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EP1907376A2 - Stereoisomeric pyridyl and pyridonyl compounds and methods for the treatment of gastrointestinal and central nervous system disorders - Google Patents

Stereoisomeric pyridyl and pyridonyl compounds and methods for the treatment of gastrointestinal and central nervous system disorders

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Publication number
EP1907376A2
EP1907376A2 EP06774511A EP06774511A EP1907376A2 EP 1907376 A2 EP1907376 A2 EP 1907376A2 EP 06774511 A EP06774511 A EP 06774511A EP 06774511 A EP06774511 A EP 06774511A EP 1907376 A2 EP1907376 A2 EP 1907376A2
Authority
EP
European Patent Office
Prior art keywords
amino
chloro
methoxypiperidin
oxo
dihydropyridine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP06774511A
Other languages
German (de)
French (fr)
Inventor
Pascal Druzgala
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
ARYx Therapeutics Inc
Original Assignee
ARYx Therapeutics Inc
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Filing date
Publication date
Application filed by ARYx Therapeutics Inc filed Critical ARYx Therapeutics Inc
Publication of EP1907376A2 publication Critical patent/EP1907376A2/en
Pending legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/10—Laxatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C07D451/06—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems

Definitions

  • Cisapride is one of a class of compounds known as benzamide derivatives, the parent compound of which is metoclopramide.
  • U.S. Patent Nos. 4,962,115 and 5,057,525 disclose N-(3- hydroxy-4-piperidenyl) benzamides of cisapride. Van Daele discloses that these compounds, the pharmaceutically acceptable acid addition salts thereof and the stereochemically isomeric forms thereof, stimulate the motility of the gastrointestinal system.
  • these benzamide derivatives have several prominent pharmacological actions.
  • the prominent pharmacological activities of the benzamide derivatives are due to their effects on the neuronal systems which are modulated by the neurotransmitter serotonin.
  • the role of serotonin, and thus the pharmacology of the benzamide derivatives, has been broadly implicated in a variety of conditions for many years. Thus, research has focused on locating the production and storage sites of serotonin as well as the location of serotonin receptors in the human body in order to determine the connection between these sites and various disease states or conditions.
  • serotonin a major site of production and storage of serotonin is the enterochromaffin cell of the gastrointestinal mucosa. It was also discovered that serotonin has a powerful stimulating action on intestinal motility by stimulating intestinal smooth muscle, speeding intestinal transit, and decreasing absorption time, as in diarrhea. This stimulating action is also associated with nausea and vomiting.
  • benzamide derivatives are effective anti-emetic agents and are commonly used to control vomiting during cancer chemotherapy or radiotherapy, especially when highly emetogenic compounds such as cisplatin are used.
  • This action is almost certainly the result of the ability of the compounds to block the actions of serotonin (5HT) at specific sites of action, called the 5HT3-receptor, which was classically designated in the scientific literature as the serotonin M-receptor.
  • Chemotherapy and radiation therapy may induce nausea and vomiting by the release of serotonin from damaged enterochromaffin cells in the gastrointestinal tract.
  • a second prominent action of the benzamide derivatives is in augmenting gastrointestinal smooth muscle activity from the esophagus through the proximal small bowel, thus accelerating esophageal and small intestinal transit as well as facilitating gastric emptying and increasing lower esophageal sphincter tone (Decktor et al., Eur. J. Pharmacol. 147: 313-316, 1988).
  • the benzamide derivatives are not cholinergic receptor agonists per se, the aforementioned smooth muscle effects may be blocked by muscarinic receptor blocking agents such as atropine or neuronal transmission inhibitors of the tetrodotoxin type which affect sodium channels.
  • 5HT receptors including the 5HT 4 receptor can be found in, for example, U.S. Patent Nos. 6, 331,401 and 6,632,827, which are incorporated by reference herein in their entirety.
  • Cisapride has been used primarily to treat gastroesophageal reflux disease (GERD). This disease is characterized as the backward flow of the stomach contents into the esophagus.
  • GUD gastroesophageal reflux disease
  • One of the most important factors in the pathogenesis of gastroesophageal reflux disease is a reduction in the pressure barrier due to the failure of the lower esophageal sphincter. Failure of the lower esophageal sphincter can arise due to a low basal pressure, sphincter relaxation, or to a non-compensated increase in intragastric pressure.
  • Cisapride is thought to strengthen the anti-reflux barrier and improve esophageal clearance by increasing the lower esophageal sphincter pressure and enhancing peristaltic contractions.
  • Dyspepsia is a condition characterized by an impairment of the power or function of digestion that can arise as a symptom of a primary gastrointestinal dysfunction or as a complication due to other disorders such as appendicitis, gallbladder disturbances, or malnutrition.
  • Gastroparesis is a paralysis of the stomach brought about by a motor abnormality in the stomach or as a complication of diseases such as diabetes, progressive systemic sclerosis, anorexia nervosa or myotonic dystrophy.
  • Constipation is a condition characterized by infrequent or difficult evacuation of feces resulting from conditions such as lack of intestinal muscle tone or intestinal spasticity.
  • Post-operative ileus is an obstruction in the intestine due to a disruption in muscle tone following surgery.
  • Intestinal pseudoobstruction is a condition characterized by constipation, colicky pain, and vomiting, but without evidence of physical obstruction.
  • Drug toxicity is an important consideration in the treatment of humans and animals. Toxic side effects (adverse effects) resulting from the administration of drugs include a variety of conditions which range from low grade fever to death. Drug therapy is justified only when the benefits of the treatment protocol outweigh the potential risks associated with the treatment. The factors balanced by the practitioner include the qualitative and quantitative impact of the drug to be used as well as the resulting outcome if the drug is not provided to the individual. Other factors considered include the physical condition of the patient, the disease stage and its history of progression, and any known adverse effects associated with a drug.
  • Drug elimination is typically the result of metabolic activity upon the drug and the subsequent excretion of the drug from the body. Metabolic activity can take place within the vascular supply and/or within cellular compartments or organs. The liver is a principal site of drug metabolism.
  • the metabolic process can be categorized into synthetic and nonsynthetic reactions. In nonsynthetic reactions, the drug is chemically altered by oxidation, reduction, hydrolysis, or any combination of the aforementioned processes. These processes are collectively referred to as Phase I reactions.
  • Phase II reactions also known as synthetic reactions or conjugations
  • the parent drug, or intermediate metabolites thereof are combined with endogenous substrates to yield an addition or conjugation product.
  • Metabolites formed in synthetic reactions are, typically, more polar and biologically inactive. As a result, these metabolites are more easily excreted via the kidneys (in urine) or the liver (in bile).
  • Synthetic reactions include glucuronidation, amino acid conjugation, acetylation, sulfoco ⁇ jugation, and methylation.
  • More than 90% of a dose of cisapride is metabolized by oxidative N-dealkylation at the piperidine nitrogen or by aromatic hydroxylation occurring on either the 4-fluorophenoxy or benzamide rings.
  • cisapride The administration of cisapride to a human has been found to cause serious adverse effects including CNS disorders, increased systolic pressure, interactions with other drugs, diarrhea, and abdominal cramping. Further, it has been reported that intravenous administration of cisapride demonstrates the occurrence of additional adverse effects not experienced after oral administration of cisapride (Stacher et al. [1987] Digestive Diseases and Sciences 32(11): 1223-1230). It is believed that these adverse effects are caused by the metabolites that result from the oxidative dealkylation or aromatic hydroxylation of the compound which occurs in the cytochrome P450 detoxification system. Cisapride is also subject to a number of undesirable drug/drug interactions that are also a result of metabolism by the cytochrome P450 system.
  • cisapride PROPULSID, Janssen Pharmaceutica Products, L.P.
  • cisapride was reportedly associated with at least 341 serious cardiac arrhythmias. These arrhythmias include ventricular tachycardia, ventricular fibrillation, torsades de pointes, and QT prolongation. Eighty (80) deaths have been reported. As a result of these adverse effects, the product was voluntarily withdrawn from the open market in the United States; however, the drug is available through an investigational limited access program.
  • GI prokinetic activity has been limited due to cardiac effects (prolongation of QTc intervals, tachycardia, torsades de pointes) and adverse drug interactions due to hepatic cytochrome P-450 metabolism.
  • a GI prokinetic agent of this class that lacks these liabilities would be very valuable in several therapeutic areas including GERD and gastric emptying disorders.
  • Certain cisapride derivatives have been described in U.S. Pat. No. 6,552,046 and WO 01/093849 (incorporated by reference herein in their entireties), however further compounds with even more advantageous properties would be desirable.
  • the subject invention provides compounds and compositions of formulae Xa and Xb, which are stereoisomeric, functional and/or structural analogs of cisapride, for the safe and effective treatment of various gastrointestinal disorders including, but not limited to, gastroparesis, gastroesophageal reflux and related conditions.
  • the compounds of the subject invention are also useful in treating a variety of conditions involving the central nervous system.
  • the compounds of the invention comprise compounds of formulae Xa and/or Xb:
  • L is -(C 1 -C 6 alkyl)- (in one aspect, -(C 3 -C 5 alkyl)-), -(Ci-C 6 alkyl)-C(O)-, or -C(O)- (C 1 -C 6 alkyl)-, wherein each of the alkyl groups is optionally substituted with 1 or 2 groups that are independently halogen, Ci-C 4 alkoxy, or OH and wherein one carbon in the alkyl portion of L may be replaced by -N(Rg)-; or
  • L is -(Ci-C 4 alkyl)-NR 9 -(Ci-C 4 alkyl)-, -(Ci-C 4 alkyl)-C(O)NR 9 -, -(Ci-C 4 alkyl)-, -(C 1 -C 4 alkyl)-NR 9 C(O)- or -C(O)NR 9 -(C 1 -C 4 alkyl)-;
  • R 1 is halogen
  • R 2 is amino, NH(Ci-C 4 alkyl) or N(C 1 -C 4 alkyl)(Ci-C 4 alkyl);
  • R 3 is H, Ci-C 4 alkyl, Ci-C 4 alkoxy, or OH;
  • R 4 is H or Ci-C 4 alkyl, and in one preferred aspect, methyl
  • Rs is -O-Ci-C ⁇ -alkyl, -0-C 3 -C 8 cycloalkyl, -O-heterocycloalkyl, heterocycloalkyl, aryl, -O-aryl, -N(R 9 )-(C 0 -C 6 alkyl)-C(O)-aryl, or -N(R 9 )-C 0 -C 6 alkyl-aryl, -O-heteroaryl, - N(R 9 )-Ci-C 6 (O)-heteroaryl, or -N(R 9 )-Co-C 6 alkyl-heteroaryl, wherein each of the cyclic groups is unsubstituted or substituted at one or more substitutable positions with Ci-C 6 alkyl, Ci-C 6 alkoxy, halogen, Q -C 6 haloalkyl, Ci-C 6 haloalkoxy, hydroxyl, hydroxy-Ci
  • R 9 at each occurrence is independently H or Ci-C 4 alkyl
  • R 10 at each occurrence is independently H, Ci-C 4 alkyl optionally substituted with one group that is selected from a 5 or 6 membered monocyclic heterocycloalkyl ring, and OH, quinuclidinyl, -C(O)NH 2 , -C(O)NH(Ci-C 4 alkyl), -C(O)N(Ci-C 4 alkyl)(Ci-C 4 alkyl) or piperidinyl optionally substituted with Ci-C 4 alkyl;
  • Rn is Ci-C 6 alkyl, or OH
  • Rn is NH 2 , -NH(Ci-C 6 alkyl), or -N(C 1 -C 6 alkyl)(Ci-C 6 alkyl); or
  • Rn is Ci-C 6 alkoxy, optionally substituted with 1 or 2 groups that are independently Ci-C 4 alkoxy, amino, -NH(Ci-C 6 alkyl), -N(Ci-C 6 alkyl)(Ci-C 6 alkyl), heterocycloalkyl, OH, -(C 0 -C 6 alkyl)-C(O)N(R 9 )-heterocycloalkyl, -O-heterocycloalkyl, -Ci-C 6 (O)N(R 9 )-heteroaryl, or heteroaryl, wherein the heterocycloalkyl groups are optionally substituted with 1, 2, or 3 groups that are independently halogen, C 1 -C 6 alkyl, C]-C 6 alkoxy, hydroxy, hydroxy Cj-C 6 alkyl, Ci-C 6 alkoxycarbonyl, -CO 2 H, CF 3 , or OCF 3 , the heteroaryl group is optionally substituted
  • Rn is heterocycloalkyl or -O-heterocycloalkyl wherein the heterocycloalkyl is optionally substituted with 1, 2, or 3 groups that are independently halogen, Ci-C 6 alkyl, C 1 - C 6 alkoxy, hydroxy, hydroxy Ci-C 6 alkyl, Ci-C 6 alkoxycarbonyl, -CO 2 H, CF 3 , or OCF 3 ; and
  • R 2 o is -H, Ci-C 6 alkoxy (preferably Ci-C 4 alkoxy, more preferably methoxy), or OH.
  • compositions comprising at least one compound of formulae Xa and Xb and at least one pharmaceutically acceptable excipient, adjuvant, carrier, or solvent.
  • the compounds of formulae Xa and Xb are useful in the treatment or prevention of gastroesophageal reflux disease and substantially reduce adverse effects associated with the administration of cisapride. These adverse effects include, but are not limited to, diarrhea, abdominal cramping and elevations of blood pressure and heart rate.
  • the compounds and compositions of the invention are useful in treating emesis and other conditions, including but not limited to dyspepsia, gastroparesis, constipation, post-operative ileus and intestinal pseudo-obstruction.
  • adverse effects associated with the administration of cisapride are also reduced in these methods of treatment.
  • the compounds of the subject invention are ligands for the 5HT 4 receptor and, accordingly, can be used to treat conditions mediated through this receptor.
  • These receptors are located in several areas of the central nervous system and the modulation of these receptors can be used to effect desired modulations of the CNS.
  • the subject invention provides stereoisomeric compounds which contain an ester moiety that does not detract from the ability of these compounds to provide a therapeutic benefit, but which makes them more susceptible to degradation by serum and/or cytosolic esterases, thereby avoiding the cytochrome P450 drug detoxification system associated with adverse effects caused by cisapride and reducing the incidence of such adverse events.
  • the subject invention further provides methods of treatment comprising the administration of the compounds of formulae Xa and Xb and therapeutically effective amounts to individuals in need of treatment for gastroesophageal reflux disease, dyspepsia, gastroparesis, constipation, post-operative ileus, and intestinal pseudo-obstruction; and related conditions.
  • the therapeutic compounds of the subject invention are stable in storage and provide for safer metabolism of the drugs as compared to other drugs; therefore, the compounds of the subject invention can be used with a lower incidence of side effects and toxicity.
  • the subject invention pertains to the breakdown products (preferably metabolic breakdown products) which are formed when the therapeutic compounds of the subject invention are acted upon by esterases. These breakdown products can be used as described herein to monitor the clearance of the therapeutic compounds from a patient.
  • breakdown products preferably metabolic breakdown products
  • the subject invention provides methods for synthesizing the therapeutic stereoisomeric compounds of the subject invention, as well as intermediates useful in preparing the compounds of interest.
  • the invention provides compounds of Formulae Xa and Xb, wherein
  • R 5 is -O-Ci-Q-alkyl, -0-C 3 -Cs cycloalkyl, -O-heterocycloalkyl, heterocycloalkyl, wherein the heterocycloalkyl group is selected from piperidinyl, piperazinyl, pyrrolidinyl, aza-bicyclo-octyl, in certain embodiments aza-bicyclo[2.2.2]octyl, aza-bicyclo[3.2.1]octyl, aza-bicyclo-nonyl, aza-bicyclo-decyl, indolinyl, morpholinyl, thiomorpholinyl, S 5 S- dioxothiomorpholinyl, and imidazolidinyl, -O-aryl, -N(R 9 )-C(O)-aryl, or -N(Rg)-Co-C 6 alkyl- aryl, wherein each of the cycl
  • R 9 at each occurrence is independently H or Cj-C 4 alkyl
  • Rn is Ci-C 6 alkyl, OH, or
  • Rn is Ci-C 6 alkoxy, optionally substituted with 1 or 2 groups that are independently C 1 -C 4 alkoxy, amino, -NH(Ci-C 6 alkyl), -N(C 1 -C 6 alkyl)(Ci-C 6 alkyl), -C(O)N(R 9 )- heterocycloalkyl, heterocycloalkyl or heteroaryl, wherein the heterocycloalkyl group is selected from pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, aza-bicyclo-octyl, in certain embodiments aza- bicyclo[2.2.2]octyl, aza-bicyclo[3.2.1]octyl, aza-bicyclo-nonyl and aza-bicyclo-decyl, wherein the heterocycloalkyl groups are optionally substituted with 1, 2, or 3 groups that are independently halogen, C 1 -C 6 alkyl, C
  • Ci-C 6 alkyl 2, or 3 groups that are independently halogen, Ci-C 6 alkyl, Ci-C 6 alkoxy, hydroxy, hydroxy
  • Ci-C 6 alkyl Ci-C 6 alkoxycarbonyl, -CO 2 H, CF 3 , or OCF 3 .
  • the invention provides compounds of Formulae Xa and Xb, wherein
  • R 1 is chloro
  • the invention provides compounds of Formulae Xa and Xb, wherein R 2 is amino.
  • the invention provides compounds of Formulae Xa and Xb, wherein R 3 is methyl.
  • the invention provides compounds of Formulae Xa and Xb, wherein
  • R 4 is H or methyl.
  • the invention provides compounds of Formulae Xa and Xb, wherein Ri is chloro; R 2 is amino; R 3 is methyl; and R 4 is H or methyl.
  • the invention provides compounds of Formulae Xa and Xb, wherein Ri is chloro; R 2 is amino; R 3 is methyl; R 4 is H, and L is -(C 4 -C 6 alkyl)-C(O)-.
  • the invention provides compounds of Formulae Xa and Xb, wherein two or more previously described aspects are combined.
  • the invention provides compounds of Formulae XIa and XIb, which are compounds of Formulae Xa and Xb wherein R 20 is OCH 3 and L is -(CH 2 ) 5 -C(O)-:
  • the invention provides compounds of Formulae XIa and XIb, wherein R 1 is chloro; R 2 is amino; R 3 is methyl; and R 4 is H or methyl.
  • the invention provides compounds of Formulae XIa and XIb, wherein R 5 is-O-heterocycloalkyl, wherein the heterocycloalkyl group is selected from aza- bicyclo-octyl, in certain embodiments l-aza-bicyclo[2.2.2]oct-3-yl or 8-aza- bicyclo[3.2.1]oct-3-yl, aza-bicyclo-nonyl, aza-bicyclo-decyl, where the aza nitrogen, is optionally substituted with methyl or ethyl; and R 4 is H or methyl.
  • the invention provides compounds of Formulae XIa and XIb, wherein R 5 is -O-heterocycloalkyl, wherein the heterocycloalkyl group is selected from piperidinyl, piperazinyl, or pyrrolidinyl, each of which is unsubstituted or substituted at one or two positions with groups that are independently C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, C 1 - C 4 haloalkyl (in one aspect, CF 3 ), C 1 -C 4 haloalkoxy (in one aspect OCF 3 ), hydroxy 1, hydroxy C 1 -C 4 alkyl, amino, -NH(C 1 -C 4 alkyl), -N(Ci-C 4 alkyl)(d-C 4 alkyl), -(Ci-C 6 alkyl)-C(O)Rn, or NO 2 ; and R 4 is H or methyl.
  • the invention provides compounds of Formulae XIa and XIb, wherein R 5 is -O-heterocycloalkyl, wherein the heterocycloalkyl group is selected from indolinyl, morpholinyl, thiomorpholinyl, S,S-dioxothiomorpholinyl, and imidazolidinyl, each of which is unsubstituted or substituted at one or two positions with groups that are independently Ci-C 4 alkyl, Cj-C 4 alkoxy, halogen, C 1 -C 4 haloalkyl (in one aspect, CF 3 ), Q- C 4 haloalkoxy (in one aspect OCF 3 ), hydroxyl, hydroxy C 1 -C 4 alkyl, amino, -NH(Ci-C 4 alkyl), -N(C 1 -C 4 alkyl)(C 1 -C 4 alkyl), -(C 0 -C 6 ⁇ yI)-
  • the invention provides compounds of Formulae XIa and XIb, wherein R 5 is -O-phenyl, N(Rg)-(C 0 -C 6 alkyl)-C(O)-phenyl, or -N(R 9 )-C 0 -C 4 alkyl-phenyl, wherein the phenyl group is substituted with one or two groups that are independently C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, C 1 -C 4 haloalkyl (in one aspect, CF 3 ), Ci-C 4 haloalkoxy (in one aspect OCF 3 ), hydroxyl, hydroxy Ci-C 4 alkyl, amino, -NH(Ci-C 4 alkyl), -N(C 1 -C 4 alkyl)(Ci- C 4 alkyl), -(Co-C 6 alkyl)-C(O)R ⁇ , or NO 2 ; and R 4 and R9
  • the invention provides compounds of Formulae XIa and XIb, wherein R 4 is H.
  • the invention provides compounds of Formulae XIa and XIb, wherein Rn is Ci-C 6 alkoxy, optionally substituted with 1 or 2 groups that are independently Ci-C 4 alkoxy, amino, -NH(Ci-C 6 alkyl), -N(C 1 -C 6 alkyl)(d-C 6 alkyl), -(C 0 -C 6 alkyl)- C(O)N(R9)-heterocycloalkyl, or heterocycloalkyl wherein the heterocycloalkyl group is selected from pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl, wherein the heterocycloalkyl groups are optionally substituted with 1, 2, or 3 groups that are independently halogen, C 1 -C 6 alkyl, Ci-C 6 alkoxy, hydroxy, hydroxy CpC 6 alkyl, Ci-C 6 alkoxycarbonyl, -CO 2 H, CF 3 , or
  • the invention provides compounds of Formulae XIa and XIb, wherein two or more previously described aspects are combined.
  • the invention provides compounds of Formulae XIIa and XIIb, i.e., compounds of Formulae Xa and Xb, of the formulae:
  • R 1 5 is H, Ci-C 6 alkyl, Ci-C 6 alkoxy, halogen, Ci-C 6 haloalkyl (in one aspect CF 3 ), Ci-C 6 haloalkoxy ( in one aspect OCF 3 ), hydroxyl, hydroxy Ci-C 4 alkyl, amino, -NH(Ci-C 6 alkyl), -N(Ci-C 6 alkylXQ-Ce alkyl), methylsulfone, C 0 -C 6 -sulfonamide OrNO 2 , and R 16 is H or -0-(C 0 -C 6 alkyl)-C(O)R n .
  • Ri 5 is H.
  • the invention provides compounds of Formulae XIIa and XIIb, wherein R 4 and R 9 are independently H or methyl and Rn is OH.
  • the invention provides compounds of Formulae XIIa and XIIb, wherein R 4 and Rg are independently H or methyl and R 11 is Ci-C 6 alkoxy, optionally substituted with 1 or 2 groups that are independently Ci-C 4 alkoxy, amino, -NH(CI-C O alkyl), -N(Ci-C 6 alkyl)(Ci-C 6 alkyl), -(C 0 -C 6 alkyl)-C(O)N(R 9 )-heterocycloalkyl, or heterocycloalkyl wherein the heterocycloalkyl group is selected from aza-bicyclo-octyl, in certain embodiments l-aza-bicyclo[2.2.2]oct-3-yl or 8-aza-bicyclo[3.2.1]oct-3-yl, aza- bicyclo-nonyl, aza-bicyclo-decyl, where the aza nitrogen is optionally substituted with methyl
  • the invention provides compounds of Formulae XIIa and XIIb, wherein R 4 and R 9 are independently H or methyl and Rn is Ci-C 6 alkoxy, optionally substituted with 1 or 2 groups that are independently Ci-C 4 alkoxy, amino, -NH(Ci-C 6 alkyl), -N(Ci-C 6 alkyl)(Ci-C 6 alkyl), or heteroaryl, wherein the heteroaryl group is selected from pyridyl, pyrimidyl, quinolinyl, isoquinolinyl, and indolyl, wherein the heteroaryl groups are optionally substituted with 1, 2, or 3 groups that are independently halogen, Ci-C 6 alkyl, Ci- C 6 alkoxy, hydroxy, hydroxy Cj-C 6 alkyl, Ci-C 6 alkoxycarbonyl, -CO 2 H, CF 3 , or OCF 3; and R 4 and R 9 are independently H or methyl.
  • R 4 and R 9
  • the invention provides compounds of Formulae XIIa and XIIb, wherein at least one OfR 4 and R 9 is H.
  • the invention provides compounds of Formulae XIIa and XIIb, wherein two or more previously described aspects are combined.
  • the invention provides compounds of Formulae XIIIa and XIIIb, i.e., compounds of Formula XIIa and XIIb, of the formulae:
  • R 15 is H, Ci-C 6 alkyl, Ci-C 6 alkoxy, halogen, Ci-C 6 haloalkyl (in one aspect CF 3 ), Ci-Ce haloalkoxy ( in one aspect OCF 3 ), hydroxyl, hydroxy Ci-C 4 alkyl, amino, -NH(Ci-C 6 alkyl), -N(Ci-C 6 alkyl)(Ci-C 6 alkyl), or methylsulfone, Co-C 6 -sulfonamide, NO 2 , and Ri 6 is H Or-O-(C 0 -C 6 alkyl)-C(O)R u .
  • R i5 is H.
  • the invention provides compounds of Formulae XIIIa and XIIIb, wherein, R 4 and R 9 are independently H or methyl, and Rn is OH, Cj-C 4 alkoxy (in another aspect, Ci-C 3 alkoxy), or Ci-C 2 alkoxy-Ci-C 3 alkoxy-.
  • R 4 , R 9 , and R 1 ] are as previously defined and Ri is chloro; R 2 is amino; and R 3 is methyl.
  • the invention provides compounds of Formulae XIIIa and XIIIb, wherein R 4 and R 9 are independently H or methyl, and Rn is Ci-C 4 alkoxy substituted with amino, -NH(Ci-C 6 alkyl), -N(Ci-C 6 alkyl)(Ci-C 6 alkyl), aza-bicyclo-octyl, in certain embodiments l-aza-bicyclo[2.2.2]oct-3-yl or 8-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo-nonyl, aza-bicyclo-decyl, where the aza nitrogen is optionally substituted with methyl or ethyl; and R 4 is H or methyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridyl, or -(C 0 -C 6 alkyl)-C(O)NH- pyrid-4-yl
  • the invention provides compounds of Formulae XIIIa and XIIIb, wherein R 4 and R9 are independently H or methyl, and Rn is Ci-C 4 alkoxy substituted with amino, -NH(Ci-C 6 alkyl), or -N(C 1 -C 6 alkyl)(Ci-C 6 alkyl).
  • R 4 , R 9 , and Rn are as previously defined and Ri is chloro; R 2 is amino; and R3 is methyl.
  • the invention provides compounds of Formulae XIIIa and XIIIb, wherein R 4 and R 9 are independently H or methyl, and R 11 is Ci-C 4 alkoxy substituted with pyrrolidinyl, piperidinyl, morpholinyl, pyridyl, or -(Co-C 6 alkyl)-C(O)NH-pyrid-4-yl.
  • R 4 , R 9 , and Rn are as previously defined and R 1 is chloro; R 2 is amino; and R3 is methyl.
  • the invention provides compounds of Formulae XIIIa and XIIIb, wherein at least one OfR 4 and R 9 is H.
  • the invention provides compounds of Formulae XIIIa and XIIIb, wherein two or more previously described aspects are combined.
  • the invention provides compounds of Fo ⁇ nulae XIVa and XIVb, i.e., compounds of Formulae Xa and Xb, of the formulae:
  • Ri 5 is H, Ci-C 6 alkyl, Ci-C 6 alkoxy, halogen, Ci-C 6 haloalkyl (in one aspect CF 3 ), Ci-C 6 haloalkoxy ( in one aspect OCF 3 ), hydroxyl, hydroxy Ci-C 4 alkyl, amino, -NH(Ci-C 6 alkyl), -N(Ci-C 6 alkyl)(Ci-C 6 alkyl), methylsulfone, C 0 -C 6 -sulfonamide, or NO 2 , and Ri 6 is H or -0-(Co-C 6 alkyl)-C(O)Rii. In another aspect, Ri 5 is H.
  • the invention provides compounds of Formulae XIVa and XIVb, wherein R 4 and Rg are independently H or methyl, and Rn is OH, C 1 -C 4 alkoxy (in another aspect, C 1 -C 3 alkoxy) or C 1 -C 2 alkoxy-C]-C 3 alkoxy-.
  • R 4 , R 9 , and Rn are as previously defined and R 1 is chloro; R 2 is amino; and R 3 is methyl.
  • at least one OfR 4 and Rg is H.
  • the invention provides compounds of Formulae XIVa and XIVb, wherein R 4 and R 9 are independently H or methyl, and R 11 is C 1 -C 4 alkoxy substituted with amino, -NH(Ci-C 6 alkyl), -N(Ci-C 6 alkyl)(Ci-C6 alkyl), aza-bicyclo-octyl, in certain embodiments l-aza-bicyclo[2.2.2]oct-3-yl or 8-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo-nonyl, aza-bicyclo-decyl, where the aza nitrogen is optionally substituted with methyl or ethyl; and R 4 is H or methyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridyl, or -(C 0 -C 6 alkyl)-C(O)NH- pyrid-4-
  • the invention provides compounds of Formulae XIVa and XIVb, wherein R 4 and R 9 are independently H or methyl, and Rn is C 1 -C 4 alkoxy substituted with amino, -NH(Ci-C 6 alkyl), or -N(Ci-C 6 alkyl)(Ci-C 6 alkyl).
  • R 4 , R 9 , and Rn are as previously defined and R 1 is chloro; R 2 is amino; and R 3 is methyl.
  • the invention provides compounds of Formulae XIVa and XIVb, wherein R 4 and R 9 are independently H or methyl, and Rn is Ci-C 4 alkoxy substituted with pyrrolidinyl, piperidinyl, morpholinyl, pyridyl, or -(Co-C 6 alkyl)-C(O)NH-pyrid-4-yl.
  • R 4 , R 9 , and Rn are as previously defined and Ri is chloro; R 2 is amino; and R 3 is methyl.
  • the invention provides compounds of Formulae XIVa and XIVb, wherein at least one OfR 4 and Rg is H.
  • the invention provides compounds of Formulae XIVa and XIVb, wherein two or more previously described aspects are combined.
  • the invention provides compounds of Formulae XVa and XVb, i.e., compounds of Formulae Xa and Xb of the formulae:
  • n 1 or 2.
  • the invention provides compounds of Formulae XVa and XVb, wherein R 4 is H or methyl, and R 11 is OH, Ci-C 4 alkoxy (in another aspect, C 1 -C 3 alkoxy) or Ci-C 2 alkoxy-Ci-C3 alkoxy-.
  • R 4 and Rn are as previously defined and R 1 is chloro; R 2 is amino; and R 3 is methyl.
  • at least one OfR 4 and R 9 is H.
  • the invention provides compounds of Formulae XVa and XVb, wherein R 4 and R 9 are independently H or methyl, and Rn is C 1 -C 4 alkoxy substituted with amino, -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkylXQ-Ce alkyl), aza-bicyclo-octyl, in certain embodiments l-aza-bicyclo[2.2.2]oct-3-yl or 8-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo-nonyl, aza-bicyclo-decyl, where the aza nitrogen is optionally substituted with methyl or ethyl; and R 4 is H or methyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridyl, or -C(0)NH-pyrid-4-yl.
  • the invention provides compounds of Formulae XVa and XVb, wherein R 4 and R9 are independently H or methyl, and R 11 is C 1 -C 4 alkoxy substituted with amino, -NH(Ci-C 6 alkyl), or -N(C 1 -C 6 alkyl)(Ci-C 6 alkyl).
  • R 4 , R 9 , and Rn are as previously defined and R 1 is chloro; R 2 is amino; and R 3 is methyl.
  • the invention provides compounds of Formulae XVa and XVb, wherein R 4 is H or methyl, and R n is Ci-C 4 alkoxy substituted with aza-bicyclo-octyl, in certain embodiments l-aza-bicyclo[2.2.2]oct-3-yl or 8-aza-bicyclo[3.2.1]oct-3-yl, aza- bicyclo-nonyl, aza-bicyclo-decyl, where the aza nitrogen is optionally substituted with methyl or ethyl; and R 4 is H or methyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridyl, or -(C 0 -C 6 alkyl)-C(O)NH-pyrid-4-yl.
  • R 4 , R 9 , and Rn are as previously defined and Ri is chloro; R 2 is amino; and R 3 is methyl.
  • the invention provides compounds of Formulae XVa and XVb, wherein two or more previously described aspects are combined.
  • the invention provides compounds according to any one of Formulae Xa, Xb, XIa, XIb, XIIa, XIIb, XIIIa, XIIIb, XIVa, XIVb, XVa or XVb, wherein Ri , and R 2 are oriented on the pyridyl and pyridonyl ring as follows:
  • the invention provides compounds according to any one of Formulae Xa, Xb, XIa, XIb, XIIa, XIIb, XIIIa, XIIIb, XIVa, XIVb 5 XVa or XVb, wherein bond 3 of the core piperidine ring has the "S" configuration and bond 4 has the "R" configuration.
  • the invention provides compounds according to any one of Formulae Xa, Xb, XIa, XIb, XIIa, XIIb, XIIIa, XIIIb, XIVa, XIVb, XVa or XVb, wherein Ri and R 2 are oriented on the pyridyl and pyridonyl ring as follows:
  • bond 3 of the core piperidine ring has the "S” configuration and bond 4 has the "R” configuration.
  • the invention provides compounds according to any one of Formulae Xa, Xb, XIa, XIb, XIIa, XIIb, XIIIa, XIIIb, XIVa, XIVb, XVa or XVb, wherein bond 3 has the "R” configuration and bond 4 has the "S" configuration.
  • the invention provides compounds according to any one of Formulae Xa, Xb, XIa, XIb, XIIa, XIIb, XIIIa, XIIIb, XIVa, XIVb, XVa or XVb, wherein Ri and R 2 are oriented on the pyridyl and pyridonyl ring as follows:
  • bond 3 of the core piperidine ring has the "R” configuration and bond 4 has the “S” configuration.
  • the invention provides compounds of Formulae Xa and Xb, wherein:
  • Ri is chloro; R 2 is amino; R 3 (for Xb) is methyl; R 4 is H, and Ri and R 2 have the following orientation on the pyridyl and pyridonyl ring:
  • L is -(C 3 -C5 alkyl)- wherein one carbon may be replaced by -N(Rg)-, or -(C 2 -C O alkyl)-C(O)-.
  • the R 1 , R 2 , and R 3 (R 3 for the pyridyl ring) are as defined and oriented on the pyridyl and pyridonyl rings as previously described, R 4 is as previously defined and Rs is-O-heterocycloalkyl, wherein the heterocycloalkyl group is selected from aza-bicyclo-octyl, in certain embodiments l-aza-bicyclo[2.2.2]oct-3-yl or 8-aza- bicyclo[3.2.1]oct-3-yl, aza-bicyclo-nonyl, aza-bicyclo-decyl, where the aza nitrogen is optionally substituted with methyl or ethyl, piperidinyl, piperaziny
  • Rn is Ci-C 6 alkoxy, optionally substituted with 1 or 2 groups that are independently Ci-C 4 alkoxy, amino, -NH(Ci-C 6 alkyl), -N(Ci-C 6 alkyl)(d-C 6 alkyl), -(C 0 -C 6 alkyl)- C(0)N(R 9 )-heterocycloalkyl, or heterocycloalkyl wherein the heterocycloalkyl group is selected from aza-bicyclo-octyl, in certain embodiments l-aza-bicyclo[2.2.2]oct-3-yl or 8- aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo-nonyl, aza-bicyclo-decyl, where the aza nitrogen is optionally substituted with methyl or ethyl; and R 4 is H or methyl, pyrrolidinyl, piperidinyl, piperazinyl, and morph
  • the invention provides compounds of Formulae Xa and Xb, wherein:
  • Ri is chloro; R 2 is amino; R 3 (for Xb) is methyl; R 4 is H, and R 1 , R 2 , and R 3 have the following orientation on the pyridyl and pyridonyl rings:
  • L is -(C 3 -C 5 alkyl)- wherein one carbon may be replaced by -N(Rg)-, or -(C 2 -C 6 alkyl)-C(O)-.
  • the R 1 , R 2 , and R 3 are as defined and oriented on the pyridyl and pyridonyl ring as previously described
  • R 4 is as previously defined
  • R 5 is heterocycloalkyl, which is selected from aza-bicyclo-octyl, in certain embodiments 1-aza- bicyclo[2.2.2]oct-3-yl or 8-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo-nonyl, aza-bicyclo-decyl, where the aza nitrogen, is optionally substituted with methyl or ethyl.
  • the invention provides compounds of Formulae Xa and Xb, wherein
  • R 1 is chloro; R 2 is amino; R 3 (for Xb) is methyl; R 4 is H, and R 1 , R 2 , and R 3 have the following orientation on the pyridyl and pyridonyl rings:
  • L is -(C3-C5 alkyl)- wherein one carbon may be replaced by -N(Rg)-, or -(C 2 -C 6 alkyl)-C(O)-.
  • R 1 , R 2 , and R 3 are as defined and oriented on the pyridyl and pyridonyl ring as previously described
  • R 4 is as previously defined and R 5 is- N(Rg)-C 0 -C 4 alkyl-aryl or -N(Rg)-(Co-C 6 alkyl)-C(O)-aryl, wherein the aryl group is unsubstituted or substituted at one or more substitutable positions with C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, C 1 -C 6 haloalkyl, Ci-C 6 haloalkoxy, hydroxyl, hydroxyalkyl, amino, -NH(Cj- C 6 alkyl), -N
  • the aryl group is a phenyl substituted with -(Co-C 6 alkyl)-C(O)R ⁇ and optionally substituted with 1 or 2 groups independently selected from Ci-C 6 alkyl, Cj-C 6 alkoxy, halogen, CF 3 , OCF 3 , hydroxyl, hydroxyalkyl, amino, -NH(C 1 -C 4 alkyl), -N(C 1 -C 4 alkyl)(d- C 4 alkyl), or NO 2 , wherein
  • R 11 is C 1 -C 6 alkoxy, optionally substituted with 1 or 2 groups that are independently C 1 -C 4 alkoxy, amino, -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl)(C r C 6 alkyl), -(C 0 -C 6 alkyl)- C(O)N(R 9 )-heterocycloalkyl, or heterocycloalkyl wherein the heterocycloalkyl group is selected from pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl, wherein the heterocycloalkyl groups are optionally substituted with 1, 2, or 3 groups that are independently halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxy, hydroxy C 1 -C 6 alkyl, C 1 -C 6 alkoxycarbonyl, -CO 2 H, CF 3 , or OCF 3 .
  • orientation of bonds 3 and 4 of the core piperidine ring is as follows:
  • the compounds of the invention comprise compounds of formulas XX-a or XX-b, i.e., compounds of formulas Xa and/or Xb having the formulas:
  • L is -(C 1 -C 4 alkyl)-NR 9 -(C 1 -C 4 alkyl)-, -(Cj-C 4 alkyl)-C(O)NR 9 -, -(C 1 -C 4 alkyl)-, -(C 1 -C 4 alkyl)-NR 9 C(O)- or -C(O)NR 9 -(C 1 -C 4 alkyl)-;
  • R 1 is halogen;
  • R 2 is amino or mono or (Ii(C 1 -C 4 alkyl)amino;
  • R 3 is C 1 -C 4 alkyl, Ci-C 4 alkoxy, or OH;
  • R 4 is H or Ci-C 4 alkyl;
  • R 5 is phenyl or naphthyl, each of which is substituted with 1 or 2 groups that are independently Ci-C 4 alkyl, Ci-C 4 alkoxy, OH, -0-C 2 -C 4 alkanoyl, halogen, halo C 1 -
  • R 9 is H or Ci-C 4 alkyl;
  • R 1 O at each occurrence is independently H, Ci-C 4 alkyl optionally substituted with one group that is selected from a 5 or 6 membered monocyclic heterocycloalkyl ring, and OH, quinuclidinyl, -C(O)NH 2 , -C(O)NH(C 1 -C 4 alkyl), -C(O)N(C 1 -C 4 alkyl)(Ci-C 4 alkyl) or piperidinyl optionally substituted with C 1 -C 4 alkyl; and
  • R 2O is Ci-C 4 alkyl, or Ci-C 4 alkoxy.
  • the invention provides compounds of Formula (XX-2a) or Formula (XX-2b) i.e., compounds of Formula (XX-a) or Formula (XX-b) having the formula:
  • Ri 7 is Ci-C 4 alkyl, C r C 4 alkoxy, OH, -0-C 2 -C 4 alkanoyl, halogen, halo C 1 -C 4 alkyl, halo C 1 -
  • Ri 8 is H, Ci-C 4 alkyl, Ci-C 4 alkoxy, OH, -0-C 2 -C 4 alkanoyl, halogen, halo Ci-C 4 alkyl (such as CF 3 ), halo Ci-C 4 alkoxy (such as OCF 3 ), -CO 2 Ri 0 , or -(C r C 4 alkyl)-CO 2 Ri 0 .
  • the invention provides compounds of either Formula (XX-2a) or Formula (XX-2b) wherein the bonds at positions 3 and 4 of the piperidinyl ring are cis to each other.
  • bonds 3 and 4 are as follows:
  • the invention provides compounds of either of Formula (XX-2a) or Formula (XX-2b), wherein L is -(Ci-C 2 alkyl)-NR 9 -(Ci-C 2 alkyl)-; R n is Ci-C 4 alkyl, Ci-C 4 alkoxy, or halogen; and Ris is H, Ci-C 4 alkyl, Ci-C 4 alkoxy, OH, or -0-C 2 -C 4 alkanoyl.
  • one of Ri 7 or Ri 8 is at the 4-position of the phenyl group.
  • the invention provides compounds of either of Formula (XX-2a) or Formula (XX-2b), wherein L is -(C]-C 2 alkyl)-NR 9 -(Ci-C 2 alkyl)-; Ri 7 is halogen, halo Ci-C 4 alkyl, or halo Ci-C 4 alkoxy; and Ri 8 is H, Ci-C 4 alkyl, Ci-C 4 alkoxy, OH.
  • one OfR n or Rj 8 is at the 4-position of the phenyl group.
  • the invention provides compounds of either of Formula (XX-2a) or Formula (XX-2b), wherein L is -(Ci-C 2 alkyl)-NR 9 -(Ci-C 2 alkyl)-; R 17 is OH, or -0-C 2 -C 4 alkanoyl; and R 18 is H, Ci-C 4 alkyl, Ci -C 4 alkoxy, or OH.
  • one of Ri 7 or Ri 8 is at the 4-position of the phenyl group.
  • the invention provides compounds of either of Formula (XX-2a) or Formula (XX-2b), wherein L is -(Ci-C 2 alkyl)-NR 9 -(Ci-C 2 alkyl)-; R n is OH, or -0-C 2 -C 4 alkanoyl; and Ri 8 is 0-C 2 -C 4 alkanoyl, halogen, halo Ci-C 4 alkyl, or halo Ci-C 4 alkoxy.
  • one OfRi 7 or Rj 8 is at the 4-position of the phenyl group.
  • the invention provides compounds of either of Formula (XX- 2a) or Formula (XX-2b), wherein L is -(Ci-C 2 alkyl)-NR 9 -(Ci-C 2 alkyl)-; Ri 0 is H, C 1 -C 4 alkyl optionally substituted with one group that is selected from morpholinyl, pyrrolidinyl, and OH, quinuclidinyl, -C(O)NH 2 , or piperidinyl optionally substituted with C 1 -C3 alkyl; Ri 7 is -CO 2 Ri 0 , or -(Ci-C 4 alkyl)-CO 2 Ri 0 ; and Ri 8 is Ci-C 4 alkyl, Ci-C 4 alkoxy, or OH.
  • one of Ri 7 or Ri 8 is at the 4-position of the phenyl group.
  • the invention provides compounds of either of Formula (XX-2a) or Formula (XX-2b), wherein L is -(C r C 2 alkyl)-NR 9 -(Ci-C 2 alkyl)-; Ri 0 is H, C 1 - C 4 alkyl optionally substituted with one group that is selected from morpholinyl, pyrrolidinyl, and OH, quinuclidinyl, -C(O)NH 2 , or piperidinyl optionally substituted with C 1 -C3 alkyl; Ri 7 is -C0 2 Rio; and Ri 8 is Ci-C 4 alkyl (such as methyl), Ci-C 4 alkoxy (such as methoxy), or OH.
  • one of Ri 7 or Rj 8 is at the 4-position of the phenyl group.
  • the invention provides compounds of either of Formula (XX- 2a) or Formula (XX-2b), wherein L is -(Ci-C 2 alkyl)-NR 9 -(Ci-C 2 alkyl)-; Ri 0 is H, Ci-C 4 alkyl optionally substituted with one group that is selected from morpholinyl, pyrrolidinyl, and OH, quinuclidinyl, -C(O)NH 2 , or piperidinyl optionally substituted with C 1 -C3 alkyl; Ri 7 is-(Ci-C 4 alkyl)-CO 2 Ri 0 ; and R !8 is C r C 4 alkyl, Ci-C 4 alkoxy, or OH.
  • one of R n or Ri 8 is at the 4-position of the phenyl group.
  • the invention provides compounds of either of Formula (XX-2a) or Formula (XX-2b), wherein L is -(Ci-C 3 alkyl)-NR9-(CrC 3 alkyl)-; Rio is H, CpC 4 alkyl optionally substituted with one group that is selected from a 5 or 6 membered monocyclic heterocycloalkyl ring, and OH, quinuclidinyl, -C(O)NH 2 , or piperidinyl optionally substituted with CpC 3 alkyl; Ri 7 is OH, -0-C 2 -C 4 alkanoyl, -CO 2 Ri 0 , Or -(Ci-C 4 alkyl)-CO 2 R 10 ; and
  • Ri 8 is H
  • R 20 is methoxy or ethoxy (in one aspect, methoxy is preferred.)
  • the invention provides compounds of either of Formula (XX-2a) or Formula (XX-2b), wherein L is -(Ci-C 3 alkyl)-NR 9 -(Ci-C 3 alkyl)-;
  • Rio is H, quinuclidinyl, -C(O)NH 2 , or piperidinyl optionally substituted with Ci-C 3 alkyl;
  • Ri 7 is OH, -0-C 2 -C 4 alkanoyl, -CO 2 Ri 0 , or -(Cj-C 4 alkyl)-CO 2 Ri 0 ; and
  • Ri 8 is H; and R 2 o is methoxy or ethoxy (in one aspect, methoxy is preferred.)
  • the invention provides compounds of either of Formula (XX-2a) or Formula (XX-2b), wherein L is -(Ci-C 3 ⁇ yI)-NR 9 -(C 1 -C 3 alkyl)-; Ri 0 is H; R n is -CO 2 Ri 0 , or -(Ci-C 4 alkyl)-C0 2 Rio; and R 18 is H.
  • the invention provides compounds of either of Formula (XX- 2a) or Formula (XX-2b), wherein L is -(C r C 3 alkyl)-NR 9 -(Ci-C 3 alkyl)-; R 17 is OH, or -O- C 2 -C 4 alkanoyl; and R 18 is H, methyl, methoxy, OH, F, or Cl.
  • the invention provides compounds of Formula (XX-3a) or Formula (XX-3b), i.e., compounds of Formula (XX-2a) or Formula (XX-2b) having the formula:
  • the invention provides compounds of Formula (XX-3a) or Formula (XX-3b), wherein R 17 is -CO 2 R 10 , or -(C 1 -C 4 alkyl)-CO 2 R 10 ; Rg is H or methyl; and Rio is H, Ci-C 4 alkyl optionally substituted with one group that is selected from morpholinyl, pyrrolidinyl, and OH, quinuclidinyl, -C(O)NH 2 , or piperidinyl optionally substituted with C 1 - C 2 alkyl.
  • the invention provides compounds of Formula (XX-2a) or Formula (XX-2b), wherein L is -(C 2 -C 4 alkyl)-; Rio is H, Ci-C 4 alkyl optionally substituted with one group that is selected from a 5 or 6 membered monocyclic heterocycloalkyl ring, and OH, quinuclidinyl, -C(O)NH 2 , or piperidinyl optionally substituted with C 1 -C 3 alkyl; Ri 7 is OH, -O-C 2 -C 4 alkanoyl, -CO 2 Ri 0 , Or -(Ci-C 4 alkyl)-CO 2 Ri 0 ; Ri 8 is H; and R 20 is methoxy or ethoxy (in one aspect, methoxy is preferred.)
  • the invention provides compounds of either of Formula (XX-2a) or Formula (XX-2b), wherein L is -(C 2 -C 4 alkyl)-; R n is Ci-C 4 alkyl, Ci-C 4 alkoxy, or halogen; and Ri 8 is H, C]-C 4 alkyl, Ci-C 4 alkoxy, OH, or -0-C 2 -C 4 alkanoyl.
  • L is -(C 2 -C 4 alkyl)-
  • R n is Ci-C 4 alkyl, Ci-C 4 alkoxy, or halogen
  • Ri 8 is H, C]-C 4 alkyl, Ci-C 4 alkoxy, OH, or -0-C 2 -C 4 alkanoyl.
  • one ofR ⁇ or Ri 8 is at the 4-position of the phenyl group.
  • the invention provides compounds of either of Formula (XX-2a) or Formula (XX-2b), wherein L is -(C 2 -C 4 alkyl)-; R 17 is halogen, halo C r C 4 alkyl, or halo Ci-C 4 alkoxy; and Ri 8 is H, Cj-C 4 alkyl, Ci-C 4 alkoxy, OH.
  • one of R J7 or Ri 8 is at the 4-position of the phenyl group.
  • the invention provides compounds of either of Formula (XX-2a) or Formula (XX-2b), wherein L is -(C 2 -C 4 alkyl)-; R 17 is OH, or -0-C 2 -C 4 alkanoyl; and Ri 8 is H, C 1 -C 4 alkyl, Ci-C 4 alkoxy, or OH.
  • one of R 17 or R 18 is at the 4-position of the phenyl group.
  • the invention provides compounds of either of Formula (XX-2a) or Formula (XX-2b), wherein L is -(C 2 -C 4 alkyl)-; Ri 7 is OH, or -0-C 2 -C 4 alkanoyl; and R] 8 is 0-C 2 -C 4 alkanoyl, halogen, halo C 1 -C 4 alkyl, or halo C 1 -C 4 alkoxy.
  • one of Ri 7 or Ri 8 is at the 4-position of the phenyl group.
  • the invention provides compounds of either of Formula (XX- 2a) or Formula (XX-2b), wherein L is -(C 2 -C 4 alkyl)-; Ri 0 is H, Ci-C 4 alkyl optionally substituted with one group that is selected from morpholinyl, pyrrolidinyl, and OH, quinuclidinyl, -C(O)NH 2 , or piperidinyl optionally substituted with Ci -C 3 alkyl; R 17 is - CO 2 Ri 0 , Or -(C 1 -C 4 alkyl)-CO 2 Ri 0 ; and R !8 is Ci-C 4 alkyl, CpC 4 alkoxy, or OH.
  • one of Ri 7 or Ri 8 is at the 4-position of the phenyl group.
  • the invention provides compounds of either of Formula (XX-2a) or Formula (XX-2b), wherein L is -(C 2 -C 4 alkyl)-; Ri 0 is H, Q-C 4 alkyl optionally substituted with one group that is selected from morpholinyl, pyrrolidinyl, and OH, quinuclidinyl, -C(O)NH 2 , or piperidinyl optionally substituted with Ci-C 3 alkyl; Ri 7 is -CO 2 Ri 0 ; and Ri 8 is Ci-C 4 alkyl (such as methyl), C 1 -C 4 alkoxy (such as methoxy), or OH.
  • one of Ri 7 or Rj 8 is at the 4-position of the phenyl group.
  • the invention provides compounds of either of Formula (XX- 2a) or Formula (XX-2b), wherein L is -(C 2 -C 4 alkyl)-; Rio is H, Ci-C 4 alkyl optionally substituted with one group that is selected from morpholinyl, pyrrolidinyl, and OH, quinuclidinyl, -C(O)NH 2 , or piperidinyl optionally substituted with Ci-C 3 alkyl; Ri 7 is— (Ci- C 4 alkyl)-C0 2 Rio; and Ri 8 is Ci-C 4 alkyl, C 1 -C 4 alkoxy, or OH. Preferably, one OfRi 7 or Ri 8 is at the 4-position of the phenyl group.
  • the invention provides compounds of either of Formula (XX-2a) or Formula (XX-2b), wherein L is -(C 2 -C 4 alkyl)-; R 1O is H, C 1 -C 4 alkyl optionally substituted with one group that is selected from a 5 or 6 membered monocyclic heterocycloalkyl ring, and OH, quinuclidinyl, -C(O)NH 2 , or piperidinyl optionally substituted with C 1 -C 3 alkyl; R n is OH, -0-C 2 -C 4 alkanoyl, -CO 2 Ri 0 , or -(Ci-C 4 alkyl)-CO 2 Ri 0 ; and Ri 8 is H; and R 20 is methoxy or ethoxy (in one aspect, methoxy is preferred.)
  • the invention provides compounds of either of Formula (XX-2a) or Formula (XX-2b), wherein L is -(C 2 -C 4 alkyl)-;
  • Rio is H, quinuclidinyl, -C(O)NH 2 , or piperidinyl optionally substituted with Ci-C 3 alkyl;
  • R n is OH, -0-C 2 -C 4 alkanoyl, -CO 2 Ri 0 , Or -(C 1 -C 4 alkyl)-CO 2 Ri 0 ;
  • Ri 8 is H; and
  • R 20 is methoxy or ethoxy (in one aspect, methoxy is preferred.)
  • the invention provides compounds of either of Formula (XK-2a) or Formula (XX-2b), wherein L is -(C 2 -C 4 alkyl)-; Ri 0 is H; R n is -CO 2 Ri 0 , or -(Ci- C 4 alkyl)-CO 2 R 10 ; and Ri 8 is H.
  • the invention provides compounds of either of Formula (XX- 2a) or Formula (XX-2b), wherein L is -(C 2 -C 4 alkyl)-; Ri 7 is OH, or -0-C 2 -C 4 alkanoyl; and Ri 8 is H, methyl, methoxy, OH, F, or Cl.
  • the invention provides compounds of either of Formula (XX-2a) or Formula (XX-2b), wherein L is -(C 1 -C 3 alkyl)-C(O)NR 9 -; Rio is H, Ci-C 4 alkyl optionally substituted with one group that is selected from a 5 or 6 membered monocyclic heterocycloalkyl ring, and OH, quinuclidinyl, -C(O)NH 2 , or piperidinyl optionally substituted with Ci-C 3 alkyl; R n is OH, -0-C 2 -C 4 alkanoyl, -CO 2 R 10 , Or -(C 1 -C 4 alkyl)-CO 2 Ri 0 ; Ri 8 is H; and R 20 is methoxy or ethoxy (in one aspect, methoxy is preferred.)
  • the invention provides compounds of either of Formula (XX-2a) or Formula (XX-2b), wherein L is -(Ci-C 2 alkyl)-C(O)NR 9 -; Ri 7 is C 1 -C 4 alkyl, Q- C 4 alkoxy, or halogen; and R 18 is H, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, OH, or -0-C 2 -C 4 alkanoyl.
  • one of R 17 or Ri 8 is at the 4-position of the phenyl group.
  • the invention provides compounds of either of Formula (XX-2a) or Formula (XX-2b), wherein L is -(C 1 -C 2 alkyl)-C(O)NR 9 -; R 17 is halogen, halo Ci -C 4 alkyl, or halo C 1 -C 4 alkoxy; and R 18 is H, Ci-C 4 alkyl, Ci-C 4 alkoxy, OH.
  • one ofR ⁇ or Ri 8 is at the 4-position of the phenyl group.
  • the invention provides compounds of either of Formula (XX-2a) or Formula (XX-2b), wherein L is -(Ci-C 2 alkyl)-C(O)NR 9 -; R n is OH, or -0-C 2 -C 4 alkanoyl; and Ri 8 is H, Ci-C 4 alkyl, Ci-C 4 alkoxy, or OH.
  • one of Ri 7 or Ri 8 is at the 4- position of the phenyl group.
  • the invention provides compounds of either of Formula (XX-2a) or Formula (XX-2b), wherein L is -(C 1 -C 2 alkyl)-C(O)NR 9 -; Ri 7 is OH, or -0-C 2 -C 4 alkanoyl; and R 18 is 0-C 2 -C 4 alkanoyl, halogen, halo Ci-C 4 alkyl, or halo Ci-C 4 alkoxy.
  • one of Ri 7 or Ri 8 is at the 4-position of the phenyl group.
  • the invention provides compounds of either of Formula (XX- 2a) or Formula (XX-2b), wherein L is -(C r C 2 alkyl)-C(O)NR 9 -; Ri 0 is H, C r C 4 alkyl optionally substituted with one group that is selected from morpholinyl, pyrrolidinyl, and OH, quinuclidinyl, -C(O)NH 2 , or piperidinyl optionally substituted with Ci-C 3 alkyl; R ]7 is - CO 2 Ri 0 , Or-(Ci-C 4 alkyl)-CO 2 Ri 0 ; and Ri 8 is Ci-C 4 alkyl, Ci-C 4 alkoxy, or OH.
  • one of Ri 7 or Ri 8 is at the 4-position of the phenyl group.
  • the invention provides compounds of either of Formula (XX-2a) or Formula (XX-2b), wherein L is -(Ci-C 2 alkyl)-C(O)NR 9 -; Ri 0 is H, Ci-C 4 alkyl optionally substituted with one group that is selected from morpholinyl, pyrrolidinyl, and OH, quinuclidinyl, -C(O)NH 2 , or piperidinyl optionally substituted with C 1 -C3 alkyl; R 17 is -C0 2 Rio; and Ri 8 is Ci-C 4 alkyl (such as methyl), Ci-C 4 alkoxy (such as methoxy), or OH.
  • one of Ri 7 or Ri 8 is at the 4-position of the phenyl group.
  • the invention provides compounds of either of Formula (XX- 2a) or Formula (XX-2b), wherein L is -(Ci-C 2 alkyl)-C(O)NR 9 -; Rio is H, Ci-C 4 alkyl optionally substituted with one group that is selected from morpholinyl, pyrrolidinyl, and OH, quinuclidinyl, -C(O)NH 2 , or piperidinyl optionally substituted with Ci-C 3 alkyl; Rn is- (Ci-C 4 alkyl)-CO 2 Ri 0 ; and R] 8 is C 1 -C 4 alkyl, C 1 -C 4 alkoxy, or OH.
  • R n or Ri 8 is at the 4-position of the phenyl group.
  • the invention provides compounds of either of Formula (XX-2a) or Formula (XX-2b), wherein L is -(C 1 -C 2 alkyl)-C(O)NR 9 -; Rio is H, C 1 -C 4 alkyl optionally substituted with one group that is selected from a 5 or 6 membered monocyclic heterocycloalkyl ring, and OH, quinuclidinyl, -C(O)NH 2 , or piperidinyl optionally substituted with Ci-C 3 alkyl; R n is OH, -0-C 2 -C 4 alkanoyl, -CO 2 Ri 0 , Or -(Ci-C 4 alkyl)-CO 2 Ri 0 ; and Ri 8 is H; and R 20 is methoxy or ethoxy (in one aspect, methoxy is preferred.)
  • the invention provides compounds of either of Formula (XX-2a) or Formula (XX-2b), wherein L is -(Ci-C 2 alkyl)-C(O)NR 9 -;
  • Rio is H, quinuclidinyl, -C(O)NH 2 , or piperidinyl optionally substituted with Ci-C 3 alkyl;
  • Ri 7 is OH, -0-C 2 -C 4 alkanoyl, -CO 2 Ri 0 , Or -(Ci-C 4 alkyl)-CO 2 Ri 0 ; and
  • Ri 8 is H; and R 20 is methoxy or ethoxy (in one aspect, methoxy is preferred.)
  • the invention provides compounds of either of Formula (XX-2a) or Formula (XX-2b), wherein L is -(Ci-C 2 alkyl)-C(O)NR 9 -; Rio is H; R n is -CO 2 Ri 0 , or -(Ci-C 4 alkyl)-C0 2 Rio; and R 18 is H.
  • the invention provides compounds of either of Formula (XX- 2a) or Formula (XX-2b), wherein L is -(Ci-C 3 alkyl)-C(O)NR 9 -; Ri 7 is OH, or -0-C 2 -C 4 alkanoyl; and Ri 8 is H, methyl, methoxy, OH, F, or Cl.
  • the invention provides compounds of Formula (XX-4a) or Formula (XX-4b), i.e., compounds of Formula (XX-2a) or Formula (XX-2b) having the formula:
  • the invention provides compounds of Formula (XX-4a) or Formula (XX-4b), wherein R 17 is -CO 2 R 10 , or -(C 1 -C 4 alkyl)-CO 2 R 10 ; R9 is H or methyl; and R 10 is H, C 1 -C 4 alkyl optionally substituted with one group that is selected from morpholinyl, pyrrolidinyl, and OH, quinuclidinyl, -C(O)NH 2 , or piperidinyl optionally substituted with C 1 - C 2 alkyl.
  • the invention provides compounds of Formula (XX-5a) or Formula (XX-5b), i.e., compounds of Formula (XX-2a) or Formula (XX-2b) having the formula:
  • the invention provides compounds of Formula (XKSa) or Formula (XX-5b), wherein R 17 is -CO 2 RiO, Or-(C 1 -C 4 alkyl)-CO 2 R 10 ; R 9 is H or methyl; and Rio is H, C 1 -C 4 alkyl optionally substituted with one group that is selected from morpholinyl, pyrrolidinyl, and OH, quinuclidinyl, -C(O)NH 2 , or piperidinyl optionally substituted with Ci- C 2 alkyl.
  • the invention provides compounds of Formula (XX-2a) or Formula (XX-2b), wherein L is -(Ci-C 4 alkyl)-NR 9 C(O)s Rio is H, Ci-C 4 alkyl optionally substituted with one group that is selected from a 5 or 6 membered monocyclic heterocycloalkyl ring, and OH, quinuclidinyl, -C(O)NH 2 , or piperidinyl optionally substituted with C 1 -C 3 alkyl; Ri 7 is OH, -0-C 2 -C 4 alkanoyl, -CO 2 Ri 0 , Or-(Ci-C 4 alkyl)-CO 2 Ri 0 ; Ri 8 is H; and R 2 o is methoxy or ethoxy (in one aspect, methoxy is preferred.)
  • the invention provides compounds of either of Formula (XX-2a) or Formula (XX-2b), wherein L is -(Ci-C 4 alkyl)-NR 9 C(O)-; R n is C 1 -C 4 alkyl, Q- C 4 alkoxy, or halogen; and Ri 8 is H, CpC 4 alkyl, Ci-C 4 alkoxy, OH, or -0-C 2 -C 4 alkanoyl.
  • one of Ri 7 or Ri 8 is at the 4-position of the phenyl group.
  • the invention provides compounds of either of Formula (XX-2a) or Formula (XX-2b), wherein L is -(Ci-C 4 alkyl)-NR 9 C(O)-; R n is halogen, halo Ci-C 4 alkyl, or halo Ci-C 4 alkoxy; and Ri 8 is H, Ci-C 4 alkyl, Ci-C 4 alkoxy, OH.
  • one of Rn or Ri 8 is at the 4-position of the phenyl group.
  • the invention provides compounds of either of Formula (XX-2a) or Formula (XX-2b), wherein L is -(Ci-C 4 alkyl)-NR 9 C(O)-; R n is OH, or -0-C 2 -C 4 alkanoyl; and Ri 8 is H, Ci-C 4 alkyl, Cj-C 4 alkoxy, or OH.
  • one of Ri 7 or Ri 8 is at the 4- position of the phenyl group.
  • the invention provides compounds of either of Formula (XX-2a) or Formula (XX-2b), wherein L is -(C r C 4 alkyl)-NR 9 C(O>; R n is OH, or -0-C 2 -C 4 alkanoyl; and Ri 8 is 0-C 2 -C 4 alkanoyl, halogen, halo Ci-C 4 alkyl, or halo Ci-C 4 alkoxy.
  • one of Ri 7 or Ri 8 is at the 4-position of the phenyl group.
  • the invention provides compounds of either of Formula (XX- 2a) or Formula (XX-2b), wherein L is -(Ci-C 4 alkyl)-NR 9 C(O)-; Ri 0 is H, Ci-C 4 alkyl optionally substituted with one group that is selected from morpholinyl, pyrrolidinyl, and OH, quinuclidinyl, -C(O)NH 2 , or piperidinyl optionally substituted with C 1 -C 3 alkyl; R 17 is - CO 2 R 10 , or -(C 1 -C 4 alkyl)-CO 2 R 10 ; and R 18 is C 1 -C 4 alkyl, C 1 -C 4 alkoxy, or OH.
  • one OfR 17 or R 18 is at the 4-position of the phenyl group.
  • the invention provides compounds of either of Formula (XX-2a) or Formula (XX-2b), wherein L is -(Ci-C 4 alkyl)-NR 9 C(O)-; R 10 is H, C 1 -C 4 alkyl optionally substituted with one group that is selected from morpholinyl, pyrrolidinyl, and OH, quinuclidinyl, -C(O)NH 2 , or piperidinyl optionally substituted with C 1 -C3 alkyl; Ri 7 is -CO 2 Ri 0 ; and Ri 8 is Ci-C 4 alkyl (such as methyl), C 1 -C 4 alkoxy (such as methoxy), or OH.
  • one of R 17 or Ri 8 is at the 4-position of the phenyl group.
  • the invention provides compounds of either of Formula (XX- 2a) or Formula (XX-2b), wherein L is -(Ci-C 4 alkyl)-NR 9 C(O)-; Ri 0 is H, C r C 4 alkyl optionally substituted with one group that is selected from morpholinyl, pyrrolidinyl, and OH, quinuclidinyl, -C(O)NH 2 , or piperidinyl optionally substituted with Q-C 3 alkyl; Rn is- (Ci-C 4 alkyl)-CO 2 R 10 ; and R 18 is Cj-C 4 alkyl, Ci-C 4 alkoxy, or OH.
  • one of R n or Ri 8 is at the 4-position of the phenyl group.
  • the invention provides compounds of either of Formula (XX-2a) or Formula (XX-2b), wherein L is -(Ci-C 4 alkyl)-NR 9 C(O)-; Rio is H, Ci-C 4 alkyl optionally substituted with one group that is selected from a 5 or 6 membered monocyclic heterocycloalkyl ring, and OH, quinuclidinyl, -C(O)NH 2 , or piperidinyl optionally substituted with C 1 -C 3 alkyl; R 17 is OH, -0-C 2 -C 4 alkanoyl, -CO 2 Ri 0 , or -(Ci-C 4 alkyl)-CO 2 R 10 ; Ris is H; and R 2O is methoxy or ethoxy (in one aspect, methoxy is preferred.)
  • the invention provides compounds of either of Formula (XX-2a) or Formula (XX-2b), wherein L is -(Ci-C 4 alkyl)-NR 9 C(O)-;
  • Rio is H, quinuclidinyl, -C(O)NH 2 , or piperidinyl optionally substituted with Ci-C 3 alkyl;
  • R 17 is OH, -0-C 2 -C 4 alkanoyl, -CO 2 R 10 , or -(Ci-C 4 alkyl)-CO 2 R 10 ;
  • Ri 8 is H; and
  • R 20 is methoxy or ethoxy (in one aspect, methoxy is preferred.)
  • the invention provides compounds of either of Formula (XX-2a) or Formula (XX-2b), wherein L is -(C 1 -C 4 alkyl)-NR 9 C(O)-; Ri 0 is H; R n is - CO 2 R 10 , or -(Ci-C 4 alkyl)-CO 2 Ri 0 ; and Ri 8 is H.
  • the invention provides compounds of either of Formula (XX- 2a) or Formula (XX-2b), wherein L is -(C 1 -C 4 alkyl)-NR 9 C(O)-; R n is OH, or -0-C 2 -C 4 alkanoyl; and Ri 8 is H, methyl, methoxy, OH, F 5 or Cl.
  • the invention provides compounds of Formula (XX-6a) or Formula (XX-6b), i.e., compounds of Formula (XX-2a) or Formula (XX-2b) having the formula:
  • the invention provides compounds of Formula (XX-6a) or Formula (XX-6b), wherein Rn is -CO 2 Ri 0 , or -(Ci-C 4 alkyl)-CO 2 Ri 0 ; R 9 is H or methyl; and Rio is H, C 1 -C 4 alkyl optionally substituted with one group that is selected from morpholinyl, pyrrolidinyl, and OH, quinuclidinyl, -C(O)NH 2 , or piperidinyl optionally substituted with Q- C 2 alkyl.
  • the invention provides compounds of Formula (XX-6a) or Formula (XX-6b), wherein Ri 7 is -CO 2 Ri 0 , and Ri 0 is H, or Ci-C 4 alkyl optionally substituted with one group that is selected from morpholinyl, pyrrolidinyl. and OH,
  • the invention provides compounds of Formula (XX-6a) or Formula (XX-6b), wherein Rn is -CO 2 Ri 0 , and Ri 0 is quinuclidinyl, -C(O)NH 2 , or piperidinyl optionally substituted with Ci-C 2 alkyl.
  • the invention provides compounds of Formula Formula (XX-6a) or Formula (XX-6b), wherein R 17 is -CO 2 R 10 , and R 1 O is H or piperidinyl substituted with C 1 - C 2 alkyl.
  • the invention further provides methods for treating emesis, dyspepsia, gastroparesis, constipation, intestinal pseudo-obstruction, gastroesophageal reflux, or post-operative ileus, the method comprising administering a therapeutically effective amount of a compound or salt according of Formulae Xa and Xb to a patient in need of such treatment.
  • the subject invention provides compounds that are more susceptible to degradation by serum and/or cytosolic esterases than cisapride, thus avoiding the adverse effects associated with metabolism by cytochrome P450.
  • the therapeutic compounds of the subject invention are stable in storage but have a relatively short half-life in the physiological environment; therefore, the compounds of the subject invention can be used with a lower incidence of side effects and toxicity.
  • therapeutic stereoisomeric compounds are provided that are useful in the treatment of gastroesophageal reflux disease and that contain an ester group, which is susceptible to degradation by esterases, thereby breaking down the compound and facilitating its efficient removal from the treated individual.
  • the therapeutic stereoisomeric compounds are metabolized by the Phase I drug detoxification system.
  • a further aspect of the subject invention pertains to the breakdown products (preferably metabolic breakdown products, i.e., metabolites, generally acids of parent esters) that are produced when the therapeutic compounds of the subject invention are acted upon by an esterase.
  • the presence of these breakdown products in the urine or serum can be used to monitor the rate of clearance of the therapeutic compound from a patient.
  • Degradation of the compounds of the subject invention by esterases is particularly advantageous for drug metabolism because these enzymes are ubiquitously distributed and their activity is not dependent on age, gender, or disease state to the same extent as oxidative hepatic drug metabolism.
  • the subject invention further provides methods of treating disorders, such as gastroesophageal reflux disease comprising the administration of a therapeutically effective amount of at least one stereoisomeric structural and/or functional analog of cisapride to an individual in need of treatment.
  • disorders such as gastroesophageal reflux disease
  • the subject invention provides stereoisomeric structural and/or functional analogs of cisapride and pharmaceutical compositions of these esterified compounds.
  • the subject invention further provides materials and methods for the treatment of emesis and such other conditions, including but not limited to dyspepsia, gastroparesis, constipation, and intestinal pseudo-obstruction, while substantially reducing adverse effects associated with the administration of cisapride.
  • therapeutic stereoisomeric compounds are provided which are useful in the treatment of gastroesophageal reflux, dyspepsia, gastroparesis, constipation, post-operative ileus, and intestinal pseudo-obstruction and which contain an ester group which is acted upon by esterases thereby breaking down the compound and facilitating its efficient removal from the treated individual.
  • the subject invention further provides methods of synthesizing the unique and advantageous compounds of the subject invention. Particularly, methods of producing and purifying such stereoisomeric compounds are taught. Methods of adding such ester moieties and of producing and purifying stereoisomers, are well known to the skilled artisan and can be readily carried out utilizing the guidance provided herein.
  • the present invention provides isolated stereoisomers of Compound I, which contains three chiral centers.
  • pharmaceutically active norcisapride is a racemic mixture of the two cis enantiomers:
  • the current invention is particularly concerned with the configuration at the third chiral center, in the quinuclidinol moiety, of the structural and/or functional analogs of cisapride. This group is eliminated in the conversion to the acid metabolite referred to herein as ⁇ Compounda Ha and lib:
  • the preferred Compound Ia and Ib stereoisomers of the present invention are made by conjugating R or S quinuclidinol to a structural/functional analog of (+)- or (-)-norcisapride characterized by the substitution of a pyridyl or pyridonyl moiety for the phenyl moiety of norcisapride, giving Compounds Ilia, IHb, IVa, IVb, Va, Vb, Via and VIb.
  • the subject invention pertains to stereoisomerically isolated compounds, and compositions comprising the compounds.
  • the isolated stereoisomeric forms of the compounds of the invention are substantially free from one another (i.e., in stereoisomeric excess).
  • the "R” forms of the compounds are substantially free from the "S” forms of the compounds and are, thus, in stereoisomeric excess of the "S” forms.
  • "S” forms of the compounds are substantially free of "R” forms of the compounds and are, thus, in stereoisomeric excess of the "R” forms.
  • the isolated stereoisomeric compounds are in at least about 80% stereoisomeric excess. In a preferred aspect, the compounds are in at least about 90% stereoisomeric excess.
  • the compounds are in at least about 95% stereoisomeric excess. In an even more preferred aspect, the compounds are in at least about 97.5% stereoisomeric excess. In a most preferred aspect, the compounds are in at least about 99% stereoisomeric excess. Similarly, the "(+)" and “(-)" forms of the compounds are also provided in stereoisomeric excess.
  • the various stereoisomers have particular unexpected properties that, advantageously, can be used to customize treatment for a particular set of circumstances.
  • compounds containing the (3'R)-isomer in the quinuclidinyl ester moiety i.e., compounds Ilia, IHb, IVa and IVb
  • compounds containing the (3'S)-isomer of quinuclidinol i.e., compounds Va and Vb and Via and VIb, can undergo a much slower metabolism.
  • the (3'R)-isomers of compounds Ia and Ib can be used, for example, when a short-duration of action is preferred, for example stimulation of gastric motility in an acute episode, such as pulsatile administration to patients with acute gastroparesis, or in acute gastroesophageal reflux.
  • a short-duration of action for example stimulation of gastric motility in an acute episode, such as pulsatile administration to patients with acute gastroparesis, or in acute gastroesophageal reflux.
  • Another advantage of rapid metabolism by esterases to an substantially less active metabolites, i.e., compound Ha or lib is the very low probability of drug-drug interactions and toxicity. Therefore these shorter-acting (R)-isomers can be advantageously used, for example, as intravenous formulations for treating gastroesophageal reflux in premature newborn who notoriously are not able to metabolize drugs as well as adults because their CYP450 system is not fully developed.
  • the (3'S)-isomers of compound I are best used in chronic situations of the same ailments, for example gastroparesis in diabetic patients or cancer patients under opiates, or in chronic gastroesophageal reflux in patients who need 24-hour coverage.
  • each compound e.g., compound Ia
  • each compound is a mixture of 4 isomers, consisting of 2 pairs of enantiomers.
  • the first pair of enantiomers is (+)(R)-compound Ia and (-)(S)- compound Ia (compounds IVa and Va, respectively)
  • the second pair of enantiomers is (-)(R)- compound I and (+)(S)-compound I (compounds Ilia and Via, respectively).
  • each separate enantiomer has different properties regarding both their rate of hydrolysis by esterases and regarding their affinity at the 5-HT4 receptor.
  • alkyl includes those alkyl groups of a designed number of carbon atoms. Alkyl groups may be straight, or branched. Examples of “alkyl” include methyl, ethyl, propyl, isopropyl, butyl, iso-, sec- and tert-butyl, pentyl, hexyl, heptyl, 3- ethylbutyl, and the like. If the number of carbon atoms is not specified, the subject "alkyl” moiety has from 1 to 6 carbons.
  • alkoxy represents an alkyl group of indicated number of carbon atoms attached to the parent molecular moiety through an oxygen bridge.
  • alkoxy groups include, for example, methoxy, ethoxy, propoxy and isopropoxy.
  • aryl is meant an aromatic carbocyclic group having a single ring (e.g., phenyl) that is optionally fused or otherwise attached to other aromatic hydrocarbon rings or non- aromatic hydrocarbon rings.
  • Aryl includes multiple condensed rings in which at least one is aromatic, (e.g., 1,2,3,4-tetrahydronaphthyl, naphthyl), wherein each ring is optionally mono-, di-, or trisubstituted with the groups identified below, as well as multiple rings that are not fused, such as, for example, biphenyl or binaphthyl.
  • Preferred aryl groups of the present invention are phenyl, 1-naphthyl, 2-naphthyl, indanyl, indenyl, dihydronaphthyl, fluorenyl, tetralinyl or 6,7,8,9-tetrahydro-5H-benzo[a]cycloheptenyl. More preferred are phenyl, biphenyl, and naphthyl. Most preferred is phenyl.
  • the aryl groups herein are unsubstituted or, as specified, substituted in one or more substitutable positions with various groups.
  • such aryl groups may be optionally substituted with, for example, C 1 -C 6 alkyl, C 1 - C 6 alkoxy, halogen, hydroxy, cyano, nitro, amino, InOnO(C 1 -C 6 )alkylamino, di(Ci- C 6 )alkylamino, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, amino(C!- C 6 )alkyl, mono(Ci-C 6 )alkylamino(C 1 -C 6 )alkyl or di(C 1 -C 6 )alkylamino(Ci-C 6 )alkyl.
  • haloalkoxy refers to an alkoxy group substituted with at least one halogen atom and optionally further substituted with at least one additional halogen atom, where each halogen is independently F, Cl, Br or I. Preferred halogens are F or Cl. Preferred haloalkoxy groups contain 1-6 carbons, more preferably 1-4 carbons, and still more preferably 1-2 carbons. "Haloalkoxy” includes perhaloalkoxy groups, such as OCF 3 or OCF 2 CF 3 .
  • heteroaryl refers to an aromatic ring system containing at least one heteroatom selected from nitrogen, oxygen, and sulfur.
  • the heteroaryl ring may be fused or otherwise attached to one or more heteroaryl rings, aromatic or non-aromatic hydrocarbon rings or heterocycloalkyl rings.
  • heteroaryl groups include, for example, pyridyl, pyrimidinyl, quinolinyl, benzothienyl, indolyl, indolinyl, pyridazinyl, pyrazinyl, isoindolyl, isoquinolyl, quinazolinyl, quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, thiazolyl, indolizinyl, indazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, furanyl, thienyl, pyrrolyl, oxadiazolyl, thiadiazolyl, benzo[l,4]oxazinyl, triazolyl, tetrazolyl, isothiazolyl, naphthyridinyl, isochromanyl, chromanyl,
  • Preferred heteroaryl groups include pyridyl, pyrimidyl, quinolinyl, indolyl, pyrrolyl, furanyl, thienyl, and imidazolyl. More preferred heteroaryl groups include pyridyl, pyrrolyl, and indolyl.
  • the heteroaryl groups herein are unsubstituted or, as specified, substituted in one or more substitutable positions with various groups.
  • heteroaryl groups may be optionally substituted with, for example, C 1 -C 6 alkyl, Ci-C 6 alkoxy, halogen, hydroxy, cyano, nitro, amino, mono(Ci-C6)alkylamino, di(Ci-C 6 )alkylamino, C 2 -C 6 alkenyl, C 2 - C ⁇ alkynyl, Ci-C 6 haloalkyl, Ci-C 6 haloalkoxy, amino(Ci-C 6 )alkyl, mono(Ci- C 6 )alkylamino(Ci-C 6 )alkyl or di(Ci-C 6 )alkylamino(Ci-C 6 )alkyl.
  • heterocycloalkyl refers to a ring or ring system containing at least one heteroatom that is preferably selected from nitrogen, oxygen, and sulfur, wherein said heteroatom is in a non-aromatic ring.
  • the heterocycloalkyl ring is optionally fused to or otherwise attached to other heterocycloalkyl rings and/or non-aromatic hydrocarbon rings and/or phenyl rings.
  • Preferred heterocycloalkyl groups have from 3 to 7 members. More preferred heterocycloalkyl groups have 5 or 6 members.
  • heterocycloalkyl groups include, for example, aza-bicyclo[2.2.2]octyl (in each case also “quinuclidinyl” or a quinuclidine derivative), aza-bicyclo[3.2.1]octyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S,S-dioxide, piperazinyl, homopiperazinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, tetrahydrofuranyl, tetrahydrothienyl, homopiperidinyl, homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl S 5 S- dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridinyl,
  • Preferred heterocycloalkyl groups include aza-bicyclo[2.2.2]octyl, aza-bicyclo[3.2.1]octyl, piperidinyl, piperazinyl, pyrrolidinyl, thiomorpholinyl, S,S-dioxothiomorpholinyl, morpholinyl, and imidazolidinyl. More preferred are aza-bicyclo[2.2.2]octyl, aza-bicyclo[3.2.1]octyl, piperidinyl, piperazinyl, pyrrolidinyl, imidazolidinyl, and morpholinyl.
  • heterocycle groups herein are unsubstituted or, as specified, substituted in one or more substitutable positions with various groups.
  • pharmaceutically acceptable salts or "a pharmaceutically acceptable salt thereof refer to salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases. Since the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids.
  • Suitable pharmaceutically acceptable acid addition salts for the compound of the present invention include acetic, benzenesulfonic (besylate), benzoic, camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic, and the like.
  • Preferred acid addition salts are the chloride and sulfate salts.
  • structural and/or functional analogs of cisapride are administered as the free base or as the mono or dihydrochloride salt.
  • treatment encompass prophylactic administration of the compound or a pharmaceutical composition comprising the compound (“prophylaxis") as well as remedial therapy to reduce or eliminate a disease or disorder mentioned herein.
  • Prophylactic administration is intended for prevention of disorders and may be used to treat a subject that is at risk of having or suffering from one or more disorders mentioned herein.
  • treatment or a derivative thereof, contemplates partial or complete inhibition of the stated disease state, when an active ingredient of the invention is administered prophylactically or following the onset of the disease state for which such active ingredient of the is administered.
  • “Prophylaxis” refers to administration of the active ingredient(s) to a mammal to protect the mammal from any of the disorders set forth herein, as well as others.
  • terapéuticaally effective amount refers to an amount necessary to achieve a derived therapeutic effect such as: 1) an amount sufficient to alleviate reflux disease, 2) an amount sufficient to alleviate nausea and vomiting, or 3) an amount sufficient to alleviate a condition caused by gastrointestinal motility dysfunction.
  • Therapeutically effective amounts of structural and/or functional analogs of cisapride are encompassed by the above-described dosage amounts and dose frequency schedule.
  • a "mammal” may be, for example, a mouse, rat, pig, horse, rabbit, goat, cow, cat, dog, or human. In a preferred aspect, the mammal is a human.
  • the term "individual(s)" is defined as a single mammal to which is administered a compound of the present invention.
  • the mammal may be, for example, a mouse, rat, pig, horse, rabbit, goat, cow, cat, dog, or human.
  • the individual is a human.
  • esterified cisapride means therapeutic compounds of the subject invention that are structural and/or functional analogs of cisapride, which contain a hydrolysable group, generally an ester, that does not detract from the ability of these compounds to provide a therapeutic benefit, but which makes these compounds more susceptible to degradation by hydrolases, particularly serum and/or cytosolic esterases, and which reduces the interaction of the cytochrome P-450 drug detoxification system with the cisapride compounds. Esterase- mediated metabolism of esterified cisapride compounds reduces the role of the cytochrome P- 450 drug detoxification system in cisapride metabolism and reduces or eliminates adverse effects caused by cisapride.
  • structural analog means that a described compound shares structural characteristics with a parent compound.
  • a structural analog of cisapride may share one or more structural characteristics with the parent cisapride compound, such as a substituted aryl ring connected to a piperdine ring through an amide linker, but differ structurally in other ways, such as the inclusion or deletion of one or more other chemical moieties.
  • Another example is the substitution of a pyridyl or pyridonyl ring for cisapride's phenyl ring.
  • a functional analog as used herein means that a described compound shares a functional characteristic with a parent compound.
  • a functional analog of cisapride may share few, if any, structural characteristics with cisapride, but affect a similar function, for example, 5-HT 4 agonism.
  • gastrointestinal disorders such as diarrhea, abdominal cramping, and abdominal grumbling; tiredness; headache; increased systolic pressure; death; ventricular tachycardia; ventricular fibrillation; torsades de pointes; QT prolongation; increased heart rate; neurological and CNS disorders; and interaction of cisapride with other drugs given concurrently such as but not limited to digoxin, diazepam, ethanol, acenocoumarol, cimetidine, ranitidine, paracetamol, and propranolol.
  • gastroesophageal reflux disease as used herein means the incidence of, and the symptoms of, those conditions causing the backward flow of the stomach contents into the esophagus.
  • eliciting an anti-emetic effect and "anti-emetic therapy” as used herein mean providing relief from or preventing the symptoms of nausea and vomiting induced spontaneously or associated with emetogenic cancer chemotherapy or irradiation therapy.
  • treating a condition caused by gastrointestinal motility dysfunction means treating the symptoms and conditions associated with this disorder which include, but are not limited to, gastroesophageal reflux disease, dyspepsia, gastroparesis, constipation, post-operative ileus, and intestinal pseudo-obstruction.
  • prokinetic means the enhancement of peristalsis in, and thus the movement through the gastrointestinal tract.
  • dispepsia as used herein means a condition characterized by an impairment of the power or function of digestion that can arise as a symptom of a primary gastrointestinal dysfunction or as a complication due to other disorders such as appendicitis, gallbladder disturbances, or malnutrition.
  • gastroparesis means a paralysis of the stomach brought about by a motor abnormality in the stomach or as a complication of diseases such as diabetes, progressive systemic sclerosis, anorexia nervosa, or myotonic dystrophy.
  • constipation means a condition characterized by infrequent or difficult evacuation of feces resulting from conditions such as lack of intestinal muscle tone or intestinal spasticity.
  • post-operative ileus means an obstruction in the intestine due to a disruption in muscle tone following surgery.
  • intestinal pseudo-obstruction means a condition characterized by constipation, colicky pain, and vomiting, but without evidence of physical obstruction.
  • N-7505 dihydrochloride contains three chiral centers and can be chemically synthesized as an enantiomerically and diastereomerically pure product.
  • the chiral purities of key starting materials can be assessed by, for example, chiral HPLC or chiral GC methods to assure the diastereomeric purity of N-7505 dihydrochloride and other compounds of the invention with one or more chiral centers.
  • An efficient chemical resolution process can be used to produce enantiomerically pure 6-amino- 5-chloro-2-methoxy-N-(3-methoxypiperidin-4-yl)nicotinamide.
  • the chiral purity of enantiomerically pure 6-amino-5 ⁇ chloro-2-methoxy-N-(3-methoxypiperidin-4- yl)nicotinamide can be assessed by a chiral HPLC method to assure greater than or equal to, for example, 98% enantiomeric excess (e.e.) quality.
  • Enantiomerically pure 6-amino-5- chloro-2-methoxy-N-(3-methoxypiperidin-4-yl)nicotinamide can then be reacted with ethyl 6-bromohexanoate under basic conditions to make the corresponding alkylated ethyl ester.
  • a transesterification reaction between the ethyl ester and (R)-(-)-3-quinuclidinol (preferably greater than or equal to 98% e.e. by chiral GC), is used to make ⁇ -7505 dihydrochloride.
  • the final product is isolated as a dihydrochloride salt.
  • Step 1 Resolution of Racemic 6-amino-5-chIoro-2-methoxy- ⁇ '-(3-methoxypiperidin-4- yl)nicotinamide
  • (-)-Dibenzoyl-L-tartaric acid ((-)-DBT, about 1 part by weight) was dissolved in ethanol and filtered to remove residual particulates.
  • racemic 6-amino-5-chloro-2- methoxy-N-(3-methoxypiperidin-4-yl)nicotinamide (about 0.8 part by weight) was dissolved in a mixture of ethanol and water and then filtered. The filtrate was heated to about 75 0 C before adding the (-)-DBT solution. After stirring at this temperature for about 30 minutes, the mixture was slowly cooled for several hours to about 5 0 C and the product salt was collected under vacuum filtration and washed with EtOHZH 2 O mixture. The wetcake was recrystallized from EtOHTH 2 O by heating to about 79 0 C and slow cooling to about 5 0 C as before. The product was collected on a vacuum filter and washed with EtOHTH 2 O to give a wetcake.
  • the wetcake was suspended in water and the pH was adjusted to about 12 using 7% (W/W) aq. NaOH. The resulting suspension was stirred for about 3 hours at room temperature before filtering under vacuum and washing the solid material with water and drying under vacuum.
  • the product was then retreated with (-)-DBT to form the salt by the same general procedure described above.
  • the isolated salt was then neutralized with aq. NaOH as described above.
  • the product was isolated on a filter and dried as before to provide (+)-6-amino-5-chloro-2-methoxy-N-(3-methoxypiperidin-4-yl)nicotinamide base (about 0.25 parts by weight). The e.e.
  • (+)-6-amino-5-chloro-2-methoxy-N-(3-methoxypiperidin-4-yl)nicotinamide (about 1 part by weight), potassium carbonate (about 0.48 part by weight) and potassium iodide (about 0.063 part by weight) were suspended in anhydrous USP ethanol.
  • Ethyl 6- bromohexanoate (about 0.76 part by weight) was added slowly to the suspension at room temperature. The mixture was heated to reflux until completion of the reaction. Subsequent cooling to room temperature the reaction mixture was filtered to remove, e.g., inorganic solids, and the filtrate was concentrated under reduced pressure to about one-half the volume.
  • the product was precipitated by slowly adding the crude material to cold water (about 13 parts by weight) with rapid stirring.
  • the precipitate was filtered under vacuum and washed with water and then reprecipitated twice more by dissolution in anhydrous ethanol and slow addition into cold water as before.
  • the resulting wetcake was washed with n-heptane and resuspended in ethyl acetate and n-heptane (1:9; v/v) and stirred for about 1 hour and before filtering and drying under vacuum to yield 0.73 parts by weight of the coupled product.
  • step (1 part by weight) and (R)-3-Quinuclidinol were suspended in toluene before slowly adding titanium (IV) ethoxide (about 0.5 part by weight) to the stirred suspension.
  • the mixture was heated to about 91 0 C under a stream of nitrogen, and partial vacuum was applied to the flask through a distillation apparatus in order to azeotropically remove the ethanol. Additional toluene was added as needed to maintain a minimum solvent volume in the flask. The reaction was considered complete after about 33 hours.
  • the resulting suspension was stirred for several hours before vacuum filtering and rinsing with, e.g., isopropanol.
  • the product was vacuum dried, initially at room temperature for several hours and then at about 55 0 C until a constant weight was achieved.
  • Step 1 Synthesis of ethyl 4-(dibenzylamino)-3-methoxypiperidine-l-carboxylate (1):
  • (-)-Dibenzoyl-L-tartaric acid (about 1.2 part by weight) is dissolved in ethanol before slowly adding to a solution of 2 (about 1 part by weight). The solution is gently warmed and then allowed to cool to room temperature to crystallize the salt product. The salt is filtered and washed with EtOH/H 2 O before suspending in water and basifying by adding aq. NaOH (7%, wt/wt) until the pH reaches about 12. The suspension is stirred vigorously at rt and the solid is filtered away, washed with water and vacuum dried to furnish the cis-isomer 3.
  • Titanium tetraethoxide is added to a mixture of 4 (1 part by mole) and (i?)-(-)-3- quinuclidinol (1 part by mole) in toluene.
  • the reaction mixture is equipped with a dean-stark apparatus before heating to about 90 0 C and partial vacuum is then applied (additional toluene is added as needed to main the requisite solvent level).
  • the mixture is then cooled to rt and the reaction is diluted with ethyl acetate and then water is added to the resulting mixture.
  • the organic layer is separated, brine washed, dried over anhyd. Na 2 SO 4 , filtered and concentrated. Purification over SiO 2 gives the enantiomerically enriched 5.
  • a debenzylation reaction by hydrogenolysis using Pd/C in methanol in the presence of atmospheric hydrogen gas set the stage for the alkylation step.
  • Treatment of 6-bromohexanenitrile in the presence of mild base and DMF generates compound 10.
  • a nitrile to ester conversion using (R)-quinuclidinol in the presence of dilute acid generates 11.
  • Subsequent removal of the Boc group using TFA furnishes the free amine, which can undergo a coupling reaction with requisite nicotinic acid in the presence of a coupling reagent such as ethyl chloroformate to afford N-7505 dihydrochloride as an enantiomerically pure material.
  • compound 9 can be alkylated using ethyl 6-bromohexanoate in the presence of mild base. Subsequent removal of the Boc group yields compound 14. Titanium mediated transesterification of 14 using (R)-quinuclidinol and titanium tetraethoxide in toluene solvent generates 15 (i?)-quinuclidin-3-yl 6-((35',4i?)-4-amino-3-methoxypiperidin-l-yl)hexanoate.
  • the free amine of 15 can undergo a coupling reaction with requisite nicotinic acid, in this exemplary case 6-aniino-5-chloro-2-methoxynicotinic acid, in the presence of a coupling reagent such as ethyl chloroformate to afford 16, N-7505 dihydrochloride, as an enantiomerically pure material.
  • Carlsburg esterase hydrolyzes esters that are of the S- configuration, therefore leaving intact esters that are of the R configuration.
  • (+) and (-)-6-amino-5-chloro-2-methoxy-N-(3-methoxypiperidin-4-yl)nicotinamide or (+) and (-)-6-amino-5-chloro-N-(3-methoxypiperidin-4-yl)-2-oxo-l,2-dihydropyridine-3- carboxamide can be made from their racemic mixtures by resolution of the enantiomers using conventional means such as optically resolving acids, according to the method described in US Patent 6,147,093, or in "Enantiomers, Racemates and Resolutions", by J. Jacques, A. Collet, and S.H. Wilen (Wiley-Interscience, New York, NY), or in S.H. Wilen et al., Tetrahedron (1977) 33:2725.
  • the 4 isomers of each of the above compounds can easily be obtained in low- milligram amounts by using preparative column chromatography followed by evaporation of the solvent. This method is useful for preparing small amounts for analytical and characterization purposes. This is a standard separation method used routinely in analytical labs in order to isolate and characterize metabolites.
  • Exemplary synthetic routes to Compound IVb, Compound VIb and (+)-Compound lib are described below using (+)-6-amino-5-chloro-2-methoxy-N-(3-methoxypiperidin-4- yl)nicotinamide as a starting material.
  • the routes to Compound IHb, Compound Vb and (-)- Compound lib are identical except that they use (-)-6 ⁇ amino-5-chloro-2-methoxy-N-(3- methoxypiperidin-4-yl)nicotinamide as a starting material.
  • Namepro software version 6.0.
  • piperidin-4-yl 4-((2-((3S,4R)-4- (6-amino-5 -chloro-2- methoxynicotinamido)-3- methoxypiperidin- 1 - yl)ethylamino)rnethyl)benzoate
  • piperidin-4-yl 4-((2-((3 S,4R)-4-(6- amino-5-chloro-2-oxo- 1 ,2- dihydropyridine-3 -carboxamido)- 3 -methoxypiperidin- 1 - yl)ethylamino)methyl)benzoate
  • piperidin-4-yl 4-(2-((3 S,4R)-4-(6- amino-5 -chloro-2-oxo- 1,2- dihydropyridine-3 -carboxamido)- 3 -methoxypiperidin- 1 - yl)ethylcarbamoyl)benzoate 3-fluorobenzyl 2-((3R,4S)-4-(6- amino-5 -chloro-2-oxo- 1,2- dihydropyridine-3 -carboxamido)- 3 -methoxypiperidin- 1 -yl)acetate
  • Dosage rates and routes of administration of the disclosed compounds are similar to those already used in the art and known to the skilled artisan (see, for example, Physicians' Desk Reference, 54th Ed., Medical Economics Company, Montvale, NJ, 2000).
  • a prophylactic or therapeutic dose of structural and/or functional analog of cisapride in the acute or chronic management of diseases and/or disorders described herein will vary with the severity of the condition to be treated, and the route of administration.
  • the dose, and perhaps the dose frequency, will also vary according to the age, body weight, and response of the individual patient.
  • the total daily dose range for structural and/or functional analogs of cisapride, for the conditions described herein is from about 1 mg to about 200 mg, in single or divided doses.
  • a daily dose range should be between about 5 mg to about 100 mg, in single or divided doses, while most preferably, a daily dose range should be between about 5 mg to about 75 mg, in single or divided doses.
  • the doses are administered from 1 to 4 times a day.
  • the therapy should be initiated at a lower dose, perhaps about 5 mg to about 10 mg, and increased up to about 50 mg or higher depending on the patient's global response. It is further recommended that children, and patients over 65 years, and those with impaired renal or hepatic function, initially receive low doses, and that they be titrated based on individual response(s) and blood level(s). It may be necessary to use dosages outside these ranges in some cases as will be apparent to those skilled in the art. Further, it is noted that the clinician or treating physician will know how and when to interrupt, adjust, or terminate therapy in conjunction with individual patient response.
  • compositions of the subject invention can be formulated according to known methods for preparing pharmaceutically useful compositions. Formulations are described in detail in a number of sources which are well known and readily available to those skilled in the art. For example, Remington's Pharmaceutical Science by E.W. Martin describes formulations which can be used in connection with the subject invention. In general, the compositions of the subject invention are formulated such that an effective amount of the bioactive compound(s) is combined with a suitable carrier in order to facilitate effective administration of the composition.
  • compositions of the subject invention include compositions such as suspensions, solutions and elixirs; aerosols; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like, in the case of oral solid preparations (such as powders, capsules, and tablets) with the oral solid preparations being preferred over the oral liquid preparations.
  • oral solid preparations such as powders, capsules, and tablets
  • a preferred oral solid preparation is capsules.
  • the most preferred oral solid preparation is tablets.
  • Preferred amounts of active ingredient (i.e., an structural and/or functional analog of cisapride) in a solid dosage form are about 5 mg, 10 mg, and 25 mg.
  • acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories and dispersible granules.
  • a solid carrier can be one or more substances which may act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents or encapsulating materials.
  • the disclosed pharmaceutical compositions may be subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, such as packeted tablets, capsules, and powders in paper or plastic containers or in vials or ampules.
  • the unit dosage can be a liquid based preparation or formulated to be incorporated into solid food products, chewing gum, or lozenge.
  • the compounds of the present invention may also be administered by controlled release means and/or delivery devices such as those described in U.S. Pat. Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719, the disclosures of which are hereby incorporated by reference in their entirety.
  • Any suitable route of administration may be employed for providing the patient with an effective dosage of a structural and/or functional analog of cisapride.
  • oral, rectal, parenteral (subcutaneous, intramuscular, intravenous), transdermal, and like forms of administration may be employed.
  • Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, patches, and the like.
  • One aspect of the invention provides a method of treating gastroesophageal reflux disease in a mammal, while substantially reducing the concomitant adverse effects associated with the administration of cisapride, which comprises administering to a human in need of such treatment, a therapeutically effective amount of a structural and/or functional analog of cisapride, or a pharmaceutically acceptable salt thereof.
  • a preferred aspect is the treatment of gastroesophageal reflux disease in humans.
  • compositions for the treatment of a human suffering from gastroesophageal reflux disease which comprises a therapeutically effective amount of a structural and/or functional analog of cisapride, or a pharmaceutically acceptable salt thereof.
  • Yet another aspect of the present invention provides a method of eliciting an antiemetic effect in a mammal, while substantially reducing the adverse effects associated with the administration of cisapride, which comprises administering to a mammal in need of such anti-emetic therapy, a therapeutically effective amount of structural and/or functional analogs of cisapride, or a pharmaceutically acceptable salt thereof.
  • the mammal is a human.
  • the present invention encompasses an anti-emetic composition for the treatment of a mammal in need of anti-emetic therapy, which comprises a therapeutically effective amount of a structural and/or functional analog of cisapride, or a pharmaceutically acceptable salt thereof.
  • a further aspect of the present invention includes a method of treating a condition caused by gastrointestinal motility dysfunction in a mammal which comprises administering to a mammal in need of treatment for gastrointestinal motility dysfunction, a therapeutically effective amount of a structural and/or functional analog of cisapride, or a pharmaceutically acceptable salt thereof.
  • Conditions caused by gastrointestinal motility dysfunction include, but are not limited to, dyspepsia, gastroparesis, constipation, post-operative ileus, and intestinal pseudo-obstruction.
  • the mammal is a human.
  • Cisapride is a potent ligand at 5HT 4 receptors, and these receptors are located in several areas of the central nervous system. Modulation of serotonergic systems has a variety of behavioral effects.
  • the compounds of the subject invention can be used in the treatment of: 1) cognitive disorders, including but not limited to Alzheimer's disease; 2) behavioral disorders, including but not limited to schizophrenia, mania, obsessive-compulsive disorder, and psychoactive substance use disorders; 3) mood disorders, including but not limited to depression and anxiety; and 4) disorders of control of autonomic function, including but not limited to essential hypertension and sleep disorders.
  • the present invention also provides methods of treating cognitive, behavioral, mood, or autonomic function control disorders in a mammal comprising the administration of a therapeutically effective amount of structural and/or functional analog of cisapride, or a pharmaceutically acceptable salt thereof.
  • the mammal is a human.

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Abstract

The subject invention provides stereoisomeric compounds of formulae (Xa) and (Xb); wherein the variables are as defined herein, and compositions for the safe and effective treatment of various gastrointestinal disorders including, but not limited to, gastroparesis, gastroesophageal reflux and related conditions. The compounds of the subject invention are also useful in treating a variety of conditions involving the central nervous system.

Description

DESCRIPTION
STEREOISOMERIC PYRIDYL AND PYRIDONYL COMPOUNDS AND METHODS FOR THE TREATMENT OF GASTROINTESTINAL AND CENTRAL NERVOUS
SYSTEM DISORDERS
Background of Invention
Cisapride is one of a class of compounds known as benzamide derivatives, the parent compound of which is metoclopramide. U.S. Patent Nos. 4,962,115 and 5,057,525 (collectively "Van Daele" and incorporated by reference in their entireties) disclose N-(3- hydroxy-4-piperidenyl) benzamides of cisapride. Van Daele discloses that these compounds, the pharmaceutically acceptable acid addition salts thereof and the stereochemically isomeric forms thereof, stimulate the motility of the gastrointestinal system.
As a class, these benzamide derivatives have several prominent pharmacological actions. The prominent pharmacological activities of the benzamide derivatives are due to their effects on the neuronal systems which are modulated by the neurotransmitter serotonin. The role of serotonin, and thus the pharmacology of the benzamide derivatives, has been broadly implicated in a variety of conditions for many years. Thus, research has focused on locating the production and storage sites of serotonin as well as the location of serotonin receptors in the human body in order to determine the connection between these sites and various disease states or conditions.
In this regard, it was discovered that a major site of production and storage of serotonin is the enterochromaffin cell of the gastrointestinal mucosa. It was also discovered that serotonin has a powerful stimulating action on intestinal motility by stimulating intestinal smooth muscle, speeding intestinal transit, and decreasing absorption time, as in diarrhea. This stimulating action is also associated with nausea and vomiting.
Because of their modulation of the serotonin neuronal system in the gastrointestinal tract, many of the benzamide derivatives are effective anti-emetic agents and are commonly used to control vomiting during cancer chemotherapy or radiotherapy, especially when highly emetogenic compounds such as cisplatin are used. This action is almost certainly the result of the ability of the compounds to block the actions of serotonin (5HT) at specific sites of action, called the 5HT3-receptor, which was classically designated in the scientific literature as the serotonin M-receptor. Chemotherapy and radiation therapy may induce nausea and vomiting by the release of serotonin from damaged enterochromaffin cells in the gastrointestinal tract. Release of the neurotransmitter serotonin stimulates both afferent vagal nerve fibers (thus initiating the vomiting reflex) and serotonin receptors in the chemoreceptor trigger zone of the area postrema region of the brain. The anatomical site for this action of the benzamide derivatives, and whether such action is central (CNS), peripheral, or a combination thereof, remains unresolved (Barnes et al., J. Pharm. Pharmacol. 40: 586-588, 1988). Cisapride, like the other benzamide derivatives would appear to be an effective antiemetic agent based on its ability to modulate the activity of serotonin at the 5HT3 receptor.
A second prominent action of the benzamide derivatives is in augmenting gastrointestinal smooth muscle activity from the esophagus through the proximal small bowel, thus accelerating esophageal and small intestinal transit as well as facilitating gastric emptying and increasing lower esophageal sphincter tone (Decktor et al., Eur. J. Pharmacol. 147: 313-316, 1988). Although the benzamide derivatives are not cholinergic receptor agonists per se, the aforementioned smooth muscle effects may be blocked by muscarinic receptor blocking agents such as atropine or neuronal transmission inhibitors of the tetrodotoxin type which affect sodium channels. Similar blocking activity has been reported for the contractile effects of serotonin in the small intestine. It is currently believed that the primary smooth muscle effects of the benzamide derivatives are the result of an agonist action upon a new class of serotonin receptors referred to as 5HT4 receptors which are located on interaeurons in the myenteric plexus of the gut wall. Activation of these receptors subsequently enhances the release of acetylcholine from parasympathetic nerve terminals located near surrounding smooth muscle fibers, and it is the combination of acetylcholine with its receptors on smooth muscle membranes which is the actual trigger for muscle contraction.
A discussion of various 5HT receptors, including the 5HT4 receptor can be found in, for example, U.S. Patent Nos. 6, 331,401 and 6,632,827, which are incorporated by reference herein in their entirety.
Cisapride has been used primarily to treat gastroesophageal reflux disease (GERD). This disease is characterized as the backward flow of the stomach contents into the esophagus. One of the most important factors in the pathogenesis of gastroesophageal reflux disease is a reduction in the pressure barrier due to the failure of the lower esophageal sphincter. Failure of the lower esophageal sphincter can arise due to a low basal pressure, sphincter relaxation, or to a non-compensated increase in intragastric pressure. Other factors in the pathogenesis of the disease are delayed gastric emptying, insufficient esophageal clearing due to impaired peristalsis and the corrosive nature of the reflux material which can damage esophageal mucosa. Cisapride is thought to strengthen the anti-reflux barrier and improve esophageal clearance by increasing the lower esophageal sphincter pressure and enhancing peristaltic contractions.
Because of its activity as a prokinetic agent, cisapride would also appear to be useful to treat dyspepsia, gastroparesis, constipation, post-operative ileus, and intestinal pseudoobstruction. Dyspepsia is a condition characterized by an impairment of the power or function of digestion that can arise as a symptom of a primary gastrointestinal dysfunction or as a complication due to other disorders such as appendicitis, gallbladder disturbances, or malnutrition. Gastroparesis is a paralysis of the stomach brought about by a motor abnormality in the stomach or as a complication of diseases such as diabetes, progressive systemic sclerosis, anorexia nervosa or myotonic dystrophy. Constipation is a condition characterized by infrequent or difficult evacuation of feces resulting from conditions such as lack of intestinal muscle tone or intestinal spasticity. Post-operative ileus is an obstruction in the intestine due to a disruption in muscle tone following surgery. Intestinal pseudoobstruction is a condition characterized by constipation, colicky pain, and vomiting, but without evidence of physical obstruction.
Drug toxicity is an important consideration in the treatment of humans and animals. Toxic side effects (adverse effects) resulting from the administration of drugs include a variety of conditions which range from low grade fever to death. Drug therapy is justified only when the benefits of the treatment protocol outweigh the potential risks associated with the treatment. The factors balanced by the practitioner include the qualitative and quantitative impact of the drug to be used as well as the resulting outcome if the drug is not provided to the individual. Other factors considered include the physical condition of the patient, the disease stage and its history of progression, and any known adverse effects associated with a drug.
Drug elimination is typically the result of metabolic activity upon the drug and the subsequent excretion of the drug from the body. Metabolic activity can take place within the vascular supply and/or within cellular compartments or organs. The liver is a principal site of drug metabolism. The metabolic process can be categorized into synthetic and nonsynthetic reactions. In nonsynthetic reactions, the drug is chemically altered by oxidation, reduction, hydrolysis, or any combination of the aforementioned processes. These processes are collectively referred to as Phase I reactions.
In Phase II reactions, also known as synthetic reactions or conjugations, the parent drug, or intermediate metabolites thereof, are combined with endogenous substrates to yield an addition or conjugation product. Metabolites formed in synthetic reactions are, typically, more polar and biologically inactive. As a result, these metabolites are more easily excreted via the kidneys (in urine) or the liver (in bile). Synthetic reactions include glucuronidation, amino acid conjugation, acetylation, sulfocoηjugation, and methylation.
More than 90% of a dose of cisapride is metabolized by oxidative N-dealkylation at the piperidine nitrogen or by aromatic hydroxylation occurring on either the 4-fluorophenoxy or benzamide rings.
The administration of cisapride to a human has been found to cause serious adverse effects including CNS disorders, increased systolic pressure, interactions with other drugs, diarrhea, and abdominal cramping. Further, it has been reported that intravenous administration of cisapride demonstrates the occurrence of additional adverse effects not experienced after oral administration of cisapride (Stacher et al. [1987] Digestive Diseases and Sciences 32(11): 1223-1230). It is believed that these adverse effects are caused by the metabolites that result from the oxidative dealkylation or aromatic hydroxylation of the compound which occurs in the cytochrome P450 detoxification system. Cisapride is also subject to a number of undesirable drug/drug interactions that are also a result of metabolism by the cytochrome P450 system.
Between July 1993 and December 1999, cisapride (PROPULSID, Janssen Pharmaceutica Products, L.P.) was reportedly associated with at least 341 serious cardiac arrhythmias. These arrhythmias include ventricular tachycardia, ventricular fibrillation, torsades de pointes, and QT prolongation. Eighty (80) deaths have been reported. As a result of these adverse effects, the product was voluntarily withdrawn from the open market in the United States; however, the drug is available through an investigational limited access program.
The safety of 5HT4 receptor agonists with gastrointestinal (GI) prokinetic activity has been limited due to cardiac effects (prolongation of QTc intervals, tachycardia, torsades de pointes) and adverse drug interactions due to hepatic cytochrome P-450 metabolism. A GI prokinetic agent of this class that lacks these liabilities would be very valuable in several therapeutic areas including GERD and gastric emptying disorders. Certain cisapride derivatives have been described in U.S. Pat. No. 6,552,046 and WO 01/093849 (incorporated by reference herein in their entireties), however further compounds with even more advantageous properties would be desirable.
It has now been discovered that certain stereoisomers of one such esterified structural and/or functional analogs of cisapride have distinct and particularly advantageous properties.
Brief Summary
The subject invention provides compounds and compositions of formulae Xa and Xb, which are stereoisomeric, functional and/or structural analogs of cisapride, for the safe and effective treatment of various gastrointestinal disorders including, but not limited to, gastroparesis, gastroesophageal reflux and related conditions. The compounds of the subject invention are also useful in treating a variety of conditions involving the central nervous system.
The compounds of the invention comprise compounds of formulae Xa and/or Xb:
and pharmaceutically acceptable salts thereof, wherein the bonds at positions 3 and 4 are cis relative to each other; L is -(C1-C6 alkyl)- (in one aspect, -(C3-C5 alkyl)-), -(Ci-C6 alkyl)-C(O)-, or -C(O)- (C1-C6 alkyl)-, wherein each of the alkyl groups is optionally substituted with 1 or 2 groups that are independently halogen, Ci-C4 alkoxy, or OH and wherein one carbon in the alkyl portion of L may be replaced by -N(Rg)-; or
L is -(Ci-C4 alkyl)-NR9-(Ci-C4 alkyl)-, -(Ci-C4 alkyl)-C(O)NR9-, -(Ci-C4 alkyl)-, -(C1-C4 alkyl)-NR9C(O)- or -C(O)NR9-(C1-C4 alkyl)-;
R1 is halogen;
R2 is amino, NH(Ci-C4 alkyl) or N(C1-C4 alkyl)(Ci-C4 alkyl);
R3 is H, Ci-C4 alkyl, Ci-C4 alkoxy, or OH;
R4 is H or Ci-C4 alkyl, and in one preferred aspect, methyl; and
Rs is -O-Ci-Cδ-alkyl, -0-C3-C8 cycloalkyl, -O-heterocycloalkyl, heterocycloalkyl, aryl, -O-aryl, -N(R9)-(C0-C6 alkyl)-C(O)-aryl, or -N(R9)-C0-C6 alkyl-aryl, -O-heteroaryl, - N(R9)-Ci-C6(O)-heteroaryl, or -N(R9)-Co-C6 alkyl-heteroaryl, wherein each of the cyclic groups is unsubstituted or substituted at one or more substitutable positions with Ci-C6 alkyl, Ci-C6 alkoxy, halogen, Q -C6 haloalkyl, Ci-C6 haloalkoxy, hydroxyl, hydroxy-Ci-C4-alkyl, amino, -NH(Ci-C6 alkyl), -N(Cj-C6 alkyl)(Ci-C6 alkyl), -(C0-C6 alkyl)-C(O)Rn, -0-(C0-C6 alkyl)-C(O)Rn, methylsulfone, Co-C6-sulfonamide, NO2, -CO2R]0, Or -(C1-C4 alkyl)- CO2Ri o; wherein
R9 at each occurrence is independently H or Ci-C4 alkyl;
R10 at each occurrence is independently H, Ci-C4 alkyl optionally substituted with one group that is selected from a 5 or 6 membered monocyclic heterocycloalkyl ring, and OH, quinuclidinyl, -C(O)NH2, -C(O)NH(Ci-C4 alkyl), -C(O)N(Ci-C4 alkyl)(Ci-C4 alkyl) or piperidinyl optionally substituted with Ci-C4 alkyl;
Rn is Ci-C6 alkyl, or OH; or
Rn is NH2, -NH(Ci-C6 alkyl), or -N(C1-C6 alkyl)(Ci-C6 alkyl); or
Rn is Ci-C6 alkoxy, optionally substituted with 1 or 2 groups that are independently Ci-C4 alkoxy, amino, -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)(Ci-C6 alkyl), heterocycloalkyl, OH, -(C0-C6 alkyl)-C(O)N(R9)-heterocycloalkyl, -O-heterocycloalkyl, -Ci-C6(O)N(R9)-heteroaryl, or heteroaryl, wherein the heterocycloalkyl groups are optionally substituted with 1, 2, or 3 groups that are independently halogen, C1-C6 alkyl, C]-C6 alkoxy, hydroxy, hydroxy Cj-C6 alkyl, Ci-C6 alkoxycarbonyl, -CO2H, CF3, or OCF3, the heteroaryl group is optionally substituted with 1, 2, or 3 groups that are independently halogen, C1-C6 alkyl, Ci-C6 alkoxy, hydroxy, hydroxy Ci-C6 alkyl, Ci-
C6 alkoxycarbonyl, -CO2H3 CF3, or OCF3; or
Rn is heterocycloalkyl or -O-heterocycloalkyl wherein the heterocycloalkyl is optionally substituted with 1, 2, or 3 groups that are independently halogen, Ci-C6 alkyl, C1- C6 alkoxy, hydroxy, hydroxy Ci-C6 alkyl, Ci-C6 alkoxycarbonyl, -CO2H, CF3, or OCF3; and
R2o is -H, Ci-C6 alkoxy (preferably Ci-C4 alkoxy, more preferably methoxy), or OH.
The invention also encompasses compositions comprising at least one compound of formulae Xa and Xb and at least one pharmaceutically acceptable excipient, adjuvant, carrier, or solvent.
The compounds of formulae Xa and Xb are useful in the treatment or prevention of gastroesophageal reflux disease and substantially reduce adverse effects associated with the administration of cisapride. These adverse effects include, but are not limited to, diarrhea, abdominal cramping and elevations of blood pressure and heart rate.
Additionally, the compounds and compositions of the invention are useful in treating emesis and other conditions, including but not limited to dyspepsia, gastroparesis, constipation, post-operative ileus and intestinal pseudo-obstruction. As an added benefit, adverse effects associated with the administration of cisapride are also reduced in these methods of treatment.
Advantageously, the compounds of the subject invention are ligands for the 5HT4 receptor and, accordingly, can be used to treat conditions mediated through this receptor. These receptors are located in several areas of the central nervous system and the modulation of these receptors can be used to effect desired modulations of the CNS.
Advantageously, the subject invention provides stereoisomeric compounds which contain an ester moiety that does not detract from the ability of these compounds to provide a therapeutic benefit, but which makes them more susceptible to degradation by serum and/or cytosolic esterases, thereby avoiding the cytochrome P450 drug detoxification system associated with adverse effects caused by cisapride and reducing the incidence of such adverse events.
The subject invention further provides methods of treatment comprising the administration of the compounds of formulae Xa and Xb and therapeutically effective amounts to individuals in need of treatment for gastroesophageal reflux disease, dyspepsia, gastroparesis, constipation, post-operative ileus, and intestinal pseudo-obstruction; and related conditions.
Advantageously, the therapeutic compounds of the subject invention are stable in storage and provide for safer metabolism of the drugs as compared to other drugs; therefore, the compounds of the subject invention can be used with a lower incidence of side effects and toxicity.
In a further aspect, the subject invention pertains to the breakdown products (preferably metabolic breakdown products) which are formed when the therapeutic compounds of the subject invention are acted upon by esterases. These breakdown products can be used as described herein to monitor the clearance of the therapeutic compounds from a patient.
In yet a further aspect, the subject invention provides methods for synthesizing the therapeutic stereoisomeric compounds of the subject invention, as well as intermediates useful in preparing the compounds of interest.
Detailed Disclosure
In a further aspect, the invention provides compounds of Formulae Xa and Xb, wherein
R5 is -O-Ci-Q-alkyl, -0-C3-Cs cycloalkyl, -O-heterocycloalkyl, heterocycloalkyl, wherein the heterocycloalkyl group is selected from piperidinyl, piperazinyl, pyrrolidinyl, aza-bicyclo-octyl, in certain embodiments aza-bicyclo[2.2.2]octyl, aza-bicyclo[3.2.1]octyl, aza-bicyclo-nonyl, aza-bicyclo-decyl, indolinyl, morpholinyl, thiomorpholinyl, S5S- dioxothiomorpholinyl, and imidazolidinyl, -O-aryl, -N(R9)-C(O)-aryl, or -N(Rg)-Co-C6 alkyl- aryl, wherein each of the cyclic groups is unsubstituted or substituted at one or more substitutable positions with C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, hydroxy-Q-Q-alkyl, amino, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(Ci-C6 alkyl), -C(O)Rn, OrNO2; wherein
R9 at each occurrence is independently H or Cj-C4 alkyl; and
Rn is Ci-C6 alkyl, OH, or
Rn is Ci-C6 alkoxy, optionally substituted with 1 or 2 groups that are independently C1-C4 alkoxy, amino, -NH(Ci-C6 alkyl), -N(C1-C6 alkyl)(Ci-C6 alkyl), -C(O)N(R9)- heterocycloalkyl, heterocycloalkyl or heteroaryl, wherein the heterocycloalkyl group is selected from pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, aza-bicyclo-octyl, in certain embodiments aza- bicyclo[2.2.2]octyl, aza-bicyclo[3.2.1]octyl, aza-bicyclo-nonyl and aza-bicyclo-decyl, wherein the heterocycloalkyl groups are optionally substituted with 1, 2, or 3 groups that are independently halogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxy, hydroxy C1-C6 alkyl, C1-C6 alkoxycarbonyl, -CO2H, CF3, or OCF3, the heteroaryl group is selected from pyridyl, pyrimidyl, quinolinyl, isoquinolinyl, and indolyl, wherein the heteroaryl groups are optionally substituted with 1, 2, or 3 groups that are independently halogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxy, hydroxy C1-C6 alkyl, Ci-C6 alkoxycarbonyl, -CO2H, CF3, or OCF3; or Rn is -O-heterocycloalkyl wherein the heterocycloalkyl is selected from piperidinyl, pyrrolidinyl, imidazolidinyl, morpholinyl, aza-bicyclo-octyl, in certain embodiments aza- bicyclo[2.2.2]octyl, aza-bicyclo[3.2.1]octyl, aza-bicyclo-nonyl, aza-bicyclo-decyl, and tetrahydrofuranyl, and wherein each heterocycloalkyl group is optionally substituted with 1,
2, or 3 groups that are independently halogen, Ci-C6 alkyl, Ci-C6 alkoxy, hydroxy, hydroxy
Ci-C6 alkyl, Ci-C6 alkoxycarbonyl, -CO2H, CF3, or OCF3.
In another aspect, the invention provides compounds of Formulae Xa and Xb, wherein
R1 is chloro.
In yet another aspect, the invention provides compounds of Formulae Xa and Xb, wherein R2 is amino.
In still another aspect, the invention provides compounds of Formulae Xa and Xb, wherein R3 is methyl.
In another aspect, the invention provides compounds of Formulae Xa and Xb, wherein
R4 is H or methyl.
In still yet another aspect, the invention provides compounds of Formulae Xa and Xb, wherein Ri is chloro; R2 is amino; R3 is methyl; and R4 is H or methyl.
In yet another aspect, the invention provides compounds of Formulae Xa and Xb, wherein Ri is chloro; R2 is amino; R3 is methyl; R4 is H, and L is -(C4-C6 alkyl)-C(O)-.
In another aspect, the invention provides compounds of Formulae Xa and Xb, wherein two or more previously described aspects are combined.
In another aspect, the invention provides compounds of Formulae XIa and XIb, which are compounds of Formulae Xa and Xb wherein R20 is OCH3 and L is -(CH2)5-C(O)-:
In yet still another aspect, the invention provides compounds of Formulae XIa and XIb, wherein R1 is chloro; R2 is amino; R3 is methyl; and R4 is H or methyl.
In still another aspect, the invention provides compounds of Formulae XIa and XIb, wherein R5 is-O-heterocycloalkyl, wherein the heterocycloalkyl group is selected from aza- bicyclo-octyl, in certain embodiments l-aza-bicyclo[2.2.2]oct-3-yl or 8-aza- bicyclo[3.2.1]oct-3-yl, aza-bicyclo-nonyl, aza-bicyclo-decyl, where the aza nitrogen, is optionally substituted with methyl or ethyl; and R4 is H or methyl.
In still yet another aspect, the invention provides compounds of Formulae XIa and XIb, wherein R5 is -O-heterocycloalkyl, wherein the heterocycloalkyl group is selected from piperidinyl, piperazinyl, or pyrrolidinyl, each of which is unsubstituted or substituted at one or two positions with groups that are independently C1-C4 alkyl, C1-C4 alkoxy, halogen, C1- C4 haloalkyl (in one aspect, CF3), C1-C4 haloalkoxy (in one aspect OCF3), hydroxy 1, hydroxy C1-C4 alkyl, amino, -NH(C1-C4 alkyl), -N(Ci-C4 alkyl)(d-C4 alkyl), -(Ci-C6 alkyl)-C(O)Rn, or NO2; and R4 is H or methyl.
In yet another aspect, the invention provides compounds of Formulae XIa and XIb, wherein R5 is -O-heterocycloalkyl, wherein the heterocycloalkyl group is selected from indolinyl, morpholinyl, thiomorpholinyl, S,S-dioxothiomorpholinyl, and imidazolidinyl, each of which is unsubstituted or substituted at one or two positions with groups that are independently Ci-C4 alkyl, Cj-C4 alkoxy, halogen, C1-C4 haloalkyl (in one aspect, CF3), Q- C4 haloalkoxy (in one aspect OCF3), hydroxyl, hydroxy C1-C4 alkyl, amino, -NH(Ci-C4 alkyl), -N(C1-C4 alkyl)(C1-C4 alkyl), -(C0-C6 ^yI)-C(O)R11; or NO2; and R4 is H or methyl.
In yet another aspect, the invention provides compounds of Formulae XIa and XIb, wherein R5 is -O-phenyl, N(Rg)-(C0-C6 alkyl)-C(O)-phenyl, or -N(R9)-C0-C4 alkyl-phenyl, wherein the phenyl group is substituted with one or two groups that are independently C1-C4 alkyl, C1-C4 alkoxy, halogen, C1-C4 haloalkyl (in one aspect, CF3), Ci-C4 haloalkoxy (in one aspect OCF3), hydroxyl, hydroxy Ci-C4 alkyl, amino, -NH(Ci-C4 alkyl), -N(C1-C4 alkyl)(Ci- C4 alkyl), -(Co-C6 alkyl)-C(O)Rπ, or NO2; and R4 and R9 are independently H or methyl.
In another aspect, the invention provides compounds of Formulae XIa and XIb, wherein R4 is H.
In yet another aspect, the invention provides compounds of Formulae XIa and XIb, wherein Rn is Ci-C6 alkoxy, optionally substituted with 1 or 2 groups that are independently Ci-C4 alkoxy, amino, -NH(Ci-C6 alkyl), -N(C1-C6 alkyl)(d-C6 alkyl), -(C0-C6 alkyl)- C(O)N(R9)-heterocycloalkyl, or heterocycloalkyl wherein the heterocycloalkyl group is selected from pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl, wherein the heterocycloalkyl groups are optionally substituted with 1, 2, or 3 groups that are independently halogen, C1-C6 alkyl, Ci-C6 alkoxy, hydroxy, hydroxy CpC6 alkyl, Ci-C6 alkoxycarbonyl, -CO2H, CF3, or OCF3.
In another aspect, the invention provides compounds of Formulae XIa and XIb, wherein two or more previously described aspects are combined.
In another aspect, the invention provides compounds of Formulae XIIa and XIIb, i.e., compounds of Formulae Xa and Xb, of the formulae:
wherein R15 is H, Ci-C6 alkyl, Ci-C6 alkoxy, halogen, Ci-C6 haloalkyl (in one aspect CF3), Ci-C6 haloalkoxy ( in one aspect OCF3), hydroxyl, hydroxy Ci-C4 alkyl, amino, -NH(Ci-C6 alkyl), -N(Ci-C6 alkylXQ-Ce alkyl), methylsulfone, C0-C6-sulfonamide OrNO2, and R16 is H or -0-(C0-C6 alkyl)-C(O)Rn. In another aspect, Ri5 is H.
In yet another aspect, the invention provides compounds of Formulae XIIa and XIIb, wherein R4 and R9 are independently H or methyl and Rn is OH.
In still yet another aspect, the invention provides compounds of Formulae XIIa and XIIb, wherein R4 and Rg are independently H or methyl and R11 is Ci-C6 alkoxy, optionally substituted with 1 or 2 groups that are independently Ci-C4 alkoxy, amino, -NH(CI-CO alkyl), -N(Ci-C6 alkyl)(Ci-C6 alkyl), -(C0-C6 alkyl)-C(O)N(R9)-heterocycloalkyl, or heterocycloalkyl wherein the heterocycloalkyl group is selected from aza-bicyclo-octyl, in certain embodiments l-aza-bicyclo[2.2.2]oct-3-yl or 8-aza-bicyclo[3.2.1]oct-3-yl, aza- bicyclo-nonyl, aza-bicyclo-decyl, where the aza nitrogen is optionally substituted with methyl or ethyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl, wherein the heterocycloalkyl groups are optionally substituted with 1, 2, or 3 groups that are independently halogen, Ci-C6 alkyl, Ci-C6 alkoxy, hydroxy, hydroxy Ci-C6 alkyl, Ci-C6 alkoxycarbonyl, -CO2H, CF3, or OCF3, and R4 and R9 are independently H or methyl. In another aspect, R4, R9, and Rn are as previously defined and R15 is H, Ri is chloro; R2 is amino; and R3 is methyl.
In yet still another aspect, the invention provides compounds of Formulae XIIa and XIIb, wherein R4 and R9 are independently H or methyl and Rn is Ci-C6 alkoxy, optionally substituted with 1 or 2 groups that are independently Ci-C4 alkoxy, amino, -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)(Ci-C6 alkyl), or heteroaryl, wherein the heteroaryl group is selected from pyridyl, pyrimidyl, quinolinyl, isoquinolinyl, and indolyl, wherein the heteroaryl groups are optionally substituted with 1, 2, or 3 groups that are independently halogen, Ci-C6 alkyl, Ci- C6 alkoxy, hydroxy, hydroxy Cj-C6 alkyl, Ci-C6 alkoxycarbonyl, -CO2H, CF3, or OCF3; and R4 and R9 are independently H or methyl. In another aspect, R4, R9, and Rn are as previously defined and R15 is H, Ri is chloro; R2 is amino; and R3 is methyl.
In still another aspect, the invention provides compounds of Formulae XIIa and XIIb, wherein at least one OfR4 and R9 is H.
In another aspect, the invention provides compounds of Formulae XIIa and XIIb, wherein two or more previously described aspects are combined.
In another aspect, the invention provides compounds of Formulae XIIIa and XIIIb, i.e., compounds of Formula XIIa and XIIb, of the formulae:
wherein R15 is H, Ci-C6 alkyl, Ci-C6 alkoxy, halogen, Ci-C6 haloalkyl (in one aspect CF3), Ci-Ce haloalkoxy ( in one aspect OCF3), hydroxyl, hydroxy Ci-C4 alkyl, amino, -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)(Ci-C6 alkyl), or methylsulfone, Co-C6-sulfonamide, NO2, and Ri6 is H Or-O-(C0-C6 alkyl)-C(O)Ru. In another aspect, Ri5 is H.
In yet another aspect, the invention provides compounds of Formulae XIIIa and XIIIb, wherein, R4 and R9 are independently H or methyl, and Rn is OH, Cj-C4 alkoxy (in another aspect, Ci-C3 alkoxy), or Ci-C2 alkoxy-Ci-C3 alkoxy-. In another aspect, R4, R9, and R1] are as previously defined and Ri is chloro; R2 is amino; and R3 is methyl.
In still yet another aspect, the invention provides compounds of Formulae XIIIa and XIIIb, wherein R4 and R9 are independently H or methyl, and Rn is Ci-C4 alkoxy substituted with amino, -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)(Ci-C6 alkyl), aza-bicyclo-octyl, in certain embodiments l-aza-bicyclo[2.2.2]oct-3-yl or 8-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo-nonyl, aza-bicyclo-decyl, where the aza nitrogen is optionally substituted with methyl or ethyl; and R4 is H or methyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridyl, or -(C0-C6 alkyl)-C(O)NH- pyrid-4-yl. In another aspect, R4, R9, and Rn are as previously defined and Ri is chloro; R2 is amino; and R3 is methyl.
In still another aspect, the invention provides compounds of Formulae XIIIa and XIIIb, wherein R4 and R9 are independently H or methyl, and Rn is Ci-C4 alkoxy substituted with amino, -NH(Ci-C6 alkyl), or -N(C1-C6 alkyl)(Ci-C6 alkyl). In another aspect, R4, R9, and Rn are as previously defined and Ri is chloro; R2 is amino; and R3 is methyl.
In yet another aspect, the invention provides compounds of Formulae XIIIa and XIIIb, wherein R4 and R9 are independently H or methyl, and R11 is Ci-C4 alkoxy substituted with pyrrolidinyl, piperidinyl, morpholinyl, pyridyl, or -(Co-C6 alkyl)-C(O)NH-pyrid-4-yl. In another aspect, R4, R9, and Rn are as previously defined and R1 is chloro; R2 is amino; and R3 is methyl.
In still another aspect, the invention provides compounds of Formulae XIIIa and XIIIb, wherein at least one OfR4 and R9 is H.
In another aspect, the invention provides compounds of Formulae XIIIa and XIIIb, wherein two or more previously described aspects are combined.
In another aspect, the invention provides compounds of Foπnulae XIVa and XIVb, i.e., compounds of Formulae Xa and Xb, of the formulae:
wherein Ri5 is H, Ci-C6 alkyl, Ci-C6 alkoxy, halogen, Ci-C6 haloalkyl (in one aspect CF3), Ci-C6 haloalkoxy ( in one aspect OCF3), hydroxyl, hydroxy Ci-C4 alkyl, amino, -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)(Ci-C6 alkyl), methylsulfone, C0-C6-sulfonamide, or NO2, and Ri6 is H or -0-(Co-C6 alkyl)-C(O)Rii. In another aspect, Ri5 is H. In still another aspect, the invention provides compounds of Formulae XIVa and XIVb, wherein R4 and Rg are independently H or methyl, and Rn is OH, C1-C4 alkoxy (in another aspect, C1-C3 alkoxy) or C1-C2 alkoxy-C]-C3 alkoxy-. In another aspect, R4, R9, and Rn are as previously defined and R1 is chloro; R2 is amino; and R3 is methyl. In still another aspect, at least one OfR4 and Rg is H.
In yet still another aspect, the invention provides compounds of Formulae XIVa and XIVb, wherein R4 and R9 are independently H or methyl, and R11 is C1-C4 alkoxy substituted with amino, -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)(Ci-C6 alkyl), aza-bicyclo-octyl, in certain embodiments l-aza-bicyclo[2.2.2]oct-3-yl or 8-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo-nonyl, aza-bicyclo-decyl, where the aza nitrogen is optionally substituted with methyl or ethyl; and R4 is H or methyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridyl, or -(C0-C6 alkyl)-C(O)NH- pyrid-4-yl. In another aspect, R4, Rg, and Rn are as previously defined and Ri is chloro; R2 is amino; and R3 is methyl.
In still another aspect, the invention provides compounds of Formulae XIVa and XIVb, wherein R4 and R9 are independently H or methyl, and Rn is C1-C4 alkoxy substituted with amino, -NH(Ci-C6 alkyl), or -N(Ci-C6 alkyl)(Ci-C6 alkyl). In another aspect, R4, R9, and Rn are as previously defined and R1 is chloro; R2 is amino; and R3 is methyl.
In yet another aspect, the invention provides compounds of Formulae XIVa and XIVb, wherein R4 and R9 are independently H or methyl, and Rn is Ci-C4 alkoxy substituted with pyrrolidinyl, piperidinyl, morpholinyl, pyridyl, or -(Co-C6 alkyl)-C(O)NH-pyrid-4-yl. In another aspect, R4, R9, and Rn are as previously defined and Ri is chloro; R2 is amino; and R3 is methyl.
In still another aspect, the invention provides compounds of Formulae XIVa and XIVb, wherein at least one OfR4 and Rg is H.
In another aspect, the invention provides compounds of Formulae XIVa and XIVb, wherein two or more previously described aspects are combined.
In another aspect, the invention provides compounds of Formulae XVa and XVb, i.e., compounds of Formulae Xa and Xb of the formulae:
wherein n is 1 or 2.
In still another aspect, the invention provides compounds of Formulae XVa and XVb, wherein R4 is H or methyl, and R11 is OH, Ci-C4 alkoxy (in another aspect, C1-C3 alkoxy) or Ci-C2 alkoxy-Ci-C3 alkoxy-. In another aspect, R4 and Rn are as previously defined and R1 is chloro; R2 is amino; and R3 is methyl. In still another aspect, at least one OfR4 and R9 is H.
In yet still another aspect, the invention provides compounds of Formulae XVa and XVb, wherein R4 and R9 are independently H or methyl, and Rn is C1-C4 alkoxy substituted with amino, -NH(C1-C6 alkyl), -N(C1-C6 alkylXQ-Ce alkyl), aza-bicyclo-octyl, in certain embodiments l-aza-bicyclo[2.2.2]oct-3-yl or 8-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo-nonyl, aza-bicyclo-decyl, where the aza nitrogen is optionally substituted with methyl or ethyl; and R4 is H or methyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridyl, or -C(0)NH-pyrid-4-yl. In another aspect, R4, R9, and Rn are as previously defined and R1 is chloro; R2 is amino; and R3 is methyl.
In still another aspect, the invention provides compounds of Formulae XVa and XVb, wherein R4 and R9 are independently H or methyl, and R11 is C1-C4 alkoxy substituted with amino, -NH(Ci-C6 alkyl), or -N(C1-C6 alkyl)(Ci-C6 alkyl). In another aspect, R4, R9, and Rn are as previously defined and R1 is chloro; R2 is amino; and R3 is methyl. In yet another aspect, the invention provides compounds of Formulae XVa and XVb, wherein R4 is H or methyl, and Rn is Ci-C4 alkoxy substituted with aza-bicyclo-octyl, in certain embodiments l-aza-bicyclo[2.2.2]oct-3-yl or 8-aza-bicyclo[3.2.1]oct-3-yl, aza- bicyclo-nonyl, aza-bicyclo-decyl, where the aza nitrogen is optionally substituted with methyl or ethyl; and R4 is H or methyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridyl, or -(C0-C6 alkyl)-C(O)NH-pyrid-4-yl. In another aspect, R4, R9, and Rn are as previously defined and Ri is chloro; R2 is amino; and R3 is methyl.
In another aspect, the invention provides compounds of Formulae XVa and XVb, wherein two or more previously described aspects are combined.
In another aspect, the invention provides compounds according to any one of Formulae Xa, Xb, XIa, XIb, XIIa, XIIb, XIIIa, XIIIb, XIVa, XIVb, XVa or XVb, wherein Ri , and R2 are oriented on the pyridyl and pyridonyl ring as follows:
In another aspect, the invention provides compounds according to any one of Formulae Xa, Xb, XIa, XIb, XIIa, XIIb, XIIIa, XIIIb, XIVa, XIVb5 XVa or XVb, wherein bond 3 of the core piperidine ring has the "S" configuration and bond 4 has the "R" configuration.
In still another aspect, the invention provides compounds according to any one of Formulae Xa, Xb, XIa, XIb, XIIa, XIIb, XIIIa, XIIIb, XIVa, XIVb, XVa or XVb, wherein Ri and R2 are oriented on the pyridyl and pyridonyl ring as follows:
and bond 3 of the core piperidine ring has the "S" configuration and bond 4 has the "R" configuration.
In another aspect, the invention provides compounds according to any one of Formulae Xa, Xb, XIa, XIb, XIIa, XIIb, XIIIa, XIIIb, XIVa, XIVb, XVa or XVb, wherein bond 3 has the "R" configuration and bond 4 has the "S" configuration.
In another aspect, the invention provides compounds according to any one of Formulae Xa, Xb, XIa, XIb, XIIa, XIIb, XIIIa, XIIIb, XIVa, XIVb, XVa or XVb, wherein Ri and R2 are oriented on the pyridyl and pyridonyl ring as follows:
and bond 3 of the core piperidine ring has the "R" configuration and bond 4 has the "S" configuration.
In still another aspect, the invention provides compounds of Formulae Xa and Xb, wherein:
Ri is chloro; R2 is amino; R3 (for Xb) is methyl; R4 is H, and Ri and R2 have the following orientation on the pyridyl and pyridonyl ring:
L is -(C3-C5 alkyl)- wherein one carbon may be replaced by -N(Rg)-, or -(C2-CO alkyl)-C(O)-. In yet another aspect, the R1, R2, and R3 (R3 for the pyridyl ring) are as defined and oriented on the pyridyl and pyridonyl rings as previously described, R4 is as previously defined and Rs is-O-heterocycloalkyl, wherein the heterocycloalkyl group is selected from aza-bicyclo-octyl, in certain embodiments l-aza-bicyclo[2.2.2]oct-3-yl or 8-aza- bicyclo[3.2.1]oct-3-yl, aza-bicyclo-nonyl, aza-bicyclo-decyl, where the aza nitrogen is optionally substituted with methyl or ethyl, piperidinyl, piperazinyl, and pyrrolidinyl, wherein the piperidinyl, piperazinyl, and pyrrolidinyl groups are unsubstituted or substituted at one or two positions with groups that are independently C1-C4 alkyl, C1-C4 alkoxy, halogen, C1-C4 haloalkyl, C1-C4 haloalkoxy, hydroxyl, hydroxy C1-C4 alkyl, amino, -NH(C1-C4 alkyl), -N(Ci-C4 alkyi)(Ci~C4 alkyl), -(C0-C6 alkyl)-C(O)Rn, Or NO2, wherein
Rn is Ci-C6 alkoxy, optionally substituted with 1 or 2 groups that are independently Ci-C4 alkoxy, amino, -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)(d-C6 alkyl), -(C0-C6 alkyl)- C(0)N(R9)-heterocycloalkyl, or heterocycloalkyl wherein the heterocycloalkyl group is selected from aza-bicyclo-octyl, in certain embodiments l-aza-bicyclo[2.2.2]oct-3-yl or 8- aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo-nonyl, aza-bicyclo-decyl, where the aza nitrogen is optionally substituted with methyl or ethyl; and R4 is H or methyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl, wherein the heterocycloalkyl groups are optionally substituted with 1, 2, or 3 groups that are independently halogen, Ci-C6 alkyl, Ci-C6 alkoxy, hydroxy, hydroxy C1-C6 alkyl, C1-C6 alkoxycarbonyl, -CO2H, CF3, or OCF3.
In still yet another aspect, the invention provides compounds of Formulae Xa and Xb, wherein:
Ri is chloro; R2 is amino; R3 (for Xb) is methyl; R4 is H, and R1, R2, and R3 have the following orientation on the pyridyl and pyridonyl rings:
L is -(C3-C5 alkyl)- wherein one carbon may be replaced by -N(Rg)-, or -(C2-C6 alkyl)-C(O)-. In yet another aspect, the R1, R2, and R3 are as defined and oriented on the pyridyl and pyridonyl ring as previously described, R4 is as previously defined and R5 is heterocycloalkyl, which is selected from aza-bicyclo-octyl, in certain embodiments 1-aza- bicyclo[2.2.2]oct-3-yl or 8-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo-nonyl, aza-bicyclo-decyl, where the aza nitrogen, is optionally substituted with methyl or ethyl.
In still yet another aspect, the invention provides compounds of Formulae Xa and Xb, wherein
R1 is chloro; R2 is amino; R3 (for Xb) is methyl; R4 is H, and R1, R2, and R3 have the following orientation on the pyridyl and pyridonyl rings:
L is -(C3-C5 alkyl)- wherein one carbon may be replaced by -N(Rg)-, or -(C2-C6 alkyl)-C(O)-. In yet another aspect, the R1, R2, and R3 are as defined and oriented on the pyridyl and pyridonyl ring as previously described, R4 is as previously defined and R5 is- N(Rg)-C0-C4 alkyl-aryl or -N(Rg)-(Co-C6 alkyl)-C(O)-aryl, wherein the aryl group is unsubstituted or substituted at one or more substitutable positions with C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl, Ci-C6 haloalkoxy, hydroxyl, hydroxyalkyl, amino, -NH(Cj- C6 alkyl), -N(C1-C6 aIkyl)(Ci-C6 alkyl), -(C0-C6 alkyl)-C(O)Rn, or NO2. In still another aspect, the aryl group is a phenyl substituted with -(Co-C6 alkyl)-C(O)Rπ and optionally substituted with 1 or 2 groups independently selected from Ci-C6 alkyl, Cj-C6 alkoxy, halogen, CF3, OCF3, hydroxyl, hydroxyalkyl, amino, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)(d- C4 alkyl), or NO2, wherein
R11 is C1-C6 alkoxy, optionally substituted with 1 or 2 groups that are independently C1-C4 alkoxy, amino, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(CrC6 alkyl), -(C0-C6 alkyl)- C(O)N(R9)-heterocycloalkyl, or heterocycloalkyl wherein the heterocycloalkyl group is selected from pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl, wherein the heterocycloalkyl groups are optionally substituted with 1, 2, or 3 groups that are independently halogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxy, hydroxy C1-C6 alkyl, C1-C6 alkoxycarbonyl, -CO2H, CF3, or OCF3. In a preferred aspect the -(C0-C6 alkyl)-C(O)Rπ group is attached to position 4 of the phenyl ring.
In still another aspect, the orientation of bonds 3 and 4 of the core piperidine ring is as follows:
In a preferred aspect, the orientation of bonds 3 and 4 of the core piperidine ring is as follows:
The compounds of the invention comprise compounds of formulas XX-a or XX-b, i.e., compounds of formulas Xa and/or Xb having the formulas:
or pharmaceutically acceptable salts thereof, wherein
L is -(C1-C4 alkyl)-NR9-(C1-C4 alkyl)-, -(Cj-C4 alkyl)-C(O)NR9-, -(C1-C4 alkyl)-, -(C1-C4 alkyl)-NR9C(O)- or -C(O)NR9-(C1-C4 alkyl)-; R1 is halogen;
R2 is amino or mono or (Ii(C1-C4 alkyl)amino; R3 is C1-C4 alkyl, Ci-C4 alkoxy, or OH; R4 is H or Ci-C4 alkyl; R5 is phenyl or naphthyl, each of which is substituted with 1 or 2 groups that are independently Ci-C4 alkyl, Ci-C4 alkoxy, OH, -0-C2-C4 alkanoyl, halogen, halo C1-
C4 alkyl, halo C1-C4 alkoxy, -CO2Ri0, -(Ci-C4 alkyl)-CO2R10; R9 is H or Ci-C4 alkyl; R1O at each occurrence is independently H, Ci-C4 alkyl optionally substituted with one group that is selected from a 5 or 6 membered monocyclic heterocycloalkyl ring, and OH, quinuclidinyl, -C(O)NH2, -C(O)NH(C1-C4 alkyl), -C(O)N(C1-C4 alkyl)(Ci-C4 alkyl) or piperidinyl optionally substituted with C1-C4 alkyl; and R2O is Ci-C4 alkyl, or Ci-C4 alkoxy.
In yet another aspect, the invention provides compounds of Formula (XX-2a) or Formula (XX-2b) i.e., compounds of Formula (XX-a) or Formula (XX-b) having the formula:
where
Ri7 is Ci-C4 alkyl, CrC4 alkoxy, OH, -0-C2-C4 alkanoyl, halogen, halo C1-C4 alkyl, halo C1-
C4 alkoxy, -CO2Ri0, or -(Ci-C4 alkyl)-CO2Ri0; and Ri8 is H, Ci-C4 alkyl, Ci-C4 alkoxy, OH, -0-C2-C4 alkanoyl, halogen, halo Ci-C4 alkyl (such as CF3), halo Ci-C4 alkoxy (such as OCF3), -CO2Ri0, or -(CrC4 alkyl)-CO2Ri0.
In still another aspect, the invention provides compounds of either Formula (XX-2a) or Formula (XX-2b) wherein the bonds at positions 3 and 4 of the piperidinyl ring are cis to each other.
In still another aspect, the orientation of bonds 3 and 4 is as follows:
In a preferred aspect, the orientation of bonds 3 and 4 is as follows:
In yet still another aspect, the invention provides compounds of either of Formula (XX-2a) or Formula (XX-2b), wherein L is -(Ci-C2 alkyl)-NR9-(Ci-C2 alkyl)-; Rn is Ci-C4 alkyl, Ci-C4 alkoxy, or halogen; and Ris is H, Ci-C4 alkyl, Ci-C4 alkoxy, OH, or -0-C2-C4 alkanoyl. Preferably, one of Ri7 or Ri8 is at the 4-position of the phenyl group.
In still yet another aspect, the invention provides compounds of either of Formula (XX-2a) or Formula (XX-2b), wherein L is -(C]-C2 alkyl)-NR9-(Ci-C2 alkyl)-; Ri7 is halogen, halo Ci-C4 alkyl, or halo Ci-C4 alkoxy; and Ri8 is H, Ci-C4 alkyl, Ci-C4 alkoxy, OH. Preferably, one OfRn or Rj8 is at the 4-position of the phenyl group. In another aspect, the invention provides compounds of either of Formula (XX-2a) or Formula (XX-2b), wherein L is -(Ci-C2 alkyl)-NR9-(Ci-C2 alkyl)-; R17 is OH, or -0-C2-C4 alkanoyl; and R18 is H, Ci-C4 alkyl, Ci -C4 alkoxy, or OH. Preferably, one of Ri7 or Ri8 is at the 4-position of the phenyl group.
In yet another aspect, the invention provides compounds of either of Formula (XX-2a) or Formula (XX-2b), wherein L is -(Ci-C2 alkyl)-NR9-(Ci-C2 alkyl)-; Rn is OH, or -0-C2-C4 alkanoyl; and Ri8 is 0-C2-C4 alkanoyl, halogen, halo Ci-C4 alkyl, or halo Ci-C4 alkoxy. Preferably, one OfRi7 or Rj8 is at the 4-position of the phenyl group.
In still another aspect, the invention provides compounds of either of Formula (XX- 2a) or Formula (XX-2b), wherein L is -(Ci-C2 alkyl)-NR9-(Ci-C2 alkyl)-; Ri0 is H, C1-C4 alkyl optionally substituted with one group that is selected from morpholinyl, pyrrolidinyl, and OH, quinuclidinyl, -C(O)NH2, or piperidinyl optionally substituted with C1-C3 alkyl; Ri7 is -CO2Ri0, or -(Ci-C4 alkyl)-CO2Ri0; and Ri8 is Ci-C4 alkyl, Ci-C4 alkoxy, or OH. Preferably, one of Ri7 or Ri8 is at the 4-position of the phenyl group.
In still yet another aspect, the invention provides compounds of either of Formula (XX-2a) or Formula (XX-2b), wherein L is -(CrC2 alkyl)-NR9-(Ci-C2 alkyl)-; Ri0 is H, C1- C4 alkyl optionally substituted with one group that is selected from morpholinyl, pyrrolidinyl, and OH, quinuclidinyl, -C(O)NH2, or piperidinyl optionally substituted with C1-C3 alkyl; Ri7 is -C02Rio; and Ri8 is Ci-C4 alkyl (such as methyl), Ci-C4 alkoxy (such as methoxy), or OH. Preferably, one of Ri7 or Rj8 is at the 4-position of the phenyl group.
In still another aspect, the invention provides compounds of either of Formula (XX- 2a) or Formula (XX-2b), wherein L is -(Ci-C2 alkyl)-NR9-(Ci-C2 alkyl)-; Ri0 is H, Ci-C4 alkyl optionally substituted with one group that is selected from morpholinyl, pyrrolidinyl, and OH, quinuclidinyl, -C(O)NH2, or piperidinyl optionally substituted with C1-C3 alkyl; Ri7 is-(Ci-C4 alkyl)-CO2Ri0; and R!8 is CrC4 alkyl, Ci-C4 alkoxy, or OH. Preferably, one of Rn or Ri8 is at the 4-position of the phenyl group.
In yet another aspect, the invention provides compounds of either of Formula (XX-2a) or Formula (XX-2b), wherein L is -(Ci-C3 alkyl)-NR9-(CrC3 alkyl)-; Rio is H, CpC4 alkyl optionally substituted with one group that is selected from a 5 or 6 membered monocyclic heterocycloalkyl ring, and OH, quinuclidinyl, -C(O)NH2, or piperidinyl optionally substituted with CpC3 alkyl; Ri7 is OH, -0-C2-C4 alkanoyl, -CO2Ri0, Or -(Ci-C4 alkyl)-CO2R10; and
Ri 8 is H; and
R20 is methoxy or ethoxy (in one aspect, methoxy is preferred.)
In yet still another aspect, the invention provides compounds of either of Formula (XX-2a) or Formula (XX-2b), wherein L is -(Ci-C3 alkyl)-NR9-(Ci-C3 alkyl)-;
Rio is H, quinuclidinyl, -C(O)NH2, or piperidinyl optionally substituted with Ci-C3 alkyl; Ri7 is OH, -0-C2-C4 alkanoyl, -CO2Ri0, or -(Cj-C4 alkyl)-CO2Ri0; and Ri 8 is H; and R2o is methoxy or ethoxy (in one aspect, methoxy is preferred.)
In yet still another aspect, the invention provides compounds of either of Formula (XX-2a) or Formula (XX-2b), wherein L is -(Ci-C3 ^yI)-NR9-(C1 -C3 alkyl)-; Ri0 is H; Rn is -CO2Ri0, or -(Ci-C4 alkyl)-C02Rio; and R18 is H.
In still another aspect, the invention provides compounds of either of Formula (XX- 2a) or Formula (XX-2b), wherein L is -(CrC3 alkyl)-NR9-(Ci-C3 alkyl)-; R17 is OH, or -O- C2-C4 alkanoyl; and R18 is H, methyl, methoxy, OH, F, or Cl.
In yet still another aspect, the invention provides compounds of Formula (XX-3a) or Formula (XX-3b), i.e., compounds of Formula (XX-2a) or Formula (XX-2b) having the formula:
In still yet another aspect, the invention provides compounds of Formula (XX-3a) or Formula (XX-3b), wherein R17 is -CO2R10, or -(C1-C4 alkyl)-CO2R10; Rg is H or methyl; and Rio is H, Ci-C4 alkyl optionally substituted with one group that is selected from morpholinyl, pyrrolidinyl, and OH, quinuclidinyl, -C(O)NH2, or piperidinyl optionally substituted with C1- C2 alkyl.
In another aspect, the invention provides compounds of Formula (XX-2a) or Formula (XX-2b), wherein L is -(C2-C4 alkyl)-; Rio is H, Ci-C4 alkyl optionally substituted with one group that is selected from a 5 or 6 membered monocyclic heterocycloalkyl ring, and OH, quinuclidinyl, -C(O)NH2, or piperidinyl optionally substituted with C1-C3 alkyl; Ri7 is OH, -O-C2-C4 alkanoyl, -CO2Ri0, Or -(Ci-C4 alkyl)-CO2Ri0; Ri 8 is H; and R20 is methoxy or ethoxy (in one aspect, methoxy is preferred.)
In yet still another aspect, the invention provides compounds of either of Formula (XX-2a) or Formula (XX-2b), wherein L is -(C2-C4 alkyl)-; Rn is Ci-C4 alkyl, Ci-C4 alkoxy, or halogen; and Ri8 is H, C]-C4 alkyl, Ci-C4 alkoxy, OH, or -0-C2-C4 alkanoyl. Preferably, one ofRπ or Ri8 is at the 4-position of the phenyl group.
In still yet another aspect, the invention provides compounds of either of Formula (XX-2a) or Formula (XX-2b), wherein L is -(C2-C4 alkyl)-; R17 is halogen, halo CrC4 alkyl, or halo Ci-C4 alkoxy; and Ri 8 is H, Cj-C4 alkyl, Ci-C4 alkoxy, OH. Preferably, one of RJ7 or Ri8 is at the 4-position of the phenyl group. In another aspect, the invention provides compounds of either of Formula (XX-2a) or Formula (XX-2b), wherein L is -(C2-C4 alkyl)-; R17 is OH, or -0-C2-C4 alkanoyl; and Ri8 is H, C1-C4 alkyl, Ci-C4 alkoxy, or OH. Preferably, one of R17 or R18 is at the 4-position of the phenyl group.
In yet another aspect, the invention provides compounds of either of Formula (XX-2a) or Formula (XX-2b), wherein L is -(C2-C4 alkyl)-; Ri7 is OH, or -0-C2-C4 alkanoyl; and R]8 is 0-C2-C4 alkanoyl, halogen, halo C1-C4 alkyl, or halo C1-C4 alkoxy. Preferably, one of Ri7 or Ri8 is at the 4-position of the phenyl group.
In still another aspect, the invention provides compounds of either of Formula (XX- 2a) or Formula (XX-2b), wherein L is -(C2-C4 alkyl)-; Ri0 is H, Ci-C4 alkyl optionally substituted with one group that is selected from morpholinyl, pyrrolidinyl, and OH, quinuclidinyl, -C(O)NH2, or piperidinyl optionally substituted with Ci -C3 alkyl; R17 is - CO2Ri0, Or -(C1-C4 alkyl)-CO2Ri0; and R!8 is Ci-C4 alkyl, CpC4 alkoxy, or OH. Preferably, one of Ri7 or Ri8 is at the 4-position of the phenyl group.
In still yet another aspect, the invention provides compounds of either of Formula (XX-2a) or Formula (XX-2b), wherein L is -(C2-C4 alkyl)-; Ri0 is H, Q-C4 alkyl optionally substituted with one group that is selected from morpholinyl, pyrrolidinyl, and OH, quinuclidinyl, -C(O)NH2, or piperidinyl optionally substituted with Ci-C3 alkyl; Ri7 is -CO2Ri0; and Ri8 is Ci-C4 alkyl (such as methyl), C1-C4 alkoxy (such as methoxy), or OH. Preferably, one of Ri7 or Rj8 is at the 4-position of the phenyl group.
In still another aspect, the invention provides compounds of either of Formula (XX- 2a) or Formula (XX-2b), wherein L is -(C2-C4 alkyl)-; Rio is H, Ci-C4 alkyl optionally substituted with one group that is selected from morpholinyl, pyrrolidinyl, and OH, quinuclidinyl, -C(O)NH2, or piperidinyl optionally substituted with Ci-C3 alkyl; Ri7 is— (Ci- C4 alkyl)-C02Rio; and Ri8 is Ci-C4 alkyl, C1-C4 alkoxy, or OH. Preferably, one OfRi7 or Ri8 is at the 4-position of the phenyl group.
In yet another aspect, the invention provides compounds of either of Formula (XX-2a) or Formula (XX-2b), wherein L is -(C2-C4 alkyl)-; R1O is H, C1-C4 alkyl optionally substituted with one group that is selected from a 5 or 6 membered monocyclic heterocycloalkyl ring, and OH, quinuclidinyl, -C(O)NH2, or piperidinyl optionally substituted with C1-C3 alkyl; Rn is OH, -0-C2-C4 alkanoyl, -CO2Ri0, or -(Ci-C4 alkyl)-CO2Ri0; and Ri 8 is H; and R20 is methoxy or ethoxy (in one aspect, methoxy is preferred.)
In yet still another aspect, the invention provides compounds of either of Formula (XX-2a) or Formula (XX-2b), wherein L is -(C2-C4 alkyl)-;
Rio is H, quinuclidinyl, -C(O)NH2, or piperidinyl optionally substituted with Ci-C3 alkyl; Rn is OH, -0-C2-C4 alkanoyl, -CO2Ri0, Or -(C1-C4 alkyl)-CO2Ri0; and Ri 8 is H; and R20 is methoxy or ethoxy (in one aspect, methoxy is preferred.)
In yet still another aspect, the invention provides compounds of either of Formula (XK-2a) or Formula (XX-2b), wherein L is -(C2-C4 alkyl)-; Ri0 is H; Rn is -CO2Ri0, or -(Ci- C4 alkyl)-CO2R10; and Ri8 is H.
In still another aspect, the invention provides compounds of either of Formula (XX- 2a) or Formula (XX-2b), wherein L is -(C2-C4 alkyl)-; Ri7 is OH, or -0-C2-C4 alkanoyl; and Ri 8 is H, methyl, methoxy, OH, F, or Cl.
In another aspect, the invention provides compounds of either of Formula (XX-2a) or Formula (XX-2b), wherein L is -(C1-C3 alkyl)-C(O)NR9-; Rio is H, Ci-C4 alkyl optionally substituted with one group that is selected from a 5 or 6 membered monocyclic heterocycloalkyl ring, and OH, quinuclidinyl, -C(O)NH2, or piperidinyl optionally substituted with Ci-C3 alkyl; Rn is OH, -0-C2-C4 alkanoyl, -CO2R10, Or -(C1-C4 alkyl)-CO2Ri0; Ri 8 is H; and R20 is methoxy or ethoxy (in one aspect, methoxy is preferred.)
In yet still another aspect, the invention provides compounds of either of Formula (XX-2a) or Formula (XX-2b), wherein L is -(Ci-C2 alkyl)-C(O)NR9-; Ri7 is C1-C4 alkyl, Q- C4 alkoxy, or halogen; and R18 is H, C1-C4 alkyl, C1-C4 alkoxy, OH, or -0-C2-C4 alkanoyl. Preferably, one of R17 or Ri8 is at the 4-position of the phenyl group.
In still yet another aspect, the invention provides compounds of either of Formula (XX-2a) or Formula (XX-2b), wherein L is -(C1-C2 alkyl)-C(O)NR9-; R17 is halogen, halo Ci -C4 alkyl, or halo C1-C4 alkoxy; and R18 is H, Ci-C4 alkyl, Ci-C4 alkoxy, OH. Preferably, one ofRπ or Ri8 is at the 4-position of the phenyl group.
In another aspect, the invention provides compounds of either of Formula (XX-2a) or Formula (XX-2b), wherein L is -(Ci-C2 alkyl)-C(O)NR9-; Rn is OH, or -0-C2-C4 alkanoyl; and Ri8 is H, Ci-C4 alkyl, Ci-C4 alkoxy, or OH. Preferably, one of Ri7 or Ri8 is at the 4- position of the phenyl group.
In yet another aspect, the invention provides compounds of either of Formula (XX-2a) or Formula (XX-2b), wherein L is -(C1-C2 alkyl)-C(O)NR9-; Ri7 is OH, or -0-C2-C4 alkanoyl; and R18 is 0-C2-C4 alkanoyl, halogen, halo Ci-C4 alkyl, or halo Ci-C4 alkoxy. Preferably, one of Ri7 or Ri8 is at the 4-position of the phenyl group.
In still another aspect, the invention provides compounds of either of Formula (XX- 2a) or Formula (XX-2b), wherein L is -(CrC2 alkyl)-C(O)NR9-; Ri0 is H, CrC4 alkyl optionally substituted with one group that is selected from morpholinyl, pyrrolidinyl, and OH, quinuclidinyl, -C(O)NH2, or piperidinyl optionally substituted with Ci-C3 alkyl; R]7 is - CO2Ri0, Or-(Ci-C4 alkyl)-CO2Ri0; and Ri8 is Ci-C4 alkyl, Ci-C4 alkoxy, or OH. Preferably, one of Ri7 or Ri8 is at the 4-position of the phenyl group.
In still yet another aspect, the invention provides compounds of either of Formula (XX-2a) or Formula (XX-2b), wherein L is -(Ci-C2 alkyl)-C(O)NR9-; Ri0 is H, Ci-C4 alkyl optionally substituted with one group that is selected from morpholinyl, pyrrolidinyl, and OH, quinuclidinyl, -C(O)NH2, or piperidinyl optionally substituted with C1-C3 alkyl; R17 is -C02Rio; and Ri8 is Ci-C4 alkyl (such as methyl), Ci-C4 alkoxy (such as methoxy), or OH. Preferably, one of Ri7 or Ri8 is at the 4-position of the phenyl group.
In still another aspect, the invention provides compounds of either of Formula (XX- 2a) or Formula (XX-2b), wherein L is -(Ci-C2 alkyl)-C(O)NR9-; Rio is H, Ci-C4 alkyl optionally substituted with one group that is selected from morpholinyl, pyrrolidinyl, and OH, quinuclidinyl, -C(O)NH2, or piperidinyl optionally substituted with Ci-C3 alkyl; Rn is- (Ci-C4 alkyl)-CO2Ri0; and R]8 is C1-C4 alkyl, C1-C4 alkoxy, or OH. Preferably, one of Rn or Ri8 is at the 4-position of the phenyl group. In yet another aspect, the invention provides compounds of either of Formula (XX-2a) or Formula (XX-2b), wherein L is -(C1-C2 alkyl)-C(O)NR9-; Rio is H, C1-C4 alkyl optionally substituted with one group that is selected from a 5 or 6 membered monocyclic heterocycloalkyl ring, and OH, quinuclidinyl, -C(O)NH2, or piperidinyl optionally substituted with Ci-C3 alkyl; Rn is OH, -0-C2-C4 alkanoyl, -CO2Ri0, Or -(Ci-C4 alkyl)-CO2Ri0; and Ri 8 is H; and R20 is methoxy or ethoxy (in one aspect, methoxy is preferred.)
In yet still another aspect, the invention provides compounds of either of Formula (XX-2a) or Formula (XX-2b), wherein L is -(Ci-C2 alkyl)-C(O)NR9-;
Rio is H, quinuclidinyl, -C(O)NH2, or piperidinyl optionally substituted with Ci-C3 alkyl; Ri7 is OH, -0-C2-C4 alkanoyl, -CO2Ri0, Or -(Ci-C4 alkyl)-CO2Ri0; and Ri 8 is H; and R20 is methoxy or ethoxy (in one aspect, methoxy is preferred.)
In yet still another aspect, the invention provides compounds of either of Formula (XX-2a) or Formula (XX-2b), wherein L is -(Ci-C2 alkyl)-C(O)NR9-; Rio is H; Rn is -CO2Ri0, or -(Ci-C4 alkyl)-C02Rio; and R18 is H.
In still another aspect, the invention provides compounds of either of Formula (XX- 2a) or Formula (XX-2b), wherein L is -(Ci-C3 alkyl)-C(O)NR9-; Ri7 is OH, or -0-C2-C4 alkanoyl; and Ri8 is H, methyl, methoxy, OH, F, or Cl.
In yet still another aspect, the invention provides compounds of Formula (XX-4a) or Formula (XX-4b), i.e., compounds of Formula (XX-2a) or Formula (XX-2b) having the formula:
In still yet another aspect, the invention provides compounds of Formula (XX-4a) or Formula (XX-4b), wherein R17 is -CO2R10, or -(C1-C4 alkyl)-CO2R10; R9 is H or methyl; and R10 is H, C1-C4 alkyl optionally substituted with one group that is selected from morpholinyl, pyrrolidinyl, and OH, quinuclidinyl, -C(O)NH2, or piperidinyl optionally substituted with C1- C2 alkyl.
In yet still another aspect, the invention provides compounds of Formula (XX-5a) or Formula (XX-5b), i.e., compounds of Formula (XX-2a) or Formula (XX-2b) having the formula:
In still yet another aspect, the invention provides compounds of Formula (XKSa) or Formula (XX-5b), wherein R17 is -CO2RiO, Or-(C1-C4 alkyl)-CO2R10; R9 is H or methyl; and Rio is H, C1-C4 alkyl optionally substituted with one group that is selected from morpholinyl, pyrrolidinyl, and OH, quinuclidinyl, -C(O)NH2, or piperidinyl optionally substituted with Ci- C2 alkyl.
In another aspect, the invention provides compounds of Formula (XX-2a) or Formula (XX-2b), wherein L is -(Ci-C4 alkyl)-NR9C(O)s Rio is H, Ci-C4 alkyl optionally substituted with one group that is selected from a 5 or 6 membered monocyclic heterocycloalkyl ring, and OH, quinuclidinyl, -C(O)NH2, or piperidinyl optionally substituted with C1-C3 alkyl; Ri7 is OH, -0-C2-C4 alkanoyl, -CO2Ri0, Or-(Ci-C4 alkyl)-CO2Ri0; Ri 8 is H; and R2o is methoxy or ethoxy (in one aspect, methoxy is preferred.)
In yet still another aspect, the invention provides compounds of either of Formula (XX-2a) or Formula (XX-2b), wherein L is -(Ci-C4 alkyl)-NR9C(O)-; Rn is C1-C4 alkyl, Q- C4 alkoxy, or halogen; and Ri8 is H, CpC4 alkyl, Ci-C4 alkoxy, OH, or -0-C2-C4 alkanoyl. Preferably, one of Ri7 or Ri8 is at the 4-position of the phenyl group.
In still yet another aspect, the invention provides compounds of either of Formula (XX-2a) or Formula (XX-2b), wherein L is -(Ci-C4 alkyl)-NR9C(O)-; Rn is halogen, halo Ci-C4 alkyl, or halo Ci-C4 alkoxy; and Ri8 is H, Ci-C4 alkyl, Ci-C4 alkoxy, OH. Preferably, one of Rn or Ri8 is at the 4-position of the phenyl group.
In another aspect, the invention provides compounds of either of Formula (XX-2a) or Formula (XX-2b), wherein L is -(Ci-C4 alkyl)-NR9C(O)-; Rn is OH, or -0-C2-C4 alkanoyl; and Ri8 is H, Ci-C4 alkyl, Cj-C4 alkoxy, or OH. Preferably, one of Ri7 or Ri8 is at the 4- position of the phenyl group.
In yet another aspect, the invention provides compounds of either of Formula (XX-2a) or Formula (XX-2b), wherein L is -(CrC4 alkyl)-NR9C(O>; Rn is OH, or -0-C2-C4 alkanoyl; and Ri8 is 0-C2-C4 alkanoyl, halogen, halo Ci-C4 alkyl, or halo Ci-C4 alkoxy. Preferably, one of Ri7 or Ri8 is at the 4-position of the phenyl group.
In still another aspect, the invention provides compounds of either of Formula (XX- 2a) or Formula (XX-2b), wherein L is -(Ci-C4 alkyl)-NR9C(O)-; Ri0 is H, Ci-C4 alkyl optionally substituted with one group that is selected from morpholinyl, pyrrolidinyl, and OH, quinuclidinyl, -C(O)NH2, or piperidinyl optionally substituted with C1-C3 alkyl; R17 is - CO2R10, or -(C1-C4 alkyl)-CO2R10; and R18 is C1-C4 alkyl, C1-C4 alkoxy, or OH. Preferably, one OfR17 or R18 is at the 4-position of the phenyl group.
In still yet another aspect, the invention provides compounds of either of Formula (XX-2a) or Formula (XX-2b), wherein L is -(Ci-C4 alkyl)-NR9C(O)-; R10 is H, C1-C4 alkyl optionally substituted with one group that is selected from morpholinyl, pyrrolidinyl, and OH, quinuclidinyl, -C(O)NH2, or piperidinyl optionally substituted with C1-C3 alkyl; Ri7 is -CO2Ri0; and Ri8 is Ci-C4 alkyl (such as methyl), C1-C4 alkoxy (such as methoxy), or OH. Preferably, one of R17 or Ri8 is at the 4-position of the phenyl group.
In still another aspect, the invention provides compounds of either of Formula (XX- 2a) or Formula (XX-2b), wherein L is -(Ci-C4 alkyl)-NR9C(O)-; Ri0 is H, CrC4 alkyl optionally substituted with one group that is selected from morpholinyl, pyrrolidinyl, and OH, quinuclidinyl, -C(O)NH2, or piperidinyl optionally substituted with Q-C3 alkyl; Rn is- (Ci-C4 alkyl)-CO2R10; and R18 is Cj-C4 alkyl, Ci-C4 alkoxy, or OH. Preferably, one of Rn or Ri8 is at the 4-position of the phenyl group.
In yet another aspect, the invention provides compounds of either of Formula (XX-2a) or Formula (XX-2b), wherein L is -(Ci-C4 alkyl)-NR9C(O)-; Rio is H, Ci-C4 alkyl optionally substituted with one group that is selected from a 5 or 6 membered monocyclic heterocycloalkyl ring, and OH, quinuclidinyl, -C(O)NH2, or piperidinyl optionally substituted with C1-C3 alkyl; R17 is OH, -0-C2-C4 alkanoyl, -CO2Ri0, or -(Ci-C4 alkyl)-CO2R10; Ris is H; and R2O is methoxy or ethoxy (in one aspect, methoxy is preferred.)
In yet still another aspect, the invention provides compounds of either of Formula (XX-2a) or Formula (XX-2b), wherein L is -(Ci-C4 alkyl)-NR9C(O)-;
Rio is H, quinuclidinyl, -C(O)NH2, or piperidinyl optionally substituted with Ci-C3 alkyl; R17 is OH, -0-C2-C4 alkanoyl, -CO2R10, or -(Ci-C4 alkyl)-CO2R10; and Ri 8 is H; and R20 is methoxy or ethoxy (in one aspect, methoxy is preferred.) In yet still another aspect, the invention provides compounds of either of Formula (XX-2a) or Formula (XX-2b), wherein L is -(C1-C4 alkyl)-NR9C(O)-; Ri0 is H; Rn is - CO2R10, or -(Ci-C4 alkyl)-CO2Ri0; and Ri8 is H.
In still another aspect, the invention provides compounds of either of Formula (XX- 2a) or Formula (XX-2b), wherein L is -(C1-C4 alkyl)-NR9C(O)-; Rn is OH, or -0-C2-C4 alkanoyl; and Ri8 is H, methyl, methoxy, OH, F5 or Cl.
In yet still another aspect, the invention provides compounds of Formula (XX-6a) or Formula (XX-6b), i.e., compounds of Formula (XX-2a) or Formula (XX-2b) having the formula:
In still yet another aspect, the invention provides compounds of Formula (XX-6a) or Formula (XX-6b), wherein Rn is -CO2Ri0, or -(Ci-C4 alkyl)-CO2Ri0; R9 is H or methyl; and Rio is H, C1-C4 alkyl optionally substituted with one group that is selected from morpholinyl, pyrrolidinyl, and OH, quinuclidinyl, -C(O)NH2, or piperidinyl optionally substituted with Q- C2 alkyl.
In yet another aspect, the invention provides compounds of Formula (XX-6a) or Formula (XX-6b), wherein Ri7 is -CO2Ri0, and Ri0 is H, or Ci-C4 alkyl optionally substituted with one group that is selected from morpholinyl, pyrrolidinyl. and OH,
In still another aspect, the invention provides compounds of Formula (XX-6a) or Formula (XX-6b), wherein Rn is -CO2Ri0, and Ri0 is quinuclidinyl, -C(O)NH2, or piperidinyl optionally substituted with Ci-C2 alkyl. In a further aspect, the invention provides compounds of Formula Formula (XX-6a) or Formula (XX-6b), wherein R17 is -CO2R10, and R1O is H or piperidinyl substituted with C1- C2 alkyl.
The invention further provides methods for treating emesis, dyspepsia, gastroparesis, constipation, intestinal pseudo-obstruction, gastroesophageal reflux, or post-operative ileus, the method comprising administering a therapeutically effective amount of a compound or salt according of Formulae Xa and Xb to a patient in need of such treatment.
The subject invention provides compounds that are more susceptible to degradation by serum and/or cytosolic esterases than cisapride, thus avoiding the adverse effects associated with metabolism by cytochrome P450.
Advantageously, the therapeutic compounds of the subject invention are stable in storage but have a relatively short half-life in the physiological environment; therefore, the compounds of the subject invention can be used with a lower incidence of side effects and toxicity.
In a preferred aspect of the subject invention, therapeutic stereoisomeric compounds are provided that are useful in the treatment of gastroesophageal reflux disease and that contain an ester group, which is susceptible to degradation by esterases, thereby breaking down the compound and facilitating its efficient removal from the treated individual. In a preferred aspect, the therapeutic stereoisomeric compounds are metabolized by the Phase I drug detoxification system.
A further aspect of the subject invention pertains to the breakdown products (preferably metabolic breakdown products, i.e., metabolites, generally acids of parent esters) that are produced when the therapeutic compounds of the subject invention are acted upon by an esterase. The presence of these breakdown products in the urine or serum can be used to monitor the rate of clearance of the therapeutic compound from a patient.
Degradation of the compounds of the subject invention by esterases is particularly advantageous for drug metabolism because these enzymes are ubiquitously distributed and their activity is not dependent on age, gender, or disease state to the same extent as oxidative hepatic drug metabolism.
The subject invention further provides methods of treating disorders, such as gastroesophageal reflux disease comprising the administration of a therapeutically effective amount of at least one stereoisomeric structural and/or functional analog of cisapride to an individual in need of treatment. In a specific aspect, the subject invention provides stereoisomeric structural and/or functional analogs of cisapride and pharmaceutical compositions of these esterified compounds.
The subject invention further provides materials and methods for the treatment of emesis and such other conditions, including but not limited to dyspepsia, gastroparesis, constipation, and intestinal pseudo-obstruction, while substantially reducing adverse effects associated with the administration of cisapride.
In a preferred aspect of the subject invention, therapeutic stereoisomeric compounds are provided which are useful in the treatment of gastroesophageal reflux, dyspepsia, gastroparesis, constipation, post-operative ileus, and intestinal pseudo-obstruction and which contain an ester group which is acted upon by esterases thereby breaking down the compound and facilitating its efficient removal from the treated individual.
The subject invention further provides methods of synthesizing the unique and advantageous compounds of the subject invention. Particularly, methods of producing and purifying such stereoisomeric compounds are taught. Methods of adding such ester moieties and of producing and purifying stereoisomers, are well known to the skilled artisan and can be readily carried out utilizing the guidance provided herein.
Preferred Compounds
In a preferred aspect, the present invention provides isolated stereoisomers of Compound I, which contains three chiral centers.
Compound Ia and Ib
Two of the chiral centers exist in cisapride and norcisapride and are in the cis configuration in the active drugs:
Thus, for example, pharmaceutically active norcisapride is a racemic mixture of the two cis enantiomers:
In one aspect, the current invention is particularly concerned with the configuration at the third chiral center, in the quinuclidinol moiety, of the structural and/or functional analogs of cisapride. This group is eliminated in the conversion to the acid metabolite referred to herein as ± Compounda Ha and lib:
Compound Ha and Hb
The preferred Compound Ia and Ib stereoisomers of the present invention are made by conjugating R or S quinuclidinol to a structural/functional analog of (+)- or (-)-norcisapride characterized by the substitution of a pyridyl or pyridonyl moiety for the phenyl moiety of norcisapride, giving Compounds Ilia, IHb, IVa, IVb, Va, Vb, Via and VIb.
Compounds IHa and IHb: (-)(R)-compounds of Ia and Ib
Compounds IVa and IVb: (+")(RVcompounds
Compounds Va and Vb: (-XS)-compounds
Compounds Via and VIb: (+VS")-compounds
In a preferred aspect, the subject invention pertains to stereoisomerically isolated compounds, and compositions comprising the compounds. The isolated stereoisomeric forms of the compounds of the invention are substantially free from one another (i.e., in stereoisomeric excess). In other words, the "R" forms of the compounds are substantially free from the "S" forms of the compounds and are, thus, in stereoisomeric excess of the "S" forms. Conversely, "S" forms of the compounds are substantially free of "R" forms of the compounds and are, thus, in stereoisomeric excess of the "R" forms. In one aspect of the invention, the isolated stereoisomeric compounds are in at least about 80% stereoisomeric excess. In a preferred aspect, the compounds are in at least about 90% stereoisomeric excess. In a more preferred aspect, the compounds are in at least about 95% stereoisomeric excess. In an even more preferred aspect, the compounds are in at least about 97.5% stereoisomeric excess. In a most preferred aspect, the compounds are in at least about 99% stereoisomeric excess. Similarly, the "(+)" and "(-)" forms of the compounds are also provided in stereoisomeric excess.
As described herein, the various stereoisomers have particular unexpected properties that, advantageously, can be used to customize treatment for a particular set of circumstances. Thus, for example, compounds containing the (3'R)-isomer in the quinuclidinyl ester moiety, i.e., compounds Ilia, IHb, IVa and IVb, can be rapidly metabolized by esterases in human plasma, whereas compounds containing the (3'S)-isomer of quinuclidinol, i.e., compounds Va and Vb and Via and VIb, can undergo a much slower metabolism.
Thus, the (3'R)-isomers of compounds Ia and Ib can be used, for example, when a short-duration of action is preferred, for example stimulation of gastric motility in an acute episode, such as pulsatile administration to patients with acute gastroparesis, or in acute gastroesophageal reflux. Another advantage of rapid metabolism by esterases to an substantially less active metabolites, i.e., compound Ha or lib, is the very low probability of drug-drug interactions and toxicity. Therefore these shorter-acting (R)-isomers can be advantageously used, for example, as intravenous formulations for treating gastroesophageal reflux in premature newborn who notoriously are not able to metabolize drugs as well as adults because their CYP450 system is not fully developed. In these newborn, a drug having rapid metabolism by a system other than CYP450, e.g., esterases, is a great advantage. On the other hand, the (3'S)-isomers of compound I are best used in chronic situations of the same ailments, for example gastroparesis in diabetic patients or cancer patients under opiates, or in chronic gastroesophageal reflux in patients who need 24-hour coverage.
In addition to their differences in metabolic fate, these separate isomers also can have different binding affinities for the 5-HT4 receptor, thus suggesting different activities as well, and therefore different therapeutic uses.
As a conclusion to these considerations: when the 3 and 4 positions are cis relative to each other, each compound (e.g., compound Ia) is a mixture of 4 isomers, consisting of 2 pairs of enantiomers. The first pair of enantiomers is (+)(R)-compound Ia and (-)(S)- compound Ia (compounds IVa and Va, respectively), the second pair of enantiomers is (-)(R)- compound I and (+)(S)-compound I (compounds Ilia and Via, respectively). Within each enantiomeric pair, each separate enantiomer has different properties regarding both their rate of hydrolysis by esterases and regarding their affinity at the 5-HT4 receptor. These different properties give them separately advantageous therapeutic uses which are not interchangeable, i.e., which are specific to each isomer, and which are not applicable to the racemic mixture. These differences of affinity at the receptor and these differences in metabolic rates are not predictable and neither is it possible to dissect these properties when testing the racemic mixture.
Definitions
As used herein, the term "alkyl" includes those alkyl groups of a designed number of carbon atoms. Alkyl groups may be straight, or branched. Examples of "alkyl" include methyl, ethyl, propyl, isopropyl, butyl, iso-, sec- and tert-butyl, pentyl, hexyl, heptyl, 3- ethylbutyl, and the like. If the number of carbon atoms is not specified, the subject "alkyl" moiety has from 1 to 6 carbons.
The term "alkoxy" represents an alkyl group of indicated number of carbon atoms attached to the parent molecular moiety through an oxygen bridge. Examples of alkoxy groups include, for example, methoxy, ethoxy, propoxy and isopropoxy.
By "aryl" is meant an aromatic carbocyclic group having a single ring (e.g., phenyl) that is optionally fused or otherwise attached to other aromatic hydrocarbon rings or non- aromatic hydrocarbon rings. "Aryl" includes multiple condensed rings in which at least one is aromatic, (e.g., 1,2,3,4-tetrahydronaphthyl, naphthyl), wherein each ring is optionally mono-, di-, or trisubstituted with the groups identified below, as well as multiple rings that are not fused, such as, for example, biphenyl or binaphthyl. Preferred aryl groups of the present invention are phenyl, 1-naphthyl, 2-naphthyl, indanyl, indenyl, dihydronaphthyl, fluorenyl, tetralinyl or 6,7,8,9-tetrahydro-5H-benzo[a]cycloheptenyl. More preferred are phenyl, biphenyl, and naphthyl. Most preferred is phenyl. The aryl groups herein are unsubstituted or, as specified, substituted in one or more substitutable positions with various groups. For example, such aryl groups may be optionally substituted with, for example, C1-C6 alkyl, C1- C6 alkoxy, halogen, hydroxy, cyano, nitro, amino, InOnO(C1 -C6)alkylamino, di(Ci- C6)alkylamino, C2-C6alkenyl, C2-C6alkynyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, amino(C!- C6)alkyl, mono(Ci-C6)alkylamino(C1-C6)alkyl or di(C1-C6)alkylamino(Ci-C6)alkyl.
The term "haloalkoxy" refers to an alkoxy group substituted with at least one halogen atom and optionally further substituted with at least one additional halogen atom, where each halogen is independently F, Cl, Br or I. Preferred halogens are F or Cl. Preferred haloalkoxy groups contain 1-6 carbons, more preferably 1-4 carbons, and still more preferably 1-2 carbons. "Haloalkoxy" includes perhaloalkoxy groups, such as OCF3 or OCF2CF3.
The term "heteroaryl" refers to an aromatic ring system containing at least one heteroatom selected from nitrogen, oxygen, and sulfur. The heteroaryl ring may be fused or otherwise attached to one or more heteroaryl rings, aromatic or non-aromatic hydrocarbon rings or heterocycloalkyl rings. Examples of heteroaryl groups include, for example, pyridyl, pyrimidinyl, quinolinyl, benzothienyl, indolyl, indolinyl, pyridazinyl, pyrazinyl, isoindolyl, isoquinolyl, quinazolinyl, quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, thiazolyl, indolizinyl, indazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, furanyl, thienyl, pyrrolyl, oxadiazolyl, thiadiazolyl, benzo[l,4]oxazinyl, triazolyl, tetrazolyl, isothiazolyl, naphthyridinyl, isochromanyl, chromanyl, tetrahydroisoquinolinyl, isoindolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isobenzothienyl, benzoxazolyl, pyridopyridinyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, purinyl, benzodioxolyl, triazinyl, pteridinyl, benzothiazolyl, imidazopyridinyl, imidazothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl, dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl, chromonyl, chromanonyl, pyridinyl-N-oxide, tetrahydroquinolinyl, dihydroquinolinyl, dihydroquinolinonyl, dihydroisoquinolinonyl, dihydrocoumarinyl, dihydroisocoumarinyl, isoindolinonyl, benzodioxanyl, benzoxazolinonyl, pyrrolyl N-oxide,, pyrimidinyl N-oxide, pyridazinyl N-oxide, pyrazinyl N-oxide, quinolinyl N-oxide, indolyl N-oxide, indolinyl N-oxide, isoquinolyl N-oxide, quinazolinyl N-oxide, quinoxalinyl N-oxide, phthalazinyl N-oxide, imidazolyl N-oxide, isoxazolyl N-oxide, oxazolyl N-oxide, thiazolyl N-oxide, indolizinyl N-oxide, indazolyl N-oxide, benzothiazolyl N-oxide, benzimidazolyl N-oxide, pyrrolyl N-oxide, oxadiazolyl N-oxide, thiadiazolyl N-oxide, triazolyl N-oxide, tetrazolyl N-oxide, benzothiopyranyl S-oxide, benzothiopyranyl S5S- dioxide. Preferred heteroaryl groups include pyridyl, pyrimidyl, quinolinyl, indolyl, pyrrolyl, furanyl, thienyl, and imidazolyl. More preferred heteroaryl groups include pyridyl, pyrrolyl, and indolyl. The heteroaryl groups herein are unsubstituted or, as specified, substituted in one or more substitutable positions with various groups. For example, such heteroaryl groups may be optionally substituted with, for example, C1-C6 alkyl, Ci-C6 alkoxy, halogen, hydroxy, cyano, nitro, amino, mono(Ci-C6)alkylamino, di(Ci-C6)alkylamino, C2-C6alkenyl, C2- Cβalkynyl, Ci-C6 haloalkyl, Ci-C6 haloalkoxy, amino(Ci-C6)alkyl, mono(Ci- C6)alkylamino(Ci-C6)alkyl or di(Ci-C6)alkylamino(Ci-C6)alkyl.
The term "heterocycloalkyl" refers to a ring or ring system containing at least one heteroatom that is preferably selected from nitrogen, oxygen, and sulfur, wherein said heteroatom is in a non-aromatic ring. The heterocycloalkyl ring is optionally fused to or otherwise attached to other heterocycloalkyl rings and/or non-aromatic hydrocarbon rings and/or phenyl rings. Preferred heterocycloalkyl groups have from 3 to 7 members. More preferred heterocycloalkyl groups have 5 or 6 members. Examples of heterocycloalkyl groups include, for example, aza-bicyclo[2.2.2]octyl (in each case also "quinuclidinyl" or a quinuclidine derivative), aza-bicyclo[3.2.1]octyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S,S-dioxide, piperazinyl, homopiperazinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, tetrahydrofuranyl, tetrahydrothienyl, homopiperidinyl, homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl S5S- dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydrofuryl, dihydropyranyl, tetrahydrothienyl S- oxide, tetrahydrothienyl S,S-dioxide and homothiomorpholinyl S-oxide. Preferred heterocycloalkyl groups include aza-bicyclo[2.2.2]octyl, aza-bicyclo[3.2.1]octyl, piperidinyl, piperazinyl, pyrrolidinyl, thiomorpholinyl, S,S-dioxothiomorpholinyl, morpholinyl, and imidazolidinyl. More preferred are aza-bicyclo[2.2.2]octyl, aza-bicyclo[3.2.1]octyl, piperidinyl, piperazinyl, pyrrolidinyl, imidazolidinyl, and morpholinyl. The heterocycle groups herein are unsubstituted or, as specified, substituted in one or more substitutable positions with various groups. For example, such heterocycle groups may be optionally substituted with, for example, Ci-C6 alkyl, Ci-C6 alkoxy, halogen, hydroxy, cyano, nitro, amino, mono(C1-C6)alkylamino, (Ii(C1 -C6)alkylamino, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, amino(Ci-C6)alkyl, mono(C1-C6)alkylamino(Ci-C6)alkyl, (Ii(C1- C6)alkylamino(C]-C6)alkyl or =O.
The term "pharmaceutically acceptable salts" or "a pharmaceutically acceptable salt thereof refer to salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases. Since the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids. Suitable pharmaceutically acceptable acid addition salts for the compound of the present invention include acetic, benzenesulfonic (besylate), benzoic, camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic, and the like. Preferred acid addition salts are the chloride and sulfate salts. In the most preferred aspect, structural and/or functional analogs of cisapride are administered as the free base or as the mono or dihydrochloride salt.
As used herein, the terms "treatment" and "treating" encompass prophylactic administration of the compound or a pharmaceutical composition comprising the compound ("prophylaxis") as well as remedial therapy to reduce or eliminate a disease or disorder mentioned herein. Prophylactic administration is intended for prevention of disorders and may be used to treat a subject that is at risk of having or suffering from one or more disorders mentioned herein. Thus, as used herein, the term "treatment", or a derivative thereof, contemplates partial or complete inhibition of the stated disease state, when an active ingredient of the invention is administered prophylactically or following the onset of the disease state for which such active ingredient of the is administered. "Prophylaxis" refers to administration of the active ingredient(s) to a mammal to protect the mammal from any of the disorders set forth herein, as well as others.
The term "therapeutically effective amount" refers to an amount necessary to achieve a derived therapeutic effect such as: 1) an amount sufficient to alleviate reflux disease, 2) an amount sufficient to alleviate nausea and vomiting, or 3) an amount sufficient to alleviate a condition caused by gastrointestinal motility dysfunction. Therapeutically effective amounts of structural and/or functional analogs of cisapride are encompassed by the above-described dosage amounts and dose frequency schedule. A "mammal" may be, for example, a mouse, rat, pig, horse, rabbit, goat, cow, cat, dog, or human. In a preferred aspect, the mammal is a human.
The term "individual(s)" is defined as a single mammal to which is administered a compound of the present invention. The mammal may be, for example, a mouse, rat, pig, horse, rabbit, goat, cow, cat, dog, or human. In a preferred aspect, the individual is a human.
The term "esterified cisapride" means therapeutic compounds of the subject invention that are structural and/or functional analogs of cisapride, which contain a hydrolysable group, generally an ester, that does not detract from the ability of these compounds to provide a therapeutic benefit, but which makes these compounds more susceptible to degradation by hydrolases, particularly serum and/or cytosolic esterases, and which reduces the interaction of the cytochrome P-450 drug detoxification system with the cisapride compounds. Esterase- mediated metabolism of esterified cisapride compounds reduces the role of the cytochrome P- 450 drug detoxification system in cisapride metabolism and reduces or eliminates adverse effects caused by cisapride.
The term "structural analog" as used herein means that a described compound shares structural characteristics with a parent compound. For example, a structural analog of cisapride may share one or more structural characteristics with the parent cisapride compound, such as a substituted aryl ring connected to a piperdine ring through an amide linker, but differ structurally in other ways, such as the inclusion or deletion of one or more other chemical moieties. Another example is the substitution of a pyridyl or pyridonyl ring for cisapride's phenyl ring.
The term "functional analog" as used herein means that a described compound shares a functional characteristic with a parent compound. For example, a functional analog of cisapride may share few, if any, structural characteristics with cisapride, but affect a similar function, for example, 5-HT4 agonism.
The term "adverse effects" includes, but is not limited to, gastrointestinal disorders such as diarrhea, abdominal cramping, and abdominal grumbling; tiredness; headache; increased systolic pressure; death; ventricular tachycardia; ventricular fibrillation; torsades de pointes; QT prolongation; increased heart rate; neurological and CNS disorders; and interaction of cisapride with other drugs given concurrently such as but not limited to digoxin, diazepam, ethanol, acenocoumarol, cimetidine, ranitidine, paracetamol, and propranolol. The term "gastroesophageal reflux disease" as used herein means the incidence of, and the symptoms of, those conditions causing the backward flow of the stomach contents into the esophagus.
The terms "eliciting an anti-emetic effect" and "anti-emetic therapy" as used herein mean providing relief from or preventing the symptoms of nausea and vomiting induced spontaneously or associated with emetogenic cancer chemotherapy or irradiation therapy.
The term "treating a condition caused by gastrointestinal motility dysfunction" as used herein means treating the symptoms and conditions associated with this disorder which include, but are not limited to, gastroesophageal reflux disease, dyspepsia, gastroparesis, constipation, post-operative ileus, and intestinal pseudo-obstruction.
The term "prokinetic" as used herein means the enhancement of peristalsis in, and thus the movement through the gastrointestinal tract.
The term "dyspepsia" as used herein means a condition characterized by an impairment of the power or function of digestion that can arise as a symptom of a primary gastrointestinal dysfunction or as a complication due to other disorders such as appendicitis, gallbladder disturbances, or malnutrition.
The term "gastroparesis" as used herein means a paralysis of the stomach brought about by a motor abnormality in the stomach or as a complication of diseases such as diabetes, progressive systemic sclerosis, anorexia nervosa, or myotonic dystrophy.
The term "constipation" as used herein means a condition characterized by infrequent or difficult evacuation of feces resulting from conditions such as lack of intestinal muscle tone or intestinal spasticity.
The term "post-operative ileus" as used herein means an obstruction in the intestine due to a disruption in muscle tone following surgery.
The term "intestinal pseudo-obstruction" as used herein means a condition characterized by constipation, colicky pain, and vomiting, but without evidence of physical obstruction.
Preparation of Compounds
The chemical synthesis of various analogs of cisapride can be performed by the methods described in European Patent Application No. 0,076,530 A2 published Apr. 13, 1983, U.S. Pat. Nos. 4,962,115 and 5,057,525 and in Van Daele et al., Drug Development Res. 8: 225-232 (1986), the disclosures of which are incorporated herein by reference in their entireties. Such syntheses can be modified, for example, by the incorporation of an ester group at a point convenient in the synthesis and by the substitution of an optionally
substituted pyridyl-
moiety for the substituted phenyl moiety of native cisapride.
Exemplary, non-limiting synthesis schemes for certain esterified cisapride analogs of the subject invention are provided in WO 01/093849.
The invention is illustrated further by the following examples, which are not to be construed as limiting the invention in scope or spirit to the specific procedures described in them. Those having skill in the art will recognize that the starting materials may be varied and additional steps employed to produce compounds encompassed by the invention, as demonstrated by the following examples. Those skilled in the art will also recognize that it may be necessary to utilize different solvents or reagents to achieve some of the above transformations. In some cases, protection of reactive functionalities may be necessary to achieve the above transformations. In general, such need for protecting groups, as well as the conditions necessary to attach and remove such groups, will be apparent to those skilled in the art of organic synthesis. When a protecting group is employed, deprotection step may be required. Suitable protecting groups and methodology for protection and deprotection such as those described in Protecting Groups in Organic Synthesis by T. Greene are well known and appreciated in the art.
Unless otherwise specified, all reagents and solvents are of standard commercial grade and are used without further purification. The appropriate atmosphere to run the reaction under, for example, air, nitrogen, hydrogen, argon and the like, will be apparent to those skilled in the art.
(i?)-quinuclidin-3-yl 6-((35',4i?)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin-l-yl)hexanoate dihydrochloride salt is a small molecule structurally and/or functionally related to the 5-HT4 receptor agonist, cisapride, which has been designed to reduce and/or eliminate QT prolongation and CYP450-dependent metabolism at anticipated therapeutically relevant concentrations. Example 1
Preparation of (i?)-quinuclidin-3-yl 6-((35r,4i?)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3-methoxypiperidin-l-yl)hexanoate, dihydrochloride salt (also referred to as N-7505 dihydrochloride)
N-7505 dihydrochloride contains three chiral centers and can be chemically synthesized as an enantiomerically and diastereomerically pure product. The chiral purities of key starting materials can be assessed by, for example, chiral HPLC or chiral GC methods to assure the diastereomeric purity of N-7505 dihydrochloride and other compounds of the invention with one or more chiral centers.
An exemplary synthetic process for (i?)-quinuclidin-3-yl 6-((35r,4i?)-4-(6-amino-5- chloro-2-methoxynicotinamido)-3-methoxypiperidin-l-yl)hexanoate dihydrochloride salt (N- 7505 dihydrochloride) is illustrated below. Racemic 6-amino-5-chloro-2-methoxy-N-(3- methoxypiperidin-4-yl)nicotinamide can be used as the starting material for the synthesis. An efficient chemical resolution process can be used to produce enantiomerically pure 6-amino- 5-chloro-2-methoxy-N-(3-methoxypiperidin-4-yl)nicotinamide. The chiral purity of enantiomerically pure 6-amino-5~chloro-2-methoxy-N-(3-methoxypiperidin-4- yl)nicotinamide can be assessed by a chiral HPLC method to assure greater than or equal to, for example, 98% enantiomeric excess (e.e.) quality. Enantiomerically pure 6-amino-5- chloro-2-methoxy-N-(3-methoxypiperidin-4-yl)nicotinamide can then be reacted with ethyl 6-bromohexanoate under basic conditions to make the corresponding alkylated ethyl ester. A transesterification reaction between the ethyl ester and (R)-(-)-3-quinuclidinol (preferably greater than or equal to 98% e.e. by chiral GC), is used to make Ν-7505 dihydrochloride. The final product is isolated as a dihydrochloride salt.
Step 1: Resolution of Racemic 6-amino-5-chIoro-2-methoxy-Λ'-(3-methoxypiperidin-4- yl)nicotinamide
(-)-Dibenzoyl-L-tartaric acid ((-)-DBT, about 1 part by weight) was dissolved in ethanol and filtered to remove residual particulates. Separately, racemic 6-amino-5-chloro-2- methoxy-N-(3-methoxypiperidin-4-yl)nicotinamide (about 0.8 part by weight) was dissolved in a mixture of ethanol and water and then filtered. The filtrate was heated to about 750C before adding the (-)-DBT solution. After stirring at this temperature for about 30 minutes, the mixture was slowly cooled for several hours to about 5 0C and the product salt was collected under vacuum filtration and washed with EtOHZH2O mixture. The wetcake was recrystallized from EtOHTH2O by heating to about 79 0C and slow cooling to about 5 0C as before. The product was collected on a vacuum filter and washed with EtOHTH2O to give a wetcake.
The wetcake was suspended in water and the pH was adjusted to about 12 using 7% (W/W) aq. NaOH. The resulting suspension was stirred for about 3 hours at room temperature before filtering under vacuum and washing the solid material with water and drying under vacuum. The product was then retreated with (-)-DBT to form the salt by the same general procedure described above. The isolated salt was then neutralized with aq. NaOH as described above. The product was isolated on a filter and dried as before to provide (+)-6-amino-5-chloro-2-methoxy-N-(3-methoxypiperidin-4-yl)nicotinamide base (about 0.25 parts by weight). The e.e. by chiral HPLC analysis was about 100% (+)-6-amino-5-chloro-2- methoxy-N-(3-methoxypiperidin-4-yl)nicotinamide. The optical rotation was about +5° (methanol; 250C and 589 nm), confirming the positive isomer of 6-amino-5-chloro-2- methoxy-N-(3-methoxypiperidin-4-yl)nicotinamide.
Step 2: Coupling with Ethyl 6-bromohexanoate
(+)-6-amino-5-chloro-2-methoxy-N-(3-methoxypiperidin-4-yl)nicotinamide (about 1 part by weight), potassium carbonate (about 0.48 part by weight) and potassium iodide (about 0.063 part by weight) were suspended in anhydrous USP ethanol. Ethyl 6- bromohexanoate (about 0.76 part by weight) was added slowly to the suspension at room temperature. The mixture was heated to reflux until completion of the reaction. Subsequent cooling to room temperature the reaction mixture was filtered to remove, e.g., inorganic solids, and the filtrate was concentrated under reduced pressure to about one-half the volume. The product was precipitated by slowly adding the crude material to cold water (about 13 parts by weight) with rapid stirring. The precipitate was filtered under vacuum and washed with water and then reprecipitated twice more by dissolution in anhydrous ethanol and slow addition into cold water as before. The resulting wetcake was washed with n-heptane and resuspended in ethyl acetate and n-heptane (1:9; v/v) and stirred for about 1 hour and before filtering and drying under vacuum to yield 0.73 parts by weight of the coupled product.
Step 3: Coupling with (R)-3-Quinuclidinol and Dihydrochloride Salt Formation
The ester product of step (1 part by weight) and (R)-3-Quinuclidinol (about 1.12 part by weight) were suspended in toluene before slowly adding titanium (IV) ethoxide (about 0.5 part by weight) to the stirred suspension. The mixture was heated to about 91 0C under a stream of nitrogen, and partial vacuum was applied to the flask through a distillation apparatus in order to azeotropically remove the ethanol. Additional toluene was added as needed to maintain a minimum solvent volume in the flask. The reaction was considered complete after about 33 hours.
The mixture was cooled to about room temperature and extracted five times with water. The organic layer was concentrated under reduced pressure and the resulting residue was redissolved in EtOH/zPrOH (about 1:1 v/v) and then filtered through a 0.45 micron membrane filter to remove any particulates. Concentrated hydrochloric acid was added slowly to the stirred filtrate to precipitate out the desired product, (i?)-quinuclidin-3-yl 6- ((35',4i?)-4-(6-amino-5-chloro-2-niethoxynicotinamido)-3-methoxypiperidin-l-yl)hexanoate as the dihydrochloride salt. The resulting suspension was stirred for several hours at room temperature and collected under vacuum filtration and rinsed with EtOH/zPrOH (1:1; v/v) to provide 0.53 part by weight of the crude product salt.
Crude (i?)-quinuclidin-3-yl 6-((35r,4i?)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3-methoxypiperidin-l-yl)hexanoate dihydrochloride salt was resuspended in ethanol and heated to reflux before cooling to room temperature over about 1 hour. The product was collected under vacuum filtration and rinsed with ethanol and then air- dried. The solids were resuspended in ethanol and warmed to about 55 0C to give a clear solution before adding warm isopropanol and the product was allowed to precipitate by slow cooling to room temperature. The resulting suspension was stirred for several hours before vacuum filtering and rinsing with, e.g., isopropanol. The product was vacuum dried, initially at room temperature for several hours and then at about 55 0C until a constant weight was achieved.
Example 2
Preparation of (i?)-quinuclidin-3-yl 6-((3JS',4i?)-4-(6-amino-4-chloro-2- methoxynicotinamido)-3-methoxypiperidin-l-yl)hexanoate
Step 1: Synthesis of ethyl 4-(dibenzylamino)-3-methoxypiperidine-l-carboxylate (1):
To a solution of racemic ethyl 4-amino-3-methoxypiperidine-l-carboxylate (1 part by mole) in DMF were added benzyl bromide (about 2.2 part by mole), potassium carbonate (about 2.4 part by mole) and potassium iodide (about 0.2 part by mole) respectively. The reaction was heated to about 800C. After about 6 hours, the reaction was slowly diluted with water (about 12 parts by volume) and extracted with, for example, ethyl acetate. The organic layer was washed with brine and then dried over anhyh. Na2SO4. Subsequent filtration and concentration of the solvent provided the 1 as the yellow-orange oil (1 part by mole). Step 2. Synthesis of N,N-dibenzyl-3-methoxypiperidin-4-amine (2):
To a solution of 1 was added NaOH (about 10 part by mole) in isopropanol and the mixture was stirred and heated to reflux. After about 3 to about 5 hours, the reaction was cooled to room temperature and the alcoholic solvent was removed via rotary evaporation. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was brined washed before drying over anhyh. Na2SO4. Subsequent filtration and concentration of the solvent provided a crude oil which was purified over SiO2 (CH2Cl2 : MeOH: NH4OH; (about) 15:1:0.01) to furnish 2.
Step 3. Synthesis of (3S,4R)-N^V-dibenzyl-3-methoxypiperidin-4-amine (3):
(-)-Dibenzoyl-L-tartaric acid (about 1.2 part by weight) is dissolved in ethanol before slowly adding to a solution of 2 (about 1 part by weight). The solution is gently warmed and then allowed to cool to room temperature to crystallize the salt product. The salt is filtered and washed with EtOH/H2O before suspending in water and basifying by adding aq. NaOH (7%, wt/wt) until the pH reaches about 12. The suspension is stirred vigorously at rt and the solid is filtered away, washed with water and vacuum dried to furnish the cis-isomer 3.
Step 4. Synthesis of ethyl 6-((3S,4R)-4-(dibenzylamino)-3-methoxypiperidin-l-yl)hexanoate (4):
To a solution of 3 (1 part by mole) in DMF are added ethyl bromohexanoate (about 1.2 part by mole), potassium carbonate (about 1.4 part by mole) and potassium iodide (about 0.2 part by mole) respectively. The reaction is then heated to 80 0C. After about 8 h, the reaction is slowly diluted with water (about 12 part by volume) and extracted with ethyl acetate. The organic layer is washed with brine and then dried over anhyd. Na2SO4. Subsequent filtration and concentration of the solvent furnishes the crude material. Purification over SiO2 and gives the alkylated material 4.
Step 5. Synthesis of (R)-quinuclidin-3-yl 6-((3S,4R)-4-(dibenzylamino)-3-methoxypiperidin- l-yl)hexanoate (5):
Titanium tetraethoxide is added to a mixture of 4 (1 part by mole) and (i?)-(-)-3- quinuclidinol (1 part by mole) in toluene. The reaction mixture is equipped with a dean-stark apparatus before heating to about 90 0C and partial vacuum is then applied (additional toluene is added as needed to main the requisite solvent level). The mixture is then cooled to rt and the reaction is diluted with ethyl acetate and then water is added to the resulting mixture. The organic layer is separated, brine washed, dried over anhyd. Na2SO4, filtered and concentrated. Purification over SiO2 gives the enantiomerically enriched 5.
Step 6. Synthesis of (R)-quinuclidin-3-yl 6-((3S,4R)-4-amino-3-methoxypiperidin-l- yl)hexanoate (6):
A solution of 5 (1 part by mole) in EtOH is added to a reaction flask containing palladium on carbon (about 0.2 part by mole). The mixture is then evacuated of air before subjecting to hydrogenolysis condition by using atmospheric H2. Upon completion of the reaction, the palladium is filtered off under a pad of celite followed by EtOH washes. The filtrated is concentrated via rotary evaporation to furnish 6. Step 7. Synthesis of (φ-qumuclidin-3-yl 6-((35',4i?)-4-(6-amino-4-chloro-2- methoxynicotinamido)-3-methoxypiperidin-l-yl)hexanoate (7):
To a solution of, for example, ethyl chloroformate (1 part by mole) in THF at about O 0C is added the (optionally substituted) nicotinic acid (1 part by mole) in portions. The mixture is warmed to room temperature (rt) for about 1 hour before cooling to about 0°C and adding dropwise a solution of compound 6 (1 part by mole). The reaction is then warmed to rt. Upon completion of the reaction, reaction is quenched by addition of a saturated solution OfNaHCO3 and extracting over EA (ethyl acetate). The organic layer is brine washed, dried over anhydrous Na2SO4, filtered and concentrated to furnish the desired product 7 (R)- quinuclidin-3-yl 6-((3S,4i?)-4-(6-amino-4-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)hexanoate.
Example 3
Alternate synthesis of (i?)-quinuclidin-3-yl 6-((3iS',4i?)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3-methoxypiperidin-l-yl)hexanoate dihydrochloride salt (N-7505 dihydrochloride):
Under acidic conditions, l-benzylpiperidin-4-one (1) and hydrobromic acid are reacted in the presence of acetic acid to generate N-benzyl-3-bromopiperidin-4-one (2). Treatment of 2 with a sodium methoxide and methanol solution provides 1-benzy 1-4,4- dimethoxypiperidin-3-ol (3). [The presence of the beta-amino group negates the possibility of a Favorskii-type reaction.] Methylation of the hydroxyl group is done using a hydride base followed by treatment with iodomethane in the presence of DMF (dimethylformamide) as the solvent to furnish compound 4.
Subsequent acetal hydrolysis using 1% sulfuric acid in the presence of heat yields a piperidine 5, which can then undergo a reductive amination using, for example, sodium cyanoborohydride and ammonium acetate in methanol to yield l-benzyl-3-methoxypiperidin- 4-amine (6). At this stage, 6 can undergo a chiral resolution technique. This can be accomplished, for example, using (-)-DBT or other variant of tartaric acid in the presence of the suitable solvent to afford exclusively asymmetrically pure compound 7. Boc group protection of the primary amine in 7 can be accomplished using Boc anhydride in the presence of THF solvent to obtain 8. A debenzylation reaction by hydrogenolysis using Pd/C in methanol in the presence of atmospheric hydrogen gas set the stage for the alkylation step. Treatment of 6-bromohexanenitrile in the presence of mild base and DMF generates compound 10. A nitrile to ester conversion using (R)-quinuclidinol in the presence of dilute acid generates 11. Subsequent removal of the Boc group using TFA furnishes the free amine, which can undergo a coupling reaction with requisite nicotinic acid in the presence of a coupling reagent such as ethyl chloroformate to afford N-7505 dihydrochloride as an enantiomerically pure material.
Alternatively, compound 9 can be alkylated using ethyl 6-bromohexanoate in the presence of mild base. Subsequent removal of the Boc group yields compound 14. Titanium mediated transesterification of 14 using (R)-quinuclidinol and titanium tetraethoxide in toluene solvent generates 15 (i?)-quinuclidin-3-yl 6-((35',4i?)-4-amino-3-methoxypiperidin-l-yl)hexanoate. The free amine of 15 can undergo a coupling reaction with requisite nicotinic acid, in this exemplary case 6-aniino-5-chloro-2-methoxynicotinic acid, in the presence of a coupling reagent such as ethyl chloroformate to afford 16, N-7505 dihydrochloride, as an enantiomerically pure material. Carlsburg esterase hydrolyzes esters that are of the S- configuration, therefore leaving intact esters that are of the R configuration. Therefore treatment of diasteriomeric mixtures of 17 with the Carlsburg esterase may also yield 18, (R)- quinuclidin-3-yl 6-((3S,4i?)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)hexanoate dihydrochloride.
Example 4
(+) and (-)-6-amino-5-chloro-2-methoxy-N-(3-methoxypiperidin-4-yl)nicotinamide or (+) and (-)-6-amino-5-chloro-N-(3-methoxypiperidin-4-yl)-2-oxo-l,2-dihydropyridine-3- carboxamide can be made from their racemic mixtures by resolution of the enantiomers using conventional means such as optically resolving acids, according to the method described in US Patent 6,147,093, or in "Enantiomers, Racemates and Resolutions", by J. Jacques, A. Collet, and S.H. Wilen (Wiley-Interscience, New York, NY), or in S.H. Wilen et al., Tetrahedron (1977) 33:2725.
The 4 isomers of each of the above compounds can easily be obtained in low- milligram amounts by using preparative column chromatography followed by evaporation of the solvent. This method is useful for preparing small amounts for analytical and characterization purposes. This is a standard separation method used routinely in analytical labs in order to isolate and characterize metabolites.
Exemplary synthetic routes to Compound IVb, Compound VIb and (+)-Compound lib are described below using (+)-6-amino-5-chloro-2-methoxy-N-(3-methoxypiperidin-4- yl)nicotinamide as a starting material. The routes to Compound IHb, Compound Vb and (-)- Compound lib are identical except that they use (-)-6~amino-5-chloro-2-methoxy-N-(3- methoxypiperidin-4-yl)nicotinamide as a starting material.
Example 5
Production of '(+) -Compound lib, ethyl ester
A equimolar mixture of (+)-6-amino-5-chloro-2-methoxy-N-(3-methoxypiperidin-4- yl)nicotinamide and ethyl 6-bromohexanoate (1 equivalent each), a catalytic amount of KI, and K2CO3 (2 equivalents) in DMF (dimethylformamide) is heated at about 60 C for several hours or until TLC analysis indicates that the reaction is over. After cooling to room temperature, water is added and the mixture is extracted with EtOAc. The combined organic extracts are washed successively with water, 10% LiCl(aq) solution and brine, then dried over Na2SO4. Concentration gives (+)-compound lib, ethyl ester.
Production of ' (+)-Compound lib
A mixture of crude (+)-compound lib, ethyl ester, from above (1 eq.), KOH (2M, 5 eq.) in MeOH (methanol) and THF (tetrahydrofuran; enough to dissolve) is stirred at room temperature for approximately 1 to 2 hours. The MeOH and THF are removed under vacuum, and the residue is diluted with water. Wash with an organic solvent such as EtOAc. The aqueous layer is acidified to pH ~5 using HCl. The precipitate is filtered off and dried to give (+)-Compound Hb.
Production of Compound IVb and Compound VIb
A mixture of (+)-Compound lib (1 eq.), (R)-(-)-3-quinuclidinol HCl salt (1 eq.), EDAC (l-ethyl-3-(3-dimethylpropyl)-carbodiimide; 1 eq.) and DMAP (4- dimethylaminopyridine; 1 eq.) in DMF is heated at around 500C overnight. After cooling and diluting with water, the mixture is purified by chromatography or by crystallization to provide Compound IVb. Similarly, using (S)-(+)-quinuclidinol, Compound VIb is obtained.
The following compounds are prepared essentially according to methods and procedures described above. The compound names were generated using either ChemDraw Ultra version 8.03 and/or 9.0, which is available from Cambridgesoft Corporation or ACD
Namepro software, version 6.0.
6-((35r,4i?)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3- methoxypiperidin- 1 -yl)hexanoic acid
6-((35',4Λ)-4-(6-amino-5-chloro-2- oxo-l,2-dihydropyridine-3-carboxamido)- 3-methoxypiperidin-l-yl)hexanoic acid 6-((3i?,41S)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3 - methoxypiperidin- 1 -yl)hexanoic acid
6-((3i?,45)-4-(6-amino-5-chloro-2- oxo-l,2-dihydropyridine-3-carboxamido)- 3 -methoxypiperidin- 1 -yl)hexanoic acid
(iQ-quinuclidin-3-yl 6-((3S,4i?)-4-
(6-amino-5-chloro-2- methoxynicotinamido)-3- methoxypiperidin- 1 -yl)hexanoate
(i?)-quinuclidin-3-yl 6-((3,S,4i?)-4- (6-amino-5 -chloro-2-oxo- 1,2- dihydropyridine-3-carboxamido)-3- methoxypiper idin- 1 -yl)hexanoate
(i?)-quinuclidin-3-yl 6-((3i?,4,S)-4-
(6-amino-5-chloro-2- methoxynicotinamido)-3 - methoxypiperidin- 1 -yl)hexanoate
(^-quinuclidin-S-yl o-^SiJ^-S)^- (6-amino-5 -chloro-2-oxo- 1,2- dihydropyridine-3-carboxamido)-3- methoxypiperidin- 1 -yl)hexanoate
(1S)-quinuclidin-3-yl 6-((3,S,4JR)-4- (6-amino-5-chloro-2-oxo- 1,2- dihydropyridine-3 -carboxamido)-3 - methoxypiperidin- 1 -yl)hexanoate (S^quinuclidin-S-yl ό-CCSS^iJM-
(6~amino-5-chloro-2- methoxynicotinamido)-3- methoxypiperidin- 1 -yl)hexanoate
(5)-quinuclidin-3-yl 6-((3R,4S)-4- (6-amino-5 -chloro-2-oxo- 1,2- dihydropyridine-3 -carboxamido)-3 - methoxypiperidin- 1 -yl)hexanoate
(5)-quinuclidin-3-yl 6-((3i?,45)-4-
(6-amino-5-chloro-2- methoxynicotinamido)-3 - methoxypiperidin- 1 -yl)hexanoate
(5)-quinuclidin-3-yl 6-((3R,4S)-4- (6-amino-5 -chloro-2-oxo- 1,2- dihydropyridine-3 -carboxamido)-3 - methoxypiperidin- 1 -yl)hexanoate
(^-quinuclidin-S-yl 6-((3R,4S)-4-
(6-amino-5-chloro-2- methoxynicotinamido)-3- methoxypiperidin- 1 -yl)hexanoate
0S)-quinuclidin-3-yl 6-((3S,4R)-4- (6-amino-5-chloro-2-oxo-l,2- dihydropyridine-3 -carboxamido)-3 - methoxypiperidin- 1 -yl)hexanoate
(S)-qumuc\idin-3-y\ 6-((3S,4R)-4-
(6-amino-5-chloro-2- methoxynicotinamido)-3 - methoxypiperidin- 1 -yl)hexanoate
(i?)-quinuclidin-3-yl 6-((3i?,4,S)-4-
(6-amino-5-chloro-2- methoxynicotinamido)-3- methoxypiper idin- 1 -yl)hexanoate (i?)-quinuclidin-3-yl 6-((3i?,45)-4- (6-amino-5-fluoro-2-oxo~l,2- dihydropyridine-3 -carboxamido)-3 - methoxypiperidin- 1 -yl)hexanoate
(i?)-quinuclidin-3-yl 6-((35,4i?)-4-
(6-amino-5-chloro-2- methoxynicotinamido)-3 - methoxypiperidin- 1 -yl)hexanoate
(iζ)-quinuclidin-3-yl 6-((3S,4i?)-4- (6-amino-5-fluoro-2-oxo- 1 ,2- dihydropyridine-3-carboxamido)-3- methoxypiperidin- 1 -yl)hexanoate
8-methyl-8~azabicyclo[3.2.1]octan- 3-yl 6-((3_S;4/Q^-(6-amino-5-cm<>ro-2- methoxynicotinamido)-3 - methoxypiperidin- 1 -yl)hexanoate
8-methyl-8-azabicyclo [3.2.1 ] octan- 3-yl 6-((36',4i?)-4-(6-amino-5-chloro-2- oxo-l,2-dihydropyridine-3-carboxamido)- 3 -methoxypiperidin- 1 -yl)hexanoate
8-methyl-8-azabicyclo[3.2.1]octan- 3-yl 6-((3i?,4,S)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3- methoxypiperidin- 1 -yl)hexanoate
8-methyl-8-azabicyclo[3.2. l]octan- 3-yl 6-((3i?,45)-4-(6-amino-5-chloro-2- oxo- 1 ,2-dihydropyridine-3 -carboxamido)- 3 -methoxypiperidin- 1 -yl)hexanoate 4-(2-((3,S,4R)-4-(6-amino-5-chloro- 2-methoxynicotinamido)-3 - methoxypiperidin- 1 -yl)acetamido)benzoic acid
4-(2-((3S,4i?)-4-(6-amino-5-chloro- 2-oxo- 1 ,2-dihydropyridine-3 - carboxamido)-3 -methoxypiperidin- 1 - yl)acetamido)benzoic acid
4-(2-((3i?,45}-4-(6-amino-5-chloro- 2-methoxynicotinamido)-3 - methoxypiperidin- 1 -yl)acetamido)benzoic acid
4-(2-((3i?,45)-4-(6-amino-5-chloro- 2-oxo- 1 ,2-dihydropyridine-3- carboxamido)-3 -methoxypiperidin- 1 - yl)acetamido)benzoic acid
methyl 4-(2-((3i?,45)-4-(6-amino-5- chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 - yl)acetamido)benzoate
methyl 4-(2-((3i?,4£)-4-(6-amino-5- chloro-2-oxo- 1 ,2-dihydropyridine-3- carboxamido)-3 -methoxypiperidin- 1 - yl)acetamido)benzoate
methyl 4-(2-((36',4i?)-4-(6-amino-5- chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 - yl)acetamido)benzoate methyl 4-(2-((3S,4i?)-4-(6-amino-5- chloro-2-oxo-l,2-dihydropyridine-3- carboxamido)-3 -methoxypiperidin- 1 - yl)acetamido)benzoate
ethyl 4-(2-((35',4i?)-4-(6-amino-5- chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 - yl)acetamido)benzoate
ethyl 4-(2-((3S,4i?)-4-(6-amino-5- chloro-2-oxo- 1 ,2-dihydropyridine-3 - carboxamido)-3 -methoxypiperidin- 1 - yl)acetamido)benzoate
ethyl 4-(2-((3i?,41S)-4-(6-amino-5- chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 - yl)acetamido)benzoate
ethyl 4-(2-((3i?,4,S)-4-(6-amino-5- chloro-2-oxo- 1 ,2-dihydropyridine-3 - carboxamido)-3 -methoxypiperidin- 1 - yl)acetamido)benzoate
isopropyl 4-(2-((3.S',4i?)-4-(6- amino-5-chloro-2-methoxynicotinamido)- 3 -methoxypiperidin- 1 - yl)acetamido)benzoate isopropyl 4-(2-((3^,4i?)-4-(6- amino-5-chloro-2-oxo-l,2- dihydropyridine-3 -carboxamido)-3 - methoxypiperidin- 1 - yl)acetamido)benzoate
isopropyl 4-(2-((3Λ,4S)-4-(6- amino-5-chloro-2-methoxynicotinamido)- 3 -methoxypiperidin- 1 - yl)acetamido)benzoate
isopropyl 4-(2-((3i?,4,S)-4-(6- amino-5 -chloro-2-oxo- 1,2- dihydropyridine-3 -carboxamido)-3 - methoxypiperidin- 1 - yl)acetamido)benzoate
2-methoxyethyl 4-(2-((35,4i?)-4-(6- amino-5-chloro-2-methoxynicotinamido)- 3 -methoxypiperidin- 1 - yl)acetamido)benzoate
2-methoxyethyl 4-(2-((35',4i?)-4-(6- amino-5 -chloro-2-oxo- 1 ,2- dihydropyridine-3 -carboxamido)-3 - methoxypiperidin- 1 - yl)acetamido)benzoate
2-methoxyethyl 4-(2-((3i?,45)-4-(6- amino-5-chloro-2-methoxynicotinamido)- 3 -methoxypiperidin- 1 - yl)acetamido)benzoate 2-methoxyethyl 4-(2-((3i?,45)-4-(6- amino-5-chloro-2-oxo-l,2- dihydropyridine-3-carboxamido)-3- methoxypiperidin- 1 - yl)acetamido)benzoate
2-(pyrrolidin-l-yl)ethyl 4-(2-
((35',4i?)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3 - methoxypiperidin- 1 - yl)acetamido)benzoate
2-(pyrrolidin-l-yl)ethyl 4-(2-
((35r,4i?)-4-(6-amino-5-chloro-2-oxo-l,2- dihydropyridine-3 -carboxamido)-3 - methoxypiperidin- 1 - yl)acetamido)benzoate
2-(pyrrolidin-l-yl)ethyl 4-(2-
((3i?,45)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3- methoxypiperidin- 1 - yl)acetamido)benzoate
2-(pyrrolidin-l-yl)ethyl 4-(2-
((3i?,45}-4-(6-amino-5-chloro-2-oxo- 1 ,2- dihydropyridine-3-carboxamido)-3- methoxypiperidin- 1 - yl)acetamido)benzoate l-methylpiρeridin-4-yl 4-(2-
((35',4i?)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3- methoxypiperidin- 1 - yl)acetamido)benzoate
l-methylpiperidin-4-yl 4-(2-
((3£4i0-4-(6-amino-5-chloro-2-oxo-l,2- dihydropyridine-3 -carboxamido)-3 - methoxypiperidin- 1 - yl)acetamido)benzoate
l-methylpiperidin-4-yl 4-(2-
((3i?,45)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3 - methoxypiperidin- 1 - yl)acetamido)benzoate
l-methylpiperidin-4-yl 4-(2-
((3i?,45)-4-(6-amino-5-chloro-2-oxo-l,2- dihydropyridine-3 -carboxamido)-3 - methoxypiperidin- 1 - yl)acetamido)benzoate
2-(pyridin-2-yl)ethyl 4-(2-((31S,4i?)-
4-(6-amino-5 -chloro-2- methoxynicotinamido)-3 - methoxypiperidin- 1 - yl)acetamido)benzoate
2-(pyridin-2-yl)ethyl 4-(2-((35,4i?)-
4-(6-amino-5-chloro-2-oxo- 1 ,2- dihydropyridine-3 -carboxamido)-3 - methoxypiperidin-1- yl)acetamido)benzoate 2-(pyridin-2-yl)ethyl 4-(2-((3i?,45)-
4-(6-amino-5 -chloro-2- methoxynicotinamido)-3 - methoxypiperidin- 1 - yl)acetamido)benzoate
2-(pyridin-2-yl)ethyl 4-(2-((3i?,45)-
4-(6-amino-5 -chloro-2-oxo- 1,2- dihydropyridine-3 -carboxamido)-3 - methoxypiperidin- 1 - yl)acetamido)benzoate
2-(dimethylamino)ethyl 4-(2-
((35',4i?)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3- methoxypiperidin- 1 - yl)acetamido)benzoate
2-(dimethylamino)ethyl 4-(2-
((35l,4i?)-4-(6-amino-5-chloro-2-oxo-l,2- dihydropyridine-3 -carboxamido)-3 - methoxypiperidin- 1 - yl)acetamido)benzoate
2-(dimethylamino)ethyl 4-(2-
((3i?,4i)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3 - methoxypiperidin- 1 - yl)acetamido)benzoate 2-(dimethylamino)ethyl 4-(2-
((3i?,45)-4-(6-amino-5-chloro-2-oxo-l,2- dihydropyridine-3 -carboxamido)-3 - methoxypiperidin- 1 - yl)acetamido)benzoate
l-methylpiperidin-3-yl 4-(2-
((31S',4i?)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3- methoxypiperidin- 1 - yl)acetamido)benzoate
l-methylpiperidin-3-yl 4-(2-
((35',4i?)-4-(6-amino-5-chloro-2-oxo-l,2- dihydropyridine-3 -carboxamido)-3 - methoxypiperidin- 1 - yl)acetamido)benzoate
l-methylpiperidin-3-yl 4-(2-
((3i?,45)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3 - methoxypiperidin- 1 - yl)acetamido)benzoate
l-methylpiperidin-3-yl 4-(2-
((3i?,45)-4-(6-amino-5-chloro-2-oxo-l,2- dihydropyridine-3 -carboxamido)-3 - methoxypiperidin- 1 - yl)acetamido)benzoate
2-morpholinoethyl 4-(2-((35',4i?)-4-
(6-amino-5-chloro-2- methoxynicotinamido)-3- methoxypiperidin- 1 - yl)acetamido)benzoate 2-morpholinoethyl 4-(2-((3S,4i?)-4-
(6-amino-5-chloro-2-oxo-l,2- dihydropyridine-3 -carboxamido)-3 - methoxypiperidin-1- yl)acetamido)benzoate
2-morpholinoethyl 4-(2-((3i?,45)-4-
(6-amino-5 -chloro-2- methoxynicotinamido)-3 - methoxypiperidin- 1 - yl)acetamido)benzoate
2-morpholinoethyl 4-(2-((3i?,45)-4-
(6-amino-5-chloro-2-oxo-l,2- dihydropyridine-3 -carboxamido)-3 - methoxypiperidin- 1 - yl)acetamido)benzoate
l,4-dimethylpiperidin-4-yl 4-(2-
((S.S'^^^-Cβ-amino-S-chloro^- methoxynicotinamido)-3 - methoxypiperidin- 1 - yl)acetamido)benzoate
l,4-dimethylpiperidin-4-yl 4-(2-
((35",4i?)-4-(6-amino-5-chloro-2-oxo-l,2- dihydropyridine-3 -carboxamido)-3 - methoxypiperidin- 1 - yl)acetamido)benzoate
l,4-dimethylpiperidin-4-yl 4-(2-
((3i?,45)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3- methoxypiperidin- 1 - yl)acetamido)benzoate l,4-dimethylpiperidin-4-yl 4-(2-
((3i?,45)-4-(6-amino-5-chloro-2-oxo- 1 ,2- dihydropyridine-3 -carboxamido)-3 - methoxypiperidin- 1 - yl)acetamido)benzoate
4-(2-((35',4i?)-4-(6-amino-5-chloro- 2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)acetamido)benzoic acid
4-(2-((35',4i?)-4-(6-amino-5-chloro- 2-oxo- 1 ,2-dihydropyridine-3 - carboxamido)-3 -methoxypiperidin- 1 - yl)acetamido)benzoic acid
4-(2-((3i?,4,S)-4-(6-amino-5-chloro- 2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)acetamido)benzoic acid
4-(2-((3i?,45)-4-(6-amino-5-chloro- 2-oxo- 1 ,2-dihydropyridine-3 - carboxamido)-3 -methoxypiperidin- 1 - yl)acetamido)benzoic acid
2-oxo-2-(piperidin-4-ylamino)ethyl
4-(2-((3,S,4i?)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3- methoxypiperidin- 1 - yl)acetamido)benzoate 2-oxo-2-(piperidin-4-ylamino)ethyl
4-(2-((35',4i?)-4-(6-amino-5-chloro-2-oxo-
1 ,2-dihydropyridine-3 -carboxamido)-3 - methoxypiperidin- 1 - yl)acetamido)benzoate
2-oxo-2-(piperidin-4-ylamino)ethyl
4-(2-((3i?,45)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3 - methoxypiperidin- 1 - yl)acetamido)benzoate
2-oxo-2-(piperidin-4-ylamino)ethyl
4-(2-((3i?,45)-4-(6-amino-5-chloro-2-oxo- l,2-dihydropyridine-3-carboxamido)-3- methoxypiperidin- 1 - yl)acetamido)benzoate
l-(2-((3£,4i?)-4-(6-amino-5-chloro- 2-methoxynicotinamido)-3 - methoxypiperidin- 1 -yl)acetyl)piperidine- 4-carboxylic acid
l-(2-((3S,4i?)-4-(6-amino-5-chloro- 2-oxo- 1 ,2-dihydropyridine-3- carboxamido)-3 -methoxypiperidin- 1 - yl)acetyl)piperidine-4-carboxylic acid
l-(2-((3i?,4S)-4-(6-amino-5-chloro- 2-methoxynicotinamido)-3 - methoxypiperidin- 1 -yl)acetyl)piperidine- 4-carboxylic acid
l-(2-((3i?,45)-4-(6-amino-5-chloro- 2-oxo- 1 ,2-dihydropyridine-3 - carboxamido)-3 -methoxypiperidin- 1 - yl)acetyl)piperidine-4-carboxylic acid
methyl 1 -(2-((3S,4i?)-4-(6-amino-5- chloro-2-methoxynicotinamido)-3 - methoxypiperidin- 1 -yl)acetyl)piperidine- 4-carboxylate
methyl l-(2-((35',4i?)-4-(6-amino-5- chloro-2-oxo- 1 ,2-dihydropyridine-3 - carboxamido)-3 -methoxypiperidin- 1 - yl)acetyl)piperidine-4-carboxylate
methyl 1 -(2-((3i?,45)-4-(6-amino-5- chloro-2-methoxynicotinamido)-3 - methoxypiperidin- 1 -yl)acetyl)piperidine- 4-carboxylate
methyl 1 -(2-((3i?,4S)-4-(6-amino-5- chloro-2-oxo- 1 ,2-dihydropyridine-3 - carboxamido)-3 -methoxypiperidin- 1 - yl)acetyl)piperidine-4-carboxylate
ethyl 1 -(2-((35',4i?)-4-(6-amino-5- chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)acetyl)piperidine- 4-carboxylate
ethyl 1 -(2-((3S,4i?)-4-(6-amino-5- chloro-2-oxo- 1 ,2-dihydropyridine-3 - carboxamido)-3 -methoxypiperidin- 1 - yl)acetyl)piperidine-4-carboxylate
ethyl l-(2-((3i?,45)-4-(6-amino-5- chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)acetyl)piperidine- 4-carboxylate
ethyl l-(2-((3i?,4,S)-4-(6-aniino-5- chloro-2-oxo- 1 ,2-dihydroρyridine-3 - carboxamido)-3-methoxypiperidin-l- yl)acetyl)piperidine-4-carboxylate
2-methoxyethyl 1 -(2-((3^,4i?)-4-(6- amino-5-chloro-2-methoxynicotinamido)-
3 -methoxypiperidin- 1 - yl)acetyl)piperidine-4-carboxylate
2-methoxyethyl l-(2-((35',4i?)-4-(6- amino-5-chloro-2-oxo-l,2- dihydropyridine-3 -carboxamido)-3 - methoxypiperidin- 1 -yl)acetyl)piperidine-
4-carboxylate 2-methoxyethyl 1 -(2-((3i?,45)-4-(6- amino-5-chloro-2-methoxynicotinamido)-
3 -methoxypiperidin- 1 - yl)acetyl)piperidine-4-carboxylate
2-methoxyethyl l-(2-((3i?,45)-4-(6- amino-5 -chloro-2-oxo- 1 ,2- dihydropyridine-3 -carboxamido)-3 - methoxypiperidin- 1 -yl)acetyl)piperidine- 4-carboxylate
4-(((2-((3S,4i?)-4-(6-amino-5- chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 - yl)ethyl)(methyl)amino)methyl)benzoic acid
4-(((2-((3,S',4i?)-4-(6-amino-5- chloro-2-oxo- 1 ,2-dihydropyridine-3 - carboxamido)-3 -methoxypiperidin- 1 - yl)ethyl)(methyl)amino)methyl)benzoic acid
4-(((2-((3i?,4^)-4-(6-amino-5- chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 - yl)ethyl)(methyl)amino)methyl)benzoic acid
4-(((2-((3i?,45)-4-(6-amino-5- chloro-2-oxo- 1 ,2-dihydropyridine-3 - carboxamido)-3-methoxypiperidin- 1 - yl)ethyl)(methyl)amino)methyl)benzoic acid
methyl 4-(((2-((31Sr,4i-)-4-(6-amino- 5 -chloro-2-methoxynicotinamido)-3 - methoxypiperidin- 1 - yl)ethyl)(methyl)amino)methyl)benzoate methyl 4-(((2-((3S,4i?)-4-(6-amino- 5 -chloro-2-oxo- 1 ,2-dihydropyridine-3 - carboxamido)-3 -methoxypiperidin- 1 - yl)ethyl)(methyl)amino)methyl)benzoate
methyl 4-(((2-((3i?,45)-4-(6-amino- 5 -chloro-2-methoxynicotinamido)-3 - methoxypiperidin- 1 - yl)ethyl)(methyl)amino)methyl)benzoate
methyl 4-(((2-((3i?,46)-4-(6-amino- 5-chloro-2-oxo-l,2-dihydropyridine-3- carboxamido)-3 -methoxypiperidin- 1 - yl)ethyl)(methyl)amino)methyl)benzoate
methyl 4-((2-((35',4i?)-4-(6-amino- 5 -chloro-2-methoxynicotinamido)-3 - methoxypiperidin- 1 - yl)ethylamino)methyl)benzoate
methyl 4-((2-((31S(,4i?)-4-(6-amino- 5 -chloro-2-oxo- 1 ,2-dihydropyridine-3 - carboxamido)-3-methoxypiperidin-l- yl)ethylamino)methyl)benzoate
methyl 4-((2-((3i?,45)-4-(6-amino- 5 -chloro-2-methoxynicotinamido)-3 - methoxypiperidin- 1 - yl)ethylamino)methyl)benzoate methyl 4-((2-((3i?,4£)-4-(6-ammo- 5 -chloro-2-oxo- 1 ,2-dihydropyridine-3 - carboxamido)-3 -methoxypiperidin- 1 - yl)ethylamino)methyl)benzoate
isopropyl 4-((2-((3S,4J?)-4-(6- amino-5-chloro-2-methoxynicotinamido)-
3-methoxypiperidin- 1 - yl)ethylamino)methyl)benzoate
isopropyl 4-((2-((3S,4i?)-4-(6- amino-5-chloro-2-oxo- 1 ,2- dihydropyridine-3 -carboxamido)-3 - methoxypiperidin- 1 - yl)ethylamino)methyl)benzoate
isopropyl 4-((2-((3i?,45)-4-(6- amino-5-chloro-2-methoxynicotinamido)-
3 -methoxypiperidin- 1 - yl)ethylamino)methyl)benzoate
isopropyl 4-((2-((3i?,45)-4-(6- amino-5 -chloro-2-oxo- 1 ,2- dihydropyridine-3-carboxamido)-3- methoxypiperidin- 1 - yl)ethylamino)methyl)benzoate
ethyl 4-((2-((3,S,4i?)-4-(6-amino-5- chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 - yl)ethylamino)methyl)benzoate dihydrochloride
ethyl 4-((2-((35',4i?)-4-(6-amino-5- chloro-2-oxo- 1 ,2-dihydropyridine-3 - carboxamido)-3 -methoxypiperidin- 1- yl)ethylamino)methyl)benzoate dihydrochloride ethyl 4-((2-((3JR,41S)-4-(6-amino-5- chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 - yl)ethylamino)methyl)benzoate dihydrochloride
ethyl 4-((2-((3i?,45)-4-(6-amino-5- chloro-2-oxo-l,2-dihydropyridine-3- carboxamido)-3-methoxypiperidin-l- yl)ethylamino)methyl)benzoate dihydrochloride
(#)-quinuclidin~3-yl 4-(2-((3S,4i?)- 4-(6-amino-5-chloro-2- methoxynicotinamido)-3 - methoxypiperidin- 1 - yl)ethylcarbamoyl)benzoate
(i?)-quinuclidin~3-yl 4-(2-((3S,4i?)- 4-(6-amino-5-chloro-2-oxo- 1 ,2- dihydropyridine-3-carboxamido)-3- methoxypiperidin- 1 - yl)ethylcarbamoyl)benzoate
(i?)-quinuclidin-3-yl 4-(2-((3i?,45)- 4-(6-amino-5-chloro-2- methoxynicotinamido)-3 - methoxypiperidin- 1 - yl)ethylcarbamoyl)benzoate
(i?)-quinuclidin-3-yl 4-(2-((3i?,45)- 4-(6-amino-5 -chloro-2-oxo- 1 ,2- dihydropyridine-3-carboxamido)-3- methoxypiperidin- 1 - yl)ethylcarbamoyl)benzoate
The following compounds may be prepared essentially according to methods and procedures described above. The compound names were generated using either ChemDraw Ultra version 8.03 and/or 9.0, which is available from Cambridgesoft Corp. benzyl 3-((3S,4R)-4-(6-amino-5- chloro-2-methoxynicotinamido)- 3 -methoxypiperidin- 1 - yl)propanoate
isopropyl 3-((3R,4S)-4-(6- amino-5 -chloro-2- methoxynicotinamido)-3- methoxypiperidin- 1- yl)propanoate
4-(methylsulfonyl)benzyl 3- ((3R,4S)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3- methoxypiperidin- 1- yl)propanoate
(tetrahydro-2H-pyran-2- yl)methyl 3-((3R,4S)-4-(6- amino-5-chloro-2- methoxynicotinamido)-3- methoxypiperidin- 1- yl)propanoate
cyclohexyl 3-((3R,4S)-4-(6- amino-5-chloro-2- methoxynicotinamido)-3- methoxypiperidin- 1- yl)propanoate
neopentyl 3-((3S,4R)-4-(6- amino-5 -chloro-2- methoxynicotinamido)-3- methoxypiperidin- 1 - yl)propanoate 4-methoxybenzyl 3-((3R,4S)-4- (6-amino-5 -chloro-2- methoxynicotinamido)-3- methoxypiperidin- 1 - yl)propanoate
pyridin-4-ylmethyl 3-((3R,4S)-4- (6-amino-5-chloro-2- methoxynicotinamido)-3- methoxypiperidin- 1 - yl)propanoate
2-((3S,4R)-4-(6-amino-5-chloro- 2-methoxynicotinamido)-3 - methoxypiperidin- 1 -yl)acetic acid
2-(pyrrolidin-l-yl)ethyl 4-(((2- ((3S,4R)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3 - methoxypiperidin- 1 - yl)ethyl)(methyl)amino)methyl)b enzoate
l-methylpiperidin-4-yl 4-(((2-
((3S,4R)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3- methoxypiperidin- 1 - yl)ethyl)(methyl)amino)rnethyl)b enzoate 2-morpholinoethyl 4-(((2-
((3S,4R)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3- methoxypiperidin- 1 - yl)ethyl)(methyl)amino)methyl)b enzoate
4-fluorobenzyl 2-((3S,4R)-4-(6- amino-5-chloro-2- methoxynicotinamido)-3- methoxypiperidin- 1 -yl)acetate
benzyl 2-((3S,4R)-4-(6-amino-5- chloro-2-methoxynicotinamido)- 3 -methoxypiperidin- 1 -yl)acetate
4-methylbenzyl 2-((3S,4R)-4-(6- amino-5 -chloro-2- methoxynicotinamido)-3- methoxypiperidin- 1 -yl)acetate
2-methoxybenzyl 2-((3S,4R)-4- (6-amino-5-chloro-2- methoxynicotinamido)-3- methoxypiperidin- 1 -yl)acetate 4-chlorobenzyl 2-((3S,4R)-4-(6- amino-5-chloro-2- methoxynicotinamido)-3 - methoxypiperidin- 1 -yl)acetate
4-methoxybenzyl 2-((3R,4R)-4- (6-amino-5-chloro-2- methoxynicotinamido)-3 - methoxypiperidin- 1 -yl)acetate
piperidin-4-yl 2-((3S,4R)-4-(6- amino-5 -chloro-2- methoxynicotinamido)-3 - methoxypiperidin- 1 -yl)acetate
2-methoxyethyl 2-((3S,4R)-4-(6- amino-5 -chloro-2- methoxynicotinamido)-3 - methoxypiperidin- 1 -yl)acetate
2-hydroxyethyl 2-((3S,4R)-4-(6- amino-5 -chloro-2- methoxynicotinamido)-3 - methoxypiperidin- 1 -yl)acetate 2-chlorobenzyl 2-((3R,4S)-4-(6- amino-5-chloro-2- methoxynicotinamido)-3- methoxypiperidin- 1 -yl)acetate
4-((2-((3S,4R)-4-(6-amino-5- chloro-2-methoxynicotinamido)- 3 -methoxypiperidin- 1 - yl)ethylamino)methyl)benzoic acid
3-hydroxypropyl 4-((2-((3S,4R)- 4-(6-amino-5-chloro-2- methoxynicotinamido)-3 - methoxypiperidin- 1 - yl)ethylamino)methyl)benzoate
piperidin-4-yl 4-((2-((3S,4R)-4- (6-amino-5 -chloro-2- methoxynicotinamido)-3- methoxypiperidin- 1 - yl)ethylamino)rnethyl)benzoate
4-(trifluoromethyl)benzyl 2- ((3R,4S)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3- methoxypiperidin- 1 -yl)acetate
3-methylbenzyl 2-((3R,4S)-4-(6- amino-5-chloro-2- methoxynicotinamido)-3 - methoxypiperidin- 1 -yl)acetate 3-chlorobenzyl 2-((3R,4S)-4-(6- amino-5 -chloro-2- methoxynicotinamido)-3- methoxypiperidin- 1 -yl)acetate
2-(trifluoromethyl)benzyl 2- ((3R,4S)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3- methoxypiperidin-l-yl)acetate
2-morpholinoethyl 2-((3R,4S)-4-
(6-amino-5 -chloro-2- methoxynicotinamido)-3- methoxypiperidin-1 -yl)acetate
(tetrahydro-2H-pyran-2- yl)methyl 2-((3R,4S)-4-(6- amino-5-chloro-2- methoxynicotinamido)-3- methoxypiperidin-1 -yl)acetate
2-fluorobenzyl 2-((3R,4S)-4-(6- amino-5-chloro-2- methoxynicotinamido)-3- methoxypiperidin-1 -yl)acetate
4-(2-((3S,4R)-4-(6-amino-5- chloro-2-methoxynicotinamido)- 3-methoxypiperidin-l- yl)ethylcarbamoyl)benzoic acid piperidin-4-yl 4-(2-((3S,4R)-4- (6-amino-5-chloro-2- methoxynicotinamido)-3 - methoxypiperidin- 1 - yl)ethylcarbamoyl)benzoate
3-fluorobenzyl 2-((3R,4S)-4-(6- amino-5 -chloro-2- methoxynicotinamido)-3- methoxypiperidin- 1 -yl)acetate
3-methoxybenzyl 2-((3R,4S)-4- (6-amino-5-chloro-2- methoxynicotinamido)-3 - methoxypiperidin- 1 -yl)acetate
2-(methylsulfonyl)ethyl 2-
((3R,4S)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3 - methoxypiperidin- 1 -yl)acetate
isopropyl 2-((3R,4S)-4-(6- amino-5 -chloro-2- methoxynicotinamido)-3 - methoxypiperidin- 1 -yl)acetate
ethyl 2-((3R,4S)-4-(6-amino-5- chloro-2-methoxynicotinamido)-
3-methoxypiperidin-l-yl)acetate
2-(pyridin-2-yl)ethyl 2-((3R,4S)- 4-(6-amino-5 -chloro-2- methoxynicotinamido)-3 - methoxypiperidin- 1 -yl)acetate pyridin-2-ylmethyl 2-((3R,4S)-4-
(6-amino-5-chloro-2- methoxynicotinamido)-3~ methoxypiperidin-1 -yl)acetate
pyridin-3-ylmethyl 2-((3R,4S)-4- (6-amino-5-chloro-2- methoxynicotinamido)-3- methoxypiperidin-l-yl)acetate
piperidin-3-ylmethyl 2-((3R,4S)-
4-(6-amino-5-chloro-2- methoxynicotinamido)-3 - methoxypiperidin- 1 -yl)acetate
cyclohexyl 2-((3R,4S)-4-(6- amino-5 -chloro-2- methoxynicotinamido)-3 - methoxypiperidin- 1 -yl)acetate
2-(4-(2-((3 S,4R)-4-(6-amino-5- chloro-2-methoxynicotinamido)- 3 -methoxypiperidin- 1 - yl)acetamido)phenyl)acetic acid
ethyl 2-(4-(2-((3S,4R)-4-(6- amino-5-chloro-2- methoxynicotinamido)-3- methoxypiperidin- 1- yl)acetamido)phenyl)acetate
l-methylpiperidin-4-yl 2-(4-(2- ((3S,4R)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3- methoxypiperidin- 1- yl)acetamido)phenyl)acetate 3-hydroxypropyl 2-(4-(2-
((3S,4R)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3- methoxypiperidin- 1 - yl)acetamido)phenyl)acetate
quinuclidin-3-yl 2-(4-(2-
((3S,4R)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3- methoxypiperidin- 1 - yl)acetamido)phenyl)acetate
l-methoxypropan-2-yl 2-
((3R,4S)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3 - methoxypiperidin- 1 -yl)acetate
2,3,4-trimethoxybenzyl 2-
((3R,4S)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3- methoxypiperidin- 1 -yl)acetate
2,3-dimethoxybenzyl 2-((3R,4S)- 4-(6-amino-5-chloro-2- methoxynicotinamido)-3- methoxypiperidin- 1 -yl)acetate
l-(4-fluorophenyl)ethyl 2-
((3R,4S)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3- methoxypiperidin- 1 -yl)acetate
3-(4-fluorophenoxy)propyl 2- ((3R,4S)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3 - methoxypiperidin- 1 -yl)acetate 3-fluoro-4-methylbenzyl 2-
((3S,4R)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3- methoxypiperidin- 1 -yl)acetate
4-fluoro-3-methylbenzyl 2-
((3S,4R)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3- methoxypiperidin- 1 -yl)acetate
2-fluoro-6-methylbenzyl 2-
((3S,4R)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3 - methoxypiperidin- 1 -yl)acetate
tetrahydro-2H-pyran-4-yl 2- ((3R,4S)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3- methoxypiperidin- 1 -yl)acetate
6-amino-5 -chloro-N-((3 S,4R)- 1 - (2-(4-hydroxyphenylamino)-2- oxoethyl)-3 -methoxypiperidin-4- yl)-2-methoxynicotinamide
4-(2-((3 S,4R)-4-(6-amino-5- chloro-2-methoxynicotinamido)- 3 -methoxypiperidin- 1 - yl)acetamido)phenyl acetate 2-(2-methoxyethoxy)ethyl 2- ((3R,4S)-4-(6-amino~5-chloro-2- methoxynicotinamido)-3 - methoxypiperidin- 1 -yl)acetate
2-(2-(2- methoxyethoxy)ethoxy)ethyl 2- ((3R,4S)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3 - methoxypiperidin- 1 -yl)acetate
neopentyl 2-((3S,4R)-4-(6- amino-5-chloro-2- methoxynicotinamido)-3- methoxypiperidin- 1 -yl)acetate
2-(piperazin-2-yl)ethyl 2-
((3S,4R)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3- methoxypiperidin- 1 -yl)acetate
pyridin-4-ylmethyl 2-((3R,4S)-4- (6-amino-5-chloro-2- methoxynicotinamido)-3 - methoxypiperidin- 1 -yl)acetate
4-(3-((3S,4R)-4-(6-amino-5- chloro-2-methoxynicotinamido)- 3 -methoxypiperidin- 1 - yl)propyl)benzoic acid 2-morpholinoethyl 4-(3-
((3 S,4R)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3 - methoxypiperidin- 1 - yl)propyl)benzoate
2-(pyrrolidin-l-yl)ethyl 4-(3- ((3S,4R)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3 - methoxypiperidin- 1 - yl)propyl)benzoate
l-methylpiperidin-4-yl 4-(3- ((3S,4R)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3 - methoxypiperidin- 1 - yl)propyl)benzoate
(R)-3-((3R,4S)-4-(6-amino-5- chloro-2-methoxynicotinamido)- 3-methoxypiperidin-l-yl)-2- methylpropanoic acid
(R)-methyl 3-((3R,4S)-4-(6- amino-5 -chloro-2- methoxynicotinamido)-3- methoxypiperidin- 1 -yl)-2- methylpropanoate
4-(methylsulfonyl)benzyl 3- ((3R,4S)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3- methoxypiperidin- 1 -yl)-2- methylpropanoate 4-fluorobenzyl 3-((3R,4S)-4-(6- amino-5 -chloro-2- methoxynicotinamido)-3- methoxypiperidin- 1 -yl)-2- methylpropanoate
(S)-4-(methylsulfonyl)benzyl 3- ((3R,4S)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3- methoxypiperidin- 1 -yl)-2- methylpropanoate
(S)-3-((3R,4S)-4-(6~amino-5- chloro-2-methoxynicotinamido)- 3 -methoxypiperidin- 1 -yl)-2- methylpropanoic acid
(S)-methyl 3-((3R,4S)-4-(6- amino-5 -chloro-2- methoxynicotinamido)-3- methoxypiperidin- 1 -yl)-2- methylpropanoate
4-((3R,4S)-4-(6-amino-5-chloro- 2-methoxynicotinamido)-3 - methoxypiperidin- 1 -yl)butanoic acid
4-fluorobenzyl 6-((3S,4R)-4-(6- amino-5 -chloro-2- methoxynicotinamido)-3- methoxypiperidin- 1 -yl)hexanoate 2-methoxyethyl 6-((3S,4R)-4-(6- amino-5-chloro-2- methoxynicotinamido)-3- methoxypiperidin- 1 -yl)hexanoate
neopentyl 6-((3S,4R)-4-(6- amino-5 -chloro-2- methoxynicotinamido)-3- methoxypiperidin- 1 -yl)hexanoate
pyridin-2-ylmethyl 6-((3S,4R)-4- (6-amino-5-chloro-2- methoxynicotinamido)-3- methoxypiperidin- 1 -yl)hexanoate
2-(piperazin-l-yl)ethyl 6-
((3S,4R)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3 - methoxypiperidin- 1 -yl)hexanoate hydrochloride
2-(dimethylamino)ethyl 6-
((3 S,4R)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3 - methoxypiperidin- 1 -yl)hexanoate
1-adamantylmethyl 6-[(3S,4K)-A- {[(6-amino-5-chloro-2- methoxypyridin-3 - yl)carbonyl] amino} -3 - methoxypiperidin- 1 -yl]hexanoate cyclohexyl 6-((3S,4R)-4-(6- amino-5-chloro-2- methoxynicotinamido)-3 - methoxypiperidin- 1 -yl)hexanoate
2-adamantyl 6-[(3S,4R)-4-{[(6- amino-5 -chloro-2- methoxypyridin-3 - yl)carbonyl]amino} -3- methoxypiperidin- 1 -yl]hexanoate
bicyclo[2.2.1]heptan-2-yl 6- ((3 S,4R)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3- methoxypiperidin- 1 -yl)hexanoate
2-(2-((3S,4R)-4-(6-amino-5- chloro-2-methoxynicotinamido)- 3 -methoxypiperidin- 1 - yl)ethoxy)acetic acid
methyl 2-(2-((3R,4S)-4-(6- amino-5-chloro-2- methoxynicotinamido)-3- methoxypiperidin- 1 - yl)ethoxy)acetate
cyclohexyl 2-(2-((3S,4R)-4-(6- amino-5-chloro-2- methoxynicotinamido)-3 - methoxypiperidin- 1 - yl)ethoxy)acetate cyclohexyl 2-(2-((3R,4S)-4-(6- amino-5-chloro-2- methoxynicotinamido)-3 - methoxypiperidin- 1 - yl)ethoxy)acetate
piperidin-4-yl 2-(2-((3R,4S)-4- (6-amino-5 -chloro-2- methoxynicotinamido)-3 - methoxypiperidin- 1 - yl)ethoxy)acetate hydrochloride
2-hydroxyethyl 4-(2-((3S,4R)-4- (6-amino-5 -chloro-2- methoxynicotinamido)-3 - methoxypiperidin- 1 - yl)acetamido)benzoate
2-amino-2-oxoethyl 4-(2-
((3 S,4R)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3 - methoxypiperidin- 1 - yl)acetamido)benzoate
2-(piperazin-l-yl)ethyl 4-(2- ((3S,4R)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3 - methoxypiperidin- 1 - yl)acetamido)benzoate
l-(2-((3S,4R)-4-(6-amino-5- chloro-2-methoxynicotinamido)- 3 -methoxypiperidin- 1 - yl)acetyl)piperidine-4-carboxylic acid methyl l-(2-((3S,4R)-4-(6- amino-5-chloro-2- methoxynicotinamido)-3- methoxypiperidin- 1 - yl)acetyl)piperidine-4- carboxylate
ethyl l-(2-((3S,4R)-4-(6-amino-
5-chloro-2- methoxynicotinamido)-3- methoxypiperidin- 1 - yl)acetyl)piperidine-4- carboxylate
2-methoxyethyl l-(2-((3S,4R)-4-
(6-amino-5-chloro-2- methoxynicotinamido)-3- methoxypiperidin- 1 - yl)acetyl)piperidine-4- carboxylate
6-amino-5-chloro-N-((3R,4S)- 1 - (2-hydroxyethyl)-3- methoxypiperidin-4-yl)-2- methoxynicotinamide
6-amino-5-chloro-2-methoxy-N- ((3R,4S)-3-methoxypiperidin-4- yl)nicotinamide
6-amino-5-chloro-N-((3R,4S)- 1 - (3 -(4-fluorophenoxy)propyl)-3 - methoxypiperidin-4-yl)-2- methoxynicotinamide benzyl 3-((3S,4R)-4-(6-amino-5- chloro-2-oxo- 1 ,2-dihydropyridine- 3-carboxamido)-3- methoxypiperidin- 1 -yl)propanoate
isopropyl 3-((3R,4S)-4-(6-amino- 5 -chloro-2-oxo- 1,2- dihydropyridine-3 -carboxamido)- 3 -methoxypiperidin- 1 - yl)propanoate
4-(methylsulfonyl)benzyl 3- ((3R,4S)-4-(6-amino-5-chloro-2- 0X0- 1 ,2-dihydropyridine-3 - carboxamido)-3- methoxypiperidin- 1 -yl)propanoate
(tetrahydro-2H-pyran-2-yl)methyl 3-((3R,4S)-4-(6-amino-5-chloro-2- oxo- 1 ,2-dihydropyridine-3 - carboxamido)-3- methoxypiperidin- 1 -yl)propanoate
cyclohexyl 3-((3R,4S)-4-(6-amino- 5 -chloro-2-oxo- 1 ,2- dihydropyridine-3 -carboxamido)- 3 -methoxypiperidin- 1 - yl)propanoate
neopentyl 3-((3S,4R)-4-(6-amino- 5 -chloro-2-oxo- 1,2- dihydropyridine-3 -carboxamido)- 3 -methoxypiperidin- 1 - yl)propanoate 4-methoxybenzyl 3-((3R,4S)-4-(6- amino-5 -chloro-2-oxo- 1 ,2- dihydropyridine-3 -carboxamido)- 3 -methoxypiperidin- 1 - yl)propanoate
pyridin-4-ylmethyl 3-((3R,4S)-4- (6-amino-5 -chloro-2-oxo- 1,2- dihydropyridine-3-carboxamido)- 3 -methoxypiperidin- 1 - yl)propanoate
2-((3S,4R)-4-(6-amino-5-chloro-2- oxo- 1 ,2-dihydropyridine-3 - carboxamido)-3- methoxypiperidin- 1 -yl)acetic acid
2-(pyrrolidin-l-yl)ethyl 4-(((2- ((3 S,4R)-4-(6-amino-5-chloro-2- oxo- 1 ,2-dihydropyridine-3 - carboxamido)-3- methoxypiperidin- 1- yl)ethyl)(methyl)amino)methyl)be nzoate
l-methylpiperidin-4-yl 4-(((2- ((3S,4R)-4-(6-amino-5-chloro-2- oxo- 1 ,2-dihydropyridine-3 - carboxamido)-3- methoxypiperidin- 1 - yl)ethyl)(methyl)amino)methyl)be nzoate
2-morpholinoethyl 4-(((2- ((3 S,4R)-4-(6-amino-5-chloro-2- oxo- 1 ,2-dihydropyridine-3 - carboxamido)-3- methoxypiperidin- 1 - yl)ethyl)(methyl)amino)methyl)be nzoate 4-fluorobenzyl 2-((3S,4R)-4-(6- amino-5 -chloro-2-oxo- 1 ,2- dihydropyridine-3 -carboxamido)- 3-methoxypiperidin-l-yl)acetate
benzyl 2-((3S,4R)-4-(6-amino-5- chloro-2-oxo- 1 ,2-dihydropyridine- 3 -carboxamido)-3 - methoxypiperidin- 1 -yl)acetate
4-methylbenzyl 2-((3S,4R)-4-(6- amino-5-chloro-2-oxo- 1 ,2- dihydropyridine-3 -carboxamido)- 3 -methoxypiperidin- 1 -yl)acetate
2-methoxybenzyl 2-((3S,4R)-4-(6- amino-5-chloro-2-oxo-l,2- dihydropyridine-3 -carboxamido)- 3 -methoxypiperidin- 1 -yl)acetate
4-chlorobenzyl 2-((3S,4R)-4-(6- amino-5-chloro-2-oxo- 1 ,2- dihydropyridine-3 -carboxamido)- 3 -methoxypiperidin- 1 -yl)acetate 4-methoxyben2yl 2-((3R,4R)-4-(6- amino-5-chloro-2-oxo-l,2- dihydropyridine-3 -carboxamido)- 3 -methoxypiperidin- 1 -yl)acetate
piρeridin-4-yl 2-((3S,4R)-4-(6- amino-5-chloro-2-oxo- 1 ,2- dihydropyridine-3 -carboxamido)- 3 -methoxypiperidin- 1 -yl)acetate
2-methoxyethyl 2-((3S,4R)-4-(6- amino-5-chloro-2-oxo- 1 ,2- dihydropyridine-3 -carboxamido)- 3 -methoxypiperidin- 1 -yl)acetate
2-hydroxyethyl 2-((3S,4R)-4-(6- amino-5-chloro-2-oxo- 1,2- dihydropyridine-3 -carboxamido)- 3 -methoxypiperidin- 1 -yl)acetate
2-chlorobenzyl 2-((3R,4S)-4-(6- amino-5-chloro-2-oxo-l,2- dihydropyridine-3-carboxamido)- 3 -methoxypiperidin- 1 -yl)acetate 4-((2-((3S,4R)-4-(6-amino~5- chloro-2-oxo-l,2-dihydropyridine- 3 -carboxamido)-3 - methoxypiperidin- 1 - yl)ethylamino)methyl)benzoic acid
3-hydroxypropyl 4-((2-((3S,4R)-4- (6-amino-5 -chloro-2-oxo- 1,2- dihydropyridine-3 -carboxamido)- 3 -methoxypiperidin- 1 - yl)ethylamino)methyl)benzoate
piperidin-4-yl 4-((2-((3 S,4R)-4-(6- amino-5-chloro-2-oxo- 1 ,2- dihydropyridine-3 -carboxamido)- 3 -methoxypiperidin- 1 - yl)ethylamino)methyl)benzoate
4-(trifluoromethyl)benzyl 2- ((3R,4S)-4-(6-amino-5-chloro-2- oxo- 1 ,2-dihydropyridine-3 - carboxamido)-3- methoxypiperidin- 1 -yl)acetate
3-methylbenzyl 2-((3R,4S)-4-(6- amino-5 -chloro-2-oxo- 1,2- dihydropyridine-3 -carboxamido)- 3-methoxypiperidin-l-yl)acetate
3-chlorobenzyl 2-((3R,4S)-4-(6- amino-5 -chloro-2-oxo- 1,2- dihydropyridine-3 -carboxamido)- 3 -methoxypiperidin- 1 -yl)acetate 2-(trifluoromethyl)benzyl 2- ((3R,4S)-4-(6-amino-5-chloro-2- oxo- 1 ,2-dihydropyridine-3 - carboxamido)-3- methoxypiperidin- 1 -yl)acetate
2-morpholinoethyl 2-((3R,4S)-4- (6-amino-5-chloro-2-oxo-l,2- dihydropyridine-3 -carboxamido)- 3 -methoxypiperidin- 1 -yl)acetate
(tetrahydro-2H-pyran-2-yl)methyl 2-((3R,4S)-4-(6-amino-5-chloro-2- oxo- 1 ,2-dihydropyridine-3 - carboxamido)-3- methoxypiperidin- 1 -yl)acetate
2-fluorobenzyl 2-((3R,4S)-4-(6- amino-5 -chloro-2-oxo- 1,2- dihydropyridine-3 -carboxamido)- 3 -methoxypiperidin- 1 -yl)acetate
4-(2-((3S,4R)-4-(6-amino-5- chloro-2-oxo- 1 ,2-dihydropyridine- 3 -carboxamido)-3 - methoxypiperidin- 1 - yl)ethylcarbamoyl)benzoic acid
piperidin-4-yl 4-(2-((3 S,4R)-4-(6- amino-5 -chloro-2-oxo- 1,2- dihydropyridine-3 -carboxamido)- 3 -methoxypiperidin- 1 - yl)ethylcarbamoyl)benzoate 3-fluorobenzyl 2-((3R,4S)-4-(6- amino-5 -chloro-2-oxo- 1,2- dihydropyridine-3 -carboxamido)- 3 -methoxypiperidin- 1 -yl)acetate
3-methoxybenzyl 2-((3R,4S)-4-(6- amino-5 -chloro-2-oxo- 1 ,2- dihydropyridine-3 -carboxamido)- 3 -methoxypiperidin- 1 -yl)acetate
2-(methylsulfonyl)ethyl 2- ((3R,4S)-4-(6-amino-5-chloro-2- oxo- 1 ,2-dihydropyridine-3- carboxamido)-3- methoxypiperidin- 1 -yl)acetate
isopropyl 2-((3R,4S)-4-(6-amino- 5 -chloro-2-oxo- 1,2- dihydropyridine-3 -carboxamido)- 3 -methoxypiperidin- 1 -yl)acetate
ethyl 2-((3R,4S)-4-(6-amino-5- chloro-2-oxo- 1 ,2-dihydropyridine- 3 -carboxamido)-3 - methoxypiperidin- 1 -yl)acetate
2-(pyridin-2-yl)ethyl 2-((3R,4S)-4- (6-amino-5 -chloro-2-oxo- 1,2- dihydropyridine-3 -carboxamido)- 3 -methoxypiperidin- 1 -yl)acetate
pyridin-2-ylmethyl 2-((3R,4S)-4- (6-amino-5-chloro-2-oxo- 1 ,2- dihydropyridine-3 -carboxamido)- 3 -methoxypiperidin- 1 -yl)acetate pyridin-3-ylmethyl 2-((3R,4S)-4- (6-amino-5 -chloro-2-oxo- 1,2- dihydropyridine-3-carboxamido)- 3-methoxypiperidin-l-yl)acetate
piperidin-3-ylmethyl 2-((3R,4S)-4- (6-amino-5-chloro-2-oxo-l,2- dihydropyridine-3-carboxamido)- 3-methoxypiperidin-l-yl)acetate
cyclohexyl 2-((3R,4S)-4-(6-amino- 5-chloro-2-oxo-l,2- dihydropyridine-3 -carboxamido)- 3 -methoxypiperidin- 1 -yl)acetate
2-(4-(2-((3S,4R)-4-(6-amino-5- chloro-2-oxo- 1 ,2-dihydropyridine- 3 -carboxamido) -3 - methoxypiperidin- 1 - yl)acetamido)phenyl)acetic acid
ethyl 2-(4-(2-((3 S,4R)-4-(6-amino- 5 -chloro-2-oxo- 1 ,2- dihydropyridine-3 -carboxamido)- 3 -methoxypiperidin- 1 - yl)acetamido)phenyl)acetate l-methylpiperidin-4-yl 2-(4-(2- ((3 S,4R)-4-(6-amino-5-chloro-2- oxo- 1 ,2-dihydropyridine-3 - carboxamido)-3- methoxypiperidin- 1 - yl)acetamido)phenyl)acetate
3-hydroxypropyl 2-(4-(2-((3S,4R)- 4-(6-amino-5 -chloro-2-oxo- 1,2- dihydropyridine-3 -carboxamido)- 3 -methoxypiperidin- 1 - yl)acetamido)phenyl)acetate quinuclidin-3-yl 2-(4-(2-((3S,4R)- 4-(6-amino-5 -chloro-2-oxo- 1,2- dihydropyridine-3 -carboxamido)- 3 -methoxypiperidin- 1 - yl)acetamido)phenyl)acetate
l-methoxypropan-2-yl 2-((3R,4S)- 4-(6-amino-5-chloro-2-oxo-l,2- dihydropyridine-3-carboxamido)- 3 -raethoxypiperidin- 1 -yl)acetate
2,3,4-trimethoxybenzyl 2- ((3R,4S)-4-(6-amino-5-chloro-2- OXO- 1 ,2-dihydropyridine-3 - carboxamido)-3- methoxypiperidin- 1 -yl)acetate
2,3-dimethoxybenzyl 2-((3R,4S)- 4-(6-amino-5 -chloro-2-oxo- 1,2- dihydropyridine-3 -carboxamido)- 3 -methoxypiperidin- 1 -yl)acetate
l-(4-fluorophenyl)ethyl 2- ((3R,4S)-4-(6-amino-5-chloro-2- oxo- 1 ,2-dihydropyridine-3 - carboxamido)-3- methoxypiperidin- 1 -yl)acetate
3-(4-fluorophenoxy)propyl 2- ((3R,4S)-4-(6-amino-5-chloro-2- oxo- 1 ,2-dihydropyridine-3 - carboxamido)-3- methoxypiperidin- 1 -yl)acetate
3-fluoro-4-methylbenzyl 2- ((3S,4R)-4-(6-amino-5-chloro-2- oxo- 1 ,2-dihydropyridine-3 - carboxamido)-3- methoxypiperidin- 1 -yl)acetate 4-fluoro-3-methylbenzyl 2- ((3S,4R)-4-(6-amino-5-chloro-2- oxo-l,2-dihydropyridine-3- carboxamido)-3- methoxypiperidin-1 -yl)acetate
2-fluoro-6-methylbenzyl 2- ((3S,4R)-4-(6-amino-5-chloro-2- OXO- 1 ,2-dihydropyridine-3- carboxamido)-3- methoxypiperidin- 1 -yl)acetate
tetrahydro-2H-pyran-4-yl 2- ((3R,4S)-4-(6-amino-5-chloro-2- oxo- 1 ,2-dihydropyridine-3 - carboxamido)-3- methoxypiperidin- 1 -yl)acetate
6-amino-5-chloro-N-((3 S,4R)- 1 -
(2-(4-hydroxyphenylamino)-2- oxoethyl)-3-methoxypiperidin-4- yl)-2-oxo-l,2-dihydropyridine-3- carboxamide
4-(2-((3S,4R)-4-(6-amino-5- chloro-2-oxo- 1 ,2-dihydropyridine- 3 -carboxamido)-3 - methoxypiperidin- 1 - yl)acetamido)phenyl acetate
2-(2-methoxyethoxy)ethyl 2- ((3R,4S)-4-(6-amino-5-chloro-2- oxo- 1 ,2-dihydropyridine-3 - carboxamido)-3- methoxypiperidin- 1 -yl)acetate
2-(2-(2- methoxyethoxy)ethoxy)ethyl 2- ((3R,4S)-4-(6-amino-5-chloro-2- oxo- 1 ,2-dihydropyridine-3 - carboxamido)-3- methoxypiperidin- 1 -yl)acetate neopentyl 2-((3S,4R)-4-(6-amino- 5 -chloro-2-oxo- 1,2- dihydropyridine-3 -carboxamido)- 3 -methoxypiperidin- 1 -yl)acetate
2-(piperazin-2-yl)ethyl 2-((3 S,4R)- 4-(6-amino-5-chloro-2-oxo- 1 ,2- dihydropyridine-3 -carboxamido)- 3-methoxypiperidin-l-yl)acetate
pyridin-4-ylmethyl 2-((3R,4S)-4- (6-amino-5-chloro-2-oxo-l,2- dihydropyridine-3-carboxamido)- 3 -methoxypiperidin- 1 -yl)acetate
4-(3-((3S,4R)-4-(6-amino-5- chloro-2-oxo- 1 ,2-dihydropyridine- 3 -carboxamido)-3 - methoxypiperidin- 1 - yl)propyl)benzoic acid
2-morpholinoethyl 4-(3-((3S,4R)- 4-(6-amino-5-chloro-2-oxo-l,2- dihydropyridine-3 -carboxamido)- 3 -methoxypiperidin- 1 - yl)propyl)benzoate
2-(pyrrolidin-l-yl)ethyl 4-(3- ((3 S,4R)-4-(6-amino-5-chloro-2- oxo- 1 ,2-dihydropyridine-3 - carboxamido)-3- methoxypiperidin- 1 - yl)propyl)benzoate l-methylpiperidin-4-yl 4-(3- ((3S,4R)-4-(6-amino-5-chloro~2- oxo- 1 ,2-dihydropyridine-3 - carboxamido)-3- methoxypiperidin- 1 - yl)propyl)benzoate
(R)-3-((3R,4S)-4-(6-amino-5- chloro-2-oxo- 1 ,2-dihydropyridine- 3 -carboxamido)-3 - methoxypiperidin- 1 -yl)-2- methylpropanoic acid
(R)-methyl 3-((3R,4S)-4-(6- amino-5 -chloro-2-oxo- 1,2- dihydropyridine-3 -carboxamido)- 3 -methoxypiperidin- 1 -yl)-2- methylpropanoate
4-(methylsulfonyl)benzyl 3- . ((3R,4S)-4-(6-amino-5-chloro-2- oxo- 1 ,2-dihydropyridine-3 - carboxamido)-3- methoxypiperidin- 1 -yl)-2- methylpropanoate
4-fluorobenzyl 3-((3R,4S)-4-(6- amino-5 -chloro-2-oxo- 1 ,2- dihydropyridine-3 -carboxamido)- 3 -methoxypiperidin- 1 -yl)-2- methylpropanoate
(S)-4-(methylsulfonyl)benzyl 3- ((3R,4S)-4-(6-amino-5-chloro-2- oxo- 1 ,2-dihydropyridine-3 - carboxamido)-3- methoxypiperidin- 1 -yl)-2- methylpropanoate (S)-3-((3R,4S)-4-(6-amino-5- chloro-2-oxo- 1 ,2-dihydropyridine- 3-carboxamido)-3~ methoxypiperidin- 1 -yl)-2- methylpropanoic acid
(S)-methyl 3-((3R,4S)-4-(6-amino- 5 -chloro-2-oxo- 1 ,2- dihydropyridine-3 -carboxamido)- 3 -methoxypiperidin- 1 -yl)-2- methylpropanoate
4-((3R,4S)-4-(6-amino-5-chloro-2- oxo- 1 ,2-dihydropyridine-3 - carboxamido)-3- methoxypiperidin- 1 -yl)butanoic acid
4-fluorobenzyl 6-((3S,4R)-4-(6- amino-5 -chloro-2-oxo- 1,2- dihydropyridine-3-carboxamido)- 3 -methoxypiperidin- 1 - yl)hexanoate
2-methoxyethyl 6-((3S,4R)-4-(6- amino-5-chloro-2-oxo- 1,2- dihydropyridine-3-carboxamido)- 3 -methoxypiperidin- 1 - yl)hexanoate
neopentyl 6-((3S,4R)-4-(6-amino- 5 -chloro-2-oxo- 1 ,2- dihydropyridine-3-carboxamido)- 3 -methoxypiperidin- 1 - yl)hexanoate pyridin-2-ylmethyl 6-((3S,4R)-4- (6-amino-5 -chloro-2-oxo- 1 ,2- dihydropyridine-3 -carboxamido)- 3 -methoxypiperidin- 1 - yl)hexanoate
2-(piperazin- 1 -yl)ethyl 6-((3 S,4R)- 4-(6-amino-5-chloro-2-oxo- 1,2- dihydropyridine-3-carboxamido)- 3 -methoxypiperidin- 1 - yl)hexanoate hydrochloride
2-(dimethylamino)ethyl 6- ((3S,4R)-4-(6-amino-5-chloro-2- oxo- 1 ,2-dihydropyridine-3 - carboxamido)-3- methoxypiperidin- 1 -yl)hexanoate
1-adamantylmethyl 6-[(3S,4R)-4- { [(6-amino-5-chloro-2-oxo-l,2- dihydropyridin-3- yl)carbonyl]amino}-3- methoxypiperidin- 1 -yl]hexanoate
cyclohexyl 6-((3 S,4R)-4-(6-amino- 5 -chloro-2-oxo- 1,2- dihydropyridine-3 -carboxamido)- 3 -methoxypiperidin- 1 - yl)hexanoate
2-adamantyl 6-[(3»S',4i?)-4-{[(6- amino-5 -chloro-2-oxo- 1,2- dihydropyridin-3 - yl)carbonyl] amino} -3 - methoxypiperidin- 1 -yljhexanoate bicyclo[2.2.1]heptan-2-yl 6- ((3S,4R)-4-(6-amino-5-chloro-2- oxo- 1 ,2-dihydropyridine-3 - carboxamido)-3- methoxypiperidin- 1 -yl)hexanoate 2-(2-((3S,4R)-4-(6-amino-5- chloro-2-oxo- 1 ,2-dihydropyridine- 3 -carboxamido)-3 - methoxypiperidin- 1 - yl)ethoxy)acetic acid
methyl 2-(2-((3R,4S)-4-(6-amino- 5 -chloro-2-oxo- 1 ,2- dihydropyridine-3 -carboxamido)- 3 -methoxypiperidin- 1 - yl)ethoxy)acetate
cyclohexyl 2-(2-((3S,4R)-4-(6- amino-5 -chloro-2-oxo- 1,2- dihydropyridine-3-carboxamido)- 3 -methoxypiperidin- 1 - yl)ethoxy)acetate
cyclohexyl 2-(2-((3R,4S)-4-(6- amino-5 -chloro-2-oxo- 1,2- dihydropyridine-3 -carboxamido)- 3 -methoxypiperidin- 1 - yl)ethoxy)acetate
piperidin-4-yl 2-(2-((3R,4S)-4-(6- amino-5 -chloro-2-oxo- 1,2- dihydropyridine-3-carboxamido)- 3 -methoxypiperidin- 1 - yl)ethoxy)acetate hydrochloride
2-hydroxyethyl 4-(2-((3S,4R)-4- (6-amino-5-chloro-2-oxo- 1 ,2- dihydropyridine-3 -carboxamido)- 3 -methoxypiperidin- 1 - yl)acetamido)benzoate 2-amino-2-oxoethyl 4-(2-((3 S,4R)- 4-(6-amino-5-chloro-2-oxo-l,2- dihydropyridine-3-carboxamido)- 3 -methoxypiperidin- 1 - yl)acetamido)benzoate
2-(piperazin-l-yl)ethyl 4-(2- ((3 S,4R)-4-(6-amino-5-chloro-2- oxo- 1 ,2-dihydropyridine-3 - carboxamido)-3- methoxypiperidin- 1 - yl)acetamido)benzoate
l-(2-((3S,4R)-4-(6-amino-5- chloro-2-oxo- 1 ,2-dihydropyridine- 3-carboxamido)-3- methoxypiperidin- 1- yl)acetyl)piperidine-4-carboxylic acid
methyl l-(2-((3S,4R)-4-(6-amino- 5 -chloro-2-oxo- 1,2- dihydropyridine-3 -carboxamido)- 3 -methoxypiperidin- 1 - yl)acetyl)piperidine-4-carboxylate
ethyl 1 -(2-((3 S,4R)-4-(6-amino-5- chloro-2-oxo- 1 ,2-dihydropyridine- 3-carboxamido)-3- methoxypiperidin- 1 - yl)acetyl)piperidine-4-carboxylate 2-methoxyethyl l-(2-((3S,4R)-4- (6-aniino-5-chloro-2-oxo- 1 ,2- dihydropyridine-3 -carboxamido)- 3 -methoxypiperidin- 1 - yl)acetyl)piperidine-4-carboxylate
6-amino-5-chloro-N-((3R,4S)-l- (2-hydroxyethyl)-3- methoxypiperidin-4-yl)-2-oxo- 1,2- dihydropyridine-3 -carboxamide
6-amino-5-chloro-N-((3R,4S)-3- methoxypiperidin-4-yl)-2-oxo- 1 ,2- dihydropyridine-3 -carboxamide
6-amino-5-chloro-N-((3R,4S)-l- (3 -(4-fluorophenoxy)propyl)-3 - methoxypiperidin-4-yl)-2-oxo- 1,2- dihydropyridine-3 -carboxamide
Formulation, Administration, and Uses
Dosage rates and routes of administration of the disclosed compounds are similar to those already used in the art and known to the skilled artisan (see, for example, Physicians' Desk Reference, 54th Ed., Medical Economics Company, Montvale, NJ, 2000).
The magnitude of a prophylactic or therapeutic dose of structural and/or functional analog of cisapride in the acute or chronic management of diseases and/or disorders described herein will vary with the severity of the condition to be treated, and the route of administration. The dose, and perhaps the dose frequency, will also vary according to the age, body weight, and response of the individual patient. In general, the total daily dose range for structural and/or functional analogs of cisapride, for the conditions described herein, is from about 1 mg to about 200 mg, in single or divided doses. Preferably, a daily dose range should be between about 5 mg to about 100 mg, in single or divided doses, while most preferably, a daily dose range should be between about 5 mg to about 75 mg, in single or divided doses. It is preferred that the doses are administered from 1 to 4 times a day. In managing the patient, the therapy should be initiated at a lower dose, perhaps about 5 mg to about 10 mg, and increased up to about 50 mg or higher depending on the patient's global response. It is further recommended that children, and patients over 65 years, and those with impaired renal or hepatic function, initially receive low doses, and that they be titrated based on individual response(s) and blood level(s). It may be necessary to use dosages outside these ranges in some cases as will be apparent to those skilled in the art. Further, it is noted that the clinician or treating physician will know how and when to interrupt, adjust, or terminate therapy in conjunction with individual patient response.
The compounds of the subject invention can be formulated according to known methods for preparing pharmaceutically useful compositions. Formulations are described in detail in a number of sources which are well known and readily available to those skilled in the art. For example, Remington's Pharmaceutical Science by E.W. Martin describes formulations which can be used in connection with the subject invention. In general, the compositions of the subject invention are formulated such that an effective amount of the bioactive compound(s) is combined with a suitable carrier in order to facilitate effective administration of the composition.
The compositions of the subject invention include compositions such as suspensions, solutions and elixirs; aerosols; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like, in the case of oral solid preparations (such as powders, capsules, and tablets) with the oral solid preparations being preferred over the oral liquid preparations. A preferred oral solid preparation is capsules. The most preferred oral solid preparation is tablets. Preferred amounts of active ingredient (i.e., an structural and/or functional analog of cisapride) in a solid dosage form are about 5 mg, 10 mg, and 25 mg.
Further, acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories and dispersible granules. A solid carrier can be one or more substances which may act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents or encapsulating materials. The disclosed pharmaceutical compositions may be subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, such as packeted tablets, capsules, and powders in paper or plastic containers or in vials or ampules. Also, the unit dosage can be a liquid based preparation or formulated to be incorporated into solid food products, chewing gum, or lozenge.
In addition to the common dosage forms set out above, the compounds of the present invention may also be administered by controlled release means and/or delivery devices such as those described in U.S. Pat. Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719, the disclosures of which are hereby incorporated by reference in their entirety.
Any suitable route of administration may be employed for providing the patient with an effective dosage of a structural and/or functional analog of cisapride. For example, oral, rectal, parenteral (subcutaneous, intramuscular, intravenous), transdermal, and like forms of administration may be employed. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, patches, and the like.
One aspect of the invention provides a method of treating gastroesophageal reflux disease in a mammal, while substantially reducing the concomitant adverse effects associated with the administration of cisapride, which comprises administering to a human in need of such treatment, a therapeutically effective amount of a structural and/or functional analog of cisapride, or a pharmaceutically acceptable salt thereof. A preferred aspect is the treatment of gastroesophageal reflux disease in humans.
Another aspect of the invention provides a composition for the treatment of a human suffering from gastroesophageal reflux disease, which comprises a therapeutically effective amount of a structural and/or functional analog of cisapride, or a pharmaceutically acceptable salt thereof.
Yet another aspect of the present invention provides a method of eliciting an antiemetic effect in a mammal, while substantially reducing the adverse effects associated with the administration of cisapride, which comprises administering to a mammal in need of such anti-emetic therapy, a therapeutically effective amount of structural and/or functional analogs of cisapride, or a pharmaceutically acceptable salt thereof. Preferably, the mammal is a human.
In an additional aspect, the present invention encompasses an anti-emetic composition for the treatment of a mammal in need of anti-emetic therapy, which comprises a therapeutically effective amount of a structural and/or functional analog of cisapride, or a pharmaceutically acceptable salt thereof.
A further aspect of the present invention includes a method of treating a condition caused by gastrointestinal motility dysfunction in a mammal which comprises administering to a mammal in need of treatment for gastrointestinal motility dysfunction, a therapeutically effective amount of a structural and/or functional analog of cisapride, or a pharmaceutically acceptable salt thereof. Conditions caused by gastrointestinal motility dysfunction include, but are not limited to, dyspepsia, gastroparesis, constipation, post-operative ileus, and intestinal pseudo-obstruction. Preferably, the mammal is a human.
The observation that cisapride enters the central nervous system and binds to 5HT4 receptors indicates that cisapride may have centrally-mediated effects. Cisapride is a potent ligand at 5HT4 receptors, and these receptors are located in several areas of the central nervous system. Modulation of serotonergic systems has a variety of behavioral effects. Accordingly, the compounds of the subject invention can be used in the treatment of: 1) cognitive disorders, including but not limited to Alzheimer's disease; 2) behavioral disorders, including but not limited to schizophrenia, mania, obsessive-compulsive disorder, and psychoactive substance use disorders; 3) mood disorders, including but not limited to depression and anxiety; and 4) disorders of control of autonomic function, including but not limited to essential hypertension and sleep disorders.
Accordingly, the present invention also provides methods of treating cognitive, behavioral, mood, or autonomic function control disorders in a mammal comprising the administration of a therapeutically effective amount of structural and/or functional analog of cisapride, or a pharmaceutically acceptable salt thereof. Preferably, the mammal is a human.
It should be understood that the examples and aspects described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and the scope of the appended claims. Further, all patents,, patent applications, provisional applications, and publications referred to or cited herein are incorporated by reference in their entirety to the extent they are not inconsistent with the explicit teachings of this specification.
The invention and the manner and process of making and using it, are now described in such full, clear, concise and exact terms as to enable any person skilled in the art to which it pertains, to make and use the same. It is to be understood that the foregoing describes preferred aspects of the invention and that modifications may be made therein without departing from the spirit or scope of the invention as set forth in the claims. To particularly point out and distinctly claim the subject matter regarded as invention, the following claims conclude this specification.

Claims

What is claimed is:
1. A compound of the formula:
and pharmaceutically acceptable salts thereof, wherein the bonds at positions 3 and 4 are cis relative to each other;
L is -(C1-C6 alkyl)-, -(C1-C6 alkyl)-C(O)-, or -C(O)-(C1-C6 alkyl)-, wherein each of the alkyl groups is optionally substituted with 1 or 2 groups that are independently halogen, C1-C4 alkoxy, or OH and wherein one carbon in the alkyl portion of L may be replaced by - N(R9)-; or
L is -(C1-C4 alkyl)-NR9-(Ci-C4 alkyl)-, -(C1-C4 alkyl)-C(O)NR9-, -(C1-C4 alkyl)-, -(C1-C4 alkyl)-NR9C(O)- or -C(O)NR9-(C1-C4 alkyl)-;
R1 is halogen;
R2 is amino, NH(C1-C4 alkyl) Or N(C1-C4 alkyl)(CrC4 alkyl);
R3 is H or Ci-C4 alkyl;
R4 is H or methyl; and
R5 is -O-Ci-C6-alkyl, -0-C3-C8 cycloalkyl, -O-heterocycloalkyl, heterocycloalkyl, aryl, -O-aryl, -N(R9HC0-C6 alkyl)-C(O)-aryl, or -N(R9)-C0-C6 alkyl-aryl, -O-heteroaryl, -N(R9)-C i-C6(O)-heteroaryl, or -N(R9)-C0-C6 alkyl-heteroaryl, wherein each of the cyclic groups is unsubstituted or substituted at one or more substitutable positions with Ci-C6 alkyl, Ci-C6 alkoxy, halogen, C1-C6 haloalkyl, Ci-C6 haloalkoxy, hydroxyl, hydroxy-Ci-C4-alkyl, amino, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(Ci-C6 alkyl), -(C0-C6 alkyl)-C(O)Rn, -0-(C0-C6 alkyl)-C(O)Rπ, methylsulfone, C0-C6-sulfonamide, NO2, -CO2Ri0, Or -(Ci-C4 alkyl)- CO2R10; wherein
R9 at each occurrence is independently H or Ci-C4 alkyl;
Rio at each occurrence is independently H, Ci-C4 alkyl optionally substituted with one group that is selected from a 5 or 6 membered monocyclic heterocycloalkyl ring, and OH, quinuclidinyl, -C(O)NH2, -C(O)NH(Ci-C4 alkyl), -C(O)N(Ci-C4 alkyl)(CrC4 alkyl) or piperidinyl optionally substituted with Ci-C4 alkyl;
Rn is Ci-C6 alkyl, OH, or
Rn is Ci-C6 alkoxy, optionally substituted with 1 or 2 groups that are independently Ci-C4 alkoxy, amino, -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)(Ci-C6 alkyl), -(C0-C6 alkyl)- C(O)N(R9)-heterocycloalkyl, -O-heterocycloalkyl, -Ci-C6(O)N(R9)-heteroaryl, or heteroaryl, wherein the heterocycloalkyl groups are optionally substituted with 1, 2, or 3 groups that are independently halogen, Ci-C6 alkyl, Ci-C6 alkoxy, hydroxy, hydroxy Ci-C6 alkyl, C1-C6 alkoxycarbonyl, -CO2H, CF3, or OCF3, the heteroaryl group is optionally substituted with 1, 2, or 3 groups that are independently halogen, Ci-C6 alkyl, Ci-C6 alkoxy, hydroxy, hydroxy Ci-C6 alkyl, Ci-
C6 alkoxycarbonyl, -CO2H, CF3, or OCF3; or
Rn is -O-heterocycloalkyl wherein the heterocycloalkyl is optionally substituted with
1. 2, or 3 groups that are independently halogen, Ci-C6 alkyl, Ci-C6 alkoxy, hydroxy, hydroxy Ci-C6 alkyl, C1-C6 alkoxycarbonyl, -CO2H, CF3, or OCF3; and
R20 is -H, Ci-C6 alkoxy (preferably Ci-C4 alkoxy, more preferably methoxy), or OH.
2. A compound according to claim 1, wherein Ri is chloro.
3. A compound according to claim 1, wherein R2 is amino.
4. A compound according to claim 1, wherein R3 is methyl.
5. A compound according to claim 1, wherein R4 is H.
6. A compound according to claim 1, wherein
Ri is chloro; R2 is amino; R3 is methyl; R4 is H, and Rj and R2 have the following orientation on the pyridyl or pyridonyl ring:
7. A Compound according to claim 6, wherein L is -(C3-C5 alkyl)- wherein one carbon may be replaced by -N(R9)-, or -(C2-C6 alkyl)-C(O)-.
8. A compound according to claim 7, wherein
R5 is-O-heterocycloalkyl, wherein the heterocycloalkyl group is selected from aza-bicyclo- octyl, aza-bicyclo-nonyl, aza-bicyclo-decyl, where the aza nitrogen is optionally substituted with methyl or ethyl, is optionally substituted with methyl or ethyl, piperidinyl, piperazinyl, and pyrrolidinyl, wherein the piperidinyl, piperazinyl, and pyrrolidinyl groups are unsubstituted or substituted at one or two positions with groups that are independently C1-C4 alkyl, C] -C4 alkoxy, halogen, Ci -C4 haloalkyl, Ci-C4 haloalkoxy, hydroxyl, hydroxy Cj-C4 alkyl, amino, -NH(C1-C4 alkyl), -N(Ci-C4 alkyl)(CrC4 alkyl), -(C0-C6 alkyl)-C(O)Rπ, or NO2, wherein
Rn is Ci-C6 alkoxy, optionally substituted with 1 or 2 groups that are independently Ci-C4 alkoxy, amino, -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)(Ci-C6 alkyl), -(C0-C6 alkyl)- C(O)N(Rc>)-heterocycloalkyl, or heterocycloalkyl wherein the heterocycloalkyl group is selected from pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl, wherein the heterocycloalkyl groups are optionally substituted with 1, 2, or 3 groups that are independently halogen, Ci-C6 alkyl, CpC6 alkoxy, hydroxy, hydroxy C1-C6 alkyl, Ci-C6 alkoxycarbonyl, -CO2H, CF3, or OCF3.
9. A compound according to claim 7, wherein
R5 is heterocycloalkyl, which is selected from l-aza-bicyclo[2.2.2]oct-3-yl, and 8-aza- bicyclo[3.2.1]oct-3-yl, where the nitrogen in the 8-aza-bicyclo[3.2.1]oct-3-yl group is optionally substituted with methyl or ethyl.
10. A compound according to claim 7, wherein
R-5 is -N(Rg)-C0-C4 alkyl-aryl or -N(R.9)-C(O)-aryl, wherein the aryl group is unsubstituted or substituted at one or more substitutable positions with C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl, Ci-C6 haloalkoxy, hydroxyl, hydroxyalkyl, amino, -NH(C1- C6 alkyl), -N(Ci-C6 alkyl)(Ci-C6 alkyl), -(C0-C6 alkyl)-C(O)Rn, or NO2.
11. A compound according to claim 10, wherein the aryl group is a phenyl substituted with -(C0-C6 alkyl)-C(O)Rπ and optionally substituted with 1 or 2 groups independently selected from Ci-C6 alkyl, Ci-C6 alkoxy, halogen, CF3, OCF3, hydroxyl, hydroxyalkyl, amino, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)(Ci- C4 alkyl), or NO2, and
Rn is Ci-C6 alkoxy, optionally substituted with 1 or 2 groups that are independently Ci-C4 alkoxy, amino, -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)(CrC6 alkyl), -(C0-C6 alkyl)- C(O)N(R9)-heterocycloalkyl, or heterocycloalkyl wherein the heterocycloalkyl group is selected from pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl, wherein the heterocycloalkyl groups are optionally substituted with 1, 2, or 3 groups that are independently halogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxy, hydroxy C1-C6 alkyl, Ci-C6 alkoxycarbonyl, -CO2H, CF3, or OCF3.
12. A compound according to claim 11, wherein the -(C0-C6 alky I)-C(O)Rn group is attached to position 4 of the phenyl ring.
13. A compound according to claim 1 that is 6-((35',4i?)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3-methoxypiperidin-l- yl)hexanoic acid ;
6-((3jS',4i?)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3-carboxamido)-3- methoxypiperidin- 1 -yl)hexanoic acid;
6-((3i?,4,S)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3-methoxypiperidin-l- yl)hexanoic acid;
6-((3i?,4iS)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3-carboxamido)-3- methoxypiperidin- 1 -yl)hexanoic acid;
(i?)-quinuclidin-3-yl 6-((35',4i?)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)hexanoate; (i?)-quinuclidin-3-yl 6-((35',4i?)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3- carboxamido)-3 -methoxypiperidin- 1 -yl)hexanoate;
(i?)-quinuclidin~3 -yl 6-((3i?,4S)-4-(6-amino-5 -chloro-2-methoxynicotinamido)-3 - methoxypiperidin- 1 -y l)hexanoate;
(i?)-quinuclidin-3-yl 6-((3i?,4.S)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3- carboxamido)-3-methoxypiperidin-l-yl)hexanoate;
(JS)-quinuclidin-3-yl 6-((35r,4i?)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3- carboxamido)-3 -methoxypiperidin- 1 -yl)hexanoate ;
(5)-quinuclidin-3-yl 6-((35',4i?)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)hexanoate;
(.S)-quinuclidin-3-yl 6-((3i?,45)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3- carboxamido)-3 -methoxypiperidin- 1 -yl)hexanoate;
(.S)-quinuclidin-3-yl 6-((3i?,45)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin-l-yl)hexanoate;
(5)-quinuclidin-3-yl 6-((3JR,4,S)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3- carboxamido)-3 -methoxypiperidin- 1 -yl)hexanoate ;
(jS)-quinuclidin-3-yl 6-((3i?,4ιS)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)hexanoate;
(5)-quinuclidin-3-yl 6-((35',4i?)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3- carboxamido)-3-methoxypiperidin-l-yl)hexanoate;
(5)-quinuclidin-3-yl 6-((35',4i?)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)hexanoate;
(i?)-quinuclidin-3-yl 6-((3i?,41S)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)hexanoate;
(i?)-quinuclidin-3-yl 6-((3i?,4iS)-4-(6-amino-5-fluoro-2-oxo-l,2-dihydropyridine-3- carboxamido)-3-methoxypiperidin-l-yl)hexanoate;
(i?)-quinuclidin-3-yl 6-((3iS',4i?)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)hexanoate;
(i?)-quinuclidin-3-yl 6-((3.S',4i?)-4-(6-amino-5-fluoro-2-oxo-l,2-dihydropyridine-3- carboxamido)-3 -methoxypiperidin- 1 -yl)hexanoate;
8-methyl-8-azabicyclo[3.2.1]octan-3-yl 6-((3iS',4i?)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3-methoxypiperidin-l-yl)hexanoate; 8-methyl-8-azabicyclo[3.2.1]octan-3-yl 6-((35',4i?)-4-(6-amino-5-chloro-2-oxo- l,2-dihydropyridine-3-carboxamido)-3-methoxypiperidin-l-yl)hexanoate;
8-methyl-8-azabicyclo[3.2.1]octan-3-yl 6-((3i?,45)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3 -methoxypiperidin- 1 -yl)hexanoate;
8-methyl-8-azabicyclo[3.2.1]octan-3-yl 6-((3i?,45)-4-(6-amino-5-chloro-2-oxo- l,2-dihydropyridine-3-carboxamido)-3-methoxypiperidin-l-yl)hexanoate;
4-(2-((35',4i?)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3-methoxypiperidin- l-yl)acetamido)benzoic acid;
4-(2-((3Sr,4i?)-4-(6-amino-5-chloro-2-oxo-l,2-dmydropyridine-3-carboxamido)-3- methoxypiperidin- 1 -yl)acetamido)benzoic acid;
4-(2-((3i?,45)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3-methoxypiperidin- l-yl)acetamido)benzoic acid;
4-(2-((3i?,45)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3-carboxamido)-3- methoxypiperidin- 1 -y l)acetamido)benzoic acid; methyl 4-(2-((3/?,4£)-4-(6-amino-5-chloro-2-memoxynicotinamido)-3- methoxypiperidin- 1 -yl)acetamido)benzoate; methyl 4-(2-((3i?,45)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3- carboxamido)-3-methoxypiperidin-l-yl)acetamido)benzoate; methyl 4-(2-((3£,4i?)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)acetamido)benzoate; methyl 4-(2-((36',4i?)-4-(6-amino-5 -chloro-2-oxo- 1 ,2-dihydropyridine-3 - carboxamido)-3 -methoxypiperidin- 1 -yl)acetamido)benzoate; ethyl 4-(2-((35',4i?)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)acetamido)benzoate; ethyl 4-(2-((35',4i?)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3- carboxamido)-3-methoxypiperidin-l-yl)acetamido)benzoate; ethyl 4-(2-((3i?,45)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin-l-yl)acetamido)benzoate; ethyl 4-(2-((3i?,45)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3- carboxamido)-3-methoxypiperidin-l-yl)acetamido)benzoate; isopropyl 4-(2-((35',4i?)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)acetamido)benzoate; isopropyl 4-(2-((35',4i?)-4-(6-amino-5 -chloro-2-oxo- 1 ,2-dihydropyridine-3 - carboxamido)-3-methoxypiperidin- 1 -yl)acetamido)benzoate; isopropyl 4-(2-((3i?,4.S)-4-(6-aniino-5-chloro-2-methoxynicotmamido)-3- methoxypiperidin- 1 -yl)acetamido)benzoate; isopropyl 4-(2-((3i?,4S)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3- carboxamido)-3-methoxypiperidin-l-yl)acetamido)benzoate;
2-methoxyethyl 4-(2-((35r,4i?)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)acetamido)benzoate;
2-niethoxyethyl 4-(2-((35',4i?)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3- carboxamido)-3-methoxypiperidin-l-yl)acetamido)benzoate;
2-methoxyethyl 4-(2-((3i?,45)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)acetamido)benzoate;
2-methoxyethyl 4-(2-((3i?,45)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3- carboxamido)-3 -methoxypiperidin- 1 -yl)acetamido)benzoate;
2-(pyrrolidin-l-yl)ethyl 4-(2-((3,S',4i?)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3-methoxypiperidin-l-yl)acetamido)benzoate;
2-(pyrrolidin- 1 -yl)ethyl 4-(2-((3.S',4i?)-4-(6-amino-5-chloro-2-oxo- 1 ,2- dihydropyridine-3-carboxamido)-3-methoxypiperidin-l-yl)acetamido)benzoate;
2-(pyrrolidin- 1 -yl)ethyl 4-(2-((3i?,45}-4-(6-amino-5-chloro-2- methoxynicotinamido)-3-methoxypiperidin-l-yl)acetamido)benzoate;
2-(pyrrolidin-l-yl)ethyl 4-(2-((3i?,45)-4-(6-amino-5-chloro-2-oxo-l,2- dihydropyridine-3-carboxamido)-3-methoxypiperidin-l-yl)acetamido)benzoate; l-methylpiperidin-4-yl 4-(2-((36',4i?)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3-methoxypiperidin-l-yl)acetamido)benzoate; l-methylpiperidin-4-yl 4-(2-((36',4i?)-4-(6-amino-5-chloro-2-oxo-l,2- dihydropyridine-3 -carboxamido)-3 -methoxypiperidin- 1 -yl)acetamido)benzoate;
1 -methylpiperidin-4-yl 4-(2-((3i?,45)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3-methoxypiperidin-l-yl)acetamido)benzoate; l-methylpiperidin-4-yl 4-(2-((3i?,45)-4-(6-amino-5-chloro-2-oxo-l,2- dihydropyridine-3-carboxamido)-3-methoxypiperidin-l-yl)acetamido)benzoate;
2-(pyridin-2-yl)ethyl 4-(2-((36',4i?)-4-(6-amino-5-chloro-2-methoxynicotinamido)- 3-methoxypiperidin- 1 -yl)acetamido)benzoate; 2-(pyridin-2-yl)ethyl 4-(2-((35r,4JR)-4-(6-amino-5-chloro-2-oxo-l,2- dihydropyridine-3-carboxamido)-3-methoxypiperidin-l-yl)acetamido)benzoate;
2-(pyridin-2-yl)ethyl 4-(2-((3i?,45)-4-(6-amino-5-chloro-2-methoxynicotinamido)- 3 -methoxypiperidin- 1 -yl)acetamido)benzoate;
2-(pyridin-2-yl)ethyl 4-(2-((3i?,41S)-4-(6-amino-5-chloro-2-oxo- 1 ,2- dihydropyridine-3 -carboxamido)-3 -methoxypiperidin- 1 -yl)acetamido)benzoate;
2-(dimethylamino)ethyl 4-(2-((35',4i?)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3-methoxypiperidin-l-yl)acetamido)benzoate;
2-(dimethylamino)ethyl 4-(2-((35',4i?)-4-(6-amino-5-chloro-2-oxo- 1,2- dihydropyridine-3 -carboxamido)-3 -methoxypiperidin- 1 -yl)acetamido)benzoate;
2-(dimethylamino)ethyl 4-(2-((3i?,45)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3-methoxypiperidin-l-yl)acetamido)benzoate;
2-(dimethylamino)ethyl 4-(2-((3i?,45)-4-(6-amino-5-chloro-2-oxo-l,2- dihydropyridine-3-carboxamido)-3-methoxypiperidin-l-yl)acetamido)benzoate;
1 -methylpiperidin-3-yl 4-(2-((3JS',4i?)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3-methoxypiperidin-l-yl)acetamido)benzoate; l-methylpiperidin-3-yl 4-(2-((3,S',4i?)-4-(6-amino-5-chloro-2-oxo-l,2- dihydropyridine-3 -carboxamido)-3 -methoxypiperidin- 1 -yl)acetamido)benzoate; l-methylpiperidin-3-yl 4-(2-((3i?,45)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3-methoxypiperidin-l-yl)acetamido)benzoate; l-methylpiperidin-3-yl 4-(2-((3i?,45)-4-(6-amino-5-chloro-2-oxo-l,2- dihydropyridine-3-carboxamido)-3-methoxypiperidin-l-yl)acetamido)benzoate;
2-morpholinoethyl 4-(2-((3iS',4i?)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)acetamido)benzoate;
2-morpholinoethyl 4-(2-((3<S',4i?)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine- 3 -carboxamido)-3 -methoxypiperidin- 1 -yl)acetamido)benzoate;
2-morpholinoethyl 4-(2-((3i?,45)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)acetamido)benzoate;
2-morpholinoethyl 4-(2-((3i?,45)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine- 3-carboxamido)-3-methoxypiperidin-l-yl)acetamido)benzoate; l,4-dimethylpiperidin-4-yl 4-(2-((3)S',4i?)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3-methoxypiperidin-l-yl)acetamido)benzoate; 1 ,4-dimethylpiperidin-4-yl 4-(2-((3S,4i?)-4-(6-amino-5-chloro-2-oxo- 1,2- dihydropyridine-3 -carboxamido)-3 -methoxypiperidin- 1 -yl)acetamido)benzoate; l,4-dimethylpiperidin-4-yl 4-(2-((3i?,45)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3-methoxypiperidin-l-yl)acetamido)benzoate; l,4-dimethylpiperidin-4-yl 4-(2-((3i?,45)-4-(6-amino-5-chloro-2-oxo-l,2- dihydropyridine-3-carboxamido)-3-methoxypiperidin-l-yl)acetamido)benzoate;
4-(2-((31S',4i?)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3-methoxypiperidin- l-yl)acetamido)benzoic acid;
4-(2-((35r,4i?)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3-carboxamido)-3- methoxypiperidin- 1 -yl)acetamido)benzoic acid;
4-(2-((3i?,45)-4-(6-amino-5-chloro-2-methoxynicotinaniido)-3-methoxypiperidin- l-yl)acetamido)benzoic acid;
4-(2-((3i?,45)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3-carboxamido)-3- methoxypiperidin- 1 -yl)acetamido)benzoic acid;
2-oxo-2-(piperidin-4-ylamino)ethyl 4-(2-((35',4i?)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3-methoxypiperidin-l-yl)acetamido)benzoate;
2-oxo-2-(piperidin-4-ylamino)ethyl 4-(2-((35',4i?)-4-(6-amino-5-chloro-2-oxo-l,2- dihydropyridine-3-carboxamido)-3-methoxypiperidin-l-yl)acetamido)benzoate;
2-oxo-2-(piperidin-4-ylamino)ethyl 4-(2-((3i?,45)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3-methoxypiperidin-l-yl)acetamido)benzoate;
2-oxo-2-(piperidin-4-ylamino)ethyl 4-(2-((3i?,45)-4-(6-amino-5-chloro-2-oxo-l,2- dihydropyridine-3-carboxamido)-3-methoxypiperidin-l-yl)acetamido)benzoate; l-(2-((35',4i?)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3-methoxypiperidin- 1 -yl)acetyl)piperidine-4-carboxylic acid; l-(2-((35',4i?)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3-carboxamido)-3- methoxypiperidin- 1 -y l)acety l)piperidine-4-carboxylic acid; l-(2-((3i?,45)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3-methoxypiperidin- 1 -yl)acetyl)piperidine-4-carboxylic acid; l-(2-((3i?,45)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3-carboxamido)-3- methoxypiperidin- 1 -yl)acetyl)piperidine-4-carboxylic acid; methyl l-(2-((35',4i?)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)acetyl)piperidine-4-carboxylate; methyl l-(2-((35',4i?)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3- carboxamido)-3-methoxypiperidin-l-yl)acetyl)piperidine-4-carboxylate; methyl l-(2-((3i?,45)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)acetyl)piperidine-4-carboxylate; methyl l-(2-((3i?,4S)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3- carboxamido)-3-methoxypiperidin-l-yl)acetyl)piperidine-4-carboxylate; ethyl l-(2-((3iS',4i?)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)acetyl)piperidine-4-carboxylate; ethyl l-(2-((35',4i?)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3- carboxamido)-3-methoxypiperidin-l-yl)acetyl)piperidine-4-carboxylate; ethyl l-(2-((3i?,45)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)acetyl)piperidine-4-carboxylate; ethyl l-(2-((3i?,45)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3- carboxamido)-3-methoxypiperidin-l-yl)acetyl)piperidine-4-carboxylate;
2-methoxyethyl l-(2-((3ιS',4i?)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)acetyl)piperidine-4-carboxylate;
2-methoxyethyl l-(2-((3S,4i?)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3- carboxamido)-3 -methoxypiperidin- 1 -yl)acetyl)piperidine-4-carboxylate;
2-methoxyethyl l-(2-((3i?,45)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)acetyl)piperidine-4-carboxylate;
2-methoxyethyl l-(2-((3i?,4S)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3- carboxamido)-3-methoxypiperidin-l-yl)acetyl)piperidine-4-carboxylate;
4-(((2-((3£4i?)-4-(6-amino-5-chloro-2-methoxynicotmamido)-3- methoxypiperidin- 1 -yl)ethyl)(methyl)amino)methyl)benzoic acid;
4-(((2-((35',4/-)-4-(6-amino-5-chloro-2-oxo- 1 ,2-dihydropyridine-3 -carboxamido)- 3-methoxypiperidin-l-yl)ethyl)(methyl)amino)methyl)benzoic acid;
4-(((2-((3i?,45)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)ethyl)(methyl)amino)methyl)benzoic acid;
4-(((2-((3i?,45)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3-carboxamido)- 3-methoxypiperidin-l-yl)ethyl)(methyl)amino)methyl)benzoic acid; methyl 4-(((2-((35',4i?)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)ethyl)(methyl)amino)methyl)benzoate; methyl 4-(((2-((3<S',4i?)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3- carboxamido)-3-methoxypiperidin-l-yl)ethyl)(methyl)amino)methyl)benzoate; methyl 4-(((2-((3i?,45)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)ethyl)(methyl)amino)methyl)benzoate; methyl 4-(((2-((3i?,45)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3- carboxamido)-3 -methoxypiperidin- 1 -yl)ethyl)(methyl)amino)methyl)benzoate; methyl 4-((2-((3S',4i?)-4-(6-amino-5 -chloro-2-methoxynicotinamido)-3 - methoxypiperidin- 1 -yl)ethylamino)methyl)benzoate ; methyl 4-((2-((3S,4i?)-4-(6-amino-5-chloro-2-oxo- 1 ,2-dihydropyridine-3- carboxamido)-3-methoxypiperidin-l-yl)ethylamino)methyl)benzoate; methyl 4-((2-((3i?,45)-4-(6-amino-5 -chloro-2-methoxynicotinamido)-3 - methoxypiperidin- 1 -yl)ethylamino)methyl)benzoate; methyl 4-((2-((3i?,45)-4-(6-amino-5-chloro-2-oxo- 1 ,2-dihydropyridine-3- carboxamido)-3-methoxypiperidin-l-yl)ethylamino)methyl)benzoate; isopropyl 4-((2-((3S,4i?)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)ethylamino)methyl)benzoate; isopropyl 4-((2-((35',4i?)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3- carboxamido)-3-methoxypiperidin-l-yl)ethylamino)methyl)benzoate; isopropyl 4-((2-((3i?,4S)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)ethylamino)methyl)benzoate; isopropyl 4-((2-((3i?,45)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3- carboxamido)-3-methoxypiperidin-l-yl)ethylamino)methyl)benzoate; ethyl 4-((2-((3jS,4i?)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)ethylamino)methyl)benzoate dihydrochloride; ethyl 4-((2-((35',4i?)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3- carboxamido)-3-methoxypiperidin-l-yl)ethylamino)methyl)benzoate dihydrochloride; ethyl 4-((2-((3i?,45)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)ethylamino)methyl)benzoate dihydrochloride ; ethyl 4-((2-((3i?,4.S)-4-(6-amino-5-chloro-2-oxo- 1 ,2-dihydropyridine-3 - carboxamido)-3 -methoxypiperidin- l-yl)ethylamino)methyl)benzoate dihydrochloride;
(i?)-quinuclidin-3-yl 4-(2-((3iS',4i?)-4-(6-amino-5-chloro-2-methoxynicotinamido)- 3-methoxypiperidin-l-yl)ethylcarbamoyl)benzoate; (i?)-quinuclidin-3 -yl 4-(2-((35r,4i?)-4-(6-amino-5-chloro-2-oxo- 1 ,2- dihydropyridine-3-carboxamido)-3-methoxypiperidin-l-yl)ethylcarbamoyl)benzoate;
(i?)-quinuclidin-3-yl 4-(2-((3i?,45)-4-(6-amino-5-chloro-2-methoxynicotinamido)- 3-methoxypiperidin-l-yl)ethylcarbamoyl)benzoate ;
(i?)-quinuclidin-3-yl 4-(2-((3i?,45)-4-(6-amino-5-chloro-2-oxo-l,2- dihydropyridine-3 -carboxamido)-3 -methoxypiperidin- 1 -yl)ethylcarbamoyl)benzoate;
2-(pyrrolidin-l-yl)ethyl 4-(((2-((3S,4R)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3-methoxypiperidin-l-yl)ethyl)(methyl)amino)methyl)benzoate;
1 -methylpiperidin-4-yl 4-(((2-((3 S,4R)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3-methoxypiperidin-l-yl)ethyl)(methyl)amino)methyl)benzoate;
2-morpholinoethyl 4-(((2-((3S,4R)-4-(6-amino-5-chloro-2-methoxynicotinamido)- 3-methoxypiperidin-l-yl)ethyl)(methyl)amino)methyl)benzoate;
4-((2-((3S,4R)-4-(6-amino-5-chloro-2-memoxynicotinamido)-3-methoxypiperidin- 1 -yl)ethylamino)methyl)benzoic acid;
3-hydroxypropyl 4-((2-((3S,4R)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)ethylamino)methyl)benzoate; piperidin-4-yl 4-((2-((3 S,4R)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3 - methoxypiperidin- 1 -yl)ethylamino)methyl)benzoate;
4-(2-((3S,4R)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3-methoxypiperidin- l-yl)ethylcarbamoyl)benzoic acid; piperidin-4-yl 4-(2-((3 S,4R)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)ethylcarbamoyl)benzoate;
2-(4-(2-((3S,4R)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)acetamido)phenyl)acetic acid; ethyl 2-(4-(2-((3S,4R)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -y l)acetamido)phenyl)acetate;
1 -methylpiperidin-4-yl 2-(4-(2-((3 S,4R)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3 -methoxypiperidin- 1 -yl)acetamido)phenyl)acetate;
3 -hydroxypropyl 2-(4-(2-((3 S,4R)-4-(6-amino-5-chloro-2-methoxynicotinamido)- 3 -methoxypiperidin- 1 -yl)acetamido)phenyl)acetate; quinuclidin-3-yl 2-(4-(2-((3S,4R)-4-(6-amino-5-chloro-2-methoxynicotinamido)- 3 -methoxypiperidin- 1 -yl)acetamido)phenyl)acetate; 6-amino-5-chloro-N-((3S,4R)-l-(2-(4-hydroxyphenylamino)-2-oxoethyl)-3- methoxypiperidin-4-yl)-2-methoxynicotinamide;
4-(2-((3S,4R)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3-methoxypiperidin- l-yl)acetamido)phenyl acetate;
4-(3-((3S,4R)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3-methoxypiperidin- l-yl)propyl)benzoic acid;
2-morpholinoethyl 4-(3-((3S,4R)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)propyl)benzoate;
2-(pyrrolidin-l-yl)ethyl 4-(3-((3S,4R)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3-methoxypiperidin-l-yl)propyl)benzoate;
1 -methylpiperidin-4-yl 4-(3-((3 S,4R)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3-methoxypiperidin- 1 -yl)propyl)benzoate;
2-hydroxyethyl 4-(2-((3S,4R)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)acetamido)benzoate;
2-amino-2-oxoethyl 4-(2-((3S,4R)-4-(6-amino-5-chloro-2-methoxynicotinamido)- 3-methoxypiperidin-l-yl)acetamido)benzoate;
2-(piperazin- 1 -yl)ethyl 4-(2-((3 S,4R)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3-methoxypiperidin-l-yl)acetamido)benzoate;
2-(pyrrolidin- 1 -yl)ethyl 4-(((2-((3 S,4R)-4-(6-amino-5-chloro-2-oxo- 1 ,2- dihydropyridine-3 -carboxamido)-3 -methoxypiperidin- 1 - yl)ethyl)(methyl)amino)methyl)benzoate; l-methylpiperidin-4-yl 4-(((2-((3S,4R)-4-(6-amino-5-chloro-2-oxo-l,2- dihydropyridine-3 -carboxamido)-3 -methoxypiperidin- 1 - yl)ethyl)(methyl)amino)methyl)benzoate;
2-morpholinoethyl 4-(((2-((3 S,4R)-4-(6-amino-5-chloro-2-oxo- 1 ,2- dihydropyridine-3 -carboxamido)-3 -methoxypiperidin- 1 - yl)ethyl)(methyl)amino)methyl)benzoate;
4-((2-((3S,4R)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3-carboxamido)-3- methoxypiperidin- 1 -yl)ethylamino)methyl)benzoic acid;
3-hydroxypropyl 4-((2-((3S,4R)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine- 3-carboxamido)-3-methoxypiperidin-l-yl)ethylamino)methyl)benzoate; piperidin-4-yl 4-((2-((3S,4R)-4-(6-amino-5~chloro-2-oxo-l,2-dihydropyridine-3- carboxamido)-3-methoxypiperidin-l-yl)ethylamino)methyl)benzoate;
4-(2-((3S,4R)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3-carboxamido)-3- methoxypiperidin- 1 -yl)ethylcarbamoyl)benzoic acid; piperidin-4-yl 4-(2-((3S,4R)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3- carboxamido)-3-methoxypiperidin-l-yl)ethylcarbamoyl)benzoate;
2-(4-(2-((3S,4R)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3-carboxamido)- 3-methoxypiperidin-l-yl)acetamido)phenyl)acetic acid; ethyl 2-(4-(2-((3S,4R)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3- carboxamido)-3-methoxypiperidin-l-yl)acetamido)phenyl)acetate; l-methylpiperidin-4-yl 2-(4-(2-((3S,4R)-4-(6-amino-5-chloro-2-oxo-l,2- dihydropyridine-3-carboxamido)-3-methoxypiperidin-l-yl)acetamido)phenyl)acetate;
3-hydroxypropyl 2-(4-(2-((3S,4R)-4-(6-amino-5-chloro-2-oxo-l,2- dihydropyridine-3-carboxamido)-3-methoxypiperidin-l-yl)acetamido)phenyl)acetate; quinuclidin-3-yl 2-(4-(2-((3S,4R)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine- 3-carboxamido)-3-methoxypiperidin-l-yl)acetamido)phenyl)acetate;
6-amino-5-chloro-N-((3S,4R)-l-(2-(4-hydroxyphenylamino)-2-oxoethyl)-3- methoxypiperidin-4-yl)-2-oxo-l,2-dihydropyridine-3-carboxamide;
4-(2-((3S,4R)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3-carboxamido)-3- methoxypiperidin- 1 -yl)acetamido)phenyl acetate;
4-(3-((3S,4R)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3-carboxamido)-3- methoxypiperidin- 1 -yl)propyl)benzoic acid;
2-moφholinoethyl 4-(3 -((3 S,4R)-4-(6-amino-5-chloro-2-oxo- 1 ,2-dihydropyridine- 3-carboxamido)-3-methoxypiperidin-l-yl)propyl)benzoate;
2-(pyrrolidin-l-yl)ethyl 4-(3-((3S,4R)-4-(6-amino-5-chloro-2-oxo-l,2- dihydropyridine-3-carboxamido)-3-methoxypiperidin-l-yl)propyl)benzoate; l-methylpiperidin-4-yl 4-(3-((3S,4R)-4-(6-amino-5-chloro-2-oxo-l,2- dihydropyridine-3-carboxamido)-3-methoxypiperidin-l-yl)propyl)benzoate;
2-hydroxyethyl 4-(2-((3S,4R)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3- carboxamido)-3-methoxypiperidin-l-yl)acetamido)benzoate;
2-amino-2-oxoethyl 4-(2-((3S,4R)-4-(6-amino-5-chloro-2-oxo-l,2- dihydropyridine-3-carboxamido)-3-methoxypiperidin-l-yl)acetamido)benzoate; 2-(piperazin- 1 -yl)ethyl 4-(2-((3 S54R)-4-(6-amino-5-chloro-2-oxo- 1 ,2- dihydropyridine-3-carboxamido)-3-methoxypiperidin-l-yl)acetamido)benzoate; or a pharmaceutically acceptable salt thereof.
14. A compound according to claim 1 that is benzyl 3-((3S,4R)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)propanoate; isopropyl 3-((3R,4S)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)propanoate;
4-(methylsulfonyl)benzyl 3-((3R,4S)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3-methoxypiperidin-l-yl)propanoate;
(tetrahydro-2H-pyran-2-yl)methyl 3-((3R,4S)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3-methoxypiperidin-l-yl)propanoate; cyclohexyl 3-((3R,4S)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)propanoate; neopentyl 3-((3S,4R)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)propanoate;
4-methoxybenzyl 3-((3R,4S)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)propanoate; pyridin-4-ylmethyl 3-((3R,4S)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)propanoate;
2-((3S,4R)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3-methoxypiperidin- l-yl)acetic acid;
4-fluorobenzyl 2-((3S,4R)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)acetate; benzyl 2-((3 S,4R)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3 - methoxypiperidin- 1 -yl)acetate;
4-methylbenzyl 2-((3S,4R)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)acetate;
2-methoxybenzyl 2-((3S,4R)-4-(6-ammo~5-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)acetate ; 4-chlorobenzyl 2-((3S,4R)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)acetate;
4-methoxybenzyl 2-((3R,4R)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)acetate; piperidin-4-yl 2-((3S,4R)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin-l-yl)acetate;
2-methoxyethyl 2-((3S,4R)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)acetate;
2-hydroxyethyl 2-((3S,4R)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)acetate;
2-chlorobenzyl 2-((3R,4S)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)acetate ;
4-(trifluoromethyl)benzyl 2-((3R,4S)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3-methoxypiperidin-l-yl)acetate;
3-methylbenzyl 2-((3R,4S)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)acetate;
3-chlorobenzyl 2-((3R,4S)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)acetate;
2-(trifluoromethyl)benzyl 2-((3R,4S)-4-(6-amino-5-chloro-2- methoxynicotinaniido)-3-methoxypiperidin-l-yl)acetate;
2-morpholinoethyl 2-((3R,4S)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)acetate ;
(tetrahydro-2H-pyran-2-yl)methyl 2-((3R,4S)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3-methoxypiperidin-l-yl)acetate;
2-fluorobenzyl 2-((3R,4S)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)acetate;
3-fluorobenzyl 2-((3R,4S)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)acetate;
3-methoxybenzyl 2-((3R,4S)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)acetate;
2-(methylsulfonyl)ethyl 2-((3R,4S)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3-methoxypiperidin- 1 -yl)acetate; isopropyl 2-((3R,4S)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)acetate; ethyl 2-((3R,4S)-4-(6-amino-5 -chloro-2-methoxynicotinamido)-3 - methoxypiperidin-l-yl)acetate;
2-(pyridin-2-yl)ethyl 2-((3R,4S)-4-(6-amino-5-chloro-2-methoxynicotinamido)- 3-methoxypiperidin-l-yl)acetate; pyridin-2-ylmethyl 2-((3R,4S)-4-(6-amino-5-chloro-2-methoxynicotinamido)~3- methoxypiperidin- 1 -yl)acetate; pyridin-3-ylmethyl 2-((3R,4S)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)acetate; piperidin-3-ylmethyl 2-((3R,4S)-4-(6-amino-5-chloro-2-methoxynicotinamido)~ 3-methoxypiperidin-l-yl)acetate; cyclohexyl 2-((3R,4S)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)acetate;
1 -methoxypropan-2-yl 2-((3R,4S)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3-methoxypiperidin-l-yl)acetate;
2,3,4-trimethoxybenzyl 2-((3R,4S)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3-methoxypiperidin-l-yl)acetate;
2,3-dimethoxybenzyl 2-((3R,4S)-4-(6-amino-5-chloro-2-methoxynicotinamido)- 3-methoxypiperidin-l-yl)acetate;
1 -(4-fluorophenyl)ethyl 2-((3R,4S)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3 -methoxypiperidin- 1 -yl)acetate ;
3-(4-fluorophenoxy)propyl 2-((3R,4S)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3 -methoxypiperidin- 1 -yl)acetate ;
3-fluoro-4-methylbenzyl 2-((3S,4R)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3-methoxypiperidin-l-yl)acetate;
4-fluoro-3 -methylbenzyl 2-((3 S,4R)-4-(6-amino-5 -chloro-2- methoxynicotinamido)-3 -methoxypiperidin- 1 -yl)acetate ;
2-fluoro-6-methylbenzyl 2-((3 S,4R)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3 -methoxypiperidin- 1 -yl)acetate ; tetrahydro-2H-pyran-4-yl 2-((3R,4S)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3-methoxypiperidin-l-yl)acetate; 2-(2-methoxyethoxy)ethyl 2-((3R,4S)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3-methoxypiperidin-l-yl)acetate;
2-(2-(2-methoxyethoxy)ethoxy)ethyl 2-((3R,4S)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3-methoxypiperidin-l-yl)acetate; neopentyl 2-((3 S,4R)-4-(6-amino-5 -chloro-2-methoxynicotinamido)-3 - methoxypiperidin-1 -yl)acetate;
2-(piperazin-2-yl)ethyl 2-((3S,4R)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3-methoxypiperidin- 1 -yl)acetate; pyridin-4-ylmethyl 2-((3R,4S)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)acetate;
(R)-3-((3R,4S)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)-2-methylpropanoic acid;
(R)-methyl 3 -((3R,4S)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3 - methoxypiperidin- 1 -yl)-2-methylpropanoate;
4-(methylsulfonyl)benzyl 3-((3R,4S)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3-methoxypiperidin-l-yl)-2-methylpropanoate;
4-fluorobenzyl 3-((3R,4S)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)-2-methylpropanoate;
(S)-4-(methylsulfonyl)benzyl 3-((3R,4S)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3-methoxypiperidin-l-yl)-2-methylpropanoate;
(S)-3 -((3R,4 S)-4-(6-amino-5 -chloro-2-methoxynicotinamido)-3 - methoxypiperidin- 1 -yl)-2-methylpropanoic acid;
(S)-methyl 3-((3R,4S)-4-(6-amino-5-chloro-2-rnethoxynicotinamido)~3- methoxypiperidin- 1 -yl)-2-methylpropanoate;
4-((3R,4S)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3-methoxypiperidin- l-yl)butanoic acid;
4-fluorobenzyl 6-((3S,4R)-4-(6-amino~5-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)hexanoate;
2-methoxyethyl 6-((3S,4R)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)hexanoate; neopentyl 6-((3S,4R)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)hexanoate; pyridin-2-ylmethyl 6-((3S,4R)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)hexanoate;
2-(piperazin-l-yl)ethyl 6-((3S,4R)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3 -methoxypiperidin- 1 -yl)hexanoate hydrochloride;
2-(dimethylamino)ethyl 6-((3 S,4R)-4-(6-amino-5~chloro-2- methoxynicotinamido)-3-methoxypiperidin- 1 -yl)hexanoate;
1 -adamantylmethyl 6-[(3 S,4R)-4- { [(6-amino-5-chloro-2-methoxypyridin-3 - yl)carbonyl]amino}-3-methoxypiperidin-l-yl]hexanoate; cyclohexyl 6-((3S,4R)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)hexanoate;
2-adamantyl 6-[(3S,4R)-4-{[(6-amino-5-chloro-2-methoxypyridin-3- yl)carbonyl]amino} -3-methoxypiperidin- 1 -yl]hexanoate; bicyclo[2.2. l]heptan-2-yl 6-((3 S,4R)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3-methoxypiperidin- 1 -yl)hexanoate;
2-(2-((3S,4R)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)ethoxy)acetic acid; methyl 2-(2-((3R,4S)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)ethoxy)acetate; cyclohexyl 2-(2-((3S,4R)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)ethoxy)acetate; cyclohexyl 2-(2-((3R,4S)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)ethoxy)acetate; piperidin-4-yl 2-(2-((3R,4S)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)ethoxy)acetate hydrochloride; l-(2-((3S,4R)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)acetyl)piperidine-4-carboxylic acid; methyl 1 -(2-((3 S,4R)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)acetyl)piperidine-4-carboxylate; ethyl l-(2-((3S,4R)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)acetyl)piperidine-4-carboxylate;
2-methoxyethyl 1 -(2-((3 S,4R)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3- methoxypiperidin- 1 -yl)acetyl)piperidine-4-carboxylate; 6-amino-5-chloro-N-((3R,4S)-l-(2-hydroxyethyl)-3-methoxypiperidin-4-yl)-2- methoxynicotinamide;
6-amino-5-chloro-2-memoxy-N-((3R,4S)-3-methoxypiperidin-4- yl)nicotinamide;
6-amino-5-chloro-N-((3R,4S)-l-(3-(4-fluorophenoxy)propyl)-3- methoxypiperidin-4-yl)-2-methoxynicotinamide; benzyl 3-((3S,4R)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3- carboxamido)-3-methoxypiperidin-l-yl)propanoate; isopropyl 3-((3R,4S)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3- carboxamido)-3-methoxypiperidin-l-yl)propanoate;
4-(memylsulfonyl)benzyl 3-((3R,4S)-4-(6-amino-5-chloro-2-oxo-l,2- dihydropyridine-3 -carboxamido)-3 -methoxypiperidin- 1 -yl)propanoate;
(tetrahydro-2H-pyran-2-yl)methyl 3-((3R,4S)-4-(6-amino-5-chloro-2-oxo-l,2- dihydropyridine-3 -carboxamido)-3 -methoxypiperidin- 1 -yl)propanoate; cyclohexyl 3-((3R,4S)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3- carboxamido)-3 -methoxypiperidin- 1 -yl)propanoate ; neopentyl 3 -((3 S,4R)-4-(6-amino-5-chloro-2-oxo- 1 ,2-dihydropyridine-3- carboxamido)-3-methoxypiperidin-l-yl)propanoate;
4-methoxybenzyl 3-((3R,4S)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3- carboxamido)-3-methoxypiperidin-l-yl)propanoate; pyridin-4-ylmethyl 3 -((3R,4S)-4-(6-amino-5-chloro-2-oxo~ 1 ,2-dihydropyridine- 3-carboxamido)-3-methoxypiperidin-l-yl)propanoate;
2-((3S,4R)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3-carboxamido)-3- methoxypiperidin- 1 -yl)acetic acid;
4-fluorobenzyl 2-((3S,4R)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3- carboxamido)-3 -methoxypiperidin- 1 -yl)acetate; benzyl 2-((3S,4R)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3- carboxamido)-3-methoxypiperidin-l-yl)acetate;
4-methylbenzyl 2-((3 S,4R)-4-(6-amino-5-chloro-2-oxo- 1 ,2-dihydropyridine-3 - carboxamido)-3-methoxypiperidin-l-yl)acetate;
2-methoxybenzyl 2-((3S,4R)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3- carboxamido)-3 -methoxypiperidin- 1 -yl)acetate; 4-chlorobenzyl 2-((3S,4R)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3- carboxamido)-3-methoxypiperidin-l-yl)acetate;
4-methoxybenzyl 2-((3R,4R)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3- carboxamido)-3-methoxypiperidin-l-yl)acetate; piperidin-4-yl 2-((3 S,4R)-4-(6-amino-5-chloro-2-oxo- 1 ,2-dihydropyridine-3- carboxamido)-3 -methoxypiperidin- 1 -yl)acetate;
2-methoxyethyl 2-((3S,4R)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3- carboxamido)-3-methoxypiperidin- 1 -yl)acetate;
2-hydroxyethyl 2-((3S,4R)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3- carboxamido)-3 -methoxypiperidin- 1 -yl)acetate;
2-chlorobenzyl 2-((3R,4S)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3- carboxamido)-3-methoxypiperidin-l-yl)acetate;
4-(trifluoromethyl)benzyl 2-((3R,4S)-4-(6-amino-5-chloro-2-oxo- 1 ,2- dihydropyridine-3-carboxamido)-3-methoxypiperidin-l-yl)acetate;
3-methylbenzyl 2-((3R,4S)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3- carboxamido)-3 -methoxypiperidin- 1 -yl)acetate;
3-chlorobenzyl 2-((3R,4S)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3- carboxamido)-3-methoxypiperidin-l-yl)acetate;
2-(trifluoromethyl)benzyl 2-((3R,4S)-4-(6-amino-5-chloro-2-oxo-l,2- dihydropyridine-3-carboxamido)-3-methoxypiperidin-l-yl)acetate;
2-morpholinoethyl 2-((3R,4S)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine- 3-carboxamido)-3-methoxypiperidin-l-yl)acetate;
(tetrahydro-2H-pyran-2-yl)methyl 2-((3R,4S)-4-(6-amino-5-chloro-2-oxo-l,2- dihydropyridine-3 -carboxamido)-3 -methoxypiperidin- 1 -yl)acetate;
2-fluorobenzyl 2-((3R,4S)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3- carboxamido)-3-methoxypiperidin-l-yl)acetate;
3-fluorobenzyl 2-((3R,4S)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3- carboxamido)-3-methoxypiperidin-l-yl)acetate;
3-methoxybenzyl 2-((3R,4S)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3- carboxamido)-3-methoxypiperidin- 1 -yl)acetate;
2-(methylsulfonyl)ethyl 2-((3R,4S)-4-(6-amino-5-chloro-2-oxo-l,2- dihydropyridine-3 -carboxamido)-3 -methoxypiperidin- 1 -yl)acetate; isopropyl 2-((3R,4S)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3- carboxamido)-3-methoxypiperidin-l-yl)acetate; ethyl 2-((3R,4S)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3- carboxamido)-3 -methoxypiperidin- 1 -yl)acetate;
2-(pyridin-2-yl)ethyl 2-((3R,4S)-4-(6-amino-5-chloro-2-oxo- 1 ,2- dihydropyridine-3-carboxamido)-3-methoxypiperidin-l-yl)acetate; pyridin-2-ylmethyl 2-((3R,4S)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine- 3 -carboxamido)-3 -methoxypiperidin- 1 -yl)acetate; pyridin-3-ylmethyl 2-((3R,4S)-4-(6-ammo-5-chloro-2-oxo-l,2-dihydropyridine- 3-carboxamido)-3-methoxypiperidin-l-yl)acetate; piperidin-3 -ylmethyl 2-((3R,4S)-4-(6-amino-5-chloro-2-oxo- 1 ,2- dihydropyridine-3-carboxamido)-3-methoxypiperidin-l-yl)acetate; cyclohexyl 2-((3R,4S)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3- carboxamido)-3 -methoxypiperidin- 1 -yl)acetate;
1 -methoxypropan-2-yl 2-((3R,4S)-4-(6-amino-5-chloro-2-oxo- 1,2- dihydropyridine-3-carboxamido)-3-methoxypiperidin-l-yl)acetate;
2,3,4-trimethoxybenzyl 2-((3R,4S)-4-(6-amino-5-chloro-2-oxo-l,2- dihydropyridine-3-carboxamido)-3-methoxypiperidin-l-yl)acetate;
2,3-dimethoxybenzyl 2-((3R,4S)-4-(6-amino-5-chloro-2-oxo-l,2- dihydropyridine-3-carboxamido)-3-methoxypiperidin-l-yl)acetate; l-(4-fluorophenyl)ethyl 2-((3R,4S)-4-(6-amino-5-chloro-2-oxo-l,2- dihydropyridine-3 -carboxamido)-3 -methoxypiperidin- 1 -yl)acetate;
3-(4-fluorophenoxy)propyl 2-((3R,4S)-4-(6-amino-5-chloro-2-oxo-l,2- dihydropyridine-3-carboxamido)-3-methoxypiperidin-l-yl)acetate;
3-fluoro-4-methylbenzyl 2-((3S,4R)-4-(6-amino-5-chloro-2-oxo-l,2- dihydropyridine-3 -carboxamido)-3 -methoxypiperidin- 1 -yl)acetate;
4-fluoro-3-methylbenzyl 2-((3S,4R)-4-(6-amino-5-chloro-2-oxo-l,2- dihydropyridine-3-carboxamido)-3-methoxypiperidin-l-yl)acetate;
2-fluoro-6-methylbenzyl 2-((3S,4R)-4-(6-amino-5-chloro-2-oxo-l,2- dihydropyridine-3-carboxamido)-3-methoxypiperidin-l-yl)acetate; tetrahydro-2H-pyran-4-yl 2-((3R,4S)-4-(6-amino-5-chloro-2-oxo-l,2- dihydropyridine-3 -carboxamido)-3 -methoxypiperidin- 1 -yl)acetate; 2-(2-methoxyethoxy)ethyl 2-((3R,4S)-4-(6-amino-5-chloro-2-oxo- 1 ,2- dihydropyridine-3 -carboxamido)-3 -methoxypiperidin- 1 -yl)acetate;
2-(2-(2-methoxyethoxy)ethoxy)ethyl 2-((3R,4S)-4-(6-amino-5-chloro-2-oxo- 1 ,2- dihydropyridine-3-carboxamido)-3-methoxypiperidin-l-yl)acetate; neopentyl 2-((3S,4R)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3- carboxamido)-3-methoxypiperidin-l-yl)acetate;
2-(piperazin-2-yl)ethyl 2-((3 S,4R)-4-(6-amino-5-chloro-2-oxo- 1 ,2- dihydropyridine-3 -carboxamido)-3 -methoxypiperidin- 1 -yl)acetate; pyridin-4-ylmethyl 2-((3R,4S)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine- 3 -carboxamido)-3 -methoxypiperidin- 1 -yl)acetate;
(R)-3-((3R,4S)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3- carboxamido)-3 -methoxypiperidin- 1 -yl)-2-methylpropanoic acid;
(R)-methyl 3-((3R,4S)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3- carboxamido)-3-methoxypiperidin-l-yl)-2-methylpropanoate;
4-(methylsulfonyl)benzyl 3-((3R,4S)-4~(6-amino-5-chloro-2-oxo-l,2- dihydropyridine-3-carboxamido)-3-methoxypiperidin-l-yl)-2-methylpropanoate;
4-fluorobenzyl 3-((3R,4S)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3- carboxamido)-3-methoxypiperidin-l-yl)-2-methylpropanoate;
(S)-4-(methylsulfonyl)benzyl 3-((3R,4S)-4-(6-amino-5-chloro-2-oxo-l,2- dihydropyridine-3-carboxamido)-3-methoxypiperidin-l-yl)-2-methylpropanoate;
(S)-3-((3R,4S)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3-carboxamido)- 3-methoxypiperidin-l-yl)-2-methylpropanoic acid;
(S)-methyl 3-((3R,4S)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3- carboxamido)-3-methoxypiperidin-l-yl)-2-methylpropanoate;
4-((3R,4S)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3-carboxamido)-3- methoxypiperidin- 1 -yl)butanoic acid;
4-fluorobenzyl 6-((3 S,4R)-4-(6-amino-5-chloro-2-oxo- 1 ,2-dihydropyridine-3 - carboxamido)-3 -methoxypiperidin- 1 -yl)hexanoate;
2-methoxyethyl 6-((3S,4R)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3- carboxamido)-3-methoxypiperidin-l-yl)hexanoate; neopentyl 6-((3S,4R)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3- carboxamido)-3-methoxypiperidin-l-yl)hexanoate; pyridin-2-ylmethyl 6-((3S,4R)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine- 3-carboxamido)-3-methoxypiperidin-l-yl)hexanoate;
2-(piperazin- 1 -yl)ethyl 6-((3 S,4R)-4-(6-amino-5-chloro-2-oxo- 1 ,2- dihydropyridine-3-carboxamido)-3-methoxypiperidin-l-yl)hexanoate hydrochloride;
2-(dimethylamino)ethyl 6-((3 S,4R)-4-(6-amino-5-chloro-2-oxo- 1 ,2- dihydropyridine-3-carboxamido)-3-methoxypiperidin-l-yl)hexanoate; l-adamantylmethyl 6-[(3S,4R)-4-{[(6-amino-5-chloro-2~oxo-l,2- dihydropyridin-3-yl)carbonyl]amino}-3-methoxypiperidin-l-yl]hexanoate; cyclohexyl 6-((3S,4R)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine~3- carboxamido)-3-methoxypiperidin-l-yl)hexanoate;
2-adamantyl 6-[(3S,4R)-4-{[(6-amino-5-chloro-2-oxo-l,2-dihydropyridin-3- yl)carbonyl] amino } -3 -methoxypiperidin- 1 -yl]hexanoate; bicyclo[2.2.1]heptan-2-yl 6-((3S,4R)-4-(6-amino-5-chloro-2-oxo-l,2- dihydropyridine-3-carboxamido)-3-methoxypiperidin-l-yl)hexanoate;
2-(2-((3S,4R)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3-carboxamido)- 3 -methoxypiperidin- 1 -yl)ethoxy)acetic acid; methyl 2-(2-((3R,4S)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3- carboxamido)-3-methoxypiperidin- 1 -yl)ethoxy)acetate; cyclohexyl 2-(2-((3S,4R)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3- carboxamido)-3 -methoxypiperidin- 1 -yl)ethoxy)acetate ; cyclohexyl 2-(2-((3R,4S)-4-(6-amino-5-chloro-2-oxo- 1 ,2-dihydropyridine-3- carboxamido)-3-methoxypiperidin- 1 -yl)ethoxy)acetate; piperidin-4-yl 2-(2-((3R,4S)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3- carboxamido)-3 -methoxypiperidin- 1 -yl)ethoxy)acetate hydrochloride; l-(2-((3S,4R)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3-carboxamido)- 3 -methoxypiperidin- 1 -yl)acetyl)piperidine-4-carboxylic acid; methyl 1 -(2-((3 S,4R)-4-(6-amino-5-chloro-2-oxo- 1 ,2-dihydropyridine-3 - carboxamido)-3-methoxypiperidin-l-yl)acetyl)piperidine-4-carboxylate; ethyl l-(2-((3S,4R)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3- carboxamido)-3-methoxypiperidin-l-yl)acetyl)piperidine-4-carboxylate;
2-methoxyethyl l-(2-((3S,4R)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine- 3-carboxamido)-3-methoxypiperidin-l-yl)acetyl)piperidine-4-carboxylate; 6-amino-5-chloro-N-((3R,4S)-l-(2-hydroxyethyl)-3-methoxypiperidin-4-yl)-2- oxo-l,2-dihydropyridine-3-carboxamide;
6-amino-5-chloro-N-((3R,4S)-3-methoxypiperidin-4-yl)-2-oxo-l,2- dihydropyridine-3-carboxamide;
6-amino-5-chloro-N-((3R,4S)-l-(3-(4-fluorophenoxy)propyl)-3- methoxypiperidin-4-yl)-2-oxo-l,2-dihydropyridine-3-carboxamide; or a pharmaceutically acceptable salt thereof.
15. A compound according to claim 1 that is (i?)-quinuclidin-3-yl 6-((3S',4.Z?)-4-(6-ammo- 5-chloro-2-methoxynicotinamido)-3-methoxypiperidin-l-yl)hexanoate or (i?)-quinuclidin-3- yl 6-((3S,4i?)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3-carboxamido)-3- methoxypiperidin- 1 -yl)hexanoate.
16. A salt according to claim 1 that is (i?)-quinuclidin-3~yl 6-((35',4i?)-4-(6-amino-5- chloro-2-methoxynicotinamido)-3-methoxypiperidin-l-yl)hexanoate or (i?)-quinuclidin-3-yl 6-((36',4i?)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3-carboxamido)-3- methoxypiperidin- 1 -yl)hexanoate.
17. A composition comprising a compound or pharmaceutically acceptable salt of claim 1 and at least one pharmaceutically acceptable carrier, solvent, adjuvant, or excipient.
18. A method of treating emesis, dyspepsia, gastroparesis, constipation, intestinal pseudoobstruction, gastroesophageal reflux, or post-operative ileus, the method comprising administering a compound or salt according to claim 1 to a patient in need of such treatment.
19. A method according to claim 17, wherein the compound or salt is administered intra venously.
20. A composition comprising at least one of (i?)-quinuclidin-3-yl 6-((35',4i?)-4-(6-amino- 5 -chloro-2-methoxynicotinamido)-3 -methoxypiperidin- 1 -yl)hexanoate, (i?)-quinuclidin-3 -yl 6-((35',4i?)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3-carboxamido)-3- methoxypiperidin-l-yl)hexanoate, (i?)-quinuclidin-3-yl 6-((3)S',4i?)-4-(6-amino-5-chloro-2- methoxynicotinamido)-3 -methoxypiperidin- l-yl)hexanoate dihydrochloride and (i?)- quinuclidin-3-yl 6-((35',4i?)-4-(6-amino-5-chloro-2-oxo-l,2-dihydropyridine-3-carboxamido)- 3-methoxypiperidin-l-yl)hexanoate dihydrochloride and at least one pharmaceutically acceptable carrier, solvent, adjuvant, or excipient.
21. A method of treating emesis, dyspepsia, gastroparesis, constipation, intestinal pseudoobstruction, gastroesophageal reflux, or post-operative ileus, the method comprising administering a compound or salt according to claim 14 to a patient in need of such treatment.
EP06774511A 2005-07-05 2006-07-05 Stereoisomeric pyridyl and pyridonyl compounds and methods for the treatment of gastrointestinal and central nervous system disorders Pending EP1907376A2 (en)

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US69666205P 2005-07-05 2005-07-05
PCT/US2006/026166 WO2007005951A2 (en) 2005-07-05 2006-07-05 Stereoisomeric pyridyl and pyridonyl compounds and methods for the treatment of gastrointestinal and central nervous system disorders

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ES2552733T3 (en) 2007-11-16 2015-12-01 Rigel Pharmaceuticals, Inc. Carboxamide, sulfonamide and amine compounds for metabolic disorders
US8129390B2 (en) 2007-12-12 2012-03-06 Rigel Pharmaceuticals, Inc. Carboxamide, sulfonamide and amine compounds and methods for using the same
BRPI0911681B8 (en) 2008-04-23 2021-05-25 Rigel Pharmaceuticals Inc compound, pharmaceutical composition, and, method of activating the 5'-amp activated protein kinase pathway in a cell in vitro
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EP2531510B1 (en) 2010-02-01 2014-07-23 Novartis AG Pyrazolo[5,1b]oxazole derivatives as crf-1 receptor antagonists
US8835444B2 (en) 2010-02-02 2014-09-16 Novartis Ag Cyclohexyl amide derivatives as CRF receptor antagonists
EP3978487A1 (en) * 2020-09-30 2022-04-06 Origo Biopharma, S.L. 2-(3-pyridin-2-yl-4-quinolin-4-yl-pyrazol-1-yl)-acetamide derivatives as inhibitors of transforming growth factor-beta receptor i/alk5

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