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Title:
NOVEL DIHYDROPYRIDINONE AND DIHYDROPYRIMIDINONE COMPOUNDS AND THEIR USE
Document Type and Number:
WIPO Patent Application WO/2017/134188
Kind Code:
A1
Abstract:
The present invention is directed to novel compounds of Formula I; pharmaceutically acceptable salts or solvates thereof, and their use.

Inventors:
CHARTON JULIE (FR)
DEPREZ BENOIT (FR)
BOULAHJAR RAJAA (FR)
LEROUX FLORENCE (FR)
HOGUET VANESSA (FR)
STAELS BART (BE)
MUHR-TAILLEUX ANNE (FR)
HENNUYER NATHALIE (FR)
BELLOY LOÏC (FR)
Application Number:
EP2017/052308
Publication Date:
August 10, 2017
Filing Date:
February 02, 2017
Export Citation:
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Assignee:
UNIV LILLE II DROIT & SANTE (FR)
PASTEUR INSTITUT (FR)
INSERM (INSTITUT NAT DE LA SANTÉ ET DE LA RECH MÉDICALE) (FR)
International Classes:
C07D405/14; A61K31/4422; A61P5/00; C07D239/22; C07D401/04; C07D405/06
Domestic Patent References:
WO2004043468A12004-05-27
WO2011071565A12011-06-16
WO2013096771A12013-06-27
Foreign References:
Other References:
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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, vol. 96, 2011, pages 2027 - 2031
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CEFALU, W. T.: "Evolving treatment strategies for the management of type 2 diabetes", AM J MED SCI, vol. 343, 2012, pages 21 - 6
GALLWITZ, B.: "Glucagon-like peptide-1 analogues for Type 2 diabetes mellitus: current and emerging agents", DRUGS, vol. 71, 2011, pages 1675 - 88
EL-KAISSI, S.; SHERBEENI, S.: "Pharmacological management of type 2 diabetes mellitus: an update", CURR DIABETES REV, vol. 7, 2011, pages 392 - 405
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, pages 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., vol. 29, 2011, pages 37 - 44
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KAWAMATA, Y.; FUJII, R.; HOSOYA, M.; HARADA, M.; YOSHIDA, H.; MIWA, M.; FUKUSUMI, S.; HABATA, Y.; ITOH, T.; SHINTANI, Y.: "A G Protein-coupled Receptor Responsive to Bile Acids", J. BIOL. CHEM., vol. 278, 2003, pages 9435 - 9440, XP002248225, DOI: doi:10.1074/jbc.M209706200
WATANABE, M.; HOUTEN, S. M.; MATAKI, C.; CHRISTOFFOLETE, M. A.; KIM, B. W.; SATO, H.; MESSADDEQ, N.; HARNEY, J. W.; EZAKI, O.; KOD: "Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation", NATURE, vol. 439, no. 7075, 2006, pages 484 - 489, XP002477286, DOI: doi:10.1038/nature04330
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, vol. 191, 2006, pages 197 - 205
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, vol. 362, 2007, pages 793 - 798, XP022249510, DOI: doi:10.1016/j.bbrc.2007.06.130
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., vol. 329, 2005, pages 386 - 390, XP004757042, DOI: doi:10.1016/j.bbrc.2005.01.139
THOMAS, C.; GIOIELLO, A.; NORIEGA, L.; STREHLE, A.; OURY, J.; RIZZO, G.; MACCHIARULO, A; YAMAMOTO, H.; MATAKI, C.; PRUZANSKI, M.: "TGR5-mediated bile acid sensing controls glucose homeostasis", CELL METAB, vol. 10, 2009, pages 167 - 177, XP055168816, DOI: doi:10.1016/j.cmet.2009.08.001
KAWAMATA, Y.; FUJII, R.; HOSOYA, M.; HARADA, M.; YOSHIDA, H.; MIWA, M; FUKUSUMI, S.; HABATA, Y.; ITOH, T.; SHINTANI, Y.: "A G Protein-coupled Receptor Responsive to Bile Acids", J. BIOL. CHEM., vol. 278, 2003, pages 9435 - 9440, XP002248225, DOI: doi:10.1074/jbc.M209706200
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, vol. 372, 2008, pages 78 - 84, XP022705346, DOI: doi:10.1016/j.bbrc.2008.04.171
POLS, T. W. H.; NOMURA, M.; HARACH, T.; LOA SASSO, G.; OOSTERVEER, M. H.; THOMAS, C.; RIZZO, G.; GIOIELLO, A.; ADORINI, L.; PELLIC: "TGR5 Activation Inhibits Atherosclerosis by Reducing Macrophage Inflammation and Lipid Loading", CELL METABOLISM, vol. 14, no. 6, 2007, pages 747 - 757, XP028338742, DOI: doi:10.1016/j.cmet.2011.11.006
PELLICCIARI, R.; GIOIELLO, A.; MACCHIARULO, A.; THOMAS, C.; ROSATELLI, E.; NATALINI, B.; SARDELLA, R.; PRUZANSKI, M.; RODA, A.; PA: "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., vol. 52, 2009, pages 7958 - 7961, XP055099941, DOI: doi:10.1021/jm901390p
GENET, C. D.; STREHLE, A.; SCHMIDT, C. 1.; BOUDJELAL, G.; LOBSTEIN, A.; SCHOONJANS, K.; SOUCHET, M.; AUWERX, J.; SALADIN, R. G.; W: "Structure-Activity Relationship Study of Betulinic Acid, A Novel and Selective TGR5 Agonist, and Its Synthetic Derivatives: Potential Impact in Diabetes", J. MED. CHEM., vol. 53, 2010, pages 178 - 190, XP055043872, DOI: doi:10.1021/jm900872z
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., vol. 410, 2011, pages 677 - 681, XP028099091, DOI: doi:10.1016/j.bbrc.2011.06.055
GIOIELLO, A.; ROSATELLI, E.; NUTI, R; MACCHIARULO, A.; PELLICCIARI, R.: "Patented TGR5 modulators: a review (2006 - present", EXPERT OPIN THER PAT, vol. 22, no. 12, 2012, pages 1399 - 1414, XP055060037, DOI: doi:10.1517/13543776.2012.733000 CR
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, vol. 25, 2011, pages 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, vol. 55, no. 23, 2012, pages 10475, XP055057045, DOI: doi:10.1021/jm301071h
ALEMI, F.; KWON, E; POOLE, D. P.; LIEU, T.; LYO, V.; CATTARUZZA, F.; CEVIKBAS, F.; STEINHOFF, M.; NASSINI, R.; MATERAZZI, S.: "The TGR5 receptor mediates bile acid-induced itch and analgesia", THE JOURNAL OF CLINICAL INVESTIGATION, vol. 123, no. 4, 2013, pages 1513, XP055254861, DOI: doi:10.1172/JCI64551
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, vol. 58, no. 8, 2015, pages 3315 - 3328
E. L. ELIEL; S. H. WILEN; L. N. MANDER: "Stereochemistry of Organic Compounds", 1994, WILEY-INTERSCIENCE
Attorney, Agent or Firm:
CABINET PLASSERAUD/GROUPEMENT N°280 (31 Rue des PoissonceauxCS, 59800 Lille, FR)
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Claims:
CLAIMS

1. A compound of general Formula I:

I or pharmaceutically acceptable salts or solvates thereof, wherein

R1 is aryl or heteroaryl, wherein said aryl moiety is independently substituted by one or more groups selected from the group consisting of halo, cyano, Cl-C2-alkyl, C1-C2- alkoxy, Cl-C2-haloalkyl, and 5- or 6-membered aryl, and said heteroaryl moiety is optionally independently substituted by one or more groups selected from the group consisting of halo, cyano, Cl-C2-alkyl, Cl-C2-alkoxy, Cl-C2-haloalkyl, and 5- or 6- membered aryl;

R is alkenyl, alkinyl, alkoxy, hydroxy, alkoxycarbonyl, carbamoyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonylamino, cyano, alkylsulfonyl, aralkyl, cycloalkyl, heterocyclyl, C5-C6-heteroaryl comprising 1 oxygen atom and 0, 1 or 2 nitrogen atoms, wherein said heterocyclyl moiety is optionally substituted by one or more substituents independently selected from the group consisting of alkyl and alkoxycarbonyl, and said C5-C6-heteroaryl moiety is optionally substituted by one methyl group;

R3 is Cl-C4-alkyl or alkoxyalkyl;

R4 is H, halo, C1-C4 alkyl, haloalkyl, alkoxy or haloalkoxy; CH2 or NH;

L1 is a single bond or (CH2)n, wherein n is 1, 2 or 3;

L is -0-, -C≡C-,

wherein R is H or CH3,

n is an integer from 0 to 4;

selected from the group consisting of:

S03 Q+ wherein Q+ is a counter cation, with the proviso that L is not -0-, wherein m1 is an integer from 3 to 500, with the proviso that L2 is not -0-, wherein R is CH2OH, CH2OS03- Q+ or COOH, wherein R is H or CH3 and R is CH2OH, CH2OS03" Q+

COOH,

R5 is H or CH3; R6 is CH2OH,

CH2OS03- Q+ or COOH; m2 is an integer from 0 to 10,

N^ r , ^COOH

p wherein p is 1 to 4, wherein m3 is an integer from 3 to 50, and Y is wherein n' is an integer from 0 to 4, or

-(CH2)n-A is H, with the proviso that X is NH.

2. The compound according to claim 1 having Formula II

II harmaceutically acceptable salts and solvates thereof.

3. The compound according to claim 1 having Formula III

III and pharmaceutically acceptable salts, and solvates thereof, wherein L -(CH2)n-A is not H.

4. The compound according to any one of claims 1 to 3 and pharmaceutically acceptable salts, and solvates thereof, wherein R5 is methyl.

5. The compound according to any one of claims 1 to 4 and pharmaceutically acceptable salts, and solvates thereof, wherein L1 and R2 are taken together to form a moiety selected from the group consisting of cycloalkylmethyl, heterocyclylmethyl, heteroarylmethyl, 2-alkoxyeth-l-yl, 3-alkoxyprop-l-yl, alkoxycarbonylmethyl, said heteroarylmethyl moiety being optionally substituted by one or more C1-C2 alkyl.

6. The compound according to any one of claims 1 to 4 and pharmaceutically acceptable salts, and solvates thereof, wherein R2 is tetrahydrofuranyl.

7. The compound according to claim 6 and pharmaceutically acceptable salts, and solvates thereof, wherein L1 is C¾.

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

m=35-51

and pharmaceutically acceptable salts, and solvates thereof.

9. A pharmaceutical composition comprising a compound according to any of Claims 1 to 8 or a pharmaceutically acceptable salt or solvate thereof and at least one pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant.

10. A compound according to any of Claims 1 to 8 for use as a medicament.

11. A compound according to any of Claims 1 to 8 or a pharmaceutically acceptable salt or solvate thereof for use in treating and/or preventing a TGR5 related disease.

12. The compound or a pharmaceutically acceptable salt or solvate thereof for use according to Claim 11, wherein the disease is selected from metabolic, gastrointestinal diseases and/or hepato-biliary diseases.

13. The compound or a pharmaceutically acceptable salt or solvate thereof for use according to Claim 12 wherein the disease is a metabolic disease 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 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.

14. The compound or a pharmaceutically acceptable salt or solvate thereof for use according to Claim 12, wherein the disease is a gastrointestinal disease 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.

15. The compound or a pharmaceutically acceptable salt or solvate thereof for use according to Claim 12, wherein the disease is a hepato-biliary disease selected from the group consisting of 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.

16. Use of a compound according to any of Claims 1 to 8 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 activity.

Description:
NOVEL DIHYDROPYRIDINONE AND DIHYDROPYRIMIDINONE

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 their 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, 2011: 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. Hyperplasia of the gall bladder 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.

On this basis, there is 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 is aryl or heteroaryl, wherein said aryl moiety is independently substituted by one or more groups selected from the group consisting of halo, cyano, Cl-C2-alkyl, C1-C2- alkoxy, Cl-C2-haloalkyl, and 5- or 6-membered aryl, and said heteroaryl moiety is optionally independently substituted by one or more groups selected from the group consisting of halo, cyano, Cl-C2-alkyl, Cl-C2-alkoxy, Cl-C2-haloalkyl, and 5- or 6- membered aryl;

R is alkenyl, alkinyl, alkoxy, hydroxy, alkoxycarbonyl, carbamoyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonylamino, cyano, alkylsulfonyl, aralkyl, cycloalkyl, heterocyclyl, C5-C6-heteroaryl comprising 1 oxygen atom and 0, 1 or 2 nitrogen atoms, wherein said heterocyclyl moiety is optionally substituted by one or more substituents independently selected from the group consisting of alkyl and alkoxycarbonyl, and said C5-C6-heteroaryl moiety is optionally substituted by one methyl group;

R 3 is Cl-C4-alkyl or alkoxyalkyl;

R 4 is H, halo, C1-C4 alkyl, haloalkyl, alkoxy or haloalkoxy; X is CH 2 or NH;

L 1 is a single bond or (CH 2 ) n , wherein n is 1, 2 or 3; L is -0-, -C≡C-

wherein R is H or CH 3 , or

n is an integer from 0 to 4;

selected from the group consisting of:

S0 3 Q + wherein Q + is a counter cation, with the proviso that L is not -0-,

not -0-, wherein R is CH 2 OH, CH 2 OS0 3 - Q + or COOH, wherein R is H or CH 3 and R is CH 2 OH, CH 2 OS0 3 " Q +

COOH, R 5 is H or CH 3 ; R 6 is CH 2 OH,

CH 2 OS0 3 - Q + or COOH; and m 2 is an integer from 0 to 10,

|\L , , .COOH

V K p wherein p is 1 to 4,

wherein m 3 is an integer from 3 to 50, and Y is

wherein n' is an integer from 0 to 4, or

-(CH 2 ) n -A is H, with the proviso that X is NH.

Suitable, generally pharmaceutically acceptable, counter anions Q ~ are well known to those skilled in the art. Non-limiting examples of suitable counter anions Q ~ 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 and 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 halides such as fluoride, chloride, bromide and iodide, especially iodide. Unless otherwise specified, the above definition of Q ~ applies at all occurrences of Q ~ throughout the application.

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.

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, and 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 , R 2 , R 3 , R 4 , X, L 1 , L 2 , n and A are defined as follows:

R 1 is 5- or 6-membered aryl or 5- to 9-membered heteroaryl, wherein said aryl moiety is independently substituted by one or more groups selected from the group consisting of halo, Cl-C2-alkyl, Cl-C2-alkoxy, Cl-C2-haloalkyl, and 5- or 6-membered aryl, and said heteroaryl moiety is optionally independently substituted by one or more groups selected from the group consisting of halo, Cl-C2-alkyl, Cl-C2-alkoxy, Cl-C2-haloalkyl, and 5- or 6-membered aryl, preferably R 1 is C2-C4-alkyl, phenyl, pyridinyl or benzothiadiazolyl, wherein said phenyl or pyridinyl moiety is independently substituted by one or more substituents selected from the group consisting of halo, Cl-C2-alkyl, Cl-C2-alkoxy, Cl- C2-haloalkyl, and 5- or 6-membered aryl, more preferably R 1 is n-propyl, phenyl or pyridinyl, independently substituted by one or more substituents selected from the group consisting of halo, Cl-C2-alkyl, Cl-C2-haloalkyl, still more preferably R 1 is phenyl or pyridinyl, independently substituted by one or more substituents selected from the group consisting of chloro, cyano, and trifluoromethyl, even more preferably R 1 is phenyl substituted by one chloro or pyridinyl substituted by one chloro;

R is alkoxy, hydroxy, alkoxycarbonyl, cycloalkyl, heterocyclyl, or C5-C6-heteroaryl comprising 1 oxygen atom and 0, 1 or 2 nitrogen atoms, said C5-C6-heteroaryl moiety being optionally substituted by one methyl group; preferably R 2 is Cl-C2-alkoxy, hydroxyl, Cl-C2-alkoxycarbonyl, C3-C5-cycloalkyl, C5-C6-heterocyclyl comprising 1 or 2 oxygen atoms, C5-C6-heteroaryl comprising 1 oxygen atom and 0, 1 or 2 nitrogen atoms, said C5-C6-heteroaryl moiety being optionally substituted by one methyl group, more preferably R 2 is methoxy, hydroxyl, methoxycarbonyl, cyclopropyl, cyclobutyl, furanyl, 3- methyl-l,2,4-oxadiazol-5-yl, tetrahydrofuranyl or 1,3-dioxolanyl, even more preferably R 2 is tetrahydrofuranyl;

R 3 is C1-C4 alkyl or alkoxyalkyl, preferably R 3 is methyl;

R 4 is H, halo, C1-C4 alkyl, haloalkyl, alkoxy or haloalkoxy, preferably R 4 is H, halo or methoxy, more preferably R 4 is H, fluoro or methoxy, even more preferably R 4 is H or methoxy;

X is CH 2 or NH;

L 1 is (CH 2 ) n , wherein n is 1, 2 or 3, preferably L 1 is CH 2 ;

L 2 is -0-, -C≡C- wherein R is H or CH 3 ,

n is an integer from 0 to 4;

A is selected from the group consisting of:

S0 3 Q + wherein Q + is a counter cation, with the proviso that L is not -0-, wherein m 1 is an integer from 3 to 500, with the proviso that L 2 is not -0-, wherein R is CH 2 OH, CH 2 OS0 3 " Q + or COOH, preferably R is CH 2 OH or COOH, more preferably R 6 is CH 2 OH. wherein R is H or CH 3 and R is CH 2 OH, CH 2 OS0 3 " Q +

COOH, preferably R 6 is CH 2 OH or COOH, more preferably R 6 is CH 2 OH. wherein R 5 is H or CH 3 ; R 6 is CH 2 OH,

CH 2 OS0 3 - Q + or COOH preferably R 6 is CH 2 OH or COOH, more preferably R 6 is CH 2 OH; m 2 is an integer from 0 to 10,

N^ r , ^COOH

p wherein p is 1 to 4,

wherein m is an integer from 3 to 50, preferably from 7 to 11, and Y is

wherein n' is an integer from 0 to 4, or

L 2 -(CH 2 ) n -A is H, with the proviso that X is NH.

Particularly preferred compounds of Formula I and pharmaceutically acceptable salts and solvates thereof are those wherein L -(CH 2 ) n - is not H. Indeed, without wanting to be bound to any theory, the present inventors believe that the L 2 - (CH 2 ) 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.

Further preferred compounds of Formula I and pharmaceutically acceptable salts and solvates thereof are those wherein L 1 and R 2 are taken together to form a moiety selected from the group consisting of cycloalkylmethyl, heterocyclylmethyl, heteroarylmethyl, 2-alkoxyeth-l-yl, 3-alkoxyprop-l-yl, alkoxycarbonylmethyl, said heteroarylmethyl moiety being optionally substituted by one or more C1-C2 alkyl groups on its heteroaryl part, preferably L 1 and R 2 are taken together to form a moiety selected from the group consisting of C3-C5-cycloalkylmethyl, C5-C6-heterocyclylmethyl, C5-C6- heteroarylmethyl, 2-Cl-C2-alkoxyeth-l-yl, 3-Cl-C2-alkoxyprop-l-yl, C1-C2- alkoxycarbonylmethyl, said C5-C6-heteroarylmethyl moiety being optionally substituted by one or more methyl groups on its heteroaryl part more preferably L 1 and R 2 are taken together to form a moiety selected from the group consisting of C3-C4-cycloalkylmethyl, C5-heterocyclylmethyl, C5-heteroarylmethyl, 2-methoxyeth-l-yl, 3-methoxyprop-l-yl, methoxycarbonylmethyl, said C5 -heteroarylmethyl moiety being optionally substituted by one methyl group on its heteroaryl part, even more preferably L and R are taken together to form a moiety selected from the group consisting of C3-C4-cycloalkylmethyl, furanylmethyl, 3-methyl-l,2,4-oxadiazol-5-ylmethyl, tetrahydrofuranylmethyl or 1,3- dioxolanylmethyl, 2-methoxyeth-l-yl, 3-methoxyprop-l-yl, methoxycarbonylmethyl, still more preferably L and R are taken together to form 2-methoxyeth-l-yl or cyclopropylmethyl or tetrahydrofuranylmethyl, and still more preferably L and R are taken together to form tetrahydrofuranylmethyl.

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 R 1 , R 2 , R 3 , R 4 , and L 1 are as defined above with respect to Formula I. Preferred compounds of Formula II and pharmaceutically acceptable salts and solvates thereof are those wherein L 1 and R 2 are taken together to form a moiety selected from the group consisting of cycloalkylmethyl, heterocyclylmethyl, heteroarylmethyl, 2-alkoxyeth-l-yl, 3-alkoxyprop-l-yl, alkoxycarbonylmethyl, said heteroarylmethyl moiety being optionally substituted by one or more C1-C2 alkyl groups on its heteroaryl part, preferably L 1 and R 2 are taken together to form a moiety selected from the group consisting of C3-C5-cycloalkylmethyl, C5-C6-heterocyclylmethyl, C5-C6- heteroarylmethyl, 2-Cl-C2-alkoxyeth-l-yl, 3-Cl-C2-alkoxyprop-l-yl, C1-C2- alkoxycarbonylmethyl, said C5-C6-heteroarylmethyl moiety being optionally substituted by one or more methyl groups on its heteroaryl part, more preferably L 1 and R 2 are taken together to form a moiety selected from the group consisting of C3-C4-cycloalkylmethyl, C5-heterocyclylmethyl, C5-heteroarylmethyl, 2-methoxyeth-l-yl, 3-methoxyprop-l-yl, methoxycarbonylmethyl, said C-5-heteroarylmethyl moiety being optionally substituted by one methyl group on its heteroaryl part, even more preferably L 1 and R 2 are taken together to form a moiety selected from the group consisting of C3-C4-cycloalkylmethyl, furanylmethyl, 3-methyl-l,2,4-oxadizol-5-ylmethyl, tetrahydrofuranylmethyl or 1,3- dioxolanylmethyl, 2-methoxyeth-l-yl, 3-methoxyprop-l-yl, methoxycarbonylmethyl, still more preferably L 1 and R 2 are taken together to form 2-methoxyeth-l-yl or cyclopropylmethyl or tetrahydrofuranylmethyl, and still more preferably L 1 and R 2 are taken together to form tetrahydrofuranylmethyl.

In one embodiment, preferred compounds of Formula II are those of

Formula Ila

Ila and pharmaceutically acceptable salts and solvates thereof, wherein R 2 , R 3 , R 4 , and L 1 are as defined above with respect to Formula II, and

R 7 and R 8 are independently selected from the group consisting of H, halo, haloalkyl, and

7 ft T ft cyano, with the proviso that at least one of R and R is not H; preferably R and R are independently selected from the group consisting of H, chloro, trifluoromethyl, and cyano, with the proviso that at least one of R 7 and R 8 is not H.

In one embodiment, preferred compounds of Formula II are those of

Formula lib

lib and pharmaceutically acceptable salts and solvates thereof, wherein R 2 , R 3 , R 4 and L 1 are as defined above with respect to Formula II.

R' and R° are independently selected from the group consisting of H, halo, haloalkyl, and cyano, with the proviso that at least one of R 7 and R 8 is not H; preferably R 7 and R 8 are independently selected from the group consisting of H, chloro, trifluoromethyl, and cyano,

7 X

with the proviso that at least one of R and R is not H.

Particularly preferred compounds of Formulae II, Ha and lib pharmaceutically acceptable salts and solvates thereof are those wherein R 3 is methyl.

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

Formula III

III and pharmaceutically acceptable salts and solvates thereof, wherein

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

L 2 -(CH 2 )„-A is not H

Preferred compounds of Formula III and pharmaceutically acceptable salts and solvates thereof are those wherein L 1 and R 2 are taken together to form a moiety selected from the group consisting of cycloalkylmethyl, heterocyclylmethyl, heteroarylmethyl, 2-alkoxyeth-l-yl, 3-alkoxyprop-l-yl, alkoxycarbonylmethyl, said heteroarylmethyl moiety being optionally substituted by one or more C1-C2 alkyl groups on its heteroaryl part, preferably L 1 and R 2 are taken together to form a moiety selected from the group consisting of C3-C5-cycloalkylmethyl, C5-C6-heterocyclylmethyl, C5-C6- heteroarylmethyl, 2-Cl-C2-alkoxyeth-l-yl, 3-Cl-C2-alkoxyprop-l-yl, C1-C2- alkoxycarbonylmethyl, said C5-C6-heteroarylmethyl moiety being optionally substituted by one or more methyl groups on its heteroaryl part, more preferably L 1 and R 2 are taken together to form a moiety selected from the group consisting of C3-C4-cycloalkylmethyl, C5-heterocyclylmethyl, C5-heteroarylmethyl, 2-methoxyeth-l-yl, 3-methoxyprop-l-yl, methoxycarbonylmethyl, said C5 -heteroarylmethyl moiety being optionally substituted by one methyl group on its heteroaryl part, even more preferably L 1 and R 2 are taken together to form a moiety selected from the group consisting of C3-C4-cycloalkylmethyl, furanylmethyl, 3-methyl-l,2,4-oxadiazol-5-ylmethyl, tetrahydrofuranylmethyl or 1,3- dioxolanylmethyl, 2-methoxyeth-l-yl, 3-methoxyprop-l-yl, methoxycarbonylmethyl, still more preferably L 1 and R 2 are taken together to form 2-methoxyeth-l-yl or cyclopropylmethyl or tetrahydrofuranylmethyl, and still more preferably L 1 and R 2 are taken together to form tetrahydrofuranylmethyl.

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

- 2 is -C≡C-, n is an integer from 2 to 4 and A is S0 3 ~ Q + wherein Q + is a counter cation, wherein m 1 = 3 to 500 or wherein m is an integer from 3 to 50;

is H, n is 0 and A is

L is -0-, n is 0 and A is wherein m is an integer from 3 to 50;

is CH 3 , n is 1 and A wherein R 6 is CH 2 OH, CH 2 OS0 3 " Q + or COOH, preferably R 6

In one embodiment, preferred compounds of Formula III are those of

Formula Ilia

Ilia harmaceutically acceptable salts and solvates thereof, wherein , R , 7, L , I , n and A are as defined above with respect to Formula III.

R 7 and R 8 are independently selected from the group consisting of H, halo, haloalkyl, and

7 ft T ft cyano, with the proviso that at least one of R and R is not H; preferably R and R are independently selected from the group consisting of H, chloro, trifluoromethyl, and cyano, with the proviso that at least one of R 7 and R 8 is not H.

In one embodiment, preferred compounds of Formula III are those of

Formula Illb

Illb harmaceutically acceptable salts and solvates thereof, wherein , R , 7, L , I , n and A are as defined above with respect to Formula III.

R 7 and R 8 are independently selected from the group consisting of H, halo, haloalkyl, and

7 ft T ft cyano, with the proviso that at least one of R and R is not H; preferably R and R are independently selected from the group consisting of H, chloro, trifluoromethyl, and cyano, with the proviso that at least one of R 7 and R 8 is not H.

Particularly preferred compounds of Formulae III, Ilia and Illb, and pharmaceutically acceptable salts and solvates thereof are those wherein R is methyl.

In a particularly preferred embodiment, the compounds of Formula I, any of its subformulae, and their pharmaceutically acceptable salts and solvates as decribed herein are those wherein R 2 is tetrahydrofuranyl, preferably L 1 is C¾ and R 2 is tetrahydrofuranyl, more preferably they have Formula IV

IV, wherein R 1 , R 3 , R 4 , X, L 2 , n and A are as defined above with respect to Formula I or any of its subformulae and corresponding embodiments.

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

TABLE 1:

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, and/or solvates thereof as agonists of TGR5, in particular 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 in particular those of Table 1 above, or pharmaceutically acceptable salts and solvates thereof, 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 diseases, gastrointestinal diseases and/or hepato-biliary diseases.

The invention thus also relates to a compound of the invention or a pharmaceutically acceptable salt and/or solvate thereof for use in treating and/or preventing a TGR5 related disease, in particular a metabolic disease, a gastrointestinal disease and/or a hepato-biliary disease. Or in other terms, the invention also releates to a method of treating and/or preventing a TGR5 related disease, in particular 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.

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 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. 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.

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.

The invention also provides for a compound of the invention or a pharmaceutically acceptable salt and/or solvate thereof for use in delaying the onset of a TGR5 related disease, such as a metabolic disease, a gastrointestinal disease and/or a hepato-biliary 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 diseases, gastrointestinal diseases and/or hepato-biliary diseases are preferably those defined above.

The invention further provides a compound of the invention or a pharmaceutically acceptable salt and/or solvate thereof for the manufacture of a medicament for use in treating and/or preventing TGR5 related diseases, in particular metabolic diseases, gastrointestinal diseases and/or hepato-biliary 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 a compound of the invention or a pharmaceutically acceptable salt and/or solvate thereof for use in 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 and/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 and/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 and 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 and/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). 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 and/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 and/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 and/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 and/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 and/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 and/or solvate thereof, as active ingredient.

Generally, for pharmaceutical use, the compounds of the invention or a pharmaceutically acceptable salt and/or solvate thereof may be formulated as a pharmaceutical preparation comprising at least one compound of the invention or a pharmaceutically acceptable salt and/or solvate thereof 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 their pharmaceutically acceptable salts and/or 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 n H 2n+1 wherein n is a number greater than or equal to 1. Suitable alkyl groups include methyl, ethyl, n-propyl, /-propyl, n-butyl, i ' -butyl, s-butyl and t-butyl.

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 terms "heterocyclyl", "heterocycloalkyl" or "heterocyclo" as used herein by itself or as part of another group refer to non-aromatic, fully saturated or partially unsaturated cyclic groups (for example, 3 to 7 member monocyclic, 7 to 11 member bicyclic, or containing a total of 3 to 10 ring atoms) which have at least one heteroatom in at least one carbon atom-containing ring. Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogen, oxygen and/or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. Any of the carbon atoms of the heterocyclic group may be substituted by oxo (for example piperidone, pyrrolidinone).The heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system, where valence allows. The rings of multi-ring heterocycles may be fused, bridged and/or joined through one or more spiro atoms. Non limiting exemplary heterocyclic groups include oxetanyl, piperidinyl, azetidinyl, 2-imidazolinyl, pyrazolidinyl imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, 3H-indolyl, indolinyl, isoindolinyl, 2-oxopiperazinyl, piperazinyl, homopiperazinyl, 2-pyrazolinyl, 3-pyrazolinyl, tetrahydro-2H-pyranyl, 2H-pyranyl, 4H- pyranyl, 3,4-dihydro-2H-pyranyl, 3-dioxolanyl, 1,4-dioxanyl, 2,5-dioximidazolidinyl, 2- oxopiperidinyl, 2-oxopyrrolodinyl, indolinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolin- 1 -yl, tetrahydroisoquinolin-2-yl, tetrahydroisoquinolin-3-yl, tetrahydroisoquinolin-4-yl, thiomorpholin-4-yl, thiomorpholin- 4-ylsulfoxide, thiomorpholin-4-ylsulfone, 1, 3-dioxolanyl, 1,4-oxathianyl, lH-pyrrolizinyl, tetrahydro-l,l-dioxothiophenyl, N- formylpiperazinyl, and morpholin-4-yl.

The term "aryl" as used herein refers to a polyunsaturated, aromatic hydrocarbyl group having a single ring (i.e. phenyl) or multiple aromatic rings fused together (e.g. naphtyl), typically containing 5 to 12 atoms; preferably 6 to 10, wherein at least one ring is aromatic. The aromatic ring may optionally include one to two additional rings (either cycloalkyl, heterocyclyl or heteroaryl) fused thereto. Non-limiting examples of aryl comprise phenyl, biphenylyl, biphenylenyl, 5- or 6-tetralinyl, naphthalen-1- or -2- yl, 4-, 5-, 6 or 7-indenyl, 1-, 2-, 3-, 4- or 5-acenaphtylenyl, 3-, 4- or 5-acenaphtenyl, 1- or 2-pentalenyl, 4- or 5-indanyl, 5-, 6-, 7- or 8-tetrahydronaphthyl, 1,2,3,4- tetrahydronaphthyl, 1,4-dihydronaphthyl, 1-, 2-, 3-, 4- or 5-pyrenyl.

The term "heteroaryl" as used herein by itself or as part of another group refers but is not limited to 5 to 12 carbon-atom aromatic rings or ring systems containing 1 to 2 rings which are fused together, typically containing 5 to 6 atoms; at least one of which is aromatic, in which one or more carbon atoms in one or more of these rings is replaced by oxygen, nitrogen and/or sulfur atoms where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. Such rings may be fused to an aryl, cycloalkyl, heteroaryl or heterocyclyl ring. Non-limiting examples of such heteroaryl, include: furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, imidazo[2,l-b][l,3]thiazolyl, thieno[3,2-b]furanyl, thieno[3,2- b]thiophenyl, thieno[2,3-d][l,3]thiazolyl, thieno[2,3-d]imidazolyl, tetrazolo[l,5- a]pyridinyl, indolyl, indolizinyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, indazolyl, benzimidazolyl, 1,3-benzoxazolyl, 1,2- benzisoxazolyl, 2,1-benzisoxazolyl, 1,3-benzothiazolyl, 1,2-benzoisothiazolyl, 2,1- benzoisothiazolyl, benzotriazolyl, 1,2,3-benzoxadiazolyl, 2,1,3-benzoxadiazolyl, 1,2,3- benzothiadiazolyl, 2,1,3-benzothiadiazolyl, thienopyridinyl, purinyl, imidazo[l,2- a]pyridinyl, 6-oxo-pyridazin-l(6H)-yl, 2-oxopyridin-l(2H)-yl, 6-oxo-pyridazin-l(6H)-yl, 2-oxopyridin-l(2H)-yl, 1,3-benzodioxolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl.

The compounds of Formula I and subformulae thereof may contain at least one asymmetric center and thus may exist as different stereoisomeric forms. Accordingly, the present invention includes all possible stereoisomers and includes not only racemic compounds but the individual enantiomers and their non-racemic mixtures as well. When a compound is desired as a single enantiomer, such may be obtained by stereospecific synthesis, by resolution of the final product or any convenient intermediate, or by chiral chromatographic methods as each are known in the art. Resolution of the final product, an intermediate, or a starting material may be carried out by any suitable method known in the art. See, for example, Stereochemistry of Organic Compounds by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-Interscience, 1994), incorporated by reference with regard to stereochemistry.

The bonds from an asymmetric carbon in compounds of the present invention may be depicted herein using a solid line (— ), a zigzag line ( ΛννΛ ), a solid wedge ( ), or a dotted wedge ( ). The use of a solid line to depict bonds from an asymmetric carbon atom is meant to indicate that all possible stereoisomers are meant to be included, unless it is clear from the context that a specific stereoisomer is intended. The use of either a solid or dotted wedge to depict bonds from an asymmetric carbon atom is meant to indicate that only the stereoisomer shown is meant to be included.

The compounds of the invention may also contain more than one asymmetric carbon atom. In those compounds, the use of a solid line to depict bonds from asymmetric carbon atoms is meant to indicate that all possible stereoisomers are meant to be included, unless it is clear from the context that a specific stereoisomer is intended.

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 group 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 ammonia (N¾) and 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.

Generally, pharmaceutically acceptable salts of compounds of Formula I may for example be prepared as follows:

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

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

(iii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of Formula I or by ring-opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid; or

(iv) by 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, 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 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-d6, CDCI3 or DMSO-d6 as the solvent. 13 C 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 CI 8 TSK-GEL Super ODS (2 μιη particle size column, 50 * 4.6 mm). LCMS gradient starting from 98% H 2 0 / 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% H 2 0 / 0.1% formic acid and reaching 5% H 2 0 / 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). LCMS gradient starting from 98% ammonium formate buffer 5 mM (pH 9.2) and reaching 95% CH3CN / 5% ammonium formate buffer 5 mM (pH 9.2) within 15 min at a flow rate of 1 mL/min was used.

Solvents, reagents and starting materials were purchased from well known chemical suppliers such as for example Sigma Aldrich, Acros Organics, Fluorochem, Eurisotop, VWR International, Sopachem and Polymer labs.

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, cHex: Cyclohexane, r.t.: Room temperature,

DIEA: N,N-diisopropylethylamine,

TEA : triethylamine,

Y: Yield, g: Grams, mg: Milligrams,

L: Liters, mL: Milliliters,

μL: 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: tert-Butyl,

Bn: Benzyl,

Rt: Retention time,

Mn: Number average molecular mass, aq: aqueous,

DCC: N,N'-Dicyclohexylcarbodiimide, HOBt: 1-Hydroxybenzotriazole, HPLC: High-performance liquid chromatography.

As illustrated in the Examples hereafter, the compounds of the invention bearing a polyethylenoxy side chain (OCH 2 CH 2 ) m may be prepared from poly(ethylene glycol) starting materials which are in the form of a polydisperse mixture of polymers having different degrees of polymerization (i.e. the chain lengths) (m). These starting materials are thus characterized by a degree of polymerization given in the form of range and/or by a Mn.

Therefore, the exemplified compounds of the invention bearing a polyethylenoxy side chain (OCH 2 CH 2 ) m may be obtained as mixtures of compounds having different degrees of polymerization (m) given as a range.

Therefore, within the meaning of the invention, a compound of the invention having a moiety of the following Formula:

wherein the degree of polymerization m is identified as range, i.e. as m is x to y or as m=x- y, x and y being integers different from one another, are comprised all compounds bearing said moiety with a polymerization degree superior or equal to x and inferior or equal to y as well as mixtures thereof.

For instance, in the compound depicted by the following formula

the indication m=43-55 means that all compounds with m superior or equal to 43 and inferior or equal to 55 as well as mixtures thereof are comprised within this formula. EXAMPLE 1.

Example la. Ethyl 4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydro-lH-pyrirnidine -5- carboxylate.

A mixture of 4-chlorobenzaldehyde (1.0 g, 7.11 mmol, 1.0 eq.), ethyl acetoacetate (999 μΐ-, 7.82 mmol, 1.1 eq.), urea (641 mg, 10.66 mmol, 1.5 eq.) and 2-chloroacetic acid (67 mg, 0.71 mmol, 0.1 eq.) under solvent-free conditions was heated to 90°C during 3h. The reaction mixture is cooled and poured into crushed ice and stirred for 10 min. The solid was filtered, washed with ice-cold water and then recrystallized from ethanol to afford pure product as a white powder (840 mg, 40 %). 1H NMR (300 MHz, DMSO): δ (ppm) 1.09 (t, 7 = 7.0 Hz, 3H), 2.24 (s, 3H), 3.94-4.01 (q, J = 14.0, 7.0 Hz, 2H), 5.13 (d, J = 3.3 Hz, 1H), 7.24 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 7.77 (s, 1H), 9.24 (s, 1H). MS: m/z = [M+H] + 295.

Example lb. Ethyl 6-(4-chlorophenyl)-3-(2-methoxyethyl)-4-methyl-2-oxo-l,6- dihydropyrimidine-5-carboxylate.

The ethyl 4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydro-lH-pyrirnidine -5-carboxylate la (500 mg, 1.70 mmol) was dissolved in dry DMF (5.65 mL), Cs 2 C0 3 (553 mg, 1.70 mmol) was added and then the l-bromo-2-methoxy-ethane (159 μί, 1.70 mmol). The reaction mixture was stirred at room temperature for 18 hours. Then 277 mg of CS2CO3 and the l-bromo-2-methoxy-ethane (80 μΐ.) were added again and stirred for 6 h. Then 80 μΐ ^ of l-bromo-2-methoxy-ethane were added at r.t. and stirred for 65 h. The solvent was removed under reduced pressure. Water was added and the aqueous phase was extracted by ethyl acetate and CH 2 C1 2 , the organic layers were washed with brine, and dried over Na 2 S0 4 . Purification of the crude by flash chromatography using as eluent a mixture of cHex/EtOAc (100/0 to 80/20) gave the desired product as white solid (310 mg, 52 %). 1H NMR (DMSO-d6): δ (ppm) 1,12 (t, J = 6.9 Hz, 3H), 2.50-2.53 (m, 3H), 3.24 (s, 3H), 3.29- 3.37 (m, 1H), 3.41-3.47 (m, 1H), 3.64-3.73 (m, 1H), 3.98-4.06 (q, J = 13.9, 7.2 Hz, 2H), 4.07-4.16 (m, 1H), 5.14 (d, J = 4.0 Hz, 1H), 7.28 (d, J = 8.6 Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H), 7.98 (d, 7 = 3.7 Hz, 1H).

Example lc. 6-(4-Chlorophenyl)-3-(2-methoxyethyl)-4-methyl-2-oxo-l,6- dihydropyrimidine-5-carboxylic acid.

The ester lb (300 mg, 0.85 mmol) was dissolved in EtOH (4.25 mL), NaOH IN (3.0 mL) was added. The reaction mixture was stirred overnight at 40°C. LCMS showed completion of the reaction. EtOH was evaporated under reduced pressure, the aqueous phase was extracted using Et 2 0, then acidified to pH = 1 with HC1 (IN). The acidic aqueous phase was extracted by EtOAc and with CH 2 C1 2 . The organic phases were assembled and washed with brine, and dried over MgS0 4 . The solvents were removed under reduced pressure to give the desired product as a white solid (257 mg, 93 %). The product was used without further purification in the next step. MS: [M-H] ~ m/z = 323.

Example 1. (2-Methoxyphenyl)methyl 6-(4-chlorophenyl)-3-(2-methoxy-ethyl)-4- methyl-2-oxo-l,6-dihydropyrimidine-5-carboxylate.

The acid lc (257 mg, 0.79 mmol) and the l-(chloromethyl)-2-methoxy-benzene (136 mg, 0.87 mmol) were dissolved in dry DMF (10 mL). Cesium carbonate (387 mg, 1.19 mmol) were added and the reaction mixture was stirred at r.t. overnight. The solvent was removed. Water was added and the aqueous phase was extracted by EtOAc, washed with brine and dried over MgS0 4 . The solvent was removed. The crude was purified on flash chromatography using as eluent a mixture of cHex/EtOAc (100/0 to 70/30) to give of the desired product (232 mg, 66 %). 1H NMR (300 MHz, DMSO): δ (ppm) 1.39 (s,3H), 3.21 (s, 3H), 3.38-3.46 (m,lH), 3.62-3.71 (m, 1H), 3.74 (s, 3H), 4.05-4.14 (m, 1H), 4.98 (d, / = 12.7Hz, 1H), 5.08 (d, J = 12.7Hz, 1H), 6.81-6.87 (m, 1H), 6.97-7.02 (m, 2H), 7.17-7.21 (m, 2H), 7.27-7.30 (m,lH), 7.31-7.35 (m, 2H), 7.94 (d, J = 3.7Hz, 1H). 13 C NMR (75 MHz, DMSO): δ (ppm) 16.47, 26.87, 41.71, 52.67, 55.81, 58.79, 61.43, 71.38, 103.03, 111.29, 120.56, 124.29, 128.62, 128.81, 129.74, 130.13, 132.39, 143.45, 151.25, 152.88, 165.74. MS: [M-H] " m z = 445.

EXAMPLE 2.

Example 2a. Ethyl 4-(6-chloro-3 rid l)-6-meth l-2-oxo-3,4-dih dΓO-lH-p rimidine- 5-carboxylate.

A mixture of aldehyde (1.0 g, 7.06 mmol, 1.0 eq.), ethyl acetoacetate (980 μΐ-, 7.76 mmol, 1.1 eq.), urea (636 mg, 10.59 mmol, 1.5 eq.) and chloroacetic acid (67 mg, 0.71 mmol, 0.1 eq.) under solvent-free conditions was heated to 90°C during 3 hours. The reaction mixture is cooled and poured into crushed ice and stirred for 10 min. The solid was filtered, washed with ice-cold water and then recrystallized from ethanol to afford pure ethyl 4-(6-chloro-3- pyridyl)-6-methyl-2-oxo-3,4-dihydro-lH-pyrimidine-5-carboxyl ate as a white solid (1.1 g, 53 %). 1H NMR (300 MHz, DMSO-d6): δ (ppm) 1.07 (t, J = 7.7 Hz, 3H), 2.24 (s, 3H), 3.93 (q, J = 14.0, 7.7 Hz, 2H), 5.19 (d, J = 3.3 Hz, 1H), 7.49 (d, J = 8.3 Hz, 1H), 7.65-7.69 (dd, J = 8.3, 2.5, 1H), 7.80 (m, 1H), 9.34 (s, 1H).

Example 2b. Methyl 6-(6-chloro-3-pyridyl)-3-(2-methoxyethyl)-4-methyl-2-oxo-l,6 - dihydropyrimidine-5-carboxylate.

The ethyl 4-(6-chloro-3-pyridyl)-6-methyl-2-oxo-3,4-dihydro- lH-pyrimidine-5- carboxylate 2a (370 mg, 1.25 mmol) was dissolved in dry DMF (4.2 mL), Cs 2 C0 3 (408 mg, 1.25 mmol) was added and then the l-bromo-2-methoxy-ethane (118 μΐ., 1.25 mmol). The reaction mixture was stirred at r.t. for 24 hours. 70 μΙ_, of bromide compound was added at the reaction mixture for 24 hours. The solvent was removed under reduced pressure. Water was added and the aqueous phase was extracted by ethyl acetate, the organic layers were washed with brine, and dried over MgS0 4 . The solvent was removed. Purification of the crude by flash chromatography using as eluent a mixture of cHex/EtOAc (100/0 to 70/30) gave the desired methyl 6-(6-chloro-3-pyridyl)-3-(2- methoxyethyl)-4-methyl-2-oxo-l,6-dihydropyrimidine-5-carboxy late as white solid (170 mg, 39 %). 1H NMR (DMSO-d6): δ (ppm) 1.09 (t, J = 7.2 Hz, 3H), 1.22-1.27 (m, 2H), 3.23 (s, 3H), 3.29-3.37 (m, 1H), 3.40-3.47 (m, 1H), 3.65-3.73 (m, 2H), 3.97-4.04 (q, / = 7.2 Hz, 2H), 4.07-4.16 (m, 1H), 5.17 (d, J = 3.7 Hz, 1H), 7.50 (d, J = 8.2 Hz, 1H), 7.68- 7.72 (dd, J = 8.2, 2.6 Hz, 1H), 8.02 (d, J = 3.7 Hz, 1H), 8.27 (d, J = 2.6 Hz, 1H).

Example 2c. 6-(6-Chloro-3-pyridyl)-3-(2-methoxyethyl)-4-methyl-2-oxo-l,6 - dihydropyrimidine-5-carboxylic acid.

The ester methyl 6-(6-chloro-3-pyridyl)-3-(2-methoxyethyl)-4-methyl-2-oxo-l,6 - dihydropyrimidine-5-carboxylate 2b (170 mg, 0.48 mmol) was dissolved in EtOH (2.5 mL), NaOH IN (1.8 mL) was added. The reaction mixture was stirred overnight at 40°C. LCMS showed completion of the reaction. The EtOH was evaporated under reduced pressure, the aqueous phase was extracted by Et 2 0, then acidified to pH = 1 with HC1 (IN). The aqueous phase was extracted by EtOAc and with CH 2 C1 2 . The organic phases were assembled and dried under Na 2 S0 4 . The crude was dissolved with CH 2 CI 2 and filtered to afford the desired 6-(6-chloro-3-pyridyl)-3-(2-methoxyethyl)-4-methyl-2-oxo- l,6-dihydropyrimidine-5-carboxylic acid as a white powder (88 mg, 54 %).

Example 2. (2-Methoxyphenyl)methyl 6-(6-chloro-3-pyridyl)-3-(2-methoxyethyl)-4- methyl-2-oxo-l,6-dihydropyrimidine-5-carboxylate.

The 6-(6-chloro-3-pyridyl)-3-(2-methoxyethyl)-4-methyl-2-oxo-l,6 -dihydropyri-midine-5- carboxylic acid 2c (88 mg, 0.27 mmol) and the l-(chloromethyl)-2-methoxy-benzene (47 mg, 0.30 mmol) were dissolved in dry DMF (3.5 mL). Cesium carbonate (132 mg, 0.40 mmol) were added and the reaction mixture was stirred at r.t. overnight. The solvent was removed. Water was added and the aqueous phase was extracted by EtOAc, washed with brine and dried over MgS0 4 . The solvent was removed. The crude was purified on flash chromatography using as eluent a mixture of cHex/EtOAc (100/0 to 70/30) to give 83 mg of the desired (2-methoxyphenyl)methyl 6-(6-chloro-3-pyridyl)-3-(2-methoxyethyl)-4- methyl-2-oxo-l,6-dihydropyrimidine-5-carboxylate (120 mg, 69 %). 1H NMR (DMSO- d6): δ (ppm) 1.19-1.34 (m, 1H), 3.22 (s, 3H), 3.32 (m, 3H), 3.40-3.47 (m, 1H), 3.63-3.71 (m, 1H), 3.72 (s, 3H), 4.07-4.16 (m, 1H), 4.97 (d, / = 12.5 Hz, 1H), 5.07 (d, / = 12.5 Hz, 1H), 5.15 (d, / = 3.7 Hz, 1H), 6.82-6.88 ( td, J = 14.8, 7.4, 1.0 Hz, 1H), 6.96-7.00 (d, J = 8.3 Hz, 1H), 7.03-7.07 (dd, J = 7.8, 1.7 Hz, 1H), '.27-7.33 (td, J = 15.7, 7.8, 1.7 Hz, 1H), 7.44 (d, J = 8.3 Hz, 1H), 7.59-7.64 (dd, J = 8.3, 2.4 Hz, 1H), 7.98 (d, / = 3.8 Hz, 1H), 8.16 (d, J = 2.4 Hz, 1H). 13 C NMR (DMSO-d6): δ (ppm) 16.4, 41.7, 50.7, 55.8, 58.8, 61.6, 71.3, 102.2, 111.2, 120.5, 124.1, 124.7, 129.9, 130.2, 138.1, 139.3, 148.6, 149.6, 152.0, 152.6, 157.6, 165.5.

EXAMPLE 3.

Example 3a. Ethyl 6-(4-chlorophenyl)-3-(cyclopropylmethyl)-4-methyl-2-oxo-l,6- dihydropyrimidine-5-carboxylate.

The ethyl 4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydro-lH-pyrimidine- 5-carboxylate la (500 mg, 3.56 mmol) was dissolved in dry DMF (6 mL), Cs 2 C0 3 (553 mg, 1.70 mmol) was added and then the bromo-methyl-cyclopropane (165 μΙ_-, 1.70 mmol). The reaction mixture was stirred at r.t. for 18 hours. Then 165 μΐ., of bromo-methyl-cyclopropane and 51 mg of Nal were added and the reaction is stirred at r.t. for 6 hours. Then 330 μΙ_. of bromo- methyl-cyclopropane was added and the reaction is stirred at r.t. for 89 hours. Then 165 μΐ. of bromo-methyl-cyclopropane, 51 mg of Nal and 553 mg of Cs 2 C0 3 were added and the reaction is stirred at r.t. for 18 hours. Then 165 uL of bromo-methyl-cyclopropane and 553 mg of Cs 2 C0 3 were added and the reaction is stirred at r.t. for 6 hours. The solvent was removed under reduced pressure. Water was added and the aqueous phase was extracted by ethyl acetate, the organic layers were washed with brine, and dried over MgS0 4 . The solvent was removed under reduced pressure. Purification of the crude by flash chromatography using as eluent a mixture of cHex/EtOAc (100/0 to 80/20) gave the desired product as a colorless oil (508 mg, 86 %). MS: [M+H] + m z = 349.

Example 3b. 6-(4-Chlorophenyl)-3-(cyclopropylmethyl)-4-methyl-2-oxo-l,6- dihydropyrimidine-5-carboxylic acid.

The ester 3a (508 mg, 1.46 mmol) was dissolved in EtOH (7.30 mL), NaOH IN (5.01 mL) was added. The reaction mixture was stirred overnight at 40°C. EtOH was evaporated under reduced pressure, the aqueous phase was extracted by Et 2 0, acidified to pH = 1 with HCl (IN). The product precipitates so the mixture was filtered. The aqueous phase was extracted by EtOAc and with CH 2 C1 2 . The organic phases were assembled and washed with brine, and dried over MgS0 4 . The solvents were removed under reduced pressure. As the product is not soluble in CH 2 C1 2 , the crude product was dissolved in CH 2 C1 2 and filtered to give the desired product as a white solid (201 mg, 43 %). 1H NMR (300 MHz, DMSO): δ (ppm) 0.12-0.26 (m, 2H), 0.32-0.42 (m,2H), 0.92-1.01 (m, 1H), 2.52 (s, 3H), 3.45-3.53 (m, 1H), 3.68-3.76 (m,lH), 5.10 (d, / = 3.6Hz, 1H), 7.28 (d, / = 8.5Hz, 2H), 7.39 (d, 7 = 8.5Hz, 2H), 7.87 (d, J = 3.8Hz, 1H), 12.20 (s, 1H). MS: [M-H] " m/z = 319.

Example 3. (2-Methoxyphenyl)methyl 6-(4-chlorophenyl)-3-(cyclopropyl-methyl)-4- methyl-2-oxo-l,6-dihydropyrimidine-5-carboxylate.

The acid 3b (200 mg, 0.62 mmol) and the l-(chloromethyl)-2-methoxy-benzene (136 mg, 0.87 mmol) were dissolved in dry DMF (10 mL). Cesium carbonate (387 mg, 1.19 mmol) were added and the reaction mixture was stirred at r.t. overnight. The solvent was removed. Water was added and the aqueous phase was extracted by EtOAc, washed with brine and dried over MgS0 4 . The solvent was removed. The crude was purified by flash chromatography using as eluent a mixture of cHex/ CH^l^eOH (50/50/0 to 0/98/2). The product was not clean. Purification by preparative chromatography gave the desired product as a white powder (106 mg, 39 %). 1H NMR (300 MHz, DMSO): δ (ppm) 0.13- 0.26 (m, 2H), 0.36-0.43 (m, 2H), 0.95-1.00 (m, 1H), 2.52 (s, 3H), 3.48-3.55 (dd, J = 14.9, 6.0 Hz, 1H), 3.75 (s, 3H), 3.69-3.77 (dd, 7 = 14.9, 8.0 Hz, 1H), 4.98 (d, / = 12.5 Hz, 1H), 5.09 (d, J = 12.5 Hz, 1H), 5.12 (d, J = 3.9 Hz, 1H), 6.82-6.87 (td, J = 7.4, 1.0 Hz, 1H), 6.99 (d, J = 8.5 Hz, 1H), 7.02-7.06 (dd, J = 7.4, 1.7 Hz, 1H), 7.18-7.23 (d , J = 8.5 Hz, 2H), 7.27-7.30 (dd, J = 8.0, 1.7 Hz, 1H), 7.35 (d, / = 8.5 Hz, 2H), 7.92 (d, / = 3.9 Hz, 1H). MS: [M-H] " m z = 441.

EXAMPLE 4.

Example 4a. Ethyl 6-(4-chlorophenyl)-4-methyl-2-oxo-3-(tetrahydrofuran-2- ylmethyl)-l,6-dihydropyrimidine-5-carboxylate.

The ethyl 4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydro-lH-pyrimidine- 5-carboxylate la (500 mg, 3.57 mmol) was dissolved in dry DMF (6.0 mL), Cs 2 C0 3 (719 mg, 2.21 mmol) and the 2-(bromomethyl)tetrahydrofuran (290 μL, 2.55 mmol) were added. The reaction mixture was stirred at 70°C for 18 hours. Little formation of product is observed by LCMS so 290 μL of 2-(bromomethyl)tetrahydrofuran are added and the reaction is putted at 75°C for 2 hours. Little formation of product is observed by LCMS so the solvent was removed under reduced pressure. Water was added and the aqueous phase was extracted by ethyl acetate, the organic layers were washed with brine, and dried over MgS0 4 . The solvent was removed and the crude obtained was dissolved in dry DMF (6.0 mL). 719 mg of CS2CO3 and the 2-(bromomethyl)tetrahydrofuran (290 μL) were added. The reaction mixture was stirred at 90°C for 18 hours. Aromatization occurred so the temperature was lowered at 70°C for 4 hours. Little formation of product is observed by LCMS so the temperature was raised at 90°C for 18 hours. Little formation of product is observed by LCMS so the solvent was removed under reduced pressure. Water was added and the aqueous phase was extracted by ethyl acetate, the organic layers were washed with brine, and dried over MgS0 4 . The solvent was removed and the crude obtained was dissolved in dry DMF (6.0 mL), 719 mg of Cs 2 C0 3 and the 2- (bromomethyl)tetrahydrofuran (290 μL) were added. The reaction mixture was stirred at 70°C for 48 hours. Reaction was stopped. The solvent was removed under reduced pressure. Water was added and the aqueous phase was extracted by ethyl acetate, the organic layers were washed with brine, and dried over MgS0 4 . The solvent was removed. Purification of the crude by flash chromatography using as eluent a mixture of CH 2 Cl 2 MeOH (100/0 to 95/5) gave a racemic mixture of 4a as white solid (113 mg, 18 %).

Example 4b. 6-(4-Chlorophenyl)-4-methyl-2-oxo-3-(tetrahydrofuran-2-ylmet hyl)-l,6- dihydropyrimidine-5-carboxylic acid.

The ester 4a (113.5 mg, 0.30 mmol) was dissolved in EtOH (1.5 mL), NaOH IN (1.05 mL) was added. The reaction mixture was stirred overnight at 40°C. LCMS showed completion of the reaction. EtOH was evaporated under reduced pressure, the aqueous phase was extracted by Et 2 0, then acidified to pH = 1 with HC1 (IN). The acidic aqueous phase was extracted by EtOAc and with CH 2 C1 2 . The organic layers were assembled and washed with brine, and dried over MgS0 4 . The solvents were removed under reduced pressure to give the desired product as a colorless oil (102.5 mg, 97.5 %). The product is not pure but it was used without further purification in the next step. MS: [M-H] " m/z = 349.

Example 4. (2-Methoxyphenyl)methyl 6-(4-chlorophenyl)-4-methyl-2-oxo-3- (tetrahydrofuran-2-ylmethyl)-l,6-dihydropyrimidine-5-carboxy late.

The acid 4b (113 mg, 0.32 mmol) and thel-(chloromethyl)-2-methoxy-benzene (55 mg, 0.35 mmol) were dissolved in dry DMF (1.1 mL). Cesium carbonate (158 mg, 0.48 mmol) was added and the reaction mixture was stirred at r.t. overnight. The solvent was removed. The crude was dissolved in EtOAc, washed with water, brine and dried over MgS0 4 . The solvent was removed. The crude was purified on flash chromatography using as eluent a mixture of CH 2 Cl 2 /MeOH (100/0 to 99.5/0.5) to give the desired product (102 mg, 67 %). 1H NMR (300 MHz, DMSO): δ (ppm) 1.19-1.28 (m, 1H), 1.58-1.74 (m, 3H), 2.52 (s, 3H), 3.55-3.59 (m, 2H), 3.62-3,65 (m, 1H), 3.74 (s, 3H), 3.85-3.90 (m, 1H), 4.00-4.08 (dd, J = 14.8, 6.2 Hz, 1H), 4.97-5.12 (q, / = 32.4, 12.6 Hz, 2H), 5.14 (d, J = 4 Hz, 1H), 6.82-6.88 (m, 1H), 6.97-7.01 (dd, J = 8.2, 0.9 Hz, 1H), 7.02-7.05 (dd, J = 7.5, 1.7 Hz, 1H), 7.20-7.24 (m, 2H), 7.27-7.31 (m, 1H), 7.31-7.34 (m, 2H), 8.01 (d, J = 4.0 Hz, 1H). 13 C NMR (75 MHz, DMSO): δ (ppm) 16.6, 25.3, 28.4, 44.5, 52.2, 55.8, 61.5, 67.5, 77.8, 103.1, 111.2, 120.6, 124.3, 128.6, 128.7, 129.7, 130.1, 132.3, 143.2, 151.6, 153.3, 157.5, 165.8. MS: [M- HV m/z = 471.

EXAMPLE 5.

xamp e

Example 5c. Methyl 4-(6-chloro-3-pyridyl)-6-methyl-2-oxo-3,4-dihydro-lH-pyridin e- 5-carboxylate.

The methyl 3-oxobutanoate (1.52 mL, 14.13 mmol) was dissolved in acetic acid (14 mL). 6-chloropyridine-3-carbaldehyde (2 g, 14.13 mmol), Meldrum's acid (2 g, 14.13 mmol) and ammonium acetate (1.63 g, 21.19 mmol) were added and the reaction mixture was stirred for 18 h at 110°C. The reaction mixture was cooled at r.t. Solvent was removed under reduced pressure and the residue was dissolved in the minimum of ethanol. The mixture was sonicated with ultrasound and the product precipitated. The mixture was cooled and the precipitate was filtered and washed with cold ethanol to give the desired product as a beige powder (1.76 g, 44 %). 1H NMR (300 MHz, Acetone): δ (ppm) 2.45 (s, 3H), 2.55 (dd, J = 16.4, 1.9 Hz, 1H), 3.02 (dd, / = 16.4, 7.8 Hz, 1H), 3.61 (s, 3H), 4.31 (d, J = 7.5 Hz, 1H), 7.36 (d, J = 8.3 Hz, 1H), 7.67 (dd, J = 8.3, 2.6 Hz, 1H), 8.27 (d, J = 2.6 Hz, 1H), 9.00 (s, 1H). MS: [M+H] + m/z = 281. Example 5a. [(2R)-Tetrahydrofuran-2-yl]methanol.

(2R)-tetrahydrofuran-2-carboxylic acid (2 g, 17.22 mmol) was dissolved in 20 mL of THF under argon and the flask was cooled in an ice bath, BH 3 .SMe 2 (2M solution in THF, 10 mL, 20.0 mmol) was added to the reaction solution over 10 minutes. The ice bath was removed and the solution was stirred for 1 h at room temperature. The solution was again cooled in an ice bath and methanol slowly added until no gas evolution was observed. The solution was concentrated in vacuum to give the desired product as oil (m = 1 g, 60 %). 1H NMR (300 MHz, CDC1 3 ): δ (ppm) 1.55-1.70 (m, 1H), 1.72-1.98 (m, 3H), 3.35-4.00 (m, 6H).

Example 5b. [(2R)-Tetrahydrofuran-2-yl]methyl 4-methylbenzenesulfonate.

The mixture of triethylamine (6.4 mL, 45.53 mmol), TsCl (6.4 g, 33.39 mmol) and 185 mg of DMAP were combined in CH 2 C1 2 (70 mL). this solution was cooled in an ice bath and to it was added a solution of tetrahydrofurfuryl alcohol 5a (3.1 g, 30.35 mmol) in 30 mL of CH 2 CI 2 over 20 min. the reaction stirred overnight and was then concentrated in vacuum, the residue was taken up in ethyl acetate and then washed 2 times with a saturated solution of NaHC0 3 and once with a brine. The organic layers were dried over MgS0 4 , filtered and concentrated in vacuum. The crude product was purified by Column chromatography on silica gel (CH 2 Cl 2 /cHex: 50/50) to give the expected product as oil (m = 5.6 g, 72 %). 1H NMR (300 MHz, CDC1 3 ): δ (ppm) 1.48-1.68 (m, 1H), 1.71-2.05 (m, 3H), 2.40 (s, 3H), 3.58-3.82 (m, 2H), 3.86-4.15 (m, 3H), 7.31 (d, / = 8.0 Hz, 2H), 7.75 (d, J = 8.2 Hz, 2H). MS: [M+H] + m/z = 257.

Example 5d. Methyl-(4S)-4-(6-chloro-3-pyridyl)-6-methyl-2-oxo-l-[[(2R)- tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxyla te.

The methyl 4-(6-chloro-3-pyridyl)-6-methyl-2-oxo-3,4-dihydro-lH-pyridin e-5-carboxylate 5c (400 mg, 1.42 mmol) and the ((2R)-tetrahydrofuran-2-yl)methyl-4- methylbenzenesulfonate 5b (470 mg, 2.85 mmol) were dissolved in dry DMF (6 mL), (929 mg, 2.85 mmol) of Cs 2 C0 3 and (11 mg, 0.05 mmol) of Nal were added and the reaction mixture was stirred at 50°C for 24h. The solvent was removed under reduced pressure. Water was added and the aqueous phase was extracted by ethyl acetate, the organic layers were washed with brine, and dried over MgS0 4 . The solvent was removed and the crude product was purified by column chromatography on silica gel (CH 2 Cl 2 /MeOH 100/0 to 95/5) to give the expected product as oil (e2: m = 109 mg, 21 %). MS: [M+H] + m z = 365. 1H NMR (300 MHz, CDC1 3 ): δ (ppm) 1.35-1.45 (m, 1H), 1.76-2.01 (m, 3H), 2.57 (s, 3H), 2.63 (dd, 7 = 15.7, 2.0 Hz, 1H), 2.91 (dd, 7 = 15.7, 7.3 Hz, 1H), 3.35 (dd, 7 = 14.2, 9.3 Hz, 1H), 3.61 (s, 3H), 3.66-3.91 (m, 3H), 4.10-4.29 (m, 2H), 7.09-7.20 (m, 1H), 7.59 (ddd, 7 = 8.3, 2.6, 0.5 Hz, 1H), 8.24 (d, 7 = 2.6 Hz, 1H).

Example 5e. (4S)-4-(6-Chloro-3-pyridyl)-6-methyl-2-oxo-l-[[(2R)-tetrahyd ro-furan-2- yl]methyl] -3,4-dihydropyridine-5-carboxylic acid.

The ester 5d (126 mg) was dissolved in MeOH (2mL), a solution of NaOH IN (2 mL) was added. The reaction mixture was stirred overnight at 40 °C. LCMS showed completion of the reaction. The MeOH was evaporated under reduced pressure, the aqueous phase was extracted by Et 2 0, then acidified to pH = 1 with HC1 (IN). The aqueous phase was extracted by EtOAC. The organic phases were assembled and dried over MgS0 4 . The solvents were removed under reduced pressure to afford a product as oil (m = 66 mg, 55 %). 1H NMR (300 MHz, CDC1 3 ): δ (ppm) 1.35-1.52 (m, 1H), 1.79-2.00 (m, 3H), 2.60 (s, 3H), 2.68 (dd, 7 = 15.8, 1.9 Hz, 1H), 2.94 (dd, 7 = 15.8, 7.4 Hz, 1H), 3.39 (dd, 7 = 14.2, 9.4 Hz, 1H), 3.65-3.89 (m, 3H), 4.17-4.28 (m, 2H), 7.13-7.20 (m, 1H), 7.58-7.64 (m, 1H), 8.28 (d, 7 = 2.6 Hz, 1H), 9.49 (s, 1H). MS: [M+H] + m/z = 351.

Example 5f. (4-Iodo-2-methoxy-phenyl) methanol.

To a solution of methyl 4-iodo-2-methoxy-benzoate (1.0 g, 3.42 mmol) in THF (20 mL) was added DIBAL (20.5 mL, 10.27 mmol, solution in cyclohexane) dropwise at -78°C. The reaction mixture was stirred at 25°C for 13 h and quenched by the slow addition of saturated solution of NH 4 C1 at 0°C, filtered and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgS0 4 and concentrated under reduced pressure to afford pure product as colorless oil (quantitatif). 1H NMR (300 MHz, CDC1 3 ): δ (ppm) 3.03 (s, 1H), 3.78 (s, 3H), 4.55 (s, 2H), 6.97 (d, 7 = 7.8 Hz, 1H), 7.12 (d, 7 = 1.5 Hz, 1H), 7.24 (dd, 7 = 7.8, 1.5 Hz, 1H).

Example 5g. [4-(6-Chlorohex-l-ynyl)-2-methoxy-phenyl]methanol.

The mixture of (4-iodo-2-methoxy-phenyl)methanol 5f (417 mg, 1.58 mmol), 6-chlorohex- 1-yne (230 μΐ, 1.89 mmol) and pyrrolidine (198 μΐ.,, 2.37 mmol) are dissolved in 30 mL of dry and degazed DMF. Then, PdCl 2 (dppf) 2 (102 mg, 79 μηιοΐ) and Cul (30 mg, 158 μηιοΐ) are added. The reaction mixture is heated at 70°C for 7 h and then cooled down to room temperature, diluted with EtOAc, washed with a saturated aqueous solution of NaHC0 3 and brine, dried over MgS0 4 and evaporated. Residue is then purified by flash chromatography (CH 2 C1 2 ) to give expected product as purple oil (m = 284 mg, 71%), 1H NMR (300 MHz, CDC1 3 ): δ (ppm) 1.67-1.85 (m, 2H), 1.87-2.05 (m, 2H), 2.23 (s, 1H), 2.46 (t, J = 6.9 Hz, 2H), 3.60 (t, J = 6.5 Hz, 2H), 3.84 (s, 3H), 4.64 (s, 2H), 6.89 (d, J = 13 Hz, 1H), 6.99 (dd, J = 1.4, 7.6 Hz, 1H), 7.19 (d, J = 7.6 Hz, 1H).

Example 5h. 4-(6-Chlorohex-l-ynyl)-l-(chloromethyl)-2-methoxy-benzene.

Thionyl chloride (102 μΐ., 1.40 mmol) was added to benzotriazole (201 mg, 1.69 mmol). The resulting solution was dissolved in CH 2 C1 2 (3 mL). After 5 min, this solution was added slowly to the solution of the alcohol 5g (284 mg, 1.12 mmol) in CH 2 C1 2 (10 mL). The benzotriazole salt started to precipitate. After 1 h of reaction, the salt was filtered. The organic phase was washed by water and NaOH solution (0.05 M). The organic phase was dried under MgS0 4 and the solvent was removed under reduced pressure to give the desired chlorinated compound as a yellow oil (m = 276 mg, 90%). 1H NMR (300 MHz, CDC1 3 ): δ (ppm) 1.73-1.82 (m, 2H), 1.87-2.04 (m, 2H), 2.47 (t, J = 6.9 Hz, 2H), 3.60 (t, J = 6.5 Hz, 2H), 3.86 (s, 3H), 4.62 (s, 2H), 6.91 (d, J = 1.1 Hz, 1H), 6.99 (dd, J = 1.3, 7.7 Hz, 1H), 7.26 (d, J = 7.7 Hz, 1H).

Example 5i. [4-(6-Chlorohex-l-ynyl)-2-methoxy-phenyl]methyl (4S)-4-(6-chloro-3- pyridyl)-6-methyl-2-oxo-l-[[(2R)-tetrahydrofuran-2-yl]methyl ]-3,4-dihydropyridine-

5-carboxylate.

The acid 5e (86 mg, 0.24 mmol) and cesium carbonate (120 mg, 0.34 mmol) were dissolved in dry DMF (3 mL). Chlorinated compound 5h (100 mg, 0.37 mmol) was added and the reaction mixture was stirred at r.t. for 18 h. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc and washed with water. The aqueous phase was extracted by EtOAc and the organic layers were assembled, washed with brine and dried over MgS0 4 . The residue was purified by flash chromatography (CH 2 C1 2 ) to afford the desired product as a colorless oil (m = 112 mg, 78 %). 1H NMR (300 MHz, CDC1 3 ): δ (ppm) 1.35-1.52 (m, 1H), 1.68-1.80 (m, 2H), 1.80-2.01 (m, 5H), 2.43 (t, J = 6.9 Hz, 2H), 2.53-2.68 (m, 4H), 2.91 (dd, / = 7.5, 15.7 Hz, 1H), 3.37 (dd, / = 9.3, 14.2 Hz, 1H), 3.58 (t, J = 6.5 Hz, 2H), 3.68 (s, 3H), 3.73 (dd, J = 4.4, 11.1 Hz, 1H), 3.77- 3.90 (m, 2H), 4.11-4.26 (m, 2H), 4.95-5.13 (m, 2H), 6.81 (s, 1H), 6.88 (dt, J = 4.5, 7.7 Hz, 2H), 7.13 (d, / = 8.3 Hz, 1H), 7.55 (dd, J = 2.6, 8.3 Hz, 1H), 8.20 (d, J = 2.5 Hz, 1H). MS: [M+H] + m/z = 585.

Example 5j. [4-(6-Iodohex-l-ynyl)-2-methoxy-phenyl]methyl (4S)-4-(6-chloro-3- pyridyl)-6-methyl-2-oxo-l-[[(2R)-tetrahydrofuran-2-yl]methyl ]-3,4-dihydropyridine-

5-carboxylate.

The chlorinated compound 5i (110 mg, 0.19 mmol) was dissolved in butanone (6 mL). Nal (113 mg, 0.75 mmol) was added and the reaction mixture stirred at 80 °C overnight. The solution was cooled to r.t, filtered and the precipitate was washed by acetone. The solvents were removed under reduced pressure to afford yellowish oil. This residue was purified by flash chromatography (CH 2 C1 2 ) to give the desired product as oil (m = 125 mg, 98 %). l H NMR (300 MHz, CDC1 3 ): δ (ppm) 1.37-1.51 (m, 1H), 1.65-1.80 (m, 2H), 1.81-2.07 (m, 5H), 2.43 (t, J = 6.9 Hz, 2H), 2.54-2.70 (m, 4H), 2.92 (dd, J = 7.5, 15.7 Hz, 1H), 3.24 (t, J = 6.9 Hz, 2H), 3.38 (dd, J = 9.2, 14.3 Hz, 1H), 3.65-3.78 (m, 4H), 3.80-3.90 (m, 2H), 4.14- 4.27 (m, 2H), 4.99-5.15 (m, 2H), 6.82 (s, 1H), 6.89 (dt, J = 4.5, 7.7 Hz, 2H), 7.14 (d, / = 8.3 Hz, 1H), 7.56 (dd, J = 2.6, 8.3 Hz, 1H), 8.21 (d, J = 2.5 Hz, 1H). MS: [M+H] + m/z = 677.

Example 5. Ammonium;6-[4-[[(4S)-4-(6-chloro-3-pyridyl)-6-methyl-2-oxo-l -[[(2R)- tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carbonyl] oxy-methyl]-3- methoxy-phenyl]hex-5-yne- 1 -sulfonate.

The iodide compound 5j (125 mg, 0.18 mmol) was dissolved in a mixture of iPrOH/water 1/1 (3 mL). Sodium sulfite (47 mg, 0.37 mmol) was added and the reaction mixture was heated at 80°C in sealed tube for 4 h. The solvents were removed under reduced pressure. Purification of the crude by HPLC (basic conditions) gave the expected product as white powder (m = 72 mg, 60 %). 1H NMR (300 MHz, CDC1 3 ): δ (ppm) 1.34-1.54 (m, 1H), 1.57- 1.75 (m, 2H), 1.78-2.05 (m, 5H), 2.37 (t, J = 7.0 Hz, 2H), 2.51-2.71 (m, 4H), 2.85-3.00 (m, 3H), 3.37 (dd, / = 9.3, 14.1 Hz, 1H), 3.65 (s, 3H), 3.72 (dd, J = 7.6, 14.5 Hz, 1H), 3.79- 3.94 (m, 2H), 4.08-4.29 (m, 2H), 5.02 (s, 2H), 6.76-6.93 (m, 3H), 7.09 (s, 4H), 7.14 (d, J = 8.3 Hz, 1H), 7.59 (dd, J = 2.5, 8.3 Hz, 1H), 8.21 (d, J = 2.2 Hz, 1H). 13 C NMR (75 MHz, CDC1 3 ): δ (ppm) 17.2, 19.2, 24.4, 25.8, 27.9, 29.3, 35.0, 38.7, 46.1, 51.1, 55.5, 61.9, 68.3, 77.7, 80.9, 90.4, 109.2, 113.5, 123.8, 124.0, 124.3, 125.1, 129.3, 136.3, 138.3, 149.1, 149.7, 152.1, 157.1, 166.7, 168.6. MS: [M] " m/z = 629.

EXAMPLE 6.

example 6 6e

Example 6a. Methyl 4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydro-lH-pyridine-5- carboxylate.

The methyl 3-oxobutanoate (3.06 mL, 28.5 mmol) was dissolved in acetic acid (28 mL). The 4-chlorobenzaldehyde (4.0 g, 28.5 mmol), Meldrum's acid (4.1 g, 28.5 mmol) and ammonium acetate (3.29 g, 42.7 mmol) were added and the reaction mixture was stirred for 18 h at 110°C. The reaction mixture was cooled at r.t. The solvent was removed under reduced pressure. The residue was dissolved in the minimum of ethanol. The mixture was sonicated with ultrasound and the product precipitated. The mixture was cooled and the precipitate was filtered, then washed with cold ethanol to give the desired product as a white powder (m = 3.6 g, 45 ). 1H NMR (300 MHz, CDC1 3 ): δ (ppm) 2.41 (s, 3H), 2.65 (dd, J = 16.5, 1.0 Hz, 1H), 2.93 (dd, J = 16.6, 8.0 Hz, 1H), 3.66 (s, 3H), 4.23 (d, J = 7.4 Hz, 1H), 7.11 (d, J = 8.4 Hz, 2H), 7.25 (d, J = 8.5 Hz, 2H), 8.68 (s, 1H). MS: [M+H] + m/z = 280.

Example 6b. Methyl-(4S)-4-(4-chlorophenyl)-6-methyl-2-oxo-l-[[(2R)-tetra - hydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate.

The dihydropyridone intermediate 6a (1.5 g, 5.36 mmol) and the [(2R)-tetrahydrofuran-2- yl]methyl 4-methylbenzenesulfonate 5b ( 2.75 g, 10.72 mmol) were dissolved in dry DMF (25 mL), Cs 2 C0 3 (3.5 g, 10.72 mmol) and Nal (40 mg, 0.27 mmol) were added and the reaction mixture was stirred at 50°C for 24 h. reaction finished. The solvent was removed under reduced pressure. Water was added and the aqueous phase was extracted by ethyl acetate, the organic layers were washed with brine, and dried over MgS0 4 . The solvent was removed and the crude was purified by flash chromatography using as eluent a mixture of CH 2 Cl 2 /cHex (30/70 to 100/0) to give the expected product as oil (m = 500 mg, 26 %). 1H NMR (300 MHz, CDC1 3 ): δ (ppm) 1.34-1.48 (m, 1H), 1.74-1.98 (m, 3H), 2.57 (d, J = 0.5 Hz, 3H), 2.66 (dd, J = 15.6, 2.2 Hz, 1H), 2.86 (dd, J = 15.6, 7.2 Hz, 1H), 3.28- 3.43 (m, 1H), 3.60 (s, 3H), 3.65-3.79 (m, 2H), 3.80-3.90 (m, 1H), 4.14 (dd, J = 7.1, 1.5 Hz, 1H), 4.22 (dd, / = 14.3, 3.3 Hz, 1H), 7.17 (s, 4H). MS: [M+H] + m/z = 364.

Example 6c. (4S)-4-(4-Chlorophenyl)-6-methyl-2-oxo-l-[[(2R)-tetrahydro-f uran-2- yl]methyl] -3,4-dihydropyridine-5-carboxylic acid.

The ester 6b (480 mg, 1.32 mmol) was dissolved in MeOH (8 mL), a solution of NaOH IN (8 mL) was added. The reaction mixture was stirred for 3h at 40 °C. LCMS showed completion of the reaction. The MeOH was evaporated under reduced pressure, the aqueous phase was extracted by Et 2 0, then acidified to pH = 1 with a solution of HC1 (IN). The aqueous phase was extracted by EtOAC and the organic phases were assembled and dried under MgS0 4 . The solvents were removed under reduced pressure to afford a product as white solid (m = 459 mg, 99 %). 1H NMR (300 MHz, CDC1 3 ): δ (ppm) 1.32-1.52 (m, 1H), 1.76-1.99 (m, 3H), 2.61 (s, 3H), 2.71 (dd, / = 15.6, 1.9 Hz, 1H), 2.89 (dd, J = 15.6,

7.2 Hz, 1H), 3.39 (dd, J = 14.2, 8.8 Hz, 1H), 3.68-3.80 (m, 2H), 3.88 (dt, / = 13.0, 6.7 Hz, 1H), 4.13-4.33 (m, 2H), 7.19 (s, 4H), 11.47 (s, 1H). MS: [M+H] + m/z = 350.

Example 6d. [4-(6-Chlorohex-l-ynyl)-2-methoxy-phenyl]methyl (4S)-4-(4- chlorophenyl)-6-methyl-2-oxo-l-[[(2R)-tetrahydrofuran-2-yl]m ethyl]-3,4- dihydropyridine-5-carboxylate.

The acid 6c (60 mg, 0.17 mmol) and cesium carbonate (84 mg, 0.26 mmol) were dissolved in dry DMF (2 mL). Chlorinated compound 5h (70 mg, 0.26 mmol) was added and the reaction mixture was stirred at r.t. for 6 h. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc and washed with water. The aqueous phase was extracted by EtOAc and the organic layers were assembled, washed with brine and dried over MgS0 4 . The residue was purified by flash chromatography (CH 2 C1 2 ) to afford the desired product as a colorless oil (m = 83 mg, 83 %). 1H NMR (300 MHz, CDC1 3 ): δ (ppm) 1.39-1.50 (m, 1H), 1.70-1.85 (m, 2H), 1.82-2.02 (m, 5H), 2.46 (t, / = 6.9 Hz, 2H), 2.61 (s, 3H), 2.68 (dd, J = 2.1, 15.6 Hz, 1H), 2.90 (dd, J = 7.3, 15.6 Hz, 1H), 3.40 (dd, J = 8.7, 14.3 Hz, 1H), 3.60 (t, J = 6.5 Hz, 2H), 3.65-3.95 (m, 6H), 4.17 (d, J = 5.9 Hz, 1H),

4.24 (dd, J = 3.3, 14.3 Hz, 1H), 5.09 (q, / = 13.3 Hz, 2H), 6.83 (d, J = 6.9 Hz, 3H), 7.10-

7.25 (m, 4H). MS: [M+H] + m/z = 584.

Example 6e. [4-(6-Iodohex-l-ynyl)-2-methoxy-phenyl]methyl (4S)-4-(4-chlorophenyl)-

6-methyl-2-oxo-l-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4- dihydropyridine-5- carboxylate.

The chlorinated compound 6d (83 mg, 0.14 mmol) was dissolved in butanone (5 mL). Nal (85 mg, 0.57 mmol) was added and the reaction mixture stirred at 80 °C overnight. The solution was cooled to r.t., filtered and the precipitate was washed by acetone. The solvents were removed under reduced pressure to afford yellowish oil. This residue was purified by flash chromatography (CH 2 C1 2 ) to give the desired product as oil (m = 95 mg, 99 %). 1H NMR (300 MHz, CDC1 3 ): δ (ppm) 1.32-1.51 (m, 1H), 1.71 (dt, J = 7.0, 14.1 Hz, 2H), 1.79-

2.03 (m, 5H), 2.44 (t, J = 6.9 Hz, 2H), 2.51-2.75 (m, 4H), 2.89 (dd, J = 7.3,15.6 Hz, 1H), 3.24 (t, J = 6.9 Hz, 2H), 3.39 (dd, J = 8.7,14.2 Hz, 1H), 3.62-3.95 (m, 6H), 4.14-4.31 (m, 2H), 5.09 (q, J = 13.3 Hz, 2H), 6.83 (d, J = 6.0 Hz, 3H), 7.18 (s, 4H). MS: [M+H] + m/z = 676.

Example 6. Ammonium;6-[4-[[(4S)-4-(4-chlorophenyl)-6-methyl-2-oxo-l-[[( 2R)- tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carbonyl] oxymethyl]-3- methoxy-phenyl]hex-5-yne- 1 -sulfonate.

The iodide compound 6e (95 mg, 0.14 mmol) was dissolved in a mixture of iPrOH/water 1/1 (2 mL). Sodium sulfite (35 mg, 0.28 mmol) was added and the reaction mixture was heated at 80 °C in sealed tube for 18 h. The solvents were removed under reduced pressure. Purification of the crude by HPLC (formate buffer pH 9.2) gave the expected product as a white powder (m = 36 mg, 40 %). 1H NMR (300 MHz, CDC1 3 ): δ (ppm) 1.30-1.50 (m, 1H), 1.58-1.65 (m, 2H), 1.78-1.92 (m, 4H), 2.38 (t, J = 6.9 Hz, 2H), 2.51-2.71 (m, 4H), 2.76-2.99 (m, 4H), 3.37 (dd, J = 8.8, 14.2 Hz, 1H), 3.64 (s, 3H), 3.64-3.93 (m, 3H), 4.06- 4.29 (m, 2H), 5.04 (q, J = 13.3 Hz, 2H), 6.81 (d, / = 9.7 Hz, 3H), 6.93 (s, 4H), 7.16 (s, 4H). 13 C NMR (75 MHz, CDC1 3 ): δ (ppm) 17.0, 19.2, 24.2, 25.6, 27.9, 29.2, 37.0, 39.0, 45.7, 51.0, 55.3, 61.5, 68.1, 77.8, 80.9, 89.8, 110.2, 113.2, 123.6, 124.5, 128.6, 128.7, 132.5, 139.6, 151.2, 156.8, 167.0, 169.1. MS: [M] " m/z = 628.

EXAMPLE 7.

m=36-51

Example 7a. (4-Iodophenyl)methyl(4S)-4-(6-chloro-3-pyridyl)-6-methyl-2-o xo-l- [[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-ca rboxylate.

The acid 5e (70 mg, 0.20 mmol) and cesium carbonate (97 mg, 0.30 mmol) were dissolved in dry DMF (2 mL). l-(Bromomethyl)-4-iodo-benzene (89 mg, 0.30 mmol) was added. The reaction mixture was stirred at r.t. for 24 h. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc and washed with water. The aqueous phase was extracted by EtOAc. The organic layers were assembled, washed with brine and dried over MgS0 4 . The crude was purified by flash chromatography using as eluent a mixture of cHex/CH 2 Cl 2 : (50/50 to 0/100) to afford the desired product as a colorless oil (m = 94 mg, 83 %). 1H NMR (300 MHz, CDC1 3 ): δ (ppm) 1.34-1.54 (m, 1H), 1.76-2.03 (m, 3H), 2.52-2.72 (m, 4H), 2.93 (dd, J = 7.4, 15.7 Hz, 1H), 3.38 (dd, J = 9.4, 14.2 Hz, 1H), 3.64- 3.78 (m, 1H), 3.78-3.94 (m, 2H), 4.12-4.32 (m, 2H), 4.99 (d, J = 2.3 Hz, 2H), 6.85 (d, / = 8.4 Hz, 2H), 7.15 (d, J = 8.3 Hz, 1H), 7.50-7.69 (m, 3H), 8.24 (d, J = 2.6 Hz, 1H). MS: [M+H] + m/z = 567.

Example 7b. Hex-5-ynyl 4-methylbenzenesulfonate.

The mixture of triethylamine (2.15 mL, 15.3 mmol), TsCl ( 2.14 g, 11.21 mmol) and 62 mg of DMAP were combined in CH 2 C1 2 (24 mL). this solution was cooled in an ice bath and to it was added a solution of hex-5-yn-l-ol (1.12 mL, 10.2 mmol) in 10 mL of CH 2 C1 2 over 20 min. the reaction stirred for 3 h and was then concentrated in vacuum, the residue was taken up in ethyl acetate and then washed 2 times with a saturated solution of NaHC0 3 and once with NaCl solution. The organic layers were dried over MgS0 4 , filtered and concentrated in vacuum. 1H NMR (300 MHz, CDC1 3 ): δ (ppm) 1.43-1.60 (m, 2H), 1.67- 1.82 (m, 2H), 1.90 (t, J = 2.7 Hz, 1H), 2.12 (td, / = 6.9, 2.7 Hz, 2H), 2.41 (s, 3H), 4.02 (t, J = 6.3 Hz, 2H), 7.32 (d, J = 8.4 Hz, 2H), 7.75 (d, J = 8.3 Hz, 2H). MS: [M+NH 4 ] + m/z = 270.

Example 7c. 6-[2-(Polyethyleneglycol)methylether]hex-l-yne (MM peg = 2000 g/mol).

The poly (ethylene glycol) methyl ether (MM = 2000 g/mol, 1 g, 0.50 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL). Sodium hydride (22 mg, 60% dispersion in mineral oil) was added into the mixture in an ice water bath, the mixture was stirred until no hydrogen gas was released. After, the hex-5-ynyl 4-methylbenzenesulfonate 7b (125 mg, 0.50 mmol) was added to the mixture in an ice water bath, the resulting mixture was stirred at 0°C for 2h, and then at room temperature overnight, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography using as eluent a mixture of CH 2 Cl 2 /MeOH (98/2) to give the expected product as white powder (m = 754 mg, 72 %). 1H NMR (300 MHz, CDC1 3 ): δ (ppm) I. SOUS (m, 2H), 1.94 (t, J = 2.7 Hz, 1H), 2.06 (d, / = 3.2 Hz, 1H), 2.18-2.25 (m, 1H), 3.31- 3.43 (m, 4H), 3.45-3.55 (m, 1H), 3.55-3.80 (m, 182H), 3.83-3.91 (m, 1H), 4.17-4.26 (m, 1H).

Example 7. [4-[6-[2-(Polyethyleneglycol)methylether]hex-l-ynyl]phenyl]m ethyl(4S)-4-

(6-chloro-3-pyridyl)-6-methyl-2-oxo-l-[[(2R)-tetra-hydrof uran-2-yl]methyl]-3,4- dihydropyridine-5-carboxylate.

The iodide 7a compound (94 mg, 0.17 mmol), the alkyne 7c (417 mg, 0.20 mmol) and pyrrolidine (21 μΐ., 0.25 mmol) are dissolved in 4 mL of dry and degazed DMF. Then, PdCl 2 (Dppf) 2 (11 mg, 8 μιηοΐ) and Cul (3 mg, 17 μιηοΐ) are added, and reaction mixture is heated at 70°C for 7 h. The mixture is then cooled down to room temperature and evaporated. Residue is then purified by flash chromatography (CH 2 C1 2 ) to give expected product as purple oil (m = 93 mg, 23 %). 1H NMR (300 MHz, CDC1 3 ): δ (ppm) 1.40-1.55 (m, 1H), 1.59-1.79 (m, 5H), 1.85-2.20 (m, 9H), 2.42 (t, J = 6.8 Hz, 2H), 2.56-2.72 (m, 4H), 2.94 (dd, / = 7.4, 15.7 Hz, 1H), 3.30-3.45 (m, 6H), 3.45-3.79 (m, 232H), 3.80-3.93 (m, 4H), 4.14-4.30 (m, 2H), 5.04 (q, / = 12.7 Hz, 2H), 7.03 (d, J = 8.3 Hz, 2H), 7.17 (d, J = 8.3 Hz, 1H), 7.30 (d, J = 8.2 Hz, 2H), 7.57 (dd, / = 2.6, 8.3 Hz, 1H), 8.26 (d, J = 2.6 Hz, 1H). 13 C NMR (75 MHz, CDC1 3 ): δ (ppm) 17.3, 19.3, 25.4, 25.7, 28.9, 29.2, 35.0, 38.8, 46.1, 59.1, 63.7, 66.0, 68.3, 70.2 70.6, 70.9, 72.0, 77.7, 80.4, 82.2, 82.5, 83.2, 90.7, 108.8, 124.0, 124.2, 127.7, 131.7, 135.2, 135.8, 137.9, 149.2, 150.1, 152.5, 166.6, 168.4. MS: [M+2H 3 0] 2+ m z = 1262. Mixture of compounds containing PEG chains ranging from n = 36 to n = 51 (centered in n = 44).

EXAMPLE 8.

Example 8a. (4-Iodo-2-methoxy-phenyl) methanol.

To a solution of methyl 4-iodo-2-methoxy-benzoate (1.0 g, 3.42 mmol) in THF (20 mL) was added DIBAL (20.5 mL, 10.27 mmol, solution in cyclohexane) dropwise at -78°C. The reaction mixture was stirred at 25°C for 13 h and quenched by the slow addition of saturated solution of NH 4 C1 at 0°C, filtered and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgS0 4 and concentrated under reduced pressure to afford pure product as colorless oil (quantitative). 1H NMR (300 MHz, CDC1 3 ): δ (ppm) 3.03 (s, 1H), 3.78 (s, 3H), 4.55 (s, 2H), 6.97 (d, J = 7.8 Hz, 1H), 7.12 (d, J = 1.5 Hz, 1H), 7.24 (dd, J = 7.8, 1.5 Hz, 1H).

Example 8b. l-(Chloromethyl)-4-iodo-2-methoxy-benzene.

Thionyl chloride (34 μΐ., 0.47 mmol) was added to benzotriazole (68 mg, 0.57 mmol). The resulting yellow solution was dissolved in CH 2 C1 2 (1 mL). After 5 min, this solution was added slowly to the solution of the alcohol 8a in CH 2 C1 2 (2 mL). The benzotriazole salt started to precipitate. After 20 min of reaction, the salt was filtered. The organic phase was washed by water and NaOH solution (0.5 M). The organic layer was dried over MgS0 4 and the solvent was removed under reduced pressure to give the desired chlorinated compound as yellow oil. (m = 102 mg, 95 %). 1H NMR (300 MHz, CDC1 3 ): δ (ppm) 3.86 (s, 3H), 4.58 (s, 2H), 7.06 (d, J = 7.9 Hz, 1H), 7.19 (dd, J = 1.5, 8.1 Hz, 1H), 7.30 (dd, J = 1.6, 7.9 Hz, 1H).

Example 8c. (4-Iodo-2-methoxy-phenyl)methyl(4S)-4-(6-chloro-3-pyridyl)-6 -methyl-2- oxo-l-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridin e-5-carboxylate.

The acid 5e (50 mg, 0.14 mmol) and cesium carbonate (70 mg, 0.21 mmol) were dissolved in dry DMF (1 mL). l-(chloromethyl)-4-iodo-2-methoxy-benzene 8b (60 mg, 0.21 mmol) was added. The reaction mixture was stirred at r.t. for 24 h. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc and washed with water. The aqueous phase was extracted by EtOAc. The organic layers were assembled, washed with brine and dried over MgS0 4 . The crude was purified by flash chromatography using as eluent a mixture of cHex/CH 2 Cl 2 (50/50 to 0/100) to afford the desired product as a colorless oil (m = 73 mg, 86 %). 1H NMR (300 MHz, CDC1 3 ): δ (ppm) 1.38-1.53 (m, 1H), 1.82-2.01 (m, 3H), 2.56-2.68 (m, 4H), 2.93 (dd, / = 7.5, 15.7 Hz, 1H), 3.39 (dd, J = 9.3, 14.2 Hz, 1H), 3.65-3.76 (m, 4H), 3.80-3.92 (m, 2H), 4.13-4.30 (m, 2H), 5.03 (q, / = 12.6 Hz, 2H), 6.73 (d, J = 7.9 Hz, 1H), 7.11 (d, J = 1.5 Hz, 1H), 7.14 (d, J = 8.2 Hz, 1H), 7.19 (dd, J = 1.5, 7.9 Hz, 1H), 7.56 (dd, J = 2.6, 8.3 Hz, 1H), 8.22 (d, J = 2.6 Hz, 1H). MS:

[M+H]+ m/z = 597.

Example 8. [2-Methoxy-4- [6-(2-polyethyleneglycol)methylether)hex- 1 - ynyl]phenyl]methyl(4S)-4-(6-chloro-3-pyridyl)-6-methyl-2-oxo -l-[[(2R)- tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxyla te.

The iodide compound 8c (73 mg, 0.12 mmol), the alkyne 7c (307 mg, 0.15 mmol) and pyrrolidine (15 μΐ , 0.18 mmol) are dissolved in 3 mL of dry and degazed DMF. Then, PdCl 2 (Dppf) 2 (8 mg, 6 μπιοΐ) and Cul (2 mg, 12 μπιοΐ) are added, and reaction mixture is heated at 70°C for 7 h. The mixture is then cooled down to room temperature and evaporated. Residue is then purified by flash chromatography (CH 2 C1 2 ) to give expected product as colorless oil (m = 62 mg, 20 %). 1H NMR (300 MHz, CDC1 3 ): δ (ppm) 1.40- 1.55 (m, 1H), 1.59-2.10 (m, 17H), 2.43 (t, J = 6.8 Hz, 2H), 2.55-2.70 (m, 4H), 2.94 (dd, / =

7.5, 15.7 Hz, 1H), 3.32-3.45 (m, 5H), 3.45-3.94 (m, 193H), 4.15-4.30 (m, 2H), 5.07 (s, 2H), 6.83 (s, 1H), 6.91 (dd, J = 7.8, 16.3 Hz, 2H), 7.15 (d, J = 8.2 Hz, 1H), 7.57 (dd, / =

2.6, 8.3 Hz, 1H), 8.23 (d, J = 2.4 Hz, 1H). 13 C NMR (75 MHz, CDC1 3 ): δ (ppm) 17.3, 19.4, 25.5, 25.7, 29.0, 29.3, 35.0, 38.8, 46.1, 55.4, 59.1, 61.9, 63.7, 68.3, 70.3, 70.7, 71.0, 72.1, 77.8, 80.7, 82.3, 90.6, 109.3, 113.4, 123.8, 123.9, 124.1, 125.3, 126.9, 129.4, 136.0, 138.0, 149.3, 151.9, 157.2, 166.8, 168.5. MS: [M+2H 3 0] 2+ m/z = 1255. Mixture of compounds containing PEG chains ranging from n = 35 to n = 51 (centered in n = 43). EXAMPLE 9. BDM 75848

Example 9a. (4-Bromophenyl)methanol.

The 4-bromobenzaldehyde (2 g, 10.81 mmol) was dissolved in 50 mL of MeOH, NaBH (818 mg, 21.62 mmol) was added by portions at 0°C. The mixture was stirred for 2 h. Water was added, MeOH was evaporated and the aqueous layer was extracted with EtOAc. The organic phases were assembled and dried over MgS0 4 . The solvent was removed under reduced pressure to afford a product as white solid (1.96 g, 97 %). 1H NMR (300 MHz, CDC1 3 ): δ (ppm) 1.90 (s, 1H), 4.64 (s, 2H), 7.23 (d, J = 8.5 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H).

Example 9b. l-Bromo-4-(chloromethyl)benzene.

Thionyl chloride (121 μL, 1.67 mmol) was added to benzotriazole (239 mg, 2.0 mmol). The resulting solution was dissolved in CH 2 C1 2 (5 mL). After 5 min, this solution was added slowly to the solution of the alcohol 9a in CH 2 C1 2 (10 mL). The benzotriazole salt started to precipitate. After lh of reaction, the salt was filtered. The organic phase was washed by water and NaOH solution (0.5 M). The organic phase was dried over MgS0 4 and the solvent was removed under reduced pressure to give the desired chlorinated compound as a yellow oil (m = 220 mg, 80 %). 1H NMR (300 MHz, CDC1 3 ): δ (ppm) 4.91 (dd, J = 12.0, 30.8 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 7.49 (d, J = 7.9 Hz, 2H).

Example 9c. (4-Bromophenyl)methyl(4S)-4-(6-chloro-3-pyridyl)-6-methyl-2- oxo-l- [[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-ca rboxylate. The acid 5e (70 mg, 0.20 mmol) and cesium carbonate (98 mg, 0.30 mmol) were dissolved in dry DMF (2 mL). The chlorinated compound 9b (61 mg, 0.30 mmol) was added. The reaction mixture was stirred at r.t. for 24 h. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc and washed with water. The aqueous phase was extracted by EtOAc. The organic layers were assembled, washed with brine and dried with MgS0 4 . The residue was purified by flash chromatography using as eluent a mixture of cHex/CH 2 Cl 2 (50/50 to 0/100) to afford the desired product as a colorless oil (m = 71 mg, 68 %). 1H NMR (300 MHz, CDC1 3 ): δ (ppm) 1.40-1.52 (m, 1H), 1.85-2.05 (m, 3H), 2.55-2.72 (m, 4H), 2.94 (dd, J = 7.4, 15.7 Hz, 1H), 3.39 (dd, J = 9.4, 14.2 Hz, 1H), 3.67-3.79 (m, 1H), 3.79-3.96 (m, 2H), 4.13-4.32 (m, 2H), 4.88-5.13 (m, 2H), 6.98 (d, J = 8.6 Hz, 2H), 7.16 (d, J = 8.2 Hz, 1H), 7.34-7.47 (m, 2H), 7.57 (dd, / = 2.6, 8.3 Hz, 1H), 8.25 (d, J = 2.6 Hz, 1H). MS: [M+H] + m/z = 520.

Example 9d. 4-(2-Polyethyleneglycol)methylether carbamoyl)phenylboronic acid.

In a 25 mL flask were added 4-boronobenzoic acid (20 mg, 0.12 mmol), PEG2000-NH 2 (243 mg, 0.12 mmol), HOBt (17 mg, 0.12 mmol), DCC (25 mg, 0.12 mmol) and 17 μΐ. of NEt 3 in 400 μΐ. of CH 2 C1 2 . The reaction mixture was stirred at r.t. for 18 hours. HOBt (17 mg, 0.12 mmol), DCC (25 mg, 0.12 mmol) and 17 μΐ. of NEt 3 were added again at the RM and it was stirred at r.t. for 24h and 18h at 40°C. The reaction mixture was filtered and concentrated under reduced pressure. Purification of the crude by preparative chromatography gave the desired product as a white powder (m = 166 mg, 64% yield). 1H NMR (300 MHz, CD 2 C1 2 ): 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, / = 7.6 Hz, 2H).

Example 9. [4-[4-(2-Polyethyleneglycol)methylether carbamoyl)phenyl]phenyl]methyl

(4S)-4-(6-chloro-3-pyridyl)-6-methyl-2-oxo-l-[[(2R)-tetra hydrofuran-2-yl]methyl]-

3,4-dihydropyridine-5-carboxylate.

In a microwave tube were added a bromide compound 9c (63 mg, 0.12 mmol), boronic acid 9d (260 mg, 0.12 mmol), Cs 2 C0 3 (118 mg, 0.36 mmol) and Pd(Ph 3 P) 4 (42 mg, 0.036 mmol). 2 mL of dry and degazed DMF was added and the reaction mixture was heated under microwave irradiation at 100°C for 10 min (absorption level high). The solvent was evaporated to dryness and the crude was purified by preparative chromatography to give the desired product as a yellow oil (20 mg, 6 %). 1H NMR (300 MHz, CDC1 3 ): δ (ppm) 1.40-1.50 (m, 1H), 1.85-1.95 (m, 3H), 2.55-2.70 (m, 4H), 2.96 (dd, J = 7.3, 15.8 Hz, 1H), 3.30-3.46 (m, 5H), 3.47-3.77 (m, 197H), 3.80-3.95 (m, 4H), 4.24 (d, J = 8.2 Hz, 2H), 5.14 (d, J = 12.3 Hz, 2H), 7.12-7.25 (m, 4H), 7.53 (d, J = 8.0 Hz, 2H), 7.55-7.65 (m, 3H), 7.90 (d, J = 8.2 Hz, 2H), 8.28 (s, 1H). 13 C NMR (75 MHz, CDC1 3 ): δ (ppm) 17.3, 25.7, 29.3, 35.0, 38.8, 39.9, 46.1, 59.1, 65.9, 68.3, 70.0, 70.3, 70.6, 72.0, 77.7, 124.2, 127.1, 127.8, 128.4, 128.5, 128.7, 133.6, 135.7, 135.9, 137.9, 140.0, 143.4, 149.2, 152.6, 166.6, 167.2, 168.4. MS: [M+2H 3 0] 2+ m/z = 1362. Mixture of compounds containing PEG chains ranging from n = 43 to n = 55 (centered in n = 48).

EXAMPLE 10.

m=33-43

Example 10a. (4-Iodophenyl)methyl-(4S)-4-(4-chlorophenyl)-6-methyl-2-oxo- l-[[(2R)- tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxyla te.

The acid 6c (70 mg, 0.20 mmol) and cesium carbonate (98 mg, 0.30 mmol) were dissolved in dry DMF (2 mL). l-(Bromomethyl)-4-iodo-benzene (89 mg, 0.30 mmol) was added. The reaction mixture was stirred at r.t. for 24h. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc and washed with water. The aqueous phase was extracted by EtOAc. The organic layers were assembled, washed with brine and dried over MgS0 4 . The residue was purified by flash chromatography using as eluent a mixture of cHex/CH 2 Cl 2 (50/50 to 0/100) to afford the desired product as a colorless oil (m = 98 mg, 87%). 1H NMR (300 MHz, CDC1 3 ): δ (ppm) 1.37-1.53 (m, 1H), 1.78-2.02 (m, 3H), 2.62 (s, 3H), 2.68 (dd, J = 15.6, 2.2 Hz, 1H), 2.90 (dd, J = 15.6, 7.4 Hz, 1H), 3.40 (dd, / = 14.3, 8.8 Hz, 1H), 3.65-3.97 (m, 3H), 4.17 (d, J = 5.8 Hz, 1H), 4.24 (dd, J = 14.3, 3.1 Hz, 1H), 5.01 (q, / = 12.9 Hz, 2H), 6.80 (d, J = 8.4 Hz, 2H), 7.12-7.24 (m, 4H), 7.57 (d, J = 8.4 Hz, 2H). MS: [M+H] + m/z = 566. Example 10. [4-[6-[2-(Polyethyleneglycol)methylether]hex-l-ynyl]phenyl]m ethyl(4S)-

4-(4-chlorophenyl)-6-methyl-2-oxo-l-[[(2R)-tetrahydrofura n-2-yl]methyl]-3,4- dihydropyridine-5-carboxylate.

The iodide compound 10a (60 mg, 0.11 mmol), the alkyne 7c (267 mg, 0.13 mmol) and pyrrolidine (13 μΐ-, 0.16 mmol) are dissolved in 3 mL of dry and degazed DMF. Then, PdCl 2 (Dppf) 2 (7 mg, 5 μιηοΐ) and Cul (2 mg, 11 μιηοΐ) are added, and reaction mixture is heated at 70°C for 7 h. the mixture is then cooled down to room temperature and evaporated. Residue is then purified by flash chromatography (CH 2 C1 2 ) to give expected product as colorless oil (m = 40 mg, 15 %). 1H NMR (300 MHz, CDC1 3 ): δ (ppm) 1.40- 1.52 (m, 1H), 1.60-1.80 (m, 4H), 1.81-2.09 (m, 6H), 2.43 (t, J = 6.7 Hz, 2H), 2.56-2.76 (m, 4H), 2.90 (dd, / = 7.3, 15.6 Hz, 1H), 3.35-3.45 (m, 5H), 3.46-3.94 (m, 167H), 4.12-4.33 (m, 2H), 4.95-5.12 (m, 2H), 6.98 (d, J = 8.1 Hz, 2H), 7.11-7.23 (m, 4H), 7.25-7.32 (m, 2H). 13 C NMR (75 MHz, CDC1 3 ): δ (ppm) 17.2, 19.3, 25.5, 25.6, 28.9, 29.3, 37.2, 39.2, 45.8, 59.1, 63.7, 65.7, 68.2, 70.2, 70.7, 70.9, 72.0, 73.0, 77.9, 80.5, 82.2, 90.6, 110.0, 123.7, 127.5, 128.8, 131.6, 132.7, 135.5, 139.5, 151.7, 167.0, 169.0. MS: [M+2H 3 0] 2+ m/z = 1108. Mixture of compounds containing PEG chains ranging from n = 33 to n = 43 (centered in n = 37).

EXAMPLE 11.

Example 11a. 4-Bromo-l-(chloromethyl)-2-methoxy-benzene.

Thionyl chloride (84 μL, 1.15 mmol) was added to benzotriazole (165 mg, 1.38 mmol). The resulting yellow solution was dissolved in CH 2 C1 2 (2 mL). After 5 min, this solution was added slowly to the solution of the (4-bromo-2-methoxy-phenyl)methanol in CH 2 C1 2 (5 mL). The benzotriazole salt started to precipitate. After 20 min of reaction, the salt was filtered. The organic phase was washed by water and NaOH solution (0.5 M). The organic phase was dried over MgS0 4 and the solvent was removed under reduced pressure to give the desired chlorinated compound as a yellow oil (m = 216 mg, 99 %). 1H NMR (300 MHz, CDC1 3 ): δ (ppm) 3.87 (s, 3H), 4.59 (s, 2H), 7.03 (d, J = 1.8 Hz, 1H), 7.09 (dd, / = 1.8, 8.0 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H).

Example lib. (4-Bromo-2-methoxy-phenyl)methyl (4S)-4-(6-chloro-3-pyridyl)-6- methyl-2-oxo-l-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihyd ro-pyridine-5- carboxylate.

The chlorinated compound 11a (47 mg, 0.20 mmol) and the (4S)-4-(6-chloro-3-pyridyl)-6- methyl-2-oxo- 1 - [ [(2R)-tetrahydrofuran-2-yl]methyl] -3 ,4-dihydropyridine-5-carboxylic acid 5e (64 mg, 0.18 mmol) were dissolved in dry DMF (3 mL). Cesium carbonate (89 mg, 0.27 mmol) was added and the reaction mixture was stirred at r.t. overnight. The solvent was removed. Water was added and the aqueous phase was extracted by EtOAc, washed with brine and dried over MgS0 4 . After filtration, the solvent was removed and the crude product was purified by Column chromatography on silica gel (CH 2 C1 2 ) to give the expected product as colorless oil (92 mg, 92 %). 1H NMR (300 MHz, CDC1 3 ): δ (ppm) 1.34-1.52 (m, 1H), 1.81-2.05 (m, 3H), 2.53-2.71 (m, 4H), 2.92 (dd, J = 7.5, 15.7 Hz, 1H), 3.38 (dd, J = 9.3, 14.2 Hz, 1H), 3.60-3.79 (m, 4H), 3.80-3.90 (m, 2H), 4.10-4.30 (m, 2H), 5.03 (q, J = 12.7 Hz, 2H), 6.87 (d, J = 8.0 Hz, 1H), 6.90-7.03 (m, 2H), 7.14 (d, J = 8.3 Hz,

1H), 7.56 (dd, / = 2.6, 8.3 Hz, 1H), 8.21 (d, J = 2.6 Hz, 1H). MS: [M+H]+ m/z = 551.

Example 11. [2-Methoxy-4-[4-(2-polyethyleneglycol)methylether carbamoyl)phenyl]phenyl]methyl (4S)-4-(6-chloro-3-pyridyl)-6-methyl-2-oxo-l- [[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-ca rboxylate.

In a microwave tube were added a bromide compound lib (43 mg, 0.079 mmol), boronic acid 9d (170 mg, 0.079 mmol), Cs 2 C0 3 (77 mg, 0.24 mmol) and Pd(Ph 3 P) 4 (27 mg, 0.024 mmol). A mixture of water, DME and EtOH (2/5/3: 1 mL) was added and the reaction mixture was heated under microwave irradiation at 100°C for 10 min (absorption level high). The solvent was evaporated to dryness and the crude was purified by preparative chromatography to give the desired product as yellow oil (40 mg, 20 %). 1H NMR (300 MHz, CDC1 3 ): δ (ppm) 1.45-1.56 (m, 1H), 1.85-2.00 (m, 3H), 2.58-2.70 (m, 4H), 2.95 (dd, 7 = 7.5, 15.8 Hz, 1H), 3.03-3.14 (m, 2H), 3.33-3.42 (m, 4H), 3.49-3.73 (m, 164H), 3.76- 3.91 (m, 8H), 4.21 (dd, J = 2.9, 14.3 Hz, 6H), 5.13 (d, J = 2.9 Hz, 2H), 7.03 (s, 1H), 7.10 (d, J = 2.1 Hz, 2H), 7.24 (d, / = 8.4 Hz, 1H), 7.38 (s, 1H), 7.62 (d, / = 8.3 Hz, 2H), 7.74 (dd, J = 2.4, 8.3 Hz, 1H), 7.90 (d, J = 8.3 Hz, 2H), 8.32 (d, J = 2.3 Hz, 1H). 13 C NMR (75 MHz, CDC1 3 ): δ (ppm) 8.8, 17.2, 25.7, 29.2, 35.1, 38.6, 39.9, 45.9, 46.1, 55.5, 59.1, 61.9, 63.6, 68.3, 70.6, 72.0, 72.9, 73.8, 82.2, 109.0, 119.3, 123.8, 124.6, 127.2, 127.8, 130.0, 133.5, 134.9, 136.7, 139.2, 141.8, 143.7, 148.1, 148.9, 152.2, 157.9, 166.6, 167.2, 168.2. MS: [M+2H 3 0] m/z = 1267. Mixture of compounds containing PEG chains ranging from n = 35 to n = 51 (centered in: n = 43).

EXAMPLE 12.

Example 12a. 2-[2-(p-Tolylsulfonyloxy)octaethoxy]ethyl 4-methylbenzene-sulfonate.

A mixture of NEt 3 (0.85 mL, 6.07 mmol), TsCl (1029 mg, 5.4 mmol) and DMAP (33 mg, 0.27 mmol) were combined in CH 2 C1 2 (4 mL). This solution was cooled in an ice bath and to it was added octaethylene glycol (500 mg, 1.35 mmol). The reaction was stirred for 3h and was then concentrated in vacuum. Purification of the crude by flash chromatography using as eluent a mixture of cHex/ CH^yMeOH (100/0/0 to 0/94/4) gave the desired product as a colorless oil (m = 833 mg, 91%). l H NMR (300 MHz, CD 2 C1 2 ): 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, / = 8.3 Hz, 4H), 7.78 (d, J = 8.3 Hz, 4H). MS: [M+NHJ+ m/z = 696.

Example 12b. [4-[2-[4-(Hydroxymethyl)phenoxy]octa-ethoxy]phenyl]methanol.

The octa(ethylene glycol)-di-tosylate 12a (C 3 oH 46 0 13 S 2 ) (200 mg, 0.30 mmol) was dissolved in MeCN (3 mL). The 4-(hydroxymethyl)phenol (110 mg, 0.88 mmol) and K 2 C0 3 (122 mg, 0.88 mmol) were added and the reaction mixture was stirred overnight under reflux. After being cooled down, the mixture was filtered. The filtrate was concentrated under vacuum and the crude product was used in the next step without purification. H NMR (300 MHz, CDC1 3 ): δ (ppm) 2.97 (s, 2H), 3.49-3.65 (m, 20H), 3.65-

3.73 (m, 4H), 3.75-3.87 (m, 4H), 4.00-4.13 (m, 4H), 4.54 (s, 4H), 6.85 (d, / = 8.6 Hz, 4H),

7.22 (d, J = 8.5 Hz, 4H). MS: [M+NH 4 ] + m z = 600.

Example 12c. l-(Chloromethyl)-4-[2-[4-(chloromethyl)phenoxy]octa-ethoxy]b enzene.

Thionyl chloride (47 μΐ., 0.65 mmol) was added to benzotriazole (93 mg, 0.78 mmol). The resulting mixture was dissolved in CH 2 C1 2 (2 mL). After 5 min, this solution was added slowly to the solution of the alcohol 12b (152 mg, 0.26 mmol) in CH 2 C1 2 (2 mL). The benzotriazole salt started to precipitate. After 24h of reaction, the salt was filtered. The organic phase was washed by water and NaOH solution (0.5 M). The organic phase was dried under MgS0 4 and the solvent was removed under reduced pressure to give the desired chlorinated compound as yellow oil. (m = 141 mg, 87 %). 1H NMR (300 MHz, CDC1 3 ): δ (ppm) 3.55-3.75 (m, 24H), 3.83 (dd, / = 5.5, 4.2 Hz, 4H), 4.11 (dd, J = 5.5, 4.3 Hz, 4H), 4.54 (s, 4H), 6.87 (d, J = 8.7 Hz, 4H), 7.28 (d, J = 8.7 Hz, 4H). MS: [M+NH 4 ] + m/z = 636.

Example 12. [4-[2-[4-[[(4S)-4-(4-Chlorophenyl)-6-methyl-2-oxo-l-(tetra-h ydrofuran- 2-ylmethyl)-3,4-dihydropyridine-5-carbonyl]oxy- methyl]phenoxy]octaethoxy]phenyl]methyl (4S)-4-(4-chlorophenyl)-6-methyl-2-oxo-l- [[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-ca rboxylate (MM peg = 370 g mol).

The acid compound 6c (56 mg, 0.16 mmol) and cesium carbonate (79 mg, 0.24 mmol) were dissolved in dry DMF (2 mL). The chlorinated compound 12c (50 mg, 0.081 mmol) was added and the reaction mixture was stirred at r.t. for 24 h. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc and washed with water. The aqueous phase was extracted by EtOAc and the organic layers were assembled, washed with brine and dried over MgS0 4 . The residue was purified by flash chromatography using as eluent a mixture of CH 2 Cl 2 MeOH (100/0 to 98/2) to afford the desired product as a colorless oil (m = 40 mg, 40 %). 1H NMR (300 MHz, CDC1 3 ): δ (ppm) 1.35-1.50 (m, 2H), 1.80-1.95 (m, 6H), 2.60 (s, 6H), 2.67 (dd, / = 15.6, 2.2 Hz, 2H), 2.88 (dd, J = 15.6, 7.4 Hz, 2H), 3.39 (dd, J = 14.3, 8.7 Hz, 2H), 3.59-3.75 (m, 27H), 3.79-3.93 (m, 7H), 4.04-4.13 (m, 4H), 4.15 (d, J = 5.9 Hz, 2H), 4.23 (dd, J = 14.3, 3.3 Hz, 2H), 5.00 (s, 4H), 6.80 (d, J = 8.7 Hz, 4H), 7.02 (d, J = 8.7 Hz, 4H), 7.10-7.23 (m, 8H). 13 C NMR (75 MHz, CDC1 3 ): δ (ppm) 17.2, 25.6, 29.3, 37.2, 39.1, 45.8, 66.0, 67.5, 68.2, 69.8, 70.7, 70.9, 78.0, 110.3, 114.6, 128.5, 128.7, 128.8, 129.5, 132.6, 139.7, 151.3, 158.7, 167.2, 169.1. MS: [M+NH 4 ] + m/z = 1262.

EXAMPLE 13.

example13

Example 13a. 2-[2-(p-Tolylsulfonyloxy)undecaethoxy]ethyl 4-methylbenzene- sulfonate.

A mixture of NEt 3 (0.57 mL, 4.12 mmol), TsCl (697 mg, 3.66 mmol) and DMAP (22 mg, 0.18 mmol) were combined in CH 2 C1 2 (4 mL). This solution was cooled in an ice bath and to it was added undecaethylene glycol (500 mg, 0.91 mmol). The reaction was stirred for 3h and was then concentrated in vacuum. Purification of the crude by flash chromatography using as eluent a mixture of cHex/ CH^l^eOH (100/0/0 to 0/94/4) gave the desired product as a colorless oil (m = 737 mg, 94%). 1H NMR (300 MHz, CD 2 C1 2 ): δ (ppm) 2.44 (s, 6H), 3.54 - 3.60 (m, 40H), 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, / = 8.3 Hz, 4H). MS: [M+NH 4 F m/z = 872.

Example 13b. [4-[2-[4-(Hydroxymethyl)phenoxy]undeca-ethoxy]phenyl]methano l

The undeca(ethylene glycol)-di-tosylate 13a (C3 8 H 62 0 17 S 2 ) (218 mg, 0.25 mmol) was dissolved in MeCN (3 mL). The 4-(hydroxymethyl)phenol (95 mg, 0.76 mmol) and K 2 C0 3 (106 mg, 0.76 mmol) were added and the reaction mixture was stirred overnight under reflux. After being cooled down, the mixture was filtered. The filtrate was concentrated under vacuum and the crude product was used in the next step without purification. 1H NMR (300 MHz, CDC1 3 ): δ (ppm) 1.76-1.86 (m, 2H), 3.52-3.75 (m, 40H), 3.76-3.86 (m, 4H), 4.01-4.15 (m, 4H), 4.55 (s, 4H), 6.86 (d, J = 8.6 Hz, 4H), 7.23 (d, J = 8.5 Hz, 4H). MS: [M+NH 4 ] + m/z = 776.

Example 13c. l-(Chloromethyl)-4-[2-[4-(chloromethyl)phenoxy]undeca- ethoxyjbenzene

Thionyl chloride (20 μΐ.,, 0.28 mmol) was added to benzotriazole (40 mg, 0.34 mmol). The resulting mixture was dissolved in CH2CI2 (2 mL). After 5 min, this solution was added slowly to the solution of the alcohol 13b (85 mg, 0.11 mmol) in CH 2 C1 2 (2 mL). The benzotriazole salt started to precipitate. After 24h of reaction, the salt was filtered. The organic phase was washed by water and NaOH solution (0.5 M). The organic phase was dried under MgS0 4 and the solvent was removed under reduced pressure to give the desired chlorinated compound as yellow oil. (m = 60 mg, 67 %). 1H NMR (300 MHz, CDC1 3 ): δ (ppm) 3.58-3.70 (m, 36H), 3.70-3.76 (m, 4H), 3.80-3.90 (m, 4H), 4.07-4.17 (m, 4H), 4.55 (s, 4H), 6.89 (d, J = 8.7 Hz, 4H), 7.29 (d, J = 8.7 Hz, 4H). MS: [M+NH 4 ] + m/z = 812.

Example 13. [4-[2-[4-[[(4S)-4-(4-Chlorophenyl)-6-methyl-2-oxo-l-(tetrahy drofuran-2- ylmethyl)-3,4-dihydropyridine-5- carbonyl]oxymethyl]phenoxy]undecaethoxy]phenyl]methyl (4S)-4-(4-chlorophenyl)-

6-methyl-2-oxo-l-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4- dihydropyridine-5- carboxylate

The acid compound 6c (53 mg, 0.15 mmol) and cesium carbonate (74 mg, 0.23 mmol) were dissolved in dry DMF (2 mL). The chlorinated compound 13c (60 mg, 0.07 mmol) was added and the reaction mixture was stirred at r.t. for 24 h. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc and washed with water. The aqueous phase was extracted by EtOAc and the organic layers were assembled, washed with brine and dried over MgS0 4 . The residue was purified by flash chromatography using as eluent a mixture of CH 2 Cl2/MeOH (100/0 to 96/4) then by preparative chromatography (basic system) to afford the desired product as a colorless oil (m = 53 mg, 49 %). 1H NMR (300 MHz, CDC1 3 ): δ (ppm) 1.34-1.53 (m, 2H), 1.80-1.97 (m, 6H), 2.59 (s, 6H), 2.66 (dd, J = 15.6, 2.2 Hz, 2H), 2.88 (dd, J = 15.6, 7.4 Hz, 2H), 3.39 (dd, J = 14.3, 8.7 Hz, 2H), 3.50-3.75 (m, 42H), 3.75-3.93 (m, 8H), 4.05-4.12 (m, 4H), 4.15 (d, J = 5.8 Hz, 2H), 4.23 (dd, J = 14.3, 3.3 Hz, 2H), 5.00 (s, 4H), 6.79 (d, J = 8.7 Hz, 4H), 7.02 (d, J = 8.7 Hz, 4H), 7.10-7.23 (m, 8H). 13 C NMR (75 MHz, CDC1 3 ): δ (ppm) 17.2, 25.6, 29.3, 37.2, 39.1, 45.7, 65.9, 67.5, 68.2, 69.8, 70.7, 70.9, 77.9, 110.3, 114.5, 128.5, 128.7, 128.8, 129.5, 132.6, 139.6, 151.2, 158.7, 167.1, 169.1. MS: [M+NH 4 ] + m/z = 1484.

EXAMPLE 14.

Example 14. [4-[2-[2-[4-[[(4S)-4-(6-Chloro-3-pyridyl)-6-methyl-2-oxo-l-

(tetrahydrofuran-2-ylmethyl)-3,4-dihydropyridine-5- carbonyl]oxymethyl]phenoxy]octaethoxy]phenyl]methyl (4S)-4-(6-chloro-3-pyridyl)-

6-methyl-2-oxo-l-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4- dihydropyridine-5- carboxylate

The acid compound 5e (80 mg, 0.23 mmol) and cesium carbonate (112 mg, 0.34 mmol) were dissolved in dry DMF (2 mL). The chlorinated compound 12c (71 mg, 0.11 mmol) was added and the reaction mixture was stirred at r.t. for 24 h. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc and washed with water. The aqueous phase was extracted by EtOAc and the organic layers were assembled, washed with brine and dried over MgS0 4 . The residue was purified by flash chromatography using as eluent a mixture of CH 2 Cl 2 /MeOH (100/0 to 96/4) then by preparative chromatography (formate buffer pH 9.2) to afford the desired product as a colorless oil (m = 20 mg, 14 %). 1H NMR (300 MHz, CDC1 3 ): δ (ppm) 1.36-1.53 (m, 2H), 1.81-2.06 (m, 6H), 2.51-2.72 (m, 8H), 2.93 (dd, J = 15.8, 7.4 Hz, 2H), 3.39 (dd, J = 14.2, 9.3 Hz, 2H), 3.55-3.80 (m, 26H), 3.80-3.96 (m, 8H), 4.03-4.14 (m, 4H), 4.15-4.30 (m, 4H), 5.00 (q, J = 12.2 Hz, 4H), 6.82 (d, J = 8.7 Hz, 4H), 7.06 (d, J = 8.7 Hz, 4H), 7.15 (d, / = 8.3 Hz, 2H), 7.56 (dd, J = 8.3, 2.5 Hz, 2H), 8.24 (d, J = 2.5 Hz, 2H). 13 C NMR (75 MHz, CDC1 3 ): δ (ppm) 17.3, 25.7, 29.3, 35.0, 38.8, 46.1, 66.2, 67.5, 68.3, 69.8, 70.7, 71.0, 77.8, 109.3, 114.7, 124.2, 128.3, 129.8, 135.9, 138.1, 149.3, 150.0, 152.1, 158.9, 166.8, 168.5. MS: [M+H] + m/z = 1247.

EXAMPLE 15.

Example 15a. 6-[2-Hex-5-ynoxyoctaethoxy]hex-l-yne.

The octaethylene glycol (100 mg, 0.27 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL). Sodium hydride (24 mg, 60% dispersion in mineral oil) was added at 0°C and the mixture was stirred until no hydrogen gas was released. After, the hex-5-ynyl 4- methylbenzenesulfonate 7b (136 mg, 0.54 mmol) was added in an ice water bath, the resulting mixture was stirred at 0°C for 2h, and then at room temperature overnight, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography using as eluent a mixture of CH 2 Cl 2 MeOH (96/4) to give the expected product as yellow oil (m = 140 mg, 97 %). 1H NMR (300 MHz, CDC1 3 ): δ (ppm) 0.71-0.88 (m, 2H), 1.10-1.29 (m, 5H), 1.45-1.69 (m, 7H), 1.85-1.95 (m, 2H), 2.16 (td, / = 6.9, 2.6 Hz, 4H), 3.43 (t, J = 6.3 Hz, 3H), 3.47-3.63 (m, 27H).

Example 15b. (4-Iodo-2-methoxy-phenyl)methyl (4S)-4-(4-chlorophenyl)-6-methyl-2- oxo-l-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridin e-5-carboxylate. The acid compound 6c (80 mg, 0.23 mmol) and cesium carbonate (112 mg, 0.34 mmol) were dissolved in dry DMF (3 mL). l-(chloromethyl)-4-iodo-2-methoxy-benzene 8b (97 mg, 0.34 mmol) was added and the reaction mixture was stirred at r.t. for 24 h. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc and washed with water. The aqueous phase was extracted by EtOAc. The organic layers were assembled, washed with brine and dried over MgS0 4 . The residue was purified by flash chromatography using as eluent a mixture of cHex/CH 2 Cl 2 (50/50 to 0/100) to afford the desired product as a colorless oil (m = 94 mg, 69 %). 1H NMR (300 MHz, CDC1 3 ): δ (ppm) 1.42-1.51 (m, 1H), 1.78-1.98 (m, 3H), 2.54-2.77 (m, 4H), 2.90 (dd, J = 15.6, 7.4 Hz, 1H), 3.40 (dd, J = 14.3, 8.7 Hz, 1H), 3.60-3.94 (m, 6H), 4.10-4.31 (m, 2H), 5.05 (dd, J = 35.3, 13.4 Hz, 2H), 6.63 (d, / = 7.9 Hz, 1H), 7.05-7.25 (m, 6H). MS: [M+H] + m/z = 596.

Example 15. [4-[6-[2-[6-[4-[[(4S)-4-(4-Chlorophenyl)-6-methyl-2-oxo-l-[[ (2R)- tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carbonyl] oxymethyl]-3- methoxy-phenyl]hex-5-ynoxy]octaethoxy]hex-l-ynyl]-2-methoxy- phenyl] methyl (4S)- 4-(4-chlorophenyl)-6-methyl-2-oxo-l-[[(2R)-tetrahydrofuran-2 -yl]methyl]-3,4- dihydropyridine-5-carboxylate.

Iodide compound 15b (45 mg, 0.075 mmol), di-alkyne compound 15a (20 mg, 0.04 mmol) and pyrrolidine (9 μ] ^ ,, 0.11 mmol) are dissolved in 2 mL of dry and degazed DMF. Then, PdCl 2 (Dppf) 2 (5 mg, 4 μιηοΐ) and Cul (1.4 mg, 8 μηιοΐ) are added, and reaction mixture is heated at 70°C for 5 h. The mixture is then cooled down to room temperature and the solvent is evaporated. Residue is then purified by flash chromatography using as eluent a mixture of CH 2 Cl 2 /MeOH (100/0 to 98/2) then by HPLC (formate buffer pH 9.2) to give the expected product as brown solid (m = 16 mg, 30 %). 1H NMR (300 MHz, CDC1 3 ): δ (ppm) 1.35-1.51 (m, 2H), 1.65-1.79 (m, 8H), 1.79-1.99 (m, 6H), 2.43 (t, J = 6.8 Hz, 4H), 2.60 (s, 6H), 2.68 (dd, J = 15.6, 2.1 Hz, 2H), 2.90 (dd, J = 15.6, 7.4 Hz, 2H), 3.40 (dd, / =

14.2, 8.7 Hz, 2H), 3.51 (t, J = 6.2 Hz, 4H), 3.55-3.98 (m, 44H), 4.10-4.31 (m, 4H), 5.09 (dd, J = 27.2, 13.2 Hz, 4H), 6.83 (d, J = 7.1 Hz, 6H), 7.10-7.24 (m, 8H). 13 C NMR (75 MHz, CDC1 3 ): δ (ppm) 17.2, 19.4, 25.5, 25.6, 29.0, 29.3, 37.2, 39.2, 45.8, 55.4, 61.6, 68.2,

70.3, 70.7, 71.0, 78.0, 80.8, 90.4, 110.4, 113.3, 123.8, 124.3, 124.8, 128.8, 128.8, 132.6, 139.7, 151.2, 156.9, 167.2, 169.1. MS: [M+NH 4 ] + m/z = 1484.

EXAMPLE 16.

Example 16a. (4-Bromophenyl)methyl (4S)-4-(4-chlorophenyl)-6-methyl-2-oxo-l- [[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-ca rboxylate.

The acid 6c (100 mg, 0.29 mmol) and cesium carbonate (140 mg, 0.43 mmol) were dissolved in dry DMF (3 mL). The l-bromo-4-(chloromethyl)benzene (59 mg, 0.29 mmol) was added. The reaction mixture was stirred at r.t. for 24 h. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc and washed with water. The aqueous phase was extracted by EtOAc. The organic layers were assembled, washed with brine and dried with MgS0 4 . The residue was purified by HPLC (formate buffer pH 9.2) to afford the desired product as a colorless oil (m =100 mg, 67 %). 1H NMR (300 MHz, CDC1 3 ): δ (ppm) 1.37-1.51 (m, 1H), 1.82-1.97 (m, 3H), 2.61 (s, 3H), 2.68 (dd, J = 15.6, 2.2 Hz, 1H), 2.83-2.89 (m, 1H), 3.40 (dd, J = 14.3, 8.8 Hz, 1H), 3.65-3.84 (m, 2H), 3.84-3.94 (m, 1H), 4.13-4.20 (m, 1H), 4.23 (dd, /= 14.3, 3.2 Hz, 1H), 5.01 (q, J = 12.9 Hz, 2H), 6.92 (d, J = 8.3 Hz, 1H), 7.13-7.24 (m, 5H), 7.36 (d, / = 8.4 Hz, 1H), 7.46 (d, / = 8.4 Hz, 1H). MS: [M+H] + m/z = 520.

Example 16b. 4-[4-[[(4S)-4-(4-Chlorophenyl)-6-methyl-2-oxo-l-[[(2R)- tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5- carbonyl]oxymethyl]phenyl]benzoic acid.

In a microwave tube were added bromide compound 16a (140 mg, 0.27 mmol), 4- boronobenzoic acid (45 mg, 0.27 mmol), Cs 2 C0 3 (193 μΐ, sol. 1M, 2.5 eq.) and Pd(Ph 3 P) 4 (78 mg, 0.067 mmol). A 3 mL of dry and degazed DMF was added to the RM. The reaction mixture was heated under microwave irradiation at 100°C for 10 min (absorption level high). The mixture was evaporated to dryness. The crude was diluted in CH2CI2 and washed with water and with NaCl sat., dried over MgS0 4 and evaporated to dryness. The product was used in the next step without purification. 1H NMR (300 MHz, CDC1 3 ): δ (ppm) 1.39-1.53 (m, 1H), 1.82-2.01 (m, 3H), 2.37 (t, J = 7.5 Hz, 1H), 2.65 (s, 2), 2.73 (dd, J = 15.6, 2.2 Hz, 1H), 2.92 (dd, J = 15.6, 7.3 Hz, 1H), 3.42 (dd, J = 14.2, 8.8 Hz, 1H), 3.67-3.95 (m, 3H), 4.18-4.34 (m, 2H), 5.14 (q, J = 13.0 Hz, 2H), 7.18 (d, / = 8.3 Hz, 2H), 7.45-7.60 (m, 5H), 7.63-7.73 (m, 4H), 8.16 (d, J = 8.3 Hz, 1H). MS: [M+H] + m/z = 560.

Example 16. [4-[4-[Methyl-[(2S,3R,4R,5R)-2,3,4,5,6-

Pentahydroxyhexyl]carbamoyl]phenyl]phenyl]methyl (4S)-4-(4-chlorophenyl)-6- methyl-2-oxo-l-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihyd ropyridine-5- carboxylate.

In a 5 mL flask were added 4-[4-[[(4S)-4-(4-chlorophenyl)-6-methyl-2-oxo-l-[[(2R)- tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carbonyl] oxymethyl]phenyl]benzoic acid 16b (150 mg, 0,27 mmol), NEt 3 (36 μΐ, 0,27 mmol), DCC (55 mg, 0,27 mmol), HOBt (36 mg, 0,27 mmol) and (2R,3R,4R,5S)-6-(methylamino)hexane-l,2,3,4,5-pentol (52 mg, 0,27 mmol) in 3 mL of CH 2 C1 2 . The reaction mixture was stirred overnight at 50°C. The reaction mixture was evaporated to dryness and purified by preparative chromatography to give the desired product as yellowish oil. 1H NMR (300 MHz, CD 2 C1 2 ): δ (ppm) 1.35-1.50 (m, 1H), 1.53-1.69 (m, 1H), 1.77- 2.05 (m, 4H), 2.47 (s, 1H), 2.55-2.70 (m, 4H), 2.87 (dd, J = 15.7, 7.2 Hz, 1H), 2.98 (s, 3H), 3.40 (dd, J = 14.2, 8.8 Hz, 2H), 3.50-4.11 (m, 11H), 4.12-4.31 (m, 3H), 5.05 (s, 2H), 7.09 (d, J = 8.2 Hz, 2H), 7.22 (s, 3H), 7.28-7.54 (m, 6H), 7.57-7.86 (m, 1H). MS: [M+H] + m/z = 737.

EXAMPLE 17.

Example 17a: (4-bromophenyl)methyl (4S)-4-(6-chloro-3-pyridyl)-6-methyl-2-oxo-l- [[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-ca rboxylate.

The acid (100 mg, 0.28 mmol) and cesium carbonate (140 mg, 0.43 mmol) were dissolved in dry DMF (3 mL). The l-bromo-4-(chloromethyl)benzene (88 mg, 0.43 mmol) was added. The reaction mixture was stirred at r.t. for 24 h. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc and washed with water. The aqueous phase was extracted by EtOAc. The organic layers were assembled, washed with brine and dried with MgS0 4 . The residue was purified by flash chromatography (CH 2 C Acetone: 100/0 to 95/5) to afford the desired product as a colorless oil (m = 91 mg, 61 %). 1H NMR (300 MHz, CDC1 3 ) δ 1.40-1.52 (m, 1H), 1.85-2.05 (m, 3H),

2.55-2.72 (m, 4H), 2.94 (dd, J = 7.4, 15.7 Hz, 1H), 3.39 (dd, J = 9.4, 14.2 Hz, 1H), 3.67- 3.79 (m, 1H), 3.79-3.96 (m, 2H), 4.13-4.32 (m, 2H), 4.88-5.13 (m, 2H), 6.98 (d, J = 8.6 Hz, 2H), 7.16 (d, J = 8.2 Hz, 1H), 7.34-7.47 (m, 2H), 7.57 (dd, J = 2.6, 8.3 Hz, 1H), 8.25

(d, J = 2.6 Hz, 1H). MS [M+H]+ 521 g/mol.

Example 17b: [4-[[(3-ethoxy-3-oxo-propyl)amino]methyl]phenyl]boronic acid.

In a dry flask was added (4-formylphenyl)boronic acid (500 mg, 3.33 mmol) in 30 mL of dichloroethane. Ethyl 3-aminopropanoate hydrochloride (768 mg, 5.0 mmol), acetic acid (1.91 ml, 33.35 mmol) were then added and the reaction mixture was stirred 30 min. at room temperature. NaBH(OAc) 3 (1.77 g, 8.34 mmol) was added and the mixture was stirred for 24h at the same temperature. The reaction mixture was filtrated and evaporated to dryness. The crude was purified by flash chromatography (CH 2 Cl 2 /MeOH: 98/2) to give the desired product as colorless oil (300 mg, 36%). 1H NMR (300 MHz, CDC1 3 ) δ 1.15 (t, J = 1.2 Hz, 3H), 1.85 (s, 2H), 2.51-2.71 (m, 2H), 2.86-3.08 (m, 2H), 3.83 (s, 1H), 4.04 (q, J

= 7.1 Hz, 2H), 6.70 (s, 4H), 7.79 (d, J = 30.6 Hz, 2H). MS [M+H]+ 252 g/mol.

Example 17c: [4-[4-[[(3-Ethoxy-3-oxo-propyl)amino]methyl]phenyl]phenyl]me thyl (4S)-4-(6- chloro-3-pyridyl)-6-methyl-2-oxo-l-[[(2R)-tetrahydrofuran-2- yl]methyl]-3,4- dihydropyridine-5-carboxylate.

A mixture of compound 17a (138 mg, 0.26 mmol), boronic acid 17b (67 mg, 0.26 mmol), Cs 2 C0 3 (528 μΐ, sol. 1M, 2.0 eq.) and Pd(Ph 3 P) 4 (18 mg, 0.02 mmol) were dissolved in 5 mL of dry and degassed DMF. The reaction mixture was heated under microwave irradiation at 100°C for 10 min (absorption level high). The solvent was evaporated to dryness. The crude was diluted in CH 2 C1 2 and washed with water and with NaCl sat., dried over MgS0 4 and evaporated to dryness. The product was used in the next step without purification. MS [M+H]+ 646 g/mol.

Example 17: 3-[[4-[4-[[(4S)-4-(6-chloro-3-pyridyl)-6-methyl-2-oxo-l-[[(2 R)-tetrahydrofuran- 2-yl]methyl]-3,4-dihydropyridine-5- carbonyl]oxymethyl]phenyl]phenyl]methylamino]propanoic acid.

To a solution of the ethyl ester 17c (50 mg, 0.077 mmol) in 2 mL of dioxane, a cold solution of NaOH (1M, 2 mL) was added at 0 °C. After stirring for 15 minutes at this temperature, a cold solution of HCl (1M, 5 mL) is added and the mixture is immediately extracted with ethyl acetate. The solvents were evaporated in vacuum. The product was purified by preparative chromatography (basic conditions) to give the desired product as colorless oil (14 mg, 29%). 1H NMR (300 MHz, CDC1 3 ) δ 1.42-1.55 (m, 1H), 1.82-2.07 (m, 3H), 2.60-2.70 (m, 6H), 2.95 (dd, J = 15.7, 7.5 Hz, 2H), 3.10-3.20 (m, 2H), 3.34-3.51 (m, 2H), 3.76 (dd, J = 14.4, 7.6 Hz, 1H), 3.82-3.96 (m, 2H), 4.08-4.20 (m, 4H), 5.04-5.19 (m, 2H), 7.17 (d, J = 8.2 Hz, 3H), 7.46 (d, J = 8.2 Hz, 2H), 7.55-7.65 (m, 5H), 8.27 (d, J = 2.5 Hz, 1H). 13 C NMR (75 MHz, CDC1 3 ) δ 17.2, 25.6, 29.2, 32.4, 34.9, 38.7, 43.7, 46.1, 51.4, 65.9, 68.2, 77.6, 108.8, 124.2, 127.2, 127.5, 127.8, 128.3, 129.7, 131.0, 135.4, 135.8, 137.9, 140.0, 141.5, 149.1, 150.0, 152.5, 166.5, 168.3, 175.5. MS [M+H] + 618 g/mol.

BIOLOGY EXAMPLES

TGR5/CRE Luciferase assay

In the following Tables TGR5 activation by compounds of the invention 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-Luciferase 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 10μΜ 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) or a Victor3™ V1420 (Perkin Elmer). Data were expressed as percentage of the 10μΜ 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 14 hereafter.

Table 14

EC50 hTGR5 EC 50 mTGR5

Example

(nM) (nM)

1 340 590

2 270 270

3 110 200

4 11 26

5 19 11 6 19 13

7 1200 2200

8 590 630

9 140 1500

10 730 500

11 130 530

12 150 120

13 140 130

14 150 190

15 800 950

16 20 65

17 33 163