WO2017042380A1

WO2017042380A1 - Novel 5-amino-2-thioimidazole compounds and their use

Info

Publication number: WO2017042380A1
Application number: PCT/EP2016/071415
Authority: WO
Inventors: Julie Charton; Benoit Deprez; Vanessa HOGUET; Manuel LASALLE; Florence Leroux; Bart Staels; Anne MUHR-TAILLEUX; Nathalie HENNUYER; Loïc BELLOY
Original assignee: Universite Lille 2 Droit et Sante; Institut Pasteur de Lille; Institut National de la Sante et de la Recherche Medicale INSERM; Institut Pasteur
Current assignee: Universite Lille 2 Droit et Sante; Institut Pasteur de Lille; Institut National de la Sante et de la Recherche Medicale INSERM; Institut Pasteur
Priority date: 2015-09-11
Filing date: 2016-09-12
Publication date: 2017-03-16
Anticipated expiration: 2018-03-11

Abstract

The present invention is directed to novel compounds of formula (I) pharmaceutically acceptable salts or solvates thereof, and their use.

Description

NOVEL 5-AMINO-2-THIOIMIDAZOLE COMPOUNDS AND THEIR USE

The present invention relates to novel compounds including their pharmaceutically acceptable salts and solvates, which are agonists of TGR5 (G protein-coupled bile acid receptor 1, also named Gpbarl or M-BAR) and are useful as therapeutic compounds, particularly in the treatment and/or prevention of TGR5 related diseases, such as Type 2 diabetes (T2D) also known as diabetes mellitus and conditions that are often associated with this disease including, lipid disorders such as dyslipidemia, hypertension, obesity, atherosclerosis and its sequelae. [BACKGROUND OF THE INVENTION]

Type 2 diabetes (T2D) also known as diabetes mellitus is a growing health problem. Recent estimates indicate there were 171 million people in the world with diabetes in the year 2000 and this is projected to increase to 366 million by 2030 (Wild S, Roglic G, Green A, Sicree R, King H. Global Prevalence of Diabetes: Estimates for the year 2000 and projections for 2030. Diabetes Care. 2004, 27, 1047- 1053). The classical treatment for type 2 diabetes developed over the past 20 years has been based on 2 types of oral anti-hyperglycemic drugs; sulfonylureas that stimulate insulin secretion and the biguanides that have a broad spectrum of effects, but act primarily on hepatic insulin resistance. Then, alpha glucosidase inhibitors (i.e. acarbose) have been developed which decrease the intestinal absorption of glucose. A new category of molecules has appeared called thiazolidinediones (TZD). They act through binding and activation of the nuclear receptor peroxisome proliferator- activated receptor gamma (PPARy). More recently, the recognition that hormones secreted by the gut play a role in maintaining blood glucose homeostasis has led to emergence of several novel class of medications acting as analogs of the incretin glucagon-like peptide (GLP- 1) or as inhibitors of its degradating enzyme dipeptidyl peptidase IV (DPP-IV inhibitors) stabilizing its half-life. GLP- 1 is an incretin hormone causing enhanced post-prandial insulin secretion, but also known to have a range of additional effects including reduced gastric motility and appetite suppression, which indirectly impact on glucose metabolism in vivo (Drucker, D. J.; Sherman, S. I.; Bergenstal, R. M.; Buse, J. B., The safety of incretin-based therapies— review of the scientific evidence. J Clin Endocrinol Metab 2011, 96, 2027-2031. Baggio, L. L.; Drucker, D. J., Biology of Incretins: GLP-1 and GIP. Gastroenterology 2007, 132, 2131-2157). These new incretin-based medications offer the advantage of highly successful efficacy associated with an exceedingly favorable side effect profile and neutral effects on weight (Cefalu, W. T., Evolving treatment strategies for the management of type 2 diabetes. Am J Med Sci 2012, 343, 21-6. Gallwitz, B., Glucagon-like peptide- 1 analogues for Type 2 diabetes mellitus: current and emerging agents. Drugs 2011, 71, 1675-88).

Despite the use of various hypoglycemic agents, current treatments often fail to achieve sufficient lowering of serum glucose and/or are often associated with deficiencies including hypoglycemic episodes, gastrointestinal problems, weight gain, and loss of effectiveness over time (El-Kaissi, S.; Sherbeeni, S., Pharmacological management of type 2 diabetes mellitus: an update. Curr Diabetes Rev 2011, 7, 392-405).

In this context, the bile acid receptor TGR5 appears as an emerging and promising therapeutic target (Chen X Fau - Lou, G.; Lou G Fau - Meng, Z.; Meng Z Fau - Huang, W.; Huang, W., TGR5: A Novel Target for Weight Maintenance and Glucose Metabolism. Exp Diabetes Res. 2011, 201 1 : 853501. Pols Tw Fau - Noriega, L. G.; Noriega Lg Fau - Nomura, M.; Nomura M Fau - Auwerx, J.; Auwerx J Fau - Schoonjans, K.; Schoonjans, K., The bile acid membrane receptor TGR5: a valuable metabolic target. Dig. Dis. 2011, 29, 37-44. Porez, G.; Prawitt, J.; Gross, B.; Staels, B. J. Lipid Res. 2012, 53, 1723-1737). TGR5 (also named Gpbarl or M-BAR) (Maruyama, T.; Miyamoto, Y.; Nakamura, T.; Tamai, Y.; Okada, H.; Sugiyama, E.; Nakamura, T.; Itadani, H.; Tanaka, K., Identification of membrane-type receptor for bile acids (M-BAR). Biochem. Biophys. Res. Commun 2002, 298, 714-719. Kawamata, Y.; Fujii, R.; Hosoya, M.; Harada, M.;

Yoshida, H.; Miwa, M.; Fukusumi, S.; Habata, Y.; Itoh, T.; Shintani, Y.; Hinuma, S.; Fujisawa, Y.; Fujino, M., A G Protein-coupled Receptor Responsive to Bile Acids. J. Biol. Chem. 2003, 278, 9435-9440) is a member of the G-protein coupled receptor (GPCR) family. TGR5 is broadly expressed in human tissues, including those that are not usually known as targets of bile acids. In particular,

TGR5 is highly expressed in adipose tissue, muscle and enteroendocrine cells. A body of evidence supports a role for TGR5 in energy homeostasis. Indeed, administration of bile acids to mice increased energy expenditure in the brown adipose tissue and prevented diet-induced obesity and insulin-resistance. This effect was ascribed to a cAMP dependant intra-cellular induction of the type 2 iodothyronine deiodase (D2) enzyme, which converts inactive thyroxine (T4) into active 3,5,5'-tri-iodothyronine (T3). By this pathway, bile acids increase energy expenditure in part through activation of mitochondrial function in brown adipose tissue and skeletal muscle, hence preventing obesity and resistance to insulin (Watanabe, M.; Houten, S. M.; Mataki, C; Christoffolete, M. A.; Kim, B. W.; Sato, H.; Messaddeq, N.; Harney, J. W.; Ezaki, O.; Kodama, T.; Schoonjans, K.; Bianco, A. C; Auwerx, J., Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature 2006, 439, (7075), 484-489). Consistent for a role of TGR5 in energy homeostasis, female TGR5 deficient mice although not obese under chow fed conditions, showed significant fat accumulation with body weight gain compared to wild-type mice when fed a high fat diet (Maruyama, T.; Tanaka, K.; Suzuki, J.; Miyoshi, H.; Harada, N.; Nakamura, T.; Miyamoto, Y.; Kanatani, A.; Tamai, Y., Targeted disruption of G protein-coupled bile acid receptor 1 (Gpbarl/M-Bar) in mice. Journal of Endocrinology 2006, 191, 197-205). Moreover, it was shown that oleanolic acid, a component of olive oil that binds to and activates TGR5, lowers glucose and insulin levels in mice fed with a high fat diet and enhances glucose tolerance (Sato, H.; Genet, C; Strehle, A.; Thomas, C; Lobstein, A.; Wagner, A.; Mioskowski, C; Auwerx, J.; Saladin, R., Anti-hyperglycemic activity of a TGR5 agonist isolated from Olea europaea. Biochem. Biophys. Res. Commun 2007, 362, 793-798). Very interestingly, bile acids and compounds that affect TGR5 activity have been shown to increase GLP-1 secretion from enteroendocrine intestinal cells (Katsuma, S.; Hirasawa, A.; Tsujimoto, G. Bile acids promote glucagon-like peptide- 1 secretion through TGR5 in a murine enteroendocrine cell line STC-1 Biochem. Biophys. Res. Commun. 2005, 329, 386-390). More recently, using a combination of pharmacological and genetic gain- and loss-of- function studies in vivo, Thomas et al. (Thomas, C; Gioiello, A.; Noriega, L.; Strehle, A.; Oury, J.; Rizzo, G.; Macchiarulo, A.; Yamamoto, H.; Mataki, C; Pruzanski, M.; Pellicciari, R.; Auwerx, J.; Schoonjans, K., TGR5-mediated bile acid sensing controls glucose homeostasis. Cell Metab 2009, 10, 167-177) showed that TGR5 signaling induced GLP- 1 release also in vivo, leading to improved liver and pancreatic function and enhanced glucose tolerance in obese mice. Therefore, pharmacological targeting of TGR5 may constitute a promising incretin-based strategy for the treatment of diabesity and associated metabolic disorders. Interestingly, in addition to its expression in enteroendocrine L cells and its incretin secretagogue activity, TGR5 has also been shown to be expressed in inflammatory cells and its activation leads to anti-inflammatory effects and to anti-atherosclerotic effects in mouse. (Kawamata, Y.; Fujii, R.; Hosoya, M.; Harada, M.; Yoshida, H.; Miwa, M.; Fukusumi, S.; Habata, Y.; Itoh, T.; Shintani, Y.; Hinuma, S.; Fujisawa, Y.; Fujino, M., A G Protein-coupled Receptor Responsive to Bile Acids. J. Biol. Chem. 2003, 278, 9435-9440. Keitel, V.; Donner, M.; Winandy, S.; Kubitz, R.; Haussinger, D., Expression and function of the bile acid receptor TGR5 in Kupffer cells. Biochem Biophys Res Commun 2008, 372, 78-84. Pols, T. W. H.; Nomura, M.; Harach, T.; LoA Sasso, G.; Oosterveer, M. H.; Thomas, C; Rizzo, G.; Gioiello, A.; Adorini, L.; Pellicciari, R.; Auwerx, J.; Schoonjans, K., TGR5 Activation Inhibits Atherosclerosis by Reducing Macrophage Inflammation and Lipid Loading. Cell Metabolism 2007, 14, (6), 747-757). TGR5 agonists including natural or semi-synthetic bile acids

(Pellicciari, R.; Gioiello, A.; Macchiarulo, A.; Thomas, C; Rosatelli, E.; Natalini, B.; Sardella, R.; Pruzanski, M.; Roda, A.; Pastorini, E.; Schoonjans, K.; Auwerx, J., Discovery of 6-Ethyl-23(S)-methylcholic Acid (S-EMCA, INT-777) as a Potent and Selective Agonist for the TGR5 Receptor, a Novel Target for Diabesity J. Med. Chem. 2009, 52, 7958.7961), bile alcohols, triterpenoid compounds such as oleanolic acid, betulinic acids (Genet, C. d.; Strehle, A.; Schmidt, C. 1.; Boudjelal, G.; Lobstein, A.; Schoonjans, K.; Souchet, M.; Auwerx, J.; Saladin, R. g.; Wagner, A. Structure- Activity Relationship Study of Betulinic Acid, A Novel and Selective TGR5 Agonist, and Its Synthetic Derivatives: Potential Impact in Diabetes J. Med. Chem. 2010, 53, 178- 190), nomilin (Ono, E.; Inoue, J.;

Hashidume, T.; Shimizu, M.; Sato, R. Anti-obesity and anti-hyperglycemic effects of the dietary citrus limonoid nomilin in mice fed a high-fat diet. Biochem. Biophys. Res. Commun. 2011, 410, 677-681) or avicholic acid and synthetic nonsteroidal small molecules (Gioiello, A.; Rosatelli, E.; Nuti, R.; Macchiarulo, A.; Pellicciari, R., Patented TGR5 modulators: a review (2006 - present). Expert

Opin Ther Pat 2012, 22, (12), 1399- 1414) have been described recently.

However, safety concerns for some systemic TGR5 agonists were recently mentioned. Increase of the gallbladder volume which becomes enlarged due to delayed emptying, increased filling, or a combination of these effects was reported by investigators working with systemic TGR5 agonists in mouse models. Li, T.; Holmstrom, S. R.; Kir, S.; Umetani, M.; Schmidt, D. R.; Kliewer, S. A.; angelsdorf, D. J. The G protein-coupled bile acid receptor, TGR5, stimulates gallbladder filling. Mol. Endocrinol. 2011, 25, 1066-1071, Duan, H.; Ning, M.; Chen, X.; Zou, Q.; Zhang, L.; Feng, Y.; Zhang, L.; Leng, Y.; Shen, J., Design, Synthesis, and Antidiabetic Activity of 4-Phenoxynicotinamide and 4- Phenoxypyrimidine-5-carboxamide Derivatives as Potent and Orally Efficacious TGR5 Agonists. Journal of Medicinal Chemistry 2012, 55, (23), 10475.

More recently, it was reported that TGR5 stimulation in skin by systemic agonists triggers intense pruritus, comparable to the effect of the naturally occurring bile acids during cholestasis (Alemi, F.; Kwon, E.; Poole, D.

P.; Lieu, T.; Lyo, V.; Cattaruzza, F.; Cevikbas, F.; Steinhoff, M.; Nassini, R.;

Materazzi, S.; Guerrero-Alba, R.; Valdez-Morales, E.; Cottrell, G. S.; Schoonjans,

K.; Geppetti, P.; Vanner, S. J.; Bunnett, N. W.; Corvera, C. U., The TGR5 receptor mediates bile acid-induced itch and analgesia. The Journal of Clinical

Investigation 2013, 123, (4), 1513). Consequently, a much lower systemic exposure or even a non systemic exposure may be necessary for the development of a nontoxic TGR5 agonist.

International patent application WO 2011/071565 describes imidazole and triazole based TGR5 agonists having a quaternary ammonium moiety and international patent application WO 2013/096771 describes TGR5 agonists having a 2,3,4,5, 6-pentahydroxyhexyl moiety.

It was also reported that dimerizing the core structure using a PEG- linker led to a series of low-absorbed TGR5 agonists (Duan, H.; Ning, M.; Zou, Q.; Ye, Y.; Feng, Y.; Zhang, L.; Leng, Y.; Shen, J.; Discovery of intestinal targeted TGR5 agonists for the treatment of type 2 diabetes. Journal of Medicinal Chemistry 2015, 58(8), 3315-3328.

There is however still a need for new compounds that may be of therapeutic value in the treatment of TGR5 related diseases, such as T2D and conditions that are associated with this disease including, lipid disorders such as dyslipidemia, hypertension, obesity, atherosclerosis and its sequelae.

[SUMMARY OF THE INVENTION] The invention thus encompasses compounds of general Formula I, their pharmaceutically acceptable salts and solvates as well as methods of use of such compounds or compositions comprising such compounds as agonists of TGR5 activity. In a general aspect, the invention provides compounds of general

Formula I:

(I) or pharmaceutically acceptable salts or solvates thereof, wherein

R 1 and R 2" are independently H, Cl-C2-alkoxy or halo;

R³ is H, Cl-C4-alkyl or allyl;

R is H or Cl-C6-alkyl unsubstituted or substituted by a group selected from - OOCH₃, -N⁺R₃ Q wherein Q is a counter anion

wherein q is an integer from 1 to 6;

R⁵ is phenyl substituted by one or more groups selected from halo, Cl-C4-alkyl, Cl-C2-alkoxy, haloalkyl;

R⁶ and R⁷ are independently H, Cl-C2-alkyl or halo; L¹ is -CO-, -(CH₂)_t- wherein t is an integer from 0 to 4, L² is -0-, -C≡C-

ein R is H or CH₃,

wherein p is an integer from 0 to 4,

wherein R is H or CH₃;

n is an integer from 0 to 4;

A is selected from the group consisting of:

wherein m¹ is an integer from 3 to 500, with the proviso that

L² is not -O- or -C≡C- when L¹ is -(CH₂)_t- with t = 0,

is an integer from 3 to 500,

wherein m³ is an integer from 3 to 500 and Q^" is a counter anion,

wherein Q⁺ is a counter cation,

wherein R is CH₂OH, CH₂OS0₃ ^~ Q⁺ or COOH,

wherein R⁸ is H or CH₃ and R* is CH₂OH,

CH₂OS0₃ Q⁺ or COOH

wherein R⁸ is H or CH₃ and R⁹ is CH₂OH, CH₂OS0₃ ^" Q⁺ or COOH,

wherein R⁹ is CH₂OH, CH₂OS0₃ ^~ Q⁺ or COOH,

R⁸ is H or CH₃; R⁹ is CH₂OH,

CH₂OS0₃ ^" Q⁺ or COOH; m is an integer from 0 to 10,

erein r is 1 to 4,

wherein m is an integer from 3 to 50,

wherein m is an integer from 0 to 11; n¹ is an integer from 0 to 3; X is CH₂, NH, O or -CH(OH)- CH(OH)-,

L -(CH₂)_n-A is H, phenyl unsubstituted or substituted with a group selected from OH, COOH, NH₂, and Cl-C4-alkoxy, with the proviso that R⁴ and L²-(CH₂)_n-A are not both H when R³ is Cl-C4-alkyl and L¹ is -(CH₂)_t- with t = 0.

Suitable, generally pharmaceutically acceptable, counter anions Q^" are well known to those skilled in the art. Non-limiting examples of suitable counter anions include acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, halides such as fluoride, chloride, bromide, iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate. Preferred counter anions Q^" are selected from formate and halides such as fluoride, chloride, bromide and iodide. Suitable, generally pharmaceutically acceptable, counter cations

Q⁺ are well known to those skilled in the art. Non-limiting examples of suitable counter cations include sodium, ammonium, potassium, lithium, calcium, magnesium, iron, zinc, copper, manganese, aluminium or organic bases such as primary amine compounds, secondary amine compounds, tertiary amine compounds, cyclic amines or basic ion exchange resins. Preferred counter cations Q⁺ are selected from sodium, ammonium, potassium, lithium, calcium, magnesium.

Preferred compounds of Formula I are those, wherein one or more of L , L , n and A are as defined as follows: L¹ is -CO-, -(CH₂)t- wherein t is an integer from 0 to 4, L² is -0-, -C≡C-

ein R is H or CH₃

wherein p is an integer from 0 to 4,

wherein R is H or CH₃, n is an integer from 0 to 4;

A is selected from the group consisting of:

wherein m¹ is an integer from 3 to 500, with the proviso that not -O- or -C≡C- when L¹ is -(CH₂)_t- with t

wherein m is an integer from 3 to 500,

wherein m³ is an integer from 3 to 500 and Q^" is a counter anion,

wherein Q⁺ is a counter cation,

wherein R is CH₂OH, CH₂OS0₃ Q⁺ or COOH,

CH₂OS0₃ ^" Q⁺ or COOH,

wherein R⁸ is H or CH₃ and R⁹ is CH₂OH,

CH₂OS0₃ ^" Q⁺ or COOH,

wherein R⁹ is CH₂OH, CH₂OS0₃ ^" Q⁺ or COOH,

wherein R⁸ is H or CH₃; R⁹ is CH₂OH,

CH₂OS0₃ ^" Q⁺ or COOH; m is an integer from 0 to 10,

N ^, ,^COOH

wherein r is an integer from 1 to 4,

herein m⁴ is an integer from 3 to 50,

wherein m⁵ is an integer from 0 to 11; n¹ is an integer from 0 to 3; X is CH₂, NH, O or -CH(OH)- CH(OH)-,

Indeed, without wanting to be bound to any theory, the present inventors believe that the L -(CH₂)_n-A moiety as defined herein and not being H limits the absorption of the compounds of the invention in the intestine and thus decreases their systemic action. The resulting compounds are thus topical agonists which have the advantage of promoting GLP- 1 secretion in intestine without side effects due to TGR5 activation in other organs.

In another aspect, the present invention provides a pharmaceutical composition comprising at least one compound according to the invention or a pharmaceutically acceptable salt or solvate thereof.

The invention also relates to the use of the above compounds or their pharmaceutically acceptable salts and solvates as modulators of TGR5, preferably as agonists of TGR5 and more preferably as agonists of TGR5 exerting their action locally in the intestine with low or even without systemic exposure. In view of the drawbacks reported for systemic TGR5 agonists, the preferred agonists of the invention have the advantage of enhancing safety and the therapeutic index for potential chronic administration. The invention further provides the use of a compound according to the invention or a pharmaceutically acceptable salt or solvate thereof as a medicament. Preferably, the medicament is used for the treatment and/or prevention of TGR5 related diseases, such as metabolic diseases, gastrointestinal diseases and/or hepato-biliary diseases. Metabolic diseases within the meaning of the present invention include, but are not limited to, type II diabetes, obesity, dyslipidemia such as mixed or diabetic dyslipidemia, hypercholesterolemia, low HDL cholesterol, high LDL cholesterol, hyperlipidemia, hypertriglyceridemia, hypoglycemia, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypertension, hyperlipoproteinemia, metabolic syndrome, syndrome X, thrombotic disorders, cardiovascular disease, atherosclerosis and their sequelae including angina, claudication, heart attack, stroke and others, kidney diseases, ketoacidosis, nephropathy, diabetic neuropathy, diabetic retinopathy, nonalcoholic fatty liver diseases such as steatosis or nonalcoholic steatohepatitis (NASH), liver cirrhosis, liver fibrosis, liver hepato-carcinogenesis.

In a preferred embodiment the metabolic disease is type II diabetes, a lipid disorder such as dyslipidemia, hypertension, obesity, or atherosclerosis and its sequelae, preferably the disease is type II diabetes. Gastrointestinal diseases within the meaning of the present invention include, but are not limited to, Inflammatory Bowel Diseases (IBD) including but not limited to colitis, Ulcerative colitis (UC) and Crohn's Disease (CD), and Irritable Bowel Syndrome (IBS), intestinal injury disorders such as short-bowel syndrome, diseases involving intestinal barrier dysfunction such as proctitis and pouchitis, and gastrointestinal disorders characterized by hypermotilenemia or gastrointestinal hypermotility, including but not limited to any type of diarrhea.

In a preferred embodiment, the gastrointestinal disease is Inflammatory Bowel Diseases (IBD) including but not limited to colitis, Ulcerative colitis (UC) and Crohn's Disease (CD).

Hepato-biliary diseases within the meaning of the present invention include, but are not limited to, fibrosing cholangiopathies such as primary sclerosing cholangitis (PSC) and primary biliary cirrhosis (PBC), secondary cholangiopathies in which the inflammatory and fibrosing biliary disease is the consequence of other conditions.

[DETAILED DESCRIPTION OF THE INVENTION] As noted above, the invention relates to compounds of Formula I, as well as their pharmaceutically acceptable salts and solvates.

Preferred compounds of Formula I and pharmaceutically acceptable salts and solvates thereof are those wherein one or more of, R 1 -R7',

L , n, and A are defined as follows:

R 1 and R 2" are independently H, methoxy, chloro or fluoro, preferably methoxy or chloro, and more preferably both of R 1 and R 2 are methoxy;

R³ is H, Cl-C2-alkyl, or allyl, preferably R³ is methyl;

R⁴ is H or Cl-C6-alkyl unsubstituted or substituted by a group selected from - -COOCH3, -N⁺R₃ Q wherein Q is a counter anion and

wherein q is an integer from 1 to 6; preferably R⁴ is H, methyl, 4-aminobutyl or 3-carboxypropyl; more preferably R⁴ is H;

R⁵ is phenyl substituted by one or more groups selected from the group consisting of fluoro, chloro, halomethyl, and Cl-C2-alkoxy; preferably R⁵ is phenyl substituted by one or more groups selected from the group consisting of fluoro, chloro, trifluoromethyl, and methoxy; more preferably R⁵ is phenyl substituted by one or more groups selected from the group consisting of fluoro and methoxy;

R⁶ and R⁷ are independently H, fluoro, chloro, or methyl; preferably R⁶ and R⁷ are both halo, and more preferably R⁶ and R⁷ are both fluoro; L¹ is -CO- or -(CH₂)_t- wherein t is an integer from 0 to 4; preferably L¹ is -CO- or -(CH₂)_t- wherein t is 0 or 1; more preferably L¹ is-(CH₂)_t- wherein t is 0;

L² is O or -C≡C-,

is H,

wherein p is an integer from 0 to 4; preferably p = 1; n is 0, 1 or 2;

A is selected from the group consisting of

wherein m 1 is an integer from 3 to 500, with the proviso that

L² is not -O- or -C≡C-

wherein m² is an integer from 3 to 500,

wherein m is an integer from 3 to 500 and Q^" is a counter anion,

wherein Q⁺ is a counter cation, herein R is CH₂OH, CH₂OS0₃ ^" Q⁺ or COOH,

Particularly preferred compounds of Formula I and pharmaceutically acceptable salts and solvates thereof are those wherein L - (CH₂)_n-A is not H. Indeed, without wanting to be bound to any theory, the present inventors believe that the L -(CH₂)_n-A moiety as defined herein and not being H limits the absorption of the compounds of the invention in the intestine and thus decrease their systemic action.

In one embodiment of the invention, the compounds of Formula I are those of Formula II

II and pharmaceutically acceptable salts, and solvates thereof, wherein

R¹, R², R³, R⁴, R⁵, R⁶, R⁷, L², n, and A are as defined above with respect to Formula I.

Preferred compounds of Formula II and pharmaceutically acceptable salts and solvates thereof are those wherein R⁵ is phenyl substituted by one or more groups selected from the group consisting of fluoro, chloro, halomethyl, and Cl-C2-alkoxy; preferably, fluoro, chloro, trifluoromethyl, and methoxy.

Particularly interesting compounds of Formula II and pharmaceutically acceptable salts and solvates thereof are those, wherein

herein R is H or CH₃,

n is 0 and A is

L is -0-, n is 3 and A is wherein m 1 is an integer

from 3 to 500,

wherein m is an integer from 3 to 500

and Q^" is a counter anion,

wherein Q⁺ is a counter cation; L is ethynylene, n is 0 and A is

; or

s H, n is 1

or COOH, preferably R⁹ is CH₂OH; or

, n is 0 and A is wherein m is an integer from 3 to 50.

In one embodiment, compounds of Formula II and pharmaceutically acceptable salts and solvates thereof as described above are those wherein R is methyl.

In another embodiment, the compounds of Formula II are those of Formula III

and pharmaceutically acceptable salts, and solvates thereof, wherein R 1 , R 2, R 3,

R 6°, R 7', L 2, n, and A are as defined above with respect to Formula I; and

R¹⁰, and R¹¹ are independently selected from the group consisting of H, fluoro, chloro, halomethyl, and Cl-C2-alkoxy; preferably H, fluoro, chloro, trifluoromethyl, and methoxy, with the proviso that at least one of R¹⁰, and R¹¹ is not H, preferably R¹⁰ is fluoro and R¹¹ is H or methoxy.

Particularly interesting compounds of Formula III and pharmaceutically acceptable salts and solvates thereof are those, wherein

L² is erein R is H or CH₃

H, n is 0 and A is

wherein m 1 is an integer from 3 to 500;

L is -0-, n is 3 and A is

wherein m² is an integer

Q ^"

from 3 to 500 ,

wherein m is an integer from 3 to 500

and Q^" is a counter anion,

wherein Q⁺ is a counter cation;

L is ethynylene, n is 0 and A is

L² is s H, n is 1

and A

or COOH, preferably R⁹ is CH₂OH; or

, n is 0 and A is wherein m is an integer from 3 to 50_; and/or wherein R¹ and R² are preferably both methoxy and wherein R⁶ and R⁷ are both fluoro; and/or wherein preferably R¹⁰ is fluoro and R¹¹ is H or methoxy.

In one embodiment, compounds of Formula III as described above are those of Formula Ilia

Ilia and pharmaceutically acceptable salts, and solvates thereof, wherein R⁴, R¹⁰, R¹¹, L², n, and A are as defined above with respect to Formula III.

In another embodiment, the compounds of Formula I are those of

Formula IV

IV and pharmaceutically acceptable salts, and solvates thereof, wherein

R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and L¹ are as defined above with respect to Formula I.

Preferred compounds of Formula IV and pharmaceutically acceptable salts and solvates thereof are those wherein R 1 and R 2 are both

1 3

methoxy; and/or L is -CO- or -(CH₂)_t- wherein t is 0 or 1; and/or R is methyl or allyl; and/or R⁴ is H, methyl, 4-aminobutyl or 3-carboxypropyl and/or R⁵ is 4- fluorophenyl; and/or R⁶ and R⁷ are both fluoro, with the proviso that R⁴ is not H when R 3 is methyl and L 1 is -(CH₂)_t- wherein t is 0.

In another embodiment, the compounds of Formula I are those of Formula V

V and pharmaceutically acceptable salts, and solvates thereof, wherein

R¹, R², R³, R⁴, R⁵ and R⁶, are as defined above with respect to Formula I, and wherein L -(CH₂)_n-A is phenyl unsubstituted or substituted with a group selected from OH, COOH, NH₂, Cl-C4-alkoxy.

Preferred compounds of Formula V and pharmaceutically acceptable salts and solvates thereof as defined above are those wherein R 1 and R 2 are both methoxy; and/or R³ is methyl; and/or R⁶ and R⁷ are both fluoro.

In one embodiment, the compounds of Formula I and pharmaceutically acceptable salts and solvates thereof and subformulae as decribed above are those wherein L -(CH₂)_n-A is H, with the proviso that R and L²-(CH₂)_n-A are not both H when R³ is Cl-C4-alkyl and L¹ is -(CH₂)_t- with t = 0.

Particularly preferred compounds of Formulae I, II, III, IV and V, and pharmaceutically acceptable salts and solvates thereof are those wherein R¹ and R² are both methoxy and R⁶ and R⁷ are both fluoro.

Particularly preferred compounds of the invention are those listed in Table 1 hereafter:

Compound Structure

1

F O

m = 4 - 1 2 A

F

F 0

m=11 -25

F 0

0

m = 100-138

The compounds of the invention and their pharmaceutically acceptable salts and solvates can be prepared by different ways with reactions known by the person skilled in the art. Reaction schemes as described in the example section illustrate by way of example different possible approaches.

The invention further provides the use of the compounds of the invention or pharmaceutically acceptable salts, or solvates thereof as agonists of TGR5, preferably agonists of TGR5 having low or no systemic activity.

Accordingly, in a particularly preferred embodiment, the invention relates to the use of compounds of formula I and subformulae or pharmaceutically acceptable salts and solvates thereof, in particular those of table 1 above, as TGR5 agonists, in particular agonists of TGR5 having low or no systemic activity.

[APPLICATIONS] The compounds of the invention are therefore useful in the prevention and/or the treatment of TGR5 related diseases, such as metabolic and/or gastrointestinal diseases.

The invention thus also relates to the use of a compound of the invention or a pharmaceutically acceptable salt or solvate thereof for use in treating and/or preventing a TGR5 related disease, in particular a metabolic and/or a gastrointestinal disease. Or in other terms, the invention also releates to a method of treating and/or preventing TGR5 related diseases, in particular metabolic diseases, gastrointestinal diseases, hepato-biliary diseases, comprising the administration of a therapeutically effective amount of a compound or pharmaceutically acceptable salt or solvate of the invention, to a patient in need thereof. Preferably the patient is a warm-blooded animal, more preferably a human.

Metabolic diseases within the meaning of the present invention include, but are not limited to, type II diabetes, obesity, dyslipidemia such as mixed or diabetic dyslipidemia, hypercholesterolemia, low HDL cholesterol, high LDL cholesterol, hyperlipidemia, hypertriglyceridemia, hypoglycemia, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia hypertension, hyperlipoproteinemia, metabolic syndrome, syndrome X, thrombotic disorders, cardiovascular disease, atherosclerosis and their sequelae including angina, claudication, heart attack, stroke, kidney diseases, ketoacidosis, nephropathy, diabetic neuropathy, diabetic retinopathy, and nonalcoholic fatty liver diseases such as steatosis or nonalcoholic steatohepatitis (NASH), liver cirrhosis, liver fibrosis, liver hepato-carcinogenesis. In a preferred embodiment, the metabolic disease is type II diabetes, a lipid disorder such as dyslipidemia, hypertension, obesity, or atherosclerosis and its sequelae.

In a particularly preferred embodiment, the diseases are type II diabetes and a lipid disorder such as dyslipidemia, preferably type II diabetes. Gastrointestinal diseases within the meaning of the present invention include, but are not limited to, Inflammatory Bowel Diseases (IBD) including but not limited to colitis, Ulcerative colitis (UC) and Crohn's Disease (CD), and Irritable Bowel Syndrome (IBS), intestinal injury disorders such as short-bowel syndrome, diseases involving intestinal barrier dysfunction such as proctitis and pouchitis, and gastrointestinal disorders characterized by hypermotilenemia or gastrointestinal hypermotility, including but not limited to any type of diarrhea.

The invention also provides for a compound of the invention or a pharmaceutically acceptable salt or solvate thereof for use in delaying the onset of a TGR5 related disease, such as a metabolic and/or a gastrointestinal disease. Or in other terms, the invention also provides for a method for delaying in patient the onset of a TGR5 related diseases, such as a metabolic and/or a gastrointestinal disease comprising the administration of a therapeutically effective amount of a compound or pharmaceutically acceptable salt or solvate of the invention, to a patient in need thereof. Preferably the patient is a warm-blooded animal, more preferably a human. The metabolic and/or gastrointestinal diseases are preferably those defined above.

The invention further provides the use of a compound of the invention or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for use in treating and/or preventing TGR5 related diseases, in particular metabolic and/or gastrointestinal diseases. Preferably, the metabolic diseases, gastrointestinal diseases and/or hepato-biliary diseases are those defined above.

According to a further feature of the present invention, there is provided the use of a compound of the invention or a pharmaceutically acceptable salt or solvate for modulating TGR5 receptor activity, in a patient, in need of such treatment, comprising administering to said patient an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof. In other terms, the invention also provides a method for modulating TGR5 receptor activity, in a patient, in need of such treatment, which comprises administering to said patient an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof. Preferably, the patient is a warm blooded animal, and even more preferably a human.

According to one embodiment, the compounds of the invention, their pharmaceutical acceptable salts or solvates may be administered as part of a combination therapy. Thus, are included within the scope of the present invention embodiments comprising coadministration of, and compositions and medicaments which contain, in addition to a compound of the present invention, a pharmaceutically acceptable salt or solvate thereof as active ingredient, additional therapeutic agents and/or active ingredients. Such multiple drug regimens, often referred to as combination therapy, may be used in the treatment and/or prevention of any of the diseases or conditions related to with TGR5 receptor modulation, particularly type II diabetes, obesity, dyslipidemia such as mixed or diabetic dyslipidemia, hypercholesterolemia, low HDL cholesterol, high LDL cholesterol, hyperlipidemia, hypertriglyceridemia, hypoglycemia, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia hypertension, hyperlipoproteinemia, metabolic syndrome, syndrome X, thrombotic disorders, cardiovascular disease, atherosclerosis and its sequelae including angina, claudication, heart attack, stroke and others, kidney diseases, ketoacidosis, nephropathy, diabetic neuropathy, diabetic retinopathy, nonalcoholic fatty liver diseases such as steatosis or nonalcoholic steatohepatitis (NASH), liver cirrhosis, liver fibrosis, liver hepato-carcinogenesis. The use of such combinations of therapeutic agents is especially pertinent with respect to the treatment of the above-mentioned list of diseases within a patient in need of treatment or one at risk of becoming such a patient.

In addition to the requirement of therapeutic efficacy, which may necessitate the use of active agents in addition to the TGR5 agonist compounds of the invention or their pharmaceutical acceptable salts or solvates thereof, there may be additional rationales which compel or highly recommend the use of combinations of drugs involving active ingredients which represent adjunct therapy, i.e., which complement and supplement the function performed by the TGR5 receptor agonist compounds of the present invention. Suitable supplementary therapeutic agents used for the purpose of auxiliary treatment include drugs which, instead of directly treating or preventing a disease or condition related to TGR5 receptor modulation, treat diseases or conditions which directly result from or indirectly accompany the basic or underlying TGR5 receptor related disease or condition.

Thus, the methods of treatment and pharmaceutical compositions of the present invention may employ the compounds of the invention or their pharmaceutical acceptable salts or solvates thereof in the form of monotherapy, but said methods and compositions may also be used in the form of multiple therapy in which one or more compounds of the invention or their pharmaceutically acceptable salts or solvates are coadministered in combination with one or more other therapeutic agents.

The invention also provides pharmaceutical compositions comprising a compound of the invention or a pharmaceutically acceptable salt or solvate thereof and at least one pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant. As indicated above, the invention also covers pharmaceutical compositions which contain, in addition to a compound of the present invention, a pharmaceutically acceptable salt or solvate thereof as active ingredient, additional therapeutic agents and/or active ingredients. Another object of this invention is a medicament comprising at least one compound of the invention, or a pharmaceutically acceptable salt or solvate thereof, as active ingredient.

Generally, for pharmaceutical use, the compounds of the inventions may be formulated as a pharmaceutical preparation comprising at least one compound of the invention and at least one pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant, and optionally one or more further pharmaceutically active compounds.

By means of non-limiting examples, such a formulation may be in a form suitable for oral administration, for parenteral administration (such as by intravenous, intramuscular or subcutaneous injection or intravenous infusion), for topical administration (including ocular), for administration by inhalation, by a skin patch, by an implant, by a suppository, etc. Such suitable administration forms - which may be solid, semi-solid or liquid, depending on the manner of administration - as well as methods and carriers, diluents and excipients for use in the preparation thereof, will be clear to the skilled person; reference is made to the latest edition of Remington's Pharmaceutical Sciences.

[DEFINITIONS]

The definitions and explanations below are for the terms as used throughout the entire application, including both the specification and the claims.

Unless otherwise stated any reference to compounds of the invention herein, means the compounds as such as well as there pharmaceutically acceptable salts and solvates.

When describing the compounds of the invention, the terms used are to be construed in accordance with the following definitions, unless indicated otherwise. The term "halo" or "halogen" means fluoro, chloro, bromo, or iodo. Preferred halo groups are fluoro and chloro, fluoro being particularly preferred.

The term "alkyl" by itself or as part of another substituent refers to a hydrocarbyl radical of Formula C_nH2_n+i wherein n is a number greater than or equal to 1.

The term "haloalkyl" alone or in combination, refers to an alkyl radical having the meaning as defined above wherein one or more hydrogens are replaced with a halogen as defined above. Non-limiting examples of such haloalkyl radicals include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1, 1-trifluoroethyl and the like. A preferred haloalkyl radical is trifluoromethyl.

The compounds of the invention containing a basic functional group and/or an acidic functional group may be in the form of pharmaceutically acceptable salts. Pharmaceutically acceptable salts of the compounds of the invention containing one or more basic functional groups include in particular the acid addition salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate salts. Compounds containing one or more acidic functional groups may be capable of forming pharmaceutically acceptable salts with a pharmaceutically acceptable base, for example and without limitation, inorganic bases based on alkaline metals or alkaline earth metals or organic bases such as primary amine compounds, secondary amine compounds, tertiary amine compounds, cyclic amines or basic ion exchange resins. Compounds containing one or more basic functional groups may be capable of forming pharmaceutically acceptable salts, e.g. amine groups may be transformed into ammonium groups by reacting the amine group with an inorganic or organic base or an alkylating agent such as e.g. an alkylhalide (e.g. methyliodide). When the compounds of the invention contain an acidic group as well as a basic group the compounds of the invention may also form internal salts, and such compounds are within the scope of the invention.

Pharmaceutically acceptable salts of compounds of Formula I may for example be prepared as follows:

(i) reacting the compound of Formula I with the desired acid;

(ii) by reacting the compound of Formula I with the desired base; or

(iii) converting one salt of the compound of Formula I to another by reaction with an appropriate acid or by means of a suitable ion exchange column.

All these reactions are typically carried out in solution. The salt, may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the salt may vary from completely ionized to almost non-ionized.

The term "solvate" is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, water or ethanol. The term 'hydrate' is employed when said solvent is water. All references to compounds of Formula I include references to salts and solvates thereof. The compounds of the invention include compounds of Formula I as hereinbefore defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) and isotopically- labeled compounds of Formula I. In addition, although generally, with respect to the salts of the compounds of the invention, pharmaceutically acceptable salts are preferred, it should be noted that the invention in its broadest sense also includes non- pharmaceutically acceptable salts, which may for example be used in the isolation and/or purification of the compounds of the invention. For example, salts formed with optically active acids or bases may be used to form diastereoisomeric salts that can facilitate the separation of optically active isomers of the compounds of Formula I above.

The term "patient" refers to a warm-blooded animal, more preferably a human, who/which is awaiting or receiving medical care or is or will be the object of a medical procedure.

The term "human" refers to subjects of both genders and at any stage of development (i.e. neonate, infant, juvenile, adolescent, adult). In one embodiment, the human is an adolescent or adult, preferably an adult.

The terms "treat", "treating" and "treatment", as used herein, are meant to include alleviating or abrogating a condition or disease and/or its attendant symptoms.

The terms "prevent", "preventing" and "prevention", as used herein, refer to a method of delaying or precluding the onset of a condition or disease and/or its attendant symptoms, barring a patient from acquiring a condition or disease, or reducing a patient's risk of acquiring a condition or disease.

The term "therapeutically effective amount" (or more simply an "effective amount") as used herein means the amount of active agent or active ingredient (e. g. TGR5 agonist) which is sufficient to achieve the desired therapeutic or prophylactic effect in the individual to which it is administered.

The term "administration", or a variant thereof (e.g. 'administering"), means providing the active agent or active ingredient (e. g. a TGR5 agonist), alone or as part of a pharmaceutically acceptable composition, to the patient in whom/which the condition, symptom, or disease is to be treated or prevented.

By "pharmaceutically acceptable" is meant that the ingredients of a pharmaceutical composition are compatible with each other and not deleterious to the patient thereof.

The term "agonist" as used herein means a ligand that activates an intracellular response when it binds to a receptor.

The term "pharmaceutical vehicle" as used herein means a carrier or inert medium used as solvent or diluent in which the pharmaceutically active agent is formulated and/or administered. Non-limiting examples of pharmaceutical vehicles include creams, gels, lotions, solutions, and liposomes.

The term "lipid disorder" as used herein means any plasma lipid disorder including but not limited to dyslipidemia such as mixed or diabetic dyslipidemia, hypercholesterolemia, low HDL cholesterol, high LDL cholesterol, hyperlipidemia and hypertriglyceridemia.

The present invention will be better understood with reference to the following examples. These examples are intended to be representative of specific embodiments of the invention, and are not intended as limiting the scope of the invention.

CHEMISTRY EXAMPLES All reagents, solvents and starting materials were purchased from commercial suppliers and used without further purification. 1H NMR spectra were recorded on a Brucker Avance 300 MHz spectrometer with methanol-d4, CDC1₃ or DMSO-d6 as the solvent. ¹³C NMR spectra are recorded at 100 MHz. All coupling constants are measured in hertz (Hz) and the chemical shifts (δ) are quoted in parts per million (ppm). Liquid chromatography mass spectroscopy analyses (LC-MS) were performed using LCMS-MS triple-quadrupole system (Waters) with a C18 TSK-GEL Super ODS (2 μιη particle size column, 50 * 4.6 mm). LCMS gradient starting from 98% H₂0 / 0.1% formic acid and reaching 2% H₂0 / 98% MeOH within 5 min (method A) at a flow rate of 2 mL/min or starting from 100% H₂0 / 0.1% formic acid and reaching 5% H₂0 / 95% MeOH within 10 min (method B) at a flow rate of 1 mL/min was used. Purity (%) was determined by Reversed Phase HPLC, using UV detection (215 nM).

Solvents, reagents and starting materials were purchased from well known chemical suppliers such as for example Sigma Aldrich, Acros Organics, Fluorochem, Eurisotop, VWR International, and the following abbreviations are used:

ACN: Acetonitrile,

DCM: Dichloromethane,

DMF: N,N-dimethylformamide,

EtOAc: Ethyl acetate,

EtOH: Ethanol,

MeOH: Methanol,

RT: Room temperature,

DIEA: N,N-diisopropylethylamine,

TEA : triethylamine,

Y: Yield,

g: Grams,

mg: Milligrams,

L: Liters, mL: Milliliters,

μί: Microliters,

mol: Moles,

mmol: Millimoles,

h: Hours,

min: Minutes,

TLC: Thin layer chromatography,

MW: Molecular weight,

eq: Equivalent,

μ\¥: Microwave,

THF: Tetrahydrofuran,

TFA: Trifluoroacetic acid,

Ac: Acetyl,

tBu: / -Butyl,

Rt: Retention time,

aq: aqueous,

DCC : N,N' -Dicyclohexylcarbodiimide

HOBt: 1-Hydroxybenzotriazole

HPLC: High-performance liquid chromatography.

General route toward 5-amino-2-thio-imidazole derivatives.

Procedure A:

In a round bottom flask was added the isothioureido-derivative (1 eq), Potassium Carbonate (1 eq), sodium Iodide (0.5 eq), and acetonitrile (QS 0.2 M). The suspension was stirred at room temperature for 10 min, benzyl halide (1 eq) was then added. The suspension was stirred at room temperature overnight. Reaction mixture was then evaporated; residue was dissolved in ethyl acetate, washed with water and brine. Organic phase was dried over Na₂S0₄ and evaporated. Residue was purified by flash chromatography (cHex/EtOAc).

Procedure B: In a microwave tube were introduced the isothioureido-acetamide derivative (1 eq), ethyl acetate (QS 0.1 M), diisopropylethylamine (6 eq), and T3P^® (3 eq). Reaction mixture was heated under microwave irradiation at 150°C for 10 min. Reaction mixture was then diluted with ethyl acetate, washed with a saturated aqueous solution of NaHC0₃, and brine. Organic phase was then dried over Na₂S0₄ and evaporated. Residue was purified by flash chromatography (cHex/EtOAc).

Procedure C:

In a microwave tubes were added 5-amino-2-thio-imidazole derivative (1 eq), phenylboronic derivative (1 eq), cesium carbonate (1.75 eq), Pd(Ph P)₄ (0.175 eq). A mixture of water (QS 0.8 M), dimethoxyethane (QS 0.3 M), and ethanol (QS 0.5 M) was prepared and poured into the microwave tube. The reaction mixture was heated under microwave irradiation at 100°C for 10 min. The reaction mixture was then evaporated to dryness, diluted in ethyl acetate, filtered on Celite, washed with water, with brine, dried over MgS0₄ and evaporated to dryness.

Synthesis of intermediat

Step 1

3,4-dimethoxy-N-methyl-anilin (Intermediate la)

In a 250 mL flask were added 3,4-dimethoxyaniline (3.57 g, 23.31 mmol) and sodium methoxide (6.3 g, 116.53 mmol) in 25 mL of methanol (dried over MgS0₄). Then, paraformaldehyde (1.4 g, 46.61 mmol) and 16 mL of methanol (dried over MgS0₄) were added. Molecular sieves (4 Angstroms) were then added and the mixture was stirred overnight at room temperature. Sodium borohydride (0.88 g, 23.31 mmol) was added, and the mixture was heated under reflux for 1.5 hour. The mixture was then evaporated, dissolved in ethyl acetate and water, the two phases were separated. The aqueous phase was then basified by addition of a saturated aqueous solution of NaHC0₃, and extracted by ethyl acetate. The organic phases were washed with a saturated aqueous solution of NaHC0₃, brine, dried over Na₂S0₄ and evaporated. The crude was purified by flash chromatography using as eluent a mixture of cyclohexane/EtOAc (85/15) to give 2.23 g of 3,4-dimethoxy-N-methyl-aniline as a yellow oil, leading to a 57% yield. MS: [M+H]⁺ m/z = 168.

1H NMR (DMSO- 6): δ 2.61 (d, J = 5.0 Hz, 3H) ; 3.61 (s, 3H) ; 3.68 (s, 3H) ; 5.20 (d, J = 5.0 Hz, 1H) ; 5.97-6.01 (dd, J = 8.5, 2.7 Hz, 1H) ; 6.21 (d, J = 2.7 Hz, 1H) ; 6.71 (d, J = 8.5 Hz, 1H).

Step 2

Tert-butyl N-[2-(3,4-dimethoxy-N-methyl-anilino)-2-oxo-ethyl]carbamate (Intermediate lb)

In a 100 mL flask were added 3,4-dimethoxy-N-methyl-aniline (2.23 g, 13.34 mmol), 27 mL of ethyl acetate, 2-(tert-butoxycarbonylamino)acetic acid (2.8 g, 16 mmol), T P^® (11.8 mL, 20 mmol), and diisopropylethylamine (7.0 mL, 40.01 mmol). Reaction mixture was then stirred at room temperature for 1 hour. The reaction mixture was diluted in ethyl acetate, washed with a saturated aqueous solution of NaHC0₃, brine, and the organic phases were dried over Na₂S0₄ and evaporated to dryness to give 4.33 g of tert-butyl N-[2-(3,4-dimethoxy-N-methyl- anilino)-2-oxo-ethyl]carbamate as a yellow powder, leading to a 100 % yield. It was used without further purification in the next step of the synthesis.

MS: [M+H]⁺ m/z = 325.

1H NMR (DMSO- 6): δ (ppm) 1.35 (s, 9H) ; 3.13 (s, 3H) ; 3.43 (d, J

2H) ; 3.76 (s, 3H) ; 3.78 (s, 3H) ; 6.68 (t, J = 5.0 Hz, 1H) ; 6.85 (dd, J

Hz, 1H) ; 6.96 (d, J = 2.7 Hz, 1H) ; 6.99 (d, J = 8.5 Hz, 1H). Step 3

2-amino-N-(3,4-dimethoxyphen l)-N-methyl-acetamide (Intermediate 1)

CF₃COO-

Tert-butyl N-[2-(3,4-dimethoxy-N-methyl-anilino)-2-oxo-ethyl]carbamate (4.33 g, 13.4 mmol) was dissolved in 34 mL of DCM. 13 mL of trifluoroacetic acid were added and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was evaporated to dryness to give 4.60 g of 2- amino-N-(3,4-dimethoxyphenyl)-N-methyl-acetamide as a dark oil, leading to a 100% yield. It was used without further purification in the next step of the synthesis.

MS: [M+H]⁺ m/z = 225.

1H NMR (DMSO- 6): δ (ppm) 3.19 (s, 3H) ; 3.43 (d, J = 5.5 Hz, 2H) ; 3.77 (s 3H) ; 3.78 (s, 3H) ; 6.87-6.92 (dd, J = 8.5, 2.7 Hz, 1H) ; 6.98 (d, J = 2.7 Hz, 1H) 7.02 (d, J = 8.5 Hz, 1H) ; 7.95 (s, 3H).

EXAMPLES 1 - 5:

Synthesis of the intermediate 2:

Step 4

N-(3,4-dimethoxyphenyl)-2-[(4-fluoro-3-methoxy- phenyl)carbamothioylamino]-N-methyl-acetamide (Intermediate 2a)

In a 250 mL flask, Ι,Γ-Thiocarbonyldiimidazole (2.67 g, 14.96 mmol) was added in 36 mL of dioxane. [2-(3,4-dimethoxy-N-methyl-anilino)-2-oxo- ethyl]ammonium;2,2,2-trifluoroacetate (4.60 g, 13.6 mmol) was dissolved in 100 mL of dioxane. The acidic solution was then neutralized by addition of triethylamine, and then added dropwise in the flask. The solution was then stirred at room temperature for 1.5 hour. Then 4-fluoro-3-methoxy-aniline (1.92 g, 13.6 mmol) and triethylamine (5.70 mL, 40.79 mmol) were added to the solution. Reaction mixture was stirred at 60°C overnight. The solvent was removed. Residue was dissolved in ethyl acetate, and washed with water, aqueous 0.1 N HCl solution, brine, and dried over MgS0₄. After evaporation, precipitation of the crude in ethanol gave 3.78 g of N-(3,4-dimethoxyphenyl)-2-[(4-fluoro-3-methoxy- phenyl)carbamothioylamino]-N-methyl-acetamide as a yellow powder, leading to a 68% yield.

MS: [M+H]⁺ m/z = 408.

1H NMR (DMSO- 6): δ (ppm) 3.17 (s, 3H) ; 3.77 (s, 3H) ; 3.79 (s, 3H) ; 3.81 (s, 3H) ; 4.01 (d, J = 4.0 Hz, 2H) ; 6.87-6.92 (m, 2H) ; 7.03 (d, J = 8.5 Hz, 1H) ; 7.12-7.19 (dd, J = 11.3, 8.5 Hz, 1H) ; 7.36-7.40 (dd, J = 8.5, 2.3 Hz, 1H) ; 7.78 (t, J = 4.0 Hz, 1H) ; 9.92 (s, 1H).

Step 5

2-[[(Z)-C-[(4-bromo-2,6-difluoro-phenyl)methylsulfanyl]-N-(4-fluoro-3- methoxy-phenyl)carbonimidoyl]amino]-N-(3,4-dimethoxyphenyl)-N-methyl- acetamide (Intermediate 2b)

The titled product was obtained as an oily residue (4.05 g, 94%), following Procedure A, using N-(3,4-dimethoxyphenyl)-2-[[(Z)-N-(4-fluoro-3-methoxy- phenyl)-C-sulfanyl-carbonimidoyl] amino] -N-methyl-acetamide (Intermediate 1 ) (3 g) and 5-bromo-2-(chloromethyl)-l,3-difluoro-benzene (Intermediate 3) (1.71 g).

MS: [M+H]⁺ m/z = 613.

1H NMR (CDC1₃): δ (ppm) 3.30 (s, 3H) ; 3.82 (s, 3H) ; 3.87 (s,3H) ; 3.91 (s, 3H) ; 3.85 (s, 2H) ; 4.07 (s, 2H) ; 5.80 (s, 1H) ; 6.31 (s, 1H) ; 6.44 (s, 1H) ; 6.70 (s, 1H) ; 6.78 (d, J = 8.3 Hz, 1H) ; 6.86 (d, J = 8.3 Hz, 1H) ; 6.93 (d, J = 9.0 Hz, 1H) ; 7.03-7.13 (m, 2H).

Synthesis of intermediate 3:

5-bromo-2-(chloromethyl)-l,3-difluoro-benzene

(4-Bromo-2,6-difluoro-phenyl)-methanol (2.5 g, 11.21 mmol) and TEA (1.66 mL, 12.33 mmol) were dissolved in dry DCM at 0°C. Mesyl chloride (0.87 mL, 11.21 mmol) was then added dropwise, and the reaction mixture was stirred at room temperature overnight. Water was then added to quench the reaction. The organic phase was then washed with water and brine, and dried over Na₂S0₄, and then evaporated to give 2.23 g of 5-bromo-2-(chloromethyl)- l,3-difluoro-benzene as a yellow oil are obtained, leading to a 83% yield. It was used without further purification in the next step of the synthesis.

Step 6

2-[(4-bromo-2,6-difluoro-phenyl)methylsulfanyl]-N-(3,4-dimethoxyphenyl)-3- (4-fluoro-3-methoxy-phenyl)-N-methyl-imidazol-4-amine (Intermediate 2)

In microwave tubes were added 2-[[(Z)-C-[(4-bromo-2,6-difluoro- phenyl)methylsulfanyl]-N-(4-fluoro-3-methoxy-phenyl)carbonimidoyl]amino]-N- (3,4-dimethoxyphenyl)-N-methyl-acetamide (Intermediate 2b) (4 g, 6.53 mmol), 33 mL of ethyl acetate, T₃P^® (11.5 mL, 19.6 mmol) and diisopropylethylamine (7.24 mL, 39.2 mmol). The reaction mixture was heated under microwave irradiation at 150°C for 10 min. The crude was diluted in ethyl acetate and was then washed with a saturated aqueous solution of NaHC0₃, and with brine. Organic phase was dried over Na₂S0₄ and evaporated to dryness. Purification of the crude by flash chromatography using as eluent a mixture of DCM/MeOH (99/1) gave 2.66 g of 2-[(4-bromo-2,6-difluoro-phenyl)methylsulfanyl]-N-(3,4- dimethoxyphenyl)-3-(4-fluoro-3-methoxy-phenyl)-N-methyl-imidazol-4-amine (Intermediate 2) as a yellow oil, leading to a 69% yield.

MS: [M+H]⁺ m/z = 595.

1H NMR (CDC1₃): δ (ppm) 2.90 (s, 3H) ; 3.55 (s, 3H) ; 3.80 (s, 3H) ; 3.82 (s, 3H) ; 4.12 (s, 2H) ; 6.13-6.18 (dd, J = 8.5, 2.8 Hz, 1H) ; 6.30 (d, J = 2.8 Hz, 1H) ; 6.51- 6.54 (dd, J = 7.6, 2.6 Hz, 1H) ; 6.58-6.63 (m, 1H) ; 6.74 (d, J = 8.5 Hz, 1H) ; 7.00- 7.04 (m, 4H). EXAMPLE 1:

Step 7

EXAMPLE la. 4-[4-[[5-(3,4-dimethoxy-N-methyl-anilino)-l-(4-fluoro-3- methoxy-phenyl)imidazol-2-yl]sulfanylmethyl]-3,5-difluoro-phenyl]benzoic acid

The titled product was obtained as a white powder, after precipitation in EtOH (194 mg, 35%), following Procedure C, using 2-[(4-bromo-2,6-difluoro- phenyl)methylsulfanyl]-N-(3,4-dimethoxyphenyl)-3-(4-fluoro-3-methoxy- phenyl)-N-methyl-imidazol-4-amine (Intermediate 2) (40 mg) and 4- boronobenzoic acid (70 mg).

MS: [M+H]⁺ m/z = 636.

1H NMR (DMSO- 6): δ (ppm) 2.92 (s, 3H) ; 3.48 (s, 3H) ; 3.59 (s, 3H) ; 3.65 (s, 3H) ; 4.13 (s, 2H) ; 6.06 (dd, J = 8.8, 2.8 Hz, 1H) ; 6.24 (d, J = 2.8 Hz, 1H) ; 6.61- 6.67 (m, 1H) ; 6.75 (d, J = 8.8 Hz, 1H) ; 6.78 (dd, J = 7.9, 2.5 Hz, 1H) ; 7.02 (s, 1H) ; 7.17 (dd, J = 11.4, 8.4 Hz, 1H) ; 7.52 (d, J = 9.2 Hz, 2H) ; 7.87 (d, J = 8.4 Hz, 2H) ; 8.01 (d, J = 8.4Hz, 2H) ; 13.08 (s, 1H). Step 8:

4-[4-[[5-(3,4-dimethoxy-N-methyl-anilino)-l-(4-fluoro-3-methoxy- phenyl)imidazol-2-yl]sulfanylmethyl] -3,5-difluoro-phenyl] -N- [2- [2- methoxypolyethyleneglycoxy]ethyl]benzamide (m = 4 - 12)

m = 4-12

In a 5 mL flask were added 4-[4-[[5-(3,4-dimethoxy-N-methyl-anilino)- 1-(4- fluoro-3-methoxy-phenyl)imidazol-2-yl]sulfanylmethyl]-3,5-difluoro- phenyfjbenzoic acid (100 mg, 0.16 mmol), NEt₃ (21.23 μί, 0.16 mmol), DCC (32.46 mg, 0.16 mmol), HOBt (21.26 mg, 0.16 mmol), and 2-[2- methoxypolyethyleneglycoxy]ethanamine (74.19 mg, 0.16 mmol) in 1 mL of DCM. The reaction mixture was stirred overnight at room temperature. The reaction mixture was evaporated and purified by preparative HPLC to give 106 mg of 4-[4-[[5-(3,4-dimethoxy-N-methyl-anilino)-l-(4-fluoro-3-methoxy- phenyl)imidazol-2-yl]sulfanylmethyl]-3,5-difluoro-phenyl]-N-[2-[2- methoxypolyethyleneglycoxy]ethyl]benzamide (m = 4 - 12) as a white powder, leading to a 62% yield.

MS: [M+ H]⁺ m/z = 1089.

1H NMR (CD₂C1₂): δ (ppm) 2.94 (s, 3H) ; 3.35 (s, 3H) ; 3.53 (s, 3H) ; 3.56-3.64 (m, 24H) ; 3.65-3.68 (m, 8H) ; 3.75 (s, 3H) ; 3.77 (s, 3H) ; 4.20 (s, 2H) ; 6.18 (dd, J = 8.7, 2.8 Hz, 1H) ; 6.32 (d, J = 2.8 Hz, 1H) ; 6.61 (dd, J = 7.7, 2.6 Hz, 1H) ; 6.63-6.69 (m, 1H) ; 6.73 (d, J = 8.7 Hz, 1H) ; 7.00 (d, J = 10.9, 8.5 Hz, 1H) ; 7.02 (s, 1H) ; 7.16 (d, J = 8.6 Hz, 2H) ; 7.63 (d, J = 8.6 Hz, 2H) ; 7.92 (d, J = 8.6 Hz, 2H).

^1JC NMR (CD₂C1₂): δ (ppm) 25.4 ; 34.3 ; 40.3 ; 56.2 ; 56.3 ; 56.9 ; 70.2 ; 70.9 ; 72.2 ; 100.5 ; 105.8 ; 110.2 (m) ; 113.4 (t, J = 9.3 Hz) ; 113.5, 116.1 (d, J = 19.5 Hz) ; 120.1 (d, J = 7.0 Hz) ; 125.1 ; 127.1 ; 128.3 ; 131.5 (d, J = 4.2 Hz) ; 135.2 ; 138.3 ; 139.8 ; 141.2 ; 142.2 ; 143.2 ; 143.9 ; 148.1 (d, J = 12.5 Hz) ; 150.3 ; 152.4 (d, J = 248.1 Hz) ; 161.8 (dd, J = 248.1, 8.9 Hz) ; 166.8.

EXAMPLE 2:

4-[4-[[5-(3,4-dimethoxy-N-methyl-anilino)-l-(4-fluoro-3-methoxy- phenyl)imidazol-2-yl]sulfanylmethyl] -3,5-difluoro-phenyl] -N- [2- [2- methoxypolyethylene lycoxy]ethyl]benzamide (m = 11-25)

m = 1 1 - 25 The titled product was obtained as an oily residue, after purification by preparative HPLC (40 mg, 43%), following Procedure C, using 2-[(4-bromo-2,6- difluoro-phenyl)methylsulfanyl]-N-(3,4-dimethoxyphenyl)-3-(4-fluoro-3- methoxy-phenyl)-N-methyl-imidazol-4-amine (Intermediate 2) (40 mg) and [4-[2- [2-methoxypolyethyleneglycoxy]ethylcarbamoyl]phenyl]boronic acid (Intermediate 4) (62.4 mg).

MS: [M+H]⁺ m/z = 1353.

1H NMR (CD₂C1₂): δ (ppm) 2.91 (s, 3H) ; 3.33 (s, 3H) ; 3.50 (s, 3H) ; 3.48-3.51 (m, 2H) ; 3.53-3.70 (m, 72H) ; 3.72 (s, 3H) ; 3.74 (s, 3H) ; 4.17 (s, 2H) ; 6.13-6.17 (dd, J = 8.7, 2.8 Hz, 1H) ; 6.29 (d, J = 2.8 Hz, 1H) ; 6.57-6.60 (dd, J = 7.9, 2.4 Hz, 1H) ; 6.61-6.60 (m, 1H) ; 6.71 (d, J = 8.7 Hz, 1H) ; 6.96 (d, J = 8.4 Hz, 1H) ; 7.00 (s, 1H) ; 6.99 (d, J = 8.4 Hz, 1H) ; 7.13 (d, J = 8.4 Hz, 2H) ; 7.61 (d, J = 8.4 Hz, 2H) ; 7.90 (d, J = 8.4 Hz, 1H).

¹³C NMR (CD₂C1₂): δ (ppm) 26.2 ; 40.3 ; 56.2 ; 56.3 ; 56.9 ; 59.0 ; 70.1 ; 70.7 ; 70.8 ; 70.9 ; 72.3 ; 100.4 ; 105.8 ; 109.8-110.5 (m) ; 113.4 (d, J = 2.6 Hz) ; 113.5 ; 113.5 (t, J = 19.7 Hz) ; 116.1 (d, J = 19.8 Hz) ; 120.1 (d, J = 7.2 Hz) ; 125.1 ; 127.2 ; 128.3 ; 131.6 (d, J = 3.5 Hz) ; 135.2 ; 138.3 ; 139.8 ; 141.2 (t, J = 1.7 Hz) ; 142.1 (t, J = 9.8 Hz) ; 143.2 ; 144.0 ; 148.0 (d, J = 11.5 Hz) ; 150.4 ; 152.4 (d, J = 247.9 Hz) ; 161.8 (dd, J = 248.9, 8.6 Hz) ; 166.8.

Synthesis of Intermediate 4:

[4- [2- [2-methoxypolyethyleneglycoxy] ethylcarbamoyl] phenyl] boronic acid (m = 15-21)

H

m = 15-21

In a 25 mL flask were added 4-boronobenzoic acid (30 mg, 0.18 mmol), 2-[2- methoxypolyethyleneglycoxy]ethanamine (141.01 mg, 0.18 mmol), hydroxybenzotriazole (24.5 mg, 0.18 mmol), dicyclohexylcarbodiimide (37.3 mg, 0.18 mmol) and triethylamine (24.39 μΐ,, 0.18 mmol) in 400 μί. of dichloromethane (QS 0.3 M). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was diluted in ethyl acetate and washed with water. The aqueous layer was extracted with dichloromethane, dried over Na₂S0₄, filtered and concentrated under reduced pressure to give 110 mg of [4- [2- [2- methoxypolyethyleneglycoxy]ethylcarbamoyl]phenyl]boronic acid (m = 15-21) as a colorless oil, leading to a 66% yield. It was used without further purification in the next step of the synthesis.

MS: [M+H₃0]⁺ m/z = 990.

1H NMR DMSO-d6): δ (ppm) 3.23 (s, 3H) ; 3.32 (s, 4H) ; 3.40-3.44 (m, 4H) ; 3.45-3.60 (m, 62H) ; 7.78 (d, J = 8.2 Hz, 2H) ; 7.84 (d, J = 8.2 Hz, 2H) ; 8.17 (s, 1H).

EXAMPLE 3: 4-[4-[[5-(3,4-dimethoxy-N-methyl-anilino)-l-(4-fluoro-3- methoxy-phenyl)imidazol-2-yl]sulfanylmethyl]-3,5-difluoro-phenyl]-N-[2-[2- methoxypolyethyleneglycoxy]ethyl]benzamide (m = 31-57)

m = 31 - 57

The titled product was obtained as an oily residue after a purification by preparative HPLC (93 mg, 47%), following Procedure C, using 2-[(4-bromo-2,6- difluoro-phenyl)methylsulfanyl]-N-(3,4-dimethoxyphenyl)-3-(4-fluoro-3- methoxy-phenyl)-N-methyl-imidazol-4-amine (Intermediate 2) (45 mg) and [4-[2- [2-methoxypolyethyleneglycoxy]ethylcarbamoyl]phenyl]boronic acid (m = 36-53) (Intermediate 5) (163.6 mg). MS: [M+H+H₃0]^/+ m/z = 1347.

1H NMR (CD₂C1₂): δ (ppm) 3.33 (s, 3H) ; 3.49 (s, 3H) ; 3.51-3.66 (m, 180H) ; 3.71 (s, 3H) ; 3.74 (s, 3H) ; 4.16 (s, 2H) ; 6.12-6.16 (dd, J = 8.6, 2.7 Hz, 1H) ; 6.29 (d, J = 2.7 Hz, 1H) ; 6.55-6.64 (m, 2H) ; 6.69 (d, J = 8.6 Hz, 1H) ; 6.94-7.00 (dd, J = 10.8, 8.4 Hz, 1H) ; 6.99 (s, 1H) ; 7.10-7.14 (m, 1H) ; 7.13 (d, J = 8.4 Hz, 2H) ; 7.59 (d, J = 8.6 Hz, 2H) ; 7.89 (d, J = 8.6 Hz, 2H).

¹³C NMR (CD₂C1₂): δ (ppm) 25.9 ; 39.9 ; 55.8 ; 55.9 ; 56.5 ; 58.6 ; 69.7 ; 70.3 ; 70.4 ; 70.5 ; 71.8 ; 100.1 ; 105.5 ; 109.5-110.0 (m) ; 113.0 (d, J = 3.0 Hz) ; 113.1 (t, J = 19.6 Hz) ; 113.1 ; 115.7 (d, J = 19.2 Hz) ; 119.8 (d, J = 7.3 Hz) ; 124.7 ; 126.8 ; 127.9 ; 131.1 (d, J = 3.5 Hz) ; 134.8 ; 137.9 ; 139.4 ; 140.8 (t, J = 2.3 Hz) ; 141.8 (t, J = 9.9 Hz) ; 142.8 ; 143.5 ; 147.6 (d, J = 11.7 Hz) ; 150.0 ; 152.0 (d, J = 248.1 Hz) ; 161.4 (dd, J = 249.2, 8.8 Hz) ; 166.4.

Synthesis of intermediate 5:

[4-[2-[2-methoxypolyethyleneglycoxy]ethylcarbamoyl]phenyl]boronic acid (m

= 36-53)

m = 36 - 53

In a 25 mL flask were added 4-boronobenzoic acid (20 mg, 0.12 mmol), 2- [2- methoxypolyethyleneglycoxy]ethanamine (243 mg, 0.12 mmol), hydroxybenzotriazole (17 mg, 0.12 mmol), dicyclohexylcarbodumide (25 mg, 0.12 mmol) and triethylamine (16.26 μί, 0.12 mmol) in 400 μΐ_^ of dichloromethane. The reaction mixture was stirred at room temperature overnight. Hydroxybenzotriazole (17 mg, 0.12 mmol), dicyclohexylcarbodumide (25 mg, 0.12 mmol) and triethylamine (16.26 μί, 0.12 mmol) were added again at the reaction mixture and it was stirred at room temperature for 24 h at 40°C. The reaction mixture was filtered and concentrated under reduced pressure. Purification of the crude by preparative HPLCgave 166 mg of [4- [2- [2- methoxypolyethyleneglycoxy]ethylcarbamoyl]phenyl]boronic acid (m = 36-53) as a white powder, leading to a 64% yield.

MS: [M+2H₃0]⁺ m/z = 1098.5.

1H NMR (CD₂C1₂): δ (ppm) 3.36 (s, 3H) ; 3.47-3.75 (m, 176H) ; 6.27( s, 2H) ; 7.04 (s, 1H) ; 7.79 (d, J = 7.6 Hz, 2H) ; 7.91 (d, J = 7.6 Hz, 2H).

EXAMPLE 4: N-[4-[4-[[5-(3,4-dimethoxy-N-methyl-anilino)-l-(4-fluoro-3- methoxy-phenyl)imidazol-2-yl]sulfanylmethyl]-3,5-difluoro-phenyl]phenyl]- -[2-methoxypolyethyleneglycoxy]acetamide (m = 99-133)

m = 99-133

Step 7:

2- [[4- (4-aminophenyl) -2,6-difluoro-phenyl] methylsulf anyl] -N- (3,4- dimethoxyphenyl)-3-(4-fluoro-3-methoxy-phenyl)-N-methyl-imidazol-4- amine

The titled product was obtained as an oily residue after purification by flash chromatography using as eluent a mixture of DCM/MeOH (97/3) (51 mg, 50%), following Procedure C, using 2-[(4-bromo-2,6-difluoro-phenyl)methylsulfanyl]- N-(3,4-dimethoxyphenyl)-3-(4-fluoro-3-methoxy-phenyl)-N-methyl-imidazol-4- amine (Intermediate 2) (100 mg) and 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)aniline (36.7 mg). MS: [M+H]⁺ m/z = 607.

1H NMR (CDC1₃): δ (ppm) 2.89 (s, 3H) ; 3.47 (s, 3H) ; 3.79 (s, 3H) ; 3.81 (s, 3H) ; 3.85 (s, 2H) ; 4.20 (s, 2H) ; 6.13-6.19 (dd, J = 8.7, 2.7 Hz, 1H) ; 6.33 (d, J = 2.7 Hz, 1H) ; 6.49-6.55 (dd, J = 1.5, 2.4 Hz, 1H) ; 6.56-6.62 (m, 1H) ; 6.72 (d, J = 8.6 Hz, 1H) ; 6.72 (d, J = 8.9 Hz, 2H) ; 6.93 (d, J = 8.6 Hz, 1H) ; 6.96 (d, J = 8.9 Hz, 1H) ; 7.06 (s, 1H) ; 7.31 (d, J = 8.6 Hz, 2H).

Step 8:

EXAMPLE 4: N-[4-[4-[[5-(3,4-dimethoxy-N-methyl-anilino)-l-(4-fluoro-3- methoxy-phenyl)imidazol-2-yl]sulfanylmethyl]-3,5-difluoro-phenyl]phenyl]- 2-[2-methoxypolyethyleneglycoxy]acetamide (m = 99-133)

m = 99-133

In a 10 mL flask were added 2-[[4-(4-aminophenyl)-2,6-difluoro- phenyl]methylsulfanyl]-N-(3,4-dimethoxyphenyl)-3-(4-fluoro-3-methoxy- phenyl)-N-methyl-imidazol-4-amine (51 mg, 0,09 mmol), 2-[2- methoxyployethyleneglycoxy]acetyl chloride (Intermediate 6) (389.54 mg, 0.08 mmol), DIEA (18.26 μί, 0.1 mmol) in 1 mL of dichloromethane. The reaction mixture was stirred at room temperature overnight. The reaction mixture was evaporated to dryness. The crude was dissolved in acetone and ether was added to precipitate the compound. The precipitate was purified by preparative HPLC to give 138 mg of N-[4-[4-[[5-(3,4-dimethoxy-N-methyl-anilino)- l-(4-fluoro-3- methoxy-phenyl)imidazol-2-yl]sulfanylmethyl]-3,5-difluoro-phenyl]phenyl]-2-[2- methoxypolyethyleneglycoxy]acetamide (m = 99- 133) as yellowish oil, leading to a 29% yield.

MS: [M+3H₃0+H]⁴⁺ m/z = 1155.4. 1H NMR (CD₂CI₂): δ (ppm) 3.35 (s, 3H) ; 3.36-3.40 (m, 3H) ; 3.51 (s, 3H) ; 3.52- 3.55 (m, 4H) ; 3.55-3.66 (m, 480H) ; 3.66-3.70 (m, 6H) ; 3.73 (s, 3H) ; 3.72-3.78 (m, 6H) ; 3.76 (s, 3H) ; 3.77-3.82 (m, 3H) ; 3.83-3.87 (m, 3H) ; 4.12 (s, 2H) ; 4.18 (s, 2H) ; 6.16 (dd, J = 8.7, 2.7 Hz, 1H) ; 6.31 (d, J = 2.7 Hz, 1H) ; 6.59 (dd, J = 7.6, 2.5 Hz, 1H) ; 6.60-6.66 (m, 1H) ; 6.72 (d, J = 8.7 Hz, 1H) ; 7.00 (dd, J = 11.0, 2.5 Hz, 1H) ; 7.02 (s, 1H) ; 7.10 (d, J = 8.7 Hz, 2H) ; 7.54 (d, J = 8.7 Hz, 2H) ; 7.75 (d, J = 8.7 Hz, 2H) ; 8.96 (s, 1H).

Synthsesis of intermediate 6:

2-[2-methoxyployethyleneglycoxy]acetyl chloride

2-[2-methoxypolyethyleneglycoxy]ethanamine (400 mg, 0.08 mmol) was dissolved in dry DCM (200 μΙ_). Thionyl chloride (58.79 μί, 0.81 mmol) was added and the reaction mixture was stirred at room temperature during 1 h. The reaction mixture was evaporated to dryness to give 401 mg of 2-[2- methoxyployethyleneglycoxy] acetyl chloride as a yellow oil, leading to a quantitative yield. The crude was used without further purification in the next step of the synthesis. EXAMPLE 5: 4-[4-[[5-(3,4-dimethoxy-N-methyl-anilino)-l-(4-fluoro-3- methoxy^henyl)imidazol-2-yl]sulfanylmethyl]-3,5-difluoro-phenyl]-N-[2-[2- methoxypolyeth leneglycoxy]ethyl]benzamide (m = 100-138)

Step 7

4-[4-[[5-(3,4-dimethoxy-N-methyl-anilino)-l-(4-fluoro-3-methoxy- phenyl)imidazol-2-yl]sulfanylmethyl]-3,5-difluoro-phenyl]benzoic acid (EXAMPLE l

MS: [M+H]⁺ m/z = 636.

1H NMR (DMSO- 6): δ (ppm) 2.92 (s, 3H) ; 3.48 (s, 3H) ; 3.59 (s, 3H) ; 3.65 (s, 3H) ; 4.13 (s, 2H) ; 6.06 (dd, J = 8.8, 2.8 Hz, 1H) ; 6.24 (d, J = 2.8 Hz, 1H) ; 6.61- 6.67 (m, 1H) ; 6.75 (d, J = 8.8 Hz, 1H) ; 6.78 (dd, J = 7.9, 2.5 Hz, 1H) ; 7.02 (s, 1H) ; 7.17 (dd, J = 11.4, 8.4 Hz, 1H) ; 7.52 (d, J = 9.2 Hz, 2H) ; 7.87 (d, J = 8.4 Hz, 2H) ; 8.01 (d, J = 8.4Hz, 2H) ; 13.08 (s, 1H).

Step 8:

EXAMPLE 5: 4-[4-[[5-(3,4-dimethoxy-N-methyl-anilino)-l-(4-fluoro-3- methoxy-phenyl)imidazol-2-yl]sulfanylmethyl]-3,5-difluoro-phenyl]-N-[2-[2- methoxypolyethyleneglycoxy]ethyl]benzamide (m = 100-138)

138

The titled product was obtained as a white powder, after purification by preparative HPLC (465 mg, 67%), following Procedure C, using 4-[4-[[5-(3,4- dimethoxy-N-methyl-anilino)-l-(4-fluoro-3-methoxy-phenyl)imidazol-2- yl]sulfanylmethyl]-3,5-difluoro-phenyl]benzoic acid (80 mg) and 2-[2- methoxypolyethyleneglycoxy]ethanamine (614 mg).

MS: [M+3H+H₃0]⁴⁺ m/z = 1377.5.

1H NMR (CD₂C1₂): δ (ppm) 2.93 (s, 3H) ; 3.35 (s, 3H) ; 3.50-3.80 (m, 480H) ; 3.68 (s, 3H) ; 3.72 (s, 3H) ; 3.76 (s, 3H) ; 4.22 (brs, 2H) ; 6.17 (dd, J = 8.8, 2.8 Hz, 1H) ; 6.30 (d, J = 2.8 Hz, 1H) ; 6.55 (brs, 1H) ; 6.71 (d, J = 8.8 Hz, 1H) ; 6.93 (brs, 1H) ; 7.00-7.27 (m, 4H) ; 7.60 (d, J = 8.3 Hz, 2H) ; 7.93 (d, J = 8.3 Hz, 2H).

Synthesis of intermediate 7:

2-[4-[2-methoxyethoxy]phenyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane

2-[2-methoxyethoxy]ethyl 4-methylbenzenesulfonate (160 mg, 0.07 mmol) was dissolved in ACN (250 mL), 4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2- yl)phenol (17.86 mg, 0.08 mmol) and K₂C0₃ (12.24 mg, 0.09 mmol) were added. The reaction mixture was stirred overnight under reflux. The reaction mixture was then cooled down, and filtered. The filtrate was concentrated under vacuum and purified by preparative HPLC to give 51 mg of 2-[4-[2-methoxyethoxy]phenyl]- 4,4,5,5-tetramethyl-l,3,2-dioxaborolane as a yellow oil, leading to a 31 % yield. MS: [M+2H₃0]⁺ m/z = 1126.

EXAMPLE 6 : 2- [[2,6-difluoro-4- [4- [2-methoxypolyethyleneglycoxy]phe- nyl]phenyl]methylsulfanyl]-N-(3,4-dimethoxyphenyl)-3-(4-fluoro-3-methoxy- phenyl)-N-methyl-imidazol-4-amine (m = 32-56)

The titled product was obtained as a yellow oil, after purification by preparative HPLC (28 mg, 46%), following Procedure C, using 2-[(4-bromo-2,6-difluoro- phenyl)methylsulfanyl]-N-(3,4-dimethoxyphenyl)-3-(4-fluoro-3-methoxy- phenyl)-N-methyl-imidazol-4-amine (Intermediate 2) (14 mg) and 2-[4-[2- methoxyethoxy]phenyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (m = 35-53) (Intermediate 7) (52.2 mg).

MS: [M+H+H₃0]²⁺ m/z = 1289.

1H NMR (CD₂C1₂): δ (ppm) 2.91 (s, 3H) ; 3.33 (s, 3H) ; 3.48 (s, 3H) ; 3.49-3.70 (m, 170H) ; 3.72 (s, 3H) ; 3.74 (s, 3H) ; 3.82-3.87 (m, 4H) ; 4.16 (m, 4H) ; 6.12- 6.16 (dd, J = 8.5, 2.7 Hz, 1H) ; 6.29 (d, J = 2.7 Hz, 1H) ; 6.53-6.57 (dd, J = 7.6, 2.2 Hz, 1H) ; 6.57-6.62 (m, 1H) ; 6.70 (d, J = 8.5 Hz, 1H) ; 6.93-7.02 (m, 4H) ; 7.05 (d, J = 8.5 Hz, 2H) ; 7.48 (d, J = 8.5 Hz, 2H).

¹³C NMR (CD₂CI₂): δ (ppm) 29.7 ; 39.9 ; 55.9 ; 56.5 ; 58.6 ; 67.7 ; 69.9 ; 70.5 (m) ; 70.8 ; 71.9 ; 100.0 ; 105.4 ; 109.0 (d, J = 24.6 Hz) ; 111.6 (t, J = 18.5 Hz) ; 113.1 ; 115.0 ; 115.7 (d, J = 19.5 Hz) ; 119.8 ; 124.8 ; 127.8 ; 130.7 ; 131.2 ; 138.1 ; 139.3 ; 142.5 ; 142.7 ; 143.6 ; 147.5 ; 147.7 ; 150.0 ; 151.9 (d, J = 249.6 Hz) ; 159.4 ; 161.4 (dd, J = 249.6, 11.0 Hz). EXAMPLE 7:

2-[[4-[4-[2-[2-[2-[2-[2-[2-[2-[2-[4-[4-[[5-(3,4-dimethoxy-N-methyl-anilino)-l- (4-fluoro-3-methoxy-phenyl)imidazol-2-yl]sulfanylmethyl]-3,5-difluoro- phenyl] phenoxy jethoxy] ethoxy] ethoxy ]ethoxy] ethoxy] ethoxy] ethoxy ]ethoxy] p henyl]-2,6-difluoro-phenyl]methylsulfanyl]-N-(3,4- dimethoxyphenyl)-3-(4- fluoro-3-methoxy-phenyl)-N-methyl-imidazol-4-amine

EXAMPLE 7A:

Step 7

4-[4-[[5-(3,4-dimethoxy-N-methyl-anilino)-l-(4-fluoro-3-methoxy- phenyl)imidazol- -yl]sulfanylmethyl]-3,5-difluoro-phenyl]phenol

The titled product was obtained as a yellow oil, after purification by flash chromatography (150 mg, 73%), following Procedure C, using 2-[(4-bromo-2,6- difluoro-phenyl)methylsulfanyl]-N-(3,4-dimethoxyphenyl)-3-(4-fluoro-3- methoxy-phenyl)-N-methyl-imidazol-4-amine (Intermediate 2) (200 mg) and 4- (4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)phenol (74.04 mg).

MS: [M+H]⁺ m/z = 608.

1H NMR (CDC1₃): δ (ppm) 2.97 (s, 3H) ; 3.63 (s, 3H) ; 3.81 (s, 2H) ; 3.83 (s, 3H) ; 3.85 (s, 3H) ; 6.23 (dd, J = 8.5, 2.7 Hz, 1H) ; 6.36 (d, J = 2.7 Hz, 1H) ; 6.70 (d, J = 8.7 Hz, 2H) ; 6.73 (s, 1H) ; 6.76 (d, J = 8.7 Hz, 1H) ; 6.87 (d, J = 9.5 Hz, 2H) ; 7.01 (s, 1H) ; 7.09 (dd, J = 10.6, 8.5 HZ, 1H) ; 7.13 (d, J = 8.6 Hz, 2H) ; 7.27 (s, 1H).

Step 8

2-[[4-[4-[2-[2-[2-[2-[2-[2-[2-[2-[4-[4-[[5-(3,4-dimethoxy-N-methyl-anilino)-l- (4-fluoro-3-methoxy-phenyl)imidazol-2-yl]sulfanylmethyl]-3,5-difluoro- phenyl] phenoxy ]ethoxy] ethoxy ] ethoxy ]ethoxy ] ethoxy ] ethoxy ] ethoxy ]ethoxy ] p henyl]-2,6-difluoro-phenyl]methylsulfanyl]-N-(3,4- dimethoxyphenyl)-3-(4- fluoro-3-methoxy-phenyl)-N-methyl-imidazol-4-amine

In a microwave tube were added 4-[4-[[5-(3,4-dimethoxy-N-methyl-anilino)-l-(4- fluoro-3-methoxy-phenyl)imidazol-2-yl]sulfanylmethyl]-3,5-difluoro- phenyl]phenol (250 mg, 0.41 mmol), potassium carbonate (68.24 mg, 0.49 mmol), and 1.30 mL of acetonitrile. 2-[2-[2-[2-[2-[2-[2-(p- tolylsulfonyloxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy] ethyl 4- methylbenzenesulfonate (Intermediate 8) (125.68 mg, 0.19 mmol) and it was stirred under microwave irradiation at 100°C for 1 h and then 30 min at 110°C. The reaction mixture was evaporated to dryness, diluted in ethyl acetate, washed with water, brine, dried over MgS0₄ and evaporated to dryness. Purification of the crude by flash chromatography using as eluent a mixture of DCM/MeOH (97/3) gave 50 mg of the desired product not clean. Purification by preparative TLC using as eluent a mixture of DCM/MeOH (95/5) gave 17.5 mg of 2- [[4- [4- [2- [2- [2-[2-[2-[2-[2-[2-[4-[4-[[5-(3,4-dimethoxy-N-methyl-anilino)-l-(4-fluoro-3- methoxy-phenyl)imidazol-2-yl]sulfanylmethyl]-3,5-difluoro- phenyl] phenoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] phe nyl]-2,6-difluoro-phenyl]methylsulfanyl]-N-(3,4-dimethoxyphenyl)-3-(4-fluoro-3- methoxy-phenyl)-N-methyl-imidazol-4-amine as a yellowish oil, leading to a 3% yield.

MS: [M+2H]²⁺ m/z = 776.

1H NMR (CD₂C1₂): δ (ppm) 2.93 (s, 6H) ; 3.51 (s, 6H) ; 3.58-3.63 (m, 16H) ; 3.63-3.67 (m, 4H) ; 3.68-3.72 (m, 4H) ; 3.74 (s, 6H) ; 3.77 (s, 6H) ; 3.84-3.89 (m, 4H) ; 4.18 (s, 4H) ; 4.15-4.20 (m, 4H) ; 6.17 (dd, J = 8.8, 2.8 Hz, 2H) ; 6.32 (d, J = 2.8 Hz, 2H) ; 6.58 (dd, J = 7.6, 2.4 Hz, 2H) ; 6.60-6.66 (m, 2H) ; 6.73 (d, J = 8.8 Hz, 2H) ; 6.95-7.11 (m, 6H) ; 7.03 (s, 2H) ; 7.07 (d, J = 8.9 Hz, 4H) ; 7.50 (d, J = 8.9 Hz, 4H).

¹³C NMR (CD₂C1₂): δ (ppm) 26.0 ; 39.9 ; 55.9 ; 55.9 ; 56.5 ; 67.6 ; 69.9 ; 70.5 ; 70.8 ; 100.0 ; 105.4 ; 109.0 (dd, J = 17.6, 7.9 Hz) ; 111.6 (t, J = 19.9 Hz) ; 113.0 (d, J = 2.6 Hz) ; 113.1 ; 115.0 ; 115.7 (d, J = 19.6 Hz) ; 119.8 (d, J = 7.2 Hz) ; 124.7 ; 127.8 ; 129.3 (d, J = 9.6 Hz) ; 130.7 ; 131.2 (d, J = 3.6 Hz) ; 138.0 ; 139.3 ; 142.7 ; 143.6 ; 147.6 (d, J = 11.4 Hz) ; 150.0 ; 152.0 (d, J = 248.1 Hz) ; 159.4 ; 161.4 (dd, J = 248.1, 8.9 Hz).

Synthesis of the intermediate 8

2-[2-[2-[2-[2-[2-[2-(p- tolylsulfonyloxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy] ethyl 4- methylbenzenesulfonate

The mixture of triethylamine (0.85 mL, 6.07 mmol), 4-Toluenesulfonyl chloride (1029.31 mg, 5.4 mmol) and 4-Dimethylaminopyridine (32.98 mg, 0.27 mmol) were diluted in CH₂CI₂ (3.5 mL). This solution was cooled in an ice bath and to it was added 2- [2- [2- [2- [2- [2- [2- (2- hydroxyethoxy)ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethanol (500 mg, 1.35 mmol). The reaction stirred for 3 h and was then concentrated under reduced pressure. Purification of the crude by flash chromatography using as eluent a mixture of DCM/MeOH (96/4) gave 833 mg of 2-[2-[2-[2-[2-[2-[2-(p- tolylsulf onyloxy)ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethyl 4- methylbenzenesulfonate as a colorless oil, leading to a 91% yield.

MS: [M+NH₄]⁺ m/z = 696.

1H NMR (CD₂CI₂): δ (ppm) 2.44 (s, 6H) ; 3.54 (s, 8H) ; 3.57 (s, 8H) ; 3.58 (s, 8H) ; 3.64 (t, J = 4.7 Hz, 4H) ; 4.12 (t, J = 4.7 Hz, 4H) ; 7.37 (d, J = 8.3 Hz, 4H) ; 7.78 (d, J = 8.3 Hz, 4H). EXAMPLE 8: 2-[[4-[4-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[4-[4-[[5-(3,4-dimethoxy-N-methyl- anilino)-l-(4-fluoro -methoxy-phenyl)imidazol-2-yl]sulfanylmethyl]-3,5- difluoro- phenyl] phenoxy ]ethoxy] ethoxy] ethoxy ]ethoxy] ethoxy] ethoxy] ethoxy ]ethoxy] e thoxy]ethoxy]ethoxy]ethoxy]phenyl]-2,6-difluoro-phenyl]methylsulfanyl]-N- (3,4- dimethoxyphenyl)-3-(4-fluoro-3-methoxy-phenyl)-N-methyl-imidazol-4- amine

Step 7

4-[4-[[5-(3,4-dimethoxy-N-methyl-anilino)-l-(4-fluoro-3-methoxy- phenyl)imidazol-2-yl]sulfanylmethyl]-3,5-difluoro-phenyl]phenol

(EXAMPLE 7a)

MS: [M+H]⁺ m/z = 608.

Step 8 EXAMPLE 8: 2-[[4-[4-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[4-[4-[[5-(3,4- dimethoxy-N-methyl-anilino)-l-(4-fluoro-3-methoxy-phenyl)imidazol-2- yl]sulfanylmethyl]-3,5-difluoro- phenyl] phenoxy ]ethoxy] ethoxy ] ethoxy ]ethoxy ] ethoxy ] ethoxy ] ethoxy ]ethoxy ] e thoxy]ethoxy]ethoxy]ethoxy]phenyl]-2,6-difluoro-phenyl]methylsulfanyl]-N- (3,4- dimethoxyphenyl)-3-(4-fluoro-3-methoxy-phenyl)-N-methyl-imidazol-4- amine

In a microwave tube were added 4-[4-[[5-(3,4-dimethoxy-N-methyl-anilino)-l-(4- fluoro-3-methoxy-phenyl)imidazol-2-yl]sulfanylmethyl]-3,5-difluoro- phenyl]phenol (200 mg, 0.33 mmol), potassium carbonate (54.59 mg, 0.39 mmol), and 1.1 mL of acetonitrile (QS 0.3 M). 2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(p- tolylsulf onyloxy)ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] eth oxy]ethoxy] ethyl 4-methylbenzenesulfonate (Intermediate 9) (126.64 mg, 0.15 mmol) and it was stirred under microwave irradiation at 100°C for 10 min and then 30 min at 100°C. 120 mg of Intermediate 9 were added at the reaction mixture and it was stirred under reflux overnight. The reaction mixture was evaporated to dryness, diluted in ethyl acetate, washed with water, brine, dried over MgS0₄ and evaporated to dryness. Purification of the crude by flash chromatography using as eluent a mixture of DCM/MeOH (97/3) gave 30 mg of the product not clean. Purification of the crude by preparative TLC(DCM/MeOH 95/5) gave 23 mg of 2-[[4-[4-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[4-[4-[[5-(3,4- dimethoxy-N-methyl-anilino)-l-(4-fluoro-3-methoxy-phenyl)imidazol-2- yl]sulfanylmethyl]-3,5-difluoro- phenyl] phenoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] etho xy] ethoxy] ethoxy] ethoxy] phenyl] -2,6-difluoro-phenyl] methylsulf anyl] -N- (3 ,4- dimethoxyphenyl)-3-(4-fluoro-3-methoxy-phenyl)-N-methyl-imidazol-4-amine as a yellowish oil, leading to a 4% yield.

MS: [M+2H]²⁺ m/z = 864. 1H NMR (CD₂CI₂): δ (ppm) 2.95 (s, 6H) ; 3.51 (s, 6H) ; 3.60-3.64 (m, 32H) ; 3.64-3.68 (m, 4H) ; 3.70-3.73 (m, 4H) ; 3.74 (s, 6H) ; 3.77 (s, 6H) ; 3.85-3.89 (m, 4H) ; 4.15-4.20 (m, 4H) ; 4.18 (s, 4H) ; 6.18 (dd, J = 8.7, 2.8 Hz, 2H) ; 6.31 (d, J = 2.8 Hz, 2H) ; 6.55 (dd, J = 7.6, 2.4 Hz, 2H) ; 6.58-6.63 (m, 2H) ; 6.72 (d, J = 8.7 Hz, 2H) ; 6.95-7.10 (m, 6H) ; 7.04 (s, 2H) ; 7.08 (d, J = 8.9 Hz, 4H) ; 7.50 (d, J = 8.9 Hz, 4H).

¹³C NMR (CD₂CI₂): δ (ppm) 26.2 ; 40.1 ; 55.9 ; 55.9 ; 56.4 ; 67.6 ; 69.6 ; 70.5 ; 70.8 ; 100.5 ; 106.0 ; 109.0 (d, J = 25.5 Hz) ; 111.4 (t, J = 19.9 Hz) ; 113.0 ; 115.0 ; 115.7 (d, J = 19.8 Hz) ; 119.8 (d, J = 7.3 Hz) ; 123.6 ; 127.8 ; 129.3 (d, J = 8.8 Hz) ; 130.7 (d, J = 16.3 Hz) ; 137.9 ; 139.6 ; 143.0 ; 143.3 ; 147.6 (d, J = 1 1.6 Hz) ; 150.0 ; 152.1 (d, J = 248.2 Hz) ; 159.4 ; 161.3 (dd, J = 248.2, 9.1 Hz).

Synthesis of the intermediate 9

2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(p- tolylsulfonyloxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]e thoxy]ethoxy] ethyl 4-methylbenzenesulfonate

A mixture of triethylamine (0.57 mL, 4.12 mmol), 4-Toluenesulfonyl chloride (697.51 mg, 3.66 mmol) and 4-Dimethylaminopyridine (22.35 mg, 0.18 mmol) were diluted in 4 mL of CH₂CI₂ (QS 0.5 M). This solution was cooled in an ice bath and to it was added 2- [2- [2- [2- [2- [2- [2- [2- [2- [2- [2- (2- hydroxyethoxy)ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethox y]ethoxy]ethanol (500 mg, 0.91 mmol). The reaction was stirred for 3 h and was then concentrated in vacuum. Purification of the crude by flash chromatography using as eluent a mixture of DCM/MeOH (94/4) gave 737 mg of 2- [2- [2- [2- [2- [2- [2-[2-[2-[2-[2-(p- tolylsulf onyloxy)ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] eth oxy] ethoxy] ethyl 4-methylbenzenesulfonate as a colorless oil, leading to a 94% yield. MS: [M+NH₄]⁺ m/z = 872.

1H NMR (CD₂C1₂): δ (ppm) 2.44 (s, 6H) ; 3.54 (s, 10H) ; 3.57 (s, 10H) ; 3.58 (s, 8H) ; 3.59 (s, 8H) ; 3.60 (s, 10H) ; 3.64 (t, J = 4.7 Hz, 4H) ; 4.12 (t, J = 4.7 Hz, 4H) ; 7.37 (d, J = 8.3 Hz, 4H) ; 7.78 (d, J = 8.3 Hz, 4H).

EXAMPLE 9: 4-[4-[[5-(3,4-dimethoxy-N-methyl-anilino)-l-(4-fluoro-3- methoxy-phenyl)imidazol-2-yl]sulfanylmethyl]-3,5-difluoro-phenyl]-N- methyl-N-[(2S, -2,3,4,5,6-pentahydroxyhexyl]benzamide

Step 7

4-[4-[[5-(3,4-dimethoxy-N-methyl-anilino)-l-(4-fluoro-3-methoxy- phenyl)imidazol-2-yl]sulfanylmethyl]-3,5-difluoro-phenyl]benzoic acid (EXAMPLE la)

The titled product was obtained as a white powder, after precipitation in EtOH (194 mg, 35%), following Procedure C, using 2-[(4-bromo-2,6-difluoro- phenyl)methylsulfanyl]-N-(3,4-dimethoxyphenyl)-3-(4-fluoro-3-methoxy- phenyl)-N-methyl-imidazol-4-amine (Intermediate 2) (250 mg) and 4- boronobenzoic acid (70 mg).

MS: [M+H]⁺ m/z = 636.

Step 8

EXAMPLE 9: 4-[4-[[5-(3,4-dimethoxy-N-methyl-anilino)-l-(4-fluoro-3- methoxy-phenyl)imidazol-2-yl]sulfanylmethyl]-3,5-difluoro-phenyl]-N- methyl-N-[(2S,3 -2,3,4,5,6-pentahydroxyhexyl]benzamide

In a 5 mL flask were added 4-[4-[[5-(3,4-dimethoxy-N-methyl-anilino)- l-(4- fluoro-3-methoxy-phenyl)imidazol-2-yl] sulfanylmethyl]-3,5-difluoro- phenyl]benzoic acid (194 mg, 0.31 mmol), NEt₃ (41.18 μΐ,, 0.31 mmol), DCC (62.97 mg, 0.31 mmol), HOBt (41.24 mg, 0.31 mmol), and (2R,3R,4R,5S)-6- (methylamino)hexane-l,2,3,4,5-pentol (59.58 mg, 0.31 mmol) in 1 mL of dichloromethane (QS 0.3 M). The reaction mixture was stirred overnight at room temperature. The reaction mixture was evaporated to dryness and purified by preparative HPLC to give 100 mg of the desired product as a yellowish oil, leading to a 40% yield.

MS: [M+H]⁺ m/z = 813.

1H NMR (MeOD): δ (ppm) 2.92 (s, 3H) ; 3.12 (s, 1.7H) ; 3.17 (s, 1.3H) ; 3.37 (s, 3H) ; 3.48-3.83 (m, 7H) ; 3.70 (s, 3H) ; 3.75 (s, 3H) ; 3.97-4.09 (m, 0.5H) ; 4.04

(s, 2H) ; 4.16-4.20 (m, 0.5H) ; 6.18 (dd, J = 8.7, 2.8 Hz, 1H) ; 6.34 (d, J = 2.8 Hz,

1H) ; 6.46 (dd, J = 7.2, 2.6 Hz, 1H) ; 6.48-6.54 (m, 1H) ; 6.80 (d, J = 8.7 Hz, 1H) ;

6.97 (dd, J = 10.9, 8.7 Hz, 1H) ; 7.05 (s, 1H) ; 7.26 (dd, J = 8.5, 3.1 Hz, 2H) ; 7.58

(t, J = 8.1 Hz, 2H) ; 7.71 (t, J = 8.1 Hz, 2H).

1³C NMR (MeOD): δ (ppm) 26.8 ; 32.5 ; 38.6 ; 39.2 ; 51.0 ; 55.3 ; 55.9 ; 63.3 ;

70.1 ; 71.2 ; 71.6 ; 72.2 ; 101.1 ; 106.8 ; 109.4 (d, J = 25.3 Hz) ; 113.3 ; 113.4 ;

113.4 (t, J = 7.4 Hz) ; 115.2 (d, J = 19.9 Hz) ; 120.3 (d, J = 7.8 Hz) ; 123.7 ; 126.4

; 126.6 ; 127.5 ; 128.0 ; 130.9 (d, J = 3.6 Hz) ; 136.5 (d, J = 16.8 Hz) ; 137.3 ; 140.3 ; 143.1 ; 143.6 ; 147.4 (d, J = 11.4 Hz) ; 149.9 ; 152.1 (d, J = 248.5 Hz), ; 161.3 (dd, J = 248.5, 8.6 Hz) ; 172.3.

EXAMPLE 10-11:

Synthesis of the intermediate 10:

2-[(4-bromo-2,6-difluoro-phenyl)methylsulfanyl]-N-(3,4-dimethoxyphi (4-fluorophenyl)-N-methyl-imidazol-4-amine

Step 4

N-(3,4-dimethoxyphenyl)-2-[[(Z)-N-(4-fluorophenyl)-C-sulfanyl- carbonimidoyl]amin -N-methyl-acetamide (Intermediate 10a)

4-fluorophenylisothiocyanate (1.9 g, 12.42 mmol) and TEA (2.01 mL, 14.9 mmol) were added in a 500 mL flask in ethanol (20 mL). Residue from [2-(3,4- dimethoxy-N-methyl-anilino)-2-oxo-ethyl]ammonium;2,2,2-trifluoroacetate (4.2 g, 12.42 mmol) was dissolved in 140 mL of ethanol, TEA (1.68 mL, 12.42 mmol) was added, and the mixture was added dropwise at room temperature. After the addition, the reaction was finished. Reaction mixture was evaporated to dryness and purified by flash chromatography using as eluent a mixture of cHex/EtOAc (6/4), to give 3.2 g of N-(3,4-dimethoxyphenyl)-2-[[(Z)-N-(4-fluorophenyl)-C- sulfanyl-carbonimidoyl] amino] -N-methyl-acetamide as a yellowish powder, leading to a 68 % yield.

MS: [M+H]⁺ m/z = 378. 1H NMR (DMSO- 6): δ (ppm) 3.16 (s, 3H) ; 3.77 (s, 3H) ; 3.78 (s, 3H) ; 4.03 (s, 2H) ; 6.90-6.94 (dd, J = 8.4, 2.1 Hz, 1H) ; 7.02 (d, J = 7.9 Hz, 2H) ; 7.15 (t, J = 8.9 Hz, 2H) ; 7.42-7.46 (m, 2H) ; 7.73 (s, 1H) ; 9.90 (s, 1H). Step 5

2-[[(Z)-C-[(4-bromo-2,6-difluoro-phenyl)methylsulfanyl]-N-(4- fluorophenyl)carbonimidoyl]amino]-N-(3,4-dimethoxyphenyl)-N-methyl- acetamide (Intermediat

In a 50 mL flask were added N-(3,4-dimethoxyphenyl)-2-[[(Z)-N-(4- fluorophenyl)-C-sulfanyl-carbonimidoyl] amino] -N-methyl-acetamide (1 g, 2.54 mmol), K₂C0₃ (0.35 g, 2.54 mmol), Nal (0.19 g, 1.27 mmol), and 13 mL of acetonitrile (QS 0.1 M). The suspension was stirred at room temperature for 10 min, and 5-bromo-2-(chloromethyl)- l,3-difluoro-benzene (Intermediate 3) (0.61 g, 2.54 mmol) was then added. The suspension was stirred at room temperature overnight. 120 mg of 5-bromo-2-(chloromethyl)- l,3-difluoro-benzene (Intermediate 3) was added at the reaction mixture and it was stirred at room temperature for 24 h. The crude was then evaporated, residue was dissolved in EtOAc, washed with water and brine, organic phase was dried over Na₂S0₄ and evaporated. Purification of the crude by flash chromatography using as eluent a mixture of DCM/Acetone (98/2) gave 1.05 g of 2-[[(Z)-C-[(4-bromo-2,6-difluoro- phenyl)methylsulfanyl]-N-(4-fluorophenyl)carbonimidoyl]amino]-N-(3,4- dimethoxyphenyl)-N-methyl-acetamide as a yellowish oil, leading to a 62% yield. MS: [M+H]⁺ m/z = 584.

1H NMR (CDCI₃): δ (ppm) 3.29 (s, 3H) ; 3.87 (m, 8H) ; 4.02 (s, 2H) ; 5.78 (s, 1H) ; 6.68-6.77 (m, 4H) ; 6.84-6.93 (m, 4H) ; 7.02-7.08 (d, J = 6.8 Hz, 2H). Step 6

2-[(4-bromo-2,6-difluoro-phenyl)methylsulfanyl]-N-(3,4-dimethoxyphi (4-fluorophenyl)-N-meth -imidazol-4-amine (Intermediate 10)

In a microwave tube were added 2-[[(Z)-C-[(4-bromo-2,6-difluoro- phenyl)methylsulfanyl]-N-(4-fluorophenyl)carbonimidoyl]amino]-N-(3,4- dimethoxyphenyl)-N-methyl-acetamide (500 mg, 0.86 mmol), 9 mL of EtOAc (dry on MgS0₄), T₃P^® (1.52 mL, 2.58 mmol)and DIEA (0.95 mL, 5.15 mmol). The reaction mixture was heated under microwave irradiation at 150°C for 10 min. The crude was diluted in EtOAc and was then washed with a saturated aqueous solution of NaHC0₃ and with brine. Organic phase was dried over Na₂S0₄ and evaporated to dryness. The crude was recrystallized in a mixture of Cy/EtOH and gave 174 mg of 2-[(4-bromo-2,6-difluoro-phenyl)methylsulfanyl]- N-(3,4-dimethoxyphenyl)-3-(4-fluorophenyl)-N-methyl-imidazol-4-amine as brown crystals, leading to a 36 % yield. Purification of the crude by flash chromatography using as eluent a mixture of DCM/MeOH (99/1) gave 25 mg of 2-[(4-bromo-2,6-difluoro-phenyl)methylsulfanyl]-N-(3,4-dimethoxyphenyl)-3-(4- fluorophenyl)-N-methyl-imidazol-4-amine as a yellow oil, leading to a 5% yield. MS: [M+H]⁺ m/z = 566.

1H NMR (CDC1₃): δ (ppm) 2.92 (s, 3H) ; 3.79 (s, 3H) ; 3.82 (s, 3H) ; 4.06 (s, 2H) ; 6.13-6.17 (dd, J = 8.7, 2.7 Hz, 1H) ; 6.26 (d, J = 2.7 Hz, 1H) ; 6.72 (d, J = 8.7 Hz, 1H) ; 6.96-7.01 (m, 7H).

EXAMPLE 10:

Step 7

2-[(2,6-difluoro-4-phenyl-phenyl)methylsulfanyl]-N-(3,4-dimethoxyphenyl)-3- (4-fluorophenyl)-N-methyl-imidazol-4-amine

The titled product was obtained as a yellow oil, after purification by flash chromatography (70 mg, 70%), following Procedure C, using 2-[(4-bromo-2,6- difluoro-phenyl)methylsulfanyl]-N-(3,4-dimethoxyphenyl)-3-(4-fluorophenyl)-N- methyl-imidazol-4-amine (Intermediate 10) (100 mg) and phenylboronic acid

(25.9 mg).

MS: [M+H]⁺ m/z = 562.

1H NMR (CDC1₃): δ (ppm) 2.91 (s, 3H) ; 3.78 (s, 3H) ; 3.79 (s, 3H) ; 4.17 (s, 2H) ; 6.13-6.17 (dd, J = 8.9, 2.8 Hz, 1H) ; 6.29 (d, J = 2.8 Hz, 1H) ; 6.68 (d, J = 8.9 Hz, 1H) ; 6.87-6.97 (m, 4H) ; 6.98-7.05 (m, 3H) ; 7.38-7.49 (m, 5H).

¹³C NMR (CDCI₃): δ (ppm) 26.9 ; 40.1 ; 55.9 ; 56.4 ; 100.0 ; 105.7 ; 109.5- 110.0 (m) ; 112.1 (t, J = 19.8 Hz) ; 112.3 ; 115.8 (d, J = 22.8 Hz) ; 124.4 ; 126.8 ; 128.6 ; 129.1 ; 129.2 (d, J = 9.0 Hz) ; 130.8 (d, J = 2.9 Hz) ; 138.1 ; 138.4 (t, J = 2.4 Hz) ; 139.7 ; 142.8 ; 143.0 (t, J = 10.0Hz) ; 143.1 ; 149.6 ; 161.3 (dd, J = 249.3, 8.8 Hz) ; 162.2 (d, J = 249.3 Hz).

EXAMPLE 11:

2-[[2,6-difluoro-4-[2-(4-methoxyphenyl)ethynyl]phenyl]methylsulfanyl]-N- (3,4-dimethoxyphenyl -3-(4-fluorophenyl)-N-methyl-imidazol-4-amine

2-[(4-bromo-2,6-difluoro-phenyl)methylsulfanyl]-N-(3,4-dimethoxyphenyl)-3-(4- fluorophenyl)-N-methyl-imidazol-4-amine (Intermediate 10) (100 mg, 0.18 mmol), l-eth- l-ynyl-4-methoxybenzene (43.0 μί, 354 μιηοΐ) , pyrrolidine (23 μί, 266 μηιοΐ) were dissolved in 890 μΐ_^ of dry and degassed DMF. Then, PdCl₂(Dppf)₂ (11.39 mg, 0.01 mmol) and Cul (3.4 mg, 18 μπιοΐ) were added, and reaction mixture was heated at 80°C overnight. The reaction mixture was degassed and l-eth- l-ynyl-4-methoxybenzene (43.0 μί, 354 μιηοΐ), PdCl₂(Dppf)₂ (11.39 mg, 0.01 mmol) and Cul (3.4 mg, 18 μιηοΐ) were added at the reaction mixture and it was stirred at 80°C for 5 h. Reaction mixture was then cooled down to room temperature evaporated to dryness, diluted with EtOAc, washed with a saturated aqueous solution of NaHC0₃, brine, dried over Na₂S0₄ and evaporated to dryness. Residue was then purified by preparative HPLC to give 8.3 mg of 2- [[2,6-difluoro-4-[2-(4-methoxyphenyl)ethynyl]phenyl]methylsulfanyl]-N-(3,4- dimethoxyphenyl)-3-(4-fluorophenyl)-N-methyl-imidazol-4-amine as a pale yellow residue, leading to a 8% yield.

MS: [M+H]⁺ m/z = 616.

1H NMR (CDC1₃): δ (ppm) 2.92 (s, 3H) ; 3.79 (s, 3H) ; 3.80 (s, 3H) ; 3.84 (s, 3H) ; 4.18 (s, 2H) ; 6.12-6.16 (dd, J = 8.7, 2.7 Hz, 1H) ; 6.27 (d, J = 2.7 Hz, 1H) ; 6.70 (d, J = 8.7 Hz, 1H) ; 6.88 (d, J = 9.0 Hz, 2H) ; 6.91-7.00 (m, 6H) ; 7.06 (s, 1H) ; 7.45 (d, J = 9.0 Hz, 2H).

EXAMPLES 12-13:

Synthesis of the intermediate 11

Step 5

2-[[(Z)-C-[[4-(3-chloropropoxy)-2,6-difluoro-phenyl]methylsulfanyl]-N-(4- fluorophenyl)carbonimidoyl]amino]-N-(3,4-dimethoxyphenyl)-N-methyl- acetamide (Intermediate 11a)

In a 50 mL flask were added N-(3,4-dimethoxyphenyl)-2-[[(Z)-N-(4- fluorophenyl)-C-sulfanyl-carbonimidoyl]amino]-N-methyl-acetamide

(Intermediate 10a) (880.37 mg, 2.33 mmol), Potassium Carbonate (354.62 mg, 2.57 mmol), and 12 mL of acetonitrile (QS 0.2 M). The suspension was stirred at room temperature for 10 min, and residue from 2-(chloromethyl)-5-(3- chloropropoxy)-l,3-difluoro-benzene (595 mg, 2.33 mmol) was then added. The suspension was stirred at room temperature overnight. The reaction mixture was then evaporated, residue was dissolved in ethyl acetate, washed with water and brine, organic phase was dried over Na₂S0₄ and evaporated. Residue was then purified by flash chromatography using as eluent a mixture of cHex/EtOAc (7/3) to give 1040 mg of 2-[[(Z)-C-[[4-(3-chloropropoxy)-2,6-difluoro- phenyl]methylsulfanyl]-N-(4-fluorophenyl)carbonimidoyl]amino]-N-(3,4- dimethoxyphenyl)-N-methyl-acetamide as a yellowish solid, leading to a 75% yield.

MS: [M+H]⁺ m/z = 595.9.

1H NMR (CDC1₃): δ (ppm) 2.15 (q, J = 5.93 Hz, 2H) ; 3.27 (s, 3H) ; 3.66 (t, J = 6.19 Hz, 2H) ; 3.76-3.93 (m, 8H) ; 3.95-4.14 (m, 4H) ; 6.32-6.46 (m, 2H) ; 6.60- 6.94 (m, 7H).

Step 6

2-[[4-(3-chloropropoxy)-2,6-difluoro-phenyl]methylsulfanyl]-N-(3,4- dimethoxyphenyl)-3-(4-fluorophenyl)-N-methyl-imidazol-4-amine

(Intermediate 11)

In 100 mL flask were introduced 2-[[(Z)-C-[[4-(3-chloropropoxy)-2,6-difluoro- phenyl]methylsulfanyl]-N-(4-fluorophenyl)carbonimidoyl]amino]-N-(3,4- dimethoxyphenyl)-N-methyl-acetamide (1040 mg, 1.74 mmol), 17 mL of dried ethyl acetate (QS 0.1 M), diisopropylethylamine (1.83 mL, 10.47 mmol), and T₃P^® (3.08 mL, 5.23 mmol). The mixture was heated at reflux for 24h. After 7 and 20 hours, diisopropylethylamine (1.83 mL, 10.47 mmol), and T₃P^® (3.08 mL, 5.23 mmol) were added again. After 30 hours, diisopropylethylamine (915 μί, 5.24 mmol), and T₃P^® (1.54 mL, 2.62 mmol) were added again. Then, reaction was over and the reaction mixture was diluted in ethyl acetate. The solution was then washed with a saturated aqueous solution of NaHC0₃. and with brine. Organic phase was dried over Na₂S0₄ and evaporated to dryness, to give 688 mg of 2-[[4-(3-chloropropoxy)-2,6-difluoro-phenyl]methylsulfanyl]-N-(3,4- dimethoxyphenyl)-3-(4-fluorophenyl)-N-methyl-imidazol-4-amine (Intermediate 9) as a brown solid, leading to a 64.8% yield.

MS: [M+H]⁺ m/z = 577.9.

1H NMR (CDCI₃): δ (ppm) 2.21 (q, J = 6.01 Hz, 2H) ; 2.91 (s, 3H) ; 3.72 (t, J = 6.19 Hz, 2H) ; 3.77-3.86 (m, 6H) ; 4.00-4.14 (m, 4H) ; 6.16 (dd, J = 8.69, 2.78 Hz, 1H) ; 6.30 (d, J = 2.73 Hz, 1H) ; 6.32-6.42 (m, 2H) ; 6.72 (d, J = 8.73 Hz, 1H) ; 6.91-7.05 (m, 5H).

Synthesis of the intermediate 12

2,6-Difluoro-4-hydroxy-benzoic acid (Intermediate 12a)

2,6-difluoro-4-hydroxy-benzonitrile (0.7 g, 4.51 mmol) was dissolved in 3 mL distilled water and a solution of NaOH (0.632 g, 15.8 mmol) in 3 mL of water was then added. Reaction mixture was then heated at 80°C overnight. Heating was then stopped, and the reaction mixture was acidified by adding concentrated HC1, extracted with DCM and then extracted with Et₂0. Organic phase was dried over Na₂S0₄, and evaporated, to give 790 mg of 2,6-difluoro-4-hydroxy-benzoic acid as a white solid, leading to a 100 % yield.

MS: [M+H]⁺ m/z = 174.

1H NMR (DMSO- 6): δ (ppm) 6.46-6.53 (m, 2H) ; 10.95 (s, 1H) ; 13.21 (s, 1H). 2,6-Difluoro-4-hydroxy-benzoic acid methyl ester (Intermediate 12b)

2,6-difluoro-4-hydroxy-benzoic acid (790 mg, 4.54 mmol) was dissolved in 9 mL of methanol, concentrated sulphuric acid (128.5 μί, 2.4 mmol) was then added, and the reaction mixture was heated at reflux overnight. Reaction mixture was then evaporated, and residue was dissolved in ethyl acetate, washed with water, brine, dried over Na₂S0₄ and evaporated to give 770 mg of methyl 2,6-difluoro-4- hydroxy-benzoate as a white powder, leading to a 90% yield.

MS: [M-H]^" m/z = 187.

1H NMR (DMSO- 6): δ (ppm) 3.80 (s, 3H) ; 6.51 (d, J = 1.6 Hz, 1H) ; 6.56 (d, J = 1.6 Hz, 1H).

3,5-Difluoro-4-hydroxymethyl-p diate 12c)

In a 100 mL flask were added methyl 2,6-difluoro-4-hydroxy-benzoate (1000 mg, 5.32 mmol), 18 mL of anhydrous THF, and DIBAL-H (22.9 mL, 22.9 mmol) at 0- 5°C. Reaction was then stirred at this temperature for 1.5 h, and reaction mixture was then poured into a 250 mL flask containing 18 mL of cold (0-5°C) 1M aqueous tartrate solution. Reaction mixture was stirred at room temperature for 30 min. Aqueous phase was extracted with ethyl acetate, and then acidified to pH = 4 by addition of concentrated HCl. It was then extracted with ethyl acetate. Organic phases were pulled together, dried over Na₂S0₄ and evaporated to give 780 mg of 3,5-difluoro-4-(hydroxymethyl)phenol as a white powder, leading to a 92 % yield. MS: [M-H]^~ m/z = 159.

1H NMR (DMSO- 6): δ (ppm) 4.36 (d, J = 5.5 Hz, 2H) ; 5.00 (t, J = 5.5 Hz, 1H) ; 6.41 (s, 1H) ; 6.43 (s, 1H) ; 10.3 (s, 1H).

[4-(3-chloropropoxy)-2,6-difluoro-phenyl]methanol (Intermediate 12d)

l-bromo-3-chloro-propane (2.64 mL, 26.9 mmol), 3,5-difluoro-4- (hydroxymethyl)phenol (Intermediate 12c) (860 mg, 5.37 mmol) and potassium carbonate (742 mg, 5.37 mmol) were added in acetonitrile (18 mL, QS 0.3 M) and the reaction mixture was stirred at reflux for 3 hours. The solvent was removed under reduced pressure. The crude was dissolved in ethyl acetate and washed by water. The aqueous phase was extracted by ethyl acetate and washed with brine, dried over Na₂S0₄. The solvents were removed under reduced pressure, to give 1.28 g of [4-(3-chloropropoxy)-2,6-difluoro-phenyl]methanol as a pale yellowish oil, leading to a 100% yield.

MS: [M+H-H₂0]⁺ m/z = 218.9.

1H NMR (CDC1₃): δ (ppm) 2.24 (q, J = 6.05 Hz, 2H) ; 3.73 (t, J = 6.26 Hz, 2H) ; 4.10 (t, J = 5.82 Hz, 2H) ; 4.71 (s, 2H) ; 6.41-6.52 (m, 2H). 2-(chloromethyl)-5-(3-chloropropoxy)-l,3-difluoro-benzene (Intermediate 12)

[4-(3-chloropropoxy)-2,6-difluoro-phenyl]methanol (Intermediate 12d) (602 mg, 2.54 mmol) and TEA (428 μί, 3.17 mmol) were dissolved in 5 mL of dry DCM at 0°C. Mesylchloride (197 μί, 2.54 mmol) was then added dropwise, and the mixture was stirred at room temperature overnight. Reaction mixture was then evaporated to dryness. Water was then added to quench the reaction. The organic phase was then washed with water and brine, and dried over Na₂S04, and then evaporated. The residue was added to a 50 mL flask loaded with N-(3,4- dimethoxy-phenyl)-2-[3-(4-fluoro-phenyl)-isothioureido]-N-methyl-acetamide (800 mg, 2.12 mmol), Potassium Carbonate (322 mg, 2.33 mmol), and 10 mL of acetonitrile (QS 0.2 M). The suspension was stirred at room temperature overnight. Potassium carbonate (146 mg, 1.51 mmol) was then added, and mixture was stirred at room temperature overnight. The medium was then evaporated, residue was dissolved in EtOAc, washed with water and brine, organic phase was dried over Na₂S0₄ and evaporated. Residue was then purified by flash chromatography using as eluent a mixture of cHex/EtOAc (7/3) to give 915 mg of 2-(chloromethyl)-5-(3-chloropropoxy)-l,3-difluoro-benzene as a yellowish solid, leading to a 73 %.

MS: [M+H]⁺ m/z = 595.9.

1H NMR (CDC1₃): δ (ppm) 2.15 (quin, J = 5.93 Hz, 2H) ; 3.27 (s, 3H) ; 3.66 (t, J = 6.19 Hz, 2H) ; 3.76-3.93 (m, 8H) ; 3.95-4.14 (m, 4H) ; 6.32-6.46 (m, 2H) ; 6.60- 6.94 (m, 7H).

EXAMPLE 12:

2-[[2,6-difluoro-4-[3-[2-[2- methoxypolyethyleneglycoxy]ethylamino]propoxy]phenyl]methylsulfanyl]-N- (3,4-dimethoxyphenyl)-3-(4-fluorophenyl)-N-methyl-imidazol-4-amine (m =

13-20)

In a microwave tube were added 2-[[4-(3-chloropropoxy)-2,6-difluoro- phenyl]methylsulfanyl]-N-(3,4-dimethoxyphenyl)-3-(4-fluorophenyl)-N-methyl- imidazol-4-amine (Intermediate 11) (37 mg, 0.06 mmol), 2-[2- methoxypolyethyleneglycoxy]ethanamine (49.92 mg, 0.06 mmol), cesium carbonate (20.85 mg, 0.06 mmol), Nal (4.8 mg, 0.03 mmol) and 640 of dimethylformamide (QS 0.1 M). The reaction mixture was heated under microwave irradiation at 150°C for lh. The reaction mixture was evaporated to dryness and purified by preparative HPLC to give 15 mg of 2-[[2,6-difluoro-4-[3- [2-[2-methoxypolyethyleneglycoxy]ethylamino]propoxy]phenyl]methylsulfanyl]- N-(3,4-dimethoxyphenyl)-3-(4-fluorophenyl)-N-methyl-imidazol-4-amine (m = 13-20) as a yellowish oil, leading to a 18 % yield.

MS: [M+H]⁺ m/z = 1233.

1H NMR (CD₂C1₂): δ (ppm) 1.91-2.00 (q, J = 13.0, 6.2 Hz, 2H) ; 2.77-2.82 (m, 4H) ; 2.93 (s, 3H) ; 3.34 (s, 3H) ; 3.48-3.52 (m, 2H) ; 3.55-3.62 (m, 68H) ; 3.73 (s, 3H) ; 3.74 (s, 3H) ; 4.00 (t, J = 6.2 Hz, 2H) ; 4.04 (s, 2H) ; 6.10-6.15 (dd, J = 8.7, 2.7 Hz, 1H) ; 6.25 (d, J = 2.7 Hz, 1H) ; 6.40 (d, J = 9.6 Hz, 2H) ; 6.69 (d, J = 8.7 Hz, 1H) ; 6.95 (s, 1H) ; 6.98-7.03 (m, 4H).

EXAMPLE 13:

3-[4-[[5-(3,4-dimethoxy-N-methyl-anilino)-l-(4-fluorophenyl)imidazol-2- yl]sulfanylmethyl]-3,5-difluoro-phenoxy]propyl-[2-[2- methoxypolyethyleneglycoxy]ethyl]-dimethyl-ammonium (m = 12-23)

In a microwave tube were added 2-[[4-(3-chloropropoxy)-2,6-difluoro- phenyl]methylsulfanyl]-N-(3,4-dimethoxyphenyl)-3-(4-fluorophenyl)-N-methyl- imidazol-4-amine (Intermediate 11) (48 mg, 0.08 mmol), 2-[2- methoxypolyethyleneglycoxy]-N,N-dimethyl-ethanamine (Intermediate 13) (67.1 mg, 0.08 mmol), cesium carbonate (21 mg, 64 μιηοΐ), Nal (6.22 mg, 0.04 mmol) and 640 μΐ_^ of DMF (QS 0.1 M). The reaction mixture was heated under microwave irradiation at 150°C for 1 h twice. The reaction mixture was evaporated to dryness under reduced pressure. The crude was purified by preparative HPLC to give 18 mg of 3-[4-[[5-(3,4-dimethoxy-N-methyl-anilino)-l- (4-fluorophenyl)imidazol-2-yl]sulfanylmethyl]-3,5-difluoro-phenoxy]propyl-[2- [2-methoxypolyethyleneglycoxy]ethyl]-dimethyl-ammonium (m = 12-23) as a colorless oil, leading to a 16% yield.

MS: [M+H]⁺ m/z = 1262.

1H NMR (CD₂C1₂): δ (ppm) 1.85- 1.94 (q, J = 13.2, 6.6 Hz, 2H) ; 2.24 (s, 6H) ; 2.51 (t, J = 6.9 Hz, 2H) ; 2.56 (t, J = 6.0 Hz, 2H) ; 2.94 (s, 3H) ; 3.33 (s, 3H) ; 3.33 (m, 2H) ; 3.48-3.52 (m, 4H) ; 3.55-3.65 (m, 68H) ; 3.72 (s, 3H) ; 3.95 (t, J = 6.3 Hz, 2H) ; 4.05 (s, 2H) ; 6.10 -6.14 (dd, J = 8.7, 2.7, 1H) ; 6.25 (d, J = 2.7 Hz, 1H) ; 6.25 (d, J = 9.6 Hz, 2H) ; 6.69 (d, J = 8.7 Hz, 1H) ; 6.95 (s, 1H) ; 6.98-7.06 (m, 4H).

Synthesis of the intermediate 13

2-[2-methoxypolyethyleneglycoxy]-N,N-dimethyl-ethanamine

2-[2-methoxypolyethyleneglycoxy]ethanamine (100 mg, 0.13 mmol) was dissolved in a mixture of DCM/ Acetic acid (10/1 - 0.1 M). Paraformaldehyde (7.7 mg, 0.26 mmol) and (polystyrylmethyl)trimethylamonium cyanoborohydride (102.34 mg, 0.26 mmol, 4 mmol/g) were added at the reaction mixture and it was stirred at room temperature for 24 h. Paraformaldehyde (7.7 mg, 0.26 mmol) and (polystyrylmethyl)trimethylamonium cyanoborohydride (102.34 mg, 0.26 mmol, 4 mmol/g) were added again at the reaction mixture and it was stirred at 30°C for 7 h and then at room temperature over the weekend. 5 mL of methanol were added to quench the reaction. The reaction mixture was filtered to remove the resin. The solvent were removed. The residue was dissolved in dichloromethane, dried over Na₂S0₄, evaporated to dryness to give 66 mg of 2- [2- methoxypolyethyleneglycoxy]-N,N-dimethyl-ethanamine as a colorless oil, leading to a 64% yield. It was used without further purification in the next step of the synthesis.

MS: [M+H]⁺ m/z = 808. EXAMPLE 14:

Diammonium;2-[3-[4-[[5-(3,4-dimethoxy-N-methyl-anilino)-l-(4- fluorophenyl)imidazol-2-yl]sulfanylmethyI]-3,5-difluoro-phenoxy]propyl-(2- sulfonatoethyl)amino]ethanesulfonate

Step 5

tert-butyl N-tert-butoxycarbonyl-N-[3-[4-[[(Z)-N-[2-(3,4-dimethoxy-N- methyl-anilino)-2-oxo-ethyl]-N ' -(4- fluorophenyl)carbamimidoyI]suIfanyImethyI]-3,5-difluoro- phenoxy]propyl]carbamate

In a 50 mL flask were added N-(3,4-dimethoxyphenyl)-2-[[(Z)-N-(4- fluorophenyl)-C-sulfanyl-carbonimidoyl]amino]-N-methyl-acetamide (411.3 mg, 1.09 mmol), DIEA (206.57 μΐ,, 1.2 mmol), and 2.5 mL of acetonitrile (QS 0.4 M). The suspension was stirred at room temperature for 10 min, and residue from tert- butyl N-tert-butoxycarbonyl-N-[3-[4-(chloromethyl)-3,5-difluoro- phenoxy]propyl]carbamate (Intermediate 13) (475 mg, 1.09 mmol) in 3 mL of ACN was then added. The suspension was stirred at room temperature overnight. The solvent was then evaporated, residue was dissolved in EtOAc, washed with water and brine, organic phase was dried over Na₂S0₄ and evaporated. Residue was then purified by flash chromatography using as eluent a mixture of cHex/EtOAc (6/4) to give 300 mg of tert-butyl N-tert-butoxycarbonyl-N-[3-[4- [[(Z)-N-[2-(3,4-dimethoxy-N-methyl-anilino)-2-oxo-ethyl]-N'-(4- fluorophenyl)carbamimidoyl]sulfanylmethyl]-3,5-difluoro- phenoxy]propyl]carbamate as a yellowish oil, leading to a 35%. It was used without further purification in the next step of the synthesis.

MS: [M+H]⁺ m/z = 777.

1H NMR DMSO-d6): δ (ppm) 1.37 (s, 18H) ; 1.89 (t, J = 6.4 Hz, 2H) ; 3.16 (s, 3H) ; 3.61 (t, J = 7.0 Hz, 2H) ; 3.68 (s, 3H) ; 3.71-3.74 (m, 2H) ; 3.76 (s, 3H) ; 3.98 (t, J = 5.4 Hz, 2H) ; 4.10 (s, 2H) ; 6.58-6.63 (m, 2H) ; 6.66 (d, J = 9.6 Hz, 2H) ; 6.88 (d, J = 8.3 Hz, 2H) ; 6.90-7.01 (m, 4H).

Step 6

tert-butyl N-tert-butoxycarbonyl-N-[3-[4-[[5-(3,4-dimethoxy-N-methyl- anilino)-l-(4-fluorophenyl)imidazol-2-yl]sulfanylmethyl]-3,5-difluoro- phenoxy]propyl]carbamate

In a 100 mL flask were introduced tert-butyl N-tert-butoxycarbonyl-N-[3-[4-[[(Z)- N-[2-(3,4-dimethoxy-N-methyl-anilino)-2-oxo-ethyl]-N'-(4- fluorophenyl)carbamimidoyl]sulfanylmethyl]-3,5-difluoro- phenoxy]propyl]carbamate (300 mg, 0,39 mmol), 4 mL of ethyl acetate (QS 0.1 M), diisopropylethylamine (0.4 mL, 2.32 mmol), and T₃P^® (0.68 mL, 1.16 mmol). The mixture was heated at reflux for 7 h. After 7 hours, diisopropylethylamine (0.4 mL, 2.32 mmol) and T₃P^® (0.68 mL, 1.16 mmol) were added again. After 24 hours, diisopropylethylamine (0.4 mL, 2.32 mmol), and T P^® (0.68 mL, 1.16 mmol) were added again. After 48 hours, the reaction was over and the reaction mixture was diluted in EtOAc. The solution was then washed with a saturated aqueous solution of NaHC0₃, and with brine. Organic phase was dried over Na₂S0₄ and evaporated to dryness. Residue was purified by flash chromatography using as eluent a mixture of DCM/MeOH (99/1) to give 183 mg of tert-butyl N- tert-butoxycarbonyl-N-[3-[4-[[5-(3,4-dimethoxy-N-methyl-anilino)- 1-(4- fluorophenyl)imidazol-2-yl]sulfanylmethyl]-3,5-difluoro- phenoxy]propyl]carbamate as an orange oil, leading to a 62% yield.

MS: [M+H]⁺ m/z = 759.

1H NMR (DMSO- 6): δ (ppm) 1.40 (s, 18H) ; 1.91 (t, J = 6.3 Hz, 2H) ; 2.92 (s, 3H) ; 3.63 (s, 3H) ; 3.64 (s, 3H) ; 3.63 (t, J = 6.3 Hz, 2H) ; 3.98 (t, J = 5.5 Hz, 2H) ; 3.98 (s, 2H) ; 6.03-6.07 (dd, J = 8.7, 2.8 Hz, 1H) ; 6.20 (d, J = 2.8 Hz, 1H) ; 6.63 (d, J = 9.8 Hz, 2H) ; 6.73 (d, J = 8.7 Hz, 1H) ; 6.95 (s, 1H) ; 7.10-7.23 (m, 4H).

Step 10

2-[[4-(3-aminopropoxy)-2,6-difluoro-phenyl]methylsulfanyl]-N-(3,4- dimethoxyphenyl)-3-(4-fluorophenyl)-N-methyl-imidazol-4-amine

Tert-butyl N-tert-butoxycarbonyl-N-[3-[4-[[5-(3,4-dimethoxy-N-methyl-anilino)- l-(4-fluorophenyl)imidazol-2-yl]sulfanylmethyl]-3,5-difluoro- phenoxy]propyl]carbamate (180 mg, 0.24 mmol) was diluted in 4 mL of dry DCM and 400 μΐ_^ of TFA were added. The reaction mixture was stirred at 0°C during 30 min and at room temperature during 5 h. The crude was diluted in DCM, washed with a saturated aqueous solution of NaHC0₃, dried over Na₂S0₄. The solvent was removed to give 130 mg of 2-[[4-(3-aminopropoxy)-2,6-difluoro- phenyl]methylsulfanyl]-N-(3,4-dimethoxyphenyl)-3-(4-fluorophenyl)-N-methyl- imidazol-4-amine as a yellow oil, leading as a 98% yield. It was used without further purification in the next step of the synthesis.

MS: [M+H]⁺ m/z = 559.

1H NMR DMSO-d6): δ (ppm) 1.74-1.79 (m, 2H) ; 2.68 (t, J = 6.6 Hz, 2H) ; 2.92 (s, 3H) ; 3.32 (s, 2H) ; 3.63 (s, 3H) ; 3.64 (s, 3H) ; 3.98 (s, 2H) ; 4.03 (t, J = 6.6 Hz, 2H) ; 6.03-6.07 (dd, J = 8.8, 2.8 Hz, 1H) ; 6.20 (d, J = 2.8 Hz, 1H) ; 6.67 (d, J = 9.8 Hz, 2H) ; 6.73 (d, J = 8.8 Hz, 1H) ; 6.96 (s, 1H) ; 7.09-7.23 (m, 4H).

Step 11 : diammonium;2-[3-[4-[[5-(3,4-dimethoxy-N-methyl-anilino)-l-(4- fluorophenyl)imidazol-2-yl]sulfanylmethyl]-3,5-difluoro-phenoxy]propyl-(2- sulfonatoethyl)amino]ethanesulfonate

In a microwave tube were added 2-[[4-(3-aminopropoxy)-2,6-difluoro- phenyl]methylsulfanyl]-N-(3,4-dimethoxyphenyl)-3-(4-fluorophenyl)-N-methyl- imidazol-4-amine (92 mg, 0.16 mmol), 2-chloroethylsulfonyloxysodium (219.44 mg, 1.32 mmol), Nal (24.69 mg, 0.16 mmol) and DIEA (114.75 μΐ,, 0.66 mmol) in 700 μΐ_^ of DMF (QS 0.2 M). The reaction mixture was heated under microwave irradiation at 100°C for 2h. The reaction mixture was evaporated to dryness and was purified by preparative HPLC to give 22 mg of diammonium;2-[3-[4-[[5-(3,4- dimethoxy-N-methyl-anilino)-l-(4-fluorophenyl)imidazol-2-yl]sulfanylmethyl]- 3,5-difluoro-phenoxy]propyl-(2-sulfonatoethyl)amino]ethanesulfonate as a colorless oil, leading to a 16% yield.

MS: [M+2H]²⁺ m/z = 775.

¹H NMR (MeOD- 4): δ (ppm) 2.26-2.32 (m, 2H) ; 2.98 (s, 3H) ; 3.26 (t, J = 6.7 Hz, 4H) ; 3.48 (t, J = 7.2 Hz, 2H) ; 3.65 (t, J = 6.7 Hz, 4H) ; 3.74 (s, 3H) ; 3.75 (s, 3H) ; 3.91 (s, 2H) ; 4.11 (t, J = 5.6 Hz, 1H) ; 6.14-6.18 (dd, J = 8.6, 2.8 Hz, 1H) ; 6.29 (d, J = 2.8 Hz, 1H) ; 6.58 (d, J = 9.5 Hz, 2H) ; 6.78 (d, J = 8.6 Hz, 1H) ; 6.92-7.07 (m, 5H).

¹³C NMR (MeOD- 4): δ (ppm) 23.7 ; 26.5 ; 39.6 ; 44.8 ; 50.3 ; 51.4 ; 55.2 ; 56.0 ; 65.7 ; 98.0-98.6 (m) ; 101.0 ; 106.0 (t, J = 20.1 Hz) ; 106.8 ; 113.3 ; 115.3 (d, J = 23.4 Hz) ; 122.8 ; 129.6 ; 129.7 ; 130.8 ; 137.4 ; 140.7 ; 143.1 ; 143.2 ; 149.8 ; 159.6 (t, J = 14.0 Hz) ; 161.5 (dd, J = 246.7, 10.9 Hz) ; 162.5 (d, J = 247.9 Hz).

Synthesis of the intermediate 14

[4-(3-bromopropoxy)-2,6-difluoro-phenyl]methanol (Intermediate 14a)

1,3-dibromopropane (950.87 μί, 9.37 mmol), 3,5-difluoro-4- (hydroxymethyl)phenol (Intermediate 12c) (300 mg, 1.87 mmol) and potassium carbonate (258.95 mg, 1.87 mmol) were added in acetonitrile (6 mL, QS 0.3 M) and the reaction mixture was stirred at reflux for 3 hours. The solvent was removed under reduced pressure. The crude was dissolved in ethyl acetate and washed with water. The aqueous phase was extracted with ethyl acetate and washed with brine, dried under Na₂S0₄. The solvents were removed under reduced pressure, and the crude was purified by flash chromatography using as eluent a mixture of Cy/EA (80/20) to give 400 mg of [4-(3-bromopropoxy)-2,6- difluoro-phenyl] methanol as a colorless oil, leading to a 76% yield.

MS: [M+H]⁺ m/z = 264.

Tert-butyl N-tert-butoxycarbonyl-N-[3-[3,5-difluoro-4- (hydroxymethyl)phenoxy]p termediate 14b)

[4-(3-bromopropoxy)-2,6-difluoro-phenyl]methanol (320 mg, 1.14 mmol) was dissolved in 11 mL of dry dimethylformamide (QS 0.1 M). Tert-butyl N-tert- butoxycarbonylcarbamate (247.33 mg, 1.14 mmol) and cesium carbonate (370.91 mg, 1.14 mmol) were added and the reaction mixture was stirred at 70°C for 30 min. The solvent was removed. The crude was dissolved in ethyl acetate, washed with water, dried over Na₂S0₄. The solvent was removed. The crude was purified by flash chromatography using as eluent a mixture of Cy/EA (90/10) to give 500 mg of tert-butyl N-tert-butoxycarbonyl-N-[3-[3,5-difluoro-4-

(hydroxymethyl)phenoxy]propyl]carbamate as a colorless oil, leading to a 95 % yield.

MS: [M+H]⁺ m/z = 344.

1H NMR DMSO-d6): δ (ppm) 1.41 (s, 18H) ; 1.87- 1.96 (q, J = 12.6, 6.1 Hz, 2H) ; 3.64 (t, J = 6.9 Hz, 2H) ; 3.99 (t, J = 5.7 Hz, 2H) ; 4.39 (d, J = 5.7 Hz, 2H) ; 5.08 (t, J = 5.4 Hz, 2H) ; 6.59-6.68 (m, 2H).

Tert-butyl N-tert-butoxycarbonyl-N-[3-[4-(chloromethyl)-3,5-difluoro- phenoxy]propyl]carbamat (Intermediate 14)

Tert-butyl N-tert-butoxycarbonyl-N-[3-[3,5-difluoro-4- (hydroxymethyl)phenoxy]propyl]carbamate (520 mg, 1.25 mmol) and TEA (420.17 μί, 3.11 mmol) were dissolved in 2.5 mL of dry dichloromethane (QS 0.5 M) at 0°C. Mesylchloride (144.91 μί, 1.87 mmol) was then added dropwise, and the mixture was stirred at room temperature overnight. Water was then added to quench the reaction. The organic phase was then washed with water and brine, and dried over Na₂S0₄, and then evaporated. 475 mg of tert-butyl-N-tert- butoxycarbonyl-N-[3-[4-(chloromethyl)-3,5-difluoro-phenoxy]propyl]carbamate as a colorless oil were obtained, leading to a 87% yield. It will be used without further purification in the next step of the synthesis.

MS: [M+H]⁺ m/z = 453. EXAMPLE 15:

[2-(2,6-Difluoro-benzylsulfanyl)-3-(4-fluoro-phenyl)-5-methyl-3H-imidazol-4- yl]-(3,4-dimethoxy-phenyl)-methyl-amine

Step 2:

tert-butyl N-[2-(3,4-dimethoxy-N-methyl-anilino)-l-methyl-2- ethyl]carbamate

In a 10 mL flask were added (3,4-Dimethoxy-phenyl)-methyl-amine (Intermediate la) (275 mg, 1.55 mmol), ethyl acetate (3 mL), Boc-Ala-OH (351 mg, 1.86 mmol), T₃P® (1366 μL·, 2.319 mmol), and DIEA (810 μΐ,, 4.64 mmol). Reaction mixture was then stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with water, saturated aqueous solution of NaHC0₃ and brine, and the organic phase was dried over Na₂S0₄ and evaporated to give 523 mg of tert-butyl N-[2-(3,4-dimethoxy-N-methyl-anilino)- l-methyl-2- oxo-ethyl] carbamate as a yellow powder, leading to a 66 % yield.

MS: [M+H]⁺ m/z = 339.2.

Step 3:

[2-(3,4-dimethoxy-N-methyl-anilino)-l-methyl-2-oxo-ethyl]ammonium;2,2,2- trifluoroacetate

Tert-butyl N-[2-(3,4-dimethoxy-N-methyl-anilino)-l-methyl-2-oxo- ethyl]carbamate (345 mg, 1.0 mmol) was dissolved in 2.3 mL of dichloromethane. 1 mL of TFA was then gently added and reaction mixture was then stirred at room temperature for 30 min. Reaction mixture was then evaporated to dryness, to give [2-(3,4-dimethoxy-N-methyl-anilino)-l-methyl-2-oxo-ethyl]ammonium;2,2,2- trifluoroacetate as a purple oil. This oil will enter the next step without further purification. Yield was considered to be 100%.

MS: [M+H]⁺ m/z = 239.1.

Step 4:

N-(3,4-Dimethoxy-phenyl)-2-[3-(4-fluoro-phenyl)-isothioureido]-N-methyl- propionamide

4-fluorophenylisothiocyanate (150 mg, 0.982 mmol) and TEA (159 μΙ_, 1.18 mmol) were added in a 50 mL flask in 3 mL Ethanol. [2-(3,4-dimethoxy-N- methyl-anilino)-l-methyl-2-oxo-ethyl] ammonium; 2,2,2-trifluoroacetate (0.982 mmol) was dissolved in 10 mL of ethanol, TEA was added until pH was over 8 and the mixture was added dropwise at room temperature. After the addition, the reaction was over. Reaction mixture was evaporated to dryness, and purified by flash chromatography using as eluent a mixture of cHex/EtOAc (7/3), to give 295 mg of N-(3,4-Dimethoxy-phenyl)-2-[3-(4-fluoro-phenyl)-isothioureido]-N- methyl-propionamide as a white powder (94% purity), leading to a 72 % yield. MS: [M+H]⁺ m/z = 392.1.

1H RMN (DMSO- 6): δ (ppm) 1.10 (d, 3H, J = 6.9 Hz) ; 3.15 (s, 3h) ; 3.75-3.80 (m, 6H) ; 4.99 (m, 1H) ; 6.96 (dd, 1H, J = 8.5, 2.3 Hz) ; 7.10 (d, 1H, J =

7.06-7.19 (m, 3H) ; 7.41-7.51 (m, 2H) ; 7.83 (d, 1H, J = 7.7 Hz).

Step 5:

2-[2-(2,6-Difluoro-benzyl)-3-(4-fluoro-phenyl)-isothioureido]-N-(3,4- dimethoxy-phenyl)-N-meth l-propionamide

In a 5 mL flask were added N-(3,4-dimethoxy-phenyl)-2-[3-(4-fluoro-phenyl)- isothioureido]-N-methyl-propionamide (75 mg, 180 μιηοΐ), potassium carbonate (26 mg, 188 μιηοΐ), sodium iodide (14 mg, 93 μιηοΐ), and 1 mL of acetonitrile (QS 0.2 M). The suspension was stirred at room temperature for 10 min, and 2- (bromomethyl)-l,3-difluoro-benzene (40 mg, 193 μιηοΐ) was then added. The suspension was stirred at room temperature for 16 hours. The medium was then evaporated, residue was dissolved in EtOAc, washed with water and brine, organic phase was dried over Na₂S0₄ and evaporated to dryness. Residue was purified by flash chromatography using as eluent a mixture of DCM/MeOH (97/3) to give 78 mg of 2-[2-(2,6-Difluoro-benzyl)-3-(4-fluoro-phenyl)-isothioureido]-N- (3,4-dimethoxy-phenyl)-N-methyl-propionamide as a white solid, leading to a 84% yield.

MS: [M+H]⁺ m/z = 518.2.

1H NMR (CD₂C1₂): δ (ppm) 1.22 (d, 3H, J = 6.4 Hz) ; 3.25 (s, 3H) ; 3.63 (s, 3H) ; 3.85 (s, 3H) ; 4.11 (s, 2H) ; 4.58 (brs, 1H) ; 6.65-7.02 (m, 10H) ; 7.28 (m, 1H).

Step 6:

EXAMPLE 15: [2-(2,6-Difluoro-benzylsulfanyl)-3-(4-fluoro-phenyl)-5- methyl-3H-imidazol-4-yl]-(3,4-dimethoxy-phenyl)-methyl-amine

2-[2-(2,6-Difluoro-benzyl)-3-(4-fluoro-phenyl)-isothioureido]-N-(3,4-dimethoxy- phenyl)-N-methyl-propionamide (78 mg, 0.15 mmol) was dissolved in 1.5 mL of dry ethyl acetate. Diisopropylethylamine (157.9 μί, 0.90 mmol), and T₃P^® in EtOAc (266 μί, 0.45 mmol) were then added. Half of the mixture was heated with microwave at 150°C for 10 min. The expected product was observed, starting material has disappeared, but unfortunately, reaction mixture was dirty. The other half of the reaction mixture was heated at reflux for 45 hours. T P^® (3 eq.) and DIEA (6 eq.) were added after 4, 19, and 24 hours. T₃P^® (1.5 eq.) and DIEA (3 eq.) were added after 42 hours. Reaction mixture was then diluted with EtOAc, washed with water, a saturated aqueous solution of NaHC0₃, and brine. Organic phase was then dried over Na₂S0₄ and evaporated. Residue was then purified by preparative HPLC (pH 3.8) to give 4.5 mg of [2-(2,6-difluoro-benzylsulfanyl)-3- (4-fluoro-phenyl)-5-methyl-3H-imidazol-4-yl]-(3,4-dimethoxy-phenyl)-methyl- amine as a yellowish solid, leading to a 6 % yield.

MS: [M+H]⁺ m/z = 500.1.

1H NMR (CDC1₃): δ (ppm) 2.11 (s, 3H) ; 2.87 (s, 3H) ; 3.84 (s, 3H) ; 3.86 (s, 3H) ; 4.13 (s, 2H) ; 6.10 (dd, 1H, J = 8.7 Hz, J = 2.8 Hz) ; 6.23 (d, 1H, / = 2.8 Hz) ; 6.76-6.83 (m, 3H) ; 6.93-6.97 (m, 4H) ; 7.19 (m, 1H).

1³C NMR (CDC1₃): δ (ppm) 12.4 ; 26.3 ; 38.6 ; 55.9 ; 56.5 ; 98.1 ; 103.5 ; 111.1- 111.3 (m) ; 112.7 ; 113.8 (t, / = 19.6 Hz) ; 115.9 (d, / = 22.9 Hz) ; 128.9 (d, / = 8.6 Hz) ; 129.1 (t, / = 10.0 Hz) ; 131.2 ; 133.6 ; 134.4 ; 136.6 ; 142.0 ; 142.9 ; 149.8 ; 161.2 (dd, / = 249.9 Hz, / = 7.7 Hz) ; 162.1 (d, / = 248.8 Hz). EXAMPLE 16:

Allyl-[2-(2,6-difluoro-benzylsulfanyl)-3-(4-fluoro-phenyl)-3H-imidazol-4-yl]- (3,4-dimethoxy-phenyl)-amine

N-allyl-3,4-dimethoxy-aniline

Allyl bromide (0.519 mL, 6.0 mmol) was added dropwise to a solution of 3,4- dimethoxyaniline (919 mg, 6.0 mmol) and K₂C0₃ (1.99 g, 14.4 mmol) in DMF (15 mL). The solution was heated to 80°C and stirred at this temperature overnight. The reaction mixture was then filtered, washed with H₂0 (3x10 mL) and extracted with EtOAc (2x10 mL). The combined organic extracts were washed with brine (15 mL), dried over Na₂S0₄ and concentrated under reduced pressure. Residue was purified by flash chromatography using as eluent a mixture of cHex/EtOAc (8/2) to give 587 mg of N-allyl-3,4-dimethoxy-aniline as a pale yellowish oil, leading to a 51% yield.

MS: [M+H]⁺ m/z = 194.0.

¹H NMR (CDC1₃): δ (ppm) 3.74 (Dt, 2H, J = 5.5, 1.5 Hz) ; 3.81 (s, 3H) ; 3.84 (s, 3H) ; 5.17 (Dq, 1H, J = 10.3, 1.5 Hz) ; 5.29 (Dq, 1H, J = 17.2, 1.6 Hz) ; 5.98 (Ddt, 1H, J =17.2, 10.6, 5.3 Hz) ; 6.18 (dd, 1H, J =8.5, 2.6 Hz) ; 6.29 (d, 1H, J = 2.6 Hz) ; 6.75 (d, 1H, J = 8.5 Hz).

Tert-butyl N-[2-(N-allyl-3,4-dimethoxy-anilino)-2-oxo-ethyl]carbamate

In a 100 mL flask were added N-allyl-3,4-dimethoxy-aniline (587.0 mg, 3.04 mmol), 6 mL ethyl acetate, Boc-Gly-OH (638.6 mg, 3.65 mmol), T₃P^® (2.69 mL, 4.56 mmol), and DIEA (1.59 mL, 9.11 mmol). Reaction mixture was then stirred at room temperature for 2 hour. The reaction mixture was diluted with ethyl acetate, washed with a saturated aqueous solution of NaHC0₃ and with brine, and the organic phase was dried over Na₂S0₄ and evaporated to give 1.07 g of tert- butyl N-[2-(N-allyl-3,4-dimethoxy-anilino)-2-oxo-ethyl]carbamate as a yellowish viscous oil, leading to a 100 % yield.

MS: [M+H]⁺ m/z = 351.1.

1H NMR (CDC1₃): δ (ppm) 1.41 (s, 9H) ; 3.66 (d, 2H, J = 4.2 Hz) ; 3.85 (s, 3H) ; 3.88 (s, 3H) ; 4.26 (d, 2H, J = 6.4 Hz) ; 5.04-5.19 (m, 2H) ; 5.39 (brs, 1H) ; 5.85 (Ddt, 1H, J = 16.8, 10.3, 6.5 Hz) ; 6.64 (d, 1H, J = 2.2 Hz) ; 6.72 (dd, 1H, J = 8.4, 2.4 Hz) ; 6.83 (d, 1H, J = 8.4 Hz).

[2-(N-allyl-3,4-dimethoxy-anilino)-2-oxo-ethyl]ammonium;2,2,2- trifluoroacetate

tert-butyl N-[2-(N-allyl-3,4-dimethoxy-anilino)-2-oxo-ethyl]carbamate (1.07 g, 3.05 mmol) was dissolved in 7 mL of dichloromethane. 3 mL of TFA were then gently added and reaction mixture was then stirred at room temperature for 30 min. Reaction mixture was then evaporated to dryness, to give [2-(N-allyl-3,4- dimethoxy-anilino)-2-oxo-ethyl]ammonium;2,2,2-trifluoroacetate as a pale orang oil. This oil will enter the next step without further purification. Yield was considered to be 100%.

MS: [M+H]⁺ m/z = 251.1. N-AUyl-N-(3,4-dimethoxy-phenyl)-2-[3-(4-fluoro-phenyl)-isothioureido]- acetamide

4-fluorophenylisothiocyanate (468 mg, 3.05 mmol) and TEA (494 μί, 3.66 mmol) were added in a 250 mL flask in 9 mL Ethanol. [2-(N-allyl-3,4-dimethoxy- anilino)-2-oxo-ethyl]ammonium;2,2,2-trifluoroacetate (3.05 mmol) was dissolved in 31 mL of ethanol, TEA was added until pH was over 8 and the mixture was added dropwise at room temperature. After the addition, the reaction was over. After one hour stirring a room temperature, a precipitate has appeared. It was then filtered, to give N-Allyl-N-(3,4-dimethoxy-phenyl)-2-[3-(4-fluoro-phenyl)- isothioureido]-acetamide as a white powder. After drying, 1.09 g of the powder, corresponding to the expected product was obtained, leading to a 88% yield.

MS: [M+H]⁺ m/z = 404.1.

1H NMR (DMSO- 6): δ (ppm) 3.75 (s, 3H) ; 3.78 (s, 3H) ; 4.01 (d, 2H, J = 4.4 Hz) ; 4.23 (d, 2H, J = 5.8 Hz) ; 5.01-5.20 (m, 2H) ; 5.80 (Ddt, 1H, J = 16.0, 11.5, 5.7 Hz) ; 6.87 (dd, 1H, J = 1.26, 1.11 Hz) ; 6.93-7.05 (m, 2H) ; 7.09-7.21 (m, 2H) ; 7.38-7.51 (m, 2H) ; 7.74 (brs, 1H) ; 9.89 (s, 1H).

N-AUyl-2-[2-(2,6-difluoro-benzyl)-3-(4-fluoro-phenyl)-isothioureido]-N-(3,4- dimethoxy-phenyl) -acetamide

In a 25 mL flask were added N-Allyl-N-(3,4-dimethoxy-phenyl)-2-[3-(4-fluoro- phenyl)-isothioureido]-acetamide (400 mg, 0.99 mmol), potassium carbonate (137 mg, 0.99 mmol), sodium iodide (74 mg, 0.50 mmol), and 5 mL of acetonitrile. The suspension was stirred at room temperature for 10 min, and 2-(bromomethyl)- 1,3-difluoro-benzene (205 mg, 0.99 mmol) was then added. The suspension was stirred at room temperature for overnight. The medium was then evaporated, residue was dissolved in EtOAc, washed with water and brine, organic phase was dried over Na₂S0₄ and evaporated to dryness to give 543 mg of N-Allyl-2-[2-(2,6- difluoro-benzyl)-3-(4-fluoro-phenyl)-isothioureido]-N-(3,4-dimethoxy-phenyl)- acetamide as an orange solid, leading to a 100 % yield.

MS: [M+H]⁺ m/z = 530.2.

1H NMR (CDC1₃): δ (ppm) 3.81-3.92 (m, 8H) ; 4.13 (brs, 2H) ; 4.29 (d, 2H, J = 6.3 Hz) ; 5.07-5.21 (m, 2H) ; 5.78-5.96 (m, 1H) ; 6.63-6.95 (m, 10H) ; 7.21 (m, 1H).

EXAMPLE 16:

Allyl-[2-(2,6-difluoro-benzylsulfanyl)-3-(4-fluoro-phenyl)-3H-imidazol-4-yl]- (3,4-dimethoxy-phenyl -amine

In a microwave tube were introduced N-Allyl-2-[2-(2,6-difluoro-benzyl)-3-(4- fluoro-phenyl)-isothioureido]-N-(3,4-dimethoxy-phenyl)-acetamide (373 mg, 0.7 mmol), 7 mL of ethyl acetate, diisopropylethylamine (738 μί, 4.2 mol), and T3P^® 50 % in EtOAc (1245 μί, 2.1 mmol). The mixture was heated with microwave at 150°C for 10 min,. Reaction mixture was then diluted with EtOAc, washed with water, with a saturated aqeous solution of NaHC0₃, and with brine. Organic phase was then dried over Na₂S0₄ and evaporated. Residue was then purified by flash chromatography using as eluent a mixture of CHCl₃/MeOH (99: 1) to give 192 mg of allyl-[2-(2,6-difluoro-benzylsulfanyl)-3-(4-fluoro-phenyl)-3H-imidazol-4-yl]- (3,4-dimethoxy-phenyl)-amine as an orange solid, leading to a 53 % yield.

M : [M+H]⁺ m/z = 512.1.

1H NMR (CDC1₃): δ (ppm) 3.75-3.86 (m, 8H) ; 4.15 (s, 2H) ; 5.2-5.14 (m, 2H) ; 5.67 (Ddt, 1H, J = 17.4, 10.0 Hz, 5.5 Hz) ; 6.17 (dd, 1H, J = 8.7, 2.8 Hz); 6.30 (d, 1H, J = 2.8 Hz) ; 6.69 (d, 1H, J = 8.8 Hz) ; 6.74-6.86 (m, 2H) ; 6.88-6.98 (m, 4H) ; 7.04 (s, lh) ; 7.18 (tt, 1H, J = 8.4, 6.5 Hz).

¹³C NMR (CDC1₃): δ (ppm) 25.9 ; 55.3 ; 55.9 ; 56.4 ; 100.7 ; 106.6 ; 111.0- 111.5 (m) ; 112.2 ; 113.6 (t, J = 19.3 Hz) ; 115.8 (d, J = 22.9 Hz) ; 117.3 ; 125.5 ; 129.2 (t, J = 10.8 Hz) ; 129.4 (d, J = 8.9 Hz) ; 130.8 (d, J = 3.2 Hz) ; 133.6 ; 138.4 ; 142.4 ; 142.7 ; 149.5 ; 161.2 (dd, J = 250.0, 7.6 Hz) ; 162.3 (d, J = 249.2 Hz). EXAMPLES 17 - 18:

General procedure:

EXAMPLE 17:

Step 2:

Methyl (4S)-4-(tert-butoxycarbonylamino)-5-(3,4-dimethoxy-N-methyl- anilino)-5-oxo-pentanoate

In a 50 niL flask were added 3,4-dimethoxy-N-methyl-aniline (Intermediate la) (500 mg, 2.99 mmol), 6 mL of ethyl acetate, (2R)-2-(tert-butoxycarbonylamino)- 5-methoxy-5-oxo-pentanoic acid (937.55 mg, 3.59 mmol), T₃P^® (2.64 mL, 4.49 mmol) and DIEA (1.57 mL, 8.97 mmol). The reaction mixture was then stirred at 50°C for 1 hour. The reaction mixture was diluted in ethyl acetate, washed with a saturated aqueous solution of NaHC0₃ and with brine, and the organic phase was dried over MgS0₄ and evaporated to dryness to give 1.187 g of Methyl (4S)-4- (tert-butoxycarbonylamino)-5-(3,4-dimethoxy-N-methyl-anilino)-5-oxo- pentanoate, as a brown oil, leading to a 97% yield. It was used without further purification in the next step of the synthesis.

MS: [M+H]⁺ m/z = 411.

Step 3:

(lS)-l-[(3,4-dimethoxyphenyl)-methyl-carbamoyl]-4-methoxy-4- butyl]ammonium;2,2,2-trifluoroacetate

Methyl (4S)-4-(tert-butoxycarbonylamino)-5-(3,4-dimethoxy-N-methyl-anilino)- 5-oxo-pentanoate (1.19 g, 2.89 mmol) and trifluoroacetic acid (1.5 mL, 19.6 mmol) were dissolved in 5 mL of DCM and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was evaporated to dryness to give 1.23 g of (lS)-l-[(3,4-dimethoxyphenyl)-methyl-carbamoyl]-4-methoxy-4-oxo- butyl]ammonium;2,2,2-trifluoroacetate as a purple oil. The product will be used in the next step of the synthesis without further purification (yield was considered to be 100%).

MS: [M+H]⁺ m/z= 311. Step 4:

Methyl (4S)-5-(3,4-dimethoxy-N-methyl-anilino)-4-[[(Z)-N-(4-fluorophi C-sulfanyl-carbonimidoyl mino]-5-oxo-pentanoate

4-fluorophenylisothiocyanate (0.44 g, 2.89 mmol) and TEA (0.39 mL, 2.89 mmol) were added in a 500 mL flask in 20 mL of ethanol. (lS)- l-[(3,4- dimethoxyphenyl)-methyl-carbamoyl]-4-methoxy-4-oxo-butyl]ammonium;2,2,2- trifluoroacetate (1.23 g, 2.89 mmol) was dissolved in 20 mL of ethanol, TEA (0.47 mL, 3.47 mmol) were added, and the mixture was added drop wise at room temperature Then 1 mL of TEA are added to reach pH 10. After 30 min of reaction, the conversion was complete. The reaction mixture was evaporated to dryness. Purification of the crude by flash chromatography using as eluent a mixture of Cy/EA (50/50) gave 940 mg of methyl (4S)-5-(3,4-dimethoxy-N- methyl-anilino)-4-[[(Z)-N-(4-fluorophenyl)-C-sulfanyl-carbonimidoyl]amino]-5- oxo-pentanoate as a yellowish oil, leading to a 70% yield.

MS: [M+H]⁺ m/z = 464.

1H NMR (CDC1₃): δ (ppm) 1.73-1.89 (m, 1H) ; 1.89-2.03 (m, 2H) ; 2.10-2.37 (m, 2H) ; 3.22 (s, 3H) ; 3.57 (s, 3H) ; 3.92 (s, 3H) ; 3.94 (s, 3H) ; 6.91 (s, 2H) ; 7.00- 7.12 (m, 3H) ; 7.27 (s, 2H) ; 7.28 (m, 1H) ; 8.26 (s, 1H).

Step 5:

methyl (4S)-4-[[(Z)-C-[(2,6-difluorophenyl)methylsulfanyl]-N-(4- fluorophenyl)carbonimidoyl]amino]-5-(3,4-dimethoxy-N-methyl-anilino)-5- oxo-pentanoate

The titled product was obtained as a dark oil (1.05 g, 87%), following Procedure A, using methyl 2-(bromomethyl)- l,3-difluoro-benzene (419.82 mg) and methyl (4S)-5-(3,4-dimethoxy-N-methyl-anilino)-4-[(4- fluorophenyl)carbamothioylamino]-5-oxo-pentanoate (940 mg).

MS: [M+H]⁺ m/z = 590.

1H NMR (CDC1₃): δ (ppm) 1.93 (brs, 2H) ; 2.29 (brs, 2H) ; 3.27 (s, 3H) ; 3.60 (s, 3H) ; 3.66 (s, 3H) ; 3.88 (s, 4H) ; 4.10 (brs, 2H) ; 4.70 (brs, 1H) ; 5.40 (brs, 1H) ; 6.72 (brs, 2H) ; 6.83-6.94 (m, 8H).

Step 6: (17A)

methyl 3-[2-[(2,6-difluorophenyl)methylsulfanyl]-5-(3,4-dimethoxy-N-methyl- anilino)-l-(4-fluorophenyl imidazol-4-yl]propanoate

In a 100 mL flask, were added methyl (4S)-4-[[(Z)-C-[(2,6- difluorophenyl)methylsulfanyl]-N-(4-fluorophenyl)carbonimidoyl]amino]-5-(3,4- dimethoxy-N-methyl-anilino)-5-oxo-pentanoate (1 g, 1.7 mmol), T₃P^® (3.01 mL, 5.1 mmol), DIE A (1.88 mL, 10.21 mmol), and 17 mL of EtOAc. The medium was stirred at 80°C for 24 hours. The reaction mixture was diluted in EtOAc and washed with water, brine, and dried over MgS0₄ and evaporated to dryness. The conversion was not complete. The residue was dissolved in 17 mL of AcOEt. T₃P (3.01 mL, 5.1 mmol), DIEA (1.88 mL, 10.21 mmol) were added at the reaction mixture and it was stirred at 80°C for 24 h. The reaction mixture was diluted in EtOAc, washed with water and brine. Organic phase was dried over MgS0₄ and evaporated. The crude was purified by flash chromatography using as eluent a mixture of Cy/EA (70/30) to give 265 mg of the desired product not clean. The crude was again dissolved in EtOAc and T₃P^® (0.6 mL, 1.018 mmol), DIEA (0.376 mL, 2.035 mmol) were added and the reaction mixture was stirred at 80°C for 24 hours. The reaction mixture was diluted in EtOAc, washed with water and brine. Organic phase was dried over MgS0₄ and evaporated. The crude was then purified by flash chromatography using as eluent a mixture of cHex/AcOEt (70/30) to give 104 mg of methyl 3-[2-[(2,6-difluorophenyl)methylsulfanyl]-5- (3,4-dimethoxy-N-methyl-anilino)- l-(4-fluorophenyl)imidazol-4-yl]propanoate as a yellowish oil, leading to a 11% yield.

MS: [M+H]⁺ m/z = 572.2.

1H NMR (CDC1₃): δ (ppm) 2.67-2.72 (m, 4H) ; 2.85 (s, 3H) ; 3.62 (s, 3H) ; 3.79 (s, 3H) ; 3.80 (s, 3H) ; 4.07 (s, 2H) ; 6.04 (dd, J = 8.7, 2.8 Hz, 1H) ; 6.17 (d, J = 2.8 Hz, 1H) ; 6.72 (d, J = 8.7 Hz, 1H) ; 6.77 (t, J = 7.7 Hz, 2H) ; 6.87-6.92 (m, 4H) ; 7.01-7.21 (m, 1H). Step 12: EXAMPLE 17

3-[2-[(2,6-difluorophenyl)methylsulfanyl]-5-(3,4-dimethoxy-N-methyl- anilino)-l-(4-fluorophenyl)imidazol-4-yl]propanoic acid

Methyl 3-[2-[(2,6-difluorophenyl)methylsulfanyl]-5-(3,4-dimethoxy-N-methyl- anilino)-l-(4-fluorophenyl)imidazol-4-yl]propanoate (104.6 mg, 0.18 mmol) was dissolved in MeOH (1.83 mL) and NaOH 1 N (640 μί, 0.64 mmol) was added. The mixture was stirred overnight at room temperature and evaporated to dryness. The residue was dissolved in DCM and washed with HCl 1 N, water and brine. The organic phase was dried over MgS0₄ and evaporated to dryness to give 95 mg of 3-[2-[(2,6-difluorophenyl)methylsulfanyl]-5-(3,4-dimethoxy-N-methyl- anilino)-l-(4-fluorophenyl)imidazol-4-yl]propanoic acid as a yellowish oil, leading to a 93% yield.

MS: [M+H]⁺ m/z = 558.3.

1H NMR (CDC1₃): δ (ppm) 2.73 (s, 4H) ; 2.84 (s, 3H) ; 3.79 (s, 3H) ; 3.80 (s, 3H) ; 4.09 (s, 2H) ; 6.03 (dd, J = 8.7, 2.6 Hz, 1H) ; 6.16 (d, J = 2.6 Hz, 1H) ; 6.73 (d, J = 8.7 Hz, 1H) ; 6.78 (t, J = 1.9 Hz, 2H) ; 6.85-6.98 (m, 4H) ; 7.11-7.23 (m, 1H) ; 8.75 (brs, 1H).

¹³C NMR (CDCI₃): δ (ppm) 21.1 ; 26.7 ; 33.5 ; 38.9 ; 56.1 ; 56.5 ; 98.4 ; 104.1 ; 111.4 (m) ; 112.9 ; 113.4 (t, J = 19.2 Hz) ; 116.2 (d, J = 23.0 Hz) ; 129.1 (d, J = 8.9 Hz) ; 129.6 (t, J = 10.2 Hz) ; 130.4 (d, J = 3.2 Hz) ; 134.6 ; 135.2 ; 137.1 ; 142.5 ; 150.0 ; 161.1 (dd, J = 250.0, 7.6 Hz) ; 162.5 (d, J = 250.0 Hz) ; 175.8.

EXAMPLE 18:

Step 2:

9H-fluoren-9-ylmethyl N-[(5S)-5-(tert-butoxycarbonylamino)-6-(3,4- dimethoxy-N-methyl-anilino)-6-oxo-hexyl]carbamate

In a 50 mL flask were added 3,4-dimethoxy-N-methyl-aniline (Intermediate la) (500 mg, 2.99 mmol), 6 mL of ethyl acetate, (2R)-2-(tert-butoxycarbonylamino)- 6-(9H-fluoren-9-ylmethoxycarbonylamino)hexanoic acid (1681.33 mg, 3.59 mmol), DIEA (1.57 mL, 8.97 mmol) and T₃P^® (2.64 mL, 4.49 mmol). The reaction mixture was then stirred at 50°C for 1 hour. The reaction mixture was diluted in ethyl acetate, washed with a saturated aqueous solution of NaHC0₃ and with brine, and the organic phase was dried over MgS0₄ and evaporated to dryness to give 1.85 g of 9H-fluoren-9-ylmethyl N-[(5S)-5-(tert- butoxycarbonylamino)-6-(3,4-dimethoxy-N-methyl-anilino)-6-oxo- hexyl] carbamate as a dark red oil, leading to a 100% yield. It was used without further purification in the next step of the synthesis.

MS: [M+H]⁺ m/z = 618. Step 3:

[(lS)-l-[(3,4-dimethoxyphenyl)-methyl-carbamoyl]-5-(9H-fluoren-9- ylmethoxycarbonylamino)pentyl]ammonium;2,2,2-trifluoroacetate

9H-fluoren-9-ylmethyl N-[(5S)-5-(tert-butoxycarbonylamino)-6-(3,4-dimethoxy- N-methyl-anilino)-6-oxo-hexyl]carbamate (1.85 g, 2.99 mmol) and TFA (2.56 mL, 33.42 mmol) were dissolved in 5 mL of DCM. The reaction mixture was stirred at room temperature for 1 h. 1 mL of TFA was added again at the reaction mixture ant it was stirred at room temperature for 30 minutes. The reaction mixture was evaporated to dryness to give 1.58 g of [(lS)-l-[(3,4- dimethoxyphenyl)-methyl-carbamoyl]-5-(9H-fluoren-9- ylmethoxycarbonylamino)pentyl]ammonium;2,2,2-trifluoroacetate as a purple oil, leading to a 100% yield. It was used without further purification in the next step of the synthesis.

MS: [M+H]⁺ m/z= 518.

Step 4:

9H-fluoren-9-ylmethyl N-[(5S)-6-(3,4-dimethoxy-N-methyl-anilino)-5-[[(Z)-N- (4-fluorophenyl)-C-sulfan l-carbonimidoyl]amino]-6-oxo-hexyl]carbamate

l-fluoro-4-isothiocyanato-benzene (0.46 g, 2.99 mmol) and TEA (0.4 mL, 2.99 mmol) were added in a 500 mL flask in 20 mL of ethanol. [(lS)-l-[(3,4- dimethoxyphenyl)-methyl-carbamoyl]-5-(9H-fluoren-9- ylmethoxycarbonylamino)pentyl]ammonium;2,2,2-trifluoroacetate (1.89 g, 2.99 mmol) was dissolved in 20 mL of ethanol, TEA (0.47 mL, 3.47 mmol) were added, and the mixture was added dropwise at room temperature. Then 1 mL of TEA was added to reach pH 10. The reaction mixture was evaporated to dryness. Purification of the crude by flash chromatography using as eluent a mixture of Cy/EA (50/50) gave 1.58 g of 9H-fluoren-9-ylmethyl N-[(5S)-6-(3,4-dimethoxy- N-methyl-anilino)-5-[[(Z)-N-(4-fluorophenyl)-C-sulfanyl-carbonimidoyl]amino]- 6-oxo-hexyl] carbamate as a yellowish oil, leading to a 79% yield.

MS: [M+H]⁺ m/z = 671.

1H NMR (CDC1₃): δ (ppm) 1.09-1.36 (m, 4H) ; 1.46-1.70 (m, 2H) ; 3.00 (s, 2H) ; 3.20 (s, 3H) ; 3.87 (s, 3H) ; 3.93 (s, 3H) ; 4.18 (d, J = 7.3 Hz, 1H) ; 4.36 (d, J = 7.1 Hz, 2H) ; 4.91 (t, J = 5.6 Hz, 1H) ; 6.88 (s, 2H) ; 6.99 (t, J = 8.5 Hz, 2H) ; 7.12 (s, 1H) ; 7.20-7.42 (m, 6H) ; 7.57 (d, J = 7.4 Hz, 2H) ; 7.67 (s, 1H) ; 7.74 (d, J = 7.4 Hz, 2H) ; 8.51 (s, 1H).

Step 5:

9H-fluoren-9-ylmethyl N-[(5S)-5-[[(Z)-C-[(2,6- difluorophenyl)methylsulfanyl]-N-(4-fluorophenyl)carbonimidoyl]amino]-6- (3,4-dimethoxy-N-methyl-anilino -6-oxo-hexyl]carbamate

In a 25 mL flask were added 2-(bromomethyl)- l,3-difluoro-benzene (486.14 mg, 2.348 mmol), K₂C0₃ (357.02 mg, 2.583 mmol) and 11.74 mL of acetonitrile. The suspension was stirred at room temperature for 10 minutes and 9H-fluoren-9- ylmethyl N-[(5S)-6-(3,4-dimethoxy-N-methyl-anilino)-5-[[(4-fluoroanilino)- sulfanyl-methyl]amino]-6-oxo-hexyl]carbamate (1.58 g, 2.35 mmol) was then added. The suspension was stirred at room temperature overnight. The reaction mixture was then evaporated, residue was dissolved in EtOAc, washed with water and brine, organic phase was dried over MgS0₄ and evaporated to dryness to give 1.87 g of the desired product as a dark oil, leading to a 89% yield. It was used without further purification in the next step of the synthesis.

MS: [M+H]+ m/z = 799.

1H NMR (CDC1₃): δ (ppm) 1.30 (brs, 4H) ; 1.62 (brs, 3H) ; 3.08 (brs, 2H) ; 3.27 (brs, 3H) ; 3.62 (s, 3H) ; 3.84 (s, 3H) ; 4.08 (brs, 2H) ; 4.19 (m, 1H) ; 4.39 (d, J = 6.9 Hz, 2H) ; 4.70 (brs, 1H) ; 5.24 (brs, 1H) ; 6.74 (brs, 1H) ; 6.75-6.95 (m, 8H) ; 7.15-7.23 (m, 1H) ; 7.30 (t, J = 7.4 Hz, 2H) ; 7.39 (t, J = 7.4 Hz, 2H) ; 7.57 (d, J = 7.2 Hz, 2H) ; 7.76 (d, J = 7.2 Hz, 2H).

Step 6:

9H-fluoren-9-ylmethyl N-[4-[2-[(2,6-difluorophenyl)methylsulfanyl]-5-(3,4- dimethoxy-N-methyl-anilino)-l-(4-fluorophenyl)imidazol-4- yl] butyl] carbamate

In a 50 mL flask were added 9H-fluoren-9-ylmethyl N-[(5S)-5-[[(Z)-C-[(2,6- difluorophenyl)methylsulfanyl]-N-(4-fluorophenyl)carbonimidoyl]amino]-6-(3,4- dimethoxy-N-methyl-anilino)-6-oxo-hexyl]carbamate (1.625 mg, 2.039 mmol), Ί₃Ρ (3.605 mL, 6.117 mmol), DIEA (2.137 mL, 12.23 mmol) and 20.39 mL of EtOAc. The suspension was stirred 24 hours at 80°C. Same quantities of T₃P^® and DIEA were added twice at 24 and 48 h. The medium was then evaporated, the residue was dissolved in EtOAc, washed with water and brine, organic phase was dried over MgS0₄ and evaporated. Purification of the crude by flash chromatography using as eluent a mixture of cyclohexane/EtOAc (7/3) gave 507 mg of 9H-fluoren-9-ylmethyl N-[4-[2-[(2,6-difluorophenyl)methylsulfanyl]-5- (3,4-dimethoxy-N-methyl-anilino)- l-(4-fluorophenyl)imidazol-4- yl]butyl]carbamate as a yellow solid, leading to a 32% yield.

MS: [M+H]⁺ m/z = 779.

1H NMR (CDC1₃): δ (ppm) 1(2H) ; 1.61-1.74 (m, 2H) ; 2.43 (t, J = 7.4 Hz, 2H) ; 2.83 (s, 3H) ; 3.15-3.22 (m, 2H) ; 3.80 (s, 3H) ; 3.81 (s, 3H) ; 4.07 (s, 2H) ; 4.21 (t, J = 6.8 Hz, 2H) ; 4.38 (d, J = 7.0 Hz, 2H) ; 5.03 (brs, 1H) ; 6.04 (dd, J = 8.7, 2.8 Hz, 1H) ; 6.18 (d, J = 2.8 Hz, 1H) ; 6.70-6.81 (m, 3H) ; 6.88-6.94 (m, 4H) ; 7.09-7.20 (m, 1H) ; 7.30(t, J = 7.4 Hz, 2H) ; 7.38 (d, J = 7.4 Hz, 2H) ; 7.60 (d, J = 7.2 Hz, 2H) ; 7.75 (d, J = 7.2 Hz, 2H).

Step 12:

EXAMPLE 18. 4-[2-[(2,6-difluorophenyl)methylsulfanyl]-5-(3,4-dimethoxy- N-methyl-anilino)-l-(4-fluorophenyl)imidazol-4-yl]butylammonium;formate

To a solution of 9H-fluoren-9-ylmethyl N-[4-[2-[(2,6- difluorophenyl)methylsulfanyl]-5-(3,4-dimethoxy-N-methyl-anilino)-l-(4- fluorophenyl)imidazol-4-yl]butyl]carbamate (0.24 g, 0.31 mmol) in ethyl acetate (1.45 mL) was added piperidine (0.06 mL, 0.62 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was then evaporated under reduced pressure. Purification of the crude by preparative HPLC (pH 3.8) gave 100 mg of 4-[2-[(2,6-difluorophenyl)methylsulfanyl]-5-(3,4-dimethoxy-N- methyl-anilino)- 1 -(4-fluorophenyl)imidazol-4-yl]butylammonium;formate as a yellowish oil, leading to a 60% yield.

MS: [M+H]⁺ m/z = 557.

1H NMR (CDC1₃): δ (ppm) 1.60-1.80 (m, 4H) ; 2.32-2.50 (m, 2H) ; 2.82 (s, 3H) ; 2.90-3.00 (m, 2H) ; 3.80 (s, 3H) ; 3.81 (s, 3H) ; 3.94 (s, 2H) ; 6.03 (dd, J = 8.7, 2.4 Hz, 1H) ; 6.17 (d, J = 2.4 Hz, 1H) ; 5.50-6.50 (m, 3H) ; 6.70-6.82 (m, 3H) ; 6.83- 6.95 (m, 4H) ; 7.10-7.21 (m, 1H) ; 8.46 (brs, 1H).

¹³C NMR (CDCI₃): δ (ppm) 25.8 ; 25.9 ; 26.9 ; 27.6 ; 39.0 ; 56.0 ; 56.6 ; 70.6 98.2 ; 103.8 ; 111.3 (m) ; 112.9 ; 114.0 (t, J = 19.3 Hz) ; 115.9 (d, J = 22.8 Hz) 129.2 (d, J = 9.0 Hz) ; 129.3 (t, J = 9.2 Hz) ; 131.1 (d, J = 3.1 Hz) ; 134.7 ; 136.4 137.2 ; 142.2 ; 142.9 ; 149.9 ; 161.1 (dd, J = 249.7, 7.8 Hz) ; 162.3 (d, J = 249.1 Hz) ; 168.6.

EXAMPLE 19: [2-(2,6-Difluoro-benzylsulfanyl)-3-(4-fluoro-phenyl)-3H- imidazol-4-yl]-(3,4-dimethoxy-benzyl)-methyl-amine

[(3,4-dimethoxy-benzyl)-methyl-carbamoyl]-methyl-ammonium formate (19a)

In a 100 mL flask was introduced a solution of 1.05 mL of 3.4-Dimethoxy-N- methylbenzylamine and 2.74 mL of DIEA in 13 mL of DCM (dried over Na₂S0₄).

The solution was stirred at 0°C. Then, a solution of 0.84 mL of chloroacetyl chloride in 13 mL of DCM (dried over Na₂S0₄) was added dropwise in the flask. The mixture was then evaporated to dryness to give a brown residue. Conversion was considered to be 100% for the next reaction. The obtained residue was dissolved in 9 mL of Ethanol 95°C and added dropwise in a 250 mL flask containing 100 mL of aqueous ammonia at 65 °C. After the addition, heating was stopped. The mixture was evaporated to dryness. The residue was then dissolved in DCM, and extracted several times by an aqueous solution of HCOOH 1 M. During this extraction, a precipitate appeared and was filtered. The filtrate was then evaporated to dryness, and the residue was triturated in acetonitrile. The supernatant was evaporated to dryness, to give 1.51 g of [(3,4-dimethoxy-benzyl)- methyl-carbamoyl] -methyl-ammonium formate as a pale brown oily residue, leading to a 90% yield over the 2 steps.

MS: [M+H]⁺ m/z = 239.0.

N-(3,4-Dimethoxy-benzyl)-2-[3-(4-fluoro-phenyl)-thioureido]-N-methyl- acetamide (19b)

732 mg of 4-fluorophenylisothiocyanate and 774 μΐ_^ of TEA were added in a 250 mL flask in ethanol (4 mL). [(3,4-dimethoxy-benzyl)-methyl-carbamoyl]-methyl- ammonium formate (19a) (1.51 g, 4.78 mmol) was dissolved in 60 mL of ethanol and 645 μΐ_^ of TEA were then added. This solution was added dropwise at room temperature. After the addition, the reaction was over. Reaction mixture was evaporated to dryness, and purified by flash chromatography using as eluent a mixture of cHex/EtOAc (6/4) to give 880 mg of N-(3,4-Dimethoxy-benzyl)-2-[3- (4-fluoro-phenyl)-thioureido]-N-methyl-acetamide as a yellowish solid (leading to a 47% yield). MS: [M+H]⁺ m/z = 391.9.

1HNMR (MeOD-i¾: δ (ppm) 2.91-2.99 (m, 3H) ; 3.81-3.84 (m, 6H)

(m, 4H) ; 6.81-6.98 (m, 3H) ; 7.08-7.15 (m, 2H) ; 7.39-7.45 (m, 2H). 2-[2-(2,6-Difluoro-benzyl)-3-(4-fluoro-phenyl)-isothioureido]-N-(3,4- dimethoxy-benzyl)-N-methyl-acetamide (19c)

The titled product was obtained as an oily residue (207 mg, 58%), following Procedure A, using N-(3,4-dimethoxy-benzyl)-2-[3-(4-fluoro-phenyl)-thioureido]- N-methyl-acetamide (19b) (0.300 g) and 2-bromomethyl-l,3-difluoro-benzene (77 mg).

MS: [M+H]⁺ m/z = 518.0.

1HNMR (DMSO- ₆): δ (ppm) 2.85 (m, 3H) ; 3.65 (m, 3H) ; 3.70 (s, 3H) ; 4.15 (m, 2H) ; 4.23 (m, 2H) ; 4.47 (m, 2H) ; 6.64 (m, 2H) ; 6.77-6.89 (m, 4H) ; 6.99 (m, 2H) ; 7.09 (m, 2H) ; 7.39 (m, 1H).

[2-(2,6-Difluoro-benzylsulfanyl)-3-(4-fluoro-phenyl)-3H-imidazol-4-yl]-(3,4- dimethoxy-benzyl)-methyl-amine (19)

The titled product was obtained as a yellowish powder (91 mg, 47 %) following procedure B using 2-[2-(2,6-difluoro-benzyl)-3-(4-fluoro-phenyl)-isothioureido]- N-(3,4-dimethoxy-benzyl)-N-methyl-acetamide (19c) (200 mg).

MS: [M+H]⁺ m/z = 499.9. 1HNMR (CDCI₃): δ (ppm) 2.48 (s, 3H) ; 3.68 (s, 2H) ; 3.77 (s, 3H) ; 3.86 (s, 3H) ; 4.10 (s, 2H) ; 6.37 (d, J = 1.9 Hz, 1H) ; 6.56 (dd, J = 8.2,1.9 Hz, 1H) ; 6.74 (d, J = 8.1 Hz, 1H) ; 6.77-6.85 (m, 3H) ; 7.10-7.22 (m, 5H).

¹³CNMR (CDCI₃): δ (ppm) 26.0 ; 40.4 ; 55.8 ; 55.9 ; 60.6 ; 110.6 ; 111.1 ; 111.3 ; 113.5 (t, J =19.0 Hz) ; 116.0 (d, J = 22.1 Hz) ; 1 17.6 ; 121.0 ; 129.1 (t, J = 10.1 Hz) ; 129.7 ; 129.9 (d, J = 8.5 Hz) ; 131.6 (d, J = 2.3 Hz) ; 136.4 ; 145.8 ; 148.3 ; 148.8 ; 161.2 (dd, J = 250.0,7.7 Hz) ; 162.3 (d, J = 248.9 Hz).

EXAMPLE 20: N-[2-(2,6-Difluoro-benzylsulfanyl)-3-(4-fluoro-phenyl)-3H- imidazol-4-yl]-3,4-dimethoxy-benzamide

1 - Cyanomethyl-3- (4-fluoro-phen -isothiourea (20a)

2-aminoacetonitrile hydrochloride (725 mg, 7.83 mmol) and TEA (1090 μί, 7.83 mmol) were added in 12 mL of DMF. Then a solution of 4-fluoro- phenylisothiocyanate (1.00 g, 6.53 mmol) in 2 mL of DMF was added and the reaction mixture was stirred at room temperature for 5 min, then cooled down to 0°C. After addition of roughly 60 mL water, a precipitate was obtained. The mixture was stirred at 0°C for 30 min and filtrated to give 1.09 g of 1- cyanomethyl-3-(4-fluoro-phenyl)-isothiourea as purple crystals, leading to a 80% yield.

MS: [M+H]⁺ m/z = 209.9.

1HNMR (DMSO- ₆): δ (ppm) 4.49 (d, J = 5.5 Hz, 2H) ; 7.20 (t, J = 8.7 Hz, 2H) ; 7.38 (dd, J = 8.6 Hz, 5.0 Hz, 2H) ; 8.03 (brs, 1H) ; 10.02 (s, 1H).

2-(2,6-Difluoro-benzylsulfanyl)-3-(4-fluoro-phenyl)-3H-imidazol-4-ylamine (20b)

In a 50 mL flask were added l-cyanomethyl-3-(4-fluoro-phenyl)-isothiourea (20a) (1.09 g, 5.21 mmol), 10 mL of dry acetonitrile, Nal (390 mg, 2.60 mmol), 2- bromomethyl-l,3-difluoro-benzene (1.08 g) and DIEA (891 μί, 5.21 mmol). Reaction mixture was stirred at room temperature for 5 min. Reaction mixture was then diluted with 20 mL EtOAc, washed with 10 mL water and 10 mL brine, dried over Na₂S0₄ and evaporated to give 2-(2,6-difluoro-benzylsulfanyl)-3-(4-fluoro- phenyl)-3H-imidazol-4-ylamine. It was used without further purification in the next step of the synthesis.

MS: [M+H]⁺ m/z = 335.9. N-[2-(2,6-Difluoro-benzylsulfanyl)-3-(4-fluoro-phenyl)-3H-imidazol-4-yl]-3,4- dimethoxy-benzamide (

3,4-dimethoxybenzoic acid (130 mg, 0.72 mmol) were dissolved in 752 μΙ_, of a mixture of thionyl chloride (SOCl₂) and DCM (2/8, v/v). After one hour stirring at room temperature, it was evaporated. Then 2-(2,6-difluoro-benzylsulfanyl)-3-(4- fluoro-phenyl)-3H-imidazol-4-ylamine (20b) (200 mg, 0.36 mmol) in 1.8 mL dry THF and Pyridine (57.9 μί, 0.72 mmol) were added over the residue, and the mixture was stirred at room temperature for 4 h. Reaction mixture was then evaporated, dissolved in EtOAc, washed with water, and a saturated aqueous solution of NaHCC"3 and brine. Organic phase was dried over Na₂S0₄ and evaporated. Residue was purified by flash chromatography using as eluent a mixture cHex/EtOAc (7/3) and then cHex/DCM/MeOH (0/98/2) to give 56 mg of N-[2-(2,6-Difluoro-benzylsulfanyl)-3-(4-fluoro-phenyl)-3H-imidazol-4-yl]-3,4- dimethoxy-benzamide as a reddish solid, leading to a 31% yield.

MS: [M+H]⁺ m/z = 499.8.

1HNMR (CDC1₃): δ (ppm) 3.87 (s, 3H) ; 3.89 (s, 3H) ; 4.13 (s, 2H) ; 6.75-6.87 (m, 3H) ; 7.05-7.26 (m, 7H) ; 7.37 (d, J = 2.0 Hz, 1H) ; 8.15 (s, 1H).

¹³CNMR (CDCI₃): δ (ppm) 26.0 ; 56.1 ; 110.4 ; 110.9 ; 111.2-111.6 (m) ; 113.2 (t, J = 19.2 Hz) ; 116.6 (d, J = 23.0 Hz) ; 120.1 ; 123.4 ; 125.5 ; 129.3 ; 129.5 (t, J = 10.2 Hz) ; 129.7 (d, J = 8.8 Hz) ; 130.1 (d, J = 3.3 Hz) ; 138.7 ; 149.2 ; 152.6 ; 161.3 (dd, J = 254.5, 3.7 Hz) ; 162.9 (d, J = 250.5 Hz) ; 165.9.

EXAMPLE 21: 4-[4-[[5-(3,4-dimethoxy-N-methyl-anilino)-l-(4-fluoro-3- methoxy-phenyl)imidazol-2-yl]sulfanylmethyl]-3,5-difluoro-phenyl]-N-

[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]benzamide

21

MS: [M+H]⁺ m/z = 636.

1H NMR (DMSO- 6): δ (ppm) 2.92 (s, 3H) ; 3.48 (s, 3H) ; 3.59 (s, 3H) ; 3.65 (s, 3H) ; 4.13 (s, 2H) ; 6.06 (dd, J = 8.8, 2.8 Hz, 1H) ; 6.24 (d, J = 2.8 Hz, 1H) ; 6.61- 6.67 (m, 1H) ; 6.75 (d, J = 8.8 Hz, 1H) ; 6.78 (dd, J = 7.9, 2.5 Hz, 1H) ; 7.02 (s, 1H) ; 7.17 (dd, J = 11.4, 8.4 Hz, 1H) ; 7.52 (d, J = 9.2 Hz, 2H) ; 7.87 (d, J = 8.4 Hz, 2H) ; 8.01 (d, J = 8.4Hz, 2H) ; 13.08 (s, 1H). 4-[4-[[5-(3,4-dimethoxy-N-methyl-anilino)-l-(4-fluoro-3-methoxy- phenyl)imidazol-2-yl]sulfanylmethyl]-3,5-difluoro-phenyl]-N-[(2S,3R,4R,5R)- 2,3,4,5,6-pentahydrox hexyl]benzamide (compound 21)

In a 5 mL flask were added 4-[4-[[5-(3,4-dimethoxy-N-methyl-anilino)- l-(4- fluoro-3-methoxy-phenyl)imidazol-2-yl]sulfanylmethyl]-3,5-difluoro- phenyl]benzoic acid (63 mg, 0.1 mmol), NEt₃ (13.37 μL·, 0, 1 mmol), EDCI (15.39 mg, 0, 1 mmol), HOBT (13.39 mg, 0.1 mmol), and D-glucamine (17.96 mg, 0.1 mmol) in 500 μΐ_^ of DCM. The reaction mixture was stirred overnight at room temperature. The reaction mixture was evaporated to dryness. The crude was purified by preparative HPLC to give 17 mg of the desired product as a white solid, leading to a 21% yield.

MS : [M+H]⁺ m/z = 799.3.

1H NMR (MeOD- 4) : δ (ppm) 2.92 (s, 3H) ; 3.36 (d, J = 4.3 Hz, 6H) ; 3.46-3.54 (m, 1H) ; 3.59-3.87 (m, 6H) ; 3.68 (s, 3H) ; 3.75 (s, 3H) ; 3.98-4.01 (m, 1H) ; 4.04 (s, 2H) ; 6.16 (dd, J = 8.7, 2.8 Hz, 1H) ; 6.33 (d, J = 2.8 Hz, 1H) ; 6.45 (dd, J = 7.6, 2.5 Hz, 1H) ; 6.48-6.53 (m, 1H) ; 6.77 (d, J = 8.7 Hz, 1H) ; 6.96 (dd, J = 11.0, 8.5 Hz, 1H) ; 7.05 (s, 1H) ; 7.27 (d, J = 8.8 Hz, 2H) ; 7.73 (d, J = 8.7 Hz, 2H) ; 7.94 (d, J = 8.7 Hz, 2H).

1³C NMR (MeOD- 4) : δ (ppm) 26.8 ; 39.2 ; 42.8 ; 55.2 ; 55.4 ; 55.9 ; 63.4 ; 70.0 ; 71.6 ; 71.9 ; 72.5 ; 101.1 ; 106.8 ; 190.4 (m) ; 113.4 ; 113.6 (t, J = 19.5 Hz) ; 113.5 ; 115.2 (d, J = 19.9 Hz) ; 120.3 (d, J = 1.1 Hz) ; 123.7 ; 126.5 ; 127.8 ; 130.9 (d, J = 3.8 Hz) ; 134.2 ; 137.3 ; 140.3 ; 140.9 ; 141.6 (t, J = 10.2 Hz) ; 143.1 ; 143.6 ; 147.4 (d, J = 11.4 Hz) ; 149.9 ; 152.1 (d, J = 248.6 Hz) ; 161.3 (dd, J = 248.5, 8.7 Hz) ; 168.5. EXAMPLE 22: 3-[[4-[4-[[5-(3,4-dimethoxy-N-methyl-anilino)-l-(4-fluoro-3- methoxy-phenyl)imidazol-2-yl]sulfanylmethyl]-3,5-difluoro- phenyl]phenyl]methylamino]propanoic acid

4-[4-[[5-(3,4-dimethoxy-N-methyl-anilino)-l-(4-fluoro-3-methoxy- phenyl)imidazol-2-yl]sulfanylmethyl]-3,5-difluoro-phenyl]benzaldehyde (Intermediate 15)

In two microwave tubes were added 2-[(4-bromo-2,6-difluoro- phenyl)methylsulfanyl]-N-(3,4-dimethoxyphenyl)-3-(4-fluoro-3-methoxy- phenyl)-N-methyl-imidazol-4-amine (Intermediate 2) (500 mg, 0.84 mmol), (4- formylphenyl)boronic acid (126.12 mg, 0.84 mmol), 1M Cs2C03 (2.52 ml), and Pd(Ph3P)4 (194.39 mg, 0.17 mmol). 8.5 mL of DMF were flushed with argon, added to the reaction mixture, which was also flushed with argon. The reaction mixture was heated under microwave irradiation at 100°C for 10 min. The reaction mixture was filtrated and evaporated to dryness. The crude was diluted in DCM and filtrated on Celite. Purification of the crude by flash chromatography using as eluent a mixture of DCM/MeOH (95/5) gave 330 mg of the desired compound as a yellow oil, leading to a 67 % yield.

MS [M+H]⁺ m/z = 620.1

1H NMR (CD₂C1₂) : δ (ppm) 2.92 (s, 3H) ; 3.50 (s, 3H) ; 3.72 (s, 3H) ; 3.75 (s, 3H) ; 4.16 (s, 2H) ; 6.16 (dd, J = 8.7, 2.8 Hz, 1H) ; 6.30 (d, J = 2.8 Hz, 1H) ; 6.59 (dd, J = 7.6, 2.4 Hz, 1H) ; 6.61-6.66 (m, 1H) ; 6.71 (d, J = 8.7 Hz, 1H) ; 6.98 (dd, J = 10.9, 8.5 Hz, 1H) ; 7.00 (s, 1H) ; 7.15 (d, J = 8.6 Hz, 2H) ; 7.71 (d, J = 8.6 Hz, 2H) ; 7.96 (d, J = 8.6 Hz, 2H) ; 10.05 (s, 1H). 3-[[4-[4-[[5-(3,4-dimethoxy-N-methyl-anilino)-l-(4-fluoro-3-methoxy- phenyl)imidazol-2-yl]sulfanylmethyl]-3,5-difluoro- phenyl]phenyl]meth lamino]propanoic acid (compound 22)

In a 25 mL flask was added 4-[4-[[5-(3,4-dimethoxy-N-methyl-anilino)-l-(4- fluoro-3-methoxy-phenyl)imidazol-2-yl] sulfanylmethyl]-3,5-difluoro- phenyl]benzaldehyde (100 mg, 0.16 mmol) in 1.7 mL of dichloroethane. Ethyl 3- aminopropanoate (28.36 mg, 0.24 mmol), NaHB(OAc)₃ (102.61 mg, 0.48 mmol) and acetic acid (92.3 μΐ, 1.61 mmol) were then added and the reaction mixture was stirred at 25°C for 5h. The reaction mixture was filtrated and evaporated to dryness. Purification of the crude by preparative HPLC (ammonium formate buffer pH 9.2) gave 10 mg of the titled compound as a white powder, leading to a 9% yield.

MS : [M+H]⁺ m/z = 693.2

Tr (min) = 2.58

1H NMR (CDC1₃) : δ (ppm) 2.47 (brs, 2H) ; 2.91 (s, 3H) ; 3.08 (brs, 2H) ; 3.51 (s, 3H) ; 3.79 (s, 3H) ; 3.80 (s, 3H) ; 4.11 (s, 2H) ; 4.13 (s, 2H) ; 6.17 (dd, J = 8.7, 2.7 Hz, 1H) ; 6.31 (d, J = 2.7 Hz, 1H) ; 6.58 (dd, J = 7.5, 2.4 Hz, 1H) ; 6.62-6.67 (m, 1H) ; 6.72 (d, J = 8.9 Hz, 1H) ; 6.92-7.00 (m, 3H) ; 7.03 (s, 1H) ; 7.44-7.54 (m, 4H).

¹³C NMR (CDC1₃) : δ (ppm) 25.9 ; 32.4 ; 40.2 ; 43.7 ; 50.9 ; 56.1 ; 56.7 ; 100.1 ; 105.8 ; 108.7-110.0 (m) ; 112.6 ; 112.7 (t, J = 10.3 Hz) ; 113.0 (d, J = 3.5 Hz) ; 116.1 (d, J = 20.3 Hz) ; 119.9 (d, J = 5.6 Hz) ; 124.6 ; 127.5 ; 130.9 ; 131.1 (d, J = 3.2 Hz) ; 131.5 ; 138.2 ; 139.4 ; 139.7 ; 142.0 ; 142.9 ; 143.5 ; 147.8 (d, J = 11.4 Hz) ; 149.8 ; 152.2 (d, J = 248.9 Hz) ; 161.5 (dd, J = 248.7, 8.2 Hz).

EXAMPLE 23:

3-[[4-[4-[[5-(3,4-dimethoxy-N-methyl-anilino)-l-(4-fluoro-3-methoxy- phenyl)imidazol-2-yl]sulfanylmethyl]-3,5-difluoro- phenyl]phenyl]methylamino]pentanedioic acid

diethyl 3-aminopentanedioate Intermediate 16) :

In a 5 mL flask was added 3-aminopentanedioic acid (75 mg, 0.510 mmol) in EtOH (1.5 mL). Thionyl chloride (0.148 mL, 2.039 mmol) was added dropwise. The reaction mixture was stirred at room temperature overnight and concentrated under reduced pressure. The crude was washed with a saturated aqueous solution of NaHC0₃, water, brine, dried over MgS0₄ and concentrated under reduced pressure to give 100 mg of diethyl 3-aminopentanedioate as colorless oil, leading to a 97 % yield.

1H NMR (CDC1₃) : δ (ppm) 1.21 (t, J = 7.1 Hz, 6H) ; 1.80 (s, 2H) ; 2.30-2.49 (m, 4H) ; 3.57-3.59 (m, 1H) ; 4.11 (q, J = 7.1 Hz, 4H). diethyl 3-[[4-[4-[[5-(3,4-dimethoxy-N-methyl-anilino)-l-(4-fluoro-3-methoxy- phenyl)imidazol-2-yl]sulfanylmethyl]-3,5-difluoro- phenyl]phenyl]meth lamino]pentanedioate (Intermediate 23a)

In the 10 mL flask were added 4-[4-[[5-(3,4-dimethoxy-N-methyl-anilino)- l-(4- fluoro-3-methoxy-phenyl)imidazol-2-yl]sulfanylmethyl]-3,5-difluoro- phenyl]benzaldehyde (Intermediate 15) (183 mg, 0.3 mmol) in DCE (3 mL). Diethyl 3-aminopentanedioate (Intermediate 16) (90 mg, 0.44 mmol) and acetic acid (0.17 mL, 2.95 mmol) were added and the reaction mixture was stirred at room temperature overnight. NaHB(OAc)₃ (157 mg, 0.741 mmol) was added at the reaction mixture and it was stirred at room room temperature for 1 h. The reaction mixture was diluted in DCM, washed with a saturated aqueous solution of NaHC0₃, brine, dried over MgS0₄ and evaporated to dryness to give 90 mg of the titled compound, as yellow oil, leading to a 38% yield. It will be used in the next step of the synthesis without further purification.

MS : [M+H]⁺ m/z = 808 3-[[4-[4-[[5-(3,4-dimethoxy-N-methyl-anilino)-l-(4-fluoro-3-methoxy- phenyl)imidazol-2-yl]sulfanylmethyl]-3,5-difluoro- phenyl]phenyl]methylamino]pentanedioic acid (compound 23)

In the 5 mL flask we added, diethyl3-[[4-[4-[[5-(3,4-dimethoxy-N-methyl- anilino)-l-(4-fluoro-3-methoxy-phenyl)imidazol-2-yl]sulfanylmethyl]-3,5- difluoro-phenyl]phenyl]methylamino]pentanedioate (90 mg, 0.112 mmol) in 1 mL of a mixture of MeOH/THF/H₂0 (1/1/1). LiOH, H₂0 (4.680 mg, 0.112 mmol) was added at the reaction mixture and it was stirred at room temperature overnight. LiOH, H₂0 (4.68 mg, 0.112 mmol) was added again and the reaction mixture was stirred at 40°C during one hour. The reaction mixture was evaporated to dryness. Purification of the crude by preparative HPLC gave 34 mg of the desired product, leading to a 40% yield.

MS: [M+H]⁺ m/z = 751.3

1H NMR (CDC1₃) : δ (ppm) 2.37-2.53 (m, 5H) ; 2.91 (s, 3H) ; 3.31 (q, J = 6.2 Hz, 1H) ; 3.46 (s, 3H) ; 3.58 (s, 3H) ; 3.65 (s, 3H) ; 3.92 (s, 2H) ; 4.11 (s, 2H) ;6.05 (dd, J = 8.7, 2.8 Hz, 1H) ; 6.23 (d, J = 2.8 Hz, 1H) ; 6.61-6.65 (m, 1H) ; 6.72- 6.68 (m, 1H) ; 7.01 (s,lH) ; 7.15 (dd, J = 11.2, 8.6 Hz, 1H) ; 7.44 (d, J = 6.8 Hz, 2H) ; 7.01 (s, 1H) ; 7,60 (dd, J =8.1 , 7.2 Hz, 2H).

¹³C NMR (CDCI₃) : δ (ppm) : 26.3 ; 37.8 ; 48.5 ; 51.4 ; 56.1 ; 56.3 ; 56.6 ; 100.2 ; 105.8 ; 109.8 (d, J = 25.3 Hz) ; 112.8 (t, J = 19.9 Hz) ; 113.9 ; 116,2 (d, J = 19.5 Hz) ; 120.5 (d, J = 7.2 Hz) ; 124.7 ; 127.1 ; 129.6 ; 131.6 (d, / = 3.1 Hz) ; 136.6 ; 137.3 ; 139.1 ; 139.8 ; 142.0 (t, J = 10.3 Hz) ; 142.5 ; 143.7 ; 147.2 (d, J = 11.7 Hz) ; 149.9 ; 151.6 (d, J = 246.5 Hz) ; 161.3 (dd, J = 247.3 , 8.9 Hz) ; 173.2.

EXAMPLE 24:

(2R,3R,4R,5S)-6-[3-[4-[[5-(3,4-dimethoxy-N-methyl-anilino)-l-(4- fluorophenyl)imidazol-2-yl]sulfanylmethyl]-3,5-difluoro-phenoxy]propyl- methyl-amino]hexane-l,2,3,4,5-pentol

To a solution of 2-[[4-(3-chloropropoxy)-2,6-difluoro-phenyl]methylsulfanyl]-N- (3,4-dimethoxyphenyl)-3-(4-fluorophenyl)-N-methyl-imidazol-4-amine

(Intermediate 11) (100 mg, 0.18 mmol) in DMF (1.6 mL) was added (2R,3R,4R,5S)-6-(methylamino)hexane-l,2,3,4,5-pentol (101.31 mg, 0.52 mmol), Cs₂C0₃ (56.37 mg, 0.17 mmol) and Nal (25.93 mg, 0.17 mmol). The reaction mixture was stirred at 75°C overnight. The reaction mixture was evaporated to dryness and was purified by preparative HPLC gave 24 mg of the desired product as yellow oil, leading to a 19% yield.

MS : [M+H]⁺ m/z = 737.3

1H NMR (CDC1₃) : δ (ppm) 2.07 (s, 2H) ; 2.65 (s, 3H) ; 2.90 (s, 3H) ; 3.03 (s, 4H) ; 3.75 (s, 3H) ; 3.76 (m, 6H) ; 3.77 (s, 3H) ; 3.86 (s, 2H) ; 3.94 (s, 2H) ; 6.12 (dd, J = 8.7, 2.6 Hz, 1H) ; 6.23 (d, J = 2.5 Hz, 1H) ; 6.36-6.39 (m, 2H) ; 6.72 (d, J = 8.8 Hz, 1H) ; 6.93-7.07 (m, 5H).

¹³C NMR (CDC1₃) : δ (ppm) 25.1 ; 25.8 ; 40.4 ; 41.8 ; 54.5 ; 55.9 ; 56.5 ; 59.4 ; 63.8 ; 66.2 ; 68.9 ; 71.1 ; 71.9 ; 72.3 ; 98.4-98.7 (m) ; 100.3 ; 105.4 (t, J = 20.1 Hz) ; 106.1 ; 112.5 ; 115.9 (d, J = 22.9 Hz) ; 123.7 ; 129.3 (d, J = 8.7 Hz) ; 130.9 (d, J = 3.1 Hz) ; 137.8 ; 140.3 ; 142.9 ; 143.1 ; 149.6 ; 159.6 (t, J = 14.1 Hz) ; 161.7 (dd, J = 247.1, 11.0 Hz) ; 162.4 (d, J = 249.2 Hz).

EXAMPLE 25:

2-[[4-[4-[3-[4-[3-[4-[4-[[5-(3,4-dimethoxy-N-methyl-anilino)-l-(4-fluoro-3- methoxy-phenyl)imidazol-2-yl]sulfanylmethyl]-3,5-difluoro- phenyl]phenoxy]propyl]piperazin-l-yl]propoxy]phenyl]-2,6-difluoro- phenyl] methylsulf anyl] -N- (3,4-dimethoxyphenyl) -3- (4-fluoro-3-methoxy- phenyl)-N-methyl-imidazol-4-amine

7A)

In a 20 mL microwave tube were added 2-[(4-bromo-2,6-difluoro- phenyl)methylsulfanyl]-N-(3,4-dimethoxyphenyl)-3-(4-fluoro-3-methoxy- phenyl)-N-methyl-imidazol-4-amine (Intermediate 2) (340 mg, 0.57 mmol), 4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenol (125.87 mg, 0.57 mmol), 1 M Cs₂C0₃ (1.72 ml) , and PdCl₂dppf (93.34 mg, 0.11 mmol) in 5.7 mL of DMF. The reaction mixture was heated under microwave irradiation at 100°C for 10 min. The reaction mixture was filtrated and evaporated to dryness. Purification of the crude by flash chromatography using as eluent a mixture of DCM/MeOH (97/3) gave 142 mg of the desired product as yellow oil, leading to a 41% yield.

MS : [M+H]⁺ m/z = 608.1

1H NMR (CDC1₃): δ (ppm) 2.97 (s, 3H) ; 3.63 (s, 3H) ; 3.81 (s, 2H) ; 3.83 (s, 3H) ; 3.85 (s, 3H) ; 6.23 (dd, J = 8.5, 2.7 Hz, 1H) ; 6.36 (d, J = 2.7 Hz, 1H) ; 6.70 (d, J = 8.7 Hz, 2H) ; 6.73 (s, 1H) ; 6.76 (d, J = 8.7 Hz, 1H) ; 6.87 (d, J = 9.5 Hz, 2H) ; 7.01 (s, 1H) ; 7.09 (dd, J = 10.6, 8.5 HZ, 1H) ; 7.13 (d, J = 8.6 Hz, 2H) ; 7.27 (s, 1H). 2-[[4-[4-(3-chloropropoxy)phenyl]-2,6-difluoro-phenyl]methylsulfanyl]-N- (3,4-dimethoxyphenyl)-3-(4-fluoro-3-methoxy-phenyl)-N-methyl-imidazol-4- amine (Intermediate 25a

l-bromo-3-chloro-propane (114.97 μί, 1.17 mmol), 4-[4-[[5-(3,4-dimethoxy-N- methyl-anilino)-l-(4-fluoro-3-methoxy-phenyl)imidazol-2-yl]sulfanylmethyl]-3,5- difluoro-phenyl]phenol (142 mg, 0.23 mmol) and K₂C0₃ (64.59 mg, 0.47 mmol) were added in acetonitrile (800 μί) and the reaction mixture was stirred at reflux for 3 hours. The solvent was removed under reduced pressure. The crude was dissolved in EtOAc and washed by water. The aqueous phase was extracted by EtOAc and washed with brine, dried over MgS0₄. The solvents were removed under reduced pressure. The crude was purified by flash chromatography using as eluent a mixture of Cy/EA (50/50) to give 150 mg of the titled compound as yellow oil, leading to a 94% yield.

MS : [M+H]⁺ m/z = 684.1

1H NMR (CDCI₃) : δ (ppm) 2.25 (q, J = 6.1 Hz, 2H) ; 2.90 (s, 3H) ; 3.47 (s, 3H) ; 3.76 (t, J = 6.4 Hz, 2H) ; 3.78 (s, 3H) ; 3.80 (s, 3H) ; 4.15 (t, J = 5.8 Hz, 2H) ; 4.22 (s, 2H) ; 6.16 (dd, J = 8.7, 2.7 Hz, 1H) ; 6.31 (d, J = 2.7 Hz, 1H) ; 6.51 (dd, J = 7.5, 2.2 Hz, 1H) ; 6.54-6.61 (m, 1H) ; 6.71 (d, J = 8.7 Hz, 1H) ; 6.92-7.00 (m, 3H) ; 6.96 (d, J = 8.7 Hz, 2H) ; 7.07 (s, 1H) ; 7.42 (d, J = 8.7 Hz, 2H).

2-[[4-[4-[3-[4-[3-[4-[4-[[5-(3,4-dimethoxy-N-methyl-anilino)-l-(4-fluoro-3- methoxy-phenyl)imidazol-2-yl]sulfanylmethyl]-3,5-difluoro- phenyl]phenoxy]propyl]piperazin-l-yl]propoxy]phenyl]-2,6-difluoro- phenyl] methylsulf anyl] -N- (3,4-dimethoxyphenyl) -3- (4-fluoro-3-methoxy- phenyl)-N-methyl-imidazol-4-amine (compound 25)

In a 5mL flask were added 2-[[4-[4-(4-bromobutoxy)phenyl]-2,6-difluoro- phenyl]methylsulfanyl]-N-(3,4-dimethoxyphenyl)-3-(4-fluoro-3-methoxy- phenyl)-N-methyl-imidazol-4-amine (Intermediate 25a, 60.35 mg, 0.08 mmol), piperazine (9 mg, 0.1 mmol), NEt₃ (28.97 μί, 0.21 mmol) in 700 μΐ. of DMF. The reaction mixture was heated at 40°C overnight. The reaction mixture was then heated at 60°C for 12 days. The reaction mixture was evaporated to dryness, diluted in EtOAc, washed with water and brine, dried over MgS0₄ and evaporated. Purification of the crude by flash chromatography using as eluent a mixture of DCM/MeOH (96/4) gave 8 mg of the desired product as yellow oil, leading to a 5% yield.

MS : [M+2H]²⁺ m/z = 691.6

1H NMR (MeOD) : δ (ppm) 2.10-2.22 (m, 4H) ; 2.92 (s, 6H) ; 2.95-3.13 (m, 6H) ; 3.35 (s, 6H) ; 3.68 (s, 6H) ; 3.75 (s, 6H) ; 4.03 (s, 4H) ; 4.10-4.20 (m, 4H) ; 6.16 (dd, J = 8.7, 2.7 Hz, 2H) ; 6.34 (d, J = 2.7 Hz, 2H) ; 6.42 (dd, J = 7.6, 2.4 Hz, 2H) ; 6.45-6.60 (m, 2H) ; 6.77 (d, J = 8.7 Hz, 2H) ; 6.96 (dd, J = 10.9, 8.6 Hz, 2H) ; 7.00-7.07 (m, 6H) ; 7.15 (d, J = 9.0 Hz, 4H) ; 7.58 (d, J = 8.9 Hz, 4H).

1³C NMR (MeOD) : δ (ppm) 26.5 ; 28.2 ; 40.6 ; 52.4 ; 55.4 ; 56.6 ; 56.7 ; 57.3 ; 66.5 ; 102.4 ; 108.2 ; 109.7-110.0 (m) ; 113.3 ; 114.6-114.7 (m) ; 114.8 ; 116.1 ; 116.6 (d, J = 19.7 Hz) ; 121.7 (d, J = 7.8 Hz) ; 125.1 ; 129.0 ; 131.9 ; 132.3 (d, J -- 4.2 Hz) ; 138.8 ; 141.6 ; 143.8 ; 144.4 ; 145.1 ; 148.8 (d, J = 10.8 Hz) ; 151.3 153.5 (d, J = 248.1 Hz) ; 160.8 ; 162.7 (dd, J = 248.2, 8.5 Hz).

EXAMPLE 26:

(2R,3R,4R,5S)-6-[2-[2-[2-[2-[4-[4-[[5-(3,4-dimethoxy-N-methyl-anilino)-l-(4- fluoro-3-methoxy-phenyl)imidazol-2-yl]sulfanylmethyl]-3,5-difluoro- phenyl]phenoxy]ethoxy]ethoxy]ethoxy]ethyl-methyl-amino]hexane-l,2,3,4,5- pentol

4-[4-[[5-(3,4-dimethoxy-N-methyl-anilino)-l-(4-fluoro-3-methoxy- phenyl)imidazol-2-yl]sulfanylmethyl]-3,5-difluoro-phenyl]phenol (Example 7A)

In a 20 mL microwave tube were added 2-[(4-bromo-2,6-difluoro- phenyl)methylsulfanyl]-N-(3,4-dimethoxyphenyl)-3-(4-fluoro-3-methoxy- phenyl)-N-methyl-imidazol-4-amine (Intermediate 2) (340 mg, 0.57 mmol), 4- (4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)phenol (125.87 mg, 0.57 mmol), 1 M Cs₂C0₃ (1.72 mL), and PdCl₂dppf (93.34 mg, 0.11 mmol) in 5.7 mL of DMF. The reaction mixture was heated under microwave irradiation at 100°C for 10 min. The reaction mixture was filtrated and evaporated to dryness. Purification of the crude by flash chromatography using as eluent a mixture of DCM/MeOH (97/3) gave 142 mg of the desired product as yellow oil, leading to a 41% yield.

MS : [M+H]⁺ m/z = 608.1

¹H NMR (CDC1₃): δ (ppm) 2.97 (s, 3H) ; 3.63 (s, 3H) ; 3.81 (s, 2H) ; 3.83 (s, 3H) ; 3.85 (s, 3H) ; 6.23 (dd, J = 8.5, 2.7 Hz, 1H) ; 6.36 (d, J = 2.7 Hz, 1H) ; 6.70 (d, J = 8.7 Hz, 2H) ; 6.73 (s, 1H) ; 6.76 (d, J = 8.7 Hz, 1H) ; 6.87 (d, J = 9.5 Hz, 2H) ; 7.01 (s, 1H) ; 7.09 (dd, J = 10.6, 8.5 HZ, 1H) ; 7.13 (d, J = 8.6 Hz, 2H) ; 7.27 (s, 1H).

2- [[4- [4- [2- [2-[2-(2-chloroethoxy)ethoxy]ethoxy ]ethoxy]phenyl] -2,6-difluoro- phenyl] methylsulf anyl] -N- (3,4-dimethoxyphenyl) -3- (4-fluoro-3-methoxy- phenyl)-N-methyl-imidazol-4-amine (Intemediate 26a)

In 25 ml flask were added 4-[4-[[5-(3,4-dimethoxy-N-methyl-anilino)- l-(4- fluoro-3-methoxy-phenyl)imidazol-2-yl]sulfanylmethyl]-3,5-difluoro- phenyl]phenol (254 mg, 0.42 mmol), l-(2-chloroethoxy)-2-[2-(2- chloroethoxy)ethoxy] ethane (966.08 mg, 4.18 mmol), Nal (62.65 mg, 0.42 mmol), K₂C0₃ (115.54 mg, 0.84 mmol) in acetonitrile (1.40 mL). The reaction mixture was stirred at reflux for 24 h then evaporated to dryness. The residue was dissolved in DCM, washed with water and brine, organic phase was dried over MgS0₄. Purification of the crude by flash chromatography using as eluent a mixture of DCM/MeOH (99/1) gave 140 mg not clean of the desired product as yellowish oil, leading to a 42% yield. It was used without further purification in the next step of the synthesis.

MS : [M+H]⁺ m/z = 803.3

(2R,3R,4R,5S)-6-[2-[2-[2-[2-[4-[4-[[5-(3,4-dimethoxy-N-methyl-anilino)-l-(4- fluoro-3-methoxy-phenyl)imidazol-2-yl]sulfanylmethyl]-3,5-difluoro- phenyl]phenoxy]ethoxy]ethoxy]ethoxy]ethyl-methyl-amino]hexane-l,2,3,4,5- pentol (compound 26)

To a solution of 2-[[4-[4-[2-[2-[2-(2-chloroethoxy)ethoxy]ethoxy]ethoxy]phenyl]- 2,6-difluoro-phenyl]methylsulfanyl]-N-(3,4-dimethoxyphenyl)-3-(4-fluoro-3- methoxy-phenyl)-N-methyl-imidazol-4-amine (1 10 mg, 0.14 mmol) in MeCN (2 mL) were added Cs₂C0₃ (44.67 mg, 0.14 mmol), Nal (20.55 mg, 0.14 mmol) and (2R,3R,4R,5S)-6-(methylamino)hexane-l,2,3,4,5-pentol (53.53 mg, 0.27 mmol). The reaction mixture was stirred at 75°C overnight. The reaction mixture was evaporated to dryness and the crude was purified by preparative HPLC to give 35 mg of desired compounds, as yellowish oil, leading to a 27% of yield.

MS : [M+H]⁺ m/z = 962 1H NMR (CDCI₃): δ (ppm) : 2.67-2.74 (m, IH) ; 2.80-2.84 (m, IH) ; 2.91 (s, 3H) ; 3.05 (s, 3H) ; 3.36-3.99 (m, 34H) ; 4.14 (s, 4H) ; 6.16 (dd, J = 8.7, 2.7 Hz, IH) ; 6.31 (d, J = 2.7 Hz, IH) ; 6.55 (dd, J = 1.5, 2.3 Hz, IH) ; 6.60-6.65 (m, IH) ; 6.71 (d, J = 8.8 Hz, IH) ; 6.92-6.99 (m, 5H) ; 7.05 (s, IH) ; 7.41 (d, J = 8.5 Hz, 2H). ¹³C NMR (CDCI₃): δ (ppm) : 25.9 ; 40.1 ; 41.9 ; 55.9 ; 56.0 ; 56.5 ; 64.8 ; 67.6 ; 69.5 ; 70.2 (m) ; 70.6 ; 100.0 ; 105.8 ; 109.1 (d, J = 26.7 Hz) ; 111.3 (d, J = 19.6 Hz) ; 112.7 (d, J = 20.9 Hz) ; 115.1 ; 115.9 (d, J = 19.9Hz) ; 119.7 (d, J = 6.9 Hz) ; 124.3 ; 127.9 ; 130.7 ; 138.3 ; 139.4 ; 142.5 (t, J = 11.1 Hz) ; 142.7 ; 143.3 ; 147.6 (d, J = 11.9 Hz) ; 152.0 (d, J = 249.1 Hz) ; 159.1 ; 161.3 (dd, J = 248.9 , 8.9 Hz).

EXAMPLE 27:

(2R3S,4S,5S)-6-[[4-[4-[[5-(3,4-dimethoxy-N-methyl-anilino)-l-(4-fluoro-3- methoxy-phenyl)imidazol-2-yl]sulfanylmethyl]-3,5-difluoro- phenyl]phenyl]methylamino]-2,3,4,5-tetrahydroxy-6-oxo-hexanoic acid

I Intermediate 27a

2-[[4-[4-(aminomethyl)phenyl]-2,6-difluoro-phenyl]methylsulfanyl]-N-(3,4- dimethoxyphenyl)-3-(4-fluoro-3-methoxy-phenyl)-N-methyl-imidazol-4- amine (Intermediate 27 a)

Step 1. In a microwave tube were added 2-[(4-bromo-2,6-difluoro- phenyl)methylsulfanyl]-N-(3,4-dimethoxyphenyl)-3-(4-fluoro-3-methoxy- phenyl)-N-methyl-imidazol-4-amine (Intermediate 2) (1000 mg, 1.682 mmol), [4- [(tert-butoxycarbonylamino)methyl]phenyl]boronic acid (422.39 mg, 1.68 mmol), 1M Cs₂C0₃ (5.047 mL), and PdCl₂(dppf) (274.54 mg, 0.34 mmol) in 8.4 mL of DMF. The reaction mixture was heated under microwave irradiation at 100°C for 10 min. The reaction mixture was filtrated and evaporated to dryness. The crude was diluted in EtOAc and washed with IN aqueous solution of HC1, with brine, dried over MgS0₄ and evaporated to dryness. Purification of the crude by flash chromatography using as eluent a mixture of DCM/MeOH gave 740 mg of the desired compound as yellow oil, leading to a 61 % yield.

MS : [M+H]⁺ m/z = 721.3

1H NMR (CDC1₃): δ (ppm) 1.48 (s, 9H) ; 2.90 (s, 3H) ; 3.50 (s, 3H) ; 3.80 (s, 3H) ; 3.81 (s, 3H) ; 4.20 (s, 2H) ; 4.32 (d, J = 5.1 Hz, 2H) ; 4.95 (brs, 1H) ; 6.17 (dd, J = 8.7, 2.7 Hz, 1H) ; 6.32 (d, J = 2.6 Hz, 1H) ; 6.55 (dd, J = 1.6, 2.5 Hz, 1H) ; 6.57- 6.63 (m, 1H) ; 6.72 (d, J = 8.7 Hz, 1H) ; 6.95 (dd, J = 10.7, 8.5 Hz, 1H) ; 7.04 (s, 1H) ; 7.06 (s, 1H) ; 7.10 (s, 1H) ; 7.30 (d, J = 8.3 Hz, 2H) ; 7.39 (d, J = 8.3 Hz, 2H).

Step 2. In a 25 mL flask was diluted tert-butyl N-[[4-[4-[[5-(3,4-dimethoxy-N- methyl-anilino)-l-(4-fluoro-3-methoxy-phenyl)imidazol-2-yl]sulfanylmethyl]-3,5- difluoro-phenyl]phenyl]methyl]carbamate (740 mg, 1.03 mmol) in 4 mL of DCM. 1.2 mL of TFA was added at the reaction mixture and it was stirred at room temperature for 30 min. The reaction mixture was diluted in DCM and washed with a saturated aqueous solution of NaHC0₃, with brine, dried over MgS0₄ and evaporated to dryness to give 590 mg of the desired product as a yellow solid, leading to 93% yield.

MS : [M+H]⁺ m/z = 621.2

1H NMR (CDC1₃) δ (ppm) : 2.88 (s, 3H) ; 3.48 (s, 3H) ; 3.77 (s, 3H) ; 3.79 (s, 3H) ; 3.91 (s, 2H); 4.19 (s, 2H) ; 6.15 (dd, J = 8.7, 2.7 Hz, 1H) ; 6.31 (d, J = 2.4 Hz, 1H) ; 6.53 (dd, J = 7.5, 2.4 Hz, 1H) ; 6.55-6.61 (m, 1H) ; 6.67 (d, J = 8.8 Hz, 1H) ; 6.89-7.01 (m, 3H) ; 7.03 (s, 1H) ; 7.37-7.46 (m, 4H).

(2R,3S,4S,5S)-6-[[4-[4-[[5-(3,4-dimethoxy-N-methyl-anilino)-l-(4-fluoro-3- methoxy-phenyl)imidazol-2-yl]sulfanylmethyl]-3,5-difluoro- phenyl]phenyl]methylamino]-2,3,4,5-tetrahydroxy-6-oxo-hexanoic acid (compound 27

To a solution of 2-[[4-[4-(aminomethyl)phenyl]-2,6-difluoro- phenyl]methylsulfanyl]-N-(3,4-dimethoxyphenyl)-3-(4-fluoro-3-methoxy- phenyl)-N-methyl-imidazol-4-amine (Intermediate 27a, 100 mg, 0.16 mmol) in 400 μΐ_^ of methanol, were added D-glucaric acid- l,4-lactone monohydrate (37.14 mg, 0.19 mmol), TEA (0.04 ml, 0.32 mmol). The suspension was stirred at 75°C for 6h. D-glucaric acid-l ,4-lactone monohydrate (6.19 mg, 0.03 mmol) was added again and the reaction mixture was stirred at 75°C for 2 h. The conversion was still not completed and was stopped. The product was purified by preparative HPLC to give 14 mg of the desired product, as yellowish oil, leading to 11% yield.

MS : [M+H]⁺ m/z = 813.3

1H NMR (DMSC 6): 2.91 (s, 3H) ; 3.48 (s,3H) ; 3.58 (s, 3H) ; 3.64 (s, 3H) ; 3.68-3.72 (m, 1H) ; 3.87-3.89 (m, 1H) ; 3.93 (t, J = 3.2 Hz, 1H) ; 4.09-4.10 (m, 1H) ; 4.11 (s, 2H) ; 6.05 (dd, J = 8.7, 2.6 Hz, 1H) ; 6.23 (d, J = 2.8 Hz, 1H) ; 6.60- 6.65 (m, 1H) ; 6.73 (d, J = 8.73 Hz, 1H) ; 6.77 (dd, J = 7.87, 2.47 Hz, 1H) ; 7.01 (s, 1H) ; 7.16 (dd, J = 11.3, 8.5 Hz, 1H) ; 7.36-7.43 (m, 4H) ; 7.65-7.68 (m, 2H) ; 8.23 (t, J = 6.2 Hz, 1H).

¹³C NMR (DMSO- 6) : δ (ppm) 26.3 ; 40.2 ; 41.9 ; 55.0 ; 56.3 ; 56.6 ; 68.6 ; 70.7 ; 71.7 ; 73.9 (d, J = 11.7 Hz) ; 100.2 ; 105.8 ; 109.7 (d, J = 25.4 Hz) ; 112.6 ; 113.9 ; 114.0 ; 116.2 (d, J = 19.5 Hz) ; 120.5 (d, J = 6.8 Hz) ; 124.7 ; 126.9 ; 128.3 ; 131.6 ; 135.8 ; 137.3 ; 139.8 ; 140.9 ; 142.2 (t, J = 9.9 Hz) ; 142.5 ; 143.6 ; 147.2 (d, J = 11.4 Hz) ; 149.8 ; 151.5 (d, J = 246.3 Hz) ; 161.3 (dd, J = 247.2, 8.8 Hz) ; 173.0 ; 175.3.

BIOLOGY EXAMPLES

TGR5/CRE Luciferase assay

In the following tables TGR5 activation by compounds and subsequent increase in intracellular cAMP were evaluated using a luciferase reporter gene assay. Human embryonic kidney (HEK) 293 cells were transiently co-transfected with pCMV tag4b-TGR5h (to follow hTGR5 activation) or pCMV AC6-TGR5m (to follow mTGR5 activation) expression plasmids and the pCRE TA-Lucif erase reporter plasmid using the JET PEI reagent (Polyplus transfection). Transfected cells were seeded in 96-well plates and incubated overnight with the test compounds at increasing concentrations tested in duplicate. Lithocolic acid (LCA) at ΙΟμΜ was used as a positive reference compound. The cAMP-dependent luciferase expression was followed using the BrightGlo reagent according to the manufacturer (Promega) instructions. Luminescence was read with a Mithras plate reader (Berthold). Data were expressed as percentage of the 10 μΜ LCA value and EC₅₀ values were calculated using XL fit 5 software or GraphPad Prism 5. Concentration-response curves were fitted by a nonlinear regression analysis to a 4 parameter logistic equation.

The results of the TGR5/CRE Luciferase assay are presented in Table 2 herafter.

Table 2: TGR5 assay results

hTGR5 mTGR5

Example Structure EC50 EC50

(nM) (nM)

1 60 4.5

F O

m = 4 - 13

1A 34 0.6

F

Claims

1. A compounds of general Formula I:

(I)

and pharmaceutically acceptable salts or solvates thereof,

wherein

R 1 and R 2" are independently H, Cl-C2-alkoxy or halo;

R is H, Cl-C4-alkyl or allyl;

R is H or Cl-C6-alkyl unsubstituted or substituted by a group selected from - NH₂, -COOH, -COOCH₃, -N⁺R₃ Q wherein Q is a counter anion and wherein q is an integer from 1 to 6;

R⁶ and R⁷ are independently H, Cl-C2-alkyl or halo;

L¹ is -CO-, -(CH₂)_t- wherein t is an integer from 0 to 4,

L is -0-, -C≡C-

ein R is H or CH₃, wherein p is an integer from 0 to 4,

wherein R⁸ is H or C¾

n is an integer from 0 to 4;

A is selected from the group consisting of:

wherein m¹ is an integer from 3 to 500, with the proviso that L is not -O- or -C≡C- when L¹ is -(CH₂)_t- with t = 0,

wherein m² is an integer from 3 to 500,

wherein m is an integer from 3 to 500 and Q^" is a counter anion,

wherein Q⁺ is a counter cation,

wherein R is CH₂OH, CH₂OS0₃ ^~ Q⁺ or COOH,

wherein R⁸ is H or CH₃ and R⁹ is CH₂OH,

CH₂OS0₃ ^~ Q⁺ or COOH,

wherein R⁸ is H or CH₃ and R⁹ is CH₂OH,

CH₂OS0₃ ^~ Q⁺ or COOH,

wherein R⁹ is CH₂OH, CH₂OS0₃ ^~ Q⁺ or COOH,

R⁸ is H or CH₃; R⁹ is CH₂OH,

CH₂OS0₃ ^" Q⁺ or COOH; m is an integer from 0 to 10,

erein r is 1 to 4,

wherein m is an integer from 3 a 50,

2. The compound according to claim 1 and pharmaceutically acceptable salts and solvates thereof, wherein L¹ is -CO-, -(CH₂)_t- wherein t is an integer from 0 to 4, preferably L¹ is -(CH₂)_t- wherein t is 0,

L² is O, -C≡C-,

is H,

wherein p is an integer from 0 to 4; preferably p = 1; n is an integer from 0 to 4; A is selected from the group consisting of

wherein m¹ is an integer from 3 to 500, with the proviso that L² is not -O- or -C≡C- when L¹ is -(CH₂)_t- with t = 0,

wherein m² is an integer from 3 to 500,

wherein m³ is an integer from 3 to 500 and Q^" is a counter anion,

wherein Q⁺ is a counter cation,

wherein R is CH₂OH, CH₂OS0₃ Q⁺ or COOH,

wherein R⁸ is H or CH₃ and R⁹ is CH₂OH,

CH₂OS0₃ ^" Q⁺ or COOH,

wherein R⁸ is H or CH₃ and R⁹ is CH₂OH,

CH₂OS0₃ ^" Q⁺ or COOH,

wherein R⁹ is CH₂OH, CH₂OS0₃ ^" Q⁺ or COOH,

wherein R⁸ is H or CH₃; R⁹ is CH₂OH,

CH₂OS0₃ ^" Q⁺ or COOH; m is an integer from 0 to 10,

N ^, ,^COOH

wherein r is an integer from 1 to 4,

herein m⁴ is an integer from 3 to 50,

3. The compound according to claim 1 or 2 and pharmaceutically acceptable salts and solvates thereof, wherein L₂-(CH₂)_n-A is H or phenyl unsubstituted or substituted with a group selected from OH, COOH, NH₂, and CI-

C4-alkoxy, with the proviso that R 4 and L 2 -(CH₂)_n-A are not both H when R 3 is Cl-C4-alkyl and L¹ is -(CH₂)_t- with t = 0.

4. The compound according to any of claims 1 to 3 and pharmaceutically acceptable salts and solvates thereof, wherein R 1 and R 2 are both methoxy.

5. The compound according to any of claims 1 to 4 and pharmaceutically acceptable salts and solvates thereof, wherein R⁶ and R⁷ are independently H, fluoro or methyl, preferably R⁶ and R⁷ are both fluoro.

6. The compound according to any of claims 1 to 5 and pharmaceutically acceptable salts and solvates thereof, having Formula II

II and pharmaceutically acceptable salts and solvates thereof.

7. The compound according to claim 6 and pharmaceutically acceptable salts and solvates thereof, having Formula III

III and pharmaceutically acceptable salts and solvates thereof, wherein

R¹⁰ and R¹¹ are independently selected from the group consisting of H, fluoro, chloro, halomethyl, and Cl-C2-alkoxy, with the the proviso that at least one of R¹⁰ and R¹¹ is not H.

8. The compound according to claim 7 and pharmaceutically acceptable salts and solvates thereof, wherein R¹⁰ is fluoro and R¹¹ is H or methoxy.

9. The compound according to claim 1 selected from the group consisting of:

146

147

148

10. A pharmaceutical composition comprising a compound according to any of claims 1 to 9 or a pharmaceutically acceptable salt or solvate thereof and at least one pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant.

11. A medicament comprising a compound according to any of claims 1 to 9.

12. A compound according to any of claims 1 to 9 or a pharmaceutically acceptable salt or solvate thereof for use in treating and/or preventing a TGR5 related disease.

13. The compound for use according to claim 12, wherein the TGR5 related disease is a metabolic and/or a gastrointestinal disease.

14. The compound for use according to claim 13, wherein the metabolic disease is selected from the group consisting of type II diabetes, obesity, dyslipidemia such as mixed or diabetic dyslipidemia, hypercholesterolemia, low HDL cholesterol, high LDL cholesterol, hyperlipidemia, hypertriglyceridemia, hypoglycemia, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypertension, hyperlipoproteinemia, metabolic syndrome, syndrome X, thrombotic disorders, cardiovascular disease, atherosclerosis and its sequelae including angina, claudication, heart attack, stroke, kidney diseases, ketoacidosis, nephropathy, diabetic neuropathy, diabetic retinopathy, and nonalcoholic fatty liver diseases such as steatosis or nonalcoholic steatohepatitis (NASH), liver cirrhosis, liver fibrosis, liver hepato-carcinogenesis.

15. The compound for use according to claim 13, wherein the gastrointestinal disease is selected from the group consisting of Inflammatory Bowel Diseases (IBD), Irritable Bowel Syndrome (IBS), intestinal injury disorders, diseases involving intestinal barrier dysfunction, and gastrointestinal disorders characterized by hypermotilenemia or gastrointestinal hypermotility.

16. Use of a compound according to any of Claims 1 to 9 or a pharmaceutically acceptable salt or solvate thereof as a modulator of TGR5 receptor activity.

17. Use according to Claim 16, wherein the compound is an agonist of TGR5 receptor.