Alkylamino-substituted dicyanopyridines and their amino acid ester prodrugs
View Patent ↗The present application relates to novel 6-alkylamino-substituted dicyanopyridines, to their amino acid ester prodrugs, to processes for their preparation, to their use for the treatment and/or prophylaxis of diseases and to their use for preparing medicaments for the treatment and/or prophylaxis of diseases, preferably for the treatment and/or prevention of cardiovascular disorders.
1. A compound of the formula (I)
in which
R 1 represents hydrogen or (C 1 -C 4 )-alkyl; and
R 2 represents (C 1 -C 6 )-alkyl, (C 2 -C 4 )-alkenyl, (C 2 -C 4 )-alkynyl, or (C 3 -C 7 )-cycloalkyl, where (C 1 -C 6 )-alkyl may be substituted by 1 to 3 substituents selected independently of one another from the group consisting of fluorine, chlorine, trifluoromethyl, trifluoromethoxy, (C 1 -C 4 )-alkoxy, (C 3 -C 7 )-cycloalkyl, (C 3 -C 7 )-cycloalkoxy, (C 1 -C 4 )-alkylsulfanyl, and (C 1 -C 4 )-alkylsulfonyl, and where (C 2 -C 4 )-alkenyl and (C 2 -C 4 )-alkynyl may be substituted by 1 or 2 substituents selected independently of one another from the group consisting of fluorine, trifluoromethyl, (C 1 -C 4 )-alkyl, trifluoromethoxy, and (C 1 -C 4 )-alkoxy, and where (C 3 -C 7 )-cycloalkyl may be substituted by 1 or 2 substituents selected independently of one another from the group consisting of fluorine, chlorine, trifluoromethyl, (C 1 -C 4 )-alkyl, trifluoromethoxy, and (C 1 -C 4 )-alkoxy;
or
R 1 and R 2 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle which may contain a further heteroatom from the group consisting of N, O, and S, where the 4- to 7-membered heterocycle may be substituted by 1 or 2 substituents selected independently of one another from the group consisting of fluorine, chlorine, oxo, trifluoromethyl, (C 1 -C 4 )-alkyl, trifluoromethoxy, and (C 1 -C 4 )-alkoxy; and
R 3 represents hydrogen or a group of the formula
wherein
# represents the point of attachment to the oxygen atom;
L 1 represents (C 2 -C 6 )-alkanediyl;
L 2 represents (C 2 -C 6 )-alkanediyl;
R 4 represents hydrogen or the side group of a natural α-amino acid or its homologs or isomers;
R 5 represents hydrogen or methyl;
R 6 represents hydrogen or (C 1 -C 4 )-alkyl; and
R 7 represents hydrogen or (C 1 -C 4 )-alkyl; or
R 6 and R 7 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocycle, where the 5- or 6-membered heterocycle may be substituted by 1 or 2 substituents independently selected from the group consisting of (C 1 -C 4 )-alkyl, amino, hydroxyl, and (C 1 -C 4 )-alkoxy; or
R 7 and R 4 , and the atoms, to which they are attached, forms a pyrrolidine, or piperidine ring;
R 8 represents hydrogen or the side group of a natural α-amino acid or its homologs or isomers;
R 9 represents hydrogen or methyl;
R 10 represents hydrogen or methyl;
R 11 represents hydrogen or the side group of a natural α-amino acid or its homologs or isomers;
R 12 represents hydrogen or methyl;
R 13 represents hydrogen or (C 1 -C 4 )-alkyl; and
R 14 represents hydrogen or (C 1 -C 4 )-alkyl; or
R 13 and R 14 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocycle, where the 5- or 6-membered heterocycle may be substituted by 1 or 2 substituents independently selected from the group consisting of (C 1 -C 4 )-alkyl, amino, hydroxyl, and (C 1 -C 4 )-alkoxy; or
R 14 and R 11 and the atoms to which they are attached form a pyrrolidine or piperidine ring;
R 15 represents hydrogen or (C 1 -C 4 )-alkyl; and
R 16 represents hydrogen or (C 1 -C 4 )-alkyl; or
R 15 and R 16 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocycle, where the 5- or 6-membered heterocycle may be substituted by 1 or 2 substituents independently selected from the group consisting of (C 1 -C 4 )-alkyl, amino, hydroxyl, and (C 1 -C 4 )-alkoxy;
R 17 represents hydrogen, or (C 1 -C 4 )-alkyl; and
R 18 represents hydrogen, or (C 1 -C 4 )-alkyl; or
R 17 and R 18 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocycle, where the 5- or 6-membered heterocycle may be substituted by 1 or 2 substituents independently selected from the group consisting of (C 1 -C 4 )-alkyl, amino, hydroxyl, and (C 1 -C 4 )-alkoxy; and
R 19 represents hydrogen or methyl;
or a salt, an N-oxide, or a salt of an N-oxides thereof.
2. The compound of the formula (I) as claimed in claim 1 in which
R 1 represents hydrogen, methyl, or ethyl;
R 2 represents (C 1 -C 3 )-alkyl, cyclopropyl, or cyclobutyl, where (C 1 -C 3 )-alkyl may be substituted by 1 or 2 substituents selected independently of one another from the group consisting of fluorine, chlorine, trifluoromethyl, methoxy, ethoxy, cyclopropyl, and cyclobutyl; or
R 1 and R 2 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocycle which may contain a further heteroatom from the group consisting of N, O, and S,
where the 4- to 6-membered heterocycle may be substituted by 1 or 2 substituents selected independently of one another from the group consisting of fluorine, trifluoromethyl, methyl, ethyl, methoxy, and ethoxy; and
R 3 represents hydrogen, or a group of the formula
where
# represents the point of attachment to the oxygen atom;
L 1 represents ethane-1,2-diyl;
L 2 represents ethane-1,2-diyl;
R 4 represents methyl or 3-aminopropan-1-yl;
R 5 represents hydrogen;
R 6 represents hydrogen;
R 7 represents hydrogen;
R 8 represents methyl or 2-methylpropan-1-yl;
R 9 represents hydrogen;
R 10 represents hydrogen;
R 11 represents methyl, 1-methylpropan-1-yl, imidazol-4-ylmethyl, 4-aminobutan-1-yl, 3-amino-propan-1-yl, 2-aminoethyl, aminomethyl, or 3-guanidinopropan-1-yl;
R 12 represents hydrogen;
R 13 represents hydrogen;
R 14 represents hydrogen; or
R 14 and R 11 and the atoms to which they are attached form a pyrrolidine ring;
R 15 represents hydrogen;
R 16 represents hydrogen;
R 17 represents hydrogen;
R 18 represents hydrogen; and
R 19 represents hydrogen.
3. The compound of the formula (I) according to claim 1 , wherein
R 1 represents hydrogen, methyl, or ethyl;
R 2 represents methyl, ethyl, or n-propyl, where methyl, ethyl, and n-propyl may be substituted by 1 or 2 substituents selected independently of one another from the group consisting of fluorine, trifluoromethyl, and methoxy; or
R 1 and R 2 together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, or piperidinyl ring, where the azetidinyl, and piperidinyl ring may be substituted by a methoxy substituent; and
R 3 represents hydrogen.
4. The compound of the formula (I) according to claim 1 , wherein
R 1 and R 2 together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, or piperidinyl ring, where the azetidinyl, and piperidinyl ring may be substituted by a methoxy substituent; and
R 3 represents a group of the formula
where
# represents the point of attachment to the oxygen atom;
L 1 represents ethane-1,2-diyl;
R 8 represents methyl or isobutyl;
R 9 represents hydrogen;
R 10 represents hydrogen;
R 11 represents hydrogen, methyl, 1-methylpropan-1-yl, 4-aminobutan-1-yl, or
3-guanidinopropan-1-yl;
R 12 represents hydrogen;
R 13 represents hydrogen;
R 14 represents hydrogen; or
R 14 and R 11 and the atoms to which they are attached form a pyrrolidine ring;
R 15 represents hydrogen; and
R 16 represents hydrogen.
5. A pharmaceutical composition comprising a compound of formula (I) according to claim 1 and a pharmaceutically suitable excipient.
6. A process for preparing a compound of the formula (I)
in which
R 1 represents hydrogen or (C 1 -C 4 )-alkyl; and
R 2 represents (C 1 -C 6 )-alkyl, (C 2 -C 4 )-alkenyl, (C 2 -C 4 )-alkynyl, or (C 3 -C 7 )-cycloalkyl, where (C 1 -C 6 )-alkyl may be substituted by 1 to 3 substituents selected independently of one another from the group consisting of fluorine, chlorine, trifluoromethyl, trifluoromethoxy, (C 1 -C 4 )-alkoxy, (C 3 -C 7 )-cycloalkyl, (C 3 -C 7 )-cycloalkoxy, (C 1 -C 4 )-alkylsulfanyl, and (C 1 -C 4 )-alkylsulfonyl, and where (C 2 -C 4 )-alkenyl and (C 2 -C 4 )-alkynyl may be substituted by 1 or 2 substituents selected independently of one another from the group consisting of fluorine, trifluoromethyl, (C 1 -C 4 )-alkyl, trifluoromethoxy, and (C 1 -C 4 )-alkoxy, and where (C 3 -C 7 )-cycloalkyl may be substituted by 1 or 2 substituents selected independently of one another from the group consisting of fluorine, chlorine, trifluoromethyl, (C 1 -C 4 )-alkyl, trifluoromethoxy, and (C 1 -C 4 )-alkoxy;
or
R 1 and R 2 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle which may contain a further heteroatom from the group consisting of N, O, and S, where the 4- to 7-membered heterocycle may be substituted by 1 or 2 substituents selected independently of one another from the group consisting of fluorine, chlorine, oxo, trifluoromethyl, (C 1 -C 4 )-alkyl, trifluoromethoxy, and (C 1 -C 4 )-alkoxy; and
R 3 represents hydrogen or a group of the formula
wherein
# represents the point of attachment to the oxygen atom;
L 1 represents (C 2 -C 6 )-alkanediyl;
L 2 represents (C 2 -C 6 )-alkanediyl;
R 4 represents hydrogen or the side group of a natural α-amino acid or its homologs or isomers;
R 5 represents hydrogen or methyl;
R 6 represents hydrogen or (C 1 -C 4 )-alkyl; and
R 7 represents hydrogen or (C 1 -C 4 )-alkyl; or
R 6 and R 7 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocycle, where the 5- or 6-membered heterocycle may be substituted by 1 or 2 substituents independently selected from the group consisting of (C 1 -C 4 )-alkyl, amino, hydroxyl, and (C 1 -C 4 )-alkoxy; or
R 7 and R 4 , and the atoms, to which they are attached, forms a pyrrolidine, or piperidine ring;
R 8 represents hydrogen or the side group of a natural α-amino acid or its homologs or isomers;
R 9 represents hydrogen or methyl;
R 10 represents hydrogen or methyl;
R 11 represents hydrogen or the side group of a natural α-amino acid or its homologs or isomers;
R 12 represents hydrogen or methyl;
R 13 represents hydrogen or (C 1 -C 4 )-alkyl; and
R 14 represents hydrogen or (C 1 -C 4 )-alkyl; or
R 13 and R 14 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocycle, where the 5- or 6-membered heterocycle may be substituted by 1 or 2 substituents independently selected from the group consisting of (C 1 -C 4 )-alkyl, amino, hydroxyl, and (C 1 -C 4 )-alkoxy; or
R 14 and R 11 and the atoms to which they are attached form a pyrrolidine or piperidine ring;
R 15 represents hydrogen or (C 1 -C 4 )-alkyl; and
R 16 represents hydrogen or (C 1 -C 4 )-alkyl; or
R 15 and R 16 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocycle, where the 5- or 6-membered heterocycle may be substituted by 1 or 2 substituents independently selected from the group consisting of (C 1 -C 4 )-alkyl, amino, hydroxyl, and (C 1 -C 4 )-alkoxy;
R 17 represents hydrogen, or (C 1 -C 4 )-alkyl; and
R 18 represents hydrogen, or (C 1 -C 4 )-alkyl; or
R 17 and R 18 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocycle, where the 5- or 6-membered heterocycle may be substituted by 1 or 2 substituents independently selected from the group consisting of (C 1 -C 4 )-alkyl, amino, hydroxyl, and (C 1 -C 4 )-alkoxy; and
R 19 represents hydrogen or methyl;
or a salt, an N-oxide, or a salt of an N-oxides thereof,
the process comprising the step of converting a compound of the formula (II)
with copper(II) chloride and isoamyl nitrite in a suitable solvent into the compound of the formula (III)
reacting the compound of formula (III), in an inert solvent and optionally in the presence of a suitable base, with a compound of the formula (IV)
in which R 1 and R 2 each have the meanings given in this claim;
to provide a compound of the formula (I-A)
optionally removing any protective groups present, and
optionally converting the compound of formula (I-A) into a salt.
7. The process of claim 6 , further comprising the steps of:
coupling a compound of the formula (I-A), in an inert solvent in the presence of a condensing agent, with a carboxylic acid of the formula (V) or (VI)
in which L 2 , R 4 , and R 5 have the meanings given in claim 6 , and R 6A , R 7A , R 17A , and R 18A have the meanings given in claim 6 for R 6 , R 7 , R 17 , and R 18 , respectively, or represent an amino protective group to provide a compound of the formula (VII) or (VIII)
and
removing any protectve groups present to give a compound of the formula (I-B) or (I-C)
in which L2, R1, R2, R4, R5, R6, R7, R17 and R18 each have the meanings given in claim 6 .
8. The process of claim 6 , further comprising the steps of:
coupling a compound of the formula (I-A) in an inert solvent in the presence of a condensing agent with a carboxylic acid of the formula (IX), (X), (XI), or (XII)
in which L 1 , L 2 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 19 each have the meanings given in claim 6 , and R 13A , R 14A , R 15A , and R 16A each have the meanings given in claim 6 for R 13 , R 14 , R 15 , and R 16 , respectively, or represent an amino protective group; and
removing any protective groups present to give a compound of the formula (I-D), (I-E), (I-F), or (I-G)
in which L 1 , L 2 , R 1 , R 2 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , and R 19 have the meanings given in claim 6 .
9. The process of claim 6 , further comprising the steps of:
removing any amino protective group from a compound of the formula (VII) or (VIII) by standard methods to give a compound of the formula (I-B-1), or (I-C-1)
in which L 2 , R 1 , R 2 , R 4 , R 5 , R 7 , and R 17 have the meanings given in claim 6 ;
coupling (I-B-1) or (I-C-1) in an inert solvent in the presence of a condensing agent with a carboxylic acid of the formula (XVII) or (XVIII)
in which L 1 , R 11 , and R 12 have the meanings given in claim 6 , and R 13A , R 14A , R 15A , and R 16A have the meanings given in claim 6 for R 13 , R 14 , R 15 , and R 16 , respectively, or represent an amino protective group, to provide a compound of the formula (XIII), (XIV), (XV), or (XVI);
removing any protective groups present to give the resulting compounds (I-D), (I-E), (I-F), or (I-G);
and
optionally converting the resulting compounds of the formula (I-B), (I-C), (I-D), (I-E), (I-F), and (I-G) into a salt.
10. A method for the treatment of hypertension, coronary heart disease, acute coronary syndrome, angina pectoris, heart failure, myocardial infarction, atrial fibrillation, diabetes, metabolic syndrome, or dyslipidemias in a human or animal comprising the step of administering to a human or animal an effective amount of a compound of the formula (I)
in which
R 1 represents hydrogen or (C 1 -C 4 )-alkyl; and
R 2 represents (C 1 -C 6 )-alkyl, (C 2 -C 4 )-alkenyl, (C 2 -C 4 )-alkynyl, or (C 3 -C 7 )-cycloalkyl, where (C 1 -C 6 )-alkyl may be substituted by 1 to 3 substituents selected independently of one another from the group consisting of fluorine, chlorine, trifluoromethyl, trifluoromethoxy, (C 1 -C 4 )-alkoxy, (C 3 -C 7 )-cycloalkyl, (C 3 -C 7 )-cycloalkoxy, (C 1 -C 4 )-alkylsulfanyl, and (C 1 -C 4 )-alkylsulfonyl, and where (C 2 -C 4 )-alkenyl and (C 2 -C 4 )-alkynyl may be substituted by 1 or 2 substituents selected independently of one another from the group consisting of fluorine, trifluoromethyl, (C 1 -C 4 )-alkyl, trifluoromethoxy, and (C 1 -C 4 )-alkoxy, and where (C 3 -C 7 )-cycloalkyl may be substituted by 1 or 2 substituents selected independently of one another from the group consisting of fluorine, chlorine, trifluoromethyl, (C 1 -C 4 )-alkyl, trifluoromethoxy, and (C 1 -C 4 )-alkoxy;
or
R 1 and R 2 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle which may contain a further heteroatom from the group consisting of N, O, and S, where the 4- to 7-membered heterocycle may be substituted by 1 or 2 substituents selected independently of one another from the group consisting of fluorine, chlorine, oxo, trifluoromethyl, (C 1 -C 4 )-alkyl, trifluoromethoxy, and (C 1 -C 4 )-alkoxy; and
R 3 represents hydrogen or a group of the formula
wherein
# represents the point of attachment to the oxygen atom;
L 1 represents (C 2 -C 6 )-alkanediyl;
L 2 represents (C 2 -C 6 )-alkanediyl;
R 4 represents hydrogen or the side group of a natural α-amino acid or its homologs or isomers;
R 5 represents hydrogen or methyl;
R 6 represents hydrogen or (C 1 -C 4 )-alkyl; and
R 7 represents hydrogen or (C 1 -C 4 )-alkyl; or
R 6 and R 7 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocycle, where the 5- or 6-membered heterocycle may be substituted by 1 or 2 substituents independently selected from the group consisting of (C 1 -C 4 )-alkyl, amino, hydroxyl, and (C 1 -C 4 )-alkoxy; or
R 7 and R 4 , and the atoms, to which they are attached, forms a pyrrolidine, or piperidine ring;
R 8 represents hydrogen or the side group of a natural α-amino acid or its homologs or isomers;
R 9 represents hydrogen or methyl;
R 10 represents hydrogen or methyl;
R 11 represents hydrogen or the side group of a natural α-amino acid or its homologs or isomers;
R 12 represents hydrogen or methyl;
R 13 represents hydrogen or (C 1 -C 4 )-alkyl; and
R 14 represents hydrogen or (C 1 -C 4 )-alkyl; or
R 13 and R 14 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocycle, where the 5- or 6-membered heterocycle may be substituted by 1 or 2 substituents independently selected from the group consisting of (C 1 -C 4 )-alkyl, amino, hydroxyl, and (C 1 -C 4 )-alkoxy; or
R 14 and R 11 and the atoms to which they are attached form a pyrrolidine or piperidine ring;
R 15 represents hydrogen or (C 1 -C 4 )-alkyl; and
R 16 represents hydrogen or (C 1 -C 4 )-alkyl; or
R 15 and R 16 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocycle, where the 5- or 6-membered heterocycle may be substituted by 1 or 2 substituents independently selected from the group consisting of (C 1 -C 4 )-alkyl, amino, hydroxyl, and (C 1 -C 4 )-alkoxy;
R 17 represents hydrogen, or (C 1 -C 4 )-alkyl; and
R 18 represents hydrogen, or (C 1 -C 4 )-alkyl; or
R 17 and R 18 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocycle, where the 5- or 6-membered heterocycle may be substituted by 1 or 2 substituents independently selected from the group consisting of (C 1 -C 4 )-alkyl, amino, hydroxyl, and (C 1 -C 4 )-alkoxy; and
R 19 represents hydrogen or methyl;
or a salt, an N-oxide, or a salt of an N-oxides thereof.
11. The compound of claim 1 wherein the compound is 2-(azetidin-1-yl)-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-4-[4-(2-hydroxyethoxy)phenyl]pyridine-3,5-dicarbonitrile, as shown in the formula:
or a salt thereof.
12. The compound of claim 1 wherein the compound is 2-((3-methoxy)-azetidin-1-yl)-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-4-[4-(2-hydroxyethoxy)phenyl]pyridine-3,5-dicarbonitrile, as shown in the formula:
or a salt thereof.
13. The compound of claim 1 wherein the compound is 2-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-6-(4,4-difluoropiperidin-1-yl)-4-[4-(2-hydroxyethoxy)phenyl]pyridine-3,5-dicarbonitrile, as shown in the formula:
or a salt thereof.
14. The compound of claim 1 wherein the compound is 2-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-4-[4-(2-hydroxyethoxy)phenyl]-6-(piperidin-1-yl)pyridine-3,5-dicarbonitrile, as shown in the formula:
or a salt thereof.
15. The compound of claim 1 wherein the compound is 2-({[2-(4-chlorophenyl)- 1,3-thiazol-4-yl]methyl}sulfanyl)-4-[4-(2-hydroxyethoxy)phenyl]-6-(pyrrolidin-1-yl)pyridine-3,5-dicarbonitrile, as shown in the formula:
or a salt thereof.
16. The compound of claim 1 wherein the compound is 2-{4-[2-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-3,5-dicyano-6-(pyrrolidin-1-yl)pyridin-4-yl]phenoxy}ethyl L-alaninate trifluoroacetate, as shown in the formula:
17. The compound of claim 1 wherein the compound is 2-{4-[2-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-3,5-dicyano-6-(pyrrolidin-1-yl)pyridin-4-yl]phenoxy}ethyl L-alanyl-L-alaninate hydrochloride, as shown in the formula:
18. The compound of claim 1 wherein the compound is 2-{4-[2-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-3,5-dicyano-6-(pyrrolidin-1-yl)pyridin-4-yl]phenoxy}ethyl L-isoleucyl-L-alaninate hydrochloride, as shown in the formula:
19. The compound of claim 1 wherein the compound is 2-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-6-(diethylamino)-4-[4-(2-hydroxyethoxy)phenyl]pyridine-3,5-dicarbonitrile, as shown in the formula:
or a salt thereof.
20. The compound of claim 1 wherein the compound is 2-{4-[2-({[2-(4-chlorophenyl)- 1,3-thiazol-4-yl]methyl}sulfanyl)-3,5-dicyano-6-(pyrrolidin-1-yl)pyridin-4-yl]phenoxy}ethyl L-lysyl-beta-alaninate dihydrochloride, as shown in the formula:
21. The compound of claim 1 wherein the compound is 2-{4-[2-(azetidin-1-yl)-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-3,5-dicyanopyridin-4-yl]phenoxy}ethyl L-lysyl-L-alaninate bis(trifluoroacetate), as shown in the formula:
22. The compound of claim 1 wherein the compound is 2-{4-[2-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-3,5-dicyano-6-(pyrrolidin-1-yl)pyridin-4-yl]phenoxy}ethyl glycyl-L-leucinate hydrochloride, as shown in the formula:
23. The compound of claim 1 wherein the compound is 2-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-4-[4-(2-hydroxyethoxy)phenyl]-6-[(2-methoxyethyl)(methyl)amino]pyridine-3,5-dicarbonitrile, as shown in the formula:
or a salt thereof.
24. The compound of claim 1 wherein the compound is 2-({[2-(4-chlorophenyl)- 1,3-thiazol-4-yl]methyl}sulfanyl)-6-(4-methoxypiperidin-1-yl)-4-[4-(2-hydroxyethoxy)phenyl]pyridine-3,5-dicarbonitrile, as shown in the formula:
25. The compound of claim 1 wherein the compound is 2-{4-[2-(azetidin-1-yl)-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-3,5-dicyanopyridin-4-yl]phenoxy}ethyl L-alaninate trifluoroacetate, as shown in the formula:
26. The compound of claim 1 wherein the compound is 2-{4-[2-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-3,5-dicyano-6-(pyrrolidin-1-yl)-pyridin-4-yl]phenoxy}ethyl L-ornithyl-L-alaninate bis(trifluoroacetate), as shown in the formula:
27. The compound of claim 1 wherein the compound is 2-{4-[2-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-3,5-dicyano-6-(pyrrolidin-1-yl)-pyridin-4-yl]phenoxy}ethyl L-prolyl-L-alaninate hydrochloride, as shown in the formula:
28. The compound of claim 1 wherein the compound is 2-{4-[2-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-3,5-dicyano-6-(pyrrolidin-1-yl)-pyridin-4-yl]phenoxy}ethyl N-(tert-butoxycarbonyl)-L-alanyl-L-leucinate hydrochloride, as shown in the formula:
29. 2-{4-[2-({[2-(4-Chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-3,5-dicyano-6-(pyrrolidin-1-yl)pyridin-4-yl]phenoxy}ethyl L-alanyl-L -alaninate as shown in the formula
or a salt thereof.