Serotonin 5-HT2B inhibitory compounds

Abstract

The present invention describes a novel serotonin c5-HT2B receptor antagonist of formula (1) and a pharmaceutically acceptable salt thereof; wherein ring A, L, X, X', R3, R4, m and n are as defined herein. Additionally, a composition comprising a compound of formula (1) or a pharmaceutically acceptable salt thereof for the treatment of myxomatous mitral valve disease (MMVD), congestive heart failure (CHF), and / or asymptomatic heart failure in animals, preferably dogs, and a method of using said compound or a pharmaceutically acceptable salt thereof are described.

Description

Technology Field

[0001] The present invention describes a novel compound that is a serotonin 5-HT2B receptor antagonist useful for the treatment of mitral valve disease and congestive heart failure in animals. The present invention also describes a composition comprising the compound of the present invention and a pharmaceutically acceptable salt thereof for treating animals with mitral valve disease, congestive heart failure and / or asymptomatic heart failure, as well as a method of using said compound. Background Technology

[0002] The serotonin 5-HT2B receptor was initially characterized as a serotonin-producing G protein-coupled receptor that regulates contraction in the base of the rat stomach (Clineschmidt, et al., 1985, J. Pharmacol. Exp. Ther., 235, 696). 5-HT2B was subsequently detected in human tissues including adipose tissue, the central nervous system, heart, liver, intestines, lungs, skeletal muscle, spleen and other organs and tissues (Kursar et al., 1994, Mal. Pharmacol., 46, 227; Sanden et al., 2000, Neurochem Int., 36, 427-435; Borman et al., 2002 Br. J. Pharmacol., 135, 1144; Schmuck et al., 1994, FEES Lett., 342, 85) and in dog tissues including lungs, heart, smooth muscle, and brain (Bonaventure et al., Eur J. Pharmacol. 2005 April 25, 513(3) 181-192; Oyama et al., J. Vet. Intern. Med. 2010, 24, 27-36). Modifiers of 5-HT2B, including antagonists, partial antagonists, inverse agonists, and 5-HT2B desensitizers, can be used as therapeutic agents for disorders of these tissues in which 5-HT2B activation plays a direct or indirect role.

[0003] Control of serotonin (5-hydroxytryptamine, 5HT) levels and signaling is used to treat disorders of the central nervous system, intestinal contractility and motility, and vascular function. 5-HT plays a role in vasoconstriction and relaxation and can affect vascular function, growth, and morphology. While wild-type mice exhibit symptoms of pulmonary arterial hypertension (PAH) under hypoxic conditions, 5-HT2B receptor knockout mice do not, suggesting that the regulation of 5-HT2B can alleviate PAH. The phenotype of 5-HT2B receptor knockout mice demonstrates the importance of this receptor in cardiac development. Surviving mice possess an immature heart due to impaired myocyte proliferation (Nebigil, et al., 2001, Circulation, 103, 2973). Conversely, overexpression of 5-HT2B in mice induces cardiac hypertrophy (Nebigil, et al., 2003, Circulation, 107 (25), 3223). Selective 5-HT2B antagonists prevent isoproterenol-induced cardiac hypertrophy (Jaffre et al., 2004, Circulation, 110, 969). More recently, genomic data from a tachypacing-induced decompensated heart failure model in dogs showed that 5-HT2B mRNA is upregulated (Ojaimi et al., 2007, Physiol. Genomics 29, 76). Therefore, regulation of 5-HT2B may treat disorders associated with cardiac hypertrophy, such as congestive heart failure. In fact, increased serotonin signaling in both human and experimental animal models can induce valvular interstitial cell differentiation and myxomatous valvular damage.

[0004] Myxomatous mitral valve disease (MMVD) is a major cause of cardiovascular disease in dogs. MMVD causes mitral valve failure, leading to mitral regurgitation that promotes sodium and water retention, activation of the neurohormonal system, volume overload, and ultimately congestive heart failure (CHF). As used herein, the medical term MMVD includes mitral valve disease (MVD), degenerative mitral valve disease (DMVD); chronic valvular disease (CVD); chronic valvular heart disease (CVHD); and atrial-ventricular valve insufficiency (AVVI). The pathology of MMVD generally involves the differentiation and activation of resting mitral interstitial cells into a more active myofibroblastic phenotype, which mediates many histological and molecular changes in the valve tissue. MMVD is present in approximately 30% of all dogs over the age of 10 and is the most common cause of CHF in dogs. MMVD is most prevalent in small dogs and breeds such as Cavalier King Charles Spaniels, Chihuahuas, Maltese, Pekingese, Toy Poodles, and Miniature Poodles. The natural history of the disease involves adult onset, varying progression with aging, and the eventual development of CHF in dogs with severe disease.

[0005] Current treatments for MMVD include angiotensin enzyme inhibitors, diuretics, vasodilators, and benign muscle contractions that focus on symptom relief rather than inhibiting disease progression. In addition, some of these treatments cause loss of appetite, lethargy, and changes in cardiac function ( for example It causes additional adverse risks to animals, such as , polarization) and kidney damage. The compound of formula (1) of the present invention has an affinity for the canine 5-HT2B (c5-HT2B) receptor and can provide veterinarians with a newer and safer drug regimen to treat canine patients with MMVD to slow the progression of MMVD, CHF and / or asymptomatic heart failure.

[0006] One aspect of the present invention is a novel serotonin canine 5HT2B (c5-HT2B) receptor antagonist useful for the treatment of myxomatous mitral valve disease, congestive heart failure, and / or asymptomatic heart failure in animals, particularly dogs. In another aspect, a composition comprises a compound of the present invention or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient, for treating animals, preferably dogs, having MMVD, CHF, and / or asymptomatic heart failure.

[0007] One aspect of the present invention is a compound of formula (1); and a pharmaceutically acceptable salt thereof:

[0008]

[0009] Here, X is CH or N and;

[0010] L is NR 1 or O and;

[0011] X' is CR 2 or N and;

[0012] R 1 is H, C1-C6 alkyl, phenyl, or pyridinyl, where phenyl or pyridinyl each has one or two R groups. 4 Selectively substituted with a substituent;

[0013] R 2 is H, C1-C4 alkyl, -CF3 or halo;

[0014] R 3 is H, cyano, halo, C1-C4 alkyl or -CF3;

[0015] or R 2 and R 3 They combine to form a 5-membered or 6-membered carbocyclic ring selectively substituted with methyl, halo, or -CF3;

[0016] Ring A is a 5-membered or 6-membered heteroaryl ring containing one or more heteroatoms selected from the group consisting of phenyl, naphthyl, N, O, and S; or a 10-membered or 11-membered fused heteroaryl ring containing at least one heteroatom selected from the group consisting of N, O, and S;

[0017] R 4 is selected from C1-C4 alkyl, halo, cyano, or -CF3;

[0018] m is an integer 0, 1, or 2;

[0019] n is an integer 0, 1, 2, or 3; and when n is an integer 2 or 3, each R 4 It may be the same or different.

[0020] In one aspect of the present invention, ring A is selected from the group consisting of phenyl, naphthyl, quinolinyl, indolyl, indazolyl, furanyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, pyrrolyl, thiazolyl, isoxazolyl, oxazolyl, isothiazolyl, triazolyl, or tetrazolyl; each is (R 4 ) n It is substituted with, where n is an integer 0, 1, or 2. In another embodiment, ring A is phenyl, indolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, or triazolyl; each is (R 4 ) n It is substituted with, where n is an integer 0, 1, or 2. In another embodiment, ring A is phenyl, indolyl, indazolyl, thiophenyl, pyridinyl, pyridazinyl, imidazolyl, thiazolyl, or isothiazolyl; each is (R 4 ) n It is substituted with, where n is an integer 0, 1, or 2. In another embodiment, ring A is phenyl, indolyl, indazolyl, thiophenyl, pyridinyl, thiazolyl, or isothiazolyl; each is (R4 ) n It is substituted with, where n is an integer 0, 1, or 2. In another embodiment, ring A is phenyl, indolyl thiophenyl, pyridinyl, thiazolyl, or isothiazolyl; each is (R 4 ) n It is substituted with, where n is an integer 0 or 1. In another embodiment, ring A is phenyl, thiophenyl, isothiazolyl, or indolyl; each is (R 4 ) n It is substituted with, where n is an integer 0 or 1. In another modality, ring A is (R 4 ) n It is a phenyl substituted with, where n is an integer 0 or 1. In another embodiment, ring A is (R 4 ) n It is an indolil substituted with, where n is an integer 0 or 1. In another modality, ring A is (R 4 ) n It is a thiophenyl substituted with, where n is an integer 0 or 1. In another embodiment, ring A is (R 4 ) n isothiazolyl substituted with, where n is an integer 0 or 1.

[0021] In one aspect of the present invention, X is CH. In another aspect, X is N.

[0022] In one aspect of the present invention, L is O. In another aspect, L is NR 1 is. In another modality, L is NR 1 and, here R 1 is H or R 1 are 1 or 2 Rs each 4 It is phenyl or pyridinyl selectively substituted with a substituent. In another embodiment, L is NR 1 and, here R 1 is H or R 1 Each has 1 R 4It is phenyl or pyridinyl selectively substituted with a substituent. In another embodiment, L is NR 1 and, here R 1 is H or R 1 is each a pyridinyl or phenyl selectively substituted with a fluoro, chloro, or -CF3 group. In another embodiment, L is NR 1 and, here R 1 is H or R 1 is a phenyl selectively substituted with a fluoro, chloro, or -CF3 group. In another embodiment, L is NR 1 and, here R 1 is H or R 1 is a phenyl selectively substituted with a fluoro. In another embodiment, L is NR 1 and, here R 1 is H.

[0023] In one aspect of the present invention, X' is N. In another aspect, X' is CR 2 and R 2 is H, methyl, halo, or -CF3. In another embodiment, X' is CR 2 and R 2 is H, methyl, fluoro, chloro, or -CF₆ 3 is. In another mode, X' is CR 2 and R 2 is H, methyl, or -CF3. In another embodiment, X' is CR 2 and R 2 is H, or X' is CH.

[0024] In one aspect of the present invention, R 3 is H, methyl, ethyl, isopropyl, fluoro, chloro, -CF3, or cyano. In another embodiment, R 3 is H, methyl, fluoro, chloro, -CF3, or cyano. In another embodiment, R 3 is H, methyl, fluoro, chloro, or cyano. In another embodiment, R 3is H, methyl, chloro, or cyano. In another embodiment, R 3 is H or cyano. In another aspect, R 3 is H.

[0025] In one aspect of the present invention, R 2 and R 3 They combine to form a fused cyclopentyl or cyclohexyl ring selectively substituted with a halo or -CF3. In another embodiment, R 2 and R 3 They combine to form a fused cyclopentyl or cyclohexyl ring selectively substituted with fluoro, chloro, or -CF3. In another embodiment, R 2 and R 3 They combine to form a fused cyclopentyl or cyclohexyl ring selectively substituted with fluoro or chloro. In another embodiment, R 2 and R 3 They combine to form a fused cyclopentyl or cyclohexyl ring. In another embodiment, R 2 and R 3 They combine together to form a fused cyclohexyl ring.

[0026] In one aspect of the present invention, R 4 is methyl, ethyl, propyl, isopropyl, butyl, t-butyl, chloro, fluoro, bromo, iodo, cyano, or -CF3. In another aspect of the present invention; R 4 is methyl, ethyl, propyl, isopropyl, chloro, fluoro, bromo, cyano, or -CF3. In another aspect of the present invention; R 4 is methyl, ethyl, isopropyl, chloro, fluoro, cyano, or -CF3. In another aspect of the present invention; R 4 is methyl, chloro, fluoro, or -CF3.

[0027] In one embodiment of the present invention, m is an integer 0 or 1. In another embodiment, m is an integer 0. In yet another embodiment of the present invention, m is an integer 1.

[0028] In one aspect of the present invention, n is an integer 0, 1, or 2; and when n is an integer 2, each R 4 may be the same or different. In another modality, n is an integer 0 or 1. In another modality, n is an integer 1. In another modality, n is an integer 0.

[0029] One aspect of the present invention is that ring A is phenyl; m is an integer 1, and n is an integer 0, 1, or 2; X is CH, and L is NR 1 and R 1 is H and; X' is CR 2 and R 2 and R 3 ... combines together to form cyclopentyl or cyclohexyl; and R 4 is a compound of formula (1) which is fluoro, chloro, or -CF3. Another embodiment is that ring A is phenyl; m is an integer 1, and n is an integer 0 or 1; X is CH; and L is NR 1 and R 1 is H and; X' is CR 2 and R 2 and R 3 ... combines to form cyclohexyl; and R 4 is a fluoro, chloro, or -CF 3 Phosphorus, a compound of formula (1); or a pharmaceutically acceptable salt thereof. Another embodiment is that ring A is phenyl; m is an integer 1 and n is an integer 0; X is CH; and L is NR 1 and R 1 is H and; X' is CR 2 and R 2 and R 3It is a compound of formula (1) that combines to form a cyclohexyl; or a pharmaceutically acceptable salt thereof.

[0030] One aspect of the present invention is that X is CH; and L is NR 1 and, here R 1 is H or R 1 is phenyl or pyridinyl, each having 1 or 2 R groups. 4 The ring A is optionally substituted with a substituent; ring A is phenyl, naphthyl, quinolinyl, indolyl, furanyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indazolyl, imidazolyl, pyrazolyl, pyrrolyl, thiazolyl, isoxazolyl, oxazolyl, isothiazolyl, triazolyl, or tetrazolyl, each of which is (R 4 ) n Replaced with; X' is CR 2 and, here R 2 is H, methyl, or -CF3; R 3 is a compound of formula (1), wherein is H or cyano; m is an integer 1, and n is an integer 0, 1, or 2; and a pharmaceutically acceptable salt thereof. Another aspect of the invention is that X is CH; and L is NR 1 and, here R 1 is H or R 1 is phenyl or pyridinyl, each having 1 or 2 R groups. 4 Optionally substituted with a substituent; ring A is phenyl, indolyl, indazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, or triazolyl, each of which is (R 4 ) n Replaced with; X' is CR 2 and, here R 2 is H, methyl, or -CF3; R 3is a compound of formula (1), wherein is H or cyano; m is an integer 1, and n is an integer 0, 1, or 2; and a pharmaceutically acceptable salt thereof. Another aspect of the invention is that X is CH; and L is NR 1 and, here R 1 is H or R 1 is phenyl or pyridinyl, each having one R 4 Optionally substituted with a substituent; ring A is phenyl, indolyl, indazolyl, thiophenyl, pyridinyl, imidazolyl, thiazolyl, or isothiazolyl, and each is (R 4 ) n Replaced with; X' is CR 2 and, here R 2 is H, methyl, or -CF3; R 3 is a compound of formula (1), wherein is H or cyano; m is an integer 1, and n is an integer 0, 1, or 2; and a pharmaceutically acceptable salt thereof. Another aspect of the invention is that X is CH; and L is NR 1 and, here R 1 is H or R 1 1 R 4 It is a phenyl selectively substituted with a substituent; ring A is a phenyl, indolyl, thiophenyl, pyridinyl, thiazolyl, or isothiazolyl, and each is (R 4 ) n Replaced with; X' is CR 2 and, here R 2 is H, methyl, or -CF3; R 3 is a compound of formula (1), wherein is H or cyano; m is an integer 1, and n is an integer 0, 1, or 2; and a pharmaceutically acceptable salt thereof. Another aspect of the invention is that X is CH; and L is NR 1 and, here R 1 is H or R 1is a phenyl selectively substituted with a fluoro; ring A is a phenyl, indolyl, thiophenyl, pyridinyl, thiazolyl, or isothiazolyl, and each is (R 4 ) n Replaced with; X' is CR 2 and, here R 2 is H, methyl, or -CF3; R 3 is a compound of formula (1), wherein is H or cyano; m is an integer 1, and n is an integer 0 or 1; and a pharmaceutically acceptable salt thereof. Another aspect of the invention is that X is CH; and L is NR 1 and, here R 1 is H or R 1 is a phenyl selectively substituted with a fluoro; ring A is a phenyl, indolyl, thiophenyl, thiazolyl, or isothiazolyl, and each is (R 4 ) n Replaced with; X' is CR 2 and, here R 2 is H, methyl, or -CF3; R 3 A compound of formula (1), wherein is H; m is an integer 1, and n is an integer 0 or 1; and a pharmaceutically acceptable salt thereof. Another aspect of the invention is that X is CH; and L is NR 1 and, here R 1 is H; ring A is phenyl, indolyl, thiophenyl, or isothiazolyl, and each is (R 4 ) n Replaced with; X' is CR 2 and, here R 2 is H, methyl, or -CF3; R 3 is a compound of formula (1), where m is an integer 1 and n is an integer 0 or 1; and a pharmaceutically acceptable salt thereof.

[0031] Another aspect of the present invention is that X is CH; L is O; and ring A is (R 4 ) nIt is a phenyl substituted with; X' is CR 2 and; R 2 and R 3 Compounds of formula (1), in which all are H; m is an integer 1; and n is an integer 0, 1, or 2; and pharmaceutically acceptable salts thereof. Another embodiment is that X is CH; L is O; and ring A is (R 4 ) n It is a phenyl substituted with; X' is CR 2 and; R 2 and R 3 Compounds of formula (1), where all are H; m is an integer 1; and n is an integer 0 or 1; and pharmaceutically acceptable salts thereof. Another embodiment is that X is CH; L is O; and ring A is (R 4 ) n It is a phenyl substituted with; X' is CR 2 and; R 2 and R 3 All are H and; R 4 is a compound of formula (1) where is methyl, fluoro, chloro, or -CF3; m is an integer 1; and n is an integer 0 or 1; and a pharmaceutically acceptable salt thereof. Another embodiment is that X is CH; L is O; and ring A is (R 4 ) n It is a phenyl substituted with; X' is CR 2 and; R 2 and R 3 All are H and; R 4 is a compound of formula (1) in which methyl, fluoro, or chloro is methyl, fluoro, or chloro; m is an integer 1; and n is an integer 0 or 1; and a pharmaceutically acceptable salt thereof.

[0032] Another aspect of the present invention is that X is CH; and L is O or NR 1 and; ring A is phenyl, pyridinyl, indolyl, thiophenyl, isothiazolyl, or thiazolyl, and each is (R 4 ) n Replaced with; X' is CR2 and; R 1 , R 2 and R 3 A compound of formula (1), wherein each is H; m is an integer 1; and n is an integer 0, 1, or 2; and a pharmaceutically acceptable salt thereof. Another embodiment is that X is CH; and L is O or NR 1 and; ring A is phenyl, pyridinyl, indolyl, thiophenyl, isothiazolyl, or thiazolyl; each is (R 4 ) n Replaced with; X' is CR 2 and; R 1 , R 2 and R 3 A compound of formula (1), wherein each is H; m is an integer 1; and n is an integer 0, 1, or 2; and a pharmaceutically acceptable salt thereof. Another embodiment is that X is CH; and L is O or NR 1 and; ring A is phenyl, indolyl, thiophenyl, isothiazolyl, or thiazolyl; and each is (R 4 ) n Replaced with; X' is CR 2 and; R 1 , R 2 and R 3 A compound of formula (1), wherein each is H; m is an integer 1; and n is an integer 0 or 1; and a pharmaceutically acceptable salt thereof. Another embodiment is that X is CH; and L is O or NR 1 and; ring A is phenyl, indolyl, thiophenyl, or isothiazolyl; and each is (R 4 ) n Replaced with; X' is CR 2 and; R 1 , R 2 and R 3 are H and R 4 is a compound of formula (1) in which methyl, fluoro, chloro, or -CF3; m is an integer 1; and n is an integer 0 or 1; and a pharmaceutically acceptable salt thereof.

[0033] Another aspect of the present invention is that X is CH or N; and L is NR 1 and; ring A is phenyl, pyridinyl, indolyl, thiophenyl, isothiazolyl, or thiazolyl, and each is (R 4 ) n Replaced with; X' is CR 2 and; R 1 , R 2 and R 3 A compound of formula (1), wherein each is H; m is an integer 1 and n is an integer 0, 1 or 2; and a pharmaceutically acceptable salt thereof. Another embodiment is that X is CH or N; and L is NR 1 and; ring A is phenyl, pyridinyl, indolyl, thiophenyl, isothiazolyl, or thiazolyl; each is (R 4 ) n Replaced with; X' is CR 2 and; R 1 , R 2 and R 3 are H and R 4 is a compound of formula (1) where is methyl, fluoro, chloro, or -CF3; m is an integer 1; and n is an integer 0, 1, or 2; and a pharmaceutically acceptable salt thereof. Another embodiment is that X is CH or N; and L is NR 1 and; ring A is phenyl, indolyl, pyridinyl, thiophenyl, or isothiazolyl; and each is (R 4 ) n Replaced with; X' is CR 2 and; R 1 , R 2 and R 3 are H and R 4 is a compound of formula (1) where is methyl, fluoro, or chloro; m is an integer 1; and n is an integer 0, 1, or 2; and a pharmaceutically acceptable salt thereof. In another embodiment, X is CH or N; and L is NR 1 and; ring A is (R4 ) n It is a phenyl substituted with; X' is CR 2 and; R 1 , R 2 and R 3 are H and R 4 is a compound of formula (1) in which fluoro or chloro is an integer 1; and n is an integer 0 or 1; and a pharmaceutically acceptable salt thereof.

[0034] Another aspect of the present invention is that ring A is phenyl, indolyl, pyridinyl, thiophenyl, or isothiazolyl; X is N; and L is NR 1 and; X' is CR 2 and; R 1 , R 2 and R 3 are H and R 4 is a compound of formula (1), in which is methyl, fluoro, chloro, or -CF3; m is an integer 1, and n is an integer 0, 1, or 2; and a pharmaceutically acceptable salt thereof. Another embodiment is that ring A is phenyl, indolyl, pyridinyl, thiophenyl, or isothiazolyl; X is N; and L is NR 1 and; X' is CR 2 and; R 1 , R 2 and R 3 are H and R 4 is a compound of formula (1) in which is methyl, fluoro, or chloro; m is an integer 1, and n is an integer 0, 1, or 2; and a pharmaceutically acceptable salt thereof. Another embodiment is that ring A is phenyl, indolyl, pyridinyl, thiophenyl, or isothiazolyl; X is N; and L is NR 1 and; X' is CR 2 and; R 1 , R 2 and R 3 are H and R 4is a compound of formula (1) in which m is an integer 1 and n is an integer 0 or 1; or a pharmaceutically acceptable salt thereof.

[0035] In another aspect of the present invention, ring A is phenyl, indolyl, pyridinyl, thiophenyl, or isothiazolyl; X is CH or N; and L is NR 1 or O and; R 1 is H and; X' is CR 2 and, here R 2 is H or methyl; R 3 is H or cyano; R 4 is a compound of formula (1), in which is a fluoro, chloro, or -CF3; m is an integer 1, and n is an integer 0, 1, or 2; and a pharmaceutically acceptable salt thereof. Another embodiment is that ring A is phenyl, indolyl, pyridinyl, thiophenyl, or isothiazolyl; X is CH or N; and L is NR 1 or O and; X' is CR 2 and; R 1 , R 2 and R 3 are H and R 4 is a compound of formula (1) in which is methyl, fluoro, or chloro; m is an integer 1, and n is an integer 0, 1, or 2; and a pharmaceutically acceptable salt thereof. Another embodiment is that ring A is phenyl, indolyl, pyridinyl, thiophenyl, or isothiazolyl; X is CH or N; and L is NR 1 or O and; X' is CR 2 and; R 1 , R 2 and R 3 are H and R 4 is a compound of formula (1) in which m is an integer 1 and n is an integer 0 or 1; and a pharmaceutically acceptable salt thereof.

[0036] Another aspect of the present invention is a compound of formula (1) selected from the group consisting of:

[0037] N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide;

[0038] N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamide;

[0039] N-((1R,3s,5S)-8-(4-chlorobenzyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamide;

[0040] N-((1R,3s,5S)-8-(4-fluorobenzyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide;

[0041] N-((1R,3s,5S)-8-(4-chlorobenzyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide;

[0042] N-((1R,3s,5S)-8-((1H-indole-5-yl)methyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide;

[0043] N-((1R,3s,5S)-8-(thiophene-2-ylmethyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide;

[0044] N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-2-methyl-1H-indole-6-carboxamide;

[0045] N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-2,3,4,9-tetrahydro-1H-carbazole-7-carboxamide;

[0046] N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-1H-indazole-6-carboxamide;

[0047] N-((1R,3s,5S)-8-(4-(trifluoromethyl)benzyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide;

[0048] N-((1R,3s,5S)-8-(pyridine-2-ylmethyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide;

[0049] N-((1R,3s,5S)-8-(pyridine-3-ylmethyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide;

[0050] N-((1R,3s,5S)-8-(pyridine-4-ylmethyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide;

[0051] N-((1R,3s,5S)-8-(pyrazine-2-ylmethyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide;

[0052] N-((1R,3s,5S)-8-((1-methyl-1H-imidazole-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide;

[0053] N-((1R,3s,5S)-8-phenyl-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide;

[0054] N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-1-(pyridine-4-yl)-1H-indole-6-carboxamide;

[0055] N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-3-cyano-1H-indole-6-carboxamide;

[0056] N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-2-(trifluoromethyl)-1H-indole-6-carboxamide;

[0057] N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-6-carboxamide;

[0058] N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-1-(4-fluorophenyl)-1H-indole-6-carboxamide;

[0059] N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-1-phenyl-1H-indole-6-carboxamide;

[0060] N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)benzofuran-6-carboxamide;

[0061] N-((1R,3s,5S)-8-(isothiazole-5-ylmethyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide;

[0062] N-((1R,3s,5S)-8-(isothiazole-3-ylmethyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide;

[0063] N-((1R,3s,5S)-8-(thiazole-2-ylmethyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide; and

[0064] N-((1R,3s,5S)-8-((4-methylthiazole-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide; and pharmaceutically acceptable salts thereof.

[0065] In another aspect of the present invention, c5-HT2B inhibitor IC 50 The compound of formula (1) with <1000 nM is selected from the group consisting of the following:

[0066] N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide;

[0067] N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamide;

[0068] N-((1R,3s,5S)-8-(4-chlorobenzyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamide;

[0069] N-((1R,3s,5S)-8-(4-fluorobenzyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide;

[0070] N-((1R,3s,5S)-8-(4-chlorobenzyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide;

[0071] N-((1R,3s,5S)-8-((1H-indole-5-yl)methyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide;

[0072] N-((1R,3s,5S)-8-(thiophene-2-ylmethyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide;

[0073] N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-2-methyl-1H-indole-6-carboxamide;

[0074] N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-2,3,4,9-tetrahydro-1H-carbazole-7-carboxamide;

[0075] N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-1H-indazole-6-carboxamide;

[0076] N-((1R,3s,5S)-8-(4-(trifluoromethyl)benzyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide;

[0077] N-((1R,3s,5S)-8-(pyridine-2-ylmethyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide;

[0078] N-((1R,3s,5S)-8-(pyridine-3-ylmethyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide;

[0079] N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-1-(pyridine-4-yl)-1H-indole-6-carboxamide;

[0080] N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-3-cyano-1H-indole-6-carboxamide;

[0081] N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-2-(trifluoromethyl)-1H-indole-6-carboxamide;

[0082] N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-1-(4-fluorophenyl)-1H-indole-6-carboxamide;

[0083] N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-1-phenyl-1H-indole-6-carboxamide;

[0084] N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)benzofuran-6-carboxamide;

[0085] N-((1R,3s,5S)-8-(isothiazole-5-ylmethyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide;

[0086] N-((1R,3s,5S)-8-(isothiazole-3-ylmethyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide;

[0087] N-((1R,3s,5S)-8-(thiazole-2-ylmethyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide; and

[0088] N-((1R,3s,5S)-8-((4-methylthiazole-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide; and pharmaceutically acceptable salts thereof.

[0089] In another aspect of the present invention, c5-HT2B inhibitor IC 50 The compound of formula (1) with <500 nM is selected from the group consisting of the following:

[0090] N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide;

[0091] N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamide;

[0092] N-((1R,3s,5S)-8-(4-chlorobenzyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamide;

[0093] N-((1R,3s,5S)-8-(4-fluorobenzyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide;

[0094] N-((1R,3s,5S)-8-(4-chlorobenzyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide;

[0095] N-((1R,3s,5S)-8-((1H-indole-5-yl)methyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide;

[0096] N-((1R,3s,5S)-8-(thiophene-2-ylmethyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide;

[0097] N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-2-methyl-1H-indole-6-carboxamide;

[0098] N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-2,3,4,9-tetrahydro-1H-carbazole-7-carboxamide;

[0099] N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-1H-indazole-6-carboxamide;

[0100] N-((1R,3s,5S)-8-(4-(trifluoromethyl)benzyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide;

[0101] N-((1R,3s,5S)-8-(pyridine-2-ylmethyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide;

[0102] N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-3-cyano-1H-indole-6-carboxamide;

[0103] N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-2-(trifluoromethyl)-1H-indole-6-carboxamide;

[0104] N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-1-(4-fluorophenyl)-1H-indole-6-carboxamide;

[0105] N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-1-phenyl-1H-indole-6-carboxamide;

[0106] N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)benzofuran-6-carboxamide;

[0107] N-((1R,3s,5S)-8-(isothiazole-5-ylmethyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide;

[0108] N-((1R,3s,5S)-8-(isothiazole-3-ylmethyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide;

[0109] N-((1R,3s,5S)-8-(thiazole-2-ylmethyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide; and

[0110] N-((1R,3s,5S)-8-((4-methylthiazole-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide; and pharmaceutically acceptable salts thereof.

[0111] In another aspect of the present invention, c5-HT2B inhibitor IC 50 The compound of formula (1) with <100 nM is selected from the group consisting of the following:

[0112] N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide;

[0113] N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamide;

[0114] N-((1R,3s,5S)-8-(4-chlorobenzyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamide;

[0115] N-((1R,3s,5S)-8-(4-fluorobenzyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide;

[0116] N-((1R,3s,5S)-8-(4-chlorobenzyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide;

[0117] N-((1R,3s,5S)-8-((1H-indole-5-yl)methyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide;

[0118] N-((1R,3s,5S)-8-(thiophene-2-ylmethyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide;

[0119] N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-2-methyl-1H-indole-6-carboxamide;

[0120] N-((1R,3s,5S)-8-(4-(trifluoromethyl)benzyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide;

[0121] N-((1R,3s,5S)-8-(pyridine-2-ylmethyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide;

[0122] N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-2-(trifluoromethyl)-1H-indole-6-carboxamide;

[0123] N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-1-(4-fluorophenyl)-1H-indole-6-carboxamide;

[0124] N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-1-phenyl-1H-indole-6-carboxamide;

[0125] N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)benzofuran-6-carboxamide;

[0126] N-((1R,3s,5S)-8-(isothiazole-5-ylmethyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide; and

[0127] N-((1R,3s,5S)-8-(isothiazole-3-ylmethyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide; and pharmaceutically acceptable salts thereof.

[0128] In another aspect of the present invention, c5-HT2B inhibitor IC 50 The compound of formula (1) with <10 nM is selected from the group consisting of the following:

[0129] N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide;

[0130] N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamide;

[0131] N-((1R,3s,5S)-8-(4-chlorobenzyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamide;

[0132] N-((1R,3s,5S)-8-(4-fluorobenzyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide;

[0133] N-((1R,3s,5S)-8-(4-chlorobenzyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide;

[0134] N-((1R,3s,5S)-8-((1H-indole-5-yl)methyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide;

[0135] N-((1R,3s,5S)-8-(thiophene-2-ylmethyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide;

[0136] N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-2-methyl-1H-indole-6-carboxamide;

[0137] N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)benzofuran-6-carboxamide; and

[0138] N-((1R,3s,5S)-8-(isothiazole-5-ylmethyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide; and pharmaceutically acceptable salts thereof.

[0139] In another aspect of the present invention, c5-HT2B inhibitor IC 50Compounds of formula (1) with <1 nM are selected from the group consisting of:

[0140] N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide;

[0141] N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamide;

[0142] N-((1R,3s,5S)-8-(4-fluorobenzyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide;

[0143] N-((1R,3s,5S)-8-(4-chlorobenzyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide;

[0144] N-((1R,3s,5S)-8-((1H-indole-5-yl)methyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide; and

[0145] N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)benzofuran-6-carboxamide; and pharmaceutically acceptable salts thereof.

[0146] Another aspect of the present invention is N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide, <1 nM c5-HT2B inhibitory IC 50 It is a compound of chemical formula (1) having [ ]; or a pharmaceutically acceptable salt thereof.

[0147] Another aspect of the present invention is N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamide, a <1 nM c5-HT2B inhibitory IC 50 It is a compound of chemical formula (1) having [ ]; or a pharmaceutically acceptable salt thereof.

[0148] Another aspect of the present invention is N-((1R,3s,5S)-8-(4-fluorobenzyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide, <1 nM c5-HT2B inhibitory IC 50 It is a compound of chemical formula (1) having [ ]; or a pharmaceutically acceptable salt thereof.

[0149] Another aspect of the present invention is N-((1R,3s,5S)-8-(4-chlorobenzyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide, <1 nM c5-HT2B inhibitory IC 50 It is a compound of chemical formula (1) having [ ]; or a pharmaceutically acceptable salt thereof.

[0150] Another aspect of the present invention is N-((1R,3s,5S)-8-((1H-indole-5-yl)methyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide, a c5-HT2B inhibitory IC <1 nM. 50 It is a compound of chemical formula (1) having [ ]; or a pharmaceutically acceptable salt thereof.

[0151] Another aspect of the present invention is N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)benzofuran-6-carboxamide, <1 nM c5-HT2B inhibitory IC 50 It is a compound of chemical formula (1) having [ ]; or a pharmaceutically acceptable salt thereof.

[0152] In another embodiment, the compound of formula (1) is the compound of formula (1A) below and a pharmaceutically acceptable salt thereof:

[0153]

[0154] Here, R 2 , R 3 and (R 4 ) n is as defined herein. Another aspect is R 2 , R 3 and R 4is as defined herein, and is a compound of formula (1A) where n is an integer 0, 1, or 2; and a pharmaceutically acceptable salt thereof. Another embodiment is R 2 ga is H, methyl, fluorochloro, or -CF3; R 3 is H, fluoro, chloro, methyl, or cyano; R 4 is a compound of formula (1A), where is methyl, halo, or -CF3; and n is an integer 0, 1, or 2; and a pharmaceutically acceptable salt thereof. Another embodiment is R 2 ga is H, methyl or -CF3 and R 3 is H or cyano; R 4 , here R 4 is a compound of formula (1A), where is methyl, fluoro, chloro, or -CF3; and n is an integer 0, 1, or 2; and a pharmaceutically acceptable salt thereof. Another embodiment is R 2 and R 3 Both of these are H and R 4 is a compound of formula (1A) and a pharmaceutically acceptable salt thereof, wherein n is an integer 0 or 1; and n is an integer 0 or 1.

[0155] Another embodiment is a compound of formula (1A) selected from the group consisting of:

[0156] N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide;

[0157] N-((1R,3s,5S)-8-(4-fluorobenzyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide;

[0158] N-((1R,3s,5S)-8-(4-chlorobenzyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide;

[0159] N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-2-methyl-1H-indole-6-carboxamide;

[0160] N-((1R,3s,5S)-8-(4-(trifluoromethyl)benzyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide;

[0161] N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-3-cyano-1H-indole-6-carboxamide; and

[0162] N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-2-(trifluoromethyl)-1H-indole-6-carboxamide; and pharmaceutically acceptable salts thereof.

[0163] In another aspect, c5-HT2B IC 50 Compounds of formula (1A) having < 100 nM are selected from the group consisting of the following:

[0164] N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide;

[0165] N-((1R,3s,5S)-8-(4-fluorobenzyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide;

[0166] N-((1R,3s,5S)-8-(4-chlorobenzyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide;

[0167] N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-2-methyl-1H-indole-6-carboxamide;

[0168] N-((1R,3s,5S)-8-(4-(trifluoromethyl)benzyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide; and

[0169] N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-2-(trifluoromethyl)-1H-indole-6-carboxamide; and pharmaceutically acceptable salts thereof.

[0170] In another aspect, c5-HT2B IC 50 Compounds of formula (1A) having < 10 nM are selected from the group consisting of the following:

[0171] N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide;

[0172] N-((1R,3s,5S)-8-(4-fluorobenzyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide;

[0173] N-((1R,3s,5S)-8-(4-chlorobenzyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide; and

[0174] N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-2-methyl-1H-indole-6-carboxamide; and pharmaceutically acceptable salts thereof.

[0175] In another aspect, c5-HT2B IC 50 Compounds of formula (1A) having < 1 nM are selected from the group consisting of the following:

[0176] N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide;

[0177] N-((1R,3s,5S)-8-(4-fluorobenzyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide; and

[0178] N-((1R,3s,5S)-8-(4-chlorobenzyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide; and pharmaceutically acceptable salts thereof.

[0179] In another aspect of the present invention, the compound of formula (1) is the compound of formula (1B); and the pharmaceutically acceptable salt thereof:

[0180]

[0181] Here, ring A is indolyl, thiophenyl, pyridinyl, pyrazinyl, isothiazolyl, or thiazolyl, and each is (R 4 ) n Replaced with; (R 4 ) n ...is as defined herein. Another embodiment is that ring A is indolyl, thiophenyl, pyridinyl, isothiazolyl, or thiazolyl, and each is (R 4 ) n Replaced with; R 4 is a compound of formula (1B) where is methyl, halo, or -CF3; and n is an integer 0, 1, or 2; and a pharmaceutically acceptable salt thereof. Another embodiment is that ring A is indolyl, thiophenyl, pyridinyl, isothiazolyl, or thiazolyl, each of which is (R 4 ) n Replaced with; R 4 is a compound of formula (1B), where is methyl, fluoro, chloro, or -CF3; and n is an integer 0, 1, or 2; and a pharmaceutically acceptable salt thereof. Another embodiment is that ring A is indolyl, thiophenyl, isothiazolyl, or thiazolyl, each being (R 4 ) n Replaced with; R 4 is a compound of formula (1B) where is methyl, fluoro, chloro, or -CF3; and n is an integer 0 or 1; and a pharmaceutically acceptable salt thereof. In another embodiment, the compound of formula (1B) is selected from the group consisting of:

[0182] N-((1R,3s,5S)-8-((1H-indole-5-yl)methyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide;

[0183] N-((1R,3s,5S)-8-(thiophene-2-ylmethyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide;

[0184] N-((1R,3s,5S)-8-(pyridine-2-ylmethyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide;

[0185] N-((1R,3s,5S)-8-(pyridine-3-ylmethyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide;

[0186] N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-1-phenyl-1H-indole-6-carboxamide;

[0187] N-((1R,3s,5S)-8-(isothiazole-5-ylmethyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide;

[0188] N-((1R,3s,5S)-8-(isothiazole-3-ylmethyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide;

[0189] N-((1R,3s,5S)-8-(thiazole-2-ylmethyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide; and

[0190] N-((1R,3s,5S)-8-((4-methylthiazole-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide; and pharmaceutically acceptable salts thereof.

[0191] In another embodiment, a compound of formula (1B) having a c5-5HT2B IC50 <100 nM is selected from the group consisting of:

[0192] N-((1R,3s,5S)-8-((1H-indole-5-yl)methyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide;

[0193] N-((1R,3s,5S)-8-(thiophene-2-ylmethyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide;

[0194] N-((1R,3s,5S)-8-(pyridine-2-ylmethyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide;

[0195] N-((1R,3s,5S)-8-(isothiazole-5-ylmethyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide; and

[0196] N-((1R,3s,5S)-8-(isothiazole-3-ylmethyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide; and pharmaceutically acceptable salts thereof.

[0197] In another embodiment, a compound of formula (1B) having a c5-5HT2B IC50 <10 nM is selected from the group consisting of:

[0198] N-((1R,3s,5S)-8-((1H-indole-5-yl)methyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide;

[0199] N-((1R,3s,5S)-8-(thiophene-2-ylmethyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide; and

[0200] N-((1R,3s,5S)-8-(isothiazole-5-ylmethyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide; and pharmaceutically acceptable salts thereof.

[0201] Another embodiment is a compound of formula (1B) having an IC50 of <1 nM, c5-5HT2B, which is N-((1R,3s,5S)-8-((1H-indole-5-yl)methyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide; and a pharmaceutically acceptable salt thereof.

[0202] In another embodiment, the compound of formula (1) is the compound of formula (1C); and the pharmaceutically acceptable salt thereof:

[0203]

[0204] Here, R 1 are each a phenyl or pyridinyl selectively substituted with a fluoro, chloro, or -CF3; and (R 4 ) n is as defined herein.

[0205] Another mode is R 1 Each is a phenyl or pyridinyl selectively substituted with a fluoro, chloro, or -CF3 group; R 4 is a compound of formula (1C), where is methyl, fluoro, chloro, or -CF3; and n is an integer 0, 1, or 2; and a pharmaceutically acceptable salt thereof. Another embodiment is R 1 Each is a phenyl or pyridinyl selectively substituted with a fluoro or chloro; R 4 is a compound of formula (1C), where is a fluoro or chloro or -CF3; and n is an integer 0 or 1; and a pharmaceutically acceptable salt thereof. Another embodiment is R 1 is a compound of formula (1C), each being a phenyl or pyridinyl selectively substituted with a fluoro or chloro; and n is an integer 0 or 1; and a pharmaceutically acceptable salt thereof. In another embodiment, the compound of formula (1C) is selected from the group consisting of:

[0206] N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-1-(pyridine-4-yl)-1H-indole-6-carboxamide;

[0207] N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-1-(4-fluorophenyl)-1H-indole-6-carboxamide; and

[0208] N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-1-phenyl-1H-indole-6-carboxamide; and pharmaceutically acceptable salts thereof.

[0209] Another embodiment is N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-1-(4-fluorophenyl)-1H-indole-6-carboxamide or N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-1-phenyl-1H-indole-6-carboxamide, 5c-5HT2B IC 50 A compound of formula (1C) having <100 nM; and a pharmaceutically acceptable salt thereof.

[0210] In another embodiment, the compound of formula (1) is the compound of formula (1D); and the pharmaceutically acceptable salt thereof:

[0211]

[0212] Here (R 4 ) n is as defined herein. Another aspect is R 4 A compound of formula (1D) in which α is methyl, halo, or -CF3 and n is an integer 0, 1, or 2; and a pharmaceutically acceptable salt thereof. Another embodiment is R 4 A is a fluoro, chloro, or -CF3; and a compound of formula (1D), where n is an integer 0, 1, or 2; and a pharmaceutically acceptable salt thereof. Another embodiment is R 4 A is a fluoro, chloro, or -CF3; and a compound of formula (1D), where n is an integer 0 or 1; and a pharmaceutically acceptable salt thereof. Another embodiment is R 4A compound of formula (1D) in which α is fluoro or chloro; and n is an integer 0 or 1; and a pharmaceutically acceptable salt thereof. Another embodiment is a compound of formula (1D) in which N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamide or N-((1R,3s,5S)-8-(4-chlorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamide; and a pharmaceutically acceptable salt thereof.

[0213] Another embodiment is a compound of formula (1D), N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamide, having an IC50 of <1 nM of 5c-5HT2B; and a pharmaceutically acceptable salt thereof.

[0214] In another embodiment, the compound of formula (1) is the compound of formula (1E); and the pharmaceutically acceptable salt thereof:

[0215]

[0216] Here (R 4 ) n is as defined herein. Another aspect is R 4 A compound of formula (1E) in which α is methyl, halo, or -CF3 and n is an integer 0, 1, or 2; and a pharmaceutically acceptable salt thereof. Another embodiment is R 4 A is a fluoro, chloro, or -CF3; and a compound of formula (1E), where n is an integer 0, 1, or 2; and a pharmaceutically acceptable salt thereof. Another embodiment is R 4 A is a fluoro, chloro, or -CF3; and a compound of formula (1E) where n is an integer 0 or 1; and a pharmaceutically acceptable salt thereof. Another embodiment is R 4A compound of formula (1E) in which α is fluoro or chloro; and n is an integer 0 or 1; and a pharmaceutically acceptable salt thereof. Another embodiment is a compound of formula (1E) in which α is N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)benzofuran-6-carboxamide; and a pharmaceutically acceptable salt thereof.

[0217] Another aspect of the present invention is a composition comprising a compound of formula (1) or a pharmaceutically acceptable salt thereof. In the compositions described below, the example numbers are interchangeable with the respective compound names described herein. In another aspect, the composition is c5-5HT2B IC 50 Compound of formula (1) having <1000 nM; or a pharmaceutically acceptable salt thereof, wherein the compound is any one of Examples 1-13, 18-20, or 22-28. In another embodiment, the composition comprises c5-5HT2B IC 50 Compound of formula (1) having <500 nM; or a pharmaceutically acceptable salt thereof, wherein the compound is any one of Examples 1-12, 19-20, or 22-28. In another embodiment, the composition comprises c5-5HT2B IC 50 Compound of formula (1) having <100 nM; or a pharmaceutically acceptable salt thereof, wherein the compound is any one of Examples 1-8, 11-12, 20, or 22-26. In another embodiment, the composition comprises c5-5HT2B IC 50 Compound of formula (1) having <10 nM; or a pharmaceutically acceptable salt thereof, wherein the compound is any one of Examples 1-8, 24, or 25. In another embodiment, the composition comprises c5-5HT2B IC 50A compound of formula (1) having <1 nM; or a pharmaceutically acceptable salt thereof, wherein the compound is any one of Examples 1, 2, 4-6 or 24. In another embodiment, the composition comprises a compound of formula (1) or a pharmaceutically acceptable salt thereof and further comprises at least one pharmaceutically acceptable excipient.

[0218] In another embodiment, the composition comprises a compound of formula (1) which is a compound of formula (1A), formula (1B), formula (1C), formula (1D), or formula (1E), or a pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises a compound of formula (1A) or a pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises a compound of formula (1B) or a pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises a compound of formula (1C) or a pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises a compound of formula (1D) or a pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises a compound of formula (1E) or a pharmaceutically acceptable salt thereof. In another embodiment, the composition further comprises at least one pharmaceutically acceptable excipient.

[0219] In another aspect, the composition is a c5-5HT2B IC 50 Compound of formula (1A) having <500 nM; or a pharmaceutically acceptable salt thereof, wherein the compound is any one of Examples 1, 4-5, 8, 11, 19, or 20. In another embodiment, the composition comprises c5-5HT2B IC 50 Compound of formula (1A) having <100 nM; or a pharmaceutically acceptable salt thereof, wherein the compound is any one of Examples 1, 4-5, 8, 11 or 20. In another embodiment, the composition comprises c5-5HT2B IC 50Compound of formula (1A) having <10 nM; or a pharmaceutically acceptable salt thereof, wherein the compound is any one of Examples 1, 4-5, or 8. In another embodiment, the composition is c5-5HT2B IC 50 Compound of formula (1A) having <1 nM; or a pharmaceutically acceptable salt thereof, wherein the compound is any one of Examples 1, 4, or 5. In another embodiment, the composition further comprises at least one pharmaceutically acceptable excipient.

[0220] In another aspect, the composition is a c5-5HT2B IC 50 Compound of formula (1B) having <1000 nM; or a pharmaceutically acceptable salt thereof, wherein the compound is any one of Examples 6-7, 12-13, or 25-28. In another embodiment, the composition comprises c5-5HT2B IC 50 Compound of formula (1B) having <500 nM; or a pharmaceutically acceptable salt thereof, wherein the compound is any one of Examples 6-7, 12 or 25-28. In another embodiment, the composition comprises c5-5HT2B IC 50 Compound of formula (1B) having <100 nM; or a pharmaceutically acceptable salt thereof, wherein the compound is any one of Examples 6, 7, 12, 25, or 26. In another embodiment, the composition comprises c5-5HT2B IC 50 Compound of formula (1B) having <10 nM; or a pharmaceutically acceptable salt thereof, wherein the compound is any one of Examples 6, 7, or 25. In another embodiment, the composition comprises c5-5HT2B IC 50 Compound of formula (1B) having <1 nM; or a pharmaceutically acceptable salt thereof, said compound is Example 6. In another embodiment, the composition further comprises at least one pharmaceutically acceptable excipient.

[0221] In another aspect, the composition is a c5-5HT2B IC 50 Compound of formula (1C) having <100 nM; or a pharmaceutically acceptable salt thereof, said compound is Example 22 or 23.

[0222] In another aspect, the composition is a c5-5HT2B IC 50 Compound of formula (1D) having <10 nM; or a pharmaceutically acceptable salt thereof, said compound is Example 2 or 3. In another embodiment, the composition is c5-5HT2B IC 50 Compound of formula (1D) having <1 nM; or a pharmaceutically acceptable salt thereof, said compound is Example 2.

[0223] In another aspect, the composition is a c5-5HT2B IC 50 Compound of formula (1E) having <1 nM; or a pharmaceutically acceptable salt thereof, said compound is Example 24. In another embodiment, the composition further comprises at least one pharmaceutically acceptable excipient.

[0224] In another embodiment, the composition is administered orally or by injection. In another embodiment, the composition is administered orally. In another embodiment, the composition is administered by subcutaneous injection or intramuscular injection. In another embodiment, the composition is administered three times a week. In another embodiment, the composition is administered five times a week. In another embodiment, the composition is administered every other day. In another embodiment, the composition is administered daily. In another embodiment, the composition is administered twice a day.

[0225] Another aspect of the present invention is a method for treating animals with MMVD, CHF, and / or asymptomatic heart failure by administering a therapeutic dose of a compound of formula (1) or a pharmaceutically acceptable salt thereof to animals in need. In the treatment method described below, the example numbers are interchangeable with the respective compound names described herein. Another aspect is a method for treating animals with MMVD, CHF, and / or asymptomatic heart failure by administering a therapeutic dose of a compound of formula (1); or a pharmaceutically acceptable salt thereof to animals in need, wherein the compound is 5c-5HT2B IC 50 It has < 1000 nM and is one of Examples 1-13, 18-20, or 22-28. Another aspect is a method for treating animals with MMVD, CHF, and / or asymptomatic heart failure by administering a therapeutic dose of a compound of formula (1); or a pharmaceutically acceptable salt thereof, to the animals in need, wherein the compound is 5c-5HT2B IC 50 It has < 500 nM and is one of Examples 1-12, 19-20, or 22-28. Another aspect is a method for treating animals with MMVD, CHF, and / or asymptomatic heart failure by administering a therapeutic dose of a compound of formula (1); or a pharmaceutically acceptable salt thereof, to the animals in need, wherein the compound is 5c-5HT2B IC 50 It has < 100 nM and is one of Examples 1-8, 11-12, 20, or 22-26. Another aspect is a method for treating animals with MMVD, CHF, and / or asymptomatic heart failure by administering a therapeutic dose of a compound of formula (1); or a pharmaceutically acceptable salt thereof, to the animals in need, wherein the compound is 5c-5HT2B IC 50It has < 10 nM and is one of Examples 1-8, 24, or 25. Another aspect is a method for treating animals with MMVD, CHF, and / or asymptomatic heart failure by administering a therapeutic dose of a compound of formula (1); or a pharmaceutically acceptable salt thereof, to the animals in need, wherein the compound is 5c-5HT2B IC 50 It has < 1 nM and is one of Examples 1, 2, 4-6 or 24. In another embodiment, the animal is a pet. In another embodiment, the pet is a dog.

[0226] Another embodiment is a method for treating animals with MMVD, CHF, and / or asymptomatic heart failure by administering to the animals in need a therapeutic amount of a compound of formula (1), which is a compound of formula (1A), formula (1B), formula (1C), formula (1D), or formula (1E), or a pharmaceutically acceptable salt thereof. In another embodiment, the animal is a companion animal. In another embodiment, the companion animal is a dog.

[0227] Another aspect is a method for treating animals with MMVD, CHF, and / or asymptomatic heart failure by administering a therapeutic dose of a compound of formula (1A); or a pharmaceutically acceptable salt thereof, to animals in need. Another aspect is 5c-5HT2B IC, which is any one of Examples 1, 4, 5, 8, 11, 19, or 20. 50 A method for treating animals with MMVD, CHF, and / or asymptomatic heart failure by administering a therapeutic dose of a compound of formula (1A) having <500 nM; or a pharmaceutically acceptable salt thereof, to the animals in need. Another aspect is 5c-5HT2B IC, which is any one of Examples 1, 4, 5, 8, 11, or 20. 50A method for treating animals with MMVD, CHF, and / or asymptomatic heart failure by administering a therapeutic dose of a compound of formula (1A) having <100 nM; or a pharmaceutically acceptable salt thereof, to the animals in need. Another aspect is 5c-5HT2B IC, which is any one of Examples 1, 4, 5, or 8. 50 A method for treating animals with MMVD, CHF, and / or asymptomatic heart failure by administering a therapeutic dose of a compound of formula (1A) having <10 nM; or a pharmaceutically acceptable salt thereof, to animals in need. Another aspect is 5c-5HT2B IC, which is any one of Examples 1, 4, or 5. 50 A method for treating animals with MMVD, CHF, and / or asymptomatic heart failure by administering a therapeutic dose of a compound of formula (1A) having <1 nM; or a pharmaceutically acceptable salt thereof to the animals in need. In another embodiment, the animal is a companion animal. In another embodiment, the companion animal is a dog.

[0228] Another aspect is a method of treating animals with MMVD, CHF and / or asymptomatic heart failure by administering a therapeutic dose of a compound of formula (1B); or a pharmaceutically acceptable salt thereof. Another aspect is 5c-5HT2B IC, which is any one of Examples 6-7, 12-13, or 25-28. 50 A method for treating animals with MMVD, CHF, and / or asymptomatic heart failure by administering a therapeutic dose of a compound of formula (1B) having <1000 nM; or a pharmaceutically acceptable salt thereof. Another aspect is 5c-5HT2B IC, which is any one of Examples 6-7, 12, or 25-26. 50 A method for treating animals with MMVD, CHF, and / or asymptomatic heart failure by administering a therapeutic dose of a compound of formula (1B) having <100 nM; or a pharmaceutically acceptable salt thereof. Another aspect is 5c-5HT2B IC, which is either Example 6-7 or 25. 50A method for treating animals with MMVD, CHF, and / or asymptomatic heart failure by administering a therapeutic dose of a compound of formula (1B) having <10 nM; or a pharmaceutically acceptable salt thereof. Another aspect is Example 6, 5c-5HT2B IC 50 A method for treating animals with MMVD, CHF and / or asymptomatic heart failure by administering a therapeutic dose of a compound of formula (1B) having <1 nM; or a pharmaceutically acceptable salt thereof. In another embodiment, the animal is a companion animal. In another embodiment, the companion animal is a dog.

[0229] Another aspect is a method of treating animals with MMVD, CHF and / or asymptomatic heart failure by administering a therapeutic dose of a compound of formula (1C); or a pharmaceutically acceptable salt thereof to the animals in need.

[0230] Another aspect is the 5c-5HT2B IC, which is any one of Examples 18, 22, or 23. 50 A method for treating animals with MMVD, CHF, and / or asymptomatic heart failure by administering a therapeutic dose of a compound of formula (1C) having <1000 nM; or a pharmaceutically acceptable salt thereof, to the animals in need. Another aspect is 5c-5HT2B IC, which is Example 22 or 23. 50 A method for treating animals with MMVD, CHF, and / or asymptomatic heart failure by administering a therapeutic dose of a compound of formula (1C) having <100 nM; or a pharmaceutically acceptable salt thereof, to the animals in need. In another embodiment, the animal is a companion animal. In another embodiment, the companion animal is a dog.

[0231] Another embodiment is a method of treating animals with MMVD, CHF, and / or asymptomatic heart failure by administering a therapeutic dose of a compound of formula (1D); or a pharmaceutically acceptable salt thereof, to animals in need. Another embodiment is a method of treating animals with MMVD, CHF, and / or asymptomatic heart failure by administering a therapeutic dose of a compound of formula (1D); or a pharmaceutically acceptable salt thereof, to animals in need. Another embodiment is 5c-5HT2B IC, which is Example 2 or 3. 50 A method for treating animals with MMVD, CHF, and / or asymptomatic heart failure by administering a therapeutic dose of a compound of formula (1D) having <10 nM; or a pharmaceutically acceptable salt thereof, to animals in need. Another aspect is Example 2, 5c-5HT2B IC 50 A method for treating animals with MMVD, CHF, and / or asymptomatic heart failure by administering a therapeutic dose of a compound of formula (1D) having <1 nM; or a pharmaceutically acceptable salt thereof to the animals in need. In another embodiment, the animal is a companion animal. In another embodiment, the companion animal is a dog.

[0232] Another aspect is a method for treating animals with MMVD, CHF, and / or asymptomatic heart failure by administering a therapeutic dose of a compound of formula (1E); or a pharmaceutically acceptable salt thereof, to animals in need. Another aspect is Example 24, 5c-5HT2B IC 50 A method for treating animals with MMVD, CHF, and / or asymptomatic heart failure by administering a therapeutic dose of a compound of formula (1E) having <1 nM; or a pharmaceutically acceptable salt thereof to the animals in need. In another embodiment, the animal is a companion animal. In another embodiment, the companion animal is a dog.

[0233] Another aspect of the present invention is the use of a compound of Formula (1) or a pharmaceutically acceptable salt thereof for preparing a drug for treating animals with MMVD, CHF, and / or asymptomatic heart failure. In the uses described below, the example numbers are interchangeable with the respective compound names described herein. Another aspect is the use of 5c-5HT2B IC for preparing a drug for treating animals with MMVD, CHF, and / or asymptomatic heart failure. 50 Use of a compound of formula (1) having <1000 nM; or a pharmaceutically acceptable salt thereof, wherein the compound is any one of Examples 1-13, 18-20, or 22-28. Another aspect is the use of a 5c-5HT2B IC for preparing a drug to treat animals with MMVD, CHF, and / or asymptomatic heart failure. 50 Use of a compound of formula (1) having <500 nM; or a pharmaceutically acceptable salt thereof, wherein the compound is any one of Examples 1-12, 19-20, or 22-28. Another aspect is the use of a 5c-5HT2B IC for preparing a drug to treat animals with MMVD, CHF, and / or asymptomatic heart failure. 50 Use of a compound of formula (1) having <100 nM; or a pharmaceutically acceptable salt thereof, wherein the compound is any one of Examples 1-8, 11-12, 20, or 22-26. Another aspect is the use of a 5c-5HT2B IC for preparing a drug to treat animals with MMVD, CHF, and / or asymptomatic heart failure. 50 Use of a compound of formula (1) having <10 nM; or a pharmaceutically acceptable salt thereof, wherein the compound is any one of Examples 1-8, 24, or 25. Another aspect is the use of a 5c-5HT2B IC for preparing a drug to treat animals with MMVD, CHF, and / or asymptomatic heart failure. 50A compound of formula (1) having <1 nM; or a pharmaceutically acceptable salt thereof, said compound is any one of Examples 1, 2, 4-6 or 24. In another embodiment, the animal is a pet. In another embodiment, the pet is a dog.

[0234] Another embodiment is the use of a compound of formula (1A), formula (1B), formula (1C), formula (1D), or formula (1E), or a pharmaceutically acceptable salt thereof, for preparing a medicine to treat animals with MMVD, CHF, and / or asymptomatic heart failure. In another embodiment, the animal is a companion animal. In another embodiment, the companion animal is a dog.

[0235] Another aspect is the use of a compound of formula (1A) or a pharmaceutically acceptable salt thereof for preparing a drug for treating animals with MMVD, CHF and / or asymptomatic heart failure. Another aspect is the use of 5c-5HT2B IC for preparing a drug for treating animals with MMVD, CHF and / or asymptomatic heart failure. 50 Use of a compound of formula (1A) having <500 nM; or a pharmaceutically acceptable salt thereof, wherein the compound is any one of Examples 1, 4, 5, 8, 11, 19, or 20. Another aspect is the use of a 5c-5HT2B IC for preparing a drug to treat animals with MMVD, CHF, and / or asymptomatic heart failure. 50 Use of a compound of formula (1A) having <100 nM; or a pharmaceutically acceptable salt thereof, wherein the compound is any one of Examples 1, 4, 5, 8, 11 or 20. Another aspect is the use of a 5c-5HT2B IC for preparing a drug to treat animals with MMVD, CHF and / or asymptomatic heart failure. 50Use of a compound of formula (1A) having <10 nM; or a pharmaceutically acceptable salt thereof, said compound being any one of Examples 1, 4, 5 or 8. Another aspect is the use of a 5c-5HT2B IC for preparing a drug to treat animals with MMVD, CHF and / or asymptomatic heart failure. 50 A compound of formula (1A) having <1 nM; or a pharmaceutically acceptable salt thereof, said compound is any one of Examples 1, 4 or 5. In another embodiment, the animal is a companion animal. In another embodiment, the companion animal is a dog.

[0236] Another aspect is the use of a compound of formula (1B), or a pharmaceutically acceptable salt thereof, for preparing a drug for treating animals with MMVD, CHF, and / or asymptomatic heart failure. Another aspect is the use of 5c-5HT2B IC for preparing a drug for treating animals with MMVD, CHF, and / or asymptomatic heart failure. 50 Use of a compound of formula (1B) having <1000 nM; or a pharmaceutically acceptable salt thereof, said compound being any one of Examples 6, 7 12-13 or 25-28. Another aspect is the use of a 5c-5HT2B IC for preparing a drug to treat animals with MMVD, CHF and / or asymptomatic heart failure. 50 Use of a compound of formula (1B) having <500 nM; or a pharmaceutically acceptable salt thereof, wherein the compound is any one of Examples 6-7, 12 or 25-28. Another aspect is the use of a 5c-5HT2B IC for preparing a drug to treat animals with MMVD, CHF and / or asymptomatic heart failure. 50Use of a compound of formula (1B) having <100 nM; or a pharmaceutically acceptable salt thereof, said compound being any one of Examples 6-7, 12, 25, or 26. Another aspect is the use of a 5c-5HT2B IC for preparing a drug to treat animals with MMVD, CHF, and / or asymptomatic heart failure. 50 Use of a compound of formula (1B) having <10 nM; or a pharmaceutically acceptable salt thereof, said compound being any one of Examples 6, 7, or 25. Another aspect is the use of a 5c-5HT2B IC for preparing a drug to treat animals with MMVD, CHF, and / or asymptomatic heart failure. 50 A compound of formula (1B) having <1 nM; or a pharmaceutically acceptable salt thereof, said compound is Example 6. In another embodiment, the animal is a companion animal. In another embodiment, the companion animal is a dog.

[0237] Another aspect is the use of a compound of formula (1C); or a pharmaceutically acceptable salt thereof, for preparing a drug for treating animals with MMVD, CHF, and / or asymptomatic heart failure. Another aspect is the use of 5c-5HT2B IC for preparing a drug for treating animals with MMVD, CHF, and / or asymptomatic heart failure. 50 Use of a compound of formula (1C) having <1000 nM; or a pharmaceutically acceptable salt thereof, said compound being any one of Examples 18, 22, or 23. Another aspect is the use of a 5c-5HT2B IC for preparing a drug to treat animals with MMVD, CHF, and / or asymptomatic heart failure. 50 A compound of formula (1C) having <100 nM; or a pharmaceutically acceptable salt thereof, said compound is Example 22 or 23. In another embodiment, the animal is a companion animal. In another embodiment, the companion animal is a dog.

[0238] Another aspect is the use of a compound of formula (1D); or a pharmaceutically acceptable salt thereof, for preparing a drug for treating animals with MMVD, CHF, and / or asymptomatic heart failure. Another aspect is the use of 5c-5HT2B IC for preparing a drug for treating animals with MMVD, CHF, and / or asymptomatic heart failure. 50 Use of a compound of formula (1D) having <10 nM; or a pharmaceutically acceptable salt thereof, said compound is Example 2 or 3. Another aspect is the use of a 5c-5HT2B IC for preparing a drug to treat animals with MMVD, CHF and / or asymptomatic heart failure. 50 A compound of formula (1D) having <1 nM; or a pharmaceutically acceptable salt thereof, said compound is Example 2. In another embodiment, the animal is a pet. In another embodiment, the pet is a dog.

[0239] Another aspect is the use of a compound of formula (1E), or a pharmaceutically acceptable salt thereof, for preparing a drug for treating animals with MMVD, CHF, and / or asymptomatic heart failure. Another aspect is the use of 5c-5HT2B IC for preparing a drug for treating animals with MMVD, CHF, and / or asymptomatic heart failure. 50 A compound of formula (1E) having <1 nM; or a pharmaceutically acceptable salt thereof, said compound is Example 24. In another embodiment, the animal is a companion animal. In another embodiment, the companion animal is a dog.

[0240] Another aspect of the present invention is a method for treating animals with MMVD, CHF, and / or asymptomatic heart failure by administering to the animals in need a therapeutically effective amount of the compound of Formula (1) of the present invention together with at least one additional cardiovascular agent; or a pharmaceutically acceptable salt thereof. Another aspect of the present invention is a therapeutically effective amount of the compound of Formula (1A); 5c-5HT2B IC, which is any one of Examples 1, 4, 5, 8, 11, 19, or 20. 50 A compound of formula (1A) having <500 nM; any one of Examples 1, 4, 5, 8, 11 or 20, 5c-5HT2B IC 50 A compound of formula (1A) having <100 nM; any one of Examples 1, 4, 5 or 8, 5c-5HT2B IC 50 A compound of formula (1A) having <10 nM; 5c-5HT2B IC, any one of Examples 1, 4 or 5 50 A method for treating animals with MMVD, CHF, and / or asymptomatic heart failure by administering a compound of formula (1A) having <1 nM, or a pharmaceutically acceptable salt thereof, to the animals in need along with at least one additional cardiovascular agent. Another aspect of the present invention is a therapeutically effective amount of a compound of formula (1B); 5c-5HT2B IC, which is any one of Examples 6, 7, 12, 13, or 25-28. 50 A compound of formula (1B) having <1000 nM; 5c-5HT2B IC, any one of Examples 6, 7, 12 or 25-28 50 A compound of formula (1B) having <500 nM; any one of Examples 6, 7, 12 or 25-26, 5c-5HT2B IC 50 A compound of formula (1B) having <100 nM; 5c-5HT2B IC, any one of Examples 6, 7 or 25 50 Compound of formula (1B) having <10 nM; 5c-5HT2B IC of Example 6 50A method for treating animals with MMVD, CHF, and / or asymptomatic heart failure by administering a compound of formula (1B) having <1 nM; or a pharmaceutically acceptable salt thereof, to the animals in need along with at least one additional cardiovascular agent. Another aspect of the invention is a therapeutically effective amount of a compound of formula (1C); 5c-5HT2B IC, which is any one of Examples 18, 22, or 23. 50 A compound of formula (1C) having <1000 nM; 5c-5HT2B IC, which is Example 22 or 23 50 A method for treating animals with MMVD, CHF, and / or asymptomatic heart failure by administering a compound of formula (1C) having <100 nM; or a pharmaceutically acceptable salt thereof, to the animals in need along with at least one additional cardiovascular agent. Another aspect of the invention is a therapeutically effective amount of a compound of formula (1D); 5c-5HT2B IC, which is Example 2 or 3. 50 Compound of formula (1D) having <10 nM; 5c-5HT2B IC, which is Example 2 50 A method for treating animals with MMVD, CHF, and / or asymptomatic heart failure by administering a compound of formula (1D) having <1 nM; or a pharmaceutically acceptable salt thereof, to the animals in need along with at least one additional cardiovascular agent. Another aspect of the invention is a therapeutically effective amount of a compound of formula (1E); 5c-5HT2B IC, which is Example 24. 50A method for treating animals with MMVD, CHF, and / or asymptomatic heart failure by administering a compound of formula (1E) having <1 nM, or a pharmaceutically acceptable salt thereof, to the animals in need along with at least one additional cardiovascular agent. In another embodiment, the animal is a companion animal. In another embodiment, the animal is a dog. In another embodiment, at least one additional cardiovascular agent is selected from the group consisting of ACE inhibitors and / or diuretics. In another embodiment, non-limiting examples of ACE inhibitors include enalapril, captopril, benazepril, ramipril, etc. In another embodiment, non-limiting examples of diuretics include furosemide, chlorothiazide, hydrochlorothiazide, spironolactone, amiloride, triamterene, isosorbide, etc. Specific details for implementing the invention

[0241] definition

[0242] For the purposes of the invention as described and claimed herein, the following terms and phrases are defined as follows:

[0243] When "approximately" is used in relation to a measurable numerical variable, the specified value of the variable and within the experimental error of the specified value ( for example Refers to all values ​​of a variable that are within the 95% confidence interval for the mean or are within 10% of a specified value, whichever is greater.

[0244] As used herein, “additional veterinary (or pharmaceutical) preparation(s)” refers, unless otherwise specified, to other veterinary or pharmaceutical compounds or products (i.e., drugs) that provide a therapeutically effective amount of said preparation(s) useful for the treatment of MMVD, CHF, and / or asymptomatic heart failure in animals, preferably dogs.

[0245] "Alkyl" as used herein refers to general formula C unless otherwise specified. n H 2n+1 It refers to the saturated monovalent hydrocarbon alkane radical. Alkane radicals may be linear or branched and may be unsubstituted or substituted, for example, the term "(C1-C4)alkyl" refers to a monovalent linear or branched aliphatic group containing 1 to 4 carbon atoms; likewise, C1-C3alkyl refers to a monovalent linear or branched aliphatic group containing 1 to 3 carbon atoms, etc. Non-exclusive examples of (C1-C4)alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, sec-butyl, t-butyl, n-propyl, n-butyl, i-butyl, s-butyl, etc. The alkyl moiety may be attached to a chemical moiety by any one of the carbon atoms of the aliphatic chain.

[0246] As used herein, “animal(s)” refers to individual animals that are mammals, unless otherwise specified. Specifically, mammals refer to humans and non-human vertebrates that are taxonomically classified as Mammalia. Non-exclusive examples of non-human mammals include companion animals. Non-exclusive examples of companion animals include dogs, cats, and horses. A desirable companion animal is a dog.

[0247] As used herein, "asymptomatic (potential, preclinical) heart failure" refers to contractile disorders or diseases of the heart caused by MMVD, unless otherwise specified.

[0248] As used herein, "carbocycle" refers to a fully saturated carbocyclic alkyl moiety, unless otherwise specified. in other words A 5- to 6-membered ring containing only carbon atoms; in other words , including cyclopentyl and cyclohexyl. The carbocycle group may be optionally substituted as described herein.

[0249] "Compound(s) of the present invention" refers to the compounds of formula (1), formula (1A), formula (1B), formula (1C), formula (1D) and formula (1E) unless otherwise specified; and in particular, the compounds of Examples 1 to 28; and / or the c5-HT2B antagonists described for pharmaceutically acceptable salts thereof.

[0250] Unless otherwise specified, "congestive heart failure" or "heart failure" refers to a specified process in which the heart is unable to keep up with the body's demand for blood supply and fluid accumulates in the lungs due to generally increased cardiac and pulmonary pressure. These term(s) are also associated with contractile disorders or diseases of the heart. Clinical signs are largely the result of changes in the cellular and molecular components of the heart and mediators that induce homeostatic regulation, which increase heart size and worsen cardiac function.

[0251] Unless otherwise specified, "halogen" or "halo" as used herein refers to fluoro, chloro, bromo, and iodo. Preferred halos include fluoro and chloro.

[0252] Unless otherwise specified, "heteroaryl" as used herein refers to a 5- to 6-membered aromatic monocyclic ring or a 10- to 11-membered fused aromatic ring, wherein each monocyclic and fused ring moiety independently contains one or more heteroatoms selected from N, O, and S, preferably from 1 to 4 heteroatoms. Non-exclusive examples of monocyclic heteroaryls include pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, etc. Non-exclusive examples of fused heteroaryls include benzofuranyl, benzothiophenyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, indazolyl, benzotriazolyl, thieno[2,3-c]pyridine, thieno[3,2-b]pyridine, benzo[1,2,5]thiadiazole, etc. Preferred heteroaryls include thiazolyl, isothiazolyl, thiophenyl, pyridinyl, and indolyl. The heteroaryl group may be attached to a chemical moiety by either a carbon atom or a nitrogen heteroatom within a monocyclic or fused ring.

[0253] "Myxomatous Mitral Valve Degeneration (MMVD)" refers to the specified process of mitral valve degeneration unless otherwise specified. MMVD is generally detected as a heart murmur through auscultation. Synonymous medical terms for MMVD include: Mitral Valve Disease (MVD); Degenerative Mitral Valve Disease (DMVD); Chronic Valve Disease (CVD); Chronic Valve Heart Disease (CVHD); and Atrial-Ventricular Valve Deficiency (AVVI).

[0254] As used herein, "optionally substituted" means that, unless otherwise specified, the referenced group may be substituted with one or more additional group(s) selected individually and independently from the groups listed according to the valence of the referenced group.

[0255] As used herein, “pharmaceuticalally acceptable” indicates that, unless otherwise specified, a substance or composition must be chemically and / or toxicologically compatible with the formulation, other components comprising the composition, and / or the animal treated therewith. The use of the phrase “and pharmaceutically acceptable salt(s)” may be interchangeable with “or pharmaceutically acceptable salt(s).”

[0256] "Therapeutic effective amount" refers to an amount of a compound of the present invention that, unless otherwise specified, (i) treats MMVD, CHF, and / or asymptomatic heart failure in animals, (ii) attenuates, improves, or eliminates one or more symptoms of MMVD, CHF, and / or asymptomatic heart failure in animals, or (iii) prevents MMVD, CHF, and / or asymptomatic heart failure in animals or delays its onset.

[0257] As used herein, terms such as “treatment,” “treating,” and “treat” refer to alleviating, halting, or slowing the progression of MMVD, CHF, and / or asymptomatic heart failure in animals, unless otherwise specified. As used herein, these terms also encompass preventing the onset of a disorder or condition, or symptoms associated with a disorder or condition, including reducing the severity of the disorder or condition or associated symptoms depending on the animal’s condition. Accordingly, treatment may refer to administering a compound of the present invention to an animal that is not diagnosed with CHF at the time of administration.

[0258] Myxomatous Mitral Valve Degeneration (MMVD) is the most common type of acquired heart disease and is a new heart murmur that appears in older dogs. A heart murmur is a sound heard with every heartbeat and is caused by turbulent blood flow in the heart. MMVD is an indication of processes that can affect the mitral valve. MMVD primarily affects small breed dogs later in life, but it can also affect large breed dogs. Some small breed dogs are affected earlier in life than others, and the most notable breed described to date is the Cavalier King Charles Spaniel.

[0259] The mitral valve is the valve located between the left atrium and the left ventricle. Oxygenated blood from the lungs enters the left atrium, passes through the mitral valve to the left ventricle, and is then pumped into the body. When the left ventricle contracts, the mitral valve closes to prevent blood from flowing back into the left atrium. A healthy mitral valve is thin, flexible, and held in place by chordae tendineae (CTs). Myxomatous degeneration is a process in which the valve thickens as small nodules form, preventing the valve from closing completely and allowing blood to flow back into the left atrium (mitral regurgitation). Over time, the atria and ventricles enlarge to compensate, and leakage gradually worsens. As the leakage volume increases, atrial pressure also increases. In some cases, the CTs rupture, causing the mitral valve to become partially unfixed (mitral prolapse). This increased pressure is transmitted to the lungs, leading to CHF.

[0260] A heart murmur is generally the fastest means of detecting MMVD. After a murmur is detected, MMVD symptoms may not appear for 3 to 4 years. The first external sign of MMVD exacerbation is often a cough or increased effort to breathe, which may be caused by airway pressure resulting from cardiac hypertrophy and / or fluid congestion in the lungs and heart.

[0261] In particular, there are no drug treatments proven to prevent the progression of MMVD in the early stages of the disease. To manage MMVD, CHF, and / or asymptomatic heart failure, furosemide, pimobendan, and ACE inhibitors ( for example Therapeutics including enalapril and spironolactone are administered alone or in combination. Furosemide is a potent diuretic that removes fluid from the body, thereby reducing pulmonary fluid congestion. Pimobendan has been shown to help the heart function more effectively, aid in reducing cardiac remodeling, and improve survival rates in MMVD patients. ACE inhibitors and spironolactone have been found to block harmful compensatory mechanisms occurring in severe heart disease and extend survival. Side effects of these drugs include allergic reactions, staggering, loss of appetite, lethargy, diarrhea, and syncope. Other medications sometimes used to treat CHF include hydrochlorothiazide, amlodipine, torsemide, and digoxin.

[0262] Despite the development of new drugs and therapeutic regimens, uncertainty remains regarding when to treat and what the best intervention is for some of these animals. In 2009, an objective classification system was developed to classify heart disease based on risk factors and clinical and diagnostic imaging signs.

[0263] Heart failure is a different classification system, for example, It is divided into different levels defined by the classification currently in use according to the International Small Animal Cardiac Health Council (ISACHC), the New York Heart Association (NYHA) functional classification system, and the 2009 Consensus Statements of the American College of Veterinary Internal Medicine (ACVIM). To eliminate ambiguity between classification systems, the classification systems listed below are considered synonyms.

[0264] Classification according to the International Small Animal Cardiac Health Council (ISACHC) system: Class I: Asymptomatic (also known as potential or preclinical); Class IA: No evidence of compensation for underlying heart disease (no volume overload or pressure overload detected radiographically or echocardiographically); Class IB: Clinical signs of compensation for underlying heart disease (volume overload or pressure overload detected radiographically or echocardiographically); Class II: Mild to moderate heart failure with clinical signs at rest or during light exercise (requires treatment); Class III: Progressive heart failure; clinical signs of severe congestive heart failure; Class IIIA: Home-care possible; and Class IIIB: Hospitalization required.

[0265] New York Heart Association (NYHA) Functional Classification System: Class I: Asymptomatic heart disease ( for example , patients with chronic valvular heart disease (CVHD) who do not show clinical signs even with exercise; Class II: patients with heart disease that causes clinical signs only during vigorous exercise; Class III: patients with heart disease that causes clinical signs during daily activities or light exercise; and Class IV: patients with heart disease that causes severe clinical signs even during rest.

[0266] The ACVIM system describes four basic stages of heart disease and failure: Stage A: Patients at high risk of developing heart disease but without currently identifiable structural cardiac abnormalities; Stage B: Structural heart disease ( for examplePatients who have a typical murmur of mitral regurgitation but have never presented with clinical signs of heart failure (the panel further subdivided Stage B into B1 and B2 due to significant clinical implications for prognosis and treatment). Stage B1: Asymptomatic patients without radiographic or echocardiographic evidence of cardiac remodeling in response to CVHD. Stage B2: Asymptomatic patients with hemodynamically significant valvular regurgitation evidenced by radiographic or echocardiographic findings of left cardiac hypertrophy. Stage C: Patients with past or present clinical signs of heart failure associated with structural heart disease. Stage D: End-stage patients with clinical signs of heart failure due to CVHD unresponsive to standard therapy.

[0267] Cardiac pathology begins in ISACHC class I, NYHA class I, and ACVIM stage B2 with heart murmurs or ventricular dilation but no clinical symptoms (ISACHC class I or asymptomatic / latent / preclinical stage). Clinical symptoms become apparent during disease progression (ISACHC class II or III, NYHA class II, III or IV, ACVIM stages C and D). Because the compound of the present invention has an affinity for c5-HT2B, the compound may potentially provide veterinarians with a new drug to treat MMVD, CHF, and / or asymptomatic heart failure.

[0268] The compound of Formula (1) of the present invention may be synthesized by a synthesis route comprising a process similar to that widely known in the chemical art, particularly in light of the description contained herein. Starting materials are generally available from commercial sources, such as Aldrich Chemicals (Milwaukee, WI), Combi-Blocks (San Diego, CA), Synthonix Chemicals (Wake Forest, NC), Enamine (Monmouth Jct. NJ), and others, and are easily prepared using methods well known to those skilled in the art ( for example (Prepared by methods generally described in Louis F. Fieser and Mary Fieser, "Reagents for Organic Synthesis", 1; 19, Wiley, New York (1967, 1999 ed.), or Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin (with appendix) (also available via the Beilstein online database). For illustrative purposes, the reaction schemes described below illustrate potential routes for synthesizing the compounds and key intermediates of the present invention. Further descriptions of individual reaction steps can be found in the Examples section. Those skilled in the art will understand that the compounds of the present invention may be prepared by the application of the methods described herein and / or by methods known in the art, e.g., the application of the techniques described herein, or by methods other than those described herein using standard textbooks, e.g., ["Comprehensive Organic Transformations - A Guide to Functional Group Transformations", RC Larock, Wiley-VCH (editions from 1999 onwards)].

[0269] Reaction Scheme 1 outlines the general procedure for the preparation and isolation of the compounds of the present invention. However, it should be understood that the present invention is not intended to be limited by the details of the reaction scheme or method of preparation as fully described herein and incorporated into the claims.

[0270] In the examples and methods described below, the following reactants and other abbreviations include: room temperature (RT); tetrahydrofuran (THF); dichloromethane (DCM); N, N- Dimethylformamide (DMF); methanol (MeOH); N,N-Diisopropylethylamine (DIPEA); (1-[Bis(Dimethylamino)Methylene]-1H-1,2,3-Triazolo[4,5-b]pyridinium 3-Oxide Hexafluorophosphate (HATU); N-Methylmorpholine (NMM); N,N-Diisopropylethylamine (i-Pr2NEt); Sodium Triacetoxyborohydride (NaBH(OAc)3); Acetic Acid (AcOH); tert-Butyloxycarbonyl (BOC); Trifluoroacetic Acid (TFA); Lithium Hydroxide (LiOH); Cesium Carbonate (Cs2CO3); Copper (l) Iodide (CuI); 1,2-Dichloroethane (DCE); Water (H2O); Hank's Balanced Salt Solution (HBSS); Fetal Bovine Serum (FBS); Dulbecco Modified Eagle Medium (DMEM); Minimum Essential Medium (MEM); and (4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid (HEPES).

[0271] Pharmaceutically acceptable salts of the compounds of the present invention can also be prepared in a conventional manner. For example, a free base solution may be treated with a suitable acid in a pure or suitable solvent, and the resulting salt may be isolated by filtration or by evaporation under reduced pressure of the reaction solvent. For a review of suitable salts, refer to the literature ["Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002)].

[0272] The compound of formula (1) of the present invention may be used in its natural form or as a salt. When the formation of a stable, non-toxic acid or base salt is required, it may be appropriate to administer the compound as a pharmaceutically acceptable salt. Pharmaceutically acceptable salts of the compounds of the present invention include, but are not limited to, the following: acetate, ascorbate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, edicilate, etoglutarate, esylate, formate, fumarate, gluteptate, gluconate, glucuronate, glycerophosphate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methyl sulfate, naphthylate, 2-naphthylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, Phosphate / hydrogen phosphate / dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate, and trifluoroacetate salts.

[0273] The compound of formula (1) of the present invention can be prepared as described by the reaction formula and procedure described herein.

[0274] Reaction Equation 1. Preparation of the compound of chemical formula (1)

[0275]

[0276] Here, W is ring A(optionally substituted ((R 4 ) n) and, where R4 and n are as described herein), and X, L and X' are also as described herein. The first Boc-protected amine intermediate (1a) can be prepared by standard reducing alkylation techniques, and the reducing agent (sodium triacetoxyborohydride) can be replaced with other reducing agents such as sodium cyanoborohydride, sodium borohydride, or Pd / C (having H2 or Et3SiH). After deprotecting the Boc-amine with TFA, the amine (1b) can be coupled with pyrrolopyridic acid (or indole-, indazole-, or benzofuran-carboxylic acid) using a traditional amide coupling agent such as HATU.

[0277] The compound of Formula (1) of the present invention is useful as a 5-HT2B antagonist for the treatment of MMVP, CHF, and / or asymptomatic heart failure in animals, particularly dogs (c5-HT2B). Another aspect of the present invention is a veterinary composition comprising a therapeutically effective amount of the compound of Formula (1) of the present invention or a pharmaceutically acceptable salt thereof. Another aspect of the present invention is a veterinary composition comprising a therapeutically effective amount of the compound of Formula (1) of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. The compound of Formula (1) of the present invention (including the composition and process used therein) or a pharmaceutically acceptable salt thereof may be used in the manufacture of a drug for therapeutic application as described herein.

[0278] The compound of Formula (1) of the present invention or a pharmaceutically acceptable salt thereof may be administered alone or in a formulation suitable for the expected specific use and the species of animal being treated. Generally, it may be administered as a formulation in association with one or more pharmaceutically acceptable excipients. The term “excipient” is used herein to describe any component other than the compound of Formula (1) of the present invention or any additional veterinary preparation. The selection of an excipient depends largely on factors such as the specific mode of administration, the effect of the excipient on solubility and stability, and the nature of the form of administration. In addition to the excipient(s), the amount of the compound of the present invention administered and the dosage regimen for treating a pathological condition or disorder with the compound may vary greatly, as they depend on various factors including the age, weight, sex, medical condition of the animal, severity of the disease, route of administration, and frequency of administration.

[0279] In one embodiment, the veterinary composition comprises a compound of Formula (1) of the present invention or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable excipient. The concentration range is the composition ( for example It depends on whether it is an oral or injectable formulation. For oral doses, the range of the active agent (i.e., the compound of the present invention) is about 0.1 to about 10 mg / kg, preferably about 0.5 to about 5 mg / kg, more preferably about 0.5 to about 3 mg / kg, and most preferably about 0.5 to about 1.5 mg / kg. For injectable solutions, the range of the active agent is about 0.1 to about 50 mg / mL, preferably about 0.5 to about 25 mg / mL, more preferably about 1 to about 10 mg / mL, and even more preferably about 2 to about 5 mg / mL. The preferred route of administration is oral. The concentration range and the preferred concentration range are considered to be therapeutically effective doses. Additionally, the dose range and the preferred dose range may be higher or lower than the concentrations described herein.

[0280] Formulations can be prepared using conventional dissolution and mixing procedures. Such compositions and methods for preparing them can be found, for example, in the literature ['Remington's Veterinary Sciences', 19th edition (Mack Publishing Company, 1995; and "Veterinary Dosage Forms: Tablets, Vol. 1" by H. Lieberman and L. Lachman, Marcel Dekker, NY, 1980 (ISBN 0-8247-6918-X)].

[0281] Typical formulations are prepared by mixing the compound of Formula (1) of the present invention or a pharmaceutically acceptable salt thereof with at least one pharmaceutically acceptable excipient. Suitable excipients are well known to those skilled in the art and include substances such as carbohydrates, waxes, water-soluble and / or swelling polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc. Specific excipient(s) will vary depending on the means and purpose for which the compound of the present invention is applied. The solvent is generally selected based on solvents recognized by those skilled in the art as safe for administration to animals. The formulation may also contain one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, lubricants, processing aids, coloring agents, sweeteners, fragrances, flavoring agents, and drugs ( in other words , providing an elegant expression of the compound of the present invention or its veterinary composition) or a veterinary product ( in other words It may include other known additives to aid in the manufacture of the drug. The compound of formula (1) of the present invention is typically formulated into a veterinary dosage form to provide an easily controllable dosage form for administration.

[0282] Methods for administering the compound of formula (1) of the present invention include oral and injection ( for exampleIncludes parenteral, subcutaneous, and intramuscular.

[0283] The compound of Formula (1) of the present invention or a pharmaceutically acceptable salt thereof may be administered orally in the form of capsules, boluses, tablets, powders, lozenges, chews, multiple and nanoparticles, gels, solid solutions, films, sprays, or liquids. Since this is a preferred method of administration, it is desirable to develop compounds for oral administration. Such formulations may be used as fillers for soft or hard capsules, or soft or hard flavored chews, which generally comprise excipients, e.g., water, ethanol, polyethylene glycol, N-methylpyrrolidone, propylene glycol, methylcellulose, or suitable oils, and one or more emulsifiers, flavoring agents, and / or suspending agents. Liquid forms include suspensions, solutions, syrups, drench, and elixirs. Liquid formulations may also be prepared, for example, by reconstituting solids from sachets.

[0284] Injectable formulations may be prepared in the form of sterile solutions, which may contain other substances, for example, salts or glucose sufficient to make the solution isotonic with blood. Acceptable liquid excipients include vegetable oils such as sesame oil and cottonseed oil, glycerides such as triacetin, esters such as benzyl benzoate, isopropyl myristate, and fatty acid derivatives of propylene glycol, as well as organic solvents such as pyrrolidine-2-one, benzyl alcohol, and glycerol formal. The formulation is prepared by dissolving or suspending the compound of the present invention alone or with additional veterinary agents in the liquid excipient(s) such that the final formulation contains about 0.01 to 30 weight percent of the active ingredient.

[0285] Devices suitable for injectable administration include needle (including micro-needles) syringes, needleless syringes, and infusion techniques. Injectable formulations are typically aqueous solutions that may contain excipients such as salts, carbohydrates, and buffers (preferably pH 3 to 9), but for some applications, they may be more suitably formulated in the form of dry powders used with a suitable vehicle, such as sterile non-aqueous solutions or sterile non-pyrogen water. Under sterile conditions, the preparation of injectable formulations, for example by lyophilization, can be easily achieved using standard veterinary techniques well known to those skilled in the art. The solubility of the compounds of the present invention used in the preparation of injectable solutions may be increased by using solubility-enhancing agents.

[0286] The administration of the compound of formula (1) of the present invention or a pharmaceutically acceptable salt thereof is considered to be once or twice a day, preferably once a day (qd).

[0287] As described above, the composition of the present invention may be administered alone or in combination with at least one other additional veterinary preparation, thereby providing a wider range of veterinary utility. These at least one other additional veterinary preparation, comprising a pharmaceutical preparation, may be administered simultaneously with the compound of the present invention or at any time throughout the entire treatment period of the animal.

[0288] Heart disease ( for example The following list of additional pharmaceutical (veterinary) cardiovascular agents that may be used with the compounds of the present invention to treat MMVD, CHF, and / or asymptomatic heart failure is intended to illustrate possible combinations but does not impose any limitations thereon. Non-limiting examples of additional pharmaceutical (veterinary) agents include diuretics that reduce edema and exudation ( for example, furosemide, chlorothiazide, indapamide, triamterene, hydrochlorothiazide, etc.); aldosterone antagonists that reduce aldosterone-mediated cardiomyopathy, slow the progression of heart disease, and can promote fluid loss by blocking sodium reabsorption ( for example , spironolactone, eplerenone, etc.); and ACE inhibitors that relax blood vessels to inhibit the action of angiotensin-converting enzyme and cause balanced vasodilation ( for example Includes enalapril, acupril, captopril, ramipril, etc.

[0289] Veterinary compositions for application to animals may be packaged in various ways depending on the method used to administer the compounds or combinations thereof of the present invention. Generally, articles for distribution comprise a container containing a veterinary composition of a suitable form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, etc. The container may also include an assembly that is not easily tampered with to prevent indiscriminate access to the contents of the package. Additionally, the container is affixed with a label stating the contents of the container. The label may include appropriate warnings.

[0290] The compound of formula (1) of the present invention (including the composition and process used therein) or a pharmaceutically acceptable salt thereof may also be used in the manufacture of a drug for therapeutic application as described herein.

[0291] The structure of the compound of Formula (1) in the following examples was confirmed by one or more of proton magnetic resonance spectroscopy and mass spectrometry. Proton magnetic resonance (1H NMR) spectra were determined using a Bruker spectrometer operating at a magnetic field strength of 400 megahertz (MHz). Chemical shifts are reported as parts per million (PPM, δ) downfield from an internal tetramethylsilane standard or residual protonated NMR solvent. Mass spectrometry (MS) data were obtained using an Agilent mass spectrometer (1290 Infinity II) employing multimode electrospray and atmospheric pressure chemical ionization (MM-ES+APCI) methods. High-performance liquid chromatography (HPLC) was performed on an Agilent 1260 Infinity II using an X-Bridge C8 (50x4.6) mm, 3.5 μm column. The mobile phase was a binary gradient of acetonitrile and 10 mM ammonium bicarbonate in water with a flow rate of 1.0 mL / min.

[0292] Examples

[0293] The following examples provide a more detailed description of the process conditions for preparing the compound of Formula (1) of the present invention. However, it should be understood that the present invention is not intended to be limited by the details of the following manufacturing method, as fully described herein and incorporated in the claims.

[0294] intermediate

[0295] Synthesis of (1R,3s,5S)-8-(4-chlorobenzyl)-8-azabicyclo[3.2.1]octane-3-amine.2,2,2-trifluoroacetate

[0296]

[0297] Step-1: Synthesis of tert-butyl ((1R,3s,5S)-8-(4-chlorobenzyl)-8-azabicyclo[3.2.1]octane-3-yl)carbamate. Tert-butyl ((1R,3s,5S)-8-azabicyclo[3.2.1]octane-3-yl)carbamate (969.3 mg, 4.28 mmol; CAS#132234-68-5)), and acetic acid (0.05 mL, 0.79 mmol) were added at 0°C to a stirred solution of 4-chlorobenzaldehyde 1 (500 mg, 3.57 mmol) in DCM (10.0 mL). The resulting reaction mixture was stirred at room temperature for 1 hour. Subsequently, sodium triacetoxy-borohydride (1.51 g, 7.14 mmol) was added to the reaction mixture and stirred overnight. After completion, the reaction mixture was diluted with water and extracted with dichloromethane. The combined organic layer was washed with brine, dried over sodium sulfate, filtered, and evaporated under reduced pressure. The unrefined product was purified by combi-flash chromatography (30% ethyl acetate-hexane) to obtain tert-butyl ((1R,3s,5S)-8-(4-chlorobenzyl)-8-azabicyclo[3.2.1]octane-3-yl)carbamate (800.0 mg) as an off-white solid.

[0298] Step-2: Synthesis of (1R,3s,5S)-8-(4-chlorobenzyl)-8-azabicyclo[3.2.1]octan-3-amine.2,2,2-trifluoroacetate. TFA (1.04 mL, 13.71 mmol) was added at 0°C to (20.0 mL) a stirred solution of tert-butyl ((1R,3s,5S)-8-(4-chlorobenzyl)-8-azabicyclo[3.2.1]-octan-3-yl)carbamate (800.0 mg, 2.28 mmol) in DCM. The resulting reaction mixture was stirred at room temperature for 2 hours. After completion, the reaction mixture was concentrated under reduced pressure and dried to obtain (1R,3s,5S)-8-(4-chlorobenzyl)-8-azabicyclo[3.2.1]octan-3-amine (500 mg) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 1.88-1.96 (m, 4H), 2.04-2.06 (m, 2H), 2.32-2.34 (m, 2H), 3.88-3.90 (m, 2H), 4.18 (bs, 2H), 4.54-4.56 (m, 1H), 7.57 (bs, 4H), 8.13 (bs, 2H).

[0299] For example: 4-chlorobenzaldehyde (Examples 3 and 5) is replaced with a) 4-fluorobenzaldehyde (Example 4); b) indole-5-carboxaldehyde (Example 6); c) thiophene-2-carboxaldehyde (Example 7); d) 4-(trifluoromethyl)benzaldehyde (Example 11); e) 2-pyridinecarboxaldehyde (Example 12); f) 3-pyridinecarboxaldehyde (Example 13); g) 4-pyridinecarboxaldehyde (Example 14); h) 2-pyrazinecarboxaldehyde (Example 15); i) 1-methyl-2-imidazolecarboxaldehyde (Example 16); j) isothiazole-5-carbaldehyde (Example 25); k) isothiazol-3-carbaldehyde (Example 26); l) thiazole-2-carbaldehyde (Example 27); and m) 4-methylthiazole-2-carbaldehyde (Example 28) were substituted to generally use the steps provided above to prepare a similar azabicyclo[3.2.1]octan-3-amine.2,2,2-trifluoroacetate analog.

[0300] Synthesis of (1R,3s,5S)-8-phenyl-8-azabicyclo[3.2.1]octan-3-amine.2,2,2-trifluoroacetate

[0301]

[0302] This N-phenyl intermediate was prepared by a Chan-Lam reaction catalyzed by copper oxide using phenyl boric acid as the phenyl source, and copper acetate is a common alternative to this catalyst. The intermediate was then deprotected with TFA to obtain the intermediate used in the synthesis of Example 17.

[0303] Step-1: Synthesis of tert-butyl ((1R,3s,5S)-8-phenyl-8-azabicyclo[3.2.1]octane-3-yl)carbamate. Tert-butyl ((1R,3s,5S)-8-azabicyclo[3.2.1]octane-3-yl)carbamate (668.21 mg, 2.95 mmol) and Cu2O (17.85 mg, 0.12 mmol) were added to a stirred solution of phenyl boric acid (300 mg, 2.46 mmol) in methanol (5.0 mL). The resulting reaction mixture was stirred at room temperature under an air atmosphere for 16 hours. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate, filtered, and evaporated under reduced pressure. The unpurified product was purified by combi-flash column chromatography (30% ethyl acetate-hexane) to obtain tert-butyl ((1R,3s,5S)-8-phenyl-8-azabicyclo[3.2.1]octane-3-yl)carbamate (100.0 mg) as an off-white solid.

[0304] Step-2: Synthesis of (1R,3s,5S)-8-phenyl-8-azabicyclo[3.2.1]octan-3-amine. TFA (0.13 mL, 1.66 mmol) was added at 0°C to a stirred solution of tert-butyl ((1R,3s,5S)-8-phenyl-8-azabicyclo[3.2.1]octan-3-yl)carbamate (100.0 mg, 0.33 mmol) in DCM (5.0 mL). The resulting reaction mixture was stirred at room temperature for 1 hour. After completion, the reaction mixture was concentrated under reduced pressure and dried to obtain (1R,3s,5S)-8-phenyl-8-azabicyclo[3.2.1]octan-3-amine.2,2,2-trifluoroacetate (50 mg) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 1.62-1.68 (m, 4H), 1.75-1.77 (m, 2H), 1.97-1.99 (m, 2H), 3.56-3.58 (m, 1H), 4.33 (bs, 2H), 6.65 (t, J = 7.20 Hz, 1H), 6.82 (d, J= 8.04 Hz, 2H), 7.20 (t, J = 7.84 Hz, 2H), 7.63 (bs, 2H).

[0305] Synthesis of 1-Phenyl-1H-Indole-6-Carboxylic Acid

[0306]

[0307] The above N-phenylindole derivatives were synthesized using a Ullman-type reaction between an indole ester and an aryl iodide catalyzed by copper(I) iodide in the presence of cesium carbonate. Acid intermediates were produced by ester hydrolysis using lithium hydroxide. This process also produced similar intermediates for Examples 18, 21, and 22. Essentially, iodobenzene (Example 23) was replaced with a) 4-iodo-pyridine (Example 18); b) 1-iodo-4-(trifluoromethyl)benzene (Example 21); and c) 1-iodo-4-fluorobenzene (Example 22).

[0308] Step 1: Synthesis of methyl 1-phenyl-1H-indole-6-carboxylate. Methyl 1H-indole-6-carboxylate ester (698.04 mg, 3.92 mmol), CuI (142.65 mg, 0.50 mmol), and Cs2CO3 (1.60 mg, 4.90 mmol) were added to a stirred degassed solution of iodobenzene (500.0 mg, 2.45 mmol) in DMF (5.0 mL). The resulting reaction mixture was heated at 120°C for 16 hours. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate, filtered, and evaporated under reduced pressure. The unpurified product was purified by combi-flash column chromatography (20% ethyl acetate-hexane) to obtain methyl 1-phenyl-1H-indole-6-carboxylate (300.0 mg) as a brown solid.

[0309] Step 2: Synthesis of 1-phenyl-1H-indole-6-carboxylic acid. LiOH·H2O (42.94 mg, 1.70 mmol) was added to a stirred solution of methyl 1-phenyl-1H-indole-6-carboxylate (300.0 mg, 1.20 mmol) in THF and water (6 mL, 1:1). The resulting reaction mixture was stirred at room temperature for 1 hour. After completion, the reaction mixture was concentrated under reduced pressure, diluted with water, and the pH adjusted to 4 using 1 M HCl. The resulting precipitate was filtered, and the crude product was ground with pentane and dried to obtain 1-phenyl-1H-indole-6-carboxylic acid (200.0 mg) as an off-white solid. LCMS [MH = 235.8].

[0310] The intermediate (1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-EXO-amine is available as a free base commercially from companies in the United States (Combi-Blocks; AstaTech; and Synthonix).

[0311]

[0312] Example 1. N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide

[0313]

[0314] Example 1 was prepared according to the following procedure:

[0315]

[0316] Step 1: 1H-indole-6-carboxylic acid (1.0 g, 6.2 mmol), HATU (1.5 equivalents, 6.588 mmol) and N,N-diisopropylethylamine (1.53 mL, 8.784 mmol) were stirred in N,N-dimethylformamide (10 mL) for 10 minutes.

[0317] Step 2: 8-benzyl-8-azabicyclo[3.2.1]octan-3-EXO-amine (1000 mg, 4.392 mmol) was added to the solution from Step 1 at room temperature and stirred for 3 hours. The mixture was purified by preparative HPLC to obtain the title compound as a white solid. 1 ¹H NMR (400 MHz, DMSO- d 6) δ ppm 1.55 - 1.70 (m, 4 H) 1.77 (t, 2 H) 1.95-2.10 (m, 2 H) 3.17 (bs, 2 H) 3.59 (bs, 1 H) 4.25 (bs, 1 H) 6.46 (bs, 1 H) 7.20 - 7.28 (m, 1 H) 7.32 (t, 2 H) 7.35 - 7.41 (m, 2 H) 7.48 (bs, 1 H) 7.50 - 7.58 (m, 2 H) 7.93 (bs, 1 H) 8.09 (d, 1 H) 11.32 (br s, 1 H). LC-MS (m / z): [M+H] = 359.

[0318] Example 2. N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamide. A compound was prepared similarly to Example 1, except that 1H-indole-6-carboxylic acid was replaced with 1H-pyrrolo[2,3-b]pyridine-6-carboxylic acid.

[0319]

[0320] 1H NMR (400 MHz, DMSO-d6) δ 1.66-1.78 (m, 6H), 1.99-2.04 (m, 2H), 3.18 (bs, 2H), 3.62 (s, 2H), 4.17-4.23 (m, 1H), 6.54 (s, 1H), 7.23-7.25 (m, 1H), 7.32 (t, J = 7.2 Hz, 2H), 7.38-7.40 (m, 2H), 7.66 (bs, 1H), 7.75 (d, J= 8.2 Hz, 1H), 8.07-8.11 (m, 2H), 11.75 (s, 1H). LC-MS (m / z): [M+H] = 360.

[0321] Example 3. N-((1R,3s,5S)-8-(4-chlorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamide. A compound was prepared similarly to Example 1, except that 1H-indole-6-carboxylic acid was replaced with 1H-pyrrolo[2,3-b]pyridine-6-carboxylic acid and 8-benzyl-8-azabicyclo[3.2.1]octan-3-EXO-amine was replaced with (1R,3s,5S)-8-(4-chlorobenzyl)-8-azabicyclo[3.2.1]octan-3-amine.2,2,2-trifluoroacetate.

[0322]

[0323] 1H NMR (400 MHz, DMSO-d6) δ 1.66-1.78 (m, 6H), 1.97-2.03 (m, 2H), 3.16 (bs, 2H), 3.61 (s, 2H), 4.17-4.22 (m, 1H), 6.54 (s, 1H), 7.37-7.43 (m, 4H), 7.64-7.68 (m, 1H), 7.75 (d, J = 8.2 Hz, 1H), 8.07-8.12 (m, 2H), 11.76 (s, 1H). LC-MS (m / z): [M+H] = 394.

[0324] Example 4. A compound was prepared similarly to Example 1, except that N-((1R,3s,5S)-8-(4-fluorobenzyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide. 8-benzyl-8-azabicyclo[3.2.1]octane-3-EXO-amine was replaced with (1R,3s,5S)-8-(4-fluorobenzyl)-8-azabicyclo[3.2.1]octane-3-amine.2,2,2-trifluoroacetate.

[0325]

[0326] 1H NMR (400 MHz, DMSO-d6) δ 1.63-1.65 (m, 4H), 1.72-1.78 (m, 2H), 1.99-2.01 (m, 2H), 3.16 (bs, 2H), 3.56 (s, 2H), 4.20-4.26 (m, 1H), 6.46 (s, 1H), 7.14 (t, J = 8.7 Hz, 2H), 7.38-7.42 (m, 2H), 7.48-7.55 (m, 3H), 7.93 (s, 1H), 8.09 (d, J = 7.9 Hz, 1H), 11.32 (s, 1H). LC-MS (m / z): [M+H] = 377.

[0327] Example 5. A compound was prepared similarly to Example 1, except that N-((1R,3s,5S)-8-(4-chlorobenzyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide. 8-benzyl-8-azabicyclo[3.2.1]octane-3-EXO-amine was replaced with (1R,3s,5S)-8-(4-chlorobenzyl)-8-azabicyclo[3.2.1]octane-3-amine.2,2,2-trifluoroacetate.

[0328]

[0329] 1H NMR (400 MHz, DMSO-d6) δ 1.64-1.66 (m, 4H), 1.73-1.79 (m, 2H), 1.98-2.02 (m, 2H), 3.17 (bs, 2H), 3.59 (s, 2H), 4.18-4.28 (m, 1H), 6.46 (s, 1H), 7.37-7.41 (m, 4H), 7.48-7.55 (m, 3H), 7.93 (s, 1H), 8.08 (d, J = 8 Hz, 1H), 11.31 (s, 1H). LC-MS (m / z): [M+H] = 393.

[0330] Example 6. A compound was prepared similarly to Example 1, except that N-((1R,3s,5S)-8-((1H-indole-5-yl)methyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide. 8-benzyl-8-azabicyclo[3.2.1]octane-3-EXO-amine was replaced with (1R,3s,5S)-8-((1H-indole-5-yl)methyl)-8-azabicyclo[3.2.1]octane-3-amine.2,2,2-trifluoroacetate.

[0331]

[0332] 1H NMR (400 MHz, DMSO-d6) δ 1.55-1.66 (m, 4H), 1.74-1.79 (m, 2H), 2.01-2.06 (m, 2H), 3.20 (bs, 2H), 3.62 (s, 2H), 4.19-4.28 (m, 1H), 6.37 (bs, 1H), 6.46 (bs, 1H), 7.12 (d, J = 8.6 Hz, 1H), 7.29-7.34 (m, 2H), 7.47-7.53 (m, 4H), 7.93 (s, 1H), 8.08 (d, J = 8.2 Hz, 1H), 10.98 (s, 1H), 11.31 (s, 1H). LC-MS (m / z): [M+H] = 398.

[0333] Example 7. A compound was prepared similarly to Example 1, except that N-((1R,3s,5S)-8-(thiophene-2-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide. 8-benzyl-8-azabicyclo[3.2.1]octan-3-EXO-amine was replaced with (1R,3s,5S)-8-(thiophene-2-ylmethyl)-8-azabicyclo[3.2.1]octan-3-amine.2,2,2-trifluoroacetate.

[0334]

[0335] 1H NMR (400 MHz, DMSO-d6) δ 1.64-1.65 (m, 4H), 1.72-1.78 (m, 2H), 1.97-1.99 (m, 2H), 3.24 (bs, 2H), 3.77 (s, 2H), 4.20-4.24 (m, 1H), 6.46 (s, 1H), 6.95 (s, 2H), 7.39-7.53 (m, 4H), 7.94 (s, 1H), 8.11 (d, J = 8.3 Hz, 1H), 11.31 (s, 1H). LC-MS (m / z): [M+H] = 365.

[0336] Example 8. N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-2-methyl-1H-indole-6-carboxamide. A compound was prepared similarly to Example 1, except that 1H-indole-6-carboxylic acid was replaced with 2-methyl-1H-indole-6-carboxylic acid.

[0337]

[0338] 1H NMR (400 MHz, DMSO-d6) δ 1.63-1.65 (m, 4H), 1.73-1.79 (m, 2H), 1.98-2.02 (m, 2H), 2.40 (s, 3H), 3.17 (bs, 2H), 3.59 (s, 2H), 4.20-4.26 (m, 1H), 6.16 (s, 1H), 7.22-7.25 (m, 1H), 7.31-7.39 (m, 5H), 7.46-7.48 (m, 1H), 7.80 (s, 1H), 8.03 (d, J = 8.2 Hz, 1H), 11.13 (s, 1H). LC-MS (m / z): [M+H] = 373.

[0339] Example 8 was prepared according to the following reaction scheme:

[0340]

[0341] Example 9. N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-2,3,4,9-tetrahydro-1H-carbazole-7-carboxamide. A compound was prepared similarly to Example 1 except that 1H-indole-6-carboxylic acid was replaced with 2,3,4,9-tetrahydro-1H-carbazole-7-carboxylic acid; a compound was prepared similarly to Example 1 except that 1H-indole-6-carboxylic acid was replaced with 2,3,4,9-tetrahydro-1H-carbazole-7-carboxylic acid.

[0342]

[0343] 1H NMR (400 MHz, DMSO-d6) δ 1.58-1.65 (m, 4H), 1.75-1.84 (m, 6H), 2.01 (bs, 2H), 2.58-2.63 (m, 2H), 2.70-2.74 (m, 2H), 3.18 (bs, 2H), 3.60 (bs, 2H), 4.20-4.26 (m, 1H), 7.22-7.26 (m, 1H), 7.31-7.35 (m, 3H), 7.38-7.39 (m, 2H), 7.48 (d, J = 8.2 Hz, 1H), 7.79 (s, 1H), 8.03 (d, J = 8 Hz, 1H), 10.88 (s, 1H). LC-MS (m / z): [M+H] = 413.

[0344] Example 10. N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-1H-indazole-6-carboxamide. A compound was prepared similarly to Example 1, except that 1H-indole-6-carboxylic acid was replaced with 1H-indazole-6-carboxylic acid.

[0345]

[0346] 1H NMR (400 MHz, DMSO-d6) δ 1.64-1.66 (m, 4H), 1.74-1.80 (m, 2H), 2.01 (bs, 2H), 3.18 (bs, 2H), 3.58 (s, 2H), 4.21-4.27 (m, 1H), 7.23-7.39 (m, 5H), 7.58 (d, J = 8.3 Hz, 1H), 7.79 (d, J = 8.3 Hz, 1H), 8.03 (bs, 1H), 8.12 (bs, 1H), 8.32 (d, J = 7.6 Hz, 1H), 13.32 (s, 1H). LC-MS (m / z): [M+H] = 360.

[0347] Example 11. A compound was prepared similarly to Example 1, except that N-((1R,3s,5S)-8-(4-(trifluoromethyl)benzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide. 8-benzyl-8-azabicyclo[3.2.1]octan-3-EXO-amine was replaced with (1R,3s,5S)-8-(4-(trifluoromethyl)benzyl)-8-azabicyclo[3.2.1]octan-3-amine.2,2,2-trifluoroacetate.

[0348]

[0349] 1H NMR (400 MHz, DMSO-d6) δ 1.64-1.67 (m, 4H), 1.75-1.81 (m, 2H), 2.00-2.04 (m, 2H), 3.18 (bs, 2H), 3.69 (s, 2H), 4.22-4.26 (m, 1H), 6.46 (s, 1H), 7.48-7.54 (m, 3H), 7.60-7.62 (m, 2H), 7.69-7.71 (m, 2H), 7.93 (s, 1H), 8.10 (d, J = 7.8 Hz, 1H), 11.33 (s, 1H). LC-MS (m / z): [M+H] = 427.

[0350] Example 12. A compound was prepared similarly to Example 1, except that N-((1R,3s,5S)-8-(pyridine-2-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide. 8-benzyl-8-azabicyclo[3.2.1]octan-3-EXO-amine was replaced with (1R,3s,5S)-8-(pyridine-2-ylmethyl)-8-azabicyclo[3.2.1]octan-3-amine.2,2,2-trifluoroacetate.

[0351]

[0352] 1H NMR (400 MHz, DMSO-d6) δ 1.61-1.68 (m, 4H), 1.78-1.84 (m, 2H), 1.98-2.02 (m, 2H), 3.23 (bs, 2H), 3.73 (s, 2H), 4.22-4.28 (m, 1H), 6.46 (s, 1H), 7.23-7.26 (m, 1H), 7.48-7.56 (m, 4H), 7.76-7.80 (m, 1H), 7.94 (s, 1H), 8.11 (d, J = 7.9 Hz, 1H), 8.48 (bs, 1H), 11.32 (s, 1H). LC-MS (m / z): [M+H] = 360.

[0353] Example 13. A compound was prepared similarly to Example 1, except that N-((1R,3s,5S)-8-(pyridine-3-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide. 8-benzyl-8-azabicyclo[3.2.1]octan-3-EXO-amine was replaced with (1R,3s,5S)-8-(pyridine-3-ylmethyl)-8-azabicyclo[3.2.1]octan-3-amine.2,2,2-trifluoroacetate.

[0354]

[0355] 1H NMR (400 MHz, DMSO-d6) δ 1.65-1.66 (m, 4H), 1.73-1.79 (m, 2H), 1.98-2.02 (m, 2H), 3.17 (bs, 2H), 3.62 (s, 2H), 4.18-4.26 (m, 1H), 6.46 (s, 1H), 7.35-7.38 (m, 1H), 7.48-7.56 (m, 3H), 7.76 (d, J = 7.4 Hz, 1H), 7.93 (s, 1H), 8.09 (d, J = 8 Hz, 1H), 8.46 (d, J = 3.7 Hz, 1H), 8.57 (s, 1H), 11.32 (s, 1H). LC-MS (m / z): [M+H] = 360.

[0356] Example 14. A compound was prepared similarly to Example 1, except that N-((1R,3s,5S)-8-(pyridine-4-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide. 8-benzyl-8-azabicyclo[3.2.1]octan-3-EXO-amine was replaced with (1R,3s,5S)-8-(pyridine-4-ylmethyl)-8-azabicyclo[3.2.1]octan-3-amine.2,2,2-trifluoroacetate.

[0357]

[0358] 1H NMR (400 MHz, DMSO-d6) δ 1.65-1.67 (m, 4H), 1.73-1.79 (m, 2H), 2.01 (bs, 2H), 3.17 (bs, 2H), 3.63 (s, 2H), 4.20-4.26 (m, 1H), 6.47 (s, 1H), 7.40 (bs, 2H), 7.48-7.54 (m, 3H), 7.93 (s, 1H), 8.10 (d, J = 7.4 Hz, 1H), 8.51 (bs, 2H), 11.33 (s, 1H). LC-MS (m / z): [M+H] = 360.

[0359] Example 15. A compound was prepared similarly to Example 1, except that N-((1R,3s,5S)-8-(pyrazine-2-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide. 8-benzyl-8-azabicyclo[3.2.1]octan-3-EXO-amine was replaced with (1R,3s,5S)-8-(pyrazine-2-ylmethyl)-8-azabicyclo[3.2.1]octan-3-amine.2,2,2-trifluoroacetate.

[0360]

[0361] 1H NMR (400 MHz, DMSO-d6) δ 1.65-1.69 (m, 4H), 1.78-1.84 (m, 2H), 1.99-2.02 (m, 2H), 3.25 (bs, 2H), 3.79 (s, 2H), 4.22-4.28 (m, 1H), 6.46 (s, 1H), 7.48-7.56 (m, 3H), 7.93 (s, 1H), 8.12 (d, J = 8 Hz, 1H), 8.55 (d, J = 13.5 Hz, 2H), 8.79 (s, 1H), 11.33 (s, 1H). LC-MS (m / z): [M+H] = 361.

[0362] Example 16. N-((1R,3s,5S)-8-((1-methyl-1H-imidazole-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide (ZTS-527811). LC-MS (m / z): [M+H] = 363. A compound was prepared similarly to Example 1, except that 8-benzyl-8-azabicyclo[3.2.1]octane-3-EXO-amine was replaced with (1R,3s,5S)-8-((1-methyl-1H-imidazole-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-amine.2,2,2-trifluoroacetate.

[0363]

[0364] 1H NMR (400 MHz, DMSO-d6) δ 1.62-1.64 (m, 4H), 1.69-1.74 (m, 2H), 1.97-1.98 (m, 2H), 3.15 (bs, 2H), 3.62 (s, 2H), 3.73 (s, 3H), 4.20-4.21 (m, 1H), 6.46 (s, 1H), 6.73 (s, 1H), 7.07 (s, 1H), 7.48-7.55 (m, 3H), 7.92 (s, 1H), 8.09 (d, J = 8.4 Hz, 1H), 11.32 (s, 1H).

[0365] Example 17. A compound was prepared similarly to Example 1, except that N-((1R,3s,5S)-8-phenyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide. 8-benzyl-8-azabicyclo[3.2.1]octan-3-EXO-amine was replaced with (1R,3s,5S)-8-phenyl-8-azabicyclo[3.2.1]octan-3-amine.2,2,2-trifluoroacetate.

[0366]

[0367] 1H NMR (400 MHz, DMSO-d6) δ 1.58-1.65 (m, 2H), 1.77-1.87 (m, 4H), 1.98-2.03 (m, 2H), 4.31 (bs, 2H), 4.47-4.52 (m, 1H), 6.43 (bs, 1H), 6.60-6.64 (m, 1H), 6.82 (d, J = 7.4 Hz, 2H), 7.18-7.21 (m, 2H), 7.45-7.48 (m, 3H), 7.90 (s, 1H), 8.08 (d, J = 7.8 Hz, 1H), 11.27 (s, 1H). LC-MS (m / z): [M+H] = 345.

[0368] Example 17 was prepared according to the following reaction scheme:

[0369]

[0370] Example 18. N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-1-(pyridine-4-yl)-1H-indole-6-carboxamide. A compound was prepared similarly to Example 1, except that 1H-indole-6-carboxylic acid was replaced with 1-(pyridine-4-yl)-1H-indole-6-carboxylic acid.

[0371]

[0372] 1H NMR (400 MHz, DMSO-d6) δ 1.59-1.65 (m, 4H), 1.72-1.76 (m, 2H), 1.98-2.04 (m, 2H), 3.18 (bs, 2H), 3.55 (s, 2H), 4.21-4.29 (m, 1H), 6.85 (d, J = 3.1 Hz, 1H), 7.24-7.36 (m, 5H), 7.71-7.77 (m, 4H), 7.96 (d, J = 3.2 Hz, 1H), 8.22-8.26 (m, 2H), 8.76 (d, J = 5.8 Hz, 2H). LC-MS (m / z): [M+H] = 436.

[0373] Example 18 was prepared according to the following reaction scheme:

[0374]

[0375] Example 19. N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-3-cyano-1H-indole-6-carboxamide. A compound was prepared similarly to Example 1, except that 1H-indole-6-carboxylic acid was replaced with 3-cyano-1H-indole-6-carboxylic acid.

[0376]

[0377] 1H NMR (400 MHz, DMSO-d6) δ 1.63-1.65 (m, 4H), 1.76 (t, J= 11.3 Hz, 2H), 2.00-2.02 (m, 2H), 3.17 (bs, 2H), 3.58 (s, 2H), 4.21-4.28 (m, 1H), 7.22-7.25 (m, 1H), 7.30-7.38 (m, 4H), 7.67 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 8.4 Hz, 1H), 8.05 (s, 1H), 8.28 (d, J = 8.1 Hz, 1H), 8.38 (s, 1H), 12.43 (s, 1H). LC-MS (m / z): [M+H] = 384.

[0378] Example 19 was prepared according to the following reaction scheme:

[0379]

[0380] Example 20. N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-2-(trifluoromethyl)-1H-indole-6-carboxamide. A compound was prepared similarly to Example 1, except that 1H-indole-6-carboxylic acid was replaced with 2-(trifluoromethyl)-1H-indole-6-carboxylic acid.

[0381]

[0382] 1H NMR (400 MHz, DMSO-d6) δ 1.63-1.65 (m, 4H), 1.75 (t, J = 11.6 Hz, 2H), 1.98-2.02 (m, 2H), 3.16 (bs, 2H), 3.60 (s, 2H), 4.19-4.25 (m, 1H), 7.07 (s, 1H), 7.21-7.25 (m, 1H), 7.31-7.38 (m, 4H), 7.63 (d, J = 8.5 Hz, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.98 (s, 1H), 8.26 (d, J = 8 Hz, 1H), 12.49 (s, 1H). LC-MS (m / z): [M+H] = 427.

[0383] Example 20 was prepared according to the following reaction scheme:

[0384]

[0385] Example 21. N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-6-carboxamide. A compound was prepared similarly to Example 1, except that 1H-indole-6-carboxylic acid was replaced with 1-(4-(trifluoromethyl)phenyl)-1H-indole-6-carboxylic acid.

[0386]

[0387] 1H NMR (400 MHz, DMSO-d6) δ 1.62-1.64 (m, 4H), 1.70-1.76 (m, 2H), 1.99-2.03 (m, 2H), 3.17 (bs, 2H), 3.55 (s, 2H), 4.20-4.26 (m, 1H), 6.82 (d, J = 3.1 Hz, 1H), 7.21-7.24 (m, 1H), 7.30-7.37 (m, 4H), 7.68-7.72 (m, 2H), 7.88-7.90 (m, 3H), 7.98 (d, J = 8.4 Hz, 2H), 8.12 (s, 1H), 8.21 (d, J = 8.2 Hz, 1H). LC-MS (m / z): [M+H] = 503.

[0388] Example 21 was prepared according to the following reaction scheme:

[0389]

[0390] Example 22. N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-1-(4-fluorophenyl)-1H-indole-6-carboxamide. A compound was prepared similarly to Example 1, except that 1H-indole-6-carboxylic acid was replaced with 1-(4-fluorophenyl)-1H-indole-6-carboxylic acid.

[0391]

[0392] 1H NMR (400 MHz, DMSO-d6) δ 1.61-1.63 (m, 4H), 1.73 (t, J = 11 Hz, 2H), 1.98-2.03 (m, 2H), 3.16 (bs, 2H), 3.55 (s, 2H), 4.20-4.26 (m, 1H), 6.74 (d, J = 3 Hz, 1H), 7.21-7.24 (m, 1H), 7.30-7.37 (m, 4H), 7.46 (t, J = 8.6 Hz, 2H), 7.64-7.68 (m, 4H), 7.75 (d, J = 3.1 Hz, 1H), 7.96 (s, 1H), 8.17 (d, J = 8.1 Hz, 1H). LC-MS (m / z): [M+H] = 453.

[0393] Example 22 was prepared according to the following reaction scheme:

[0394]

[0395] Example 23. N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-1-phenyl-1H-indole-6-carboxamide. A compound was prepared similarly to Example 1, except that 1H-indole-6-carboxylic acid was replaced with 1-phenyl-1H-indole-6-carboxylic acid.

[0396]

[0397] 1H NMR (400 MHz, DMSO-d6) δ 1.62-1.64 (m, 4H), 1.71-1.76 (m, 2H), 2.00 (bs, 2H), 3.16 (bs, 2H), 3.56 (s, 2H), 4.19-4.27 (m, 1H), 6.75 (d, J= 2.5 Hz, 1H), 7.21-7.25 (m, 1H), 7.30-7.37 (m, 4H), 7.42-7.48 (m, 1H), 7.62-7.69 (m, 6H), 7.79 (d, J = 2.8 Hz, 1H), 8.03 (s, 1H), 8.19 (d, J = 8 Hz, 1H). LC-MS (m / z): [M+H] = 435.

[0398] Example 23 was prepared according to the following reaction scheme:

[0399]

[0400] Example 24. N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)benzofuran-6-carboxamide. A compound was prepared similarly to Example 1, except that 1H-indole-6-carboxylic acid was replaced with benzofuran-6-carboxylic acid. LC-MS (m / z): [M+H] = 360.

[0401]

[0402] 1H NMR (400 MHz, DMSO-d6 at 100ºC) δ 1.77-1.92 (m, 6H), 2.08 (bs, 2H), 3.32 (bs, 2H), 3.75 (bs, 2H), 4.26-4.30 (m, 1H), 6.98 (s, 1H), 7.27-7.29 (m, 1H), 7.33-7.37 (t, J = 8.0 Hz, 2H), 7.40-7.44 (m, 2H), 7.68 (d, J = 13 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.90-7.92 (m, 1H), 8.02 (bs, 1H), 8.06 (s, 1H).

[0403] Example 25. N-((1R,3s,5S)-8-(isothiazole-5-ylmethyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide. A compound was prepared similarly to Example 1, except that 8-benzyl-8-azabicyclo[3.2.1]octane-3-EXO-amine was replaced with (1R,3s,5S)-8-(isothiazole-5-ylmethyl)-8-azabicyclo[3.2.1]octane-3-amine.2,2,2-trifluoroacetate. LC-MS (m / z): [M+H] = 366.

[0404]

[0405] 1H NMR (400 MHz, DMSO-d6) δ 1.66-1.68 (m, 4H), 1.74-1.80 (m, 2H), 1.96-1.99 (m, 2H), 3.25 (bs, 2H), 3.93 (s, 2H), 4.21-4.23 (m, 1H), 6.47 (s, 1H), 7.22 (s, 1H), 7.48 (s, 1H), 7.52-7.54 (m, 2H), 7.94 (s, 1H), 8.14 (d, J = 7.56 Hz, 1H), 8.46 (s, 1H), 11.33 (s, 1H).

[0406] Example 26. N-((1R,3s,5S)-8-(isothiazole-3-ylmethyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide. A compound was prepared similarly to Example 1, except that 8-benzyl-8-azabicyclo[3.2.1]octane-3-EXO-amine was replaced with (1R,3s,5S)-8-(isothiazole-3-ylmethyl)-8-azabicyclo[3.2.1]octane-3-amine.2,2,2-trifluoroacetate. LC-MS (m / z): [M+H] = 366.

[0407]

[0408] 1H NMR (400 MHz, DMSO-d6) δ 1.64-1.66 (m, 4H), 1.75-1.81 (m, 2H), 1.99 (bs, 2H), 3.20 (s, 2H), 3.78 (s, 2H), 4.23-4.27 (m, 1H), 6.46 (s, 1H), 7.38 (d, J = 4.36 Hz, 1H), 7.48-7.56 (m, 3H), 7.93 (s, 1H), 8.11 (d, J = 8.16 Hz, 1H), 9.01 (bs, 1H), 11.32 (s, 1H).

[0409] Example 27. N-((1R,3s,5S)-8-(thiazole-2-ylmethyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide. A compound was prepared similarly to Example 1, except that 8-benzyl-8-azabicyclo[3.2.1]octane-3-EXO-amine was replaced with (1R,3s,5S)-8-(thiazole-2-ylmethyl)-8-azabicyclo[3.2.1]octane-3-amine.2,2,2-trifluoroacetate. LC-MS (m / z): [M+H] = 366.

[0410]

[0411] 1H NMR (400 MHz, DMSO-d6) δ 1.68-1.69 (m, 4H), 1.78-1.84 (m, 2H), 2.00 (bs, 2H), 3.30 (s, 2H), 3.92 (s, 2H), 4.23-4.26 (m, 1H), 6.47 (s, 1H), 7.48 (s, 1H), 7.52-7.54 (m, 2H), 7.62 (s, 1H), 7.72 (bs, 1H), 7.95 (s, 1H), 8.16 (d, J = 7.72 Hz, 1H), 11.33 (s, 1H).

[0412] Example 27 was prepared according to the following reaction scheme:

[0413]

[0414] Example 28. N-((1R,3s,5S)-8-((4-methylthiazole-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide. A compound was prepared similarly to Example 1, except that 8-benzyl-8-azabicyclo[3.2.1]octane-3-EXO-amine was replaced with (1R,3s,5S)-8-(4-methylthiazole-2-ylmethyl)-8-azabicyclo[3.2.1]octane-3-amine.2,2,2-trifluoroacetate. LC-MS (m / z): [M+H] = 380.

[0415]

[0416] 1H NMR (400 MHz, DMSO-d6) δ 1.67-1.69 (m, 4H), 1.76-1.82 (m, 2H), 1.98-2.00 (m, 2H), 2.32 (s, 3H), 3.29 (s, 2H), 3.85 (s, 2H), 4.23-4.26 (m, 1H), 6.47 (s, 1H), 7.13 (s, 1H), 7.47-7.49 (m, 1H), 7.51-7.56 (m, 2H), 7.94 (s, 1H), 8.15 (d, J = 8.04 Hz, 1H), 11.32 (s, 1H).

[0417] In vitro test of 5-HT2B (c5-HT2B)

[0418] CHO-K1 cells stably expressing the 5-HT2B receptor in 20 μl of culture medium (GlutaMAX) in a clear-bottomed 384-well black plate TM 20,000 cells per well were seeded in high-glucose DMEM (+ 5% dialyzed FBS + 10 mM HEPES + 1X MEM non-essential amino acids) at 37°C and 5% CO2 for at least 18 hours. FLIPR prepared in HBSS containing calcium and magnesium supplemented with 20 mM HEPES and 5 mM probenecid at pH 7.4 was placed in the cell plates. ®20 μl / well of the Calcium 5 assay kit was loaded and incubated for 30 minutes at 37°C and 5% CO2, followed by an additional 30 minutes at room temperature. Intracellular calcium responses were evaluated using FLIPR, which measures the kinetics of the Calcium 5 dye at excitation wavelengths of 470 to 495 nm and emission wavelengths of 515 to 575 nm at room temperature. ® Measurements were taken using a Tetra instrument. After recording the initial baseline, the cells were first challenged with a 5X concentration of antagonist (10 μl / well), and the calcium response was recorded for nearly 2 minutes. After the completion of the initial antagonist challenge, the cell plates were placed on a FLIPR Tetra ® Incubated in the device at room temperature for 10 minutes. Finally, EC after initial baseline recording 80 To measure the inhibitory response to serotonin concentration (15 μl / well), a second kinetic assay was performed after incubation at room temperature for 10 minutes. IC 50 The concentration was determined for each antagonist test.

[0419] According to the aforementioned in vitro assay, the IC of the c5-HT2B receptor for the compound of the present invention 50 Affinity is provided in Table 1.

[0420]

[0421] As can be seen in Table 1, the compounds of the present invention have an affinity for c5-HT2B receptors. Based on the data provided in Table 1, the preferred compounds of the present invention have a c5-HT2B inhibitory IC5 of <1000 nM. 50 It has a value. A more preferred compound of the present invention is a c5-HT2B inhibitory IC. 50 The value is <100 nM. A more preferred compound of the present invention is a c5-HT2B inhibitory IC 50 The value is <10 nM.

Claims

Claim 1 Compound of chemical formula (1) or pharmaceutically acceptable salt thereof: Here, X is CH or N and L is NR 1 or O and;X' is CR 2 or N and;R 1 is H, C1-C6 alkyl, phenyl, or pyridinyl, where phenyl or pyridinyl each has one or two R groups. 4 Optionally substituted with a substituent;R 2 is H, C1-C4 alkyl, -CF3 or halo, and R 3 is H, cyano, halo, C1-C4 alkyl or -CF3; or R 2 and R 3 ... are joined together to form a 5-membered or 6-membered carbocyclic ring optionally substituted with methyl, halo, or -CF3; ring A is a 5-membered or 6-membered heteroaryl ring containing one or more heteroatoms selected from the group consisting of phenyl, naphthyl, N, O, and S; or a 10-membered or 11-membered fused heteroaryl ring containing at least one heteroatom selected from the group consisting of N, O, and S; and R 4 is selected from C1-C4 alkyl, halo, cyano, or -CF3, m is an integer 0, 1, or 2; n is an integer 0, 1, 2, or 3; and when n is an integer 2 or 3, each R 4 It may be the same or different. Claim 2 In claim 1, ring A is selected from the group consisting of phenyl, thiophenyl, pyridinyl, thiazolyl, isothiazolyl, and indolyl; and L is NR 1 A compound of formula (1), where m is an integer 1; or a pharmaceutically acceptable salt thereof. Claim 3 In claim 1, a compound of formula (1) or a pharmaceutically acceptable salt thereof selected from the group consisting of: N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide; N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamide; N-((1R,3s,5S)-8-(4-chlorobenzyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamide; N-((1R,3s,5S)-8-(4-fluorobenzyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide; N-((1R,3s,5S)-8-(4-chlorobenzyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide; N-((1R,3s,5S)-8-((1H-indole-5-yl)methyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide; N-((1R,3s,5S)-8-(thiophene-2-ylmethyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide; N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-2-methyl-1H-indole-6-carboxamide; N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-2,3,4,9-tetrahydro-1H-carbazole-7-carboxamide; N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-1H-indazole-6-carboxamide; N-((1R,3s,5S)-8-(4-(trifluoromethyl)benzyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide; N-((1R,3s,5S)-8-(pyridine-2-ylmethyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide; N-((1R,3s,5S)-8-(pyridine-3-ylmethyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide; N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-1-(pyridine-4-yl)-1H-indole-6-carboxamide; N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-3-cyano-1H-indole-6-carboxamide; N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-2-(trifluoromethyl)-1H-indole-6-carboxamide; N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-1-(4-fluorophenyl)-1H-indole-6-carboxamide; N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-1-phenyl-1H-indole-6-carboxamide; N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)benzofuran-6-carboxamide; N-((1R,3s,5S)-8-(isothiazole-5-ylmethyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide; N-((1R,3s,5S)-8-(isothiazole-3-ylmethyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide; N-((1R,3s,5S)-8-(thiazole-2-ylmethyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide; and N-((1R,3s,5S)-8-((4-methylthiazole-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide. Claim 4 In paragraph 3, a compound of formula (1) or a pharmaceutically acceptable salt thereof selected from the group consisting of: N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide; N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamide; N-((1R,3s,5S)-8-(4-chlorobenzyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamide; N-((1R,3s,5S)-8-(4-fluorobenzyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide; N-((1R,3s,5S)-8-(4-chlorobenzyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide; N-((1R,3s,5S)-8-((1H-indole-5-yl)methyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide; N-((1R,3s,5S)-8-(thiophene-2-ylmethyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide; N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-2-methyl-1H-indole-6-carboxamide; N-((1R,3s,5S)-8-(4-(trifluoromethyl)benzyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide; N-((1R,3s,5S)-8-(pyridine-2-ylmethyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide; N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-2-(trifluoromethyl)-1H-indole-6-carboxamide; N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-1-(4-fluorophenyl)-1H-indole-6-carboxamide; N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-1-phenyl-1H-indole-6-carboxamide; N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]Octane-3-yl)benzofuran-6-carboxamide; N-((1R,3s,5S)-8-(isothiazole-5-ylmethyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide; and N-((1R,3s,5S)-8-(isothiazole-3-ylmethyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide. Claim 5 In paragraph 4, a compound of formula (1) or a pharmaceutically acceptable salt thereof selected from the group consisting of: N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide; N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamide; N-((1R,3s,5S)-8-(4-chlorobenzyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamide; N-((1R,3s,5S)-8-(4-fluorobenzyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide; N-((1R,3s,5S)-8-(4-chlorobenzyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide; N-((1R,3s,5S)-8-((1H-indole-5-yl)methyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide; N-((1R,3s,5S)-8-(thiophene-2-ylmethyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide; N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-2-methyl-1H-indole-6-carboxamide; N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)benzofuran-6-carboxamide; and N-((1R,3s,5S)-8-(isothiazole-5-ylmethyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide. Claim 6 In paragraph 2, a compound of formula (1) or a pharmaceutically acceptable salt thereof, which is a compound of formula (1A): Here, R 2 is H, methyl, or -CF3; R 3 ≡ is H, methyl, or cyano; n is an integer 0, 1, or 2. Claim 7 In claim 6, the compound of formula (1) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (1A) is selected from the group consisting of: N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide; N-((1R,3s,5S)-8-(4-fluorobenzyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide; N-((1R,3s,5S)-8-(4-chlorobenzyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide; N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-2-methyl-1H-indole-6-carboxamide; N-((1R,3s,5S)-8-(4-(trifluoromethyl)benzyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide; and N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-2-(trifluoromethyl)-1H-indole-6-carboxamide. Claim 8 In claim 1, a compound of formula (1), which is a compound of formula (1B); or a pharmaceutically acceptable salt thereof: Here, ring A is selected from the group consisting of indolyl, thiophenyl, pyridinyl, isothiazolyl, and thiazolyl; R 4 is methyl or halo; n is an integer 0 or 1. Claim 9 In claim 8, the compound of formula (1) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (1B) is selected from the group consisting of: N-((1R,3s,5S)-8-((1H-indole-5-yl)methyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide; N-((1R,3s,5S)-8-(thiophene-2-ylmethyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide; N-((1R,3s,5S)-8-(pyridine-2-ylmethyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide; N-((1R,3s,5S)-8-(isothiazole-5-ylmethyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide; and N-((1R,3s,5S)-8-(isothiazole-3-ylmethyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide. Claim 10 In claim 1, a compound of formula (1) or a pharmaceutically acceptable salt thereof, which is a compound of formula (1C), a compound of formula (1D), or a compound of formula (1E): or Here, R 1 is a phenyl selectively substituted with a fluoro or chloro group; R 4 is a halo or -CF3; n is an integer 0 or 1. Claim 11 In claim 10, a compound of formula (1C) which is N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-1-(4-fluorophenyl)-1H-indole-6-carboxamide or N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-1-phenyl-1H-indole-6-carboxamide; A compound of formula (1), which is N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamide or N-((1R,3s,5S)-8-(4-chlorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamide; or a compound of formula (1E), which is N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)benzofuran-6-carboxamide, or a pharmaceutically acceptable salt thereof. Claim 12 In paragraph 4, a compound of formula (1) or a pharmaceutically acceptable salt thereof selected from the group consisting of: N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide; N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamide; N-((1R,3s,5S)-8-(4-chlorobenzyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamide; N-((1R,3s,5S)-8-(4-fluorobenzyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide; N-((1R,3s,5S)-8-(4-chlorobenzyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide; N-((1R,3s,5S)-8-((1H-indole-5-yl)methyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide; N-((1R,3s,5S)-8-(thiophene-2-ylmethyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide; N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-2-methyl-1H-indole-6-carboxamide; N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)benzofuran-6-carboxamide; and N-((1R,3s,5S)-8-(isothiazole-5-ylmethyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide. Claim 13 In claim 12, a compound of formula (1) or a pharmaceutically acceptable salt thereof selected from the group consisting of: N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide; N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamide; N-((1R,3s,5S)-8-(4-fluorobenzyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide; N-((1R,3s,5S)-8-(4-chlorobenzyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide; N-((1R,3s,5S)-8-((1H-indole-5-yl)methyl)-8-azabicyclo[3.2.1]octane-3-yl)-1H-indole-6-carboxamide; and N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octane-3-yl)benzofuran-6-carboxamide. Claim 14 A composition comprising a compound of formula (1) of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, and further comprising at least one pharmaceutically acceptable excipient. Claim 15 A composition comprising a compound of formula (1) according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, for preparing a drug for treating animals with MMVD, CHF and / or asymptomatic heart failure, wherein the animal is a companion animal.

Images