2-OXO-3,4-DIHYDROPYRIDINE-5-CARBOXYLATES AND THEIR USE

Abstract

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

##STR00001##

Claims

1. A compound of general Formula I: ##STR00432## or pharmaceutically acceptable salts or solvates thereof, wherein R.sup.1 is C1-C6-alkyl, aryl or heteroaryl, wherein said aryl moiety is independently substituted by one or more groups selected from the group consisting of halo, cyano, C1-C2-alkyl, C1-C2-alkoxy, C1-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, C1-C2-alkyl, C1-C2-alkoxy, C1-C2-haloalkyl, and 5- or 6-membered aryl; L.sup.1 is a single bond or (CH.sub.2).sub.n, wherein n is 1, 2 or 3; R.sup.2 is H, C1-C4 alkyl, alkenyl, alkinyl, alkoxy, hydroxy, hydroxycarbonyl, alkoxycarbonyl, carbamoyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonylamino, cyano, alkylsulfonyl, aralkyl, cycloalkyl, heterocyclyl, heteroaryl, wherein said heterocyclyl moiety is optionally substituted by one or more substituents independently selected from the group consisting of alkyl and alkoxycarbonyl, and said heteroaryl moiety is optionally substituted by one or more C1-C2-alkyl; L.sup.2 is a single bond or (CH.sub.2).sub.n, wherein n is 1 or 2; R.sup.3 is aryl, heteroaryl, cycloalkyl or arylcarbonyl wherein each of said moieties is optionally substituted by one or more substituents independently selected from the group consisting of halo, alkyl, haloalkyl, aryl, cyano, alkoxy, haloalkoxy, alkoxycarbonyl, aminoalkoxy, alkylaminoalkoxy, dialkylaminoalkoxy, HO.sub.3S-alkoxy, ##STR00433## wherein m is 1 to 500, [N(R.sup.8).sub.3-alkoxy].sup.+Q.sup., wherein R.sup.8 is linear C1-C4-alkyl and Q.sup. is a counter anion, and a cyclic moiety selected from the group consisting of ##STR00434## wherein R.sup.A is H, OH, C0-C4-alkyl-COOH or C1-C6-alkyl, R.sup.B is C1-C6-alkyl optionally substituted with COOH, R.sup.C is C1-C6-alkyl, and Q.sup. is a counter anion; or wherein said cycloalkyl moiety is fused to a an aryl, preferably phenyl, moiety; R.sup.4 is H, C1-C2-alkyl or 5- or 6-membered aryl; R.sup.5 is H, C1-C4-alkyl, 5- or 6-membered aryl, alkoxyalkyl; and X is O or NR, wherein R is H, C1-C2-alkyl or R taken together with L.sup.2 and R.sup.3 form a 5- or 6-membered heterocyclyl moiety which is optionally fused to an aryl moiety.

2. The compound according to claim 1 having Formula II ##STR00435## and pharmaceutically acceptable salts and solvates thereof.

3. The compound according to claim 2 having Formula IIa ##STR00436## and pharmaceutically acceptable salts, and solvates thereof, wherein R.sup.6 is halo, alkyl, haloalkyl, aryl, cyano, alkoxy, haloalkoxy, alkoxycarbonyl, aminoalkoxy, alkylaminoalkoxy, dialkylaminoalkoxy, HO.sub.3S-alkoxy, ##STR00437## wherein m is 1 to 500, [N(R.sup.8).sub.3-alkoxy].sup.+Q.sup., wherein R.sup.8 is linear C1-C4-alkyl and Q.sup. is a counter anion, or a cyclic moiety selected from the group consisting of ##STR00438## wherein R.sup.A is H, OH, C0-C4-alkyl-COOH or C1-C6-alkyl, R.sup.B is C1-C6-alkyl optionally substituted with COOH, R.sup.C is C1-C6-alkyl, and Q.sup. is a counter anion.

4. The compound according to claim 1 having Formula III ##STR00439## and pharmaceutically acceptable salts, and solvates thereof, wherein R.sup.7 and R.sup.8 are independently selected from the group consisting of H, halo, haloalkyl, and cyano, with the proviso that at least one of R.sup.7 and R.sup.8 is not H.

5. The compound according to claim 1 having Formula IV ##STR00440## and pharmaceutically acceptable salts, and solvates thereof, wherein R.sup.9 and R.sup.10 are independently selected from the group consisting of H, halo, haloalkyl, and cyano, with the proviso that at least one of R.sup.9 and R.sup.10 is not H.

6. The compound according to claim 1 having Formula V ##STR00441## and pharmaceutically acceptable salts, and solvates thereof.

7. The compound according to claim 1 and pharmaceutically acceptable salts, and solvates thereof, wherein R.sup.5 is methyl.

8. The compound according to claim 1 and pharmaceutically acceptable salts, and solvates thereof, wherein L.sup.1 and R.sup.2 are taken together to form a moiety selected from the group consisting of cycloalkylmethyl, heterocyclylmethyl, heteroarylmethyl, 2-alkoxyeth-1-yl, 3-alkoxyprop-1-yl, alkoxycarbonylmethyl, said heteroarylmethyl moiety being optionally substituted by one or more C1-C2 alkyl.

9. The compound according to claim 1 and pharmaceutically acceptable salts, and solvates thereof, wherein R.sup.2 is tetrahydrofuranyl.

10. The compound according to claim 9 and pharmaceutically acceptable salts, and solvates thereof, wherein L.sup.1 is CH.sub.2.

11. The compound according to claim 1 selected from the group consisting of: ##STR00442## ##STR00443## ##STR00444## ##STR00445## ##STR00446## ##STR00447## ##STR00448## ##STR00449## ##STR00450## ##STR00451## ##STR00452## ##STR00453## ##STR00454## ##STR00455## ##STR00456## ##STR00457## ##STR00458## ##STR00459## ##STR00460## ##STR00461## ##STR00462## ##STR00463## ##STR00464## ##STR00465## ##STR00466## ##STR00467## ##STR00468## ##STR00469## ##STR00470## ##STR00471## ##STR00472## ##STR00473## ##STR00474## ##STR00475## ##STR00476## ##STR00477## ##STR00478## ##STR00479## ##STR00480## ##STR00481## ##STR00482## ##STR00483## ##STR00484## ##STR00485## ##STR00486## and pharmaceutically acceptable salts, and solvates thereof.

12. A pharmaceutical composition comprising a compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof and at least one pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant.

13. A medicament comprising a compound according to claim 1.

14. A method for treating and/or preventing a TGR5 related disease comprising the administration of a therapeutically effective amount of a compound according to claim 1 or pharmaceutically acceptable salt or solvate thereof, to a patient in need thereof.

15. The method according to claim 14, wherein the disease is selected from metabolic and/or gastrointestinal diseases.

16. The method according to claim 15 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 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).

17. The method according to claim 15, 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.

18. 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 according to claim 1, or a pharmaceutically acceptable salt and/or solvate thereof.

19. The method according to claim 18, wherein the compound is an agonist of TGR5 receptor activity.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0019] As noted above, the invention relates to compounds of Formula I, as well as their pharmaceutically acceptable salts and solvates.

[0020] Preferred compounds of Formula I and pharmaceutically acceptable salts and solvates thereof are those wherein one or more of R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, L.sup.1, L.sup.2 and X are defined as follows:

R.sup.1 is C1-C4 alkyl, 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, C1-C2-alkyl, C1-C2-alkoxy, C1-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, C1-C2-alkyl, C1-C2-alkoxy, C1-C2-haloalkyl, and 5- or 6-membered aryl, preferably R.sup.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, C1-C2-alkyl, C1-C2-alkoxy, C1-C2-haloalkyl, and 5- or 6-membered aryl, more preferably R.sup.1 is n-propyl, phenyl or pyridinyl, independently substituted by one or more substituents selected from the group consisting of halo, C1-C2-alkyl, C1-C2-haloalkyl, still more preferably R.sup.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.sup.1 is phenyl substituted by one chloro;
L.sup.1 is (CH.sub.2).sub.n, wherein n is 1, 2 or 3, preferably L.sup.1 is CH.sub.2;
R.sup.2 is alkoxy, hydroxy, alkoxycarbonyl, cycloalkyl, heterocyclyl, or heteroaryl, said heteroaryl moiety being optionally substituted by one or more C1-C2 alkyl preferably methyl groups; preferably R.sup.2 is C1-C2-alkoxy, hydroxyl, C1-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.sup.2 is methoxy, hydroxyl, methoxycarbonyl, cyclopropyl, cyclobutyl, furanyl, 3-methyl-1,2,4-oxadiazol-5-yl, tetrahydrofuranyl or 1,3-dioxolanyl, even more preferably R.sup.2 is tetrahydrofuranyl;
L.sup.2 is a single bond;
R.sup.3 is phenyl, substituted by one or more substituents independently selected from the group consisting of halo, C1-C2-alkyl, C1-C2-haloalkyl, phenyl, cyano, C1-C2-alkoxy, C1-C2-haloalkoxy, C1-C2-alkoxycarbonyl, aminoalkoxy, C1-C2-alkylaminoalkoxy, di-C1-C2-alkylaminoalkoxy, HO.sub.3SC2-C8-alkoxy,

##STR00005##

wherein m is 1 to 500, preferably 1 to 50, and [N(R.sup.8).sub.3C2-C6-alkoxy].sup.+Q.sup., wherein R.sup.8 is C1-C2-alkyl and Q.sup. is a counter anion,
preferably R.sup.3 is phenyl, substituted by one or more substituents independently selected from the group consisting of halo, C1-C2-alkyl, C1-C2-haloalkyl, phenyl, cyano, C1-C2-alkoxy, C1-C2-haloalkoxy, C1-C2-alkoxycarbonyl, aminoalkoxy, C1-C2-alkylaminoalkoxy, di-C1-C2-alkylaminoalkoxy, HO.sub.3SC2-C6-alkoxy,

##STR00006##

wherein m is 1 to 500, preferably 1 to 50, and [N(R.sup.8).sub.3C2-C6-alkoxy].sup.+Q.sup., wherein R.sup.8 is C1-C2-alkyl and Q.sup. is a counter anion,
more preferably R.sup.3 is phenyl, substituted by one or more substituents independently selected from the group consisting of halo, methyl, trifluoromethyl, phenyl, cyano, methoxy, trifluoromethoxy, methoxycarbonyl, di-methylaminoalkoxy, HO.sub.3SCH.sub.2CH.sub.2O

##STR00007##

wherein m is 1 to 500, preferably 1 to 50, and [N(R.sup.8).sub.3C2-C6-alkoxy].sup.+Q.sup., wherein R.sup.8 is methyl and Q.sup. is a counter anion,
still more preferably R.sup.3 is phenyl, substituted by one or more substituents independently selected from the group consisting of chloro, fluoro, methyl, trifluoromethyl, phenyl, cyano, methoxy, trifluoromethoxy, methoxycarbonyl, di-methylaminoalkoxy,

##STR00008##

wherein m is 1 to 500, preferably 1 to 50, and [N(R.sup.8).sub.3C2-C6-alkoxy].sup.+Q.sup., wherein R.sup.8 is methyl and Q.sup. is a counter anion;

R.SUP.4 .is H;

[0021] R.sup.5 is methyl;

X is O.

[0022] Particularly preferred compounds of Formula I and pharmaceutically acceptable salts and solvates thereof are those wherein R.sup.3 is aryl, heteroaryl, cycloalkyl or arylcarbonyl, preferably aryl or heterorayl, more preferably phenyl or pyridinyl, even more preferably phenyl, wherein each of said moieties is substituted by one or more substituents independently selected from HO.sub.3S-alkoxy, preferably HO.sub.3SC2-C8-alkoxy, more preferably HO.sub.3SC2-C6-alkoxy, even more preferably HO.sub.3SCH.sub.2CH.sub.2O, in particular in form of one of its salts, such as ammonium salts, preferably its NH.sub.4.sup.+ salt,

##STR00009##

wherein m is 1 to 500, preferably 1 to 50, and [N(R.sup.8).sub.3-alkoxy].sup.+Q.sup., wherein R.sup.8 is linear C1-C4-alkyl and Q.sup. is a counter anion, preferably [N(R.sup.8).sub.3C2-C6-alkoxy].sup.+Q.sup., wherein R.sup.8 is C1-C2-alkyl and Q.sup. is a counter anion, more preferably [N(R.sup.8).sub.3C2-C6-alkoxy].sup.+Q.sup., wherein R.sup.8 is methyl and Q.sup. is a counter anion. Indeed, without wanting to be bound to any theory, the present inventors believe that the HO.sub.3S-alkoxy, polyethyleneglycol, and [N(R.sup.8).sub.3-alkoxy].sup.+Q.sup., moieties on the R.sup.3 substituent as defined herein (in the case of the HO.sub.3S-alkoxy moiety especially its pharmaceutically acceptable salts) particularly limit the absorption of the compounds of the invention in the intestine and thus decrease their systemic action.

[0023] Further preferred compounds of Formula I and pharmaceutically acceptable salts and solvates thereof are those wherein L.sup.1 and R.sup.2 are taken together to form a moiety selected from the group consisting of cycloalkylmethyl, heterocyclylmethyl, heteroarylmethyl, 2-alkoxyeth-1-yl, 3-alkoxyprop-1-yl, alkoxycarbonylmethyl, said heteroarylmethyl moiety being optionally substituted by one or more C1-C2 alkyl groups on its heteroaryl part, preferably L.sup.1 and R.sup.2 are taken together to form a moiety selected from the group consisting of C3-C5-cycloalkylmethyl, C5-C6-heterocyclylmethyl, C5-C6-heteroarylmethyl, 2-C1-C2-alkoxyeth-1-yl, 3-C1-C2-alkoxyprop-1-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.sup.1 and R.sup.2 are taken together to form a moiety selected from the group consisting of C3-C4-cycloalkylmethyl, C5-heterocyclylmethyl, C5-heteroarylmethyl, 2-methoxyeth-1-yl, 3-methoxyprop-1-yl, methoxycarbonylmethyl, said C5-heteroarylmethyl moiety being optionally substituted by one methyl group on its heteroaryl part, even more preferably L.sup.1 and R.sup.2 are taken together to form a moiety selected from the group consisting of C3-C4-cycloalkylmethyl, furanylmethyl, 3-methyl-1,2,4-oxadiazol-5-ylmethyl, tetrahydrofuranylmethyl or 1,3-dioxolanylmethyl, 2-methoxyeth-1-yl, 3-methoxyprop-1-yl, methoxycarbonylmethyl, still more preferably L.sup.1 and R.sup.2 are taken together to form 2-methoxyeth-1-yl or tetrahydrofuranylmethyl, and still more preferably L.sup.1 and R.sup.2 are taken together to form tetrahydrofuranylmethyl.

[0024] In one embodiment of the invention, the compounds of Formula I are those of Formula II

##STR00010##

and pharmaceutically acceptable salts and solvates thereof, wherein
R.sup.1, R.sup.2, R.sup.3, R.sup.5, and L.sup.1 are as defined above with respect to Formula I.

[0025] Preferred compounds of Formula II and pharmaceutically acceptable salts and solvates thereof are those wherein L.sup.1 and R.sup.2 are taken together to form a moiety selected from the group consisting of cycloalkylmethyl, heterocyclylmethyl, heteroarylmethyl, 2-alkoxyeth-1-yl, 3-alkoxyprop-1-yl, alkoxycarbonylmethyl, said heteroarylmethyl moiety being optionally substituted by one or more C1-C2 alkyl groups on its heteroaryl part, preferably L.sup.1 and R.sup.2 are taken together to form a moiety selected from the group consisting of C3-C5-cycloalkylmethyl, C5-C6-heterocyclylmethyl, C5-C6-heteroarylmethyl, 2-C1-C2-alkoxyeth-1-yl, 3-C1-C2-alkoxyprop-1-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.sup.1 and R.sup.2 are taken together to form a moiety selected from the group consisting of C3-C4-cycloalkylmethyl, C5-heterocyclylmethyl, C5-heteroarylmethyl, 2-methoxyeth-1-yl, 3-methoxyprop-1-yl, methoxycarbonylmethyl, said C-5-heteroarylmethyl moiety being optionally substituted by one methyl group on its heteroaryl part, even more preferably L.sup.1 and R.sup.2 are taken together to form a moiety selected from the group consisting of C3-C4-cycloalkylmethyl, furanylmethyl, 3-methyl-1,2,4-oxadizol-5-ylmethyl, tetrahydrofuranylmethyl or 1,3-dioxolanylmethyl, 2-methoxyeth-1-yl, 3-methoxyprop-1-yl, methoxycarbonylmethyl, still more preferably L.sup.1 and R.sup.2 are taken together to form 2-methoxyeth-1-yl or tetrahydrofuranylmethyl, and still more preferably L.sup.1 and R.sup.2 are taken together to form tetrahydrofuranylmethyl.

[0026] In one embodiment, preferred compounds of Formula II are those of Formula IIa

##STR00011##

and pharmaceutically acceptable salts and solvates thereof, wherein
R.sup.1, R.sup.2, R.sup.5 and L.sup.1 are as defined above with respect to Formula II, and
R.sup.6 is halo, alkyl, haloalkyl, aryl, cyano, alkoxy, haloalkoxy, alkoxycarbonyl, aminoalkoxy, alkylaminoalkoxy, dialkylaminoalkoxy, HO.sub.3S-alkoxy,

##STR00012##

wherein m is 1 to 500, preferably 1 to 50, [N(R.sup.8).sub.3-alkoxy].sup.+Q.sup., wherein R.sup.8 is linear C1-C4-alkyl and Q.sup. is a counter anion, or
a cyclic moiety selected from the group consisting of

##STR00013##

wherein R.sup.A is H, OH, C0-C4-alkyl-COOH or C1-C6-alkyl, R.sup.B is C1-C6-alkyl optionally substituted with COOH, R.sup.C is C1-C6-alkyl, and Q is a counter anion; [0027] preferably R.sup.6 is halo, C1-C2-alkyl, C1-C2-haloalkyl, phenyl, cyano, C1-C2-alkoxy, C1-C2-haloalkoxy, C1-C2-alkoxycarbonyl, aminoalkoxy, C1-C2-alkylaminoalkoxy, di-C1-C2-alkylaminoalkoxy, HO.sub.3SC2-C8-alkoxy,

##STR00014##

wherein m is 1 to 500, preferably 1 to 50, or [N(R.sup.8).sub.3C2-C6-alkoxy].sup.+Q.sup., wherein R.sup.8 is C1-C2-alkyl and Q is a counter anion,
more preferably R.sup.6 is halo, C1-C2-alkyl, C1-C2-haloalkyl, phenyl, cyano, C1-C2-alkoxy, C1-C2-haloalkoxy, C1-C2-alkoxycarbonyl, aminoalkoxy, C1-C2-alkylaminoalkoxy, di-C1-C2-alkylaminoalkoxy, HO.sub.3SC2-C6-alkoxy,

##STR00015##

wherein m is 1 to 500, preferably 1 to 50, or [N(R.sup.8).sub.3C2-C6-alkoxy].sup.+Q.sup., wherein R.sup.8 is C1-C2-alkyl and Q.sup. is a counter anion,
still more preferably R.sup.6 is halo, methyl, trifluoromethyl, phenyl, cyano, methoxy, trifluoromethoxy, methoxycarbonyl, di-methylaminoalkoxy, HO.sub.3SCH.sub.2CH.sub.2O, or

##STR00016##

wherein m is 1 to 500, preferably 1 to 50, or [N(R.sup.8).sub.3C2-C6-alkoxy].sup.+Q.sup., wherein R.sup.8 is methyl and Q.sup. is a counter anion,
even more preferably R.sup.6 is chloro, fluoro, methyl, trifluoromethyl, phenyl, cyano, methoxy, trifluoromethoxy, methoxycarbonyl, di-methylaminoalkoxy, HO.sub.3SCH.sub.2CH.sub.2O,

##STR00017##

wherein m is 1 to 500, preferably 1 to 50, or [N(R.sup.8).sub.3C2-C6-alkoxy].sup.+Q.sup., wherein R.sup.8 is methyl and Q.sup. is a counter anion.

[0028] Particularly interesting compounds of Formula IIa and pharmaceutically acceptable salts and solvates thereof are those, wherein R.sup.6 is HO.sub.3S-alkoxy, preferably HO.sub.3SC2-C8-alkoxy, more preferably HO.sub.3SC2-C6-alkoxy, still more preferably HO.sub.3SCH.sub.2CH.sub.2O, in particular in form of one of its salts, such as ammonium salts,

##STR00018##

wherein m is 1 to 500 preferably 1 to 50, or [N(R.sup.8).sub.3-alkoxy].sup.+Q.sup., wherein R.sup.8 is linear C1-C4-alkyl and Q.sup. is a counter anion, preferably [N(R.sup.8).sub.3C2-C6-alkoxy].sup.+Q.sup., wherein R.sup.8 is C1-C2-alkyl and Q.sup. is a counter anion, more preferably [N(R.sup.8).sub.3C2-C6-alkoxy].sup.+Q.sup., wherein R.sup.8 is methyl and Q.sup. is a counter anion.

[0029] In one embodiment, the compounds of Formula IIa are selected from the group consisting of Formulae IIa-1, IIa-2, and IIa-3:

##STR00019##

and pharmaceutically acceptable salts and solvates thereof,
wherein R.sup.1, R.sup.2, R.sup.5, L.sup.1, and R.sup.6 are as defined above with respect to Formula IIa.

[0030] Particularly preferred compounds of Formulae II, IIa, IIa-1, IIa-2, IIa-3 and IIb and pharmaceutically acceptable salts and solvates thereof are those wherein R.sup.5 is methyl.

[0031] In another embodiment, preferred compounds of Formula I are those of Formula III

##STR00020##

and pharmaceutically acceptable salts and solvates thereof, wherein
R.sup.2, R.sup.3, R.sup.4, R.sup.5, L.sup.1 and L.sup.2 are as defined above with respect to Formula I; and
R.sup.7 and R.sup.8 are independently selected from the group consisting of H, halo, haloalkyl, and cyano, with the proviso that at least one of R.sup.7 and R.sup.8 is not H; preferably R.sup.7 and R.sup.8 are independently selected from the group consisting of H, chloro, trifluoromethyl, and cyano, with the proviso that at least one of R.sup.7 and R.sup.8 is not H.

[0032] Preferred compounds of Formula III and pharmaceutically acceptable salts and solvates thereof are those wherein L.sup.1 and R.sup.2 are taken together to form a moiety selected from the group consisting of cycloalkylmethyl, heterocyclylmethyl, heteroarylmethyl, 2-alkoxyeth-1-yl, 3-alkoxyprop-1-yl, alkoxycarbonylmethyl, said heteroarylmethyl moiety being optionally substituted by one or more C1-C2 alkyl groups on its heteroaryl part, preferably L.sup.1 and R.sup.2 are taken together to form a moiety selected from the group consisting of C3-C5-cycloalkylmethyl, C5-C6-heterocyclylmethyl, C5-C6-heteroarylmethyl, 2-C1-C2-alkoxyeth-1-yl, 3-C1-C2-alkoxyprop-1-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.sup.1 and R.sup.2 are taken together to form a moiety selected from the group consisting of C3-C4-cycloalkylmethyl, C5-heterocyclylmethyl, C5-heteroarylmethyl, 2-methoxyeth-1-yl, 3-methoxyprop-1-yl, methoxycarbonylmethyl, said C5-heteroarylmethyl moiety being optionally substituted by one methyl group on its heteroaryl part, even more preferably L.sup.1 and R.sup.2 are taken together to form a moiety selected from the group consisting of C3-C4-cycloalkylmethyl, furanylmethyl, 3-methyl-1,2,4-oxadiazol-5-ylmethyl, tetrahydrofuranylmethyl or 1,3-dioxolanylmethyl, 2-methoxyeth-1-yl, 3-methoxyprop-1-yl, methoxycarbonylmethyl, still more preferably L.sup.1 and R.sup.2 are taken together to form 2-methoxyeth-1-yl or tetrahydrofuranylmethyl, and still more preferably L.sup.1 and R.sup.2 are taken together to form tetrahydrofuranylmethyl.

[0033] In one embodiment, preferred compounds of Formula III are those of Formula IIIa

##STR00021##

and pharmaceutically acceptable salts and solvates thereof, wherein
R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.7, R.sup.8, and L.sup.1 are as defined above with respect to Formula Ill.

[0034] Particularly preferred compounds of Formula IIIa are those of Formula IIIb

##STR00022##

and pharmaceutically acceptable salts and solvates thereof, wherein
R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.7, R.sup.8, and L.sup.1 are as defined above with respect to Formula IIIa; and
R.sup.6 is halo, alkyl, haloalkyl, aryl, cyano, alkoxy, haloalkoxy, alkoxycarbonyl, aminoalkoxy, alkylaminoalkoxy, dialkylaminoalkoxy, HO.sub.3S-alkoxy,

##STR00023##

wherein m is 1 to 500, preferably 1 to 50, [N(R.sup.8).sub.3-alkoxy].sup.+Q.sup., wherein R.sup.8 is linear C1-C4-alkyl and Q.sup. is a counter anion, or
a cyclic moiety selected from the group consisting of

##STR00024##

wherein R.sup.A is H, OH, C0-C4-alkyl-COOH or C1-C6-alkyl, R.sup.B is C1-C6-alkyl optionally substituted with COOH, R.sup.C is C1-C6-alkyl, and Q is a counter anion;
preferably R.sup.6 is halo, C1-C2-alkyl, C1-C2-haloalkyl, phenyl, cyano, C1-C2-alkoxy, C1-C2-haloalkoxy, C1-C2-alkoxycarbonyl, aminoalkoxy, C1-C2-alkylaminoalkoxy, di-C1-C2-alkylaminoalkoxy, HO.sub.3SC2-C8-alkoxy,

##STR00025##

wherein m is 1 to 500, preferably 1 to 50, or [N(R.sup.8).sub.3C2-C6-alkoxy].sup.+Q.sup., wherein R.sup.8 is C1-C2-alkyl and Q.sup. is a counter anion,
more preferably R.sup.6 is halo, C1-C2-alkyl, C1-C2-haloalkyl, phenyl, cyano, C1-C2-alkoxy, C1-C2-haloalkoxy, C1-C2-alkoxycarbonyl, aminoalkoxy, C1-C2-alkylaminoalkoxy, di-C1-C2-alkylaminoalkoxy, HO.sub.3SC2-C6-alkoxy,

##STR00026##

wherein m is 1 to 500, preferably 1 to 50, or [N(R.sup.8).sub.3C2-C6-alkoxy].sup.+Q.sup., wherein R.sup.8 is C1-C2-alkyl and Q.sup. is a counter anion,
still more preferably R.sup.6 is halo, methyl, trifluoromethyl, phenyl, cyano, methoxy, trifluoromethoxy, methoxycarbonyl, di-methylaminoalkoxy, HO.sub.3SCH.sub.2CH.sub.2O,

##STR00027##

wherein m is 1 to 500, preferably 1 to 50, or [N(R.sup.8).sub.3C2-C6-alkoxy].sup.+Q.sup., wherein R.sup.8 is methyl and Q.sup. is a counter anion,
even more preferably R.sup.6 is chloro, fluoro, methyl, trifluoromethyl, phenyl, cyano, methoxy, trifluoromethoxy, methoxycarbonyl, di-methylaminoalkoxy, HO.sub.3SCH.sub.2CH.sub.2O,

##STR00028##

wherein m is 1 to 500, preferably 1 to 50, or [N(R.sup.8).sub.3C2-C6-alkoxy].sup.+Q.sup., wherein R.sup.8 is methyl and Q.sup. is a counter anion.

[0035] Particularly interesting compounds of Formula IIIb and pharmaceutically acceptable salts and solvates thereof are those, wherein R.sup.6 is HO.sub.3S-alkoxy, preferably HO.sub.3SC2-C8-alkoxy, more preferably HO.sub.3SC2-C6-alkoxy, still more preferably HO.sub.3SCH.sub.2CH.sub.2O, in particular in form of one of its salts, such as ammonium salts, or

##STR00029##

wherein m is 1 to 500 preferably 1 to 50, or [N(R.sup.8).sub.3-alkoxy].sup.+Q.sup., wherein R.sup.8 is linear C1-C4-alkyl and Q.sup. is a counter anion, preferably [N(R.sup.8).sub.3C2-C6-alkoxy].sup.+Q.sup., wherein R.sup.8 is C1-C2-alkyl and Q.sup. is a counter anion, more preferably [N(R.sup.8).sub.3C2-C6-alkoxy].sup.+Q.sup., wherein R.sup.8 is methyl and Q.sup. is a counter anion.

[0036] In one embodiment, the compounds of Formula IIIb are selected from the group consisting of Formulae IIIb-1, IIIb-2, and IIIb-3:

##STR00030##

and pharmaceutically acceptable salts and solvates thereof,
wherein R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.7, R.sup.8, L.sup.1, and R.sup.6 are as defined above with respect to Formula IIIb.

[0037] Particularly preferred compounds of Formulae III, IIIa, IIIb, IIIb-1, IIIb-2 and IIIb-3 and pharmaceutically acceptable salts and solvates thereof are those wherein R.sup.5 is methyl.

[0038] In another embodiment, preferred compounds of Formula I are those of Formula IV

##STR00031##

and pharmaceutically acceptable salts and solvates thereof, wherein
R.sup.2, R.sup.3, R.sup.4, R.sup.5, L.sup.1 and L.sup.2 are as defined above with respect to Formula I; and
R.sup.9 and R.sup.10 are independently selected from the group consisting of H, halo, haloalkyl, and cyano, with the proviso that at least one of R.sup.9 and R.sup.10 is not H, preferably R.sup.9 and R.sup.10 are independently selected from the group consisting of H, chloro, trifluoromethyl, and cyano, with the proviso that at least one of R.sup.9 and R.sup.10 is not H, more preferably R.sup.9 and R.sup.10 are independently selected from the group consisting of H, chloro, and trifluoromethyl, with the proviso that at least one of R.sup.9 and R.sup.10 is not H.

[0039] Preferred compounds of Formula IV and pharmaceutically acceptable salts and solvates thereof are those wherein L.sup.1 and R.sup.2 are taken together to form a moiety selected from the group consisting of cycloalkylmethyl, heterocyclylmethyl, heteroarylmethyl, 2-alkoxyeth-1-yl, 3-alkoxyprop-1-yl, alkoxycarbonylmethyl, said heteroarylmethyl moiety being optionally substituted by one or more C1-C2 alkyl groups on its heteroaryl part, preferably L.sup.1 and R.sup.2 are taken together to form a moiety selected from the group consisting of C3-C5-cycloalkylmethyl, C5-C6-heterocyclylmethyl, C5-C6-heteroarylmethyl, 2-C1-C2-alkoxyeth-1-yl, 3-C1-C2-alkoxyprop-1-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.sup.1 and R.sup.2 are taken together to form a moiety selected from the group consisting of C3-C4-cycloalkylmethyl, C5-heterocyclylmethyl, C5-heteroarylmethyl, 2-methoxyeth-1-yl, 3-methoxyprop-1-yl, methoxycarbonylmethyl, said C5-heteroarylmethyl moiety being optionally substituted by one methyl group on its heteroaryl part, even more preferably L.sup.1 and R.sup.2 are taken together to form a moiety selected from the group consisting of C3-C4-cycloalkylmethyl, furanylmethyl, 3-methyl-1,2,4-oxadiazol-5-ylmethyl, tetrahydrofuranylmethyl or 1,3-dioxolanylmethyl, 2-methoxyeth-1-yl, 3-methoxyprop-1-yl, methoxycarbonylmethyl, still more preferably L.sup.1 and R.sup.2 are taken together to form 2-methoxyeth-1-yl or tetrahydrofuranylmethyl, and still more preferably L.sup.1 and R.sup.2 are taken together to form tetrahydrofuranylmethyl.

[0040] In one embodiment, preferred compounds of Formula IV are those of Formula IVa

##STR00032##

and pharmaceutically acceptable salts and solvates thereof, wherein
R.sup.2, R.sup.3, R.sup.5, R.sup.9, R.sup.10, and L.sup.1 are as defined above with respect to Formula IV.

[0041] Particularly preferred compounds of Formula IVa and pharmaceutically acceptable salts and solvates thereof are those of Formula IVb

##STR00033##

and pharmaceutically acceptable salts, and solvates thereof, wherein
R.sup.2, R.sup.5, R.sup.9, R.sup.10, and L.sup.1 are as defined above with respect to Formula IVa; and
R.sup.6 is halo, alkyl, haloalkyl, aryl, cyano, alkoxy, haloalkoxy, alkoxycarbonyl, aminoalkoxy, alkylaminoalkoxy, dialkylaminoalkoxy, HO.sub.3S-alkoxy, or

##STR00034##

wherein m is 1 to 500, preferably 1 to 50, [N(R.sup.8).sub.3-alkoxy].sup.+Q.sup., wherein R.sup.8 is linear C1-C4-alkyl and Q is a counter anion, or
a cyclic moiety selected from the group consisting of

##STR00035##

wherein R.sup.A is H, OH, C0-C4-alkyl-COOH or C1-C6-alkyl, R.sup.B is C1-C6-alkyl optionally substituted with COOH, R.sup.C is C1-C6-alkyl, and Q is a counter anion;
preferably R.sup.6 is halo, C1-C2-alkyl, C1-C2-haloalkyl, phenyl, cyano, C1-C2-alkoxy, C1-C2-haloalkoxy, C1-C2-alkoxycarbonyl, aminoalkoxy, C1-C2-alkylaminoalkoxy, di-C1-C2-alkylaminoalkoxy, HO.sub.3SC2-C8-alkoxy,

##STR00036##

wherein m is 1 to 500, preferably 1 to 50, or [N(R.sup.8).sub.3C2-C6-alkoxy].sup.+Q.sup., wherein R.sup.8 is C1-C2-alkyl and Q.sup. is a counter anion,
more preferably R.sup.6 is halo, C1-C2-alkyl, C1-C2-haloalkyl, phenyl, cyano, C1-C2-alkoxy, C1-C2-haloalkoxy, C1-C2-alkoxycarbonyl, aminoalkoxy, C1-C2-alkylaminoalkoxy, di-C1-C2-alkylaminoalkoxy, HO.sub.3SC2-C6-alkoxy,

##STR00037##

wherein m is 1 to 500, preferably 1 to 50, or [N(R.sup.8).sub.3C2-C6-alkoxy].sup.+Q.sup., wherein R.sup.8 is C1-C2-alkyl and Q.sup. is a counter anion,
still more preferably R.sup.6 is halo, methyl, trifluoromethyl, phenyl, cyano, methoxy, trifluoromethoxy, methoxycarbonyl, di-methylaminoalkoxy, HO.sub.3SCH.sub.2CH.sub.2O, or

##STR00038##

wherein m is 1 to 500, preferably 1 to 50, or [N(R.sup.8).sub.3C2-C6-alkoxy].sup.+Q.sup., wherein R.sup.8 is methyl and Q.sup. is a counter anion,
even more preferably R.sup.6 is chloro, fluoro, methyl, trifluoromethyl, phenyl, cyano, methoxy, trifluoromethoxy, methoxycarbonyl, di-methylaminoalkoxy, HO.sub.3SCH.sub.2CH.sub.2O,

##STR00039##

wherein m is 1 to 500, preferably 1 to 50, or [N(R.sup.8).sub.3C2-C6-alkoxy].sup.+Q.sup., wherein R.sup.8 is methyl and Q.sup. is a counter anion.

[0042] Particularly interesting compounds of Formula IVb and pharmaceutically acceptable salts and solvates thereof are those, wherein R.sup.6 is HO.sub.3S-alkoxy, preferably HO.sub.3SC2-C8-alkoxy, more preferably HO.sub.3SC2-C6-alkoxy, still more preferably HO.sub.3SCH.sub.2CH.sub.2O, in particular in form of one of its salts, such as ammonium salts, or

##STR00040##

wherein m is 1 to 500 preferably 1 to 50, or [N(R.sup.8).sub.3-alkoxy].sup.+Q.sup., wherein R.sup.8 is linear C1-C4-alkyl and Q.sup. is a counter anion, preferably [N(R.sup.8).sub.3C2-C6-alkoxy].sup.+Q.sup., wherein R.sup.8 is C1-C2-alkyl and Q.sup. is a counter anion, more preferably [N(R.sup.8).sub.3C2-C6-alkoxy].sup.+Q.sup., wherein R.sup.8 is methyl and Q.sup. is a counter anion.

[0043] In one embodiment, the compounds of Formula IVb are selected from the group consisting of Formulae IVb-1, IVb-2, and IVb-3:

##STR00041##

and pharmaceutically acceptable salts and solvates thereof,
wherein R.sup.2, R.sup.5, R.sup.9, R.sup.10, L.sup.1, and R.sup.6 are as defined above with respect to Formula IVb.

[0044] Particularly preferred compounds of Formulae IV, IVa, IVb, IVb-1, IVb-2, and IVb-3, and pharmaceutically acceptable salts and solvates thereof are those wherein R.sup.5 is methyl.

[0045] In another embodiment, preferred compounds of Formula I are those of Formula V

##STR00042##

and pharmaceutically acceptable salts, and solvates thereof, wherein
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R, L.sup.1, and L.sup.2 are as defined above with respect to Formula I.

[0046] Preferred compounds of Formula V and pharmaceutically acceptable salts and solvates thereof are those wherein R is H, methyl or R taken together with L.sup.2 and R.sup.3 form a 5- or 6-membered heterocyclyl moiety which is optionally fused to an aryl moiety, preferably R is H, methyl or R taken together with L.sup.2 and R.sup.3 form a 6-membered heterocyclyl moiety which is optionally fused to a phenyl moiety, more preferably R is H, methyl or R taken together with L.sup.2 and R.sup.3 form a piperazinyl moiety which is optionally fused to a phenyl moiety, even more preferably R is H, methyl or R taken together with L.sup.2 and R.sup.3 form a piperazinyl moiety which is fused to a phenyl moiety; and/or L.sup.1 and R.sup.2 are taken together to form a moiety selected from the group consisting of cycloalkylmethyl, heterocyclylmethyl, heteroarylmethyl, 2-alkoxyeth-1-yl, 3-alkoxyprop-1-yl, alkoxycarbonylmethyl, said heteroarylmethyl moiety being optionally substituted by one or more C1-C2 alkyl groups on its heteroaryl part, preferably L.sup.1 and R.sup.2 are taken together to form a moiety selected from the group consisting of C3-C5-cycloalkylmethyl, C5-C6-heterocyclylmethyl, C5-C6-heteroarylmethyl, 2-C1-C2-alkoxyeth-1-yl, 3-C1-C2-alkoxyprop-1-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.sup.1 and R.sup.2 are taken together to form a moiety selected from the group consisting of C3-C4-cycloalkylmethyl, C5-heterocyclylmethyl, C5-heteroarylmethyl, 2-methoxyeth-1-yl, 3-methoxyprop-1-yl, methoxycarbonylmethyl, said C5-heteroarylmethyl moiety being optionally substituted by one methyl group on its heteroaryl part, even more preferably L.sup.1 and R.sup.2 are taken together to form a moiety selected from the group consisting of C3-C4-cycloalkylmethyl, furanylmethyl, 3-methyl-1,2,4-oxadiazol-5-ylmethyl, tetrahydrofuranylmethyl or 1,3-dioxolanylmethyl, 2-methoxyeth-1-yl, 3-methoxyprop-1-yl, methoxycarbonylmethyl, still more preferably L.sup.1 and R.sup.2 are taken together to form 2-methoxyeth-1-yl or tetrahydrofuranylmethyl, and still more preferably L.sup.1 and R.sup.2 are taken together to form tetrahydrofuranylmethyl.

[0047] Preferred compounds of Formula V are those of Formula Va

##STR00043##

and pharmaceutically acceptable salts and solvates thereof, wherein
R.sup.1, R.sup.2, R.sup.3, R.sup.5, R and L.sup.1 are as defined above with respect to Formula V.

[0048] In one embodiment, preferred compounds of Formula Va are those of Formula Vb

##STR00044##

and pharmaceutically acceptable salts and solvates thereof, wherein
R.sup.1, R.sup.2, R.sup.5, R, and L.sup.1 are as defined above with respect to Formula Va; and
R.sup.6 is halo, alkyl, haloalkyl, aryl, cyano, alkoxy, haloalkoxy, alkoxycarbonyl, aminoalkoxy, alkylaminoalkoxy, dialkylaminoalkoxy, HO.sub.3S-alkoxy,

##STR00045##

wherein m is 1 to 500, preferably 1 to 50, [N(R.sup.8).sub.3-alkoxy].sup.+Q.sup., wherein R.sup.8 is linear C1-C4-alkyl and Q is a counter anion, or
a cyclic moiety selected from the group consisting of

##STR00046##

wherein R.sup.A is H, OH, C0-C4-alkyl-COOH or C1-C6-alkyl, R.sup.B is C1-C6-alkyl optionally substituted with COOH, R.sup.C is C1-C6-alkyl, and Q.sup. is a counter anion,
preferably R.sup.6 is halo, C1-C2-alkyl, C1-C2-haloalkyl, phenyl, cyano, C1-C2-alkoxy, C1-C2-haloalkoxy, C1-C2-alkoxycarbonyl, aminoalkoxy, C1-C2-alkylaminoalkoxy, di-C1-C2-alkylaminoalkoxy, HO.sub.3SC2-C8-alkoxy,

##STR00047##

wherein m is 1 to 500, preferably 1 to 50, or [N(R.sup.8).sub.3C2-C6alkoxy].sup.+Q.sup., wherein R.sup.8 is C1-C2-alkyl and Q.sup. is a counter anion, more preferably R.sup.6 is halo, C1-C2-alkyl, C1-C2-haloalkyl, phenyl, cyano, C1-C2-alkoxy, C1-C2-haloalkoxy, C1-C2-alkoxycarbonyl, aminoalkoxy, C1-C2-alkylaminoalkoxy, di-C1-C2-alkylaminoalkoxy, HO.sub.3SC2-C6-alkoxy,

##STR00048##

wherein m is 1 to 500, preferably 1 to 50, or [N(R.sup.8).sub.3C2-C6alkoxy].sup.+Q.sup., wherein R.sup.8 is C1-C2-alkyl and Q.sup. is a counter anion,
still more preferably R.sup.6 is halo, methyl, trifluoromethyl, phenyl, cyano, methoxy, trifluoromethoxy, methoxycarbonyl, di-methylaminoalkoxy, HO.sub.3SCH.sub.2CH.sub.2O,

##STR00049##

wherein m is 1 to 500, preferably 1 to 50, or [N(R.sup.8).sub.3C2-C6-alkoxy].sup.+Q.sup., wherein R.sup.8 is methyl and Q.sup. is a counter anion,
even more preferably R.sup.6 is chloro, fluoro, methyl, trifluoromethyl, phenyl, cyano, methoxy, trifluoromethoxy, methoxycarbonyl, di-methylaminoalkoxy, HO.sub.3SCH.sub.2CH.sub.2O, or

##STR00050##

wherein m is 1 to 500, preferably 1 to 50, [N(R.sup.8).sub.3C2-C6-alkoxy].sup.+Q.sup., wherein R.sup.8 is methyl and Q.sup. is a counter anion.

[0049] Particularly interesting compounds of Formula Vb and pharmaceutically acceptable salts and solvates thereof are those, wherein R.sup.6 is HO.sub.3S-alkoxy, preferably HO.sub.3SC2-C8-alkoxy, more preferably HO.sub.3SC2-C6-alkoxy, still more preferably HO.sub.3SCH.sub.2CH.sub.2O, in particular in form of one of its salts, such as ammonium salts, or

##STR00051##

wherein m is 1 to 500 preferably 1 to 50, or [N(R.sup.8).sub.3-alkoxy].sup.+Q.sup., wherein R.sup.8 is linear C1-C4-alkyl and Q.sup. is a counter anion, preferably [N(R.sup.8).sub.3C2-C6-alkoxy].sup.+Q.sup., wherein R.sup.8 is C1-C2-alkyl and Q.sup. is a counter anion, more preferably [N(R.sup.8).sub.3C2-C6-alkoxy].sup.+Q.sup., wherein R.sup.8 is methyl and Q.sup. is a counter anion.

[0050] In one embodiment, the compounds of Formula Vb are selected from the group consisting of Formulae Vb-1, Vb-2, and Vb-3:

##STR00052##

and pharmaceutically acceptable salts and solvates thereof,
wherein R.sup.1, R.sup.2, R.sup.5, R, L.sup.1, and R.sup.6 are as defined above with respect to Formula Vb.

[0051] In one embodiment, preferred compounds of Formula Vb are those of Formula Vc

##STR00053##

and pharmaceutically acceptable salts, and solvates thereof,
wherein R.sup.2, R.sup.5, R.sup.6, R and L.sup.1 are as defined above with respect to Formula Vb; and
R.sup.7 and R.sup.8 are independently selected from the group consisting of H, halo, haloalkyl, and cyano, with the proviso that at least one of R.sup.7 and R.sup.8 is not H; preferably R.sup.7 and R.sup.8 are independently selected from the group consisting of H, chloro, trifluoromethyl, and cyano, with the proviso that at least one of R.sup.7 and R.sup.8 is not H, more preferably R.sup.7 is H and R.sup.8 is chloro.

[0052] In one embodiment, the compounds of Formula Vc are selected from the group consisting of Formulae Vc-1, Vc-2, and Vc-3:

##STR00054##

and pharmaceutically acceptable salts and solvates thereof,
wherein R.sup.2, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R, and L.sup.1 are as defined above with respect to Formula Vc.

[0053] Particularly preferred compounds of Formulae V, Va, Vb, Vb-1, Vb-2, Vb-3, Vc, Vc-1, Vc-2, Vc-3 and pharmaceutically acceptable salts and solvates thereof are those wherein R.sup.5 is methyl.

[0054] In a particularly preferred embodiment, the compounds of Formula I, any of its subformulae, and their pharmaceutically acceptable salts and solvates as described herein are those wherein R.sup.2 is tetrahydrofuranyl, preferably L.sup.1 is CH.sub.2 and R.sup.2 is tetrahydrofuranyl, more preferably they have Formula VI

##STR00055##

wherein R.sup.1, R.sup.3, R.sup.4, R.sup.5, X, and L.sup.2 are as defined above with respect to Formula I or any of its subformulae and corresponding embodiments.

[0055] Particularly preferred compounds of the invention are those listed in Table 1 hereafter:

TABLE-US-00001 TABLE 1 Compound Structure 1 [00056] 2 [00057] 3 [00058] 4 [00059] 5 [00060] 6 [00061] 7 [00062] 8 [00063] 9 [00064] 10 [00065] 11 [00066] 12 [00067] 13 [00068] 14 [00069] 15 [00070] 16 [00071] 17 [00072] 18 [00073] 19 [00074] 22 [00075] 23 [00076] 24 [00077] 25 [00078] 26 [00079] 27 [00080] 29 [00081] 30 [00082] 32 [00083] 33 [00084] 33a [00085] 34 [00086] 35 [00087] 36 [00088] 37 [00089] 38 [00090] 39 [00091] 40 [00092] 41 [00093] 42 [00094] 43 [00095] 44 [00096] 45 [00097] 46 [00098] 47 [00099] 48 [00100] 49 [00101] 50 [00102] 51 [00103] 52 [00104] 53 [00105] 54 [00106] 55 [00107] 56 [00108] 57 [00109] 58 [00110] 59 [00111] 60 [00112] 61 [00113] 62 [00114] 63 [00115] 64 [00116] 65 [00117] 66 [00118] 67 [00119] [00120] 68 [00121] [00122] 69 [00123] 70 [00124] 71 [00125] 72 [00126] 73 [00127] 75 [00128] 76 [00129] 77 [00130] 79 [00131] 80 [00132] 81 [00133] 82 [00134] 83 [00135] 84 [00136] 85 [00137] 86 [00138] 87 [00139] 88 [00140] 89 [00141] 90 [00142] 91 [00143] 92 [00144] 93 [00145] 94 [00146] 95 [00147] 96 [00148] 97 [00149] 98 [00150] 99 [00151] 100 [00152] 101 [00153] 103 [00154] 104 [00155] 105 [00156] 106 [00157] 107 [00158] 108 [00159] 109 [00160] 110 [00161] 111 [00162] 112 [00163] 113 [00164] 116 [00165] 117 [00166] 119 [00167] 121 [00168] 122 [00169] 123 [00170] 124 [00171] 125 [00172] 126 [00173] 127 [00174] 128 [00175] 129 [00176] 130 [00177] 131 [00178] 132 [00179] 133 [00180] 136 [00181] [00182] 137 [00183] [00184] 138 [00185] [00186] [00187] [00188] 141 [00189] m = 8-13 [00190] m = 8-13 144 [00191] [00192] 145 [00193] [00194] 146 [00195] [00196] 147 [00197] [00198] 148 [00199] [00200] 149 [00201] [00202] 150 [00203] [00204] 151 [00205] [00206] 152 [00207] [00208] 153 [00209] [00210] 154 [00211] m = 7-10 [00212] m = 7-10 155 [00213] m = 18-23 [00214] m = 18-23 156 [00215] m = 35-44 [00216] m = 35-44 157 [00217] m = 10-14 [00218] m = 10-14 158 [00219] [00220] 159 [00221] [00222] 160 [00223] m = 11-18 [00224] m = 11-18 161 [00225] m = 38-48 [00226] m = 38-48 162 [00227] 163 [00228] 164 [00229] 165 [00230] 166 [00231] 167 [00232] 168 [00233] 169 [00234]

[0056] 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.

[0057] 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.

[0058] 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

[0059] The compounds of the invention are therefore useful in the prevention and/or the treatment of TGR5 related diseases, such as metabolic and/or gastrointestinal diseases.

[0060] The invention thus also relates to the use of 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 and/or a gastrointestinal disease. Or in other terms, the invention also relates 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.

[0061] 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).

[0062] In a preferred embodiment, the metabolic disease is type II diabetes, a lipid disorder such as dyslipidemia, hypertension, obesity, or atherosclerosis and its sequelae.

[0063] In a particularly preferred embodiment the diseases are type II diabetes and a lipid disorder such as dyslipidemia, preferably type II diabetes.

[0064] 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.

[0065] 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).

[0066] 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 and/or a gastrointestinal disease. Or in other terms, the invention also provides for a method for delaying in patient the onset of a TGR5 related diseases, such as a metabolic and/or a gastrointestinal disease comprising the administration of a therapeutically effective amount of a compound or pharmaceutically acceptable salt or solvate of the invention, to a patient in need thereof. Preferably the patient is a warm-blooded animal, more preferably a human. The metabolic and/or gastrointestinal diseases are preferably those defined above.

[0067] The invention further provides the use of a compound of the invention or a pharmaceutically acceptable salt and/or solvates thereof for the manufacture of a medicament for use in treating and/or preventing TGR5 related diseases, in particular metabolic and/or gastrointestinal diseases. Preferably, the metabolic and/or gastrointestinal diseases are those defined above.

[0068] According to a further feature of the present invention, there is provided the use of a compound of the invention or a pharmaceutically acceptable salt and/or solvate for modulating TGR5 receptor activity, in a patient, in need of such treatment, comprising administering to said patient an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt and/or solvate thereof. In other terms, the invention also provides a 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.

[0069] 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.

[0070] 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.

[0071] 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.

[0072] 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.

[0073] 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.

[0074] 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.

[0075] 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 formswhich may be solid, semi-solid or liquid, depending on the manner of administrationas 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

[0076] The definitions and explanations below are for the terms as used throughout the entire application, including both the specification and the claims.

[0077] Unless otherwise stated any reference to compounds of the invention herein, means the compounds as such as well as there pharmaceutically acceptable salts and/or solvates.

[0078] When describing the compounds of the invention, the terms used are to be construed in accordance with the following definitions, unless indicated otherwise.

[0079] The term halo or halogen means fluoro, chloro, bromo, or iodo. Preferred halo groups are fluoro and chloro, fluoro being particularly preferred.

[0080] The term alkyl by itself or as part of another substituent refers to a hydrocarbyl radical of Formula C.sub.nH.sub.2n+1 wherein n is a number greater than or equal to 1. Suitable alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl and t-butyl.

[0081] 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.

[0082] 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, 1H-pyrrolizinyl, tetrahydro-1,1-dioxothiophenyl, N-formylpiperazinyl, and morpholin-4-yl.

[0083] 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.

[0084] 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[2,1-b][1,3]thiazolyl, thieno[3,2-b]furanyl, thieno[3,2-b]thiophenyl, thieno[2,3-d][1,3]thiazolyl, thieno[2,3-d]imidazolyl, tetrazolo[1,5-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[1,2-a]pyridinyl, 6-oxo-pyridazin-1(6H)-yl, 2-oxopyridin-1(2H)-yl, 6-oxo-pyridazin-1(6H)-yl, 2-oxopyridin-1(2H)-yl, 1,3-benzodioxolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl.

[0085] 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.

[0086] The bonds from an asymmetric carbon in compounds of the present invention may be depicted herein using a solid line (), a zigzag line (), 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.

[0087] 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.

[0088] 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 (NH.sub.3) 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.

[0089] Generally, pharmaceutically acceptable salts of compounds of Formula I may for example be prepared as follows:

[0090] (i) by reacting the compound of Formula I with the desired acid;

[0091] (ii) by reacting the compound of Formula I with the desired base;

[0092] (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

[0093] (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.

[0094] 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.

[0095] 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.

[0096] All references to compounds of Formula I include references to salts and solvates thereof.

[0097] 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.

[0098] 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.

[0099] 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.

[0100] 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.

[0101] 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.

[0102] 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.

[0103] 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.

[0104] 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.

[0105] By pharmaceutically acceptable is meant that the ingredients of a pharmaceutical composition are compatible with each other and not deleterious to the patient thereof.

[0106] The term agonist as used herein means a ligand that activates an intracellular response when it binds to a receptor.

[0107] 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.

[0108] 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.

[0109] 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

[0110] All reagents, solvents and starting materials were purchased from commercial suppliers and used without further purification. .sup.1H NMR spectra were recorded on a Brucker Avance 300 MHz spectrometer with methanol-d6, CDCl.sub.3 or DMSO-d6 as the solvent. .sup.13C NMR spectra are recorded at 100 MHz. All coupling constants are measured in hertz (Hz) and the chemical shifts () are quoted in parts per million (ppm). Liquid chromatography mass spectroscopy analyses (LC-MS) were performed using LCMS-MS triple-quadrupole system (Waters) with a C18 TSK-GEL Super ODS (2 m particle size column, 50*4.6 mm). LCMS gradient starting from 98% H.sub.2O/0.1% formic acid and reaching 2% H2O/98% MeOH within 5 min (method A) at a flow rate of 2 mL/min or starting from 100% H.sub.2O/0.1% formic acid and reaching 5% H.sub.2O/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). High resolution mass spectroscopy (HRMS) were carried out on an Waters LCT Premier XE (TOF), ESI ionization mode, with a Waters XBridge C18 (150*4.6 mm, 3.5 m particle size). 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.

[0111] 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.

[0112] 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,

[0113] EtOAc: Ethyl acetate,

EtOH: Ethanol,

MeOH: Methanol,

[0114] RT: Room temperature,

DIEA: N,N-diisopropylethylamine,

Y: Yield,

g: Grams,

mg: Milligrams,

L: Liters,

mL: Milliliters,

L: Microliters,

mol: Moles,

[0115] mmol: Millimoles,

h: Hours,

min: Minutes,

[0116] TLC: Thin layer chromatography,
MW: Molecular weight,

eq: Equivalent,

W: Microwave,

THF: Tetrahydrofuran,

[0117] TFA: Trifluoroacetic acid,

Ac: Acetyl,

[0118] tBu: tert-Butyl,

Bn: Benzyl,

[0119] Rt: Retention time,
Mn: Number average molecular mass.

[0120] As illustrated in the Examples hereafter, the compounds of the invention bearing a polyethylenoxy side chain (OCH.sub.2CH.sub.2).sub.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.

[0121] Therefore, the exemplified compounds of the invention bearing a polyethylenoxy side chain (OCH.sub.2CH.sub.2).sub.m may be obtained as mixtures of compounds having different degrees of polymerization (m) given as a range.

[0122] Therefore, within the meaning of the invention, a compound of the invention having a moiety of the following Formula

##STR00235##

wherein the degree of polymerization m is identified as range, i.e. as m is x to y or as m=xy, 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.

[0123] For instance, in the compound depicted by the following formula

##STR00236##

the indication m=8-13 means that all compounds with m superior or equal to 8 and inferior or equal to 13 as well as mixtures thereof are comprised within this formula.

General Procedure A

[0124] Appropriate aldehyde (1 equiv), meldrum acid (1 equiv), acetoacetate (1 equiv) and ammonium acetate (1.5 equiv) were dissolved in acetic acid (1N). The reaction mixture was stirred overnight under reflux. The solvent was removed. The crude was precipitated in EtOH and filtered to give the desired compound.

TABLE-US-00002 TABLE 2 [00237] Example R 1 o-Me 2 m-Me 3 p-Me 4 o-OMe 5 m-OMe 6 p-OMe 7 o-CF.sub.3 8 m-CF.sub.3 9 p-CF.sub.3 10 o-Cl 11 m-Cl 12 p-Cl 13 p-F 14 15 2-F, 4-Cl 16 p-Br

Example 1: 2-Methyl-6-oxo-4-o-tolyl-1,4,5,6-tetrahydro-pyridine-3-carboxylic Acid benzyl ester

[0125] 2-Methyl-6-oxo-4-o-tolyl-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid benzyl ester was prepared according to general protocol A, starting from 2-methylbenzaldehyde (0.27 mL), benzoyl acetylacetate (384 mg) and obtained as a white powder (137 mg, 20%) after purification by preparative LC-MS, .sup.1H NMR (CDCl.sub.3) 7.61 (s, 1H); 7.30-6.95 (m, 9H); 5.14 (d, J=12.6 Hz, 1H); 5.08 (d, J=12.6 Hz, 1H); 4.26 (d, J=7.4 Hz, 1H); 2.93 (dd, J=16.5 Hz and 8.6 Hz, 1H); 2.70 (dd, J=16.5 Hz and 1.2 Hz, 1H); 2.43 (s, 3H); 2.29 (s, 3H); MS [M+H].sup.+=336; HRMS: calcd for C.sub.21H.sub.22NO.sub.3, (MH.sup.+) 336.1600, found 336.1588.

Example 2: 2-Methyl-6-oxo-4-m-tolyl-1,4,5,6-tetrahydro-pyridine-3-carboxylic Acid benzyl ester

[0126] 2-Methyl-6-oxo-4-m-tolyl-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid benzyl ester was prepared according to general protocol A, starting from 3-methylbenzaldehyde (0.27 mL), benzoyl acetylacetate (384 mg) and obtained as a white powder (78 mg, 11%) after precipitation in ethanol. .sup.1H NMR (CDCl.sub.3) 7.41 (s, 1H); 7.30-6.95 (m, 9H); 5.14 (d, J=12.6 Hz, 1H); 5.08 (d, J=12.6 Hz, 1H), 4.26 (d, J=7.4 Hz, 1H); 2.93 (dd, J=16.5 Hz and 8.1 Hz, 1H); 2.70 (dd, J=16.5 Hz and 1.1 Hz, 1H); 2.43 (s, 3H); 2.29 (s, 3H); MS[M+H].sup.+=336; HRMS: calcd for C.sub.21H.sub.22NO.sub.3, (MH.sup.+) 336.1600, found 336.1596.

Example 3: 2-Methyl-6-oxo-4-p-tolyl-1,4,5,6-tetrahydro-pyridine-3-carboxylic Acid benzyl ester

[0127] 2-Methyl-6-oxo-4-p-tolyl-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid benzyl ester was prepared according to general protocol A, starting from 4-methylbenzaldehyde (0.27 mL), benzoyl acetylacetate (384 mg) and obtained as a white powder (137 mg, 20%) after precipitation in ethanol. .sup.1H NMR (CDCl.sub.3) 7.58 (s, 1H); 7.30-7.04 (m, 9H); 5.12 (s, 2H); 4.27 (d, J=7.5 Hz, 1H); 2.93 (dd, J=16.5 Hz and 8 Hz, 1H); 2.68 (dd, J=16.5 Hz and 1.2 Hz, 1H); 2.42 (s, 3H); 2.32 (s, 3H); MS[M+H].sup.+=336; HRMS: calcd for C.sub.21H.sub.22NO.sub.3, (MH.sup.+) 336.1600, found 336.1591.

Example 4: 4-(2-Methoxy-phenyl)-2-methyl-6-oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic Acid benzyl ester

[0128] 4-(2-Methoxy-phenyl)-2-methyl-6-oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid benzyl ester was prepared according to general protocol A, starting from 2-methoxybenzaldehyde (150 mg), benzoyl acetylacetate (210 mg) and obtained as a white powder (63 mg) after precipitation in ethanol (16%). .sup.1H NMR (CDCl.sub.3) 7.51 (s, 1H); 7.25-6.81 (m, 9H); 5.07 (d, J=12.7.0 Hz, 1H); 5.03 (d, J=12.7.0 Hz, 1H); 4.67 (d, J=8.2 Hz, 1H); 3.79 (s, 3H); 2.86 (dd, J=16.6 Hz and 7.9 Hz, 1H); 2.70 (d, J=16.7 Hz, 1H); 2.46 (s, 3H); MS [M+H].sup.+ 352; HRMS: calcd for C.sub.21H.sub.22NO.sub.4, (MH.sup.+) 352.1549, found 352.1548.

Example 5: 4-(3-Methoxy-phenyl)-2-methyl-6-oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic Acid benzyl ester

[0129] 4-(3-Methoxy-phenyl)-2-methyl-6-oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid benzyl ester was prepared according to general protocol A, starting from 3-methoxylbenzaldehyde (0.3 mL), benzoyl acetylacetate (384 mg) and obtained as a white powder (36 mg, 5% after precipitation in ethanol. .sup.1H NMR (CDCl.sub.3) 7.52 (s, 1H); 7.30-6.70 (m, 9H); 5.14 (d, J=12.7 Hz, 1H); 5.09 (d, J=12.7 Hz, 1H); 4.27 (d, J=7.2 Hz, 1H); 3.74 (s, 3H); 2.93 (dd, J=16.5 Hz and 8.1 Hz, 1H); 2.70 (dd, J=16.5 Hz and 1.1 Hz, 1H); 2.43 (s, 3H.sub.3); MS[M+H].sup.+=352; HRMS: calcd for C.sub.21H.sub.22NO.sub.4, (MH.sup.+) 352.1549, found 352.1546.

Example 6: 4-(4-Methoxy-phenyl)-2-methyl-6-oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic Acid benzyl ester

[0130] 4-(4-Methoxy-phenyl)-2-methyl-6-oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid benzyl ester was prepared according to general protocol A, starting from 4-methoxylbenzaldehyde (0.3 mL), benzoyl acetylacetate (384 mg) and obtained as a yellow powder (27 mg, 5%) after purification by preparative LC-MS.; .sup.1H NMR (CDCl.sub.3) 7.59 (s, 1H); 7.31-6.79 (m, 9H); 5.14 (d, J=12.5 Hz, 1H); 5.09 (d, J=12.5 Hz, 1H); 4.25 (d, J=7.3 Hz, 1H); 3.79 (s, 3H); 2.91 (dd, J=16.4 Hz and 8.0 Hz, 1H); 2.68 (d, J=15.4 Hz, 1H); 2.42 (s, 3H); MS [M+H].sup.+=352; HRMS: calcd for C.sub.21H.sub.22NO.sub.4, (MH.sup.+) 352.1549, found 352.1542.

Example 7: 2-Methyl-6-oxo-4-(2-trifluoromethyl-phenyl)-1,4,5,6-tetrahydro-pyridine-3-carboxylic Acid benzyl ester

[0131] 2-Methyl-6-oxo-4-(2-trifluoromethyl-phenyl)-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid benzyl ester was prepared according to general protocol A, starting from 2-trifluoromethylbenzaldehyde (0.27 mL), benzoyl acetylacetate (384 mg) and obtained as a white powder (138 mg, 18%) after precipitation in ethanol. .sup.1H NMR (CDCl.sub.3) 7.66 (s, 1H); 7.64-6.96 (m, 9H); 5.04 (d, J=12.3 Hz, 1H); 4.98 (d, J=12.3 Hz, 1H); 4.70 (d, J=8.7 Hz, 1H); 3.00 (dd, J=16.8 Hz and 9 Hz, 1H); 2.65 (d, J=17.3 Hz, 1H); 2.48 (s, 3H); MS[M+H].sup.+=390; HRMS: calcd for C.sub.21H.sub.19NO.sub.3F.sub.3, (MH.sup.+) 390.1317, found 390.1306.

Example 8: 2-Methyl-6-oxo-4-(3-trifluoromethyl-phenyl)-1,4,5,6-tetrahydro-pyridine-3-carboxylic Acid benzyl ester

[0132] 2-Methyl-6-oxo-4-(3-trifluoromethyl-phenyl)-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid benzyl ester was prepared according to general protocol A, starting from 3-trifluoromethylbenzaldehyde (0.45 mL), benzoyl acetylacetate (384 mg) and obtained as a white powder (141 mg, 18%) after precipitation in ethanol. .sup.1H NMR (CDCl.sub.3) 7.71 (s, 1H); 7.51-7.11 (m, 9H); 5.14 (d, J=12.6 Hz, 1H); 5.07 (d, J=12.6 Hz, 1H); 4.35 (d, J=7.9 Hz, 1H); 2.99 (dd, J=16.6 Hz and 8.3 Hz, 1H); 2.69 (d, J=16.5 Hz, 1H); 2.46 (s, 3H); MS [M+H].sup.+=390; HRMS: calcd for C.sub.21H.sub.19NO.sub.3F.sub.3, (MH.sup.+) 390.1317, found 390.1319.

Example 9: 2-Methyl-6-oxo-4-(4-trifluoromethyl-phenyl)-1,4,5,6-tetrahydro-pyridine-3-carboxylic Acid benzyl ester

[0133] 2-Methyl-6-oxo-4-(4-trifluoromethyl-phenyl)-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid benzyl ester was prepared according to general protocol A, starting from 4-trifluoromethylbenzaldehyde (0.44 mL), benzoyl acetylacetate (384 mg) and obtained as a white powder (96 mg, 13%) after precipitation in ethanol. .sup.1H NMR (CDCl.sub.3) 7.59 (s, 1H); 7.54-7.09 (m, 9H); 5.15 (d, J=12.5 Hz, 1H); 5.06 (d, J=12.5 Hz, 1H); 4.34 (d, J=7.7 Hz, 1H); 2.99 (dd, J=16.6 Hz and 8.2 Hz, 1H); 2.69 (d, J=16.7 Hz, 1H); 2.45 (s, 3H); MS [M+H].sup.+=390; HRMS: calcd for C.sub.21H.sub.19NO.sub.3F.sub.3, (MH.sup.+) 390.1317, found 390.1311.

Example 10: 4-(2-Chloro-phenyl)-2-methyl-6-oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic Acid benzyl ester

[0134] 4-(2-Chloro-phenyl)-2-methyl-6-oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid benzyl ester was prepared according to general protocol A, starting from 2-chlorobenzaldehyde (0.19 mL), benzoyl acetylacetate (205 mg). 26 mg of white powder were obtained after precipitation in ethanol. .sup.1H NMR (CDCl.sub.3) : 7.65 (s, 1H, NH); 7.41-7.05 (m, 9H, ArH); 5.08 (d, J=12.7 Hz, 1H, CH.sub.2); 5.04 (d, J=12.7 Hz, 1H, CH.sub.2); 4.79 (d, J=8.25 Hz, 1H, CH); 2.94 (dd, J=16.7 Hz and 8.5 Hz, 1H, CH.sub.2); 2.73 (d, J=16.7 Hz, 1H, CH.sub.2); 2.50 (s, 3H, CH.sub.3); MS [M+H].sup.+ 356; HRMS: calcd for C.sub.20H.sub.19NO.sub.3Cl, (MH.sup.+) 356.1053, found 356.1048.

Example 11: 4-(3-Chloro-phenyl)-2-methyl-6-oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic Acid benzyl ester

[0135] 4-(3-Chloro-phenyl)-2-methyl-6-oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid benzyl ester was prepared according to general protocol A, starting from 3-chlorobenzaldehyde (0.35 mL), benzoyl acetylacetate (384 mg) and obtained as a white powder (185 mg, 26%) after precipitation in ethanol .sup.1H NMR (CDCl.sub.3) 7.54 (s, 1H); 7.32-7.03 (m, 9H); 5.14 (d, J=12.4 Hz, 1H); 5.07 (d, J=12.4 Hz, 1H); 4.27 (d, J=7.7 Hz, 1H); 2.95 (dd, J=16.6 Hz and 8.2 Hz, 1H); 2.68 (dd, J=16.6 Hz and 0.9 Hz, 1H); 2.45 (s, 3H); MS [M+H].sup.+=356; HRMS: calcd for C.sub.20H.sub.19NO.sub.3Cl, (MH.sup.+) 390.1053, found 390.1058.

Example 12: Benzyl 4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate

[0136] Benzyl 4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate was prepared according to general protocol A, starting from p-chlorobenzaldehyde (15 mmol, 2.108 g), benzoyl acetylacetate (15 mmol, 2.58 mL) and obtained as a pale yellow powder (1.54 g, 29%) after precipitation in ethanol. .sup.1H NMR (300 MHz, CDCl.sub.3) 2.44 (s, 3H), 2.66 (dd, J=16.6 Hz and 1.5 Hz, 1H), 2.95 (dd, J=16.6 hz and 8.2 Hz, 1H), 4.27 (d, J=8.2 Hz, 1H), 5.08 (d, J=12.6 Hz, 1H), 5.15 (d, J=12.6 Hz, 1H), 7.10 (d, J=8.5 Hz, 2H), 7.13-7.18 (m, 2H), 7.25 (d, J=8.5 Hz, 2H), 7.29-7.33 (m, 3H), 8.40 (s, 1H). MS [M+H].sup.+ 356

Example 13: 4-(4-Fluoro-phenyl)-2-methyl-6-oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic Acid benzyl ester

[0137] 4-(4-Fluoro-phenyl)-2-methyl-6-oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid benzyl ester was prepared according to general protocol A, starting from 4-fluorobenzaldehyde (0.22 mL), benzoyl acetylacetate (384 mg) and obtained as a white powder (122 mg) after precipitation in ethanol (18%). .sup.1H NMR (CDCl.sub.3) 7.76 (s, 1H); 7.30-6.92 (m, 9H); 5.14 (d, J=12.5 Hz, 1H); 5.08 (d, J=12.5 Hz, 1H); 4.27 (d, J=7.74 Hz, 1H); 2.94 (dd, J=16.5 Hz and 8.1 Hz, 1H); 2.66 (dd, J=16.5 Hz and 0.9 Hz, 1H); 2.43 (3H, s, 3H), MS [M+H].sup.+ 340

Example 14: 2-Methyl-6-oxo-4-phenyl-1,4,5,6-tetrahydro-pyridine-3-carboxylic Acid benzyl ester

[0138] 2-Methyl-6-oxo-4-phenyl-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid benzyl ester was prepared according to general protocol A, starting from benzaldehyde (0.22 mL), benzoyl acetylacetate (384 mg) and obtained as a white powder (171 mg, 26%) after precipitation in ethanol. .sup.1H NMR (CDCl.sub.3) 7.79 (s, 1H); 7.29-7.12 (m, 10H); 5.13 (d, J=12.6 Hz, 1H); 5.08 (d, J=12.6 Hz, 1H); 4.30 (d, J=7.8 Hz, 1H); 2.95 (dd, J=16.5 Hz and 8.1 Hz, 1H); 2.70 (d, J=16.5 Hz, 1H); 2.43 (s, 3H); MS[M+H].sup.+=322; HRMS: calcd for C.sub.20H.sub.20NO.sub.3, (MH.sup.+) 322.1443, found 322.1436.

Example 15: benzyl 4-(4-chloro-2-fluoro-phenyl)-6-methyl-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate

[0139] benzyl 4-(4-chloro-2-fluoro-phenyl)-6-methyl-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate was prepared according to general protocol A, starting from 4-Chloro-2-fluorobenzaldehyde (800 mg), benzoyl acetylacetate (860 L) and obtained as a white powder (730 mg, 39%) after precipitation in ethanol. .sup.1H NMR (CDCl.sub.3) 8.17 (s, 1H); 7.29 (m, 3H); 7.12-6.91 (m, 5H), 5.11 (d, J=12.6 Hz, 1H), 5.05 (d, J=12.6 Hz, 1H), 4.57 (d, J=8.1 Hz, 1H); 2.96 (dd, J=16.5 Hz and 8.4 Hz, 1H); 2.64 (d, J=15.6 Hz, 1H); 2.46 (s, 3H); MS [M+H].sup.+=373

Example 16: benzyl 4-(4-bromophenyl)-6-methyl-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate

[0140] p-bromobenzaldehyde (15.0 mmol, 2.77 g), meldrum acid (15.0 mmol, 2.16 g), benzyl acetoacetate (15.0 mmol, 2.58 mL) and ammonium acetate (22.5 mmol, 1.73 g) were dissolved in acetic acid (15 mL). The reaction mixture was stirred at 110 C. for 18 h. The solvent was removed. The crude was precipitated in EtOH, cooled to 0 C. and filtered to give the desired benzyl 4-(4-bromophenyl)-6-methyl-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate as a white powder (2.35 g, 39%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.42 (s, 3H), 2.64 (dd, J=16.6, 1.5 Hz, 1H), 2.93 (dd, J=16.6, 8.2 Hz, 1H), 4.23 (d, J=8.2 Hz, 1H), 5.05 (d, J=12.5 Hz, 1H), 5.13 (d, J=12.5 Hz, 1H), 7.01 (d, J=8.4 Hz, 2H), 7.09-7.16 (m, 2H), 7.26-7.32 (m, 3H), 7.38 (dt, J=8.4, 2.0 Hz, 2H), 7.93 (brs, 1H). MS [M+H].sup.+ 400. HRMS: calcd for C.sub.20H.sub.19NO.sub.3Br, [M+H].sup.+ 400.0548, found 400.0567.

TABLE-US-00003 TABLE 3 [00238] Example RX RY RZ 17 CH.sub.3 CH.sub.3 [00239] 18 CH.sub.3 [00240] [00241] 19 CH.sub.3 [00242] [00243] 20 CH.sub.3 [00244] [00245] 21 CH.sub.3 [00246] [00247] 22 H [00248] [00249]

Example 17: 4-(4-Chloro-phenyl)-1,2-dimethyl-6-oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic Acid benzyl ester

[0141] Benzyl 4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate (300 mg, 0.84 mmol) was dissolved in DMF (4 mL). NaH (33 mg) and iodomethan (52 L) were added. After completion, water was added and reaction mixture was extracted with Et.sub.2O. The organic layer was dried over MgSO.sub.4 and evaporated under reduced pression. The product was purified by flash chromatography (Cyclohexane/EtOAc 4:1) to give 4-(4-Chloro-phenyl)-1,2-dimethyl-6-oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid benzyl ester as a white powder (31 mg, 10%). MS(ESI)=370[M+H].sup.+; .sup.1H NMR (CDCl.sub.3) 7.31-7.00 (m, 9H); 5.14 (d, J=12.5 Hz, 1H), 5.09 (d, J=12.5 Hz, 1H), 4.21 (d, J=5.79 Hz, 1H, CH); 3.21 (s, 3H); 2.90 (dd, J=16.0 Hz and 7.4 Hz, 1H); 2.75 (dd, J=16.0 Hz and 2.4 Hz, 1H); 2.58 (s, 3H); HRMS: calcd for C.sub.21H.sub.21NO.sub.3Cl, (MH.sup.+) 370.1210, found 370.1205.

Example 18: Benzyl 4-(4-chlorophenyl)-6-ethyl-1-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate

[0142] Step 1.

[0143] p-chlorobenzaldehyde (15 mmol, 2.108 g), meldrum acid (15 mmol, 2.16 g), ethyl propionylacetate (15 mmol, 2.13 mL) and ammonium acetate (22.5 mmol, 1.73 g) were dissolved in acetic acid (15 mL). The reaction mixture was stirred overnight under reflux. The solvent was removed. The crude was dissolved in EtOAc and washed by an aqueous solution of HCl 1N and a saturated solution of NaHCO.sub.3. The organic layer was dried on MgSO.sub.4, the solvent was removed under reduced pressure. The crude product was purified by flash chromatography using a mixture of Cyclohexane/EtOAc (8/2) as eluent to give the desired compound as yellow oil (470 mg, 11%).

[0144] .sup.1H NMR (300 MHz, CDCl.sub.3) 1.20 (t, J=7.2 Hz, 3H), 1.26 (t, J=7.2 Hz, 3H), 2.60-3.00 (m, 4H), 4.07-4.18 (m, 2H), 4.24 (dd, J=8.0, 2.0 Hz, 1H), 7.12 (d, J=8.6 Hz, 2H), 7.25 (d, J=8.6 Hz, 2H). MS [M+H].sup.+ 308.

[0145] Step 2.

[0146] The dihydropyridone intermediate obtained in step 1 (180 mg, 0.58 mmol) was dissolved in anhydrous DMF (2 mL). Cesium carbonate (377 mg, 1.16 mmol) and iodomethane (72 L, 1.16 mmol) were added. The reaction mixture was stirred at 60 C. for 3 h. The DMF was removed under reduced pressure. The residue was diluted in water and extracted by EtOAc. The organic layers were assembled, washed by brine and dried on MgSO.sub.4. The solvent was removed under reduced pressure. The crude product was purified by flash chromatography using a mixture of Cyclohexane/DCM (1/1) as eluent to give the desired compound as a colorless oil (143 mg, 76%).

[0147] .sup.1H NMR (300 MHz, CDCl.sub.3) 1.16-1.28 (m, 6H), 2.75 (dd, J=15.9, 2.8 Hz, 1H), 2.82-2.97 (m, 2H), 3.03-3.19 (m, 1H), 3.21 (s, 3H), 4.03-4.22 (m, 3H), 7.07 (d, J=8.6 Hz, 2H), 7.22 (d, J=8.6 Hz, 2H). MS [M+H].sup.+ 322. HRMS: calcd for C.sub.17H.sub.21NO.sub.3Cl, [M+H].sup.+ 322.1210, found 322.1217.

[0148] Step 3.

[0149] The dihydropyridone intermediate obtained in step 2 (83 mg, 0.26 mmol) was dissolved in MeOH (1 mL) and a solution of aqueous NaOH 1 N (1 mL, 4.0 equiv.) was added. The reaction mixture was stirred at 60 C. for 18 h. The reaction mixture was cooled to RT and extracted once with diethyl ether. The aqueous phase was then acidified until pH=1 with an aqueous solution of hydrochloric acid. The aqueous phase was extracted by EtOAc. The organic layer was then washed with brine and dried with MgSO.sub.4. The solvent was removed under reduced pressure to give the desired acid (56 mg, 0.19 mmol). The crude product was then used without further purification in the next step. The acid was dissolved in anhydrous DMF (2 mL) then Cs.sub.2CO.sub.3 (123 mg, 0.38 mmol) and benzyl bromide (45 L, 0.38 mmol) were added. The reaction mixture was stirred for 1 h at RT. Water was then added and the aqueous phase was extracted with diethyl ether. The organic layer was then washed with brine and dried with MgSO.sub.4. The solvent was removed under reduced pressure. The crude product was purified by flash chromatography using a mixture of cyclohexane/dichloromethane 3/1 to give the desired benzyl 4-(4-chlorophenyl)-6-ethyl-1-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate (28 mg, 28%). .sup.1H NMR (300 MHz, CDCl.sub.3) 1.24 (dd, J=7.7 Hz, 3H), 2.76 (t, J=16.2, 2.8 Hz, 1H), 2.83-2.89 (m, 2H), 3.07-3.20 (m, 2H), 3.24 (s, 3H), 4.18 (dd, J=7.3, 2.8 Hz, 1H), 5.13 (s, 2H), 7.02 (d, J=8.4 Hz, 2H), 7.12-7.19 (m, 2H), 7.23 (d, J=8.4 Hz, 2H), 7.28-7.34 (m, 3H). MS [M+H].sup.+ 384; HRMS: calcd for C.sub.22H.sub.23NO.sub.3Cl, [M+H].sup.+ 384.1366, found 384.1375.

Example 19: Benzyl 4-(4-chlorophenyl)-1-methyl-2-oxo-6-phenyl-3,4-dihydropyridine-5-carboxylate

[0150] Step 1.

[0151] p-chlorobenzaldehyde (15 mmol, 2.108 g), meldrum acid (15 mmol, 2.16 g), ethyl benzoylacetate (15 mmol, 2.6 mL) and ammonium acetate (22.5 mmol, 1.73 g) were dissolved in acetic acid (15 mL). The reaction mixture was stirred overnight under reflux. The solvent was removed. The crude was precipitated in EtOH and filtered to give the desired compound as a white powder (1.1 g, 21%). .sup.1H NMR (300 MHz, CDCl.sub.3) 0.85 (t, J=7.1 Hz, 3H), 2.78 (dd, J=16.5, 2.4 Hz, 1H), 3.08 (dd, J=16.5, 8.0 Hz, 1H), 3.89 (q, J=6.9 Hz, 2H), 4.33 (dd, J=8.0, 2.4 Hz, 1H), 7.17 (brs, 1H), 7.27-7.60 (m, 9H). MS [M+H].sup.+ 356

[0152] Step 2.

[0153] The dihydropyridone intermediate obtained in step 1 (213 mg, 0.6 mmol) was dissolved in anhydrous DMF (2 mL). Cesium carbonate (292 mg, 0.9 mmol) and iodomethane (56 L, 0.9 mmol) were added. The reaction mixture was stirred at 60 C. for 1 h. The DMF was removed under reduced pressure. The residue was diluted in water and extracted by EtOAc. The organic layers were assembled, washed by brine and dried on MgSO.sub.4. The solvent was removed under reduced pressure to give the desired compound as a white powder (224 mg, 100%). .sup.1H NMR (300 MHz, CDCl.sub.3) 0.80 (t, J=7.1 Hz, 3H), 2.78 (s, 3H), 2.91 (dd, J=16.2, 2.8 Hz, 1H), 3.10 (dd, J=16.2, 7.2 Hz, 1H), 3.83 (q, J=7.1 Hz, 2H), 4.23 (dd, J=7.2, 2.8 Hz, 1H), 7.20-7.35 (m, 6H), 7.41-7.49 (m, 3H). MS [M+H].sup.+=370. HRMS: calcd for C.sub.21H.sub.21NO.sub.3Cl, [M+H].sup.+ 370.1210, found 370.1219.

[0154] Step 3.

[0155] The dihydropyridone intermediate obtained in step 2 (184 mg, 0.50 mmol) was dissolved in MeOH (2 mL) and a solution of aqueous NaOH 1 N (2 mL, 4.0 equiv.) was added. The reaction mixture was stirred at 60 C. for 18 h. The reaction mixture was cooled to RT and extracted once with diethyl ether. The aqueous phase was then acidified until pH=1 with an aqueous solution of hydrochloric acid. The aqueous phase was extracted by EtOAc. The organic layer was then washed with brine and dried with MgSO.sub.4. The solvent was removed under reduced pressure to give the desired acid (116 mg, 0.34 mmol). The crude product was then used without further purification in the next step. The acid was dissolved in anhydrous DMF (3 mL) then Cs.sub.2CO.sub.3 (221 mg, 0.68 mmol) and benzyl bromide (81 L, 0.68 mmol) were added. The reaction mixture was stirred for 1 h at RT. Water was then added and the aqueous phase was extracted with diethyl ether. The organic layer was then washed with brine and dried with MgSO.sub.4. The solvent was removed under reduced pressure. The crude product was purified by flash chromatography using a mixture of cyclohexane/dichloromethane 7/3 to give the benzyl 4-(4-chlorophenyl)-1-methyl-2-oxo-6-phenyl-3,4-dihydropyridine-5-carboxylate as a white powder (21 mg, 10%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.77 (s, 3H), 2.91 (dd, J=16.3, 2.9 Hz), 3.10 (dd, J=16.3, 7.2 Hz, 1H), 4.23 (dd, J=7.2, 2.9 Hz, 1H), 4.81 (d, J=12.3 Hz, 1H), 4.87 (d, J=12.3 Hz, 1H), 6.91 (dd, J=7.3, 2.1 Hz, 2H), 7.19-7.33 (m, 9H), 7.36-7.44 (m, 3H). MS [M+H].sup.+ 433. HRMS: calcd for C.sub.26H.sub.23NO.sub.3Cl, [M+H].sup.+ 432.1366, found 432.1360.

Example 20: Ethyl 4-(4-chlorophenyl)-1-methyl-2-oxo-6-phenyl-3,4-dihydropyridine-5-carboxylate (Intermediate Product)

[0156] Step 1.

[0157] p-chlorobenzaldehyde (15 mmol, 2.108 g), meldrum acid (15 mmol, 2.16 g), ethyl benzoylacetate (15 mmol, 2.6 mL) and ammonium acetate (22.5 mmol, 1.73 g) were dissolved in acetic acid (15 mL). The reaction mixture was stirred overnight under reflux. The solvent was removed. The crude was precipitated in EtOH and filtered to give the desired compound as a white powder (1.1 g, 21%). .sup.1H NMR (300 MHz, CDCl.sub.3) 0.85 (t, J=7.1 Hz, 3H), 2.78 (dd, J=16.5, 2.4 Hz, 1H), 3.08 (dd, J=16.5, 8.0 Hz, 1H), 3.89 (q, J=6.9 Hz, 2H), 4.33 (dd, J=8.0, 2.4 Hz, 1H), 7.17 (brs, 1H), 7.27-7.60 (m, 9H). MS [M+H].sup.+ 356.

[0158] Step 2.

[0159] The intermediate obtained in step 1 (213 mg, 0.6 mmol) was dissolved in anhydrous DMF (2 mL). Cesium carbonate (292 mg, 0.9 mmol) and iodomethane (56 L, 0.9 mmol) were added. The reaction mixture was stirred at 60 C. for 1 h. The DMF was removed under reduced pressure. The residue was diluted in water and extracted by EtOAc. The organic layers were assembled, washed by brine and dried on MgSO.sub.4. The solvent was removed under reduced pressure to give the desired compound as a white powder (224 mg, 100%). .sup.1H NMR (300 MHz, CDCl.sub.3) 0.80 (t, J=7.1 Hz, 3H), 2.78 (s, 3H), 2.91 (dd, J=16.2, 2.8 Hz, 1H), 3.10 (dd, J=16.2, 7.2 Hz, 1H), 3.83 (q, J=7.1 Hz, 2H), 4.23 (dd, J=7.2, 2.8 Hz, 1H), 7.20-7.35 (m, 6H), 7.41-7.49 (m, 3H). MS [M+H].sup.+ 370. HRMS: calcd for C.sub.21H.sub.21NO.sub.3Cl, [M+H].sup.+ 370.1210, found 370.1219.

Example 21: Ethyl 4-(4-chlorophenyl)-6-ethyl-1-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate (Intermediate Product)

[0160] Step 1.

[0161] p-chlorobenzaldehyde (15 mmol, 2.108 g), meldrum acid (15 mmol, 2.16 g), ethyl propionylacetate (15 mmol, 2.13 mL) and ammonium acetate (22.5 mmol, 1.73 g) were dissolved in acetic acid (15 mL). The reaction mixture was stirred overnight under reflux. The solvent was removed. The crude was dissolved in EtOAc and washed by an aqueous solution of HCl 1N and a saturated solution of NaHCO.sub.3. The organic layer was dried on MgSO.sub.4, the solvent was removed under reduced pressure. The crude product was purified by flash chromatography using a mixture of Cyclohexane/EtOAc (8/2) as eluent to give the desired compound as yellow oil (470 mg, 11%). .sup.1H NMR (300 MHz, CDCl.sub.3) 1.20 (t, J=7.2 Hz, 3H), 1.26 (t, J=7.2 Hz, 3H), 2.60-3.00 (m, 4H), 4.07-4.18 (m, 2H), 4.24 (dd, J=8.0, 2.0 Hz, 1H), 7.12 (d, J=8.6 Hz, 2H), 7.25 (d, J=8.6 Hz, 2H). MS [M+H].sup.+ 308.

[0162] Step 2.

[0163] The intermediate obtained in step 1 (180 mg, 0.58 mmol) was dissolved in anhydrous DMF (2 mL). Cesium carbonate (377 mg, 1.16 mmol) and iodomethane (72 L, 1.16 mmol) were added. The reaction mixture was stirred at 60 C. for 3 h. The DMF was removed under reduced pressure. The residue was diluted in water and extracted by EtOAc. The organic layers were assembled, washed by brine and dried on MgSO.sub.4. The solvent was removed under reduced pressure. The crude product was purified by flash chromatography using a mixture of Cyclohexane/DCM (1/1) as eluent to give the desired compound as a colorless oil (143 mg, 76%). .sup.1H NMR (300 MHz, CDCl.sub.3) 1.16-1.28 (m, 6H), 2.75 (dd, J=15.9, 2.8 Hz, 1H), 2.82-2.97 (m, 2H), 3.03-3.19 (m, 1H), 3.21 (s, 3H), 4.03-4.22 (m, 3H), 7.07 (d, J=8.6 Hz, 2H), 7.22 (d, J=8.6 Hz, 2H). MS [M+H].sup.+ 322. HRMS: calcd for C.sub.17H.sub.21NO.sub.3Cl, [M+H].sup.+ 322.1210, found 322.1217.

Example 22: benzyl 4-(4-chlorophenyl)-6-(2-methoxyethyl)-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate

[0164] Step 1.

[0165] p-chlorobenzaldehyde (12 mmol, 1.68 g), meldrum acid (12 mmol, 1.73 g), Methyl 5-methoxy-3-oxovalerate (12 mmol, 1.5 mL) and ammonium acetate (18 mmol, 1.39 g) were dissolved in acetic acid (12 mL). The reaction mixture was stirred overnight under reflux. The solvent was removed. The crude was dissolved in EtOAc and washed by an aqueous solution of HCl 1N and a saturated solution of NaHCO.sub.3. The organic layer was dried on MgSO.sub.4, the solvent was removed under reduced pressure. The crude product was purified by flash chromatography using a mixture of Cyclohexane/EtOAc (8/2) as eluent to give the desired compound as yellow oil (344 mg, 10%).

[0166] Step 2.

[0167] The dihydropyridone intermediate obtained (300 mg, 0.93 mmol) was dissolved in MeOH (4 mL) and a solution of aqueous NaOH 1 N (3.3 mL) was added. The reaction mixture was stirred at 60 C. for 8 h. The reaction mixture was cooled to RT. The aqueous phase was acidified until pH=1 with an aqueous solution of hydrochloric acid. The aqueous phase was extracted by EtOAc. The organic layer was then washed with brine and dried with MgSO.sub.4. The solvent was removed under reduced pressure to give the desired acid as an oil (260 mg, 0.91 mmol, 97%).

[0168] Step 3.

[0169] A fraction of this crude (80 mg, 0.26 mmol) was then used without further purification in the next step. The acid was dissolved in anhydrous DMF (3 mL) then DIEA (54 L, 0.31 mmol) and benzyl bromide (31 L, 0.26 mmol) were added. The reaction mixture was stirred for 18 h at RT. The reaction was controlled by LCMS and showed an incomplete conversion of the starting material. DIEA (54 L, 0.31 mmol) and benzyl bromide (31 L, 0.26 mmol) were added. The reaction mixture was stirred for 18 h at r.t. and then 3 h at 40 C. The reaction mixture was cooled to RT. Water was then added and the aqueous phase was extracted with EtOAc. The organic layer was then washed with brine and dried with MgSO.sub.4. The solvent was removed under reduced pressure. The crude product was purified by flash chromatography using a mixture of cyclohexane/EtOAc 9/1 to give the desired compound (44 mg, 43%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.62 (d, J=16.3 Hz, 1H), 2.86-3.02 (m, 2H), 3.95 (s, 3H), 3.48 (ddd, J=15.5, 6.3, 3.5 Hz, 1H), 3.59-3.75 (m, 2H), 4.25 (d, J=8.5 Hz, 1H), 5.04 (d, J=12.0 Hz, 1H), 5.11 (d, J=12.0 Hz, 1H), 7.04-7.16 (m, 4H), 7.23 (dt, J=8.5, 2.2 Hz, 2H), 7.28-7.33 (m, 3H), 8.11 (s, 1H). MS [M+H].sup.+ 400. HRMS: calcd for C.sub.22H.sub.23NO.sub.4Cl, [M+H].sup.+ 400.1316, found 400.1306.

TABLE-US-00004 TABLE 4 [00250] Example R11 X 23 H O 24 CH.sub.3 O 25 H NH 26 CH.sub.3 NH 27 H NCH.sub.3 29 [00251] O 30 [00252] NH 32 [00253] O 33 [00254] NH 33a CH.sub.3 NCH.sub.3

Example 23: benzyl 4-(4-chlorophenyl)-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate

[0170] The methyl 4-(4-chlorophenyl)-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate (265 mg, 1.0 mmol) was dissolved in anhydrous methanol (2 mL) and water (2 mL). LiOH.H.sub.2O (72 mg, 3.0 mmol) was added. The reaction mixture was stirred for 4 h at 60 C. Water was added, the aqueous phase was washed with Et.sub.2O and then extracted by EtOAc. The organic phase was washed with brine and dried over MgSO.sub.4. The solvent was removed under reduced pressure to give the desired 4-(4-chlorophenyl)-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylic acid as a white powder (160 mg, 64%). The 4-(4-chlorophenyl)-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylic acid (89 mg, 0.35 mmol) was dissolved in anhydrous DMF (1 mL) then DIEA (122 L, 0.71 mmol) and benzyl bromide (63 L, 0.53 mmol) were added. The reaction mixture was stirred for 1 h at RT. The solvent was removed under reduced pressure to give the desired benzyl 4-(4-chlorophenyl)-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate as a white powder (90 mg, 74%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.72 (d, J=16.5 Hz, 1H), 3.01 (dd, J=16.5, 8.4 Hz, 1H), 4.20 (dd, J=8.4, 1.3 Hz, 1H), 5.09 (d, J=12.2 Hz, 1H), 5.20 (d, J=12.2 Hz, 1H), 7.15 (d, J=8.6 Hz, 2H), 7.22-7.27 (m, 4H), 7.31-7.37 (m, 3H), 7.53 (d, J=5.7 Hz, 1H). MS [M+H].sup. 340.

Example 24: Benzyl 4-(4-chlorophenyl)-1-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate

[0171] The benzyl 4-(4-chlorophenyl)-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate (70 mg, 0.20 mmol) was dissolved in anhydrous DMF (1 mL). Cesium carbonate (133 mg, 0.41 mmol) and iodomethane (26 L, 0.41 mmol) were added. The reaction mixture was stirred at 60 C. for 3 h. The DMF was removed under reduced pressure. The residue was diluted in water and extracted by EtOAc. The organic layers were assembled, washed by brine and dried on MgSO.sub.4. The solvent was removed under reduced pressure. The crude product was purified by flash chromatography using a mixture of Cyclohexane/EtOAc (95/5) as eluent to give the desired benzyl 4-(4-chlorophenyl)-1-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate as a yellow oil (48 mg, 68%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.72 (d, J=16.5 Hz, 1H), 3.01 (dd, J=16.5, 8.4 Hz, 1H), 4.20 (dd, J=8.4, 1.3 Hz, 1H), 5.09 (d, J=12.2 Hz, 1H), 5.20 (d, J=12.2 Hz, 1H), 7.15 (d, J=8.6 Hz, 2H), 7.22-7.27 (m, 4H), 7.31-7.37 (m, 3H), 7.53 (d, J=5.7 Hz, 1H). MS [M+H].sup. 340. HRMS: calcd for C.sub.22H.sub.22N.sub.2O.sub.3Cl, [M+CH.sub.3CN+H].sup.+ 397.1319, found 397.1350.

Example 25: N-benzyl-4-(4-chlorophenyl)-2-oxo-3,4-dihydro-1H-pyridine-5-carboxamide

[0172] The methyl 4-(4-chlorophenyl)-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate (265 mg, 1.0 mmol) was dissolved in anhydrous methanol (2 mL) and water (2 mL). LiOH.H.sub.2O (72 mg, 3.0 mmol) was added. The reaction mixture was stirred for 4 h at 60 C. Water was added, the aqueous phase was washed with Et.sub.2O and then extracted by EtOAc. The organic phase was washed with brine and dried over MgSO.sub.4. The solvent was removed under reduced pressure to give the desired 4-(4-chlorophenyl)-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylic acid as a white powder (160 mg, 64%).

[0173] The 4-(4-chlorophenyl)-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylic acid S was used without further purification in the next step. The acid (77 mg, 0.31 mmol) was dissolved in anh. EtOAc (3 mL). Benzylamine (51 L, 0.46 mmol), DIEA (158 L, 0.93 mmol) and a 50% solution of T3P in EtOAc (365 L, 0.62 mmol) were added. The same amount of all the reactants (except substrate) were added again 3 times more. The reaction mixture was stirred at RT. for 48 h overall. The solvent was removed under reduced pressure. The crude was purified by flash chromatography on silica using a mixture DCM/EA/acetone 2/1/1 to afford the desired N-benzyl-4-(4-chlorophenyl)-2-oxo-3,4-dihydro-1H-pyridine-5-carboxamide as a white powder (12 mg, 11%). .sup.1H NMR (300 MHz, DMSO d6) 2.40 (d, J=16.2 Hz, 1H), 2.45-2.55 (s, 3H), 2.96 (dd, J=16.2, 8.2 Hz, 1H), 4.14-4.38 (m, 3H), 7.10-7.32 (m, 8H), 7.36 (d, J=8.5 Hz, 1H), 8.31 (t, J=5.7 Hz, 1H), 9.76 (d, J=5.4 Hz, 1H). MS [M+H].sup.+ 351. HRMS: calcd for C.sub.19H.sub.18N.sub.2O.sub.2Cl, [M+H].sup.+ 341.1057, found 341.1056.

Example 26: N-benzyl-4-(4-chlorophenyl)-1-methyl-2-oxo-3,4-dihydropyridine-5-carboxamide

[0174] The methyl 4-(4-chlorophenyl)-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate (131 mg, 0.50 mmol) was dissolved in anhydrous DMF (2 mL). Cesium carbonate (325 mg, 1.0 mmol) and iodomethane (62 L, 1.0 mmol) were added. The reaction mixture was stirred at 30 C. for 1 h. The DMF was removed under reduced pressure. The residue was diluted in water and extracted by EtOAc. The organic layers were assembled, washed by brine and dried on MgSO.sub.4. The solvent was removed under reduced pressure. The crude 4-(4-chlorophenyl)-1-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate (143 mg) was used in the next step without further purification. The crude methyl 4-(4-chlorophenyl)-1-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate was dissolved in methanol (0.75 mL) and water (1.5 ml). Lithium hydroxide (36 mg, 1.5 mmol) was added. The reaction mixture was stirred at 50 C. for 3 h. The reaction mixture was washed with diethyl ether. The aqueous phase was then acidified to pH=1 and extracted by EtOAc. The organic phases were assembled, washed with brine and dried over MgSO.sub.4. The solvents were removed under reduced pressure to afford the crude 4-(4-chlorophenyl)-1-methyl-2-oxo-3,4-dihydropyridine-5-carboxylic acid as a whitish powder (100 mg). The crude 4-(4-chlorophenyl)-1-methyl-2-oxo-3,4-dihydropyridine-5-carboxylic acid (100 mg) was dissolved in anhydrous EtOAc (2 mL). Benzylamine (66 L, 0.60 mmol), DIEA (215 L, 1.25 mmol) and a 50% solution of T3P in EtOAc (454 L, 0.75 mmol) were added. The reaction mixture was stirred 4 h at RT. The solvent was removed under reduced pressure. The reaction mixture was washed with water and extracted with EtOAc. The organic phases were assembled, washed with brine and dried over MgSO.sub.4. The solvent was removed under reduced pressure. The crude was purified by flash chromatography on silica using a mixture cyclohexane/EA (7/3 to 3/7) to afford the desired N-benzyl-4-(4-chlorophenyl)-1-methyl-2-oxo-3,4-dihydropyridine-5-carboxamide as a white powder (68 mg, 38% over the 3 steps). .sup.1H NMR (300 MHz, DMSO d6) 2.50-2.56 (m, 1H), 3.01 (dd, J=16.0, 7.7 Hz, 1H), 3.06 (s, 3H), 4.15-4.41 (m, 3H), 7.10-7.30 (m, 7H), 7.35 (d, J=8.3 Hz, 2H), 7.47, s, 1H), 7.53 (t, J=6.0 Hz, 1H). MS [M+H].sup.+ 355. HRMS: calcd for C.sub.20H.sub.20N.sub.2O.sub.2Cl, [M+H].sup.+ 355.1213, found 355.1212.

##STR00255##

Example 27: N-benzyl-4-(4-chlorophenyl)-N-methyl-2-oxo-3,4-dihydro-1H-pyridine-5-carboxamide

[0175] Step 1.

[0176] Nicotinic acid (472 mg, 3.0 mmol) was dissolved in ethyl acetate (30 mL). DIEA (1.29 mL, 7.5 mmol), N-methylbenzylamine (460 L, 3.6 mmol) and a solution of propylphosphonic anhydride 50% in ethyl acetate (2.64 mL, 4.5 mmol) were added. The reaction mixture was stirred 18 h at RT. A 5% aqueous solution of NaHCO.sub.3 was added and the aqueous phase extracted with ethyl acetate. The organic phases were assembled, washed with brine and dried over MgSO.sub.4. The solvent was removed under reduced pressure. The crude was purified by flash chromatography using a mixture of Cy/EA (8/2) as eluent to give the desired N-benzyl-6-chloro-N-methylnicotinamide as a yellow oil (421 mg, 54%).

[0177] Step 2.

[0178] The N-benzyl-6-chloro-N-methylnicotinamide (390 mg, 1.5 mmol) was dissolved in anh. THF (1.5 mL). The solution was cooled to 0 C. A solution 1.0 M of 4-chlorophenylmagnesium chloride in Et.sub.2O (3.0 mL, 3.0 mmol) was added slowly over a period of 30 min. The reaction mixture was allowed to warm to r.t. and stirred for 18 h at RT. The reaction was stopped by addition of AcOH (1.0 mL). The reaction mixture was stirred for 10 min then a saturated solution of ammonium chloride was added and the reaction mixture extracted with ethyl acetate. The organic phases were assembled and dried over MgSO.sub.4, the solvents were removed under reduced pressure. The crude was purified by flash chromatography using a mixture of DCM/MeOH (9/1) as eluent to give the desired N-benzyl-4-(4-chlorophenyl)-N-methyl-2-oxo-3,4-dihydro-1H-pyridine-5-carboxamide as a white powder (151 mg, 28%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.71 (dd, J=16.7, 6.1 Hz, 1H), 2.83 (s, 3H), 2.98 (dd, J=16.7, 8.0 Hz, 1H), 4.22 (dd, J=8.0, 6.1 Hz, 1H), 4.51 (s, 2H), 6.50 (d, J=5.0 Hz, 2H), 6.93 (m, 2H), 7.16 (d, J=8.5 Hz, 2H), 7.23-7.30 (m, 4H), 7.82 (brs, 1H). MS [M+H].sup.+ 355. HRMS: calcd for C.sub.20H.sub.20N.sub.2O.sub.2Cl, [M+H].sup.+ 355.1213, found 355.1212.

Preparation of Benzyl 4-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxo-3,4-dihydropyridine-5-carboxylate (Example 29) and N-benzyl-4-(4-chlorophenyl)-1-(cyclopropyl methyl)-2-oxo-3,4-dihydropyridine-5-carboxamide (Example 30)

[0179] ##STR00256##

[0180] Step 1.

[0181] To a solution of diisopropylamine (1.52 mL, 10.8 mmol) in anh. THF (6 mL) at 0 C. was added slowly a 2.5 M solution of n-BuLi in hexane (4.32 mL, 10.8 mmol). The reaction mixture was stirred 20 min at r.t. and then cooled at 55 C. To this LDA solution, a solution of 3-(4-chlorophenyl)-5-methoxy-5-oxo-pentanoic acid (1.38 g, 5.4 mmol) in anh. THF (6 mL) was added over 20 min. After 40 min at 45 C., methyl formate (826 L, 13.5 mmol) was added. The mixture was slowly warmed to 20 C. and then stirred at 20 C. for 1 h. The mixture was slowly quenched with conc. HCl until pH=1 and the aqueous phase was extracted with EtOAc. The organic layer was separated, washed with brine and dried over MgSO.sub.4. The solvents were removed under reduced pressure to give 3-(4-chlorophenyl)-4-formyl-5-methoxy-5-oxo-pentanoic acid as a thick oil.

[0182] Step 2.

[0183] This thick oil was then dissolved into acetic acid (18 mL) and ammonium acetate was added (1.25 g, 16.2 mmol). The reaction mixture was stirred at 80 C. for 18 h. The solvent was removed under reduced pressure. Precipitation of the crude in EtOH afforded the desired methyl 4-(4-chlorophenyl)-2-oxo-3,4-dihydropyridine-5-carboxylate as a white powder (487 mg, 34%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.70 (d, J=16.8 Hz, 1H), 3.00 (dd, J=16.8, 8.5 Hz, 1H), 3.71 (s, 3H), 4.18 (d, J=8.5 Hz, 1H), 7.16 (d, J=8.4 Hz, 2H), 7.27 (d, J=8.4 Hz, 2H), 7.48 (d, J=5.4 Hz, 1H), 7.83 (brs, 1H). MS [MH].sup. 264.

[0184] Step 3.

[0185] methyl 4-(4-chlorophenyl)-)-2-oxo-3,4-dihydropyridine-5-carboxylate (240 mg, 0.9 mmol) was dissolved in anhydrous DMF (3 mL). Cesium carbonate (585 mg, 1.8 mmol) and (bromomethyl)cyclopropane (172 L, 1.8 mmol) were added. The reaction mixture was stirred at 60 C. for 4 h. The DMF was removed under reduced pressure. The residue was diluted in water. The aqueous phase was extracted by EtOAc and the combined organic layers were washed with brine and dried over MgSO.sub.4. Removal of the solvent was removed under reduced pressure gave the desired (methyl 4-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxo-3,4-dihydropyridine-5-carboxylate as a colorless oil (287 mg, 100%).

[0186] Step 4.

[0187] The (methyl 4-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxo-3,4-dihydropyridine-5-carboxylate (287 mg, 0.90 mmol) was dissolved an aqueous solution of NaOH 1 N (20 mL, 20.0 mmol). The reaction mixture was stirred at 60 C. for 18 h. The reaction mixture was cooled to r.t. and extracted once with diethyl ether. The aqueous phase was then acidified until pH=1 with an aqueous solution of hydrochloric acid. The aqueous phase was extracted by EtOAc. The organic layer was then washed with brine and dried over MgSO.sub.4. The solvent was removed under reduced pressure to give the desired 4-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxo-3,4-dihydropyridine-5-carboxylic acid (example 28) (210 mg, 78%).

Example 29: Benzyl 4-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxo-3,4-dihydropyridine-5-carboxylate

[0188] Step 5.

[0189] 4-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxo-3,4-dihydropyridine-5-carboxylic acid (example 28, 70 mg, 0.23 mmol) was dissolved in anhydrous DMF (1 mL) then cesium carbonate (160 mg, 0.45 mmol) and benzyl bromide (38 L, 0.36 mmol) were added. The reaction mixture was stirred at RT for 18 h. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc and water. The aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine and dried over MgSO.sub.4. The solvent was removed under reduced pressure to give the desired benzyl 4-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxo-3,4-dihydropyridine-5-carboxylate as a colorless oil (76 mg, 83%). .sup.1H NMR (300 MHz, CDCl.sub.3) 0.28-0.36 (m, 2H), 0.54-0.63 (m, 2H), 1.04-1.18 (m, 1H), 2.75 (dd, J=16.2, 1.6 Hz, 1H), 3.00 (dd, J=16.2, 8.2 Hz, 1H), 3.25 (dd, J=14.1, 7.1 Hz, 1H), 3.72 (dd, J=14.1, 7.2 Hz, 1H), 5.10 (d, J=12.6 Hz, 1H), 5.22 (d, J=12.6 Hz, 1H), 7.15 (d, J=8.5 Hz, 2H), 7.22-7.28 (m, 4H), 7.30-7.42 (m, 3H), 7.61 (s, 1H). MS [M+H].sup.+ 396. HRMS: calcd for C.sub.23H.sub.23NO.sub.3Cl, [M+H].sup.+ 396.1366, found 396.1371.

Example 30: N-benzyl-4-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxo-3,4-dihydropyridine-5-carboxamide

[0190] Step 5.

[0191] 4-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxo-3,4-dihydropyridine-5-carboxylic acid (example 28, 90 mg, 0.30 mmol) was dissolved in anhydrous EtOAc (2 mL) then benzylamine (52 L, 0.48 mmol), DIEA (172 L, 1.0 mmol) and a 50% solution of T3P in EtOAc (353 L, 0.6 mmol) were added. The reaction mixture was stirred at RT for 24 h. The same amount of reactants was added again twice every 24 h. After 72 h at RT overall, water was added and the aqueous phase was extracted with EtOAc. The organic phases were combined, washed with brine and dried over MgSO.sub.4. The solvent was removed under reduced pressure. Purification of the crude by flash chromatography using a mixture of Cyclohexane/EtOAc (8/2) as eluent gave the desired N-benzyl-4-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxo-3,4-dihydropyridine-5-carboxamide as a yellow oil (67 mg, 55%). .sup.1H NMR (300 MHz, CDCl.sub.3) 0.27-0.38 (m, 2H), 0.53-0.62 (m, 2H), 1.04-1.14 (m, 1H), 2.69 (dd, J=16.1, 2.5 Hz, 1H), 3.02 (dd, J=16.1, 8.1 Hz, 1H), 3.24 (dd, J=13.9, 7.0 Hz, 1H), 3.91 (dd, J=13.9, 7.2 Hz, 1H), 4.41 (t, J=6.3 Hz, 1H), 5.66 (t, J=5.5 Hz, 1H), 7.03-7.09 (m, 2H), 7.16 (d, J=8.5 Hz, 2H), 7.23-7.32 (m, 5H), 7.54 (s, 1H). MS [M+H].sup.+ 395. HRMS: calcd for C.sub.23H.sub.24N.sub.2O.sub.2Cl, [M+H].sup.+ 395.1526, found 395.1530.

Preparation of Benzyl 4-(4-chlorophenyl)-1-(2-methoxyethyl)-2-oxo-3,4-dihydropyridine-5-carboxylate (Example 32) and N-benzyl-4-(4-chlorophenyl)-1-(2-methoxyethyl)-2-oxo-3,4-dihydropyridine-5-carboxamide (Example 33)

[0192] ##STR00257##

[0193] Step 1.

[0194] Methyl 4-(4-chlorophenyl)-2-oxo-3,4-dihydropyridine-5-carboxylate (227 mg, 0.86 mmol) was dissolved in anhydrous DMF (3 mL). Cesium carbonate (556 mg, 1.71 mmol) and 2-bromoethyl methyl ether (161 L, 1.71 mmol) were added. The reaction mixture was stirred at 60 C. for 18 h. The DMF was removed under reduced pressure. The residue was diluted in water. The aqueous phase was extracted by EtOAc and the combined organic layers were washed with brine and dried over MgSO.sub.4. Removal of the solvents under reduced pressure gave the desired methyl 4-(4-chlorophenyl)-1-(2-methoxyethyl)-2-oxo-3,4-dihydropyridine-5-carboxylate as a colorless oil (254 mg, 91%). MS [M+H].sup.+ 324.

[0195] Step 2.

[0196] The methyl 4-(4-chlorophenyl)-1-(2-methoxyethyl)-2-oxo-3,4-dihydropyridine-5-carboxylate (254 mg, 0.78 mmol) was dissolved in methanol (5 mL) and an aqueous solution of NaOH 1 N (20 mL, 20.0 mmol). The reaction mixture was stirred at 60 C. for 4 h. The reaction mixture was cooled to RT and extracted once with diethyl ether. The aqueous phase was then acidified until pH=1 with an aqueous solution of hydrochloric acid. The aqueous phase was extracted by EtOAc. The organic layer was then washed with brine and dried over MgSO.sub.4. Removal of the solvent under reduced pressure gave the desired 4-(4-chlorophenyl)-1-(2-methoxyethyl)-2-oxo-3,4-dihydropyridine-5-carboxylic acid (example 31) (214 mg, 89%). MS [MH].sup. 308.

Example 32: Benzyl 4-(4-chlorophenyl)-1-(2-methoxyethyl)-2-oxo-3,4-dihydropyridine-5-carboxylate

[0197] 4-(4-chlorophenyl)-1-(2-methoxyethyl)-2-oxo-3,4-dihydropyridine-5-carboxylic acid (97 mg, 0.31 mmol) was dissolved in anhydrous DMF (1 mL) then cesium carbonate (305 mg, 0.86 mmol) and benzyl bromide (69 L, 0.65 mmol) were added. The reaction mixture was stirred at RT for 24 h. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc and water. The aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine and dried over MgSO.sub.4. The solvent was removed under reduced pressure. Purification of the crude by flash chromatography using a mixture of Cyclohexane/EtOAc (8/2) as eluent gave the desired benzyl 4-(4-chlorophenyl)-1-(2-methoxyethyl)-2-oxo-3,4-dihydropyridine-5-carboxylate as a yellow oil (59 mg, 47%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.72 (dd, J=16.4, 1.8 Hz, 1H), 3.00 (dd, J=16.4, 8.2 Hz, 1H), 3.37 (s, 3H), 3.46-3.57 (m, 3H), 3.96-4.07 (m, 1H), 4.13 (dd, J=8.2, 1.8 Hz, 1H), 5.09 (d, J=12.6 Hz, 1H), 5.22 (d, J=12.6 Hz, 1H), 7.16 (d, J=8.7 Hz, 2H), 7.22-7.28 (m, 4H), 7.30-7.38 (m, 3H), 7.59 (s, 1H). MS [M+H].sup.+ 400. HRMS: calcd for C.sub.22H.sub.23NO.sub.4Cl, [M+H].sup.+ 400.1316, found 400.1317.

Example 33 N-benzyl-4-(4-chlorophenyl)-1-(2-methoxyethyl)-2-oxo-3,4-dihydropyridine-5-carboxamide

[0198] 4-(4-chlorophenyl)-1-(2-methoxyethyl)-2-oxo-3,4-dihydropyridine-5-carboxylic acid (116 mg, 0.38 mmol) was dissolved in anhydrous EtOAc (2 mL) then benzylamine (168 L, 1.55 mmol), DIEA (555 L, 1.0 mmol) and a 50% solution of T3P in EtOAc (1.14 mL, 0.6 mmol) were added. The reaction mixture was stirred at RT for 18 h. Water was added and the aqueous phase was extracted with EtOAc. The organic phases were combined, washed with brine and dried over MgSO.sub.4. The solvent was removed under reduced pressure. Purification of the crude by flash chromatography using a mixture of Cyclohexane/EtOAc (1/1) as eluent gave the desired N-benzyl-4-(4-chlorophenyl)-1-(2-methoxyethyl)-2-oxo-3,4-dihydropyridine-5-carboxamide as a yellow powder (67 mg, 55%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.67 (dd, J=16.2, 2.2 Hz, 1H), 3.00 (dd, J=16.2, 8.3 Hz, 1H), 3.36 (s, 3H), 3.43-3.55 (m, 3H), 3.92-4.02 (m, 2H), 4.40 (t, J=5.5 Hz, 2H), 5.77 (t, J=5.5 Hz, 1H), 7.07 (dd, J=7.0, 1.7 Hz, 2H), 7.16 (d, J=8.4 Hz, 2H), 7.23-7.30 (m, 5H), 7.42 (s, 1H). MS [M+H].sup.+ 399. HRMS: calcd for C.sub.22H.sub.24N.sub.2O.sub.3Cl, [M+H].sup.+ 399.1475, found 399.1479.

Example 33a N-benzyl-4-(4-chlorophenyl)-N,1-dimethyl-2-oxo-3,4-dihydropyridine-5-carboxamide

[0199] N-benzyl-4-(4-chlorophenyl)-N-methyl-2-oxo-3,4-dihydro-1H-pyridine-5-carboxamide (example 27, 120 mg, 0.34 mmol) was dissolved in anhydrous DMF (1 mL). Cesium carbonate (220 mg, 0.68 mmol) and iodomethane (42 L, 0.68 mmol) were added. The reaction mixture was stirred at 60 C. for 1 h. The DMF was removed under reduced pressure. The residue was diluted in water and extracted by EtOAc. The organic layers were assembled, washed by brine and dried on MgSO.sub.4. The solvent was removed under reduced pressure. The crude product was purified by flash chromatography using a mixture of DCM/EtOAc (8/2) as eluent to give the desired N-benzyl-4-(4-chlorophenyl)-N,1-dimethyl-2-oxo-3,4-dihydropyridine-5-carboxamide as a colorless oil (72 mg, 58%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.74 (dd, J=16.4, 7.2 Hz, 1H), 2.84 (s, 3H), 2.95 (dd, J=16.4, 7.6 Hz, 1H), 3.09 (s, 3H), 4.16 (t, J=7.4 Hz, 1H), 4.46 (d, J=15.4 Hz, 1H), 4.52 (d, J=15.4 Hz, 1H), 6.47 (d, J=1.2 Hz, 1H), 6.93 (dd, J=6.5, 1.8 Hz, 2H), 7.13 (d, J=8.5 Hz, 2H), 7.23-7.31 (in, 6H). [M+H].sup.+=369 g/mol, HRMS: calcd for C.sub.21H.sub.22N.sub.2O.sub.2Cl, [M+H].sup.+ 369.1370, found 369.1378.

TABLE-US-00005 TABLE 5 [00258] Example R12 34 [00259] 35 [00260] 36 [00261] 37 [00262] 38 [00263] 39 [00264] 40 [00265] 41 [00266] 42 [00267] 43 [00268] 44 [00269] 45 [00270] 46 [00271] 47 [00272] 48 [00273] 49 [00274] 50 [00275] 51 [00276] 52 [00277] 53 [00278] 54 [00279] 55 [00280] 56 [00281] 57 [00282] 58 [00283] 59 [00284] 60 [00285] 61 [00286] 62 [00287] 63 [00288]

General Procedure B

[0200] The benzyl 4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate (1 equiv.) was dissolved in anhydrous DMF (0.1-0.3 M). Cesium carbonate (1.5 equiv.) and R12-X (1-3 equiv.) were added. The reaction mixture was stirred at 60 C. until completion. The DMF was removed under reduced pressure. The residue was diluted in water and extracted by EtOAc. The organic layers were assembled, washed by brine, dried on MgSO.sub.4 and evaporated under reduced pressure.

##STR00289##

Example 34: Benzyl 4-(4-chlorophenyl)-1-ethyl-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate

[0201] Benzyl 4-(4-chlorophenyl)-1-ethyl-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate was obtained according general procedure B starting from benzyl 4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate (0.42 mmol) and obtained as a colorless oil (100 mg, 62%) after flash chromatography purification (cyclohexane/EtOAc). .sup.1H NMR (300 MHz, CDCl.sub.3) 1.14 (t, J=7.2 Hz, 3H), 2.60 (s, 3H), 2.74 (dd, J=2.4 and 15.6 Hz, 1H), 2.91 (dd, J=7.5 and 15.6 Hz, 1H),3.67 (m, 1H), 3.97 (m, 1H), 4.21 (d, J=5.7 Hz, 1H), 5.09 (d, J=12.6 Hz, 1H), 5.15 (d, J=12.6 Hz, 1H), 7.03 (d, J=8.4 Hz, 2H), 7.12-7.16 (m, 2H), 7.22 (d, J=8.4 Hz, 2H), 7.28-7.32 (m, 3H). MS [M+H].sup.+ 384.

Example 35: Benzyl 4-(4-chlorophenyl)-6-methyl-2-oxo-1-propyl-3,4-dihydropyridine-5-carboxylate

[0202] Benzyl 4-(4-chlorophenyl)-6-methyl-2-oxo-1-propyl-3,4-dihydropyridine-5-carboxylate was obtained according general procedure B starting from benzyl 4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate (0.42 mmol) and obtained as a colorless oil (108 mg, 65%) after flash chromatography purification (cyclohexane/EtOAc). .sup.1H NMR (300 MHz, CDCl.sub.3) 0.88 (t, J=7.5 Hz, 3H), 1.51 (m, 2H), 2.59 (s, 3H), 2.76 (dd, J=2.4 and 15.9 Hz, 1H), 2.91 (dd, J=7.5 and 15.9 Hz, 1H), 3.48 (m, 1H), 3.91 (m, 1H), 4.22 (d, J=5.7 Hz, 2H), 5.09 (d, J=12.6 Hz, 1H), 5.15 (d, J=12.6 Hz, 1H), 7.04 (d, J=8.4 Hz, 2H), 7.13-7.16 (m, 2H), 7.22 (d, J=8.4 Hz, 2H), 7.29-7.31 (m, 3H). MS [M+H].sup.+ 398.

Example 36: Benzyl 1-butyl-4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate

[0203] Benzyl 1-butyl-4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate was obtained according general procedure B starting from benzyl 4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate (0.42 mmol) and obtained as a colorless oil (111 mg, 64%) after flash chromatography purification (cyclohexane/EtOAc). .sup.1H NMR (300 MHz, CDCl.sub.3) 0.90 (t, J=7.2 Hz, 3H), 1.27 (m, 2H), 1.44 (m, 2H), 2.58 (s, 3H), 2.75 (dd, J=2.4 and 15.6 Hz, 1H), 2.89 (dd, J=7.2 and 15.6 Hz, 1H), 3.51 (m, 1H), 3.95 (m, 1H), 4.21 (d, J=5.7 Hz, 2H), 5.08 (d, J=12.6 Hz, 1H), 5.14 (d, J=12.6 Hz, 1H), 7.03 (d, J=8.4 Hz, 2H), 7.12-7.15 (m, 2H), 7.21 (d, J=8.4 Hz, 2H), 7.28-7.30 (m, 3H). MS [M+H].sup.+ 412.

Example 37: Benzyl 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate

[0204] Benzyl 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate was obtained according general procedure B starting from benzyl 4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate (0.42 mmol) and obtained as a yellow oil (142 mg, 81%).

[0205] .sup.1H NMR (300 MHz, CDCl.sub.3) 2.63 (s, 3H), 2.72 (dd, J=15.8, 2.1 Hz, 1H), 2.93 (dd, J=15.8, 7.4 Hz, 1H), 3.33 (s, 3H), 3.36-3.52 (m, 4H), 3.76 (ddd, J=14.5, 8.6, 3.8 Hz, 1H), 4.13-4.26 (m, 2H), 5.08 (d, J=11.9 Hz, 1H), 5.14 (d, J=11.9 Hz, 1H), 7.07-7.15 (m, 4H), 7.22 (d, J=8.3 Hz, 2H), 7.25-7.33 (m, 3H). MS [M+H].sup.+ 414. HRMS: calcd for C.sub.23H.sub.25NO.sub.4Cl, [M+H].sup.+ 414.1472, found 414.1459.

Example 38: Benzyl 1-allyl-4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate

[0206] Benzyl 1-allyl-4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate was obtained according general procedure B starting from benzyl 4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate (0.50 mmol) and obtained as a colorless oil (152 mg, 77%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.58 (s, 3H), 2.79 (dd, J=2.4 and 15.6 Hz, 1H), 2.94 (dd, J=7.2 and 15.6 Hz, 1H), 4.33-4.23 (m, 2H), 4.52-4.45 (m, 1H), 5.19-5.05 (m, 1H), 5.08 (d, J=12.6 Hz, 1H), 5.14 (d, J=12.6 Hz, 1H), 5.82-5.69 (m, 1H), 7.04 (d, J=8.4 Hz, 2H), 7.12-7.15 (m, 2H), 7.22 (d, J=8.4 Hz, 2H), 7.28-7.30 (m, 3H). MS [M+H].sup.+ 396.

Example 39: Benzyl 4-(4-chlorophenyl)-6-methyl-1-(2-methylallyl)-2-oxo-3,4-dihydropyridine-5-carboxylate

[0207] Benzyl 4-(4-chlorophenyl)-6-methyl-1-(2-methylallyl)-2-oxo-3,4-dihydropyridine-5-carboxylate was obtained according general procedure B starting from benzyl 4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate (0.42 mmol) and obtained as a colorless oil (125 mg, 72%). .sup.1H NMR (300 MHz, CDCl.sub.3) 1.66 (s, 3H), 2.53 (s, 3H), 2.86 (dd, J=3.0 and 15.9 Hz, 1H), 2.96 (dd, J=7.2 and 15.9 Hz, 1H), 4.25 (m, 1H), 4.28 (m, 2H), 4.54 (m, 1H), 4.82 (m, 1H), 5.09 (d, J=12.6 Hz, 1H), 5.15 (d, J=12.6 Hz, 1H), 7.07 (d, J=8.4 Hz, 2H), 7.14-7.17 (m, 2H), 7.21 (d, J=8.4 Hz, 2H), 7.29-7.31 (m, 3H). MS [M+H].sup.+ 410.

Example 40: Benzyl 4-(4-chlorophenyl)-6-methyl-2-oxo-1-prop-2-ynyl-3,4-dihydropyridine-5-carboxylate

[0208] Benzyl 4-(4-chlorophenyl)-6-methyl-2-oxo-1-prop-2-ynyl-3,4-dihydropyridine-5-carboxylate was obtained according general procedure B starting from benzyl 4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate (0.42 mmol) and obtained as a colorless oil (85 mg, 51%)%) after flash chromatography purification (cyclohexane/EtOAc). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.29 (m, 1H), 2.71 (s, 3H), 2.76 (dd, J=2.1 and 15.9 Hz, 1H), 2.93 (dd, J=7.5 and 15.9 Hz, 1H), 4.21 (d, J=6.3 Hz, 1H), 4.33 (dd, J=2.1 and 18.0 Hz, 1H), 4.83 (dd, J=2.1 and 17.7 Hz, 1H), 5.09 (d, J=12.6 Hz, 1H), 5.14 (d, J=12.6 Hz, 1H), 7.07 (d, J=8.4 Hz, 2H), 7.12-7.15 (m, 2H), 7.21 (d, J=8.4 Hz, 2H), 7.29-7.31 (m, 3H). MS [M+H].sup.+ 394.

Example 41: Benzyl 1-benzyl-4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate

[0209] Benzyl 1-benzyl-4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate was obtained according general procedure B starting from benzyl 4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate (0.42 mmol) and obtained as a colorless oil (70 mg, 37%) after flash chromatography purification (cyclohexane/EtOAc). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.55 (s, 3H), 2.93 (dd, J=2.7 and 15.9 Hz, 1H), 3.03 (dd, J=6.9 and 15.9 Hz, 1H), 4.28 (d, J=4.8 Hz, 1H), 4.72 (d, J=15.9 Hz, 1H), 5.07 (d, J=12.6 Hz, 1H), 5.13 (d, J=12.6 Hz, 1H), 5.33 (d, J=15.9 Hz, 1H), 7.02 (d, J=8.4 Hz, 2H), 7.05-7.00 (m, 2H), 7.11-7.14 (m, 2H), 7.21 (d, J=8.4 Hz, 2H), 7.25-7.31 (m, 6H). MS [M+H].sup.+ 446.

Example 42: Benzyl 4-(4-chlorophenyl)-1-isopropyl-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate

[0210] Benzyl 4-(4-chlorophenyl)-1-isopropyl-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate was obtained according general procedure B starting from benzyl 4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate (0.42 mmol) and obtained as a colorless oil (23 mg, 14%) after flash chromatography purification (cyclohexane/Et.sub.2O). .sup.1H NMR (300 MHz, CDCl.sub.3) 1.34 (d, J=6.8 Hz, 1H), 1.46 (d, J=6.8 Hz, 1H), 2.53 (s, 3H), 2.69 (dd, J=16.1, 2.4 Hz, 1H), 2.87 (dd, J=16.1, 7.1 Hz, 1H), 4.12 (s.sup.P, J=6.8 Hz, 1H), 5.11 (d, J=12.5 Hz, 1H), 5.18 (d, J=12.5 Hz, 1H), 7.07 (d, J=8.4 Hz, 2H), 7.15-7.21 (m, 2H), 7.23 (d, J=8.4 Hz, 1H), 7.28-7.33 (m, 3H). .sup.13C NMR (75 MHz, CDCl.sub.3) 17.9, 20.2, 20.6, 35.9, 39.6, 49.3, 66.2, 111.8, 127.9, 128.1, 128.3, 128.5, 128.7, 132.6, 136.0, 139.2, 151.3, 166.9, 169.5. MS [M+H].sup.+ 398. HRMS: calcd for C.sub.23H.sub.25NO.sub.3Cl, [M+H].sup.+ 398.1523, found 398.1505.

Example 43: Benzyl 4-(4-chlorophenyl)-1-(cyclopropylmethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate

[0211] Benzyl 4-(4-chlorophenyl)-1-(cyclopropylmethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate was obtained according general procedure B starting from benzyl 4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate (0.42 mmol) and obtained as a colorless oil (140 mg, 81%) after flash chromatography purification (cyclohexane/EtOAc). .sup.1H NMR (300 MHz, CDCl.sub.3) 0.24-0.58 (m, 4H), 0.88-1.04 (m, 1H), 2.63 (s, 3H), 2.74 (dd, J=15.7, 2.1 Hz, 1H), 2.91 (dd, J=15.7, 7.3 Hz, 1H), 3.52 (dd, J=14.7, 6.1 Hz, 1H), 3.91 (dd, J=14.7, 8.2 Hz, 1H), 4.23 (dd, J=7.3, 2.1 Hz, 1H), 5.09 (d, J=12.8 Hz, 1H), 5.15 (d, J=12.8 Hz, 1H), 7.09-7.18 (m, 4H), 7.22 (dt, J=8.6, 2.2 Hz, 2H), 7.26-7.32 (m, 3H). MS [M+H].sup.+ 410. HRMS: calcd for C.sub.24H.sub.25NO.sub.3Cl, [M+H].sup.+ 410.1523, found 410.1510.

Example 44: Benzyl 4-(4-chlorophenyl)-1-(cyclobutylmethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate

[0212] Benzyl 4-(4-chlorophenyl)-1-(cyclobutylmethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate was obtained according general procedure B starting from benzyl 4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate (0.70 mmol) and obtained as a colorless oil (163 mg, 55%) after flash chromatography purification (cyclohexane/EtOAc). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.44 (m, 1H), 1.97-1.64 (m, 6H), 2.55 (s, 3H), 2.77 (dd, J=2.7 and 15.9 Hz, 1H), 2.89 (dd, J=6.9 and 15.9 Hz, 1H), 3.44 (dd, J=6.0 and 14.4 Hz, 1H), 4.25-4.18 (m, 1H+1H), 5.09 (d, J=12.6 Hz, 1H), 5.15 (d, J=12.6 Hz, 1H), 7.04 (d, J=8.4 Hz, 2H), 7.13-7.16 (m, 2H), 7.21 (d, J=8.4 Hz, 2H), 7.28-7.30 (m, 3H). MS [M+H].sup.+ 324

Example 45: Benzyl 1-[(1-tert-butoxycarbonylazetidin-3-yl)methyl]-4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate

[0213] Benzyl 1-[(1-tert-butoxycarbonylazetidin-3-yl)methyl]-4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate was obtained according general procedure B starting from benzyl 4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate (0.62 mmol) and obtained as a colorless oil (228 mg, 70%) after flash chromatography purification (cyclohexane/EtOAc). .sup.1H NMR (300 MHz, CDCl.sub.3) 1.44 (s, 9H), 2.55 (s, 3H), 2.61 (brs, 1H), 2.80-2.87 (m, 2H), 3.44-3.89 (m, 5H), 4.22 (dd, J=5.7, 3.3 Hz, 1H), 4.27-4.46 (brs, 1H), 5.10 (d, J=12.5 Hz, 1H), 5.17 (d, J=12.5 Hz, 1H), 6.99 (d, J=8.3 Hz, 2H), 7.12-7.19 (m, 2H), 7.22, (d, J=8.3 Hz, 2H), 7.26-7.33 (m, 3H). MS [M+H].sup.+ 469. HRMS: calcd for C.sub.29H.sub.34N.sub.2O.sub.5Cl, [M+H].sup.+ 525.2156, found 525.2155.

Example 46: Benzyl 1-(azetidin-3-ylmethyl)-4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate

[0214] Benzyl 1-[(1-tert-butoxycarbonylazetidin-3-yl)methyl]-4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate (180 mg, 0.34 mmol) was dissolved in DCM (255 L). TFA (255 L) was added and the reaction mixture was stirred at RT for 2 h. An aqueous saturated solution of ammonium chloride was added and the aqueous phase was extracted by DCM. The organic phase was dried under MgSO.sub.4. The solvent was removed under reduced pressure. The crude was purified by flash chromatography on silica using a mixture of DCM/MeOH (98/2 to 9/1) to give the desired benzyl 1-(azetidin-3-ylmethyl)-4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate as a white powder (105 mg, 72%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.55 (s, 3H), 2.74 (dd, J=15.7, 2.6 Hz, 1H), 2.84 (dd, J=15.7, 6.6 Hz, 1H), 2.98 (q.sup.t, J=7.6 Hz, 1H), 3.68-3.89 (m, 5H), 4.12-4.26 (m, 2H), 5.09 (d, J=17.4 Hz, 1H), 5.15 (d, J=17.4 Hz, 1H), 6.95 (d, J=8.4 Hz, 2H), 7.12-7.17 (m, 2H), 7.22 (d, J=8.4 Hz, 2H), 7.25-7.31 (m, 3H), 9.10-10.0 (brs, 1H). MS [M+H].sup.+ 425. HRMS: calcd for C.sub.22H.sub.26N.sub.2O.sub.3Cl, [M+H].sup.+ 425.1632, found 425.1638.

Example 47: Benzyl 4-(4-chlorophenyl)-6-methyl-1-[(1-methylazetidin-3-yl)methyl]-2-oxo-3,4-dihydropyridine-5-carboxylate

[0215] Benzyl 1-(azetidin-3-ylmethyl)-4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate (180 mg, 0.42 mmol), sodium methoxide (34 mg, 0.63 mmol) and paraformaldehyde (19 mg, 0.63 mmol) were dissolved in methanol (4 mL). The reaction mixture was stirred at RT for 2 h. Sodium borohydride (16 mg, 0.42 mmol) was then added. The reaction mixture was stirred at RT for 2 h. An aqueous solution of sodium hydroxide 1N was added. The aqueous phase was extracted by EtOAc. The organic phases were assembled, washed with brine and dried over MgSO.sub.4. The solvents were removed under reduced pressure. Purification of the crude by Flash chromatography on silica using a mixture of DCM/methanol (95/5) as eluent afforded the desired benzyl 4-(4-chlorophenyl)-6-methyl-1-[(1-methylazetidin-3-yl)methyl]-2-oxo-3,4-dihydropyridine-5-carboxylate (23 mg, 12%) as a colorless oil. .sup.1H NMR (300 MHz, CDCl.sub.3) 2.27 (s, 3H), 2.57 (s, 3H), 2.78 (dd, J=16.1, 2.8 Hz, 1H), 2.81-2.94 (m, 4H), 3.17 (t, J=7.1 Hz, 1H), 3.30 (t, J=7.1 Hz, 1H), 3.65 (dd, J=14.5, 6.4 Hz, 1H), 4.22 (dd, J=7.1, 2.0 Hz, 1H), 4.27 (dd, J=14.5, 6.4 Hz, 1H), 5.09 (d, J=13.5 Hz, 1H), 5.15 (d, J=13.5 Hz, 1H), 7.00 (d, J=8.5 Hz, 2H), 7.11-7.17 (m, 2H), 7.22 (d, J=8.5 Hz, 2H), 7.26-7.32 (m, 3H). MS [M+H].sup.+ 439; HRMS: calcd for C.sub.25H.sub.28N.sub.2O.sub.3Cl, [M+H].sup.+ 439.1788, found 439.1796.

Example 48: Benzyl 4-(4-chlorophenyl)-1-[(1,1-dimethylazetidin-1-ium-3-yl)methyl]-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate iodide

[0216] Benzyl 4-(4-chlorophenyl)-6-methyl-1-[(1-methylazetidin-3-yl)methyl]-2-oxo-3,4-dihydropyridine-5-carboxylate (14 mg, 0.032 mmol) was dissolved in anh. DMF (0.1 mL). Iodomethane (3 L, 0.048 mmol) was added. The reaction mixture was stirred at RT for 1 h. Removal of the solvent under reduced pressure gave the desired benzyl 4-(4-chlorophenyl)-1-[(1,1-dimethylazetidin-1-ium-3-yl)methyl]-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate iodide as a colorless oil (18 mg, 100%). .sup.1H NMR (300 MHz, DMSO d6) 2.50 (s, 3H), 2.40-2.60 (m, 1H), 2.93-3.19 (m, 1H), 3.09 (s, 3H), 3.14 (s, 3H), 3.30-3.50 (m, 1H), 3.70-3.89 (m, 2H), 3.94-4.12 (m, 2H), 4.15-4.29 (m, 3H), 5.04 (d, J=13.0 Hz, 1H), 5.12 (d, J=13.0 Hz, 1H), 7.06-7.18 (m, 4H), 7.22-7.30 (m, 3H), 7.36 (d, J=8.6 Hz, 2H). .sup.13C NMR (75 MHz, DMSO d6) 16.9, 27.7, 36.6, 43.3, 51.7, 53.3, 65.8, 68.7, 69.2, 110.4, 127.8, 128.3, 128.7, 129.1, 131.9, 136.7, 140.5, 150.5, 166.7, 170.0. MS [M+H].sup.+ 453 HRMS: calcd for C.sub.26H.sub.30N.sub.2O.sub.3Cl, [M+H].sup.+ 453.1945, found 453.1923.

Example 49: Benzyl 4-(4-chlorophenyl)-1-isobutyl-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate

[0217] Benzyl 4-(4-chlorophenyl)-1-isobutyl-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate was obtained according general procedure B starting from benzyl 4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate (0.56 mmol) and obtained as a colorless oil (171 mg, 74%) after flash chromatography purification (cyclohexane/EtOAc). .sup.1H NMR (300 MHz, CDCl.sub.3) 0.70 (d, J=6.6 Hz, 3H), 0.84 (d, J=6.6 Hz, 3H), 1.74 (m, 1H), 2.55 (s, 3H), 2.94-2.86 (m, 2H), 3.25 (dd, J=6.3 and 14.4 Hz, 1H), 3.91 (dd, J=8.1 and 14.1 Hz, 1H), 4.2 (m, 1H), 5.10 (d, J=12.6 Hz, 1H), 5.16 (d, J=12.6 Hz, 1H), 7.08 (d, J=8.4 Hz, 2H), 7.14-7.17 (m, 2H), 7.21 (d, J=8.4 Hz, 2H), 7.28-7.30 (m, 3H). MS [M+H].sup.+ 412.

Example 50: Benzyl 4-(4-chlorophenyl)-1-[2-(dimethylamino)ethyl]-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate

[0218] Benzyl 4-(4-chlorophenyl)-1-[2-(dimethylamino)ethyl]-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate was obtained according general procedure B starting from benzyl 4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate (0.42 mmol) and obtained as a colorless oil (177 mg, 98%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.26 (s, 6H), 2.26-2.43 (m, 2H), 2.60 (m, 3H), 2.73 (dd, J=15.7, 2.2 Hz, 2H), 2.90 (dd, J=15.7, 7.1 Hz, 2H), 3.58-3.67 (m, 1H), 4.02-4.12 (m, 1H), 4.22 (d, J=7.0 Hz, 1H), 5.06 (d, J=12.7 Hz, 1H), 5.13 (d, J=12.7 Hz, 1H), 7.07 (d, J=8.4 Hz, 2H), 7.09-7.14 (m, 2H), 7.21 (d, J=8.4 Hz, 2H), 7.25-7.31 (m, 3H). MS [M+H].sup.+ 427. HRMS: calcd for C.sub.24H.sub.28N.sub.2O.sub.3Cl, [M+H].sup.+ 427.1788, found 427.1775.

Example 51: 2-[5-benzyloxycarbonyl-4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydropyridin-1-yl]ethyl-trimethyl-ammonium iodide

[0219] The benzyl 4-(4-chlorophenyl)-1-[2-(dimethylamino)ethyl]-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate (65 mg, 0.15 mmol) was dissolved in anh. DMF (1 mL). Iodomethane (14 L, 0.23 mmol) was added. The reaction mixture was stirred at RT for 2 h. The solvent was removed under reduced pressure to afford the desired 2-[5-benzyloxycarbonyl-4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydropyridin-1-yl]ethyl-trimethyl-ammonium iodide as a yellow powder (79 mg, 93%). .sup.1H NMR (300 MHz, DMSO d6) 2.61 (s, 3H), 2.61-2.68 (dd, J=15.5, 2.3 Hz, 1H), 3.02-3.12 (1H, J=15.5, 7.0 Hz, 1H), 3.12 (s, 3H), 3.12-3.24 (m, 1H), 3.32 (s, 3H), 3.32-3.52 (m, 1H), 3.90-4.20 (m, 2H), 4.25 (d, J=6.0 Hz, 1H), 5.07 (d, J=12.9 Hz, 1H), 5.14 (d, J=12.9 HZ, 1H), 7.09-7.16 (m, 2H), 7.18 (d, J=8.3 Hz, 2H), 7.24-7.30 (m, 3H), 7.34 (d, J=8.3 Hz, 2H). MS [M]+441. HRMS: calcd for C.sub.25H.sub.30N.sub.2O.sub.3Cl, [M+H].sup.+ 441.1945, found 441.1943.

Example 52: Benzyl 1-[2-(tert-butoxycarbonylamino)ethyl]-4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate

[0220] Benzyl 1-[2-(tert-butoxycarbonylamino)ethyl]-4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate was obtained according general procedure B starting from benzyl 4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate (0.60 mmol) and obtained as a colorless oil (157 mg, 52%) after flash chromatography purification (cyclohexane/EtOAc). .sup.1H NMR (300 MHz, CDCl.sub.3) 1.44 (s, 9H), 2.59 (s, 3H), 2.80 (dd, J=16.0, 2.7 Hz, 1H), 2.91 (dd, J=16.0, 7.1 Hz, 1H), 3.15 (q, J=6.2 Hz, 1H), 3.69-3.81 (m, 1H), 3.89-4.01 (m, 1H), 4.24 (dd, J=7.1, 2.7 Hz, 1H), 4.50 (t, J=5.5 Hz, 1H), 5.10 (d, J=12.6 Hz, 1H), 5.16 (d, J=12.6 Hz, 1H), 7.05 (d, J=8.4 Hz, 2H), 7.13-7.20 (m, 2H), 7.24 (d, J=8.4 Hz, 2H), 7.26-7.33 (m, 3H). MS [M+H].sup.+ 499; HRMS: calcd for C.sub.27H.sub.32N.sub.2O.sub.5Cl, [M+H].sup.+ 499.2000, found 499.2008.

Example 53: Hydrochloride salt of benzyl 1-(2-aminoethyl)-4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate

[0221] Benzyl 1-[2-(tert-butoxycarbonylamino)ethyl]-4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate (38 mg, 0.076 mmol) was dissolved in a 4M solution of hydrochloric acid in dioxane (1 mL). The reaction mixture was stirred 1 h at RT. The solvents were removed under reduced pressure to give the desired hydrochloride salt of benzyl 1-(2-aminoethyl)-4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate as a colorless oil (32 mg, 97%). .sup.1H NMR (300 MHz, DMSO d6) 2.57 (s, 3H), 2.67-2.81 (m, 1H), 2.81-2.95 (m, 1H), 3.02 (dd, J=15.9, 7.5 Hz, 1H), 3.62-3.75 (m, 1H), 3.80-4.04 (m, 2H), 4.20 (d, J=6.0 Hz, 1H), 5.04 (d, J=13.5 Hz, 1H), 5.10 (d, J=13.5 Hz, 1H), 7.07-7.13 (m, 1H), 7.16 (d, J=7.9 Hz, 2H), 7.21-7.28 (m, 4H), 7.31 (d, J=7.9 Hz, 2H), 8.21 (brs, 3H). MS [M+H].sup.+ 399; HRMS: calcd for C.sub.22H.sub.24N.sub.2O.sub.3Cl, [M+H].sup.+ 399.1475, found 399.1486.

Example 54: Benzyl 4-(4-chlorophenyl)-1-[3-(dimethylamino)propyl]-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate

[0222] Benzyl 4-(4-chlorophenyl)-1-[3-(dimethylamino)propyl]-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate was obtained according general procedure B starting from benzyl 4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate (0.28 mmol) and obtained as a colorless oil (66 mg, 53%) after flash chromatography purification (cyclohexane/EtOAc). .sup.1H NMR (300 MHz, CDCl.sub.3) 1.37-1.62 (m, 2H), 2.06 (s, 6H), 2.08 (t, J=7.2 Hz, 2H), 2.56 (s, 3H), 2.57-2.62 (m, 1H), 2.97 (dd, J=15.7, 7.2 Hz, 1H), 3.51 (ddd, J=14.6, 9.1, 3.7 Hz, 1H), 3.82 (ddd, J=14.6, 9.1, 5.4 Hz, 1H), 4.18 (d, J=6.4 Hz, 1H), 5.05 (d, J=13.2 Hz, 1H), 5.12 (d, J=13.2 Hz, 1H), 7.12-7.16 (m, 4H), 7.26 (m, 3H), 7.32 (d, J=8.1 Hz, 2H). MS [M+H].sup.+ 441. HRMS: calcd for C.sub.25H.sub.30N.sub.2O.sub.3Cl, [M+H].sup.+ 441.1945, found 441.1950.

Example 55: Benzyl 4-(4-chlorophenyl)-6-methyl-2-oxo-1-(2-pyrrolidin-1-ylethyl)-3,4-dihydropyridine-5-carboxylate

[0223] The benzyl 4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate (71 mg, 0.20 mmol) was dissolved in anhydrous DMF (1 mL). Sodium hydride (14 mg, 0.60 mmol) was added. The reaction mixture was stirred at r.t. for 15 min. N(-2-chloroethyl)pyrrolidine hydrochloride (55 mg, 0.30 mmol) were added. The reaction mixture was stirred at 60 C. for 4 h. LCMS analysis showed the reaction was incomplete. Sodium hydride (7 mg, 0.30 mmol) and N(-2-chloroethyl)pyrrolidine hydrochloride (18 mg, 0.10 mmol) were added The reaction mixture was stirred for an additional hour at 60 C. The DMF was removed under reduced pressure. The residue was diluted in water and extracted by EtOAc. The organic layers were assembled, washed by brine and dried on MgSO.sub.4. The solvent was removed under reduced pressure. The crude product was purified by flash chromatography using a mixture of DCM/Acetone (8/2) as eluent to give the desired compound as a white powder (55 mg, 61%). .sup.1H NMR (300 MHz, CDCl.sub.3) 1.72-1.86 (m, 4H), 2.45-2.66 (m, 6H), 2.62 (s, 3H), 2.74 (dd, J=15.9, 2.3 Hz, 1H), 2.92 (dd, J=15.9, 7.5 Hz, 1H), 3.69 (ddd, J=14.5, 8.8, 5.9 Hz, 1H), 4.14 (ddd, J=14.5, 8.8, 5.9 Hz, 1H), 4.22 (dd, J=7.5, 2.3 Hz, 1H), 5.09 (d, J=12.6 Hz, 1H), 5.15 (d, J=12.6 Hz, 1H), 7.07 (dt, J=8.6, 2.2 Hz, 2H), 7.11-7.18 (m, 2H), 7.22 (dt, J=8.6, 2.2 Hz, 2H), 7.26-7.34 (m, 3H). MS [M+H].sup.+ 453. HRMS: calcd for C.sub.26H.sub.30N.sub.2O.sub.3Cl, [M+H].sup.+ 453.1945, found 453.1920.

Example 56: Benzyl 4-(4-chlorophenyl)-6-methyl-2-oxo-1-[2-(1-piperidyl)ethyl]-3,4-dihydropyridine-5-carboxylate

[0224] The benzyl 4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate (71 mg, 0.20 mmol) was dissolved in anhydrous DMF (1 mL). Sodium hydride (14 mg, 0.60 mmol) was added. The reaction mixture was stirred at RT for 15 min. N(-2-chloroethyl)piperidine hydrochloride (55 mg, 0.30 mmol) were added. The reaction mixture was stirred at 60 C. for 4 h. LCMS analysis showed the reaction was incomplete. Sodium hydride (7 mg, 0.30 mmol) and N(-2-chloroethyl)piperidine hydrochloride (18 mg, 0.10 mmol) were added The reaction mixture was stirred for an additional hour at 60 C. The DMF was removed under reduced pressure. The residue was diluted in water and extracted by EtOAc. The organic layers were assembled, washed by brine and dried on MgSO.sub.4. The solvent was removed under reduced pressure. The crude product was purified by flash chromatography using a mixture of DCM/Acetone (8/2) as eluent to give the desired compound as a white powder (48 mg, 52%). .sup.1H NMR (300 MHz, CDCl.sub.3) 1.40-1.50 (m, 2H), 1.53-1.66 (m, 4H), 2.29-2.53 (m, 6H), 2.61 (s, 3H), 2.74 (dd, J=15.8, 2.3 Hz, 1H), 2.92 (dd, J=15.8, 7.5 Hz, 1H), 3.67 (dt, J=14.0, 7.5 Hz, 1H), 4.07 (ddd, J=14.0, 7.5, 5.5 Hz, 1H), 4.22 (dd, J=7.5, 2.3 Hz, 1H), 5.10 (d, J=12.8 Hz, 1H), 5.15 (d, J=12.8 Hz, 1H), 7.08 (dt, J=8.5, 2.3 Hz, 2H), 7.11-7.17 (m, 2H), 7.22 (dt, J=8.5, 2.3 Hz, 2H), 7.26-7.33 (m, 3H). MS [M+H].sup.+ 467. HRMS: calcd for C.sub.27H.sub.32N.sub.2O.sub.3Cl, [M+H].sup.+ 467.2101, found 467.2120.

Example 57: Benzyl 4-(4-chlorophenyl)-1-(2-methoxy-2-oxo-ethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate

[0225] The benzyl 4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate (75 mg, 0.21 mmol) was dissolved in anhydrous DMF (1 mL). Sodium hydride (10 mg, 0.42 mmol) and methylbromoacetate (45 L, 0.42 mmol) were added. The reaction mixture was stirred at RT for 5 h. The DMF was removed under reduced pressure. The residue was diluted in water and extracted by EtOAc. The organic layers were assembled, washed by brine and dried on MgSO.sub.4. The solvent was removed under reduced pressure to give the desired compound as a yellow oil (90 mg, 100%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.50 (s, 3H), 2.78 (dd, J=16.0, 2.0 Hz, 1H), 2.99 (dd, J=16.0, 7.9 Hz, 1H), 3.76 (s, 3H), 4.25 (d, J=7.9 Hz, 1H), 4.43 (d, J=18.0 Hz, 1H), 4.65 (d, J=18.0 Hz, 1H), 5.07 (d, J=12.6 Hz, 1H), 5.14 (d, J=12.6 Hz, 1H), 7.07-7.14 (m, 2H), 7.16 (d, J=8.6 Hz, 2H), 7.23 (d, J=8.6 Hz, 2H), 7.26-7.33 (m, 3H). MS [M+H].sup.+ 428. HRMS: calcd for C.sub.23H.sub.23NO.sub.5Cl, [M+H].sup.+ 428.1265, found 428.1251.

Example 58: Benzyl 1-(2-tert-butoxy-2-oxo-ethyl)-4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate

[0226] The benzyl 4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate (106 mg, 0.30 mmol) was dissolved in anhydrous DMF (2 mL). Sodium hydride (9 mg, 0.36 mmol) was added. The reaction mixture was stirred at RT for 30 min. tert-butylbromoacetate (73 L, 0.45 mmol) were added. The reaction mixture was stirred at r.t. for 4 h. LCMS analysis showed the reaction was incomplete. Sodium hydride (4 mg, 0.15 mmol) and tert-butylbromoacetate (24 L, 0.15 mmol) were added. The reaction mixture was stirred for 1 h at RT The DMF was removed under reduced pressure. The residue was diluted in water and extracted by EtOAc. The organic layers were assembled, washed by brine and dried on MgSO.sub.4. The solvent was removed under reduced pressure. The crude product was purified by flash chromatography using a mixture of Cyclohexane/EtOAc (9/1) as eluent to give the desired benzyl 1-(2-tert-butoxy-2-oxo-ethyl)-4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate as a white powder (112 mg, 79%). .sup.1H NMR (300 MHz, CDCl.sub.3) 1.49 (s, 9H), 2.50 (s, 3H), 2.76 (dd, J=16.1, 2.4 Hz, 1H), 2.99 (dd, J=16.1, 7.9 Hz, 1H), 4.24 (d, J=7.9 Hz, 1H), 4.38 (d, J=17.8 Hz, 1H), 4.52 (d, J=17.8 Hz, 1H), 5.06 (d, J=12.5 Hz, 1H), 5.13 (d, J=12.5 Hz, 1H), 7.08-7.14 (m, 2H), 7.17 (d, J=8.7 Hz, 2H), 7.23 (d, J=8.7 Hz, 2H), 7.28-7.32 (m, 3H). MS [M+H].sup.+ 470. HRMS: calcd for C.sub.26H.sub.32N.sub.2O.sub.5Cl, [M+NH.sub.4].sup.+ 487.2000, found 487.1992.

Example 59: Benzyl 4-(4-chlorophenyl)-6-methyl-1-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]-2-oxo-3,4-dihydropyridine-5-carboxylate

[0227] ##STR00290##

Step 1. 2-[5-benzyloxycarbonyl-4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydropyridin-1-yl]acetic acid

[0228] Benzyl 1-(2-tert-butoxy-2-oxo-ethyl)-4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate (100 mg, 0.21 mmol) was dissolved in DCM (160 L). Trifluoroacetic acid (160 L, 2.3 mmol) was added. The reaction mixture was stirred at RT for 1 h. Water was added. The acid was extracted by EtOAc. The organic layers were assembled, washed by brine and dried on MgSO.sub.4. The solvent was removed under reduced pressure. The crude product was purified by flash chromatography using a mixture of Cyclohexane/Acetone/EtOAc (3/1/1) as eluent to give a mixture of the desired compound and unidentified byproducts (80 mg). This mixture was diluted in diethyl ether and washed with an aqueous solution of NaHCO.sub.3 1 M. The aqueous solution was acidified by hydrochloric acid until pH=1 and extracted by EtOAc. The organic layers were assembled, washed by brine and dried on MgSO.sub.4. The solvent was removed under reduced pressure to give the desired 2-[5-benzyloxycarbonyl-4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydropyridin-1-yl]acetic acid as a white powder (44 mg, 50%) .sup.1H NMR (300 MHz, CDCl.sub.3) 2.48 (s, 3H), 2.75 (d, J=16.0 Hz, 1H), 2.97 (dd, J=16.0, 7.5 Hz, 1H), 4.38-4.67 (m, 4H), 5.05 (d, J=12.6 Hz, 1H), 5.12 (d, J=12.6 Hz, 1H), 6.34 (brs, 1H), 7.05-7.15 (m, 4H), 7.18 (d, J=8.4 Hz, 2H), 7.24-7.31 (m, 3H). MS [M+H].sup.+ 414. HRMS: calcd for C.sub.22H.sub.21NO.sub.5Cl, [M+H].sup.+ 414.1108, found 414.1121.

Step 2. Benzyl 4-(4-chlorophenyl)-6-methyl-1-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]-2-oxo-3,4-dihydropyridine-5-carboxylate

[0229] The 2-[5-benzyloxycarbonyl-4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydropyridin-1-yl]acetic acid (207 mg, 0.5 mmol) of step 1 was dissolved in anh. DMF (2 mL). DIEA (430 L, 2.5 mmol) and HBTU (228 mg, 0.6 mmol) were added. The reaction mixture was stirred at RT for 10 min. The amidoxime (41 mg, 0.55 mmol) was then added. The reaction mixture was stirred at RT for 1 h. Water was added. The aqueous phase was extracted with EtOAc. The organic phases were assembled, washed with brine and dried over MgSO.sub.4. The solvents were removed under reduced pressure. The crude was dissolved in anh. DMF (2 mL). The reaction mixture was stirred at 110 C. for 3 h. The solvent was removed under reduced pressure. Water was added. The aqueous phase was extracted with EtOAc. The organic phases were assembled, washed with brine and dried over MgSO.sub.4. The solvents were removed under reduced pressure. Purification of the crude by Flash chromatography using a mixture Cyclohexane/EtOAc (8/2) gave the desired benzyl 4-(4-chlorophenyl)-6-methyl-1-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]-2-oxo-3,4-dihydropyridine-5-carboxylate as a white powder (124 mg, 55%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.38 (s, 3H), 2.56 (s, 3H), 2.81 (dd, J=16.0, 2.3 Hz, 1H), 3.01 (dd, J=16.0, 7.6 Hz, 1H), 4.28 (d, J=7.6 Hz, 1H), 5.03 (d, J=17.5 Hz, 1H), 5.07 (d, J=12.4 Hz, 1H), 5.14 (d, J=12.4 Hz, 1H), 5.28 (d, J=17.5 Hz, 1H), 7.08-7.17 (m, 4H), 7.21 (d, J=8.2 Hz, 2H), 7.24-7.32 (m, 3H). .sup.13C NMR (75 MHz, CDCl.sub.3) 11.6, 16.8, 36.9, 37.9, 38.1, 66.5, 111.5, 127.9, 128.2, 128.5, 128.9, 132.9, 135.7, 139.3, 148.2, 166.5, 167.5, 168.9, 174.6. MS [M+H].sup.+ 452. HRMS: calcd for C.sub.24H.sub.23N.sub.3O.sub.4Cl, [M+H].sup.+ 452.1377, found 452.1355.

Example 60: Benzyl 1-(2-amino-2-oxo-ethyl)-4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate

[0230] The benzyl 4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate (106 mg, 0.30 mmol) was dissolved in anhydrous DMF (2 mL). Sodium hydride (9 mg, 0.36 mmol) was added. The reaction mixture was stirred at RT for 30 min. 2-bromoacetamide (62 mg, 0.45 mmol) were added. The reaction mixture was stirred at RT for 4 h. LCMS analysis showed the reaction was incomplete. Sodium hydride (4 mg, 0.15 mmol) and 2-bromoacetamide (21 mg, 0.15 mmol) were added. The reaction mixture was stirred for 1 h at RT The DMF was removed under reduced pressure. The residue was diluted in water and extracted by EtOAc. The organic layers were assembled, washed by brine and dried on MgSO.sub.4. The solvent was removed under reduced pressure. The crude product was purified by flash chromatography using a mixture of Cyclohexane/EtOAc (9/1) as eluent to give the desired compound as a white powder (100 mg, 81%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.58 (s, 3H), 2.83 (dd, J=16.0, 2.4 Hz, 1H), 3.00 (dd, J=16.0, 7.3 Hz, 1H), 4.27 (dd, J=7.3, 2.4 Hz, 1H), 4.31 (d, J=16.2 Hz, 1H), 4.51 (d, J=16.2 Hz, 1H), 5.09 (d, J=12.5 Hz, 1H), 5.16 (d, J=12.5 Hz, 1H), 5.46 (brs, 1H), 5.68 (brs, 1H), 7.10-7.18 (m, 4H), 7.24 (dt, J=8.6, 2.2 Hz, 2H), 7.28-7.34 (m, 3H). MS [MH].sup. 411. HRMS: calcd for C.sub.22H.sub.22N.sub.2O.sub.4Cl, [M+H].sup.+ 413.1268, found 413.1250.

Example 61: 2-[5-benzyloxycarbonyl-4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydropyridin-1-yl]acetic acid

[0231] The benzyl 1-(2-tert-butoxy-2-oxo-ethyl)-4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate (100 mg, 0.21 mmol) was dissolved in DCM (160 L). Trifluoroacetic acid (160 L, 2.3 mmol) was added. The reaction mixture was stirred at RT for 1 h. Water was added. The acid was extracted by EtOAc. The organic layers were assembled, washed by brine and dried on MgSO.sub.4. The solvent was removed under reduced pressure. The crude product was purified by flash chromatography using a mixture of Cyclohexane/Acetone/EtOAc (3/1/1) as eluent to give a mixture of the desired compound and unidentified byproducts (80 mg). This mixture was diluted in diethyl ether and washed with an aqueous solution of NaHCO.sub.3 1 M. The aqueous solution was acidified by hydrochloric acid until pH=1 and extracted by EtOAc. The organic layers were assembled, washed by brine and dried on MgSO.sub.4. The solvent was removed under reduced pressure to give the desired 2-[5-benzyloxycarbonyl-4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydropyridin-1-yl]acetic acid as a white powder (44 mg, 50%) .sup.1H NMR (300 MHz, CDCl.sub.3) 2.48 (s, 3H), 2.75 (d, J=16.0 Hz, 1H), 2.97 (dd, J=16.0, 7.5 Hz, 1H), 4.38-4.67 (m, 4H), 5.05 (d, J=12.6 Hz, 1H), 5.12 (d, J=12.6 Hz, 1H), 6.34 (brs, 1H), 7.05-7.15 (m, 4H), 7.18 (d, J=8.4 Hz, 2H), 7.24-7.31 (m, 3H). MS [M+H].sup.+ 414. HRMS: calcd for C.sub.22H.sub.21NO.sub.5Cl, [M+H].sup.+ 414.1108, found 414.1121.

Example 62: Benzyl 4-(4-chlorophenyl)-6-methyl-1-(2-methylsulfonylethyl)-2-oxo-3,4-dihydropyridine-5-carboxylate

[0232] Benzyl 4-(4-chlorophenyl)-6-methyl-1-(2-methylsulfonylethyl)-2-oxo-3,4-dihydropyridine-5-carboxylate was obtained according general procedure B starting from benzyl 4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate (0.50 mmol) and obtained as a white powder (51 mg, 22%) after flash chromatography purification (cyclohexane/EtOAc). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.61 (s, 3H), 2.79 (dd, J=16.0, 2.7 Hz, 1H), 2.87-2.97 (m, 1H), 2.94 (s, 3H), 3.17 (t, J=7.3 Hz, 2H), 3.98-4.28 (m, 2H), 4.26 (d, J=7.6 Hz, 1H), 5.10 (d, J=12.4 Hz, 1H), 5.16 (d, J=7.4 Hz, 2H), 7.03 (d, J=8.3 Hz, 2H), 7.12-7.18 (m, 2H), 7.24 (d, J=8.3 Hz, 2H), 7.27-7.33 (m, 3H). .sup.13C NMR (75 MHz, CDCl.sub.3) 16.8, 36.3, 36.5, 38.2, 41.1, 52.8, 66.5, 111.8, 127.9, 128.1, 128.2, 128.5, 129.0, 133.0, 135.7, 138.9, 148.3, 166.5, 169.4. MS [M+H].sup.+ 462. HRMS: calcd for C.sub.26H.sub.21NO.sub.5Cl, [M+H].sup.+ 462.1108, found 462.1138.

Example 63: Benzyl 4-(4-chlorophenyl)-1-(cyanomethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate

[0233] Benzyl 4-(4-chlorophenyl)-1-(cyanomethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate was obtained according general procedure B starting from benzyl 4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate (0.50 mmol) and obtained as a colorless oil (162 mg, 88%) after flash chromatography purification (dichloromethane). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.68 (s, 3H), 2.82 (dd, J=16.1, 2.5 Hz, 1H), 2.96 (dd, J=16.1, 7.3 Hz, 1H), 4.27 (dd, J=7.3, 2.5 Hz, 1H), 4.53 (d, J=17.7 Hz, 1H), 4.81 (d, J=17.7 Hz, 1H), 5.10 (d, J=12.4 Hz, 1H), 5.15 (d, J=12.4 Hz, 1H), 7.01 (d, J=8.5 Hz, 2H), 7.12-7.18 (m, 2H), 7.24 (d, J=8.5 Hz, 2H), 7.28-7.35 (m, 3H). .sup.13C NMR (75 MHz, CDCl.sub.3) 16.7, 29.5, 36.7, 38.1, 66.6, 112.8, 114.7, 127.9, 128.0, 128.3, 128.5, 129.1, 133.2, 135.5, 138.4, 146.8, 166.1, 168.3. MS [M+H].sup.+ 395; HRMS: calcd for C.sub.22H.sub.20N.sub.2O.sub.3Cl, [M+H].sup.+ 395.1162, found 395.1167.

TABLE-US-00006 TABLE 6 [00291] [00292] [00293] Examples R14 64 [00294] 65 [00295] 66 [00296] 67 [00297] 68 [00298] 69 [00299] 70 [00300] 71 [00301] 72 [00302] 73 [00303]

Example 64: (2-methoxyphenyl)methyl 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate

[0234] 2-methoxybenzyl alcohol (268 L, 2.0 mmol) and triethylamine (335 L, 2.4 mmol) were dissolved in anh. DCM (7 mL). Thionyl chloride (218 L, 3.0 mmol) was added slowly. The reaction mixture was stirred at RT for 1 h. The reaction mixture was washed with an aqueous solution of HCl 1N. The organic phase was dried over MgSO.sub.4. The solvent was removed under reduced pressure to give the desired 2-methoxybenzyl chloride (300 mg, 96%) as a yellowish oil. 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylic acid (example 74, 85 mg, 0.26 mmol) was dissolved in anhydrous DMF (1 mL) then cesium carbonate (169 mg, 0.52 mmol) and 2-methoxybenzyl chloride (81 mg, 0.52 mmol) were added. The reaction mixture was stirred at RT for 18 h. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc and water. The aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine and dried over MgSO.sub.4. The solvent was removed under reduced pressure. Purification of the crude by flash chromatography using a mixture of Cyclohexane/EtOAc (8/2) as eluent gave the desired (2-methoxyphenyl) methyl 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate as a yellowish oil (36 mg, 31%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.60 (s, 3H), 2.71 (dd, J=15.9, 2.4 Hz, 1H), 2.91 (dd, J=15.9, 7.6 Hz, 1H), 3.31 (s, 3H), 3.36 (ddd, J=9.8, 8.3, 3.7 Hz, 1H), 3.46 (dt, J=9.8, 4.2 Hz, 1H), 3.74 (s, 3H), 3.69-3.78 (m, 1H), 4.13-4.21 (m, 2H), 5.10 (d, J=12.9 Hz, 1H), 5.19 (d, J=12.9 Hz, 1H), 6.80-6.85 (m, 2H), 6.98 (dd, J=7.8, 1.6 Hz, 1H), 7.09 (d, J=8.4 Hz, 2H), 7.19 (d, J=8.4 Hz, 2H), 7.26 (t, J=7.8 Hz, 1H). .sup.13C NMR (75 MHz, CDCl.sub.3) 17.0, 36.8, 38.6, 41.8, 55.1, 58.8, 61.8, 71.0, 110.1, 110.3, 120.2, 124.2, 128.4, 128.6, 129.1, 129.2, 132.4, 139.8, 150.6, 157.2, 167.1, 169.0. MS [M+H].sup.+ 444. HRMS: calcd for C.sub.24H.sub.27NO.sub.5Cl, [M+H].sup.+ 444.1578, found 444.1585.

Example 65a o-methoxybenzyl 4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate (Intermediate)

[0235] ##STR00304##

[0236] The (2-methoxyphenyl)methyl 3-oxobutanoate (1334 mg, 6.0 mmol) was dissolved in acetic acid (6 mL). p-chlorobenzaldehyde (843 mg, 6.0 mmol), meldrum acid (865 mg, 6.0 mmol) and ammonium acetate (676 mg, 9.0 mmol) were added and the reaction mixture was stirred at 110 C. for 18 h. The reaction mixture was cooled to RT. The solvent was removed under reduced pressure. The crude was precipitated in EtOH, cooled to 0 C. and filtered to give the desired o-methoxybenzyl 4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate as a white powder (1.041 g, 45%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.42 (s, 3H), 2.64 (d, J=16.5 Hz, 1H), 2.94 (dd, J=16.5, 8.1 Hz, 1H), 3.75 (s, 3H), 4.26 (d, J=8.1 Hz, 1H), 5.10 (d, J=12.7 Hz, 1H), 5.21 (d, J=12.7 Hz, 1H), 6.80-6.90 (m, 2H), 7.03 (d, J=7.5 Hz, 1H), 7.08 (d, J=8.5 Hz, 2H), 7.22 (d, J=8.5 Hz, 2H), 7.28 (td, J=8.1, 2.1 Hz, 1H), 8.47 (s, 1H). .sup.13C NMR (75 MHz, CDCl.sub.3) . 106.8, 110.2, 120.3, 124.2, 128.2, 128.8, 129.4, 129.4, 132.6, 140.7, 146.7, 157.4, 166.5, 170.9

Example 65: (2-methoxyphenyl)methyl 4-(4-chlorophenyl)-1-(2-hydroxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate

[0237] o-methoxybenzyl 4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate (example 65a, 96 mg, 0.25 mmol) was dissolved in anhydrous DMF (1 mL). Cesium carbonate (162 mg, 0.50 mmol) and 2-bromoethanol (35 L, 0.50 mmol) were added. The reaction mixture was stirred at 60 C. for 24 h. The reaction was uncomplete. Cesium carbonate (324 mg, 1.00 mmol) and 2-bromoethanol (70 L, 1.00 mmol) were added 4 times more every 24 h. The DMF was removed under reduced pressure. The residue was diluted in water. The aqueous phase was extracted by EtOAc and the combined organic layers were washed with brine and dried over MgSO.sub.4. The solvent was removed under reduced pressure. Purification of the crude by flash chromatography using a mixture of Cyclohexane/EtOAc (4/6) as eluent gave the desired (2-methoxyphenyl) methyl 4-(4-chlorophenyl)-1-(2-hydroxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate as a colorless oil (9 mg, 8%). .sup.1H NMR (300 MHz, CDCl.sub.3) 1.88 (brs, 1H), 2.58 (s, 3H), 2.78 (dd, J=16.0, 2.4 Hz, 1H), 2.95 (dd, J=16.0, 7.5 Hz, 1H), 3.74 (s, 3H), 3.74-3.85 (m, 3H), 4.02-4.13 (m, 1H), 4.24 (d, J=7.0 Hz, 1H), 5.12 (d, J=12.8 Hz, 1H), 5.23 (d, J=12.8 Hz, 1H), 6.84-6.90 (m, 2H), 6.99-7.07 (m, 1H), 7.10 (d, J=8.3 Hz, 2H), 7.21 (d, J=8.3 Hz, 2H), 7.25-7.32 (m, 1H). MS [M+H].sup.+ 430. HRMS: calcd for C.sub.23H.sub.25NO.sub.5Cl, [M+H].sup.+ 430.1421, found 430.1425.

Example 66: 2-benzyl 4-(4-chlorophenyl)-1-(2-furylmethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate

[0238] o-methoxybenzyl 4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate (example 65a, 96 mg, 0.25 mmol) was dissolved in anhydrous DMF (1 mL). Cesium carbonate (162 mg, 0.50 mmol) and 2-chloromethylfuran (145 mg, 0.50 mmol) were added. The reaction mixture was stirred at 60 C. for 18 h. The DMF was removed under reduced pressure. The residue was diluted in water. The aqueous phase was extracted by EtOAc and the combined organic layers were washed with brine and dried over MgSO.sub.4. The solvent was removed under reduced pressure. Purification of the crude by flash chromatography using a mixture of Cyclohexane/EtOAc (9/1) as eluent gave the desired 2-benzyl 4-(4-chlorophenyl)-1-(2-furylmethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate=as a yellow oil (43 mg, 50%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.70 (s, 3H), 2.74 (dd, J=16.1, 2.1 Hz, 1H), 2.94 (dd, J=16.1, 7.3 Hz, 1H), 3.73 (s, 3H), 4.18 (d, J=7.3 Hz, 1H), 4.66 (d, J=15.8 Hz, 1H), 5.11 (d, J=12.8 Hz, 1H), 5.20 (d, J=12.8 Hz, 1H), 5.28 (d, J=15.8 Hz, 1H), 6.20 (d, J=3.2 Hz, 1H), 6.34 (dd, J=3.2, 1.8 Hz, 1H), 6.80-6.88 (m, 2H), 7.00 (dd, J=7.4, 1.3 Hz, 1H), 7.09 (d, J=8.5 Hz, 2H), 7.24-7.32 (m, 1H), 7.33-7.36 (m, 1H). .sup.13C NMR (75 MHz, CDCl.sub.3) 16.9, 36.8, 37.9, 38.4, 55.2, 61.9, 108.9, 110.2, 110.5, 111.5, 120.2, 124.1, 128.3, 128.6, 129.3, 129.4, 132.4, 139.5, 142.0, 149.2, 150.3, 157.3, 166.9, 168.7. MS [M+H].sup.+ 466. HRMS: calcd for C.sub.26H.sub.25NO.sub.5Cl, [M+H].sup.+ 466.1421, found 466.1433.

Example 67: (4S)-4-(4-chlorophenyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate (Racemic)

[0239] The o-methoxybenzyl 4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate (example 65a, 96 mg, 0.25 mmol) was dissolved in anhydrous DMF (1 mL). Cesium carbonate (162 mg, 0.50 mmol) and tetrahydrofurfuryl bromide (57 L, 0.50 mmol) were added. The reaction mixture was stirred at 60 C. for 18 h. Cesium carbonate (162 mg, 0.50 mmol) and tetrahydrofurfuryl bromide (57 L, 0.50 mmol) were added 3 times more every 12 h. Overall, the reaction mixture was stirred at 60 C. for 66 h. The DMF was removed under reduced pressure. The residue was diluted in water. The aqueous phase was extracted with EtOAc and the combined organic layers were washed with brine and dried over MgSO.sub.4. The solvent was removed under reduced pressure. Purification of the crude by flash chromatography using a mixture of Cyclohexane/EtOAc (9/1) as eluent gave the desired (2-methoxyphenyl)methyl (4S)-4-(4-chlorophenyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate as a colorless oil (25 mg, 21%) .sup.1H NMR (300 MHz, CDCl.sub.3) 1.41-1.53 (m, 1H), 1.78-1.99 (m, 3H), 2.63 (s, 3H), 2.92 (dd, J=15.7, 2.4 Hz, 1H), 2.92 (dd, J=15.7, 7.3 Hz, 1H), 3.41 (dd, J=14.4, 8.6 Hz, 1H), 3.73 (s, 3H), 3.63-3.95 (m, 3H), 4.21 (d, J=7.3 Hz, 1H), 4.26 (dd, J=14.4, 3.7 Hz, 1H), 5.10 (d, J=13.2 Hz, 1H), 5.20 (d, J=13.2 Hz, 1H), 6.79-6.87 (m, 2H), 6.97 (dd, J=7.7, 1.7 Hz, 1H), 7.15-7.30 (m, 5H). .sup.13C NMR (75 MHz, CDCl.sub.3) 17.1, 25.5, 29.2, 37.0, 39.0, 45.6, 55.2, 61.8, 68.1, 77.9, 110.2, 110.5, 120.2, 124.4, 128.6, 128.7, 129.0, 129.2, 132.5, 139.6, 150.9, 157.2, 167.1, 169.0. MS [M+H].sup.+ 470 HRMS: calcd for C.sub.26H.sub.29NO.sub.5Cl, [M+H].sup.+ 470.1734, found 470.1714.

Example 68: (4S)-4-(4-chlorophenyl)-6-methyl-2-oxo-1-[[(2S)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate (Racemic)

[0240] The o-methoxybenzyl 4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate (example 65a, 96 mg, 0.25 mmol) was dissolved in anhydrous DMF (1 mL). Cesium carbonate (162 mg, 0.50 mmol) and tetrahydrofurfuryl bromide (57 L, 0.50 mmol) were added. The reaction mixture was stirred at 60 C. for 18 h. Cesium carbonate (162 mg, 0.50 mmol) and tetrahydrofurfuryl bromide (57 L, 0.50 mmol) were added 3 times more every 12 h. Overall, the reaction mixture was stirred at 60 C. for 66 h. The DMF was removed under reduced pressure. The residue was diluted in water. The aqueous phase was extracted by EtOAc and the combined organic layers were washed with brine and dried over MgSO.sub.4. The solvent was removed under reduced pressure. Purification of the crude by flash chromatography using a mixture of Cyclohexane/EtOAc (9/1) as eluent gave the (4S)-4-(4-chlorophenyl)-6-methyl-2-oxo-1-[[(2S)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate as a colorless oil (21 mg, 18%). .sup.1H NMR (300 MHz, CDCl.sub.3) 1.25-1.37 (m, 1H), 1.74-1.94 (m, 3H), 2.62 (s, 3H), 2.79 (dd, J=15.9, 2.4 Hz, 1H), 2.94 (dd, J=15.9, 7.4 Hz, 1H), 3.75 (s, 3H), 3.65-3.84 (m, 3H), 3.89-4.06 (m, 2H), 4.23 (dd, J=7.4, 2.4 Hz, 1H), 5.11 (d, J=12.6 Hz, 1H), 5.23 (d, J=12.6 Hz, 1H), 6.82-6.89 (m, 2H), 7.05 (dd, J=7.6, 1.5 Hz, 1H), 7.10 (d, J=8.6 Hz, 2H), 7.19 (d, J=8.6 Hz, 2H), 7.24-7.32 (m, 1H). .sup.13C NMR (75 MHz, CDCl.sub.3) 17.4, 25.3, 28.9, 36.3, 38.2, 45.1, 55.2, 61.8, 67.7, 77.5, 110.2, 110.7, 120.2, 124.2, 128.5, 129.3, 132.4, 139.8, 150.3, 157.3, 167.1, 169.5. MS [M+H].sup.+ 470; HRMS: calcd for C.sub.26H.sub.29NO.sub.5Cl, [M+H].sup.+ 470.1734, found 470.1746.

Example 69: (2-methoxyphenyl)methyl 4-(4-chlorophenyl)-1-(2-ethoxy-2-oxo-ethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate

[0241] o-methoxybenzyl 4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate (example 65a, 75 mg, 0.19 mmol) was dissolved in anhydrous DMF (0.3M). Cesium carbonate (114 mg, 0.35 mmol) and Methylbromoacetate (33 L, 0.35 mmol) were added. The reaction mixture was stirred at RT for 2 hours. The DMF was removed under reduced pressure. The residue was diluted in water. The aqueous phase was extracted by EtOAc and the combined organic layers were washed with brine and dried over Na.sub.2SO.sub.4. The solvent was removed under reduced pressure. EtOH was added and was removed under reduced pressure (transesterification). Purification of the crude by flash chromatography using a DCM as eluent gave the desired compound as a colorless oil. .sup.1H NMR (300 MHz, CDCl.sub.3) 1.29 (t, J=7.1 Hz, 3H), 2.49 (s, 3H), 2.77 (dd, J=15.9, 2.1 Hz, 1H), 3.00 (dd, J=15.9, 7.9 Hz, 1H), 3.74 (s, 3H), 4.22 (q, J=7.1 Hz, 2H), 4.22-4.28 (m, 1H), 4.43 (d, J=17.9 Hz, 1H), 4.61 (d, J=17.9 Hz, 1H), 5.10 (d, J=12.8 Hz, 1H), 5.21 (d, J=12.8 Hz, 1H), 6.81-6.89 (m, 2H), 7.02 (dd, J=7.2, 1.4 Hz, 1H), 7.16 (d, J=8.8 Hz, 2H), 7.21 (d, J=8.8 Hz, 2H), 7.28 (td, J=8.1, 2.1 Hz, 1H). MS [MH].sup. 472; HRMS: calcd for C.sub.31H.sub.22NO.sub.4, [M+H].sup.+ 472.1549, found 472.1545.

Example 70: o-methoxybenzyl 4-(4-chlorophenyl)-1-(cyclopropylmethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate

[0242] The o-methoxybenzyl 4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate (example 65a, 96 mg, 0.25 mmol) was dissolved in anhydrous DMF (1 mL). Cesium carbonate (162 mg, 0.50 mmol) and (bromomethyl)cyclopropane (48 L, 0.50 mmol) were added. The reaction mixture was stirred at 60 C. for 18 h. The DMF was removed under reduced pressure. The residue was diluted in water. The aqueous phase was extracted by EtOAc and the combined organic layers were washed with brine and dried over MgSO.sub.4. The solvent was removed under reduced pressure. Purification of the crude by flash chromatography using a mixture of Cyclohexane/EtOAc (9/1) as eluent gave the desired o-methoxybenzyl 4-(4-chlorophenyl)-1-(cyclopropylmethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate as a yellow oil (77 mg, 71%). .sup.1H NMR (300 MHz, CDCl.sub.3) 0.22-0.36 (m, 2H), 0.36-0.46 (m, 1H), 0.46-0.56 (m, 1H), 0.86-1.04 (m, 1H), 2.61 (s, 3H), 2.73 (dd, J=15.8, 2.4 Hz, 1H), 2.91 (dd, J=15.8, 7.3 Hz, 1H), 3.50 (dd, J=14.6, 5.8 Hz, 1H), 3.74 (s, 3H), 3.90 (dd, J=14.6, 7.9 Hz, 1H), 4.22 (d, J=7.3 Hz, 1H), 5.12 (d, J=12.8 Hz, 1H), 5.23 (d, J=12.8 Hz, 1H), 6.82-6.89 (m, 2H), 7.04 (dd, J=7.4, 1.1 Hz, 1H), 7.12 (d, J=7.6 Hz, 2H), 7.20 (d, J=7.6 Hz, 2H), 7.28 (td, J=7.7, 1.8 Hz, 1H). .sup.13C NMR (75 MHz, CDCl.sub.3) 4.0, 4.1, 11.0, 16.9, 36.6, 38.5, 45.5, 55.14, 61.8, 110.2, 111.4, 120.2, 124.2, 128.4, 128.5, 129.2, 129.3, 132.4, 139.7, 132.4, 139.7, 149.5, 157.3, 166.9, 169.0. MS [M+H].sup.+ 440. HRMS: calcd for C.sub.25H.sub.27NO.sub.4Cl, [M+H].sup.+ 440.1629, found 440.1618.

Example 71: (2-methoxyphenyl)methyl 4-(4-chlorophenyl)-1-(3-methoxypropyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate

[0243] The (2-methoxyphenyl)methyl 4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate (115 mg, 0.30 mmol) was dissolved in anhydrous DMF (1 mL). Cesium carbonate (195 mg, 0.60 mmol) and 1-bromo-3-methoxypropane (68 L, 0.60 mmol) were added. The reaction mixture was stirred at 60 C. for 18 h. The DMF was removed under reduced pressure. The residue was diluted in water and extracted by EtOAc. The organic layers were assembled, washed by brine and dried on MgSO.sub.4. The solvent was removed under reduced pressure. The crude product was purified by flash chromatography using a mixture of Cyclohexane/EtOAc (9/1) as eluent to give the desired (2-methoxyphenyl)methyl 4-(4-chlorophenyl)-1-(3-methoxypropyl)-6-methyl-2-oxo-3,4-ihydropyridine-5-carboxylate as a colorless oil (96 mg, 70%). .sup.1H NMR (300 MHz, CDCl.sub.3) 1.62-1.84 (m, 2H), 2.57 (s, 3H), 2.76 (dd, J=15.9, 2.4 Hz, 1H), 2.89 (dd, J=15.9, 7.5 Hz, 1H), 3.18-3.35 (m, 2H), 3.28 (s, 3H), 3.64 (ddd, J=14.6, 8.9, 6.0 Hz, 1H), 3.74 (s, 3H), 3.99 (ddd, J=14.6, 8.7, 6.5 Hz, 1H), 4.22 (td, J=7.5, 2.4 Hz, 1H), 5.12 (d, J=12.7 Hz, 1H), 5.23 (d, J=12.7 Hz, 1H), 6.82-6.89 (m, 2H), 7.02-7.08 (m, 3H), 7.20 (d, J=8.5 Hz, 2H), 7.28 (td, J=7.8, 1.7 Hz, 1H). .sup.13C NMR (75 MHz, CDCl.sub.3) 16.6, 29.3, 36.3, 38.2, 39.5, 55.2, 58.6, 61.9, 69.8, 110.2, 111.0, 120.2, 124.1, 128.2, 128.6, 129.3, 129.4, 132.5, 139.6, 149.5, 157.3, 167.0, 169.0. MS [M+H].sup.+ 458; HRMS: calcd for C.sub.25H.sub.29NO.sub.5Cl, [M+H].sup.+ 458.1734, found 458.1744.

Example 72: (2-methoxyphenyl)methyl 4-(4-chlorophenyl)-1-(1,3-dioxolan-2-ylmethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate

[0244] The (2-methoxyphenyl)methyl 4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate (115 mg, 0.30 mmol) was dissolved in anhydrous DMF (1 mL). Cesium carbonate (195 mg, 0.60 mmol) and 2-Bromomethyl-1,3-dioxolane (62 L, 0.60 mmol) were added. The reaction mixture was stirred at 60 C. for 18 h. The DMF was removed under reduced pressure. The residue was diluted in water and extracted by EtOAc. The organic layers were assembled, washed by brine and dried on MgSO.sub.4. The solvent was removed under reduced pressure. The crude product was purified by flash chromatography using a mixture of Cyclohexane/EtOAc (8/2) as eluent to give the desired (2-methoxyphenyl)methyl 4-(4-chlorophenyl)-1-(1,3-dioxolan-2-ylmethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate as a colorless oil (73 mg, 52%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.61 (s, 3H), 2.76 (dd, J=15.9, 2.2 Hz, 1H), 2.93 (dd, J=15.9, 7.4 Hz, 1H), 3.64 (dd, J=14.6, 5.4 Hz, 1H), 3.83 (s, 3H), 3.78-3.94 (m, 4H), 4.23 (dd, J=7.4, 2.2 Hz, 1H), 4.34 (dd, J=14.6, 3.1 Hz, 1H), 4.86 (dd, J=5.4, 3.1 Hz, 1H), 5.11 (d, J=12.9 Hz, 1H), 5.23 (d, J=12.9 Hz, 1H), 6.81-6.87 (m, 2H), 7.01 (dd, J=7.4, 1.5 Hz, 1H), 7.13 (d, J=8.6 Hz, 2H), 7.19 (d, J=8.6 Hz, 2H), 7.27 (td, J=7.9, 1.9 Hz, 1H). .sup.13C NMR (75 MHz, CDCl.sub.3) 17.1, 36.6, 38.4, 43.6, 55.1, 61.8, 64.9, 101.3, 110.1, 110.8, 120.2, 124.2, 128.5, 128.5, 129.1, 129.3, 132.4, 139.5, 150.0, 157.2, 167.0, 169.2. MS [M+H].sup.+ 472. HRMS: calcd for C.sub.25H.sub.27NO.sub.6Cl, [M+H].sup.+ 472.1527, found 472.1533.

Example 73: (2-methoxyphenyl)methyl 4-(4-chlorophenyl)-1-(2-methoxy-2-oxo-ethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate

[0245] (2-methoxyphenyl)methyl 4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate (116 mg, 0.30 mmol) was dissolved in anh. DMF (1 mL). 2-bromomethylacetate (41 L, 0.45 mmol) and Cs.sub.2CO.sub.3 were added. The reaction mixture was stirred at RT for 18 h. 2-bromomethylacetate (28 L, 0.30 mmol) was added again and the reaction mixture was stirred at 50 C. during 6 h. The solvent was removed under reduced pressure. Water was added and the aqueous phase was extracted by Et.sub.2O, washed with brine and dried over Na.sub.2SO.sub.4. Removal of the solvent afforded the desired (2-methoxyphenyl)methyl 4-(4-chlorophenyl)-1-(2-methoxy-2-oxo-ethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate as a colorless oil (120 mg, 87%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.48 (s, 3H), 2.78 (dd, J=16.0, 2.3 Hz, 1H), 3.00 (dd, J=16.0, 7.8 Hz, 1H), 3.74-3.74 (s, 3H), 3.76 (s, 3H), 4.25 (d, J=7.8 Hz, 1H), 4.45 (d, J=17.8 Hz, 1H), 4.62 (d, J=17.8 Hz, 1H), 5.10 (d, J=12.5 Hz, 1H), 5.20 (d, J=12.5 Hz, 1H), 6.86 (m, 2H), 7.02 (dd, J=7.5, 1.5 Hz, 1H), 7.15 (d, J=8.8 Hz, 2H), 7.21 (d, J=8.8 Hz, 2H), 7.25-7.30 (m, 2H). .sup.13C NMR (75 MHz, CDCl.sub.3) 16.7, 36.8, 38.0, 43.4, 52.5, 55.2, 62.0, 110.2, 110.9, 120.3, 124.1, 128.7, 129.5, 129.5, 132.6, 139.8, 148.2, 166.8, 169.1, 169.2. MS [M+H]+ 458, HRMS: calcd for C24H25NO6Cl, [M+H]+ 458.1370, found 458.1378.

TABLE-US-00007 TABLE 7 [00305] Example R15 75 [00306] 76 [00307] 77 [00308]

Example 74: 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylic acid (Intermediate Product)

[0246] ##STR00309##

[0247] The methyl 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate (4.55 g, 13.5 mmol) was dissolved in methanol (47 mL). An aqueous solution of NaOH 1M (47 mL) was added. The reaction mixture was stirred at 50 C. for 18 h. The reaction mixture was washed with diethyl ether. The aqueous phase was acidified to pH=1 with a concentrated solution of hydrochloric acid and then extracted with EtOAc. The organic phases were assembled, washed with brine and dried over MgSO.sub.4. The solvent was removed under reduced pressure. Precipitation of the crude in diethyl ether gave the desired 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylic acid as a white powder (2.82 g, 65%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.62 (s, 3H), 2.75 (dd, J=15.7, 2.1 Hz, 1H), 2.91 (dd, J=15.7, 7.1 Hz, 1H), 3.09 (s, 3H), 3.30-3.38 (m, 1H), 3.46 (dt, J=9.9, 4.0 Hz, 1H), 3.76 (ddd, J=14.7, 8.9, 3.8 Hz, 1H), 4.13-4.23 (m, 2H), 7.13 (d, J=8.5 Hz, 2H), 7.23 (d, J=8.5 Hz, 2H). .sup.13C NMR (300 MHz, CDCl.sub.3) 17.4, 36.5, 38.7, 42.0, 58.8, 71.0, 109.1, 128.3, 128.8, 132.7, 139.3, 153.6, 169.1, 172.7. MS [MH].sup. 322.

Example 75: N-benzyl-4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxamide

[0248] 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylic acid (example 74, 323 mg, 1.0 mmol), benzylamine (262 L, 2.4 mmol), DIEA (860 L, 5.0 mmol) and a 50% solution of T3P in ethyl acetate (883 L, 3.0 mmol) were dissolved in anhydrous EtOAc (3 mL). After stirring the reaction mixture at RT for 24 h, the reaction was uncomplete. Benzylamine (131 L, 1.2 mmol), DIEA (430 L, 2.5 mmol) and a 50% solution of T3P in ethyl acetate (441 L, 1.5 mmol) were added. The reaction mixture was stirred at r.t. for 6 h. 1 M hydrochloric acid aqueous solution (20 mL) was added and the aqueous phase was extracted by EtOAc. The organic phases were combined, washed with brine and dried over MgSO.sub.4. The solvent was removed under reduced pressure. Purification of the crude by flash chromatography on silica using a mixture of DCM/MeOH 9/1 gave the desired (2-methoxyphenyl)methyl 1-(2-methoxyethyl)-6-methyl-2-oxo-4-propyl-3,4-dihydropyridine-5-carboxylate as a white powder (267 mg, 65%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.34 (s, 3H), 2.67 (dd, J=15.8, 2.6 Hz, 1H), 3.01 (dd, J=15.8, 7.6 Hz, 1H), 3.35 (s, 3H), 3.43-3.52 (m, 2H), 3.66 (ddd, J=14.5, 7.9, 4.7 Hz, 1H), 3.87 (dd, J=7.6, 2.6 Hz, 1H), 4.14 (dt, J=14.5, 4.7 Hz, 1H), 4.33 (dd, J=14.9, 5.4 Hz, 1H), 4.49 (dd, J=14.9, 5.4 Hz, 1H), 5.55 (t, J=5.4 Hz, 1H), 7.05-7.13 (m, 2H), 7.17 (d, J=8.4 Hz, 1H), 7.25 (d, J=8.4 Hz, 1H), 7.27-7.35 (m, 3H). MS [M+H].sup.+ 413. HRMS: calcd for C.sub.23H.sub.26N.sub.2O.sub.3Cl, [M+H].sup.+ 413.1632, found 413.1641.

Example 76: 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-N-phenyl-3,4-dihydropyridine-5-carboxamide

[0249] 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylic acid (example 74, 97 mg, 0.30 mmol), aniline (31 L, 0.33 mmol), EDCl (69 mg, 0.36 mmol) and DMAP (36 mg, 0.30 mmol) were dissolved in anh. DCM (2 mL). The reaction mixture was stirred for 18 h at RT. An aqueous solution of hydrochloric acid 1 M was added. The aqueous phase was extracted with DCM. The organic phases were assembled and dried over MgSO.sub.4. The solvent was removed under reduced pressure. Purification of the crude by flash chromatography on silica using a mixture of Cyclohexane/EtOAc 7/3 gave the desired 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-N-phenyl-3,4-dihydropyridine-5-carboxamide as a white powder (62 mg, 52%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.42 (s, 3H), 2.69 (dd, J=15.8, 2.3 Hz, 1H), 3.03 (dd, J=15.8, 7.6 Hz, 1H), 3.38 (s, 3H), 3.45-3.55 (m, 2H), 3.70 (ddd, J=14.5, 8.2, 4.5 Hz, 1H), 3.93 (dd, J=7.6, 2.3 Hz, 1H), 4.19 (dt, J=14.6, 3.5 Hz, 1H), 6.99-7.15 (m, 2H), 7.20-7.38 (m, 7H). .sup.13C NMR (75 MHz, CDCl.sub.3) 16.8, 38.6, 39.2, 41.7, 58.9, 71.2, 114.2, 119.8, 124.4, 128.6, 128.9, 129.5, 133.6, 137.5, 138.7, 143.1, 167.1, 168.2. MS [M+H].sup.+ 399. HRMS: calcd for C.sub.22H.sub.24N.sub.2O.sub.3Cl, [M+H].sup.+ 399.1475, found 399.1498.

Example 77: 4-(4-chlorophenyl)-5-(3,4-dihydro-2H-quinoline-1-carbonyl)-1-(2-methoxyethyl)-6-methyl-3,4-dihydropyridin-2-one

[0250] 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylic acid (example 74, 97 mg, 0.30 mmol), tetrahydroquinoline (44 L, 0.33 mmol), EDCl (69 mg, 0.36 mmol) and DMAP (36 mg, 0.30 mmol) were dissolved in anh. DCM (2 mL). The reaction mixture was stirred for 72 h at RT. The reaction was uncomplete; tetrahydroquinoline (44 L, 0.33 mmol) and EDCl (69 mg, 0.36 mmol) were added. The reaction mixture was stirred for 24 h at RT. An aqueous solution of hydrochloric acid 1 M was added. The aqueous phase was extracted with DCM. The organic phases were assembled and dried over MgSO.sub.4. The solvent was removed under reduced pressure. Purification of the crude by flash chromatography on silica using a mixture of Cyclohexane/EtOAc 6/4 gave the desired 4-(4-chlorophenyl)-5-(3,4-dihydro-2H-quinoline-1-carbonyl)-1-(2-methoxyethyl)-6-methyl-3,4-dihydropyridin-2-one as a colorless oil (62 mg, 52%). MS [M+H].sup.+ 439. HRMS: calcd for C.sub.25H.sub.28N.sub.2O.sub.3Cl, [M+H].sup.+ 439.1788, found 439.1767.

##STR00310##

TABLE-US-00008 TABLE 8 [00311] Example R16 R17 79 CH.sub.3 4-Me-Bn 80 CH.sub.3 4-CF.sub.3-Bn 81 CH.sub.3 2-Cl,4-F-Bn 82 CH.sub.3 2,6-diF-Bn 83 CH.sub.3 3,4-diOMe-Bn 84 [00312] 2-F-Bn 85 [00313] 3-F-Bn 86 [00314] 4-F-Bn 87 [00315] 2-Cl-Bn 88 [00316] 3-Cl-Bn 89 [00317] 4-Cl-Bn 90 [00318] 2-CF.sub.3-Bn 91 [00319] 3-CF.sub.3-Bn 92 [00320] 4-CF.sub.3-Bn 93 [00321] 2-CN-Bn 94 [00322] 3-CN-Bn 95 [00323] 4-CN-Bn 96 [00324] 3-COOMe-Bn 97 [00325] 4-COOMe-Bn 98 [00326] 2-Me-Bn 99 [00327] 3-Me-Bn 100 [00328] 4-Me-Bn 101 [00329] 2,4,6-triMe-Bn 103 [00330] 3-OMe-Bn 104 [00331] 4-OMe-Bn 105 [00332] 2-OCF.sub.3 106 [00333] [00334] 107 [00335] [00336] 108 [00337] [00338] 109 [00339] [00340] 110 [00341] [00342] 111 [00343] [00344] 112 [00345] [00346] 113 [00347] [00348] 116 [00349] [00350] 117 [00351] [00352] 119 [00353] [00354]

Example 78: 4-(4-chlorophenyl)-1,6-dimethyl-2-oxo-3,4-dihydropyridine-5-carboxylic Acid (Intermediate Product)

[0251] ##STR00355##

[0252] Step 1.

[0253] The dihydropyridone intermediate obtained following general procedure A (1.05 g, 3.75 mmol) was dissolved in anhydrous DMF (12.5 mL). Cesium carbonate (1.83 g, 5.63 mmol) and iodomethane (350 L, 5.63 mmol) were added. The reaction mixture was stirred at 60 C. for 1 h. The DMF was removed under reduced pressure. The residue was diluted in water and extracted by EtOAc. The organic layers were assembled, washed by brine and dried on MgSO.sub.4. Removal of the solvents under reduced pressure gave the desired compound as a yellow oil (1.10 g, quantitative). MS [M+H].sup.+ 294.

##STR00356##

[0254] Step 2.

[0255] The intermediate obtained in step 1 (1.10 mg, 3.75 mmol) was dissolved in MeOH (15 mL) and an aqueous solution of NaOH 1 N (13 mL, 13.1 mmol) was added. The reaction mixture was stirred at 60 C. for 18 h. The reaction mixture was cooled to r.t. and extracted once with diethyl ether. The aqueous phase was then acidified until pH=1 with an aqueous solution of hydrochloric acid. The aqueous phase was extracted by EtOAc. The organic layer was then washed with brine and dried with MgSO.sub.4. The solvent was removed under reduced pressure to give the 4-(4-chlorophenyl)-1,6-dimethyl-2-oxo-3,4-dihydropyridine-5-carboxylic acid (680 mg, 62%).

Example 79: p-tolylmethyl 4-(4-chlorophenyl)-1,6-dimethyl-2-oxo-3,4-dihydropyridine-5-carboxylate

[0256] 4-(4-chlorophenyl)-1,6-dimethyl-2-oxo-3,4-dihydropyridine-5-carboxylic acid (example 78, 0.36 mmol) was dissolved in anhydrous DMF (1.2 mL) then Cs.sub.2CO.sub.3 (349 mg, 1.07 mmol) and alpha bromo-p-xylene (66 mg, 0.36 mmol) were added. The reaction mixture was stirred for 1 h at RT.

[0257] Water was then added and the aqueous phase was extracted with EtOAc. The organic layer was then washed with brine and dried with MgSO.sub.4. The solvent was removed under reduced pressure to give the desired compound as a white solid (87 mg, 63%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.35 (s, 3H), 2.56 (s, 3H), 2.75 (dd, J=2.7 and 15.9 Hz, 1H), 2.89 (dd, J=7.2 and 15.9 Hz, 1H), 3.20 (s, 3H) 5.20 (d, J=5.4 Hz, 1H), 5.07 (s, 2H), 7.00 (d, J=8.4 Hz, 2H), 7.05 (d, J=8.1 Hz, 2H), 7.11 (d, J=8.1 Hz, 2H), 7.20 (d, J=8.4 Hz, 2H), MS [M+H].sup.+ 384.

Example 80: [4-(trifluoromethyl)phenyl]methyl 4-(4-chlorophenyl)-1,6-dimethyl-2-oxo-3,4-dihydropyridine-5-carboxylate

[0258] 4-(4-chlorophenyl)-1,6-dimethyl-2-oxo-3,4-dihydropyridine-5-carboxylic acid (example 78, 0.36 mmol) was dissolved in anhydrous DMF (1.2 mL) then Cs.sub.2CO.sub.3 (349 mg, 1.07 mmol) and 4-(trifluoromethyl)benzyl bromide (85 mg, 0.36 mmol) were added. The reaction mixture was stirred for 1 h at RT. Water was then added and the aqueous phase was extracted with EtOAc. The organic layer was then washed with brine and dried with MgSO.sub.4. The solvent was removed under reduced pressure to give the desired compound as a white solid (117 mg, 75%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.59 (s, 3H), 2.76 (dd, J=2.4 and 15.9 Hz, 1H), 2.92 (dd, J=7.5 and 15.9 Hz, 1H), 3.23 (s, 3H), 4.21 (d, J=6.3 Hz, 1H), 5.11 (d, J=13.0 Hz, 1H), 5.19 (d, J=13.1 Hz, 1H), 7.02 (d, J=8.4 Hz, 2H), 7.21 (d, J=6.2 Hz, 2H), 7.23 (d, J=8.4 Hz, 2H), 7.53 (d, J=6.0 Hz, 2H), MS [M+H].sup.+ 438.

Example 81: (2-chloro-4-fluoro-phenyl)methyl 4-(4-chlorophenyl)-1,6-dimethyl-2-oxo-3,4-dihydropyridine-5-carboxylate

[0259] 4-(4-chlorophenyl)-1,6-dimethyl-2-oxo-3,4-dihydropyridine-5-carboxylic acid (example 78, 0.36 mmol) was dissolved in anhydrous DMF (1.2 mL) then Cs.sub.2CO.sub.3 (349 mg, 1.07 mmol) and 2-Chloro-4-fluorobenzyl bromide (85 mg, 0.36 mmol) were added. The reaction mixture was stirred at RT. Water was then added and the aqueous phase was extracted with EtOAc. The organic layer was then washed with brine and dried with MgSO.sub.4. The solvent was removed under reduced pressure to give the desired compound as a colorless oil (38 mg, 26%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.59 (s, 3H), 2.76 (dd, J=2.4 and 15.9 Hz, 1H), 2.92 (dd, J=7.5 and 15.9 Hz, 1H), 3.22 (s, 3H), 4.19 (d, J=5.7 Hz, 1H), 5.12 (d, J=13.2 Hz, 1H), 5.21 (d, J=12.9 Hz, 1H), 6.86 (dt, J=2.4 and 8.1 Hz, 1H), 7.00 (d, J=8.4 Hz, 2H), 7.12-7.04 (m, 2H) 7.20 (d, J=8.4 Hz, 2H), MS [M+H].sup.+ 422.

Example 82: (2,6-difluorophenyl)methyl 4-(4-chlorophenyl)-1,6-dimethyl-2-oxo-3,4-dihydropyridine-5-carboxylate

[0260] 4-(4-chlorophenyl)-1,6-dimethyl-2-oxo-3,4-dihydropyridine-5-carboxylic acid (example 78, 75 mg, 0.27 mmol) was dissolved in anhydrous DMF (1 mL) then Cs.sub.2CO.sub.3 (131 mg, 0.68 mmol) and 2,6-difluorobenzyl bromide (83 mg, 0.40 mmol) were added. The reaction mixture was stirred for 1 h at RT. Water was then added and the aqueous phase was extracted with EtOAc. The organic layer was then washed with brine and dried with MgSO.sub.4. The solvent was removed under reduced pressure. The crude product was purified by flash chromatography using a mixture of cyclohexane/EtOAc 9/1 to give the desired compound as a colorless oil (73 mg, 66%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.53 (s, 3H), 2.72 (dd, J=16.0, 2.4 Hz, 1H), 2.87 (dd, J=16.0, 7.5 Hz, 1H), 3.19 (s, 3H), 4.12 (dd, J=7.5, 2.4 Hz, 1H), 5.18 (d, J=12.6 Hz, 1H), 5.23 (d, J=12.6 Hz, 1H), 6.82-6.92 (m, 2H), 6.96 (d, J=8.4 Hz, 2H), 7.14 (d, J=8.4 Hz, 2H), 7.23-7.36 (m, 3H). MS [M+H].sup.+ 406. HRMS: calcd for C.sub.23H.sub.22N.sub.2O.sub.3Cl, [M+CH.sub.3CN+H]+447.1287, found 447.1310.

Example 83: (3,4-dimethoxyphenyl)methyl 4-(4-chlorophenyl)-1,6-dimethyl-2-oxo-3,4-dihydropyridine-5-carboxylate

[0261] The appropriate acid intermediate (75 mg, 0.27 mmol) was dissolved in anhydrous DMF (1 mL) then Cs.sub.2CO.sub.3 (104 mg, 0.32 mmol) and 3,4-dimethoxybenzyl chloride (60 mg, 0.32 mmol) were added. The reaction mixture was stirred for 1 h at RT. The solvents were removed under reduced pressure. The residue was dissolved in EtOAc and water. The aqueous phase was extracted 3 times with EtOAc. The organic layer was then washed with brine and dried with MgSO.sub.4. The solvent was removed under reduced pressure. The crude product was purified by flash chromatography using a mixture of cyclohexane/EtOAc 95/5 to give the desired compound as a colorless oil (115 mg, 100%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.58 (d, J=0.7 Hz, 3H), 2.76 (dd, J=16.1, 2.5 Hz, 1H), 2.91 (dd, J=16.1, 7.5 Hz, 1H), 3.21 (s, 3H), 3.77 (s, 3H), 3.89 (s, 3H), 4.21 (d, J=7.5 Hz, 1H), 5.02 (d, J=12.3 Hz, 1H), 5.09 (d, J=12.3 Hz, 1H), 6.68 (d, J=1.8 Hz, 1H), 6.73-6.82 (m, 2H), 7.02 (d, J=8.4 Hz, 2H), 7.22 (d, J=8.4 Hz, 2H). MS [M+H].sup.+ 430. HRMS: calcd for C.sub.23H.sub.25NO.sub.5Cl.sub.2, [M+H].sup.+ 430.1421, found 430.1421.

Example 84: (2-fluorophenyl)methyl 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate

[0262] 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylic acid (example 74, 75 mg, 0.23 mmol) was dissolved in anhydrous DMF (1 mL) then cesium carbonate (114 mg, 0.35 mmol) and 2-fluorobenzyl bromide (30 L, 0.25 mmol) were added. The reaction mixture was stirred for 1 h at RT. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc and water. The aqueous phase was extracted with EtOAc. The organic layers were assembled, washed with brine and dried over MgSO.sub.4. The solvent was removed under reduced pressure to give the desired (2-fluorophenyl)methyl 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate as a colorless oil (94 mg, 95%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.53 (s, 3H), 2.64 (dd, J=15.7, 2.2 Hz, 1H), 2.84 (dd, J=15.7, 7.6 Hz, 1H), 3.24 (s, 3H), 3.31 (ddd, J=9.9, 8.6, 4.0 Hz, 1H), 3.39 (dt, J=9.9, 4.0 Hz, 1H), 3.68 (ddd, J=14.2, 8.6, 4.0 Hz, 1H), 4.04-4.13 (m, 2H), 5.06 (d, J=14.0 Hz, 1H), 5.11 (d, J=14.0 Hz, 1H), 6.91-6.98 (m, 3H), 7.01 (d, J=8.6 Hz, 2H), 7.12 (d, J=8.6 Hz, 2H), 7.16-7.24 (m, 1H). MS [M+H].sup.+ 432. HRMS: calcd for C.sub.23H.sub.24NO.sub.4FCl, [M+H].sup.+ 432.1378, found 432.1378.

Example 85: (3-fluorophenyl)methyl 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate

[0263] 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylic acid (example 74, 75 mg, 0.23 mmol) was dissolved in anhydrous DMF (1 mL) then cesium carbonate (114 mg, 0.35 mmol) and 3-fluorobenzyl bromide (31 L, 0.25 mmol) were added. The reaction mixture was stirred at RT. for 1 h. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc and water. The aqueous phase was extracted with EtOAc. The organic layers were assembled, washed with brine and dried over MgSO.sub.4. The solvent was removed under reduced pressure to give the desired (3-fluorophenyl)methyl 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate as a white powder (95 mg, 95%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.63 (s, 3H), 2.72 (dd, J=15.7, 2.3 Hz, 1H), 2.93 (dd, J=15.7, 7.5 Hz, 1H), 3.32 (s, 3H), 3.38 (ddd, J=9.9, 8.6, 3.5 Hz, 1H), 3.47 (dt, J=9.9, 3.9 Hz, 1H), 3.76 (ddd, J=14.6, 8.6, 3.9 Hz, 1H), 4.14-4.21 (m, 2H), 5.04 (d, J=13.1 Hz, 1H), 5.12 (d, J=13.1 Hz, 1H), 6.76 (dt, J=9.6, 1.7 Hz, 1H), 6.86 (d, J=7.6 Hz, 1H), 6.95 (td, J=8.7, 2.4 Hz, 1H), 7.10 (d, J=8.4 Hz, 2H), 7.19-7.24 (m, 3H). MS [M+H].sup.+ 432. HRMS: calcd for C.sub.23H.sub.24NO.sub.4ClF, [M+H].sup.+ 432.1378, found 432.1384.

Example 86: (4-fluorophenyl)methyl 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate

[0264] 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylic acid (example 74, 45 mg, 0.14 mmol) was dissolved in anhydrous DMF (1 mL) then cesium carbonate (68 mg, 0.21 mmol) and 4-fluorobenzyl bromide (19 L, 0.15 mmol) were added. The reaction mixture was stirred for 18 h at RT. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc and water. The aqueous phase was extracted with EtOAc. The organic layers were assembled, washed with brine and dried over MgSO.sub.4. The solvent was removed under reduced pressure to give the desired (4-fluorophenyl)methyl 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate as a colorless oil (48 mg, 80%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.53 (s, 3H), 2.63 (dd, J=15.7, 2.3 Hz, 1H), 2.84 (dd, J=15.7, 7.3 Hz, 1H), 3.24 (s, 3H), 3.30 (ddd, J=9.9, 8.6, 4.0 Hz, 1H), 3.39 (dt, J=9.9, 4.0 Hz, 1H), 3.68 (ddd, J=14.8, 8.6, 3.6 Hz, 1H), 4.06-4.13 (m, 2H), 4.94 (d, J=12.6 Hz, 1H), 5.00 (d, J=12.6 Hz, 1H), 6.88 (t, J=8.6 Hz, 2H), 6.97-7.03 (m, 4H), 7.14 (d, J=8.4 Hz, 2H). MS [M+H].sup.+ 432.

Example 87: (2-chlorophenyl)methyl 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate

[0265] 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylic acid (example 74, 75 mg, 0.23 mmol) was dissolved in anhydrous DMF (1 mL) then cesium carbonate (114 mg, 0.35 mmol) and 2-chlorobenzyl bromide (33 L, 0.25 mmol) were added. The reaction mixture was stirred at RT. for 1 h. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc and water. The aqueous phase was extracted with EtOAc. The organic layers were assembled, washed with brine and dried over MgSO.sub.4. The solvent was removed under reduced pressure to give the desired (2-chlorophenyl)methyl 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate as a white powder (99 mg, 96%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.55 (s, 3H), 2.65 (dd, J=15.8, 2.2 Hz, 1H), 2.86 (dd, J=15.8, 7.7 Hz, 1H), 3.25 (s, 3H), 3.31 (ddd, J=9.9, 8.6, 3.6 Hz, 1H), 3.40 (dt, J=9.9, 4.0 Hz, 1H), 3.69 (ddd, J=14.5, 8.6, 4.0 Hz, 1H), 4.04-4.16 (m, 2H), 5.09 (d, J=13.4 Hz, 1H), 5.16 (d, J=13.4 Hz, 1H), 6.93 (dd, J=7.5, 1.4 Hz, 1H), 7.01-7.07 (m, 3H), 7.11-7.17 (m, 3H), 7.26 (dd, J=8.0, 1.3 Hz, 1H). MS [M+H].sup.+ 448. HRMS: calcd for C.sub.23H.sub.24NO.sub.4Cl.sub.2, [M+H].sup.+ 448.1082, found 448.1083.

Example 88: (3-chlorophenyl)methyl 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate

[0266] 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylic acid (example 74, 75 mg, 0.23 mmol) was dissolved in anhydrous DMF (1 mL) then cesium carbonate (114 mg, 0.35 mmol) and 3-chlorobenzyl bromide (33 L, 0.25 mmol) were added. The reaction mixture was stirred for 1 h at RT. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc and water. The aqueous phase was extracted with EtOAc. The organic layers were assembled, washed with brine and dried over MgSO.sub.4. The solvent was removed under reduced pressure to give the desired (3-chlorophenyl)methyl 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate as a colorless oil (100 mg, 97%). .sup.1H NMR (300 MHz, CDCl.sub.3), 2.56 (s, 3H), 2.65 (dd, J=15.7, 2.1 Hz, 1H), 2.86 (dd, J=15.7, 7.3 Hz, 1H), 3.26 (s, 3H), 3.32 (ddd, J=9.6, 8.5, 3.7 Hz, 1H), 3.41 (dt, J=9.6, 3.7 Hz, 1H), 3.70 (ddd, J=14.5, 8.5, 3.7 Hz, 1H), 4.07-4.14 (m, 2H), 4.93 (d, J=12.9 Hz, 1H), 5.04 (d, J=12.9 Hz, 1H), 6.89 (d, J=7.3 Hz, 1H), 6.96 (s, 1H), 7.03 (d, J=8.4 Hz, 2H), 7.13 (d, J=7.3 Hz, 1H), 7.15-7.18 (m, 3H). MS [M+H].sup.+ 448. HRMS: calcd for C.sub.23H.sub.24NO.sub.4Cl.sub.2, [M+H].sup.+ 448.1082, found 448.1085.

Example 89: (4-chlorophenyl)methyl 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate

[0267] 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylic acid (example 74, mg, 0.23 mmol) was dissolved in anhydrous DMF (1 mL) then cesium carbonate (114 mg, 0.35 mmol) and 4-chlorobenzyl bromide (51 mg, 0.25 mmol) were added. The reaction mixture was stirred at RT. for 1 h. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc and water. The aqueous phase was extracted with EtOAc. The organic layers were assembled, washed with brine and dried over MgSO.sub.4. The solvent was removed under reduced pressure to give the desired (4-chlorophenyl)methyl 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate as a white powder (68 mg, 66%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.54 (s, 3H), 2.64 (dd, J=15.8, 2.4 Hz, 1H), 2.84 (dd, J=15.8, 7.5 Hz, 1H), 3.25 (s, 3H), 3.30 (ddd, J=9.9, 8.7, 3.6 Hz, 1H), 3.39 (dt, J=9.9, 4.2 Hz, 1H), 3.68 (ddd, J=14.7, 8.7, 4.2 Hz, 1H), 4.06-4.13 (m, 2H), 4.93 (d, J=12.9 Hz, 1H), 5.01 (d, J=12.9 Hz, 1H), 6.94 (d, J=8.4 Hz, 2H), 7.01 (d, J=8.4 Hz, 2H), 7.10-7.21 (m, 4H). MS [M+H].sup.+ 448. HRMS: calcd for C.sub.23H.sub.24NO.sub.4Cl.sub.2, [M+H].sup.+ 448.1082, found 448.1085.

Example 90: [2-(trifluoromethyl)phenyl]methyl 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate

[0268] 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylic acid (example 74, 75 mg, 0.23 mmol) was dissolved in anhydrous DMF (1 mL) then cesium carbonate (114 mg, 0.35 mmol) and 2-trifluoromethylbenzyl bromide (38 L, 0.25 mmol) were added. The reaction mixture was stirred for 2 h at RT. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc and water. The aqueous phase was extracted 3 times with EtOAc. The organic layers were assembled, washed with brine and dried over MgSO.sub.4. The solvent was removed under reduced pressure to give the desired [2-(trifluoromethyl)phenyl]methyl 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate as a colorless oil (100 mg, 90%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.63 (s, 3H), 2.72 (dd, J=15.7, 2.1 Hz, 1H), 2.94 (dd, J=15.7, 7.4 Hz, 1H), 3.33 (s, 3H), 3.35-3.42 (m, 1H), 3.48 (dt, J=10.0, 3.7 Hz, 1H), 3.77 (ddd, J=14.5, 8.5, 3.7 Hz, 1H), 4.14-4.22 (m, 2H), 5.24 (d, J=13.5 Hz, 1H), 5.34 (d, J=13.5 Hz, 1H), 7.03-7.06 (m, 1H), 7.10 (d, J=8.3 Hz, 2H), 7.21 (d, J=8.3 Hz, 2H), 7.32-7.42 (m, 2H), 7.61-7.64 (m, 1H). MS [M+H].sup.+ 482. HRMS: calcd for C.sub.24H.sub.24NO.sub.4F.sub.3Cl, [M+H].sup.+ 482.1346, found 482.1352.

Example 91: [3-(trifluoromethyl)phenyl]methyl 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate

[0269] The 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylic acid (example 74, 75 mg, 0.23 mmol) was dissolved in anhydrous DMF (1 mL) then cesium carbonate (114 mg, 0.35 mmol) and 3-trifluoromethylbenzyl bromide (38 L, 0.25 mmol) were added. The reaction mixture was stirred for 1 h at RT. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc and water. The aqueous phase was extracted 3 times with EtOAc. The organic layers were assembled, washed with brine and dried over MgSO.sub.4. The solvent was removed under reduced pressure to give the desired [3-(trifluoromethyl)phenyl]methyl 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate as a colorless oil (108 mg, 98%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.64 (s, 3H), 2.72 (dd, J=15.7, 2.2 Hz, 1H), 2.93 (dd, J=15.7, 7.5 Hz, 1H), 3.33 (s, 3H), 3.35-3.42 (m, 1H), 3.48 (dt, J=9.8, 4.0 Hz, 1H), 3.77 (ddd, J=14.7, 8.9, 4.0 Hz, 1H), 4.09-4.22 (m, 2H), 5.09 (d, J=13.1 Hz, 1H), 5.17 (d, J=13.1 Hz, 1H), 7.10 (d, J=8.4 Hz, 2H), 7.22 (d, J=8.4 Hz, 2H), 7.20-7.26 (m, 1H), 7.35-7.40 (m, 2H), 7.53 (d, J=8.1 Hz, 1H). MS [M+H].sup.+ 482. HRMS: calcd for C.sub.24H.sub.24NO.sub.4F.sub.3Cl, [M+H].sup.+ 482.1346, found 482.1356.

Example 92: [4-(trifluoromethyl)phenyl]methyl 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate

[0270] The 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylic acid (example 74, 75 mg, 0.23 mmol) was dissolved in anhydrous DMF (1 mL) then cesium carbonate (114 mg, 0.35 mmol) and 4-trifluoromethylbenzyl bromide (60 mg, 0.25 mmol) were added. The reaction mixture was stirred for 1 h at RT. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc and water. The aqueous phase was extracted 3 times with EtOAc. The organic layers were assembled, washed with brine and dried over MgSO.sub.4. The solvent was removed under reduced pressure to give the desired [4-(trifluoromethyl)phenyl]methyl 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate as a white powder (103 mg, 93%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.63 (s, 3H), 2.73 (dd, J=15.7, 2.3 Hz, 1H), 2.93 (dd, J=15.7, 7.6 Hz, 1H), 3.33 (s, 3H), 3.34-3.50 (m, 2H), 3.72-3.81 (m, 1H), 4.13-4.21 (m, 2H), 5.09 (d, J=13.0 Hz, 1H), 5.18 (d, J=13.0 Hz, 1H), 7.10 (d, J=8.5 Hz, 2H), 7.17 (d, J=8.3 Hz), 7.23 (d, J=8.5 Hz), 7.51 (d, J=8.3 Hz, 2H). MS [M+H].sup.+ 482. HRMS: calcd for C.sub.24H.sub.24NO.sub.4F.sub.3Cl, [M+H].sup.+ 482.1346, found 482.1343.

Example 93: (2-cyanophenyl)methyl 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate

[0271] 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylic acid (example 74, 75 mg, 0.23 mmol) was dissolved in anhydrous DMF (1 mL) then cesium carbonate (114 mg, 0.35 mmol) and 2-cyanobenzyl bromide (49 mg, 0.25 mmol) were added. The reaction mixture was stirred for 18 h at RT. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc and water. The aqueous phase was extracted with EtOAc. The organic layers were assembled, washed with brine and dried over MgSO.sub.4. The solvent was removed under reduced pressure to give the desired (2-cyanophenyl)methyl 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate as a colorless oil (100 mg, 99%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.56 (s, 3H), 2.65 (dd, J=15.8, 2.3 Hz, 1H), 2.87 (dd, J=15.8, 7.6 Hz, 1H), 3.25 (s, 3H), 3.29-3.35 (m, 1H), 3.40 (dt, J=9.8, 3.9 Hz, 1H), 3.70 (ddd, J=14.6, 8.5, 3.6 Hz, 1H), 4.10 (dt, J=14.6, 3.9 Hz, 1H), 4.17 (d, J=7.6 Hz, 1H), 5.15 (d, J=13.3 Hz, 1H), 5.26 (d, J=13.3 Hz, 1H), 7.00-7.05 (m, 3H), 7.12 (d, J=8.5 Hz, 2H), 7.30 (td, J=7.5, 1.6 Hz, 1H), 7.38 (td, J=7.5, 1.6 Hz, 1H), 7.55 (dd, J=7.5, 1.7 Hz, 1H). MS [M+H].sup.+ 439. HRMS: calcd for C.sub.24H.sub.24N.sub.2O.sub.4Cl, [M+H].sup.+ 439.1425, found 439.1425.

Example 94: (3-cyanophenyl)methyl 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate

[0272] 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylic acid (example 74, 75 mg, 0.23 mmol) was dissolved in anhydrous DMF (1 mL) then cesium carbonate (114 mg, 0.35 mmol) and 3-cyanobenzyl bromide (49 mg, 0.25 mmol) were added. The reaction mixture was stirred for 18 h at RT. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc and water. The aqueous phase was extracted with EtOAc. The organic layers were assembled, washed with brine and dried over MgSO.sub.4. The solvent was removed under reduced pressure to give the desired (3-cyanophenyl)methyl 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate as a colorless oil (100 mg, 99%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.57 (s, 3H), 2.66 (dd, J=15.7, 2.2 Hz, 1H), 2.87 (dd, J=15.7, 7.6 Hz, 1H), 3.26 (s, 3H), 3.28-3.36 (m, 1H), 3.41 (dt, J=9.8, 3.9 Hz, 1H), 3.71 (ddd, J=14.5, 8.8, 3.9 Hz, 1H), 4.07-4.15 (m, 2H), 4.97 (d, J=13.4 Hz, 1H), 5.08 (d, J=13.4 Hz, 1H), 7.03 (d, J=8.4 Hz, 2H), 7.16-7.20 (m, 3H), 7.26-7.31 (m, 2H), 7.48 (d, J=7.4 Hz, 1H). MS [M+H].sup.+ 439. HRMS: calcd for C.sub.24H.sub.24N.sub.2O.sub.4Cl, [M+H].sup.+ 439.1425, found 439.1422.

Example 95: (4-cyanophenyl)methyl 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate

[0273] 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylic acid (example 74, 75 mg, 0.23 mmol) was dissolved in anhydrous DMF (1 mL) then cesium carbonate (114 mg, 0.35 mmol) and 4-cyanobenzyl bromide (49 mg, 0.25 mmol) were added. The reaction mixture was stirred for 3 h at RT. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc and water. The aqueous phase was extracted with EtOAc. The organic layers were assembled, washed with brine and dried over MgSO.sub.4. The solvent was removed under reduced pressure. The crude product was purified by flash chromatography using a mixture of Cyclohexane/EtOAc (9/1 to 8/2) as eluent to give the desired (4-cyanophenyl)methyl 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate as a white powder (62 mg, 62%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.64 (s, 3H), 2.74 (dd, J=15.6, 2.1 Hz, 1H), 2.95 (dd, J=15.6, 7.6 Hz, 1H), 3.34 (s, 3H), 3.36-3.43 (m, 1H), 3.78 (ddd, J=14.5, 8.6, 3.9 Hz, 1H), 4.15-4.23 (m, 2H), 5.06 (d, J=13.7 Hz, 1H), 5.21 (d, J=13.7 Hz, 1H), 7.08-7.14 (m, 4H), 7.25 (d, J=8.4 Hz, 2H), 7.54 (d, J=8.4 Hz, 2H). MS [M+H].sup.+ 439. HRMS: calcd for C.sub.24H.sub.24N.sub.2O.sub.4Cl, [M+H].sup.+ 439.1425, found 439.1425.

Example 96: (3-methoxycarbonylphenyl)methyl 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate

[0274] 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylic acid (example 74, 75 mg, 0.23 mmol) was dissolved in anhydrous DMF (1 mL) then cesium carbonate (114 mg, 0.35 mmol) and 3-(Bromomethyl)benzoic acid methyl ester (57 mg, 0.25 mmol) were added. The reaction mixture was stirred for 3 h at RT. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc and water. The aqueous phase was extracted with EtOAc. The organic layers were assembled, washed with brine and dried over MgSO.sub.4. The solvent was removed under reduced pressure. The crude product was purified by flash chromatography using a mixture of Cyclohexane/EtOAc (9/1 to 8/2) as eluent to give the desired (3-methoxycarbonylphenyl)methyl 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate as a yellowish oil (108 mg, 99%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.62 (s, 3H), 2.71 (dd, J=15.7, 2.2 Hz, 1H), 2.92 (dd, J=15.7, 7.4 Hz, 1H), 3.32 (s, 3H), 3.38 (ddd, J=9.9, 8.6, 3.7 Hz, 1H), 3.46 (dt, J=9.9, 4.2 Hz, 1H), 3.76 (ddd, J=14.5, 8.6, 3.8 Hz, 1H), 3.92 (s, 3H), 4.13-4.21 (m, 2H), 5.10 (d, J=12.9 Hz, 1H), 5.15 (d, J=12.9 Hz, 1H), 7.09 (d, J=8.5 Hz, 2H), 7.20 (d, J=8.5 Hz, 2H), 7.24-7.27 (m, 1H), 7.34 (t, J=7.7 Hz, 1H), 7.88 (s, 1H), 7.95 (d, J=7.7 Hz, 1H). MS [M+H].sup.+ 472. HRMS: calcd for C.sub.25H.sub.27NO.sub.6Cl, [M+H].sup.+ 472.1527, found 472.1539.

Example 97: (4-methoxycarbonylphenyl)methyl 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate

[0275] 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylic acid (example 74, 75 mg, 0.23 mmol) was dissolved in anhydrous DMF (1 mL) then cesium carbonate (114 mg, 0.35 mmol) and 4-(Bromomethyl)benzoic acid methyl ester (57 mg, 0.25 mmol) were added. The reaction mixture was stirred for 3 h at RT. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc and water. The aqueous phase was extracted with EtOAc. The organic layers were assembled, washed with brine and dried over MgSO.sub.4. The solvent was removed under reduced pressure to give the desired (4-methoxycarbonylphenyl)methyl 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate as a white powder (101 mg, 93%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.64 (s, 3H), 2.73 (dd, J=15.8, 2.1 Hz, 1H), 2.94 (dd, J=15.8, 7.4 Hz, 1H), 3.34 (s, 3H), 3.35-3.43 (m, 1H), 3.48 (dt, J=9.9, 4.8 Hz, 1H), 3.77 (ddd, J=14.5, 8.4, 3.8 Hz, 1H), 3.93 (s, 3H), 4.12-4.23 (m, 2H), 5.11 (d, J=13.4 Hz, 1H), 5.19 (d, J=13.4 Hz, 1H), 7.11 (d, J=8.4 Hz, 2H), 7.15 (d, J=8.1 Hz, 2H), 7.24 (d, J=8.4 Hz, 2H), 7.94 (d, J=8.1 Hz, 2H). MS [M+H].sup.+ 472. HRMS: calcd for C.sub.25H.sub.27NO.sub.6Cl, [M+H].sup.+ 472.1527, found 472.1539.

Example 98: o-tolylmethyl 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate

[0276] The 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylic acid (example 74, 75 mg, 0.23 mmol) was dissolved in anhydrous DMF (1 mL) then cesium carbonate (114 mg, 0.35 mmol) and o-methylbenzyl bromide (34 L, 0.25 mmol) were added. The reaction mixture was stirred for 1 h at RT. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc and water. The aqueous phase was extracted 3 times with EtOAc. The organic layers were assembled, washed with brine and dried over MgSO.sub.4. The solvent was removed under reduced pressure to give the desired o-tolylmethyl 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate as a white powder (91 mg, 93%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.05 (s, 3H), 2.55 (s, 3H), 2.63 (dd, J=15.7, 2.1 Hz, 1H), 2.83 (dd, J=15.7, 7.4 Hz, 1H), 3.25 (s, 3H), 3.30 (ddd, J=12.3, 8.5, 3.7 Hz, 1H), 3.39 (dt, J=9.9, 4.1 Hz, 1H), 3.68 (ddd, J=14.6, 8.5, 4.1 Hz, 1H), 4.06-4.14 (m, 2H), 5.00 (d, J=13.4 Hz, 1H), 5.04 (d, J=13.4 Hz, 1H), 6.95-7.08 (m, 5H), 7.09-7.17 (m, 3H). MS [M+H].sup.+ 428. HRMS: calcd for C.sub.24H.sub.27NO.sub.4Cl, [M+H].sup.+ 428.1629, found 428.1636.

Example 99: m-tolylmethyl 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate

[0277] The 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylic acid (example 74, 75 mg, 0.23 mmol) was dissolved in anhydrous DMF (1 mL) then cesium carbonate (114 mg, 0.35 mmol) and m-methylbenzyl bromide (34 L, 0.25 mmol) were added.

[0278] The reaction mixture was stirred for 1 h at RT. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc and water. The aqueous phase was extracted 3 times with EtOAc. The organic layers were assembled, washed with brine and dried over MgSO.sub.4. The solvent was removed under reduced pressure to give the desired m-tolylmethyl 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate as a colorless oil (91 mg, 93%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.27 (s, 3H), 2.62 (s, 3H), 2.71 (dd, J=15.6, 2.2 Hz, 1H), 2.93 (dd, J=15.6, 7.4 Hz, 1H), 3.33 (s, 3H), 3.35-3.51 (m, 2H), 3.71-3.81 (m, 1H), 4.14-4.23 (m, 2H), 5.03 (d, J=12.8 Hz, 1H), 5.12 (d, J=12.8 Hz, 1H), 6.85 (s, 1H), 6.91 (d, J=7.7 Hz, 1H), 7.05-7.19 (m, 4H), 7.22 (d, J=8.6 Hz, 2H). MS [M+H].sup.+ 428. HRMS: calcd for C.sub.24H.sub.27NO.sub.4Cl, [M+H].sup.+ 428.1629, found 428.1627.

Example 100: p-tolylmethyl 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate

[0279] The 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylic acid (example 74, 75 mg, 0.23 mmol) was dissolved in anhydrous DMF (1 mL) then cesium carbonate (114 mg, 0.35 mmol) and p-methylbenzyl bromide (34 L, 0.25 mmol) were added. The reaction mixture was stirred for 1 h at RT. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc and water. The aqueous phase was extracted 3 times with EtOAc. The organic layers were assembled, washed with brine and dried over MgSO.sub.4. The solvent was removed under reduced pressure to give the desired p-tolylmethyl 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate as a colorless oil (94 mg, 96%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.26 (s, 3H), 2.53 (s, 3H), 2.63 (dd, J=15.8, 2.2 Hz, 1H), 2.83 (dd, J=15.8, 7.6 Hz, 1H), 3.24 (s, 3H), 3.30 (ddd, J=9.8, 8.5, 3.9 Hz, 1H), 3.39 (dt, J=9.8, 3.9 Hz, 1H), 3.67 (ddd, J=14.4, 8.3, 4.0 Hz, 1H), 4.04-4.13 (m, 2H), 4.98 (s, 2H), 6.94 (d, J=8.4 Hz, 2H), 6.99-7.05 (m, 4H), 7.14 (d, J=8.4 Hz, 2H). MS [M+H].sup.+ 428. HRMS: calcd for C.sub.24H.sub.27NO.sub.4Cl, [M+H].sup.+ 428.1629, found 428.1642.

Example 101: (2,4,6-trimethylphenyl)methyl 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate

[0280] Step 1.

[0281] 2,4,6-trimethylbenzyl alcohol (150 mg, 1.0 mmol) was dissolved in anh. DCM (4 mL). Thionyl chloride (87 L, 1.2 mmol) was added slowly at 0 C. The reaction mixture was stirred at RT. for 1 h. Removal of the solvent under reduced pressure gave the desired 2,4,6-trimethylbenzyl chloride (168 mg, 100%) as a white powder. .sup.1H NMR (300 MHz, CDCl.sub.3) 2.29 (s, 3H), 2.42 (s, 6H), 4.68 (s, 2H), 6.89 (s, 2H). MS [M+H].sup.+ 133.

[0282] Step 2.

[0283] 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylic acid (example 74, 97 mg, 0.3 mmol) was dissolved in anhydrous DMF (1 mL) then cesium carbonate (97 mg, 0.3 mmol) and 2,4,6-trimethylbenzyl chloride (50 mg, 0.3 mmol) were added. The reaction mixture was stirred at RT. for 1 h. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc and water. The aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine and dried over MgSO.sub.4. Removal of the solvent under reduced pressure gave the desired (2,4,6-trimethylphenyl)methyl 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate as a yellowish oil (111 mg, 81%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.16 (s, 6H), 2.28 (s, 3H), 2.61 (s, 3H), 2.67 (dd, J=15.7, 2.3 Hz, 1H), 2.88 (dd, J=15.7, 7.7 Hz, 1H), 3.32 (s, 3H), 3.35-3.51 (m, 2H), 3.75 (ddd, J=14.7, 8.3, 4.0 Hz, 1H), 3.10 (dd, J=7.7, 2.3 Hz, 1H), 4.16 (dt, J=14.7, 4.2 Hz, 1H), 5.01 (d, J=12.1 Hz, 1H), 5.25 (d, J=12.1 Hz, 1H), 6.83 (s, 2H), 7.02 (d, J=8.6 Hz, 1H), 7.17 (d, J=8.6 Hz, 1H). .sup.13C NMR (75 MHz, CDCl.sub.3) 17.1, 19.3, 21.0, 36.8, 38.6, 41.9, 58.8, 60.9, 71.0, 110.1, 128.3, 128.6, 128.9, 129.0, 132.5, 138.1, 138.3, 139.7, 150.8, 167.2, 168.9. MS [M+H].sup.+ 456. HRMS: calcd for C.sub.26H.sub.31NO.sub.4Cl, [M+H].sup.+ 456.1942, found 456.1938.

Example 103: (3-methoxyphenyl)methyl 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate

[0284] 3-methoxybenzyl alcohol (248 L, 2.0 mmol) and triethylamine (335 L, 2.4 mmol) were dissolved in anh. DCM (7 mL). Thionyl chloride (218 L, 3.0 mmol) was added slowly. The reaction mixture was stirred at RT. for 1 h. The reaction mixture was washed with an aqueous solution of HCl 1N. The organic phase was dried over MgSO.sub.4. The solvent was removed under reduced pressure to give the desired 2-methoxybenzyl chloride (313 mg, 100%) as a yellowish oil. 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylic acid (example 74, 85 mg, 0.26 mmol) was dissolved in anhydrous DMF (1 mL) then cesium carbonate (169 mg, 0.52 mmol) and 3-methoxybenzyl chloride (81 mg, 0.52 mmol) were added. 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 water. The aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine and dried over MgSO.sub.4. The solvent was removed under reduced pressure. Purification of the crude by flash chromatography using a mixture of Cyclohexane/EtOAc (8/2) as eluent gave the desired (3-methoxyphenyl)methyl 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate as a yellowish oil (11 mg, 9%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.62 (s, 3H), 2.71 (dd, J=15.8, 2.2 Hz, 1H), 2.92 (dd, J=15.8, 7.5 Hz, 1H), 3.31 (s, 3H), 3.37 (ddd, J=10.0, 8.5, 3.6 Hz, 1H), 3.46 (dt, J=10.0, 4.1 Hz, 1H), 3.70-3.79 (m, 4H), 4.13-4.23 (m, 2H), 5.04 (d, J=12.7 Hz, 1H), 5.11 (d, J=12.7 Hz, 1H), 6.64 (s, 1H), 6.70 (d, J=7.5, 1H), 6.81 (dd, J=8.2, 2.5 Hz, 1H), 7.10 (d, J=8.4 Hz, 2H), 7.16-7.23 (m, 3H). MS [M+H].sup.+ 444. HRMS: calcd for C.sub.24H.sub.27NO.sub.5Cl, [M+H].sup.+ 444.1578, found 444.1579.

Example 104: (4-methoxyphenyl)methyl 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate

[0285] p-methoxybenzyl alcohol (54 mg, 0.39 mmol) was dissolved in anh. THF (1 mL). 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylic acid (example 74, 85 mg, 0.26 mmol) and triphenylphosphine (102 mg, 0.39 mmol) were added. A solution of DEAD (61 L, 68 mg) in anh. THF (0.4 mL) was added slowly. The reaction mixture was stirred for 18 h at RT. The reaction was uncompleted. Triphenylphosphine (102 mg, 0.39 mmol), p-methoxybenzyl alcohol (54 mg, 0.39 mmol) and a solution of DEAD (61 L, 68 mg) in anh. THF (0.4 mL) were added at 0 C. and the reaction mixture was stirred at 60 C. for 24 h. A saturated aqueous solution of NaHCO.sub.3 was added. The aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine and dried over MgSO.sub.4. Purification of the crude by flash chromatography on silica using a mixture Cy/EtOAc (8/2) gave the desired (4-methoxyphenyl)methyl 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate as a colorless oil (74 mg, 64%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.59 (s, 3H), 2.70 (dd, J=15.8, 2.3 Hz, 1H), 2.89 (dd, J=15.8, 7.5 Hz, 1H), 3.31 (s, 3H), 3.37 (ddd, J=9.9, 8.6, 3.9 Hz, 1H), 3.45 (dt, J=9.9, 3.9 Hz, 1H), 3.74 (ddd, J=14.3, 8.6, 3.9 Hz, 1H), 3.80 (s, 3H), 4.10-4.20 (m, 2H), 5.02 (s, 2H), 6.80 (d, J=8.7 Hz, 2H), 7.05-7.09 (m, 4H), 7.20 (d, J=8.7 Hz, 2H). MS [M+H].sup.+ 444. HRMS: calcd for C.sub.24H.sub.27NO.sub.5Cl, [M+H].sup.+ 444.1578, found 444.1576.

Example 105: (2-trifluoromethoxyphenyl)methyl 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate

[0286] 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylic acid (example 74, 97 mg, 0.3 mmol) was dissolved in anhydrous DMF (1 mL) then cesium carbonate (146 mg, 0.45 mmol) and 2-trifluoromethoxybenzyl bromide (63 L, 0.33 mmol) were added. The reaction mixture was stirred at RT. for 18 h. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc and water. The aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine and dried over MgSO.sub.4. The solvents were removed under reduced pressure. Purification of the crude by flash chromatography on silica using a mixture of Cyclohexane/EtOAc 9/1 gave the desired (2-trifluoromethoxyphenyl)methyl 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate as a colorless oil (121 mg, 81%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.63 (s, 3H), 2.72 (dd, J=15.7, 2.2 Hz, 1H), 2.94 (dd, J=15.7, 7.5 Hz, 1H), 3.33 (s, 3H), 3.34-3.52 (m, 2H), 4.18 (ddd, J=14.7, 8.6, 4.0 Hz, 1H), 4.13-4.23 (m, 2H), 5.16 (d, J=13.4 Hz, 1H), 5.22 (d, J=13.4 Hz, 1H), 7.04 (dd, J=7.7, 1.6 Hz, 1H), 7.10 (d, J=8.6 Hz, 2H), 7.15 (td, J=7.6, 1.2 Hz, 1H), 7.22 (d, J=8.6 Hz, 2H), 7.19-7.25 (m, 1H), 7.33 (td, J=7.9, 1.8 Hz, 1H). .sup.13C NMR (75 MHz, CDCl.sub.3) 17.2, 36.9, 38.8, 41.9, 58.9, 60.6, 71.1, 109.5, 120.4, 126.7, 128.4, 128.8, 129.4, 129.8, 132.6, 139.7, 151.7, 166.7, 168.9. MS [M+H].sup.+ 498. HRMS: calcd for C.sub.33H.sub.21NO.sub.2Cl, [M+H].sup.+ 498.1261, found 498.1294.

Example 106: 2-naphthylmethyl 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate

[0287] The 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylic acid (example 74, 75 mg, 0.23 mmol) was dissolved in anhydrous DMF (1 mL) then cesium carbonate (114 mg, 0.35 mmol) and 4-(bromomethyl)pyridine hydrobromide (63 mg, 0.25 mmol) were added. The reaction mixture was stirred for 1 h at RT. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc and water. The aqueous phase was extracted 3 times with EtOAc. The organic layers were assembled, washed with brine and dried over MgSO.sub.4. The solvent was removed under reduced pressure to give the desired product as a white powder (92 mg, 87%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.63 (s, 3H), 2.71 (dd, J=15.7, 2.0 Hz, 1H), 2.93 (dd, J=15.7, 7.5 Hz, 1H), 3.32 (s, 3H), 3.34-3.42 (m, 1H), 3.47 (dt, J=9.9, 4.2 Hz, 1H), 3.76 (ddd, J=14.7, 8.7, 4.2 Hz, 1H), 4.17 (dt, J=14.7, 3.9 Hz, 1H), 4.23 (d, J=7.5 Hz, 1H), 5.20 (d, J=12.9 Hz, 1H), 5.31 (d, J=12.9 Hz, 1H), 7.12 (d, J=8.6 Hz, 2H), 7.19 (dd, J=8.4, 1.6 Hz, 1H), 7.22 (d, J=8.4 Hz, 2H), 7.46-7.50 (m, 3H), 7.67-7.70 (m, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.79-7.82 (m, 1H). MS [M+H].sup.+ 464. HRMS: calcd for C.sub.27H.sub.27NO.sub.4Cl, [M+H].sup.+ 464.1629, found 464.1629.

Example 107: 4-pyridylmethyl 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate

[0288] The 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylic acid (example 74, 75 mg, 0.23 mmol) was dissolved in anhydrous DMF (1 mL) then cesium carbonate (114 mg, 0.35 mmol) and 4-(bromomethyl)pyridine hydrobromide (63 mg, 0.25 mmol) were added. The reaction mixture was stirred for 1 h at RT. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc and water. The aqueous phase was extracted 3 times with EtOAc. The organic layers were assembled, washed with brine and dried over MgSO.sub.4. The solvent was removed under reduced pressure to give the desired 4-pyridylmethyl 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate as a white powder (95 mg, 99%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.58 (s, 3H), 2.67 (dd, J=15.7, 2.2 Hz, 1H), 2.88 (dd, J=15.7, 7.5 Hz, 1H), 3.26 (s, 3H), 3.29-3.36 (m, 1H), 3.41 (dt, J=9.9, 4.0 Hz, 1H), 3.71 (ddd, J=14.5, 8.7, 3.7 Hz, 1H), 4.08-4.17 (m, 2H), 4.96 (d, J=14.1 Hz, 1H), 5.11 (d, J=14.1 Hz, 1H), 6.87 (d, J=5.2 Hz, 2H), 7.06 (d, J=8.3 Hz, 2H), 7.18 (d, J=8.3 Hz, 2H), 8.41 (d, J=5.2 Hz, 2H). MS [M+H].sup.+ 415. HRMS: calcd for C.sub.22H.sub.24N.sub.2O.sub.4Cl, [M+H].sup.+ 415.1425, found 415.1424.

Example 108: (4-phenylphenyl)methyl 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate

[0289] 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylic acid (example 74, 75 mg, 0.23 mmol) was dissolved in anhydrous DMF (1 mL) then cesium carbonate (114 mg, 0.35 mmol) and 4-phenylbenzyl chloride (65 mg, 0.33 mmol) were added. The reaction mixture was stirred for 18 h at RT. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc and water. The aqueous phase was extracted with EtOAc. The organic layers were assembled, washed with brine and dried over MgSO.sub.4. The solvent was removed under reduced pressure. The crude product was purified by flash chromatography using a mixture of Cyclohexane/EtOAc (9/1 to 8/2) as eluent to give the desired (4-phenylphenyl)methyl 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate as a colorless oil (67 mg, 60%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.56 (s, 3H), 2.65 (dd, J=15.8, 2.0 Hz, 1H), 2.86 (dd, J=15.8, 7.4 Hz, 1H), 3.25 (s, 3H), 3.27-3.34 (m, 1H), 3.40 (dt, J=10.0, 4.1 Hz, 1H), 3.69 (ddd, J=14.7, 8.7, 4.0 Hz, 1H), 4.10 (dt, J=14.7, 4.0 Hz, 1H), 4.16 (d, J=7.7 Hz, 1H), 5.04 (d, J=12.7 Hz, 1H), 5.09 (d, J=12.7 Hz, 1H), 7.04 (d, J=8.4 Hz, 2H), 7.10 (d, J=8.1 Hz, 2H), 7.15 (d, J=8.4 Hz, 2H), 7.28 (t, J=7.9 Hz, 1H), 7.37 (t, J=7.5 Hz, 2H), 7.43 (d, J=8.1 Hz, 2H), 7.50 (d, J=7.5 Hz, 2H). MS [M+H].sup.+ 490. HRMS: calcd for C.sub.29H.sub.29NO.sub.4Cl, [M+H].sup.+ 490.1785, found 490.1767.

Example 109: Benzhydryl 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate

[0290] 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylic acid (example 74, 97 mg, 0.3 mmol) was dissolved in anhydrous DMF (1 mL) then cesium carbonate (146 mg, 0.45 mmol) and chlorodiphenylmethane (58 L, 0.33 mmol) were added. The reaction mixture was stirred at RT for 18 h. The reaction wasn't complete. Chlorodiphenylmethane (58 L, 0.33 mmol) was added again. The reaction mixture was stirred at 50 C. for 24 h. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc and water. The aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine and dried over MgSO.sub.4. The solvents were removed under reduced pressure. Purification of the crude by flash chromatography on silica using a mixture of Cy/EtOAc 9/1 gave the desired benzhydryl 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate as a white powder (107 mg, 73%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.63 (s, 3H), 2.75 (dd, J=15.7, 2.0 Hz, 1H), 2.96 (dd, J=15.7, 7.7 Hz, 1H), 3.33 (s, 3H), 3.36-3.52 (m, 2H), 3.77 (ddd, J=14.6, 8.6, 4.0 Hz, 1H), 4.18 (dt, J=14.6, 4.0 Hz, 1H), 4.29 (d, J=7.7 Hz, 1H), 6.81-6.87 (m, 3H), 7.08-7.19 (m, 5H), 7.24-7.37 (m, 7H). MS [M+H].sup.+ 490. HRMS: calcd for C.sub.29H.sub.29NO.sub.4Cl, [M+H].sup.+ 490.1785, found 490.1806.

Example 110: 2-phenylethyl 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate

[0291] 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylic acid (example 74, 75 mg, 0.23 mmol) was dissolved in anhydrous DMF (1 mL) then cesium carbonate (114 mg, 0.35 mmol) and (2-Bromoethyl)benzene (43 L, 0.33 mmol) were added. The reaction mixture was stirred for 18 h at RT. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc and water. The aqueous phase was extracted with EtOAc. The organic layers were assembled, washed with brine and dried over MgSO.sub.4. The solvent was removed under reduced pressure. The crude product was purified by flash chromatography using a mixture of Cyclohexane/EtOAc (9/1 to 8/2) as eluent to give the desired 2-phenylethyl 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate as a colorless oil (64 mg, 65%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.56 (s, 3H), 2.69 (dd, J=15.5, 2.1 Hz, 1H), 2.83-2.92 (m, 3H), 3.32 (s, 3H), 3.34-3.38 (m, 1H), 3.45 (dt, J=9.9, 4.0 Hz, 1H), 3.72 (ddd, J=14.6, 8.7, 4.0 Hz, 1H), 4.07 (d, J=7.3 Hz, 1H), 4.17 (dt, J=14.6, 4.0 Hz, 1H), 4.29 (t, J=6.6 Hz, 1H), 4.31 (d, J=6.6 Hz, 1H), 7.02-7.07 (m, 4H), 7.20-7.23 (m, 5H). MS [M+H].sup.+ 428. HRMS: calcd for C.sub.24H.sub.27NO.sub.4Cl, [M+H].sup.+ 428.1629, found 428.1624.

Example 111: 3-phenylpropyl 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate

[0292] 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylic acid (example 74, 75 mg, 0.23 mmol) was dissolved in anhydrous DMF (1 mL) then cesium carbonate (114 mg, 0.35 mmol) and (3-Bromopropyl)benzene (38 L, 0.25 mmol) were added. The reaction mixture was stirred for 3 h at RT. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc and water. The aqueous phase was extracted with EtOAc. The organic layers were assembled, washed with brine and dried over MgSO.sub.4. The solvent was removed under reduced pressure. The crude product was purified by flash chromatography using a mixture of Cyclohexane/EtOAc (9/1 to 8/2) as eluent to give the desired 3-phenylpropyl 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate as a colorless oil (58 mg, 57%). .sup.1H NMR (300 MHz, CDCl.sub.3) 1.72-1.82 (m, 2H), 2.41 (t, J=7.7 Hz, 2H), 2.55 (s, 3H), 2.65 (dd, J=15.7, 2.1 Hz, 1H), 2.85 (dd, J=15.7, 7.4 Hz, 1H), 3.25 (s, 3H), 3.27-3.34 (m, 1H), 3.40 (dt, J=9.9, 3.9 Hz, 1H), 3.68 (ddd, J=14.6, 8.5, 3.9 Hz, 1H), 3.99 (t, J=6.2 Hz, 2H), 4.06-4.14 (m, 2H), 6.92 (d, J=7.6 Hz, 2H), 7.06 (d, J=8.7 Hz, 2H), 7.09-7.13 (m, 1H), 7.14-7.20 (m, 4H). MS [M+H].sup.+ 442. HRMS: calcd for C.sub.25H.sub.29NO.sub.4Cl, [M+H].sup.+ 442.1785, found 442.1779.

Example 112: Phenacyl 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate

[0293] 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylic acid (example 74, 75 mg, 0.23 mmol) was dissolved in anhydrous DMF (1 mL) then cesium carbonate (114 mg, 0.35 mmol) and 2-bromoacetophenone (65 mg, 0.33 mmol) were added. The reaction mixture was stirred for 18 h at RT. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc and water. The aqueous phase was extracted with EtOAc. The organic layers were assembled, washed with brine and dried over MgSO.sub.4. The solvent was removed under reduced pressure. The crude product was purified by flash chromatography using a mixture of Cyclohexane/EtOAc (9/1 to 8/2) as eluent to give the desired phenacyl 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate as a colorless oil (99 mg, 98%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.64 (s, 3H), 2.77 (dd, J=15.7, 2.0 Hz, 1H), 3.00 (dd, J=15.7, 7.2 Hz, 1H), 3.31 (s, 3H), 3.33-3.39 (m, 1H), 3.46 (dt, J=9.9, 4.0 Hz, 1H), 3.75 (ddd, J=14.7, 8.8, 4.2 Hz, 1H), 4.19 (dt, J=14.7, 4.0 Hz, 1H), 4.33 (d, J=6.8 Hz, 1H), 5.21 (d, J=16.3 Hz, 1H), 5.42 (d, J=16.3 Hz, 1H), 7.17 (d, J=8.6 Hz, 2H), 7.23 (d, J=8.6 Hz, 2H), 7.45 (t, J=7.0 Hz, 2H), 7.59 (t, J=6.4 Hz, 1H), 7.87 (d, J=7.9 Hz, 2H). MS [M+H].sup.+ 442. HRMS: calcd for C.sub.24H.sub.25NO.sub.5Cl, [M+H].sup.+ 442.1421, found 442.1422.

Example 113: [cyclohexylmethyl 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate

[0294] 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylic acid (example 74, 75 mg, 0.23 mmol) was dissolved in anhydrous DMF (1 mL) then cesium carbonate (114 mg, 0.35 mmol) and cyclohexylmethylbromide (49 L, 0.35 mmol) were added. The reaction mixture was stirred at 50 C. for 24 h. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc and water. The aqueous phase was extracted with EtOAc. The organic layers were assembled, washed with brine and dried over MgSO.sub.4. The solvent was removed under reduced pressure to give the desired [cyclohexylmethyl 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate as a yellowish oil (95 mg, 99%). .sup.1H NMR (300 MHz, CDCl.sub.3) 0.71-1.18 (m, 5H), 1.46-1.63 (m, 6H), 2.61 (s, 3H), 2.71 (dd, J=15.7, 2.3 Hz, 1H), 2.92 (dd, J=15.7, 7.5 Hz, 1H), 3.32 (s, 3H), 3.38 (ddd, J=9.8, 8.5, 3.7 Hz, 1H), 3.47 (dt, J=9.8, 3.9 Hz, 1H), 3.75 (ddd, J=14.6, 8.5, 3.9 Hz, 1H), 3.81-3.91 (m, 2H), 4.13-4.21 (m, 2H), 7.11 (d, J=8.5 Hz, 2H), 7.22 (d, J=8.5 Hz, 2H). MS [M+H].sup.+ 420. HRMS: calcd for C.sub.23H.sub.31NO.sub.4Cl, [M+H].sup.+ 420.1942, found 420.1937.

##STR00357## ##STR00358##

Example 114: Methyl 4-[3-(dimethylamino)propoxy]benzoate (Intermediate Product)

[0295] ##STR00359##

Methyl 4-hydroxybenzoate (3.04 g, 20.0 mmol), potassium carbonate (4.14 g, 30.0 mmol) and 3-dimethylaminopropyl chloride hydrochloride (4.74 g, 30.0 mmol) were dissolved in anh. DMF (30 mL). The reaction mixture was stirred at 60 C. for 18 h. The reaction was uncomplete; potassium carbonate (4.14 g, 30.0 mmol) and 3-dimethylaminopropyl chloride hydrochloride (4.74 g, 30.0 mmol) were added again. The reaction mixture was stirred for a further 24 h at 60 C. Removal of the solvent under reduced pressure afforded the desired methyl 4-[3-(dimethylamino)propoxy]benzoate (1.6 g, 34%) that was used in the next step without purification.

Example 115: [4-[3-(dimethylamino)propoxy]phenyl]methanol (Intermediate Product)

[0296] ##STR00360##

[0297] Methyl 4-[3-(dimethylamino)propoxy]benzoate (474 mg, 2.0 mmol) was dissolved in anh. THF (7 mL). The reaction mixture was cooled to 0 C. A 1 M solution of lithium aluminium hydride in diethyl ether (2.4 mL, 2.4 mmol) was added slowly. The reaction mixture was then stirred for 5 h at RT. Water was added and the aqueous phase was extracted with diethyl ether. The organic phases were assembled, washed with brine and dried over MgSO.sub.4. Removal of the solvent under reduced pressure gave the desired [4-[3-(dimethylamino)propoxy]phenyl]methanol as a white oil (208 mg, 50%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.00 (q.sup.t, J=6.8 Hz, 2H), 2.31 (s, 6H), 2.52 (t, J=7.2 Hz, 2H), 4.02 (t, J=7.2 Hz, 2H), 4.02 (t, J=6.2 Hz, 2H), 4.62 (s, 2H), 6.89 (d, J=8.8 Hz, 2H), 7.28 (d, J=8.8 Hz, 2H).

Example 116: [4-[3-(dimethylamino)propoxy]phenyl]methyl 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate

[0298] 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylic acid (example 74, 330 mg, 1.02 mmol), [4-[3-(dimethylamino)propoxy]phenyl]methanol (194 mg, 0.93 mmol), EDCl (213 mg, 1.12 mmol) and DMAP (113 mg, 0.93 mmol) were dissolved in anh. DCM (4 mL). The reaction mixture was stirred for 18 h at RT. An aqueous solution of NaHCO.sub.3 5% was added. The aqueous phase was extracted with DCM. The organic phases were assembled and dried over MgSO.sub.4. The solvent was removed under reduced pressure.

[0299] Purification of the crude by flash chromatography on silica using a mixture of DCM/MeOH 97/3 gave the desired [4-[3-(dimethylamino)propoxy]phenyl]methyl 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate as a colorless oil (87 mg, 18%). .sup.1H NMR (300 MHz, CDCl.sub.3) 1.94 (q.sup.t, J=6.8 Hz, 2H), 2.24 (s, 6H), 2.43 (t, J=7.3 Hz, 2H), 2.58 (s, 3H), 2.69 (dd, J=15.9, 2.2 Hz, 1H), 2.89 (dd, J=15.9, 7.5 Hz, 1H), 3.30 (s, 3H), 3.31-3.48 (m, 2H), 3.72 (ddd, J=14.3, 8.2, 3.8 Hz, 1H), 3.99 (t, J=6.2 Hz, 2H), 4.10-4.20 (m, 2H), 5.01 (s, 2H), 6.79 (d, J=8.7 Hz, 2H), 7.04 (d, J=8.7 Hz, 2H), 7.07 (d, J=8.4 Hz, 2H), 7.20 (d, J=8.4 Hz, 2H). .sup.13C NMR (75 MHz, CDCl.sub.3) 17.0, 27.4, 36.7, 38.6, 41.7, 45.4, 56.2, 58.7, 65.8, 66.1, 70.9, 110.0, 114.2, 127.9, 128.3, 128.6, 129.4, 132.4, 139.7, 150.8, 158.8, 166.9, 168.8. MS [M+H].sup.+ 515. HRMS: calcd for C.sub.28H.sub.36N.sub.2O.sub.5Cl, [M+H].sup.+ 515.2313, found 515.2307.

Example 117: 3-[4-[[4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carbonyl]oxymethyl]phenoxy]propyl-trimethyl-ammonium; iodide

[0300] [4-[3-(dimethylamino)propoxy]phenyl]methyl 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate (example 116) 27 mg, 0.05 mmol) was dissolved in anh. DMF (150 L). Iodomethane (8 L, 0.12 mmol) was added. The reaction mixture was stirred at RT for 24 h. The solvent was removed under reduced pressure to afford the desired 3-[4-[[4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carbonyl]oxymethyl]phenoxy]propyl-trimethyl-ammonium iodide as a colorless oil (34 mg, 100%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.24-2.36 (m, 2H), 2.60 (s, 3H), 2.63 (dd, J=15.4, 2.0 Hz, 1H), 2.98 (dd, J=15.4, 7.5 Hz, 1H), 3.22 (s, 9H), 3.30-3.33 (m, 5H), 3.33-3.40 (m, 1H), 3.46 (dt, J=9.7, 4.1 Hz, 1H), 3.57-3.67 (m, 2H), 3.81 (ddd, J=14.8, 8.4, 3.8 Hz, 1H), 4.11 (t, J=5.9 Hz, 2H), 4.12-4.18 (m, 1H), 4.20 (d, J=7.5 Hz, 1H), 4.98 (d, J=12.1 Hz, 1H), 5.07 (d, J=12.1 Hz, 1H), 6.85 (d, J=8.8 Hz, 2H), 7.08 (d, J=8.8 Hz, 2H), 7.14 (d, J=8.5 Hz, 2H), 7.25 (d, J=8.5 Hz, 2H). MS [M+H].sup.+ 529. HRMS: calcd for C.sub.29H.sub.38N.sub.2O.sub.5Cl, [M+H].sup.+ 529.2469, found 529.2458.

Example 118: 1-(chloromethyl)-4-(2-methoxyethoxy)benzene (Intermediate Product)

[0301] ##STR00361##

Step 1: [4-(2-methoxyethoxy)phenyl]methanol

[0302] 4-hydroxybenzoic methyl ester (5.0 mmol, 760 mg) was dissolved in DMF (6 mL), potassium carbonate (7.5 mmol, 1.036 g) was added then bromoethylmethyl ether (7.5 mmol, 704 L). The reaction mixture was stirred at 60 C. for 18 h. The solvents were removed under reduced pressure. Water was added to the residue. The aqueous phase was extracted with EtOAc. The organic phase were assembled, washed with brine and dried over Na.sub.2SO.sub.4. The solvents were removed under reduced pressure to afford the desired methyl 4-(2-methoxyethoxy)benzoate as a colorless oil (m=960 mg, 91%).

Step 2: 4-(2-methoxyethoxy)phenyl]methanol

[0303] Methyl 4-(2-methoxyethoxy)benzoate was dissolved in anhydrous DMF (15 mL). The reaction mixture was cooled to 0 C. and a solution of LiAlH.sub.4 in THF (1 M, 4.6 mL) was added slowly. The reaction mixture was stirred at 0 C. for 3 h. The reaction was quenched by slow addition of an aqueous solution of HCl 1N. The organic phase was extracted with Et.sub.2O, washed with brine and dried over Na.sub.2SO.sub.4. The solvents were removed under reduced pressure to afford the desired [4-(2-methoxyethoxy)phenyl]methanol as a colorless oil (m=554 mg, 67%) .sup.1H NMR (300 MHz, CDCl.sub.3) 3.46 (s, 3H), 3.74-3.78 (m, 2H), 4.11-4.16 (m, 2H), 4.63 (s, 2H), 6.93 (d, J=8.6 Hz, 2H), 7.29 (d, J=8.6 Hz, 2H).

Step 3: 1-(chloromethyl)-4-(2-methoxyethoxy)benzene

[0304] Thionyl chloride (109 L, 1.5 mmol) was added to benzotriazole (179 mg, 1.5 mmol). The resulting yellow solution was dissolved in dry DCM (2 mL). After 5 min, this solution was added slowly to a solution of [4-(2-methoxyethoxy)phenyl]methanol (218 mg, 1.2 mmol) in DCM (8 mL). The benzotriazole salt started to precipitate. After 20 min of reaction, the salt was filtered. The organic phase was washed with water (10 mL) and NaOH solution (0.05 M, 10 mL). The organic phase was dried on Na.sub.2SO.sub.4 and the solvents were removed under reduced pressure to give the desired 1-(chloromethyl)-4-(2-methoxyethoxy)benzene as a yellow oil (190 mg, 79%). .sup.1H NMR (300 MHz, CDCl.sub.3) 3.46 (s, 3H), 3.74-3.79 (m, 2H), 4.11-4.16 (m, 2H), 4.57 (s, 2H), 6.92 (d, J=8.7 Hz, 2H), 7.31 (d, J=8.7 Hz, 2H).

Example 119: [4-(2-methoxyethoxy)phenyl]methyl 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate

[0305] 1-(chloromethyl)-4-(2-methoxyethoxy)benzene (180 mg, 0.9 mmol) and 4-(4-chlorophenyl)-1-(2-methoxyethyl)-2-oxo-3,4-dihydropyridine-5-carboxylic acid (example 74, 194 mg, 0.6 mmol) were dissolved in anh. DMF (2 mL). Cesium carbonate (293 mg, 0.9 mmol) was added and the reaction mixture stirred at RT. for 4 h. The solvents were removed. Water was added and the aqueous phase was extracted with EtOAc. The organic layers were assembled, washed with brine and dried over Na.sub.2SO.sub.4. The solvents were removed under reduced pressure. Purification of the crude by flash chromatography using a mixture Cy/EA (95/5) as eluent gave the desired [4-(2-methoxyethoxy)phenyl]methyl 4-(4-chlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate as a white powder (123 mg, 42%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.59 (s, 3H), 2.70 (dd, J=15.7, 2.2 Hz, 1H), 2.91 (dd, J=15.7, 7.6 Hz, 1H), 3.31 (s, 3H), 3.30-3.54 (m, 2H), 3.46 (s, 3H), 3.68-3.80 (m, 3H), 4.08-4.22 (m, 4H), 5.02 (s, 2H), 6.83 (d, J=8.5 Hz, 2H), 7.02-7.12 (m, 4H), 7.21 (d, J=8.5 Hz, 2H). .sup.13C NMR (75 MHz, CDCl.sub.3) 17.1, 36.8, 38.7, 41.8, 58.8, 59.2, 65.9, 67.2, 71.0, 71.0, 110.0, 114.4, 128.3, 128.4, 128.7, 129.4, 132.5, 139.8, 150.9, 158.6, 167.0, 168.9. MS [M+H].sup.+ 488; HRMS: calcd for C.sub.26H.sub.31NO.sub.6Cl, [M+H].sup.+ 488.1840, found 488.1820.

TABLE-US-00009 TABLE 9 [00362] Examples R18 R19 121 Pr 2-OMe-Bn 123 4-Ph-Ph Bn 125 4-CN-Ph 2-OMe-Bn 127 3,4-diCl-Ph 2-OMe-Bn 129 2,4-diCl-Ph 2-OMe-Bn 131 2,5-diCl-Ph 2-OMe-Bn 133 4-Pyridyl 2-OMe-Bn

Example 120: (2-methoxyphenyl)methyl 6-methyl-2-oxo-4-propyl-3,4-dihydro-1H-pyridine-5-carboxylate (Intermediate Product)

[0306] The (2-methoxyphenyl)methyl 3-oxobutanoate (444 mg, 2.0 mmol) was dissolved in acetic acid (2 mL). n-butanal (180 L, 2.0 mmol), meldrum acid (288 mg, 2.0 mmol) and ammonium acetate (231 mg, 3.0 mmol) were added and the reaction mixture was stirred at 110 C. for 18 h. The reaction mixture was cooled to RT. The solvent was removed under reduced pressure. Purification of the crude by flash chromatography on silica using as eluent a mixture of Cyclohexane/EtOAc (85/15) gave the desired (2-methoxyphenyl)methyl 6-methyl-2-oxo-4-propyl-3,4-dihydro-1H-pyridine-5-carboxylate as a yellow oil (42 mg, 6%). .sup.1H NMR (300 MHz, CDCl.sub.3) 0.84 (t, J=6.7 Hz, 3H), 1.13-1.54 (m, 4H), 2.31 (s, 3H), 2.46 (dd, J=16.6, 1.8 Hz, 1H), 2.57 (dd, J=16.6, 6.8 Hz, 1H), 2.94-3.05 (m, 1H), 3.84 (s, 3H), 5.21 (d, J=12.7 Hz, 1H), 5.27 (d, J=12.7 Hz, 1H), 6.89 (d, J=8.2 Hz, 1H), 6.95 (td, J=7.1, 0.9 Hz, 1H), 7.26-7.36 (m, 2H), 8.43 (brs, 1H). .sup.13C NMR (75 MHz, CDCl.sub.3) 13.9, 19.0, 19.7, 31.9, 34.9, 55.3, 61.6, 109.1, 110.3, 120.3, 124.6, 129.4, 129.6, 145.0, 157.6, 167.1, 172.3. MS [M+H].sup.+ 318. HRMS: calcd for C18H24NO4, [M+H]+ 318.1705, found 318.1708.

Example 121: (2-methoxyphenyl)methyl 1-(2-methoxyethyl)-6-methyl-2-oxo-4-propyl-3,4-dihydropyridine-5-carboxylate

[0307] (2-methoxyphenyl)methyl 6-methyl-2-oxo-4-propyl-3,4-dihydro-1H-pyridine-5-carboxylate (42 mg, 0.13 mmol) was dissolved in anhydrous DMF (1 mL). Cesium carbonate (85 mg, 0.26 mmol) and 2-bromoethyl methyl ether (25 L, 0.26 mmol) were added. The reaction mixture was stirred at 60 C. for 4 days. The same amount of cesium carbonate (85 mg, 0.26 mmol) and 2-bromoethyl methyl ether (25 L, 0.26 mmol) were added everyday. After 4 days at 60 C., the DMF was removed under reduced pressure. The residue was diluted in water. The aqueous phase was extracted by EtOAc and the combined organic layers were washed with brine and dried over MgSO.sub.4. The solvent was removed under reduced pressure. Purification of the crude by flash chromatography using a mixture of Cyclohexane/EtOAc (8/2) as eluent gave the desired (2-methoxyphenyl)methyl 1-(2-methoxyethyl)-6-methyl-2-oxo-4-propyl-3,4-dihydropyridine-5-carboxylate as a colorless oil (32 mg, 67%). .sup.1H NMR (300 MHz, CDCl.sub.3) 0.82 (t, J=7.0 Hz, 3H), 1.10-1.50 (m, 4H), 2.43 (s, 3H), 2.49 (dd, J=15.7, 2.4 Hz, 1H), 2.57 (dd, J=15.7, 5.9 Hz, 1H), 2.87-2.98 (m, 1H), 3.30 (s, 3H), 3.40-3.55 (m, 2H), 3.69 (ddd, J=14.4, 6.5, 5.1 Hz, 1H), 3.84 (s, 3H), 4.13 (dt, J=14.4, 5.6 Hz, 1H), 5.19 (d, J=12.8 Hz, 1H), 5.26 (d, J=12.8 Hz, 1H), 6.89 (d, J=8.2 Hz, 1H), 6.95 (td, J=7.5, 0.9 Hz, 1H), 7.27-7.37 (m, 2H). .sup.13C NMR (75 MHz, CDCl.sub.3) 14.0, 16.9, 19.7, 31.3, 34.1, 35.8, 41.5, 55.2, 58.8, 61.7, 70.7, 110.3, 113.6, 120.3, 124.4, 129.4, 129.6, 147.7, 157.5, 167.7, 170.4. MS [M+H].sup.+ 376. HRMS: calcd for C.sub.21H.sub.30NO.sub.5, [M+H].sup.+ 376.2124, found 376.2135.

Example 122: Benzyl 4-(4-bromophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate (Intermediate Product)

[0308] Benzyl 4-(4-bromophenyl)-6-methyl-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate (2.04 g, 5.1 mmol) was dissolved in anhydrous DMF (20 mL). Cesium carbonate (3.31 mg, 10.2 mmol) and (bromoethyl)methyl ether (960 L, 10.2 mmol) were added. The reaction mixture was stirred at 60 C. for 24 h. The DMF was removed under reduced pressure. The residue was diluted in water and extracted by EtOAc. The organic layers were assembled, washed with brine and dried over MgSO.sub.4. Removal of the solvent under reduced pressure gave the desired benzyl 4-(4-bromophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate as a colorless oil (2.08 g, 89%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.61 (s, 3H), 2.71 (dd, J=15.8, 2.3 Hz, 1H), 2.91 (dd, J=15.8, 7.7 Hz, 1H), 3.32 (s, 3H), 3.34-3.51 (m, 2H), 3.75 (ddd, J=14.8, 8.5, 2.0 Hz, 1H), 4.12-4.21 (m, 2H), 5.06 (d, J=12.7 Hz, 1H), 5.12 (d, J=12.7 Hz, 1H), 7.04 (d, J=8.4 Hz, 2H), 7.07-7.14 (m, 2H), 7.25-7.30 (m, 3H), 7.36 (d, J=8.4 Hz, 2H). MS [M+H].sup.+ 458. HRMS: calcd for C.sub.23H.sub.25NO.sub.4Br, [M+H].sup.+ 458.0967, found 458.0970.

Example 123: Benzyl 1-(2-methoxyethyl)-6-methyl-2-oxo-4-(4-phenylphenyl)-3,4-dihydropyridine-5-carboxylate

[0309] Benzyl 4-(4-bromophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate (120 mg, 0.26 mmol), phenylboronic acid (63 mg, 0.52 mmol), sodium carbonate (41 mg, 0.39 mmol) and PdCl.sub.2 dppf (21 mg, 0.026 mmol) were dissolved in a mixture DME/water 1/1 (1 mL). The reaction mixture was warmed at 115 C. under microwaves for 30 min. The reaction mixture was cooled to r.t. then, filtered on celite and washed with Et.sub.2O. The organic phase was washed with a saturated aqueous solution of NaHCO.sub.3. The aqueous phase was extracted with EtOAc. The organic phases were combined, washed with brine and dried over MgSO.sub.4. The solvents were removed under reduced pressure. Purification of the crude by flash chromatography using a mixture of Cyclohexane/EtOAc (85/15) as eluent gave the desired benzyl 1-(2-methoxyethyl)-6-methyl-2-oxo-4-(4-phenylphenyl)-3,4-dihydropyridine-5-carboxylate as a white powder (56 mg, 46%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.63 (s, 3H), 2.80 (dd, J=15.6, 2.2 Hz, 1H), 2.95 (dd, J=15.6, 7.4 Hz, 1H), 3.32 (s, 3H), 3.35-3.52 (m, 2H), 3.76 (ddd, J=14.7, 8.3, 4.0 Hz, 1H), 4.18 (dd, J=14.6, 6.1 Hz, 1H), 4.29 (dd, J=7.4, 2.2 Hz, 1H), 5.09 (d, J=12.7 Hz, 1H), 5.15 (d, J=12.7 Hz, 1H), 7.08-7.14 (m, 2H), 7.22-7.26 (m, 5H), 7.29-7.36 (m, 1H), 7.38-7.50 (m, 4H), 7.52-7.58 (m, 2H). .sup.13C NMR (75 MHz, CDCl.sub.3) 17.2, 37.0, 38.8, 41.9, 58.9, 65.9, 71.1, 110.2, 127.0, 127.1, 127.4, 127.4, 127.5, 127.8, 128.3, 128.7, 136.1, 139.8, 140.2, 140.9, 150.9, 167.1, 169.2. MS [M+H].sup.+ 456 HRMS: calcd for C.sub.29H.sub.30NO.sub.4, [M+H].sup.+ 456.2175, found 456.2177.

Example 124: (2-methoxyphenyl)methyl 4-(4-cyanophenyl)-6-methyl-2-oxo-3,4-dihydro-1 H-pyridine-5-carboxylate (Intermediate Product)

[0310] The (2-methoxyphenyl)methyl 3-oxobutanoate (667 mg, 3.0 mmol) was dissolved in acetic acid (3 mL). 4-cyanobenzaldehyde (393 mg, 3.0 mmol), meldrum acid (432 mg, 3.0 mmol) and ammonium acetate (338 mg, 4.5 mmol) were added and the reaction mixture was stirred at 110 C. for 18 h. The reaction mixture was cooled to RT. The solvent was removed under reduced pressure. The crude was precipitated in EtOH, cooled to 0 C. and filtered to give the desired (2-methoxyphenyl)methyl 4-(4-cyanophenyl)-6-methyl-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate as a white powder (476 mg, 42%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.43 (s, 3H), 2.64 (d, J=16.7 Hz, 1H), 2.97 (dd, J=16.7 Hz, 1H), 3.74 (s, 3H), 4.31 (d, J=8.4 Hz, 1H), 5.09 (d, J=12.4 Hz, 1H), 5.21 (d, J=12.4 Hz, 1H), 6.81-6.89 (m, 2H), 7.04 (d, J=7.5 Hz, 1H), 7.26 (d, J=8.5 Hz, 2H), 7.30 (dd, J=8.0, 1.5 Hz, 1H), 7.53 (d, J=8.5 Hz, 2H). .sup.13C NMR (75 MHz, CDCl.sub.3) 18.9, 37.3, 38.0, 55.1, 61.7, 105.9, 110.2, 110.7, 118.6, 120.2, 123.9, 127.6, 129.5, 129.6, 132.5, 147.2, 147.7, 157.4. MS [MH].sup. 375

Example 125: (2-methoxyphenyl)methyl 4-(4-cyanophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate

[0311] o-methoxybenzyl 4-(4-cyanophenyl)-6-methyl-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate (113 mg, 0.30 mmol) was dissolved in anhydrous DMF (1 mL). Cesium carbonate (195 mg, 0.60 mmol) and 2-bromoethyl methyl ether (56 L, 0.60 mmol) were added. The reaction mixture was stirred at 60 C. for 18 h. The reaction was incomplete and Cesium carbonate (39 mg, 0.12 mmol) and 2-bromoethyl methyl ether (11 L, 0.12 mmol) were added. The reaction mixture was stirred at 60 C. for 18 h. The DMF was removed under reduced pressure. The residue was diluted in water and extracted by EtOAc. The organic layers were assembled, washed by brine and dried on MgSO.sub.4. The solvent was removed under reduced pressure. The crude product was purified by flash chromatography using a mixture of Cyclohexane/EtOAc (100/0 to 95/5) as eluent to give the desired (2-methoxyphenyl)methyl 4-(4-cyanophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate as a colorless oil (102 mg, 78%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.62 (s, 3H), 2.72 (dd, J=15.9, 2.2 Hz, 1H), 2.96 (dd, J=15.9, 7.7 Hz, 1H), 3.31 (s, 3H), 3.33-3.50 (m, 2H), 3.73 (s, 3H), 3.75 (ddd, J=14.6, 8.5, 3.8 Hz, 1H), 4.18 (dt, J=14.6, 3.8 Hz, 1H), 4.26 (d, J=7.7 Hz, 1H), 5.10 (d, J=13.1 Hz, 1H), 5.18 (d, J=13.1 Hz, 1H), 6.79-6.87 (m, 2H), 6.99 (dd, J=7.8, 1.9 Hz, 1H), 7.23-7.32 (m, 3H), 7.52 (d, J=8.3 Hz, 2H). .sup.13C NMR (75 MHz, CDCl.sub.3) 17.0, 37.5, 38.2, 41.8, 55.1, 58.8, 61.9, 70.9, 109.4, 110.2, 110.6, 118.7, 120.2, 124.0, 127.9, 129.2, 129.4, 132.3, 147.0, 151.2, 157.3, 166.8, 168.5. MS [M+H].sup.+ 435; HRMS: calcd for C25H27N2O5Cl, [M+H]+ 435.1920, found 435.1918.

Example 126: 4-(3,4-dichlorophenyl)-6-methyl-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate (Intermediate Product)

[0312] ##STR00363##

[0313] 3,4-dichlorobenzaldehyde (3.0 mmol, 525 g), meldrum acid (3.0 mmol, 432 g), o-methoxybenzyl acetoacetate (3.0 mmol, 666 mg) and ammonium acetate (4.5 mmol, 338 mg) were dissolved in acetic acid (3 mL). The reaction mixture was stirred at 110 C. for 18 h. The solvent was removed. The crude didn't precipitate in EtOH. The crude has been purified by flash chromatography (Cy/EA (85/15) and precipitated in EtOH to give the desired (2-methoxyphenyl)methyl 4-(3,4-dichlorophenyl)-6-methyl-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate as a white powder (384 mg, 30%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.43 (s, 3H), 2.63 (dd, J=16.7, 1.3 Hz, 1H), 2.94 (dd, J=16.7, 8.1 Hz, 1H), 3.76 (s, 3H), 4.23 (d, J=7.7 Hz, 1H), 5.12 (d, J=12.6 Hz, 1H), 5.22 (d, J=12.6 Hz, 1H), 6.86 (d, J=8.3 Hz, 1H), 6.88 (td, J=7.4, 1.0 Hz, 1H), 6.99 (dd, J=8.5, 2.3 Hz, 1H), 7.08 (dd, J=7.4, 1.7 Hz, 1H), 7.22 (d, J=2.0 Hz, 1H), 7.26-7.33 (m, 2H), 8.34 (brs, 1H). .sup.13C NMR (75 MHz, CDCl.sub.3) 19.1, 37.3, 37.7, 55.2, 61.8, 106.3, 110.3, 120.3, 124.0, 126.2, 128.9, 129.6, 130.6, 130.9, 132.6, 142.5, 147.0, 157.4, 166.3, 170.3. MS [MH].sup. 418.

Example 127: (2-methoxyphenyl)methyl 4-(3,4-dichlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate

[0314] o-methoxybenzyl 4-(3,4-dichlorophenyl)-6-methyl-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate (126 mg, 0.30 mmol) was dissolved in anhydrous DMF (1 mL). Cesium carbonate (195 mg, 0.60 mmol) and 2-bromoethyl methyl ether (56 L, 0.60 mmol) were added. The reaction mixture was stirred at 60 C. for 18 h. The DMF was removed under reduced pressure. The residue was diluted in water and extracted by EtOAc. The organic layers were assembled, washed by brine and dried on MgSO.sub.4. The solvent was removed under reduced pressure. The crude product was purified by flash chromatography using a mixture of Cyclohexane/EtOAc (100/0 to 85/15) as eluent to give the desired (2-methoxyphenyl)methyl 4-(3,4-dichlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate as a colorless oil (102 mg, 71%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.63 (s, 3H), 2.71 (dd, J=15.7, 2.0 Hz, 1H), 2.93 (dd, J=15.7, 7.5 Hz, 1H), 3.33 (s, 3H), 3.37-3.51 (m, 2H), 3.74 (s, 3H), 3.70-3.81 (m, 1H), 4.15-4.26 (m, 2H), 5.11 (d, J=12.8 Hz, 1H), 5.20 (d, J=12.8 Hz, 1H), 6.81-6.90 (m, 2H), 6.98-7.06 (m, 2H), 7.21-7.32 (m, 3H). .sup.13C NMR (75 MHz, CDCl.sub.3) 17.1, 36.8, 38.4, 41.9, 55.2, 59.0, 61.9, 71.0, 109.6, 110.2, 120.2, 124.1, 126.5, 129.1, 129.3, 129.4, 130.4, 130.7, 132.4, 141.8, 151.1, 157.3, 166.9, 168.7. MS [M+H].sup.+ 478; HRMS: calcd for C.sub.24H.sub.26NO.sub.5Cl.sub.2, [M+H].sup.+ 478.1188, found 478.1190.

Example 128: (2-methoxyphenyl)methyl 4-(2,4-dichlorophenyl)-6-methyl-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate (Intermediate Product)

[0315] ##STR00364##

[0316] 2,4-dichlorobenzaldehyde (3.0 mmol, 525 mg), meldrum acid (3.0 mmol, 432 mg), the o-methoxybenzyl acetoacetate (3.0 mmol, 666 mg) and ammonium acetate (4.5 mmol, 338 g) were dissolved in acetic acid (3 mL). The reaction mixture was stirred at 110 C. for 18 h. The solvent was removed. The crude was precipitated in EtOH, cooled to 0 C. and filtered to give the desired (2-methoxyphenyl)methyl 4-(2,4-dichlorophenyl)-6-methyl-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate as a white powder (600 mg, 48%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.48 (s, 3H), 2.67 (dd, J=16.9, 1.5 Hz, 1H), 2.92 (dd, J=16.9, 8.7 Hz, 1H), 3.73 (s, 3H), 4.70 (d, J=8.7 Hz, 1H), 5.06 (d, J=12.9 Hz, 1H), 5.70 (d, J=12.9 Hz, 1H), 6.78-6.87 (m, 2H), 6.94-7.01 (m, 2H), 7.13 (dd, J=8.5, 2.3 Hz, 1H), 725 (td, J=8.0, 1.6 Hz, 1H), 7.37 (d, J=2.0 Hz, 1H), 8.73 (brs, 1H). .sup.13C NMR (75 MHz, CDCl.sub.3) 18.8, 34.7, 36.1, 55.1, 61.6, 105.6, 110.1, 120.1, 124.1, 127.3, 128.2, 128.8, 129.2, 129.8, 133.3, 134.0, 137.2, 148.0, 157.1, 166.0, 170.7. MS [MH] 418

Example 129: (2-methoxyphenyl)methyl 4-(2,4-dichlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate

[0317] o-methoxybenzyl 4-(2,4-dichlorophenyl)-6-methyl-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate (126 mg, 0.30 mmol) was dissolved in anhydrous DMF (1 mL). Cesium carbonate (195 mg, 0.60 mmol) and 2-bromoethyl methyl ether (56 L, 0.60 mmol) were added. The reaction mixture was stirred at 60 C. for 18 h. The DMF was removed under reduced pressure. The residue was diluted in water and extracted by EtOAc. The organic layers were assembled, washed by brine and dried on MgSO.sub.4. The solvent was removed under reduced pressure. The crude product was purified by flash chromatography using a mixture of Cyclohexane/EtOAc (100/0 to 85/15) as eluent to give the desired (2-methoxyphenyl)methyl 4-(2,4-dichlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate as a colorless oil (111 mg, 77%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.67 (s, 3H), 2.78 (dd, J=15.9, 2.1 Hz, 1H), 2.89 (dd, J=15.9, 7.6 Hz, 1H), 3.38 (s, 3H), 3.43-3.53 (m, 2H), 3.73 (s, 3H), 3.74-3.85 (m, 1H), 4.20 (td, J=14.6, 3.6 Hz, 1H), 4.62 (d, J=7.6 Hz, 1H), 5.09 (d, J=12.9 Hz, 1H), 5.15 (d, J=12.9 Hz, 1H), 6.78-6.86 (m, 2H), 6.96 (d, J=7.4 Hz, 1H), 7.05-7.15 (m, 2H), 7.21-7.31 (m, 1H), 7.36 (d, J=1.8 Hz, 1H). .sup.13C NMR (75 MHz, CDCl.sub.3) 17.0, 26.9, 34.4, 36.5, 41.9, 55.1, 58.9, 61.7, 71.2, 109.1, 110.0, 120.1, 124.2, 127.1, 128.7, 128.9, 129.1, 129.6, 133.2, 134.3, 136.6, 152.1, 157.1, 166.7, 168.7. MS [M+H].sup.+ 478. HRMS: calcd for C.sub.24H.sub.26NO.sub.5Cl.sub.2, [M+H].sup.+ 478.1188, found 478.1173.

Example 130: o-methoxybenzyl 4-(2,4-dichlorophenyl)-6-methyl-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate (Intermediate Product)

[0318] ##STR00365##

2-methoxybenzoyl acetoacetate (3.0 mmol, 666 mg) was dissolved in acetic acid (3 mL). Meldrum acid (3.0 mmol, 432 mg), 2,5-dichlorobenzaldehyde (3.0 mmol, 432 mg) and ammonium acetate (4.5 mmol, 338 mg) were added and the reaction mixture was stirred for 18 h at 110 C. The reaction mixture was cooled at RT. 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 o-methoxybenzyl 4-(2,4-dichlorophenyl)-6-methyl-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate as a white powder (686 mg, 54%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.50 (s, 3H), 2.70 (d, J=16.8 Hz, 1H), 2.94 (dd, J=16.8, 8.7 Hz, 1H), 3.74 (s, 3H), 4.72 (d, J=8.7 Hz, 1H), 5.09 (d, J=12.9 Hz, 1H), 5.17 (d, J=12.9 Hz, 1H), 6.77-6.87 (m, 2H), 6.95-7.02 (m, 2H), 7.14 (dd, J=8.5, 2.3 Hz, 1H), 7.21-7.32 (m, 2H), 8.72 (brs, 1H). .sup.13C NMR (75 MHz, CDCl.sub.3) 18.9, 35.2, 36.0, 55.1, 61.6, 105.1, 110.0, 120.2, 124.1, 127.3, 128.4, 128.7, 129.1, 131.1, 133.0, 140.3, 166.0, 170.5. MS [M+H].sup.+422

Example 131: (2-methoxyphenyl)methyl 4-(2,5-dichlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate

[0319] o-methoxybenzyl 4-(2,4-dichlorophenyl)-6-methyl-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate (126 mg, 0.30 mmol) was dissolved in anhydrous DMF (1 mL). Cesium carbonate (195 mg, 0.60 mmol) and 2-bromoethyl methyl ether (56 L, 0.60 mmol) were added. The reaction mixture was stirred at 60 C. for 18 h. The DMF was removed under reduced pressure. The residue was diluted in water and extracted by EtOAc. The organic layers were assembled, washed by brine and dried on MgSO.sub.4. The solvent was removed under reduced pressure. The crude product was purified by flash chromatography using a mixture of Cyclohexane/EtOAc (9/1) as eluent to give the desired (2-methoxyphenyl)methyl 4-(2,5-dichlorophenyl)-1-(2-methoxyethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate as a white powder (91 mg, 63%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.71 (s, 3H), 2.79 (dd, J=15.9, 2.1 Hz, 1H), 2.90 (dd, J=15.9, 7.8 Hz, 1H), 3.42 (s, 3H), 3.44-3.56 (m, 2H), 3.73 (s, 3H), 3.78 (ddd, J=14.2, 7.8, 3.2 Hz, 1H), 4.24 (dt, J=14.6, 4.0 Hz, 1H), 4.64 (d, J=7.8 Hz, 1H), 5.09 (d, J=13.2 Hz, 1H), 5.17 (d, J=13.2 Hz, 1H), 6.78-6.85 (m, 2H), 6.96 (dd, J=7.4, 1.2 Hz, 1H), 7.07-7.16 (m, 2H), 7.20-7.30 (m, 2H). .sup.13C NMR (75 MHz, CDCl.sub.3) 17.0, 34.9, 36.3, 41.9, 55.1, 59.4, 61.7, 71.2, 108.5, 110.0, 120.1, 124.2, 127.8, 128.4, 128.6, 129.0, 131.0, 131.8, 132.9, 139.9, 152.3, 157.0, 166.6, 168.7. MS [M+H].sup.+ 478. HRMS: calcd for C.sub.24H.sub.26NO.sub.5Cl.sub.2, [M+H].sup.+ 478.1188, found 478.1187.

Example 132: (2-methoxyphenyl)methyl 6-methyl-2-oxo-4-(4-pyridyl)-3,4-dihydro-1H-pyridine-5-carboxylate (Intermediate Product)

[0320] ##STR00366##

[0321] 4-pyridylcarboxaldehyde (3.0 mmol, 280 L), meldrum acid (3.0 mmol, 432 mg), o-methoxybenzyl acetoacetate (3.0 mmol, 666 mg) and ammonium acetate (3.0 mmol, 338 mg) were dissolved in acetic acid (3 mL). The reaction mixture was stirred at 110 C. for 18 h. The solvent was removed. The crude product was purified by flash chromatography using a mixture of DCM/MEOH (99/1 to 99/2) as eluent and then precipitated in EtOH and filtered to afford the desired (2-methoxyphenyl)methyl 6-methyl-2-oxo-4-(4-pyridyl)-3,4-dihydro-1H-pyridine-5-carboxylate as a white powder (164 mg, 16%). .sup.1H NMR (300 MHz, CDCl.sub.3)) 2.43 (s, 3H), 2.67 (d, J=16.7 Hz, 1H), 2.95 (dd, J=16.7, 8.0 Hz, 1H), 3.73 (s, 3H), 4.25 (d, J=8.0 Hz, 1H), 5.11 (d, J=12.3 Hz, 1H), 5.21 (d, J=12.3 Hz, 1H), 6.80-6.90 (m, 2H), 7.02-7.12 (m, 3H), 7.28 (td, J=7.6, 1.7 Hz, 1H), 8.43-8.53 (m, 2H), 8.60 (brs, 1H). .sup.13C NMR (75 MHz, CDCl.sub.3) 19.0, 37.0, 37.3, 55.2, 61.9, 105.6, 110.3, 120.2, 122.1, 124.0, 129.6, 147.4, 150.0, 151.1, 157.4, 166.3, 170.3. MS [MH].sup. 351

Example 133: (2-methoxyphenyl)methyl 1-(2-methoxyethyl)-6-methyl-2-oxo-4-(4-pyridyl)-3,4-dihydropyridine-5-carboxylate

[0322] (2-methoxyphenyl)methyl 6-methyl-2-oxo-4-(4-pyridyl)-3,4-dihydropyridine-5-carboxylate (105 mg, 0.30 mmol) was dissolved in anhydrous DMF (1 mL). Cesium carbonate (195 mg, 0.6 mmol) and 2-bromoethyl methyl ether (56 L, 0.6 mmol) were added. The reaction mixture was stirred at 60 C. for 18 h. Water (25 mL) was added. The product was extracted by EtOAc. The organic layers were assembled, washed with brine and dried on MgSO.sub.4. The solvent was removed under reduced pressure. The crude product was purified by flash chromatography using a mixture of Cyclohexane/EtOAc (8/2-6/4 to 1/1) as eluent to give the desired (2-methoxyphenyl)methyl 1-(2-methoxyethyl)-6-methyl-2-oxo-4-(4-pyridyl)-3,4-dihydropyridine-5-carboxylate as a colorless oil (104 mg, 84%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.62 (s, 3H), 2.74 (dd, J=16.0, 2.2 Hz, 1H), 2.94 (dd, J=16.0 and 7.5 Hz, 1H), 3.28 (s, 3H), 3.28-3.38 (m, 1H), 3.44 (dt, J=9.8, 4.0 Hz, 1H), 3.70 (s, 3H), 3.74 (ddd, J=14.6, 8.2, 3.6 Hz, 1H), 4.13-4.23 (m, 2H), 5.10 (d, J=12.7 Hz, 1H), 5.20 (d, J=12.7 Hz, 1H), 6.79-6.87 (m, 2H), 7.04 (dd, J=7.3, 1.8 Hz, 1H), 7.08-7.13 (m, 2H), 7.26 (td, J=7.8, 1.7 Hz, 1H), 8.43-8.47 (m, 2H). .sup.13C NMR (75 MHz, CDCl.sub.3) 17.0, 36.7, 37.7, 41.8, 55.1, 58.7, 62.0, 70.9, 109.1, 110.2, 120.2, 122.3, 124.0, 129.3, 129.5, 149.8, 150.5, 151.4, 157.3, 166.8, 168.6. MS [M+H].sup.+ 412. HRMS: calcd for C.sub.23H.sub.27N.sub.2O.sub.5, [M+H].sup.+ 411.1920, found 411.1930.

TABLE-US-00010 TABLE 10 [00367] Example R20 136 [00368] 137 [00369] 138 [00370] 141 [00371] 144 [00372] 145 [00373] 146 [00374]

Example 134: Methyl (4S)-4-(4-chlorophenyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate and Methyl (4R)-4-(4-chlorophenyl)-6-methyl-2-oxo-1-[[(2S)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate (Intermediate Product)

[0323] ##STR00375##

[0324] The methyl 4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate (3.40 g, 12.15 mmol) was dissolved in anh. DMF (10 mL). Cesium carbonate (7.92 g, 24.31 mmol) and sodium iodide (91 mg, 0.61 mmol) were added followed by tetrahydrofurfuryl bromide (2.77 mL, 24.31 mmol). The reaction mixture was stirred at 50 C. for 18 h. The solvents were removed under reduced pressure. Water was added and the aqueous phase extracted by EtOAc. The organic phases were assembled, washed with brine and dried over MgSO.sub.4. The crude was dissolved again in anh. DMF (10 mL). Cesium carbonate (7.92 g, 24.31 mmol) and sodium iodide (91 mg, 0.61 mmol) were added followed by tetrahydrofurfuryl bromide (2.77 mL, 24.31 mmol). The reaction mixture was stirred at 50 C. for 18 h. The solvents were removed under reduced pressure. Water was added and the aqueous phase extracted by EtOAc. The organic phases were assembled, washed with brine and dried over MgSO.sub.4. The solvent was removed under reduced pressure. The crude was purified by flash chromatography on silica using a mixture Cy/EA (95/5 to 88/12) as eluent to give methyl (4S)-4-(4-chlorophenyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate and its enantiomer as a colorless oil (1.58 g, 36%)

[0325] .sup.1H NMR (300 MHz, CDCl.sub.3) 1.40-1.50 (m, 1H), 1.80-2.00 (m, 3H), 2.62 (s, 3H), 2.71 (dd, J=15.5, 2.2 Hz, 1H), 2.91 (dd, J=15.5, 7.0 Hz, 1H), 3.41 (dd, J=14.3, 8.8 Hz, 1H), 3.65 (s, 3H), 3.65-3.82 (m, 2H), 3.86-3.96 (m, 2H), 3.86-3.96 (m, 1H), 4.18 (dd, J=7.0, 2.2 Hz, 1H), 4.27 (dd, J=14.3, 3.2 Hz, 1H), 7.21 (s, 4H). MS [M+H].sup.+ 364.

Example 135: (4S)-4-(4-chlorophenyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylic acid and (4R)-4-(4-chlorophenyl)-6-methyl-2-oxo-1-[[(2S)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylic acid (Intermediate Product)

[0326] ##STR00376##

[0327] An aqueous solution of NaOH 1N (15 mL) was added to a solution of methyl (4S)-4-(4-chlorophenyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate and its enantiomer (example 134, 1.58 g, 4.35 mmol) in MeOH (15 mL). The reaction mixture was stirred overnight at 40 C. The solvent was removed under reduced pressure, the aqueous phase was washed with Et.sub.2O, then acidified to pH=1 with HCl conc. The aqueous phase was extracted with DCM. The organic phases were assembled and dried over Na.sub.2SO.sub.4. The solvent was removed under reduced pressure to afford the desired (4S)-4-(4-chlorophenyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylic acid as a white powder (m=1.3 g, 88%). .sup.1H NMR (300 MHz, DMSO d6) 1.34-1.48 (m, 1H), 1.74-1.88 (m, 3H), 2.49 (dd, J=15.5, 1.9 Hz, 1H), 2.53 (s, 3H), 2.95 (dd, J=15.5, 6.9 Hz, 1H), 3.42 (dd, J=14.2, 8.6 Hz, 1H), 3.60-3.72 (m, 2H), 3.78-3.88 (m, 1H), 4.05 (dd, J=14.8, 3.5 Hz, 1H), 4.11 (d, J=6.9 Hz, 1H), 7.25 (d, J=8.7 Hz, 2H), 7.29 (d, J=8.7 Hz, 2H), 12.24 (brs, 1H). .sup.13C NMR (75 MHz, DMSO d6) 17.1, 25.4, 29.0, 37.0, 39.3, 45.3, 67.9, 78.1, 110.6, 128.7, 129.4, 131.6, 140.9, 150.5, 168.8, 169.0. MS [M+H].sup.+ 348. HRMS: calcd for C.sub.18H.sub.19NO.sub.4Cl, [MH].sup. 348.1003, found 348.1025.

Example 136: 4-(2-methoxyethoxy)phenyl]methyl (4S)-4-(4-chlorophenyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate and 4-(2-methoxyethoxy)phenyl]methyl (4R)-4-(4-chlorophenyl)-6-methyl-2-oxo-1-[[(2S)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate

[0328] 1-(chloromethyl)-4-(2-methoxyethoxy)benzene (example 118, 125 mg, 0.60 mmol) and racemic mixture of (4 S)-4-(4-chlorophenyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylic acid and its enantiomer (example 135, 192 mg, 0.55 mmol) were dissolved in anhydrous DMF (2 mL). Cesium carbonate (269 mg, 0.825 mmol) was added and the reaction mixture was stirred at r.t. for 18 h. The solvents were removed under reduced pressure. Water was added and the aqueous phase was extracted with diethyl ether, washed with brine and dried over Na.sub.2SO.sub.4. The solvents were removed under reduced pressure. Purification of the crude by flash chromatography using a mixture of Cy/EtOAc (9/1) as eluent gave the expected [4-(2-methoxyethoxy)phenyl]methyl (4S)-4-(4-chlorophenyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate as a colorless oil (m=105 mg, 37%) .sup.1H NMR (300 MHz, CDCl.sub.3) 1.23-1.30 (m, 1H), 1.78-1.98 (m, 3H), 2.61 (s, 3H), 2.70 (dd, J=15.5, 2.0 Hz, 1H), 2.90 (dd, J=15.5, 7.3 Hz, 1H), 3.41 (dd, J=14.5, 8.9 Hz, 1H), 3.46 (s, 3H), 3.64-3.94 (m, 5H), 4.11 (dd, J=4.8, 3.4 Hz, 2H), 4.17 (dd, J=7.3, 2.0 Hz, 1H), 4.25 (dd, J=14.5, 3.4 Hz, 1H), 5.02 (s, 2H), 6.82 (d, J=8.6 Hz, 2H), 7.04 (d, J=8.6 Hz, 2H), 7.16 (d, J=9.0 Hz, 2H), 7.20 (d, J=9.0 Hz, 2H). .sup.13C NMR (75 MHz, CDCl.sub.3) 17.0, 25.4, 29.1, 36.9, 38.9, 45.5, 59.1, 65.7, 67.1, 68.0, 70.9, 77.7, 110.1, 114.3, 128.3, 128.5, 128.6, 129.2, 132.3, 139.5, 151.0, 158.4, 166.9, 168.8. MS [M+H].sup.+ 514, HRMS: calcd for C.sub.28H.sub.33NO.sub.6Cl, [M+H].sup.+ 514.1996, found 514.2004.

Example 137: Indan-1-yl (4S)-4-(4-chlorophenyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate (Racemic)

[0329] 1-chloroindane (55 mg, 0.36 mmol) and (4S)-4-(4-chlorophenyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylic acid and its enantiomer (example 135, 115 mg, 0.33 mmol) were dissolved in anh. DMF (2 mL). Cesium carbonate (107 mg, 0.33 mmol) and sodium iodide (2.5 mg, 0.017 mmol) were added. The reaction mixture was stirred at r.t. for 24 h, at 60 C. for 2 h and at 80 C. for 1 h. The reaction mixture was cooled down to r.t. Water was added and the aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine and dried over MgSO.sub.4. The solvent was removed under reduced pressure. Purification of the crude by flash chromatography using a mixture of Cyclohexane/EtOAc (93/7) as eluent gave the desired indan-1-yl (4S)-4-(4-chlorophenyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate as a single diastereomer and a yellow oil (30 mg, 17%). .sup.1H NMR (300 MHz, CDCl.sub.3) 1.38-1.52 (m, 1H), 1.71-1.82 (m, 1H), 1.82-1.98 (m, 3H), 2.26-2.40 (m, 1H), 2.63 (s, 3H), 2.65 (dd, J=15.9, 2.2 Hz, 1H), 2.72-2.96 (m, 3H), 3.42 (dd, J=14.3, 8.5 Hz, 1H), 3.69-3.96 (m, 3H), 4.08 (d, J=7.6 Hz, 1H), 4.25 (dd, J=14.3, 3.4 Hz, 1H), 6.19 (dd, J=6.9, 3.7 Hz, 1H), 7.14 (d, J=8.4 Hz, 2H), 7.19 (d, J=8.4 Hz, 2H), 7.21-7.34 (m, 3H), 7.43 (d, J=7.3 Hz, 1H). MS [M+H].sup.+ 466; HRMS: calcd for C.sub.27H.sub.29NO.sub.4Cl, [M+H].sup.+ 466.1785, found 466.1798.

Example 138: 1-(2-methoxyphenyl)ethyl (4S)-4-(4-chlorophenyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate (Diastereoisomers Mixture)

[0330] 1-(1-chloroethyl)-2-methoxy-benzene (68 mg, 0.36 mmol) and racemic mixture of (4S)-4-(4-chlorophenyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylic acid and its enantiomer (example 135, 126 mg, 0.36 mmol) were dissolved in anh. DMF (2 mL). Cesium carbonate (117 mg, 0.36 mmol) was added and the reaction mixture was stirred at RT for 24 h, at 60 C. for 24 h and at 90 C. for 6 h. The reaction mixture was cooled down to r.t. Water was added and the aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine and dried over MgSO.sub.4. The solvent was removed under reduced pressure. Purification of the crude by flash chromatography using a mixture of Cyclohexane/EtOAc (93/7) as eluent gave the desired 1-(2-methoxyphenyl)ethyl (4 S)-4-(4-chlorophenyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate as a yellow oil and a mixture of diastereomers 1/1 (m=30 mg, 17%). .sup.1H NMR (300 MHz, CDCl.sub.3) 1.25-1.32 (d, J=6.5 Hz, 1.5H), 1.38-1.52 (m, 2.5H), 1.80-2.00 (m, 3H), 2.61 (s, 3H), 2.68-2.78 (m, 1H), 2.86-3.02 (m, 1H), 3.36-3.46 (m, 1H), 3.66-3.93 (m, 3H), 3.74 (s, 1.5H), 3.82 (s, 3H), 4.18-4.32 (m, 2H), 6.17-6.28 (m, 1H), 6.50 (dd, J=7.7, 1.7 Hz, 0.5H), 6.63 (t, J=7.6 Hz, 0.5H), 6.76 (d, J=8.5 Hz, 0.5H), 6.86 (d, J=8.0 Hz, 0.5H), 6.91 (t, J=7.0 Hz, 0.5H), 7.10-7.17 (m, 1H), 7.22-7.25 (m, 4.5H). MS [M+H].sup.+ 484; HRMS: calcd for C.sub.26H.sub.29NO.sub.5Cl, [M+H].sup.+ 484.1904, found 484.1896.

##STR00377##

Example 139: [4-(polyethyleneglycoxymethylether)phenyl]methanol (Intermediate Product)

[0331] ##STR00378##

[0332] Poly(ethylene glycol) methyl ether (Sigma-Aldrich, ref 202487, average Mn 550, 1 mmol) was dissolved in THF (3 mL). The solution was cooled at 0 C. NaH (36 mg, 1.5 mmol) was added and the reaction mixture was stirred at 0 C. to 20 C. for 2 h. Then p-toluenesulfonyl chloride (381 mg, 2 mmol) was added at 0 C. and the reaction mixture was stirred at r.t. until completion. The solvent was removed under reduced pressure. Purification of the crude by flash chromatography using a mixture of DCM/MeOH 97/3 as eluent gave the desired poly(ethylene glycol) methyl ether tosylate (515 mg, 73%). Poly(ethylene glycol) methyl ether tosylate (0.73 mmol, 502 mg) was dissolved in MeCN (3 mL), the phenol (1.10 mmol, 136 mg) and K.sub.2CO.sub.3 (1.10 mmol, 151 mg) were added. The reaction mixture was stirred overnight under reflux. The reaction mixture became pink and, after being cooled down, it has been filtered. The filtrate has been concentrated under vacuum and purified by Flash Chromatography (DCM/MeOH 100/0 to 8/2) to give the expected [4-(polyethyleneglycoxy methylether)phenyl]methanol as a yellow oil (390 mg, 78%) 1H NMR (300 MHz, CDCl3) 3.38 (s, 3H), 3.52-3.77 (m, 47H), 3.84-3.90 (m, 2H), 4.10-4.17 (m, 2H), 4.62 (s, 2H), 6.91 (d, J=8.7 Hz, 2H), 7.29 (d, J=8.7 Hz, 2H). MS [M+NH.sup.4].sup.+ 684

Example 140: 1-chloromethyl-4-(polyethyleneglycoxy methylether)benzene (Intermediate Product)

[0333] ##STR00379##

[0334] Thionyl chloride (0.71 mmol, 52 L) was added to benzotriazole (0.71 mmol, 85 mg). The resulting yellow solution was dissolved in dry DCM (1 mL). After 5 min, this solution was added slowly to a solution of [4-(polyethyleneglycoxy methylether)phenyl]methanol in DCM (6 mL). After 1 h of reaction, the reaction mixture was quenched by addition of MgSO.sub.4.7H.sub.20 and then filtered. The solvents were removed under reduced pressure to afford 1-chloromethyl-4-(polyethyleneglycoxy methylether)benzene as a yellow oil (m=400 mg, quantitative). .sup.1H NMR (300 MHz, CDCl.sub.3) 3.38 (s, 3H), 3.52-3.77 (m, 47H), 3.84-3.90 (m, 2H), 4.10-4.17 (m, 2H), 4.57 (s, 2H), 6.89 (d, J=8.7 Hz, 2H), 7.30 (d, J=8.7 Hz, 2H).

Example 141: [4-(polyethyleneglycoxy methylether)phenyl]methyl (4S)-4-(4-chlorophenyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate (Mixture m=8-13)

[0335] ##STR00380##

[0336] 1-chloromethyl-4-(polyethyleneglycoxymethylether)benzene (example 140, 125 mg, 0.60 mmol) and (4S)-4-(4-chlorophenyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylic acid (example 135, 192 mg, 0.55 mmol) were dissolved in anh. DMF (2 mL). Cesium carbonate (269 mg, 0.82 mmol) was added and the reaction mixture stirred at RT for 24 h. An aqueous hydrochloric acid solution 1N and brine were added. The aqueous phase was extracted with ethyl acetate. The crude was purified by flash chromatography using a mixture DCM/MeOH (100/0 to 9/1) to give the desired product but not clean. A second purification by HPLC (acidic conditions) afforded the desired [4-(polyethyleneglycoxy methylether)phenyl]methyl(4S)-4-(4-chlorophenyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate as a colorless oil (m=87 mg, 17%). .sup.1H NMR (300 MHz, CDCl.sub.3) 1.38-1.52 (m, 1H), 1.80-2.04 (m, 3H), 2.61 (s, 3H), 2.68 (dd, J=15.6, 2.2 Hz, 1H), 2.89 (dd, J=15.6, 7.2 Hz, 1H), 3.38 (s, 3H), 3.40 (dd, J=14.6, 8.8 Hz, 1H), 3.52-3.59 (m, 2H), 3.60-3.95 (m, 44H), 4.08-4.13 (m, 2H), 4.16 (dd, J=7.2, 2.2 Hz, 1H), 4.25 (dd, J=14.3, 3.1 Hz, 1H), 5.02 (s, 2H), 6.81 (d, J=8.5 Hz, 2H), 7.04 (d, J=8.5 Hz, 2H), 7.16 (d, J=8.9 Hz, 2H), 7.20 (d, J=8.9 Hz, 2H). .sup.13C NMR (75 MHz, CDCl.sub.3) 17.1, 25.5, 29.2, 37.0, 39.0, 45.6, 59.0, 65.8, 67.4, 68.1, 69.7, 70.5, 70.8, 71.9, 77.8, 110.2, 114.4, 128.3, 128.6, 129.4, 132.5, 139.5, 151.1, 158.6, 167.0, 169.0. MS [M+NH.sub.4].sup.+ 884, 928, 972, 1016, 1060, HRMS: calcd for C.sub.50H.sub.80N.sub.2O.sub.17Cl, [M+NH.sub.4].sup.+ 1015.5146, found 1015.5122.

Example 144: Ammonium 2-[4-[[(4S)-4-(4-chlorophenyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carbonyl]oxymethyl]phenoxy]ethanesulfonate

[0337] ##STR00381## ##STR00382##

Example 142: [4-(2-chloroethoxy)phenyl]methanol (Intermediate Product)

[0338] ##STR00383##

[0339] 1-bromo-2-chloroethane (30 mmol, 2.5 mL), 4-hydroxybenzyl alcohol (6 mmol, 745 mg) and potassium carbonate (30 mmol, 4.15 g) were added in acetonitrile (20 mL). The reaction mixture was stirred under reflux for 60 h. The solvent was removed under reduced pressure. The crude was dissolved in EtOAc and washed with water. The aqueous phase was extracted by EtOAc and washed with brine, dried under Na.sub.2SO.sub.4. The solvent was removed under reduced pressure to and the crude was purified by flash chromatography (Cy/EA 85/15) to afford the desired compound as a white powder (m=888 mg, 79%). .sup.1H NMR (300 MHz, CDCl.sub.3) 1.67 (brs, 1H), 3.82 (t, J=5.9 Hz, 2H), 4.24 (t, J=5.9 Hz, 2H), 4.63 (brs, 2H), 6.92 (d, J=8.7 Hz, 2H), 7.31 (d, J=8.7 Hz, 2H).

Example 143: 1-(2-chloroethoxy)-4-(chloromethyl)benzene (Intermediate Product)

[0340] ##STR00384##

[0341] Thionyl chloride (45 L, 0.63 mmol) was added to benzotriazole (75 mg, 0.63 mmol). The resulting yellow solution was dissolved in dry DCM (0.5 mL). After 5 min, this solution was added slowly to a solution of the alcohol 142 (93 mg, 0.50 mmol) in DCM (4 mL). After 20 min of reaction, the salt was filtered. The organic phase was washed with water (4 mL) and an aqueous solution of NaOH (0.05 M, 4 mL). The organic phase was dried on Na.sub.2SO.sub.4 and the solvent was removed under reduced pressure to give the desired chlorinated compound as a colorless oil (70 mg, 68%). .sup.1H NMR (300 MHz, CDCl.sub.3) 3.82 (t, J=6.1 Hz, 2H), 4.25 (t, J=6.1 Hz, 2H), 4.58 (s, 2H), 6.90 (d, J=8.8 Hz, 2H), 7.34 (d, J=8.8 Hz, 2H).

Example 143a: [4-(2-chloroethoxy)phenyl]methyl (4S)-4-(4-chlorophenyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate (Racemic Mixture) (Intermediate Product)

[0342] ##STR00385##

[0343] The (4S)-4-(4-chlorophenyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylic acid (example 135, 105 mg, 0.30 mmol) and cesium carbonate (108 mg, 0.33 mmol) were dissolved in anh. DMF (2 mL). 1-(2-chloroethoxy)-4-(chloromethyl)benzene 143 (67 mg, 0.33 mmol) was added. The reaction mixture was stirred at RT for 18 h. The solvents were 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 Na.sub.2SO.sub.4. The orange residue was purified by flash chromatography (Cy/DCM 1/1 to DCM) to afford the desired [4-(2-chloroethoxy)phenyl]methyl (4S)-4-(4-chlorophenyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate as a colorless oil (m=145 mg, 93%). .sup.1H NMR (300 MHz, CDCl.sub.3) 1.40-1.50 (m, 1H), 1.80-2.00 (m, 3H), 2.62 (s, 3H), 2.69 (dd, J=15.8, 2.2 Hz, 1H), 2.89 (dd, J=15.8, 7.4 Hz, 1H), 3.41 (dd, J=14.3, 8.8, 1H), 3.68-3.96 (m, 3H), 3.82 (t, J=6.0 Hz, 2H), 4.17 (d, J=7.4 Hz, 1H), 4.22 (t, J=6.0 Hz, 2H), 4.22-4.29 (m, 1H), 5.03 (s, 2H), 6.81 (d, J=8.6 Hz, 2H), 7.05 (d, J=8.6 Hz, 2H), 7.17 (d, J=8.8 Hz, 2H), 7.21 (d, J=8.8 Hz, 2H). MS [M+H].sup.+ 518.

Example 143b: 4-(2-iodoethoxy)phenyl]methyl (4S)-4-(4-chlorophenyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl (Intermediate Product)

[0344] ##STR00386##

[0345] [4-(2-chloroethoxy)phenyl]methyl (4S)-4-(4-chlorophenyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate 143a (145 mg, 0.288 mmol) was dissolved in butanone (1 mL). Sodium iodide (168 mg, 1.12 mmol) was added and the reaction mixture was stirred at 80 C. for 32 h. The solution was cooled to RT, filtered and washed by acetone. The solvents were removed under reduced pressure. Purification of the crude by flash chromatography using a mixture of Cy/DCM (1/1 to 0/1) gave the desired [4-(2-iodoethoxy)phenyl]methyl (4S)-4-(4-chlorophenyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate as a colorless oil (m=137 mg, 80%) .sup.1H NMR (300 MHz, CDCl.sub.3) 1.39-1.51 (m, 1H), 1.81-2.00 (m, 3H), 2.62 (s, 3H), 2.69 (dd, J=15.6, 2.4 Hz, 1H), 2.90 (dd, J=15.6, 7.4 Hz, 1H), 3.36-3.46 (m, 3H), 3.68-3.96 (m, 3H), 4.17 (d, J=7.4 Hz, 1H), 4.20-4.30 (m, 3H), 5.03 (s, 2H), 6.81 (d, J=8.7 Hz, 2H), 7.05 (d, J=8.7 Hz, 2H), 7.16 (d, J=8.7 Hz, 2H), 7.21 (d, J=8.7 Hz, 2H). MS [M+H].sup.+ 610

Example 144: Ammonium 2-[4-[[(4S)-4-(4-chlorophenyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carbonyl]oxymethyl]phenoxy]ethanesulfonate

[0346] The [4-(2-iodoethoxy)phenyl]methyl (4S)-4-(4-chlorophenyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate 143b (145 mg, 0.24 mmol) was dissolved in a mixture iPrOH/water 1/1 (1 mL). Sodium sulfite (60 mg, 0.48 mmol) was added and the reaction mixture was stirred under reflux for 48 h. The solvents were removed under reduced pressure. Purification of the crude by HPLC (basic conditions) gave the ammonium 2-[4-[[(4S)-4-(4-chlorophenyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carbonyl]oxymethyl]phenoxy]ethanesulfonate as a white powder (m=60 mg, 45%). .sup.1H NMR (300 MHz, CDCl.sub.3) 1.34-1.48 (m, 1H), 1.74-1.96 (m, 3H), 2.56 (s, 3H), 2.60 (d, J=15.9 Hz, 1H), 2.70-2.88 (m, 3H), 3.26 (t, J=6.1 Hz, 2H), 3.35 (dd, J=14.3-9.0 Hz, 1H), 3.62-3.90 (m, 3H), 4.09 (d, J=6.1 Hz, 1H), 4.14-4.28 (m, 3H), 4.82 (d, J=12.5 Hz, 1H), 4.94 (d, J=12.5 Hz, 1H), 6.73 (d, J=8.5 Hz, 2H), 6.89 (brs, 4H), 6.96 (d, J=8.5 Hz, 2H), 7.13 (s, 3H). .sup.13C NMR (75 MHz, CDCl.sub.3) 17.1, 25.5, 29.1, 36.9, 38.9, 45.6, 50.6, 63.5, 65.6, 68.1, 77.2, 77.8, 110.0, 114.6, 128.7, 129.1, 129.5, 132.4, 139.5, 151.1, 157.8, 167.0, 169.0. MS [MH]=562; HRMS: calcd for C.sub.27H.sub.29NO.sub.8SCl, [M+H].sup.+ 562.1302, found 562.1322.

Example 145: 2-pyridylmethyl (4S)-4-(4-chlorophenyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate and 2-pyridylmethyl (4R)-4-(4-chlorophenyl)-6-methyl-2-oxo-1-[[(2S)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate

[0347] Racemic mixture of (4S)-4-(4-chlorophenyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylic acid and its enantiomer (example 135, 105 mg, 0.30 mmol) was dissolved in anhydrous DMF (1 mL) then cesium carbonate (215 mg, 0.66 mmol) and 2-(Chloromethyl)pyridine hydrochloride (132 mg, 0.36 mmol) were added. The reaction mixture was stirred at RT for 18 h. Cesium carbonate (60 mg, 0.18 mmol) and 2-(Chloromethyl)pyridine hydrochloride (30 mg, 0.18 mmol) were added again. The reaction mixture was stirred at 60 C. for 12 h. The solvent was removed under reduced pressure. Water was added. The aqueous phase was extracted with Et.sub.2O. The combined organic layers were washed with brine and dried over MgSO.sub.4. The solvent was removed under reduced pressure. Purification of the crude by flash chromatography on silica using a mixture of DCM/EtOAc (7/3) gave the desired (2-pyridylmethyl (4S)-4-(4-chlorophenyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate as a colorless oil (83 mg, 63%). .sup.1H NMR (300 MHz, CDCl.sub.3) 1.42-1.51 (m, 1H), 1.83-2.00 (m, 3H), 2.65 (s, 3H), 2.71 (dd, J=15.8, 2.2 Hz, 1H), 2.94 (dd, J=15.5, 7.4 Hz, 1H), 3.42 (dd, J=14.4, 8.8 Hz, 1H), 3.70-3.77 (m, 1H), 3.79-3.84 (m, 1H), 3.87-3.94 (m, 1H), 4.23-4.29 (m, 2H), 5.13 (d, J=14.0 Hz, 1H), 5.29 (d, J=14.0 Hz, 1H), 6.80 (d, J=8.1 Hz, 1H), 7.15 (dd, J=7.4, 5.0 Hz, 2H), 7.22 (s, 4H), 7.51 (td, J=7.7, 2.2 Hz, 1H), 8.51 (d, J=5.0 Hz, 1H). .sup.13C NMR (75 MHz, CDCl.sub.3) 17.3, 25.6, 29.2, 37.1, 39.2, 46.1, 66.3, 68.1, 77.9, 109.6, 121.2, 122.7, 128.7, 128.8, 132.6, 136.8, 139.5, 149.0, 152.1, 156.0, 166.7, 168.9. MS [M+H].sup.+ 441, HRMS: calcd for C.sub.26H.sub.28NO.sub.5Cl.sub.2, [M+H].sup.+ 441.1581, found 441.1584.

Example 146: 3-pyridylmethyl (4S)-4-(4-chlorophenyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate and 3-pyridylmethyl (4R)-4-(4-chlorophenyl)-6-methyl-2-oxo-1-[[(2S)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate

[0348] Racemic mixture of (4S)-4-(4-chlorophenyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylic acid and its enantiomer (example 135, 105 mg, 0.30 mmol) was dissolved in anhydrous DMF (1 mL) then cesium carbonate (215 mg, 0.66 mmol) and 3-(Chloromethyl)pyridine hydrochloride (132 mg, 0.36 mmol) were added. The reaction mixture was stirred at RT for 18 h. The solvent was removed under reduced pressure. Water was added. The aqueous phase was extracted with Et.sub.2O. The combined organic layers were washed with brine and dried over MgSO.sub.4. The solvent was removed under reduced pressure. Purification of the crude by flash chromatography on silica using a mixture of DCM/EtOAc (8/2) gave the desired (3-pyridylmethyl (4S)-4-(4-chlorophenyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate (Racemic) as a colorless oil (101 mg, 76%). .sup.1H NMR (300 MHz, CDCl.sub.3) 1.42-1.51 (m, 1H), 1.83-2.00 (m, 3H), 2.65 (s, 3H), 2.71 (dd, J=15.5, 2.2 Hz, 1H), 2.94 (dd, J=15.5, 7.4 Hz, 1H), 3.42 (dd, J=14.4, 8.8 Hz, 1H), 3.70-3.77 (m, 1H), 3.79-3.84 (m, 1H), 3.87-3.94 (m, 1H), 4.23-4.29 (m, 2H), 5.13 (d, J=14.0 Hz, 1H), 5.29 (d, J=14.0 Hz, 1H), 6.80 (d, J=8.1 Hz, 1H), 7.15 (dd, J=7.4, 5.0 Hz, 2H), 7.22 (s, 4H), 7.51 (td, J=7.7, 2.2 Hz, 1H), 8.51 (d, J=5.0 Hz, 1H). .sup.13C NMR (75 MHz, CDCl.sub.3) 17.2, 25.5, 29.2, 37.1, 39.1, 45.8, 63.4, 68.1, 77.8, 109.49, 123.4, 128.6, 128.7, 131.8, 132.6, 135.5, 139.4, 149.0, 149.3, 152.2, 166.7, 168.9. MS [M+H].sup.+ 441, HRMS: calcd for C.sub.24H.sub.26N.sub.2O.sub.4Cl, [M+H].sup.+ 441.1581, found 441.1580.

TABLE-US-00011 TABLE 11 [00387] example R21 147 [00388]

Example 147: [4-(2-methoxyethoxy)phenyl]methyl (4S)-4-(4-chlorophenyl)-6-methyl-2-oxo-1-[[(2S)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate and [4-(2-methoxyethoxy)phenyl]methyl (4R)-4-(4-chlorophenyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate

[0349] 1-(chloromethyl)-4-(2-methoxyethoxy)benzene (example 118, 125 mg, 0.60 mmol) and (4S)-4-(4-chlorophenyl)-6-methyl-2-oxo-1-[[(2S)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylic acid (192 mg, 0.55 mmol) were dissolved in anh. DMF (2 mL). Cesium carbonate (269 mg, 0.825 mmol) was added and the reaction mixture was stirred at RT for 18 h. The solvents were removed under reduced pressure. Water was added and the aqueous phase was extracted with diethyl ether, washed with brine and dried over Na.sub.2SO.sub.4. The solvents were removed under reduced pressure. Purification of the crude by flash chromatography using a mixture of Cy/DCM 1/1 to DCM gave the expected [4-(2-methoxyethoxy)phenyl]methyl (4S)-4-(4-chlorophenyl)-6-methyl-2-oxo-1-[[(2S)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate as a colorless oil (59 mg, 21%) .sup.1H NMR (300 MHz, CDCl.sub.3) 1.24-1.36 (m, 1H), 1.74-1.94 (m, 3H), 2.61 (s, 3H), 2.78 (dd, J=15.9, 2.7 Hz, 1H), 2.91 (dd, J=15.9, 7.3 Hz, 1H), 3.46 (s, 3H), 3.66-3.84 (m, 5H), 3.88-4.06 (m, 2 h), 4.09-4.14 (m, 2H), 4.18 (dd, J=7.3, 2.1 Hz, 1H), 5.01 (d, J=12.2 Hz, 1H), 5.07 (d, J=12.2 Hz, 1H), 6.85 (d, J=8.6 Hz, 2H), 7.06 (d, J=8.4 Hz, 2H), 7.08 (d, J=8.6 Hz, 2H), 7.19 (d, J=8.4 Hz, 2H). .sup.13C NMR (75 MHz, CDCl.sub.3) 17.4, 25.3, 28.9, 36.4, 38.3, 45.2, 59.2, 65.9, 67.2, 67.7, 71.0, 110.4, 114.4, 128.3, 128.4, 128.6, 129.6, 132.5, 139.8, 150.6, 158.6, 167.0, 169.4. MS [M+H].sup.+ 514, HRMS: calcd for C.sub.28H.sub.33NO.sub.6Cl, [M+H].sup.+ 514.1996, found 514.2003.

TABLE-US-00012 TABLE 12 [00389] Example R22 148 [00390] 149 [00391] 150 [00392] 151 [00393] 152 [00394]

Example 148: (2-methoxyphenyl)methyl (4S)-4-(6-chloro-3-pyridyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate and 2-methoxyphenyl) methyl (4R)-4-(6-chloro-3-pyridyl)-6-methyl-2-oxo-1-[[(2S)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate

[0350] Step 1.

[0351] 6-chloropyridine-3-carbaldehyde (3 mmol), meldrum acid (3 mmol), (2-methoxyphenyl)methyl-3-oxobutanoate (3 mmol) and ammonium acetate (4.5 equiv) were dissolved in acetic acid (1N). The reaction mixture was stirred overnight under reflux. The solvent was removed. The crude product was purified by flash chromatography and engaged in step 2.

[0352] Step 2.

[0353] The intermediate obtained in step 1 (1.3 g, 3.36 mmol) was dissolved in anh. DMF (12 mL). Tetrahydrofurfuryl bromide (573 L, 5.04 mmol), Cs.sub.2CO.sub.3 (1.64 g, 5.04 mmol), sodium iodide (25 mg, 0.17 mmol) were added. The reaction mixture was stirred at 50 C. for 18 h. The DMF was removed under reduced pressure. The residue was diluted in water. The aqueous phase was extracted by EtOAc and the combined organic layers were washed with brine and dried over MgSO.sub.4. The solvent was removed under reduced pressure. The crude was dissolved again in anh. DMF (1 mL). Tetrahydrofurfuryl bromide (573 L, 5.04 mmol) and Cs.sub.2CO.sub.3 (1.64 g, 5.04 mmol) were added. The reaction mixture was stirred at 50 C. for 18 h. The DMF was removed under reduced pressure. The residue was diluted in water. The aqueous phase was extracted by EtOAc and the combined organic layers were washed with brine and dried over MgSO.sub.4. The solvent was removed under reduced pressure. Purification of the crude by flash chromatography using a mixture of Cyclohexane/EtOAc (8/2) as eluent gave the desired (2-meth oxyphenyl)methyl (4S)-4-(6-chloro-3-pyridyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate and its enantiomer as a colorless oil (204 mg, 13%). .sup.1H NMR (300 MHz, CDCl.sub.3) 1.39-1.51 (m, 1H), 1.81-2.07 (m, 3H), 2.60 (s, 3H), 2.64 (dd, J=16.0, 2.0 Hz, 1H), 2.92 (dd, J=15.7, 7.5 Hz, 1H), 3.39 (dd, J=14.2, 9.3 Hz, 1H), 3.70 (s, 3H), 3.72-3.77 (m, 1H), 3.83-3.90 (m, 2H), 4.23 (dd, J=14.0, 2.8 Hz, 2H), 5.08 (d, J=12.5 Hz, 1H), 5.14 (d, J=12.5 Hz, 1H), 6.80-6.87 (m, 2H), 7.02 (dd, J=7.5, 1.7 Hz, 1H), 7.13 (d, J=8.3 Hz, 1H), 7.22-7.28 (td, J=7.8, 1.7 Hz, 1H), 7.57 (dd, J=8.3, 2.5 Hz, 1H), 8.21 (d, J=2.5 Hz, 1H). .sup.13C NMR (75 MHz, CDCl.sub.3) 17.08, 25.61, 29.18, 34.88, 38.62, 45.96, 55.21, 62.04, 68.16, 77.63, 109.31, 110.30, 120.25, 123.97, 124.02, 129.46, 129.58, 135.94, 137.88, 149.16, 149.79, 151.66, 157.42, 166.71, 168.4. MS [M+H].sup.+ 471 g/mol. HRMS: calcd for C.sub.25H.sub.28N.sub.2O.sub.5Cl.sub.2, [M+H].sup.+ 471.1687, found 471.1695.

Example 149a: 4-(3,4-dichlorophenyl)-6-methyl-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate (Intermediate Product)

[0354] ##STR00395##

[0355] 3,4-dichlorobenzaldehyde (3.0 mmol, 525 g), meldrum acid (3.0 mmol, 432 g), o-methoxybenzyl acetoacetate (3.0 mmol, 666 mg) and ammonium acetate (4.5 mmol, 338 mg) were dissolved in acetic acid (3 mL). The reaction mixture was stirred at 110 C. for 18 h. The solvent was removed. The crude didn't precipitate in EtOH. The crude has been purified by flash chromatography (Cy/EA (85/15) to and precipitated in EtOH. Then, a filtration yielded the desired (2-methoxyphenyl)methyl 4-(3,4-dichlorophenyl)-6-methyl-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate as a white powder (384 mg, 30%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.43 (s, 3H), 2.63 (dd, J=16.7, 1.3 Hz, 1H), 2.94 (dd, J=16.7, 8.1 Hz, 1H), 3.76 (s, 3H), 4.23 (d, J=7.7 Hz, 1H), 5.12 (d, J=12.6 Hz, 1H), 5.22 (d, J=12.6 Hz, 1H), 6.86 (d, J=8.3 Hz, 1H), 6.88 (td, J=7.4, 1.0 Hz, 1H), 6.99 (dd, J=8.5, 2.3 Hz, 1H), 7.08 (dd, J=7.4, 1.7 Hz, 1H), 7.22 (d, J=2.0 Hz, 1H), 7.26-7.33 (m, 2H), 8.34 (brs, 1H). .sup.13C NMR (75 MHz, CDCl.sub.3) 19.1, 37.3, 37.7, 55.2, 61.8, 106.3, 110.3, 120.3, 124.0, 126.2, 128.9, 129.6, 130.6, 130.9, 132.6, 142.5, 147.0, 157.4, 166.3, 170.3. MS [MH].sup. 418

Example 149: (2-methoxyphenyl)methyl (4S)-4-(3,4-dichlorophenyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate and (2-methoxyphenyl) methyl (4R)-4-(3,4-dichlorophenyl)-6-methyl-2-oxo-1-[[(2S)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate

[0356] 4-(3,4-dichlorophenyl)-6-methyl-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate (example 149a, 150 mg, 0.36 mmol) was dissolved in anh. DMF (1 mL). Tetrahydrofurfuryl bromide (81 L, 0.72 mmol) and Cs.sub.2C03 (232 mg, 0.72 mmol) were added. The reaction mixture was stirred at 50 C. for 18 h. The DMF was removed under reduced pressure. The residue was diluted in water. The aqueous phase was extracted by EtOAc and the combined organic layers were washed with brine and dried over MgSO.sub.4. The solvent was removed under reduced pressure. The crude was dissolved again in anh. DMF (1 mL). Tetrahydrofurfuryl bromide (81 L, 0.72 mmol) and Cs.sub.2CO.sub.3 (232 mg, 0.72 mmol) were added. The reaction mixture was stirred at 50 C. for 18 h. The DMF was removed under reduced pressure. The residue was diluted in water. The aqueous phase was extracted by EtOAc and the combined organic layers were washed with brine and dried over MgSO.sub.4. The solvent was removed under reduced pressure. Purification of the crude by flash chromatography using a mixture of Cyclohexane/EtOAc (8/2) as eluent gave the desired (2-methoxyphenyl)methyl (4S)-4-(3,4-dichlorophenyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate as a colorless oil (52 mg, 29%) and its diastereomer as a colorless oil (33 mg, 18%). .sup.1H NMR (300 MHz, CDCl.sub.3) 1.46-1.52 (m, 1H), 1.87-2.00 (m, 3H), 2.64 (s, 3H), 2.69 (dd, J=15.6, 2.1 Hz, 1H), 2.91 (dd, J=15.6, 7.5 Hz, 1H), 3.41 (dd, J=14.3, 9.0 Hz, 1H), 3.73 (s, 3H), 3.76-3.95 (m, 3H), 4.17 (d, J=6.7 Hz, 1H), 4.29 (dd, J=14.3, 3.1 Hz, 1H), 5.10 (d, J=13.0 Hz, 1H), 5.20 (d, J=13.0 Hz, 1H), 6.84 (t, J=8.0 Hz, 2H), 7.00 (dd, J=7.3, 1.5 Hz, 1H), 7.08 (dd, J=8.4, 2.1 Hz, 1H), 7.27 (td, J=5.8, 1.8 Hz, 2H), 7.38 (d, J=2.1 Hz, 1H). .sup.13C NMR (75 MHz, CDCl.sub.3) 17.1, 25.6, 26.9, 29.3, 37.1, 38.9, 45.9, 55.2, 61.9, 68.2, 77.8, 109.8, 110.2, 120.2, 124.3, 127.0, 129.1, 129.2, 129.3, 130.4, 130.7, 132.5, 141.6, 151.5, 157.3, 166.9, 168.7. MS [M+H].sup.+ 504, HRMS: calcd for C.sub.26H.sub.28NO.sub.5Cl.sub.2, [M+H].sup.+ 504.1345, found 504.1351.

Example 150 (2-Methoxyphenyl)methyl (4S)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-4-[6-(trifluoromethyl)-3-pyridyl]-3,4-dihydropyridine-5-carboxylate and (2-methoxyphenyl)methyl (4R)-6-methyl-2-oxo-1-[[(2S)-tetrahydrofuran-2-yl]methyl]-4-[6-(trifluoromethyl)-3-pyridyl]-3,4-dihydropyridine-5-carboxylate

[0357] ##STR00396##

Example 150a. Methyl 6-methyl-2-oxo-4-[6-(trifluoromethyl)-3-pyridyl]-3,4-dihydro-1H-pyridine-5-carboxylate

[0358] The methyl 3-oxobutanoate (0.37 mL, 3.43 mmol) was dissolved in acetic acid (9 mL). 6-(trifluoromethyl)pyridine-3-carbaldehyde (600 mg, 3.43 mmol), Meldrum's acid (494 mg, 3.43 mmol) and ammonium acetate (396 mg, 5.14 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 white powder (394 mg, 37%).

[0359] .sup.1H NMR (300 MHz, CDCl.sub.3) 2.39 (s, 3H), 2.64 (d, J=16.2 Hz, 1H), 2.99 (dd, J=16.7, 8.2 Hz, 1H), 3.63 (s, 3H), 4.33 (d, J=7.7 Hz, 1H), 7.59 (d, J=8.1 Hz, 1H), 7.65 (dd, J=8.1, 1.9 Hz, 1H), 8.57 (d, J=1.4 Hz, 1H), 9.20 (s, 1H). .sup.13C NMR (75 MHz, CDCl.sub.3) 19.0, 35.7, 37.4, 51.7, 105.4, 119.7, 120.7, 123.4, 135.7, 141.1, 148.1, 149.0, 166.8, 170.7. MS [M+H].sup.+ 315 g/mol.

Example 150b. Methyl (4S)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-4-[6-(trifluoromethyl)-3-pyridyl]-3,4-dihydropyridine-5-carboxylate and methyl (4R)-6-methyl-2-oxo-1-[[(2S)-tetrahydrofuran-2-yl]methyl]-4-[6-(trifluoromethyl)-3-pyridyl]-3,4-dihydropyridine-5-carboxylate

[0360] The methyl 6-methyl-2-oxo-4-[6-(trifluoromethyl)-3-pyridyl]-3,4-dihydro-1H-pyridine-5-carboxylate (150a, 328 mg, 1.04 mmol) and the 2-(bromomethyl)tetrahydrofuran (345 mg, 2.09 mmol) were dissolved in anhydrous DMF (3 mL), Cs.sub.2CO.sub.3 (681 mg, 2.09 mmol) and NaI (8 mg, 0.05 mmol) were added and the reaction mixture was stirred at 50 C. overnight. The solvent was removed under reduced pressure. Water was added and the mixture was extracted by ethyl acetate, the organic layers washed with brine, and dried over Na.sub.2SO.sub.4 and filtered. The solvent was removed and the crude product was purified by column chromatography on silica gel (CH.sub.2Cl.sub.2/Cy 70/30 to 100/0 and CH.sub.2Cl.sub.2/MeOH 100/0 to 96/4) to give the expected product as oil (100 mg, 24%).

[0361] .sup.1H NMR (300 MHz, CDCl.sub.3) 1.34-1.52 (m, 1H), 1.78-2.01 (m, 3H), 2.60 (s, 3H), 2.69 (dd, J=15.8, 2.0 Hz, 1H), 2.89-3.04 (m, 1H), 3.38 (dd, J=14.2, 9.4 Hz, 1H), 3.61 (s, 3H), 3.66-3.93 (m, 3H), 4.15-4.35 (m, 2H), 7.50 (d, J=8.1 Hz, 1H), 7.79-7.87 (m, 1H), 8.59 (d, J=1.9 Hz, 1H). .sup.13C NMR (75 MHz, CDCl.sub.3) 17.2, 25.7, 29.2, 35.3, 38.6, 46.0, 51.8, 68.2, 77.7, 108.8, 119.9, 120.4, 123.5, 136.1, 140.1, 149.8, 152.2, 167.3, 168.3. MS [M+H].sup.+ 399 g/mol.

Example 150c. (4S)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-4-[6-(trifluoromethyl)-3-pyridyl]-3,4-dihydropyridine-5-carboxylic acid and (4R)-6-methyl-2-oxo-1-[[(2S)-tetrahydrofuran-2-yl]methyl]-4-[6-(trifluoromethyl)-3-pyridyl]-3,4-dihydropyridine-5-carboxylic Acid

[0362] 150b (95 mg, 0.24 mmol) was dissolved in MeOH (2 mL), NaOH 1N (1 mL) was added. The reaction mixture was stirred overnight at 40 C. The MeOH was evaporated under reduced pressure, the aqueous phase was extracted by Et.sub.2O, then acidified to pH=1 with HCl (1N). The aqueous phase was extracted by EtOAc. The organic phases were assembled, dried under Na.sub.2SO.sub.4 and filtered. The solvents were removed under reduced pressure to afford a product as oil. (m=86 mg, 92%).

[0363] .sup.1H NMR (300 MHz, CDCl.sub.3) 1.37-1.50 (m, 1H), 1.80-1.99 (m, 3H), 2.61 (s, 3H), 2.73 (dd, J=15.8, 1.8 Hz, 1H), 2.98 (dd, J=15.8, 7.5 Hz, 1H), 3.40 (dd, J=14.2, 9.4 Hz, 1H), 3.65-3.90 (m, 3H), 4.22 (dd, J=14.3, 2.7 Hz, 1H), 4.31 (d, J=6.8 Hz, 1H), 7.51 (d, J=8.2 Hz, 1H), 7.83 (dd, J=8.1, 2.0 Hz, 1H), 8.62 (d, J=2.0 Hz, 1H), 10.40 (s, 1H). .sup.13C NMR (75 MHz, CDCl.sub.3) 17.5, 25.7, 29.2, 35.2, 38.4, 46.2, 68.3, 77.6, 108.2, 120.4, 123.5, 136.2, 140.1, 149.7, 154.5, 168.6, 172.0, 175.6. MS [M+H].sup.+ 385 g/mol.

Example 150 (2-Methoxyphenyl)methyl (4S)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-4-[6-(trifluoromethyl)-3-pyridyl]-3,4-dihydropyridine-5-carboxylate and (2-methoxyphenyl)methyl (4R)-6-methyl-2-oxo-1-[[(2S)-tetrahydrofuran-2-yl]methyl]-4-[6-(trifluoromethyl)-3-pyridyl]-3,4-dihydropyridine-5-carboxylate

[0364] The 1-(chloromethyl)-2-methoxy-benzene (39 mg, 0.25 mmol) and the acid 150c (86 mg, 0.22 mmol) were dissolved in dry DMF (2 mL). Cesium carbonate (109 mg, 0.34 mmol) was added and the reaction mixture was stirred at RT overnight. The solvent was removed. Water was added and the aqueous phase was extracted by Et.sub.2O, washed with brine and dried under Na.sub.2SO.sub.4. After filtration the solvent was removed and the crude product was purified by column chromatography on silica gel (Cy/EA 100 to 80/20) then by HPLC (acid conditions) to give the expected product as white solid (65 mg, 58%).

[0365] .sup.1H NMR (300 MHz, CDCl.sub.3) 1.50-1.67 (m, 1H), 1.79-2.12 (m, 3H), 2.58-2.80 (m, 4H), 2.99 (dd, J=15.4, 7.2 Hz, 1H), 3.42 (dd, J=14.1, 9.3 Hz, 1H), 3.59-3.80 (m, 4H), 3.81-3.99 (m, 2H), 4.17-4.38 (m, 2H), 5.12 (q, J=12.3 Hz, 2H), 6.82 (dd, J=11.2, 7.9 Hz, 2H), 7.01 (d, J=7.1 Hz, 1H), 7.25 (d, J=7.5 Hz, 1H), 7.49 (d, J=8.0 Hz, 1H), 7.81 (d, J=7.4 Hz, 1H), 8.55 (s, 1H). .sup.13C NMR (75 MHz, CDCl.sub.3) 17.2, 25.7, 29.3, 35.5, 38.5, 46.2, 55.3, 62.3, 68.3, 77.7, 109.1, 110.4, 120.3, 120.4, 123.6, 124.0, 129.7, 129.8, 136.1, 140.5, 146.7, 149.9, 152.1, 157.6, 166.8, 168.4. MS [M+H].sup.+ 505 g/mol.

Example 151: (2-Methoxyphenyl)methyl (4R)-4-(2-chloro-3-pyridyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate and (2-methoxyphenyl) methyl (4S)-4-(2-chloro-3-pyridyl)-6-methyl-2-oxo-1-[[(2S)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate

[0366] ##STR00397##

Example 151a. Methyl 4-(2-chloro-3-pyridyl)-6-methyl-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate

[0367] The methyl 3-oxobutanoate (0.68 mL, 6.30 mmol) was dissolved in acetic acid (7 mL). 2-chloropyridine-3-carbaldehyde (892 mg, 6.30 mmol), Meldrum's acid (908 mg, 6.30 mmol) and ammonium acetate (729 mg, 9.45 mmol) were added and the reaction mixture was stirred for 18 h at 110 C. The reaction mixture was cooled at RT. Solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel (CH.sub.2Cl.sub.2) to give the desired product as a white powder (850 mg, 48%).

[0368] .sup.1H NMR (300 MHz, CDCl.sub.3) 2.44 (s, 3H), 2.74 (dd, J=16.8, 1.1 Hz, 1H), 2.92 (dd, J=16.9, 8.3 Hz, 1H), 3.58 (s, 3H), 4.60 (d, J=7.8 Hz, 1H), 7.13 (dd, J=7.6, 4.7 Hz, 1H), 7.33 (dd, J=7.6, 1.8 Hz, 1H), 8.25 (dd, J=4.7, 1.9 Hz, 1H), 9.05 (s, 1H). .sup.13C NMR (75 MHz, CDCl.sub.3) 18.9, 35.0, 35.9, 51.7, 104.8, 123.0, 135.0, 136.3, 148.2, 148.7, 150.8, 166.7, 170.8. MS [MH].sup. 279 g/mol.

Example 151b. Methyl (4R)-4-(2-chloro-3-pyridyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate and methyl (4S)-4-(2-chloro-3-pyridyl)-6-methyl-2-oxo-1-[[(2S)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate

[0369] The Methyl 4-(2-chloro-3-pyridyl)-6-methyl-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate (151a, 700 mg, 2.5 mmol) and the 2-(bromomethyl)tetrahydrofuran (0.57 mL, 5.0 mmol) were dissolved in dry DMF (6 mL), Cs.sub.2CO.sub.3 (1.63 g, 5.0 mmol) and NaI (19 mg, 0.13 mmol) were added and the reaction mixture was stirred at 50 C. overnight. 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 Na.sub.2SO.sub.4. The solvent was removed. The residue was dissolved again in 6 mL of DMF, 1.63 g of Cs.sub.2CO.sub.3, 19 mg of NaI and the alkyl bromide (0.57 mL) were added and the mixture was stirred at 50 C. for 18 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 Na.sub.2SO.sub.4. The solvent was removed. The purification by columns chromatography on silica (CH.sub.2Cl.sub.2/Cy 50/50 to 100/0) give the desired product as white product (m=245 mg, 27%).

[0370] .sup.1H NMR (300 MHz, CDCl.sub.3) 1.42-1.56 (m, 1H), 1.81-2.07 (m, 3H), 2.63 (s, 3H), 2.82-2.91 (m, 2H), 3.31-3.44 (m, 1H), 3.61 (s, 3H), 3.68-3.86 (m, 2H), 3.87-3.98 (m, 1H), 4.24 (dd, J=14.3, 2.5 Hz, 1H), 4.53 (t, J=4.7 Hz, 1H), 7.07 (dd, J=7.7, 4.7 Hz, 1H), 7.76 (dd, J=7.7, 1.8 Hz, 1H), 8.22 (dd, J=4.7, 1.8 Hz, 1H). .sup.13C NMR (75 MHz, CDCl.sub.3) 17.2, 25.8, 29.2, 34.8, 36.4, 46.1, 51.9, 68.3, 78.0, 108.8, 122.9, 134.3, 137.8, 148.1, 151.0, 152.7, 167.5

Example 151c. (4R)-4-(2-chloro-3-pyridyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylic acid and (4S)-4-(2-chloro-3-pyridyl)-6-methyl-2-oxo-1-[[(2S)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylic acid

[0371] 151b (130 mg, 0.36 mmol) was dissolved in MeOH (3 mL), NaOH 1N (2 mL) was added. The reaction mixture was stirred overnight at 40 C. The MeOH was evaporated under reduced pressure and the aqueous phase was extracted by Et.sub.2O, then acidified to pH=1 with HCl (1N). The aqueous phase was extracted by EtOAc and the organic layers were assembled and dried under Na.sub.2SO.sub.4. The solvent was removed under reduced pressure to afford a product as white solid (m=110 mg, 88%).

[0372] .sup.1H NMR (300 MHz, CDCl.sub.3) 1.40-1.55 (m, 1H), 1.78-2.07 (m, 3H), 2.63 (s, 3H), 2.88 (d, J=4.5 Hz, 2H), 3.38 (dd, J=14.1, 9.7 Hz, 1H), 3.70-3.85 (m, 2H), 3.90 (dd, J=14.5, 6.9 Hz, 1H), 4.23 (d, J=14.2 Hz, 1H), 4.55 (t, J=4.2 Hz, 1H), 7.07 (dd, J=7.5, 4.8 Hz, 1H), 7.74 (d, J=7.5 Hz, 1H), 8.23 (d, J=3.4 Hz, 1H), 9.84 (s, 1H). .sup.13C NMR (75 MHz, CDCl.sub.3) 17.6, 25.8, 29.2, 34.7, 36.2, 46.1, 68.3, 77.9, 108.1, 122.9, 134.2, 137.8, 148.0, 150.9, 155.0, 168.9, 172.1. MS [M+H].sup.+ 351 g/mol.

Example 151. (2-Methoxyphenyl)methyl (4R)-4-(2-chloro-3-pyridyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate and (2-methoxyphenyl) methyl (4S)-4-(2-chloro-3-pyridyl)-6-methyl-2-oxo-1-[[(2S)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate

[0373] The 1-(chloromethyl)-2-methoxy-benzene (44 mg, 0.28 mmol) and the acid 151c (90 mg, 0.26 mmol) were dissolved in dry DMF (2 mL). Cesium carbonate (125 mg, 0.38 mmol) was added and the reaction mixture was stirred at RT overnight.

[0374] The solvent was removed. Water was added and the aqueous phase was extracted by Et.sub.2O, organic layer was washed with brine and dried under Na.sub.2SO.sub.4. The solvent was removed. The purification by column chromatography on silica gel (Cy/EtOAc 100/0 to 80/20) give the expected product as white powder (m=90 mg, 75%).

[0375] .sup.1H NMR (300 MHz, CDCl.sub.3) 1.39-1.56 (m, 1H), 1.77-2.06 (m, 3H), 2.65 (s, 3H), 2.86 (dd, J=5.8, 4.6 Hz, 2H), 3.39 (dd, J=14.2, 9.5 Hz, 1H), 3.69 (s, 3H), 3.70-3.87 (m, 2H), 3.87-3.97 (m, 1H), 4.23 (dd, J=14.3, 2.6 Hz, 1H), 4.59 (dd, J=6.7, 2.6 Hz, 1H), 5.09 (s, 2H), 6.81 (ddd, J=8.2, 7.4, 3.5 Hz, 2H), 6.96-7.10 (m, 2H), 7.17-7.26 (m, 1H), 7.72-7.82 (m, 1H), 8.20 (dd, J=4.7, 1.9 Hz, 1H). .sup.13C NMR (75 MHz, CDCl.sub.3) 17.1, 25.8, 29.2, 34.9, 36.3, 46.0, 55.3, 62.0, 68.3, 77.9, 108.9, 110.2, 120.3, 122.8, 124.2, 129.0, 129.4, 134.5, 137.8, 148.0, 151.0, 152.6, 157.3, 166.7, 168.7. MS [M+H].sup.+ 471 g/mol.

Example 152 (2-Methoxyphenyl)methyl (4S)-4-(2,1,3-benzothiadiazol-5-yl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate and (2-methoxyphenyl) methyl (4R)-4-(2,1,3-benzothiadiazol-5-yl)-6-methyl-2-oxo-1-[[(2S)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate

[0376] ##STR00398##

Example 152a. Methyl 4-(2,1,3-benzothiadiazol-5-yl)-6-methyl-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate

[0377] The methyl 3-oxobutanoate (0.4 mL, 3.65 mmol) was dissolved in acetic acid (9 mL). 2,1,3-benzothiadiazole-5-carbaldehyde (600 mg, 3.65 mmol), Meldrum's acid (527 mg, 3.65 mmol) and ammonium acetate (422 mg, 5.48 mmol) were added and the reaction mixture was stirred for 18 h at 110 C. The reaction mixture was cooled at RT. 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 (490 mg, 44%).

[0378] .sup.1H NMR (300 MHz, CDCl.sub.3) 2.44 (s, 3H), 2.77 (d, J=16.6 Hz, 1H), 3.02 (dd, J=16.6, 8.2 Hz, 1H), 3.64 (s, 3H), 4.41 (d, J=7.8 Hz, 1H), 7.46 (dd, J=9.1, 1.7 Hz, 1H), 7.70 (s, 1H), 7.93 (d, J=9.1 Hz, 1H), 8.75 (s, 1H). .sup.13C NMR (75 MHz, CDCl.sub.3) 19.3, 37.7, 38.1, 51.7, 105.8, 118.1, 122.1, 130.2, 143.5, 147.8, 154.3, 155.2, 167.1, 170.7. MS [M+H].sup.+ 304 g/mol.

Example 152b. Methyl (4S)-4-(2,1,3-benzothiadiazol-5-yl)-6-methyl-2-oxo-1-[[(2S)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate and methyl (4R)-4-(2,1,3-benzothiadiazol-5-yl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate

[0379] The methyl 4-(2,1,3-benzothiadiazol-5-yl)-6-methyl-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate (152a, 400 mg, 1.32 mmol) and the 2-(bromomethyl)tetrahydrofuran (435 mg, 2.64 mmol) were dissolved in anhydrous DMF (3 mL), Cs.sub.2CO.sub.3 (861 mg, 2.64 mmol) and NaI (10 mg, 0.07 mmol) were added and the reaction mixture was stirred at 50 C. overnight. The solvent was removed under reduced pressure. Water was added and the mixture was extracted by ethyl acetate, the organic layers washed with brine, and dried over Na.sub.2SO.sub.4 and filtered. The solvent was removed and the crude product was purified by column chromatography on silica gel (CH.sub.2Cl.sub.2/MeOH 100/0 to 96/4) to give the expected product as oil (m=120 mg, 24%).

[0380] .sup.1H NMR (300 MHz, CDCl.sub.3) 1.25-1.28 (m, 1H), 1.57-1.88 (m, 3H), 2.68 (s, 3H), 2.89 (dd, J=16.0, 2.3 Hz, 1H), 3.03 (dd, J=15.9, 7.4 Hz, 1H), 3.59-3.73 (m, 4H), 3.74-3.92 (m, 2H), 3.92-4.07 (m, 2H), 4.36 (d, J=7.1 Hz, 1H), 7.47 (dd, J=9.1, 1.8 Hz, 1H), 7.60-7.72 (m, 1H), 7.91 (dd, J=9.1, 0.7 Hz, 1H). .sup.13C NMR (75 MHz, CDCl.sub.3) 17.6, 25.3, 29.2, 37.3, 38.3, 45.2, 51.8, 67.9, 77.5, 109.4, 118.6, 121.8, 130.4, 142.8, 151.7, 154.2, 155.2, 167.7, 169.2. MS [M+H].sup.+ 388 g/mol.

Example 152c. (4S)-4-(2,1,3-benzothiadiazol-5-yl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylic acid and (4R)-4-(2,1,3-benzothiadiazol-5-yl)-6-methyl-2-oxo-1-[[(2S)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylic Acid

[0381] Example 152b (88 mg, 0.23 mmol) was dissolved in MeOH (2 mL), NaOH 1N (1 mL) was added. The reaction mixture was stirred overnight at 40 C. The MeOH was evaporated under reduced pressure, the aqueous phase was extracted by Et.sub.2O, then acidified to pH=1 with HCl (1N). The aqueous phase was extracted by EtOAc. The organic layers were assembled, dried under Na.sub.2SO.sub.4 and filtered. The solvents were removed under reduced pressure to afford a product as oil (m=70 mg, 82%).

[0382] .sup.1H NMR (300 MHz, CDCl.sub.3) 1.30-1.47 (m, 1H), 1.70-1.93 (m, 3H), 2.66 (s, 3H), 2.80 (dd, J=15.7, 2.0 Hz, 1H), 2.97 (dd, J=15.7, 7.3 Hz, 1H), 3.42 (dd, J=14.2, 8.9 Hz, 1H), 3.67-3.70 (m, 1H), 3.77-4.01 (m, 2H), 4.20-4.40 (m, 2H), 7.46 (dd, J=9.1, 1.8 Hz, 1H), 7.86 (dd, J=8.9, 0.8 Hz, 2H), 10.42 (s, 1H). .sup.13C NMR (75 MHz, CDCl.sub.3) 17.6, 25.4, 29.2, 37.6, 38.5, 45.8, 68.1, 78.0, 109.0, 118.9, 121.7, 130.5, 142.2, 154.3, 154.4, 155.3, 168.9, 172.4. MS [M+H].sup.+ 374 g/mol.

Example 152: (2-Methoxyphenyl)methyl (4S)-4-(2,1,3-benzothiadiazol-5-yl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate and (2-methoxyphenyl)methyl (4R)-4-(2,1,3-benzothiadiazol-5-yl)-6-methyl-2-oxo-1-[[(2S)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate

[0383] The 1-(chloromethyl)-2-methoxy-benzene (32 mg, 0.21 mmol) and the acid 152c (70 mg, 0.19 mmol) were dissolved in dry DMF (2 mL). Cesium carbonate (92 mg, 0.28 mmol) was added and the reaction mixture was stirred at RT overnight.

[0384] The solvent was removed. Water was added and the aqueous phase was extracted by Et.sub.2O, washed with brine and dried under Na.sub.2SO.sub.4. After filtration the solvent was removed and the crude product was purified by column chromatography on silica gel (Cy/EA 100 to 80/20) to give the expected product as oil (80 mg, 86%).

[0385] .sup.1H NMR (300 MHz, CDCl.sub.3) 1.35-1.51 (m, 1H), 1.75-1.97 (m, 3H), 2.69 (s, 3H), 2.79 (dd, J=15.7, 2.1 Hz, 1H), 3.01 (dd, J=15.7, 7.5 Hz, 1H), 3.45 (dd, J=14.2, 8.8 Hz, 1H), 3.64 (s, 3H), 3.71-3.83 (m, 1H), 3.82-3.40 (m, 2H), 4.29 (dd, J=14.2, 3.2 Hz, 1H), 4.38 (d, J=6.5 Hz, 1H), 5.13 (d, J=3.8 Hz, 2H), 6.65-6.75 (m, 2H), 6.99 (dd, J=7.4, 1.5 Hz, 1H), 7.18 (ddd, J=8.2, 7.5, 1.8 Hz, 1H), 7.47 (dd, J=9.1, 1.8 Hz, 1H), 7.89 (ddd, J=9.8, 5.4, 0.8 Hz, 2H). .sup.13C NMR (75 MHz, CDCl.sub.3) 17.3, 25.4, 29.3, 37.9, 38.6, 45.7, 55.2, 62.0, 68.1, 78.0, 110.0, 110.2, 119.1, 120.2, 121.5, 124.3, 129.2, 129.3, 130.6, 142.8, 151.8, 154.3, 155.4, 157.3, 167.0, 168.8. MS [M+H].sup.+ 494 g/mol.

TABLE-US-00013 TABLE 13 [00399] Examples R23 153 [00400] 154 [00401] 155 [00402] 156 [00403] 157 [00404] 158 [00405]

Example 153

[0386] ##STR00406## ##STR00407## ##STR00408##

Example 153a. Methyl 4-(6-chloro-3-pyridyl)-6-methyl-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate

[0387] 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 RT. 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%).

[0388] .sup.1H NMR (300 MHz, Acetone) 2.45 (s, 3H), 2.55 (dd, J=16.4, 1.9 Hz, 1H), 3.02 (dd, J=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). .sup.13C NMR (75 MHz, Acetone) 18.8, 36.1, 38.4, 51.5, 105.2, 125.0, 138.7, 149.5, 149.7, 149.8, 150.2, 167.5, 169.5. MS [M+H].sup.+ 281 g/mol.

Example 153b. Methyl (4S)-4-(6-chloro-3-pyridyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate and methyl (4R)-4-(6-chloro-3-pyridyl)-6-methyl-2-oxo-1-[[(2S)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate

[0389] The methyl 4-(6-chloro-3-pyridyl)-6-methyl-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate (600 mg, 2.14 mmol) and the 2-(bromomethyl)tetrahydrofuran (0.49 mL, 4.27 mmol) were dissolved in dry DMF (5 mL), Cs.sub.2CO.sub.3 (1,395 g, 4.28 mmol) and NaI (16.34 mg, 0.11 mmol) were added and the reaction mixture was stirred at 50 C. overnight. 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 Na.sub.2SO.sub.4. The solvent was removed. The residue was dissolved again in 5 mL of DMF, 1,395 g of Cs.sub.2CO.sub.3, 16 mg of NaI and the alkyl bromide (0.5 mL) were added and the mixture was stirred at 50 C. for 18 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 Na.sub.2SO.sub.4. The solvent was removed. The purification by columns chromatography on silica gel (Cy/EtOAc 100/0 to 70/30 and CH.sub.2Cl.sub.2/Cy 70/30 to 100/0) give the desired product as white product (m=200 mg, 26%).

[0390] .sup.1H NMR (300 MHz, CDCl.sub.3) 1.40-1.51 (m, 1H), 1.76-2.03 (m, 3H), 2.58 (s, 3H), 2.65 (dd, J=15.7, 2.0 Hz, 1H), 2.92 (dd, J=15.7, 7.3 Hz, 1H), 3.36 (dd, J=14.2, 9.3 Hz, 1H), 3.61 (s, 3H), 3.67-3.92 (m, 3H), 4.13-4.30 (m, 2H), 7.16 (d, J=8.3 Hz, 1H), 7.60 (dd, J=8.3, 2.6 Hz, 1H), 8.25 (d, J=2.5 Hz, 1H). .sup.13C NMR (75 MHz, CDCl.sub.3) 17.2, 25.7, 29.2, 34.8, 38.8, 46.0, 51.8, 68.2, 77.7, 109.1, 124.2, 135.6, 137.9, 149.2, 150.0, 151.9, 167.4, 168.4. MS [M+H].sup.+ 365 g/mol.

Example 153c. (4S)-4-(6-chloro-3-pyridyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylic acid and (4R)-4-(6-chloro-3-pyridyl)-6-methyl-2-oxo-1-[[(2S)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylic Acid

[0391] The previous ester (200 mg, 0.55 mmol) was dissolved in MeOH (3 mL), NaOH 1N (2 mL) was added. The reaction mixture was stirred overnight at 40 C.

[0392] The MeOH was evaporated under reduced pressure and the aqueous phase was extracted by Et.sub.2O, then acidified to pH=1 with HCl (1 N). The aqueous phase was extracted by EtOAc and the organic layers were assembled and dried under Na.sub.2SO.sub.4. The solvent was removed under reduced pressure to afford a product as white solid (m=175 mg, 91%).

[0393] .sup.1H NMR (300 MHz, CDCl.sub.3) 1.35-1.50 (m, 1H), 1.74-1.95 (m, 3H), 2.56 (s, 3H), 2.65 (dd, J=15.8, 1.8 Hz, 1H), 2.90 (dd, J=15.8, 7.3 Hz, 1H), 3.35 (dd, J=14.2, 9.3 Hz, 1H), 3.61-3.72 (m, 1H), 3.73-3.87 (m, 2H), 4.18 (dd, J=14.0, 3.0 Hz, 2H), 7.13 (d, J=8.3 Hz, 1H), 7.59 (dd, J=8.3, 2.6 Hz, 1H), 8.25 (d, J=2.6 Hz, 1H), 10.00 (s, 1H). .sup.13C NMR (75 MHz, CDCl.sub.3) 17.5, 25.7, 29.2, 34.7, 38.6, 46.1, 68.2, 77.7, 108.5, 124.2, 135.6, 138.1, 149.1, 149.9, 154.0, 168.7, 171.9. MS [M+H].sup.+ 351 g/mol.

Example 153d. [4-(2-Chloroethoxy)phenyl]methanol

[0394] The 1-bromo-2-chloroethane (2.5 mL, 30 mmol), the 4-hydroxybenzyl alcohol (1.24 g, 10 mmol) and the potassium carbonate (1.38 g, 10 mmol) were added in acetonitrile (33 mL) and the reaction mixture was stirred at 50 C. for 24 h. 4 equivalent of reactant and base were added and the reaction stirred under reflux over the week end. Reaction finished. The solvent was removed under reduced pressure. The crude was dissolved in EtOAc and washed by water. The aqueous phase was extracted by EtOAc and the organic layers were washed with brine, dried under Na.sub.2SO.sub.4. The solvent was removed under reduced pressure to afford the title compound. This crude was purified by flash chromatography (Cy/EA 100/0 to 70/30) to afford the desired compound as a white powder (m=1.2 g, 64%).

Example 153e. 1-(2-Chloroethoxy)-4-(chloromethyl)benzene

[0395] Thionyl chloride (0.10 mL, 1.34 mmol) was added to benzotriazole (192 mg, 1.61 mmol). The resulting mixture was dissolved in dry CH.sub.2Cl.sub.2 (1 mL). After 5 min, this solution was added slowly to a solution of the alcohol (200 mg, 1.07 mmol) in CH.sub.2Cl.sub.2 (8 mL). The benzotriazole salt started to precipitate. After 20 min of reaction, the salt was filtered. The organic phase was washed by water (8 mL) and NaOH solution (0.05 M, 8 mL) then, dried under Na.sub.2SO.sub.4, the solvent was removed under reduced pressure to give the desired chlorinated compound as colorless oil (m=120 mg, 55%).

[0396] .sup.1H NMR (300 MHz, CDCl.sub.3) 3.81 (t, J=5.9 Hz, 2H), 4.23 (t, J=5.9 Hz, 2H), 4.57 (s, 2H), 6.90 (d, J=8.7 Hz, 2H), 7.32 (d, J=8.7 Hz, 2H). .sup.3C NMR (75 MHz, CDCl.sub.3) 41.9, 46.2, 68.2, 115.1, 130.3, 130.6, 158.4.

Example 153f. [4-(2-Chloroethoxy)phenyl]methyl (4S)-4-(6-chloro-3-pyridyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate and [4-(2-chloroethoxy)phenyl]methyl (4R)-4-(6-chloro-3-pyridyl)-6-methyl-2-oxo-1-[[(2S)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate

[0397] The (4S)-4-(6-chloro-3-pyridyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylic acid and its enantiomer (162 mg, 0.46 mmol) and cesium carbonate (165 mg, 0.51 mmol) were dissolved in dry DMF (2 mL). The 1-(2-Chloroethoxy)-4-(chloromethyl)benzene (104 mg, 0.51 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 with Na.sub.2SO.sub.4. The purification by flash chromatography (Cy/CH.sub.2Cl.sub.2 1/1 to CH.sub.2Cl.sub.2) afford the desired product as a colorless oil (m=170 mg, 71%).

[0398] .sup.1H NMR (300 MHz, CDCl.sub.3) 1.42-1.56 (m, 1H), 1.81-2.06 (m, 3H), 2.56-2.71 (m, 4H), 2.93 (dd, J=15.7, 7.4 Hz, 1H), 3.40 (dd, J=14.2, 9.3 Hz, 1H), 3.69-3.95 (m, 5H), 4.13-4.32 (m, 4H), 5.02 (d, J=4.4 Hz, 2H), 6.83 (d, J=8.8 Hz, 2H), 7.08 (d, J=8.8 Hz, 2H), 7.16 (d, J=8.6 Hz, 1H), 7.57 (dd, J=8.7, 2.6 Hz, 1H), 8.24 (d, J=2.5 Hz, 1H). .sup.13C NMR (75 MHz, CDCl.sub.3) 17.5, 25.8, 29.3, 35.1, 38.8, 42.0, 46.3, 66.1, 68.2, 68.3, 77.8, 109.1, 114.8, 124.3, 129.9, 136.0, 138.1, 149.2, 150.1, 152.2, 158.3, 166.8, 168.5. MS [M]+519 g/mol.

Example 153g. [4-(2-Iodoethoxy)phenyl]methyl (4S)-4-(6-chloro-3-pyridyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate and [4-(2-iodoethoxy)phenyl]methyl (4R)-4-(6-chloro-3-pyridyl)-6-methyl-2-oxo-1-[[(2S)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate

[0399] The previous compound (164 mg, 0.32 mmol) was dissolved in butanone (1.5 mL). NaI (189 mg, 1.26 mmol) was added and the reaction mixture stirred at 80 C. for 32 h. The solution was cooled to RT and then filtered. The solvent was removed under reduced pressure to afford yellowish oil. This residue was purified by flash chromatography (Cy/CH.sub.2Cl.sub.2 1/1 to CH.sub.2Cl.sub.2) to give the desired product as white powder (m=130 mg, 67%).

[0400] .sup.1H NMR (300 MHz, CDCl.sub.3) 1.36-1.53 (m, 1H), 1.80-2.03 (m, 3H), 2.55-2.69 (m, 4H), 2.92 (dd, J=15.7, 7.5 Hz, 1H), 3.35-3.48 (m, 3H), 3.67-3.78 (m, 1H), 3.78-3.91 (m, 2H), 4.12-4.29 (m, 4H), 5.00 (d, J=4.2 Hz, 2H), 6.80 (d, J=8.7 Hz, 2H), 7.06 (d, J=8.7 Hz, 2H), 7.14 (d, J=8.3 Hz, 1H), 7.56 (dd, J=8.3, 2.6 Hz, 1H), 8.22 (d, J=2.3 Hz, 1H). .sup.13C NMR (75 MHz, CDCl.sub.3) 1.2, 17.2, 25.7, 29.2, 35.0, 38.7, 46.1, 66.0, 68.2, 68.7, 77.7, 109.1, 114.8, 124.1, 128.8, 129.8, 135.9, 137.9, 149.2, 150.0, 152.1, 157.9, 166.7, 168.4. MS [M+H].sup.+ 611 g/mol.

Example 153 Ammonium,2-[4-[[(4S)-4-(6-chloro-3-pyridyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carbonyl]oxymethyl]phenoxy]ethanesulfonate and ammonium,2-[4-[[(4R)-4-(6-chloro-3-pyridyl)-6-methyl-2-oxo-1-[[(2S)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carbonyl]oxymethyl]phenoxy]ethanesulfonate

[0401] The [4-(2-iodoethoxy)phenyl]methyl(4S)-4-(6-chloro-3-pyridyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate (130 mg, 0.213 mmol) was dissolved in a mixture of iPrOH/water 1/1 (1 mL). Sodium sulfite (54 mg, 0.426 mmol) was added and the reaction mixture was stirred under reflux for 48 h. The solvents were removed under reduced pressure. Purification of the crude by HPLC (basic conditions) gave the ammonium,2-[4-[[(4S)-4-(6-chloro-3-pyridyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carbonyl]oxymethyl]phenoxy]ethanesulfonate as a white powder (m=30 mg, 24%).

[0402] .sup.1H NMR (300 MHz, CDCl.sub.3) 1.35-1.55 (m, 1H), 1.77-2.04 (m, 3H), 2.50-2.65 (m, 4H), 2.83 (dd, J=15.6, 7.5 Hz, 2H), 3.25-3.45 (m, 3H), 3.70 (dd, J=14.5, 7.5 Hz, 1H), 3.77-3.91 (m, 2H), 4.04-4.36 (m, 4H), 4.83 (dd, J=26.9, 12.1 Hz, 2H), 6.73 (d, J=8.4 Hz, 2H), 6.90 (d, J=8.6 Hz, 2H), 7.09 (d, J=8.2 Hz, 4H), 7.56 (dd, J=8.3, 2.4 Hz, 1H), 8.12 (d, J=2.3 Hz, 1H). .sup.13C NMR (75 MHz, CDCl.sub.3) 17.2, 25.8, 29.3, 35.0, 38.6, 46.1, 58.1, 63.8, 66.0, 68.3, 77.7, 109.1, 114.9, 124.3, 128.5, 129.8, 136.4, 138.3, 149.2, 149.7, 152.2, 158.2, 166.6, 168.5. MS [M+H].sup.+ 565 g/mol.

Example 154

[0403] ##STR00409## ##STR00410##

Example 154a. Poly (ethylene glycol) methyl ether tosylate

[0404] The Poly(ethylene glycol) methyl ether (Sigma-Aldrich, ref 202487, average Mn=550, (1.06 mmol) was dissolved in dry THF (3 mL). The solution was cooled at 0 C. NaH (56 mg, 60% in oil, 1.59 mmol) was added and the reaction mixture was stirred at 0 C. to 20 C. for 2 h. the 4-methylbenzenesulfonyl chloride (403 mg, 2.12 mmol) was added at 0 C. and the reaction mixture was stirred at RT. for 24 hours.

[0405] The solvent was evaporated and the residue was purified by flash chromatography (CH.sub.2Cl.sub.2 to CH.sub.2Cl.sub.2/MeOH 94/6) to give 497 mg of colorless oil corresponding to the expected product (m=497 mg, 75%).

[0406] .sup.1H NMR (300 MHz, CDCl.sub.3) 2.36 (s, 3H), 3.28 (s, 3H), 3.39-3.69 (m, 42H), 4.01-4.10 (m, 2H), 7.26 (d, J=7.9 Hz, 2H), 7.70 (d, J=8.5 Hz, 2H). .sup.13C NMR (75 MHz, CDCl.sub.3) 21.5, 58.9, 68.5, 69.2, 70.3, 70.4, 70.6, 71.8, 127.8, 129.7, 132.9, 144.6. MS [M+NH.sub.4].sup.+ 688 g/mol.

Example 154b. 1-(Methanol)-4-[poly (ethylene glycol) methyl ether] benzene

[0407] The poly (ethylene glycol) methyl ether tosylate (0.48 mmol, 300 mg) was dissolved in dry MeCN (3 mL), the 4-(hydroxymethyl) phenol (0.72 mmol, 89 mg) and K.sub.2CO.sub.3 (0.72 mmol, 99 mg) were added. The reaction mixture was stirred overnight under reflux. After being cooled down, the mixture was filtered. The filtrate was concentrated under vacuum and purified by flash chromatography (CH.sub.2Cl.sub.2/MeOH 97/3) to give the product as oil (m=122 mg, 44%).

[0408] .sup.1H NMR (300 MHz, CDCl.sub.3) 2.43 (s, 3H), 3.33 (s, 3H), 3.50 (dd, J=5.3, 3.3 Hz, 2H), 3.54-3.71 (m, 36H), 3.77-3.85 (m, 2H), 4.04-4.12 (m, 2H), 4.55 (s, 2H), 6.85 (d, J=8.7 Hz, 2H), 7.23 (d, J=8.7 Hz, 2H). .sup.13C NMR (75 MHz, CDCl.sub.3) 59.0, 64.7, 67.5, 69.7, 70.5, 70.5, 70.6, 70.6, 70.8, 71.9, 114.6, 128.5, 133.6, 158.3. MS [M+NH.sub.4].sup.+ 596 g/mol.

Example 154c. 1-(Chloromethyl)-4-[poly (ethylene glycol) methyl ether] benzene

[0409] Thionyl chloride (0.26 mmol, 0.02 mL) was added to benzotriazole (0.26 mmol, 31 mg). The resulting mixture was dissolved in dry CH.sub.2Cl.sub.2 (1 mL). After 5 min, this solution was added slowly to a solution of the benzyl alcohol in CH.sub.2Cl.sub.2 (5 mL). The benzotriazole salt started to precipitate. After 1 h of reaction, the reaction mixture was quenched by addition of MgSO.sub.4.7H.sub.20 and then filtered. The solvent was removed under reduced pressure to afford yellow oil (m=125 mg, 99%). .sup.1H NMR (300 MHz, CDCl.sub.3) 3.30 (s, 3H), 3.42-3.68 (m, 36H), 3.73-3.81 (m, 2H), 4.00-4.09 (m, 2H), 4.48 (s, 2H), 6.81 (d, J=8.6 Hz, 2H), 7.21 (d, J=8.5 Hz, 2H).

Example 154 [4-([Poly (ethylene glycol) methyl ether])phenyl]methyl (4S)-4-(6-chloro-3-pyridyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate and [4-([poly (ethylene glycol) methyl ether])phenyl]methyl (4R)-4-(6-chloro-3-pyridyl)-6-methyl-2-oxo-1-[[(2S)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate (Mixture m=7-10)

[0410] The chlorinated compound 1-(Chloromethyl)-4-[poly (ethylene glycol) methyl ether] benzene (117 mg, 0.20 mmol) and the acid (69 mg, 0.20 mmol) were dissolved in dry DMF (2 mL). Cesium carbonate (64 mg, 0.20 mmol) and NaI (1.5 mg, 0.01 mmol) were added and the reaction mixture stirred at RT for 18 h. Reaction stopped by addition of water. Solvent was removed under reduced pressure. The residue was extracted by EtOAc and the organics layers were washed by a solution of saturated NaCl, dried over Na.sub.2SO.sub.4 and the solvent was removed to give a crude product. Purification by flash chromatography (CH.sub.2Cl.sub.2/MeOH 100/0 to 80/20) then, by HPLC (basic conditions) give the expected product as white powder (m=63 mg, 35%).

[0411] .sup.1H NMR (300 MHz, CDCl.sub.3) 1.38-1.54 (m, 1H), 1.80-2.04 (m, 3H), 2.36 (s, 1H), 2.53-2.70 (m, 4H), 2.91 (dd, J=15.8, 7.5 Hz, 1H), 3.31-3.44 (m, 4H), 3.47-3.56 (m, 2H), 3.56-3.76 (m, 33H), 3.78-3.93 (m, 5H), 4.04-4.13 (m, 2H), 4.13-4.29 (m, 2H), 4.99 (q, J=12.2 Hz, 2H), 6.81 (d, J=8.7 Hz, 2H), 7.05 (d, J=8.6 Hz, 2H), 7.13 (d, J=8.3 Hz, 1H), 7.54 (dd, J=8.3, 2.6 Hz, 1H), 8.22 (d, J=2.5 Hz, 1H). .sup.13C NMR (75 MHz, CDCl.sub.3) 17.2, 25.7, 29.2, 35.0, 38.7, 46.1, 59.1, 66.2, 67.5, 68.2, 69.7, 70.6, 70.6, 70.7, 70.7, 70.9, 72.0, 77.7, 109.2, 114.6, 124.1, 128.2, 129.7, 135.9, 138.0, 149.2, 150.0, 152.0, 158.8, 166.7, 168.4. MS [M+NH.sub.4].sup.+ 928 g/mol.

Example 155

[0412] ##STR00411## ##STR00412##

Example 155a. 1-(Methanol)-4-[poly (ethylene glycol) methyl ether] benzene (Mixture m=18-23)

[0413] The poly(ethylene glycol) methyl ether tosylate (Sigma-Aldrich, ref 729116, average Mn=900, 1.12 mmol) was dissolved in acetonitrile (4 mL), the 4-(hydroxymethyl)phenol (209 mg, 1.68 mmol) and K.sub.2CO.sub.3 (233 mg, 1.68 mmol) were added. The mixture was stirred overnight under reflux. The reaction became pink and after being cooled down, it has been filtered. The filtrate has been concentrated under vacuum and purified by flash chromatography (CH.sub.2Cl.sub.2/MeOH:100/0 to 97/3) to give the expected product as oil (900 mg, 95%). .sup.1H NMR (300 MHz, CDCl.sub.3) 3.31 (s, 3H), 3.44-3.70 (m, 100H), 3.75-3.85 (m, 3H), 4.01-4.11 (m, 2H), 4.52 (s, 2H), 6.83 (d, J=8.6 Hz, 2H), 7.21 (d, J=8.6 Hz, 2H).

Example 155b. 1-(Chloromethyl)-4-[poly (ethylene glycol) methyl ether] benzene (Mixture m=18-23)

[0414] In dry CH.sub.2Cl.sub.2 (1 mL), thionyl chloride (0.01 mL, 0.19 mmol) and benzotriazole (22 mg, 0.19 mmol) were added. The resulting mixture was stirred 5 min, this solution was added slowly to a solution of the 1-(Methanol)-4-[poly (ethylene glycol) methyl ether] benzene in CH.sub.2Cl.sub.2 (9 mL). The benzotriazole salt started to precipitate. After 1 h of reaction, the reaction mixture was quenched by addition of MgSO.sub.4.7H.sub.20 and then filtered. The solvent was removed under reduced pressure to afford yellow oil (quantitative).

Example 155: [4-([Poly (ethylene glycol) methyl ether])phenyl]methyl (4S)-4-(6-chloro-3-pyridyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate and [4-([poly (ethylene glycol) methyl ether])phenyl]methyl (4R)-4-(6-chloro-3-pyridyl)-6-methyl-2-oxo-1-[[(2S)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate (Mixture m=18-23)

[0415] The chlorinated compound 155b (127 mg, 0.15 mmol) and the acid (67 mg, 0.19 mmol) were dissolved in dry DMF (2 mL). Cesium carbonate (63 mg, 0.19 mmol) and NaI (1.1 mg, 0.01 mmol) were added and the reaction mixture was stirred at room temperature for 18 h. Reaction stopped by addition of water. Solvent was removed under reduced pressure and the residue was extracted by EtOAc. The organics layers were washed by a solution of saturated NaCl, dried over Na.sub.2SO.sub.4, filtered and the solvent was removed to give the crude product. Purification by HPLC (acid conditions) gives the expected mixture of products (n=18-23) as oil (28 mg, 14%). .sup.1H NMR (300 MHz, CDCl.sub.3) 1.38-1.52 (m, 1H), 1.80-2.04 (m, 3H), 2.51-2.71 (m, 4H), 2.92 (dd, J=15.7, 7.4 Hz, 1H), 3.31-3.45 (m, 5H), 3.50-3.78 (m, 99H), 3.78-3.93 (m, 5H), 4.04-4.14 (m, 2H), 4.13-4.29 (m, 2H), 4.99 (q, J=12.1 Hz, 2H), 6.81 (d, J=8.8 Hz, 2H), 7.05 (d, J=8.8 Hz, 2H), 7.14 (d, J=8.3 Hz, 1H), 7.55 (dd, J=8.3, 2.6 Hz, 1H), 8.23 (d, J=2.6 Hz, 1H). .sup.13C NMR (75 MHz, CDCl.sub.3) 17.3, 25.7, 29.3, 35.0, 38.7, 46.1, 59.1, 66.2, 67.5, 68.3, 69.8, 70.6, 70.7, 70.9, 72.0, 77.4, 77.7, 109.2, 114.6, 124.2, 128.2, 129.7, 135.9, 138.0, 149.2, 150.0, 152.0, 158.8, 166.7, 168.5. MS [M+NH.sub.4].sup.+ 1412 g/mol.

Example 156

[0416] ##STR00413##

Example 156a. 1-(Methanol)-4-[poly (ethylene glycol) methyl ether] benzene

[0417] The poly (ethylene glycol) methyl ether tosylate (sigma-Aldrich, ref 729124, average Mn=2000) (1 g, 0.48 mmol) was dissolved in MeCN (4 mL). The 4-(hydroxymethyl) phenol (89 mg, 0.72 mmol) and K.sub.2CO.sub.3 (100 mg, 0.72 mmol) were added. The reaction mixture was stirred overnight under reflux. After being cooled down, the mixture was filtered. The filtrate was concentrated under vacuum and purified by flash chromatography (CH.sub.2Cl.sub.2/MeOH 97/3) to give the expected product (m=778 mg, 80%).

[0418] .sup.1H NMR (300 MHz, CDCl.sub.3) 3.33-3.42 (m, 6H), 3.48-3.79 (m, 164H), 3.80-3.92 (m, 4H), 4.07-4.15 (m, 2H), 4.59 (s, 2H), 6.88 (d, J=8.7 Hz, 2H), 7.26 (d, J=8.6 Hz, 2H). .sup.13C NMR (75 MHz, CDCl.sub.3) 59.1, 67.6, 69.8, 70.6, 70.7, 70.9, 72.0, 114.8, 128.7.

Example 156b. 1-(Chloromethyl)-4-[poly (ethylene glycol) methyl ether] benzene

[0419] Thionyl chloride (0.03 mL, 0.46 mmol) was added to benzotriazole (55 mg, 0.46 mmol). The resulting yellow solution was dissolved in dry CH.sub.2Cl.sub.2 (2 mL). After 5 min, this solution was added slowly to a solution of the 1-(Methanol)-4-[poly (ethylene glycol) methyl ether] benzene (750 mg, 0.37 mmol) in CH.sub.2Cl.sub.2 (10 mL). The benzotriazole salt started to precipitate. After 1 h of reaction, the mixture was quenched by addition of MgSO.sub.4.7H.sub.20 and then filtered. The solvents were removed under reduced pressure to afford the desired compound as yellow oil (m=756 mg, 100%).

[0420] .sup.1H NMR (300 MHz, CDCl.sub.3) 3.17-3.28 (m, 6H), 3.33-3.66 (m, 163H), 3.66-3.76 (m, 4H), 3.92-4.02 (m, 2H), 4.40 (s, 2H), 6.73 (d, J=8.6 Hz, 2H), 7.13 (d, J=8.6 Hz, 2H).

Example 156: [4-([Poly (ethylene glycol) methyl ether])phenyl]methyl (4S)-4-(6-chloro-3-pyridyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate and [4-([poly (ethylene glycol) methyl ether])phenyl]methyl (4R)-4-(6-chloro-3-pyridyl)-6-methyl-2-oxo-1-[[(2S)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate

[0421] 1-(Methanol)-4-[poly (ethylene glycol) methyl ether] benzene (156b, 680 mg, 0.33 mmol) and the acid 153c (158 mg, 0.43 mmol) were dissolved in dry DMF (4 mL). Cesium carbonate (140 mg, 0.43 mmol) and NaI (2.5 mg, 0.02 mmol) were added and the reaction mixture stirred at RT for 18 h. Reaction stopped by addition of water. Solvent was removed under reduced pressure. The residue was extracted by EtOAc and the organics layers were washed by a solution of saturated NaCl, dried over Na.sub.2SO.sub.4 and the solvent was removed to give a crude product. Purification by HPLC (acid conditions) give the expected product as white powder (m=60 mg, 8%).

[0422] .sup.1H NMR (300 MHz, CDCl.sub.3) 1.35-1.52 (m, 1H), 1.78-2.00 (m, 3H), 2.53-2.72 (m, 5H), 2.90 (dd, J=15.7, 7.5 Hz, 1H), 3.28-3.44 (m, 5H), 3.44-3.92 (m, 159H), 4.01-4.11 (m, 2H), 4.12-4.29 (m, 2H), 4.87-5.06 (m, 2H), 6.79 (d, J=8.7 Hz, 2H), 7.03 (d, J=8.7 Hz, 2H), 7.12 (d, J=8.2 Hz, 1H), 7.53 (dd, J=8.3, 2.6 Hz, 1H), 8.21 (d, J=2.5 Hz, 1H). .sup.13C NMR (75 MHz, CDCl.sub.3) 17.2, 25.6, 29.2, 34.9, 38.7, 46.0, 59.1, 66.1, 67.5, 68.2, 69.7, 70.5, 70.6, 70.8, 72.0, 77.6, 109.1, 114.7, 124.1, 128.2, 129.6, 135.9, 137.9, 149.1, 149.9, 152.0, 158.8, 166.7, 168.4. MS [M/2+NH.sub.4].sup.+ 1134 g/mol.

Example 157

[0423] ##STR00414##

Example 157a. 1-(Methanol)-2-[poly (ethylene glycol) methyl ether] benzene

[0424] The poly(ethylene glycol) methyl ether tosylate 154a (564 mg, 0.9 mmol) was dissolved in MeCN (3 mL), the 2-(hydroxymethyl)phenol (168 mg, 1.35 mmol) and K.sub.2CO.sub.3 (187 mg, 1.35 mmol) were added. The reaction mixture was stirred overnight under reflux. After being cooled down, it has been filtered. The filtrate has been concentrated under vacuum and purified by flash chromatography (CH.sub.2Cl.sub.2/MeOH: 100/0 to 97/3) to give the expected product as oil (460 mg, 77%). .sup.1H NMR (300 MHz, CDCl.sub.3) 3.29 (s, 3H), 3.40-3.65 (m, 45H), 3.76 (dd, J=5.4, 3.8 Hz, 2H), 4.10 (dd, J=5.4, 3.8 Hz, 2H), 4.58 (s, 2H), 6.79 (d, J=8.1 Hz, 1H), 6.85 (td, J=7.5, 0.9 Hz, 1H), 7.10-7.25 (m, 2H). MS [M+NH.sub.4].sup.+ 684 g/mol.

Example 157b. 1-(Chloromethyl)-2-[poly (ethylene glycol) methyl ether] benzene

[0425] In dry CH.sub.2Cl.sub.2 (3 mL), thionyl chloride (0.02 mL, 0.34 mmol) and benzotriazole (40 mg, 0.34 mmol) were added. The resulting mixture was stirred 5 min, this solution was added slowly to a solution of the alcohol Example 157a. (MM.sub.peg=550 g/mol) in CH.sub.2Cl.sub.2 (15 mL). The benzotriazole salt started to precipitate. After 1 h of reaction, the reaction mixture was quenched by addition of MgSO.sub.4.7H.sub.20 and then filtered. The solvent was removed under reduced pressure to afford a yellow oil (quantitative).

Example 157: [2-([Poly (ethylene glycol) methyl ether])phenyl]methyl (4S)-4-(6-chloro-3-pyridyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate and [2-([poly (ethylene glycol) methyl ether])phenyl]methyl (4R)-4-(6-chloro-3-pyridyl)-6-methyl-2-oxo-1-[[(2S)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate (Mixture m=10-14)

[0426] Example 157b (152 mg, 0.25 mmol) and the acid 153c (98 mg, 0.28 mmol) were dissolved in dry DMF (3 mL). Cesium carbonate (108 mg, 0.33 mmol) and NaI (2 mg, 0.01 mmol) were added and the reaction mixture stirred at room temperature for 18 h. Reaction stopped by addition of water. DMF was removed under reduced pressure. The residue was extracted by EtOAc and the organics layers were washed by a solution of saturated NaCl, dried over Na.sub.2SO.sub.4, filtered and the solvent was removed. Purification by preparative HPLC gives the expected compound (Mixture of products (m=10-14) as oil (45 mg, 17%). .sup.1H NMR (300 MHz, CDCl.sub.3) 1.36-1.55 (m, 1H), 1.80-2.04 (m, 3H), 2.54-2.72 (m, 4H), 2.93 (dd, J=15.7, 7.5 Hz, 1H), 3.32-3.46 (m, 4H), 3.48-3.57 (m, 2H), 3.57-3.70 (m, 46H), 3.70-3.80 (m, 3H), 3.80-3.92 (m, 2H), 3.97-4.13 (m, 2H), 4.18-4.31 (m, 2H), 5.13 (s, 2H), 6.80-6.90 (m, 2H), 6.99 (dd, J=7.5, 1.7 Hz, 1H), 7.12 (d, J=8.3 Hz, 1H), 7.18-7.25 (m, 1H), 7.56 (dd, J=8.3, 2.6 Hz, 1H), 8.21 (d, J=2.6 Hz, 1H). .sup.13C NMR (75 MHz, CDCl.sub.3) 17.2, 25.7, 29.3, 35.0, 38.7, 46.1, 59.1, 61.9, 67.8, 68.3, 69.7, 70.6, 70.7, 70.9, 72.0, 77.4, 77.7, 109.4, 111.6, 120.7, 124.1, 124.5, 129.2, 129.5, 136.0, 138.0, 149.2, 149.9, 151.8, 156.6, 166.7, 168.5. MS [M+H].sup.+ 1043 g/mol.

Example 158

[0427] ##STR00415## ##STR00416##

Example 158a. [2-(2-Chloroethoxy)phenyl]methanol

[0428] The 1-bromo-2-chloro-ethane (0.33 mL, 4.03 mmol), 2-(hydroxymethyl)phenol (500 mg, 4.03 mmol) and potassium carbonate (557 mg, 4.03 mmol) were assembled in acetonitrile and the reaction mixture was stirred overnight at reflux. 4 eq. of bromide compound (1.34 mL) and K.sub.2CO.sub.3 (2.23 g) were added and the reaction mixture was stirred at reflux overnight again. End of the reaction. The solvent was removed under reduced pressure and water was added, aqueous phase was extracted with EtOAc, then the organic layer was washed with brine and dried over Na.sub.2SO.sub.4. The solvent was removed under reduced pressure. The crude was purified by flash chromatography on Silica gel using as eluant a mixture of Cy/EtOAc (100/0 to 70/30) to give the expected product as a yellow oil (m=500 mg, 66%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.76 (s, 1H), 3.78-3.92 (m, 2H), 4.21-4.30 (m, 2H), 4.71 (s, 2H), 6.85 (d, J=8.2 Hz, 1H), 6.99 (td, J=7.5, 1.0 Hz, 1H), 7.23-7.35 (m, 2H).

Example 158b. 1-(2-Chloroethoxy)-2-(chloromethyl)benzene

[0429] In dry CH.sub.2Cl.sub.2 (5 mL), thionyl chloride (0.15 mL, 2.01 mmol) and benzotriazole (287 mg, 2.41 mmol) were added. The resulting mixture was stirred 5 min, this solution was added slowly to a solution of the alcohol 158a in CH.sub.2Cl.sub.2 (10 mL). The benzotriazole salt started to precipitate. After 20 min of reaction, the salt was filtered. The organic phase was washed with water (10 mL) and NaOH solution (0.05 M, 10 mL). The organic phase was dried on Na.sub.2SO.sub.4 and the solvent was removed under reduced pressure to give the desired chlorinated compound as colorless oil (300 mg, 91%). .sup.1H NMR (300 MHz, CDCl.sub.3) 3.86 (t, J=5.8 Hz, 2H), 4.30 (t, J=5.8 Hz, 2H), 4.70 (s, 2H), 6.88 (d, J=8.2 Hz, 1H), 7.00 (td, J=7.5, 1.0 Hz, 1H), 7.27-7.35 (m, 1H), 7.39 (dd, J=7.5, 1.6 Hz, 1H).

Example 158c. [2-(2-Chloroethoxy)phenyl]methyl (4S)-4-(6-chloro-3-pyridyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate and [2-(2-chloroethoxy)phenyl]methyl (4R)-4-(6-chloro-3-pyridyl)-6-methyl-2-oxo-1-[[(2S)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate

[0430] The acid 153c (93 mg, 0.27 mmol) and cesium carbonate (95 mg, 0.29 mmol) were dissolved in dry DMF (2 mL). Compound example 158b (60 mg, 0.29 mmol) was added. The reaction mixture was stirred at room temperature 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. The organic layers were assembled, washed with brine and dried with Na.sub.2SO.sub.4. The residue was purified by flash chromatography (Cy/CH.sub.2Cl.sub.2: 50/50 to 0/100) to afford the desired product as a colorless oil (m=112 mg, 81%). MS [M+H].sup.+ 519 g/mol.

Example 158d. [2-(2-Iodoethoxy)phenyl]methyl (4S)-4-(6-chloro-3-pyridyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate and [2-(2-iodoethoxy)phenyl]methyl (4R)-4-(6-chloro-3-pyridyl)-6-methyl-2-oxo-1-[[(2S)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate

[0431] Example 158c (200 mg, 0.39 mmol) was dissolved in butanone (3 mL). NaI (231 mg, 1.54 mmol) was added and the reaction mixture stirred at 80 C. overnight. The solution was cooled to room temperature, filtered and washed by acetone. The solvents were removed under reduced pressure to afford yellowish oil. This residue was purified by flash chromatography (Cy/CH.sub.2Cl.sub.2: 50/50 to 0/100) to give the desired product as oil (m=204 mg, 87%). .sup.1H NMR (300 MHz, CDCl.sub.3) 1.34-1.50 (m, 1H), 1.77-2.02 (m, 3H), 2.54-2.67 (m, 4H), 2.91 (dd, J=15.8, 7.5 Hz, 1H), 3.25-3.45 (m, 3H), 3.64-3.78 (m, 1H), 3.78-3.92 (m, 2H), 4.08-4.27 (m, 4H), 5.15 (q, J=12.6 Hz, 2H), 6.74 (d, J=7.7 Hz, 1H), 6.85 (td, J=7.5, 0.9 Hz, 1H), 7.02 (dd, J=7.5, 1.7 Hz, 1H), 7.10 (d, J=8.3 Hz, 1H), 7.17-7.25 (m, 1H), 7.55 (dd, J=8.3, 2.6 Hz, 1H), 8.19 (d, J=2.5 Hz, 1H). MS [M+H].sup.+ 611 g/mol.

Example 158: Ammonium, 2-[2-[[(4S)-4-(6-chloro-3-pyridyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carbonyl]oxymethyl]phenoxy]ethanesulfonate and ammonium,2-[2-[[(4R)-4-(6-chloro-3-pyridyl)-6-methyl-2-oxo-1-[[(2S)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carbonyl]oxymethyl]phenoxy]ethanesulfonate

[0432] The compound 158d (200 mg, 0.33 mmol) was dissolved in a mixture of iPrOH/water 1/1 (2 mL). Sodium sulfite (83 mg, 0.65 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 (basic conditions) gave the expected product as a white powder (m=112 mg, 59%). .sup.1H NMR (300 MHz, CDCl.sub.3) 1.39-1.45 (m, 1H), 1.74-2.05 (m, 3H), 2.49-2.67 (m, 4H), 2.87 (dd, J=15.6, 7.3 Hz, 1H), 3.27 (t, J=6.8 Hz, 2H), 3.31-3.43 (m, 1H), 3.70 (dd, J=14.4, 7.5 Hz, 1H), 3.76-3.90 (m, 2H), 4.16 (d, J=10.7 Hz, 2H), 4.25 (t, J=6.8 Hz, 2H), 5.06 (s, 2H), 6.77 (dd, J=16.3, 8.1 Hz, 2H), 6.88-6.96 (m, 1H), 7.07-7.40 (m, 6H), 7.56 (dd, J=8.3, 2.5 Hz, 1H), 8.28 (d, J=2.5 Hz, 1H). .sup.13C NMR (75 MHz, CDCl.sub.3) 17.2, 25.7, 29.3, 34.9, 38.6, 46.1, 50.8, 61.9, 63.9, 68.3, 77.7, 109.1, 111.9, 120.9, 124.4, 124.5, 129.2, 129.6, 136.6, 138.6, 149.0, 149.3, 152.3, 156.1, 167.0, 168.6. MS [M+H].sup.+ 565 g/mol.

Example 159

[0433] ##STR00417##

Example 159a. Methyl-(4S)-4-(6-chloro-3-pyridyl)-6-methyl-2-oxo-1-[[(2S)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate and methyl (4R)-4-(6-chloro-3-pyridyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate

[0434] The methyl 4-(6-chloro-3-pyridyl)-6-methyl-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate 153a (600 mg, 2.14 mmol) and the 2-(bromomethyl)tetrahydrofuran (0.5 mL, 4.27 mmol) were dissolved in dry DMF (5 mL), Cs.sub.2CO.sub.3 (1.4 g, 4.28 mmol) and NaI (16 mg, 0.11 mmol) were added and the reaction mixture was stirred at 50 C. overnight. 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 Na.sub.2SO.sub.4. The solvent was removed. The residue was dissolved again in 5 mL of DMF, 1.4 g of Cs.sub.2CO.sub.3, 16 mg of NaI and the alkyl bromide (0.5 mL) were added and the mixture was stirred at 50 C. for 18 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 MgSO.sub.4. The solvent was removed. The purification by columns chromatography on silica (Cy/EtOAc 100/0 to 70/30 and CH.sub.2Cl.sub.2/Cy 70/30 to 100/0) give the desired product as white product (m=300 mg, 39%). .sup.1H NMR (300 MHz, CDCl.sub.3) 1.19-1.35 (m, 1H), 1.77-1.97 (m, 3H), 2.61 (s, 3H), 2.76 (dd, J=16.0, 2.2 Hz, 1H), 2.95 (dd, J=16.0, 7.4 Hz, 1H), 3.66 (s, 3H), 3.67-3.86 (m, 3H), 3.93-4.09 (m, 2H), 4.19 (d, J=6.2 Hz, 1H), 7.19 (d, J=8.3 Hz, 1H), 7.51 (dd, J=8.3, 2.6 Hz, 1H), 8.19 (d, J=2.5 Hz, 1H). .sup.13C NMR (75 MHz, CDCl.sub.3) 17.2, 25.7, 29.2, 34.8, 38.8, 46.0, 51.7, 68.2, 77.7, 109.1, 124.1, 135.6, 137.9, 149.2, 150.0, 151.9, 167.4, 168.4. MS [M+H].sup.+ 365 g/mol.

Example 159b. (4 S)-4-(6-chloro-3-pyridyl)-6-methyl-2-oxo-1-[[(2S)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylic acid and (4R)-4-(6-chloro-3-pyridyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylic Acid

[0435] The ester 159a (300 mg, 0.82 mmol) was dissolved in MeOH (5 mL), NaOH 1N (3 mL) was added. The reaction mixture was stirred overnight at 40 C. The MeOH was evaporated under reduced pressure and the aqueous phase was extracted by Et.sub.2O, then acidified to pH=1 with HCl (1N). The aqueous phase was extracted by EtOAc and the organic layers were assembled and dried under Na.sub.2SO.sub.4. The solvent was removed under reduced pressure to afford a product as oil (m=200 mg, 69%). .sup.1H NMR (300 MHz, CDCl.sub.3) 1.20-1.34 (m, 1H), 1.72-1.92 (m, 3H), 2.60 (s, 3H), 2.76 (dd, J=16.1, 2.0 Hz, 1H), 2.93 (dd, J=16.1, 7.4 Hz, 1H), 3.58-3.84 (m, 3H), 3.89-4.02 (m, 2H), 4.19 (d, J=6.6 Hz, 1H), 7.17 (d, J=8.3 Hz, 1H), 7.51 (dd, J=8.3, 2.6 Hz, 1H), 8.21 (d, J=2.5 Hz, 1H), 10.53 (s, 1H). MS [M+H].sup.+ 351 g/mol.

Example 159. (2-Methoxyphenyl)methyl-(4S)-4-(6-chloro-3-pyridyl)-6-methyl-2-oxo-1-[[(2S)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate and (2-methoxyphenyl)methyl-(4R)-4-(6-chloro-3-pyridyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate

[0436] The 1-(chloromethyl)-2-methoxy-benzene (98 mg, 0.63 mmol) and the acid 159b (200 mg, 0.57 mmol) were dissolved in dry DMF (2 mL). Cesium carbonate (279 mg, 0.86 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 Et.sub.2O, washed with brine and dried under MgSO.sub.4. After filtration the solvent was removed and the crude product was purified by column chromatography on silica gel (Cy/AcOEt 100 to 80/20) to give the expected product as white solid (110 mg, 41%). .sup.1H NMR (300 MHz, CDCl.sub.3) 1.15-1.40 (m, 1H), 1.73-1.96 (m, 3H), 2.61 (s, 3H), 2.73 (dd, J=16.0, 2.3 Hz, 1H), 2.95 (dd, J=16.0, 7.6 Hz, 1H), 3.62-3.89 (m, 6H), 3.92-4.07 (m, 2H), 4.20 (d, J=6.1 Hz, 1H), 5.14 (q, J=12.4 Hz, 2H), 6.80-6.92 (m, 2H), 7.08-7.20 (m, 2H), 7.23-7.32 (m, 1H), 7.47 (ddd, J=8.3, 2.6, 0.5 Hz, 1H),8.16 (d, J=2.6 Hz, 1H). .sup.13C NMR (75 MHz, CDCl.sub.3) 17.4, 25.4, 29.2, 34.5, 38.1, 45.3, 55.3, 62.3, 67.9, 77.3, 109.9, 110.5, 120.4, 124.0, 124.0, 129.8, 129.9, 136.1, 137.8, 149.0, 149.9, 151.0, 157.7, 166.8, 169.0. MS [M+H].sup.+ 471 g/mol.

Example 160

[0437] ##STR00418##

Example 160. [4-([Poly (ethylene glycol) methyl ether])phenyl]methyl (4S)-4-(4-chlorophenyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate and [4-([poly (ethylene glycol) methyl ether])phenyl]methyl (4R)-4-(4-chlorophenyl)-6-methyl-2-oxo-1-[[(2S)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate. (m=11-18)

[0438] The 1-(Chloromethyl)-4-[poly (ethylene glycol) methyl ether] benzene. (MMpeg=900 g/mol) 155b (225 mg, 0.26 mmol) and the acid 135 (119 mg, 0.34 mmol) were dissolved in dry DMF (4 mL). Cesium carbonate (111 mg, 0.34 mmol) and NaI (2.0 mg, 0.01 mmol) were added and the reaction mixture was stirred at room temperature for 18 h. Reaction stopped by addition of water. Solvent was removed under reduced pressure. The residue was extracted by EtOAc and the organics layers were washed by a solution of saturated NaCl, dried over MgSO.sub.4, filtered and the solvent was removed to give the crude product. Purification by HPLC (acid conditions) gives the expected product as oil (m=139 mg, 44%). .sup.1H NMR (300 MHz, CDCl.sub.3) 1.30-1.49 (m, 1H), 1.71-1.95 (m, 3H), 2.52-2.67 (m, 5H), 2.84 (dd, J=15.6, 7.4 Hz, 1H), 3.31-3.41 (m, 4H), 3.48-3.53 (m, 2H), 3.55-3.71 (m, 61H), 3.71-3.90 (m, 5H), 4.02-4.09 (m, 2H), 4.12 (d, J=5.8 Hz, 1H), 4.19 (dd, J=14.3, 3.2 Hz, 1H), 4.96 (s, 2H), 6.83 (d, J=8.8 Hz, 2H), 6.98 (d, J=8.7 Hz, 2H), 7.07-7.20 (m, 4H). .sup.13C NMR (75 MHz, CDCl.sub.3) 17.1, 25.5, 29.2, 37.0, 39.0, 45.6, 59.0, 65.8, 67.4, 68.1, 69.7, 70.5, 70.5, 70.6, 70.8, 71.9, 77.8, 110.2, 114.4, 128.3, 128.6, 128.7, 129.4, 132.4, 139.5, 151.1, 158.6, 167.0, 168.9. MS [M+NH.sub.4].sup.+ 1059 g/mol. [n=11 (11%), n=12 (21%), n=13 (24%), n=14 (23%), n=15 (22%), n=16 (15%), n=17 (9%), n=18 (7%)].

Example 161

[0439] ##STR00419##

Example 161. [4-([Poly (ethylene glycol) methyl ether])phenyl]methyl (4S)-4-(4-chlorophenyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate and [4-([poly (ethylene glycol) methyl ether])phenyl]methyl (4R)-4-(4-chlorophenyl)-6-methyl-2-oxo-1-[[(2S)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate. (m=38-48)

[0440] The 1-(Chloromethyl)-4-[poly (ethylene glycol) methyl ether] benzene (MMpeg=2000 g/mol) 156b (580 mg, 0.28 mmol) and the acid 135 (128 mg, 0.37 mmol) were dissolved in dry DMF (4 mL). Cesium carbonate (120 mg, 0.37 mmol) and NaI (2 mg, 0.05 mmol) were added and the reaction mixture stirred at r.t. for 18 h. Reaction stopped by addition of water. Solvent was removed under reduced pressure. The residue was extracted by EtOAc and the organics layers were washed by a solution of saturated NaCl, dried over MgSO.sub.4 and the solvent was removed to give a crude product. Purification by HPLC (acid conditions) gives the expected product as oil (m=115 mg, 18%). .sup.1H NMR (300 MHz, CDCl.sub.3) 1.40-1.50 (m, 1H), 1.85-1.95 (m, 3H), 2.59 (s, 3H), 2.67 (dd, J=15.6, 2.3 Hz, 1H), 2.88 (dd, J=15.7, 7.3 Hz, 1H), 3.30-3.47 (m, 5H), 3.49-3.95 (m, 190H), 4.05-4.18 (m, 3H), 4.23 (dd, J=14.2, 3.3 Hz, 1H), 5.00 (s, 2H), 6.79 (d, J=8.7 Hz, 2H), 7.02 (d, J=8.7 Hz, 2H), 7.11-7.22 (m, 4H). .sup.13C NMR (75 MHz, CDCl.sub.3) 17.0, 25.4, 29.1, 36.9, 38.9, 45.5, 51.8, 63.4, 65.7, 67.3, 68.0, 68.9, 69.5, 70.4, 71.2, 71.8, 72.7, 73.6, 77.4, 81.9, 88.9, 110.1, 114.3, 128.2, 128.5, 128.6, 129.2, 132.3, 139.4, 151.0, 158.4, 166.9, 168.8. MS [M+2H.sub.3O].sup.2+ 806 g/mol. Mixture of compounds containing PEG chains ranging from n=38 to n=48 (centered in: n=43).

Example 162

[0441] ##STR00420## ##STR00421##

Example 162a. [(2S)-Tetrahydrofuran-2-yl)methanol

[0442] (2S)-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.sub.3.SMe.sub.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 was slowly added until no gas evolution was observed then the solution was concentrated under vacuum to give the desired product as oil (m=1.7 g, 99%). .sup.1H NMR (300 MHz, CDCl.sub.3) 1.44-1.63 (m, 1H), 1.69-1.88 (m, 3H), 3.23-3.44 (m, 1H), 3.51 (dd, J=11.6, 3.5 Hz, 1H), 3.59-3.82 (m, 3H), 3.83-3.96 (m, 1H).

Example 162b. (2S)-2-(Iodomethyl)tetrahydrofuran

[0443] The mixture of triethylamine (1.65 mL, 11.75 mmol), TsCl (1.64 g, 8.62 mmol) and 48 mg of DMAP were combined in CH.sub.2Cl.sub.2 (25 mL). This solution was cooled in an ice bath and to it was added a solution of tetrahydrofurfuryl alcohol 162a (800 mg, 7.83 mmol) in 10 mL of CH.sub.2Cl.sub.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 NaHCO.sub.3 and once with a saturated solution of NaCl. The organic layers were dried over MgSO.sub.4, filtered and concentrated in vacuum. LiI (3.1 g, 23.41 mmol) was dried under vacuum for 30 min. then added to a solution of [(2S)-tetrahydrofuran-2-yl]methyl 4-methylbenzenesulfonate (2 g, 7.8 mmol) in 40 mL of acetone, the mixture was refluxed for 24 h and cooled to room temperature. The mixture was filtered and concentrated in vacuum to give brown oil. This oil was taken up in Et.sub.2O and washed with water. The organic layer was dried over MgSO.sub.4, filtered and concentrated in vacuum to give the product as brown oil (m=1.24 g, 75%). .sup.1H NMR (300 MHz, CDCl.sub.3) 1.52-1.70 (m, 1H), 1.78-1.99 (m, 2H), 2.00-2.13 (m, 1H), 3.05-3.28 (m, 2H), 3.70-3.80 (m, 1H), 3.85-3.95 (m, 2H).

Example 162c1. Methyl (4R)-4-(6-chloro-3-pyridyl)-6-methyl-2-oxo-1-[[(2S)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate and Example 162c2. Methyl (4S)-4-(6-chloro-3-pyridyl)-6-methyl-2-oxo-1-[[(2S)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate

[0444] The methyl 4-(6-chloro-3-pyridyl)-6-methyl-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate 153a (200 mg, 0.71 mmol) and the (2S)-2-(iodomethyl)tetrahydrofuran 162b (302 mg, 1.42 mmol) were dissolved in dry DMF (3 mL), (464 mg, 1.42 mmol) of Cs.sub.2C03 and (5 mg, 0.04 mmol) of NaI were added and the reaction mixture was stirred at 50 C. overnight. Little formation of product was observed by TLC and LCMS. 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 MgSO.sub.4, filtered and concentrated in vacuum. The crude was dissolved again in 3 mL of DMF, 464 mg of Cs.sub.2CO.sub.3, 5 mg of NaI and the alkyl iodide (300 mg) were added and the mixture was stirred at 50 C. for 18 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 MgSO.sub.4. The solvent was removed and the residue was purified by flash chromatography (CH.sub.2Cl.sub.2/CyHex: 100/0) and (MeOH/CH.sub.2Cl.sub.2: 0.5%) to give the desired products as oil (E1: m=58 mg, 22%) (E2: m=41 mg, 16%). MS [M+H].sup.+ 365 g/mol.

[0445] 162c1: 1H NMR (300 MHz, CDCl3) 1.40-1.50 (m, 1H), 1.80-2.01 (m, 3H), 2.58 (s, 3H), 2.65 (dd, J=15.7, 2.0 Hz, 1H), 2.92 (dd, J=15.7, 7.3 Hz, 1H), 3.37 (dd, J=14.2, 9.3 Hz, 1H), 3.62 (s, 3H), 3.67-3.94 (m, 3H), 4.09-4.32 (m, 2H), 7.16 (d, J=8.3 Hz, 1H), 7.60 (dd, J=8.3, 2.6 Hz, 1H), 8.26 (d, J=2.5 Hz, 1H).

[0446] 162c2: 1H NMR (300 MHz, CDCl3) 1.18-1.36 (m, 1H), 1.73-1.95 (m, 3H), 2.61 (s, 3H), 2.76 (dd, J=16.0, 2.2 Hz, 1H), 2.95 (dd, J=16.0, 7.4 Hz, 1H), 3.58-3.87 (m, 6H), 3.90-4.08 (m, 2H), 4.19 (d, J=6.1 Hz, 1H), 7.20 (d, J=8.3 Hz, 1H), 7.51 (ddd, J=8.3, 2.6, 0.5 Hz, 1H), 8.20 (d, J=2.6 Hz, 1H).

Example 162d1. (4R)-4-(6-Chloro-3-pyridyl)-6-methyl-2-oxo-1-[[(2S)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylic Acid

[0447] The ester 162c1 (58 mg) was dissolved in MeOH (2 mL), a solution of NaOH 1N (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.sub.2O, then acidified to pH=1 with a solution of HCl (1N). The aqueous phase was extracted by EtOAC. The organics layers were assembled and dried over MgSO.sub.4, the solvent was removed under reduced pressure to afford a product as oil (m=55 mg, 98%). .sup.1H NMR (300 MHz, CDCl.sub.3) 1.36-1.51 (m, 1H), 1.80-2.00 (m, 3H), 2.56-2.74 (m, 4H), 2.93 (dd, J=15.8, 7.3 Hz, 1H), 3.38 (dd, J=14.2, 9.3 Hz, 1H), 3.65-3.90 (m, 3H), 4.15-4.30 (m, 2H), 7.17 (d, J=8.3 Hz, 1H), 7.61 (dd, J=8.3, 2.6 Hz, 1H), 8.28 (d, J=2.4 Hz, 1H), 9.64 (s, 1H). MS [M+H].sup.+ 351 g/mol.

Example 162. (2-Methoxyphenyl)-methyl-(4R)-4-(6-chloro-3-pyridyl)-6-methyl-2-oxo-1-[[(2S)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate

[0448] The 1-(chloromethyl)-2-methoxy-benzene (27 mg, 0.17 mmol) and the acid 162d1 (55 mg, 0.16 mmol) were dissolved in dry DMF (2 mL). Cesium carbonate (77 mg, 0.24 mmol) was added and the reaction mixture was stirred at room temperature overnight. The solvent was removed. Water was added and the aqueous phase was extracted by Et.sub.2O, washed with brine and dried over MgSO.sub.4. After filtration the solvent was removed and the crude product was purified by Column chromatography on silica gel (CH.sub.2Cl.sub.2/MeOH: 100/0 to 99/1) to give the expected product as oil (m=60 mg, 81%). .sup.1H NMR (300 MHz, CDCl.sub.3) 1.35-1.55 (m, 1H), 1.77-2.05 (m, 3H), 2.54-2.73 (m, 4H), 2.93 (dd, J=15.7, 7.5 Hz, 1H), 3.39 (dd, J=14.2, 9.2 Hz, 1H), 3.64-3.78 (m, 4H), 3.81-3.94 (m, 2H), 4.14-4.31 (m, 2H), 4.99-5.21 (m, 2H), 6.74-6.90 (m, 2H), 7.03 (dd, J=7.4, 1.6 Hz, 1H), 7.14 (d, J=8.3 Hz, 1H), 7.20-7.32 (m, 1H), 7.57 (dd, J=8.3, 2.6 Hz, 1H), 8.22 (d, J=2.5 Hz, 1H). .sup.13C NMR (75 MHz, CDCl.sub.3) 17.2, 25.7, 29.3, 35.0, 38.7, 46.1, 55.3, 62.2, 68.3, 77.7, 109.4, 110.4, 120.3, 124.1, 124.1, 129.6, 129.7, 136.0, 138.0, 149.2, 149.9, 151.8, 157.5, 166.8, 168.5. MS [M+H].sup.+ 471 g/mol.

Example 163

[0449] ##STR00422##

Example 162d2. (4S)-4-(6-Chloro-3-pyridyl)-6-methyl-2-oxo-1-[[(2S)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylic Acid

[0450] The ester 162c2 (40 mg) was dissolved in MeOH (2 mL), a solution of NaOH 1N (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.sub.2O, then acidified to pH=1 with a solution of HCl (1N). The aqueous phase was extracted by EtOAC. The organics phases were assembled and dried over MgSO.sub.4, the solvents were removed under reduced pressure to afford a product as oil (quantitative). .sup.1H NMR (300 MHz, CDCl.sub.3) 1.20-1.34 (m, 1H), 1.76-1.95 (m, 3H), 2.64 (s, 3H), 2.79 (dd, J=16.1, 2.0 Hz, 1H), 2.96 (dd, J=16.0, 7.4 Hz, 1H), 3.64-3.84 (m, 3H), 3.93-4.06 (m, 2H), 4.22 (d, J=6.2 Hz, 1H), 7.20 (d, J=8.3 Hz, 1H), 7.46-7.57 (m, 1H), 8.23 (d, J=2.6 Hz, 1H), 9.55 (s, 1H). MS [M+H].sup.+ 351 g/mol.

Example 163. (2-Methoxyphenyl)methyl-(4S)-4-(6-chloro-3-pyridyl)-6-methyl-2-oxo-1-[[(2S)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate

[0451] The 1-(chloromethyl)-2-methoxy-benzene (19 mg, 0.12 mmol) and the acid 162d2 (38 mg, 0.11 mmol) were dissolved in dry DMF (2 mL). Cesium carbonate (53 mg, 0.16 mmol) was added and the reaction mixture was stirred at r.t. overnight. The solvent was removed. Water was added and the aqueous layer was extracted by Et.sub.2O, washed with brine and dried over MgSO.sub.4. After filtration the solvent was removed and the crude product was purified by Column chromatography on silica gel (CH.sub.2Cl.sub.2/MeOH: 100/0 to 99/1) to give the expected product as oil (m=28 mg, 55%). .sup.1H NMR (300 MHz, CDCl.sub.3) 1.19-1.41 (m, 1H), 1.78-1.98 (m, 3H), 2.62 (s, 3H), 2.73 (dd, J=16.0, 2.3 Hz, 1H), 2.95 (dd, J=16.0, 7.6 Hz, 1H), 3.62-3.88 (m, 6H), 3.93-4.05 (m, 2H), 4.21 (d, J=6.2 Hz, 1H), 5.14 (q, J=12.4 Hz, 2H), 6.77-6.94 (m, 2H), 7.04-7.19 (m, 2H), 7.28 (dt, J=7.8, 1.4 Hz, 1H), 7.47 (dd, J=8.3, 2.6 Hz, 1H), 8.17 (d, J=2.6 Hz, 1H). .sup.13C NMR (75 MHz, CDCl.sub.3) 17.5, 25.4, 29.2, 34.5, 38.1, 45.3, 55.4, 62.3, 67.9, 77.3, 109.9, 110.5, 120.4, 124.0, 124.1, 129.9, 130.0, 136.1, 137.8, 149.0, 149.9, 151.0, 157.7, 166.8, 169.1. MS [M+H].sup.+ 471 g/mol.

Example 164

[0452] ##STR00423## ##STR00424##

Example 164a. [(2R)-Tetrahydrofuran-2-yl]methanol

[0453] (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.sub.3.SMe.sub.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%). .sup.1H NMR (300 MHz, CDCl.sub.3) 1.55-1.70 (m, 1H), 1.72-1.98 (m, 3H), 3.35-4.00 (m, 6H).

Example 164b. [(2R)-Tetrahydrofuran-2-yl]methyl 4-methylbenzenesulfonate

[0454] 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.sub.2Cl.sub.2 (70 mL). This solution was cooled in an ice bath and to it was added a solution of tetrahydrofurfuryl alcohol 164a (3.1 g, 30.35 mmol) in 30 mL of CH.sub.2Cl.sub.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 NaHCO.sub.3 and once with a brine. The organic layers were dried over MgSO.sub.4, filtered and concentrated in vacuum. The crude product was purified by Column chromatography on silica gel (CH.sub.2Cl.sub.2/CyHex: 50/50) to give the expected product as oil (m=5.6 g, 72%). .sup.1H NMR (300 MHz, CDCl.sub.3) 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, J=8.0 Hz, 2H), 7.75 (d, J=8.2 Hz, 2H). MS [M+H].sup.+ 257 g/mol.

Example 164c1. Methyl-(4R)-4-(6-chloro-3-pyridyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate and Example 164c2. Methyl-(4S)-4-(6-chloro-3-pyridyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate

[0455] The methyl 4-(6-chloro-3-pyridyl)-6-methyl-2-oxo-3,4-dihydro-1H-pyridine-5-carboxylate 153a (400 mg, 1.42 mmol) and the ((2R)-tetrahydrofuran-2-yl)methyl-4-methylbenzenesulfonate 164b (470 mg, 2.85 mmol) were dissolved in dry DMF (6 mL), (929 mg, 2.85 mmol) of Cs.sub.2CO.sub.3 and (11 mg, 0.05 mmol) of NaI were added and the reaction mixture was stirred at 50 C. for 24 h. 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 MgSO.sub.4. The solvent was removed and the crude product was purified by column chromatography on silica gel (CH.sub.2Cl.sub.2/MeOH 100/0 to 95/5) to give the expected products as oil (e1: m=126 mg, 24%) (e2: m=109 mg, 21%). MS [M+H].sup.+ 365 g/mol.

[0456] 164c1: .sup.1H NMR (300 MHz, CDCl.sub.3) 1.14-1.32 (m, 1H), 1.71-1.92 (m, 3H), 2.58 (s, 3H), 2.72 (dd, J=16.0, 2.2 Hz, 1H), 2.92 (dd, J=16.0, 7.4 Hz, 1H), 3.53-3.83 (m, 6H), 3.97 (dt, J=6.4, 4.4 Hz, 2H), 4.16 (d, J=5.9 Hz, 1H), 7.16 (d, J=8.2 Hz, 1H), 7.49 (dd, J=8.3, 2.6 Hz, 1H), 8.16 (d, J=2.6 Hz, 1H).

[0457] 164c2: .sup.1H NMR (300 MHz, CDCl.sub.3) 1.35-1.45 (m, 1H), 1.76-2.01 (m, 3H), 2.57 (s, 3H), 2.63 (dd, J=15.7, 2.0 Hz, 1H), 2.91 (dd, J=15.7, 7.3 Hz, 1H), 3.35 (dd, J=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, J=8.3, 2.6, 0.5 Hz, 1H), 8.24 (d, J=2.6 Hz, 1H).

Example 164d2. (4 S)-4-(6-Chloro-3-pyridyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylic Acid

[0458] The ester 164c2 (126 mg) was dissolved in MeOH (2 mL), a solution of NaOH 1N (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.sub.2O, then acidified to pH=1 with HCl (1N). The aqueous phase was extracted by EtOAC. The organic phases were assembled and dried over MgSO.sub.4. The solvents were removed under reduced pressure to afford a product as oil (m=66 mg, 55%). .sup.1H NMR (300 MHz, CDCl.sub.3) 1.35-1.52 (m, 1H), 1.79-2.00 (m, 3H), 2.60 (s, 3H), 2.68 (dd, J=15.8, 1.9 Hz, 1H), 2.94 (dd, J=15.8, 7.4 Hz, 1H), 3.39 (dd, J=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, J=2.6 Hz, 1H), 9.49 (s, 1H). MS [M+H].sup.+ 351 g/mol.

Example 164. (2-Methoxyphenyl)methyl-(4S)-4-(6-chloro-3-pyridyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate

[0459] The 1-(chloromethyl)-2-methoxy-benzene (33 mg, 0.21 mmol) and the acid 164d2 (66 mg, 0.19 mmol) were dissolved in dry DMF (3 mL). Cesium carbonate (92 mg, 0.28 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 Et.sub.2O, washed with brine and dried over MgSO.sub.4. After filtration the solvent was removed and the crude product was purified by Column chromatography on silica gel (CH.sub.2Cl.sub.2/MeOH: 100/0 to 99/1) to give the expected product as oil (m=48 mg, 54%). .sup.1H NMR (300 MHz, CDCl.sub.3) 1.40-1.55 (m, 1H), 1.82-2.06 (m, 3H), 2.56-2.71 (m, 4H), 2.94 (dd, J=15.8, 7.5 Hz, 1H), 3.40 (dd, J=14.2, 9.2 Hz, 1H), 3.67-3.79 (m, 4H), 3.80-3.94 (m, 2H), 4.16-4.29 (m, 2H), 5.03-5.20 (m, 2H), 6.79-6.90 (m, 2H), 7.04 (dd, J=7.4, 1.7 Hz, 1H), 7.14 (d, J=8.3 Hz, 1H), 7.22-7.31 (m, 1H), 7.58 (ddd, J=8.3, 2.6, 0.4 Hz, 1H), 8.22 (d, J=2.6 Hz, 1H). .sup.13C NMR (75 MHz, CDCl.sub.3) 17.2, 25.7, 29.3, 35.0, 38.7, 46.1, 55.3, 62.2, 68.3, 77.7, 109.4, 110.4, 120.4, 124.1, 124.1, 129.6, 129.7, 136.0, 138.0, 149.3, 149.9, 151.8, 157.6, 166.8, 168.5. MS [M+H].sup.+ 471 g/mol.

Example 165

[0460] ##STR00425##

Example 164d1. (4R)-4-(6-Chloro-3-pyridyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylic Acid

[0461] The ester 164c1 (109 mg) was dissolved in MeOH (2 mL), a solution of NaOH 1N (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.sub.2O, then acidified to pH=1 with HCl (1N). The aqueous phase was extracted by EtOAC. The organic phases were assembled and dried over MgSO.sub.4. The solvents were removed under reduced pressure to afford a product as oil (m=98 mg, 94%). .sup.1H NMR (300 MHz, CDCl.sub.3) 1.21-1.31 (m, 1H), 1.73-1.93 (m, 3H), 2.61 (s, 3H), 2.77 (dd, J=16.1, 2.0 Hz, 1H), 2.94 (dd, J=16.0, 7.4 Hz, 1H), 3.61-3.81 (m, 3H), 3.93-4.03 (m, 2H), 4.20 (d, J=6.2 Hz, 1H), 7.18 (d, J=8.3 Hz, 1H), 7.52 (dd, J=8.3, 2.6 Hz, 1H), 8.22 (d, J=2.5 Hz, 1H), 10.47 (s, 1H). MS [M+H].sup.+ 351 g/mol.

Example 165. (2-Methoxyphenyl)methyl-(4R)-4-(6-chloro-3-pyridyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate

[0462] The 1-(chloromethyl)-2-methoxy-benzene (48 mg, 0.31 mmol) and the acid 164d1 (98 mg, 0.28 mmol) were dissolved in dry DMF (4 mL). Cesium carbonate (137 mg, 0.42 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 Et.sub.2O, washed with brine and dried over MgSO.sub.4. After filtration the solvent was removed and the crude product was purified by Column chromatography on silica gel (CH.sub.2Cl.sub.2/MeOH: 100/0 to 99/1) to give the expected product as oil (m=100 mg, 76%). .sup.1H NMR (300 MHz, CDCl.sub.3) 1.20-1.40 (m, 1H), 1.75-1.97 (m, 3H), 2.61 (s, 3H), 2.72 (dd, J=16.0, 2.2 Hz, 1H), 2.94 (dd, J=16.0, 7.6 Hz, 1H), 3.62-3.86 (m, 6H), 3.93-4.06 (m, 2H), 4.20 (d, J=6.1 Hz, 1H), 5.13 (q, J=12.4 Hz, 2H), 6.79-6.90 (m, 2H), 7.09 (dd, J=7.4, 1.7 Hz, 1H), 7.13 (d, J=8.3 Hz, 1H), 7.27 (td, J=8.1, 1.8 Hz, 1H), 7.47 (dd, J=8.3, 2.6 Hz, 1H), 8.16 (d, J=2.6 Hz, 1H). .sup.13C NMR (75 MHz, CDCl.sub.3) 17.4, 25.3, 29.1, 34.4, 38.0, 45.3, 55.3, 62.2, 67.9, 77.2, 109.8, 110.4, 120.3, 124.0, 124.0, 129.8, 129.9, 136.1, 137.8, 148.9, 149.9, 151.0, 157.6, 166.8, 169.0. MS [M+H].sup.+ 471 g/mol.

Example 166

[0463] ##STR00426## ##STR00427##

Example 166a. [4-(3-Chloropropoxy)phenyl)methanol

[0464] A mixture of 1-bromo-3-chloro-propane (2.4 mL, 24 mmol), 4-hydroxybenzyl alcohol (1.0 g, 8 mmol) and potassium carbonate (1.11 g, 8 mmol) was added in acetonitrile (27 mL) and the reaction was stirred overnight at 50 C. Little formation of product was observed by TLC and LCMS. RM stirred at reflux for 8 h. little progress (20% conv. to 30% cony.). 3 equivalents of reactant and base were added. Reaction stirred under reflux overnight. Reaction finished. The solvent was removed under reduced pressure. The crude was dissolved in EtOAc and washed by water. The aqueous phase was extracted by EtOAc and the organic phase was washed with brine, dried under MgSO.sub.4. The solvents were removed under reduced pressure to afford the title compound. This crude was purified by flash chromatography (Cy/EA 100/0 to 75/25) to afford the desired compound as an oil (m=1.34 g, 84%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.03 (s, 1H), 2.14-2.42 (m, 2H), 3.75 (t, J=6.3 Hz, 2H), 4.12 (t, J=5.8 Hz, 2H), 4.59 (s, 2H), 6.90 (d, J=8.4 Hz, 2H), 7.28 (d, J=8.2 Hz, 2H).

Example 166b. 1-(Chloromethyl)-4-(3-chloropropoxy)benzene

[0465] Thionyl chloride (90 L, 1.25 mmol) was added to benzotriazole (178 mg, 1.50 mmol). The resulting mixture was dissolved in CH.sub.2Cl.sub.2 (3 mL). After 5 min, this solution was added slowly to the solution of the [4-(3-Chloropropoxy)phenyl)methanol 166a (200 mg, 1.0 mmol) in CH.sub.2Cl.sub.2 (7 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. The organic phase was dried under MgSO.sub.4 and the solvent was removed under reduced pressure to give the desired chlorinated compound as yellow oil (m=184 mg, 84%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.17-2.33 (m, 2H), 3.75 (t, J=6.3 Hz, 2H), 4.12 (t, J=5.9 Hz, 2H), 4.58 (s, 2H), 6.90 (d, J=8.7 Hz, 2H), 7.32 (d, J=8.8 Hz, 2H).

Example 166c. [4-(3-Chloropropoxy)phenyl]methyl-(4S)-4-(6-chloro-3-pyridyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate

[0466] The acid 164d2 (80 mg, 0.23 mmol) and cesium carbonate (111 mg, 0.34 mmol) were dissolved in dry DMF (2 mL). The chlorinated compound 166b (75 mg, 0.34 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 MgSO.sub.4. The residue was purified by flash chromatography (Cy/CH.sub.2Cl.sub.2: 50/50 to 0/100) to afford the desired product as a colorless oil (m=97 mg, 80%). .sup.1H NMR (300 MHz, CDCl.sub.3) 1.37-1.54 (m, 1H), 1.80-2.08 (m, 3H), 2.17-2.31 (m, 2H), 2.54-2.73 (m, 4H), 2.92 (dd, J=15.7, 7.5 Hz, 1H), 3.39 (dd, J=14.2, 9.3 Hz, 1H), 3.67-3.78 (m, 3H), 3.79-3.94 (m, 2H), 4.09 (t, J=5.8 Hz, 2H), 4.14-4.28 (m, 2H), 5.00 (q, J=12.2 Hz, 2H), 6.81 (d, J=8.7 Hz, 2H), 7.07 (d, J=8.7 Hz, 2H), 7.15 (d, J=8.3 Hz, 1H), 7.56 (dd, J=8.3, 2.6 Hz, 1H), 8.23 (d, J=2.6 Hz, 1H). MS [M+H].sup.+ 533 g/mol.

Example 166 d. [4-(3-Iodopropoxy)phenyl]methyl(4S)-4-(6-chloro-3-pyridyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-di hydropyridine-5-carboxylate

[0467] The chlorinated compound 166c (96 mg, 0.18 mmol) was dissolved in butanone (4 mL). NaI (108 mg, 0.72 mmol) was added and the reaction mixture stirred at 80 C. overnight. The solution was cooled to r.t., filtered and the filtrate washed by acetone. The solvents were removed under reduced pressure to afford yellowish oil. This residue was purified by flash chromatography (CH.sub.2Cl.sub.2) to give the desired product as oil (m=103 mg, 92%). .sup.1H NMR (300 MHz, CDCl.sub.3) 1.40-1.52 (m, 1H), 1.82-2.03 (m, 3H), 2.19-2.30 (m, 2H), 2.54-2.70 (m, 4H), 2.91 (dd, J=15.8, 7.5 Hz, 1H), 3.27-3.47 (m, 3H), 3.65-3.78 (m, 1H), 3.78-3.93 (m, 2H), 4.01 (t, J=5.8 Hz, 2H), 4.11-4.29 (m, 2H), 5.00 (q, J=12.2 Hz, 2H), 6.80 (d, J=8.7 Hz, 2H), 7.06 (d, J=8.5 Hz, 2H), 7.14 (d, J=8.3 Hz, 1H), 7.56 (dd, J=8.3, 2.6 Hz, 1H), 8.23 (d, J=2.5 Hz, 1H). MS [M+H].sup.+ 625 g/mol.

Example 166. Ammonium, 3-[4-[[(4S)-4-(6-chloro-3-pyridyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carbonyl]oxymethyl]phenoxy]propane-1-sulfonate

[0468] The iodide compound 166d (100 mg, 0.16 mmol) was dissolved in a mixture of iPrOH/water (1/1, 2 mL). Sodium sulfite (40 mg, 0.32 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 product by HPLC (acid conditions) gave the ammonium; 3-[4-[[(4S)-4-(6-chloro-3-pyridyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carbonyl]oxymethyl]phenoxy]propane-1-sulfonate as a white powder (m=52 mg, 54%). .sup.1H NMR (300 MHz, CDCl.sub.3) 1.35-1.50 (m, 1H), 1.80-2.00 (m, 3H), 2.17 (s, 2H), 2.50-2.65 (m, 4H), 2.85 (dd, J=15.8, 7.1 Hz, 1H), 3.04 (s, 2H), 3.36 (dd, J=14.0, 9.2 Hz, 1H), 3.70 (dd, J=14.2, 7.1 Hz, 1H), 3.80-3.95 (m, 4H), 4.10-4.25 (m, 2H), 4.87 (dd, J=29.3, 12.1 Hz, 2H), 6.69 (d, J=6.7 Hz, 2H), 6.85-7.40 (m, 3H+NH4+), 7.57 (d, J=7.9 Hz, 1H), 8.17 (s, 1H). .sup.13C NMR (75 MHz, CDCl.sub.3) 17.3, 25.0, 25.8, 29.3, 34.9, 38.7, 46.1, 66.1, 66.6, 68.3, 77.7, 109.1, 114.7, 124.3, 128.2, 129.7, 136.3, 138.2, 149.7, 152.2, 158.7, 166.7, 168.5. MS [M].sup. 577 g/mol.

Example 167

[0469] ##STR00428##

Example 167a. Methyl-(4S)-4-(4-chlorophenyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate

[0470] The dihydropyridone intermediate obtained following general procedure A (1.5 g, 5.36 mmol) and the [(2R)-tetrahydrofuran-2-yl]methyl 4-methylbenzenesulfonate 164b (2.75 g, 10.72 mmol) were dissolved in dry DMF (25 mL), Cs.sub.2CO.sub.3 (3.5 g, 10.72 mmol) and NaI (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 MgSO.sub.4. The solvent was removed and the crude was purified by flash chromatography (CH.sub.2Cl.sub.2/CyHex 30/70 to 100/0) to give the expected product as oil (m=500 mg, 26%). .sup.1H NMR (300 MHz, CDCl.sub.3) 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, J=14.3, 3.3 Hz, 1H), 7.17 (s, 4H). MS [M+H].sup.+ 364 g/mol.

Example 167b. (4S)-4-(4-Chlorophenyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylic acid

[0471] The ester 167a (480 mg, 1.32 mmol) was dissolved in MeOH (8 mL), a solution of NaOH 1N (8 mL) was added. The reaction mixture was stirred for 3 h at 40 C. LCMS showed completion of the reaction. The MeOH was evaporated under reduced pressure, the aqueous phase was extracted by Et.sub.2O, then acidified to pH=1 with a solution of HCl (1N). The aqueous phase was extracted by EtOAC and the organic phases were assembled and dried under MgSO.sub.4. The solvents were removed under reduced pressure to afford a product as white solid (m=459 mg, 99%). .sup.1H NMR (300 MHz, CDCl.sub.3) 1.32-1.52 (m, 1H), 1.76-1.99 (m, 3H), 2.61 (s, 3H), 2.71 (dd, J=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, J=13.0, 6.7 Hz, 1H), 4.13-4.33 (m, 2H), 7.19 (s, 4H), 11.47 (s, 1H). MS [M+H].sup.+ 350 g/mol.

Example 167. (2-Methoxyphenyl)methyl-(4S)-4-(4-chlorophenyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate

[0472] The 1-(chloromethyl)-2-methoxy-benzene (50 mg, 0.31 mmol) and the acid 167b (100 mg, 0.29 mmol) were dissolved in dry DMF (5 mL). Cesium carbonate (140 mg, 0.43 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 AcOEt, washed with brine and dried over MgSO.sub.4. After filtration the solvent was removed and the crude product was purified by Column chromatography on silica gel (CH.sub.2Cl.sub.2/MeOH: 100/0 to 99/1) to give the expected product as oil (m=125 mg, 93%). .sup.1H NMR (300 MHz, CDCl.sub.3) 1.36-1.52 (m, 1H), 1.77-1.98 (m, 3H), 2.61 (d, J=0.5 Hz, 3H), 2.68 (dd, J=15.6, 2.2 Hz, 1H), 2.90 (dd, J=15.6, 7.4 Hz, 1H), 3.40 (dd, J=14.2, 8.6 Hz, 1H), 3.66-3.96 (m, 6H), 4.15-4.30 (m, 2H), 5.14 (dd, J=28.9, 13.0 Hz, 2H), 6.82 (ddd, J=8.5, 5.6, 1.1 Hz, 2H), 6.93-6.98 (m, 1H), 7.18 (s, 4H), 7.21-7.28 (m, 1H). .sup.13C NMR (75 MHz, CDCl.sub.3) 17.0, 25.6, 29.3, 37.0, 39.1, 45.6, 55.2, 61.8, 68.1, 77.9, 110.2, 110.4, 120.2, 124.4, 128.6, 128.7, 128.9, 129.2, 132.5, 139.7, 150.9, 157.3, 167.2, 169.0. MS [M+H].sup.+ 470 g/mol.

Example 168

[0473] ##STR00429##

Example 168a. [4-(3-Chloropropoxy)phenyl]methyl-(4S)-4-(4-chlorophenyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate

[0474] The acid 167b (100 mg, 0.29 mmol) and cesium carbonate (140 mg, 0.43 mmol) were dissolved in dry DMF (3 mL), chlorinated compound 166b (94 mg, 0.43 mmol) was added and the reaction mixture was stirred at room temperature 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 MgSO.sub.4. The residue was purified by flash chromatography (Cy/CH.sub.2Cl.sub.2: 50/50 to 0/100) to afford the desired product as a colorless oil (m=80 mg, 53%). .sup.1H NMR (300 MHz, CDCl.sub.3) 1.34-1.54 (m, 1H), 1.79-2.01 (m, 3H), 2.18-2.32 (m, 2H), 2.61 (s, 3H), 2.67 (dd, J=15.6, 2.2 Hz, 1H), 2.88 (dd, J=15.6, 7.4 Hz, 1H), 3.40 (dd, J=14.3, 8.7 Hz, 1H), 3.63-3.84 (m, 4H), 3.84-3.96 (m, 1H), 4.09 (t, J=5.8 Hz, 2H), 4.16 (d, J=5.7 Hz, 1H), 4.24 (dd, J=14.3, 3.3 Hz, 1H), 5.01 (s, 2H), 6.79 (d, J=8.7 Hz, 2H), 7.04 (d, J=8.7 Hz, 2H), 7.12-7.24 (m, 4H). MS [M+H].sup.+ 532 g/mol.

Example 168b. [4-(3-Iodopropoxy)phenyl]methyl-(4S)-4-(4-chlorophenyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate

[0475] The chlorinated compound 168a (80 mg, 0.15 mmol) was dissolved in butanone (4 mL), NaI (90 mg, 0.6 mmol) was added and the reaction mixture stirred at 80 C. overnight. The solution was cooled to room temperature, filtered and the filtrate washed by acetone. The solvents were removed under reduced pressure to afford yellowish oil. This residue was purified by flash chromatography (CH.sub.2Cl.sub.2) to give the desired product as oil (m=76 mg, 81%). .sup.1H NMR (300 MHz, CDCl.sub.3) 1.33-1.53 (m, 1H), 1.78-1.99 (m, 3H), 2.25 (qd, J=6.3, 4.7 Hz, 2H), 2.60 (d, J=0.6 Hz, 3H), 2.67 (dd, J=15.6, 2.2 Hz, 1H), 2.88 (dd, J=15.6, 7.4 Hz, 1H), 3.30-3.45 (m, 3H), 3.63-3.93 (m, 3H), 4.01 (t, J=5.8 Hz, 2H), 4.16 (d, J=5.7 Hz, 1H), 4.23 (dd, J=14.3, 3.3 Hz, 1H), 5.01 (s, 2H), 6.79 (d, J=8.8 Hz, 2H), 7.03 (d, J=8.8 Hz, 2H), 7.14-7.20 (m, 4H). MS [M+H].sup.+ 624 g/mol.

Example 168. Ammonium, 3-[4-[[(4S)-4-(4-chlorophenyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carbonyl]oxymethyl]phenoxy]propane-1-sulfonate

[0476] The iodide compound 168b (75 mg, 0.12 mmol) was dissolved in a mixture of iPrOH/water (1/1, 2 mL). Sodium sulfite (30 mg, 0.24 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 (acid conditions) gave the ammonium; 3-[4-[[(4S)-4-(6-chloro-3-pyridyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carbonyl]oxymethyl]phenoxy]propane-1-sulfonate as a white powder (m=45 mg, 63%). .sup.1H NMR (300 MHz, CDCl.sub.3) 1.28-1.50 (m, 1H), 1.72-1.96 (m, 3H), 2.14 (s, 2H), 2.50-2.65 (m, 4H), 2.80 (dd, J=15.6, 7.2 Hz, 1H), 3.02 (s, 2H), 3.35 (dd, J=14.2, 8.7 Hz, 1H), 3.62-3.90 (m, 5H), 4.09 (d, J=6.6 Hz, 1H), 4.19 (dd, J=14.2, 2.7 Hz, 1H), 4.89 (dd, J=25.4, 12.5 Hz, 2H), 6.66 (d, J=8.3 Hz, 2H), 6.75-7.23 (m, 10H). .sup.13C NMR (75 MHz, CDCl.sub.3) 17.2, 25.0, 25.6, 29.3, 37.1, 39.1, 45.8, 48.4, 65.8, 66.4, 68.2, 77.9, 110.1, 114.5, 128.7, 128.8, 128.8, 129.5, 132.5, 139.7, 151.4, 158.4, 167.1, 169.2. MS [M].sup. 576 g/mol.

Example 169

[0477] ##STR00430## ##STR00431##

Example 169c. [4-(4-Chlorobutoxy)phenyl]methanol

[0478] The mixture of 1-bromo-4-chloro-butane (1.67 mL, 14.5 mmol), 4-(hydroxymethyl)phenol (600 mg, 4.83 mmol) and potassium carbonate (668 mg, 4.83 mmol) were added in acetonitrile (16 mL) and the reaction was stirred overnight at 50 C. Little formation of product observed by TLC (CH.sub.2Cl.sub.2/MeOH: 98/2) and LCMS. 3 equivalents of reactant and base were added and the reaction stirred under reflux overnight. Reaction finished. The solvent was removed under reduced pressure. The crude was dissolved in EtOAc and washed by water. The aqueous phase was extracted by EtOAc and the organic phase washed with brine, dried over MgSO.sub.4. The solvents were removed under reduced pressure and the crude product was purified by flash chromatography (Cy/EA 100/0 to 75/25) to afford the desired compound as an oil (m=1 g, 96%). .sup.1H NMR (300 MHz, CDCl.sub.3) 1.88 (s, 1H), 1.90-2.10 (m, 4H), 3.63 (t, J=6.3 Hz, 2H), 4.00 (t, J=5.8 Hz, 2H), 4.60 (s, 2H), 6.88 (d, J=8.7 Hz, 2H), 7.28 (d, J=8.7 Hz, 2H).

Example 169d. 1-(4-Chlorobutoxy)-4-(chloromethyl)benzene

[0479] The thionyl chloride (0.13 mL, 1.75 mmol) was added to benzotriazole (250 mg, 2.1 mmol). The resulting mixture was dissolved in CH.sub.2Cl.sub.2 (5 mL). After 5 min, this solution was added slowly to the solution of the alcohol 167a (300 mg, 1.4 mmol) in CH.sub.2Cl.sub.2 (10 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 (0.05 M). The organic phase was dried over MgSO.sub.4 and the solvent was removed under reduced pressure to give the desired chlorinated compound as yellow oil (m=306 mg, 94%). .sup.1H NMR (300 MHz, CDCl.sub.3) 1.87-2.08 (m, 4H), 3.62 (t, J=6.2 Hz, 2H), 4.00 (t, J=5.7 Hz, 2H), 4.57 (s, 2H), 6.88 (d, J=8.7 Hz, 2H), 7.32 (d, J=8.7 Hz, 2H).

Example 169a. [4-(4-Chlorobutoxy)phenyl]methyl-(4S)-4-(4-chlorophenyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate

[0480] The acid 167b (60 mg, 0.17 mmol) and cesium carbonate (84 mg, 0.26 mmol) were dissolved in dry DMF (2 mL). The chlorinated compound 169d (60 mg, 0.26 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 MgSO.sub.4. The residue was purified by flash chromatography (CH.sub.2Cl.sub.2) to afford the desired product as a colorless oil (m=54 mg, 58%). .sup.1H NMR (300 MHz, CDCl.sub.3) 1.33-1.55 (m, 1H), 1.75-2.07 (m, 7H), 2.60 (s, 3H), 2.67 (dd, J=15.6, 2.2 Hz, 1H), 2.88 (dd, J=15.6, 7.4 Hz, 1H), 3.40 (dd, J=14.3, 8.7 Hz, 1H), 3.62 (t, J=6.2 Hz, 2H), 3.67-3.94 (m, 3H), 3.98 (t, J=5.7 Hz, 2H), 4.16 (d, J=5.8 Hz, 1H), 4.24 (dd, J=14.3, 3.3 Hz, 1H), 5.01 (s, 2H), 6.77 (d, J=8.7 Hz, 2H), 7.03 (d, J=8.7 Hz, 2H), 7.09-7.23 (m, 4H). MS [M+H].sup.+ 546 g/mol.

Example 169b. [4-(4-Iodobutoxy)phenyl]methyl-(4S)-4-(4-chlorophenyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate

[0481] The chlorinated compound 169a (54 mg, 0.1 mmol) was dissolved in butanone (3 mL). NaI (59 mg, 0.4 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.sub.2Cl.sub.2) to give the desired product as oil (m=49 mg, 78%). .sup.1H NMR (300 MHz, CDCl.sub.3) 1.40-1.55 (m, 1H), 1.76-2.11 (m, 7H), 2.60 (s, 3H), 2.67 (dd, J=15.6, 2.2 Hz, 1H), 2.88 (dd, J=15.6, 7.4 Hz, 1H), 3.26 (t, J=6.8 Hz, 2H), 3.40 (dd, J=14.3, 8.7 Hz, 1H), 3.70-3.92 (m, 3H), 3.96 (t, J=6.0 Hz, 2H), 4.16 (d, J=5.8 Hz, 1H), 4.24 (dd, J=14.3, 3.3 Hz, 1H), 5.01 (s, 2H), 6.77 (d, J=8.6 Hz, 2H), 7.03 (d, J=8.6 Hz, 2H), 7.09-7.23 (m, 4H). MS [M+H].sup.+ 638 g/mol.

Example 169. Ammonium; 4-[4-[[(4S)-4-(4-chlorophenyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carbonyl]oxymethyl]phenoxy]butane-1-sulfonate

[0482] The iodide compound 169b (49 mg, 0.077 mmol) was dissolved in a mixture of iPrOH/water 1/1 (1 mL). Sodium sulfite (19 mg, 0.154 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 (basic conditions) gave the expected product as a yellow powder (m=40 mg, 85%). .sup.1H NMR (300 MHz, CDCl.sub.3) 1.30-1.52 (m, 1H), 1.65-1.99 (m, 7H), 2.48-2.69 (m, 4H), 2.73-3.02 (m, 3H), 3.36 (dd, J=14.2, 8.7 Hz, 1H), 3.61-3.91 (m, 5H), 4.04-4.27 (m, 2H), 4.92 (dd, J=23.7, 12.4 Hz, 2H), 6.48-7.64 (m, 12H). .sup.13C NMR (75 MHz, CDCl.sub.3) 17.2, 21.6, 25.6, 28.3, 29.3, 37.1, 39.1, 45.8, 51.2, 65.9, 67.4, 68.2, 77.9, 110.2, 114.4, 128.5, 128.8, 128.7, 129.6, 132.6, 139.7, 151.4, 158.7, 167.1, 169.1. MS [M].sup. 590 g/mol.

BIOLOGY EXAMPLES

[0483] TGR5/CRE Luciferase Assay

[0484] 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-TGR5 h (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 10 M 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 10 M LCA value and EC.sub.50 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

[0485] The results of the TGR5/CRE Luciferase assay are presented in Table 14 hereafter.

TABLE-US-00014 TABLE 14 hTGR5 mTGR5 Example EC.sub.50 (M) % trans EC.sub.50 (M) % trans 3 7.4 65 10.4 45 4 10 17 8.5 18 5 10.6 31 11.1 34 6 12.8 19 NC 11 7 5.0 22 NC 14 9 1.5 48 1.4 37 11 4.5 17 NC 10 12 1.9 68 4.5 52 13 2.6 40 4.2 37 14 7.6 30 10.3 18 15 3.9 49 16 1.5 47 1.7 21 17 0.6 72 1.4 67 18 1.4 34 1.2 43 20 3.0 42 2.5 53 22 3.51 36 4.3 44 24 1.45 60 5.8 34 25 1.22 43 0.5 36 26 4.6 10 1.8 20 29 1.26 59 1.5 37 30 1.5 16 3.9 12 32 0.6 77 1.1 55 33 6.4 42 11 14 33a 39 37 1.1 16 34 0.6 73 0.8 70 35 0.6 89 0.8 76 36 0.6 54 1.1 63 37 0.3 75 0.6 78 38 1.1 75 1.5 54 39 1.3 82 1.4 73 40 0.9 81 0.9 76 41 1.3 55 1.2 55 43 0.3 75 0.3 78 44 0.3 59 0.4 77 47 6.6 22 NC 0 48 12 13 NC 0 49 0.7 63 1.0 60 50 1.7 100 3.6 77 52 2.5 18 NC 0 53 4.3 16 NC 0 54 4.2 10 NC 0 55 4.5 47 NC 5 56 3.6 50 NC 3 57 0.1 95 0.2 95 58 1.34 50 0.42 70 59 1.1 21 12.4 18 60 13.5 42 14.4 32 62 2.3 69 5.9 42 63 2.2 50 2.0 57 64 0.1 82 0.2 100 65 0.1 91 0.3 107 66 0.2 62 0.1 78 67 0.02 101 0.03 92 68 0.2 82 0.2 82 69 0.3 105 0.4 104 70 0.07 65 0.08 102 71 0.2 94 0.8 85 72 0.08 99 0.2 92 73 0.02 99 0.03 93 75 7.8 34 18.3 25 77 2.9 71 12.3 73 79 0.7 80 0.7 73 80 1.5 60 1.4 67 81 0.5 86 1.3 62 82 0.7 74 1.5 59 83 1.2 69 0.4 88 84 0.4 71 0.5 71 85 0.5 78 0.7 82 86 0.4 71 0.4 82 87 0.5 67 0.8 70 88 0.2 75 0.4 91 89 0.4 65 0.3 84 90 1.1 57 1.3 34 91 0.5 78 0.7 83 92 0.6 56 0.3 59 93 0.6 58 0.8 53 94 0.6 61 0.4 65 95 0.2 78 0.3 76 96 1.1 63 0.6 83 97 0.4 76 0.4 76 98 0.3 91 0.5 86 99 0.2 84 0.3 67 100 0.6 72 0.4 89 101 0.2 75 0.2 84 103 0.5 85 0.4 95 104 0.2 71 0.2 85 105 0.4 87 0.8 63 106 0.4 83 0.2 96 107 1.2 71 0.6 83 108 0.5 72 0.6 72 110 2.3 50 1.6 42 111 1.1 55 0.8 72 112 5.2 20 3.2 46 113 1.1 57 1.1 56 116 1.4 76 1.6 82 117 1.6 74 4.2 77 119 0.1 85 0.1 83 121 1.1 51 1.2 49 123 1.4 17 2.8 10 125 0.2 86 0.2 100 127 0.1 89 0.1 109 129 0.4 89 0.9 81 133 8.6 72 4.9 83 136 0.02 93 0.04 111 137 0.38 70 0.93 40 138 0.38 70 1.11 36 141 0.22 67 0.32 106 144 0.06 95 0.10 158 145 1.00 72 2.50 74 146 0.35 78 0.45 77 147 0.19 77 0.45 112 148 0.001 103 0.002 104 149 0.02 91 0.07 89 150 0.025 110 0.1 99 151 2.2 87 12.5 44 152 0.03 106 0.048 66 153 0.13 101 0.13 102 154 0.17 105 0.22 104 155 1.0 102 0.98 102 156 0.12 107 0.67 91 157 7.9 60 4.6 34 158 3.6 74 1.3 97 159 0.037 107 0.036 104 160 0.29 90 0.50 93 161 2.6 80 13 92 162 0.32 92 0.32 86 163 0.017 105 0.011 102 164 0.001 120 0.004 96 165 0.13 99 0.40 71 166 0.16 103 0.10 113 167 0.008 103 0.018 92 168 0.065 106 0.026 120 169 0.03 103 0.009 103 NC: not calculated