Serotonin 5-HT2B inhibitory compound

Abstract

The present invention describes novel serotonin c5-HT2B receptor antagonists of formula (1), and pharma- ceutically acceptable salts thereof, wherein rings A, L, X, X', R 3 , (1)R 4 , m, and n are as described herein. Also described are compositions comprising a compound of formula (1), or a pharma- ceutically acceptable salt thereof, and methods of using the compound, or a pharma- ceutically acceptable salt thereof, for the treatment of myxomatous mitral valve disease (MMVD), congestive heart failure (CHF), and / or asymptomatic heart failure in an animal, preferably a dog. JPEG2024527976000056.jpg58132

Description

Technical Field

[0001] The present invention describes novel compounds that are serotonin 5-HT2B receptor antagonists useful for the treatment of mitral valve disease and congestive heart failure in animals. The present invention also describes compositions comprising the compounds of the present invention, and pharmaceutically acceptable salts thereof, and methods of using the compounds for treating animals having mitral valve disease, congestive heart failure, and / or asymptomatic heart failure.

Background Art

[0002] The serotonin 5-HT2B receptor was first characterized as a serotonergic G protein-coupled receptor that controls the contraction of the rat fundus (Clineschmidt, et al., 1985, J. Pharmacol. Exp. Ther., 235, 696). 5-HT2B has since been detected in human tissues including adipose tissue, central nervous system, heart, liver, intestine, lung, 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 canine tissues including lung, 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). Modulators of 5-HT2B, including antagonists, partial antagonists, inverse agonists, and 5-HT2B desensitizers, can be used as treatments for disorders in these tissues where activation of 5-HT2B plays a direct or indirect role.

[0003] The control of serotonin (5-hydroxytryptamine, 5HT) levels and signaling is used to treat disorders of the central nervous system, intestinal contraction and motility, and vascular function. 5-HT has roles in vasoconstriction and relaxation and can affect vascular function, growth, and morphology. Wild-type mice develop symptoms of pulmonary arterial hypertension (PAH) under hypoxic conditions, while 5-HT2B receptor knockout mice do not, suggesting that regulation of 5-HT2B can alleviate PAH. The phenotype of 5-HT2B receptor knockout mice demonstrates the importance of this receptor for heart development. Surviving mice have an underdeveloped heart due to impaired myocyte proliferation (Nebigil, et al., 2001, Circulation, 103, 2973). Conversely, overexpression of 5-HT2B in mice results in 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 model of tachy pacing-induced decompensated heart failure in dogs showed upregulation of 5-HT2B mRNA (Ojaimi et al., 2007, Physiol. Genomics 29, 76). Thus, regulation of 5-HT2B can treat disorders associated with cardiac hypertrophy such as congestive heart failure. Indeed, in both human and experimental animal models, increased serotonin signaling can induce valvular interstitial cell differentiation and myxomatous valvular lesions.

[0004] Myxomatous mitral valve disease (MMVD) is a major cause of cardiovascular disease in dogs. MMVD causes mitral valve insufficiency, leading to mitral regurgitation that promotes sodium and water retention, activation of the neurohormonal system, volume overload, and ultimately congestive heart failure (CHF). Synonymous medical terms for MMVD used herein include mitral valve disease (MVD), degenerative mitral valve disease (DMVD), chronic valvular disease (CVD), chronic valvular heart disease (CVHD), and atrioventricular valvular insufficiency (AVVI). The pathogenesis of MMVD is usually accompanied by the differentiation and activation of normally quiescent mitral interstitial cells into a more active myofibroblast phenotype, which mediates many of the histological and molecular changes in the valve tissue. MMVD is present in approximately 30% of all dogs over 10 years of age and is the most frequent cause of CHF in dogs. MMVD is most common in breeds such as small dogs, Cavalier King Charles Spaniels, Chihuahuas, Maltese, Pekingese, Toy and Miniature Poodles. The natural history of the disease is one of adult onset, variable progression with aging, and ultimately the development of CHF in dogs with severe disease.

[0005] Current treatments for MMVD include angiotensin enzyme inhibitors, diuretics, vasodilators, and positive inotropes that focus on symptomatic relief rather than halting the progression of the disease. Furthermore, some of these treatments pose additional harmful risks to the animal, such as anorexia, lethargy, changes in cardiac function (e.g., depolarization), and kidney damage. The compounds of formula (1) of the present invention have an affinity for the canine 5-HT2B (c5-HT2B) receptor and can provide veterinarians with a newer and safer drug therapy for treating canine patients with MMVD to slow the progression of MMVD, CHF, and / or asymptomatic heart failure. SUMMARY OF THE INVENTION

[0006] In one aspect of the present invention, it 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, it is a composition comprising 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] In one aspect of the present invention, it is a compound of formula (1),

Chemical formula

[0008] In one embodiment 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 substituted with (R 4 ) n and 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 substituted with (R 4 ) n and 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 substituted with (R 4 ) n and n is an integer 0, 1, or 2. In another embodiment, ring A is phenyl, indolyl, indazolyl, thiophenyl, pyridinyl, thiazolyl, or isothiazolyl, each substituted with (R 4 ) n and n is an integer 0, 1, or 2. In another embodiment, ring A is phenyl, indolyl, thiophenyl, pyridinyl, thiazolyl, or isothiazolyl, each substituted with (R 4 ) n and n is an integer 0 or 1. In another embodiment, ring A is phenyl, thiophenyl, isothiazolyl, or indolyl, each substituted with (R 4 ) n and n is an integer 0 or 1. In another embodiment, ring A is phenyl substituted with (R 4 ) n and n is an integer 0 or 1. In another embodiment, ring A is (R4 ) n and is indolyl substituted with (R 4 ), and n is an integer 0 or 1. In another embodiment, ring A is thiophenyl substituted with (R n ), and n is an integer 0 or 1. In another embodiment, ring A is isothiazolyl substituted with (R 4 ), and n is an integer 0 or 1. n

[0009] In one embodiment of the present invention, X is CH. In another embodiment, X is N.

[0010] In one embodiment of the present invention, L is O. In another embodiment, L is NR 1 . In another embodiment, L is NR 1 , and R 1 is H, or R 1 is phenyl or pyridinyl, each optionally substituted with one or two R 4 substituents. In another embodiment, L is NR 1 , and R 1 is H, or R 1 is phenyl or pyridinyl, each optionally substituted with one R 4 substituent. In another embodiment, L is NR 1 , and R 1 is H, or R 1 is pyridinyl or phenyl, each optionally substituted with fluoro, chloro, or -CF3. In another embodiment, L is NR 1 , and R 1 is H, or R 1 is phenyl optionally substituted with fluoro, chloro, or -CF3. In another embodiment, L is NR 1 , and R 1 is H, or R 1 is phenyl optionally substituted with fluoro. In another embodiment, L is NR 1 , and R 1 is H.

[0011] ​In one embodiment of the present invention, X’ is N. In another embodiment, X’ is CR 2 wherein R 2 is H, methyl, halo, or -CF3. In another embodiment, X’ is CR 2 wherein R 2 is H, methyl, fluoro, chloro, or -CF3. In another embodiment, X’ is CR 2 wherein R 2 is H, methyl, or -CF3. In another embodiment, X’ is CR 2 wherein R 2 is H or X’ is CH.

[0012] In one embodiment 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 3 is H, methyl, chloro, or cyano. In another embodiment, R 3 is H or cyano. In another embodiment, R 3 is H.

[0013] In one embodiment of the present invention, R 2 and R 3 join together to form a fused cyclopentyl or cyclohexyl ring optionally substituted with halo or -CF3. In another embodiment, R 2 and R 3 join together to form a fused cyclopentyl or cyclohexyl ring optionally substituted with fluoro, chloro, or -CF3. In another embodiment, R 2 and R 3 join together to form a fused cyclopentyl or cyclohexyl ring optionally substituted with fluoro or chloro. In another embodiment, R 2 and R 3 join together to form a fused cyclopentyl or cyclohexyl ring. In another embodiment, R 2and R 3 are joined together to form a condensed cyclohexyl ring.

[0014] In one embodiment of the present invention, R 4 is methyl, ethyl, propyl, isopropyl, butyl, t-butyl, chloro, fluoro, bromo, iodine, cyano, or -CF3. In another embodiment of the present invention, R 4 is methyl, ethyl, propyl, isopropyl, chloro, fluoro, bromo, cyano, or -CF3. In another embodiment of the present invention, R 4 is methyl, ethyl, isopropyl, chloro, fluoro, cyano, or -CF3. In another embodiment of the present invention, R 4 is methyl, chloro, fluoro, or -CF3.

[0015] In one embodiment of the present invention, m is the integer 0 or 1. In another embodiment, m is the integer 0. In another embodiment of the present invention, m is the integer 1.

[0016] In one embodiment of the present invention, n is the integer 0, 1, or 2, and when n is the integer 2, each R 4 may be the same or different. In another embodiment, n is the integer 0 or 1. In another embodiment, n is the integer 1. In another embodiment, n is the integer 0.

[0017] In one embodiment of the present invention, a compound of formula (1) wherein ring A is phenyl, m is the integer 1, n is the integer 0, 1, or 2, X is CH, L is NR 1 , R 1 is H, X' is CR 2 , R 2 and R 3 are joined together to form cyclopentyl or cyclohexyl, and R 4 is fluoro, chloro, or -CF3. In another embodiment, a compound of formula (1) wherein ring A is phenyl, m is the integer 1, n is the integer 0 or 1, X is CH, L is NR 1 and R1 is H, and X' is CR 2 and R 2 and R 3 are joined together to form cyclohexyl, and R 4 is fluoro, chloro, or -CF3, a compound, or a pharmaceutically acceptable salt thereof. In another aspect, a compound of formula (1) wherein ring A is phenyl, m is the integer 1, n is the integer 0, X is CH, L is NR 1 and R 1 is H, and X' is CR 2 and R 2 and R 3 are joined together to form cyclohexyl, a compound, and a pharmaceutically acceptable salt thereof.

[0018] In one aspect of the invention, a compound of formula (1) wherein X is CH, L is NR 1 and R 1 is H or R 1 is phenyl or pyridinyl, each optionally substituted with one or two R 4 substituents, 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 substituted with (R 4 ), X' is CR n and R 2 is H, methyl, or -CF3, R 2 is H or cyano, m is the integer 1, n is the integer 0, 1, or 2, a compound, and a pharmaceutically acceptable salt. In another aspect, a compound of formula (1) wherein X is CH, L is NR 3 and R 1 is H or R 1 is H or R 1 is phenyl or pyridinyl, each optionally substituted with one or two R 4Optionally 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 substituted, X' is CR 2 , R 2 is H, methyl, or -CF3, R3 is H or cyano, m is the integer 1, n is the integer 0, 1, or 2, a compound, and a pharmaceutically acceptable salt thereof. In another aspect, a compound of formula (1) wherein X is CH, L is NR 1 , R 1 is H, or R 1 is phenyl or pyridinyl, each optionally substituted with one R 4 substituent, ring A is phenyl, indolyl, indazolyl, thiophenyl, pyridinyl, imidazolyl, thiazolyl, or isothiazolyl, each of which is (R 4 ) n substituted, X' is CR 2 , R 2 is H, methyl, or -CF3, R 3 is H or cyano, m is the integer 1, n is the integer 0, 1, or 2, a compound, and a pharmaceutically acceptable salt thereof. In another aspect, a compound of formula (1) wherein X is CH, L is NR 1 , R 1 is H, or R 1 is phenyl optionally substituted with one R 4 substituent, ring A is phenyl, indolyl, thiophenyl, pyridinyl, thiazolyl, or isothiazolyl, each of which is (R 4 ) n substituted, X' is CR 2 , R 2 is H, methyl, or -CF3, R 3is H or cyano, m is the integer 1, n is the integer 0, 1, or 2, a compound, and a pharmaceutically acceptable salt thereof. In another aspect, a compound of formula (1) wherein X is CH, L is NR 1 wherein R 1 is H or R 1 is phenyl optionally substituted with fluoro, ring A is phenyl, indolyl, thiophenyl, pyridinyl, thiazolyl, or isothiazolyl, each substituted with (R 4 ) n X' is CR 2 wherein R 2 is H, methyl, or -CF3, R 3 is H or cyano, m is the integer 1, n is the integer 0 or 1, a compound, and a pharmaceutically acceptable salt thereof. In another aspect, a compound of formula (1) wherein X is CH, L is NR 1 wherein R 1 is H or R 1 is phenyl optionally substituted with fluoro, ring A is phenyl, indolyl, thiophenyl, thiazolyl, or isothiazolyl, each substituted with (R 4 ) n X' is CR 2 wherein R 2 is H, methyl, or -CF3, R 3 is H, m is the integer 1, n is the integer 0 or 1, a compound, and a pharmaceutically acceptable salt thereof. In another aspect, a compound of formula (1) wherein X is CH, L is NR 1 wherein R 1 is H, ring A is phenyl, indolyl, thiophenyl, or isothiazolyl, each substituted with (R 4 ) n X' is CR 2 wherein R 2 is H, methyl, or -CF3, R 3 is H, m is the integer 1, n is the integer 0 or 1, a compound, and a pharmaceutically acceptable salt thereof.

[0019] In another aspect of the present invention, a compound of formula (1), wherein X is CH, L is O, ring A is phenyl substituted with (R 4 ), n X' is CR 2 , R 2 and R 3 are both H, m is the integer 1, and n is the integer 0, 1, or 2, and a pharmaceutically acceptable salt thereof. In another aspect, a compound of formula (1), wherein X is CH, L is O, ring A is phenyl substituted with (R 4 ), n X' is CR 2 , R 2 and R 3 are both H, m is the integer 1, and n is the integer 0 or 1, and a pharmaceutically acceptable salt thereof. In another aspect, a compound of formula (1), wherein X is CH, L is O, ring A is phenyl substituted with (R 4 ), n X' is CR 2 , R 2 and R 3 are both H, R 4 is methyl, fluoro, chloro, or -CF3, m is the integer 1, and n is the integer 0 or 1, and a pharmaceutically acceptable salt thereof. In another aspect, a compound of formula (1), wherein X is CH, L is O, ring A is phenyl substituted with (R 4 ), n X' is CR 2 , R 2 and R 3 are both H, R 4 is methyl, fluoro, or chloro, m is the integer 1, and n is the integer 0 or 1, and a pharmaceutically acceptable salt thereof.

[0020] In another aspect of the present invention, a compound of formula (1), wherein X is CH, L is O or NR 1and ring A is phenyl, pyridinyl, indolyl, thiophenyl, isothiazolyl, or thiazolyl, each substituted with (R 4 ), n X’ is CR 2 , R 1 , R 2 , and R 3 are each H, m is the integer 1, and n is the integer 0, 1, or 2, and the compound, and pharmaceutically acceptable salts thereof. In another aspect, a compound of formula (1) wherein X is CH, L is O or NR 1 , ring A is phenyl, pyridinyl, indolyl, thiophenyl, isothiazolyl, or thiazolyl, each substituted with (R 4 ), n X’ is CR 2 , R 1 , R 2 , and R 3 are each H, m is the integer 1, and n is the integer 0, 1, or 2, and the compound, and pharmaceutically acceptable salts thereof. In another aspect, a compound of formula (1) wherein X is CH, L is O or NR 1 , ring A is phenyl, indolyl, thiophenyl, isothiazolyl, or thiazolyl, each substituted with (R 4 ), n X’ is CR 2 , R 1 , R 2 , and R 3 are each H, m is the integer 1, and n is the integer 0 or 1, and the compound, and pharmaceutically acceptable salts thereof. In another aspect, a compound of formula (1) wherein X is CH, L is O or NR 1 , ring A is phenyl, indolyl, thiophenyl, or isothiazolyl, each substituted with (R 4 ), n X’ is CR 2 , R 1 , R 2 , and R 3 are each H, R 4is methyl, fluoro, chloro, or -CF3, m is the integer 1, n is the integer 0 or 1, a compound, and a pharmaceutically acceptable salt thereof.

[0021] In another aspect of the present invention, a compound of formula (1) wherein X is CH or N, L is NR 1 wherein ring A is phenyl, pyridinyl, indolyl, thiophenyl, isothiazolyl, or thiazolyl, each substituted with (R 4 ) n X' is CR 2 R 1 , R 2 , and R 3 are each H, m is the integer 1, n is the integer 0, 1, or 2, a compound, and a pharmaceutically acceptable salt thereof. In another aspect, a compound of formula (1) wherein X is CH or N, L is NR 1 wherein ring A is phenyl, pyridinyl, indolyl, thiophenyl, isothiazolyl, or thiazolyl, each substituted with (R 4 ) n X' is CR 2 R 1 , R 2 , and R 3 are each H, R 4 is methyl, fluoro, chloro, or -CF3, m is the integer 1, n is the integer 0, 1, or 2, a compound, and a pharmaceutically acceptable salt thereof. In another aspect, a compound of formula (1) wherein X is CH or N, L is NR 1 wherein ring A is phenyl, indolyl, pyridinyl, thiophenyl, or isothiazolyl, each substituted with (R 4 ) n X' is CR 2 R 1 , R 2 , and R 3 are each H, R 4is methyl, fluoro, or chloro, m is the integer 1, n is the integer 0, 1, or 2, the compound, and a pharmaceutically acceptable salt thereof. In another aspect, a compound of formula (1) wherein X is CH or N, L is NR 1 and ring A is phenyl substituted with (R 4 ) n X' is CR 2 and R 1 , R 2 , and R 3 are each H, R 4 is fluoro or chloro, m is the integer 1, n is the integer 0 or 1, the compound, and a pharmaceutically acceptable salt thereof.

[0022] In another aspect of the present invention, a compound of formula (1) wherein ring A is phenyl, indolyl, pyridinyl, thiophenyl, or isothiazolyl, X is N, L is NR 1 X' is CR 2 and R 1 , R 2 , and R 3 are each H, R 4 is methyl, fluoro, chloro, or -CF3, m is the integer 1, n is the integer 0, 1, or 2, the compound, and a pharmaceutically acceptable salt thereof. In another aspect, a compound of formula (1) wherein ring A is phenyl, indolyl, pyridinyl, thiophenyl, or isothiazolyl, X is N, L is NR 1 X' is CR 2 and R 1 , R 2 , and R 3 are each H, R 4 is fluoro or chloro, m is the integer 1, n is the integer 0, 1, or 2, the compound, and a pharmaceutically acceptable salt thereof. In another aspect, a compound of formula (1) wherein ring A is phenyl, indolyl, pyridinyl, thiophenyl, or isothiazolyl, X is N, L is NR 1 X' is CR 2 and R1 , R 2 , and R 3 are each H, R 4 is fluoro or chloro, m is the integer 1, and n is the integer 0 or 1, a compound, or a pharmaceutically acceptable salt thereof.

[0023] In another aspect of the present invention, a compound of formula (1) wherein ring A is phenyl, indolyl, pyridinyl, thiophenyl, or isothiazolyl, X is CH or N, L is NR 1 or O, R 1 is H, X' is CR 2 , R 2 is H or methyl, R 3 is H or cyano, R 4 is fluoro, chloro, or -CF3, m is the integer 1, and n is the integer 0, 1, or 2, a compound, and a pharmaceutically acceptable salt thereof. In another aspect, a compound of formula (1) wherein ring A is phenyl, indolyl, pyridinyl, thiophenyl, or isothiazolyl, X is CH or N, L is NR 1 or O, X' is CR 2 , R 1 , R 2 , and R 3 are each H, R 4 is fluoro or chloro, m is the integer 1, and n is the integer 0, 1, or 2, a compound, as well as a pharmaceutically acceptable salt thereof. In another aspect, a compound of formula (1) wherein ring A is phenyl, indolyl, pyridinyl, thiophenyl, or isothiazolyl, X is CH or N, L is NR 1 or O, X' is CR 2 , R 1 , R 2 , and R 3 are each H, R 4 is fluoro or chloro, m is the integer 1, and n is the integer 0 or 1, a compound, as well as a pharmaceutically acceptable salt thereof.

[0024] In another aspect of the present invention, a compound of formula (1), N-((1R,3s,5S)-8-Benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3s,5S)-8-Benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamide, N-((1R,3s,5S)-8-(4-Chlorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamide, N-((1R,3s,5S)-8-(4-Fluorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3s,5S)-8-(4-Chlorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3s,5S)-8-((1H-Indol-5-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3s,5S)-8-(Thiophen-2-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3s,5S)-8-Benzyl-8-azabicyclo[3.2.1]octan-3-yl)-2-methyl-1H-indole-6-carboxamide, N-((1R,3s,5S)-8-Benzyl-8-azabicyclo[3.2.1]octan-3-yl)-2,3,4,9-tetrahydro-1H-carbazole-7-carboxamide, N-((1R,3s,5S)-8-Benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-indazole-6-carboxamide, N-((1R,3s,5S)-8-(4-(Trifluoromethyl)benzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3s,5S)-8-(pyridin-2-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3s,5S)-8-(pyridin-3-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3s,5S)-8-(pyridin-4-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3s,5S)-8-(pyrazin-2-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3s,5S)-8-((1-methyl-1H-imidazol-2-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3s,5S)-8-phenyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1-(pyridin-4-yl)-1H-indole-6-carboxamide, N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-3-cyano-1H-indole-6-carboxamide, N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-2-(trifluoromethyl)-1H-indole-6-carboxamide, N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-6-carboxamide, N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1-(4-fluorophenyl)-1H-indole-6-carboxamide, N-((1R,3s,5S)-8-Benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1-phenyl-1H-indole-6-carboxamide, N-((1R,3s,5S)-8-Benzyl-8-azabicyclo[3.2.1]octan-3-yl)benzofuran-6-carboxamide, N-((1R,3s,5S)-8-(Isothiazol-5-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3s,5S)-8-(Isothiazol-3-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3s,5S)-8-(Thiazol-2-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, and A compound selected from the group consisting of N-((1R,3s,5S)-8-((4-methylthiazol-2-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, and pharmaceutically acceptable salts thereof.

[0025] In another aspect of the present invention, a compound of formula (1), wherein N-((1R,3s,5S)-8-Benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3s,5S)-8-Benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamide; N-((1R,3s,5S)-8-(4-Chlorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamide, N-((1R,3s,5S)-8-(4-Fluorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3s,5S)-8-(4-chlorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3s,5S)-8-((1H-indol-5-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3s,5S)-8-(thiophen-2-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-2-methyl-1H-indole-6-carboxamide, N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-2,3,4,9-tetrahydro-1H-carbazole-7-carboxamide, N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-indazole-6-carboxamide, N-((1R,3s,5S)-8-(4-(trifluoromethyl)benzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3s,5S)-8-(pyridin-2-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3s,5S)-8-(pyridin-3-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1-(pyridin-4-yl)-1H-indole-6-carboxamide, N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-3-cyano-1H-indole-6-carboxamide, N-((1R,3s,5S)-8-Benzyl-8-azabicyclo[3.2.1]octan-3-yl)-2-(trifluoromethyl)-1H-indole-6-carboxamide, N-((1R,3s,5S)-8-Benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1-(4-fluorophenyl)-1H-indole-6-carboxamide, N-((1R,3s,5S)-8-Benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1-phenyl-1H-indole-6-carboxamide, N-((1R,3s,5S)-8-Benzyl-8-azabicyclo[3.2.1]octan-3-yl)benzofuran-6-carboxamide, N-((1R,3s,5S)-8-(Isothiazol-5-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3s,5S)-8-(Isothiazol-3-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3s,5S)-8-(Thiazol-2-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, and N-((1R,3s,5S)-8-((4-Methylthiazol-2-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide selected from the group consisting of compounds having a c5-HT2B inhibitory IC of less than 1000 nM 50 A compound having the same, and a pharmaceutically acceptable salt thereof.

[0026] In another aspect of the present invention, a compound of formula (1), N-((1R,3s,5S)-8-Benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3S,5S)-8-Benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamide, N-((1R,3S,5S)-8-(4-Chlorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamide, N-((1R,3S,5S)-8-(4-Fluorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3S,5S)-8-(4-Chlorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3S,5S)-8-((1H-Indol-5-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3S,5S)-8-(Thiophen-2-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3S,5S)-8-Benzyl-8-azabicyclo[3.2.1]octan-3-yl)-2-methyl-1H-indole-6-carboxamide, N-((1R,3S,5S)-8-Benzyl-8-azabicyclo[3.2.1]octan-3-yl)-2,3,4,9-tetrahydro-1H-carbazole-7-carboxamide, N-((1R,3S,5S)-8-Benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-indazole-6-carboxamide, N-((1R,3S,5S)-8-(4-(Trifluoromethyl)benzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3S,5S)-8-(Pyridin-2-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3S,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-3-cyano-1H-indole-6-carboxamide, N-((1R,3S,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-2-(trifluoromethyl)-1H-indole-6-carboxamide, N-((1R,3S,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1-(4-fluorophenyl)-1H-indole-6-carboxamide, N-((1R,3S,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1-phenyl-1H-indole-6-carboxamide, N-((1R,3S,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)benzofuran-6-carboxamide, N-((1R,3S,5S)-8-(isothiazol-5-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3S,5S)-8-(isothiazol-3-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3S,5S)-8-(thiazol-2-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, and N-((1R,3S,5S)-8-((4-methylthiazol-2-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide selected from the group consisting of, with a c5-HT2B inhibitory IC of less than 500 nM 50 A compound having the same, and a pharmaceutically acceptable salt thereof.

[0027] In another aspect of the present invention, a compound of formula (1), N-((1R,3s,5S)-8-Benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3s,5S)-8-Benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamide, N-((1R,3s,5S)-8-(4-Chlorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamide, N-((1R,3s,5S)-8-(4-Fluorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3s,5S)-8-(4-Chlorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3s,5S)-8-((1H-Indol-5-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3s,5S)-8-(Thiophen-2-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3s,5S)-8-Benzyl-8-azabicyclo[3.2.1]octan-3-yl)-2-methyl-1H-indole-6-carboxamide, N-((1R,3s,5S)-8-(4-(Trifluoromethyl)benzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3s,5S)-8-(Pyridin-2-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3s,5S)-8-Benzyl-8-azabicyclo[3.2.1]octan-3-yl)-2-(trifluoromethyl)-1H-indole-6-carboxamide, N-((1R,3S,5S)-8-Benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1-(4-fluorophenyl)-1H-indole-6-carboxamide, N-((1R,3S,5S)-8-Benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1-phenyl-1H-indole-6-carboxamide, N-((1R,3S,5S)-8-Benzyl-8-azabicyclo[3.2.1]octan-3-yl)benzofuran-6-carboxamide, N-((1R,3S,5S)-8-(Isothiazol-5-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, and N-((1R,3S,5S)-8-(Isothiazol-3-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, selected from the group consisting of compounds having a c5-HT2B inhibitory IC of less than 100 nM 50 A compound having the same, and a pharmaceutically acceptable salt thereof.

[0028] In another aspect of the present invention, a compound of formula (1), N-((1R,3S,5S)-8-Benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3S,5S)-8-Benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamide, N-((1R,3S,5S)-8-(4-Chlorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamide, N-((1R,3S,5S)-8-(4-Fluorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3S,5S)-8-(4-Chlorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3s,5S)-8-((1H-Indol-5-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3s,5S)-8-(Thiophen-2-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3s,5S)-8-Benzyl-8-azabicyclo[3.2.1]octan-3-yl)-2-methyl-1H-indole-6-carboxamide, N-((1R,3s,5S)-8-Benzyl-8-azabicyclo[3.2.1]octan-3-yl)benzofuran-6-carboxamide, and selected from the group consisting of N-((1R,3s,5S)-8-(isothiazol-5-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, with a c5-HT2B inhibitory IC of less than 10 nM 50 a compound having the same, and a pharmaceutically acceptable salt thereof.

[0029] In another aspect of the present invention, a compound of formula (1), N-((1R,3s,5S)-8-Benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3s,5S)-8-Benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamide, N-((1R,3s,5S)-8-(4-Fluorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3s,5S)-8-(4-Chlorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3s,5S)-8-((1H-Indol-5-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, and a c5-HT2B inhibitory IC of less than 1 nM selected from the group consisting of N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)benzofuran-6-carboxamide 50 a compound having the same, and a pharmaceutically acceptable salt thereof.

[0030] In another aspect of the present invention, a c5-HT2B inhibitory IC of less than 1 nM, which is N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide 50 a compound of formula (1) having the same, or a pharmaceutically acceptable salt thereof.

[0031] In another aspect of the present invention, a c5-HT2B inhibitory IC of less than 1 nM, which is N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamide 50 a compound of formula (1) having the same, or a pharmaceutically acceptable salt thereof.

[0032] In another aspect of the present invention, a c5-HT2B inhibitory IC of less than 1 nM, which is N-((1R,3s,5S)-8-(4-fluorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide 50 a compound of formula (1) having the same, or a pharmaceutically acceptable salt thereof.

[0033] In another aspect of the present invention, a c5-HT2B inhibitory IC of less than 1 nM, which is N-((1R,3s,5S)-8-(4-chlorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide 50 a compound of formula (1) having the same, or a pharmaceutically acceptable salt thereof.

[0034] In another aspect of the present invention, an N-((1R,3S,5S)-8-((1H-indol-5-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide with a c5-HT2B inhibitory IC of less than 1 nM 50 is a compound of formula (1) or a pharmaceutically acceptable salt thereof.

[0035] In another aspect of the present invention, an N-((1R,3S,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)benzofuran-6-carboxamide with a c5-HT2B inhibitory IC of less than 1 nM 50 is a compound of formula (1) or a pharmaceutically acceptable salt thereof.

[0036] In another aspect, a compound of formula (1) which is a compound of formula (1A),

Chemical formula

[0037] In another aspect, it is a compound of formula (1A), N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3s,5S)-8-(4-fluorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3s,5S)-8-(4-chlorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-2-methyl-1H-indole-6-carboxamide, N-((1R,3s,5S)-8-(4-(trifluoromethyl)benzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-3-cyano-1H-indole-6-carboxamide, and N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-2-(trifluoromethyl)-1H-indole-6-carboxamide, a compound selected from the group consisting of, and a pharmaceutically acceptable salt thereof.

[0038] In another aspect, it is a compound of formula (1A), N-((1R,3s,5S)-8-Benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3s,5S)-8-(4-Fluorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3s,5S)-8-(4-Chlorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3s,5S)-8-Benzyl-8-azabicyclo[3.2.1]octan-3-yl)-2-methyl-1H-indole-6-carboxamide, N-((1R,3s,5S)-8-(4-(Trifluoromethyl)benzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, and N-((1R,3s,5S)-8-Benzyl-8-azabicyclo[3.2.1]octan-3-yl)-2-(trifluoromethyl)-1H-indole-6-carboxamide selected from the group consisting of compounds having a c5-HT2B inhibitory IC of less than 100 nM 50 A compound having the same, and a pharmaceutically acceptable salt thereof.

[0039] In another aspect, a compound of formula (1A), N-((1R,3s,5S)-8-Benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3s,5S)-8-(4-Fluorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3s,5S)-8-(4-Chlorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, and A compound selected from the group consisting of N-((1R,3S,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-2-methyl-1H-indole-6-carboxamide, having a c5-HT2B inhibitory IC of less than 10 nM 50 and its pharmaceutically acceptable salts.

[0040] In another aspect, a compound of formula (1A) wherein N-((1R,3S,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3S,5S)-8-(4-fluorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, and N-((1R,3S,5S)-8-(4-chlorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, having a c5-HT2B inhibitory IC of less than 1 nM 50 and its pharmaceutically acceptable salts.

[0041] In another aspect of the invention, a compound of formula

Chemical formula

[0042] In another aspect, a compound of formula (1B) which is N-((1R,3s,5S)-8-((1H-indol-5-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3s,5S)-8-(thiophen-2-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3s,5S)-8-(pyridin-2-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3s,5S)-8-(isothiazol-5-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, and A compound having a c5-5HT2B inhibitory IC50 of less than 100 nM selected from the group consisting of N-((1R,3s,5S)-8-(isothiazol-3-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, and a pharmaceutically acceptable salt thereof.

[0043] In another aspect, a compound of formula (1B) which is N-((1R,3s,5S)-8-((1H-indol-5-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3s,5S)-8-(thiophen-2-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, and a compound selected from the group consisting of N-((1R,3s,5S)-8-(isothiazol-5-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide having a c5-5HT2B inhibitory IC50 of less than 10 nM, and a pharmaceutically acceptable salt thereof.

[0044] In another aspect, a compound of formula (1B) having a c5-5HT2B inhibitory IC50 of less than 1 nM, which is N-((1R,3s,5S)-8-((1H-indol-5-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, and a pharmaceutically acceptable salt thereof.

[0045] In another aspect, a compound of formula (1) which is a compound of formula (1C), [Chemical formula] wherein R 1 is phenyl or pyridinyl, each optionally substituted with fluoro, chloro, or -CF3, (R 4 ) n is as defined herein, a compound, and a pharmaceutically acceptable salt thereof. In another aspect, a compound of formula (1C), wherein R 1 is phenyl or pyridinyl, each optionally substituted with fluoro, chloro, or -CF3, R 4 is methyl, fluoro, chloro, or -CF3, and n is an integer 0, 1, or 2, a compound, and a pharmaceutically acceptable salt thereof. In another aspect, a compound of formula (1C), wherein R 1is phenyl or pyridinyl, each optionally substituted with fluoro or chloro, R 4 is fluoro, chloro, or -CF3, n is an integer 0 or 1, a compound, and a pharmaceutically acceptable salt thereof. In another aspect, a compound of formula (1C) wherein R 1 is phenyl or pyridinyl, each optionally substituted with fluoro or chloro, n is an integer 0 or 1, a compound, and a pharmaceutically acceptable salt thereof. In another aspect, a compound of formula (1C) wherein N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1-(pyridin-4-yl)-1H-indole-6-carboxamide, N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1-(4-fluorophenyl)-1H-indole-6-carboxamide, and N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1-phenyl-1H-indole-6-carboxamide, a compound selected from the group consisting of, and a pharmaceutically acceptable salt thereof.

[0046] In another aspect, N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1-(4-fluorophenyl)-1H-indole-6-carboxamide or N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1-phenyl-1H-indole-6-carboxamide, having a 5c-5HT2B IC of less than 100 nM 50 a compound of formula (1C), and a pharmaceutically acceptable salt thereof.

[0047] In another aspect, a compound of formula (1) which is a compound of formula (1D) wherein

Chemical formula

[0048] In another aspect, a compound of formula (1D) having a 5c-5HT2B IC50 of less than 1 nM is N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamide, and a pharmaceutically acceptable salt thereof.

[0049] In another aspect, a compound of formula (1) is a compound of formula (1E), wherein

Chemical formula

[0050] In yet another aspect of the present invention, 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 each of the compound names described herein. In another aspect, a compound of formula (1) having a c5-5HT2B IC 50 of less than 1000 nM, wherein the compound is any one of Examples 1 to 13, 18 to 20, or 22 to 28, is a composition comprising the compound, or a pharmaceutically acceptable salt thereof. In another aspect, a compound of formula (1) having a c5-5HT2B IC 50 of less than 500 nM, wherein the compound is any one of Examples 1 to 12, 19 to 20, or 22 to 28, is a composition comprising the compound, or a pharmaceutically acceptable salt thereof. In another aspect, a compound of formula (1) having a c5-5HT2B IC 50A compound of formula (1) having the following, wherein the compound is any one of Examples 1 to 8, 11 to 12, 20, or 22 to 26, or a composition comprising a pharmaceutically acceptable salt thereof. In another aspect, a c5-5HT2B IC of less than 10 nM 50 A compound of formula (1) having the following, wherein the compound is any one of Examples 1 to 8, 24, or 25, or a composition comprising a pharmaceutically acceptable salt thereof. In another aspect, a c5-5HT2B IC of less than 1 nM 50 A compound of formula (1) having the following, wherein the compound is any one of Examples 1, 2, 4 to 6, or 24, or a composition comprising a pharmaceutically acceptable salt thereof. In another aspect, the composition comprising the compound of formula (1) or a pharmaceutically acceptable salt thereof further comprises at least one pharmaceutically acceptable excipient.

[0051] In another aspect, a composition comprising 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 aspect, a composition comprising a compound of formula (1A) or a pharmaceutically acceptable salt thereof. In another aspect, a composition comprising a compound of formula (1B) or a pharmaceutically acceptable salt thereof. In another aspect, a composition comprising a compound of formula (1C) or a pharmaceutically acceptable salt thereof. In another aspect, a composition comprising a compound of formula (1D) or a pharmaceutically acceptable salt thereof. In another aspect, a composition comprising a compound of formula (1E) or a pharmaceutically acceptable salt thereof. In another aspect, the composition further comprises at least one pharmaceutically acceptable excipient.

[0052] In another aspect, a 5c-5HT2B IC of less than 500 nM 50 A compound of formula (1A) having the following, wherein the compound is any one of Examples 1, 4 to 5, 8, 11, 19, or 20, or a composition comprising a pharmaceutically acceptable salt thereof. In another aspect, a 5c-5HT2B IC of less than 100 nM 50A compound of formula (1A) having, wherein the compound is any one of Examples 1, 4 - 5, 8, 11, or 20, or a composition comprising a pharmaceutically acceptable salt thereof. In another aspect, 5c - 5HT2B IC less than 10 nM 50 A compound of formula (1A) having, wherein the compound is any one of Examples 1, 4 - 5, or 8, or a composition comprising a pharmaceutically acceptable salt thereof. In another aspect, 5c - 5HT2B IC less than 1 nM 50 A compound of formula (1A) having, wherein the compound is any one of Examples 1, 4, or 5, or a composition comprising a pharmaceutically acceptable salt thereof. In another aspect, the composition further comprises at least one pharmaceutically acceptable excipient.

[0053] In another aspect, 5c - 5HT2B IC less than 1000 nM 50 A compound of formula (1B) having, wherein the compound is any one of Examples 6 - 7, 12 - 13, or 25 - 28, or a composition comprising a pharmaceutically acceptable salt thereof. In another aspect, 5c - 5HT2B IC less than 500 nM 50 A compound of formula (1B) having, wherein the compound is any one of Examples 6 - 7, 12, or 25 - 28, or a composition comprising a pharmaceutically acceptable salt thereof. In another aspect, 5c - 5HT2B IC less than 100 nM 50 A compound of formula (1B) having, wherein the compound is any one of Examples 6, 7, 12, 25, or 26, or a composition comprising a pharmaceutically acceptable salt thereof. In another aspect, 5c - 5HT2B IC less than 10 nM 50 A compound of formula (1B) having, wherein the compound is any one of Examples 6, 7, or 25, or a composition comprising a pharmaceutically acceptable salt thereof. In another aspect, 5c - 5HT2B IC less than 1 nM 50A compound of formula (1B) having the following, wherein the composition comprises the compound which is Example 6, or a pharmaceutically acceptable salt thereof. In another aspect, the composition further comprises at least one pharmaceutically acceptable excipient.

[0054] In another aspect, a 5c-5HT2B IC of less than 100 nM 50 A compound of formula (1C) having the following, wherein the composition comprises the compound which is Example 22 or 23, or a pharmaceutically acceptable salt thereof.

[0055] In another aspect, a 5c-5HT2B IC of less than 10 nM 50 A compound of formula (1D) having the following, wherein the composition comprises the compound which is Example 2 or 3, or a pharmaceutically acceptable salt thereof. In another aspect, a 5c-5HT2B IC of less than 1 nM 50 A compound of formula (1D) having the following, wherein the composition comprises the compound which is Example 2, or a pharmaceutically acceptable salt thereof.

[0056] In another aspect, a 5c-5HT2B IC of less than 1 nM 50 A compound of formula (1E) having the following, wherein the composition comprises the compound which is any one of Example 24, or a pharmaceutically acceptable salt thereof. In another aspect, the composition further comprises at least one pharmaceutically acceptable excipient.

[0057] In another aspect, the composition is administered orally or by injection. In another aspect, the composition is administered orally. In another aspect, the composition is administered by subcutaneous injection or intramuscular injection. In another aspect, the composition is administered three times a week. In another aspect, the composition is administered five times a week. In another aspect, the composition is administered every other day. In another aspect, the composition is administered daily. In another aspect, the composition is administered twice a day.

[0058] In yet another aspect of the present invention, a method of treating an animal having MMVD, CHF, and / or asymptomatic heart failure comprises administering a therapeutically effective amount of a compound of formula (1), or a pharmaceutically acceptable salt thereof, to an animal in need thereof. In the treatment methods described below, the example numbers are interchangeable with each of the compound names described herein. In another aspect, a method of treating an animal having MMVD, CHF, and / or asymptomatic heart failure comprises a therapeutically effective amount of a compound of formula (1), wherein the compound has a 5c-5HT2B IC 50 of less than 1000 nM and is Example 1-13, 18-20, or 22-28, or a pharmaceutically acceptable salt thereof, by administering to an animal in need thereof. In another aspect, a method of treating an animal having MMVD, CHF, and / or asymptomatic heart failure comprises a therapeutically effective amount of a compound of formula (1), wherein the compound has a 5c-5HT2B IC 50 of less than 500 nM and is Example 1-12, 19-20, or 22-28, or a pharmaceutically acceptable salt thereof, by administering to an animal in need thereof. In another aspect, a method of treating an animal having MMVD, CHF, and / or asymptomatic heart failure comprises a therapeutically effective amount of a compound of formula (1), wherein the compound has a 5c-5HT2B IC 50 of less than 100 nM and is Example 1-8, 11-12, 20, or 22-26, or a pharmaceutically acceptable salt thereof, by administering to an animal in need thereof. In another aspect, a method of treating an animal having MMVD, CHF, and / or asymptomatic heart failure comprises a therapeutically effective amount of a compound of formula (1), wherein the compound has a 5c-5HT2B IC 50 of less than 10 nM and is Example 1-8, 24, or 25, or a pharmaceutically acceptable salt thereof, by administering to an animal in need thereof. In another aspect, a method of treating an animal having MMVD, CHF, and / or asymptomatic heart failure comprises a therapeutically effective amount of a compound of formula (1), wherein the compound has a 5c-5HT2B IC 50by administering to an animal in need thereof a compound having the formula of Example 1, 2, 4 - 6, or 24, or a pharmaceutically acceptable salt thereof. In another aspect, the animal is a companion animal. In another aspect, the companion animal is a dog.

[0059] In another aspect, a method of treating an animal having MMVD, CHF, and / or asymptomatic heart failure is by administering to an animal in need thereof a therapeutically effective 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 aspect, the animal is a companion animal. In another aspect, the companion animal is a dog.

[0060] In another aspect, a method of treating an animal having MMVD, CHF, and / or asymptomatic heart failure is by administering to an animal in need thereof a therapeutically effective amount of a compound of formula (1A), or a pharmaceutically acceptable salt thereof. In another aspect, a method of treating an animal having MMVD, CHF, and / or asymptomatic heart failure is by administering to an animal in need thereof a therapeutically effective amount of a compound of formula (1A) having a 5c - 5HT2B IC 50 less than 500 nM, which is any one of Examples 1, 4, 5, 8, 11, 19, or 20, or a pharmaceutically acceptable salt thereof. In another aspect, a method of treating an animal having MMVD, CHF, and / or asymptomatic heart failure is by administering to an animal in need thereof a therapeutically effective amount of a compound of formula (1A) having a 5c - 5HT2B IC 50 less than 100 nM, which is any one of Examples 1, 4, 5, 8, 11, or 20, or a pharmaceutically acceptable salt thereof. In another aspect, a method of treating an animal having MMVD, CHF, and / or asymptomatic heart failure is by administering to an animal in need thereof a therapeutically effective amount of a compound of formula (1A) having a 5c - 5HT2B IC 50 less than 10 nM, which is any one of Examples 1, 4, 5, or 8, or a pharmaceutically acceptable salt thereof.By administering to an animal in need thereof a compound of formula (1A) having , or a pharmaceutically acceptable salt thereof. In another aspect, a method of treating an animal having MMVD, CHF, and / or asymptomatic heart failure is a therapeutically effective amount of any one of Examples 1, 4, or 5, a 5c-5HT2B IC less than 1 nM 50 By administering to an animal in need thereof a compound of formula (1A) having , or a pharmaceutically acceptable salt thereof. In another aspect, the animal is a companion animal. In another aspect, the companion animal is a dog.

[0061] In another aspect, a method of treating an animal having MMVD, CHF, and / or asymptomatic heart failure is by administering to an animal in need thereof a therapeutically effective amount of a compound of formula (1B), or a pharmaceutically acceptable salt thereof. In another aspect, a method of treating an animal having MMVD, CHF, and / or asymptomatic heart failure is a therapeutically effective amount of any one of Examples 6 - 7, 12 - 13, or 25 - 28, a 5c-5HT2B IC less than 1000 nM 50 By administering to an animal in need thereof a compound of formula (1B) having , or a pharmaceutically acceptable salt thereof. In another aspect, a method of treating an animal having MMVD, CHF, and / or asymptomatic heart failure is a therapeutically effective amount of any one of Examples 6 - 7, 12, or 25 - 26, a 5c-5HT2B IC less than 100 nM 50 By administering to an animal in need thereof a compound of formula (1B) having , or a pharmaceutically acceptable salt thereof. In another aspect, a method of treating an animal having MMVD, CHF, and / or asymptomatic heart failure is a therapeutically effective amount of any one of Examples 6 - 7, or 25, a 5c-5HT2B IC less than 10 nM 50 By administering to an animal in need thereof a compound of formula (1B) having , or a pharmaceutically acceptable salt thereof. In another aspect, a method of treating an animal having MMVD, CHF, and / or asymptomatic heart failure is a therapeutically effective amount of Example 6, a 5c-5HT2B IC less than 1 nM 50By administering a compound of formula (1B) having the same, or a pharmaceutically acceptable salt thereof, to an animal in need thereof. In another aspect, the animal is a companion animal. In another aspect, the companion animal is a dog.

[0062] In another aspect, a method of treating an animal having MMVD, CHF, and / or asymptomatic heart failure is by administering a therapeutically effective amount of a compound of formula (1C), or a pharmaceutically acceptable salt thereof, to an animal in need thereof.

[0063] In another aspect, a method of treating an animal having MMVD, CHF, and / or asymptomatic heart failure is by administering a therapeutically effective amount of a compound of formula (1C) having a 5c-5HT2B IC of less than 1000 nM, which is any one of Examples 18, 22, or 23, or a pharmaceutically acceptable salt thereof, to an animal in need thereof. 50 By administering a compound of formula (1C) having the same, or a pharmaceutically acceptable salt thereof, to an animal in need thereof. In another aspect, a method of treating an animal having MMVD, CHF, and / or asymptomatic heart failure is by administering a therapeutically effective amount of a compound of formula (1C) having a 5c-5HT2B IC of less than 100 nM, which is Example 22 or 23, or a pharmaceutically acceptable salt thereof, to an animal in need thereof. 50 By administering a compound of formula (1C) having the same, or a pharmaceutically acceptable salt thereof, to an animal in need thereof. In another aspect, the animal is a companion animal. In another aspect, the companion animal is a dog.

[0064] In another aspect, a method of treating an animal having MMVD, CHF, and / or asymptomatic heart failure is by administering a therapeutically effective amount of a compound of formula (1D), or a pharmaceutically acceptable salt thereof, to an animal in need thereof. In another aspect, a method of treating an animal having MMVD, CHF, and / or asymptomatic heart failure is by administering a therapeutically effective amount of a compound of formula (1D), or a pharmaceutically acceptable salt thereof, to an animal in need thereof. In another aspect, a method of treating an animal having MMVD, CHF, and / or asymptomatic heart failure is by administering a therapeutically effective amount of a compound of formula (1D) having a 5c-5HT2B IC of less than 10 nM, which is Example 2 or 3, or a pharmaceutically acceptable salt thereof, to an animal in need thereof. 50By administering to an animal in need thereof a compound of formula (1D) having [specific condition], or a pharmaceutically acceptable salt thereof. In another aspect, a method of treating an animal having MMVD, CHF, and / or asymptomatic heart failure is by administering a therapeutically effective amount of a compound of Example 2, which is less than 1 nM of 5c-5HT2B IC 50 By administering to an animal in need thereof a compound of formula (1D) having [specific condition], or a pharmaceutically acceptable salt thereof. In another aspect, the animal is a companion animal. In another aspect, the companion animal is a dog.

[0065] In another aspect, a method of treating an animal having MMVD, CHF, and / or asymptomatic heart failure is by administering a therapeutically effective amount of a compound of formula (1E), or a pharmaceutically acceptable salt thereof, to an animal in need thereof. In another aspect, a method of treating an animal having MMVD, CHF, and / or asymptomatic heart failure is by administering a therapeutically effective amount of a compound of Example 24, which is less than 1 nM of 5c-5HT2B IC 50 By administering to an animal in need thereof a compound of formula (1E) having [specific condition], or a pharmaceutically acceptable salt thereof. In another aspect, the animal is a companion animal. In another aspect, the companion animal is a dog.

[0066] In yet another aspect of the present invention, there is provided the use of a compound of formula (1), or a pharmaceutically acceptable salt thereof, for preparing a medicament for treating an animal having MMVD, CHF, and / or asymptomatic heart failure. In the uses described below, the example numbers are interchangeable with each of the compound names described herein. In another aspect, for preparing a medicament for treating an animal having MMVD, CHF, and / or asymptomatic heart failure, a compound of formula (1) having a 5c-5HT2B IC of less than 1000 nM 50 which is a compound of formula (1) having [specific condition], and the compound is any one of Examples 1 to 13, 18 to 20, or 22 to 28, or a pharmaceutically acceptable salt thereof. In another aspect, for preparing a medicament for treating an animal having MMVD, CHF, and / or asymptomatic heart failure, a 5c-5HT2B IC of less than 500 nM 50A compound of formula (1) having the following, wherein the compound is any one of Examples 1 to 12, 19 to 20, or 22 to 28, or a pharmaceutically acceptable salt thereof. In another aspect, for preparing a pharmaceutical for treating an animal having MMVD, CHF, and / or asymptomatic heart failure, a 5c-5HT2B IC of less than 100 nM 50 A compound of formula (1) having the following, wherein the compound is any one of Examples 1 to 8, 11 to 12, 20, or 22 to 26, or a pharmaceutically acceptable salt thereof. In another aspect, for preparing a pharmaceutical for treating an animal having MMVD, CHF, and / or asymptomatic heart failure, a 5c-5HT2B IC of less than 10 nM 50 A compound of formula (1) having the following, wherein the compound is any one of Examples 1 to 8, 24, or 25, or a pharmaceutically acceptable salt thereof. In another aspect, for preparing a pharmaceutical for treating an animal having MMVD, CHF, and / or asymptomatic heart failure, a 5c-5HT2B IC of less than 1 nM 50 A compound of formula (1) having the following, wherein the compound is any one of Examples 1, 2, 4 to 6, or 24, or a pharmaceutically acceptable salt thereof. In another aspect, the animal is a companion animal. In another aspect, the companion animal is a dog.

[0067] In another aspect, for preparing a pharmaceutical for treating an animal having MMVD, CHF, and / or asymptomatic heart failure, the use of a compound of formula (1A), formula (1B), formula (1C), formula (1D), or formula (1E), or a pharmaceutically acceptable salt thereof. In another aspect, the animal is a companion animal. In another aspect, the companion animal is a dog.

[0068] In another aspect, it is the use of a compound of formula (1A), or a pharmaceutically acceptable salt thereof, for preparing a medicament for treating an animal having MMVD, CHF and / or asymptomatic heart failure. In another aspect, it is the use of a compound of formula (1A), or a pharmaceutically acceptable salt thereof, having a 5c-5HT2B IC of less than 500 nM, which is any one of Examples 1, 4, 5, 8, 11, 19, or 20, for preparing a medicament for treating an animal having MMVD, CHF and / or asymptomatic heart failure. 50 In another aspect, it is the use of a compound of formula (1A), or a pharmaceutically acceptable salt thereof, having a 5c-5HT2B IC of less than 100 nM, which is any one of Examples 1, 4, 5, 8, 11, or 20, for preparing a medicament for treating an animal having MMVD, CHF and / or asymptomatic heart failure. 50 In another aspect, it is the use of a compound of formula (1A), or a pharmaceutically acceptable salt thereof, having a 5c-5HT2B IC of less than 10 nM, which is any one of Examples 1, 4, 5, or 8, for preparing a medicament for treating an animal having MMVD, CHF and / or asymptomatic heart failure. 50 In another aspect, it is the use of a compound of formula (1A), or a pharmaceutically acceptable salt thereof, having a 5c-5HT2B IC of less than 1 nM, which is any one of Examples 1, 4, or 5, for preparing a medicament for treating an animal having MMVD, CHF and / or asymptomatic heart failure. 50 In another aspect, it is the use of a compound of formula (1A), or a pharmaceutically acceptable salt thereof, having a 5c-5HT2B IC as described above. In another aspect, the animal is a companion animal. In another aspect, the companion animal is a dog.

[0069] In another aspect, it is the use of a compound of formula (1B), or a pharmaceutically acceptable salt thereof, for preparing a medicament for treating an animal having MMVD, CHF and / or asymptomatic heart failure. In another aspect, it is the use of a compound of formula (1B), or a pharmaceutically acceptable salt thereof, having a 5c-5HT2B IC of less than 1000 nM, which is any one of Examples 6, 7, 12 - 13, or 25 - 28, for preparing a medicament for treating an animal having MMVD, CHF and / or asymptomatic heart failure. 50The use of a compound of formula (1B) having the same, or a pharmaceutically acceptable salt thereof. In another aspect, it is any one of Examples 6-7, 12, or 25-28 for preparing a pharmaceutical for treating an animal having MMVD, CHF, and / or asymptomatic heart failure, with a 5c-5HT2B IC of less than 500 nM 50 The use of a compound of formula (1B) having the same, or a pharmaceutically acceptable salt thereof. In another aspect, it is any one of Examples 6-7, 12, 25, or 26 for preparing a pharmaceutical for treating an animal having MMVD, CHF, and / or asymptomatic heart failure, with a 5c-5HT2B IC of less than 100 nM 50 The use of a compound of formula (1B) having the same, or a pharmaceutically acceptable salt thereof. In another aspect, it is any one of Examples 6, 7, or 25 for preparing a pharmaceutical for treating an animal having MMVD, CHF, and / or asymptomatic heart failure, with a 5c-5HT2B IC of less than 10 nM 50 The use of a compound of formula (1B) having the same, or a pharmaceutically acceptable salt thereof. In another aspect, it is Example 6 for preparing a pharmaceutical for treating an animal having MMVD, CHF, and / or asymptomatic heart failure, with a 5c-5HT2B IC of less than 1 nM 50 The use of a compound of formula (1B) having the same, or a pharmaceutically acceptable salt thereof. In another aspect, the animal is a companion animal. In another aspect, the companion animal is a dog.

[0070] In another aspect, it is the use of a compound of formula (1C), or a pharmaceutically acceptable salt thereof, for preparing a pharmaceutical for treating an animal having MMVD, CHF, and / or asymptomatic heart failure. In another aspect, it is any one of Examples 18, 22, or 23 for preparing a pharmaceutical for treating an animal having MMVD, CHF, and / or asymptomatic heart failure, with a 5c-5HT2B IC of less than 1000 nM 50Use of a compound of formula (1C) having the same, or a pharmaceutically acceptable salt thereof. In another aspect, Example 22 or 23 for preparing a pharmaceutical for treating an animal having MMVD, CHF and / or asymptomatic heart failure, 5c-5HT2B IC less than 100 nM 50 Use of a compound of formula (1C) having the same, or a pharmaceutically acceptable salt thereof. In another aspect, the animal is a companion animal. In another aspect, the companion animal is a dog.

[0071] In another aspect, use of a compound of formula (1D) or a pharmaceutically acceptable salt thereof for preparing a pharmaceutical for treating an animal having MMVD, CHF and / or asymptomatic heart failure. In another aspect, Example 2 or 3 for preparing a pharmaceutical for treating an animal having MMVD, CHF and / or asymptomatic heart failure, 5c-5HT2B IC less than 10 nM 50 Use of a compound of formula (1D) having the same, or a pharmaceutically acceptable salt thereof. In another aspect, Example 2 for preparing a pharmaceutical for treating an animal having MMVD, CHF and / or asymptomatic heart failure, 5c-5HT2B IC less than 1 nM 50 Use of a compound of formula (1D) having the same, or a pharmaceutically acceptable salt thereof. In another aspect, the animal is a companion animal. In another aspect, the companion animal is a dog.

[0072] In another aspect, use of a compound of formula (1E) or a pharmaceutically acceptable salt thereof for preparing a pharmaceutical for treating an animal having MMVD, CHF and / or asymptomatic heart failure. In another aspect, Example 24 for preparing a pharmaceutical for treating an animal having MMVD, CHF and / or asymptomatic heart failure, 5c-5HT2B IC less than 1 nM 50 Use of a compound of formula (1E) having the same, or a pharmaceutically acceptable salt thereof. In another aspect, the animal is a companion animal. In another aspect, the companion animal is a dog.

[0073] In another aspect of the invention, a method of treating an animal having MMVD, CHF, and / or asymptomatic heart failure comprises administering to the animal in need thereof a therapeutically effective amount of a compound of formula (1), or a pharmaceutically acceptable salt thereof, in combination with at least one additional cardiovascular agent. In another aspect of the invention, a method of treating an animal having MMVD, CHF, and / or asymptomatic heart failure comprises a therapeutically effective amount of a compound of formula (1A), any one of Examples 1, 4, 5, 8, 11, 19, or 20, having a 5c-5HT2B IC 50 A compound of formula (1A) having, any one of Examples 1, 4, 5, 8, 11, or 20, having a 5c-5HT2B IC less than 100 nM 50 A compound of formula (1A) having, any one of Examples 1, 4, 5, or 8, having a 5c-5HT2B IC less than 10 nM 50 A compound of formula (1A) having, any one of Examples 1, 4, or 5, having a 5c-5HT2B IC less than 1 nM 50 A compound of formula (1A) having, or a pharmaceutically acceptable salt thereof, in combination with at least one additional cardiovascular agent, and administering it to the animal in need thereof. In another aspect of the invention, a method of treating an animal having MMVD, CHF, and / or asymptomatic heart failure comprises a therapeutically effective amount of a compound of formula (1B), any one of Examples 6, 7, 12, 13, or 25-28, having a 5c-5HT2B IC less than 1000 nM 50 A compound of formula (1B) having, any one of Examples 6, 7, 12, or 25-28, having a 5c-5HT2B IC less than 500 nM 50 A compound of formula (1B) having, any one of Examples 6, 7, 12, or 25-26, having a 5c-5HT2B IC less than 100 nM 50 A compound of formula (1B) having, any one of Examples 6, 7, or 25, having a 5c-5HT2B IC less than 10 nM 50 A compound of formula (1B) having, Example 6, having a 5c-5HT2B IC less than 1 nM 50A compound of formula (1B) having the same, or a pharmaceutically acceptable salt thereof, is administered to an animal in need thereof in combination with at least one additional cardiovascular agent. In another aspect of the invention, a method of treating an animal having MMVD, CHF, and / or asymptomatic heart failure is a therapeutically effective amount of a compound of formula (1C), any one of Examples 18, 22, or 23, with a 5c-5HT2B IC of less than 1000 nM 50 A compound of formula (1C) having the same, Example 22 or 23, with a 5c-5HT2B IC of less than 100 nM 50 A compound of formula (1C) having the same, or a pharmaceutically acceptable salt thereof, is administered to an animal in need thereof in combination with at least one additional cardiovascular agent. In another aspect of the invention, a method of treating an animal having MMVD, CHF, and / or asymptomatic heart failure is a therapeutically effective amount of a compound of formula (1D), Examples 2 or 3, with a 5c-5HT2B IC of less than 10 nM 50 A compound of formula (1D) having the same, Example 2, with a 5c-5HT2B IC of less than 1 nM 50 A compound of formula (1D) having the same, or a pharmaceutically acceptable salt thereof, is administered to an animal in need thereof in combination with at least one additional cardiovascular agent. In another aspect of the invention, a method of treating an animal having MMVD, CHF, and / or asymptomatic heart failure is a therapeutically effective amount of a compound of formula (1E), Example 24, with a 5c-5HT2B IC of less than 1 nM 50 A compound of formula (1E) having the same, or a pharmaceutically acceptable salt thereof, is administered to an animal in need thereof in combination with at least one additional cardiovascular agent. In another aspect, the animal is a companion animal. In another aspect, the animal is a dog. In another aspect, the at least one additional cardiovascular agent is selected from the group consisting of an ACE inhibitor and / or a diuretic. In another aspect, non-limiting examples of ACE inhibitors include enalapril, captopril, benazepril, ramipril, etc. In another aspect, non-limiting examples of diuretics include furosemide, chlorothiazide, hydrochlorothiazide, spironolactone, amiloride, triamterene, isosorbide, etc. Description of the Invention

[0074] Definition For the purposes of the present invention as described and claimed herein, the following terms and phrases are defined as follows.

[0075] "About", when used in connection with a measurable numerical variable, refers to either the indicated value of the variable and all values of the variable that are within the experimental error of the indicated value (e.g., within the 95% confidence interval of the mean value) or within 10 percent of the indicated value, whichever is the greater.

[0076] As used herein, "additional veterinary (or pharmaceutical) agent(s)" refers to another veterinary or pharmaceutical compound or product (i.e., drug) that provides a therapeutically effective amount of the agent(s) that is useful for the treatment of MMVD, CHF, and / or asymptomatic heart failure in animals, preferably dogs, unless otherwise indicated.

[0077] As used herein, "alkyl" refers to a saturated monovalent hydrocarbon alkane radical of the general formula C n H 2n+1 The alkane radical may be straight-chain or branched-chain and may be unsubstituted or substituted. For example, the term "(C1-C4)alkyl" refers to a monovalent straight-chain or branched-chain aliphatic group containing 1 to 4 carbon atoms, and similarly, C1-C3 alkyl refers to a monovalent straight-chain or branched-chain aliphatic group containing 1 to 3 carbon atoms. 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 the chemical moiety by any one of the carbon atoms of the aliphatic chain.

[0078] As used herein, "animal(s)" refers to an individual animal that is a mammal, unless otherwise indicated. Specifically, mammals refer to vertebrate animals that are human and non-human, and these are members of the class Mammalia in taxonomy. Non-exclusive examples of non-human mammals include companion animals. Non-exclusive examples of companion animals include dogs, cats, and horses. A preferred companion animal is a dog.

[0079] As used herein, "asymptomatic (occult, preclinical) heart failure" refers to any contractile disorder or disease of the heart resulting from MMVD, unless otherwise indicated.

[0080] As used herein, "carbocyclic" refers to a fully saturated carbocyclic alkyl moiety, i.e., a 5- to 6-membered ring containing only carbon atoms, i.e., cyclopentyl and cyclohexyl, unless otherwise indicated. The carbocyclic group may be optionally substituted as described herein.

[0081] "The compound(s) of the present invention" refers to the c5-HT2B antagonists described for the compounds of formula (1), formula (1A), formula (1B), formula (1C), formula (1D), and formula (1E), in particular the compounds of Examples 1 to 28, and / or their pharmaceutically acceptable salts, unless otherwise indicated.

[0082] "Congestive heart failure", or "heart failure" refers to an overt process in which the heart is unable to keep up with the demands for blood supply to the body and generally results in the accumulation of fluid in the lungs due to increased pressure in the heart and lungs. The term(s) also relate to any contractile disorder or disease of the heart. Clinical symptoms are generally the result of changes in the cellular and molecular components of the heart, as well as changes in mediators that drive homeostatic control leading to an increase in heart size and a deterioration of heart function.

[0083] As used herein, "halogen" or "halo" refers to fluoro, chloro, bromo, and iodo, unless otherwise indicated. Preferred halos include fluoro and chloro.

[0084] As used herein, "heteroaryl", unless otherwise indicated, refers to a 5- to 6-membered aromatic monocyclic ring, or a 10- to 11-membered fused aromatic ring, and the monocyclic and fused ring moieties each independently contain one or more heteroatoms selected from N, O, and S, preferably 1 to 4 heteroatoms. Non-exclusive examples of monocyclic heteroaryl include pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and the like. Non-exclusive examples of fused heteroaryl include benzofuranyl, benzothiophenyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, indazolyl, benzotriazolyl, thieno[2,3-c]pyridine, thieno[3,2-b]pyridine, benzo[1,2,5]thiadiazole, and the like. Preferred heteroaryl includes thiazolyl, isothiazolyl, thiophenyl, pyridinyl, and indolyl. The heteroaryl group can be attached to the chemical moiety by any one of the carbon atoms or nitrogen heteroatoms within the monocyclic or fused ring.

[0085] "Myxomatous mitral valve degeneration (MMVD)", unless otherwise indicated, refers to the apparent process of mitral valve degeneration. MMVD is generally detected as a heart murmur by auscultation. MMVD also includes the synonymous medical terms mitral valve disease (MVD), degenerative mitral valve disease (DMVD), chronic valvular disease (CVD), chronic valvular heart disease (CVHD), and atrioventricular valvular insufficiency (AVVI).

[0086] As used herein, "optionally substituted", unless otherwise indicated, means that the reference group can be substituted with one or more additional group(s) (plural possible) individually and independently selected from the listed groups, depending on the valence of the reference group.

[0087] As used herein, "pharmaceutically acceptable" indicates that a substance or composition is chemically and / or toxicologically compatible with the formulation, other ingredients of the composition, and / or the animal being treated, unless otherwise indicated. The use of the phrase "and pharmaceutically acceptable salts (if any)" can be exchanged with "or pharmaceutically acceptable salts (if any)".

[0088] "Therapeutically effective amount" means, unless otherwise indicated, (i) the amount of a compound of the invention that treats MMVD, CHF, and / or asymptomatic heart failure in an animal, (ii) reduces, ameliorates, or eliminates one or more symptoms of MMVD, CHF, and / or asymptomatic heart failure in an animal, or (iii) prevents or delays the onset of MMVD, CHF, and / or asymptomatic heart failure in an animal.

[0089] As used herein, "treatment", "treating", "treat", etc. mean, unless otherwise indicated, alleviating, halting, or delaying the progression of MMVD, CHF, and / or asymptomatic heart failure in an animal. As used herein, these terms also include preventing the onset of a disorder or condition, or symptoms associated with a disorder or condition, and reducing the severity of a disorder or condition or symptoms associated therewith, depending on the condition of the animal. Thus, treatment can refer to the administration of a compound of the invention to an animal not diagnosed with CHF at the time of administration.

[0090] Myxomatous mitral valve degeneration (MMVD) is the most common acquired heart disease in older dogs and is a new heart murmur. A heart murmur is a sound heard with every heartbeat and is caused by turbulent blood flow in the heart. MMVD is a symptom of a process that can affect the mitral valve. MMVD mainly affects older small breed dogs, but can also affect larger breed dogs. Some small breed dogs are affected earlier than other dogs, and the Cavalier King Charles Spaniel is the most prominent among those described so far.

[0091] The mitral valve is the valve between the left atrium and the left ventricle. Oxygenated blood from the lungs enters the left atrium, passes through the mitral valve into the left ventricle, and is then pumped to the body. The mitral valve closes when the left ventricle contracts, preventing blood from flowing back into the left atrium. A healthy mitral valve is thin, flexible, and fixed in place by chordae tendineae (CT). Myxomatous degeneration is a process that occurs when the valve thickens due to the formation of nodules that prevent complete closure of the valve, allowing backflow of blood into the left atrium (mitral regurgitation). Over time, the atrium and ventricle compensate by enlarging, and the leak gradually worsens. As the amount of leakage increases, the atrial pressure rises. In some cases, the CT can rupture, causing a mitral valve that is not partially fixed (mitral valve prolapse). The increased pressure is transmitted to the lungs, resulting in CHF.

[0092] Heart murmur is generally the earliest means by which MMVD can be detected. After a murmur is detected, MMVD symptoms may not appear for 3 to 4 years. In many cases, the first external sign of MMVD deterioration is an increase in cough or respiratory effort, which can be due to airway pressure from the enlarged heart and / or fluid congestion in the lungs and heart.

[0093] There is no drug that has been proven to prevent the progression of MMVD, especially in the early stages of the disease. Treatments, either alone or in combination, including furosemide, pimobendan, ACE inhibitors (e.g., enalapril), and spironolactone, are administered to manage MMVD, CHF, and / or asymptomatic heart failure. Furosemide is a powerful diuretic that removes water from the body, thereby reducing pulmonary fluid congestion. Pimobendan has been shown to help the heart work more effectively, reduce cardiac remodeling, and improve the survival rate of patients with MMVD. ACE inhibitors and spironolactone have also been shown to block harmful compensatory mechanisms that occur in severe heart disease and extend survival. Side effects of these drugs include allergic reactions, dizziness, loss of appetite, lethargy, diarrhea, and fainting. Other medications that may be used in the treatment of CHF include hydrochlorothiazide, amlodipine, torsemide, and digoxin.

[0094] Despite the development of new drugs and treatment regimens, uncertainties remain regarding when to treat and what the best interventions are for some of these animals. In 2009, an objective classification system for classifying heart disease based on risk factors and clinical and diagnostic imaging signs was developed.

[0095] Heart failure is divided into different stages, which are defined by different classification systems, such as the International Small Animal Cardiac Health Council (ISACHC), the New York Heart Association (NYHA) functional classification system, and the current classification used in the American College of Veterinary Internal Medicine (ACVIM) Consensus Statement (2009). To remove any ambiguity between classification systems, the classification systems described below are considered synonymous.

[0096] Classification by the International Small Animal Health Council (ISACHC) system: Class I: Asymptomatic (also known as occult or preclinical), Class IA: No evidence of compensation for underlying heart disease (no volume or pressure overload detected by X-ray or echocardiogram), Class IB: Clinical signs of compensation for underlying heart disease (volume or pressure overload detected by X-ray or echocardiogram), Class II: Mild to moderate heart failure with clinical signs at rest or during mild exercise (treatment required), Class III: Advanced heart failure, clinical signs of severe congestive heart failure, Class IIIA: Can be treated at home, Class IIIB: Requires hospitalization.

[0097] New York Heart Association (NYHA) functional classification system: Class I: Represents patients with asymptomatic heart disease (e.g., chronic valvular heart disease (CVHD) is present but no clinical signs are evident during exercise), Class II: Represents patients with heart disease that causes clinical signs only during severe exercise, Class III: Represents patients with heart disease that causes clinical signs during daily activities or mild exercise, Class IV: Represents patients with heart disease that causes severe clinical signs even at rest.

[0098] The ACVIM system describes four basic stages of heart disease and heart failure. Stage A: Patients who have a high risk of developing heart disease but do not currently have identifiable structural heart abnormalities. Stage B: Patients who have structural heart disease (e.g., typical murmur of mitral regurgitation is present) but have not developed clinical symptoms caused by heart failure (for important clinical significance for prognosis and treatment, the panel further subdivided stage B into stage B1 and B2). Stage B1: Asymptomatic patients without evidence of cardiac remodeling on chest X-ray or echocardiogram in response to CVHD. Stage B2: Asymptomatic patients with hemodynamically significant valvular regurgitation as demonstrated by chest X-ray or echocardiogram findings of left heart enlargement. Stage C: Patients who have past or current clinical symptoms of heart failure related to structural heart disease. Stage D: Patients with end-stage disease having clinical symptoms of heart failure caused by CVHD that is resistant to standard therapy.

[0099] The heart pathology begins with ISACHC class I, NYHA class I, and ACVIM stage B2, where there are heart murmurs or atrial enlargement but no clinical symptoms (ISACHC class I or asymptomatic / occult / preclinical stage). Clinical symptoms manifest during the progression of the disease (ISACHC class II or III, NYHA class II, III, or IV, ACVIM stages C and D). Since the compounds of the present invention have an affinity for c5-HT2B, the compounds may provide veterinarians with potentially new drugs for treating MMVD, CHF, and / or asymptomatic heart failure.

[0100] The compounds of formula (1) of the present invention can be synthesized by synthetic routes involving processes similar to those well-known in the field of chemistry, particularly in view of the descriptions included herein. Starting materials are generally readily prepared using Aldrich Chemicals (Milwaukee, WI), Combi-Blocks (San Diego, CA), Synthonix Chemicals (Wake Forest, NC), Enamine (Monmouth Jct. NJ) and others, or methods well-known to those skilled in the art (e.g., generally, Louis F. Fieser and Mary Fieser, “Reagents for Organic Synthesis”, 1;19, Wiley, New York (1967, 1999 ed.), or by the methods described in Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin (also available via the Beilstein online database), including supplements). For illustrative purposes, the following reaction scheme shows a possible route and the major intermediates for synthesizing the compounds of the present invention. Further detailed descriptions of the individual reaction steps can be found in the Examples section. Those skilled in the art will understand that the compounds of the present invention can be prepared by methods other than those described herein by adaptation of the methods described herein and / or the art, e.g., by adaptation of methods known in the art described herein, or using standard texts such as “Comprehensive Organic Transformations - A Guide to Functional Group Transformations”, R.C. Larock, Wiley-VCH (1999 or later editions).

[0101] Scheme 1 shows an overview of the general procedure for the preparation and isolation of the compounds of the present invention. However, it should be understood that the present invention, as fully described herein and recited in the claims, is not intended to be limited by the details of the following scheme or mode of preparation.

[0102] In the examples and methods described below, the following reactants and other abbreviations are included: 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(I) iodide (CuI), 1,2-dichloroethane (DCE), water (H2O), Hank's balanced salt solution (HBSS), fetal bovine serum (FBS), Dulbecco's modified Eagle's medium (DMEM), minimum essential medium (MEM), and (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES).

[0103] Pharmaceutically acceptable salts of the compounds of the present invention can be prepared in a conventional manner. For example, a solution of the free base can be treated with a suitable acid, either in a pure or suitable solvent, and the resulting salt is isolated by filtration of the reaction solvent or evaporation under reduced pressure. For a review of suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0104] The compounds of formula (1) of the present invention can be used in their natural form or as salts. When the formation of stable, non-toxic acid or base salts is desired, administration of the compounds as pharmaceutically acceptable salts may be appropriate. Pharmaceutically acceptable salts of the compounds of the present invention include, but are not limited to, acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, edisylate, etoglutarate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, glycerophosphate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, maleate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-naphthylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, saccharate, stearate, succinate, tartrate, tosylate, and trifluoroacetate salts.

[0105] The compounds of formula (1) of the present invention can be prepared as described by the schemes and procedures set forth herein.

[0106] Scheme 1. Preparation of the compounds of formula (1)

Chemical formula

[0107] The compounds of formula (1) of the present invention are useful as 5-HT2B antagonists 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 a 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 a compound of formula (1) of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. The compounds of formula (1) of the present invention (including the compositions and methods used therein), or pharmaceutically acceptable salts thereof, can be used in the manufacture of pharmaceuticals for the therapeutic uses described herein.

[0108] The compound of formula (1) of the present invention, or a pharmaceutically acceptable salt thereof, can be administered alone or in a formulation suitable for the particular use contemplated and the species of animal to be treated. Generally, they will be administered as a formulation in combination 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 agent. The choice of excipient(s) will depend largely on factors such as the particular mode of administration, the effect of the excipient(s) on solubility and stability, and the nature of the dosage form. In addition to the excipient(s), the amount of the compound of the present invention to be administered, and the dosing regimen for treating the condition or disorder with the compound, can vary widely depending on various factors including the age, weight, sex, and medical condition of the animal, the severity of the disease, and the route and frequency of administration.

[0109] In one aspect, the veterinary composition comprises a compound of formula (1) of the present invention, or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable carrier. The concentration range will vary depending on the composition (e.g., oral or injectable). For oral dosing, the range of the active agent (i.e., the compound of the present invention) is from about 0.1 to about 10 mg / kg, preferably from about 0.5 to about 5 mg / kg, even more preferably from about 0.5 to about 3 mg / kg, and most preferably from about 0.5 to about 1.5 mg / kg. For injectable solutions, the range of the active agent is from about 0.1 to about 50 mg / mL, preferably from about 0.5 to about 25 mg / mL, more preferably from about 1 to about 10 mg / mL, and even more preferably from 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 dosages. Further, the dosage range and the preferred dosage range may be higher or lower than the concentrations described herein.

[0110] The complexes can be prepared using conventional dissolution and mixing procedures. Such compositions and methods for their preparation can be found, for example, in “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, N.Y., 1980 (ISBN 0-8247-6918-X).

[0111] Typical formulations are prepared by mixing a 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 materials such as carbohydrates, waxes, water-soluble and / or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc. The specific excipient(s) will depend on the means and purpose for which the compounds of the present invention are applied. The solvent is generally selected based on solvents recognized by those skilled in the art to be safe for administration to animals. The formulations may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifying agents, lubricants, processing aids, colorants, sweeteners, fragrances, flavoring agents, and other known additives to provide an elegant appearance of the drug (i.e., the compound of the present invention, or its veterinary composition) or to assist in the manufacture of veterinary products (i.e., pharmaceuticals). The compounds of formula (1) of the present invention will typically be formulated into veterinary dosage forms in order to provide dosage forms that are readily controllable for administration.

[0112] Methods by which the compounds of formula (1) of the present invention can be administered include oral and injectable (e.g., parenteral, subcutaneous, and intramuscular).

[0113] The compound of formula (1) of the present invention, or a pharmaceutically acceptable salt thereof, can be administered orally in the form of capsules, boluses, tablets, powders, troches, chewable tablets, multi- and nanoparticles, gels, solid solutions, films, sprays, or liquid forms. This is the preferred method of administration, and thus it is desirable to develop compounds for oral administration. Such formulations can be used as fillers for soft or hard capsules, palatable soft or hard chewable tablets, which typically contain excipients such as water, ethanol, polyethylene glycol, N-methylpyrrolidone, propylene glycol, methylcellulose, or suitable oils, as well as one or more emulsifiers, flavoring agents, and / or suspending agents. Liquid forms include suspensions, solutions, syrups, elixirs, and aqueous solutions. Liquid formulations may be prepared, for example, by reconstituting a solid from a sachet.

[0114] Injectable formulations can be prepared in the form of a sterile aqueous solution that can contain other substances, such as sufficient salts and glucose 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, and organic solvents such as pyrrolidin-2-one, benzyl alcohol, and glycerol formal. The formulation is prepared by dissolving or suspending the compound of the present invention, alone or together with additional veterinary agents, in the liquid excipient(s) such that the final formulation contains from about 0.01 to 30% by weight of the active ingredient.

[0115] Suitable devices for injectable administration include needle (including microneedle) syringes, needleless syringes, and infusion techniques. Injectable formulations are typically aqueous solutions that may contain excipients such as salts, carbohydrates, and buffers (preferably up to a pH of 3 to 9), but for some applications they may be more preferably formulated as sterile non-aqueous solutions or in dry powder form for use with a suitable vehicle such as sterile pyrogen-free water. For example, the preparation of injectable formulations under sterile conditions by lyophilization can be readily achieved by 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 can be increased by using solubility enhancers.

[0116] Administration of the compound of formula (1) of the present invention, or a pharmaceutically acceptable salt thereof, is contemplated to be once or twice daily. Preferably, once daily (qd).

[0117] The compositions of the present invention, as described herein, can be administered alone or in combination with at least one other additional veterinary agent to provide a broader range of veterinary utility. These at least one other additional veterinary agents, including pharmaceutical agents, can be administered simultaneously with the compounds of the present invention or at any time during the treatment period of the animal.

[0118] The following list of additional pharmaceutical (veterinary) cardiovascular agents that can be used in conjunction with the compounds of the present invention to treat heart disease (e.g., MMVD, CHF, and / or asymptomatic heart failure) is intended to show possible combinations and is not intended to impose any limitation thereon. Non-limiting examples of additional pharmaceutical (veterinary) agents include diuretics for reducing edema and exudation (e.g., furosemide, chlorothiazide, indapamide, triamterene, hydrochlorothiazide, etc.); aldosterone antagonists for reducing aldosterone-mediated myocardial fibrosis, which may block sodium reabsorption and slow the progression of heart disease and promote water loss (e.g., spironolactone, eplerenone, etc.); and ACE inhibitors for inhibiting the action of angiotensin-converting enzyme to produce balanced vasodilation by relaxing blood vessels (e.g., enalapril, accupril, captopril, ramipril, etc.).

[0119] Veterinary compositions for administration to animals can be packaged in a variety of ways depending on the method used to administer the compounds of the present invention or combinations thereof. Generally, the article for distribution includes a container having the veterinary composition deposited therein in 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 anti-tampering assembly to prevent inadvertent access to the contents of the package. In addition, the container is labeled with a label describing the contents of the container. The label may also include appropriate warnings.

[0120] The compound of formula (1) of the present invention (including the compositions and methods used therein), or a pharmaceutically acceptable salt thereof, can also be used in the manufacture of a medicament for the therapeutic uses described herein.

[0121] 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. The proton magnetic resonance (1H NMR) spectrum was determined using a Bruker spectrometer operating at a magnetic field strength of 400 megahertz (MHz). Chemical shifts are reported in parts per million (ppm, δ) units from low field relative to the internal tetramethylsilane standard or the residual protonated NMR solvent. Mass spectrum (MS) data were obtained using an Agilent mass spectrometer (1290 Infinity II) with 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 (50×4.6) mm, 3.5 μm column. The mobile phase was a two-component gradient of acetonitrile in water and 10 mM ammonium bicarbonate at a flow rate of 1.0 mL / min.

Example

[0122] The following examples provide a more detailed description of the processing conditions for preparing the compounds of formula (1) of the present invention. However, it should be understood that the present invention, which is fully described herein and recited in the claims, is not intended to be limited by the details of the following preparation methods.

[0123] Intermediate (1R,3s,5S)-8-(4-Chlorobenzyl)-8-azabicyclo[3.2.1]octan-3-amine 2,2,2-trifluoroacetate synthesis

Chem.

[0124] Step - 2: Synthesis of (1R,3S,5S)-8-(4-chlorobenzyl)-8-azabicyclo[3.2.1]octan-3-amine 2,2,2-trifluoroacetate. To 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 (20.0 mL) was added TFA (1.04 mL, 13.71 mmol) at 0 °C. The resulting reaction mixture was stirred at room temperature for 2 h. After completion, the reaction mixture was concentrated under reduced pressure and dried to give (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).

[0125] The steps provided above can generally be used to prepare similar azabicyclo[3.2.1]octan-3-amine.2,2,2-trifluoroacetic acid analogs by replacing, for example, 4-chlorobenzaldehyde (Examples 3 and 5) 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) isothiazole-3-carbaldehyde (Example 26), l) thiazole-2-carbaldehyde (Example 27), and m) 4-methylthiazole-2-carbaldehyde (Example 28).

[0126] Synthesis of (1R,3S,5S)-8-phenyl-8-azabicyclo[3.2.1]octan-3-amine 2,2,2-trifluoroacetate

Chemical Structure

[0127] Step 1: Synthesis of tert-butyl ((1R,3S,5S)-8-phenyl-8-azabicyclo[3.2.1]octan-3-yl)carbamate. To a stirred solution of phenylboronic acid (300 mg, 2.46 mmol) in methanol (5.0 mL) was added tert-butyl ((1R,3S,5S)-8-azabicyclo[3.2.1]octan-3-yl)carbamate (668.21 mg, 2.95 mmol) and Cu2O (17.85 mg, 0.12 mmol). The resulting reaction mixture was stirred at room temperature for 16 h under an air atmosphere. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and evaporated under reduced pressure. The crude product was purified by combiflash column chromatography (30% ethyl acetate - hexane) to give tert-butyl ((1R,3S,5S)-8-phenyl-8-azabicyclo[3.2.1]octan-3-yl)carbamate (100.0 mg) as an off-white solid.

[0128] Step - 2: Synthesis of (1R,3S,5S)-8-phenyl-8-azabicyclo[3.2.1]octan-3-amine. 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) was added TFA (0.13 mL, 1.66 mmol) at 0 °C. The resulting reaction mixture was stirred at room temperature for 2 h. After completion, the reaction mixture was concentrated under reduced pressure and dried to afford (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).

[0129] Synthesis of 1-phenyl-1H-indole-6-carboxylic acid

Chemical Structure

[0130] Step - 1: Synthesis of methyl 1 - phenyl - 1H - indole - 6 - carboxylate. To a stirred degassed solution of iodobenzene (500.0 mg, 2.45 mmol) in DMF (5.0 mL), methyl 1H - indole - 6 - carboxylate (698.04 mg, 3.92 mmol), CuI (142.65 mg, 0.50 mmol), and Cs2CO3 (1.60 g, 4.90 mmol) were added. The resulting reaction mixture was heated at 120 °C for 16 h. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and evaporated under reduced pressure. The crude product was purified by combiflash column chromatography (20% ethyl acetate - hexane) to afford methyl 1 - phenyl - 1H - indole - 6 - carboxylate (300.0 mg) as a brown solid.

[0131] Step - 2: Synthesis of 1 - phenyl - 1H - indole - 6 - carboxylic acid. 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), LiOH·H2O (42.94 mg, 1.70 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. After completion, the reaction mixture was concentrated under reduced pressure, diluted with water, and the pH was adjusted to 4 by using 1 M HCl. The precipitate thus formed was filtered, and the crude product was triturated with pentane and dried to afford 1 - phenyl - 1H - indole - 6 - carboxylic acid (200.0 mg) as an off - white solid. LCMS [M - H = 235.8].

[0132] The intermediate (1R,3s,5S) - 8 - benzyl - 8 - azabicyclo[3.2.1]octan - 3 - exo - amine can be purchased commercially as the free base from US companies (Combi - Blocks, AstaTech, and Synthonix). [Chemical formula]

[0133] Example 1. N-((1R,3S,5S)-8-Benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide

Chem.

Chem.

[0134] Step 1: 1H-Indole-6-carboxylic acid (1.0 g, 6.2 mmol), HATU (1.5 eq, 6.588 mmol), and N,N-diisopropylethylamine (1.53 mL, 8.784 mmol) were stirred in N,N-dimethylformamide (10 mL) for 10 minutes.

[0135] Step 2: To the solution of Step 1, 8-benzyl-8-azabicyclo[3.2.1]octan-3-exo-amine (1000 mg, 4.392 mmol) was added at room temperature and stirred for 3 hours. The mixture was generated by preparative HPLC to obtain the title compound as a white solid. 1 1H NMR (400 MHz, DMSO-d6) δ ppm 1.55 - 1.70 (m, 4H) 1.77 (t, 2H) 1.95 - 2.10 (m, 2H) 3.17 (bs, 2H) 3.59 (bs, 1H) 4.25 (bs, 1H) 6.46 (bs, 1H) 7.20 - 7.28 (m, 1H) 7.32 (t, 2H) 7.35 - 7.41 (m, 2H) 7.48 (bs, 1H) 7.50 - 7.58 (m, 2H) 7.93 (bs, 1H) 8.09 (d, 1H) 11.32 (br s, 1H). LC-MS (m / z): [M + H] = 359.

[0136] Example 2. N-((1R,3S,5S)-8-Benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamide. The compound was prepared in the same manner as in Example 1, except that 1H-indole-6-carboxylic acid was replaced with 1H-pyrrolo[2,3-b]pyridine-6-carboxylic acid. [Chemical formula] 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.

[0137] 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. The compound was prepared in the same manner as in 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. [Chemical formula] 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.

[0138] Example 4. N-((1R,3S,5S)-8-(4-Fluorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide. The compound was prepared in the same manner as in Example 1, except that 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.

Chem.

[0139] Example 5. N-((1R,3S,5S)-8-(4-Chlorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide. The compound was prepared in the same manner as in Example 1, except that 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.

Chem.

[0140] Example 6. N-((1R,3S,5S)-8-((1H-Indol-5-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide. The compound was prepared in the same manner as in Example 1, except that 8-benzyl-8-azabicyclo[3.2.1]octan-3-exo-amine was replaced with (1R,3S,5S)-8-((1H-indol-5-yl)methyl)-8-azabicyclo[3.2.1]octan-3-amine.2,2,2-trifluoroacetate.

Chem.

[0141] Example 7. N-((1R,3S,5S)-8-(Thiophen-2-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide. The compound was prepared in the same manner as in Example 1, except that 8-benzyl-8-azabicyclo[3.2.1]octan-3-exo-amine was replaced with (1R,3S,5S)-8-(thiophen-2-ylmethyl)-8-azabicyclo[3.2.1]octan-3-amine.2,2,2-trifluoroacetate.

Chem.

[0142] Example 8. N-((1R,3S,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-2-methyl-1H-indole-6-carboxamide. The compound was prepared in the same manner as in Example 1, except that 1H-indole-6-carboxylic acid was replaced with 2-methyl-1H-indole-6-carboxylic acid.

Chem.

[0143] Example 8 was prepared according to the following reaction scheme.

Chemical formula

[0144] Example 9. N-((1R,3S,5S)-8-Benzyl-8-azabicyclo[3.2.1]octan-3-yl)-2,3,4,9-tetrahydro-1H-carbazole-7-carboxamide. The compound was prepared in the same manner as in Example 1, but 1H-indole-6-carboxylic acid was replaced with 2,3,4,9-tetrahydro-1H-carbazole-7-carboxylic acid, and was prepared in the same manner as in Example 1, but 1H-indole-6-carboxylic acid was replaced with 2,3,4,9-tetrahydro-1H-carbazole-7-carboxylic acid.

Chemical formula

[0145] Example 10. N-((1R,3S,5S)-8-Benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-indazole-6-carboxamide. The compound was prepared in the same manner as in Example 1, but 1H-indole-6-carboxylic acid was replaced with 1H-indazole-6-carboxylic acid.

Chemical formula

[0146] Example 11. N-((1R,3S,5S)-8-(4-(Trifluoromethyl)benzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide. The compound was prepared in the same manner as in Example 1, except that 8-benzyl-8-azabicyclo[3.2.1]octane-3-exo-amine was replaced with (1R,3S,5S)-8-(4-(trifluoromethyl)benzyl)-8-azabicyclo[3.2.1]octane-3-amine.2,2,2-trifluoroacetate.

Chemical Structure

[0147] Example 12. N-((1R,3S,5S)-8-(pyridin-2-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide. The compound was prepared in the same manner as in Example 1, except that 8-benzyl-8-azabicyclo[3.2.1]octan-3-exo-amine was replaced with (1R,3S,5S)-8-(pyridin-2-ylmethyl)-8-azabicyclo[3.2.1]octan-3-amine.2,2,2-trifluoroacetate.

Chem.

[0148] Example 13. N-((1R,3S,5S)-8-(pyridin-3-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide. The compound was prepared in the same manner as in Example 1, except that 8-benzyl-8-azabicyclo[3.2.1]octan-3-exo-amine was replaced with (1R,3S,5S)-8-(pyridin-3-ylmethyl)-8-azabicyclo[3.2.1]octan-3-amine.2,2,2-trifluoroacetate.

Chem.

[0149] Example 14. N-((1R,3s,5S)-8-(Pyridin-4-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide. The compound was prepared in the same manner as in Example 1, but 8-benzyl-8-azabicyclo[3.2.1]octane-3-exo-amine was replaced with (1R,3s,5S)-8-(pyridin-4-ylmethyl)-8-azabicyclo[3.2.1]octane-3-amine.2,2,2-trifluoroacetate.

Chemical Structure

[0150] Example 15. N-((1R,3s,5S)-8-(pyrazin-2-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide. The compound was prepared in the same manner as in Example 1, except that 8-benzyl-8-azabicyclo[3.2.1]octan-3-exo-amine was replaced with (1R,3s,5S)-8-(pyrazin-2-ylmethyl)-8-azabicyclo[3.2.1]octan-3-amine.2,2,2-trifluoroacetate. [Chemical formula] 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.

[0151] Example 16. N-((1R,3s,5S)-8-((1-methyl-1H-imidazol-2-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide (ZTS-527811). LC-MS (m / z): [M+H] = 363. The compound was prepared in the same manner as in Example 1, except that 8-benzyl-8-azabicyclo[3.2.1]octan-3-exo-amine was replaced with (1R,3s,5S)-8-((1-methyl-1H-imidazol-2-yl)methyl)-8-azabicyclo[3.2.1]octan-3-amine.2,2,2-trifluoroacetate. [Chemical formula] 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).

[0152] Example 17. N-((1R,3S,5S)-8-Phenyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide. The compound was prepared in the same manner as in Example 1, except that 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.

Chemical Structure

[0153] Example 17 was prepared according to the following reaction scheme.

Chemical Structure

[0154] Example 18. N-((1R,3S,5S)-8-Benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1-(pyridin-4-yl)-1H-indole-6-carboxamide. The compound was prepared in the same manner as in Example 1, except that 1H-indole-6-carboxylic acid was replaced with 1-(pyridin-4-yl)-1H-indole-6-carboxylic acid.

Chemical Structure

[0155] Example 18 was prepared according to the following reaction scheme.

Chemical Structure

[0156] Example 19. N-((1R,3S,5S)-8-Benzyl-8-azabicyclo[3.2.1]octan-3-yl)-3-cyano-1H-indole-6-carboxamide. The compound was prepared in the same manner as in Example 1, except that 1H-indole-6-carboxylic acid was replaced with 3-cyano-1H-indole-6-carboxylic acid.

Chemical Structure

[0157] Example 19 was prepared according to the following reaction scheme. [Chemical formula]

[0158] Example 20. N-((1R,3S,5S)-8-Benzyl-8-azabicyclo[3.2.1]octan-3-yl)-2-(trifluoromethyl)-1H-indole-6-carboxamide. The compound was prepared in the same manner as in Example 1, but 1H-indole-6-carboxylic acid was replaced with 2-(trifluoromethyl)-1H-indole-6-carboxylic acid. [Chemical formula] 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.

[0159] Example 20 was prepared according to the following reaction scheme. [Chemistry]

[0160] Example 21. N-((1R,3S,5S)-8-Benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-6-carboxamide. The compound was prepared in the same manner as in Example 1, except that 1H-indole-6-carboxylic acid was replaced with 1-(4-(trifluoromethyl)phenyl)-1H-indole-6-carboxylic acid. [Chemistry] 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.

[0161] Example 21 was prepared according to the following reaction scheme. [Chemistry]

[0162] Example 22. N-((1R,3S,5S)-8-Benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1-(4-fluorophenyl)-1H-indole-6-carboxamide. The compound was prepared in the same manner as in Example 1, except that 1H-indole-6-carboxylic acid was replaced with 1-(4-fluorophenyl)-1H-indole-6-carboxylic acid. [Chemistry] 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.

[0163] Example 22 was prepared according to the following reaction scheme. [Chemical formula]

[0164] Example 23. N-((1R,3S,5S)-8-Benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1-phenyl-1H-indole-6-carboxamide. The compound was prepared in the same manner as in Example 1, except that 1H-indole-6-carboxylic acid was replaced with 1-phenyl-1H-indole-6-carboxylic acid. [Chemical formula] 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.

[0165] Example 23 was prepared according to the following reaction scheme. [Chemical formula]

[0166] Example 24. N-((1R,3S,5S)-8-Benzyl-8-azabicyclo[3.2.1]octan-3-yl)benzofuran-6-carboxamide. The compound was prepared in the same manner as in Example 1, except that 1H-indole-6-carboxylic acid was replaced with benzofuran-6-carboxylic acid. LC-MS (m / z): [M+H] = 360.

Chemical Structure

[0167] Example 25. N-((1R,3S,5S)-8-(Isothiazol-5-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide. The compound was prepared in the same manner as in Example 1, except that 8-benzyl-8-azabicyclo[3.2.1]octane-3-exo-amine was replaced with (1R,3S,5S)-8-(isothiazol-5-ylmethyl)-8-azabicyclo[3.2.1]octane-3-amine.2,2,2-trifluoroacetate. LC-MS (m / z): [M+H] = 366.

Chemical Structure

[0168] Example 26. N-((1R,3S,5S)-8-(Isothiazol-3-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide. The compound was prepared in the same manner as in Example 1, except that 8-benzyl-8-azabicyclo[3.2.1]octane-3-exo-amine was replaced with (1R,3S,5S)-8-(isothiazol-3-ylmethyl)-8-azabicyclo[3.2.1]octane-3-amine.2,2,2-trifluoroacetate. LC-MS (m / z): [M+H] = 366.

Chemical Structure

[0169] Example 27. N-((1R,3S,5S)-8-(thiazol-2-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide. The compound was prepared in the same manner as in Example 1, except that 8-benzyl-8-azabicyclo[3.2.1]octan-3-exo-amine was replaced with (1R,3S,5S)-8-(thiazol-2-ylmethyl)-8-azabicyclo[3.2.1]octan-3-amine.2,2,2-trifluoroacetate. LC-MS (m / z): [M+H] = 366.

Chem.

[0170] Example 27 was prepared according to the following reaction scheme.

Chem.

[0171] Example 28. N-((1R,3S,5S)-8-((4-methylthiazol-2-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide. The compound was prepared in the same manner as in Example 1, except that 8-benzyl-8-azabicyclo[3.2.1]octan-3-exo-amine was replaced with (1R,3S,5S)-8-(4-methylthiazol-2-ylmethyl)-8-azabicyclo[3.2.1]octan-3-amine.2,2,2-trifluoroacetate. LC-MS (m / z): [M+H] = 380.

Chem.

[0172] Canine 5-HT2B (c5-HT2B) In Vitro Assay CHO-K1 cells stably expressing canine 5-HT2B receptor were seeded at 20,000 cells per well in a clear-bottom 384-well black plate of DMEM containing GlutaMAX™ high glucose + 5% dialyzed FBS + 10 mM HEPES + 1×MEM non-essential amino acids in 20 μl of culture medium at 37 °C and 5% CO2 for at least 18 hours. The cell plate was loaded with 20 μl / well of FLIPR® Calcium 5 Assay Kit prepared in HBSS containing calcium and magnesium supplemented with 20 mM HEPES and 5 mM probenecid at pH 7.4, incubated at 37 °C and 5% CO2 for 30 minutes, and then further incubated at room temperature for 30 minutes. The intracellular calcium response was measured using a FLIPR® Tetra instrument that measures the kinetic response of Calcium 5 dye at an excitation wavelength of 470 - 495 nm and an emission wavelength of 515 - 575 nm at room temperature. After the first baseline recording, the cells were first challenged with a 5-fold concentrated antagonist (10 μl / well), and the calcium response was recorded for approximately 2 minutes. After the first antagonist challenge was completed, the cell plate was incubated in the FLIPR Tetra® instrument at room temperature for 10 minutes. Finally, a second kinetic assay was performed after a 10-minute incubation at room temperature, and the inhibition response of serotonin (15 μl / well) at the EC 80 concentration was measured. For each antagonist tested, the IC 50 concentration was determined.

[0173] According to the in vitro assay described above, the IC 50 affinity of the compounds of the present invention for the c5-HT2B receptor is provided in Table 1. [Table 1]

[0174] As can be seen in Table 1, the compounds of the present invention have an affinity for the c5-HT2B receptor. Based on the data provided in Table 1, preferred compounds of the present invention have a c5-HT2B inhibitory IC 50 value of less than 1000 nM. More preferred compounds of the present invention have a c5-HT2B inhibitory IC 50 value of less than 100 nM. Even more preferred compounds of the present invention have a c5-HT2B inhibitory IC 50 value of less than 10 nM.

Claims

1. A compound of formula (1), 【Chemical 1】 wherein X is CH or N, L is NR １ or O, X’ is CR ２ or N, R １ is H, C １ -C ６ alkyl, phenyl, or pyridinyl, said phenyl or pyridinyl each being optionally substituted with one or two R ４ substituents, R ２ is H, C １ -C ４ alkyl, -CF ３ or halo, R ３ is H, cyano, halo, C １ -C ４ alkyl, or -CF ３ or alternatively R ２ and R ３ are joined together to form a 5- or 6-membered carbocyclic ring optionally substituted with methyl, halo, or -CF ３ and ring A is a 5- or 6-membered heteroaryl ring containing at least one heteroatom selected from the group consisting of phenyl, naphthyl, N, O, and S, or a 10- or 11-membered fused heteroaryl ring containing at least one heteroatom selected from the group consisting of N, O, and S, R ４ is selected from C １ -C ４ alkyl, halo, cyano, or -CF ３ and 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 may be the same or different, a compound, and a pharmaceutically acceptable salt thereof.

2. Ring A is selected from the group consisting of phenyl, thiophenyl, pyridinyl, thiazolyl, isothiazolyl, and indolyl, and L is NR １ The compound of formula (1) according to claim 1, wherein m is an integer 1, and a pharmaceutically acceptable salt thereof.

3. as follows: N-((1R,3S,5S)-8-Benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3S,5S)-8-Benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamide, N-((1R,3S,5S)-8-(4-Chlorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamide, N-((1R,3S,5S)-8-(4-Fluorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3S,5S)-8-(4-Chlorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3S,5S)-8-((1H-Indol-5-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3S,5S)-8-(Thiophen-2-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3S,5S)-8-Benzyl-8-azabicyclo[3.2.1]octan-3-yl)-2-methyl-1H-indole-6-carboxamide, N-((1R,3S,5S)-8-Benzyl-8-azabicyclo[3.2.1]octan-3-yl)-2,3,4,9-tetrahydro-1H-carbazole-7-carboxamide, N-((1R,3S,5S)-8-Benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-indazole-6-carboxamide, N-((1R,3S,5S)-8-(4-(Trifluoromethyl)benzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3S,5S)-8-(Pyridin-2-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3S,5S)-8-(Pyridin-3-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3S,5S)-8-Benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1-(pyridin-4-yl)-1H-indole-6-carboxamide, N-((1R,3S,5S)-8-Benzyl-8-azabicyclo[3.2.1]octan-3-yl)-3-cyano-1H-indole-6-carboxamide, N-((1R,3S,5S)-8-Benzyl-8-azabicyclo[3.2.1]octan-3-yl)-2-(trifluoromethyl)-1H-indole-6-carboxamide, N-((1R,3S,5S)-8-Benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1-(4-fluorophenyl)-1H-indole-6-carboxamide, N-((1R,3S,5S)-8-Benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1-phenyl-1H-indole-6-carboxamide, N-((1R,3S,5S)-8-Benzyl-8-azabicyclo[3.2.1]octan-3-yl)benzofuran-6-carboxamide, N-((1R,3S,5S)-8-(Isothiazol-5-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3S,5S)-8-(isothiazol-3-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3S,5S)-8-(thiazol-2-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, and A compound of formula (1) according to claim 1, selected from the group consisting of N-((1R,3S,5S)-8-((4-methylthiazol-2-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, and pharmaceutically acceptable salts thereof.

4. as follows: N-((1R,3S,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3S,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamide, N-((1R,3S,5S)-8-(4-chlorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamide, N-((1R,3S,5S)-8-(4-fluorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3S,5S)-8-(4-chlorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3S,5S)-8-((1H-indol-5-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3S,5S)-8-(thiophen-2-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3S,5S)-8-Benzyl-8-azabicyclo[3.2.1]octan-3-yl)-2-methyl-1H-indole-6-carboxamide, N-((1R,3S,5S)-8-(4-(Trifluoromethyl)benzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3S,5S)-8-(Pyridin-2-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3S,5S)-8-Benzyl-8-azabicyclo[3.2.1]octan-3-yl)-2-(trifluoromethyl)-1H-indole-6-carboxamide, N-((1R,3S,5S)-8-Benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1-(4-fluorophenyl)-1H-indole-6-carboxamide, N-((1R,3S,5S)-8-Benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1-phenyl-1H-indole-6-carboxamide, N-((1R,3S,5S)-8-Benzyl-8-azabicyclo[3.2.1]octan-3-yl)benzofuran-6-carboxamide, N-((1R,3S,5S)-8-(Isothiazol-5-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, and The compound of formula (1) according to claim 3, selected from the group consisting of N-((1R,3S,5S)-8-(isothiazol-3-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, and pharmaceutically acceptable salts thereof.

5. The following: N-((1R,3S,5S)-8-Benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3S,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamide, N-((1R,3S,5S)-8-(4-chlorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamide, N-((1R,3S,5S)-8-(4-fluorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3S,5S)-8-(4-chlorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3S,5S)-8-((1H-indol-5-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3S,5S)-8-(thiophen-2-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3S,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-2-methyl-1H-indole-6-carboxamide, N-((1R,3S,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)benzofuran-6-carboxamide, and A compound of formula (1) selected from the group consisting of N-((1R,3S,5S)-8-(isothiazol-5-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, and pharmaceutically acceptable salts thereof.

6. A compound of formula (1A) 【Chemical Formula 2】 (wherein R ２ is H, methyl, or -CF ３ and R ３wherein R is H, methyl, or cyano, and n is an integer of 0, 1, or 2), the compound of formula (1) according to claim 2, and a pharmaceutically acceptable salt thereof.

7. as follows: N-((1R,3S,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3S,5S)-8-(4-fluorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3S,5S)-8-(4-chlorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3S,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-2-methyl-1H-indole-6-carboxamide, N-((1R,3S,5S)-8-(4-(trifluoromethyl)benzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, and N-((1R,3S,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-2-(trifluoromethyl)-1H-indole-6-carboxamide, the compound of formula (1) according to claim 4, and a pharmaceutically acceptable salt thereof.

8. The compound of formula (1B) 【Chemical Formula 3】 (wherein ring A is selected from the group consisting of indolyl, thiophenyl, pyridinyl, isothiazolyl, and thiazolyl, R ４ is methyl or halo, and n is an integer of 0 or 1), the compound of formula (1) according to claim 1, and a pharmaceutically acceptable salt thereof.

9. as follows: N-((1R,3S,5S)-8-((1H-indol-5-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3S,5S)-8-(thiophen-2-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3S,5S)-8-(pyridin-2-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3S,5S)-8-(isothiazol-5-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, and The compound of formula (1B) according to claim 8, selected from the group consisting of N-((1R,3S,5S)-8-(isothiazol-3-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, and pharmaceutically acceptable salts thereof.

10. A compound of formula (1C), a compound of formula (1D), or a compound of formula (1E) 【Chemical Formula 4】 (Wherein R １ is phenyl optionally substituted with fluoro or chloro, R ４ is halo or -CF ３ and n is an integer 0 or 1), the compound of formula (1) according to claim 1, and pharmaceutically acceptable salts thereof.

11. N-((1R,3S,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1-(4-fluorophenyl)-1H-indole-6-carboxamide, or The compound of formula (1C) according to claim 10, which is N-((1R,3S,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1-phenyl-1H-indole-6-carboxamide, N-((1R,3S,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamide, or The compound of formula (1D) according to claim 10, which is N-((1R,3S,5S)-8-(4-chlorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamide, or the compound of formula (1E) according to claim 10, which is N-((1R,3S,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)benzofuran-6-carboxamide, and pharmaceutically acceptable salts thereof.

12. as follows: N-((1R,3S,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3S,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamide, N-((1R,3S,5S)-8-(4-fluorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3S,5S)-8-(4-chlorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, N-((1R,3S,5S)-8-((1H-indol-5-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide, and The compound of formula (1) according to claim 4, which is selected from the group consisting of N-((1R,3S,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)benzofuran-6-carboxamide, and pharmaceutically acceptable salts thereof.

13. A composition comprising the compound of formula (1) according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein the composition further comprises at least one pharmaceutically acceptable excipient.

14. Use of the compound of formula (1) according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating an animal having MMVD, CHF, and / or asymptomatic heart failure, wherein the animal is a companion animal.

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