl" refers to an alkyl substituent further substituted with one or more amino groups. The term "hydroxyalkyl" or "hydroxyalkyl" refers to an alkyl substituent further substituted with one or more hydroxyl groups. The alkyl or aryl portion of alkylamino, aminoalkyl, mercaptoalkyl, hydroxyalkyl, mercaptoalkoxy, sulfonylalkyl, sulfonylaryl, alkylcarbonyl, and alkylcarbonylalkyl can optionally be substituted with one or more substituents.

[0482] Acids and bases useful in the methods herein are known in the art. Acid catalysts are any acidic chemical, which can be inorganic (e.g. hydrochloric acid, sulfuric acid, nitric acid, aluminum trichloride) or organic (e.g. camphor sulfonic acid, p-toluenesulfonic acid, acetic acid, ytterbium triflate) in nature. The acid is used in catalytic or stoichiometric amounts to facilitate a chemical reaction. Bases are any basic chemical, which can be inorganic (e.g. sodium bicarbonate, potassium hydroxide) or organic (e.g. triethylamine, pyridine) in nature. The base is used in catalytic or stoichiometric amounts to facilitate a chemical reaction.

[0483] An alkylating agent is any reagent capable of effecting the alkylation of 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, including 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 alkyl-leaving group combinations known in the art. A leaving group is any stable species that can be separated from a molecule during a reaction (e.g. an elimination reaction, a substitution reaction) and is known in the art, including in the references cited herein, and includes halides (e.g. I-, CI-, Br-, F-), hydroxyl, alkoxyl (e.g. -OMe, -Ot-Bu), acyloxy anions (e.g. -OAc, -OC(O)CF3), sulfonates (e.g. mesyl, tosyl), acetamides (e.g. -NHC(O)Me), carbamates (e.g. N(Me)C(O)Ot-Bu), phosphonates (e.g. -OP(O)(OEt)2), water or alcohols (proton conditions), and the like.

[0484] In certain embodiments, substituents on any group (e.g., alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, heterocycloalkyl) can be on any atom of the group, wherein any group that can be substituted (e.g., alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, heterocycloalkyl) can be optionally substituted with one or more than one substituent, which can 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, heteroaryl, halo, haloalkyl, cyano, nitro, alkoxy, aryloxy, hydroxy, hydroxyalkyl, oxo (i.e., carbonyl), carboxy, formyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkylcarbonyloxy, aryloxycarbonyl, heteroaryloxy, heteroaryloxycarbonyl, thio, mercapto, mercaptoalkyl, arylsulfonyl, amino, aminoalkyl, dialkylamino, alkylcarbonylamino, alkylaminocarbonyl, alkoxycarbonylamino, alkylamino, arylamino, diarylamino, alkylcarbonyl, or arylamino; arylalkylamino, aralkylaminocarbonyl, amido, alkylaminosulfonyl, arylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, imino, carboxamido, carbamido, carbamyl, thiocarbamido, thiocyanato, sulfonamido, sulfonylalkyl, sulfonylaryl, mercaptoalkoxy, N-hydroxyamidinyl, or N'-aryl, N"-hydroxyamidinyl.

[0485] The compounds of the present disclosure can be prepared by methods known in the art of organic synthesis. Reaction conditions should be optimized if desired to minimize competing side products as much as possible, methods for which 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, 2ndEdition, Carlson R, Ed, 2005; Elsevier Science Ltd.; Oxford, UK; K et al., Angew. Chem. Int. Ed. Engl. 2004 43 :406; and references therein). The skilled artisan can determine additional reaction schemes and protocols by using commercially available searchable structural database software such as (CAS Division of the American Chemical Society) and CrossFire (Beilby, UK; Elsevier MDL, San Leandro, CA), or by using appropriate keyword searches of internet search engines such as Google or keyword databases such as the United States Patent and Trademark Office Text Database.

[0486] As will be appreciated by those skilled in the art, methods of synthesizing the compounds of the formulae herein are apparent to those of ordinary skill in the art, including in the schemes and examples herein. Additionally, the various synthetic steps can be performed in an alternate sequence or in an alternate order to give the desired compounds. Further, the solvents, temperatures, reaction durations, etc. described herein are intended to be illustrative only and those of ordinary skill in the art will recognize that variations of the reaction conditions can produce the desired compounds of the disclosure.

[0487] The compounds herein can also contain linkages (e.g., carbon-carbon bonds) in which bond rotation is restricted by the particular bond, for example, by the presence of a ring or double bond. Thus, all cis / trans and E / Z isomers are expressly included in the present disclosure. The compounds herein can also be represented in multiple tautomeric forms, in which case the present disclosure expressly includes all tautomeric forms of the compounds described herein, although only a single tautomeric form can be shown. All such isomeric forms of the compounds herein are expressly included in the present disclosure. All crystalline forms and polymorphs of the compounds described herein are expressly included in the present disclosure. Extracts and fractions comprising the compounds of the disclosure are also embodied. The term isomers is intended to include diastereomers, enantiomers, regioisomers, structural isomers, rotamers, tautomers, and the like. For compounds containing one or more stereocenters, e.g., chiral compounds, the methods of the present disclosure can be performed with a compound enriched in an enantiomer, a racemate, or a mixture of diastereomers.

[0488] Preferred compounds enriched in an enantiomer have an enantiomeric excess of 50% or greater, more preferably the compound has an enantiomeric excess of 60%, 70%, 80%, 90%, 95%, 98%, or 99% or greater. In preferred embodiments, only one enantiomer or diastereomer of a chiral compound of the present disclosure is administered to a cell or subject.

[0489] Methods of treatment

[0490] In one aspect, methods of treating a subject having or susceptible to a disorder or disease are provided, comprising administering to the subject an effective amount of a compound of Formula I or a pharmaceutical composition.

[0491] In other aspects, methods of treating a subject having or susceptible to a disorder or disease are provided, wherein the subject has been identified as in need of treatment for a metalloenzyme-mediated disorder or disease, the method comprising administering to the subject in need thereof an effective amount of a compound of Formula I or a pharmaceutical composition, such that the subject receives treatment for the disorder.

[0492] In one aspect, a method of modulating metalloenzyme activity in a subject is provided, comprising contacting the subject with a compound of Formula I in an amount and under conditions sufficient to modulate metalloenzyme activity.

[0493] In one embodiment, the modulation is inhibition.

[0494] In another aspect, a method of treating a subject suffering from or susceptible to a metalloenzyme-mediated disorder or disease is provided, comprising administering to the subject an effective amount of a compound of Formula I or a pharmaceutical composition.

[0495] In other aspects, a method of treating a subject suffering from or susceptible to a metalloenzyme-mediated disorder or disease is provided, wherein the subject has been identified as in need of treatment for a metalloenzyme-related disorder or disease, the method comprising administering to the subject in need thereof an effective amount of a compound of Formula I or a pharmaceutical composition, such that the subject receives treatment for the disorder.

[0496] In certain embodiments, a method of treating a disease, disorder, or symptoms thereof is provided, wherein the disorder is cancer, cardiovascular disease, endocrine disease, inflammatory disease, infectious disease, gynecological disease, metabolic disease, ophthalmic disease, central nervous system (CNS) disease, urological disease, or gastrointestinal disease. In certain embodiments, the disease is hypertension, resistant hypertension, disorders associated with primary or secondary aldosteronism and adrenal hyperplasia, pulmonary arterial hypertension, heart failure, diastolic dysfunction, left ventricular diastolic dysfunction, diastolic heart failure, systolic dysfunction, systolic heart failure, hypokalemia, renal failure, chronic renal failure, restenosis, nephropathy, post-myocardial infarction syndrome, coronary heart disease, fibrosis, a disease characterized by increased collagen formation after hypertension, fibrosis and matrix remodeling, a disease characterized by fibrosis and matrix remodeling after endothelial cell dysfunction, cardiovascular disease such as atherosclerosis, atrial fibrillation, renal dysfunction, liver disease, nonalcoholic steatohepatitis, vascular disease, retinopathy, neuropathy, insulinopathy, endothelial dysfunction, myocardial fibrosis, vascular fibrosis, myocardial necrotic lesions, vascular injury, myocardial infarction, left ventricular hypertrophy, vascular wall hypertrophy, endothelial thickening, arterial fibrinoid necrosis, renal disease, diabetic nephropathy, glomerulosclerosis, glomerulonephritis, nephrotic syndrome, polycystic kidney disease, diabetes, metabolic syndrome, insulin resistance, sleep apnea, obstructive sleep apnea, muscular dystrophy, cirrhosis, nonalcoholic fatty liver, renal disease, diabetic nephropathy, or stroke.

[0497] In certain embodiments, the subject is a mammal, preferably a primate or human.

[0498] In another embodiment, a method as described above is provided, wherein the effective amount of the compound of Formula I is as described above.

[0499] In another embodiment, there is provided a method as described above, wherein the compound of Formula I is administered intravenously, intramuscularly, subcutaneously, intracerebroventricularly, orally, or topically.

[0500] In another embodiment, there is provided a method as described herein, wherein the compound of Formula I exhibits selectivity in the range of activity against the target enzyme (e.g., aldosterone synthase (CYP11B2) IC 50 <1.0 μM).

[0501] In other embodiments, there is provided a method as described above, wherein the compound of Formula I is administered alone or in combination with one or more other therapeutic agents. In further embodiments, the additional therapeutic agent is an anti-cancer agent, an anti-fungal agent, a cardiovascular therapeutic agent, an anti-inflammatory agent, a chemotherapeutic agent, an anti-angiogenic agent, a cytotoxic agent, an anti-proliferative agent, a metabolic disease therapeutic agent, an ophthalmic disease therapeutic agent, a central nervous system (CNS) disease agent, a urologic disease therapeutic agent, or a gastrointestinal disease therapeutic agent.

[0502] In certain embodiments, the additional therapeutic agent is an agent for treating hypertension, an agent for treating primary hyperaldosteronism, an agent for treating kidney disease, an agent for treating congestive heart failure, an agent for treating an atherosclerotic condition, an agent for treating diabetes, an agent for treating obesity, or an agent for treating a metabolic disease.

[0503] Exemplary additional therapeutic agents include, but are not limited to, renin inhibitors, angiotensin converting enzyme (ACE) inhibitors, dual angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP) inhibitors, angiotensin II receptor blockers (ARBs), mineralocorticoid receptor antagonists (MRAs), neutral endopeptidase inhibitors (NEP), 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, soluble guanylate cyclase stimulators, vasodilators, HMG-CoA reductase inhibitors, niacin and niacin receptor agonists, Niemann-Pick Cl-like 1 (NPC1L1) inhibitors, insulin or insulin analogs, biguanides (e.g., metformin), sulfonylureas, peroxisome proliferator-activated receptor (PPAR) agonists and partial agonists including PPAR gamma agonists and other PPAR ligands, dipeptidyl peptidase 4 (DPP4) inhibitors, glucagon-like peptide 1 (GLP-1), GLP-1 receptor agonists, and sodium-glucose co-transporter 2 (SGLT2) inhibitors.

[0504] Another object of the present disclosure is the use of a compound described herein (e.g., a compound of Formula I) in the manufacture of a medicament for the treatment of a metalloenzyme-mediated disorder or disease. Another object of the present disclosure is the use of a compound as described herein (e.g., a compound of Formula I) for the treatment of a metalloenzyme-mediated disorder or disease. Another object of the present disclosure is the use of a compound as described herein (e.g., a compound of Formula I) in the manufacture of an agricultural composition for the treatment or prevention of a metalloenzyme-mediated disorder or disease in an agricultural or agronomic setting.

[0505] Pharmaceutical compositions

[0506] In one aspect, there is provided a pharmaceutical composition comprising a compound of Formula I and a pharmaceutically acceptable carrier.

[0507] In another embodiment, there is provided a pharmaceutical composition further comprising an additional therapeutic agent. In further embodiments, the additional therapeutic agent is an anti-cancer agent, an anti-fungal agent, a cardiovascular therapeutic agent, an anti-inflammatory agent, a chemotherapeutic agent, an anti-angiogenic agent, a cytotoxic agent, an anti-proliferative agent, a metabolic disease agent, an ophthalmic disease agent, a central nervous system (CNS) disease agent, a urologic disease therapeutic agent, or a gastrointestinal disease therapeutic agent.

[0508] In certain embodiments, the additional therapeutic agent is an agent for the treatment of hypertension, an agent for the treatment of primary hyperaldosteronism, an agent for the treatment of kidney disease, an agent for the treatment of congestive heart failure, an agent for the treatment of an atherosclerotic disorder, an agent for the treatment of diabetes, an agent for the treatment of obesity, or an agent for the treatment of a metabolic disease.

[0509] Exemplary other 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 (NEP), 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, soluble guanylate cyclase stimulators, vasodilators, HMG-CoA reductase inhibitors, niacin and niacin receptor agonists, Niemann-Pick Cl-like 1 (NPC1L1) inhibitors, insulin or insulin analogs, biguanides (e.g., metformin), sulfonylureas, peroxisome proliferator-activated receptor (PPAR) agonists and partial agonists including PPAR gamma agonists and other PPAR ligands, dipeptidyl peptidase 4 (DPP4) inhibitors, glucagon-like peptide 1 (GLP-1), GLP-1 receptor agonists, and sodium-glucose co-transporter 2 (SGLT2) inhibitors.

[0510] In one aspect, a kit is provided comprising an effective amount of a compound of Formula I in unit dosage form, and instructions for administering the compound to a subject suffering from or susceptible to a metalloenzyme-mediated disease or condition, including cancer, cardiovascular disease, endocrine disease, inflammatory disease, infectious disease, gynecological disease, metabolic disease, ophthalmic disease, central nervous system (CNS) disease, urologic disease, or gastrointestinal disease. In other embodiments, the disease, condition, or symptom thereof is hypertension, resistant hypertension, conditions associated with primary or secondary hyperaldosteronism and adrenal hyperplasia, pulmonary arterial hypertension, heart failure, diastolic dysfunction, left ventricular diastolic dysfunction, diastolic heart failure, systolic dysfunction, systolic heart failure, hypokalemia, renal failure, chronic renal failure, restenosis, nephropathy, post-myocardial infarction syndrome, coronary heart disease, fibrosis, a disease characterized by increased collagen formation following hypertension, fibrosis and matrix remodeling, a disease characterized by fibrosis and matrix remodeling following endothelial cell dysfunction, cardiovascular disease such as atherosclerosis, atrial fibrillation, renal dysfunction, liver disease, nonalcoholic steatohepatitis, vascular disease, retinopathy, neuropathy, insulinopathy, endothelial dysfunction, myocardial fibrosis, vascular fibrosis, myocardial necrotic lesions, vascular injury, myocardial infarction, left ventricular hypertrophy, vascular wall hypertrophy, endothelial thickening, arterial fibrinoid necrosis, kidney disease, diabetic nephropathy, glomerulosclerosis, glomerulonephritis, nephrotic syndrome, polycystic kidney disease, diabetes, metabolic syndrome, insulin resistance, sleep apnea, obstructive sleep apnea, muscular dystrophy, cirrhosis, nonalcoholic fatty liver, kidney disease, diabetic nephropathy, or stroke.

[0511] The term "pharmaceutically acceptable salt" or "pharmaceutically acceptable carrier" refers to salts of the active compound which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present application contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salts, or like- salts. When compounds of the present application contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, monobasic, phosphoric, diphosphoric, sulfuric, hydrosulfuric, hydroiodic, or phosphorous acids, and the like, as well as salts derived from relatively nontoxic organic acids such as acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, e.g., Berge et al., Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain specific compounds of the present application contain both basic and acidic functionalities as a result of which, the compounds are converted to salts by suitable inorganic or organic acids or bases. Other pharmaceutically acceptable carriers known to those skilled in the art are suitable for use in the present disclosure.

[0512] The neutral forms of the compounds are re-obtained by contacting the salt with a base or an acid and isolating the parent compound in the 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 otherwise the salts are equivalent to the parent form of the compound for the purposes of the present disclosure.

[0513] In addition to salt forms, the present application provides compounds which are in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present application. Additionally, prodrugs can be converted by chemical or biochemical methods in an ex vivo environment to provide the compounds of the present disclosure. For example, a prodrug can be slowly converted to a compound of the present disclosure when placed in a transdermal patch container with a suitable enzyme or chemical reagent.

[0514] Certain compounds of the present disclosure can exist in unsolvated as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present disclosure. Certain compounds of the present disclosure can exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent and intended to be within the scope of the present disclosure.

[0515] The present disclosure also provides pharmaceutical compositions comprising an effective amount of a compound described herein and a pharmaceutically acceptable carrier. In embodiments, a compound of Formula I is administered to a subject using a pharmaceutically acceptable formulation, e.g., the pharmaceutically acceptable formulation 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 after administration of the pharmaceutically acceptable formulation to the subject.

[0516] Actual dosage levels and time course of administration of the active ingredients in the pharmaceutical compositions of the present disclosure can be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic (or unacceptably toxic) to the patient.

[0517] In use, at least one compound according to the present application is administered to a subject in need thereof in a pharmaceutically effective amount in a pharmaceutical carrier, either by intravenous, intramuscular, subcutaneous or intracerebroventricular injection or by oral or topical administration. The compounds of the present disclosure can be administered alone or in combination with a second, different therapeutic agent, in accordance with the present disclosure. By "in combination with" is meant administration substantially simultaneously or sequentially together. In one embodiment, the compounds of the present disclosure are administered acutely. Thus, the compounds of the present application can be administered for short term treatment, e.g., for about 1 day to about 1 week. In another embodiment, the compounds of the present disclosure can be administered over a longer period of time to ameliorate chronic conditions, e.g., for about one week to several months, depending on the condition to be treated.

[0518] "Pharmaceutically effective amount" as used herein means that amount of a compound of the present disclosure which is high enough to significantly positively alter the condition being treated, but low enough to avoid serious side effects (at a reasonable benefit / risk ratio) within the scope of sound medical judgment. The pharmaceutically effective amount of the compounds of the present disclosure will vary with the particular objectives of the treatment, the age and physical condition of the patient being treated, the severity of the underlying disease, the duration of the treatment, the nature of concurrent therapy, and the particular compound employed. For example, the therapeutically effective amount of a compound of the present application to be administered to a child or neonate will be proportionally reduced from that for an adult, according to sound medical judgment. Thus, an effective amount of a compound of the present disclosure will be the minimum amount necessary to provide the desired effect.

[0519] One of the decisive practical advantages of the present disclosure is that the compounds can be administered in a convenient manner, for example by intravenous, intramuscular, subcutaneous, oral or intracerebroventricular injection routes or by topical administration, for example in the form of a cream or a gel. Depending on the route of administration, it can be necessary to coat the active ingredient comprising the compounds of the present disclosure in a material to protect the compound from the action of enzymes, acids and other natural conditions which can inactivate the compound. In order to administer the compounds of the present invention other than by parenteral administration, the compounds can be coated with or co-administered with a material to prevent inactivation.

[0520] The compounds can be administered parenterally or intraperitoneally. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils and in injectable organic solvents.

[0521] Some examples of substances which can serve as pharmaceutical 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; malt; gelatin; talc; stearic acid; magnesium stearate; calcium sulfate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma; polyols such as propylene glycol, glycerin, sorbitol, mannitol and polyethylene glycol; agar; alginic acid; pyrogen-free water; isotonic saline; and phosphate buffer solutions; dried skim milk; and other nontoxic compatible substances used in pharmaceutical formulations such as Vitamin C, estrogen and echinacea. Wetting agents and lubricants such as sodium lauryl sulfate, and coloring agents, flavoring agents, lubricants, excipients, tableting agents, stabilizers, antioxidants and preservatives can also be present. Solubilizing agents such as Cremaphore and beta-cyclodextrin can also be used in the pharmaceutical compositions herein.

[0522] Pharmaceutical compositions comprising the active compounds (or prodrugs thereof) of the present disclosure can be manufactured by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes. One or more physiologically acceptable carriers, diluents, excipients or auxiliaries useful in making these compositions can be used in a conventional manner.

[0523] The pharmaceutical compositions of the presently disclosed subject matter can take any form suitable for virtually any mode of administration, including, for example, topical administration, ocular administration, oral administration, buccal administration, systemic administration, nasal administration, injectable administration, transdermal administration, rectal administration, vaginal administration, and the like, or in a form suitable for administration by inhalation or insufflation.

[0524] For topical administration, the active compounds or prodrugs can be formulated in solutions, gels, ointments, creams, suspensions and the like.

[0525] Systemic formulations include formulations designed for administration by injection, e.g., subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection, as well as formulations designed for transdermal, transmucosal, oral or respiratory tract administration.

[0526] Useful injectable formulations include sterile suspensions of the active compound in aqueous or oleaginous vehicles, solutions or emulsions. The compositions can also contain formulatory agents such as suspending, stabilizing and / or dispersing agents. Formulations for injection can be presented in unit dosage form (e.g., in ampoules or in multi-dose containers) and can contain added preservatives.

[0527] Alternatively, injectable formulations can be provided in powder form for reconstitution with a suitable vehicle, including but not limited to sterile pyrogen-free water, buffer, dextrose solution, and the like, prior to use. To this end, the active compound can be dried, e.g., by lyophilization, by any art-known technique, and reconstituted prior to use.

[0528] For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are known in the art.

[0529] For oral administration, the pharmaceutical compositions can take the form of, for example, tablets, pills, or capsules, prepared by conventional methods with pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinized maize 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 starch glycolate); or wetting agents (e.g., sodium lauryl sulfate). The tablets can be coated by methods well known in the art.

[0530] Liquid formulations for oral administration can take the form of, for example, elixirs, solutions, syrups or suspensions, or they can be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid formulations can be prepared by conventional methods with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated eatable fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid). The formulations can also contain buffer salts, preservatives, flavoring, coloring and sweetening agents as appropriate.

[0531] As is well known, formulations for oral administration can be formulated to provide controlled release of the active compound or prodrug.

[0532] For buccal administration the compositions can take the form of tablets or lozenges formulated in conventional manner.

[0533] For rectal and vaginal administration, the active compound can be formulated in the form of solutions (for retention enemas), suppositories or ointments containing conventional suppository bases such as cocoa butter or other glycerides.

[0534] For nasal administration or administration by inhalation or insufflation, the active compounds or prodrugs can be conveniently delivered in the form of an aerosol spray containing a propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator can be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

[0535] A specific example of an aqueous suspension formulation suitable for nasal administration using a commercially available nasal spray device includes the following ingredients: 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 (0.5 mg / ml to 5 mg / ml); sodium carboxymethylcellulose or microcrystalline cellulose (1 mg / ml to 15 mg / ml); phenyl ethanol (1 mg / ml to 4 mg / ml); and dextrose (20 mg / ml to 50 mg / ml). The pH of the final suspension can be adjusted to about pH 5 to pH 7, with a typical pH of about 5.5. For ophthalmic administration, the active compounds or prodrugs can be formulated in the form of solutions, emulsions, suspensions, etc., which are suitable for administration to the eye. Various carriers suitable for administration of compounds to the eye are known in the art. Specific non-limiting examples are described in U.S. Patent No. 6,261,547; U.S. Patent No. 6,197,934; U.S. Patent No. 6,056,950; U.S. Patent No. 5,800,807; U.S. Patent No. 5,776,445; U.S. Patent No. 5,698,219; U.S. Patent No. 5,521,222; U.S. Patent No. 5,403,841; U.S. Patent No. 5,077,033; U.S. Patent No. 4,882,150; U.S. Patent No. 4,738,851, each of which is incorporated herein by reference in its entirety.

[0536]

[0537] ​For prolonged delivery, the active compound or prodrug can be formulated in a long-acting formulation for administration by implantation or intramuscular injection. The active ingredient can be formulated with a suitable polymeric or hydrophobic material (for example, as an emulsion in an acceptable oil) or ion exchange resin, or as a sparingly soluble derivative, such as a sparingly soluble salt. Alternatively, transdermal delivery systems can be used, which are manufactured to release the active compound slowly into the body for absorption through the skin. For this purpose, penetration enhancers can be used to facilitate the percutaneous penetration of the active compound. Suitable transdermal patches are described, for example, in U.S. Patent No. 6,407,713; U.S. Patent No. 5,352,456; U.S. Patent No. 5,332,213; U.S. Patent No. 5,336,168; U.S. Patent No. 5,290,561; U.S. Patent No. 5,254,346; U.S. Patent No. 5,164,189; U.S. Patent No. 5,163,899; U.S. Patent No. 5,088,977; U.S. Patent No. 5,087,240; U.S. Patent No. 5,008,110; U.S. Patent No. 4,921,475, each of which is incorporated herein by reference in its entirety.

[0538] Alternatively, other drug delivery systems can be used. Liposomes and emulsions are well-known examples of delivery vehicles that can be used to deliver the active compound or prodrug. Certain organic solvents, such as dimethyl sulfoxide (DMSO), can also be used.

[0539] If desired, the pharmaceutical composition can be presented in a pack or dispenser device which can contain one or more unit dosage forms containing the active compound. The pack can, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device can be accompanied by instructions for administration.

[0540] The active compound or prodrug of the present disclosure, or a composition thereof, is typically used in an amount effective to achieve its intended purpose, e.g., in an amount effective to treat or prevent the particular disease for which treatment is being sought. The compound can be administered therapeutically to obtain therapeutic benefit or prophylactically to obtain prophylactic benefit. A therapeutic benefit refers to the eradication or amelioration of the underlying disorder being treated and / or one or more of the symptoms associated with the disorder such that the patient reports an improvement in feeling or status, although the patient can still be afflicted with the underlying disease. For example, the administration of a compound to a patient suffering from an allergy provides a therapeutic benefit not only when the underlying allergic reaction is eradicated or ameliorated, but also when the patient reports a decrease in severity or duration of symptoms associated with the allergy after exposure to an allergen. As another example, a therapeutic benefit for asthma includes an improvement in breathing after the onset of an asthma attack, or a decrease in the frequency or severity of asthma attacks. A therapeutic benefit also includes halting or slowing the progression of a disease, whether or not improvement is realized.

[0541] 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.

[0542] 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.

[0543] 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.

[0544] 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.

[0545] Doses are typically in the range of 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 on, inter alia, the activity of the compound, its bioavailability, the mode of delivery, and the various factors described above. Dosage amounts and intervals can be adjusted to provide plasma levels of the compound that are sufficient to maintain therapeutic or prophylactic effects. In the case of local delivery, e.g., local topical delivery, effective local concentrations of the active compound can be achieved without necessarily achieving systemic concentrations. The skilled artisan will be able to optimize effective local dosages without undue experimentation.

[0546] The compounds can be administered once a day, several times a day or even multiple times a day, depending inter alia on the indication being treated and the judgment of the prescribing physician.

[0547] Preferably, the compounds will provide a therapeutic or prophylactic benefit without causing substantial toxicity. Toxicity of the compounds can be determined using standard pharmaceutical procedures. The dose ratio between toxic and therapeutic (or prophylactic) effect is the therapeutic index. Compounds that exhibit large therapeutic indices are preferred.

[0548] Any definition of a variable anywhere herein includes recitation of that variable as any single group or combination of listed groups. Any recitation of an embodiment herein includes that embodiment as any single embodiment or in combination with any other embodiment or portion thereof. Any recitation of an embodiment includes that embodiment as any single embodiment or in combination with any other embodiment or portion thereof.

[0549] Examples

[0550] In order that the application herein described can be more fully understood, the following examples are set forth. The examples described in this application are provided to illustrate the compounds, pharmaceutical compositions, and methods provided herein and should not be construed to limit their scope in any way.

[0551] General Experimental Procedures

[0552] The definitions of the variables in the schemes herein are equivalent to the definitions of the variables in the corresponding positions in the formulae described herein. The example compounds listed in Table 2 were characterized by the HPLC and LCMS methods described in Table 1.

[0553] Table 1. HPLC and LCMS Methods

[0554]

[0555] Commonly used abbreviations:

[0556] ACN acetonitrile

[0557] br broad

[0558] d doublet

[0559] dd doublet of doublets

[0560] dba dibenzylideneacetone

[0561] DIPEA diisopropylethylamine

[0562] dppf 1,1'-bis(diphenylphosphino)ferrocene

[0563] h hours

[0564] HRMS high resolution mass spectrometry

[0565] HPLC high performance liquid chromatography

[0566] LCMS liquid chromatography and mass spectrometry

[0567] MS mass spectrometry

[0568] MW microwave

[0569] m multiplet

[0570] min minutes

[0571] mL milliliters

[0572] m / z mass to charge ratio

[0573] NMR nuclear magnetic resonance

[0574] ppm parts per million

[0575] rt or RT room temperature

[0576] s singlet

[0577] t triplet

[0578] TLC thin layer chromatography Preparation of Int-1

[0579] Scheme:

[0580]

[0581] N-cyclopropyl-5-fluoro-2-nitroaniline

[0582] 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.

[0583] 1 H NMR (500MHz, CDCl3): δ8.20 (dd, J=9.3, 6.1Hz, 1H), 6.95 (dd, J=11.4, 2.7Hz, 1H ), 6.45-6.39(m,1H), 2.59-2.53(m,1H), 0.97-0.92(m,2H), 0.71-0.65(m,2H).

[0584] N 1 -Cyclopropyl-5-fluorobenzene-1,2-diamine (Int-1)

[0585] 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 feedstock was consumed (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%).

[0586] 1 H NMR (400MHz, DMSO-d6): δ6.52 (dd, J=11.6, 2.8Hz, 1H), 6.45 (dd, J=8.4, 6.0Hz, 1H), 6.18 (td, J=8.5, 2.9Hz, 1H), 5.28 (s, 1H), 4.30 (br s, 2H), 2.36-2.28 (m, 1H), 0.74-0.68 (m, 2H), 0.42-0.37 (m, 2H).

[0587] LC-MS: at 1.64 RT, m / z 166.8 [M+H] + (purity 72.46 %).

[0588] Preparation of Int-2

[0589] Scheme:

[0590]

[0591] (5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methanol

[0592] To a stirred solution of methyl 5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2- yl)pyridazine-3-carboxylate (250 mg, 0.8 mmol) in a mixture of methanol / tetrahydrofuran (THF) (2:1, 15 mL) was added sodium borohydride (152 mg, 4.01 mmol) at 0 °C under inert atmosphere. The reaction mixture was gradually warmed to room temperature and stirred for 4 h. After consumption of starting material (monitored by TLC), the reaction mixture was concentrated under reduced pressure. The mixture was diluted with water (25 mL) and extracted with EtOAc (2 x 40 mL). The combined organic extracts were dried over anhydrous Na2S04and concentrated under reduced pressure to afford 5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methanol (130 mg, 0.46 mmol, 57%) as a brown solid which was used for the next step without further purification.

[0593] LC-MS: at 1.94 RT, m / z 284.9 [M+H] + (purity 72.20 %).

[0594] 5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-carbaldehyde (Int-2)

[0595] To a stirred solution of (5-(l-cyclopropyl-6-fluoro-lH-benzo[d]imidazol-2-yl)pyridazin-3- yl)methanol (130 mg, 0.46 mmol) in CH2CI2(10 mL) was added Dess-Martin periodinane (DMP) (291 mg, 0.69 mmol) at 0 °C under inert atmosphere. The reaction mixture was gradually warmed to room temperature and stirred for 2 h. After consumption of starting material (by TLC), the reaction mixture was quenched with saturated sodium bicarbonate solution (20 mL) and extracted with CH2CI2(2 x 20 mL). The combined organic extracts were dried over anhydrous Na2S04and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 50% EtOAc / hexane) to afford 5-(l-cyclopropyl-6-fluoro-lH-benzo[d]imidazol-2-yl)pyridazine-3-carbaldehyde Int-2 (50 mg, 0.18 mmol, 39%) as a brown solid.

[0596] 1 H NMR (500 MHz, CDC13): δ 10.50 (s, 1H), 10.06 (d, J = 2.0 Hz, 1H), 8.64 (d, J = 2.3 Hz, 1H), 7.80 (dd, J = 8.8, 4.8 Hz, 1H), 7.34 (dd, J = 8.4, 2.3 Hz, 1H), 7.13 (td, J = 9.3, 2.3 Hz, 1H), 3.73-3.69 (m, 1H), 1.37-1.31 (m, 2H), 0.90-0.85 (m, 2H).

[0597] LC-MS: m / z 282.9 [M+H] at 1.85 RT + (purity 90.42%).

[0598] Preparation of Int-3

[0599] Scheme:

[0600]

[0601] (E)-5-(l-cyclopropyl-6-fluoro-lH-benzo[d]imidazol-2-yl)pyridazin-3-yl)oxime

[0602] To a stirred solution of 5-(l-cyclopropyl-6-fluoro-lH-benzo[d]imidazol-2-yl)pyridazine-3- carboxylic acid (Int-4) (100 mg, 0.35 mmol) in DMF (2 mL) was added HATU (138 mg, 0.36 mmol) and NH2OH (31 mg, 0.71 mmol) at room temperature under inert atmosphere. The reaction mixture was stirred at room temperature for 3 h. After consumption of starting material (monitored by TLC), the reaction mixture 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 get (E)-5-(l-cyclopropyl-6-fluoro-lH-benzo[d]imidazol-2-yl)pyridazine-3- carboxylic acid oxime (70 mg, 0.23 mmol, 67%) as off-white solid.

[0603] 1 H NMR (500 MHz, DMSO-d6): δ 12.25 (s, 1H), 9.81 (s, 1H), 8.56 (s, 1H), 8.48 (s, 1H), 7.80 (dd, J = 8.7, 4.9 Hz, 1H), 7.55 (dd, J = 9.0, 1.7 Hz, 1H), 7.20 (td, J = 9.8, 2.3 Hz, 1H), 3.95-3.89 (m, 1H), 1.20-1.16 (m, 2H), 0.84-0.79 (m, 2H).

[0604] LC-MS: m / z 297.9 [M+H] at 1.95 RT + (purity 99.11%).

[0605] (5-(l-cyclopropyl-6-fluoro-lH-benzo[d]imidazol-2-yl)pyridazin-3-yl)methanamine (Int-3)

[0606] To a stirred solution of (E)-5-(l-cyclopropyl-6-fluoro-lH-benzo[d]imidazol-2-yl)pyridazine-3- carboxaldehyde oxime (70 mg, 0.23 mmol) in ethanol (5 mL) was added 10% Pd / C (50% wet basis, 25 mg) at room temperature under inert atmosphere. The reaction mixture was stirred under hydrogen atmosphere (balloon pressure) at room temperature for 5 h. After consumption of starting material (monitored by TLC), the reaction mixture was filtered through a pad of celite and washed with MeOH / CH2Cl2(10:1, 20 mL). The filtrate was concentrated under reduced pressure to get (5-(l-cyclopropyl-6-fluoro-lH-benzo[d]imidazol-2-yl)pyridazin-3-yl)methanamine Int-3 (50 mg, crude) as off-white solid which was used for the next step without further purification.

[0607] LC-MS: m / z 283.9 [M+H] at 1.62 RT + (purity 64.40 %).

[0608] Preparation of Int-4

[0609] Scheme:

[0610]

[0611] 3-(Ethylamino)-4-nitrobenzonitrile

[0612] To a stirred solution of 3-fluoro-4-nitrobenzonitrile (2 g, 12.05 mmol) in CH2Cl2(250 mL) was added potassium carbonate (3.32 g, 24.09 mmol) and ethylamine (70% aqueous solution, 2.17 g, 48.19 mmol) at room temperature under inert atmosphere. The reaction mixture was stirred at room temperature for 6 h. After consumption of starting material (monitored by TLC), the reaction mixture was quenched with water (60 mL) and extracted with EtOAc (2 x 60 mL). The combined organic extracts were dried over anhydrous Na2SO4and concentrated under reduced pressure to afford 3-(ethylamino)-4-nitrobenzonitrile (1.9 g, crude) as a yellow solid which was used for the next step without further purification.

[0613] 1 H NMR (500 MHz, DMSO-d6): δ 8.22-8.10 (m, 2H), 7.58 (br s, 1H), 7.00 (br d, J = 8.7 Hz, 1H), 3.48-3.38 (m, 2H), 1.21 (br t, J = 6.9 Hz, 3H).

[0614] LC-MS: m / z 192.1 [M+H] at 4.10 RT + (purity 98.96 %).

[0615] 4-Amino-3-(ethylamino)benzonitrile (Int-4)

[0616] To a stirred solution of 3-(ethylamino)-4-nitrobenzonitrile (1.9 g, crude) in ethanol (20 mL) was added 10% Pd / C (50% wet basis, 190 mg) at room temperature under inert atmosphere. The reaction mixture was stirred at room temperature under hydrogen atmosphere (balloon pressure) for 5 h. After consumption of starting material (monitored by TLC), the reaction mixture was filtered through a pad of celite and washed with methanol (50 mL) and EtOAc (30 mL). The filtrate was concentrated under reduced pressure to get 4-amino-3-(ethylamino)benzonitrile Int-4 (1.5 g, crude) as off-white solid which was used for the next step without further purification.

[0617] LC-MS: m / z 161.9 [M+H] at 2.11 RT + (purity 60.88%).

[0618] Preparation of Int-5

[0619] Scheme:

[0620]

[0621] N-cyclopropyl-4,5-difluoro-2-nitroaniline

[0622] To a stirred solution of 3-(ethylamino)-4-nitrobenzonitrile (1.9 g, crude) in ethanol (20 mL) was added 10% Pd / C (50% wet basis, 190 mg) at room temperature under inert atmosphere. The reaction mixture was stirred at room temperature under hydrogen atmosphere (balloon pressure) for 5 h. After consumption of starting material (monitored by TLC), the reaction mixture was filtered through a pad of celite and washed with methanol (50 mL) and EtOAc (30 mL). The filtrate was concentrated under reduced pressure to get 4-amino-3-(ethylamino)benzonitrile Int-4 (1.5 g, crude) as off-white solid which was used for the next step without further purification.

[0623] LC-MS: m / z 215.4 [M+H] at 4.43 RT + (purity 69.03%).

[0624] N 1 -cyclopropyl-4,5-difluorobenzene-1,2-diamine (Int-5)

[0625] To a stirred solution of N-cyclopropyl-4,5-difluoro-2-nitroaniline (300 mg, 1.4 mmol) in EtOAc (10 mL) was added 10% Pd / C (50% wet basis, 30 mg) at room temperature under inert atmosphere. The reaction mixture was stirred at room temperature under hydrogen atmosphere (balloon pressure) for 4 h. After consumption of starting material (monitored by TLC), the reaction mixture was filtered through a pad of celite and washed with methanol (15 mL) and EtOAc (10 mL). The filtrate was concentrated under reduced pressure to get N-cyclopropyl-4,5-difluoro-benzene-1,2-diamine Int-5 (100 mg, crude) which was used in the next step without further purification. 1 N-cyclopropyl-4,5-difluoro-benzene-1,2-diamine Int-5 (100 mg, crude) which was used in the next step without further purification.

[0626] LC-MS: m / z 184.9 [M+H] at 2.12 RT. + (purity 83.53%).

[0627] Preparation of Int-6 and Int-7

[0628] Scheme:

[0629]

[0630] 3-(cyclopropylamino)-4-nitrobenzonitrile

[0631] To a stirred solution of 3-fluoro-4-nitrobenzonitrile (1 g, 6.02 mmol) in CH2CI2 (5 mL) was added potassium carbonate (1.66 g, 12.05 mmol) and cyclopropylamine (3.33 mL, 48.19 mmol) dropwise at room temperature under inert atmosphere. The reaction mixture was stirred at room temperature for 4 h. After consumption of starting material (monitored by TLC), the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2 x 40 mL). The combined organic extracts were dried over anhydrous Na2S04and concentrated under reduced pressure to get 3-(cyclopropylamino)-4-nitrobenzonitrile (900 mg, crude) as a yellow solid which was used in the next step without further purification.

[0632] 1 H NMR (400 MHz, CDCI3): δ 8.24 (d, J = 8.7 Hz, 1 H), 8.07 (br s, 1 H), 7.64 (d, J = 1.7 Hz, 1 H), 6.93 (dd, J = 8.7, 1.7 Hz, 1 H), 2.62-2.57 (m, 1 H), 1.03-0.97 (m, 2H), 0.72-0.67 (m, 2H).

[0633] LC-MS: m / z 201.9 [M-H] at 3.25 RT.+ (99.61% purity).

[0634] 4-amino-3-(cyclopropylamino)benzonitrile (Int-6)

[0635] To a stirred solution of 3-(cyclopropylamino)-4-nitrobenzonitrile (900 mg, 4.43 mmol) in ethanol (10 mL) was added 10% Pd / C (50% wet basis, 500 mg) at room temperature under inert atmosphere. The reaction mixture was stirred at room temperature under hydrogen atmosphere (balloon pressure) for 5 h. After consumption of starting material (monitored by TLC), the reaction mixture was filtered through a pad of celite and washed with EtOAc (30 mL). The filtrate was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 20% EtOAc / hexane) to afford 4-amino-3-(cyclopropylamino)benzonitrile Int-6 (500 mg, 2.89 mmol, 65%) as off-white solid.

[0636] 1 H NMR (400 MHz, DMSO-d6): δ 6.93 (d, J = 1.9 Hz, 1H), 6.87 (dd, J = 8.0, 1.9 Hz, 1H), 6.55 (d, J = 8.0 Hz, 1H), 5.49 (s, 2H), 5.43 (s, 1H), 2.40-2.34 (m, 1H), 0.77-0.71 (m, 2H), 0.42-0.37 (m, 2H).

[0637] 1-cyclopropyl-1H-benzo[d]imidazole-6-carbonitrile (Int-7)

[0638] A solution of 4-amino-3-(cyclopropylamino)benzonitrile Int-6 (500 mg, 2.89 mmol) in formic acid (5 mL) was heated to reflux temperature and stirred for 5 h under inert atmosphere. After consumption of starting material (monitored by TLC), the volatiles were removed under reduced pressure. The residue was diluted with water (10 mL), neutralized with saturated sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic extracts were dried over anhydrous Na2S04and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 50% EtOAc / hexane) to afford 1-cyclopropyl-1H-benzo[d]imidazole-6-carbonitrile Int-7 (250 mg, 1.37 mmol, 56%) as off-white solid.

[0639] 1H NMR (500 MHz, DMSO-d6): δ 8.50 (s, 1H), 8.21 (d, J = 0.9 Hz, 1H), 7.82 (d, J = 8.1 Hz, 1H), 7.62 (dd, J = 8.4, 1.4 Hz, 1H), 3.59-3.54 (m, 1H), 1.15-1.05 (m, 4H).

[0640] LC-MS: m / z 184.0 [M+H] at 2.46 RT + (Purity 87.33 %).

[0641] Preparation of Int-8

[0642] Scheme:

[0643]

[0644] 6-chloro-N-cyclopropyl-3-nitropyridin-2-amine

[0645] To a stirred solution of 2,6-dichloro-3-nitropyridine (5 g, 26.04 mmol) in toluene (25 mL) was added cyclopropylamine (3.7 mL, 52.08 mmol) at 0 °C under inert atmosphere. The reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. After consumption of starting material (monitored by TLC), the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2S04and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 10% EtOAc / hexane) to afford 6-chloro-N-cyclopropyl-3-nitropyridin-2-amine (4 g, 18.77 mmol, 72%) as a light yellow solid.

[0646] 1 H NMR (500 MHz, CDCl3): δ 8.34 (d, J = 8.7 Hz, 2H), 6.66 (d, J = 8.7 Hz, 1H), 3.10-3.05 (m, 1H), 0.97-0.93 (m, 2H), 0.67-0.64 (m, 2H)

[0647] 6-chloro-N 2 -cyclopropylpyridine-2,3-diamine (Int-8)

[0648] To a stirred solution of 6-chloro-N-cyclopropyl-3-nitropyridin-2-amine (1 g, 4.69 mmol) in EtOH: water (1 : 1, 10 mL) was added iron (1.3 g, 23.47 mmol) and ammonium chloride (1.2 g, 23.47 mmol) at room temperature under inert atmosphere. The reaction mixture was heated at 80 °C for 1 h. After consumption of starting material (monitored by TLC), the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2S04and concentrated under reduced pressure to get 6-chloro-N-cyclopropylpyridine-2,3-diamine Int-8 (700 mg, crude) which was used in the next step without further purification. 2 - cyclopropylpyridine-2,3-diamine Int-8 (700 mg, crude), which can be used in the next step without further purification.

[0649] LC-MS: m / z 183.9 [M+H] at 2.07 RT (Purity 58.13 %). +

[0650] Preparation of Int-9

[0651] Scheme:

[0652]

[0653] N-cyclopropyl-6-methoxy-3-nitropyridin-2-amine

[0654] To a stirred solution of 2-chloro-6-methoxy-3-nitropyridine (5 g, 26.5 mmol) in toluene (50 mL) was added cyclopropylamine (3.69 mL, 53 mmol) at 0 °C under inert atmosphere. The reaction mixture was stirred at 0 °C for 1 h and allowed to warm to room temperature and stirred for 6 h. After consumption of starting material (monitored by TLC), the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2S04and concentrated under reduced pressure. The crude material was triturated with n-pentane to get N-cyclopropyl-6-methoxy-3-nitropyridin-2-amine (800 mg, 3.82 mmol, 83 %) as a yellow solid.

[0655] N 2 - cyclopropyl-6-methoxypyridine-2,3-diamine (Int-9)

[0656] ​To a stirred solution of N-cyclopropyl-6-methoxy-3-nitropyridin-2-amine (1 g, 4.78 mmol) in ethanol / water (1 : 1, 10 mL) was added iron powder (1.3 g, 24 mmol) and ammonium chloride (1.29 g, 23.9 mmol) at room temperature. The reaction mixture was heated to 80 °C for 1 h. After consumption of starting material (monitored by TLC), the reaction mixture was filtered through a pad of celite and the celite bed was washed with EtOAc (50 mL). The filtrate was concentrated under reduced pressure to get N-cyclopropyl-6-methoxy-pyridin-2,3-diamine Int-9 (150 mg) as black liquid. The crude material was used for the next step without further purification. 2 - cyclopropyl-6-methoxy-pyridin-2,3-diamine Int-9 (150 mg). The crude material was used for the next step without further purification.

[0657] 1 H NMR (400 MHz, DMSO-d6): δ 6.71 (d, J = 7.9 Hz, 1H), 5.78 (d, J = 7.9 Hz, 1H), 4.09-4.06 (m, 2H), 3.84-3.81 (m, 1H), 3.70 (s, 3H), 2.77-2.68 (m, 1H), 0.69-0.61 (m, 2H), 0.43-0.37 (m, 2H)

[0658] LC-MS: m / z 180.1 [M+H] at 2.11 RT + (purity 75.36%)

[0659] Preparation of Int-10

[0660] Scheme:

[0661]

[0662] N-ethyl-4,5-difluoro-2-nitroaniline

[0663] To a stirred solution of 1,2,4-trifluoro-5-nitrobenzene (2 g, 11.29 mmol) in CH2Cl2(10 mL) was added potassium carbonate (3.1 g, 22.59 mmol) and ethylamine (559 mg, 12.42 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 h. After consumption of starting material (monitored by TLC), the reaction mixture was diluted with water (100 mL) and extracted with CH2Cl2(2 x 100 mL). The combined organic extracts were dried over anhydrous Na2SO4and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 10% EtOAc / hexane) to get N-ethyl-4,5-difluoro-2-nitroaniline (800 mg, 3.96 mmol, 35%) as a yellow solid.

[0664] 1 H NMR (500 MHz, DMSO-d6): δ 8.19 (br s, 1H), 8.13 (dd, J = 11.0, 8.7 Hz, 1H), 7.14 (dd, J = 13.9, 7.0 Hz, 1H), 3.40-3.33 (m, 2H), 1.20 (t, J = 7.2 Hz, 3H)

[0665] LC-MS: m / z 203.1 [M+H] at 3.53 RT + (purity 98.40%)

[0666] N 1 -ethyl-4,5-difluoro-benzene-1,2-diamine (Int-10)

[0667] To a stirred solution of N-ethyl-4,5-difluoro-2-nitroaniline (800 mg, 3.96 mmol) in ethyl acetate (5 mL) was added 10% Pd / C (50% wet basis, 500 mg) at room temperature under inert atmosphere. The reaction mixture was stirred at room temperature under hydrogen atmosphere (balloon pressure) for 16 h. After consumption of starting material (monitored by TLC), the reaction mixture was filtered through a pad of celite and the bed was washed with EtOAc (50 mL). The filtrate was concentrated under reduced pressure to afford N-ethyl-4,5-difluoro-benzene-1,2-diamine Int-10 (500 mg, 2.90 mmol, 73%) which was used in the next step without further purification. 1 -ethyl-4,5-difluoro-benzene-1,2-diamine Int-10 (500 mg, 2.90 mmol, 73%) which was used in the next step without further purification.

[0668] 1 H NMR (500 MHz, DMSO-d6): δ 6.47 (dd, J = 12.8, 8.1 Hz, 1H), 6.30 (dd, J = 13.3, 8.1 Hz, 1H), 4.64 (br s, 2H), 4.44 (t, J = 5.2 Hz, 1H), 3.00-2.94 (m, 2H), 1.17 (t, J = 7.2 Hz, 3H)

[0669] LC-MS: m / z 173.2 [M+H] at 3.16 RT + (purity 64.65%)

[0670] Preparation of Int-11

[0671] Scheme:

[0672]

[0673] 6-chloro-N-ethyl-3-nitropyridin-2-amine

[0674] To a stirred solution of 2,6-dichloro-3-nitropyridine (2 g, 10.40 mmol) in toluene (8.5 mL) was added ethylamine (1.35 mL) at 0 °C under inert atmosphere. The reaction mixture was allowed to warm to room temperature and stirred for 3 h. After consumption of starting material (monitored by TLC), the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed dried over anhydrous Na2S04and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 2% EtOAc / hexane) to afford 6-chloro-N-ethyl-3-nitropyridin-2-amine (800 mg, 3.98 mmol, 38%) as a yellow solid.

[0675] 1 H NMR (500 MHz, DMSO-d6): δ 8.70 (br s, 1H), 8.40 (d, J = 7.5 Hz, 1H), 6.75 (d, J = 8.1 Hz, 1H), 3.55-3.50 (m, 2H), 1.18 (t, J = 7.0 Hz, 3H)

[0676] LC-MS: m / z 202 [M+H] at 2.63 RT + (purity 99.85%)

[0677] 6-chloro-N 2 -ethylpyridine-2,3-diamine (Int-11)

[0678] To a stirred solution of 6-chloro-N-ethyl-3-nitropyridin-2-amine (550 mg, 2.73 mmol) in ethanol / water (1 : 1, 20 mL) was added iron powder (763.4 g, 13.68 mmol) and ammonium chloride (738.7 mg, 13.68 mmol) at room temperature. The reaction mixture was heated at 80 °C for 1 h. The mixture was diluted with water (30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous Na2S04and concentrated under reduced pressure to afford 6-chloro-N-ethylpyridine-2,3-diamine Int-11 (452 mg) as a black solid. The crude material was used for the next step without further purification. 2 -ethylpyridine-2,3-diamine (Int-11)

[0679] 1 H NMR (500 MHz, DMSO-d6): δ 6.67 (d, J = 7.5 Hz, 1H), 6.33 (d, J = 8.1 Hz, 1H), 5.85 (br s, 1H), 4.88 (br s, 2H), 3.37-3.25 (m, 2H), 1.15 (t, J = 7.0 Hz, 3H)

[0680] LC-MS: m / z 172.8 [M-H] at 2.49 RT + (purity 85.88%)

[0681] Preparation of Int-12

[0682] Scheme:

[0683]

[0684] 4,5-difluoro-2-nitroaniline

[0685] To a stirred solution of 1,2,4-trifluoro-5-nitrobenzene (5 g, 28.24 mmol) in methanol (5 mL) was added methanolic ammonia (15 mL) at 0 °C under inert atmosphere. The reaction mixture was heated to 90 °C in a sealed tube and stirred for 2 h. After consumption of starting material (monitored by TLC), the reaction mixture was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 2% EtOAc / hexane) to afford 4,5-difluoro-2-nitroaniline (800 mg, 4.59 mmol, 16%) as a light yellow solid.

[0686] 1 H NMR (500 MHz, CDC13): δ 8.00 (dd, J = 10.4, 8.7 Hz, 1H), 6.60 (dd, J = 11.0, 6.4 Hz, 1H), 6.09 (br s, 2H)

[0687] LC-MS: m / z 172.8 [M-H] at 2.49 RT - (purity 88.25%).

[0688] 4,5-difluorobenzene-1,2-diamine (Int-12)

[0689] To a stirred solution of 4,5-difluoro-2-nitroaniline (800 mg, 4.59 mmol) in methanol (15 mL) was added 10% Pd / C (50% wet basis, 200 mg) at room temperature under inert atmosphere. The reaction mixture was stirred for 3 h at room temperature under hydrogen atmosphere (balloon pressure). After consumption of starting material (monitored by TLC), the reaction mixture was filtered through a pad of celite and washed with methanol (15 mL) and CH2CI2(10 mL). The filtrate was concentrated under reduced pressure. The crude material was washed with n-hexane (15 mL) to afford 4,5-difluorobenzene-1,2-diamine Int-12 (500 mg, 3.47 mmol, 80%) as a black solid.

[0690] 1 H NMR (500 MHz, DMSO-d6): δ 6.47-6.41 (m, 2H), 4.55 (br s, 4H)

[0691] LC-MS: m / z 145 [M+H] at 1.59 RT + (purity 75.16%)

[0692] Preparation of Int-13

[0693] Scheme:

[0694]

[0695] 5-chloro-N-cyclopropyl-3-nitropyridin-2-amine

[0696] To a stirred solution of 2,5-dichloro-3-nitropyridine (1 g, 5.23 mmol) in toluene (10 mL) was added cyclopropylamine (0.73 mL, 10.47 mmol) at 0 °C under inert atmosphere. The reaction mixture was stirred at room temperature for 48 h. After consumption of starting material (monitored by TLC), the reaction mixture was diluted with water (40 mL) and extracted with EtOAc (2 x 60 mL). The combined organic extracts were dried over anhydrous Na2S04and concentrated under reduced pressure to afford 5-chloro-N-cyclopropyl-3-nitropyridin-2-amine (700 mg, 3.28 mmol, 63%) as an orange solid.

[0697] 1 H NMR (400 MHz, CDC13): δ 8.45 (d, J = 2.5 Hz, 1H), 8.41 (d, J = 2.4 Hz, 1H), 8.18 (br S, 1H), 3.05-2.97 (m, 1H), 0.98-0.91 (m, 2H), 0.68-0.62 (m, 2H)

[0698] LC-MS: m / z 214 [M+H] at 3.03 RT + (purity 98.66%)

[0699] 5-chloro-N 2 -cyclopropylpyridine-2,3-diamine (Int-13)

[0700] To a stirred solution of 5-chloro-N-cyclopropyl-3-nitropyridin-2-amine (200 mg, 0.938 mmol) in ethanol / water (1 : 1, 20 mL) was added iron powder (262 mg, 4.69 mmol) and ammonium chloride (253 mg, 4.69 mmol) at room temperature. The reaction mixture was heated to 80 °C and stirred for 3 h. After consumption of starting material (monitored by TLC), the reaction mixture was filtered through a pad of celite and washed with EtOAc. The filtrate was diluted with water (30 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over anhydrous Na2S04and concentrated under reduced pressure to afford 5-chloro-N-cyclopropylpyridine-2,3-diamine Int-13 (120 mg) as a black solid. The crude material was used for the next step without further purification. 2 - cyclopropylpyridine-2,3-diamine Int-13 (120 mg). The crude material was used for the next step without further purification.

[0701] 1 H NMR (500 MHz, DMSO-d6): δ 7.35 (d, J = 1.7 Hz, 1H), 6.67 (d, J = 2.3 Hz, 1H), 6.00 (br s, 1H), 5.02 (br s, 2H), 2.72-2.63 (m, 1H), 0.68-0.63 (m, 2H), 0.41-0.37 (m, 2H)

[0702] LC-MS: m / z 183.9 [M+H] at 1.87 RT + (purity 88.05%)

[0703] Preparation of Int-14

[0704] Scheme:

[0705]

[0706] N-cyclopropyl-2-fluoro-6-nitroaniline

[0707] To a stirred solution of 1,2-difluoro-3-nitrobenzene (200 mg, 1.26 mmol) in ethanol (2 mL) was added cyclopropylamine (0.13 mL, 1.89 mmol) and stirred for 16 h at room temperature under inert atmosphere. After consumption of starting material (monitored by TLC), the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried over anhydrous Na2S04and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 5% EtOAc / hexane) to afford N-cyclopropyl-2-fluoro-6-nitroaniline (200 mg, 1.02 mmol, 81%) as a yellow gummy paste.

[0708] 1 H NMR (400 MHz, CDC13): δ 7.93 (dt, J = 8.8, 1.5 Hz, 1H), 7.82 (br s, 1H), 7.24-7.19 (m, 1H), 6.63-6.58 (m, 1H), 3.12-3.07 (m, 1H), 0.87-0.79 (m, 2H), 0.67-0.61 (m, 2H)

[0709] LC-MS: m / z 197.0 [M+H] at 3.28 RT + (purity 99.89%)

[0710] N 1 - Cyclopropyl-6-fluoro-benzene-1,2-diamine (Int-14)

[0711] To a stirred solution of N-cyclopropyl-2-fluoro-6-nitroaniline (200 mg, 1.02 mmol) in ethyl acetate (5 mL) was added 10% Pd / C (50% wet basis, 30 mg) at room temperature under inert atmosphere. The reaction mixture was stirred at room temperature under hydrogen atmosphere (balloon pressure) for 4 h. After consumption of starting material (monitored by TLC), the reaction mixture was filtered through a pad of celite and the bed was washed with EtOAc (15 mL). The filtrate was concentrated under reduced pressure to afford N-cyclopropyl-2-fluoro-6-nitroaniline as a colorless viscous syrup. 1 - Cyclopropyl-6-fluoro-benzene-1,2-diamine Int-14 (160 mg). The crude material was used for the next step without further purification.

[0712] 1 H NMR (500 MHz, DMSO-d6): δ 6.61-6.51 (m, 1H), 6.40-6.24 (m, 3H), 4.89 (br s, 2H), 2.62-2.58 (m, 1H), 0.49-0.38 (m, 4H)

[0713] Preparation of Int-15

[0714] Scheme:

[0715]

[0716] 4,5-Difluoro-N-methyl-2-nitroaniline

[0717] To a stirred solution of 1,2,4-trifluoro-5-nitrobenzene (5 g, 28.25 mmol) in THF (50 mL) was added methylamine (2 M in THF, 28.25 mL, 56.5 mmol) dropwise at -20 °C under inert atmosphere and stirred for 2 h at same temperature. After consumption of starting material (monitored by TLC), the reaction mixture was quenched with brine (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over anhydrous Na2S04and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 3% EtOAc / hexane) to afford 4,5-difluoro-N-methyl-2-nitroaniline (1.1 g, 5.85 mmol, 20%) as a light yellow solid.

[0718] 1 H NMR (400 MHz, CDC13): δ 8.06 (dd, J = 10.7, 8.4 Hz, 2H), 6.61 (dd, J = 12.5, 6.7 Hz, 1H), 3.01 (d, J = 5.1 Hz, 3H)

[0719] 4,5-Difluoro-N 1 -methylbenzene-1,2-diamine (Int-15)

[0720] To a stirred solution of 4,5-difluoro-N-methyl-2-nitroaniline (1 g, 5.32 mmol) in ethyl acetate (15 mL) was added 10% Pd / C (50% wet basis, 250 mg) at room temperature under inert atmosphere. The reaction mixture was stirred for 3 h at room temperature under hydrogen atmosphere (balloon pressure). After consumption of starting material (monitored by TLC), the reaction mixture was filtered through a pad of celite and the bed was washed with methanol (30 mL). The filtrate was concentrated under reduced pressure to afford 4,5-difluoro-N-methylbenzene-1,2-diamine Int-15 (700 mg) as a brown syrup. The crude material was used for the next step without further purification. 1 -methylbenzene-1,2-diamine Int-15 (700 mg). The crude material was used for the next step without further purification.

[0721] 1 H NMR (500 MHz, DMSO-d6): δ 6.48 (dd, J = 12.5, 8.4 Hz, 1H), 6.28 (dd, J = 13.3, 8.1 Hz, 1H), 4.71 (s, 1H), 4.59 (brs, 2H) 2.66 (d, J = 5.2 Hz, 3H)

[0722] LC-MS: m / z 158.8 [M+H] at 2.20 RT + (purity 99.55%)

[0723] Preparation of Int-16

[0724] Scheme:

[0725]

[0726] 4,5-difluoro-2-nitro-N-propyl aniline

[0727] To a stirred solution of 1,2,4-trifluoro-5-nitrobenzene (5 g, 28.25 mmol) in THF (150 mL) was added potassium carbonate (5.07 g, 36.72 mmol) and 1-aminopropane (3.48 mL, 42.37 mmol) dropwise at room temperature under inert atmosphere and stirred for 16 h. After consumption of starting material (monitored by TLC), the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over anhydrous Na2S04and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 3% EtOAc / hexane) to afford 4,5-difluoro-2-nitro-N-propyl aniline (600 mg, 2.77 mmol, 10%) as a yellow solid.

[0728] 1 H NMR (400 MHz, DMSO-d6): δ 8.25 (br s, 1H), 8.14 (dd, J = 11.3, 8.7 Hz, 1H), 7.17 (dd, J = 13.7, 7.2 Hz, 1H), 3.35-3.26 (m, 2H), 1.68-1.56 (m, 2H), 0.93 (t, J = 7.4 Hz, 3H)

[0729] 4,5-difluoro-N 1 -propylbenzene-1,2-diamine (Int-16)

[0730] To a stirred solution of 4,5-difluoro-2-nitro-N-propyl aniline (500 mg, 2.31 mmol) in ethyl acetate (10 mL) was added 10% Pd / C (50% wet basis, 150 mg) at room temperature under inert atmosphere. The reaction mixture was stirred for 4 h at room temperature under hydrogen atmosphere (balloon pressure). After consumption of starting material (monitored by TLC), the reaction mixture was filtered through a pad of celite and the bed was washed with methanol (20 mL). The filtrate was concentrated under reduced pressure to afford 4,5-difluoro-N 1 -propylbenzene-1,2-diamine Int-16 (350 mg) as a brown syrup. The crude material was used for the next step without further purification.

[0731] 1H NMR (500 MHz, DMSO-d6): δ 6.48 (dd, J = 12.8, 8.1 Hz, 1H), 6.30 (dd, J = 13.3, 8.1 Hz, 1H), 4.66 (s, 2H), 4.47 (br t, J = 4.6 Hz, 1H), 2.96-2.88 (m, 2H), 1.62-1.54 (m, 2H), 0.95 (t, J = 7.5 Hz, 3H)

[0732] LC-MS: m / z 186.9 [M+H] at 2.88 RT + (purity 89.94%)

[0733] Preparation of Int-17

[0734] Scheme:

[0735]

[0736] 3-(Cyclopropylamino)-4-nitrophenol

[0737] To a stirred solution of 3-fluoro-4-nitrophenol (1 g, 6.37 mmol) in THF (20 mL) was added cyclopropylamine (726 mg, 12.74 mmol) in a sealed tube at room temperature under inert atmosphere. The reaction mixture was heated to 80 °C and stirred for 6 h. After consumption of starting material (monitored by TLC), the reaction mixture was poured into ice cold water (30 mL) and extracted with EtOAc (2 x 40 mL). The combined organic extracts were dried over anhydrous Na2S04and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 30% EtOAc / hexane) to afford 3-(cyclopropylamino)-4-nitrophenol (1.2 g, 6.18 mmol, 75%) as a yellow solid.

[0738] 1 H NMR (500 MHz, DMSO-d6): δ 10.86 (br s, 1H), 8.15 (br s, 1H), 7.97 (d, J = 9.3 Hz, 1H), 6.61 (d, J = 1.7 Hz, 1H), 6.22 (dd, J = 9.3, 2.3 Hz, 1H), 2.57-2.55 (m, 1H), 0.91-0.82 (m, 2H), 0.67-0.57 (m, 2H)

[0739] LC-MS: m / z 194.9 [M+H] at 2.51 RT + (purity 99.35%)

[0740] 4-Amino-3-(cyclopropylamino)phenol (Int-17)

[0741] To a stirred solution of 3-(cyclopropylamino)-4-nitrophenol (1 g, 5.15 mmol) in ethyl acetate (10 mL) was added 10% Pd / C (50% wet basis, 250 mg) at room temperature under inert atmosphere. The reaction mixture was stirred at room temperature under hydrogen atmosphere (balloon pressure) for 4 h. After consumption of starting material (monitored by TLC), the reaction mixture was filtered through a pad of celite and the bed was washed with methanol (30 mL). The filtrate was concentrated under reduced pressure to get 4-amino-3-(cyclopropylamino)phenol Int-17 (600 mg) as a brownish syrup. The crude material was used for the next step without further purification.

[0742] 1 H NMR (500 MHz, DMSO-d6): δ 8.18 (br s, 1H), 6.37-6.29 (m, 2H), 5.86 (dd, J = 8.1, 2.3 Hz, 1H), 4.92 (s, 1H), 3.81 (br s, 2H), 2.27-2.25 (m, 1H), 0.69-0.62 (m, 2H), 0.41-0.35 (m, 2H)

[0743] LC-MS: m / z 164.8 [M+H] at 1.09 RT + (purity 74.22%)

[0744] Preparation of Int-18

[0745] Scheme:

[0746]

[0747] N-cyclopropyl-5-methyl-2-nitroaniline

[0748] To a stirred solution of 2-fluoro-4-methyl-1-nitrobenzene (500 mg, 3.22 mmol) in THF (5 mL) was added triethylamine (1.35 mL, 9.68 mmol) followed by cyclopropylamine (919 mg, 16.13 mmol) at room temperature under inert atmosphere. The reaction mixture was heated to 60 °C and stirred for 16 h. After consumption of starting material (monitored by TLC), the reaction mixture was diluted with ice cold water (30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were dried over anhydrous Na2SO4and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 5% EtOAc / hexane) to get N-cyclopropyl-5-methyl-2-nitroaniline (500 mg, 2.6 mmol, 80%) as a yellow solid.

[0749] 1 H NMR (500 MHz, CDC13): δ 8.10 (br s, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.07 (s, 1H), 6.50 (d, J = 8.8 Hz, 1H), 2.58-2.55 (m, 1H), 2.37 (s, 3H), 0.94-0.88 (m, 2H), 0.67-0.62 (m, 2H).

[0750] LC-MS: m / z 192.9 [M+H] at 3.35 RT + (purity 99.53%).

[0751] N 1 - cyclopropyl-5-methylbenzene-1, 2-diamine (Int-18)

[0752] To a stirred solution of N-cyclopropyl-5-methyl-2-nitroaniline (150 mg, 0.78 mmol) in ethyl acetate (1 mL) was added 10% Pd / C (50% wet basis, 50 mg) at room temperature under inert atmosphere. The reaction mixture was stirred at room temperature under hydrogen atmosphere (balloon pressure) for 3 h. After consumption of starting material (monitored by TLC), the reaction mixture was filtered through a pad of celite and the bed was washed with ethyl acetate (15 mL). The filtrate was concentrated under reduced pressure to afford N-cyclopropyl-5-methylbenzene-1, 2-diamine (Int-18) as a black solid (120 mg). The crude material was used for the next step without further purification. 1 - cyclopropyl-5-methylbenzene-1, 2-diamine Int-18 (120 mg). The crude material was used for the next step without further purification.

[0753] 1 H NMR (500 MHz, DMSO-d6): δ 6.60 (s, 1H), 6.41 (d, J = 8.1 Hz, 1H), 6.24 (br d, J = 7.5 Hz, 1H), 4.91 (s, 1H), 4.21 (br s, 2H), 2.32-2.30 (m, 1H), 2.14 (s, 3H), 0.71-0.64 (m, 2H), 0.41-0.35 (m, 2H)

[0754] LC-MS: m / z 162.9 [M+H] at 2.49 RT + (purity 81.92%)

[0755] Preparation of Int-19

[0756] Scheme:

[0757]

[0758] N-cyclopropyl-2-nitro-5-(trifluoromethyl)aniline

[0759] To a stirred solution of 2-fluoro-1-nitro-4-(trifluoromethyl)benzene (1 g, 4.78 mmol) in CH2Cl2(40 mL) was added potassium carbonate (1.32 g, 9.57 mmol) and cyclopropylamine (1.09 g, 19.14 mmol) at 0 °C under inert atmosphere. The reaction mixture was gradually warmed to room temperature and stirred for 16 h. After consumption of starting material (monitored by TLC), the reaction mixture was diluted with ice cold water (30 mL) and extracted with CH2Cl2(2 x 40 mL). The combined organic extracts were dried over anhydrous Na2SO4and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 5% EtOAc / hexane) to afford N-cyclopropyl-2-nitro-5- (trifluoromethyl)aniline (1 g, 4.06 mmol, 85%) as a yellow solid.

[0760] 1 H NMR (400 MHz, DMSO-d6): δ 8.25 (d, J = 8.9 Hz, 1H), 8.13 (br s, 1H), 7.62 (d, J = 1.0 Hz, 1H), 7.04 (dd, J = 8.8, 1.8 Hz, 1H), 2.76-2.69 (m, 1H), 0.95-0.87 (m, 2H), 0.69-0.63 (m, 2H)

[0761] LC-MS: m / z 245.0 [M-H] at 4.33 RT - (purity 78.90%).

[0762] N 1 - cyclopropyl-5-(trifluoromethyl)benzene-1,2-diamine (Int-19)

[0763] To a stirred solution of N-cyclopropyl-2-nitro-5-(trifluoromethyl)aniline (1 g, 4.06 mmol) in methanol (20 mL) was added 10% Pd / C (50% wet basis, 100 mg) at room temperature under inert atmosphere. The reaction mixture was stirred at room temperature under hydrogen atmosphere (balloon pressure) for 3 h. After consumption of starting material (monitored by TLC), the reaction mixture was filtered through a pad of celite and the bed was washed with methanol (20 mL). The filtrate was concentrated under reduced pressure to afford N-cyclopropyl-5-(trifluoromethyl)benzene-1,2-diamine (Int-19) as a brown syrup (700 mg). The crude material was used for the next step without further purification. 1 - cyclopropyl-5-(trifluoromethyl)benzene-1,2-diamine (Int-19)

[0764] Preparation of Int-20

[0765] Scheme:

[0766]

[0767] N-Cyclopropyl-2,3-Difluoro-6-nitroaniline

[0768] 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.

[0769] 1 H NMR (500MHz, DMSO-d6): δ7.95-7.91(m,1H),7.75(brs,1H),6.85-6.80(m,1H),3.02-2.98(m,1H),0.79-0.72(m,2H),0.67-0.65(m,2H)

[0770] LC-MS: at 4.06 RT, m / z 213.4 [MH] + (Purity 99.81%)

[0771] N 1 -Cyclopropyl-5,6-difluorobenzene-1,2-diamine (Int-20)

[0772] 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) at room temperature and under an inert atmosphere. 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.

[0773] 1H NMR (500MHz, DMSO-d6): δ6.55-6.47(m, 1H), 6.33-6.27(m, 1H), 4.70(br s, 2H), 4.54(br s,1H),2.74-2.66(m,1H),0.59-0.52(m,2H),0.48-0.43(m,2H)

[0774] LC-MS: at 2.60 RT, m / z 185.0 [M+H] + (Purity 67.33%)

[0775] Preparation of Int-21

[0776] Scheme:

[0777]

[0778] N-Cyclobutyl-4,5-difluoro-2-nitroaniline

[0779] 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.

[0780] 1 H NMR (400MHz, DMSO-d6): δ8.18-8.08(m,2H),7.00(dd,J=13.4,7.0Hz,1H),4.16-4.07(m,1H),2.48-2.39(m,2H),2.06-1.94(m,2H),1.83-1.69(m,2H)

[0781] LC-MS: at 2.90 RT, m / z 229.0 [M+H] + (Purity 97.77%)

[0782] N 1 -Cyclobutyl-4,5-difluorobenzene-1,2-diamine (Int-21)

[0783] 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 (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.

[0784] 1 H NMR (500MHz, CDCl3): δ6.52 (dd, J=11.3, 8.0Hz, 1H), 6.33 (dd, J=12.1, 7.1Hz, 1 H), 3.86-3.76(m,1H),3.40-3.18(m,3H),2.52-2.39(m,2H),1.91-1.78(m,4H)

[0785] LC-MS: at 2.92 RT, m / z 199.0 [M+H] + (Purity 83.44%)

[0786] Preparation of Int-22

[0787] Scheme:

[0788]

[0789] 4-(cyclopropylamino)-3-nitrobenzene

[0790] 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.

[0791] 1H NMR (400 MHz, CDC13): δ 8.49 (d, J = 1.9 Hz, 1H), 8.41 (br s, 1H), 7.66-7.63 (m, 1H), 7.40 (d, J = 9.0 Hz, 1H), 2.68-2.61 (m, 1H), 1.04-0.98 (m, 2H), 0.75-0.70 (m, 2H)

[0792] LC-MS: at 2.88 RT, m / z 202.0 [M-H] - (purity 99.48 %).

[0793] 3-amino-4-(cyclopropylamino)benzonitrile (Int-22)

[0794] To a stirred solution of 4-(cyclopropylamino)-3-nitrobenzonitrile (1.1 g, crude) in ethanol (40 mL) was added 10% Pd / C (50% wet basis, 350 mg) at room temperature under inert atmosphere. The reaction mixture was stirred at room temperature under hydrogen atmosphere (balloon pressure) for 3 h. After consumption of starting material (monitored by TLC), the reaction mixture was filtered through a pad of celite and the bed was washed with ethyl acetate (20 mL). The filtrate was concentrated under reduced pressure to afford 3-amino-4-(cyclopropylamino)benzonitrile Int-22 (900 mg) as a yellow solid. The crude material was used for the next step without further purification.

[0795] 1 H NMR (400 MHz, CDC13): δ 7.18 (dd, J = 8.2, 1.8 Hz, 1H), 7.00 (d, J = 8.3 Hz, 1H), 6.92 (d, J = 1.9 Hz, 1H), 4.41 (br s, 1H), 3.24 (br s, 2H), 2.51-2.43 (m, 1H), 0.85-0.78 (m, 2H), 0.59-0.53 (m, 2H)

[0796] LC-MS: at 2.40 RT, m / z 173.9 [M+H] + (purity 84.82 %)

[0797] Preparation of Int-23

[0798] Scheme:

[0799]

[0800] 1-chloro-2,5-difluoro-4-nitrobenzene

[0801] To a stirred solution of 1 -chloro-2,5-difluoro-4-nitrobenzene (500 mg, 2.59 mmol) in CH2CI2(10 mL) was added potassium carbonate (715 mg, 5.18 mmol) and cyclopropylamine (305 mg, 5.18 mmol) at 0 °C under inert atmosphere. The reaction mixture was stirred at room temperature for 24 h. After consumption of starting material (monitored by TLC), the reaction mixture was diluted with water (20 mL) and extracted with CH2CI2(2 x 20 mL). The combined organic extracts were dried over anhydrous Na2S04and concentrated under reduced pressure to afford 1 -chloro-2,5-difluoro-4-nitrobenzene (400 mg, 1.73 mmol, 67%) as a yellow solid.

[0802] 1 H NMR (500 MHz, CDCI3): δ 7.97 (d, J = 9.3 Hz, 2H), 7.37 (d, J = 6.4 Hz, 1 H), 2.57-2.54 (m, 1 H), 1.00-0.91 (m, 2H), 0.71-0.59 (m, 2H)

[0803] 5-chloro-N 1 -cyclopropyl-4-fluoro-benzene-1,2-diamine (Int-23)

[0804] To a stirred solution of 1 -chloro-2,5-difluoro-4-nitrobenzene (400 mg, 1.74 mmol) in EtOAc (10 mL) was added 10% Pd / C (50% wet basis, 100 mg) at room temperature under inert atmosphere. The reaction mixture was evacuated and stirred at room temperature under hydrogen atmosphere (balloon pressure) for 5 h. After consumption of starting material (monitored by TLC), the reaction mixture was filtered through a pad of celite and the bed was washed with EtOAc (40 mL). The filtrate was concentrated under reduced pressure to afford 5-chloro-N 1 -cyclopropyl-4-fluoro-benzene-1,2-diamine Int-23 (280 mg, 1.40 mmol, 81 %).

[0805] 1 H NMR (500 MHz, DMSO-d6): δ 6.68 (d, J = 7.5 Hz, 1 H), 6.47 (d, J = 11.6 Hz, 1 H), 5.16 (br s, 1 H), 4.96 (br s, 2H), 2.34-2.27 (m, 1 H), 0.74-0.67 (m, 2H), 0.42-0.28 (m, 2H)

[0806] Preparation of Int-24

[0807] Scheme:

[0808]

[0809] 4-chloro-N-cyclopropyl-2-nitroaniline

[0810] To 4-chloro-l-fluoro-2-nitrobenzene (2 g, 11.43 mmol) was added cyclopropylamine (2.6 g, 45.71 mmol) drop wise at 10 °C under inert atmosphere. The reaction mixture was gradually warmed to room temperature and stirred for 5 h. After consumption of starting material (monitored by TLC), the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over anhydrous Na2S04and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 3 to 5% EtOAc / hexane) to afford 4-chloro-N-cyclopropyl-2-nitroaniline (2.08 g, 0.98 mmol, 83%) as a yellow solid.

[0811] 1 H NMR (500 MHz, CDC13): δ 8.16 (d, J = 2.2 Hz, 1H), 8.04 (br s, 1H), 7.42 (dd, J = 8.8, 2.2 Hz, 1H), 7.29 (d, J = 9.3 Hz, 1H), 2.61-2.55 (m, 1H), 0.96-0.90 (m, 2H), 0.69-0.63 (m, 2H)

[0812] LC-MS: m / z 213.1 [M+H] at 2.85 RT + (purity 99.81%)

[0813] 4-chloro-N 1 -cyclopropylbenzene-l,2-diamine (Int-24)

[0814] To a stirred solution of 4-chloro-N-cyclopropyl-2-nitroaniline (1 g, 4.72 mmol) in methanolic ammonia (2 M, 50 mL) was added Raney nickel (500 mg) at room temperature under inert atmosphere. The reaction mixture was stirred at room temperature under hydrogen atmosphere (balloon pressure) for 4 h. After consumption of starting material (monitored by TLC), the reaction mixture was filtered through a pad of celite and the bed was washed with ethyl acetate (30 mL). The filtrate was concentrated under reduced pressure to afford 4-chloro-N-cyclopropylbenzene-l,2-diamine Int-24 (700 mg) as a brown liquid. The crude material was used for the next step without further purification. 1 -cyclopropylbenzene-l,2-diamine Int-24 (700 mg). The crude material was used for the next step without further purification.

[0815] 1H NMR (500 MHz, DMSO-d6): δ 6.70 (d, J = 8.3 Hz, 1H), 6.55-6.45 (m, 2H), 5.10 (s, 1H), 4.77 (br s, 2H), 2.31-2.29 (m, 1H), 0.72-0.65 (m, 2H), 0.41-0.34 (m, 2H)

[0816] LC-MS: m / z 213.1 [M+H] at 2.74 RT + (purity 87.51%)

[0817] Preparation of Int-25

[0818] Scheme:

[0819]

[0820] 3-chloro-N-cyclopropyl-2-nitroaniline

[0821] To 1-chloro-3-fluoro-2-nitrobenzene (500 mg, 2.85 mmol) was added dropwise cyclopropylamine (0.78 mL, 11.4 mmol) at room temperature under inert atmosphere and stirred for 4 h. After consumption of starting material (monitored by TLC), the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were dried over anhydrous Na2S04and concentrated under reduced pressure to get 3-chloro-N-cyclopropyl-2-nitroaniline (500 mg) as a yellow solid. The crude material was used for the next step without further purification.

[0822] 1 H NMR (400 MHz, CDC13): δ 7.28-7.22 (m, 1H), 7.15 (dd, J = 8.5, 1.3 Hz, 1H), 6.80 (dd, J = 7.8, 1.3 Hz, 1H), 6.01 (br s, 1H), 2.54-2.46 (m, 1H), 0.88-0.82 (m, 2H), 0.60-0.55 (m, 2H).

[0823] LC-MS: m / z 213.1 [M+H] at 2.74 RT + (purity 98.57%)

[0824] 3-chloro-N 1 -cyclopropylbenzene-1,2-diamine (Int-25)

[0825] To a stirred solution of 3-chloro-N-cyclopropyl-2-nitroaniline (200 mg, crude) in acetic acid (2 mL) was added iron powder (157 mg, 2.83 mmol) at room temperature under inert atmosphere. The reaction mixture was heated to 80 °C and stirred for 1 h. After consumption of starting material (monitored by TLC), the reaction mixture was quenched with saturated NaHC03solution (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried over anhydrous Na2S04and concentrated under reduced pressure to get 3-chloro-N-cyclopropyl-2- nitroaniline (200 mg) as a brown syrup. The crude material was used for the next step without further purification. 1 - cyclopropylbenzene-1,2-diamine Int-25 (200 mg). The crude material was used for the next step without further purification.

[0826] LC-MS: m / z 183.0 [M+H] at 2.47 RT + (purity 43.71 %)

[0827] Preparation of Int-26

[0828] Scheme:

[0829]

[0830] 4-isopropyl-2-(trifluoromethyl) oxazol-5(2H)-one

[0831] To DL-valine (30 g, 256.41 mmol) was added trifluoroacetic anhydride (72 mL) drop wise at room temperature. The reaction mixture was heated to reflux and stirred for 8 h. After consumption of starting material (monitored by TLC), the reaction mixture was diluted with water (100 mL) and extracted with CH2CI2(250 mL). The combined organic extracts were dried over anhydrous Na2S04and concentrated under reduced pressure to get 4-isopropyl-2-(trifluoromethyl) oxazol-5(2H)-one 2 (45 g) as a light yellow liquid. The crude material was used for the next step without further purification.

[0832] 1 H NMR (400 MHz, CDCI3): δ 6.11-6.05 (m, 1 H), 3.12-3.02 (m, 1 H), 1.34 (d, J = 3.0 Hz, 3 H), 1.32 (d, J = 3.0 Hz, 3 H)

[0833] LC-MS: m / z 193.9 [M-H] at 2.94 RT - (purity 75.69 %).

[0834] 2-((4-Isopropyl-5-oxo-2-(trifluoromethyl)-2,5-dihydro diethyl 2-azolyl)methyl)malonate

[0835] Under an inert atmosphere at 0°C, 4-isopropyl-2-(trifluoromethyl) was stirred. Diethyl 2-methylenemalonate (47.63 g, crude) and triethylamine (48.2 mL, 346.14 mmol) were added to a CH2Cl2 (450 mL) solution of 45 g crude azole-5(2H)-one. The reaction mixture was warmed to room temperature and stirred for 16 h. After the starting material was consumed (as 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 2-((4-isopropyl-5-oxo-2-(trifluoromethyl)-2,5-dihydro-2-(4-isopropyl-5-oxo-2-(trifluoromethyl)-2,5-dihydro-2-(4-isopropyl-5-oxo-2-(trifluoromethyl)-2,5-dihydro-2-(4-isopropyl-5-oxo-2-(trifluoromethyl)-2,5-dihydro-2-(4-isopropyl-5-oxo-2-(trifluoromethyl)-2,5-dihydro-2-(4-isopropyl-5-oxo-2-(trifluoromethyl)-2-(4-isopropyl-5-oxo-2-(trifluoromethyl)-2,5-dihydro-2-(4-isopropyl-5-oxo-2-(trifluoromethyl)-2-(4-isopropyl-5-oxo-2-(2-dihydro ... Diethyl 2-(2-yl)methyl)malonate (50 g, crude). The crude product can be used in the next step without further purification.

[0836] LC-MS: at 3.70 RT, m / z 368.1 [M+H] + (Purity 82.98%)

[0837] 3-Oxo-6-(trifluoromethyl)-2,3,4,5-tetrahydropyridazine-4-carboxylic acid ethyl ester

[0838] Under room temperature and an inert atmosphere, 2-((4-isopropyl-5-oxo-2-(trifluoromethyl)-2,5-dihydrogen precipitate was stirred. Diethyl 2-oxo-2-(trifluoromethyl)malonate (25 g, crude) was added to an acetic acid (200 mL) solution with hydrazine hydrochloride (23.16 g, 340.59 mmol). 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.

[0839] LC-MS: at 2.19RT, m / z 237.0 [MH] - (Purity 87.20%).

[0840] 3-Hydroxy-6-(trifluoromethyl)pyridazine-4-carboxylic acid ethyl ester

[0841] To a stirred solution of 3-oxo-6-(trifluoromethyl)-2,3,4,5-tetrahydropyridazine-4- carboxylic acid ethyl ester (7.5 g, 31.51 mmol) in acetic acid (40 mL) was added a solution of bromine (5.03 g, 31.51 mmol) in acetic acid (35 mL) at 0 °C under inert atmosphere. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. After consumption of starting material (monitored by TLC), the reaction mixture was basified with saturated sodium bicarbonate solution and extracted with EtOAc (2 x 200 mL). The combined organic extracts were dried over anhydrous Na2SO4and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 30% to 40% EtOAc / hexane) to afford 3-hydroxy-6-(trifluoromethyl)pyridazine-4-carboxylic acid ethyl ester (2.5 g, 10.59 mmol, 34%) as off-white solid.

[0842] 1 H NMR (400 MHz, DMSO-d6): δ 14.16 (br s, 1H), 8.12 (s, 1H), 4.30 (q, J = 7.1 Hz, 2H), 1.29 (t, J = 7.2 Hz, 3H)

[0843] LC-MS: m / z 235.0 [M-H] at 2.03 RT - (purity 98.67%).

[0844] 3-chloro-6-(trifluoromethyl)pyridazine-4-carboxylic acid ethyl ester

[0845] To a stirred solution of 3-hydroxy-6-(trifluoromethyl)pyridazine-4-carboxylic acid ethyl ester (5.0 g, 21.19 mmol) in 1,4-dioxane (50 mL) was added phosphorous trichloride (19.6 mL, 211.86 mmol) at 0 °C under inert atmosphere. The reaction mixture was heated to 100 °C and stirred for 4 h. After consumption of starting material (monitored by TLC), the reaction mixture was basified with sodium bicarbonate solution (100 mL) and extracted with EtOAc (2 x 200 mL). The combined organic extracts were dried over anhydrous Na2SO4and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 15% to 20% EtOAc / hexane) to afford 3-chloro-6-(trifluoromethyl)pyridazine-4-carboxylic acid ethyl ester (3 g, 11.81 mmol, 55%) as light yellow liquid.

[0846] 1 H NMR (500 MHz, CDCl3): δ 8.15 (s, 1H), 4.53 (q, J = 7.0 Hz, 2H), 1.47 (t, J = 7.2 Hz, 3H)

[0847] LC-MS: m / z 255.4 [M+H] at 3.61 RT + (purity 98.51 %)

[0848] 6-(trifluoromethyl)pyridazine-4-carboxylic acid ethyl ester

[0849] To a stirred solution of 3-chloro-6-(trifluoromethyl)pyridazine-4-carboxylic acid ethyl ester (500 mg, 1.96 mmol) in ethanol (10 mL) was added triethylamine (0.5 mL) and 10% Pd / C (50% wet basis, 100 mg) at room temperature under inert atmosphere. The headspace of the reaction was briefly placed under vacuum and quickly charged with hydrogen gas. The reaction mixture was stirred at room temperature under hydrogen atmosphere (balloon pressure) for 1 h. After consumption of starting material (monitored by TLC), the reaction mixture was filtered through a pad of celite and washed with EtOAc (50 mL). The filtrate was concentrated under reduced pressure. The crude material obtained was purified by silica gel column chromatography (eluent: 30% EtOAc / hexane) to afford 6-(trifluoromethyl)pyridazine-4-carboxylic acid ethyl ester (300 mg, 1.36 mmol, 69%) as off-white solid.

[0850] 1 H NMR (400 MHz, CDC13): δ 9.85 (d, J = 1.8 Hz, 1H), 8.32 (d, J = 1.9 Hz, 1H), 4.53 (q, J = 7.2 Hz, 2H), 1.47 (t, J = 7.2 Hz, 3H)

[0851] LC-MS: m / z 221.1 [M+H] at 3.09 RT + (purity 92.69 %)

[0852] 6-(trifluoromethyl)pyridazine-4-carboxylic acid (Int-26)

[0853] To a stirred solution of 6-(trifluoromethyl)pyridazine-4-carboxylic acid ethyl ester (300 mg, 1.36 mmol) in THF: water (4: 1, 5 mL) was added lithium hydroxide (171.6 g, 4.09 mmol) at 0 °C. The reaction mixture was gradually warmed to room temperature and stirred for 1 h. After consumption of starting material (monitored by TLC), the volatiles were concentrated under reduced pressure. The residue was then acidified using concentrated HC1 (pH 3 to pH 4) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were dried over anhydrous Na2S04and concentrated under reduced pressure. The solid obtained was washed with n-pentane (10 mL) and dried under vacuum to afford 6-(trifluoromethyl)pyridazine-4-carboxylic acid Int-26 (210 mg) as off-white solid. The crude material was used for the next step without further purification.

[0854] 1 H NMR (400 MHz, DMSO-d6): δ 14.08 (br s, 1H), 9.83 (br s, 1H), 8.43 (br s, 1H)

[0855] LC-MS: m / z 191.0 [M-H] at 3.79 RT - (purity 94.51 %).

[0856] Preparation of Int-27

[0857] Scheme:

[0858]

[0859] 1 -cyclopropyl-5, 6-difluoro-2-(6-vinylpyridazin-4-yl)-1 H-benzo[d]imidazole

[0860] To a stirred solution of 2-(6-chloropyridazin-4-yl)-1 -cyclopropyl-5, 6-difluoro-1 H- benzo[d]imidazole Ex. 22 (150 mg, 0.50 mmol) in 1,4-dioxane (3 mL) and water (0.5 mL) was added vinylboronic acid pinacol ester (76 mg, 0.50 mmol) and potassium carbonate (203 mg, 1.47 mmol) at room temperature under inert atmosphere. 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 consumption of starting material (monitored by TLC), the volatiles were concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 50% EtOAc / hexane) to afford 1 -cyclopropyl-5, 6-difluoro-2-(6-vinylpyridazin-4-yl)-1 H- benzo[d]imidazole as off-white solid (70 mg, 0.23 mmol, 48%).

[0861] 1 H NMR (400 MHz, DMSO-d6): δ 9.69 (s, 1H), 8.45 (s, 1H), 7.90-7.83 (m, 2H), 7.18-7.11 (m, 1H), 6.53 (d, J = 17.7 Hz, 1H), 5.82 (d, J = 11.4 Hz, 1H), 3.99-3.97 (m, 1H), 1.22-1.13 (m, 2H), 0.82-0.60 (m, 2H)

[0862] 5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-carbaldehyde (Int-27)

[0863] To a stirred solution of 5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3- carboxylic acid (Int-26) (300 mg, 1.00 mmol) in DMF (10 mL) was added NaH (60% in mineral oil, 150 mg, 3.75 mmol) at 0 °C under inert atmosphere. The reaction mixture was stirred at 0 °C for 30 min. Then, iodomethane (0.1 mL, 1.50 mmol) was added dropwise. The reaction mixture was stirred at 0 °C for 1 h. After consumption of starting material (monitored by TLC), the reaction mixture was quenched with ice cold water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with water (100 mL), dried over anhydrous Na2S04and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 2% MeOH / CH2Cl2) to afford 5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-carbaldehyde Int-27 (200 mg) as a black solid. The crude product was used without further purification. t To a stirred solution of 5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3- carboxylic acid (Int-26) (300 mg, 1.00 mmol) in DMF (10 mL) was added NaH (60% in mineral oil, 150 mg, 3.75 mmol) at 0 °C under inert atmosphere. The reaction mixture was stirred at 0 °C for 30 min. Then, iodomethane (0.1 mL, 1.50 mmol) was added dropwise. The reaction mixture was stirred at 0 °C for 1 h. After consumption of starting material (monitored by TLC), the reaction mixture was quenched with ice cold water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with water (100 mL), dried over anhydrous Na2S04and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 2% MeOH / CH2Cl2) to afford 5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-carbaldehyde Int-27 (200 mg) as a black solid. The crude product was used without further purification.

[0864] 1 H NMR (500 MHz, DMSO-d6): δ 10.36 (s, 1H), 10.03 (s, 1H), 8.58 (s, 1H), 7.93-7.81 (m, 2H), 4.00-3.94 (m, 1H), 1.21-1.13 (m, 2H), 0.81-0.72 (m, 2H)

[0865] Preparation of Int-28

[0866] Scheme:

[0867]

[0868] (E)-5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-carbaldehyde oxime

[0869] To a stirred solution of 5-(1-cyclopropyl-5,6-difluoro-1H- benzo[d]imidazol-2-yl)pyridazine-3-carbaldehyde Int-27 (600 mg, 2 mmol) in ethanol (10 mL) was added hydroxylamine hydrochloride (276 mg, 4 mmol) and potassium carbonate (552 mg, 4 mmol) at room temperature under inert atmosphere. The reaction mixture was heated to 80 °C and stirred for 3 h. After consumption of starting material (monitored by TLC), the reaction mixture was concentrated under reduced pressure. The residue was diluted with water (70 mL) and extracted with CH2CI2(100 mL x 3). The organic layer was dried over anhydrous Na2S04and concentrated under reduced pressure. The crude material was washed with n-hexane (20 mL) and dried under vacuum to afford (E)-5-(1-cyclopropyl-5,6-difluoro-1H- benzo[d]imidazol-2-yl)pyridazine-3-carbaldehyde oxime (500 mg, 1.58 mmol, 79%) as off-white solid.

[0870] 1 H NMR (500 MHz, DMSO-d6): δ 12.26 (s, 1H), 9.80 (d, J = 1.7 Hz, 1H), 8.56 (d, J = 2.3 Hz, 1H), 8.48 (s, 1H), 7.91-7.80 (m, 2H), 3.97-3.88 (m, 1H), 1.22-1.14 (m, 2H), 0.85-0.78 (m, 2H)

[0871] LC-MS: m / z 315.9 [M+H] at 2.33 RT + (purity 97.99%)

[0872] (5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methanamine (Int-28)

[0873] To a stirred solution of (E)-5-(1-cyclopropyl-5,6-difluoro-1H- benzo[d]imidazol-2-yl)pyridazine-3-carbaldehyde oxime (500 mg, 1.58 mmol) in ethanol (10 mL) was added sodium hydroxide (190 mg, 4.76 mmol) and 10% Pd / C (50% wet basis, 150 mg) at room temperature under inert atmosphere. The reaction mixture was stirred at room temperature under hydrogen atmosphere (balloon pressure) for 3 h. After consumption of starting material (monitored by TLC), the reaction mixture was filtered through a pad of celite. 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 Na2SO4and concentrated under reduced pressure to afford (5-(1-cyclopropyl-5,6-difluoro-1H- benzo[d]imidazol-2-yl)pyridazin-3-yl)methanamine Int-28 (400 mg, 1.32 mmol, 84%) as off-white solid. The crude material was used for the next step without further purification.

[0874] 1 H NMR (500 MHz, DMSO-d6): δ 9.68 (d, J = 1.7 Hz, 1H), 8.35 (d, J = 1.7 Hz, 1H), 7.89-7.81 (m, 2H), 4.12 (s, 2H), 3.95-3.89 (m, 1H), 2.13 (br s, 2H), 1.27-1.14 (m, 2H), 0.79-0.66 (m, 2H)

[0875] LC-MS: m / z 301.9 [M+H] at 1.91 RT + (purity 95.51%)

[0876] Preparation of Int-29

[0877] Scheme:

[0878]

[0879] 6-(difluoromethyl)pyridazine-4-carboxylic acid (Int-29) was prepared in a similar manner to Int-26 using alanine and difluoroacetic anhydride (DFAA) as starting materials.

[0880] Preparation of Int-30

[0881] Scheme:

[0882]

[0883] 1-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)ethan-1-one oxime

[0884] To a stirred solution of 1-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2- yl)pyridazin-3-yl)ethan-1-one Ex. 64 (170 mg, 0.54 mmol) in EtOH (10 mL) was added hydroxylamine hydrochloride (75 mg, 1.08 mmol) and potassium carbonate (149 mg, 1.08 mmol) at 0 °C under inert atmosphere. The reaction mixture was heated to 80 °C and stirred for 3 h. After consumption of starting material (monitored by TLC), the volatiles were concentrated under reduced pressure. The residue was diluted with water (30 mL) and extracted with CH2CI2(2 x 40 mL). The combined organic extracts were dried over anhydrous Na2S04and concentrated under reduced pressure to afford 1-(5-(1-cyclopropyl-5,6-difluoro-1H- benzo[d]imidazol-2-yl)pyridazin-3-yl)ethan-1-one oxime (100 mg) as off-white solid. The crude material was used for the next step without further purification.

[0885] 1 H NMR (500 MHz, DMSO-d6): δ 12.07 (s, 1H), 9.81 (d, J = 1.7 Hz, 1H), 8.63 (d, J = 1.7 Hz, 1H), 7.91-7.80 (m, 2H), 3.94-3.87 (m, 1H), 2.41 (s, 3H), 1.21-1.14 (m, 2H), 0.85-0.76 (m, 2H)

[0886] LC-MS: m / z 329.9 [M+H] at 2.52 RT + (purity 86.46%)

[0887] 1-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)ethan-1- amine (Int-30)

[0888] To a stirred solution of 1-(5-(1-cyclopropyl-5,6-difluoro-1H- benzo[d]imidazol-2-yl)pyridazin-3-yl)ethan-1-one oxime (100 mg, crude) in ethanol (10 mL) was added sodium hydroxide (37 mg, 0.91 mmol) and 10% Pd / C (50% wet basis, 80 mg) at room temperature under inert atmosphere. The reaction mixture was stirred at room temperature under hydrogen atmosphere (balloon pressure) for 8 h. After consumption of starting material (monitored by TLC), the reaction mixture was filtered through a pad of celite and the celite bed was washed with MeOH (20 mL). The filtrate was concentrated under reduced pressure. The residue was diluted with water (20 mL) and extracted with CH2Cl2(2 x 30 mL). The combined organic extracts were dried over anhydrous Na2SO4and concentrated under reduced pressure to afford 1-(5-(1-cyclopropyl-5,6-difluoro-1H- benzo[d]imidazol-2-yl)pyridazin-3-yl)ethan-1-amine Int-30 (80 mg) as off-white solid. The crude product was used without further purification.

[0889] LC-MS: m / z 315.9 [M+H] at 1.71 RT + (purity 85.70%)

[0890] Example 1

[0891] Scheme:

[0892]

[0893] N-(2-(cyclopropylamino)-4-fluorophenyl)pyridazine-4-carboxamide

[0894] To a stirred solution of N 1To 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: 50% EtOAc / hexane) to obtain N-(2-(cyclopropylamino)-4-fluorophenyl)pyridazine-4-carboxamide (220 mg, 0.81 mmol, 44%) as a brown solid.

[0895] 1 H NMR (400MHz, DMSO-d6): δ9.89 (s, 1H), 9.66 (dd, J=2.2, 1.3Hz, 1H), 9.47 (dd, J=5.2, 1.1Hz, 1H), 8.12 (dd, J=5.3, 2.3Hz, 1H), 7.13 (dd, J=8.5, 6.4Hz, 1H), 6.75 (dd, J = 11.9, 2.9Hz, 1H), 6.43 (td, J = 8.5, 2.9Hz, 1H), 6.12 (s, 1H), 2.38-2.32 (m, 1H), 0.77-0.71 (m, 2H), 0.47-0.40 (m, 2H).

[0896] LC-MS: at 2.66 RT, m / z 272.9 [M+H] + (Purity 89.14%).

[0897] 1-Cyclopropyl-6-fluoro-2-(pyridazin-4-yl)-1H-benzo[d]imidazolium (Ex 1)

[0898] 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 1-cyclopropyl-6-fluoro-2-(pyridazin-4-yl)-1H-benzo[d]imidazole Ex 1 (68 mg, 0.27 mmol, 48%) as a grayish-white solid.

[0899] 1 H NMR (400MHz, DMSO-d6): δ9.82(dd,J=2.2,1.3Hz,1H), 9.45(dd,J=5.4,1.1Hz,1H), 8.29(dd,J=5.4,2.4Hz,1H), 7.79(dd,J =8.9, 4.9Hz, 1H), 7.55 (dd, J = 9.1, 2.4Hz, 1H), 7.22-7.15 (m, 1H), 3.94-3.87 (m, 1H), 1.22-1.16 (m, 2H), 0.78-0.73 (m, 2H).

[0900] LC-MS: at 2.98 RT, m / z 255.0 [M+H] + (Purity 97.13%).

[0901] HPLC: 98.24%.

[0902] Example 2 and Example 3

[0903] Scheme:

[0904]

[0905] 6-Chloro-N-(2-(cyclopropylamino)-4-fluorophenyl)pyridazine-4-carboxamide

[0906] At room temperature and under an inert atmosphere, N was stirred. 1To a solution of cyclopropyl-5-fluorobenzene-1,2-diamine Int-1 (500 mg, 3.01 mmol) in DMF (3 mL) was added 6-chloropyridazine-4-carboxylic acid (475 mg, 3.01 mmol), HATU (1.37 g, 3.61 mmol) and diisopropylethylamine (2.2 mL, 12.04 mmol). The reaction mixture was stirred at room temperature for 4 h. After consumption of starting material (monitored by TLC), the reaction mixture was quenched with ice cold water (30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were dried over anhydrous Na2S04and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 20% EtOAc / hexane) to afford 6-chloro-N-(2-(cyclopropylamino)-4-fluorophenyl)pyridazine-4- carboxamide (550 mg, 1.79 mmol, 60%) as a brown solid.

[0907] 1 H NMR (500 MHz, DMSO-d6): δ 9.96 (s, 1 H), 9.63 (d, J = 1.4 Hz, 1 H), 8.36 (d, J = 1.2 Hz, 1 H), 7.13 (dd, J = 8.4, 6.7 Hz, 1 H), 6.75 (dd, J = 1 1.7, 2.7 Hz, 1 H), 6.43 (td, J = 8.5, 2.7 Hz, 1 H), 6.14 (s, 1 H), 2.37-2.33 (m, 1 H), 0.77-0.73 (m, 2H), 0.46-0.42 (m, 2H).

[0908] LC-MS: m / z 305.0 [M-H] at 3.00 RT + (purity 83.53%).

[0909] 2-(6-chloropyridazin-4-yl)-1 -cyclopropyl-6-fluoro-1 H-benzo[d]imidazole (Ex. 3)

[0910] To a stirred solution of 6-chloro-N-(2-(cyclopropylamino)-4-fluorophenyl) pyridazine-4-carboxamide (550 mg, 1.79 mmol) in CH2Cl2(10 mL) was added trifluoroacetic acid (0.6 mL) drop wise at room temperature under inert atmosphere. The reaction mixture was stirred at room temperature for 16 h. After consumption of starting material (monitored by TLC), the volatiles were removed under reduced pressure. The residue was diluted with EtOAc (50 mL) and washed with saturated sodium bicarbonate solution (20 mL). The organic layer was separated, dried over anhydrous Na2SO4and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 50% EtOAc / hexane) to afford 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-6-fluoro-1H- benzo[d]imidazole Ex. 3 (200 mg, 0.69 mmol, 38%) as off-white solid.

[0911] 1 H NMR (500 MHz, DMSO-d6): δ 9.82 (s, 1H), 8.46 (s, 1H), 7.81 (dd, J = 9.0, 4.9 Hz, 1H), 7.58 (dd, J = 9.0, 2.0 Hz, 1H), 7.21 (td, J = 9.3, 2.2 Hz, 1H), 3.97-3.93 (m, 1H), 1.22-1.17 (m, 2H), 0.83-0.79 (m, 2H).

[0912] LC-MS: m / z 288.9 [M+H] at 2.59 RT + (purity 98.16%).

[0913] HPLC: 98.76%.

[0914] 5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-carbonitrile (Ex. 2);

[0915] To a stirred solution of 2-(6-chloropyridazin-4-yl)-l-cyclopropyl-6-fluoro-lH- benzo[d]imidazole Ex. 2 (100 mg, 0.35 mmol) in DMF (1 mL) was added Zn(CN)2(24 mg, 0.21 mmol) at room temperature under inert atmosphere. The reaction mixture was degassed for 10 min under argon. 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 for 5 min under argon. The reaction mixture was heated to 100 °C and stirred for 2 h. After consumption of starting material (monitored by TLC), the reaction mixture was diluted with EtOAc (40 mL), filtered through a pad of celite and the celite bed was washed with EtOAc (15 mL). The organic layer was washed with water (20 mL), dried over anhydrous Na2S04and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 40% EtOAc / hexane) to afford 5-(l-cyclopropyl-6-fluoro-lH-benzo[d]imidazol-2-yl)pyridazine-3- carbonitrile Ex. 2 (30 mg, 0.11 mmol, 31%) as off-white solid.

[0916] 1 H NMR (500 MHz, DMSO-d6): δ 10.06 (d, J = 1.7 Hz, 1H), 8.92 (d, J = 1.7 Hz, 1H), 7.83 (dd, J = 8.7, 4.9 Hz, 1H), 7.59 (dd, J = 9.0, 2.0 Hz, 1H), 7.25-7.20 (m, 1H), 3.98-3.93 (m, 1H), 1.24-1.19 (m, 2H), 0.82-0.78 (m, 2H).

[0917] LC-MS: m / z 279.8 [M+H] at 2.92 RT + (purity 99.44%).

[0918] HPLC: 99.21%.

[0919] Example 4

[0920] Scheme:

[0921]

[0922] 1-cyclopropyl-6-fluoro-2-(6-vinylpyridazin-4-yl)-lH-benzo[d]imidazole (Ex. 4)

[0923] To a stirred solution of 2-(6-chloropyridazin-4-yl)-l-cyclopropyl-6-fluoro-lH- benzo[d]imidazole Ex. 3 (300 mg, 1.04 mmol) in a mixture of 1,4-dioxane (15 mL) and water (2 mL) was added potassium carbonate (431 mg, 3.12 mmol) and 4,4,5,5-tetramethyl-2-vinyl- 1,3,2-dioxaborolane (160 mg, 1.04 mmol) at room temperature under inert atmosphere. The reaction mixture was degassed for 15 min under argon. To this was added Pd(dppf)Cl2.CH2Cl2(8.5 mg, 0.01 mmol) at room temperature. The reaction mixture was heated to 80 °C and stirred for 4 h. After consumption of starting material (monitored by TLC), the reaction mixture was diluted with EtOAc (60 mL), filtered through a pad of celite and the celite bed was washed with EtOAc (15 mL). The organic layer was washed with water (20 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 40% EtOAc / hexane) to afford l-cyclopropyl-6-fluoro-2-(6-vinylpyridazin-4-yl)-lH- benzo[d]imidazole (150 mg, 0.53 mmol, 51%) as off-white solid.

[0924] 1 H NMR (500 MHz, DMSO-d6): δ 9.68 (d, J = 1.7 Hz, 1H), 8.44 (d, J = 1.7 Hz, 1H), 7.78 (dd, J = 9.0, 4.9 Hz, 1H), 7.55 (dd, J = 9.0, 2.3 Hz, 1H), 7.21-7.09 (m, 2H), 6.52 (d, J = 17.6 Hz, 1H), 5.80 (d, J = 11.0 Hz, 1H), 3.97-3.93 (m, 1H), 1.20-1.14 (m, 2H), 0.77-0.72 (m, 2H).

[0925] LC-MS: m / z 280.9 [M+H] at 2.43 RT + (purity 93.90%).

[0926] HPLC: 95.00%.

[0927] Example 5

[0928] Scheme:

[0929]

[0930] 5-(l-cyclopropyl-6-fluoro-lH-benzo[d]imidazol-2-yl)pyridazine-3-carboxylic acid methyl ester (Ex. 5)

[0931] To a stirred solution of 2-(6-chloropyridazin-4-yl)-l-cyclopropyl-6-fluoro-lH- benzo[d]imidazole Ex. 3 (200 mg, 0.69 mmol) in MeOH (3 mL) was added sodium acetate (171 mg, 2.08 mmol), l,l'-ferrocenediyl-bis(diphenylphosphine) (19 mg, 0.03 mmol) and palladium(II) acetate (7.8 mg, 0.03 mmol) at room temperature in a steel reaction vessel. The steel reaction vessel was charged with CO gas (15 bar pressure). The resulting reaction mixture was stirred at 50 °C for 2 h. After consumption of starting material (monitored by TLC), the reaction mixture was filtered through a pad of celite and the celite bed was washed with methanol (30 mL). The filtrate was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 50% EtOAc / hexane) to afford methyl 5-(l-cyclopropyl-6-fluoro-lH-benzo[d]imidazol-2-yl)pyridazine-3-carboxylate Ex. 5 (70 mg, 0.22 mmol, 32%) as off-white solid.

[0932] 1 H NMR (500 MHz, DMSO-d6): δ 10.04 (d, J = 2.0 Hz, 1H), 8.74 (d, J = 2.0 Hz, 1H), 7.82 (dd, J = 9.0, 4.9 Hz, 1H), 7.57 (dd, J = 9.1, 2.5 Hz, 1H), 7.21 (td, J = 9.3, 2.3 Hz, 1H), 4.03 (s, 3H), 3.99-3.95 (m, 1H), 1.23-1.18 (m, 2H), 0.82-0.78 (m, 2H).

[0933] LC-MS: m / z 312.9 [M+H] at 2.36 RT + (purity 95.19%).

[0934] HPLC: 99.01%.

[0935] Example 6

[0936] Scheme:

[0937]

[0938] 1-cyclopropyl-2-(6-ethylpyridazin-4-yl)-6-fluoro-lH-benzo[d]imidazole (Ex. 6)

[0939] To a stirred solution of 1-cyclopropyl-6-fluoro-2-(6-vinylpyridazin-4-yl)-1H- benzo[d]imidazole Ex. 4 (70 mg, 0.25 mmol) in ethyl acetate (8 mL) was added triethylamine (cat. amount) and 10% Pd / C (50% wet basis, 20 mg) at room temperature under inert atmosphere. The reaction mixture was evacuated and stirred at room temperature under hydrogen atmosphere (balloon pressure) for 3 h. After consumption of starting material (monitored by TLC), the reaction mixture was filtered through a pad of celite and the celite bed was washed with EtOAc (40 mL). The filtrate was concentrated under reduced pressure. The crude material 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 off-white solid.

[0940] 1 H NMR (400 MHz, DMSO-d6): δ 9.66 (d, J = 2.1 Hz, 1H), 8.18 (d, J = 2.0 Hz, 1H), 7.78 (dd, J = 8.8, 4.9 Hz, 1H), 7.55 (dd, J = 9.0, 2.4 Hz, 1H), 7.22-7.14 (m, 1H), 3.95-3.90 (m, 1H), 3.07 (q, J = 7.6 Hz, 2H), 1.37 (t, J = 7.7 Hz, 3H), 1.21-1.15 (m, 2H), 0.77-0.71 (m, 2H).

[0941] LC-MS: m / z 282.9 [M+H] at 2.37 RT + (purity 98.84%).

[0942] HPLC: 98.29%.

[0943] Example 7

[0944] Scheme:

[0945]

[0946] 1-(5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)-2,2,2- trifluoroethan-1-ol (Ex. 7)

[0947] To a stirred solution of 5-(l-cyclopropyl-6-fluoro-lH-benzo[d]imidazol-2-yl)pyridazine-3- carboxaldehyde Int-2 (50 mg, 0.18 mmol) in THF (3 mL) was added trimethyl(trifluoromethyl)silane (0.05 mL, 0.35 mmol) at 0 °C under inert atmosphere. Cesium fluoride (81 mg, 0.53 mmol) was added and stirred at room temperature for 16 h to carry out the reaction. After consumption of starting material (monitored by TLC), the reaction mixture was quenched with saturated ammonium chloride solution (15 mL) and extracted with EtOAc (2 x 15 mL). The combined organic extracts were dried over anhydrous Na2S04and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 5% MeOH / CH2Cl2) to afford l-(5-(l-cyclopropyl-6-fluoro-lH-benzo[d]imidazol-2-yl)pyridazin-3-yl)-2,2,2- trifluoroethan-l-ol Ex. 7 (15 mg, 0.04 mmol, 24%) as off-white solid.

[0948] 1 H NMR (400 MHz, CD3OD): δ 9.83 (d, J = 2.1 Hz, 1H), 8.57 (d, J = 2.1 Hz, 1H), 7.76 (dd, J = 8.9, 4.8 Hz, 1H), 7.52 (dd, J = 8.8, 2.3 Hz, 1H), 7.20-7.13 (m, 1H), 5.54 (q, J = 6.9 Hz, 1H), 3.90-3.85 (m, 1H), 1.33-1.20 (m, 2H), 0.87-0.79 (m, 2H).

[0949] LC-MS: m / z 352.9 [M+H] at 2.59 RT + (purity 96.11 %).

[0950] HPLC: 93.29 %.

[0951] Example 8

[0952] Scheme:

[0953]

[0954] N-((5-(l-cyclopropyl-6-fluoro-lH-benzo[d]imidazol-2-yl)pyridazin-3-yl)methyl)propionamide (Ex. 8)

[0955] To a stirred solution of (5-(l-cyclopropyl-6-fluoro-lH-benzo[d]imidazol-2-yl)pyridazin-3- yl)methanamine Int-3 (140 mg, 0.49 mmol) in CH2CI2(5 mL) was added propionyl chloride (0.05 mL, 0.59 mmol) and triethylamine (0.14 mL, 0.1 mmol) at 0 °C under inert atmosphere. The reaction mixture was stirred at 0 °C for 3 h. After consumption of starting material (monitored by TLC), the reaction mixture was diluted with water (20 mL) and extracted with CH2CI2(2 x 20 mL). The combined organic extracts were dried over anhydrous Na2S04and concentrated under reduced pressure. The crude material was purified by preparative high-performance liquid chromatography (HPLC) to afford N-((5-(l-cyclopropyl-6-fluoro-lH-benzo[d]imidazol-2-yl)pyridazin-3-yl)methyl)propanamide (40 mg, 0.12 mmol, 24%) as a white solid.

[0956] 1 H NMR (500 MHz, DMSO-d6): δ 9.72 (d, J = 1.4 Hz, 1H), 8.60 (br t, J = 5.1 Hz, 1H), 8.13 (d, J = 1.4 Hz, 1H), 7.79 (dd, J = 8.7, 4.9 Hz, 1H), 7.54 (dd, J = 9.0, 2.0 Hz, 1H), 7.18 (td, J = 9.8, 2.3 Hz, 1H), 4.67 (d, J = 6.1 Hz, 2H), 3.89-3.84 (m, 1H), 2.22 (q, J = 7.5 Hz, 2H), 1.25-1.16 (m, 2H), 1.04 (t, J = 7.7 Hz, 3H), 0.77-0.71 (m, 2H).

[0957] LC-MS: m / z 340.1 [M+H] at 2.07 RT + (purity 99.22%).

[0958] HPLC: 99.08%.

[0959] Example 9

[0960] Scheme:

[0961]

[0962] Ethyl (5-(l-cyclopropyl-6-fluoro-lH-benzo[d]imidazol-2-yl)pyridazin-3-yl)methyl)carbamate (Ex. 9)

[0963] To a stirred solution of (5-(l-cyclopropyl-6-fluoro-lH-benzo[d]imidazol-2-yl)pyridazin-3- yl)methanamine Int-3 (125 mg, 0.44 mmol) in THF (6 mL) was added ethyl chloroformate (0.05 mL, 0.53 mmol) and triethylamine (0.12 mL, 0.88 mmol) at 0 °C under inert atmosphere. The reaction mixture was allowed to warm to room temperature and stirred for 3 h. After consumption of starting material (by TLC), the reaction mixture was diluted with saturated ammonium chloride solution (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried over anhydrous Na2S04and concentrated under reduced pressure. The crude material was purified by preparative HPLC to afford ethyl (5-(l-cyclopropyl-6-fluoro-lH-benzo[d]imidazol-2-yl)pyridazin-3-yl)methyl)carbamate Ex. 9 (40 mg, 0.11 mmol, 26%) as off-white solid.

[0964] 1 H NMR (400 MHz, DMSO-d6): δ 9.75 (d, J = 2.1 Hz, 1H), 8.18 (d, J = 2.0 Hz, 1H), 7.93 (br t, J = 6.0 Hz, 1H), 7.79 (dd, J = 8.9, 4.9 Hz, 1H), 7.55 (dd, J = 9.1, 2.4 Hz, 1H), 7.22-7.15 (m, 1H), 4.60 (d, J = 6.1 Hz, 2H), 4.03 (q, J = 7.1 Hz, 2H), 3.91-3.84 (m, 1H), 1.22-1.16 (m, 5H), 0.78-0.73 (m, 2H).

[0965] LC-MS: m / z 356.1 [M+H] at 2.33 RT + (purity 98.62 %).

[0966] HPLC: 99.15 %.

[0967] Example 10

[0968] Scheme:

[0969]

[0970] 4-(5-(l-cyclopropyl-6-fluoro-lH-benzo[d]imidazol-2-yl)pyridazin-3-yl)morpholine (Ex. 10)

[0971] To a stirred solution of 2-(6-chloropyridazin-4-yl)-l-cyclopropyl-6-fluoro-lH- benzo[d]imidazole Ex. 3 (150 mg, 0.52 mmol) in ethanol (0.9 mL) was added triethylamine (0.11 mL, 0.78 mmol) and morpholine (0.07 mL, 0.78 mmol) at room temperature under inert atmosphere. The reaction mixture was heated to 90 °C and stirred for 16 h. After consumption of starting material (monitored by TLC), the reaction mixture was quenched with saturated ammonium chloride solution (20 mL) and extracted with CH2Cl2(2 x 20 mL). The combined organic extracts were dried over anhydrous Na2SO4and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 100% EtOAc) to afford 4-(5-(l-cyclopropyl-6-fluoro-lH-benzo[d]imidazol-2-yl)pyridazin-3-yl)morpholine Ex. 10 (40 mg, 0.12 mmol, 23%) as off-white solid.

[0972] 1 H NMR (500 MHz, DMSO-d6): δ 9.14 (s, 1H), 7.81-7.71 (m, 2H), 7.53 (br d, J = 7.8 Hz, 1H), 7.16 (br t, J = 7.1 Hz, 1H), 3.93-3.91 (m, 1H), 3.83-3.61 (m, 8H), 1.18-1.16 (m, 2H), 0.75-0.73 (m, 2H).

[0973] LC-MS: m / z 340.0 [M+H] at 2.33 RT + (purity 97.11%).

[0974] HPLC: 97.09%.

[0975] Example 11

[0976] Scheme:

[0977]

[0978] 1-cyclopropyl-6-fluoro-2-(6-(4-(4-fluorophenyl)piperazin-l-yl)pyridazin-4-yl)-lH- benzo[d]imidazole (Ex. 11)

[0979] To a stirred solution of 2-(6-chloropyridazin-4-yl)-l-cyclopropyl-6-fluoro-lH- benzo[d]imidazole Ex. 3 (50 mg, 0.17 mmol) in EtOH (0.3 mL) was added triethylamine (0.036 mL, 0.26 mmol) and l-(4-fluorophenyl)piperazine (47 mg, 0.26 mmol) at room temperature under inert atmosphere. The reaction mixture was stirred at 90 °C for 7 h. After consumption of starting material (monitored by TLC), volatiles were evaporated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 90% EtOAc / hexane) to afford l-cyclopropyl-6-fluoro-2-(6-(4-(4-fluorophenyl)piperazin-l- yl)pyridazin-4-yl)-lH-benzo[d]imidazole Ex. 11 (40 mg, 0.09 mmol, 53%) as off-white solid.

[0980] 1 H NMR (400 MHz, DMSO-d6): δ 9.13 (d, J = 1.6 Hz, 1H), 7.80 (d, J = 1.5 Hz, 1H), 7.77 (dd, J = 8.9, 4.9 Hz, 1H), 7.54 (dd, J = 9.1, 2.4 Hz, 1H), 7.20-7.14 (m, 1H), 7.12-7.02 (m, 4H), 3.96-3.92 (m, 1H), 3.89-3.83 (m, 4H), 3.28-3.24 (m, 4H), 1.21-1.15 (m, 2H), 0.78-0.72 (m, 2H)

[0981] LC-MS: m / z 433.1 [M+H] at 2.38 RT + (purity 99.63%).

[0982] HPLC: 96.82%.

[0983] Example 12

[0984] Scheme:

[0985]

[0986] 5-(l-cyclopropyl-6-fluoro-lH-benzo[d]imidazol-2-yl)pyridazine-3-carbaldehyde (Int-2)

[0987] To a stirred solution of l-cyclopropyl-6-fluoro-2-(6-vinylpyridazin-4-yl)-lH- benzo[d]imidazole Ex. 4 (600 mg, 2.14 mmol) in acetone: t-butanol (3 mL) was added 2- methoxyphenylhydrazine hydrochloride (1.02 g, 6.42 mmol) at 0 °C under inert atmosphere. The reaction mixture was stirred at 60 °C for 7 h. After consumption of starting material (monitored by TLC), volatiles were evaporated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 90% EtOAc / hexane) to afford 2-(6-(l-cyclopropyl-6-fluoro-lH-benzo[d]imidazol-2-yl)pyridazin-4- yl)-2-methoxy-N-(2-methoxyphenyl)acetamide Ex. 10 (600 mg, 1.42 mmol, 66%) as off-white solid. tSodium 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.

[0988] 1 H NMR (500MHz, CDCl3): δ10.52 (s, 1H), 10.08 (s, 1H), 8.65 (s, 1H), 7.81 (dd, J = 9.0, 4.9Hz, 1H), 7.35 (dd,J=8.4,2.3Hz,1H),7.17-7.12(m,1H),3.78-3.67(m,1H),1.39-1.30(m,2H),0.94-0.82(m,2H)

[0989] 1-[5-(1-Cyclopropyl-6-fluoro1H-1,3-benzodiazol-2-yl)pyridazin-3-yl]ethanol-1-ol

[0990] 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.

[0991] 1H NMR (500 MHz, DMSO-d6): δ 9.72 (s, 1H), 8.34 (s, 1H), 7.79 (dd, J = 9.0, 4.9 Hz, 1H), 7.55 (dd, J = 9.0, 2.0 Hz, 1H), 7.23-7.14 (m, 1H), 5.78 (d, J = 4.6 Hz, 1H), 5.16-5.05 (m, 1H), 3.95-3.90 (m, 1H), 1.52 (d, J = 6.7 Hz, 3H), 1.25-1.15 (m, 2H), 0.77-0.75 (m, 2H)

[0992] 1 -(5-(1 -cyclopropyl-6-fluoro- 1 H-benzo[d]imidazol-2-yl)pyridazin-3-yl)ethan- 1 -one

[0993] To a stirred solution of 1-[5-(1-cyclopropyl-6-fluoro-1H-1,3-benzoxazol-2-yl)pyridazin-3-yl]ethan-1-ol (100 mg, 0.33 mmol) in CH2Cl2(10 mL) was added Dess-Martin reagent (213 mg, 0.51 mmol) at 0 °C under inert atmosphere. The reaction mixture was allowed to warm to room temperature and stirred for 3 h. After consumption of starting material (monitored by TLC), the reaction mixture was quenched with saturated sodium bicarbonate solution (20 mL) and extracted with CH2Cl2(2 x 50 mL). The organic layer was washed with saturated sodium bicarbonate (20 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 2% to 3% MeOH / CH2Cl2) to afford 1-(5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)ethan-1-one (80 mg, 0.27 mmol, 81%) as off-white solid.

[0994] 1 H NMR (500 MHz, DMSO-d6): δ 10.04 (s, 1H), 8.64 (s, 1H), 7.82 (dd, J = 9.0, 4.9 Hz, 1H), 7.57 (dd, J = 9.0, 2.0 Hz, 1H), 7.23-7.11 (m, 1H), 4.02-3.91 (m, 1H), 2.87 (s, 3H), 1.20-1.15 (m, 2H), 0.79-0.76 (m, 2H)

[0995] 2-(5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)propan-2-ol (Ex. 12)

[0996] To a stirred solution of 1-(5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)ethan-1-one (60 mg, 0.20 mmol) in THF (2 mL) was added methyl magnesium bromide (2 M in diethyl ether, 0.1 mL, 0.20 mmol) dropwise at -78 °C under inert atmosphere. The reaction mixture was stirred at -78 °C for 1 h. After consumption of starting material (monitored by TLC), the reaction mixture was quenched with saturated ammonium chloride solution (20 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were dried over anhydrous Na2S04and concentrated under reduced pressure. The crude material was purified by preparative HPLC to afford 2-(5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)propan-2-ol Ex. 12 (15 mg, 0.05 mmol, 24%) as off-white solid.

[0997] 1 H NMR (400 MHz, CD3OD): δ 9.65 (s, 1H), 8.57 (s, 1H), 7.73 (dd, J = 8.9, 4.8 Hz, 1H), 7.50 (dd, J = 8.8, 2.4 Hz, 1H), 7.21-7.08 (m, 1H), 3.91-3.76 (m, 1H), 1.71 (s, 6H), 1.30-1.18 (m, 2H), 0.83-0.76 (m, 2H)

[0998] LC-MS: m / z 313 [M+H] at 2.19 RT + (purity 95.83 %).

[0999] HPLC: 95.47 %.

[1000] Example 13

[1001] Scheme:

[1002]

[1003] 5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)-N-(tetrahydro-2H-pyran-4-yl)pyridaz-3-amine (Ex. 13)

[1004] To a stirred solution of 2-(6-chloropyridazin-4-yl)-l-cyclopropyl-6-fluoro-lH- benzo[d]imidazole Ex. 3 (150 mg, 0.52 mmol) in EtOH (1.5 mL) was added triethylamine (0.2 mL, 1.56 mmol) and tetrahydro-2H-pyran-4-amine (105 mg, 1.04 mmol) at room temperature under inert atmosphere. The reaction mixture was stirred at reflux for 16 h. After consumption of starting material (monitored by TLC), the volatiles were evaporated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: EtOAc) to afford 5-(l-cyclopropyl-6-fluoro-lH-benzo[d]imidazol-2-yl)-N-(tetrahydro-2H-pyran-4- yl)pyridazin-3-amine Ex. 13 (40 mg, 0.11 mmol, 22%) as off-white solid.

[1005] 1 H NMR (500 MHz, DMSO-d6): δ 9.01 (s, 1H), 7.74 (dd, J = 8.7, 4.9 Hz, 1H), 7.51 (dd, J = 9.1, 2.5 Hz, 1H), 7.41 (s, 1H), 7.18 - 7.11 (m, 1H), 7.07 (d, J = 7.2 Hz, 1H), 4.17 - 4.07 (m, 1H), 3.93 - 3.86 (m, 2H), 3.80 - 3.75 (m, 1H), 3.49 - 3.44 (m, 2H), 2.05 - 1.95 (m, 2H), 1.59 - 1.42 (m, 2H), 1.30 - 1.02 (m, 2H), 0.87 - 0.74 (m, 2H)

[1006] LC-MS: m / z 354 [M+H] at 1.74 RT + (purity 97.97 %).

[1007] HPLC: 97.95 %.

[1008] Example 14

[1009] Scheme:

[1010]

[1011] N-(2-(cyclopropylamino)-4-fluorophenyl)picolinamide

[1012] To a stirred solution of N 1To a stirred solution of 4-(l-cyclopropyl-6-fluoro-lH-benzo[d]imidazol-2-yl)benzoic acid (Ex. 13) (200 mg, 0.63 mmol) in DMF (5 mL) was added K2CO3(174 mg, 1.26 mmol) and l-bromo-3-methoxypropane (0.1 mL, 0.84 mmol) at room temperature under inert atmosphere. The reaction mixture was stirred at 80 °C for 16 h. After consumption of starting material (by TLC), the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed with water (20 mL), dried over anhydrous Na2S04and concentrated under reduced pressure. The crude material was purified by preparative HPLC to afford 4-(l-cyclopropyl-6-fluoro-lH-benzo[d]imidazol-2-yl)-3- methoxybenzoic acid (Ex. 15) (100 mg, 0.25 mmol, 40%) as a white solid.

[1013] LC-MS: m / z 322.9 [M+H] at 2.71 RT + Purity: 38.30 %.

[1014] 4-(l-cyclopropyl-6-fluoro-lH-benzo[d]imidazol-2-yl)benzoic acid (Ex. 13)

[1015] To a stirred solution of N-(2-(cyclopropylamino)-4-fluorophenyl)cinnoline-4- carboxamide (400 mg, 1.24 mmol) in EtOH (5 mL) was added 6 N HC1 (4 mL) at room temperature under inert atmosphere. The reaction mixture was stirred at 80 °C for 1 h. After consumption of starting material (monitored by TLC), the reaction mixture was diluted with saturated sodium bicarbonate solution (20 mL) and extracted with CH2CI2(2 x 20 mL). The combined organic extracts were dried over anhydrous Na2S04and concentrated under reduced pressure. The crude material was purified by preparative HPLC to afford 4-(l-cyclopropyl-6-fluoro-lH-benzo[d]imidazol-2-yl)cinnoline (Ex. 14) (160 mg, 0.52 mmol, 43%) as an off-white solid.

[1016] 1 H NMR (400 MHz, CD3OD): δ 9.69 (s, 1H), 8.65 (d, J = 8.2 Hz, 1H), 8.23 (d, J = 8.5 Hz, 1H), 8.12-8.07 (m, 1H), 8.01-7.97 (m, 1H), 7.82-7.79 (m, 1H), 7.58 (dd, J = 8.8, 2.3 Hz, 1H), 7.25-7.18 (m, 1H), 3.76-3.71 (m, 1H), 0.98-0.93 (m, 2H), 0.65-0.54 (m, 2H)

[1017] LC-MS: at 2.59 RT, m / z 304.9 [M+H] + (Purity 99.51%).

[1018] HPLC: 99.30%.

[1019] Example 15

[1020] Scheme:

[1021]

[1022] N-(2-(cyclopropylamino)-4-fluorophenyl)-6-methylpyridazine-4-carboxamide

[1023] 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.

[1024] LC-MS: at 3.53 RT, m / z 287.2 [M+H] + (Purity 54.60%).

[1025] 1-Cyclopropyl-6-fluoro-2-(6-methylpyridazin-4-yl)-1H-benzo[d]imidazolium (Ex. 15)

[1026] To a stirred solution of N-(2-(cyclopropylamino)-4-fluorophenyl)-6-methylpyridazine-4- carboxamide (250 g, 0.87 mmol) in EtOH (1.5 mL) was added 6N HC1 (3.5 mL) at room temperature under inert atmosphere. The reaction mixture was stirred at 80 °C for 2 h. After consumption of starting material (monitored by TLC), the reaction mixture was diluted with saturated sodium carbonate solution (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed with water (20 mL), brine (20 mL), dried over anhydrous Na2S04and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 4 to 5% MeOH / CH2Cl2) to afford 1-cyclopropyl-6-fluoro-2-(6-methylpyridazin-4-yl)-1H- benzo[d]imidazole Ex. 15 (80 mg, 0.29 mmol, 34%) as off-white solid.

[1027] 1 H NMR (400 MHz, CD3OD): δ 9.64 (s, 1H), 8.21 (s, 1H), 7.74 (dd, J = 9.0, 4.6 Hz, 1H), 7.51 (dd, J = 8.8, 2.1 Hz, 1H), 7.19-7.13 (m, 1H), 3.89-3.83 (m, 1H), 2.84 (s, 3H), 1.31-1.23 (m, 2H), 0.86-0.79 (m, 2H)

[1028] LC-MS: m / z 268.9 [M+H] at 2.19 RT + (purity 95.85%).

[1029] HPLC: 97.59%.

[1030] Example 16

[1031] Scheme:

[1032]

[1033] N-(5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)ethanesulfonamide (Ex. 16)

[1034] To a stirred solution of 2-(6-chloropyridazin-4-yl)-l-cyclopropyl-6-fluoro-lH- benzo[d]imidazole Ex. 3 (100 mg, 0.34 mmol) in 1,4-dioxane (4 mL) was added ethanesulfonamide (57 mg, 0.52 mmol) and cesium carbonate (283 mg, 0.86 mmol) and the mixture was purged under argon for 5 minutes. Pd(OAc)2(7.8 mg, 0.004 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthphos (30 mg, 0.05 mmol) were then added to the reaction mixture. The reaction mixture was heated to 120 °C and stirred for 16 h. After consumption of starting material (monitored by TLC), the reaction mixture was diluted with water (50 mL) and extracted with 10% MeOH:CH2Cl2(2 x 50 mL). The combined organic extracts were dried over anhydrous Na2SO4and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 2% to 3% MeOH / CH2Cl2) to give N-(5-(l-cyclopropyl-6-fluoro-lH-benzo[d]imidazol-2-yl)pyridazin-3-yl)ethanesulfonamide Ex. 16 (30 mg, 0.08 mmol, 24%) as a colorless syrup.

[1035] 1 H NMR (400 MHz, CD3OD): δ 8.96 (br s, 1H), 8.45 (br s, 1H), 7.76-7.73 (m, 1H), 7.50 (dd, J = 8.8, 2.3 Hz, 1H), 7.25-7.12 (m, 1H), 3.79-3.73 (m, 1H), 3.30-3.21 (m, 2H), 1.46-1.37 (m, 5H), 1.03-0.82 (m, 2H)

[1036] LC-MS: m / z 362 [M+H] at 2.04 RT + (purity 95.41%).

[1037] HPLC: 94.11%.

[1038] Example 17

[1039] Scheme:

[1040]

[1041] 6-chloro-N-(4-cyano-2-(ethylamino)phenyl)pyridazine-4-carboxamide

[1042] To a stirred solution of 4-amino-3-(ethylamino)benzonitrile Int-4 (322 mg, 2 mmol) in DMF (6 mL) was added 6-chloropyridazine-4-carboxylic acid (316 mg, 2 mmol), HATU (1.14 g, 3 mmol) and diisopropylethylamine (1.38 mL, 8 mmol) at room temperature under inert atmosphere. The reaction mixture was stirred at room temperature for 16 h. After consumption of starting material (monitored by TLC), the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were dried over anhydrous Na2S04and concentrated under reduced pressure to afford 6-chloro-N-(4-cyano-2- (ethylamino)phenyl)pyridazine-4-carboxamide (350 mg, crude) as off-white solid.

[1043] LC-MS: m / z 300.1 [M-H] at 2.07 RT - (purity 18.03%)

[1044] 2-(6-chloropyridazin-4-yl)-1-ethyl-1H-benzo[d]imidazole-6-carbonitrile (Ex. 17)

[1045] To a stirred solution of 6-chloro-N-(4-cyano-2-(ethylamino)phenyl)pyridazine-4- carboxamide (350 mg, 1.16 mmol) in CH2CI2(3 mL) was added trifluoroacetic acid (TFA) (1 mL) at room temperature under inert atmosphere. The reaction mixture was stirred at room temperature for 6 h. After consumption of starting material (monitored by TLC), the reaction mixture was diluted with saturated sodium carbonate solution (30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were washed with water (20 mL), brine (20 mL), dried over anhydrous Na2S04and concentrated under reduced pressure. The crude material was purified by preparative HPLC to afford 2-(6-chloropyridazin-4-yl)-1-ethyl-1H-benzo[d]imidazole-6-carbonitrile Ex. 17 (25 mg, 0.08 mmol, 7.5%) as off-white solid.

[1046] 1 H NMR (400 MHz, CD3OD): δ 9.63 (d, J = 1.9 Hz, 1H), 8.27 (d, J = 1.8 Hz, 2H), 7.93 (dd, J = 8.4, 0.6 Hz, 1H), 7.69 (dd, J = 8.5, 1.4 Hz, 1H), 4.56-4.51 (m, 2H), 1.51 (t, J = 7.3 Hz, 3H)

[1047] LC-MS: m / z 284.2 [M+H] at 3.50 RT + (purity 99.67%).

[1048] HPLC: 99.48%.

[1049] Example 18

[1050] Scheme:

[1051]

[1052] 2-(4-(5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)piperazin-1- yl)-N-isopropylacetamide (Ex. 18)

[1053] To a stirred solution of 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-6-fluoro-1H- benzo[d]imidazole Ex. 3 (56 mg, 0.19 mmol) in EtOH (2 mL) was added triethylamine (0.04 mL, 0.28 mmol) and N-isopropyl-2-(4-(2,2,2-trifluoroacetyl)-4,5- piperazin-1-yl)acetamide (60 mg, 0.27 mmol) at room temperature under inert atmosphere. The reaction mixture was stirred at reflux for 16 h. After consumption of starting material (monitored by TLC), the volatiles were evaporated under reduced pressure. The crude material was purified by preparative HPLC to get 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 off-white solid.

[1054] 1 H NMR (400 MHz, CD3OD): δ 9.08 (s, 1H), 7.76 (s, 1H), 7.72 (dd, J = 8.9, 4.8 Hz, 1H), 7.50 (dd, J = 8.8, 2.5 Hz, 1H), 7.15 (dt, J = 9.3, 2.4 Hz, 1H), 4.13-4.02 (m, 1H), 3.87-3.81 (m, 4H), 3.34-3.31 (m, 1H), 3.10 (s, 2H), 2.73-2.69 (m, 4H), 1.28-1.23 (m, 2H), 1.20 (d, J = 6.7 Hz, 6H), 0.86-0.80 (m, 2H)

[1055] LC-MS: m / z 438.4 [M+H] at 3.76 RT + (purity 94.38%).

[1056] HPLC: 94.23%.

[1057] Example 19

[1058] Scheme:

[1059]

[1060] N-(2-(cyclopropylamino)-4,5-difluorophenyl)-6-methylpyridazine-4-carboxamide

[1061] To a stirred solution of N-(2-(cyclopropylamino)-4,5-difluorophenyl)-6- methylpyridazine-4-carboxamide (220 mg, 0.72 mmol) in EtOH (1.5 mL) was added 6N HC1 (3.5 mL) at room temperature under inert atmosphere. The reaction mixture was stirred at 80 °C for 2 h. After consumption of starting material (monitored by TLC), the reaction mixture was diluted with saturated sodium carbonate solution (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over anhydrous Na2S04and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 3 to 5% MeOH / CH2Cl2) to afford 1-cyclopropyl-5,6-difluoro-2-(6-methylpyridazin-4-yl)-1H- benzo[d]imidazole Ex. 19 (60 mg, 0.20 mmol, 29%) as off-white solid. 1 To a stirred solution of N-(2-(cyclopropylamino)-4,5-difluorophenyl)-6- methylpyridazine-4-carboxamide (220 mg, 0.72 mmol) in EtOH (1.5 mL) was added 6N HC1 (3.5 mL) at room temperature under inert atmosphere. The reaction mixture was stirred at 80 °C for 2 h. After consumption of starting material (monitored by TLC), the reaction mixture was diluted with saturated sodium carbonate solution (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over anhydrous Na2S04and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 3 to 5% MeOH / CH2Cl2) to afford 1-cyclopropyl-5,6-difluoro-2-(6-methylpyridazin-4-yl)-1H- benzo[d]imidazole Ex. 19 (60 mg, 0.20 mmol, 29%) as off-white solid.

[1062] LC-MS: m / z 305.2 [M+H] at 3.78 RT + (purity 44.76%).

[1063] 1-cyclopropyl-5,6-difluoro-2-(6-methylpyridazin-4-yl)-1H-benzo[d]imidazole (Ex.19)

[1064] To a stirred solution of N-(2-(cyclopropylamino)-4,5-difluorophenyl)-6- methylpyridazine-4-carboxamide (220 mg, 0.72 mmol) in EtOH (1.5 mL) was added 6N HC1 (3.5 mL) at room temperature under inert atmosphere. The reaction mixture was stirred at 80 °C for 2 h. After consumption of starting material (monitored by TLC), the reaction mixture was diluted with saturated sodium carbonate solution (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over anhydrous Na2S04and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 3 to 5% MeOH / CH2Cl2) to afford 1-cyclopropyl-5,6-difluoro-2-(6-methylpyridazin-4-yl)-1H- benzo[d]imidazole Ex. 19 (60 mg, 0.20 mmol, 29%) as off-white solid.

[1065] 1H NMR (400 MHz, CD3OD): δ 9.63 (d, J = 1.9 Hz, 1H), 8.20 (d, J = 2.1 Hz, 1H), 7.72 (dd, J = 10.1, 7.1 Hz, 1H), 7.62 (dd, J = 10.4, 7.3 Hz, 1H), 3.90-3.83 (m, 1H), 2.84 (s, 3H), 1.31-1.24 (m, 2H), 0.85-0.80 (m, 2H)

[1066] LC-MS: at 2.32 RT, m / z 286.9 [M+H] + (purity 99.57 %).

[1067] HPLC: 99.70 %.

[1068] Example 20

[1069] Scheme:

[1070]

[1071] 4-(2-ethoxy-2-oxoethyl)piperazine-1-carboxylic acid tert-butyl ester

[1072] To a stirred solution of piperazine-1-carboxylic acid tert-butyl ester (2 g, 10.7 mmol) in DMF (14 mL) was added potassium carbonate (3.71 g, 26.8 mmol) and ethyl bromoacetate (1.2 mL, 10.8 mmol) at room temperature under inert atmosphere. The reaction mixture was stirred at room temperature for 16 h. After consumption of starting material (monitored by TLC), the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over anhydrous Na2S04and concentrated under reduced pressure to afford 4-(2-ethoxy-2-oxoethyl)piperazine-1-carboxylic acid tert-butyl ester (2.8 g, 10.29 mmol, 95%) as a yellow oil.

[1073] 1 H NMR (500 MHz, DMSO-d6): δ 4.12-4.00 (m, 2H), 3.30 (s, 4H), 3.23 (s, 2H), 2.45 (t, J = 4.6 Hz, 4H), 1.39 (s, 9H), 1.18 (t, J = 7.1 Hz, 3H)

[1074] 2-(4-tert-butoxycarbonyl)piperazin-1-yl)acetic acid

[1075] To a stirred solution of tert-butyl 4-(2-ethoxy-2-oxoethyl)piperazine-l- carboxylate (2.8 g, 10.29 mmol) in a mixture of THF:MeOH:water (3:1:1, 30 mL) was added lithium hydroxide (1.29 g, 30.8 mmol) at 0 °C. The reaction mixture was gradually warmed to room temperature and stirred for 3 h. After consumption of starting material (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 x 100 mL). The combined organic extracts were dried over anhydrous Na2S04and concentrated under reduced pressure to afford 2-(4-tert-butoxycarbonyl)piperazin-l-yl)acetic acid (200 mg, crude) as a yellow oil which was used for the next step without further purification.

[1076] LC-MS: m / z 245.1 [M-H] at 1.06 RT + (purity 71.81 %).

[1077] tert-Butyl 4-(2-oxo-2-(pyrrolidin-l-yl)ethyl)piperazine-l-carboxylate

[1078] To a stirred solution of 2-(4-tert-butoxycarbonyl)piperazin-l-yl)acetic acid (500 mg, 2.04 mmol) in CH2CI2(15 mL) was added pyrrolidine (0.2 mL, 2.45 mmol), HATU (1.1 g, 3.07 mmol) and diisopropylethylamine (1.5 mL, 8.19 mmol) at room temperature under inert atmosphere. The reaction mixture was stirred at room temperature for 16 h. After consumption of starting material (monitored by TLC), the reaction mixture was diluted with water (30 mL) and extracted with CH2CI2(2 x 30 mL). The combined organic extracts were dried over anhydrous Na2S04and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 2% MeOH / CH2CI2) to afford tert-butyl 4-(2-oxo-2-(pyrrolidin-l-yl)ethyl)piperazine-l-carboxylate (100 mg, 0.33 mmol, 16%) as a brown solid.

[1079] 1 H NMR (500 MHz, DMSO-d6): δ 3.43 (t, J = 6.7 Hz, 2H), 3.31 (s, 2H), 3.29-3.25 (m, 4H), 2.43 (br s, 4H), 1.87-1.82 (m, 2H), 1.78-1.71 (m, 2H), 1.39 (s, 9H), 1.29-1.23 (m, 2H)

[1080] 4-(2-oxo-2-(pyrrolidone-1-yl)ethyl)piperazin-1-yl 2,2,2-trifluoroacetate

[1081] 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.

[1082] 1 H NMR (500MHz, DMSO-d6): δ3.72(brs,1H),3.40-3.37(m,4H),3.33-3.30(m,4H),3.24(s,2H),3.08(brs,4H),1.92-1.85(m,2H),1.81-1.76(m,2H)

[1083] 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)

[1084] 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.

[1085] 1H NMR (400 MHz, CDC13): δ 9.16 (s, 1H), 7.75-7.71 (m, 1H), 7.47 (s, 1H), 7.30 (dd, J = 8.6, 2.4 Hz, 1H), 7.11-7.06 (m, 1H), 3.87-3.85 (m, 4H), 3.63-3.57 (m, 1H), 3.53-3.43 (m, 4H), 3.28 (s, 2H), 2.83 (br s, 4H), 2.03-1.93 (m, 2H), 1.89-1.84 (m, 2H), 1.30-1.22 (m, 2H), 0.88-0.80 (m, 2H)

[1086] LC-MS: m / z 450.2 [M+H] at 1.74 RT + (97.66% purity).

[1087] HPLC: 97.81%.

[1088] Example 21 and Example 22

[1089] Scheme:

[1090]

[1091] 6-chloro-N-(2-(cyclopropylamino)-4,5-difluorophenyl)pyridazine-4-carboxamide

[1092] To a stirred solution of N 1 To a stirred solution of 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) in DMF (10 mL) was added 2-(cyclopropylamino)-4,5-difluoro-6-nitrophenol (1 g, 5.43 mmol) at room temperature under inert atmosphere. The reaction mixture was stirred at room temperature for 16 h. After consumption of starting material (monitored by TLC), the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were dried over anhydrous Na2S04and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 0% to 2% MeOH / CH2Cl2) to afford 6-chloro-N-(2-(cyclopropylamino)-4,5-difluorophenyl)pyridazine-4-carboxamide (800 mg, 2.46 mmol, 45%) as a brown solid.

[1093] 1H NMR (400 MHz, CDC13): δ 9.50 (s, 1H), 7.95 (d, J = 1.6 Hz, 1H), 7.74 (br s, 1H), 7.37 (dd, J = 10.5, 8.5 Hz, 1H), 7.06 (dd, J = 12.4, 7.7 Hz, 1H), 4.16-4.03 (m, 1H), 2.51-2.40 (m, 1H), 0.83-0.75 (m, 2H), 0.56-0.47 (m, 2H)

[1094] 2-(6-Chloropyridazin-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole (Ex. 22)

[1095] To a stirred solution of 6-chloro-N-(2-(cyclopropylamino)-4,5-difluorophenyl)pyridazine-4- carboxamide (700 mg, 2.16 mmol) in EtOH (7 mL) was added 6N HC1 (10.5 mL) at room temperature under inert atmosphere. The reaction mixture was stirred at 70 °C for 30 min. After consumption of starting material (monitored by TLC), the reaction mixture was diluted with saturated sodium bicarbonate solution (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over anhydrous Na2S04and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 20% to 30% EtOAc / hexane) to afford 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole Ex. 22 (280 mg, 0.91 mmol, 42%) as off-white solid.

[1096] 1 H NMR (400 MHz, CDC13): δ 9.78 (d, J = 1.9 Hz, 1H), 8.15 (d, J = 1.9 Hz, 1H), 7.60 (dd, J = 10.0, 7.2 Hz, 1H), 7.44 (dd, J = 9.5, 6.9 Hz, 1H), 3.70-3.62 (m, 1H), 1.41-1.33 (m, 2H), 0.93-0.84 (m, 2H)

[1097] LC-MS: m / z 306.9 [M+1] at 2.52 RT + (99.86% purity).

[1098] HPLC: 99.51%.

[1099] 5-(1-Cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-N-methylpyridazin-3-amine (Ex. 21)

[1100] To a stirred solution of 2-(6-chloropyridazin-4-yl)-l-cyclopropyl-5,6-difluoro-lH- benzo[d]imidazole Ex. 22 (600 mg, 1.96 mmol) in 2 M methylamine solution (2 M in diethyl ether, 3 mL) was added and the reaction mixture was stirred at room temperature for 16 h. After consumption of starting material (monitored by TLC), the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over anhydrous Na2S04and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 2 to 3% MeOH / CH2Cl2) to afford 5-(l-cyclopropyl-5,6-difluoro-lH-benzo[d]imidazol-2-yl)-N- methylpyridazin-3-amine Ex. 21 (50 mg, 0.16 mmol, 8%) as a light green solid.

[1101] 1 H NMR (400 MHz, CDC13): δ 9.13 (d, J = 1.8 Hz, 1H), 7.57 (dd, J = 10.2, 7.3 Hz, 1H), 7.41 (dd, J = 9.7, 7.0 Hz, 1H), 7.20 (d, J = 1.8 Hz, 1H), 5.03 (d, J = 4.5 Hz, 1H), 3, 59 (tt, J = 7.0, 3.6 Hz, 1H), 3.12 (d, J = 5.1 Hz, 3H), 1.32 - 1.24 (m, 2H), 0.87 - 0.80 (m, 2H) LC-MS: at 1.76 RT, m / z 301.9 [M+1] + (98.78% purity).

[1102] HPLC: 99.48%.

[1103] Example 23

[1104] Scheme:

[1105]

[1106] 1-cyclopropyl-5,6-difluoro-2-(6-methoxypyridazin-4-yl)-lH-benzo[d]imidazole (Ex. 23)

[1107] To a stirred solution of 2-(6-chloropyridazin-4-yl)-l-cyclopropyl-5,6-difluoro-lH- benzo[d]imidazole Ex. 22 (100 mg, 0.32 mmol) in MeOH (5 mL) was added sodium methoxide (53 mg, 0.98 mmol) at room temperature under inert atmosphere. The reaction mixture was stirred at 70 °C for 2 h. After consumption of starting material (monitored by TLC), the volatiles were evaporated under reduced pressure. The residue was diluted with water (10 mL) and extracted with CH2Cl2(2 x 10 mL). The combined organic extracts were dried over anhydrous Na2SO4and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 40% EtOAc / hexane) to afford l-cyclopropyl-5,6-difluoro-2-(6-methoxypyridazin-4-yl)-lH- benzo[d]imidazole Ex. 23 (40 mg, 0.13 mmol, 41%) as off-white solid.

[1108] 1 H NMR (400 MHz, DMSO-d6): δ 9.45 (s, 1H), 7.89-7.80 (m, 2H), 7.77 (s, 1H), 4.13 (s, 3H), 3.93-3.89 (m, 1H), 1.23-1.12 (m, 2H), 0.82-0.70 (m, 2H)

[1109] LC-MS: m / z 302.9 [M+H] at 2.30 RT + (99.80% purity).

[1110] HPLC: 99.68%.

[1111] Example 24

[1112] Scheme:

[1113]

[1114] 1-cyclopropyl-5,6-difluoro-2-(6-isopropoxypyridazin-4-yl)-lH-benzo[d]imidazole (Ex. 24)

[1115] To a stirred solution of 2-(6-chloropyridazin-4-yl)-l-cyclopropyl-5,6-difluoro-lH- benzo[d]imidazole Ex. 22 (70 mg, 0.23 mmol) in DMF (0.5 mL) was added sodium hydride (55% in mineral oil, 20 mg, 0.46 mmol) in portions at 0 °C under inert atmosphere. The reaction mixture was stirred at 0 °C for 30 min. To the reaction mixture was added propan-2-ol (27.5 mg, 0.46 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. After consumption of starting material (monitored by TLC), the reaction mixture was quenched with ice cold water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed with water (10 mL), brine (10 mL), dried over anhydrous Na2S04and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 5% EtOAc / hexane) to afford l-cyclopropyl-5,6-difluoro-2-(6-isopropoxy-pyridazin-4-yl)-lH- benzo[d]imidazole Ex. 24 (30 mg, 0.09 mmol, 40%) as off-white solid.

[1116] 1 H NMR (400 MHz, DMSO-d6): δ 9.39 (s, 1H), 7.89-7.80 (m, 2H), 7.67 (s, 1H), 5.57-5.51 (m, 1H), 3.93-3.89 (m, 1H), 1.42 (d, J = 6.1 Hz, 6H), 1.20-1.11 (m, 2H), 0.86-0.68 (m, 2H)

[1117] LC-MS: m / z 330.9 [M+H] at 2.88 RT + (93.72% purity).

[1118] HPLC: 95.25%.

[1119] Example 25

[1120] Scheme:

[1121]

[1122] 5-(l-cyclopropyl-5,6-difluoro-lH-benzo[d]imidazol-2-yl)-N,N-dimethylpyridazin-3- amine (Ex. 25)

[1123] To a stirred solution of 2-(6-chloropyridazin-4-yl)-l-cyclopropyl-5,6-difluoro-lH- benzo[d]imidazole Ex. 22 (60 mg, 0.19 mmol) in 2 M dimethylamine solution (2 M in THF, 3 mL) was added and the reaction mixture was stirred for 16 h. After consumption of starting material (monitored by TLC), the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over anhydrous Na2S04and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 2 to 3% MeOH / CH2Cl2) to afford 5-(l-cyclopropyl-5,6-difluoro-lH-benzo[d]imidazol-2-yl)-N,N- dimethylpyridazin-3-amine Ex. 25 (16 mg, 0.05 mmol, 26%) as off-white solid.

[1124] 1 H NMR (400 MHz, CDC13): δ 9.08 (s, 1H), 7.58 (dd, J = 10.2, 7.3 Hz, 1H), 7.41 (dd, J = 9.7, 7.0 Hz, 1H), 7.32 (s, 1H), 3.62-3.57 (m, 1H), 3.28 (s, 6H), 1.29-1.23 (m, 2H), 0.87-0.77 (m, 2H)

[1125] LC-MS: m / z 316.1 [M+l] at 1.81 RT + (98.32% purity).

[1126] HPLC: 95.98%.

[1127] Example 26

[1128] Scheme:

[1129]

[1130] 2-bromo-l-ethyl-6-fluoro-lH-indole

[1131] To a stirred solution of 2-bromo-6-fluoro-lH-indole (250 mg, 1.16 mmol) in DMF (2 mL) was added potassium carbonate (476 mg, 3.50 mmol) followed by iodoethane (364 mg, 2.33 mmol) at room temperature under inert atmosphere. The reaction mixture was stirred at room temperature for 4 h. After consumption of starting material (monitored by TLC), the reaction mixture was diluted with ice cold water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over anhydrous Na2S04and concentrated under reduced pressure to afford 2-bromo-l-ethyl-6-fluoro-lH-indole (280 mg, crude) as a yellow solid.

[1132] 1 H NMR (400 MHz, CDC13): δ 7.43 (dd, J = 8.6, 5.3 Hz, 1H), 6.98 (dd, J = 9.7, 2.3 Hz, 1H), 6.86-6.84 (m, 1H), 6.54 (d, J = 0.8 Hz, 1H), 4.21-4.16 (m, 2H), 1.34 (t, J = 7.2 Hz, 3H)

[1133] 1 -Ethyl-6-fluoro-2-(6-methylpyridazin-4-yl)- 1 H-indole (Ex. 26)

[1134] To a stirred solution of 2-bromo-l-ethyl-6-fluoro-lH-indole (200 mg, 0.83 mmol) in 1,4-dioxane (2 mL) was added (6-methylpyridazin-4-yl)boronic acid (214 mg, 1.24 mmol), sodium carbonate solution (2 M, 0.5 mL) and purged for 10 min under argon. Then Pd(dppf)Cl2(60 mg, 0.08 mmol) was added to the reaction mixture and the reaction mixture was stirred in a sealed tube at 80 °C for 16 h. The progress of the reaction was monitored by TLC; the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2S04and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 2% MeOH / CH2Cl2) to afford 1-ethyl-6-fluoro-2-(6-methylpyridazin-4-yl)-lH-indole Ex. 26 (50 mg, 0.19 mmol, 20%) as a yellow solid.

[1135] 1H NMR (400 MHz, CD3OD): δ 9.25 (d, J = 2.0 Hz, 1H), 7.76 (d, J = 2.1 Hz, 1H), 7.61 (dd, J = 8.7, 5.3 Hz, 1H), 7.28 (dd, J = 10.1, 2.2 Hz, 1H), 6.96-6.90 (m, 2H), 4.35-4.30 (m, 2H), 2.77 (s, 3H), 1.29 (t, J = 7.2 Hz, 3H)

[1136] LC-MS: at 2.73 RT, m / z 256 [M+H] + (98.24% purity).

[1137] HPLC: 97.70%.

[1138] Example 27

[1139] Scheme:

[1140]

[1141] 1 -cyclopropyl-5, 6-difluoro-2-(6-(2,2,2-trifluoroethoxy)pyridazin-4-yl)- 1 H- benzo[d]imidazole (Ex. 27)

[1142] To a stirred solution of 2-(6-chloropyridazin-4-yl)-1 -cyclopropyl-5, 6-difluoro-1 H- benzo[d]imidazole Ex. 22 (70 mg, 0.23 mmol) in DMF (0.5 mL) was added sodium hydride (55% in mineral oil, 20 mg, 0.46 mmol) in portions at 0 °C under inert atmosphere. The reaction mixture was stirred at 0 °C for 30 min. To the reaction mixture was added 2,2,2-trifluoroethan-1 -ol (46 mg, 0.46 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. After consumption of starting material (monitored by TLC), the reaction mixture was quenched with ice cold water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed with water (10 mL), brine (10 mL), dried over anhydrous Na2S04and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 30% EtOAc / hexane) to afford 1 -cyclopropyl-5, 6-difluoro-2-(6-(2,2,2- trifluoroethoxy)pyridazin-4-yl)-1 H-benzo[d]imidazole Ex. 27 (50 mg, 0.13 mmol, 62%) as off-white solid.

[1143] 1H NMR (400 MHz, DMSO-d6): δ 9.55 (s, 1H), 7.97 (s, 1H), 7.89-7.85 (m, 2H), 5.39-5.27 (m, 2H), 3.96-3.93 (m, 1H), 1.21-1.13 (m, 2H), 0.82-0.69 (m, 2H)

[1144] LC-MS: m / z 370.9 [M+1] at 3.18 RT + (99.73% purity).

[1145] HPLC: 98.32%.

[1146] Example 28

[1147] Scheme:

[1148]

[1149] 5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-N-(2-methoxyethyl)pyridazin-3-amine (Ex. 28)

[1150] 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) was added 2- methoxyethan-1-amine (0.5 mL, 75.11 mmol) and diisopropylethylamine (0.5 mL) at room temperature under inert atmosphere. The reaction mixture was stirred at 110 °C for 16 h. After consumption of starting material (monitored by TLC), the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over anhydrous Na2S04and concentrated under reduced pressure. The crude material was washed with CH2Cl2: hexane (1 :9, 10 mL) to afford 5-(1-cyclopropyl-5,6-difluoro-1H- benzo[d]imidazol-2-yl)-N-(2-methoxyethyl)pyridazin-3-amine Ex. 28 (40 mg, 0.13 mmol, 92%) as a light yellow solid.

[1151] 1H NMR (400 MHz, CDC13): δ 9.12 (s, 1H), 7.56 (dd, J = 10.1, 7.2 Hz, 1H), 7.41 (dd, J = 9.7, 6.9 Hz, 1H), 7.22 (s, 1H), 5.21 (br s, 1H), 3.76-3.73 (m, 2H), 3.69-3.64 (m, 2H), 3.61-3.59 (m, 1H), 3.41 (s, 3H), 1.31-1.25 (m, 2H), 0.87-0.81 (m, 2H)

[1152] LC-MS: m / z 346 [M+H] at 1.80 RT + (97.27% purity).

[1153] HPLC: 97.05%.

[1154] Example 29

[1155] Scheme:

[1156]

[1157] N-(4-cyano-2-(cyclopropylamino)phenyl)-6-methoxypyridazine-4-carboxamide

[1158] To a stirred solution of 4-amino-3-(cyclopropylamino)benzonitrile Int-6 (300 mg, 1.72 mmol) in DMF (5 mL) was added 6-methoxypyridazine-4-carboxylic acid (281 mg, 1.72 mmol), HATU (720 mg, 1.89 mmol) and diisopropylethylamine (0.8 mL, 5.17 mmol) at room temperature under inert atmosphere. The reaction mixture was stirred at room temperature for 16 h. After consumption of starting material (monitored by TLC), the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were dried over anhydrous Na2S04and concentrated under reduced pressure to afford N-(4-cyano-2-(cyclopropylamino)phenyl)-6-methoxypyridazine-4-carboxamide (300 mg, crude) as a yellow liquid which was used for the next step without further purification.

[1159] 1-cyclopropyl-2-(6-methoxypyridazin-4-yl)-1H-benzo[d]imidazole-6-carbonitrile (Ex. 29)

[1160] To a stirred solution of N-(4-cyano-2-(cyclopropylamino)phenyl)-6- methoxypyridazine-4-carboxamide (300 mg, crude) in CH2Cl2(10 mL) was added trifluoroacetic acid (0.5 mL) dropwise at 0 °C under inert atmosphere. The reaction mixture was stirred at 0 °C for 2 h. After consumption of starting material (monitored by TLC), the volatiles were removed under reduced pressure. The residue was diluted with water (5 mL), basified with saturated sodium carbonate solution (20 mL) and extracted with CH2Cl2(2 x 20 mL). The combined organic extracts were dried over anhydrous Na2SO4and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 2% MeOH / CH2Cl2) to give 1-cyclopropyl-2-(6-methoxypyridazin-4-yl)-1H- benzo[d]imidazole-6-carbonitrile Ex. 29 (40 mg, 0.13 mmol, 14% (over two steps)) as a light yellow solid.

[1161] 1 H NMR (400 MHz, DMSO-d6): δ 9.48 (s, 1H), 8.32 (s, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.82 (s, 1H), 7.71 (dd, J = 8.4, 1.5 Hz, 1H), 4.14 (s, 3H), 4.01 - 3.85 (m, 1H), 1.23 - 1.14 (m, 2H), 0.87 - 0.77 (m, 2H)

[1162] LC-MS: m / z 291.9 [M+H] at 2.25 RT + (95.84% purity).

[1163] HPLC: 97.16%.

[1164] Example 30

[1165] Scheme:

[1166]

[1167] 1-(2,2-dibromoethenyl)-4-fluoro-2-nitrobenzene

[1168] To a stirred solution of 4-fluoro-2-nitrobenzaldehyde (2 g, 11.83 mmol) in CH2Cl2(100 mL) was added carbon tetrabromide (5.8 g, 17.75 mmol) and triphenylphosphine (9.3 g, 35.50 mmol) at 0 °C under inert atmosphere. The reaction mixture was stirred at 5 °C for 2 h. The progress of the reaction was monitored by TLC; the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to get 1-(2,2-dibromoethenyl)-4-fluoro-2-nitrobenzene (3.2 g, crude) as a brown solid which was used for the next step without further purification.

[1169] 2-(2,2-dibromoethenyl)-5-fluoroaniline

[1170] To a stirred solution of 1-(2,2-dibromoethenyl)-4-fluoro-2-nitrobenzene (3.2 g, 9.87 mmol) in EtOH (20 mL) was added SnCl2.H2O (11.1 g, 46.29 mmol) at room temperature under inert atmosphere. The reaction mixture was stirred at reflux for 2 h. The progress of the reaction was monitored by TLC; the volatiles were concentrated under reduced pressure. The resulting residue was basified with potassium carbonate solution to pH ~ 10 and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over anhydrous Na2SO4and concentrated under reduced pressure. The crude material was purified by column chromatography over silica gel (eluent: 10% EtOAc / hexane) to get 2-(2,2-dibromoethenyl)-5-fluoroaniline (2.1 g, 7.14 mmol, 72%) as a brown solid.

[1171] LC-MS: m / z 295.6 [M+2H] at 3.34 RT + (96.98% purity).

[1172] N-(2-(2,2-dibromoethenyl)-5-fluorophenyl)methanesulfonamide

[1173] To a stirred solution of 2-(2,2-dibromoethenyl)-5-fluoroaniline (1 g, 3.40 mmol) in CH2Cl2(10 mL) was added pyridine (0.54 mL, 6.80 mmol) and methylsulfonyl chloride (0.38 mL, 5.10 mmol) at 0 °C under inert atmosphere. The reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC; the reaction mixture was quenched with NaHSO4solution and extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 10% EtOAc / hexane) to afford N-(2-(2,2-dibromoethenyl)-5-fluorophenyl)methanesulfonamide (1.1 g, 2.94 mmol, 87%) as a brown solid.

[1174] 1 H NMR (500 MHz, DMSO-d6): δ 9.57 (s, 1H), 7.69 (s, 1H), 7.59 (dd, J = 8.7, 6.4 Hz, 1H), 7.23 (dd, J = 10.4, 2.3 Hz, 1H), 7.14 (dt, J = 8.4, 2.3 Hz, 1H), 3.06 (s, 3H)

[1175] 2-bromo-6-fluoro-1H-indole

[1176] To a stirred solution of N-(2-(2,2-dibromoethenyl)-5-fluorophenyl)methanesulfonamide (200 mg, 0.53 mmol) in THF (2 mL) was added 1 M TBAF in THF (1 mL) at room temperature under inert atmosphere. The reaction mixture was stirred in microwave at 100 °C for 5 min. The progress of the reaction was monitored by TLC; the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure to afford 2-bromo-6-fluoro-1H-indole 5 (100 mg, crude) as a brown solid which was used for the next step without further purification.

[1177] LC-MS: m / z 295.6 [M+2H] at 3.34 RT + (96.98% purity).

[1178] 2-bromo-1-cyclopropyl-6-fluoro-1H-indole

[1179] To a stirred solution of 2-bromo-6-fluoro-lH-indole 5 (400 mg, 1.86 mmol) in 1,2-dichloroethane (5 mL) was added cyclopropylboronic acid (321 mg, 3.73 mmol), sodium carbonate (571 mg, 5.60 mmol), copper acetate (371 mg, 1.86 mmol) and bipyridine (291 mg, 1.86 mmol) under inert atmosphere at room temperature. The reaction mixture was stirred in a sealed tube at 80 °C for 16 h. The progress of the reaction was monitored by TLC; the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2S04and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 10% EtOAc / hexane) to afford 2-bromo-l-cyclopropyl-6-fluoro-lH-indole (300 mg, 1.19 mmol, 63%) as a brown solid.

[1180] 1 H NMR (400 MHz, CDC13): δ 7.39 (dd, J = 8.6, 5.4 Hz, 1H), 7.23 (dd, J = 10.1, 2.3 Hz, 1H), 6.88-6.83 (m, 1H), 6.51 (s, 1H), 3.14-3.09 (m, 1H), 1.27-1.19 (m, 2H), 1.13-1.08 (m, 2H)

[1181] 1 -cyclopropyl-6-fluoro-2-(6-methylpyridazin-4-yl)- 1 H-indole (Ex. 30)

[1182] To a stirred solution of 2-bromo-l-cyclopropyl-6-fluoro-lH-indole (200 mg, 0.79 mmol) in 1,4-dioxane (5 mL) was added 3-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridazine (261 mg, 1.19 mmol), sodium carbonate solution (2 M, 0.5 mL) and purged for 10 min under argon. Pd(dppf)Cl2(58 mg, 0.08 mmol) was then added to the reaction mixture and the reaction mixture was stirred in a sealed tube at 80 °C for 16 h. The progress of the reaction was monitored by TLC; the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2S04and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 2% MeOH / CH2Cl2) to afford l-cyclopropyl-6-fluoro-2-(6-methylpyridazin-4-yl)-lH-indole Ex. 30 (36 mg, 0.13 mmol, 17%) as a light yellow solid.

[1183] 1 H NMR (400 MHz, CD3OD): δ 9.42 (d, J = 2.1 Hz, 1H), 7.97 (d, J = 2.1 Hz, 1H), 7.60 (dd, J = 8.7 5.3 Hz, 1H), 7.37 (dd, J = 10.0, 2.4 Hz, 1H), 6.98 (s, 1H), 6.96-6.91 (m, 1H), 3.83-3.68 (m, 1H), 2.80-2.79 (m, 3H), 1.25-1.09 (m, 2H), 0.78-0.63 (m, 2H)

[1184] LC-MS: m / z 267.9 [M+H] at 2.78 RT + (98.96% purity).

[1185] HPLC: 97.98%.

[1186] Example 31

[1187] Scheme:

[1188]

[1189] N-((5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methyl)ethane sulfonamide (Ex. 31)

[1190] To a solution of (5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methanamine Int-3 (30 mg, 0.10 mmol) in THF (2 mL) was added ethanesulfonyl chloride (16 mg, 0.12 mmol) and triethylamine (0.03 mL, 0.21 mmol) at 0 °C under inert atmosphere. The reaction mixture was stirred at room temperature for 1 h. After consumption of starting material (monitored by TLC), the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried over anhydrous Na2S04and concentrated under reduced pressure. The crude material was purified by preparative HPLC to afford N-((5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methyl)ethane sulfonamide Ex. 31 (15 mg, 0.04 mmol, 38%) as a white solid.

[1191] 1H NMR ((400 MHz, CD3OD): δ 9.73 (s, 1 H), 8.52 (s, 1 H), 7.78-7.74 (m, 1 H), 7.53 (dd, J = 8.9, 2.4 Hz, 1 H), 7.20-7.14 (m, 1 H), 4.71 (s, 2 H), 3.87-3.82 (m, 1 H), 3.24-3.19 (m, 2 H), 1.47-1.31 (m, 5 H), 0.89-0.80 (m, 2 H)

[1192] LC-MS: m / z 376 [M+H] at 2.21 RT + (99.12% purity).

[1193] HPLC: 98.34%.

[1194] Example 32

[1195] Scheme:

[1196]

[1197] 5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-N-(2,2,2-trifluoroethyl)pyridazin-3-amine (Ex. 32)

[1198] To a stirred solution of 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-5,6-difluoro-1H- benzo[d]imidazole Ex. 22 (80 mg, 0.26 mmol) in NMP (1.2 mL) was added 2,2,2- trifluoroethan-1-amine (1.2 mL) at room temperature under inert atmosphere. The reaction mixture was stirred in microwave at 130 °C for 6 h. After consumption of starting material (monitored by TLC), the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried over anhydrous Na2S04and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 3% MeOH / CH3Cl2) to afford 5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-N-(2,2,2- trifluoroethyl)pyridazin-3-amine Ex. 32 (15 mg, 0.04 mmol, 15%) as a light yellow solid.

[1199] 1H NMR (400 MHz, CDC13): δ 9.28 (s, 1H), 7.59 (dd, J = 10.1, 7.2 Hz, 1H), 7.44 (dd, J = 9.6, 7.0 Hz, 1H), 7.37 (s, 1H), 5.09 (t, J = 6.0 Hz, 1H), 4.43-4.30 (m, 2H), 3.66-3.60 (m, 1H), 1.36-1.29 (m, 2H), 0.91-0.84 (m, 2H)

[1200] LC-MS: m / z 370 [M+H] at 2.21 RT + (97.23% purity).

[1201] HPLC: 97.15%.

[1202] Example 33

[1203] Scheme:

[1204]

[1205] 1 -cyclopropyl-5, 6-difluoro-2-(6-vinylpyridazin-4-yl)- 1 H-benzo[d]imidazole

[1206] To a stirred solution of 2-(6-chloropyridazin-4-yl)-l-cyclopropyl-5,6-difluoro-lH- benzo[d]imidazole Ex. 22 (150 mg, 0.50 mmol) in 1,4-dioxane (3 mL) and water (0.5 mL) at room temperature under inert atmosphere, was added 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, Pd(dppf)Cl2(4 mg, 0.005 mmol) was added and the reaction mixture was degassed with argon for another 10 min. The reaction mixture was heated to 80 °C and stirred for 5 h. After consumption of starting material (monitored by TLC), the volatiles were concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 50% EtOAc / hexane) to afford 1 -cyclopropyl-5, 6-difluoro-2-(6-vinylpyridazin-4-yl)- 1 H-benzo[d]imidazole as off-white solid (70 mg, 0.23 mmol, 48%).

[1207] 1H NMR (400 MHz, DMSO-d6): δ 9.69 (s, 1H), 8.45 (s, 1H), 7.90-7.83 (m, 2H), 7.18-7.11 (m, 1H), 6.53 (d, J = 17.7 Hz, 1H), 5.82 (d, J = 11.4 Hz, 1H), 3.99-3.97 (m, 1H), 1.22-1.13 (m, 2H), 0.82-0.60 (m, 2H)

[1208] 1 -cyclopropyl-2-(6-ethy lpyridazin-4-yl)-5, 6-difluoro-1 H-benzo[d]imidazole (Ex. 33)

[1209] To a solution of 1 -cyclopropyl-5, 6-difluoro-2-(6-vinylpyridazin-4-yl)-1 H- benzo[d]imidazole (70 mg, 0.23 mmol) in EtOAc (3 mL) was added 10% Pd / C (20 mg) and triethylamine (cat.) at room temperature under inert atmosphere. The reaction mixture was stirred at room temperature under hydrogen atmosphere (balloon pressure) for 5 h. After consumption of starting material (monitored by TLC), the reaction mixture was filtered through a pad of celite and washed, the pad was washed with methanol (30 mL). The filtrate was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 2% MeOH / CH2Cl2) to afford 1 -cyclopropyl-2-(6- ethylpyridazin-4-yl)-5, 6-difluoro-1 H-benzo[d]imidazole Ex. 33 (35 mg, 0.11 mmol, 50%) as off-white solid.

[1210] 1 H NMR (400 MHz, DMSO-d6): δ 9.65 (s, 1H), 8.17 (s, 1H), 7.89-7.81 (m, 2H), 3.95-3.91 (m, 1H), 3.10-3.04 (m, 2H), 1.36 (t, J = 7.6 Hz, 3H), 1.24-1.12 (m, 2H), 0.79-0.64 (m, 2H)

[1211] LC-MS: m / z 300.9 [M+H] at 2.51 RT + (98.98% purity).

[1212] HPLC: 97.01%.

[1213] Example 34

[1214] Scheme:

[1215]

[1216] 2-(6-chloropyridazin-4-yl)-l-cyclopropyl-lH-benzo[d]imidazole-6-carbonitrile (Ex. 34)

[1217] To a stirred solution of l-cyclopropyl-2-(6-methoxypyridazin-4-yl)-lH- benzo[d]imidazole-6-carbonitrile Ex. 29 (60 mg, 0.20 mmol) was added phosphoryl chloride (POCI3) (0.38 mL, 4.13 mmol) at room temperature under inert atmosphere. The reaction mixture was heated to 100 °C and stirred for 2 h. After consumption of starting material (monitored by TLC), the reaction mixture was basified with saturated sodium carbonate solution (30 mL), extracted with EtOAc (2 x 30 mL). The combined organic extracts were dried over anhydrous Na2SO4and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 50% EtOAc / hexane) to afford 2-(6-chloropyridazin-4-yl)-l-cyclopropyl-lH- benzo[d]imidazole-6-carbonitrile Ex. 34 (10 mg, 0.03 mmol, 16%) as a white solid.

[1218] 1 H NMR (400 MHz, CD3OD): δ 9.82 (s, 1H), 8.47 (s, 1H), 8.26 (s, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.68 (dd, J = 8.4, 1.5 Hz, 1H), 3.95-3.90 (m, 1H), 1.36-1.29 (m, 2H), 0.94-0.84 (m, 2H)

[1219] LC-MS: m / z 296.2 [M+H] at 3.28 RT + (96.40% purity).

[1220] HPLC: 96.31%.

[1221] Example 35

[1222] Scheme:

[1223]

[1224] 3-cyclopropyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazole-5-carbonitrile

[1225] To a stirred solution of 4-amino-3-(cyclopropylamino)benzonitrile Int-6 (500 mg, 2.89 mmol) in DMF (10 mL) was added 1,1'-carbonyldiimidazole (CDI) (702 mg, 4.33 mmol) at room temperature under inert atmosphere. The reaction mixture was stirred at room temperature for 16 h. After consumption of starting material (monitored by TLC), the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed with water (20 mL), dried over anhydrous Na2S04and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 30% to 40% EtOAc / hexane) to afford 3-cyclopropyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazole-5-carbonitrile (200 mg, 1.00 mmol, 35%) as off-white solid.

[1226] 1 H NMR (500 MHz, DMSO-d6): δ 11.29 (br s, 1H), 7.55 (s, 1H), 7.45 (dd, J = 8.0, 1.3 Hz, 1H), 7.09 (d, J = 8.1 Hz, 1H), 2.91-2.85 (m, 1H), 1.05-1.00 (m, 2H), 0.92-0.83 (m, 2H)

[1227] 2-bromo-1-cyclopropyl-1H-benzo[d]imidazole-6-carbonitrile

[1228] To a stirred solution of 2-bromo-3-cyclopropyl-2,3-dihydro-1H-benzo[d]imidazole-5- carbonitrile (200 mg, 1.0 mmol) in 1,2-dichloroethane (DCE) (4 mL) was added phosphoryl bromide (1.2 g, 4.02 mmol) at room temperature under inert atmosphere. The reaction mixture was heated to 80 °C and stirred for 16 h. After consumption of starting material (monitored by TLC), the reaction mixture was diluted with water (20 mL), basified with saturated sodium carbonate solution (30 mL), extracted with CH2Cl2(2 x 30 mL). The combined organic extracts were dried over anhydrous Na2S04and concentrated under reduced pressure to afford 2-bromo-3-cyclopropyl-2,3-dihydro-1H- benzo[d]imidazole-5-carbonitrile (50 mg, 0.20 mmol, 19%) as white solid which was used for the next step without further purification.

[1229] LC-MS: m / z 261.8 [M+] at 2.52 RT + (96.21% purity).

[1230] 1-cyclopropyl-2-(6-methylpyridazin-4-yl)-1H-benzo[d]imidazole-6-carbonitrile (Ex. 35)

[1231] To a stirred solution of 2-bromo-3-cyclopropyl-2,3-dihydro-lH- benzo[d]imidazole-5-carbonitrile (100 mg, 0.38 mmol) in 1,4-dioxane (3 mL) was added 3-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridazine (126.9 mg, 0.57 mmol) and 2M aqueous sodium carbonate solution (0.3 mL, 0.64 mmol) at room temperature under inert atmosphere. The reaction mixture was degassed with argon for 10 min, Pd(dppf)Cl2(23 mg, 0.03 mmol) was added and the mixture was degassed with argon for another 10 min. The reaction mixture was heated to 90 °C and stirred for 16 h. After consumption of starting material (monitored by TLC), the volatiles were concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 50% EtOAc / hexane) to give l-cyclopropyl-2-(6-methylpyridazin-4-yl)-lH- benzo[d]imidazole-6-carbonitrile Ex. 35 (20 mg, 0.07 mmol, 12%) as off-white solid.

[1232] 1 H NMR (400 MHz, CD3OD): δ 9.68 (d, J = 1.8 Hz, 1H), 8.26 (s, 2H), 7.91 (d, J = 8.5 Hz, 1H), 7.68 (dd, J = 8.4, 1.4 Hz, 1H), 3.94-3.90 (m, 1H), 2.86 (s, 3H), 1.36-1.25 (m, 2H), 0.90-0.81 (m, 2H)

[1233] LC-MS: m / z 275.9 [M+H] at 2.02 RT + (99.65% purity).

[1234] HPLC: 99.26%.

[1235] Example 36

[1236] Scheme:

[1237]

[1238] 1-cyclopropyl-5,6-difluoro-2-(6-(4-methylpiperazin-l-yl)pyridazin-4-yl)-lH- benzo[d]imidazole (Ex. 36)

[1239] A solution of 2-(6-chloropyridazin-4-yl)-l-cyclopropyl-5,6-difluoro-lH- benzo[d]imidazole Ex. 22 (50 mg, 0.16 mmol) in 1-methylpiperazine (0.5 mL) was stirred at 130 °C for 3 h under inert atmosphere. After consumption of starting material (monitored by TLC), the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried over anhydrous Na2S04and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 5% MeOH / CH2Cl2) to give l-cyclopropyl-5,6-difluoro-2-(6-(4-methylpiperazin-l- yl)pyridazin-4-yl)-lH-benzo[d]imidazole Ex. 36 (25 mg, 0.06 mmol, 41%) as a light yellow solid.

[1240] 1 H NMR (400 MHz, CDC13): δ 9.13 (s, 1H), 7.57 (dd, J = 10.2, 7.3 Hz, 1H), 7.46 (s, 1H), 7.41 (dd, J = 9.6, 7.0 Hz, 1H), 3.86 - 3.74 (m, 4H), 3.63 - 3.57 (m, 1H), 2.64 - 2.52 (m, 4H), 2.37 (s, 3H), 1.30 - 1.25 (m, 2H), 0.85 - 0.81 (m, 2H)

[1241] LC-MS: m / z 371 [M+H] at 1.71 RT + (98.46% purity).

[1242] HPLC: 97.35%.

[1243] Example 37

[1244] Scheme:

[1245]

[1246] 1-cyclopropyl-5,6-difluoro-2-(6-(piperazin-l-yl)pyridazin-4-yl)-lH-benzo[d]imidazole

[1247] To a stirred solution of tert-butyl 4-(5-(1-cyclopropyl-5,6-difluoro-1H- benzo[d]imidazol-2-yl)pyridazin-3-yl)piperazine-1-carboxylate Ex. 39 (200 mg, 0.43 mmol) in CH2Cl2(2 mL) was added trifluoroacetic acid (0.6 mL) at 0 °C under inert atmosphere. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. After consumption of starting material (monitored by TLC), the volatiles were removed under reduced pressure. The residue was neutralized with saturated sodium bicarbonate solution (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried over anhydrous Na2SO4and concentrated under reduced pressure. The crude material was washed with diethyl ether: n-pentane (1 : 1, 2 x 2 mL) to afford 1-cyclopropyl-5,6-difluoro-2-(6-(piperazin-1-yl)pyridazin-4-yl)-1H- benzo[d]imidazole (90 mg, crude) as a brown solid which was used in the next step without further purification.

[1248] LC-MS: m / z 357 [M+H] at 1.78 RT + (98.01% purity).

[1249] 1-(4-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)piperazin-1- yl)ethan-1-one (Ex. 37)

[1250] To a stirred solution of 1-cyclopropyl-5,6-difluoro-2-(6-(piperazin-1-yl)pyridazin-4-yl)-1H- benzo[d]imidazole (50 mg, 0.14 mmol) in CH2Cl2(1 mL) was added triethylamine (0.05 mL, 0.42 mmol) and acetyl chloride (0.01 mL, 0.14 mmol) at 0 °C under inert atmosphere. The reaction mixture was stirred at 0 °C for 10 min. After consumption of starting material (monitored by TLC), the reaction mixture was diluted with saturated sodium bicarbonate solution (20 mL) and extracted with CH2Cl2(2 x 20 mL). The combined organic extracts were dried over anhydrous Na2SO4and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 5% MeOH / CH2Cl2) to afford 1-(4-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)piperazin-1- yl)ethan-1-one Ex. 37 (14 mg, 0.03 mmol, 25%) as a light yellow solid.

[1251] 1H NMR (400 MHz, CDC13): δ 9.20 (s, 1H), 7.57 (dd, J = 10.1, 7.2 Hz, 1H), 7.49 (s, 1H), 7.42 (dd, J = 9.6, 6.9 Hz, 1H), 3.94-3.89 (m, 2H), 3.84-3.78 (m, 2H), 3.75-3.70 (m, 2H), 3.69-3.64 (m, 2H), 3.64-3.59 (m, 1H), 2.18 (s, 3H), 1.32-1.26 (m, 2H), 0.86-0.81 (m, 2H)

[1252] LC-MS: m / z 399.1 [M+H] at 1.57 RT + (93.31% purity).

[1253] HPLC: 92.89%.

[1254] Example 38

[1255] Scheme:

[1256]

[1257] 1 -cyclopropyl-5, 6-difluoro-2-(6-(4-(methylsulfonyl)piperazin- 1 -yl)pyridazin-4-yl)- 1 H- benzo[d]imidazole (Ex. 38)

[1258] To a stirred solution of 1 -cyclopropyl-5, 6-difluoro-2-(6-(piperazin- 1 -yl)pyridazin-4-yl)- 1 H- benzo[d]imidazole (50 mg, 0.14 mmol) in CH2CI2(1 mL) was added triethylamine (0.05 mL, 0.42 mmol) and methylsulfonyl chloride (0.01 mL, 0.14 mmol) at 0 °C under inert atmosphere. The reaction mixture was stirred for 10 min. After consumption of starting material (monitored by TLC), the reaction mixture was diluted with saturated sodium bicarbonate solution (20 mL) and extracted with CH2CI2(2 x 20 mL). The combined organic extracts were dried over anhydrous Na2S04and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 5% MeOH / CH2CI2) to afford 1 -cyclopropyl-5, 6-difluoro-2-(6-(4-(methylsulfonyl)piperazin- 1 -yl)pyridazin-4-yl)- 1 H- benzo[d]imidazole Ex. 38 (14 mg, 0.03 mmol, 25%) as a light yellow solid.

[1259] 1H NMR (400 MHz, CDC13): δ 9.22 (s, 1H), 7.57 (dd, J = 10.1, 7.2 Hz, 1H), 7.51 (s, 1H), 7.42 (dd, J = 9.6, 6.9 Hz, 1H), 3, 96-3.91 (m, 4H), 3.65-3.60 (m, 1H), 3.43-3.38 (m, 4H), 2.84 (s, 3H), 1.34-1.24 (m, 2H), 0.91-0.80 (m, 2H)

[1260] LC-MS: m / z 435.1 [M+H] at 2.09 RT + (98.86% purity).

[1261] HPLC: 97.10%.

[1262] Example 39

[1263] Scheme:

[1264]

[1265] 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)

[1266] To a stirred solution of 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-5,6-difluoro-1H- benzo[d]imidazole Ex. 22 (200 mg, 0.65 mmol) in dimethyl sulfoxide (DMSO) (4 mL) was added piperazine-1-carboxylic acid tert-butyl ester (729 mg, 3.97 mmol) at room temperature under inert atmosphere. The reaction mixture was stirred at 130 °C for 3 h. After consumption of starting material (monitored by TLC), the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were washed with water (20 mL), brine (20 mL), dried over anhydrous Na2S04and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 5% MeOH / CH2Cl2) to afford Ex. 39 (230 mg, 0.50 mmol, 77%) as a brown solid.

[1267] 1H NMR (400 MHz, CDC13): δ 9.17 (s, 1H), 7.57 (dd, J = 10.0, 7.2 Hz, 1H), 7.47 (s, 1H), 7.41 (dd, J = 9.7, 6.9 Hz, 1H), 3.78-3.75 (m, 4H), 3.64-3.58 (m, 5H), 1.50 (s, 9H), 1.31-1.26 (m, 2H), 0.86-0.81 (m, 2H)

[1268] LC-MS: at 2.52 RT, m / z 457.1 [M+H] + (97.87% purity).

[1269] HPLC: 95.78%.

[1270] Example 40 and Example 41

[1271] Scheme:

[1272]

[1273] 6-chloro-N-(4-cyano-2-(ethylamino)phenyl)pyridazine-4-carboxamide

[1274] To a stirred solution of 6-chloropyridazine-4-carboxylic acid (100 mg, 0.64 mmol) in DMF (2 mL) was added 4-amino-3-(ethylamino)benzonitrile Int-4 (104 mg, 0.64 mmol), HATU (369.9 mg, 0.97 mmol) and diisopropylethylamine (0.45 mL, 2.59 mmol) at room temperature under inert atmosphere. The reaction mixture was stirred at room temperature for 16 h. After consumption of starting material (monitored by TLC), the reaction mixture was diluted with aqueous ammonium chloride solution (30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were dried over anhydrous Na2S04and concentrated under reduced pressure to afford 6-chloro-N-(4-cyano-2- (ethylamino)phenyl)pyridazine-4-carboxamide (90 mg, crude) as a yellow solid.

[1275] LC-MS: at 2.07 RT, m / z 300.9 [M] + (36.25% purity).

[1276] 1-ethyl-2-(6-methoxypyridazin-4-yl)-1H-benzo[d]imidazole-6-carbonitrile (Ex. 40)

[1277] To a stirred solution of 6-chloro-N-(4-cyano-2-(ethylamino)phenyl)pyridazine-4- carboxamide (100 mg, 0.33 mmol) in CH2Cl2(1.6 mL) was added trifluoroacetic acid (0.4 mL) at 0 °C under inert atmosphere. The reaction mixture was stirred at 0 °C for 6 h. After consumption of starting material (monitored by TLC), the reaction mixture was diluted with saturated sodium bicarbonate solution (20 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were washed with water (20 mL), brine (20 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure. The crude material was triturated with diethyl ether (2 x 10 mL) and n-pentane (2 x 10 mL) to afford 1-ethyl-2-(6-methoxypyridazin-4-yl)-1H- benzo[d]imidazole-6-carbonitrile Ex. 40 (25 mg, 0.09 mmol, 26%) as off-white solid.

[1278] 1 H NMR (400 MHz, CD3OD): δ 9.27 (d, J = 1.9 Hz, 1H), 8.24 (s, 1H), 7.91 (dd, J = 8.4, 0.6 Hz, 1H), 7.68 (dd, J = 8.5, 1.4 Hz, 1H), 7.59 (s, 1H), 4.53-4.49 (m, 2H), 4.22 (s, 3H), 1.48 (t, J = 7.3 Hz, 3H)

[1279] LC-MS: m / z 279.8 [M+H] at 2.15 RT + (98.27% purity).

[1280] HPLC: 98.65%.

[1281] 2-(6-chloropyridazin-4-yl)-1-ethyl-1H-benzo[d]imidazole-6-carbonitrile (Ex. 17)

[1282] To a stirred solution of 1 -ethyl-2-(6-methoxypyridazin-4-yl)-1 H- benzo[d]imidazole-6-carbonitrile Ex. 40 (85 mg, 0.30 mmol) was added phosphorous oxychloride (0.57 mL, 6.09 mmol) at room temperature under inert atmosphere. The reaction mixture was heated to 100 °C for 2 h. After consumption of starting material (monitored by TLC), the reaction mixture was basified with aqueous sodium carbonate (20 mL), extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed with water (10 mL), dried over anhydrous Na2S04and concentrated under reduced pressure. The crude material was triturated with diethyl ether (2 x 5 mL) and n-pentane (2 x 5 mL) to afford 2-(6-chloropyridazin-4-yl)-1 -ethyl-1 H- benzo[d]imidazole-6-carbonitrile Ex. 17 (100 mg, crude) as a light yellow paste which was used in the next step without further purification.

[1283] 1 -Ethyl-2-(6-ethoxypyridazin-4-yl)-1 H-benzo[d]imidazole-6-carbonitrile

[1284] To a stirred solution of 2-(6-chloropyridazin-4-yl)-1 -ethyl-1 H- benzo[d]imidazole-6-carbonitrile Ex. 17 (130 mg, 0.46 mmol) in 1,4-dioxane (3 mL) and water (0.5 mL) was added vinylboronic acid pinacol ester (70 mg, 0.46 mmol) and potassium carbonate (190 mg, 1.37 mmol) at room temperature under inert atmosphere. The reaction mixture was degassed with argon for 10 min. To this was added Pd(dppf)Cl2(3.7 mg, 0.005 mmol) at room temperature 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 consumption of starting material (monitored by TLC), the reaction mixture was filtered. The filtrate was concentrated under reduced pressure to afford 1 -ethyl-2-(6-ethoxypyridazin-4-yl)-1 H- benzo[d]imidazole-6-carbonitrile (110 mg, crude) as a brown paste.

[1285] LC-MS: m / z 275.9 [M+H] at 2.18 RT + (78.16% purity).

[1286] 1 -Ethyl-2-(6-ethoxypyridazin-4-yl)-1 H-benzo[d]imidazole-6-carbonitrile (Ex. 41 )

[1287] To a solution of 1 -ethyl-2-(6-vinylpyridazin-4-yl)-1 H-benzo[d]imidazole-6- carbonitrile (110 mg, 0.40 mmol) in EtOAc (5 mL) was added 10% Pd / C (50% wet basis, 20 mg) and triethylamine (0.005 mL, 0.04 mmol) at room temperature under inert atmosphere. The reaction mixture was stirred at room temperature under hydrogen atmosphere (balloon pressure) for 2 h. After consumption of starting material (monitored by TLC), the reaction mixture was filtered through a pad of celite and washed with EtOAc (20 mL). The filtrate was concentrated under reduced pressure. The crude material was purified by preparative HPLC to afford 1 -ethyl-2-(6-ethylpyridazin-4-yl)-1 H- benzo[d]imidazole-6-carbonitrile Ex. 41 (4 mg, 14.44 mmol, 4%) as off-white solid.

[1288] 1 H NMR (400 MHz, CD3OD): δ 9.51 (d, J = 2.0 Hz, 1 H), 8.26 (s, 1 H), 8.06 (d, J = 2.1 Hz, 1 H), 7.92 (d, J = 8.4 Hz, 1 H), 7.69 (dd, J = 8.5, 1.4 Hz, 1 H), 4.55-4.50 (m, 2H), 3.21 -3.15 (m, 2H), 1.53-1.45 (m, 6H)

[1289] LC-MS: m / z 277.9 [M+H] at 2.12 RT + (96.23% purity).

[1290] HPLC: 96.66%.

[1291] Example 42

[1292] Scheme:

[1293]

[1294] 1 -cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1 H- benzo[d]imidazole (Ex. 42)

[1295] To a stirred solution of 5-(l-cyclopropyl-5,6-difluoro-lH-benzo[d]imidazol-2-yl)pyridazine-3- carboxaldehyde Int-27 (100 mg, 0.33 mmol) in CH2CI2(5 mL) was added (diethylamino)sulfur trifluoride (DAST) (0.09 mL, 0.66 mmol) at 0 °C under inert atmosphere. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. After consumption of starting material (monitored by TLC), the reaction mixture was diluted with saturated sodium carbonate solution (20 mL) and extracted with CH2CI2(2 x 20 mL). The combined organic extracts were dried over anhydrous Na2S04and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 50% EtOAc / hexane) to afford l-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-lH- benzo[d]imidazole Ex. 42 (40 mg, 0.12 mmol, 37%) as a brown solid.

[1296] 1 H NMR (400 MHz, DMSO-d6): δ 9.99 (s, 1H), 8.55 (s, 1H), 7.93-7.85 (m, 2H), 7.42 (t, J = 54.5 Hz, 1H), 4.01-3.97 (m, 1H), 1.25-1.13 (m, 2H), 0.84-0.72 (m, 2H)

[1297] LC-MS: m / z 323.3 [M+H] at 3.53 RT + (98.91% purity).

[1298] HPLC: 99.33%.

[1299] Example 43

[1300] Scheme:

[1301]

[1302] 2-(6-cyclobutyloxy pyridazin-4-yl)-l-cyclopropyl-5,6-difluoro-lH-benzo[d]imidazole (Ex. 43)

[1303] To a stirred solution of 2-(6-chloropyridazin-4-yl)-l-cyclopropyl-5,6-difluoro-lH- benzo[d]imidazole Ex. 22 (50 mg, 0.16 mmol) in DMF (2 mL) was added sodium hydride (60% in mineral oil, 16.3 mg, 0.41 mmol) portion wise at 0 °C under inert atmosphere. The reaction mixture was stirred at 0 °C for 10 min. Then cyclobutanone (141 mg, 0.20 mmol) was added to the reaction mixture at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. After consumption of starting material (monitored by TLC), the reaction mixture was quenched with ice cold water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried over anhydrous Na2S04and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 3% MeOH / CH2Cl2) to afford 2-(6-cyclobutoxy pyridazin-4-yl)-l-cyclopropyl-5,6-difluoro-lH- benzo[d]imidazole Ex. 43 (45 mg, 0.13 mmol, 57%) as off-white solid.

[1304] 1 H NMR (400 MHz, CDC13): δ 9.42 (s, 1H), 7.59 (dd, J = 10.1, 7.2 Hz, 1H), 7.47 (s, 1H), 7.44-7.40 (m, 1H), 5.53-5.48 (m, 1H), 3.62-3.57 (m, 1H), 2.67-2.50 (m, 2H), 2.31-2.08 (m, 2H), 1.99-1.83 (m, 1H), 1.78-1.73 (m, 1H), 1.37-1.24 (m, 2H), 0.89-0.77 (m, 2H)

[1305] LC-MS: m / z 343 [M+H] at 2.61 RT + (95.30% purity).

[1306] HPLC: 95.28%.

[1307] Example 44

[1308] Scheme:

[1309]

[1310] 1-cyclopropyl-2-(6-(4,4-difluoropiperidin-l-yl)pyridazin-4-yl)-5,6-difluoro-lH- benzo[d]imidazole (Ex. 44)

[1311] To a stirred solution of 2-(6-chloropyridazin-4-yl)-l-cyclopropyl-5,6-difluoro-lH- benzo[d]imidazole Ex. 22 (100 mg, 0.32 mmol) in DMSO (2 mL) was added 4,4- difluoropiperidine (59 mg, 0.49 mmol) at room temperature under inert atmosphere. The reaction mixture was heated to 120-130 °C and stirred for 16 h. After consumption of starting material (monitored by TLC), the reaction mixture was diluted with ice cold water (20 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were dried over anhydrous Na2S04and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 50-60% EtOAc / hexane) to afford l-cyclopropyl-2-(6-(4,4-difluoropiperidin-l-yl)pyridazin-4-yl)-5,6-difluoro-lH- benzo[d]imidazole Ex. 44 (40 mg, 0.10 mmol, 32%) as off-white solid.

[1312] 1 H NMR (400 MHz, CD3OD): δ 9.09 (s, 1H), 7.82 (s, 1H), 7.72-7.68 (m, 1H), 7.62-7.57 (m, 1H), 3.99-3.92 (m, 4H), 3.86-3.83 (m, 1H), 2.19-2.00 (m, 4H), 1.27-1.19 (m, 2H), 0.87-0.76 (m, 2H)

[1313] LC-MS: m / z 392.1 [M+H] at 2.98 RT + (93.89% purity).

[1314] HPLC: 92.05%.

[1315] Example 45

[1316] Scheme:

[1317]

[1318] 6-methylpyridazine-4-carboxylic acid

[1319] To a stirred solution of 3-chloro-6-methylpyridazine-4-carboxylic acid 1 (500 mg, 2.90 mmol) in MeOH (50 mL) was added sodium hydroxide (395 mg, 9.80 mmol) and 10% Pd / C (50% wet basis, 150 mg) at room temperature under inert atmosphere. The reaction mixture was stirred at room temperature under hydrogen atmosphere (balloon pressure) for 1 h. After consumption of starting material (monitored by TLC), the reaction mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure, 6 N HCI was added to pH ~ 6 and concentrated under reduced pressure to get 6-methylpyridazine-4-carboxylic acid as a yellow liquid (410 mg, crude), which was used for the next step without further purification.

[1320] 1 H NMR (500 MHz, DMSO-d6): δ 9.24 (s, 1H), 7.69 (s, 1H), 2.62 (s, 3H)

[1321] N-(6-chloro-2-(cyclopropylamino)pyridin-3-yl)-6-methylpyridazine-4-carboxamide

[1322] To a stirred solution of 6-chloro-N 2 cyclopropylpyridine-2,3-diamine Int-8 (400 mg, 2.18 mmol) in DMF (5 mL) was added compound 6-methylpyridazine-4-carboxylic acid (362 mg, 2.62 mmol), HATU (996 mg, 2.62 mmol) and diisopropylethylamine (1.6 mL, 8.75 mmol) at room temperature under inert atmosphere. The reaction mixture was stirred at room temperature for 16 h. After consumption of starting material (monitored by TLC), the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were dried over anhydrous Na2S04and concentrated under reduced pressure to get N-(6-chloro-2-(cyclopropylamino)pyridin-3-yl)-6-methylpyridazine-4-carboxamide as a black solid (200 mg, 0.66 mmol, 30%) which was used for the next step without further purification.

[1323] LC-MS: m / z 303.9 [M+H] at 2.06 RT + (93.73% purity).

[1324] 5-chloro-3-cyclopropyl-2-(6-methylpyridazin-4-yl)-3H-imidazo[4,5-b]pyridine (Ex. 45)

[1325] To a stirred solution of N-(6-chloro-2-(cyclopropylamino)pyridin-3-yl)-6- methylpyridazine-4-carboxamide (100 mg, 0.33 mmol) in EtOH (2 mL) was added 6N HC1 (3 mL) at 0°C under inert atmosphere. The reaction mixture was stirred at room temperature for 1 h. After consumption of starting material (monitored by TLC), the reaction mixture was diluted with saturated sodium bicarbonate solution (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried over anhydrous Na2S04and concentrated under reduced pressure. The crude material was purified by preparative HPLC to afford 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.

[1326] 1 H NMR (400 MHz, CD3OD): δ 9.67 (s, 1H), 8.26 (s, 1H), 8.12 (d, J = 8.4 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 3.83-3.78 (m, 1H), 2.84 (s, 3H), 1.29-1.25 (m, 2H), 0.94-0.92 (m, 2H)

[1327] LC-MS: m / z 285.9 [M+H] at 2.03 RT + (98.73% purity).

[1328] HPLC: 95.65%.

[1329] Example 46

[1330] Scheme:

[1331]

[1332] 1-cyclopropyl-2-(6-(3,3-difluoropyrrolidin-1-yl)pyridazin-4-yl)-5,6-difluoro-1H- benzo[d]imidazole (Ex. 46)

[1333] To a stirred solution of 2-(6-chloropyridazin-4-yl)-l-cyclopropyl-5,6-difluoro-lH- benzo[d]imidazole Ex. 22 (100 mg, 0.32 mmol) in DMSO (2 mL) was added 3,3- difluoropyrrolidine hydrochloride (70 mg, 0.50 mmol) and triethylamine (0.06 mL, 0.49 mmol) at room temperature under inert atmosphere. The reaction mixture was heated to 130 °C and stirred for 48 h. After consumption of starting material (monitored by TLC), the reaction mixture was diluted with ice cold water (20 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were dried over anhydrous Na2S04and concentrated under reduced pressure. The crude material was purified by preparative HPLC to afford l-cyclopropyl-2-(6-(3,3-difluoropyrrolidin-l-yl)pyridazin-4-yl)-5,6-difluoro-lH- benzo[d]imidazole Ex. 46 (15 mg, 0.04 mmol, 12%) as off-white solid.

[1334] 1 H NMR (400 MHz, CD3OD): δ 9.10 (s, 1H), 7.72-7.68 (m, 1H), 7.62-7.57 (m, 1H), 7.49 (d, J = 1.8 Hz, 1H), 4.03 (t, J = 12.9 Hz, 2H), 3.90-3.77 (m, 3H), 2.69-2.54 (m, 2H), 1.30-1.22 (m, 2H), 0.86-0.80 (m, 2H)

[1335] LC-MS: m / z 378.1 [M+H] at 2.80 RT + (97.60% purity).

[1336] HPLC: 99.55%.

[1337] Example 47

[1338] Scheme:

[1339]

[1340] 1-(5-(l-cyclopropyl-5,6-difluoro-lH-benzo[d]imidazol-2-yl)pyridazin-3-yl)-2,2,2- trifluoroethan-l-ol (Ex. 47)

[1341] To a stirred solution of 5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3- carboxylic acid (Int-26) (50 mg, 0.16 mmol) in DMF (1 mL) was added HATU (63 mg, 0.16 mmol) and DIEA (0.035 mL, 0.20 mmol) at room temperature under inert atmosphere. The reaction mixture was stirred at room temperature for 2 h. After consumption of starting material (monitored by TLC), the reaction mixture was diluted with water (5 mL) and extracted with EtOAc (2 x 15 mL). The combined organic extracts were dried over anhydrous Na2SO4and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 50% EtOAc / hexane) to give 5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazine-3-carboxylic acid methyl ester Ex. 45 (30 mg, 0.10 mmol, 62%) as a white solid.

[1342] 1 H NMR (400 MHz, CD3OD): δ 9.83 (s, 1H), 8.58 (s, 1H), 7.75-7.71 (m, 1H), 7.67-7.63 (m, 1H), 5.60-5.52 (m, 1H), 3.94-3.81 (m, 1H), 1.35-1.21 (m, 2H), 0.93-0.78 (m, 2H)

[1343] LC-MS: m / z 371 [M+H] at 2.69 RT. + (95.24% purity).

[1344] HPLC: 95.69%.

[1345] Example 48

[1346] Scheme:

[1347]

[1348] 1-(5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)-N,N- dimethylpyrrolidin-3-amine (Ex. 48)

[1349] To a stirred solution of 2-(6-chloropyridazin-4-yl)-l-cyclopropyl-5,6-difluoro-lH- benzo[d]imidazole Ex. 22 (115 mg, 0.37 mmol) in DMSO (2 mL) was added triethylamine (0.116 mL, 0.84 mmol) and l-(3-(dimethylamino)-l,5-pyrrolidin-l-yl)-2,2,2- trifluoroethan-l-one (120 mg, 0.56 mmol) at 0 °C under inert atmosphere. The reaction mixture was stirred at 90 °C for 5 h. After consumption of starting material (monitored by TLC), the reaction mixture was diluted with ice cold water (10 mL) and extracted with EtOAc (2 x 10 mL). The combined organic extracts were dried over anhydrous Na2S04and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 5% to 10% MeOH / CH2Cl2) to afford l-(5-(l-cyclopropyl-5,6-difluoro-lH-benzo[d]imidazol-2-yl)pyridazin-3-yl)-N,N- dimethylpyrrolidin-3-amine Ex. 48 (10 mg, 0.02 mmol, 7%) as off-white solid.

[1350] 1 H NMR (400 MHz, CD3OD): δ 9.01 (s, 1H), 7.72-7.67 (m, 1H), 7.61-7.57 (m, 1H), 7.44 (s, 1H), 3.96-3.93 (m, 1H), 3.86-3.81 (m, 2H), 3.62-3.55 (m, 1H), 3.45-3.37 (m, 1H), 3.09-2.99 (m, 1H), 2.38 (s, 6H), 2.08-1.95 (m, 1H), 1.32-1.20 (m, 3H), 0.87-0.78 (m, 2H)

[1351] LC-MS: m / z 385.1 [M+H] at 2.06 RT + (97.17% purity).

[1352] HPLC: 98.58%.

[1353] Example 49

[1354] Scheme:

[1355]

[1356] 1-cyclopropyl-5,6-difluoro-2-(6-(4-fluorophenyl)pyridazin-4-yl)-lH-benzo[d]imidazole (Ex. 49)

[1357] Pd(PPh3)2Cl2(11.5 mg, 0.01 mmol) and sodium carbonate (86.4 mg, 0.81 mmol) were purged in 1,4-dimethoxyethane (DME): water (4:1, 1.25 mL) under argon for 5 min at room temperature. To the reaction mixture was added 3-(6-chloropyridazin-4-yl)-1- cyclopropyl-5,6-difluoro-1H-benzo[d]imidazole Ex. 22 (50 mg, 0.16 mmol) and (4- fluorophenyl)boronic acid (25.1 mg, 0.17 mmol) at room temperature. The reaction mixture was stirred in a sealed tube at 80 °C for 12 h. After consumption of starting material (monitored by TLC), the reaction mixture was diluted with water (20 mL) and extracted with CH2Cl2(2 x 20 mL). The combined organic extracts were dried over anhydrous Na2SO4and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 2% MeOH / CH2Cl2) to give 1-cyclopropyl-5,6-difluoro-2-(6-(4-fluorophenyl)pyridazin-4-yl)-1H- benzo[d]imidazole Ex. 49 (40 mg, 0.10 mmol, 48%) as off-white solid.

[1358] 1 H NMR (400 MHz, CD3OD): δ 9.75 (s, 1H), 8.68 (s, 1H), 8.32-8.18 (m, 2H), 7.76-7.72 (m, 1H), 7.67-7.62 (m, 1H), 7.35 (t, J = 8.8 Hz, 2H), 3.98-3.93 (m, 1H), 1.32-1.25 (m, 2H), 0.90-0.84 (m, 2H)

[1359] LC-MS: m / z 367 [M+H] at 2.58 RT + (98.75% purity).

[1360] HPLC: 98.72%.

[1361] Example 50

[1362] Scheme:

[1363]

[1364] 1-cyclopropyl-5,6-difluoro-2-(6-((4-fluorophenyl)ethynyl)pyridazin-4-yl)-1H- benzo[d]imidazole (Ex. 50)

[1365] To a stirred solution of 2-(6-chloropyridazin-4-yl)-l-cyclopropyl-5,6-difluoro-lH- benzo[d]imidazole Ex. 22 (100 mg, 0.32 mmol) in N,N-dimethylacetamide (DMA) (3 mL) was added 1-ethynyl-4-fluorobenzene (40 mg, 0.32 mmol) and potassium carbonate (90 mg, 0.65 mmol) at room temperature under inert atmosphere. The reaction mixture was degassed with argon for 10 min. At room temperature, Pd2(dba)3 (14.8 mg, 0.01 mmol) and 2-(dicyclohexylphosphino)-2',4',6'-triisopropylbiphenyl (X-phos) (8 mg, 0.01 mmol) were added and the mixture was degassed with argon for another 5 min. The reaction mixture was heated to 80 °C and stirred for 2 h. After consumption of starting material (monitored by TLC), the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried over anhydrous Na2S04and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 30% EtOAc / hexane) to afford l-cyclopropyl-5,6-difluoro-2-(6-((4-fluorophenyl)ethynyl)pyridazin-4-yl)-lH- benzo[d]imidazole Ex. 50 (50 mg, 0.13 mmol, 39%) as a brown solid.

[1366] 1 H NMR (400 MHz, DMSO-d6): δ 9.81 (s, 1H), 8.49 (s, 1H), 7.91-7.84 (m, 2H), 7.84-7.76 (m, 2H), 7.38 (t, J = 9.0 Hz, 2H), 4.01-3.93 (m, 1H), 1.24-1.16 (m, 2H), 0.85-0.71 (m, 2H)

[1367] LC-MS: m / z 391.3 [M+H] at 4.58 RT + (97.94% purity).

[1368] HPLC: 96.14%.

[1369] Example 51

[1370] Scheme:

[1371]

[1372] 1-cyclopropyl-5,6-difluoro-2-(6-(prop-1-en-2-yl)pyridazin-4-yl)-lH-benzo[d]imidazole

[1373] To a stirred solution of 2-(6-chloropyridazin-4-yl)-1-cyclopropyl-5,6-difluoro-1H- benzo[d]imidazole Ex. 22 (120 mg, 0.40 mmol) in 1,4-dioxane (3.2 mL) and water (0.8 mL) was added 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (219 mg, 1.17 mmol) and sodium carbonate (164.6 mg, 1.56 mmol) and the mixture was purged with argon for 10 minutes at room temperature. 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 consumption of starting material (monitored by TLC), the reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The crude material was triturated with n-pentane (2 x 5 mL) to afford 1-cyclopropyl-5,6-difluoro-2-(6-(prop-1-en-2-yl)pyridazin-4-yl)-1H- benzo[d]imidazole (100 mg, crude) as off-white solid which was used in the next step without further purification.

[1374] LC-MS: m / z 313.1 [M+H] at 2.38 RT + (94.08% purity).

[1375] 1-cyclopropyl-5,6-difluoro-2-(6-isopropylpyridazin-4-yl)-1H-benzo[d]imidazole (Ex. 51)

[1376] To a stirred solution of 1-cyclopropyl-5,6-difluoro-2-(6-(prop-1-en-2-yl)pyridazin-4- yl)-1H-benzo[d]imidazole (100 mg, 0.32 mmol) in ethyl acetate (5 mL) was added triethylamine (0.04 mL), sodium hydroxide (25 mg, 0.64 mmol) and 10% Pd / C (50% wet basis, 30 mg) at room temperature under inert atmosphere. The reaction mixture was stirred at room temperature under hydrogen atmosphere (balloon pressure) for 1 h. After consumption of starting material (monitored by TLC), the reaction mixture was filtered through a pad of celite and the celite bed was washed with EtOAc (20 mL). The filtrate was concentrated under reduced pressure. The crude material was washed with n-pentane (2 x 2 mL) and diethyl ether (2 x 2 mL) to afford 1-cyclopropyl-5,6-difluoro-2-(6-isopropylpyridazin-4-yl)-1H-benzo[d]imidazole Ex. 51 (55 mg, 0.17 mmol, 55%) as off-white solid.

[1377] 1H NMR (400 MHz, CD3OD): δ 9.63 (s, 1H), 8.22 (s, 1H), 7.73-7.69 (m, 1H), 7.64-7.60 (m, 1H), 3.91-3.86 (m, 1H), 3.49-3.31 (m, 1H), 1.47 (d, J = 7.0 Hz, 6H), 1.31-1.20 (m, 2H), 0.86-0.73 (m, 2H)

[1378] LC-MS: m / z 315.1 [M+H] at 2.31 RT + (97.95% purity).

[1379] HPLC: 99.16%.

[1380] Example 52

[1381] Scheme:

[1382]

[1383] N-((5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methyl)ethane sulfonamide (Ex. 52)

[1384] To a stirred solution of (5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methanamine (140 mg, 0.46 mmol) in CH2Cl2(4 mL) was added triethylamine (0.19 mL, 0.79 mmol) and ethanesulfonyl chloride (65.7 mg, 0.51 mmol) at room temperature under inert atmosphere. The reaction mixture was stirred at room temperature for 1 h. After consumption of starting material (monitored by TLC), the reaction mixture was diluted with water (20 mL) and extracted with CH2Cl2(2 x 20 mL). The combined organic extracts were dried over anhydrous Na2SO4and concentrated under reduced pressure. The crude material was purified by preparative HPLC to afford N-((5-(1-cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridazin-3-yl)methyl)ethane sulfonamide Ex. 52 (18 mg, 0.04 mmol, 10%) as a white solid.

[1385] 1H NMR (400 MHz, CD3OD): δ 9.72 (s, 1H), 8.52 (s, 1H), 7.76-7.70 (m, 1H), 7.66-7.61 (m, 1H), 4.71 (s, 2H), 3.88-3.82 (m, 1H), 3.24-3.19 (m, 2H), 1.43-1.33 (m, 5H), 0.86-0.79 (m, 2H)

[1386] LC-MS: m / z 394 [M+H] at 2.32 RT + (99.29% purity).

[1387] HPLC: 98.78%.

[1388] Example 53

[1389] Scheme:

[1390]

[1391] 1 -cyclopropyl-5, 6-difluoro-2-(6-((1, 1, 1 -trifluoropropan-2-yl)oxy)pyridazin-4-yl)- 1 H- benzo[d]imidazole (Ex. 53)

[1392] To a stirred solution of 2-(6-chloropyridazin-4-yl)-1 -cyclopropyl-5, 6-difluoro-1 H- benzo[d]imidazole Ex. 22 (75 mg, 0.24 mmol) in DMF (2.25 mL) was added sodium hydride (60% in mineral oil, 24.5 mg, 0.61 mmol) in portions at 0 °C under inert atmosphere. The reaction mixture was stirred at 0 °C for 10 min. Then 1,1,1 -trifluoropropan-2-ol (34 mg, 0.30 mmol) was added to the reaction mixture at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. After consumption of starting material (monitored by TLC), the reaction mixture was quenched with ice cold water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried over anhydrous Na2S04and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 3% MeOH / CH2Cl2) to afford 1 -cyclopropyl-5, 6-difluoro-2-(6-((1,1,1 - trifluoropropan-2-yl)oxy)pyridazin-4-yl)-1 H-benzo[d]imidazole Ex. 53 (60 mg, 0.15 mmol, 84%) as a brown solid.

[1393] 1H NMR (400 MHz, CDC13): δ 9.54 (s, 1H), 7.63 (s, 1H), 7.62-7.58 (m, 1H), 7.45-7.41 (m, 1H), 6.15-6.04 (m, 1H), 3.69-3.42 (m, 1H), 1.64 (d, J = 6.3 Hz, 3H), 1.36-1.24 (m, 2H), 0.92-0.81 (m, 2H)

[1394] LC-MS: m / z 385.1 [M+H] at 2.76 RT + (97.88% purity).

[1395] HPLC: 97.83%.

[1396] Example 54

[1397] Scheme:

[1398]

[1399] 3-cyclopropyl-2-(6-methylpyridazin-4-yl)-3H-imidazo[4,5-b]pyridine-5-carbonitrile (Ex. 54)

[1400] 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) was added zinc cyanide (61.5 mg, 0.52 mmol) and Pd(PPh3)4(30.3 mg, 0.02 mmol) at room temperature. The mixture was purged with argon for 10 min and then heated to 170 °C for 4.5 h. After consumption of starting material (monitored by TLC), the reaction mixture was diluted with ice cold water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried over anhydrous Na2S04and concentrated under reduced pressure. The crude material was purified by preparative HPLC to give 3-cyclopropyl-2-(6-methylpyridazin-4-yl)-3H- imidazo[4,5-b]pyridine-5-carbonitrile Ex. 54 (25 mg, 0.09 mmol, 35%) as off-white solid.

[1401] 1 H NMR (400 MHz, CDC13): δ 9.75 (s, 1H), 8.19 (d, J = 8.2 Hz, 1H), 8.01 (s, 1H), 7.72 (d, J = 8.2 Hz, 1H), 3.70-3.64 (m, 1H), 2.90 (s, 3H), 1.41-1.36 (m, 2H), 1.06-0.81 (m, 2H)

[1402] LC-MS: at 1.88 RT, m / z 276.9 [M+H] + (98.98% purity).

[1403] HPLC: 95.03%.

[1404] Example 55

[1405] Scheme:

[1406]

[1407] N-(2-(cyclopropylamino)-4,5-difluorophenyl)pyridazine-4-carboxamide

[1408] 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.

[1409] LC-MS: at 2.34 RT, m / z 291 [M+H] + (96.97% purity).

[1410] 1-Cyclopropyl-5,6-Difluoro-2-(pyridazin-4-yl)-1H-benzo[d]imidazolium (Ex. 55)

[1411] To a stirred solution of N-(2-(cyclopropylamino)-4,5-difluorophenyl)pyridazine-4- carboxamide (200 mg, 0.68 mmol) in EtOH (4 mL) was added 6 N HC1 (2 mL) at room temperature under inert atmosphere. The reaction mixture was stirred at 70 °C for 1 h. After consumption of starting material (monitored by TLC), the reaction mixture was diluted with saturated sodium bicarbonate solution (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried over anhydrous Na2S04and concentrated under reduced pressure. The crude material was washed with n-pentane (2 x 5 mL) to get 1-cyclopropyl-5,6-difluoro-2-(pyridazin-4-yl)-1H- benzo[d]imidazole Ex. 55 (120 mg, 0.44 mmol, 64%) as off-white solid.

[1412] 1 H NMR (400 MHz, CD3OD): δ 9.81 (s, 1H), 9.41 (dd, J = 5.4, 1.3 Hz, 1H), 8.33 (dd, J = 5.5, 2.3 Hz, 1H), 7.4-7.69 (m, 1H), 7.65-7.61 (m, 1H), 3.87-3.84 (m, 1H), 1.30-1.24 (m, 2H), 0.88-0.73 (m, 2H)

[1413] LC-MS: m / z 272.9 [M+H] at 2.21 RT + (99.23% purity).

[1414] HPLC: 99.54%.

[1415] Example 56

[1416] Scheme:

[1417]

[1418] 1-cyclopropyl-5,6-difluoro-2-(pyridazin-4-yl)-4-(trifluoromethyl)-1H- benzo[d]imidazole (Ex. 56)

[1419] To a stirred solution of 1-cyclopropyl-5,6-difluoro-2-(pyridazin-4-yl)-1H- benzo[d]imidazole Ex. 55 (100 mg, 0.36 mmol) in DMSO (1.5 mL) was added zinc trifluoromethylsulfinate (243 mg, 0.73 mmol) at room temperature under inert atmosphere. To this was added TBHP (141 mg, 1.10 mmol) at 0 °C. The reaction mixture was stirred at 50 °C for 16 h. After consumption of starting material (monitored by TLC), the reaction mixture was basified with saturated sodium bicarbonate solution (20 mL) and extracted with CH2Cl2(2 x 20 mL). The combined organic extracts were dried over anhydrous Na2SO4and concentrated under reduced pressure. The crude material was purified by preparative HPLC to afford 1-cyclopropyl-5,6-difluoro-2-(pyridazin-4-yl)-4- (trifluoromethyl)-1H-benzo[d]imidazole Ex. 56 (19 mg, 0.05 mmol, 15%) as off-white solid.

[1420] 1 H NMR (500 MHz, CD3OD): δ 9.85 (s, 1H), 9.44 (dd, J = 5.2, 1.2 Hz, 1H), 8.38 (dd, J = 5.2, 2.3 Hz, 1H), 8.06 (dd, J = 9.3, 7.0 Hz, 1H), 3.92-3.86 (m, 1H), 1.38-1.20 (m, 2H), 0.89-0.83 (m, 2H)

[1421] LC-MS: m / z 340.9 [M+H] at 2.75 RT + (91.67% purity).

[1422] HPLC: 91.79%.

[1423] Example 57

[1424] Scheme:

[1425]

[1426] 1-cyclopropyl-2-(6-(2,2-difluoropropoxy)pyridazin-4-yl)-5,6-difluoro-1H- benzo[d]imidazole (Ex. 57)

[1427] To a stirred solution of 2-(6-chloropyridazin-4-yl)-l-cyclopropyl-5,6-difluoro-lH- benzo[d]imidazole Ex. 22 (50 mg, 0.16 mmol) in DMF (1.5 mL) was added sodium hydride (60% in mineral oil, 16.2 mg, 0.40 mmol) portion wise at 0 °C under inert atmosphere and the mixture was stirred for 5 min. 2,2-difluoropropan-l-ol (18.8 mg, 0.19 mmol) was added to the reaction mixture and stirred at room temperature for 1 h. After consumption of starting material (monitored by TLC), the reaction mixture was quenched with ice cold water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried over anhydrous Na2S04and concentrated under reduced pressure. The crude material was washed with CH2Cl2:n-pentane (5:95, 10 mL) to get l-cyclopropyl-2-(6-(2,2-difluoropropoxy)pyridazin-4-yl)-5,6-difluoro-lH- benzo[d]imidazole Ex. 57 (45 mg, 0.12 mmol, 82%) as off-white solid.

[1428] 1 H NMR (400 MHz, CDC13): δ 9.53 (s, 1H), 7.65 (d, 1H), 7.60 (dd, J = 10.0, 7.3 Hz, 1H), 7.43 (dd, J = 9.7, 6.9 Hz, 1H), 4.80 (t, J = 12.1 Hz, 2H), 3.67-3.58 (m, 1H), 1.80 (t, J = 18.6 Hz, 3H), 1.39-1.27 (m, 2H), 0.92-0.76 (m, 2H)

[1429] LC-MS: m / z 367 [M+H] at 3.08 RT + (96.40% purity).

[1430] HPLC: 94.40%.

[1431] Example 58

[1432] Scheme:

[1433]

[1434] 1-cyclopropyl-5,6-difluoro-2-(5-isopropylpyridazin-4-yl)-lH-benzo[d]imidazole (Ex. 58)

[1435] To a stirred solution of 1-cyclopropyl-5,6-difluoro-2-(pyridazin-4-yl)-1H- benzo[d]imidazole Ex. 55 (100 mg, 0.37 mmol) in DMSO (1 mL) was added zinc isopropylsulfinate (205 mg, 0.73 mmol) at room temperature under inert atmosphere. 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 for 16 h. After consumption of starting material (monitored by TLC), the reaction mixture was basified with saturated NaHC03solution (pH ~ 8) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were dried over anhydrous Na2S04and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 70% EtOAc / hexane) and then triturated with n-pentane (2 x 4 mL) and dried under vacuum to give 1-cyclopropyl-5,6-difluoro-2-(5-isopropylpyridazin-4-yl)-1H- benzo[d]imidazole Ex. 58 (15 mg, 0.05 mmol, 13%) as off-white solid.

[1436] 1 H NMR (400 MHz, CD3OD): δ 9.48 (d, J = 0.8 Hz, 1H), 9.31 (d, J = 1.0 Hz, 1H), 7.71 (dd, J = 10.1, 7.1 Hz, 1H), 7.61 (dd, J = 10.5, 7.3 Hz, 1H), 3.62-3.56 (m, 1H), 3.27-3.20 (m, 1H), 1.33 (d, J = 7.0 Hz, 6H), 1.08-1.03 (m, 2H), 0.73-0.68 (m, 2H)

[1437] LC-MS: m / z 315.0 [M+H] at 2.70 RT + (95.37% purity).

[1438] HPLC: 92.84%.

[1439] Example 59

[1440] Scheme:

[1441]

[1442] 1-cyclopropyl-2-(6-cyclopropylpyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (Ex. 59)

[1443] To a stirred solution of 2-(6-chloropyridazin-4-yl)-l-cyclopropyl-5,6-difluoro-lH- benzo[d]imidazole Ex. 22 (70 mg, 0.22 mmol) in toluene / water (3: 1, 2 mL) in a sealed tube was added cyclopropylboronic acid (24 mg, 0.27 mmol) and cesium carbonate (186 mg, 0.57 mmol) and the mixture was purged with argon for 10 minutes. Pd(dppf)Cl2(18.6 mg, 0.02 mmol) was added to the reaction mixture and further degassed for 5 minutes. The reaction was heated to 110 °C for 16 h and then cooled. After consumption of starting material (monitored by TLC), the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2S04and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 30% EtOAc / hexane) to afford l-cyclopropyl-2-(6-cyclopropylpyridazin-4-yl)-5,6-difluoro-lH- benzo[d]imidazole Ex. 23 (8 mg, 0.02 mmol, 11%) as a light yellow solid.

[1444] 1 H NMR (400 MHz, CDC13): δ 9.57 (s, 1H), 7.81 (s, 1H), 7.59 (dd, J = 10.2, 7.3 Hz, 1H), 7.43 (dd, J = 9.7, 7.0 Hz, 1H), 3.67-3.60 (m, 1H), 2.32-2.24 (m, 1H), 1.35-1.27 (m, 4H), 1.25-1.19 (m, 2H), 0.86-0.80 (m, 2H)

[1445] LC-MS: m / z 313.1 [M+H] at 2.22 RT + (93.72% purity).

[1446] HPLC: 96.07%.

[1447] Example 60

[1448] Scheme:

[1449]

[1450] 6-chloro-N-(2-(cyclopropylamino)-6-methoxypyridin-3-yl)pyridazine-4-carboxamide

[1451] To a stirred solution of 6-chloropyridazine-4-carboxylic acid (500 mg, 3.16 mmol) in DMF (10 mL) was added N2 - cyclopropyl-6-methoxy pyridine-2,3-diamine Int-9 (566 mg, 3.16 mmol), HATU (1.8 g, 4.74 mmol) and diisopropyl ethyl amine (2.19 mL, 12.64 mmol). The reaction mixture was stirred at room temperature for 16 h. After consumption of starting material (monitored by TLC), the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed with water (20 mL), brine (20 mL), dried over anhydrous Na2S04and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 30% to 40% EtOAc / hexane) to afford 6-chloro-N-(2-(cyclopropylamino)-6-methoxypyridin-3-yl)pyridazine-4- carboxamide (225 mg, 0.70 mmol, 22%) as off-white sol...

Claims

1. A compound selected from: a) ； b) ； c) ； d) ;and e) 。 2. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

3. Use of the pharmaceutical composition according to claim 2 in the preparation of a medicament for downregulating the activity of aldosterone synthase CYP11B2.

4. Use of the pharmaceutical composition according to claim 2 in the preparation of a medicament for inhibiting the activity of aldosterone synthase CYP11B2.

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