Pyrrolo[1,2-b]-2-pyridazinone compounds as 5-HT4 receptor agonists

Abstract

The present invention relates to 5-HT 4 As a receptor agonist, The present invention relates to pyrrolo[1,2-b]-2-pyridazinone compounds of formula JPEG2025502182000059.jpg37170, or isotopes, stereoisomers, or pharma- ceutically acceptable salts thereof. The present invention also describes methods of making such compounds, pharmaceutical compositions containing such compounds, and their use in the treatment of gastrointestinal diseases or disorders.

Description

[Technical field]

[0001] The present invention relates to pyrrolo[1,2-b]-2-pyridazinone compounds of formula (I) or their isotopes, stereoisomers, or pharma- ceutically acceptable salts as 5-HT4 receptor agonists. The present invention also describes methods for making such compounds, pharmaceutical compositions containing such compounds, and their use in treating gastrointestinal diseases or disorders. [Background technology]

[0002] Extensive prior literature suggests the potential of serotonin type 4 (5-HT4) receptor agonists for the treatment of reduced and / or abnormal gastrointestinal motility. This reduced and / or abnormal motility can be caused by various disorders such as irritable bowel syndrome (IBS) (constipation-predominant IBS, diarrhea-predominant IBS, mixed IBS, and unclassified IBS), chronic constipation, functional dyspepsia, gastroparesis, gastroesophageal reflux disease, postoperative ileus, pseudo-obstruction, drug-induced delayed transit, Crohn's disease, celiac disease, etc. These disorders have a tremendous impact on the quality of life of patients and impose a considerable economic burden (Gastroenterology. 2006 Apr; 130(5): 1377-90).

[0003] 5-HT4 receptor agonists activate the release of acetylcholine from endogenous cholinergic neurons to stimulate smooth muscle contraction in the gastrointestinal tract. 5-HT4 receptor agonists, such as cisapride and tegaserod, have been successfully developed to treat gastrointestinal hypomotility in the upper or lower gastrointestinal tract. Prucalopride, another 5-HT4 receptor agonist, has been approved for the treatment of chronic intestinal pseudo-obstruction (Aliment Pharmacol Ther. 2012 Feb; 35(3): 398-9). Drugs that interact with the hERG potassium channel are associated with QT interval prolongation, which can lead to life-threatening arrhythmias (Br J Clin Pharmacol. 2012 Feb; 73(2): 203-9). Both prokinetic agents, cisapride and tegaserod, have shown poor selectivity for 5-HT4 receptors and strong interactions with the hERG potassium channel, resulting in poor profit-loss profiles. Both prokinetic agents have been withdrawn from the global market due to cardiovascular risks (Aliment Pharmacol Ther. 2012 Apr;35(7):745-67). Prucalopride has extensive brain penetration, which may not be an ideal requirement for compounds intended to act on peripheral receptors (Journal of Pharmacology and Experimental Therapeutics June 2012, 341(3)681-691). Therefore, there is an urgent need for new 5-HT4 receptor agonists with the desired pharmacological effects, with no / minimal brain penetration and side effect profile. It is also expected that such agents should have minimal or no side effects.

[0004] WO2006052640, WO2006052889, WO2006094063, and US2005228014A1 disclose 5-HT4 receptor agonists. Murray et al. describe 5-HT4 receptor agonists for the potential treatment of gastrointestinal motility-related disorders (Journal of Medicinal Chemistry (2009), 52(17), 5330-5343). Suzuki et al. describe novel 2-oxo-1,2-dihydro-3-quinolinecarboxamide derivatives as potent and selective serotonin 5-HT4 receptor agonists useful for improving gastrointestinal failure (Chem. Pharm. Bull. 49(1) 29-39 (2001). Long et al. describe velsetrag, a highly selective 5-HT4 receptor agonist, for chronic idiopathic constipation (Bioorganic & Medicinal Chemistry Letters 22 (2012) 6048-6052). [Prior art documents] [Patent documents]

[0005] [Patent Document 1] WO2006052640 [Patent Document 2] WO2006052889 [Patent Document 3] WO2006094063 [Patent Document 4] US2005228014A1 [Non-patent literature]

[0006] [Non-Patent Document 1] Gastroenterology.2006 Apr;130(5):1377-90 [Non-Patent Document 2] Aliment Pharmacol Ther.2012 Feb;35(3):398-9 [Non-Patent Document 3] Br J Clin Pharmacol.2012 Feb;73(2):203-9 [Non-Patent Document 4] Aliment Pharmacol Ther.2012 Apr;35(7):745-67 [Non-Patent Document 5] Journal of Pharmacology and Experimental Therapeutics June 2012, 341(3)681-691 [Non-Patent Document 6] Journal of Medicinal Chemistry (2009), 52(17), 5330-5343 [Non-Patent Document 7] Chem. Pharm. Bull.49(1) 29-39 (2001) Summary of the Invention [Problem to be solved by the invention]

[0007] The present invention provides potent and selective 5-HT4 receptor agonists with acceptable pharmacokinetic properties, including good oral bioavailability, no / minimal brain penetration, no interaction with the hERG potassium channel and therefore no tendency for cardiovascular burden, and exhibits robust efficacy in animal models. [Means for solving the problem]

[0008] In one aspect, the present invention provides a compound represented by formula (I):

[0009] [ka]

[0010] or an isotope, stereoisomer, or pharma- ceutically acceptable salt thereof, wherein: R 1 represents hydrogen, alkyl, or cycloalkyl; R 2represents hydrogen, hydroxy, halogen, alkyl, or cycloalkyl; A is:

[0011] [ka]

[0012] is a heterocyclic ring selected from the group consisting of: R 3 is hydrogen, or:

[0013] [ka]

[0014] selected from the group consisting of; B is hydrogen, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, -SO2-alkyl, -COCH3, -COO-alkyl, or -CO-(CH2) m -OH; where m is an integer from 0 to 5; Y, at each occurrence, is independently hydrogen, hydroxy, halogen, haloalkyl, hydroxyalkyl, -COOH, -COO-alkyl, -O-alkyl, -S-alkyl, or -NR a R b Selected from; D represents CH or N; n is an integer from 0 to 5; R a is independently selected at each occurrence from hydrogen, alkyl, cycloalkyl, or alkoxy; R b is independently selected at each occurrence from hydrogen, alkyl, cycloalkyl, or alkoxy; R 4 represents hydrogen, hydroxy, halogen, alkyl, or cycloalkyl; and b represents 1 to 3.

[0015] In another aspect, the present invention relates to a process for preparing a compound of formula (I), or an isotope, stereoisomer, or a pharma- ceutically acceptable salt thereof.

[0016] In yet another aspect, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of formula (I), its isotopes, stereoisomers, or pharma- ceutically acceptable salts, and a pharma- ceutically acceptable excipient or carrier.

[0017] In yet another aspect, the present invention relates to a compound of formula (I) or an isotope, stereoisomer, or a pharma- ceutically acceptable salt thereof for use as a 5-hydroxytryptamine 4 receptor agonist.

[0018] In yet another aspect, the present invention relates to a compound of formula (I) or an isotope, stereoisomer, or a pharma- ceutically acceptable salt thereof, for use in the treatment of a gastrointestinal disease or disorder.

[0019] In another aspect, the present invention relates to a method for treating a gastrointestinal disease or disorder, comprising administering a therapeutically effective amount of a compound of formula (I), or an isotope, stereoisomer, or a pharma- ceutically acceptable salt thereof, to a patient in need thereof.

[0020] In yet another aspect, the present invention relates to the use of a compound of formula (I), or an isotope, stereoisomer, or a pharma- ceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a gastrointestinal disease or disorder.

[0021] In yet another aspect, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of formula (I) or an isotope, stereoisomer, or pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient or carrier, for use in the treatment of a gastrointestinal disease or disorder. [Brief description of the drawings]

[0022] [Figure 1] FIG. 1 shows the gastric emptying effect of Example 2 in beagle dogs. [Diagram 2] FIG. 1 shows the colonic transport effect of Example 2 in Swiss mice. [Diagram 3] FIG. 2 shows intestinal myoelectrical activity in male Wistar rats according to Example 2. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0023] Unless otherwise stated, the following terms used in the specification and claims have the meanings indicated:

[0024] The term "alkyl" as used herein refers to a straight or branched chain aliphatic hydrocarbon. Examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and the like.

[0025] The term "cycloalkyl" as used herein refers to a saturated monocyclic hydrocarbon ring containing from 3 to 6 carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0026] The term "alkoxy" as used herein refers to an alkyl group singly bonded to an oxygen atom. Examples of alkoxy groups include methoxy, ethoxy, propoxy, methoxypropoxy, butoxy, and the like.

[0027] As used herein, the term "halogen" or "halo" refers to fluorine, chlorine, bromine, or iodine. Preferably, the halogen is fluorine, chlorine, or bromine. More particularly, the halogen is fluorine or chlorine.

[0028] The term "haloalkyl" as used herein refers to an alkyl as defined above, in which one or more hydrogens of the same or different carbon atoms are replaced with the same or different halogens. Examples of haloalkyl include fluoromethyl, chloromethyl, fluoroethyl, difluoromethyl, dichloromethyl, trifluoromethyl, difluoroethyl, and the like.

[0029] The term "hydroxyalkyl" as used herein refers to an alkyl as defined above in which one or more hydrogens of the same or different carbon atoms are replaced with a hydroxy group. Examples of hydroxyalkyl include hydroxymethyl, hydroxyethyl, hydroxypropyl, and hydroxybutyl.

[0030] The term "protecting group" or "PG" as used herein refers to a substituent that is commonly used to block or protect a particular functional group while reacting with other functional groups on a compound. For example, an "amino protecting group" refers to a substituent attached to an amino group that blocks or protects the amino functionality in the compound. Some non-limiting examples of suitable amino protecting groups include acetyl, trifluoroacetyl, tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), and 9-fluorenylmethyloxycarbonyl (Fmoc).

[0031] The phrase "therapeutically effective amount" is defined as an amount of a compound of the invention that (i) treats a particular disease, condition, or disorder; (ii) eliminates one or more symptoms of a particular disease, condition, or disorder; or (iii) delays the onset of one or more symptoms of a particular disease, condition, or disorder, as described herein.

[0032] The term "isotopes" as used herein refers to compounds of formula (I) where one or more atoms of the compounds of formula (I) are replaced by their respective isotopes. For example, isotopes of hydrogen are 2 H (deuterium) and 3 Contains H (tritium).

[0033] The term "stereoisomer" as used herein refers to an isomer of a compound of formula (I) that differs in the arrangement of their atoms in space. The compounds disclosed herein may exist as single stereoisomers, racemates, and / or mixtures of enantiomers and / or diastereomers. All such single stereoisomers, racemates, and mixtures thereof are intended to be within the scope of the present invention.

[0034] The term "pharmaceutically acceptable salts" as used herein refers to salts of active compounds, i.e., compounds of formula (I), which, depending on the particular substituents found on the compounds described herein, are prepared by reaction with a suitable acid or acid derivative.

[0035] The term "gastrointestinal disease or disorder" as used herein refers to a disease or disorder related to the gastrointestinal tract, including, but not limited to, delayed gastric emptying caused by irritable bowel syndrome (IBS), constipation-predominant IBS, diarrhea-predominant IBS, mixed IBS, undifferentiated IBS, chronic constipation, functional dyspepsia, gastroparesis, gastroesophageal reflux disorder, post-operative ileus, pseudo-obstruction, drug-induced slow transit, Barrett's esophagus, intestinal pseudo-ileus, acute gastritis, chronic gastritis, gastric ulcer, duodenal ulcer, non-ulcer dyspepsia, Crohn's disease, celiac disease, and / or gastric neurosis.

[0036] Embodiment The present invention encompasses all compounds described by compounds of formula (I) without any limitation, however preferred aspects and elements of the present invention are discussed herein in the form of embodiments below.

[0037] In one embodiment, the present invention provides a compound of formula (I) or an isotope, stereoisomer, or pharma- ceutically acceptable salt thereof, wherein: A is,

[0038] [ka]

[0039] and R 3 is hydrogen, or:

[0040] [ka]

[0041] is selected from the group consisting of In the formula, B, D, Y, R a , R b and n is as defined in the first aspect.

[0042] In another embodiment, the present invention provides a compound of formula (I) or an isotope, stereoisomer, or pharma- ceutically acceptable salt thereof, A,

[0043] [ka]

[0044] and; R 3 is hydrogen, or:

[0045] [ka]

[0046] is selected from the group consisting of In the formula, B, D, Y, R a , R b and n is as defined in the first aspect.

[0047] In another embodiment, the present invention provides a compound of formula (I) or an isotope, stereoisomer, or pharma- ceutically acceptable salt thereof, wherein: A,

[0048] [ka]

[0049] and R 3 is hydrogen, or:

[0050] [ka]

[0051] selected from the group consisting of; In the formula, B, D, Y, R a , R b and n is as defined in the first aspect.

[0052] In another embodiment, the present invention provides a compound of formula (I) or an isotope, stereoisomer, or pharma- ceutically acceptable salt thereof, wherein: A,

[0053] [ka]

[0054] and R 2 is hydrogen or hydroxy; R 3 but:

[0055] [ka]

[0056] selected from the group consisting of; B is -SO2-alkyl, -COCH3, -COO-alkyl, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, or -CO-(CH2) m -OH; where m is an integer from 0 to 5; Y is independently selected at each occurrence from hydrogen or hydroxy; D represents CH or N; n is an integer from 0 to 5; R ais independently selected at each occurrence from hydrogen or alkyl; R b is independently selected at each occurrence from hydrogen, alkyl, cycloalkyl, or alkoxy; and R 4 But it concerns those that represent hydrogen.

[0057] In yet another embodiment, the present invention relates to a compound of formula (I) or an isotope, stereoisomer, or pharma- ceutically acceptable salt thereof, R3,

[0058] [ka]

[0059] wherein Y is hydrogen or hydroxy; R a is hydrogen or alkyl; R b is alkyl; and n is 0, 1, or 2.

[0060] In yet another embodiment, the present invention relates to a compound of formula (I) or an isotope, stereoisomer, or pharma- ceutically acceptable salt thereof, R 3 but,

[0061] [ka]

[0062] wherein Y is hydrogen or hydroxy; B is -SO2-alkyl, D is N; and n is 0, 1, or 2.

[0063] In yet another embodiment, the present invention relates to a compound of formula (I) or an isotope, stereoisomer, or pharma- ceutically acceptable salt thereof, R 3 but,

[0064] [ka]

[0065] wherein Y is hydrogen or hydroxy; R a is hydrogen or alkyl; R b is alkyl; and n is 0, 1, or 2.

[0066] In yet another embodiment, the present invention relates to a compound of formula (I) or an isotope, stereoisomer, or pharma- ceutically acceptable salt thereof, R 3 but,

[0067] [ka]

[0068] wherein Y is hydrogen or hydroxy; R a is hydrogen or alkyl; R b is alkyl; and n is 0, 1, or 2.

[0069] In yet another embodiment, the present invention provides a compound of formula (I), or an isotope, stereoisomer, or pharma- ceutically acceptable salt thereof, wherein R 1 is hydrogen or alkyl. In some embodiments, B is -SO2-alkyl or -COCH3.

[0070] In another embodiment, the present invention provides a method for producing a composition comprising: (R)-N-{8-[2-hydroxy-3-[(N-methyl)methanesulfonamido]propyl]-8-azabicyclo[3.2.1]oct-3-yl}[1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide; (R)-N-{8-[2-hydroxy-3-[(N-methyl)methanesulfonamido]propyl]-8-azabicyclo[3.2.1]oct-3-yl}[1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide L-(+)-tartarate; (S)-N-{8-[2-hydroxy-3-[(N-methyl)methanesulfonamido]propyl]-8-azabicyclo[3.2.1]oct-3-yl}[1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide; (S)-N-{8-[2-hydroxy-3-[(N-methyl)methanesulfonamido]propyl]-8-azabicyclo[3.2.1]oct-3-yl}[1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide L(+)-tartarate; Racemic-N-{8-[2-hydroxy-3-[(N-methyl)methanesulfonamido]propyl]-8-azabicyclo[3.2.1]oct-3-yl}[1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide; Racemic-N-{8-[2-hydroxy-3-[(N-methyl)methanesulfonamido]propyl]-8-azabicyclo[3.2.1]oct-3-yl}[1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide L(+)-tartarate; (R)-N-{8-[2-hydroxy-3-[(N-methyl)methanesulfonamido]propyl]-8-azabicyclo[3.2.1]oct-3-yl}[4-hydroxy-1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide; (R)-N-{8-[2-hydroxy-3-[(N-methyl)methanesulfonamido]propyl]-8-azabicyclo[3.2.1]oct-3-yl}[4-hydroxy-1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide L-(+)-tartarate; (S)-N-{8-[2-hydroxy-3-[(N-methyl)methanesulfonamido]propyl]-8-azabicyclo[3.2.1]oct-3-yl}[4-hydroxy-1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide; (S)-N-{8-[2-hydroxy-3-[(N-methyl)methanesulfonamido]propyl]-8-azabicyclo[3.2.1]oct-3-yl}[4-hydroxy-1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide L-(+)-tartarate; Racemic-N-{8-[2-hydroxy-3-[(N-methyl)methanesulfonamido]propyl]-8-azabicyclo[3.2.1]oct-3-yl}[4-hydroxy-1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide; Racemic-N-{8-[2-hydroxy-3-[(N-methyl)methanesulfonamido]propyl]-8-azabicyclo[3.2.1]oct-3-yl}[4-hydroxy-1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide L-(+)-tartarate; (R)-N-{8-[2-hydroxy-3-(methanesulfonamido)propyl]-8-azabicyclo[3.2.1]oct-3-yl}[1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide; (R)-N-{8-[2-hydroxy-3-(methanesulfonamido)propyl]-8-azabicyclo[3.2.1]oct-3-yl}[1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide L-(+)-tartarate; (R)-N-{8-[2-hydroxy-3-[(N-methyl)acetamido]propyl]-8-azabicyclo[3.2.1]oct-3-yl}[1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide; (R)-N-{8-[2-hydroxy-3-[(N-methyl)acetamido]propyl]-8-azabicyclo[3.2.1]oct-3-yl}[1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide L-(+)-tartarate; (R)-N-{8-[2-hydroxy-3-[(1-methanesulfonylpiperazin)-4-yl]propyl]-8-azabicyclo[3.2.1]oct-3-yl}[1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide; (R)-N-{8-[2-hydroxy-3-[(1-methanesulfonylpiperazin)-4-yl]propyl]-8-azabicyclo[3.2.1]oct-3-yl}[1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide L(+)tartarate; (R)-N-{8-[2-hydroxy-3-[(1-methanesulfonylpiperazin)-4-yl]propyl]-8-azabicyclo[3.2.1]oct-3-yl}[4-hydroxy-1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide; (R)-N-{8-[2-hydroxy-3-[(1-methanesulfonylpiperazin)-4-yl]propyl]-8-azabicyclo[3.2.1]oct-3-yl}[4-hydroxy-1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide L-(+)-tartarate; N-{8-[3-[(N-methyl)methanesulfonamido]propyl]-8-azabicyclo[3.2.1]oct-3-yl}[1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide; N-{8-[3-[(N-methyl)methanesulfonamido]propyl]-8-azabicyclo[3.2.1]oct-3-yl}[1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide L-(+)-tartarate; N-{8-[3-[methanesulfonamido]propyl]-8-azabicyclo[3.2.1]oct-3-yl}[1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide; N-{8-[3-[methanesulfonamido]propyl]-8-azabicyclo[3.2.1]oct-3-yl}[1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide L-(+)-tartarate; N-{8-[3-isopropylsulfonylaminopropyl]-8-azabicyclo[3.2.1]oct-3-yl}[1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide; N-{8-[3-isopropylsulfonylaminopropyl]-8-azabicyclo[3.2.1]oct-3-yl}[1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide L-(+)-tartarate; N-{8-[2-methanesulfonylaminoethyl]-8-azabicyclo[3.2.1]oct-3-yl}[1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide; N-{8-[2-methanesulfonylaminoethyl]-8-azabicyclo[3.2.1]oct-3-yl}[1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide L-(+)-tartarate; N-{8-[2-isopropylsulfonylaminoethyl]-8-azabicyclo[3.2.1]oct-3-yl}[1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide; N-{8-[2-isopropylsulfonylaminoethyl]-8-azabicyclo[3.2.1]oct-3-yl}[1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide L-(+)-tartarate; N-{8-[3-acetamidopropyl]-8-azabicyclo[3.2.1]oct-3-yl}[1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide; N-{8-[3-acetamidopropyl]-8-azabicyclo[3.2.1]oct-3-yl}[1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide L-(+)-tartarate; N-{8-[3-carbomethoxyaminopropyl]-8-azabicyclo[3.2.1]oct-3-yl}[1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide; N-{8-[3-carbomethoxyaminopropyl]-8-azabicyclo[3.2.1]oct-3-yl}[1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide L-(+)-tartarate; N-{8-[2-carbomethoxyaminoethyl]-8-azabicyclo[3.2.1]oct-3-yl}[1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide; N-{8-[2-carbomethoxyaminoethyl]-8-azabicyclo[3.2.1]oct-3-yl}[1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide L-(+)-tartarate; N-{8-[2-(4-acetylpiperazin-1-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}[1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide; N-{8-[2-(4-acetylpiperazin-1-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}[1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide L-(+)-tartarate; N-{8-[2-(4-acetylpiperazin-1-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}[4-hydroxy-1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide; and N-{8-[2-(4-acetylpiperazin-1-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}[4-hydroxy-1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide L-(+)-tartarate The present invention relates to a compound of formula (I), its isotopes, stereoisomers, or pharma- ceutically acceptable salts, selected from the group consisting of:

[0071] In another embodiment, the present invention relates to a process for preparing a compound of formula (I) as described below.

[0072] Testing Procedure: Scheme-1 shows a schematic process for preparing compounds of formula (I): T is hydrogen or alkyl; PG is a protecting group; R 1 , R 2 , R 3 , R 4 , A, and 'b' are as defined above.

[0073] Scheme-1

[0074] [ka]

[0075] Step 1: Preparation of Compounds of Formula 2 Method-A: The compound of formula 2 is prepared by reacting a compound of formula 1 (wherein T is hydrogen) with a compound of formula

[0076] [ka]

[0077] with a selected amine of formula (I) in the presence of a coupling reagent selected from DIPEA, TBTU, HATU, DCC, HOBt, or EDC.HCl and a solvent selected from DMF, THF, DCM, 1,4-dioxane, or two or more of the aforementioned solvents at room temperature for 1 to 10 hours; or Method-B: Compounds of formula 2 can be prepared by adding an organic base such as K2CO3, Cs2CO3, or Na2CO3 to a stirred solution of a compound of formula 1, where T is alkyl, and

[0078] [ka]

[0079] to a solvent selected from toluene, DMF, DMSO, CH3CN, DCM, and 1,4-dioxane at room temperature and heated at reflux for 10 to 24 hours, preferably 20 hours.

[0080] Step 2: Preparation of Compounds of Formula 3 The compound of formula 3 can be obtained by reacting the compound of formula 2 with either trifluoroacetic acid, ethanolic HCl, methanolic HCl, or IPA HCl in the presence of a solvent selected from DCM, 1,2-dichloroethane, chlorobenzene, THF, and the like at a temperature between 0 and 10° C., followed by stirring at room temperature for 18 to 24 hours.

[0081] Step 3: Preparation of Compounds of Formula (I) Method-A: Compounds of formula (I) can be prepared by reacting an organic base such as K2CO3, Cs2CO3, or Na2CO3 with a compound of formula 1 (wherein T is alkyl) and a compound of formula

[0082] [ka]

[0083] to a stirred solution of the amine in a solvent selected from toluene, DMF, DMSO, CH3CN, DCM, and 1,4-dioxane at room temperature and heated at reflux for 20 hours; or Method-B: The compound of formula (I) is prepared by reacting a compound of formula 1 (wherein T is hydrogen) with a compound of formula

[0084] [ka]

[0085] with an amine of formula (I) in the presence of a coupling reagent selected from DIPEA, HATU, DCC, or EDC.HCl and a solvent selected from DMF, THF, DCM, 1,4-dioxane, or a mixture of two or more of the above mentioned solvents at room temperature for 15 to 25 hours.

[0086] Step 4: Preparation of Compounds of Formula (I) Method-A: The compound of formula (I) is prepared by reacting a compound of formula 3 with a compound of formula

[0087] [ka]

[0088] (wherein R5 is -NR a COR b , -NR a COOR b , -NR a SO2R b , -SO2NR a R b or

[0089] [ka]

[0090] in the presence of a coupling reagent selected from an organic base such as triethylamine, DIPEA, or an inorganic base such as K2CO3 or Cs2CO3, and a solvent selected from a protic solvent such as methanol or ethanol, or an aprotic solvent such as DMF, DMSO, CH3CN, DCM, and 1,4-dioxane, at room temperature for 20 to 30 hours; or Method-B: Compounds of formula (I) can be prepared by reacting an inorganic base such as K2CO3, Cs2CO3, or Na2CO3 with a compound of formula 3 and a compound of formula (Br-R 3 ) in a solvent selected from protic solvents such as methanol or ethanol or aprotic solvents such as DMF, DMSO, CH3CN, DCM, and 1,4-dioxane at room temperature and heated at reflux for 8 hours.

[0091] Scheme 2 Scheme-2 shows a schematic process for preparing compounds of formula (I), wherein: X is halogen; R is alkyl; R 1 , R 2 , R 3 , R 4 , A, and 'b' are as defined above.

[0092] [ka]

[0093] Preparation of Compounds of Formula 3 Compounds of formula 3 can be obtained through the procedure described in Scheme-1.

[0094] Step-5: Preparation of compounds of formula 4 The compound of formula 4 can be prepared by reacting the compound of formula 3 with the compound of formula X-(CH2) n-X, where each occurrence of X represents either the same or different halogen atom, and n is an integer from 1 to 5, by alkylation using an inorganic base such as K2CO3, Cs2CO3, or Na2CO3 in the presence of a solvent selected from CH3CN, DCM, DMF, or DMSO at reflux temperature for 20 to 25 hours.

[0095] Step-6: Preparation of Compound of Formula (I) The compound of formula (I) can be prepared by reacting a compound of formula 4 with HNR a COR b , HNR a COOR b , HNR a SO2R b or

[0096] [ka]

[0097] and 20 to 25 hours in the presence of a solvent selected from CHCN, DCM, DMF, or DMSO, using an inorganic base such as K2CO3, Cs2CO3, or Na2CO3 at reflux temperature.

[0098] Preparation of Pharmacologically Acceptable Salts of Compounds of Formula (I) The compound of formula (I) can be converted into its pharma- ceutically acceptable salt by reaction with a suitable acid or acid derivative, if necessary. Suitable pharma-ceutically acceptable salts will be clear to those skilled in the art. Salts are formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, or organic acids, such as oxalic acid, succinic acid, maleic acid, acetic acid, fumaric acid, citric acid, malic acid, tartaric acid, benzoic acid, toluic acid, toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, camphorsulfonic acid, or naphthalenesulfonic acid.

[0099] Preparation of stereoisomers of compounds of formula (I) Stereoisomers of compounds of formula (I) may be prepared by one or more of the conventional procedures set out below:

[0100] a. One or more of the reagents may be used in their optically active form.

[0101] b. The mixture of stereoisomers may be resolved by conventional methods, such as forming diastereomeric salts with chiral acids, chiral amines, chiral amino alcohols, or chiral amino acids. The resulting mixture of diastereomers may then be separated by methods such as fractional crystallization, chromatography, and the like, followed by an additional step of isolating the optically active products from the resolved material / salt.

[0102] c. Mixtures of stereoisomers may be resolved by conventional methods such as microbial resolution, which resolves chiral salts or diastereomeric salts formed with chiral bases. Chiral acids that may be used may be tartaric acid, mandelic acid, lactic acid, camphorsulfonic acid, amino acids, and the like. Chiral bases that may be used may be cinchona alkaloids, brucine, or basic amino acids such as lysine, arginine, and the like.

[0103] In another embodiment, suitable pharma- ceutically acceptable salts include hydrochloride, hydrobromide, oxalate, fumarate, tartrate, maleate, benzoate, and succinate salts.

[0104] In another embodiment of the invention, the compounds of formula (I) or stereoisomers or pharma- ceutically acceptable salts thereof are 5-hydroxytryptamine 4 receptor agonists.

[0105] In another embodiment, the present invention relates to a method for treating a gastrointestinal disease or disorder related to the 5-hydroxytryptamine 4 receptor selected from delayed gastric emptying caused by irritable bowel syndrome, chronic constipation, functional dyspepsia, gastroparesis, gastroesophageal reflux disorder, postoperative ileus, intestinal pseudo-obstruction, drug-induced delayed transit, Barrett's esophagus, intestinal pseudo-ileus, acute gastritis, chronic gastritis, gastric ulcer, duodenal ulcer, non-ulcer dyspepsia, Crohn's disease, celiac disease, and gastric neuropathy, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a stereoisomer or pharma- ceutically acceptable salt thereof.

[0106] In yet another embodiment, the present invention relates to a compound of formula (I) or a stereoisomer or a pharma- ceutically acceptable salt thereof for use in the treatment of a gastrointestinal disease or disorder selected from irritable bowel syndrome, chronic constipation, functional dyspepsia, gastroparesis, gastroesophageal reflux disorder, post-operative ileus, intestinal pseudo-obstruction, drug-induced slow transit, Barrett's esophagus, intestinal pseudo-ileus, acute gastritis, chronic gastritis, gastric ulcer, duodenal ulcer, non-ulcer dyspepsia, Crohn's disease, celiac disease, and delayed gastric emptying caused by gastric neurosis.

[0107] In yet another embodiment, the present invention relates to the use of a compound of formula (I) or a stereoisomer or a pharma- ceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a gastrointestinal disease or disorder selected from delayed gastric emptying caused by irritable bowel syndrome, chronic constipation, functional dyspepsia, gastroparesis, gastroesophageal reflux disorder, post-operative ileus, intestinal pseudo-obstruction, drug-induced slow transit, Barrett's esophagus, intestinal pseudo-ileus, acute gastritis, chronic gastritis, gastric ulcer, duodenal ulcer, non-ulcer dyspepsia, Crohn's disease, celiac disease, and gastric neurosis.

[0108] In embodiments, the irritable bowel syndrome is selected from constipation-predominant irritable bowel syndrome, diarrhea-predominant irritable bowel syndrome, mixed-predominant irritable bowel syndrome, and unspecified bowel syndrome.

[0109] In another embodiment, the invention relates to pharmaceutical compositions of the compounds of formula (I). For therapeutic use of the compounds of formula (I) or their stereoisomers or pharma- ceutically acceptable salts, they are normally formulated into pharmaceutical compositions in accordance with standard pharmaceutical practice.

[0110] The pharmaceutical compositions of the present invention may be formulated in a conventional manner using one or more pharma- ceutically acceptable excipients, such as diluents, disintegrants, binders, lubricants, glidants, polymers, coating agents, solvents, cosolvents, preservatives, wetting agents, thickeners, antifoaming agents, sweeteners, flavoring agents, antioxidants, colorants, solubilizers, plasticizers, dispersants, and the like.

[0111] In another embodiment, the pharmaceutical compositions containing the compounds of the present invention may be formulated in the form of pills, tablets, coated tablets, capsules, powders, granules, pellets, patches, implants, films, liquids, semisolids, gels, aerosols, emulsions, elixirs, and the like. Such pharmaceutical compositions and methods for preparing them are well known in the art.

[0112] In another embodiment, the pharmaceutical composition of the invention contains 1 to 90%, 5 to 75%, or 10 to 60% by weight of the compound of the invention or a pharma- ceutically acceptable salt thereof. The amount of active compound or a pharma- ceutically acceptable salt thereof in the pharmaceutical composition can range from about 1 mg to about 500 mg, about 5 mg to about 400 mg, about 5 mg to about 250 mg, about 7 mg to about 150 mg, or any range encompassed within the broader ranges of 1 mg to 500 mg.

[0113] The dose of the active compound can vary depending on factors such as the age and weight of the patient, the nature and severity of the disease to be treated, and other such factors. Therefore, any reference to a therapeutically effective amount of the compound of general formula (I), its stereoisomers and pharma- ceutically acceptable salts refers to the aforementioned factors.

[0114] The following abbreviations are used herein: 5-HT: 5-hydroxytryptamine 5-HT4: 5-hydroxytryptamine 4 ANOVA: analysis of variance APAP: N-acetyl-para-aminophenol AUC: Area under the curve CH3CN:Acetonitrile Cs2CO3: Cesium carbonate C max :Maximum concentration cAMP: cyclic adenosine monophosphate DCM: dichloromethane DCC: N,N'-dicyclohexylcarbodiimide DIPEA: N,N-diisopropylethylamine DMEM: Dulbecco's modified Eagle's medium DMF: N,N-dimethylformamide DMSO: Dimethyl sulfoxide EC 50 : 50% effective concentration EDC.HCl: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide.HCl EtOH: Ethanol EtOAc: ethyl acetate g: grams hERG: human ether-a-go-go related gene HATU: 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate HEPES: 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid HEK293: Human Embryonic Kidney 293 cells HOBt: 1-hydroxybenzotriazole H3PO4: Phosphoric acid HCOONH4: Ammonium formate h: time IPA HCL: Isopropanol hydrochloride kg: kilogram K2CO3: Potassium carbonate KOH: Potassium hydroxide LC-MS / MS: Liquid Chromatography-Mass Spectrometry / Mass Spectrometry LAH: Lithium aluminum hydride LiOH: Lithium hydroxide min:minutes mg: milligram mL: milliliter mmol: millimolar ng: nanogram nM: nanomolar Na2CO3: Sodium carbonate NaHCO3: Sodium bicarbonate NaOH: Sodium hydroxide Na2SO4: Sodium sulfate NaBH3CN: Sodium cyanoborohydride NaBH(OAc)3: Sodium triacetoxyborohydride Pd(OH)2: Palladium hydroxide po: oral ppm: parts per million RT: room temperature rpm: revolutions per minute THF: tetrahydrofuran TBTU: 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate t 1 / 2 :Half-life μg: microgram μL: microliter μM: micromolar

[0115] Intermediate 1: 1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine-3-carboxylic acid Step 1: Acetone (69.7 mL, 1.2 mol) was added dropwise to a stirred mixture of 1-amino-1H-pyrrole-2-carboxamide (100 g, 0.8 mol) and acetic acid (48 g, 0.8 mol) in methanol (700 mL) at RT and the resulting solution was stirred for 1 h, after which NaBH3CN (100.5 g, 1.59 mol) was added in portions at 25-30 °C and stirred for 3 h. The reaction was concentrated to give a residue which was diluted with cold water (1000 mL), basified with aqueous NH3 (pH approx. 9), and extracted with EtOAc (1000 mL x 4). The combined organic layers were washed with brine solution (500 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the crude material, which was triturated with EtOAc:n-hexane (10:90) to give 1-isopropylamino-1H-pyrrole-2-carboxamide. Yield: quantitative; 1 H - NMR (DMSO-d6, 400 MHz) δ ppm: 0.91 - 0.92 (d, J = 6.1 Hz, 6H), 4.07 - 4.11 (m, 1H), 5.95 - 5.96 (t, J = 3.3 Hz, 1H), 6.68 - 6.69 (dd, J = 1.7, 4.0 Hz, 1H), 6.95 - 6.97 (m, 2H), 7.09 (bs, 1H), 7.94 (bs, 1H); Mass (m / z): 168.2 (M+H) + .

[0116] Step 2: KOH flakes (715 g, 12.76 mol) were added in portions to a stirred mixture of 1-isopropylamino-1H-pyrrole-2-carboxamide (Step 1, 133 g, 0.79 mol) in methanol:water (200 mL:800 mL) and then refluxed for 20 h. The reaction mixture was cooled to RT, acidified with concentrated HCl (pH approx. 2) and extracted with EtOAc (1000 mL×4). The combined organic layers were washed with brine solution (500 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give 1-isopropylamino-1H-pyrrole-2-carboxylic acid. Yield: 120.9 g; 1H - NMR (DMSO-d6, 400 MHz) δ ppm: 0.92 - 0.94 (d, J = 6.3 Hz, 6H), 3.18 - 3.28 (m, 1H), 6.02 - 6.03 (t, J = 3.6 Hz, 1H), 6.74 - 6.79 (m, 2H), 7.09 - 7.10 (d, J = 2.0 Hz, 1H), 12.74 (bs, 1H); Mass (m / z): 169.1 (M+H) + .

[0117] Step 3: DIPEA (236 mL, 1.35 mol), HOBt (100.8 g, 0.74 mol), and EDC.HCl (168.4 g, 0.88 mol) were added to a stirred solution of 1-isopropylamino-1H-pyrrole-2-carboxylic acid (114 g, 0.678 mol) in DMF (300 mL) at RT and stirred for an additional 2 h, after which N,O-dimethylhydroxylamine hydrochloride (79.4 g, 0.81 mol) was added. The reaction mixture was stirred for an additional 24 h at RT, poured into water (2000 mL) and extracted with EtOAc (1000 mL×4). The combined organic layers were washed with brine solution (500 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the crude material, which was purified by column chromatography using EtOAc:n-hexane (10:90) to give N-methoxy-N-methyl-1-isopropylamino-1H-pyrrole-2-carboxamide. Yield: 56.2 g; 1 H - NMR (CDCl3, 400 MHz) δ ppm: 0.99 - 1.00 (d, J = 6.3 Hz, 6H), 3.06 - 3.09 (m, 1H), 3.33 (s, 3H), 3.70 (s, 3H), 5.99 - 6.00 (t, J = 3.4 Hz, 1H), 6.91 - 6.92 (d, J = 3.3 Hz, 2H), 6.95 - 6.96 (d, J = 1.0 Hz, 1H); Mass (m / z): 212.1 (M+H) + .

[0118] Step 4: LAH (545 mL, 0.54 mol, 1M in THF) was added dropwise to a stirred solution of N-methoxy-N-methyl-1-isopropylamino-1H-pyrrole-2-carboxamide (76.7 g, 0.36 mol) in THF (800 mL) at -20 to -15 °C and maintained at this temperature for 1 h. Water was carefully added dropwise to the reaction mixture at -10 to 5 °C, after which EtOAc (2000 mL) was added and the mixture was filtered through hyflow. The organic layer was separated, washed with brine solution (250 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give 1-isopropylamino-1H-pyrrole-2-carboxaldehyde. Yield: 50.9 g; 1 H - NMR (CDCl3, 400 MHz) δ ppm: 1.03 - 1.04 (d, J = 6.2 Hz, 6H), 3.18 - 3.24 (m, 1H), 6.09 - 6.14 (m, 2H), 6.86 - 6.87 (dd, J = 1.6, 4.3 Hz, 1H), 7.01 (s, 1H), 9.52 (s, 1H); Mass (m / z): 153.1 (M+H) + .

[0119] Step 5: A stirred solution of 1-isopropylamino-1H-pyrrole-2-carboxaldehyde (54.3 g, 0.35 mol), piperidine (70.5 mL, 0.71 mol), and diethyl malonate (109 mL, 0.71 mol) in o-xylene (200 mL) was heated at 120° C. for 22 h. The reaction mixture was cooled to RT, diluted with water (1000 mL), and extracted with EtOAc (1000 mL×3). The combined organic layers were washed with brine solution (500 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the crude product, which was purified by column chromatography using methanol:DCM (1:99) to give ethyl 1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine-3-carboxylate. Yield: 79 g; 1H - NMR (DMSO-d6, 400 MHz) δ ppm: 1.25 - 1.28 (t, J = 7.1 Hz, 3H), 1.49 - 1.51 (d, J = 7.7 Hz, 6H), 4.18 - 4.23 (q, 2H), 5.31 (m, 1H), 6.59 - 6.60 (dd, J = 2.9, 4.1 Hz, 1H), 6.78 - 6.79 (d, J = 4.0 Hz, 1H), 7.98 (s, 1H), 8.26 (s, 1H); Mass (m / z): 249.2 (M+H) + .

[0120] Step 6: LiOH·H2O (23.2 g, 0.553 mol) in 125 mL of water was added in portions to a stirred solution of ethyl 1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine-3-carboxylate (68.7 g, 0.27 mol) in THF (500 mL) at 0 °C. The resulting material was stirred for 2 h at RT. The reaction mixture was concentrated in vacuo to remove excess THF, and 500 mL of cold water was added to the material and acidified with dilute HCl (pH approx. 2) during which time the solids precipitated. These solids were filtered and dissolved in DCM (500 mL). The organic layer was washed with brine solution (250 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound. Yield: 56.3 g; 1 H - NMR (DMSO-d6, 400 MHz) δ ppm: 1.59 - 1.60 (d, J = 6.4 Hz, 6H), 5.44 (s, 1H), 6.77 - 6.78 (dd, J = 2.9, 4.3 Hz, 1H), 7.00 - 7.02 (d, J = 4.2 Hz, 1H), 8.20 (s, 1H), 8.60 (s, 1H), 14.08 (s, 1H); Mass (m / z): 221.1 (M+H) + .

[0121] Intermediate 2: Ethyl 4-hydroxy-1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine-3-carboxylate Step 1: Triphosgene (200 g, 0.67 mol) was added in portions to a stirred solution of 1-isopropylamino-1H-pyrrole-2-carboxylic acid (Intermediate 1 Step 2, 113.7 g, 0.67 mol) in a mixture of DMF (10.4 mL, 0.13 mol) and DCM (1000 mL) at 0-5 °C under nitrogen atmosphere and the reaction mixture was stirred at 25 °C for 48 h. The reaction mixture was diluted with DCM (1500 mL), washed with aqueous NaHCO3 (1000 mL), water (500 mL), brine solution (500 mL), dried over Na2SO4, and concentrated in vacuo to give 4-isopropyl-6-oxa-3a,4-diazaindene-5,7-dione. Yield: 91 g; 1 H - NMR (CDCl3, 400 MHz) δ ppm: 1.03 - 1.05 (d, J = 6.7 Hz, 3H), 1.29 - 1.31 (d, J = 6.6 Hz, 3H), 4.66 - 4.73 (m, 1H), 6.32 - 6.36 (m, 1H), 6.99 - 7.00 (m, 1H), 7.33 -7.35 (m, 1H); Mass (m / z): 195.2.

[0122] Step 2: A solution of diethyl malonate (375 g, 2.34 mol) in DMF (100 mL) was added to a stirred suspension of sodium hydride (37 g, 0.93 mol; 60% dispersion in mineral oil) in DMF (100 mL) under nitrogen atmosphere at 0-5° C., then stirred at RT for 1 h, after which a solution of 4-isopropyl-6-oxa-3a,4-diazaindene-5,7-dione (91 g, 0.46 mol) was added. The reaction mixture was heated to 120° C. and maintained for 15 h, cooled to 0-5° C., acidified with concentrated HCl (pH approx. 2), and extracted with EtOAc (1000 mL×3). The combined organic layers were washed with brine solution (500 mL), dried over Na2SO4 and concentrated in vacuo to give the crude compound, which was purified by column chromatography using DCM:n-hexane (50:50) to give the title compound. Yield: 42g; 1 H-NMR (CDCl 3,400 MHz) δ ppm: 1.41 - 1.48 (t, J = 7.1 Hz, 3H), 1.56 - 1.57 (d, J = 7.1 Hz, 6H), 4.26 - 4.48 (m, 2H), 5.56 - 5.59 (m, 1H), 6.49 - 6.51 (m, 1H), 6.91 - 6.92 (m, 1H), 7.36 (s, 1H), 14.08 (s, 1H); Mass (m / z): 265.2 (M+H) + .

[0123] Intermediate 3: tert-Butyl 3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate tert-Butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate [CAS: 185099-67-6] (60 g, 0.26 mol) was added to a stirred suspension of Pd / C (30 g) and HCOONH4 (336 g, 5.33 mol) in methanol:water (840 mL:120 mL) at RT and the resulting mass was stirred for 48 h. The reaction mixture was filtered through hyflow and the filtrate was concentrated in vacuo to give a residual solid mass which was diluted with cold water (1000 mL), acidified with 1M H3PO4 and washed with DCM (200 mL x 3). The aqueous layer was separated, basified with lye (pH approx. 12) and extracted with DCM (1000 mL x 3). The combined organic layers were washed with brine solution (250 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound. Yield: 47.2g; 1 H - NMR (CDCl3, 400 MHz) δ ppm: 1.31 (bs, 2H), 1.40 - 1.42 (m, 2H), 1.44 (s, 9H), 1.94 - 1.95 (m, 2H), 2.07 - 2.15 (m, 4H), 3.29 - 3.32 (t, J = 6.0 Hz, 1H), 4.12 - 4.20 (wide d, 2H); Mass (m / z): 227.2 (M+H) + .

[0124] Intermediate 4: (S)-N-Methyl-N-oxiranylmethylmethanesulfonamide A solution of N-methylmethanesulfonamide (20 g, 0.18 mol) in water (50 mL) was added dropwise to a stirred solution of NaOH (7.3 g, 0.18 mol) in water (200 mL) at 0-5 °C and stirred for 1 h, after which (S)-(+)-epichlorohydrin [CAS 67843-74-7] (33.9 g, 0.36 mol) was added at 0-5 °C. The reaction mixture was stirred for an additional 20 h at 0-5 °C, diluted with DCM (450 mL), stirred for 1 h at 0-5 °C, and washed with 1M H3PO4 (170 mL). The organic layer was separated, washed with brine solution (25 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the title compound. Yield: 10 g; Mass (m / z): 166.2 (M+H) + .

[0125] Intermediate 5: (R)-N-methyl-N-oxiranylmethylmethanesulfonamide A solution of N-methylmethanesulfonamide (3 g, 0.027 mol) in water (7.5 mL) was added dropwise to a stirred solution of NaOH (1.1 g, 0.027 mol) in water (15 mL) at 0-5 °C and stirred for 1 h, after which (R)-(-)-epichlorohydrin [CAS 51594-55-9] (5 g, 0.054 mol) was added at 0-5 °C. The reaction mixture was stirred for an additional 20 h at 0-5 °C, diluted with DCM (50 mL), stirred for 20 min at 0-5 °C, and washed with 1M H3PO4 (25 mL). The organic layer was separated, washed with brine solution (25 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the title compound. Yield: 2.5 g; Mass (m / z): 166.2 (M+H) + .

[0126] Intermediate 6: N-Methyl-N-oxiranylmethylmethanesulfonamide A solution of N-methylmethanesulfonamide (6 g, 0.055 mol) in water (15 mL) was added dropwise to a stirred solution of NaOH (2.2 g, 0.055 mol) in water (30 mL) at 0-5 °C and stirred for 1 h, after which racemic-epichlorohydrin (10.1 g, 0.11 mol) was added at 0-5 °C. The reaction mixture was stirred for an additional 20 h at 0-5 °C, diluted with DCM (100 mL), stirred for 30 min at 0-5 °C and washed with 1M H3PO4 (50 mL). The organic layer was separated, washed with brine solution (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound. Yield: 4.6 g; Mass (m / z): 166.2 (M+H) + .

[0127] Intermediate 7: (S)-N-oxiranylmethylmethanesulfonamide Using a procedure similar to that given in the preparation of intermediate 4, the methanesulfonamide, intermediate 7, was prepared. Yield: 0.6g; Mass (m / z): 152.2 (M+H). + .

[0128] Intermediate 8: (S)-N-Methyl-N-oxiranylmethylacetamide Using a procedure similar to that given in the preparation of intermediate 4, N-methylacetamide, intermediate 8, was prepared. Yield: 0.9g; Mass (m / z): 130.2 (M+H). + .

[0129] Intermediate 9: (S)-1-Methanesulfonyl-4-oxiranylmethylpiperazine Using a procedure similar to that given in the preparation of intermediate 4, 1-methanesulfonylpiperazine, intermediate 9, was prepared. Yield: 0.8g; Mass (m / z): 221.3 (M+H). + .

[0130] Intermediate 10: 1-{4-[2-(3-amino-8-azabicyclo[3.2.1]oct-8-yl)ethyl]piperazin-1-yl}ethanone Step 1: A mixture of benzaldehyde (2 g, 0.018 mol) and tert-butyl 3-amino-8-aza-bicyclo[3.2.1]octane-8-carboxylate (5.1 g, 0.022 mol) in DCM (100 mL) was stirred for 3 h, after which NaBH(OAc)3 (5.9 g, 0.028 mol) was added in three equal lots, each at 15 min intervals, and the reaction mixture was stirred for 18 h at RT. The reaction mixture was poured into water (100 mL), basified with aqueous NH3 (pH approx. 9), and extracted with DCM (100 mL x 3). The combined organic extracts were washed with brine solution (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the crude material, which was purified by column chromatography using EtOAc:n-hexane (5:95) to give tert-butyl 3-dibenzylamino-8-azabicyclo[3.2.1]octane-8-carboxylate. Yield: 6.1 g; 1 H - NMR (DMSO-d6, 400 MHz) δ ppm: 1.23 (s, 9H), 1.33 - 1.40 (m, 2H), 1.51 - 1.60 (m, 4H), 1.97 - 1.99 (m, 2H), 2.29 - 2.36 (m, 1H), 2.44 - 2.46 (m, 1H), 2.70 - 2.78 (m, 1H), 3.58 (s, 2H), 3.60 (s, 2H), 7.16 - 7.34 (m, 10H); Mass (m / z): 407.3 (M+H) + .

[0131] Step 2: EtOH·HCl (12 mL) was added dropwise to a stirred solution of tert-butyl 3-dibenzylamino-8-azabicyclo[3.2.1]octane-8-carboxylate (6 g, 0.014 mol) in DCM (300 mL) at 0-5 °C, and the resulting mixture was stirred overnight at RT. The reaction was concentrated to give a syrupy material, which was diluted with cold water (50 mL), basified with aqueous NH3 (pH approx. 9), and extracted with DCM (100 mL x 3). The combined organic extracts were washed with brine solution (25 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give (8-azabicyclo[3.2.1]oct-3-yl)dibenzylamine. Yield: 4.4 g; 1 H - NMR (DMSO-d6, 400 MHz) δ ppm: 1.13 - 1.19 (m, 2H), 1.48 - 1.59 (m, 4H), 2.03 - 2.11 (m, 2H), 2.49 (s, 1H), 2.50 - 2.51 (m, 2H), 2.86 - 2.91 (m, 1H), 3.49 (s, 4H), 7.16 - 7.32 (m, 10H); Mass (m / z): 307.3 (M+H) + .

[0132] Step 3: KCO (1.44 g, 0.01 mol) was added in portions to a stirred solution of (8-azabicyclo[3.2.1]oct-3-yl)dibenzylamine (1.6 g, 0.005 mol) and tert-butyl 4-(2-chloroacetyl)piperazine-1-carboxylate [CAS 190001-40-2] (1.23 g, 0.004 mol) in CHCN (40 mL) at RT, and the resulting mixture was refluxed for 5 h, then cooled to RT, poured into water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic extracts were washed with brine solution (25 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the crude material, which was purified by column chromatography using EtOAc:n-hexane (2:98) to give tert-butyl 4-[2-(3-dibenzylamino-8-azabicyclo[3.2.1]oct-8-yl)acetyl]piperazine-1-carboxylate. Yield: 2.19g; Mass (m / z): 533.5 (M+H). + .

[0133] Step 4: EtOH·HCl (20 mL) was added dropwise to a stirred solution of tert-butyl 4-[2-(3-dibenzylamino-8-azabicyclo[3.2.1]oct-8-yl)acetyl]piperazine-1-carboxylate (2.1 g, 0.003 mol) in DCM (300 mL) at 0-5 °C, and the resulting mixture was stirred overnight at RT. The reaction was concentrated to give a syrupy material, which was diluted with cold water (50 mL), basified with aqueous NH3 (pH approx. 9), and extracted with DCM (100 mL x 3). The combined organic extracts were washed with brine solution (25 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give 2-(3-dibenzylamino-8-azabicyclo[3.2.1]oct-8-yl)-1-piperazin-1-ylethanone. Yield: 1.55g; 1H - NMR (DMSO-d6, 400 MHz) δ ppm: 1.21 - 1.22 (m, 3H), 1.46 - 1.48 (m, 2H), 1.91 - 1.93 (m, 4H), 2.12 - 2.21 (m, 4H), 2.53 - 2.57 (m, Mass (m / z): 433.5 (M+H) + .

[0134] Step 5: LAH solution (5.2 mL, 0.005 mol, 1M in THF) was added dropwise to a stirred solution of 2-(3-dibenzylamino-8-azabicyclo[3.2.1]oct-8-yl)-1-piperazin-1-ylethanone (1.5 g, 0.003 mol) in THF (30 mL) at 0-5°C and the resulting mixture was stirred for another 1 h at the same temperature. Cold water (10 mL) was carefully added dropwise to the above reaction mixture, followed by the addition of EtOAc (50 mL) and the mixture was filtered through hyflow. The organic layer was separated, washed with brine solution (25 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give {8-[2-(piperazin-1-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}dibenzylamine. Yield: 1.20g; Mass (m / z): 419.5 (M+H) + .

[0135] Step 6: Acetyl chloride (0.2 mL, 0.0024 mol) was added dropwise to a stirred solution of {8-[2-(piperazin-1-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}dibenzylamine (1.2 g, 0.002 mol) and triethylamine (0.6 mL, 0.004 mol) in DCM (30 mL) at 0-5° C., and the resulting mixture was stirred for 1 h at RT. The reaction mixture was poured into water (50 mL) and extracted with DCM (50 mL×3). The combined organic extracts were washed with brine solution (25 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the crude material, which was purified by column chromatography using methanol:chloroform (10:90) to give 1-{4-[2-(3-dibenzylamino-8-azabicyclo[3.2.1]oct-8-yl)ethyl]piperazin-1-yl}ethanone. Yield: 0.75g; Mass (m / z): 461.4 (M+H) + .

[0136] Step 7: A mixture of 1-{4-[2-(3-dibenzylamino-8-azabicyclo[3.2.1]oct-8-yl)ethyl]piperazin-1-yl}ethanone (0.7 g, 1.52 mmol) and Pd(OH)2 on carbon (0.7 g) in methanol (10 mL) was stirred under a hydrogen gas balloon for 20 hours and the reaction mixture was filtered through hyflow. The filtrate was concentrated in vacuo to give the title compound. Yield: 467 mg; 1 H - NMR (CDCl3, 400 MHz) δ ppm: 1.40 - 1.42 (m, 2H), 1.57 - 1.61 (m, 2H), 2.01 - 2.12 (m, 5H), 2.38 - 2.47 (m, 2H), 2.57 - 2.59 (m, 4H), 2.78 - 2.80 (m, 2H), 2.95 - 2.97 (m, 4H), 3.46 - 3.60 (m, 5H), 3.81 - 3.97 (m, 2H); Mass (m / z): 281.3 (M+H) + .

[0137] Intermediate 11: N-(3-bromo-propyl)-methanesulfonamide Mesyl chloride (0.39 mL, 0.0045 mol) was added dropwise to a stirred solution of 3-bromo-propylamine hydrobromide (1 g, 0.0045 mol) and triethylamine (1.86 mL, 0.013 mol) in DCM (30 mL) at 0-10 °C, and the resulting mixture was stirred for 3 h at RT. The reaction mixture was poured into water (50 mL) and extracted with DCM (50 mL x 3). The combined organic extracts were washed with brine solution (25 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the title compound. Yield: 0.93 g; Mass (m / z): 217.1, 219.2 (M+H) + .

[0138] Intermediate 12: N-(3-bromopropyl)isopropylsulfonamide Using a procedure similar to that given in the preparation of intermediate 11, isopropylsulfonyl chloride, intermediate 12, was prepared. Yield: 0.7g; Mass (m / z): 245.2, 247.1 (M+H). + .

[0139] Intermediate 13: N-(2-bromo-ethyl)-methanesulfonamide Using a procedure similar to that given in the preparation of intermediate 11, mesyl chloride and 2-bromo-ethylamine, intermediate 13 was prepared. Yield: 0.7g; Mass (m / z): 203.1, 205.1 (M+H). + .

[0140] Intermediate 14: N-(2-bromomethyl)isopropylsulfonamide Using a procedure similar to that given in the preparation of intermediate 11, isopropylsulfonyl chloride and 2-bromo-ethylamine, intermediate 14 was prepared. Yield: 0.5g; Mass (m / z): 231.1, 232.2 (M+H). + .

[0141] Intermediate 15: N-(3-Bromo-propyl)-acetamide Using a procedure similar to that given in the preparation of intermediate 11, acetyl chloride, intermediate 15 was prepared. Yield: 0.7g; Mass (m / z): 181, 183.1 (M+H). + .

[0142] Intermediate 16: Methyl N-(3-bromopropyl)carbamate Using a procedure similar to that given in the preparation of intermediate 11, methyl chloroform, intermediate 16 was prepared. Yield: 0.3g; Mass (m / z): 197.1, 199.1 (M+H) + .

[0143] Intermediate 17: (2-Bromo-ethyl)-carbamic acid methyl ester Using a procedure similar to that given in the preparation of intermediate 11, 2-bromo-ethylamine and methyl chloroformate, intermediate 17 was prepared. Yield: 0.3g; Mass (m / z): 183.1, 185.1 (M+H). + .

[0144] Intermediate 18: [N-(8-azabicyclo[3.2.1]oct-3-yl)]-1-isopropyl-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxamide Step 1: DIPEA (47.4 mL, 0.272 mol), TBTU (35 g, 0.109 mol), and tert-butyl-3-amino-8-aza-bicyclo[3.2.1]octane-8-carboxylate (Intermediate 3, 20.36 g, 0.09 mol) were added to a stirred solution of 1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine-3-carboxylic acid (Intermediate 1, 20 g, 0.09 mol) in DMF (100 mL) at RT and maintained for 3 h. The reaction mixture was poured into cold water (1000 mL) with stirring, during which time the solid was allowed to precipitate. These solids were filtered, dissolved in DCM (500 mL), washed with brine solution (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give tert-butyl-3-[(1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine-3-carbonyl)amino]-8-azabicyclo[3.2.1]octane-8-carboxylate. Yield: 35.1 g; 1 H - NMR (DMSO-d6, 400 MHz) δ ppm: 1.41 (s, 9H), 1.55 - 1.57 (d, J = 6.8 Hz, 6H), 1.64 - 1.67 (m, 2H), 2.00 - 2.05 (m, 6H), 4.09 (bs, 2H), 4.17 - 4.19 (m, 1H), 5.51 (s, 1H), 6.64 - 6.66 (dd, J = 2.9, 6.4 Hz, 1H), 6.85 - 6.86 (d, J = 4.0 Hz, 1H), 8.01 (s, 1H), 8.49 (s, 1H), 10.11 - 10.13 (d, J = 7.6 Hz, 1H); Mass (m / z): 429.3 (M+H) + .

[0145] Step 2: Trifluoroacetic acid (161 mL, 2.1 mol) was added dropwise to a stirred solution of tert-butyl 3-[(1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine-3-carbonyl)amino]-8-azabicyclo[3.2.1]octane-8-carboxylate (30 g, 0.07 mol) in DCM (300 mL) at 0° C., then stirred overnight at RT. The reaction mixture was poured into cold water (700 mL), basified with aqueous ammonia (pH approx. 9), and extracted with DCM (500 mL×4). The combined organic layers were washed with brine solution (250 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the title compound. Yield: 22.7 g; 1 H - NMR (CDCl3, 400 MHz) δ ppm: 1.63 - 1.64 (d, J = 7.1 Hz, 6H), 1.82 - 1.85 (d, J = 14.6 Hz, 2H), 1.95 - 1.98 (m, 2H), 2.13 - 2.20 (m, 4H), 2.79 (s, 1H), 3.60 (s, 2H), 4.30 - 4.35 (m, 1H), 5.71 (bs, 1H), 6.57 - 6.58 (dd, J = 2.9, 4.2 Hz, 1H), 6.67 - 6.68 (d, J = 4.0 Hz, 1H), 7.44 (s, 1H), 8.55 (s, 1H), 10.11 - 10.12 (d, J = 7.2 Hz, 1H); Mass (m / z): 329.2 (M+H) + .

[0146] Intermediate 19: N-(8-azabicyclo[3.2.1]oct-3-yl){4-hydroxy-1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine}-3-carboxamide Step 1: K2CO3 (0.026 g, 0.18 mmol) was added in portions to a stirred solution of ethyl 4-hydroxy-1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine-3-carboxylate (Intermediate 2, 0.5 g, 1.89 mmol) and tert-butyl 3-amino-8-aza-bicyclo[3.2.1]octane-8-carboxylate (Intermediate 3, 0.51 g, 2.27 mmol) in toluene (10 mL) at RT and then refluxed for 18 h. The reaction mixture was cooled to RT, poured into water (25 mL) and extracted with EtOAc (50 mL x 3). The combined organic extracts were washed with brine solution (25 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the crude material, which was purified by column chromatography using EtOAc:n-hexane (25:75) to give tert-butyl-3-[(4-hydroxy-1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine-3-carbonyl)amino]-8-azabicyclo[3.2.1]octane-8-carboxylate. Yield: 0.98g; Mass (m / z): 445.3 (M+H). + .

[0147] Step 2: EtOH·HCl (1.2 mL, 5 vol) was added dropwise to a stirred solution of tert-butyl-3-[(4-hydroxy-1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine-3-carbonyl)amino]-8-azabicyclo[3.2.1]octane-8-carboxylate (0.23 g, 0.52 mmol) in DCM (20 mL) at 0° C. and stirred at RT for 18 h, then concentrated in vacuo to give a syrupy material. This material was diluted with water (10 mL), basified with aqueous NH3 (pH approx. 9), and extracted with DCM (25 mL×3). The combined organic layers were washed with brine solution (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the title compound. Yield: 0.72g; Mass (m / z): 345.2 (M+H) + . EXAMPLES

[0148] Example 1 (R)-N-{8-[2-hydroxy-3-[(N-methyl)methanesulfonamido]propyl]-8-azabicyclo[3.2.1]oct-3-yl}[1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide

[0149] [ka]

[0150] (S)-N-Methyl-N-oxiranylmethylmethanesulfonamide (Intermediate 4, 5 g, 0.03 mol) followed by DIPEA (2.65 mL, 0.015 mol) were added to a stirred solution of [N-(8-azabicyclo[3.2.1]oct-3-yl)]-1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine-3-carboxamide (Intermediate 18, 5 g, 0.015 mol) in methanol (75 mL) at RT and the reaction mixture was heated at reflux for 24 h. The reaction mixture was cooled to RT, diluted with EtOAc (500 mL), washed with water (100 mL), brine solution (25 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the crude material, which was purified by column chromatography using methanol:DCM (1:99) to give the title compound. Yield: 3.75 g; 1 H - NMR (DMSO-d6, 400 MHz) δ ppm: 1.56 - 1.58 (d, J = 6.8 Hz, 6H), 1.94 - 2.32 (m, 8H), 2.84 (s, 3H), 2.89 (s, 3H), 3.04 - 3.32 (m, 4H), 3.70 (bs, 1H), 4.10 (bs, 2H), 4.70 (bs, 1H), 5.53 (bs, 1H), 5.75 (bs, 1H), 6.65 (s, 1H), 6.85 (s, 1H), 8.01 (s, 1H), 8.48 (s, 1H), 10.02 (bs, 1H); Mass (m / z): 494.4 (M+H) + .

[0151] Example 2 (R)-N-{8-[2-hydroxy-3-[(N-methyl)methanesulfonamido]propyl]-8-azabicyclo[3.2.1]oct-3-yl}[1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide L-(+)-tartarate

[0152] [ka]

[0153] L-(+)-Tartaric acid (1.11 g, 0.007 mol) was added to a stirred solution of (R)-N-{8-[2-hydroxy-3-[(N-methyl)methanesulfonamido]propyl]-8-azabicyclo[3.2.1]oct-3-yl}[1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide (Example 1, 3.7 g, 0.007 mol) in DCM:methanol (30:10) under nitrogen, stirred at RT for a further 2 h, and concentrated in vacuo to give the title compound. Yield: 4.73 g; 1 H - NMR (CD3OD, 400 MHz) δ ppm: 1.66 - 1.68 (d, J = 6.9 Hz, 6H), 2.15 - 2.19 (m, 2H), 2.48 - 2.49 (m, 4H), 2.59 - 2.60 (m, 2H), 2.91 (s, 3H), 2.99 (s, 3H), 3.10 - 3.20 (m, 1H), 3.24 - 3.25 (m, 2H), 4.12 (bs, 1H), 4.26 - 4.30 (m, 3H), 4.47 (s, 2H), 5.56 (bs, 1H), 6.69 - 6.71 (dd, J = 2.9, 4.1 Hz, Mass (m / z): 494.4 (M+H) + .

[0154] The following Examples 3 to 20 were prepared by using the procedures as described for Examples 1 and 2, with some minor variations using the appropriate intermediates.

[0155] [Table 1A]

[0156] [Table 1B]

[0157] [Table 1C]

[0158] [Table 1D]

[0159] [Table 1E]

[0160] [Table 1F]

[0161] [Table 1G]

[0162] [Table 1H]

[0163] [Table 1I]

[0164] Example 21 N-{8-[3-[(N-methyl)methanesulfonamido]propyl]-8-azabicyclo[3.2.1]oct-3-yl}[1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide

[0165] [ka]

[0166] Step 1: K2CO3 (0.019 g, 0.13 mmol) was added in portions to a stirred solution of [N-(8-azabicyclo[3.2.1]oct-3-yl)]-1-isopropyl-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxamide (Intermediate 18, 30 mg, 0.091 mmol) and 1-bromo-3-chloropropane (0.013 mL, 0.13 mmol) in CH3CN (10 mL) at RT, then refluxed for 22 h. The reaction mixture was cooled to RT, filtered and concentrated in vacuo to give N-[8-(3-chloropropyl)-8-azabicyclo[3.2.1]oct-3-yl][1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide. Yield: 0.02g; Mass (m / z): 406.3 (M+H). + .

[0167] Step 2: K2CO3 (0.019 g, 0.13 mmol) was added in portions to a stirred solution of N-methylmethanesulfonamide (10 mg, 0.091 mmol) and N-[8-(3-chloropropyl)-8-azabicyclo[3.2.1]oct-3-yl][1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide (0.044 mg, 0.11 mmol) in CH3CN (10 mL) at RT, then refluxed for 22 h. The reaction mixture was cooled to RT, filtered, and concentrated in vacuo to give the crude material, which was purified by preparative thin layer chromatography using methanol:chloroform (25:75) to give the title compound. Yield: 15 mg; 1 H - NMR (CD3OD, 400 MHz) δ ppm: 1.66 - 1.68 (d, J = 6.9 Hz, 6H), 2.04 - 2.07 (m, 2H), 2.17 - 2.21 (m, 2H), 2.43 - 2.48 (m, 6H), 2.91 (s, 6H), 3.15 - 3.17 (m, 2H), 4.09 (s, 2H), 4.29 - 4.30 (m, 1H), 4.42 (s, 2H), 5.50 - 5.57 (m, 1H), 6.70 - 6.71 (d, J = 2.6 Hz, 1H), 6.85 - 6.86 (d, J = 4.2 Hz, 1H), 7.90 (s, 1H), 8.53 (s, 1H), 10.66 - 10.67 (d, J = 6.2 Hz, 1H); Mass (m / z): 478.4 (M+H) + .

[0168] Example 22 N-{8-[3-[(N-methyl)methanesulfonamido]propyl]-8-azabicyclo[3.2.1]oct-3-yl}[1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide L-(+)-tartarate

[0169] [ka]

[0170] The compound of Example 21 was converted to the L-(+)-tartrate salt, Example 22, using a procedure similar to that given in the preparation of Example 2. 1 H - NMR (CD3OD, 400 MHz) δ ppm: 1.66 - 1.68 (d, J = 6.9 Hz, 6H), 2.04 - 2.07 (m, 2H), 2.17 - 2.21 (m, 2H), 2.43 - 2.48 (m, 4H), 2.91 (s, 6H), 3.15 - 3.17 (m, 3H), 4.09 (s, 2H), 4.29 - 4.30 (m, 1H), 4.42 (s, 2H), 5.50 - 5.57 (m, 2H), 6.70 - 6.71 (d, J = 2.6 Hz, 1H), 6.85 - 6.86 (d, J = 4.2 Hz, 1H), 7.90 (s, 1H), 8.53 (s, 1H), 10.66 - 10.67 (d, J = 6.2 Hz, 1H); Mass (m / z): 478.4 (M+H) + .

[0171] Example 23 N-{8-[3-[methanesulfonamido]propyl]-8-azabicyclo[3.2.1]oct-3-yl}[1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide

[0172] [ka]

[0173] K2CO3 (0.019 g, 0.13 mmol) was added in portions to a stirred solution of N-(3-bromo-propyl)-methanesulfonamide (Intermediate 11, 0.13 g, 0.609 mmol) and [N-(8-azabicyclo[3.2.1]oct-3-yl)]-1-isopropyl-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxamide (Intermediate 18, 0.1 g, 0.304 mmol) in CH3CN (5 mL) at RT and the reaction mixture was heated at reflux for 8 h. The reaction mixture was cooled to RT, poured onto ice-cold water, extracted with EtOAc (30 mL×3), washed with brine solution (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the crude material, which was purified by column chromatography using methanol:DCM (1:99) to give the title compound. Yield: 0.1 g; 1 H - NMR (DMSO-d6, 400 MHz) δ ppm: 1.56 - 1.57 (d, J = 6.9 Hz, 6H), 1.88 - 1.90 (m, 2H), 2.01 - 2.04 (m, 2H), 2.22 - 2.32 (m, 4H), 2.48 - 2.49 (m, 2H), 2.92 (s, 3H), 3.01 (m, 3H), 4.01 (s, 2H), 4.14 (s, 1H), 5.52 (s, 1H), 6.66 (s, 1H), 6.87 (s, 1H), 7.13 (s, 1H), 8.03 (s, 1H), 8.50 (s, 1H), 9.30 (s, 1H), 10.09 (s, 1H); Mass (m / z): 464.3 (M+H) + .

[0174] The following Examples 24 to 36 were prepared by using procedures as described for Example 23 and Example 2 with some minor variations using the appropriate intermediates.

[0175] [Table 2A]

[0176] [Table 2B]

[0177] [Table 2C]

[0178] [Table 2D]

[0179] [Table 2E]

[0180] [Table 2F]

[0181] [Table 2G]

[0182] (Example 37) N-{8-[2-(4-acetylpiperazin-1-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}[1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide

[0183] [ka]

[0184] DIPEA (0.47 mL, 2.72 mmol), HATU (0.28 g, 0.75 mmol) were added to a stirred solution of 1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine-3-carboxylic acid (Intermediate 1, 0.15 g, 0.68 mmol) in DMF (2 mL) at RT and stirred for 2 h, followed by addition of 1-{4-[2-(3-amino-8-azabicyclo[3.2.1]oct-8-yl)ethyl]piperazin-1-yl}ethanone (Intermediate 10, 0.23 g, 0.81 mmol) and stirring for 20 h. The reaction mixture was poured into water (50 mL) with stirring, during which time the solid was allowed to precipitate. The solids were filtered, dissolved in DCM (50 mL), washed with brine solution (25 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound. Yield: 0.06 g; 1 H - NMR (DMSO-d6, 400 MHz) δ ppm: 1.56 - 1.57 (d, J = 6.9 Hz, 6H), 1.88 - 1.90 (m, 2H), 1.97 (s, 3H), 2.06 - 2.08 (m, 2H), 2.33 (m, 2H), 2.40 - 2.41 (m, 7H), 3.18 (bs, 3H), 3.37 - 3.39 (m, 6H), 4.06 - 4.10 (m, 1H), 5.53 (bs, 1H), 6.64 - 6.66 (dd, J = 2.9, 4.0 Hz, 1H), 6.84 - 6.85 (d, J = 4.1 Hz, 1H), 8.0 (s, 1H), 8.48 (s, 1H), 9.99 - 10.01 (d, J = 8.0 Hz, 1H); Mass (m / z): 483.4 (M+H) + .

[0185] (Example 38) N-{8-[2-(4-acetylpiperazin-1-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}[1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide L-(+)-tartarate

[0186] [ka]

[0187] The compound of Example 37 was converted to the L-(+)-tartrate salt, Example 38, using a procedure similar to that given in the preparation of Example 2. Yield: 0.05 g; 1 H - NMR (CD3OD, 400 MHz) δ ppm: 1.61 - 1.64 (d, J = 6.9 Hz, 6H), 2.04 - 2.11 (m, 2H), 2.20 (s, 3H), 2.26 - 2.32 (m, 2H), 2.38 (m, 2H), 2.40 - 2.45 (m, 7H), 3.28 (bs, 3H), 3.38 - 3.40 (m, 6H), 4.21 - 4.38 (m, 1H), 5.58 (bs, 1H), 6.66 (s, 1H), 6.84 - 6.85 (d, J = 4.1 Hz, 1H), 7.98 (s, 1H), 8.48 (s, 1H), 10.62 (s, 1H); Mass (m / z): 483.4 (M+H) + .

[0188] (Example 39) N-{8-[2-(4-acetylpiperazin-1-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}[4-hydroxy-1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide

[0189] [ka]

[0190] KCO (0.05 g, 0.36 mmol) was added to a stirred solution of ethyl 4-hydroxy-1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine-3-carboxylate (Intermediate 2, 0.1 g, 0.36 mmol) and 1-{4-[2-(3-amino-8-azabicyclo[3.2.1]oct-8-yl)ethyl]piperazin-1-yl}ethanone (Intermediate 10, 0.13 g, 0.46 mmol) in toluene (10 mL) at RT and the reaction mixture was heated at reflux for 20 h. The reaction mixture was cooled to RT, poured onto ice-cold water, extracted with EtOAc (30 mL×3), washed with brine solution (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the crude material, which was purified by column chromatography using methanol:DCM (5:95) to give the title compound. Yield: 0.06 g; Mass (m / z): 499.5 (M+H). + .

[0191] (Example 40) N-{8-[2-(4-acetylpiperazin-1-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}[4-hydroxy-1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide L-(+)-tartarate

[0192] [ka]

[0193] The compound of Example 39 was converted to the L-(+)-tartrate salt, Example 40, using a procedure similar to that given in the preparation of Example 2. Yield: 0.05 g; 1H - NMR (CD3OD, 400 MHz) δ ppm: 1.63 - 1.66 (d, J = 6.9 Hz, 6H), 2.03 - 2.11 (m, 2H), 2.20 (s, 3H), 2.28 - 2.32 (m, 2H), 2.38 (m, 2H), 2.42 - 2.46 (m, 7H), 3.28 (bs, 3H), 3.38 - 3.40 (m, 6H), 4.28 - 4.38 (m, 1H), 5.56 (bs, 2H), 6.66 (s, 1H), 6.84 - 6.85 (d, J = 4.1 Hz, 1H), 7.89 (s, 1H), 10.80 (bs, 1H); Mass (m / z): 499.6 (M+H) + .

[0194] (Example 41) EC for 5-HT4 receptor 50 Determining Values A stable CHO cell line expressing recombinant human 5-HT4 receptor and pCRE-Luc reporter system was used in the cell-based assay. The assay provides a non-radioactive based approach to determine the binding of compounds to GPCR. In this specific assay, the level of intracellular cyclic AMP regulated by activation or inhibition of the receptor is measured. The recombinant cells harbor a luciferase reporter gene under the control of a cAMP response element.

[0195] The cells were grown in 96-well clear bottom white plates in Ham's F12 medium containing 10% fetal bovine serum. Prior to the addition of compounds or standard agonists, cells were serum-starved overnight. Increasing concentrations of test compounds were added to the cells in OptiMEM medium. Incubation continued for 4 hours in a CO2 incubator with 37°C and 5% CO2 conditions. The medium was removed and the cells were washed with phosphate buffered saline. The cells were lysed and luciferase activity was measured in a luminometer. Concentration response data was generated using a luciferase assay, followed by incubation of cells with receptor ligands and analysis by subtracting basal levels (i.e., medium alone), then normalizing values ​​as a percentage of the control (endogenous agonist serotonin (10 μM)). The data was analyzed by nonlinear regression with variable slopes using the computer package GraphPad Prism 4. Compound EC 50 Values ​​were defined as the concentration required to stimulate luciferase activity by 50%.

[0196] Using this protocol, the compounds described herein were found to exhibit binding affinity towards the 5-HT4 receptor.

[0197] [Table 3]

[0198] (Example 42) Pharmacokinetic studies in rats Male Wistar rats (250±50 g) were used as experimental animals. Animals were individually housed in polypropylene cages. Two days before the study, rats were anesthetized with isoflurane for surgical placement of a carotid artery catheter. Rats were randomized for oral (3 mg / kg and 10 mL / kg, as dose volume) and intravenous (1 mg / kg and 2 mL / kg, as dose volume) dosing (n=3 / group) and fasted overnight before oral dosing (po). However, food and water were provided ad libitum in rats assigned to intravenous dosing.

[0199] Intravenous formulations were prepared by using water for injection as the excipient. For oral administration, formulations were prepared by using reagent grade water as the excipient. Dose formulations were prepared fresh on the day of administration.

[0200] After dosing of the animals, at each time point, 200 μL blood samples were collected through the carotid artery and supplemented with an equal volume of normal saline. The collected blood samples were transferred to labeled Eppendorf tubes containing 10 μL of sodium heparin (1000 IU / mL) as an anticoagulant. Typically, blood samples were collected at the following time points: 0.08, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after dosing. Blood was centrifuged at 4000 rpm for 10 minutes. Plasma was separated and stored frozen at -80°C until analysis. The concentration of the test compound was quantified in plasma by a qualitative LC-MS / MS method using appropriate extraction techniques. The test compound was quantified in plasma with a calibration range of approximately 1-2000 ng / mL. Study samples were analyzed using calibration samples within the batch and quality control samples across the batch.

[0201] Pharmacokinetic parameter C max , AUC t , t 1 / 2 , and bioavailability was calculated by non-compartmental model using standard non-compartmental model by using Phoenix WinNonlin 6.4 version software.

[0202] [Table 4]

[0203] (Example 43) Rat brain permeability studies Male Wistar rats (225±25 g) were used as experimental animals. Three animals were housed in each cage. The animals were provided with water and food ad libitum throughout the experiment and maintained on a 12-hour light / dark cycle.

[0204] Brain permeability was determined in rats in an individual manner. Male Wistar rats were acclimated one day before the administration day. After acclimation, the rats were grouped according to their body weight. In each group, three animals were kept in individual cages and given food and water ad libitum. At each time point (0.5, 1, and 2 hours), n=3 animals were used.

[0205] Compounds of formula (I) were appropriately preformulated and orally administered at 3mg / kg (free base equivalent).Blood samples were collected via cardiac puncture by using isoflurane anesthesia.Brain tissue was collected upon sacrifice of animals.Plasma was separated and brain samples were homogenized and stored frozen at -20°C until analysis.

[0206] The concentration of the compound of formula (I) was quantified in plasma and brain homogenates by a qualitative LC-MS / MS method using appropriate extraction techniques. The compound of formula (I) was quantified in plasma and brain homogenates with a calibration range of 1-2000 ng / mL. Study samples were analyzed using calibration samples within the batch and using quality control samples across batches. The brain-plasma ratio range was calculated (C b / C p ). Brain concentrations were found to be below the LLOQ and a value of zero was considered for calculation purposes.

[0207] [Table 5]

[0208] (Example 44) Effect on gastric emptying in beagle dogs Six beagle dogs were used in the study in a crossover fashion so that all six dogs received all treatments. Each dog was kept in an individual cage after overnight fasting and removal of water. To provide a model of gastroparesis, clonidine (an alpha2 adrenergic agonist) at a dose of 10 μg / kg was injected subcutaneously 30 minutes before the test meal was administered.

[0209] Dogs were orally administered the test compound of Example 2 at 1, 3, and 10 mg / kg, or vehicle or cisapride at 10 mg / kg immediately prior to administration of clonidine. A test meal (10 mL / kg) consisting of a commercially available semi-solid food containing 10 mg / kg acetaminophen (APAP) was provided 30 minutes after clonidine injection. Blood samples were collected from the brachiocephalic vein at 0, 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, and 2.0 hours after administration of the test meal, and plasma was then separated by centrifugation. Plasma concentrations of APAP were determined by an in-house method using LC-MS / MS.

[0210] Results: Subcutaneous administration of clonidine (10 μg / kg) reduced postprandial muscle contractions and significantly delayed gastric emptying of liquids and solids. Cisapride (10 mg / kg) restored the rate of gastric emptying in clonidine-treated dogs. The test compound of Example 2 at 3 and 10 mg / kg increased gastric motility and enhanced gastric emptying in a dose-dependent manner, confirming its prokinetic potential (Figure 1).

[0211] (Example 45) Effects on colonic transit in Swiss mice Male Swiss mice weighing approximately 20-30 g were fasted for 16 h with free access to water prior to the experiment. Mice were administered the compound of Example 2 or vehicle 30 min after administration of 0.5 ml of carmine dye solution. Mice were sacrificed 3 h after dye administration and the distance the dye had migrated from the proximal colon was measured. Colonic translocation was expressed as % colonic translocation = 100 x (length of colon translocated by carmine / total length of colon).

[0212] Results: The test compound of Example 2 at doses of 1 and 3 mg / kg, po, increased colonic transit (Figure 2).

[0213] (Example 46) hERG patch-clamp assay HEK293-hERG cells for patch-clamp assays were cultured in T-75 flasks in DMEM:Ham's F12 (1:1 ratio) containing 10% fetal bovine serum containing 0.5 mg / ml of the selective antibody, G-418 sulfate (Calbiochem), and 0.1% penicillin and streptomycin (Thermofisher, MA, USA). 2+ and Ca 2+ Cells were harvested at 70-80% confluency by washing with ion-free Hanks' balanced salt solution, followed by the addition of accumax (2.5 mL) (Sigma Aldrich, MO, USA), and the flask was incubated at 5% CO2 and 37 °C until the cells started to slide on the surface. After the cells were completely detached from the surface, approximately 10 mL of complete medium without selective antibodies was added and pipetted to dissociate the cell clumps. An additional 7.5 mL of complete medium was added to collect the remaining cells in the flask, and the cell suspension was incubated at 5% CO2 and 37 °C for 30 min. After centrifugation at 200 × g for 2 min, the supernatant was discarded, and the cell pellet was resuspended in the external solution that will be used for the patch-clamp assay. hERG patch-clamp assays were performed using an external solution of 140 mM NaCl, 4 mM KCl, 1 mM MgCl2, 2 mM CaCl2, 5 mM D-glucose monohydrate, 10 mM HEPES / NaOH, pH 7.4, osmolarity: 298 mOsmol, and an internal solution of 50 mM KCl, 10 mM NaCl, 60 mM KF, 20 mM ethylene glycol tetraacetic acid, 10 mM HEPES / KOH, pH 7.2, osmolarity 285 mOsmol. Whole-cell patch-clamp recordings were performed by holding HEK293-hERG cells at -80 mV, stepping to +40 mV for 500 ms, then stepping to -40 mV for 500 ms, then stepping back to the original holding potential using an IV protocol. Peak currents were measured at -40 mV tail currents using a Patchliner instrument. The IV pulse protocol delivers a pulse every 10 seconds and online analysis records the IC by replacing the leakage current from the peak current. 50Values ​​were calculated using IGOR PRO software (WaveMetrics, Inc., Portland, OR, USA).

[0214] Results: Example 2 was evaluated in the hERG patch-clamp assay, and the half-inhibitory concentration of the hERG tail current was IC 50 >10μM.

[0215] (Example 47) Intestinal myoelectrical activity in male Wistar rats Methods: Telementary transmitters (F40-EET; DSI, MA, USA) were implanted subcutaneously in rats under isoflurane anesthesia, and spring electrodes were embedded in the intestinal (jejunal) wall. After 2 weeks of post-operative recovery, animals were fasted for 14 hours and transferred to recording cages. The transmitter was switched on using a magnetic switch, and baseline intestinal EMG activity was recorded for 3 hours. Rats were treated with vehicle, administered the test compound of Example 2 (10 or 30 mg / kg, po) or the positive control, prucalopride (10 mg / kg, po), and EMG signals were recorded for an additional 3 hours using Ponemah software (DSI, MA, USA). Animals had access to only water throughout the study. Recorded EMG signals were filtered using a 20-50 Hz band filter, and spike activity was measured over a 30-minute period using NeuroScore software (DSI, MA, USA).

[0216] Results: Example 2 produced a dose-dependent increase in myoelectrical activity, with a 97±31% increase at 30 mg / kg po. The increased spiking activity is consistent with prucalopride, a 5-HT4 receptor agonist used in chronic constipation (FIG. 3).

Claims

1. Formula (I) 【Chemistry 1】 or an isotope, stereoisomer, or pharma- ceutically acceptable salt thereof, During the ceremony, R 1 represents hydrogen, alkyl, or cycloalkyl; R 2 represents hydrogen, hydroxy, halogen, alkyl, or cycloalkyl; A is, 【Chemistry 2】 is a heterocyclic ring selected from the group consisting of R 3 is hydrogen, or 【Chemistry 3】 is selected from the group consisting of B is hydrogen, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, -SO 2 -Alkyl, -COCH 3 , -COO-alkyl, or -CO-(CH 2 ) m —OH, where m is an integer from 0 to 5; Y, at each occurrence, is independently hydrogen, hydroxy, halogen, haloalkyl, hydroxyalkyl, -COOH, -COO-alkyl, -O-alkyl, -S-alkyl, or -NR a R b is selected from D represents CH or N; n is an integer from 0 to 5, R a is independently selected at each occurrence from hydrogen, alkyl, cycloalkyl, or alkoxy; R b is independently selected at each occurrence from hydrogen, alkyl, cycloalkyl, or alkoxy; R 4 represents hydrogen, hydroxy, halogen, alkyl, or cycloalkyl, and b represents 1 to 3, A compound of formula (I) or an isotope, stereoisomer, or pharma- ceutically acceptable salt thereof.

2. A, 【Chemistry 4】 and R 2 is hydrogen or hydroxy; R 3 but, 【Chemistry 5】 is selected from the group consisting of B is -SO 2 -Alkyl, -COCH 3 , -COO-alkyl, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, or -CO-(CH 2 ) m —OH, where m is an integer from 0 to 5; Y is independently selected at each occurrence from hydrogen or hydroxy; D is CH or N; n is an integer from 0 to 5; R a is independently selected at each occurrence from hydrogen or alkyl; R b is independently selected at each occurrence from hydrogen, alkyl, cycloalkyl, or alkoxy; and R 4 represents hydrogen, 2. A compound of formula (I) according to claim 1, or an isotope, stereoisomer, or pharma- ceutically acceptable salt thereof.

3. The compound is (R)-N-{8-[2-hydroxy-3-[(N-methyl)methanesulfonamido]propyl]-8-azabicyclo[3.2.1]oct-3-yl}[1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide; (R)-N-{8-[2-hydroxy-3-[(N-methyl)methanesulfonamido]propyl]-8-azabicyclo[3.2.1]oct-3-yl}[1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide L-(+)-tartarate; (S)-N-{8-[2-hydroxy-3-[(N-methyl)methanesulfonamido]propyl]-8-azabicyclo[3.2.1]oct-3-yl}[1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide; (S)-N-{8-[2-hydroxy-3-[(N-methyl)methanesulfonamido]propyl]-8-azabicyclo[3.2.1]oct-3-yl}[1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide L(+)-tartarate; Racemic-N-{8-[2-hydroxy-3-[(N-methyl)methanesulfonamido]propyl]-8-azabicyclo[3.2.1]oct-3-yl}[1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide; Racemic-N-{8-[2-hydroxy-3-[(N-methyl)methanesulfonamido]propyl]-8-azabicyclo[3.2.1]oct-3-yl}[1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide L(+)-tartarate; (R)-N-{8-[2-hydroxy-3-[(N-methyl)methanesulfonamido]propyl]-8-azabicyclo[3.2.1]oct-3-yl}[4-hydroxy-1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide; (R)-N-{8-[2-hydroxy-3-[(N-methyl)methanesulfonamido]propyl]-8-azabicyclo[3.2.1]oct-3-yl}[4-hydroxy-1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide L-(+)-tartarate; (S)-N-{8-[2-hydroxy-3-[(N-methyl)methanesulfonamido]propyl]-8-azabicyclo[3.2.1]oct-3-yl}[4-hydroxy-1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide; (S)-N-{8-[2-hydroxy-3-[(N-methyl)methanesulfonamido]propyl]-8-azabicyclo[3.2.1]oct-3-yl}[4-hydroxy-1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide L-(+)-tartarate; Racemic-N-{8-[2-hydroxy-3-[(N-methyl)methanesulfonamido]propyl]-8-azabicyclo[3.2.1]oct-3-yl}[4-hydroxy-1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide; Racemic-N-{8-[2-hydroxy-3-[(N-methyl)methanesulfonamido]propyl]-8-azabicyclo[3.2.1]oct-3-yl}[4-hydroxy-1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide L-(+)-tartarate; (R)-N-{8-[2-hydroxy-3-(methanesulfonamido)propyl]-8-azabicyclo[3.2.1]oct-3-yl}[1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide; (R)-N-{8-[2-hydroxy-3-(methanesulfonamido)propyl]-8-azabicyclo[3.2.1]oct-3-yl}[1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide L-(+)-tartarate; (R)-N-{8-[2-hydroxy-3-[(N-methyl)acetamido]propyl]-8-azabicyclo[3.2.1]oct-3-yl}[1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide; (R)-N-{8-[2-hydroxy-3-[(N-methyl)acetamido]propyl]-8-azabicyclo[3.2.1]oct-3-yl}[1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide L-(+)-tartarate; (R)-N-{8-[2-hydroxy-3-[(1-methanesulfonylpiperazin)-4-yl]propyl]-8-azabicyclo[3.2.1]oct-3-yl}[1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide; (R)-N-{8-[2-hydroxy-3-[(1-methanesulfonylpiperazin)-4-yl]propyl]-8-azabicyclo[3.2.1]oct-3-yl}[1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide L(+)tartarate; (R)-N-{8-[2-hydroxy-3-[(1-methanesulfonylpiperazin)-4-yl]propyl]-8-azabicyclo[3.2.1]oct-3-yl}[4-hydroxy-1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide; (R)-N-{8-[2-hydroxy-3-[(1-methanesulfonylpiperazin)-4-yl]propyl]-8-azabicyclo[3.2.1]oct-3-yl}[4-hydroxy-1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide L-(+)-tartarate; N-{8-[3-[(N-methyl)methanesulfonamido]propyl]-8-azabicyclo[3.2.1]oct-3-yl}[1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide; N-{8-[3-[(N-methyl)methanesulfonamido]propyl]-8-azabicyclo[3.2.1]oct-3-yl}[1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide L-(+)-tartarate; N-{8-[3-[methanesulfonamido]propyl]-8-azabicyclo[3.2.1]oct-3-yl}[1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide; N-{8-[3-[methanesulfonamido]propyl]-8-azabicyclo[3.2.1]oct-3-yl}[1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide L-(+)-tartarate; N-{8-[3-isopropylsulfonylaminopropyl]-8-azabicyclo[3.2.1]oct-3-yl}[1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide; N-{8-[3-isopropylsulfonylaminopropyl]-8-azabicyclo[3.2.1]oct-3-yl}[1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide L-(+)-tartarate; N-{8-[2-methanesulfonylaminoethyl]-8-azabicyclo[3.2.1]oct-3-yl}[1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide; N-{8-[2-methanesulfonylaminoethyl]-8-azabicyclo[3.2.1]oct-3-yl}[1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide L-(+)-tartarate; N-{8-[2-isopropylsulfonylaminoethyl]-8-azabicyclo[3.2.1]oct-3-yl}[1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide; N-{8-[2-isopropylsulfonylaminoethyl]-8-azabicyclo[3.2.1]oct-3-yl}[1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide L-(+)-tartarate; N-{8-[3-acetamidopropyl]-8-azabicyclo[3.2.1]oct-3-yl}[1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide; N-{8-[3-acetamidopropyl]-8-azabicyclo[3.2.1]oct-3-yl}[1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide L-(+)-tartarate; N-{8-[3-carbomethoxyaminopropyl]-8-azabicyclo[3.2.1]oct-3-yl}[1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide; N-{8-[3-carbomethoxyaminopropyl]-8-azabicyclo[3.2.1]oct-3-yl}[1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide L-(+)-tartarate; N-{8-[2-carbomethoxyaminoethyl]-8-azabicyclo[3.2.1]oct-3-yl}[1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide; N-{8-[2-carbomethoxyaminoethyl]-8-azabicyclo[3.2.1]oct-3-yl}[1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide L-(+)-tartarate; N-{8-[2-(4-acetylpiperazin-1-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}[1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide; N-{8-[2-(4-acetylpiperazin-1-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}[1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide L-(+)-tartarate; N-{8-[2-(4-acetylpiperazin-1-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}[4-hydroxy-1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide; and N-{8-[2-(4-acetylpiperazin-1-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}[4-hydroxy-1-isopropyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine]-3-carboxamide L-(+)-tartarate 2. The compound of formula (I) according to claim 1, selected from the group consisting of:

4. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) as defined in any one of claims 1 to 3, or a stereoisomer or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient or carrier.

5. 5. The pharmaceutical composition of claim 4 for use in the treatment of a gastrointestinal disease or disorder selected from irritable bowel syndrome, chronic constipation, functional dyspepsia, gastroparesis, gastroesophageal reflux disorder, postoperative ileus, pseudo-obstruction, drug-induced slow transit, Barrett's esophagus, intestinal pseudo-ileus, acute gastritis, chronic gastritis, gastric ulcer, duodenal ulcer, non-ulcer dyspepsia, Crohn's disease, celiac disease, and delayed gastric emptying caused by gastric neurosis.

6. A method for treating a gastrointestinal disease or disorder associated with the 5-hydroxytryptamine 4 receptor, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) as defined in any one of claims 1 to 3, or a stereoisomer or pharma- ceutically acceptable salt thereof.

7. 7. The method of claim 6, wherein the gastrointestinal disease or disorder is selected from delayed gastric emptying caused by irritable bowel syndrome, chronic constipation, functional dyspepsia, gastroparesis, gastroesophageal reflux disorder, postoperative ileus, intestinal pseudo-obstruction, drug-induced slow transit, Barrett's esophagus, intestinal pseudo-ileus, acute gastritis, chronic gastritis, gastric ulcer, duodenal ulcer, non-ulcer dyspepsia, Crohn's disease, celiac disease, and gastric neurosis.

8. 8. The method of claim 7, wherein the irritable bowel syndrome is selected from constipation-predominant irritable bowel syndrome, diarrhea-predominant irritable bowel syndrome, mixed-predominant irritable bowel syndrome, and unclassifiable irritable bowel syndrome.

9. 4. Use of a compound of formula (I) as defined in any one of claims 1 to 3, or a stereoisomer or a pharma- ceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a gastrointestinal disease or disorder.

10. 10. The use according to claim 9, wherein the gastrointestinal disease or disorder is selected from delayed gastric emptying caused by irritable bowel syndrome, chronic constipation, functional dyspepsia, gastroparesis, gastroesophageal reflux disorder, postoperative ileus, pseudo-obstruction, drug-induced slow transit, Barrett's esophagus, intestinal pseudo-ileus, acute gastritis, chronic gastritis, gastric ulcer, duodenal ulcer, non-ulcer dyspepsia, Crohn's disease, celiac disease, and gastric neurosis.

11. 4. A compound of formula (I) as defined in any one of claims 1 to 3, or a stereoisomer or a pharma- ceutically acceptable salt thereof, for use in treating a gastrointestinal disease or disorder.

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